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INTERNAL!TOPICS!
GASTROENTEROLOGY!
5 TH !YEAR , ! 1 ST !SEMESTER !
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ANDREA!SÓL!KRISTJÁNSDÓTTIR!
BERGLIND!ÁRNADÓTTIR!
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 Reflux esophagitis is a chronic mucosal inflammation and damage caused by acid reflux

Topic!#1.!Reflux!oesophagitis!(GERD):!symptoms,!staging,!therapy:!
chronic bronchitis
GERD!develops!as!consequence!of!the!complex!motility!disorder!of!the!upper!GI! chronic laryngitis
tract,!leading!to!the!reflux!of!gastric/duodenal!content!into!esophagus,!mouth!or!
respiratory!system.!This!causes!clinical!symptoms:!esophageal,!extraesophageal!and!
up!to!1/3!of!patients!have!reflux!esophagitis!(esophageal!mucosal!damage).!The!
prevalence!of!GERD!in!western!countries!is!20Q30%.!
!
!In!most!cases!it!is!the!gastric!acid!itself!refluxing!which!causes!the!mucosal!damage,!
in!some!cases!reflux!of!bile!and!alkaline!pancreatic!secretions!may!be!contributory.!
The!damage!is!directly!related!to!the!potency!of!the!refluxate!and!the!amount!of!
time!it!is!in!contact!with!the!mucosa.!Most!of!the!episodes!occur!after!meals,!despite!
the!buffering!effect!of!food!that!raises!the!intragastric!pH.!In!fact,!meal!stimulated! Alarming signs:
Anaemia
acid!secretion!from!the!proximal!stomach!mixes!poorly!with!the!gastric!contents,! Weight loss
forming!an!“acid!pocket”!that!floats!on!top!of!the!meal!content.!This!“acid!pocket”!is! N/V
located!near!gastroesophageal!junction!in!patients!with!GERD.! persistent vomit,
early satiety,
! dysphagia, anemia,
! gross/occult
bleeding
! !
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Symptoms of CP worse on
spicy food, recumbent! position
Tx: PPI and lifestyle changes for
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better with sitting, antacids
6 weeks
! no improve: Endoscopy.
Improve: put lowest dx of PPI
NISSEN FUNDOPLICATION !
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We!have!3!types!of!GERD:!!
1. NonMerosive!reflux!disease!(NERD)!which!is!endoscopically!negative.!This!
there are episodes of acid reflux but there are no erosions on the esophageal mucosa
accounts!for!60%!of!GERD!cases.!!
2. Erosive!reflux!disease!(ERD),!also!just!called!reflux!esophagitis,!35%.!Single!or!
multiple!erosions!in!the!distal!esophagus!at!the!squamoesophageal!junction.!
3. Complicated!ERD,!where!the!patient!might!have!ulcers,!strictures,!Barrett!
metaplasia!or!adenocarcinoma,!5%.!!
Pathophysiology:!!
• Motility!disorders:!
o Esophageal*clearance*decreased!due!to!hypotensive!peristaltic!
contraction!or!intermittent!failed!peristalsis!after!swallowing.!
Normally!acid!refluxate!is!cleared!and!neutralized!by!esophageal!
peristalsis!and!salivary!bicarbonate.!But!when!the!clearance!is!
decreased!this!is!not!working!normally.!This!happens!especially!in!
those!with!hiatal!hernia,!scleroderma,!Sjögren!syndrome,!
anticholinergic!medication!and!oral!radiation!therapy!(may!
exacerbate!GERD!due!to!impaired!salivation).!

! 1!
 o Lower*esophageal*sphincter!(LES)!pressure!decreased!(resting!
pressure!is!normally!10Q40mmHg).!!
! I!most!cases!the!baseline!LES!pressure!is!normal,!however!
most!reflux!episodes!occur!during!transient!relaxation!of!the!
LES!that!are!triggered!by!gastric!distention!by!a!vagovagal!
reflex.!!
! A!subset!of!patients!have!incompetent!LES!(<10mmHg)!that!
results!in!increased!acid!reflux,!especially!when!supine!or!
when!intraQabdominal!pressure!
are!increased!by!lifting!or!
bending.!A!hypotensive!sphincter!
is!present!in!up!to!50%!of!
patients!with!severe!erosive!
GERD.!
o Delayed*Gastric*emptying!(DM!)!
o LES*relaxation*frequency*is*increased*
o Duodeno<gastric*reflux*is*increased*
*
• Hiatus!hernia!is!found!in!¼!of!patients!with!
GERD,!¾!of!patients!with!severe!erosive!
esophagitis!and!>90%!of!patients!with!Barret!
esophagus.!This!is!caused!by!movement!of!LES!above!the!diaphragm,!
resulting!in!dysfunction!of!the!gastroesophageal!junction!reflux!barrier.!Hiatal!
hernia!by!itself!may!cause!no!symptoms,!but!when!associated!with!GERD!it!
can!increase!the!acid!reflux!a!lot!and!therefore!increase!symptoms!and!
severe!GERD!diseases.! sliding hiatal hernia
paraesophageal hernia
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• Truncal!obesity!may!contribute!to!GERD,!presumably!due!to!increased!intraQ
abdominal!pressure,!which!contributes!to!dysfunction!of!gastroesophageal!
junction!and!increased!likelihood!of!hiatal!hernia.!
Etiologic!factors:!
• Certain!food!and!drinks!
o Fatty!food!and!increased!caloric!intake!causes!distention!of!the!
stomach,!increased!TLOSR! Transient Lower Oesophageal Sphincter Relaxations
o High!carbohydrate!content!(chocolate),!or!spicy,!fatty!food!makes!the!
emptying!of!the!stomach!slower.!!
o Drinks!with!gas!cause!gastric!distention!(cola!etc.)!
o Wine!(especially!white!wine)!and!citrus!juices!increase!gastric!
secretion.!Concentrated!alcoholic!drinks!cause!direct!mucosal!
irritation.!
• Alcohol!"!Regular!drinkers!(>7x!per!week)!(OR!1,9)!
• Overweight!"!If!BMI!>!30!(OR!2,8)!
• Age!

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 • Smoking!history!(OR!1,6)!
• Smooth!muscle!relaxing!drugs!
• Genetic!factors!"!If!near!relatives!with!typical!GERD!or!gastric!problems!(OR!
2,6)!
• Increased!stress!load!(OR!1,4)!
Clinical!symptoms:!severity!of!symptoms!are!not!associated!with!the!degree!of!
tissue!damage.!
• Heartburn!(retrosternal!or!epigastric!burning!sensation).!Most!often!30Q60!
aka acid indigestion - burning sensation.
min!after!meal!and!upon!reclining.!! Pain can radiate to neck, lower jaw and throat - differentiate from ACS
• Acid!regurgitation!(spontaneous!reflux!of!sour!or!bitter!gastric!contents!into!
the!mouth)!
• Salivation,!nausea,!vomiting!
• Odynophagia! pain in swallowing
• Dysphagia!(can!be!due!to!erosive!esophagitits,!abnormal!esophageal!
peristalsis!or!esophageal!strictures)!
Alarming*symptoms*are*when*the*patient*has*vomitus,*dysphagia,*bleeding,*develops*
anemia*or*loses*weight*(could*indicate*adenocarcinoma).*
*
Atypical/extraesophageal!symptoms!clinical!symptoms:!!
• Esophageal:!dysphagia,!odynophagia,!non!cardial!chest!pain!
feeling of a lump in the throat
• Extraesophageal:!epigastric!pain,!dyspepsia,!globus!feeling,!ear!pain,!throat!
sore,!chronic!cough,!asthmatic!disturbances,!nocturnal!sweeting,!dental!
erosions.!
• GERD!associated!disorders:!peptic!ulcer,!motility!disorders,!esophageal!
spasm,!otitis!media,!pharyngitis,!laryngitis,!asthma!bronchiale,!chronic!cough!
and!bronchitis,!sore!throat,!aspirative!pneumonia,!interstitial!fibrosis,!
snoring,!insomnia,!nocturnal!pain.!
• In!the!absence!of!heartburn!or!regurgitation,!atypical!symptoms!are!unlikely!
to!be!related!to!gastroesophageal!reflux.!
How!to!diagnose!GERD:!!
1. Clinical!symptoms!(only!65%!sensitivity!and!specificity!if!you!only!base!your!
diagnosis!on!the!clinical!symptoms,!which!may!be!typical,!atypical!and!
alarming!symptoms.)!
2. PPI!test!(usually!the!patient!is!given!PPI!empirical!treatment!for!4Q8!weeks,!if!
it!doesn’t!work!and!the!patient!still!has!symptoms!after!this!time!we!continue!
the!investigation!by!doing!endoscopy)!
3. Endoscopy!with!biopsy!is!an!excellent!way!to!diagnose!GERD!and!related!
disorders!such!as!Barret!metaplasia!or!adenocarcinoma.!!
4. Barium!esophagography!–!only!done!in!patients!with!severe!dysphagia!and!
GERD!symptoms!due!to!that.!Its!sometimes!done!prior!to!the!endoscopy!to!
identify!strictures.!!

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 5. Ph!metry,!manometry.!pH!monitoring!is!unnecessary!in!most!patients,!but!
may!be!indicated!to!document!abnormal!esophageal!acid!exposure!in!
patients!who!have!atypical!or!extraesophageal!symptoms!who!are!being!
considered!for!antireflux!surgery.!It!may!also!be!indicated!in!patients!who!
have!severe!symptoms!despite!having!PPI!therapy!to!determine!if!the!
symptoms!are!caused!by!acid!reflux!or!unrelated!to!the!reflux!and!indicative!
of!a!functional!disorder.!
6. Other!specific!tests!
! Savary-Miller classification (I-IV)
! Los! Angeles classification (A-D)
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Treatment!options:!the!goal!is!to!provide!symptom!relief,!to!heal!esophagitis!(if!
present)!and!to!prevent!complications.!In!mild!to!intermittent!cases!you!could!advise!
the!patient!to!change!diet!and!life!style,!f.ex!don’t!eat!or!drink!foods!that!provoke!
the!symptoms,!don’t!lie!down!3!hours!after!having!a!meal,!use!antacids!or!H2!
antagonists!when!having!the!symptoms.!Antacids!only!work!<2!hours!but!work!
immediately,!but!H2!antagonists!work!for!8!hours,!but!have!30!minutes!delay!in!
onset.!Patients!with!kidney!disease!should!be!advised!to!NOT!take!antiacids,!which!
contain!Mg.!!
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Patients!with!troublesome!symptoms!and!patients!with!
known!complications!of!GERD!should!be!treated!with!once!
per!day!oral!PPI!therapy!(taken!30!min!before!breakfast).!All!
of!the!PPI’s!have!similar!efficacy!so!which!drug!to!use!should!
omeprazole be!determined!by!cost.!Usually!people!go!with!omeprazole!or!
lansoprazole lansoprazole.!The!therapy!should!be!continued!for!4Q8!weeks.!
pantoprazole
In!most!cases!(80Q90%)!there!is!adequate!control!of!heartburn!
20mg and!healing!of!erosive!esophagitis!(when!present).!If!1x!per!
day!is!not!enough!and!symptoms!do!not!disappear!after!2Q4!
weeks!of!therapy,!patient!can!take!the!PPI!2x!per!day!(30!min!
before!breakfast,!and!30!min!before!dinner).!!
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In!patients!with!complications!of!GERD!(severe!erosive!
esophagitis,!Barret!esophagus,!peptic!strictures)!long!term!
therapy!can!be!initiated!with!a!onceQ!or!twiceQdaily!PPI!
titrated!to!the!lowest!dose!effective!to!achieve!satisfactory!
symptom!control.!

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 NISSEN - for pt who cannot tolerate lifelong PPI

Surgery:!Surgical!antiQreflux!intervention!(fundoplication)!affords!good!to!excellent!
relief!of!symptoms!and!healing!of!esophagitis!in!>85%!of!properly!selected!patients.!
It!can!be!performed!laparoscopically!with!low!complication!rates!in!most!instances.! increased bloating
Side!effects!are:!dysphagia!and!diarrhea!(develops!in!30%!of!patients).! and flatulence, and
! inability to belch or
vomit, infections
Surgery!should!not!be!done!on!patients!who!respond!well!to!medical!therapy.!
Surgery!can!be!done!on!those!who!have!extraesophageal!manifestations!of!reflux!
which!is!often!difficult!to!control!with!medication.!Surgery!can!also!be!done!on!those!
who!have!severe!reflux!disease!who!are!unwilling!to!accept!lifelong!medical!therapy!
due!to!its!expense,!inconvenience!or!theoretical!risk.!Patients!with!large!hiatal!
hernias!and!persistent!regurgitation!despite!PPI!therapy!can!also!be!considered!for!
surgery.!Gastric!bypass!(rather!than!fundoplication)!should!be!considered!for!obese!
patients.!!
! Esomeprazole
Proton!pump!inhibitors:!! Pantoprazole
Lansoprazole
Side!effects!of!PPI’s!are!uncommon!but!headache,!diarrhea!and!abdominal!pain!may!
occur!with!any!of!the!agents.!Potential!risk!of!long!term!use!of!PPI’s!include!
infectious!gastroenteritis!(including!C.diff),!iron!and!vitamin!B12!deficiency,!
hypomagnesemia,!pneumonia,!hip!fracture!(possibly!due!to!impaired!Ca!absorption)!
and!fundic!gland!polyps!(no!clinical!significance).!!
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Drugs!are!absorbed!from!the!jejunum,!and!in!the!liver!the!CYP!system!is!responsible!
for!the!degradation,!namely!CYP2C19!and!CYP3A4!degrade!half!of!the!amount!of!
omeprazole!and!lansoprazole.!The!rest!is!protonated!and!turned!into!sulphenamid!at!
low!pH!value!in!the!parietal!cell,!where!it!binds!covalently!to!the!HQK!adenosine!
triphosphatase,!thus!inhibiting!acid!secretion!for!several!hours.!The!majority!of!
caucasian!population!is!extensive!metabolizing!phenotype!regarding!CYP2C19,!while!
only!5!%!is!weak!metabolizer.!This!is!the!reason!why!at!night!PPI!taken!in!the!
morning!is!not!effective!any!more.!Rabeprazole!is!not!converted!in!the!liver.!
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The esophagus is a fibromuscular tube connecting the pharynx with the stomach. about 25cm. The wall of the esophagus consists of
mucosa, submucosa, muscularis propria and adventitia. The mucosa is a stratified squamous epithelium. Most of the muscle is smooth
muscle although striated muscle predominates in its upper 2/3. transition between the stratified squamous epithelium of the esophagus
and the simple columnar epithelium of the stomach : squamocolumnar junction
Motor disorders of the esophagus can result in complete loss of peristalsis, as in achalasia, or decreased strength of contractions such as
in ineffective esophageal motility.
Topic!#2.!Motor!disorders!of!the!oesophagus:!achalasia!and!oesophageal!spasm:!

Achalasia:!!
Idiopathic!motility!disorder!where!there!seems!to!be!denervation!of!esophagus!
resulting!primarily!in!loss!of!NOQproducing!inhibitory!neurons!in!myenteric!plexus.!
The!cause!of!neuronal!degeneration!is!unknown.!Incidence!increase!with!age.!
• Loss!of!peristalsis!in!distal!2/3!of!esophagus!!
• Impaired!relaxation!of!LES!

Achalasia: a failure of smooth muscle fibers to

relax, which can cause a sphincter to remain
closed and fail to open when needed.
Esophageal achalasia is an esophageal motility
disorder involving the smooth muscle layer of
the esophagus and LES. It is characterized by
incomplete LES relaxation, increased LES tone,
and lack of peristalsis of the esophagus in the
absence of other explanations like cancer or
fibrosis.

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Signs!and!symptoms:!may!have!persisted!for!months!or!years!
• gradual!onset!of!dysphagia!for!solid!foods,!and!in!the!majority,!liquids!also.!!
• Substernal!discomfort!or!fullness!may!be!noted!after!eating!
• Patient!might!eat!more!slowly!and!adopt!specific!maneuvers!such!as!lifting!
the!neck!or!throwing!the!shoulders!back!to!enhance!esophageal!emptying.!
• Regurgitation!of!undigested!food!
• Nocturnal!regurgitation!can!provoke!coughing!and!aspiration!
• Substernal!chest!pain!unrelated!to!meals!or!exercise,!may!last!up!to!hours!
• Weight!loss!!
Diagnosis:!!
• Usually!physical!examination!in!unhelpful!
• Chest!radiographs!may!show!an!airQfluid!level!in!the!enlarged,!fluidQfilled!
esophagus.!
• Barium!esophagography!discloses!characteristic!findings,!including!
esophageal!emptying!and!smooth,!symmetric!bird’s!beak!tapering!of!the!
distal!esophagus.!!
• Without!treatment!the!esophagus!becomes!markedly!dilated!(sigmoid!
esophagus)!
• Special!examinations:!!
Bird’s beak
Sigmoid (dilated) esophagus

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 xray
barium esography
endoscopy biopsy
manometry
o Endoscopy!is!always!performed!after!esophagography!to!exclude!
strictures!or!carcinoma.!
o Diagnosis!is!confirmed!with!esophageal!manometry,!which!will!show!
complete!absence!of!normal!peristalsis!and!incomplete!LES!relaxation!
and!swallowing.!!
Treatment:!!
• Botulinum!toxic!injections!–!done!with!endoscopic!technique.!Improving!
initially!symptoms!in!up!to!65Q85%!of!patients.!However!relapse!occurs!in!
almost!all!patients!within!2!years.!Repeated!injections!can!be!done!in!
patients!who!do!not!have!comorbidities!or!are!poor!candidates!for!invasive!
procedures.!!
• Pneumatic!dilation!of!LES!–!upto!90%!of!patients!have!excellent!relief!of!
dysphagia!after!1Q3!sessions!of!pneumatic!dilation.!It!is!less!effective!in!
patients!<!50!!years!of!age!or!those!who!already!!have!dilated!esophagus.!!
• Surgery!Q!modified!Heller!cardiomyotomy!of!LES!and!cardia!result!in!good!to!
excellent!symptomatic!improvement!in!over!90%!of!patients.!Done!with!
laparoscopy!(can!be!done!in!open!surgery!as!well).!Surgery!may!be!preferred!
in!young!males!(<45!years!old)!where!pneumatic!dilation!has!been!proven!to!
be!less!effective.!GERD!develops!in!20%!of!patients!after!myotomy,!thus!most!
surgeons!also!do!a!fundoplication!(antireflux!procedure),!and!all!patients!are!
prescribed!PPI’s.!
Complete!esophagectomy!may!be!required!in!patients!with!megaesophagus,!
in!whom!dilation!and!myotomy!are!less!effectiv!!
! CCB: Sublingual nifedipine significantly improves outcomes in 75% of people with mild or moderate disease
Laparoscopic Heller's Myotomy !
! of water with meals, and avoid eating near bedtime
Lifestyle changes: eat slowly, chew very well, drink plenty
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Esophageal!spasm:!!
Broadly,!esophageal!spasm!can!be!divided!into!2!major!variants!that!are!distinct!
entities:!(1)!diffuse!esophageal!spasm!and!(2)!hypertensive!peristalsis.!Etiology!is!
unknown.!!Increased!release!of!acetylcholine!appears!to!be!a!factor!(sensitive!to!
cholinergic!stimulation),!but!the!triggering!event!is!not!known.!Other!theories!
include!gastric!reflux!or!a!primary!nerve!or!motor!disorder.!Body!mass!index!(BMI)!
and!total!cholesterol!may!be!highly!predictive!factors!for!esophageal!body!
contractility,!whereas!BMI!and!glucose!may!be!predictive!factors!for!
lower!esophageal!sphincter!contractile!function.!!
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Diffuse!esophageal!spasm!is!characterized!by!contractions!that!are!of!normal!
amplitude!but!are!uncoordinated,!simultaneous,!or!rapidly!propagated.!
Hypertensive!peristalsis,!also!known!as!nutcracker!esophagus,!is!diagnosed!when!
contractions!proceed!in!a!coordinated!manner!but!the!amplitude!is!excessive.!!
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Symptoms!can!include!dysphagia,!regurgitation,!and!nonMcardiac!chest!pain.!
Because!of!the!vague!symptoms!and!
difficulty!in!diagnosis,!esophageal!
spasm!is!often!underdiagnosed!and!
therefore!not!adequately!treated.!In!
many!patients,!manometric!and!
radiologic!abnormalities!may!not!
correlate!with!symptom!
presentation.!
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Barium!swallow!radiography!should!
be!performed!in!patients!with!chest! xray
pain!and!dysphagia,!to!look!for! barium
evidence!for!achalasia!or!diffuse! endoscopy
esophageal!spasm.!Certain! manometry
abnormalities!on!xQray!imaging!are! HR manometry
commonly!observed!in!DES,!such!as!a!
"corkscrew"!or!"rosary!bead!
esophagus,"!although!these!findings!
are!not!unique!to!this!condition.!
Upper!endoscopy!(to!exclude!
mechanical!obstruction!or!
eosinophilic!esophagitis)!and!esophageal!manometry!can!also!be!done.!Currently,!
highMresolution!manometry!is!the!best!diagnostic!modality.!!
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Treatment!includes!calcium!channel!blockers,!botulinum!toxin,!nitrates,!tricyclic!
antidepressants,!sildenafil,!dilatation,!myotomy,!and!esophagectomy.!
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calcium channel blockers such as nifedipine
! nitrates such as isosorbide dinitrate and nitroglycerin.
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Topic!#3.!Barret!esophagus:!
Barret!esophagus!is!a!part!of!the!gastroesophageal!reflux!diseases!(GERD).!It’s!a!
condition!in!which!the!squamous!epithelium!of!esophagus!is!replaced!by!metaplastic!
columnar!epithelium!containing!goblet!and!columnar!cells!(specialized!intestinal!
metaplasia).!In!simple!matter!the!epithelium!of!esophagus!is!trying!to!„look!more!
like“!the!epithelium!in!the!stomach!due!to!reflux!and!irritation!from!gastric!acid!and!
stomach!content.!!It’s!present!in!up!to!10%!of!patients!with!chronic!reflux!and!
therefore!these!patients!have!chronic!injury!of!the!squamous!epithelium!and!that!
induces!the!metaplasia.!However,!Barret!esophagus!is!also!present!in!patients!with!
truncal!obesity,!independent!of!GERD.!!
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Symptoms:!!Barret!esophagus!does!not!provoke!specific!symptoms,!but!GERD!does,!
so!the!symptoms!are!the!typical!reflux!symptoms!such!as!heartburn!and!
regurgitation.!1/3!of!patients!report!minimal!or!no!symptoms!of!GERD!which!
suggests!decreased!acid!sensitivity!of!Barret!epithelium.!Due!to!this!90%!of!patients!
in!the!general!population!do!not!seek!medical!attention.!!
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Diagnosis:!!
• Endoscopy:!orange,!gastric!type!epithelium!that!extends!up!from!the!
stomach!into!the!distal!tubular!esophagus!in!tongueQlike!or!circumferential!
fashion.!!
• Biopsy!from!endoscopy:!3!types!of!columnar!epithelium! !
o Gastric!cardia! fundic glands: secrete hydrochloric acid (HCl) and intrinsic factor
o Gastric!fundic! cardial glands: primarily secrete mucus
o Specialized!intestinal!metaplasia!–!which!carries!an!increased!risk!of!
dysplasia!(which!can!result!in!cancer)!
Complications:!the!most!serious!complication!of!Barret!esophagus!is!esophageal!
adenocarcinoma.!It!is!believed!that!most!cases!of!adenocarcinoma!of!esophagus!and!
gastric!cardia!arise!from!dysplastic!epithelium!of!Barret!esophagus.!!!
!
Incidence!of!adenocarcinoma!in!patients!with!Barret!esophagus!is!estimated!0,12!–!
0,33%/year.!This!is!11x!increased!risk!from!those!who!do!not!have!Barret!esophagus,!
even!so,!adenocarcinoma!of!esophagus!remains!a!relatively!uncommon!malignancy!
(in!USA).!Due!to!this!endoscopic!screening!for!Barret!esophagus!in!adults!with!GERD!
is!not!recommended,!only!in!those!with!multiple!risk!factors!"!chronic!GERD,!hiatal!
hernia,!obesity,!white!race,!male!gender!and!>50!years!of!age.!!
!
In!patients!who!have!been!diagnosed!with!Barret!esophagus,!surveillance!endoscopy!
every!3Q5!years!is!recommended!to!look!for!lowQ!or!highQgrade!dysplasia!or!
adenocarcinoma.!Patients!with!low!grade!dysplasia!require!repeat!endoscopic!
surveillance!in!6!months!to!exclude!coexisting!high!grade!dysplasia!or!cancer.!If!low!
grade!dysplasia!persists!endoscopic!surveillance!should!be!repeated!yearly.!!
!
Patients!with!highQrisk!dysplasia!may!harbor!an!unrecognized!invasive!esophageal!
cancer.!Therefore!we!need!to!take!a!biopsy!from!a!few!different!random!places!in!
the!esophageal!mucosa!in!order!to!exclude!invasive!cancer.!!!
!
Treatment:!Barret!esophagus!should!be!treated!with!longQterm!proton!pump!
inhibitors!(PPI’s)!1xQ2x!daily!to!control!reflux!symptoms.!These!medication!do!not!
cause!regression!of!Barret!esophagus!but!they!decrease!the!risk!of!cancer!(decrease!
progression!of!Barret!esophagus).!!
!
Treatment!of!patients!that!have!high!grade!dysplasia!or!esophageal!cancer!(detected!
by!endoscopic!surveillance):!until!recently!esophagectomy!was!recommended!for!
patients!deemed!to!have!low!operative!risk.!However,!this!procedure!is!associated!
with!high!morbidity!and!mortality!rate.!Therefore!now!it!is!recommended!that!
endoscopic!therapy!be!performed,!which!remove!or!ablate!Barret!epithelium,!using!
mucosal!snare!resection!and!radiofrequency!wave!ablation!electrocautery.!When!
high!dose!PPI’s!are!administered!to!normalize!intraepithelial!pH,!radiofrequency!
wave!ablation!electrocautery!eradication!of!Barret!columnar!epithelium!is!followed!
by!complete!healing!with!normal!squamus!epithelium!in!>90%!of!cases.!
!

! 10!
Endoscopic!ablation!techniques!have!risk!of!complications!such!as!bleeding,!
perforation!and!strictures.!Therefore!this!kind!of!treatment!is!not!recommended!for!
patients!with!nonQdysplastic!Barret!esophagus,!because!it’s!not!risk!and!costQ
effective.!!
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Topic!#4.!Esophageal!tumors:!
Esophageal!malignant!tumors!represent!about!1Q2%!of!all!malignancies.!There!is!
male!predominance!(male:female!10:1).!In!the!male!population!it’s!the!9th!most!
common!tumor.!Esophageal!cancer!usually!develop!between!50!and!70!years!of!age.!!
!
Promoting!factors:!!
• Male!sex!
• Resected!stomach,!previous!tumors!in!the!head!Q!neck!region!
• Corrosive!esophageal!stenosis!
• Persisting!achalasia!
chronic
• Lasting!reflux!disease,!Barret!metaplasia!
• Smoking,!alcohol,!obesity,!problems!in!oral!hygiene!
• Eating!habits:!spicy!food,!hot!food!etc.!!
• Tylosis!(hyperkeratosis);!HPV!(type!16/18)! Howel-Evans syndrome: palmar keratosis with eso. cancer
Signs!and!symptoms!in!general:!!
• Progressive!solid!food!dysphagia!
• Weight!loss!is!common!
Diagnosis!is!established!by!endoscopy!with!biopsy.!!
! The 2 major risk factors for SCC are tobacco (smoking
Types!of!esophageal!tumors:!! or chewing) and alcohol. strong synergistic effect,
CAUSTIC, NITROSAMINE, HOT DRINKS, BBQ
Malignant!tumors!
1. Squamus!cell!cancers!"!half!of!cases!occur!in!distal!1/3!of!esophagus,!higher!
incidence!in!China!and!SAQAsia,!and!more!common!in!blacks!that!whites.!
Chronic!alcohol!and!tobacco!use!are!strongly!associated!to!it.!!
2. Adenocarcenoma!(Barret)!"!more!common!in!whites!than!blacks.!Incidence!
is!increasing!dramatically!and!it!is!more!common!than!squamuc!cell!
carcinoma.!The!majority!develops!as!complications!of!Barret!esophagus!due!
to!GERD.!Most!of!them!arise!in!distal!third!of!esophagus.!Obesity!is!strongly!
associated!with!adenocarcinoma!of!esophagus,!even!after!controlling!for!
GERD.!!
3. Sarcoma!"!these!are!rare!and!account!for!approximately!0,1!–!1,5%!of!all!
esophageal!tumors.!There!are!different!types!of!sarcomas!(leiomyosarcoma,!
spindle!cell!carcinoma!etc).!Usually!the!tumor!is!polypoid!in!nature!and!has!
large!volume!which!protrudes!into!the!esophagus.!! malignant melanoma, rhabdomyosarcoma and
lymphoma,
There!is!male!predominance,!promoting!factors!are!smoking,!concentrated!alcoholic!
beverages,!opium,!HIV,!corrosive!esophageal!stricture,!achalasia,!Barret!metaplasia,!
palmoplantar!keratoderma.!
!
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! 12!
Symptoms:!most!patients!with!esophageal!cancer!present!with!advanced!incurable!
disease.!
• Over!90%!have!solid!food!dysphagia,!which!progresses!over!weeks!to!
months.!Sometimes!odynophagia!is!also!present!(pain!swallowing).!!
• Vomiting!nonQdigested!food,!!
• Occult!bleeding!anemia,!! Common sites of spread include nearby LN, liver,
lungs and bone. Liver metastasis can cause jaundice
• Massive!acute!bleeding,!! and ascites. Lung metastasis can cause impaired
• Chest!and!epigastrial!pain,!! breathing due to pleural effusion, and dyspnea.

• Chest!or!back!pain!may!indicate!mediastinal!extension!
• Palpable!epigastric!mass!!
• Local!tumor!extension!may!result!in!tracheoQesophageal!fistula,!characterized!
by!coughing!on!swallowing!or!pneumonia.!!
• Recurrent!laryngeal!involvement!may!produce!hoarsness!
• Sometimes!presence!of!supraclavicular!or!cervical!lymphadenopathy!!
• If!hepatomegaly!it!implies!metastatic!disease!
occlusive tumor may be suspected on
a barium swallow or barium meal,
Diagnostic!possibilities:!! the diagnosis is best made with an
• Inspection,!biopsy,!cytology!! examination
• ChromoMendoscopy:!1%!Lugol!solution!will!stain!glycogen!content!of!normal!
squamus!cell!epithelium,!nonQstaining!areas!may!be!pathologic.!ToluidinQblue!
stains!dysplasia,!cc!!
• Fluorescent!spectroscopy:!410nm!low!energy!laser!stimulation!improves!
detection!of!dysplasia!
• Magnifying!–!zoom!–!endoscopy!(40Q80x!magnification!possible)!
• Endoscopy!Ultrasound!for!correct!staging!of!esophageal!tumors:!evaluation!
of!depth!of!infiltration!of!the!wall,!involvement!of!lymph!nodes,!relation!of!
the!tumor!to!surrounding!organs,!possibility!for!better!biopsy!sampling.!!
After!confirmation!of!the!diagnosis!of!esophageal!carcinoma,!the!stage!of!the!
disease!should!be!determined!since!doing!so!influences!the!choice!of!therapy.!Chest!
and!abdominal!CT!should!be!done!to!look!for!pulmonary!or!hepatic!metastasis,!
lymphadenopathy,!and!local!tumor!extension.!If!no!evidence!of!metastasis!on!CT!
then!endoscopic!ultrasonography!should!be!done!and!biopsy!lymph!nodes!(this!is!
superior!to!CT!to!demonstrate!level!of!local!metastasis).!PETQCT!should!be!done!
before!invasive!surgery!to!check!for!local!metastasis.!Bronchoscopy!is!sometimes!
required!to!evaluate!tracheobronchial!extension.!Sometimes!laparoscopy!is!needed!
to!check!for!peritoneal!metastasis.!!
!
Treatment:!curable!vs!incurable!disease!
!
• Operable!tumors!"!esophageal!cancers!confined!to!the!epithelium!"!radical!
resection,!replacement!(esophagectomy)!
• Locally!advanced!"!neoadjuvant!chemoradiotherapy,!thereafter!restaging!
and!then!surgery!+!removal!of!at!least!15!lymph!nodes!to!check!for!
metastasis.!!
Esophagectomy is normally done to remove cancerous tumor. It is normally done when esophageal cancer
is detected early, before it has spread to other parts of the body. Esophagectomy of early stage cancer
represents much the best chance of a cure. Despite significant improvements in technique and
! postoperative care, the long-term survival for esophageal cancer is still poor. Currently multimodality 13!
treatment is needed (chemotherapy and radiation therapy) for advanced tumors.
In those who have had an esophagectomy for cancer, omentoplasty appears to improve outcomes.
 o Patients!with!stage!I!tumors!have!high!cure!rates!with!surgery!alone!
and!do!not!require!radiation!or!chemotherapy.!If!reginal!lymph!node!
metastases!have!occurred!(stage!IIB!and!III)!the!rate!of!cure!with!
surgery!alone!is!reduced!to!<20%.!MetaQanalysis!of!trials!comparing!
neoadjucant!therapy!followed!by!surgery!alone!suggesta!a!13%!
absolute!improvement!in!2!years!survival!with!combined!therapy.!
Preoperative!(neoadjuvant)!therapy!is!recommended!in!Stage!IIA,!IIB,!
and!III!tumors!in!fit!patients.!!
• Inoperable!regional!"!radiotherapy!and!chemotherapy!(5FU!+!cisplatinum)!–!
more!likely!to!cure!patients!with!squamous!cell!carcinoma!than!
adenocarcinoma!(see!specific!treatment!next!page)!
• Inoperable!distant!metastasis!"!palliative!chemotherapy!+!irradiation.!But!
there!are!significant!side!effects.!
• Incurable,!significant!progression!"!nutrition,!stenting,!palliative!radiation!to!
the!area!to!relief!pain!and!dysphagia,!analgetics,!BSC!
Endoscopy!–!therapeutic!possibilities:!!
• Transtoric!nasogastric!untubation!of!nutritive!tube!
• Mucosectomy,!if!diameter!<!2cm!
• Photodynamic!thermoQablation!
• Argon!plasma!coagulation,!stop!of!bleeding!
• Dilation!(balloon,!bougie)!
• Implantation!of!different!stents.!!
The!overall!5Qyear!survival!rate!of!esophageal!carcinoma!is!<!20%.!The!most!
important!predictors!of!poor!survival!is!metastasis,!mediastinal!and!lymph!node!
involvement.!Cure!may!be!reached!in!patients!with!regional!lymph!node!
involvement,!however!if!lymph!node!involvement!outside!the!chest!it!is!indicative!of!
metastatic!disease!that!is!incurable.!!
!
Specific!treatment!of!planocellular!/squamus!cell!tumors!of!esophagus:!
• Chemotherapy:!cycles!are!repeated!every!3!weeks.!!
o Carboplatin:!100mg/m2!IV!infusion!1st!day!
o 5MFluorouracil:!600!mg/m2!infusion!1.Q5th!day!
o CaMfolinat:!20mg/m2!infusion!1Q5th!day!(before!5QFU)!
• Radiotherapy:!Telekobalt!30Q35!Gy!(250cGy/day)!
o Intraluminal!afterlaoding!1Q3!occasions,!500cGy!
Neoadjuvant!chemoradiotherapy!can!increase!the!operability!of!a!tumor!by!50Q60%!

! 14!
 !
!
!
TNM staging system
!
The most common system used to stage esophageal cancer is the TNM system of the American Joint Committee on Cancer (AJCC).
!
T: extent ! N: cancer spread to lymph nodes M: metastasis G: grade how the patterns of cancer cells appear

! into account the cell type of the cancer (SCC or ACC).

Staging also takes
!
TX: The primary tumor can’t be assessed.
!
T0: There is no evidence of a primary tumor.
! only in the epithelium, also known as high-grade dysplasia. In the past it was called carcinoma in situ.
Tis: The cancer is
T1: The cancer is growing into the tissue under the epithelium, such as the lamina propria, muscularis mucosa, or submucosa.
T1a: The cancer!is growing into the lamina propria or muscularis mucosa
T1b: The cancer!has grown through the other layers and into the submucosa
T2: The cancer is growing into the muscularis propria
!
T3: The cancer is growing into the adventitia
T4: The cancer is! growing into nearby structures.
!
T4a: The cancer is growing into the pleura, pericardium, diaphragm
T4b: The cancer cannot be removed with surgery because it has grown into the trachea, the aorta, the spine, or other crucial structures.
!
!
NX: Nearby lymph nodes can’t be assessed.
! not spread to nearby lymph nodes.
N0: The cancer has
!
N1: The cancer has spread to 1 or 2 nearby lymph nodes.
N2: The cancer has spread to 3 to 6 nearby lymph nodes.
! spread to 7 or more nearby lymph nodes.
N3: The cancer has
!
M0: The cancer has not spread (metastasized) to distant organs or lymph nodes.
M1: The cancer !has spread to distant lymph nodes and/or other organs. (Common sites of spread include the liver and lungs.)
!
Grade: how normal (or differentiated) the cells look under the microscope.
!
The higher the number, the more abnormal the cells look. Higher grade tumors tend to grow and spread faster than lower grade tumors..
!
GX: The grade cannot be assessed (treated in stage grouping as G1).
G1: The cells are! well-differentiated.
G2: The cells are moderately differentiated
G3: The cells are poorly differentiated
G4: The cells are undifferentiated (these cells are so abnormal that doctors can’t tell if they are ACC or SCC).

! 15!
Topic!#5.!Diagnostics!and!treatment!of!gastrointestinal!bleeding:!
Acute!upper!GI!bleeding:!
Mortality!rate!is!4Q10%.!About!50%!of!the!patients!are!over!50!years!of!age!(where!
mortality!rate!is!higher).!Patients!usually!do!not!die!of!blood!loss!but!complications!
from!underlying!disease.!Upper!Gi!bleeding!is!selfQlimiting!in!80%!of!cases.!Urgent!
medical!therapy!and!endoscopy!is!obligatory!in!the!rest.!!
!
Signs!and!symptoms:!!
• Most!common!symptom!is!hematemesis!(vomiting!fresh!blood,!either!bright!
red!or!“coffee!ground”!material)!or!melena!(digested!blood!in!stool,!usually!
black!color).!!
• Hematochezia!(fresh!blood!in!stool)!may!be!present!in!10%!of!the!cases.!!
Etiology:!(in!order!of!frequency)!
• Peptic!ulcer!disease! major risk for variceal bleeding: cherry red spots

• Portal!hypertension!(esophageal!varices)! drugs for usage for the reduction of portal hypertension

• Mallory!Weiss!tears! during variceal bleeding: terlepressin, octrotide

• Vascular!anomalies! What can be used for the treatment of oesophageal

variceal bleeding
• Gastric!neoplasms! A. sclerotherapy
• Erosive!gastritis! C. Histoacrilate
D. Sengstaken-tube
• Erosive!esophagitis!
• Other:!aorticoenteric!fistula,!aneurysm!etc.!
Initial!evaluation!and!treatment:!!
1. Stabilization!(assessment!of!hemodynamic!status)!
a. Systolic!pressure!<!100mg!=!high!risk!of!severe!acute!bleeding.!Start!
IV!lactated!Ringer!infusion!or!0.9%!saline!solution!therapy!right!away!
before!further!testing.!Blood!sample!for!complete!blood!count,!PT,!
INR,!serum!creatinine,!liver!enzymes,!blood!typing!and!screening.!
After!knowing!the!patient’s!blood!type,!he/she!is!given!2Q4!units!of!
packed!RBCs.!!
Heart!rate!>!100bpm!with!systolic!BP!>100mmHg!=!moderate!acute!
blood!loss!
Normal!systolic!BP!and!HR!=!minor!hemorrhage!
b. In!some!cases!a!patient!might!need!nasogastric!tube!due!to!risk!of!
aspiration.!!
c. Erythromycin!IV!(250mg)!30!minutes!prior!to!endoscopy!may!induce!
gastric!emptying!and!improve!the!quality!of!endoscopy.!!
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2. Blood!replacement!
a. The!amount!is!based!on!initial!vital!signs!(see!1a.),!and!evidence!of!
active!bleeding!from!nasogastric!aspirate!and!lab!tests.!!
b. If!massive!active!bleeding!–!give!the!patient!blood!transfusion!!!
c. If!hemodynamically!stable:!packed!RBCs!should!be!given!to!maintain!
hemoglobin!levels!of!7Q9g/dL.!In!absence!of!bleeding!the!Hb!levels!
should!rise!1g/dL!with!every!unit!of!transfused!RBC!given.!!
d. Check!if!patient!is!on!clopidogrel!or!aspirin!which!could!interfere!with!
platelet!function!
!
3. Initial!triage!(decide!the!order!of!treatment!Q!endoscopy!first!or!not)!
a. Increased!risk!if:!patient!is!>!60!years!of!age,!comorbid!illnesses,!
systolic!BP!<!100mmHg,!pulse!>!100!bpm,!and!bright!red!blood!in!the!
nasogastric!aspirate!or!on!rectal!examination.!
b. High!risk:!requires!admission!to!ICU.!After!resuscitation,!endoscopy!
should!be!performed!2Q24!hours!.!high!risk!patients!have!these!signs:!
i. Hematemesis!or!bright!red!blood!on!nasogastric!aspirate!
ii. Shock!
iii. Persistent!hemodynamic!derangement!despite!fluid!
resuscitation!
iv. Serious!comorbid!medical!illness!
v. Evidence!of!advanced!liver!disease!
c. Low!to!moderate!risk:!after!appropriate!stabilization!these!patients!
are!admitted!to!a!stepQdown!or!medical!ward!after!appropriate!
stabilization!for!further!evaluation!and!treatment.!These!patients!
usually!undergo!nonemergent!endoscopy.!!
!
4. Subsequent!evaluation!and!treatment!
a. Upper!endoscopy!
i. Virtually!all!patients!with!upper!GI!bleeding!should!undergo!
upper!endoscopy!within!24!hours!of!onset!of!bleeding.!!
1. To#identify#source#of#bleeding!(patients!with!portal!
hypertension!are!treated!differently!than!the!ones!with!
peptic!ulcer)!
2. To#determine#risk#of#rebleeding#and#guide#triage!"!
nonQbleeding!Mallory!weizz!tears,!esophagitis,!gastritis!
and!ulcers!with!a!clean!white!base!have!a!very!low!risk!
of!rebleeding!(<5%).!Patients!with!ulcers!that!are!
Forrest IIA
actively!bleeding!or!have!a!visible!vessel!or!adherent!
clot,!or!who!have!variceal!bleeding!usually!need!!at!
least!3Qday!hospitalization.!#

! 17!
 3. To#render#endoscopic#therapy!"!cautery,!injections!or!
endoclips!used!to!stop!bleeding!if!needed.!!
!
b. Acute!pharmacological!therapies!
i. Acid!inhibitory!therapy!!
1. IV!PPI’s!(esomeprazole!or!pantoprazole!80mg!bolus,!
followed!by!8mg/h!continuous!infusion!for!72!hours)!
reduces!risk!of!rebleeding!in!patients!with!peptic!ulcers!
who!also!have!high!risk!features!(active!bleeding,!
visible!vessels!or!adherent!clot)!after!endoscopic!
treatment.!!
2. Oral!PPI’s!once!or!twice!daily!are!sufficient!for!low!risk!
patients!for!reQbleeding!(esophagitis,!gastritis,!clean!
base!ulcers,!Mallory!Weiss!tears.!
3. Giving!either!oral!or!IV!PPI!therapy!before!endoscopy!
limits!decreases!the!no.!of!lesions!that!require!
endoscopic!therapy.!Therefore!it!is!standard!to!start!
this!therapy!before!doing!an!endoscopy!in!patients!
with!significant!upper!Gi!bleedings.!!
ii. Octreotide!(mimics!somatostatin)!
more potent inhibitor of growth 1. Continuous!infusion!of!octreotide!decreases!splanchnic!
hormone, glucagon, and insulin.
blood!flow!and!portal!blood!pressures!and!is!effective!
management of acute in!the!initial!control!of!bleeding!related!to!portal!
haemorrhage from esophageal hypertension!w.!upper!GI!bleedings!and!evidence!of!
varices in liver cirrhosis by
reducing portal venous pressure liver!disease!until!source!of!bleeding!can!be!
established.!!
!
iii. Other!treatments:!!
1. IntraMarterial!embolization:!if!persistant!bleeding!after!
endoscopic!therapiese!
2. Transvenous!intrahepatic!portosystemic!shunts!(TIPS):!
wire!stent!in!hepatic!vein!through!the!liver!to!the!
portal!vein!decrease!the!portal!hypertension.!Good!in!
control!of!acute!variceal!bleeding.!Indicated!in!patients!
where!endoscopic!modalities!have!failed!to!control!
acute!variceal!bleeding.!!
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! 18!
Acute!lower!GI!bleeding!(small!intestine!or!colon)!
Up!to!95%!of!cases!arise!in!the!colon.!The!symptoms!can!be!mild!anorectal!bleeding!
to!massive,!largeQvolume!hematochezia!(fresh!blood!through!anus).!Patients!
hospitalized!with!lower!GI!bleeding!are!less!likely!to!present!with!shock!or!
orthostasis!or!to!require!transfusion!compared!to!upper!GI!bleeding!patients.!
Spontaneous!cessation!of!bleeding!occurs!in!75%!of!cases,!and!hospital!mortality!is!
<4%.!!
!
Etiology!–!depends!on!both!age!and!patient!and!severity!of!bleeding.!Most!common!
causes!of!lower!GI!bleeding!are:!
• <!50!years!of!age:!!
o Infectious!colitis,!! Shigella, Campylobacter, Salmonella, and Shiga Toxin-producing Escherichia coli
o Anorectal!disease!10%!(hemorrhoids,!fissures,!rectal!ulcer)!
o Inflammatory!bowel!disease!(especially!ulcerative!colitis),!often!with!
diarrhea,!abdominal!pain,!tenesmus!and!urgency.!!
• >50!years!of!age!
o Diverticulosis!50%.!Painless!bleeding!
! !Increased!risk!if!the!patient!uses!aspirin!or!NSAIDs.!
o Angiectasis!4%!(most!often!in!cecum!and!ascending!colon).!Painless!
19leeding! Colonic angioectasia is a common source of lower gastrointestinal bleeding. Direct visualization during colonoscopy is
the preferred method to diagnose colonic angioectasia and these lesions often have a distinctive “coral reef” appearance
o Malignancy!7%!!
o Ischemia!(ischemic!colitis).!Usually!in!patients!with!atherosclerosis.!!
! Most!cases!occur!spontaneously!with!nonocclusive!ischemia,!it!
can!also!occur!after!surgery!for!ileoarotic!or!abdominal!aortic!
aneurysm.!
! Can!also!be!due!to!vasculitis,!coagulation!disorders,!estrogen!
therapy,!long!distance!running.!!
• Other:!radiation!induced!proctisis!can!induce!anorectal!bleeding!that!may!
develop!months!after!pelvic!radiation.!Also!colonic!varices!may!occur.!!
Signs!and!symptoms:!!
• Color!of!stool!
o Brown!stool!mixed!or!streaked!with!blood!"!source!of!blood!in!
rectosigmoid!or!anus.!
o Large!volumes!of!bright!red!blood!"!source!in!colon!
o Maroon!stool!"!lesion!in!the!right!colon!or!small!intestine!
o Black!stool!(melena)!"!upper!GI!tract.!(upper!GI!bleeding!may!be!
present!with!hematochezia!in!10%!of!cases!f.ex!due!to!peptic!ulcer!
etc.!
• If!cramping!abdominal!pain,!urgency!or!tenesmus!"!characteristic!of!
inflammatory!bowel!disease,!infectious!colitis!or!ischemic!colitis.!!
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! 19!
Diagnosis:!!
• Exclude!an!upper!GI!source!of!bleeding:!upper!endoscopy!
• Anoscopy!and!sigmoidoscopy!
• Colonoscopy:!preferred!as!an!initial!study!in!patients!with!acute,!large!
volume!bleeding!requiring!hospitalization.!!
• Nuclear!bleeding!scans!and!angiography:!technetiumQlabeled!RBC!scanning!
can!detect!significant!active!bleeding!and!in!some!cases!localize!the!source!to!
the!small!intestine!or!right/left!colon.!The!main!point!of!scintigraphy!is!to!
determine!whether!the!bleeding!is!ongoing!in!order!to!determine!whether!
angiography!should!be!pursued.!In!patients!with!massive!lower!GI!bleeding!
manifested!by!continued!hemodynamic!instability!and!hematochezia,!urgent!
angiography!should!be!performed!without!attempt!at!colonoscopy!or!
scintigraphy.!!
• Small!intestine!push!enteroscopy!or!capsule!imaging:!small!intestine!is!a!
rare!source!of!lower!GI!bleeding,!thus!its!evaluation!is!usually!not!done!as!
initial!evaluation!of!a!GI!bleeding!patient.!However!the!small!intestine!is!
investigated!in!patients!with!unexplained!recurrent!hemorrhage!of!obscure!
origin.!!
Treatment:!initial!stabilization!and!blood!replacement!and!triage!are!managed!the!
same!manner!as!described!for!upper!GI!tract!bleeding.!!
• Therapeutic!colonoscopy!(epinephrine!injection!+!cautery!or!application!of!
metallic!endoclips!or!bands):!for!high!risk!lesions!(angioectasia,!diverticulum,!
rectal!ulcer!with!active!bleeding!or!a!visible!vessel)!!
• IntraMarterial!embolization:!angiography!with!selective!embolization!
achieves!immediate!hemostasis!in!more!than!95%!of!patients.!
• Surgery:!emergency!surgery!is!required!in!<5%!of!cases!with!lower!GI!
bleeding!due!to!efficacy!of!colonoscopy!and!angiographic!therapies.!It!is!
indicated!in!patients!with!ongoing!bleeding!that!require!more!than!6!units!of!
blood!within!24!hours!or!more!than!10!total!units!in!whom!attempts!at!
endoscopic!or!angiographic!therapy!failed!(most!caused!by!diverticulum!or!
angioectasia).!!
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More!info:!!
MalloryMWeiss!syndrome!(mucosal!laceration!of!gastroesophageal!junction)!
This!is!a!syndrome!characterized!by!a!nonpenetrating!mucosal!tear!at!the!
gastroesophageal!junction!that!is!hypothesized!to!arise!from!events!that!suddenly!
raise!transabdominal!pressure,!such!as!lifting,!retching,!or!vomiting.!Alcoholism!is!a! think drinking bullimic teen
strong!predisposing!factor.!MalloryQWeiss!tears!are!responsible!for!approximately!
5%!of!upper!GI!bleeding.!
!
Symptoms:!patients!
usually!have!
hematemesis!with!or!
without!melena.!The!
patient!usually!has!
history!of!retching!
(gag),!vomiting!or!
straining.!!
!
Diagnosis:!upper!
endoscopy!should!be!
done!
!
!
!
!
!
Differential!diagnosis:!peptic!ulcer,!erosive!gastritis,!arteriovenous!malformation,!
esophageal!varices.!!
!
Patients#with#underlying#portal#hypertension#are#at#higher#risk#for#continued#or#
recurrent#bleeding.##
!
Treatment:!patients!are!initially!treated!as!needed!with!fluid!resuscitation!and!
blood!transfusion.!In!most!patients!bleedings!stops!spontaneously!and!they!require!
no!therapy.!Endoscopic!hemostatic!therapy!is!done!in!patients!who!have!continuing!
active!bleeding.!!
• Injection!with!epinephrine,!cautery!with!a!bipolar!or!heater!probe!
coagulation!device!
• Mechanical!compression!of!an!artery!by!application!of!an!endoclip!or!band!
• Angiographic!arterial!embolization!or!operative!intervention!is!required!in!
patients!who!fail!endoscopic!therapy.!!
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! 21!
 Esophageal!varices!(dilated!submucosal!veins!that!develop!in!patients!with!
underlying!portal!hypertension):!
The!most!common!cause!of!portal!hypertension,!which!leads!to!esophageal!varices!
and!bleeding,!is!liver!cirrhosis.!Esophageal!varices!may!result!in!serious!upper!GI!
bleeding!(30%).!The!bleeding!usually!occurs!in!the!distal!most!5cm!of!esophagus.!In!
50%!of!the!cases!the!bleeding!results!spontaneously.!Patients!surviving!this!bleeding!
episode!have!60%!chance!of!recurrant!bleeding!episodes!(usually!within!6!weeks).!
With!current!therapies!the!in!hospital!mortality!is!15%.!!
!
A!few!factors!increase!the!risk!of!bleeding!in!patients!with!esophageal!varices:!!
• Size!of!varices!
CHERRY RED SPOTS • Presence!at!endoscopy!of!red!wale!markings!(longitudinal!dilated!venules!on!
the!varix!surface)!
• Severity!of!liver!disease!
• Active!alcohol!abuse!–!patients!with!cirrhosis!who!continue!to!drink!have!an!
extremely!high!risk!of!bleeding.!!

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 Complications only and no Sx in 20% : gastric perforation, bleeding, obstruction, pyloric stenosis

gnawing pain

Topic!#6.!Peptic!ulcer:!aetiology,!symptoms,!diagnosis:!

Peptic!ulcer!disease!(PUD)!definition:!a!break!in!the!mucosa,!usually!larger!than!5mm!
in!diameter,!spreading!beyond!the!muscularis!mucosae!of!the!GI!tract!in!sites!
exposed!to!acidQpepsin!effect.!It!happens!when!normal!mucosal!defensive!factors!
main digestive enzyme
are!impaired!or!are!overwhelmed!by!aggressive!luminal!factors!such!as!acid!and!
protein to polypeptides pepsin.!Ulcers!are!5x!more!common!in!the!duodenum,!where!over!95%!are!in!the!
bulb!or!pyloric!channel.!Ulcers!are!slightly!more!common!in!males!than!in!females!
(1,3:1)!and!most!commonly!between!the!age!of!30!and!55!years!old!(gastric!ulcers! gastric ulcers old people
are!more!common!between!55!and!70!years).!Disturbed!microcirculation,!hypoxia,!
stress!and!life!style!(tobacco,!alcohol,!diet)!can!all!cause!peptic!ulcer.!

Etiology:!!
Etiology:
• H.pylori!–!one!of!the!most!common!factor!leading!to!peptic!ulcer! Helicobacter pylori
• NSAIDs!–!one!of!the!most!common!factor!leading!to!peptic!ulcer! NSAID
Zollinger-Ellison syndrome
• less!than!10%!of!peptic!ulcers!are!due!to!other!reasons:! Stress - ulcer
„idiopathic” ulcer
o Zollinger!Ellison!syndrome!
o CMV!infection!(immunocompromised!patients)!
o Crohns!disease!
o Lymphoma!!
o Medication!(Alendronate)!
o Chronic!medical!illness!(cirrhosis,!chronic!kidney!disease)!
o StressQulcer!(?!According!to!lectures,!not!to!book)!
o Idiopathic!ulcer!
Protective factors of the gastric and duodenal mucosa:
Mucus-buffers-phospholipid layer, prostaglandins and epidermal growth factor maintains a neutral pH at the surface epithelial luminal
Pathogenesis:!! interface.
mucins, buffers, phospholipids, prostaglandins, trefoil peptides, peptide growth factor and their receptors, heat shock proteins, cathelicidins,
and β-defensins, potent vasodilators like nitric oxide and prostacyclins and through release of angiogenic growth factors, securing adequate
blood flow and representing the third and an ultimate line of mucosal protection.
There!should!be!a!balance!between!aggressive!and!defensive!factors.!Questions!that!
should!be!asked!are!why!in!that!patient?!Why!in!that!time?!And!why!at!that!point?!!

Schwartz’s!postulate:!“no!acid!–!no!ulcer”!but!the!problems!with!that!postulation!is!
that!inachlorhydria!there!is!no!peptic!ulcer!(cancer),!in!Zollinger!Ellison!syndrome!
there!are!multiple!ulcers!and!acid!suppression!is!the!main!target!of!therapy.!!

Contraindications!are:!hypersecretion!is!necessary!but!not!sufficient!condition!of!
ulceration!(rare!cases!of!Zollinger!Ellison!syndrome).!!

H.pylori!associated!ulcer:!
Prevalence!of!H.pylori!infection!in!duodenal!ulcer!patients!is!75Q90%!and!H.pylori!is!
found!in!most!patients!whom!NSAIDs!cannot!be!implicated.!The!association!with!
gastric!ulcer!and!H.pylori!is!lower.!After!eradication!of!the!organism,!ulcer!
recurrence!rates!are!reduced!dramatically!to!5Q20%.!Most!of!these!ulcer!recurrences!
are!due!to!NSAID!use,!or,!rarely,!reinfection!with!H.pylori.!
!
!
!

! 23!
NSAID!related!peptic!ulcer:!!
15Q40%!of!NSAID!users!develop!dyspepsia,!30Q50%!develop!erosions,!10Q30%!ulcers!
and!2Q4%!serious!complications.!30%!of!bleeding!peptic!ulcer!cases!are!NSAIDQ
related.!In!60%!of!the!cases!the!first!event!is!the!serious!complication!without!
preliminary!symptoms.!700!deaths/year!can!be!attributed!to!NSAIDQrelated!
complications!in!Hungary!and!20.000!deaths/year!in!USA.!Complications!(ulcer,!
bleeding,!perforation!and!stenosis)!do!not!only!appear!in!the!GI!tract.!!
!
Coxibs!(Celecoxib,!selective!COXQ2!inhibitor)!decrease!the!incidence!of!
endoscopically!visible!ulcers!by!approximately!75%!compared!with!nsNSAIDs.!Also,!
the!risk!of!significant!clinical!events!(obstruction,!perforation,!bleeding)!is!reduced!
by!up!to!50%!in!patients!taking!coxibs!versus!nsNSAIDs.!However,!a!twofold!increase!
in!the!incidence!of!cardiovascular!complications!(MI,!stroke,!and!death)!in!patients!
taking!coxib!compared!to!placebo.!!
!
Use!of!low!dose!Aspirin!(81Q325mg/d,!irreversible!inhibitor!of!COXQ1!and!Q2)!leads!to!
a!2xfold!increased!risk!of!GI!bleeding!complications.!
!
Risk!factors!of!NSAID!related!peptic!ulcer:!!
• Low!or!average!risk:!<!age!of!65,!no!ASA!therapy,!dyspepsia!or!peptic!ulcer!in!
history!
• Increased!risk:!>65!years!of!age,!male,!serious!associated!disorders,!
dyspepsia,!peptic!ulcer!in!history,!coexistent!ASA,!steroid,!anticoagulant,!
cytostatic!therapy,!alcohol,!tobacco!use.!
• Very!high!risk:!multiple!coexistent!risk!factor.!
H.pylori#infection#increases#the#risk#of#ulcer#disease#and#complications#over#
threefold#in#patients#taking#NSAIDs#or#low#doseBaspirin.#
!
Stress!ulcers:!
ICU!patients!with!serious!illnesses!(hypotension,!hypoperfusion,!hypoxia).!Hypoxia!or!
metabolic!trouples!of!gastric!mucosa.!Acid!rediffusion,!erosions,!dysfunction!of!
regenerative!processes,!low!intramucosal!pH.!!
!
Refractory!ulcer:!! It means there is something in the background for example
Definition:!if!8!weeks!of!therapy!has!failed!to!heal!duodenal!ulcer!and!12!weeks!of!
therapy!failed!to!heal!gastric!ulcer.!This!is!uncommon!!
Causes:!ulcerate!factors!(NSAIDs,!H.pylori,!lifestyle,!tobacco),!malignancy!(lymphoma!
or!carcinoma),!Crohn’s!disease,!Zollinger!Ellison!syndrome,!Amyloidosis,!sarcoidosis,!
eosinophilic!gastritis,!infections!(CMV,!TBC,!syphilis),!hiatal!hernia.!!
!

! 24!
Signs!and!symptoms!of!PUD:!!

# Epigastric!pain!(and!dyspepsia)!is!the!hallmark!of!peptic!ulcer!disease.!The!
pain!is!not!severe.!It!is!described!as!gnawing,!dull,!aching!or!“hunger!like”.!
Approximately!50%!of!patients!report!relief!of!pain!with!food!or!antacids!
(especially!duodenal!ulcers)!and!recurrence!of!pain!2Q4!hours!later.!
# History!of!dyspepsia!is!present!in!80Q90%!of!patients!with!variable!
relationship!to!meals!–!it!has!low!sensitivity!and!specificity!
# Ulcer!symptoms!characterized!by!rhythmicity!and!periodicity!(sometimes!
symptomatic!periods!lasting!up!to!several!weeks!with!intervals!of!months!to!
years!in!which!they!are!pain!free)!
# Nocturnal!pain!can!sometimes!awaken!the!patient!
# Vomiting,!loss!of!appetite!and!weight,!abdominal!defense,!hemorrhage,!
anemia!(alarm!symptoms)!refer!to!suspicion!of!complications!or!malignancy!
# Complications!can!occur!in!10Q20%!of!cases!without!preliminary!symptoms!!
# Bleeding,!!
# Perforation!(penetration)!!
# Pyloric!stenosis!(obstruction)!
# Usually!the!physical!examination!is!normal!but!sometimes!epigastric!
tenderness!

Diagnosis:!!

The!main!standpoints!are!history!and!symptoms.!Then!you!can!do!an!upper!
endoscopy,!which!is!a!preferred!diagnostic!tool!for!duodenal!and!gastric!ulcers.!
Duodenal!ulcers!are!virtually!never!malignant!and!do!not!require!biopsy.!3Q5%!of!
benignQappearing!gastric!ulcers!prove!to!be!malignant.!Hence,!biopsies!of!the!ulcer!
margin!are!almost!always!performed.!!

You!can!also!do!an!airMcontrast!upper!GI!barium!radiography:!this!is!a!
complementary!method,!alternative!(disorders!of!gastric!emptying,!motility,!at!
patient’s!request).!Endoscopy!cannot!be!replaced!with!H.pylori!testing.!Abdominal!
CT!imaging!is!obtained!in!patients!with!suspected!complications!of!peptic!ulcer!
disease!(perforation,!penetration!or!obstruction).!!

Indications!of!repeated!endoscopy:!gastric!ulcer!with!biopsy,!duodenal!ulcer!with!
alarm!symptoms!and!complications,!refractory!ulcers.!!

! 25!
 !

Topic!#7.!Peptic!ulcer:!therapy,!complications!and!their!treatment:!

Aims!of!the!therapy!should!be!to!heal!the!peptic!ulcer,!relieve!the!complaints!and!
improve!quality!of!life.!We!should!try!to!prevent!complications!and!relapses.!!
!
Therapy!can!be:!
# Medical!therapy:!the!aim!is!to!do!primary!hemostasis,!prevent!bleeding!and!
promote!ulcer!healing.!The!main!drug!groups!are:!!
o Drugs!that!neutralize!gastric!acid!and/or!suppress!acid!secretion!
" Antacids!!
" H2!receptor!blockers!–!no!effect!on!reQbleeding,!emergency!
surgery!and!mortality.!!
• 4!types!of!H2!antagonists!are!available:!cimetidine,!
ranitidine,!famotidine!and!nixatidine.!Healing!time!is!
85Q90%!with!8!week!therapy!for!both!duodenal!and!
Forrest classification - Peptic ulcer bleeding -
classification of upper gastrointestinal hemorrhage
gastric!ulcers.!
used for purposes of comparison and in selecting
patients for endoscopic treatment.
" PPIs!=!covalently!bind!to!H+K+ATPase,!permanently!
Acute hemorrhage inactivataing!it.!Restoration!of!acid!secretion!requires!
Forrest I a (Spurting hemorrhage) synthesis!of!new!pumps,!which!have!half!life!of!18!hours.!The!
Forrest I b (Oozing hemorrhage)
Signs of recent hemorrhage duration!of!action!of!PPI’s!exceeds!24!hours.!They!are!a!
Forrest II a (Visible vessel) remarkably!safe!short!term!therapy.!Long!term!may!lead!to!
Forrest II b (Adherent clot)
Forrest II c (Flat pigmented haematin on ulcer base) milk!decrease!in!vitamin!B12!and!calcium!absorption.!There!
Lesions without active bleeding
might!also!be!increased!risk!in!C.diff!and!other!bacterial!
Forrest III (Lesions without signs of recent
hemorrhage or fibrin-covered clean ulcer base)

! 26!
 gastroenteritis,!a!modest!increase!in!hip!fracture!and!
pneumonia.!
• High!dose!PPI’s!+!endoscopic!therapy!decrease!reQ
bleeding!and!mortality!rate.!!
• 90%!healing!of!duodenal!ulcers!after!4!week!therapy,!
90%!gastric!ulcer!healing!after!8!week!therapy.!
• There!are!6!types!of!PPIs!available:!Omeprazole,!
rabeprazole,!esomeprazole,!lansoprazole!
dexlansoprazole,!pantoprazole.!
• 80mg!Omeprazol!or!Pantoprazole!IV!8mg/h!infusion!72!
hours!
o Cytoprotective!agents!(Fortifying!defensive!factors,!Increase!
prostaglandin!and!bicarbonate!release,!Mucus!production!(enhance!
mucosal!defense!mechanism)).!These!are!not!used!as!first!line!agents!
due!to!efficacy!of!PPI’s!and!H2!antagonists!
" Sucralfate!
" Bismuth!
" Misoprostol!
o Antibiotics:!for!treating!H.pylori!infection!(test!and!eradicate)!!
" First!line!therapy:!PPI’s!2x!a!day,!or!Bismuth!2x!a!day!+!
Amoxicillin!(2x!1000mg)!+!Clarithromycin!(2x!500mg)!for!
PPI plus BMT
minimum!of!7!days!(up!to!14!day).!If!penicillin!allergy,!use!
metronidazole.!Unfortunately!this!only!reaches!full!eradication!
in!75%!of!cases.!!
" If!it!doesn’t!work!then!try:!2x!PPI’s!+!4x120mg!Bismuth!+!
metronidazole!(3x500mg)!+!tetracycline!(4x500mg)!for!7Q14!
days.!Eradication!accomplished!in!93%!of!cases.!
" If!no!therapy!works,!then!do!a!rescue!therapy:!check!
antimicrobial!susceptibility!and!treat!
# Endoscopic!therapy!(bleeding)!
o Take!biopsy!in!gastric!ulcers.!
# Surgical!therapy!(complications)!
o Indications:!perforation,!pyloric!stenosis,!obstruction,!bleeding!(after!
complex!endoscopic!and!medical!therapy!failed),!intractable!ulcer,!
malignancy!
# Lifestyle!modifications!(Diet,!tobacco,!alcohol,!stress)!"!eat!balanced!meals!
at!regular!intervals,!moderate!alcohol!intake!is!not!harmful.!Patients!should!
not!smoke,!it!retards!the!rate!of!ulcer!healing!and!increases!the!frequency!of!
recurrences.!!
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Repeat!endoscopy!and!biopsy!of!gastric!ulcer,!do!second!therapy!of!H.pylori!if!
necessary!and!2!months!of!antiQsecretory!treatment!afterwards.!Urea!Breath!Test!
control!6Q8!weeks!after!the!eradication!in!DU!(H2RA,!PPI!should!be!withheld!for!2!
weeks!prior!to!the!test).!Repeated!(second!line)!eradication!if!H.pylori!test!is!positive!
again,!or!3Q6!months!maintenance!antiQsecretory!treatment.!!
!
Urea!breath!test!control,!H.pylori!culture!and!antimicrobial!susceptibility!testing!if!
necessary.!Repeated!endoscopy!and!biopsy!of!gastric!ulcer!3!months!later,!do!
surgery!if!no!healing!detected!(refractory!ulcer!or!cancer!)!
!
How!to!treat!patient!with!NSAID!related!complications:!
# Avoid!continuous!NSAID!therapy!
# Identify!risk!groups!(history!)!
# Lowest!effective!dose,!shortest!treatment!period,!individual!treatment!
# Avoid!high!risk!combinations!(antiplatelet!therapy,!anticoagulant!therapy,!
corticosteroids)!
# H.pylori!testing!and!eradication!in!positive!history!of!PUD!
# Prophylaxis!in!high!risk!groups!with!proton!pump!inhibitors!(PPI).!!
How!to!prevent!NSAIDMrelated!complications:!!
# Treatment!strategies:!
o Low!risk!patients:!traditional!NSAIDs!
o Increased!risk!patients:!PPIQprophylaxis!and!traditional!NSAIDs!or!
COXibs!
o Very!high!risk!patients:!PPI!prophylaxis!and!COXibs!
Treatment!of!stress!ulcers:!!
# Prophylaxis!of!the!tissue!hypoxia,!mucosal!lesions.!
# Early!PPIQtherapy!!
o 2x40mg!PAN,!or!OME!IV!or!8mg/h!with!perfusion,!72!hours.!

Drugs neutralizing gastric acid and/or

suppressing acid secretion: antacids, H2-
receptor blockers, proton pump inhibitors

Cytoprotective agents (fortifying defensive

factors, increase prostaglandin and
bicarbonate release, mucus production):
sucralfate, bismuth, (misoprostol)

Antibiotics: treating Helicobacter pylori

infection (eradication

! 28!
Zollinger–Ellison syndrome (ZES) is caused by a non–beta islet cell, gastrin-secreting tumor of the pancreas that stimulates the parietal
cells of the stomach to maximal activity, with consequent mucosal ulceration. ZES may occur sporadically or as part of an AD familial
syndrome called multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually located in the pancreas, duodenum or
abdominal lymph nodes. The diagnosis is also suspected in patients without symptoms who have severe ulceration of the stomach and small
bowel, especially if they fail to respond to treatment. Gastrin works on the parietal cells of gastric glands causing them to secrete more
hydrogen ions into the stomach lumen. In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell hyperplasia.

Topic!#8.!ZollingerMEllison’s!syndrome:!
This!is!a!syndrome!caused!by!gastrinQsecreting!gut!neuroendocrine!tumors!
(gastrinomas,!solitary!or!multifocal!nodules),!which!result!in!hypergastrinemia!and!
acid!hypersecretion.!Less!than!1%!of!peptic!ulcer!disease!is!caused!by!gastrinomas.!
Primary!gastrinomas!usually!arise!in!pancreas,!duodenal!wall!or!lymph!nodes!the!
rest!are!in!unknown!primary!places.!Approximately!80%!are!located!within!the!
gastrinoma!triangle!(porta!hepatis,!neck!of!pancreas!and!third!portion!of!
duodenum).!
!
Over!2/3!are!malignant,!and!1/3!have!already!metastasized!to!the!liver!at!initial!
presentation.!About!25%!are!associated!with!MEN!1!that!are!more!difficult!to!resect.!
!
! Diarrhea,
! Multiple ulcers
refractory ulcers
!
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!
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!
!
!
Signs!and!symptoms:!
• >90%!develop!peptic!ulcers,!and!in!most!cases!the!symptoms!are!like!in!other!
peptic!ulcer!diseases.!Therefore!the!syndrome!may!go!undetected!for!years.!
• The!ulcers!are!usually!solitary!and!located!in!duodenum,!sometimes!there!are!
multiple!ulcers.!
• GERD!
• Gastric!acid!hypersecretion!can!cause!direct!intestinal!mucosal!injury,!
pancreatic!inactivation,!which!results!in!diarrhea,!steatorrhea!and!weigh!loss.!
Screening!for!Zollinger!Ellison!syndrome!with!fasting!gastrin!levels!should!be!
optained!in!patients!with!ulcers!that!are!refractory!(doesn’t!heal!completely!despite!
PPI!therapy!for!8Q12!weeks),!giant!ulcers!(>2cm),!ulcers!located!distal!to!duodenal!
bulb,!multiple!duodenal!ulcers,!frequent!ulcer!recurrences,!ulcers!associtated!with!
diarrhea,!ulcers!occurring!after!ulcer!surgery,!and!patients!with!ulcer!complications!
etc.!
!
! suspicion of Zollinger–Ellison syndrome may be aroused when the above symptoms prove resistant to treatment, when the
Clinical
!
symptoms are especially suggestive of the syndrome, or endoscopy is suggestive. The diagnosis of Zollinger–Ellison syndrome is
made by several laboratory tests and imaging studies.
!
- Secretin stimulation test, which measures evoked gastrin levels
!
- Fasting gastrin levels, on at least three separate occasions
- Gastric acid secretion and pH. Normal basal gastric acid secretion is less than 10 mEq/hour, while in Zollinger–Ellison syndrome
it is usually more than 15 mEq/hour.
- AN INCREASED LEVEL OF CHROMOGRANIN A IS A COMMON MARKER OF NEUROENDOCRINE TUMORS
- somatostatin receptor scintigraphy
! addition, the source of the increased gastrin production must be discovered.
- In 29!
This is either done using MRI or somatostatin receptor scintigraphy, the investigation of choice.
BAO/MAO:To Maximal Acid Output : Production of gastric H+ under baseline conditions, normal: 0-10 mmol/hour. The
BAO serves to evaluate the completeness of vagotomy; patients with Zollinger-Ellison syndrome have a ratio of basal to
maximal acid output (BAO:MAO) of > 60%. BAO is also increased in pernicious anaemia, gastric cancer, myxoedema and
rheumatoid arthritis.

Lab!findings:!gastrin!fasting!levels!↑,!gastric!pH!↓!
• Most!specific!method!for!identification!of!Zollinger!Ellison!syndrome!is!
increased!fasting!serum!gastrin!concentration!(>150!pg/mL).!Patient!should!
not!be!taking!H2!antagonists!for!24!hours!or!PPI’s!for!6!days!before!taking!the!
blood!sample.!Median!gastrin!level!is!500Q700!pg/mL.!60%!of!patients!have!
gastrin!levels!<1000!pg/mL.!
• Gastric!pH!should!also!be!measured!if!the!patient!has!fasting!
hypergastrinemia.!If!the!pH!is!>3,0!it!implies!hypochlorhydria!and!excludes!
gastrinoma.!
• Secretin!stimulatin!test!may!be!performed!in!patients!with!intermediate!
levels!of!gastrin!and!gastric!acid!to!distinguish!Zollinger!Ellison!syndrome.!IV!
secretin!produces!a!rise!in!gastrin!of!>200pg/mL!within!2Q30!min!in!85%!of!
patients!with!gastrinoma.!
• Elevated!serum!calcium!suggests!hyperparathyroidism!and!MEN!1!syndrome.!
• In!all!patients!with!ZollingerQEllison!syndrome!serum!PTH,!prolactin,!LH,!FSH!
and!GH!should!be!obtained!to!exclude!MEN!1.!
Imaging:!!CT!and!MRI!are!obtained!first!to!look!for!large!hepatic!metastasis!and!
primary!lesion,!but!they!have!low!sensitivity!for!small!lesions.!Gastrinomas!express!
somatostatin!receptors!that!bind!to!radioactive!somatostatin.!Thus,!somatostatin!
receptor!scintigraphy!with!SPECT!should!be!obtained!(patient!is!injected!with!
octreotide).!This!has!80%!sensitivity!for!tumor!detection!which!exceeds!all!other!
imaging!studies!combined.!
!
Differential!diagnosis:!Carcinoid,!insulinoma,!VIPoma,!glucagonoma,!
somatostatinoma.!These!tumors!can!be!distinguished!form!each!other!by!the!gut!
peptide!that!they!secrete,!however!poorly!differentiated!neuroendocrine!tumors!
may!not!secrete!any!hormones.!Hypergastrinemia!due!to!gastrinoma!must!be!
distinguished!from!other!hypergastrinemias!(atrophic!gastritis,!gastric!outlet!
obstruction,!vagotomy,!chronic!kidney!disease).!These!other!hypergastrinemias!have!
negative!secretin!stimulation!test.!
!
Treatment:!the!most!important!predictor!of!survival!is!the!presence!of!metastasis.!
• If!multiple!hepatic!metastasis:!initial!therapy!should!be!directed!at!controlling!
hypersecretion!w.!oral!PPI’s!for!complete!symptomatic!relief!and!ulcer!
healing.!
o Due!to!slow!growth!of!these!tumors,!30%!of!patients!with!metastasis!
have!10!years!survival!rate.!
• If!localized!disease:!the!gastrinoma!needs!to!be!resected!before!hepatic!
metastasis!occurs.!Lymph!node!metastasis!do!not!affect!the!prognosis!
adversely.!Surgery!is!usually!not!recommended!in!patients!with!MEN!1!due!to!
presence!of!multifocal!tumors!and!longQterm!survival!rate!in!the!absence!of!
surgery!in!most!patients.!
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 Gastritis
ACUTE: 1. H.Pylori 2. Infectious Phlegmonous/Necrotizing 3. Chemicals-hypoxia-stress-alcohol
CHRONIC: 1. non-atrophic (hpylori) 2. atrophic (a: autoimmune AMAG, b: hpylori EMAG)
3. specials (portal hypertension, chronic chemical, haemorrhagic)

Topic!#9.!Gastritis:!classification.!Special!categories!of!gastritis:!

Gastritis!is!a!disease!with!heterogeneous!etiology!and!more!than!100!classification!
systems.!Classification!can!be!based!on!time!course!(acute!vs!chronic),!histology,!
pathogenic!mechanism,!anatomical!distribution!etc.!There!is!histological!
inflammation!in!60%!of!mucosal!biopsy!specimens,!however!poor!correlation!is!
between!histology,!clinical!picture!(dyspepsia)!and!endoscopic!findings.!!
! Updated Sydney system for the classification and grading of gastritis - lecture
Classification!(according!to!lectures)! Nonatrophic
Atrophic
H.pylori, other

1. Acute!gastritis!
Atrophic gastritis: inflammation
is associated with mucosal
thinning, gland loss, and
metaplasia in epithelial cell type
2. Chronic!gastritis!!
Autoimmune: Autoimmunity
Mulifocal atrophic H.pylori Environmental factors
special form
a. Acute!H.pylori!infection!
b. Other!acute!infections!(other!bacterial,!phlegmonous,!mycobacterial,!
syphilitic,!viral,!parasitic,!fungal!infections)!
c. Chemical!(drugs,!NSAID’s,!bile),!hypoxia!(stress,!trauma,!burns,!sepsis)!
a. Chronic!nonMatrophic!gastritis!(H.pylori)!
b. Chronic!atrophic!gastritis!
i. Type!A:!autoimmune,!bodyQpredominant!(AMAG)!
Text
ii. Type!B:!H.pylori!related,!antral!predominant!(EMAG)!
environmental metaplastic atrophic gastritis
iii. NonQmetaplastic!
c. Special!forms:!!
i. Chemical,!radiation,!lymphocytis,!eosinophilic,!Crohn’s!
disease,!sarcoidosis,!granulomatous.!!

Disappearance of glands

Disappearance of crypts

Type A chronic
Autosomal dominant disorder
Associated with pernicious anaemia (autoimmune gastritis: antibodies against parietal cells and intrinsic factor)
Associated autoimmune disorders
!
!
Autoimmune metaplastic atrophic gastritis (AMAG)

!
Involves gastric body and fundus (antral sparing)
Achlorhydria

!
Antral sparing → G-cells → hypergastrinemia → ECL cell hyperplasia (→carcinoid tumor)
Intestinal metaplasia (risk of adenocarcinoma:3-18x)

Type B chronic

! 32!
H.pylori associated, antral-predominant, frequent form
Environmental metaplastic atrophic gastritis (EMAG)
Inflammation of the body (corpus and pan-gastritis)

Histology improves after H.p. eradication (but atrophy)

Acute!gastritis:!!
!
Most!common!causes!are!infectious!and!chemical.!!
a. H.pylori!infection:!acute!infection!with!H.pylori!may!cause!transient!clinical!
illness!characterized!with!nausea!and!abdominal!pain!that!may!last!for!
several!days!and!is!associated!with!acute!histologic!gastritis!with!
polymorphonuclear!cells!(PMNs).!After!these!symptoms!resolve!the!majority!
progress!to!chronic!infection!with!chronic,!diffuse!mucosal!inflammation! most resolve
some people chronic
(gastritis)!characterized!with!PMNs!and!lymphocytes!=!chronic!gastritis.!
Although!h.pylori!infection!is!present!in!30Q50%!of!the!population!most!
persons!are!asymptomatic!and!suffer!no!sequelae.!
!
b. Phlegmonous/necrotizing!gastritis:!Acute!infection!of!the!gastric!submucosa!
and!muscularis!with!variety,!aerobic!or!anerobic!organisms!produce!a!rare,!
rapidly!progressive,!life!threatening!condition!known!as!phlegmonous!or!
nectrotizing!gastritis,!which!requires!broadQspectrum!antibiotic!therapy!and!
in!many!cases!emergency!gastric!resection.!!
There!is!marked!diffuse!infiltration!of!the!entire!wall!and!necrosis.!
Predisposing!factors!can!be:!alcoholics,!immunocompromised!individuals!or!
iatrogenic!causes:!polypectomy,!mucosal!injection.!
!
Viral!infection:!CMV!(in!AIDS!or!transplant!patients).!!
Fungal!infection:!Candida!or!mucomycosis!(immunocompromised!and!
diabetic!patients)!
Parasitic!infection:!Larvae!of!Anisakis!marina!ingested!in!raw!fish!or!sushi!
Bacterial!infection:!strept,!staph,!E.coli,!proteus,!haemophilus!
!
c. Chemical!or!hypoxia!acute!gastritis:!! irritation to gastric mucosa
Stress!acute!gastritis:!stress!related!mucosal!erosions!and!subepithelial!
hemorrhages!may!develop!within!72!hours!in!critically!ill!patients.!Clinically!
apparent!bleeding!occurs!in!6%!of!ICU!patients,!however!in!nonQICU!patients!
<!1,5!%.!Bleeding!is!associated!with!higher!mortality!rate!but!is!seldom!the!
cause!of!death.!!
• Risk!factors!for!bleeding!are!coagulopathy!(platelets!<!50.000!or!
INR!>!1,5)!and!!
• Respiratory!failure!with!the!need!for!mechanical!ventilation!for!
over!48!hours.!!
• If!these!two!risk!factors!are!not!present,!the!risk!of!bleeding!is!
only!0.1%.!!
These!patients!should!be!routinely!administered!prophylaxis!(H2!antagonists!
or!PPI).!Once!bleeding!occurs!the!patient!should!receive!continuous!IV!
infusion!of!PPI!(esomeprazole!or!pantoprazole!80mg!IV!bolus!followed!by!
8mg/h!continuous!infusion)!as!well!as!sucralfate!suspension.!!

! 33!
 Stress!gastritis!risk!factors:!mechanical!ventilation,!coagulopathy,!trauma,!
burns,!shock,!sepsis,!CNS,!liver!failure,!kidney!disease,!multiorgan!failure.!Use!
of!enteral!nutrition!reduces!the!risk!of!stress!related!bleeding.!
!
Alcoholic!gastritis!(drugs):!
Excessive!alcohol!consumption!may!lead!to!dyspepsia,!nausea,!emesis!and!
minor!hematemesis!–!sometimes!labeled!“alcoholic!gastritis”,!however!it!is!
not!proven!that!alcohol!alone!causes!significant!erosive!gastritis.!Therapy!
with!PPI!or!H2!antagonist!for!2Q4!weeks!is!usually!sufficient.!
!
Chronic!gastritis:!!
In!chronic!gastritis!the!mucosa!is!infiltrated!mainly!with!lymphocytes.!In!the!early!
phase!there!is!superficial!gastritis!(lamina!propria,!intact!gastric!glands).!Then!there!
is!atrophic!gastritis!with!deeper!infiltration!and!glandular!destruction.!Gastric!
atrophy!is!where!there!is!loss!of!glandular!structure!and!endoscopically!thin!mucosa.!
This!can!lead!to!intestinal!metaplasia,!where!there!is!conversion!of!glands!to!small!
intestinal!phenotype!which!is!predisposition!for!cancer.!!
!
H.pylori!infection!often!leads!to!chronic!gastritis.!In!general!it!can!have!3!different!
outcomes:!
simple infection
a. Mild,!diffuse!gastritis!(most!people)!that!does!not!disturb!acid!secretion.!!
b. 15%!have!inflammation!that!predominates!in!gastric!antrum!and!spares!the! antrum predominant
spares body
gastric!body!(where!acid!is!secreted).!People!with!this!type!tend!to!have! spares acid secretion
3 outcomes of H.Pylori increased!gastrin!and!acid!production!and!increased!risk!of!developing!peptic!therefore increase acids
ulcers,!especially!duodenal!ulcers.!! results in peptic and duo

c. Inflammation!that!predominates!in!the!gastric!body.!Over!time,!this!may!lead!
body predominant
to!destruction!of!acid!secreting!glands!with!resultant!mucosal!atrophy,! destroys acid glands
decreased!acid!secretion!and!intestinal!metaplasia.!It!has!increased!risk!of! mucosa atrophy
gastric!ulcers!and!gastric!cancers.!! decreased acids
gastric ulcers and canc
!
a. Chronic!nonMatrophic!gastritis!(H.pylori)!
This!is!the!first!two!outcomes!with!H.pylori!infection!mentioned!above!(a!and!b).!
Either!people!get!mild,!diffuse!gastritis!that!does!not!disturb!the!acid!secretion,!or!
people!get!inflammation!that!predominates!in!antrum,!spares!the!body.!There!is!
increased!risk!of!peptic!ulcer.!
!
b. Type!A!chronic!gastritis:!Autoimmune!metaplastic!atrophic!gastritis!
(AMAG)!=!pernicious!anemia!gastritis!
Pernicious!anemia!gastritis!is!an!autoimmune!disorder!involving!fundic!glands!
(Involves!the!body!and!fundus,!antral!sparing).!It’s!an!autosomal!dominant!disorder!
with!resultant!achlorhydria,!decreased!intrinsic!factor!secretion!and!vitamin!B12!
malabsorption.!Off!patients!with!B12!deficiency,!less!than!half!have!pernicious!
anemia.!Fundic!histology!in!pernicious!anemia!is!characterized!by!severe!gland!
atrophy!and!intestinal!metaplasia!caused!by!autoimmune!destruction!for!the!gastric!
fundic!mucosa.!AntiQintrinsic!factor!antibodies!are!present!in!70%!of!patients.!

! 34!
Achlorhydria!is!a!symptom,!it!leads!to!pronounced!hypergastrinema!due!to!loss!of!
acid!inhibition!of!gastrin!G!cells.!Hypergastrinemia!may!induce!hyperplasia!of!gastric!
enterochromaffinQlike!cells!that!may!lead!to!development!of!small,!multicentric!
carcinoid!tumors!in!5%!of!patients.!
!
There!is!antral!sparing:!Gcells!"!hypergastrinemia!"!ECL!cells!hyperplasia!
("!carcinoid!tumor).!!
!
There!can!be!intestinal!metaplasia!which!increases!the!risk!of!adenocarcinoma!3Q18!
fold.!Metastatic!spread!is!uncommon!in!tumors!smaller!than!2cm.!!
!
Endoscopy!with!biopsy!is!indicated!in!patients!with!pernicious!anemia!at!the!time!of!
diagnosis.!Patients!with!dysplasia!or!small!carcinoids!require!periodic!endoscopic!
surveillance.!
!
b.!Type!B!chronic!gastritis!(H.pylori):!Environmental!metaplastic!atrophic!
gastritis!(EMAG)!=!the!third!kind!of!inflammation!with!H.pylori!infection!(c.!from!
above)!
!
Environmental!metaplastic!atrophic!gastritis!(EMAG)!is!a!type!of!chronic!gastritis!
which!progresses!toward!the!body!(panQgastritis)!and!increases!with!age.!Over!time,!
this!may!lead!to!destruction!of!acid!secreting!glands!with!resultant!mucosal!
atrophy,!decreased!acid!secretion!and!intestinal!metaplasia.!It!has!increased!risk!of!
gastric!ulcers!and!gastric!cancers.!!The!infection!can!lead!to!chronic!atrophic!
gastritis,!gastric!atrophy,!metaplasia,!dysplasia!and!carcinoma.!!The!histology!
improves!after!H.pylori!eradication.!H.pylori!is!an!independent!risk!factor!(6Q9x)!for!
gastric!cancer.!
!
c. Special!forms!of!chronic!gastritis:!
Chronic!chemical!gastritis:!
Can!be!due!to!drugs,!NSAIDs!or!bile!reflux.!It!can!lead!to!dyspepsia,!mucosal!injury,!
inflammation!or!erosions.!Patient!usually!has!dyspepsia,!however!the!symptoms!
correlate!poorly!with!the!significant!mucosal!abnormalities!that!may!occur!or!
adverse!clinical!events!(ulcer!bleeding!or!perforation).!Given!how!many!patients!take!
NSAIDs!it!is!not!feasible!to!investigate!every!patient!with!dyspepsia.!However,!
patient!with!alarming!symptoms,!such!as!severe!pain,!weight!loss,!vomiting,!GI!
bleeding!or!anemia!should!undergo!upper!endoscopy.!Symptoms!may!improve!if!
patient!discontinues!the!therapy,!reduce!it!to!the!lowest!does!or!administration!with!
meals.!Empirical!treatment!of!PPI’s!for!2Q4!weeks!is!recommended!for!patients!with!
NSAID!related!dyspepsia,!especially!in!those!who!continued!NSAID!treatment!is!
required.!If!symptoms!do!not!improve!upper!endoscopy!is!required.!
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! 35!
Portal!hypertension!gastropathy!
Portal!hypertension!commonly!results!in!gastric!mucosal!and!submucosal!congestion!
of!capillaries!and!venules,!which!correlate!with!the!severity!of!the!portal!
hypertension!and!underlying!liver!disease.!It!is!usually!asymptomatic!but!may!cause!
bleeding!in!10%!of!cases.!Treatment!with!propranolol!or!Nadolol!reduces!the!
incidence!of!recurrent!acute!bleeding!by!lowering!portal!pressures.!!
!
Erosive!and!hemorrhagic!gastritis!
It´s!most!commonly!seen!in!alcoholics!or!critically!ill!patients,!or!patients!taking!
NSAIDs,!it!can!also!be!due!to!severe!medical!or!surgical!illness!or!portal!
hypertension.!!!
!
Signs!and!symptoms:!
• Often!asymptomatic,!but!may!cause!epigastric!pain,!nausea!and!vomiting.!!
• May!also!cause!hematemesis,!or!“coffee!grounds”!emesis!however!usually!
there!is!not!significant!bleeding.!Sometimes!there!is!bloody!aspirate!or!
melena!
• Dyspepsia!
• Anorexia!!
• In!lab!findings!you!may!find!low!hematocrit!or!iron!deficiency!anemia.!!
Diagnosis:!!
• Upper!Endoscopy:!supepithelial!hemorrhages!petechiae!and!erosions.!!
• Superficial!lesions!that!vary!in!size!and!number,!may!be!focal!or!diffused.!
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 Three!things!that!can!happen!with!H.pylori!infection,!and!their!result:!

increased acid

simple

decreased acid
atrophy of mucosa

!
!
!
! non-atrophic mild gastritis which becomes asymptomatic infection
Simple
!
! predominant gastritis: inflammation that predominates in gastric antrum and spares the
Antral
gastric body (where acid is secreted). Increased gastrin and acid production and increased risk of
!
developing peptic ulcers, especially duodenal ulcers.
!
! predominant atrophic gastritis: Inflammation that predominates in the gastric body. Over
Corpus-
time, this may lead to destruction of acid secreting glands with resultant mucosal atrophy, decreased
acid !secretion and intestinal metaplasia.
It has! increased risk of gastric ulcers and gastric cancers.
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 Helicobacter pylori is a spiral-shaped Gram-negative bacterium that colonizes the stomach and can
establish a chronic infection of the gastric mucosa - risk of developping chronic gastritis, peptic ulcer
disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. Chronic gastritis (obligate)
Peptic ulcer (lifetime risk is 15% among
infected pts)
Topic!#10.!Significance!and!treatment!of!Helicobacter!pylori!infection.! Gastric cancer (lifetime risk is 1.0% among
infected pts)
Relative risk of peptic ulcer and cancer 2-10x
Transition of chronic H.p.gastritis to atrophic
gastritis
Warren!JR!and!Marshall!BJ!got!the!nobel!prize!2005!due!to!their!discovery!of! (incidence 1-2%/year) (role of
maintenance PPI- treatment of GERD ?)

correlation!between!H.pylori!infection!and!gastroduodenal!pathology.!It!was!a!
Chronic gastritis outcomes 1: pan-gastritis:→
atrophic gastritis with reduced acid
production → intestinal metaplasia →
milestone!in!gastroenterology.!! dysplasia → cancer. 2.: antral-predominant
gastritis with high acid production and
! duodenal ulcer
Differences in host, immune response,
H.pylori!is!indigenous!in!the!stomach,!one!of!the!most!common!human! environment and bacterial factors

microorganisms!and!it!infects!about!half!of!the!world!population.!Infection!rates!vary!
(40Q90%)!among!developed!and!developing!countries.!It!depends!on!personal!
hygiene!and!community!sanitation.!H.pylori!doesn’t!cause!serious!illness!in!most!
cases!(85%).!The!outcome!of!its!acquisition!is!not!predictable,!it!depends!on!bacterial!
pathogenic!and!immunogenic!mechanisms,!host!immune!response!and!
environmental!factors.!The!infection!can!lead!to!chronic!gastritis!(usually!always),!
peptic!ulcer!disease!(lifetime!risk!15%!of!infected!persons),!gastric!cancer!(lifetime!
risk!1,0%!of!infected!persons)!and!MALT!lymphoma.!!
!
Chronic!gastritis!can!either!lead!to:!
1.!!PanQgastritis!"!atrophic!gastritis!with!reduced!acid!production!"!
intestinal!metaplasia!"!dysplasia!"!cancer.!!
2.!!AntralQpredominant!gastritis!with!high!production!and!duodenal!
ulcer.!
!
The!difference!between!these!two!depends!on!the!host,!immune!response,!
environment!and!bacterial!factors.!!
!
H.pylori!infection!is!usually!acquired!during!childhood!and!is!transmitted!by!the!
fecalQoral!(gastroQoral,!oralQoral)!routes!f.ex!via!family!members,!endoscopy!
personnel,!positive!stool!cultures!and!contaminated!water!or!food.!The!acute!
infection!often!runs!unapparent!(dyspepsia,!vomiting,!gastritis).!Chronic!infection!
lasts!during!lifetime,!spontaneous!clearing!is!very!low!(1%/year).!!

! 38!
H.pylori!virulence!factors:!!
The!bacteria!uses!its!flagellum!for!migration.!It!has!urease!enzyme!(urea!+!H2O!"!
NH4!+!bicarbonate)!which!has!cytotoxic!effect!and!protects!the!microenvironment!
of!the!bacteria!by!increasing!the!pH!(making!it!more!basic).!H.pylori!also!has!
protease,!phospholipase,!catalase,!superoxide!dismutase!which!cause!mucus!and!
membrane!disintegration,!invasion!and!protection.!Adherence!factors!(Adhesins)!
are!used!for!the!epithelial!adhesion!"!Blood!group!(Lewis!B)!antigenQbinding!
adhesion!(adhesion!babA2)!"!To!achieve!colonization!of!the!stomach,!H.pylori!
adheres!to!Lewisb!(Leb)!antigens!in!the!gastric!mucosa!using!its!outer!membrane!
protein!BabA.!
!
• CagQpathogenicity!island!(cagQPAI).!CagA!is!encoded!by!“cytotoxinQassociated!
gene”!(cagA)!in!cagPAI.!!
• Cag!E!gene!(interleukinQ8!secretion,!neutrophil!activation).!!
• VacA!gene!(vacuolating!cytotoxin),!VacA:!production!depends!on!cagA!+).!!
• IceA!=!protein!induced!by!contact!with!epithelium.!!
• HPQNAP!=!neutrophil!activation!protein.!OipA!=!outer!inflammatory!protein!A!
–!predictor!of!peptic!ulcer.!!

!
Clinical!significance:!
• After!the!eradication!of!H.pylori!the!relapse!rate!of!peptic!ulcer!remains!low.!!
• Regression!of!low!grade!MALT!lymphoma!may!occur!after!H.pylori!is!
eradicated.!!
• H.pylori!may!be!a!predisposing!factor!for!developing!gastric!
adenomcarcinoma.!WHO#classified#H.pylori#infection#as#a#group#I#
carcinogenic#exposure.!
• Eradication!of!H.pylori!has!the!potential!to!reduce!the!risk!of!gastric!cancer!
development.!!
• Cancers!of!the!cardia!are!not!associated!with!h.pylori.!!

! 39!
 !
#
#
Urea#breath#test#is#the#golden#standard#of#diagnosis#of#H.pylori#diagnostic#tests.#
!
Indications!of!testing:!!
1. “Test!and!treat”!strategy:!!
a. Dyspeptic!patients!under!the!age!of!40/45!years!of!age,!!
b. without!alarm!symptoms,!!
c. patients!with!familiar!history!of!gastric!cancer,!!
d. NSAIDs!users!and!reflux!symptoms!excluded.!!
2. “Search!and!treat”!strategy:!!
a. Peptic!ulcer!patients!(acute!or!chronic!phase,!with/without!
symptoms).!Intermittently!treated!with!antiQsecretory!drugs!
b. Symptomless!first!degree!relatives!of!patients!with!distal!gastric!
cancer.!!
3. Do!not!test!if!there!is!no!indication!of!eradication!
4. Screening!of!asymptomatic!individuals!at!average!risk!of!gastroduodenal!
pathology!is!not!indicated.!!
5. Alarm!symptoms!and!dyspepsia!above!the!age!of!40/45!years!indicate!
endoscopy.!
Eradication!of!H.pylori!is!strongly!recommended!(based!on!evidences)!in!cases!of:!!
• Peptic!ulcer!(in!every!stage!–!acute,!chronic,!asymptomatic,!complicated!
etc.),!!
• Low!grade!gastric!MALT!lymphoma,!!
• Atrophic!gastritis,!!
• After!gastric!resection!due!to!cancer,!!
• In!first!degree!relatives!of!gastric!cancer!patients!!
• At!the!request!of!patient.!!
• Functional!dyspepsia,!!
• Before!longQterm!treatment!of!PPI’s!(GERD),!!
• If!long!term!treatment!of!NSAID’s!or!Aspirin!is!necessary!for!high!risk!patients!
• In!unexplained!iron!deficient!anemia.!!
Eradication!is!not!recommended!in!extragastrointestinal!diseases.!!
!

! 40!
 Medical!treatment!of!H.pylori!infection:!
Eradication!of!H.pylori!has!been!proved!difficult.!Combination!regimens!that!use!two!
or!three!antibiotics!with!proton!pump!inhibitor!or!Bismuth!are!required!to!achieve!
adequate!rates!of!eradication!and!to!reduce!the!number!of!failures!due!to!antibiotic!
resistance.!
!
• First!line!therapy:!PPI!or!RBC!based!combinations:!!
o 2x!per!day!PPI,!or!2x/day!RBC!(rantidin!bismuth!citrate)!+!Amoxicillin!
(2x1000mg)!+!Clarythromycin!(2x500mg)!for!minimum!of!7!days.! PPI + Amx+ Claryth
! In!the!case!of!penicillin!allergy!Amoxicilin!can!be!replaced!by!
Metonidrazole!(2x500mg)!
• In!case!the!first!line!therapy!fails,!the!second!line!therapy!is!bismuthMbased!
quadruple!therapy:!
o 2x!per!day!PPI!+!Bismuth!(4x120mg)!+!Metonidrazole!(3x500mg)!+!PPI, Bismuth, Metro, Tetra
Tetracycline!(4x500mg)!for!minimum!of!7!days.!
• In!the!case!of!subsequent!failure!the!rescue!therapy!should!be!based!on!
antimicrobial!susceptibility!testing.!Success!of!eradication!therapy!must!be!
tested!after!6Q8!weeks.!!
!
!
The mechanisms of actions of bismuth on gastrointestinal pathogens including H. pylori are complex and include
inhibition
! of protein and cell wall synthesis, membrane function and ATP synthesis. Adherence of H. pylori to surface
epithelial cells is also impaired.
!
! monotherapy is effective in vivo to suppress H. pylori but cure rates are low.
Bismuth
!
CBS, BSS and RBC have synergistic activity with one or two antibiotics and are effective in eradicating H. pylori.
!
! RBC also exert other effects on the mucosa including cytoprotective and ulcer healing properties.
CBS and
!
In addition, RBC is effective in inhibiting gastric acid secretion.
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!

! 41!
 Motility: Normal motility or peristalsis is an orderly sequence of muscular contractions.
In functional motility disorders, muscular spasms can cause pain, or contractions can be very rapid or very slow, altering the speed or direction of gut transit.

Stomach Motility Disorders - Muscle or Nerve

Gastroparesis - Delayed Gastric Emptying: causes difficulty eating Dyspepsia, and severe, chronic vomiting and nausea. Some patients may even require tube-feeding to ensure adequate
nutrition. There are a number of causes for gastroparesis, including DM, anorexia, bulimia, lupus, and brain disorders. 40% of the cases have an unknown origin. Patients who have not
responded or are intolerant of conservative therapies are candidates for injection of Botox into a hypertensive pyloric sphincter or Gastric Electrical Stimulation (GES).

Topic!#11.!Motility!disorders!of!the!stomach,!dyspepsia:!
!
Dyspepsia! indigestion
Dyspepsia!refers!to!acute,!chronic!or!recurrent!pain!or!discomfort!centered!in!the!
upper!abdomen.!Dyspepsia!is!a!common!condition!and!usually!describes!a!group!of!
symptoms!rather!than!one!predominant!symptom!or!a!disease.!It!occurs!in!15%!of!
adult!population!and!accounts!for!3%!of!general!medical!office!visits.!
!
Etiology:!dyspepsia!can!be!caused!by!many!other!diseases!or!states.!
• Self!limited!indigestion!"!overeating,!eating!too!quickly,!high!fat!foods,!
eating!during!stressful!situations,!drinking!too!much!alcohol!or!coffee!etc.!
• Medications!"!aspirin,!NSAIDs,!antibiotics!(metronidazole,!macrolides),!
diabetic!drugs!(metformin,!glucosidase!inhibitors!etc.),!antihypertensive!
medication!(ACE!inhibitors,!ARBs),!cholesterol!lowering!agents!(niacin,!
fibrates),!neuropsychic!medication!(donepezil,!rivastigmine;!cholinesterase!
inhibitors),!SSRIs,!Parkinson‘s!drugs,!steroids,!estrogen,!digoxin,!iron,!opioids.!
• Functional!dyspepsia!
Functional Dyspepsia (Nonulcer
Dyspepsia): An ABNORMAL
o Most!common!cause!of!chronic!dyspepsia!
GASTRIC
ACCOMMODATION REFLEX
o No!obvious!organic!cause!of!the!symptoms!
or decreased relaxation of the
fundus may cause functional
o These!patients!are!often!younger,!report!a!variety!of!abdominal!and!
dyspepsia.
Patients’ symptoms include pain
extragastrointestinal!complaints,!show!signs!of!anxiety!or!depression!
or discomfort and bloating in the
upper abdomen, fullness, and
or!have!a!history!of!psychotropic!medications.!
nausea. • Luminal!GI!tract!dysfunction!can!cause!dyspepsia! Mechanical Dyspepsia
o Peptic!ulcer!disease!
o GERD!
o Gastric!or!esophageal!cancer!
o Gastroparesis!
o Lactose!intolerance!or!malabsorptive!conditions!
o Parasitic!infections!
• H.pylori!infection!can!cause!dyspepsia!
o H.pylori!is!an!uncommon!cause!of!dyspepsia,!it!usually!causes!chronic!
gastritis.!!
• Pancreatic!disease!can!cause!dyspepsia!
o Pancreatic!carcinoma!or!chronic!pancreatitis!may!be!mistaken!as!
dyspepsia!
o Usually!there!is!more!pain,!anorexia!and!rapid!weight!loss,!
steatorrhea!and!jaundice!
• Biliary!tract!disease!
o This!should!be!distinguished!from!dyspepsia!due!to!abrupt!onset,!
right!upper!quadrant!pain!and!cholelithiasis!or!choledocholithiasis.!!
• Other!conditions:!DM,!thyroid!disease,!chronic!kidney!disease,!myocardial!
ischemia,!intrabdominal!malignancies!etc.!!
!
!

! 42!
Clinical!symptoms:!
• Epigastric!pain!or!burning! pain and discomfort in the upper abdomen
• When!heartburn!is!dominant,!gastroesophageal!reflux!is!nearly!always!
present!
• Early!satiety!
• Postprandial!fullness!
• Bloating,!nausea,!or!vomiting!
Physical!examination!is!rarely!helpful.!Concomitant!weight!loss,!persistent!vomiting,!
constant!severe!pain,!dysphagia,!hematemesis!or!melena!"!do!an!endoscopy!!
!
Lab!findings:!!
• Blood!test:!Blood!count,!electrolytes,!liver!enzymes,!calcium,!thyroid!function!
test!
• Noninvasive!H.pylori!test!(urea!breath!test,!fecal!antigen!test!or!IgG!
serology)!should!be!performed!first.!!
o If!H.pylori!test!is!negative!and!the!patient!is!not!taking!NSAIDs!–!
peptic!ulcer!disease!can!be!excluded.!!
Further!examination:!!
• Upper!endoscopy:!look!for!gastric!cancer!or!other!serious!organic!disease!in!
all!patients!>55!years!or!younger!patients!with!alarming!symptoms.!!
o Look!for!erosive!esophagitis,!ulcers!and!malignancy!
• Check!for!antibodies!for!celiac!disease!
• Check!for!Giardia!antigen!
• Abdominal!imaging!(CT!or!US)!is!performed!when!pancreatic,!biliary!tract,!
vascular!disease!or!volvulus!is!suspected!
• Gastric!emptying!studies!is!done!when!patient!has!recurrent!vomiting.!
• Esophageal!pH!testing!(ambulatory)!if!atypical!GERD!is!suspected!
Treatment:!!
• Empiric!treatment!of!PPI‘s!for!4!weeks!is!the!initial!step!when!patient!is!<!55!
years!and!no!alarming!symptoms.!
• If!H.pylori!test!is!positive!it!needs!to!be!treated.!
• If!patient!has!relapse!of!symptoms!after!discontinouing!the!4!week!PPI!
therapy,!long!term!PPI!therapy!may!be!considered.!!
• Treatment!of!functional!dyspepsia:!usually!these!patients!have!mild!
symptoms!that!respond!to!life!style!changes.!Alcohol!and!caffaine!should!be!
discontinued,!consume!small!meals!at!a!time,!low!fat.!Low!dose!
antidepressants!may!help!some!patients.!Some!patients!are!H.pylori!positive!
and!should!be!treated.!Psycho!or!hypnotherapies!may!be!tried!in!selected!
motivated!patients.!Herpal!therapies!as!well.!!

! 43!
Dyspepsia means indigestion and it is a complex of symptoms rather than one symptom. It is described as pain or discomfort
causing indigestion accompanied by nausea, chronic vomiting, weight loss, feeling of satiety, postprandial fullness,
Belching, upper abdomen bloating, epigastric pain.

It can be caused by: self-limited dyspepsia, medications, h.pylori, functional dyspepsia (impaired reflex, decreased accomodation)
, mechanical dyspepsia, pancreatic, biliary tree, other causes such as DM, thyroid diseases, coliac disease

!
!

!
!
!
!

! 44!
bowel cancer is 2nd after lung
ACC: Intestinal type
Worldwide, stomach cancer is the fifth most common cancer. It is more common in men and in developing countries.
ACC: diffuse type
Gastric cancer death is the 3rd most common cause of cancer-related death in the world
difficult to cure in Western countries, primarily because most patients present with advanced disease.
malt lymphoma
gastric cancer incidence and mortality have fallen dramatically over the past 70 years linitis plastica
The two main tumor sites of gastric adenocarcinoma are proximal (cardia) and distal (noncardia). Metastasis
Despite a decline in distal gastric cancers, proximal tumors have been increasing in incidence epidermal tumours
Topic!#12.!Gastric!cancer:!epidemiology,!etiology!and!classification:! carcinoma, adenoma
non-epidermal tumours
Gastric!cancers!are!the!second!most!common!cause!of!tumor!death!worldwide.!The!
5!year!survival!is!20%!in!USA!and!40%!in!Japan.!Number!of!gastric!cancers!is!
decreasing!owing!to!changes!in!diet!(more!fruits!and!vegetables),!food!refrigeration,!
reduced!toxic!environmental!exposures,!and!a!decline!in!H.pylori!infections.!The!
number!of!distal!gastric!cancers!is!decreasing,!while!the!number!of!proximal!cancers!
Part of the decline may be due to the recognition of certain risk factors
is!growing!(cardia).!! such as H. pylori and other dietary and environmental risks.
!
There!are!two!main!histological!variants!of!gastric!cancer,!intestinal!type!(which!
resembles!intestinal!cancers!in!forming!glandular!structures)!and!diffuse!type!(which!
is!poorly!differentiated,!has!signet!ringed!cells!and!lacks!glandular!formation).!!
!
• Intestinal!type!is!more!common!(even!though!prevalence!is!declining)!and!it!
affects!more!males!than!females,!increase!with!age!and!is!more!associated!
with!environmental!factors.!Intestinal!type!gastric!cancer!is!believed!to!arise!
from!atrophic!gastritis!and!h.pylori!infection!to!intestinal!metaplasia!and!
finally!dysplasia!or!cancer.!!
• Diffuse!gastric!cancer!accounts!for!20Q30%!of!gastric!cancers.!It!affects!men!
and!women!equally,!occurs!commonly!in!young!people!and!not!as!strongly!
related!to!h.pylori!infection!as!the!intestinal!type!gastric!cancer.!Most!of!the!
diffuse!gastric!cancers!are!related!to!hereditary!or!acquired!mutations!in!the!
genes!regulating!the!EQcadherin!cell!adhesion!protein.!The!diffuse!gastric!
cancer!has!poor!prognosis.!
Most!gastric!cancers!arise!in!the!body!and!antrum.!They!occur!in!variety!of!
morphological!patterns:!
!
1. Polypoid!or!fungating!intraluminal!masses!
2. Ulcerating!masses!
3. Diffusely!spreading!(linitis!plastiac)!in!which!the!tumor!spreads!through!the!
submucosa!resulting!in!rigid!atonic!stomach!with!thickened!folds!
4. Superficially!spreading!or!“early”!gastric!cancer,!confined!to!the!mucosa!or!
submucosa!(with!or!without!lymph!node!metastases)!and!associated!with!
favorable!prognosis.!!
!
Promoting!factors:!!
• Less!vegetables!
• Less!protein!intake!
• Less!vitamin!C!and!A,!
• Smoked!meat!
• A!lot!of!starch!
• A!lot!of!salt!and!nitrate!uptake!
• Smoking!
• H.pylori!
• Atrophic!gastritis!
• Pernicious!anemia!

! 45!
 • Intestinal!metaplasia,!
• Resected!stomach!
• Higher!age!
• Real!polyps!(adenomas)!of!the!stomach!
• Blood!group!A!
• Accumulation!in!family!
Symptoms:!it’s!generally!asymptomatic!until!the!disease!is!advanced.!!
! Early gastric cancer has no associated symptoms. Most symptoms of gastric
cancer reflect advanced disease. By the time they develop, the disease is almost
• Loss!of!appetite,! invariably too far advanced for curative procedures.
Signs and symptoms of gastric cancer include the following:
• Early!satiety! Indigestion, Nausea or vomiting, Dysphagia
Postprandial fullness, Loss of appetite
• Changes!of!taste! Melena or pallor from anemia
Hematemesis
• Dysphagia! Weight loss
Palpable enlarged stomach with succussion splash
• Loss!of!weight! ENLARGED LYMPH NODES SUCH AS VIRCHOW NODES (IE, LEFT
SUPRACLAVICULAR) AND IRISH NODE (ANTERIOR AXILLARY)
• Occult!bleeding!–!anemia,!massive!acute!bleeding,!hematemesis,!melena!
• Pain!–!epigastric,!dull!character,!like!a!belt!!
• If!tumor!in!pylorus!–!postprandial!vomiting.!If!tumor!obstructs!lower!
esophagus!–!progressive!dysphagia.!!
• Physical!signs!of!progression:!!
o Supraclavicular!lymph!node!enlargement!(Virchow)! Late complications of gastric cancer may include the following features:
o Epigastric!palpable!mass,!! Pathologic peritoneal and pleural effusions
Obstruction of the gastric outlet, gastroesophageal junction, or small bowel
o Ascites! Bleeding in the stomach from esophageal varices
Intrahepatic jaundice caused by hepatomegaly
o Inhomogeneous!liver! Extrahepatic jaundice

o Pelvic!mass!(Krukenberg!tumor!(ovarian!metastasis))!
Inanition from starvation or cachexia of tumor origin

• Laboratory!results:!!
o Iron!deficiency!anemia!(chronic!blood!loss!or!anemia!of!chronic!
disease),!high!CA!72Q4,!high!CA!19Q9,!alkaline!phosphatase!(if!liver!
metastasis)!
Leser-Trelat sign
• Paraneoplasia:!migrating!phlebitis,!acanthosis!nigricans!
!
!
From!lectures:!Gastric!neoplasms!classification:!!
There!are!many!classification!systems.!F.ex!Lauren!classification!(intestinal!and!
diffuse!type),!Borrmann!classes!(I.!polypoid,!intraluminal,!II!sharp!margin!ulcer!form,!
III!unclear!margin,!infiltrative!ulcer,!IV!diffuse!infiltrative!cirrhus),!Japanease!early!cc!
class.!(nonpenetrating!muscularis!propriae:!I!protruding,!polypoid!II,!a.b.c!superficial,!
III!excavated!(malignant)),!Goseki!classification:!(based!on!tubular!differentiation!
and!mucin!production).!Then!we!also!have!TNM!classification!(T!=!size!of!tumor,!N!=!
lymph!node!involvement,!M!=!metastasis!or!not)!
!
!
! Lauren
Borrmann
! Japanese early
Goseki
! TNM

!
!

! 46!
 a. Epidermal!tumors!!
a. Intraepithelial!neoplasia!–!adenoma!
b. Carcinoma!
i. Adenocarcinoma!(95%)!
1. Intestinal!type!
2. Diffuse!type!
ii. Papillary!adenocarcinoma!
iii. Tubular!adenocarcinoma!
iv. Mucinous!adenocarcinoma!
v. Sigillocellular!carcinoma!
vi. Adenosquamus!carcinoma!!
vii. Squamus!cell!carcinoma!
viii. NonQdifferenciated!carcinoma!
c. Carcinoid!tumors!(well!differentiated!neuroendocrine!neoplasm)!
b. NonMepidermal!tumors!
a. Leiomyoma!
b. Schwannoma!
c. Granular!cell!tumor!
d. Glomustumor!
e. Gastrointestinal!stromal!tumor!
f. Kaposi!sarcoma!
g. Malignant!lymphoma!(3%)!(MALT,!marginal!zone!B!cell!lymphoma,!
mantle!cell,!diffuse!large!B!cell!lymphoma)!
h. Egyéb!
c. Metastatic!tumors!
!
!
!
Gastric !adenocarcinoma is a malignant epithelial tumour, originating from glandular epithelium of the gastric mucosa. Stomach
cancers !are overwhelmingly adenocarcinomas (90%).
Histologically, there are two major types of gastric adenocarcinoma (Lauren classification): intestinal type or diffuse type.
!
!
Adenocarcinomas tend to aggressively invade the gastric wall, infiltrating the muscularis mucosae, the submucosa and thence the
muscularis propria.
!
! type adenocarcinoma tumour cells describe irregular tubular structures, harbouring pluristratification, multiple lumens,
Intestinal
reduced stroma ("back to back" aspect). Often, it associates intestinal metaplasia in neighbouring mucosa. Depending on glandular
!
architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and
!
poorly differentiated.
!
Diffuse type adenocarcinoma (mucinous, colloid, linitis plastica, leather-bottle stomach) tumour cells are discohesive and secrete
!
mucus, which is delivered in the interstitium, producing large pools of mucus/colloid (optically "empty" spaces). It is poorly
!
differentiated. If the mucus remains inside the tumour cell, it pushes the nucleus to the periphery: "signet-ring cell".

!
Around!5% of gastric malignancies are lymphomas (MALTomas, or MALT lymphoma).

! and stromal tumors may occur.

Carcinoid
!
!
!
!
!

! 47!
MALT lymphoma (MALToma) is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually
any mucosal site can be afflicted. It is originating from the B cells in the marginal zone of the MALT, and is also called extranodal marginal zone B cell
lymphoma.
Gastric MALT lymphoma is frequently associated (72–98%) with chronic inflammation as a result of the presence of Helicobacter pylori, potentially
involving chronic inflammation, or the action of H. pylori virulence factors such as CagA. The initial diagnosis is made by biopsy of suspicious lesions on
esophagogastroduodenoscopy (EGD, upper endoscopy). Simultaneous tests for H. pylori are also done to detect the presence of this microbe.

Gastric!lymphoma:!!
They!may!be!primary!or!secondary!cancers!and!it!may!be!important!to!distinguish!
between!the!two,!due!to!treatment.!Primary!gastric!lymphomas!is!the!second!most!
common!gastric!malignancy,!accounting!for!3%!of!gastric!cancers.!More!than!9%!are!
nonQHodgkin!B!cell!lymphomas.!Most!primary!lymphomas!are!believed!to!arise!from!
mucosaQassociated!lymphoid!tissue!(MALT).!!
!
Clinical!findings!and!staging:!
• Dyspepsia,!weight!loss!or!anemia!
• Variable!abnormalities!on!upper!GI!series!or!endoscopy!including!thickened!
folds,!ulcers,!mass!or!infiltrating!lesions;!diagnosis!is!established!by!
endoscopic!biopsy.!
• Abdominal,!chest!and!pelvis!CT!and!endoscopic!ultrasound!is!required!for!
staging.!
Treatment:!!
• Depends!on!histology,!grade!and!stage!
• Marginal!B!cell!lymphomas!of!MALT!that!are!low!grade!have!excellent!
prognosis!(the!patient!should!be!tested!for!H.pylori)!
• Complete!lymphoma!regression!after!successful!H!pylori!eradication!occurs!in!
approximately!75%!of!cases!of!low!grade!lymphomas.!If!a!patient!do!not!
respond!to!eradication!therapy!or!are!not!infected!with!H!pylori!radiation!
therapy!and!rituximab!may!be!tried.!
Long!term!survival!of!low!grade!MALT!lymphoma!stage!I!is!>90%!and!for!stage!II!35Q
65%.!!
!
Gastric!carcinoid!tumors:!!
These!are!neuroendocrine!tumors!that!make!up!<1%!of!gastric!neoplasms.!They!may!
occur!sporadically!or!secondary!to!chronic!hypergastrinemia!that!results!in!
hyperplasia!and!transformation!of!enterochromaffin!cells.!Majority!of!carcinoid!
tumors!occur!in!association!with!either!pernicious!anemia!(75%,!called!type!1)!or!
Zollinger!Ellison!syndrome!(5%,!called!type!2).!If!associated!with!Zollinger!Ellison!
syndrome!it!is!almost!exclusively!in!patients!with!MEN!1!and!Octreotide!therapy!may!
be!appropriate!for!those!patients.!If!tumors!are!>!2cm!in!size!the!patient!should!
undergo!surgical!resection.!There!is!also!a!type!3!gastric!carcinoid!tumors!which!arise!
sporadically!independent!on!gastrin!production!and!account!for!up!to!20%!of!gastrin!
carcinoids.!Most!of!them!are!solitary,!>!2cm!in!size!and!have!strong!propensity!for!
hepatic!or!pulmonary!metastasis!and!thus!carcinoid!syndrome!is!the!initial!
presentation.!They!should!be!treated!with!radical!gastrectomy!and!regional!
lymphadenectomy.!!
!
Gastric carcinoid tumours
!
- Sporadic neoplasm
!
- Secondary to hypergastrinaemia
! 1 - associated with pernicious anemia, treat with resection
Type
Type 2 - associated with ZES, treat with octreotide
!
Type 3 - not associated with anything, treat with radical gastrectomy and regional lymphadenectomy
!

! 50!
 Gastrointestinal!mesenchymal!tumors!!
These!tumors!arise!from!mesenchymal!stem!cells!(stromal!tumors,!leiomyomas!and!
schwannomas)!and!have!epithelioid!or!spindle!cell!histological!pattern,!resembling!
smooth!muscle.!The!most!common!stromal!tumors!are!gastrointestinal!stromal!
tumors!(GIST,!sarcomaQlike!naoplasms!of!GI!tract),!which!originate!from!interstitial!
cells!of!Cajal.!GIST!occur!throughout!the!GI!tract!but!most!commonly!in!the!stomach!
(60%)!and!small!intestine!(35%).!Usually!they!are!discovered!incidentally!but!may!
cause!symptoms!such!as!bleeding,!pain!and!obstruction.!Endoscopy!and!biopsy!is!the!
best!diagnosis!technique.!All!of!these!tumors!have!malignant!potential!and!a!risk!of!
developing!metastasis,!which!is!related!to!the!size!of!the!tumor.!Surgery!is!
recommended!if!tumor!is!>2cm!or!increasing!in!size,!have!an!endoscopic!
ultrasonographic!appearance!of!suspicious!for!malignancy!or!are!symptomatic.!
!
The!metastasis!formation!may!occur!rapidly,!but!in!more!benignant!forms!it!may!
take!even!some!years.!They!can!be!differentiated!from!other!sarcoma’s!by!having!a!
special!protein!on!the!surface!of!the!tumour!cells!(CDM117),!that!is!production!of!the!
protooncogen!cMkit,!and!the!intracellular!domain!has!tyrosin!kinase!activity.!If!the!
patient!cannot!be!operated,!the!tumors!can!be!rather!effectively!treated!by!imatinib!
(antiQCD117!antibody,!Glivec)!400!mg/day.!This!drug!is!also!used!in!Philadelphia!
chromosome!+!CML,!as!tyrosine!kinase!inhibitor!(for!BcrQAbl,!KitQprotein,!PDGF!
receptor!βQtyrosine!kinase).!
!
Untreated!and!metastatic!GIST!tumors!are!aggressive!and!carry!a!poor!prognosis.!
!
!
!
!
! tumours GIST are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise
GI stromal
!
in the smooth muscle pacemaker interstitial cell of Cajal.
!
They are defined as tumors whose behavior is driven by mutations in the c-KIT gene (85%), PDGFRA gene
(10%), or! BRAF kinase (rare). 95% of GISTs stain positively for CD117.
!
! in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in
Most occur
the GI tract
!
GISTs are! tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial.
!
!
!
!
!
!
!
!
!
!
!
!

! 51!
 Topic!#13.!Gastric!cancer:!diagnostics!and!treatment:!!
!
Diagnosis:!!
Endoscopy and biopsy
• Endoscopy!–!upper!endoscopy!is!to!be!obtained!in!all!patients!over!age!55!
years!with!new!onset!of!epigastric!symptoms!(dyspepsia)!an!in!anyone!with!
dyspepsia!that!fail!to!respond!to!a!short!trial!of!antiQsecretory!therapy.!Biopsy!
of!suspicious!lesion!is!highly!sensitive!for!detecting!gastric!carcinoma.!!
• Gastric!X!ray!–!passage,!emptying!
• Other!options:!ultrasound,!hydroQCT!
After!diagnosis!is!established!(mostly!by!endoscopy!+!biopsy)!a!chest!and!abdominal!
CT!is!done!to!evaluate!the!cancer’s!stage!(TNM).!Also!pelvic!CT!in!females.!PETQCT!is!
recommended!for!detection!of!distant!metastasis.!
!!
• Laboratory!investigations:!!
o Anemia!
o Iron!deficiency!
o Serum!pepsinogen!
o Tumor!markers!(CA!72Q4,!CA!199,!CEA)!
o Special!mutations:!EQcadherin,!!
o HLA!DQB1!0301,!ill.0401!
o ILQ1!beta!polymorphism!(31T+,!511T+)!genotypes!are!attached!to!
development!of!atrophy!and!carcinoma.!!
Treatment:!surgical!resection!is!the!only!therapy!with!curative!potential.!!
• Endoscopic!mucosal!resection!if!the!tumor!is!small!(<!2cm),!early!(intraQ
mucosal!or!T1aN0)!after!careful!staging!with!endoscopic!ultrasound.!
gastrojejunostomy
• Curative!resection:!Billroth!II,!total!gastrectomy,!regional!lymphadenectomy,!
if!indicated!together!with!splenectomy.!Laparoscopy!has!lower!overall!
complication!rates!as!open!gastrectomy.!If!the!tumor!is!the!distal!2/3!of!the!
stomach!a!subtotal!gastrectomy!should!be!performed,!if!the!tumor!is!in!the!
proximal!third!of!the!stomach!a!total!gastrectomy!is!necessary.!Vitamin!B12!
supplementation!is!required!after!gastrectomy.!15!lymph!nodes!need!to!be!
resected!and!evaluated.!
• If!nonMoperable:!palliative!resection,!palliative!anastomosis!
(gastrojejunustomy!to!prevent!obstruction).!Palliative!chemotherapy!may!be!
done!in!selective!cases.!!
• Adjuvant!chemotherapy!(postoperative):!following!curative!resection!there!
is!debate!about!efficacy.!FAM,!FAMtx,!ELF!protocols.!newly,!rather!with!aim!
of!palliation:!Paclitaxel!+!Carboplatin!+!Etoposide,!!or!Irinotecan!+!
Gemcitabine!
ECF:
Epirubicin /
• Neoadjuvant!(preoperative):!increases!survival.!ECF!protocol:!every!21st!day!
Cisplatin / 5- Epirubicin!50mg/m2!IV!+!Cisplatin!60mg/m2!IV!+!5FR!200mg!/m2!continous!
Fluorouracil infusion!for!12!weeks!
• Radiotherapy:!intraoperative!and!postop!in!NHL!

! 48!
 Chemotherapy:!first!line!treatment!"!fluoropyrimydine!or!a!taxane!agent!plus!a!
platinum!agent.!A!3!drug!combination!of!epirubicin!or!docetaxel!plus!cisplatin!and!5Q
FU!is!the!first!line!treatment!in!a!medically!fit!patient.!Adding!a!biological!agent!such!
as!trastuzumab!in!the!cases!of!HER2mutation!has!shown!to!increase!survival!rate.!!
!
Second!line!therapy:!irinotecan!or!ramucirumab!
!
Prognosis:!long!term!survival!of!gastric!carcinoma!is!<!15%.!However!if!successful!
resection!the!survival!is!45%.!Survival!is!related!to!tumor!stage,!location!and!
histological!features.!Diffuse!type!is!worse!than!intestinal!type,!proximal!tumors!is!
far!worse!than!distal!gastric!tumors.!!
!
!
!
!
!
!
!
!
5-fluorouracil, adriamycin and methotrexate
!
!
!
CF: Epirubicin / Cisplatin / 5-Fluorouracil
!
!
!
!
!
Preop!chemotherapy,!why?!
• Poor!longQterm!results!of!conventional!treatment!
• Better!effectiveness!due!to!intact!tumor!vascularization!
• Improved!tolerance!
• Better!general!condition!of!the!patient!
• Downstaging!of!the!primary!tumor!–!better!resectability!
• Response!to!therapy!also!adds!prognostic!information!
The!conclusion!is!that!preop!chemotherapy!is!feasible!without!increase!in!
perioperative!morbidity!and!mortality.!About!50%!chance!of!a!T0!resection!in!
patients!with!primarily!not!curatively!resectable!tumors.!Neoadjuvant!use!of!the!
most!active!regimens!in!case!of!T3,!T4!or!N+!M0!should!be!considered.!!
!
Over!half!of!the!patients!who!undergo!“curative”!resection!have!locoregional!
recurrence.!In!metaQanalyses!of!adjuvant!chemotherapy,!risk!reduction!for!death!is!
12%!to!28%!(but!these!were!old!regimens!and!small!patient!numbers!in!individual!
studies).!Results!of!metaQanalyses!need!to!be!confirmed!by!prospective!studies.!New!
combination!regimens!remain!to!be!tested!in!adjuvant!setting.!Not!accepted!as!a!
standard!care,!but!be!considered!in!cases!of!high!risk!for!recurrence/inadequate!
surgery.!!

! 49!
 Topic!#14.!Tumors!of!the!small!intestine:!
Small!intestine!cancers!are!rare.!There!are!5!types!of!cancer!found!in!the!small!
intestine!are!adenocarcinoma,!sarcoma,!carcinoid!tumors,!GI!stromal!tumors!and!
lymphoma.!The!benign!tumors!(adenomas,!leiomyomas)!can!become!malignant.!The!
lipomas, neurogenic, hemangiomas

benign!tumors!are!usually!found!incidentally.!
!
Benign!tumors:!!
smooth muscle cells tumour
Leiomyoma!–!Leiomyomas!are!tumors!of!one!of!the!muscle!layers!of!the!
intestinal!wall.!Some!can!grow!into!the!lumen!of!the!bowel!and!become!
ulcerated!and!cause!bleeding!or!anemia,!which!is!the!most!common!symptom!
and!finding.!They!can!be!very!difficult!to!diagnose,!especially!when!they!occur!
in!the!small!intestine.!Endoscopic!ultrasound!is!a!useful!way!to!determine!the!
site!of!the!tumor!within!the!bowel!wall.!Some!leiomyomas!do!have!malignant!
potential.!Biopsy!sampling!and!surgical!resection!is!the!normal!course!of!action.!

Adenomas!–!Adenomas!are!benign!tumors!that!do!have!malignant!potential.!
They!cause!symptoms!due!to!blockage.!When!they!arise!in!the!region!of!the!
papilla!or!the!area!of!the!duodenum!where!the!bile!duct!and!pancreas!drain!
they!can!cause!jaundice.!Because!of!the!risk!of!malignant!degeneration,!
adenomas!are!usually!removed!(by!surgery!or!endoscopy).!
Adenomas of the colon, also called adenomatous polyps, are quite prevalent. They are found commonly at colonoscopy. They are removed because of their tendency to become malignant

Lipomas!–!Lipomas!are!collections!of!fatty!tissue!within!the!wall!of!the!intestine!
that,!when!viewed!endoscopically,!have!a!mild!yellowish!appearance.!These!are!
completely!benign!tumors!with!no!malignant!potential.!Lipomas!do!not!need!to!
be!removed!unless!they!become!very!large!and!cause!obstructive!symptoms!(or!
bleeding!due!to!ulceration).!

Hemangiomas!–!Hemangiomas!are!collections!of!blood!vessels!that!form!a!
benign!vascular!tumor!in!the!wall!of!the!stomach!or!intestine.!They!are!benign!
and!sometimes!found!in!conjunction!with!other!syndromes.!Hemangiomas!can!
cause!gastrointestinal!bleeding!and!anemia.!They!are!detected!by!endoscopy.!
They!can!be!treated!endoscopically!with!application!of!a!heater!probe!to!burn!
the!vessels.!Patients!may!need!resection!of!areas!of!intestine!heavily!involved!
with!hemangiomas!if!they!cause!significant!bleeding.!Various!medicinal!
therapies!(i.e.!estrogens)!have!been!tried!to!reduce!the!amount!of!bleeding!
from!hemangiomas.!Reports!of!success!have!been!variable.!

Neurogenic!Tumors!–!Neurogenic!tumors!are!benign!growths!arising!from!
neural!(nerve)!tissue.!The!most!common!variety!is!neurofibroma.!These!usually!
solitary!tumors!can!be!confirmed!by!their!microscopic!appearance!after!biopsy!
sampling.!

!neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. They are solitary tumours but can be assosiated with neurofibromatosis
type I (NF1), an autosomal dominant genetically inherited disease.
!they can result in a range of symptoms from physical disfiguration and pain to cognitive disability.
!Neurofibromas arise from nonmyelinating-type Schwann cells that exhibit inactivation of the NF1 gene that codes for the protein neurofibromin.
!
This protein is responsible for regulating the RAS-mediated cell growth signaling pathway.

In contrast to schwannomas, another type of tumor arising from Schwann cells, neurofibromas incorporate many additional types of cells and
structural elements in addition to Schwann cells, making it difficult to identify and understand all the mechanisms through which they originate and
develop.
! 52!
Malignant!tumors:!
!
Small!intestine!adenocarcinomas:!
This!cancer!is!aggressive,!so!prognosis!is!poor,!mostly!occur!in!duodenum!and!
proximal!jejunum.!Ampulla!of!Vater!is!the!most!common!site!of!small!bowel!
carcinoma.!Approximately!32%!patients!are!at!stage!IV!at!diagnosis!(the!worst!
stage).!Incidence!of!ampullary!carcinoma!increases!more!than!200!fold!in!patients!
with!adenomatous!polyposis,!and!therefore!periodis!endoscopic!surveillance!is!
recommended.!!
!
Ampullary!carcinoma!may!present!with!jaundice!due!to!bile!duct!obstruction!or!
bleeding.!Surgical!resection!of!early!lesion!is!curative!in!up!to!40%!of!patients.!!
!
Small!intestine!lymphomas:!
Lymphomas!in!GI!tract!may!be!primary!or!secondary!and!account!for!5%!of!overall!
lymphomas.!Lymphomas!of!the!GI!tract!occur!most!frequently!in!the!small!intestine.!!
!
There!is!increased!incidence!in!patients!with!AIDS,!immunosuppressive!therapy,!and!
Crohns!disease.!!
• The!most!common!subtype!is!nonQHodgkin!extranodal!marginal!zone!(MALT)!
B!lymphoma.!!
• EnteropathyQassociated!T!cell!lymphoma!appear!to!be!increasing!in!incidence!
in!USA!(associated!with!celiac!disease).!!
• Primary!intestinal!follicular!cell!lymphoma!
• Mantle!cell!lymphoma! Lymphoma: Responsible for 15-20% of small intestine cancers. Small intestine
lymphoma starts in the lymph tissue of the small bowel and usually occurs in the
• Burkitt!lymphoma! JEJUNUM. The typical subtype is non-Hodgkin's lymphoma; more specifically
MALT lymphomas, large B cell lymphoma and Burkitt’s lymphoma.

Symptoms!and!signs:!can!be!chronic!or!intermittent!
• Abdominal!pain!
• Weight!loss!
• Nausea!
• Vomiting!
• Distention!
• Anemia!
• Occult!blood!in!stool!
• Protein!!losing!enteropathy!may!result!in!hypoalbuminemia.!But!other!signs!
of!malabsorption!are!unusual.!!
• Fever!is!unusual!
Diagnosis:!Endoscopic,!percutanous!or!laparascopic!biopsy.!Imaging!and!bone!
marrow!biopsy!are!required!to!determine!stage.!!
!
Imaging:!to!localize!site!of!lesion!
• Barium!radiography!!
• CT!enterography!

! 53!
Treatment:!depends!on!the!stage!and!histological!subtype.!Surgical!resection!of!
primary!intestinal!lymphomas!is!feasible!and!may!be!appropriate!for!localized!
tumors.!Role!of!adjuvant!chemotherapy!is!unclear!in!patients!where!resection!is!
performed!with!negative!margins.!Radiation!should!be!considered!if!surgical!margins!
are!positive.!!
!
Intestinal!carcinoid!tumors! Carcinoid: Accounts for 35-42% of small bowel cancers. Carcinoid cancers of the small bowel
tend to occur in the ileum. Carcinoid tumors are a type of neuroendocrine tumor.
Slow!growing!neuroendocrine!tumors,!account!for!apperoximately!1/3!of!tumors!in!
small!intestine.!Carcinoid!tumors!can!occur!anywhere!in!the!GI!tract!(rectum,!colon,!
appendix),!but!most!commonly!occur!in!small!intestine!"!mostly!in!distal!ileum,!
within!60cm!of!ileocecal!valve.!These!tumors!may!contain!hormones!that!may!or!
may!not!be!secreted!(serotonin,!somatostatin,!gastrin!and!substance!P).!If!the!tumor!
metastasizes!(the!risk!of!metastasis!is!related!to!the!size,!invasion!of!muscularis!
propria!and!location!of!tumor)!the!patient!has!poorer!prognosis.!!
!
Signs!and!symptoms:!!
• Smaller!lesions!are!usually!asymptomatic!(<1Q2cm)!and!difficult!to!detect!
on!endoscopy!or!imaging!studies!
• Abdominal!pain!
• Bowel!obstruction!
• Bleeding!or!bowel!infarction!
• Appendiceal!and!rectal!carcinoids!usually!are!small!and!asymptomatic!but!
they!can!cause!bleeding,!obstruction!or!altered!bowel!habits.!
• Carcinoid!syndrome!occurs!in!10%!of!patients!
o More!than!90%!of!patients!with!carcinoid!syndrome!have!hepatic!
metastasis!
o About!10%!of!patients!with!carcinoid!syndrome!have!primary!
tumors!in!bronchus!or!ovary!without!hepatic!metastasis!
o Carcinoid!syndrome!is!caused!by!the!tumor!secretion!of!hormonal!
mediators.!Symptoms:!!
! Facial!flushing!
! Edema!of!head!and!neck!(especially!with!bronchial!tumors!
carcinoid)!
serotonin
! Abdominal!cramps! gastrin
somatostatin
! Diarrhea! substance P

! Bronchospasm!
! Cardiac!lesion!(pulmonary!or!tricuspid!stenosis!or!
regurgitation)!
! Telangiectases!
!
!
!
!
!
!

! 54!
Lab!findings:! in carcinoid small intestinal tumours
• Serum!chromogranin!A!(CgA)!is!elevated!in!majority!of!tumors!
o This!is!a!neuroendocrine!secretory!protein!
o It!is!located!in!secretory!vesicles!of!neurons!and!endocrine!cells!such!
as!chromaffin!cells!of!the!adrenal!
medulla,!paraganglia,enterochromaffinQlike!cells!and!beta!cells!of!the!
pancreas.!It!is!present!in!islet!beta!cell!secretory!granules.!
o Chromogranin!A!is!the!precursor!to!several!functional!peptides!
including!vasostatinQ1,!vasostatinQ2,!pancreastatin,!catestatin!and!
parastatin.!These!peptides!negatively!modulate!the!neuroendocrine!
function!of!the!releasing!cell!(autocrine)!or!nearby!cells!(paracrine).!
Chromogranin!A!induces!and!promotes!the!generation!ofsecretory!
granules!such!as!those!containing!insulin!in!pancreatic!islet!beta!cells.!
• Urinary!5Mhydroxyindoleacetat!acid!(5MHIAA)!elecated!in!metastatic!carcinoid!
tumors!(less!sensitive!that!CgA)!>!25mg/day!in!urine!
• Platelet!serotonin!is!elevated!in!metastatic!carcinoid!tumors!(less!sensitive!
than!CgA)!
Imaging:!
• Abdominal!CT!may!demonstrate!mesenteric!mass!with!tethering!of!bowel,!
lymphadenopathy!and!hepatic!metastasis!
• Somatostatin!receptor!scintigraphy!is!positive!in!up!to!90%!of!patients!with!
metastatic!carcinoid,!it!is!routinely!used.!!
Treatment!and!outcome:!
• Surgical!resection!!
• After!complete!resection!there!is!no!point!in!chemotherapy!
• In!patients!with!metastatic!disease,!surgery!should!be!directed!toward!
palliation!of!obstructive!symptoms!or!bleeding.!!
• If!patient!has!carcinoid!syndrome,!octreotide!(somatostatin!analog)!should!
be!administered!SC!or!IM!daily!(150Q250mcg)!
• Chemotherapy!is!being!investigated,!today!it!does!not!achieve!significant!
response!
Small!intestine!sarcoma! malignant connective tissue tumours
Most!of!the!sarcomas!arise!from!stromal!tumosr!(GISTs)!that!stain!positive!for!
CD117,!a!minority!arises!from!smooth!muscle!tumors!(leiomyosarcomas).!Kaposi!
sarcoma!was!at!one!time!a!common!complciation!of!AIDS,!however!it!has!declined!
much!after!HAART!therapy.!It!can!also!occur!in!setting!of!immunosuppression!after!
organ!transplantation!and!is!caused!by!HHV8!(human!herpes!virus!8).!!
!
Lesions!may!be!present!anywhere!in!the!intestinal!tract.!Mostly!they!are!
asymptomatic,!but!large!lesions!may!have!symptoms.!!
Chemotherapy!is!used!if!the!tumor!is!widespread!using!single!agent!thearpy!or!
combinations!of!pegylated!doxorubicin!(Doxil),!paclitaxel,!cinvristine,!cleomycin!or!
etoposide.!

! 55!
Surgery!or!radiation!may!be!indicated!for!isolated!high!risk!lesions.!!
!
Further!info:!
There!are!four!important!polyposis!syndromes!that!involve!the!small!intestine:!
Familial!Adenomatous!Polyposis;!PeutzQJeghers!Syndrome;!Generalized!Juvenile!
Polyposis;!and,!CronkhiteQCanada!Syndrome.!These!are!a!group!of!disorders!
characterized!by!the!presence!of!multiple!polyps!affecting!all!or!parts!of!the!
gastrointestinal!tract.!They!are!distinguished!by!the!way!they!can!be!inherited!
but!also!by!the!microscopic!appearance!of!the!polyps.!

Familial!Adenomatous!Polyposis!–!Familial!Adenomatous!Polyposis!are!very!
strongly!inherited!(autosomal!dominant).!They!are!characterized!by!the!
presence!of!multiple!adenomatous!polyps!in!the!colon!and!thus!place!the!
patient!in!a!high!risk!of!developing!colon!cancer.!Over!80%!of!patients!with!
these!syndromes!can!also!have!adenomas!involving!the!small!intestine,!which!
are!also!preQmalignant.!They!tend!to!be!most!common!in!the!upper!part!of!the!
small!intestine!(duodenum).!In!patients!who!have!had!their!colonremoved!to!
avoid!death!from!colon!cancer,!the!most!common!cause!of!death!from!cancer!is!
the!development!of!cancer!in!the!duodenum!(the!periampullary!region).!
Unfortunately,!it!is!not!possible!to!remove!all!of!the!adenomas!in!the!small!
intestine.!Therefore,!surgical!or!endoscopic!removal!is!used!only!for!large!
polyps.!Certain!medications!related!to!aspirin!appear!to!halt!or!at!least!reduce!
the!growth!of!some!of!these!adenomas!in!the!small!intestine.!Patients!are!
usually!advised!to!have!examinations!of!the!small!intestine!every!few!years.!

PeutzMJeghers!Syndrome!–!This!is!a!syndrome!essentially!characterized!by!
excessive!growth!of!normal!intestinal!tissue!that!occurs!mainly!in!the!jejunum!
and!ileum,!and!most!often!present!problems!with!bleeding!and!obstruction!of!
the!bowel.!There!is!a!small!risk!of!cancer,!but!far!less!than!familial!adenomatous!
polyposis.!There!is!also!a!slightly!increased!incidence!of!malignancy!in!the!
gynecological!organs,!as!well!as!pigmentation!(dark!spots)!in!the!region!of!the!
lips!and!mouth.!Although!it!tends!to!fade!after!puberty,!this!pigmentaton!can!
also!sometimes!affect!the!genital!areas!and!limbs.!

Generalized!Juvenile!Polyposis!–!Generalized!juvenile!polyposis!can!be!
inherited!or!sporadic.!The!polyps!may!be!found!anywhere!in!the!intestinal!tract!
and!are!characterized!by!their!microscopic!appearance.!Large!polyps!may!
present!with!symptoms!of!obstruction!or!bleeding!and!there!is!a!small!
increased!risk!of!developing!gastrointestinal!cancer.!

CronkhiteMCanada!Syndrome!–!This!is!a!syndrome!characterized!by!many!
intestinal!polyps,!pigmentation,!diarrhea,!protein!loss!from!the!intestine!and!
alopecia!(local!hair!loss).!The!polyps!are!most!commonly!found!in!the!small!
intestine!and!usually!do!not!become!malignant.!The!patient's!main!problem!is!
usually!malnutrition.!Aggressive!nutritional!support!is!usually!necessary.!

! 56!
Malabsorption is a condition that is due to abnormality in absorption of food nutrients across the gastrointestinal tract. If there is impairment of any of the many steps involved in the complex process of digestion and
absorption, malabsorption may ensue. Impairment can be of SINGLE OR MULTIPLE NUTRIENTS depending on the abnormality. This may lead to malnutrition and a variety of anaemias.

100 g of fat, 400 g of carbohydrate, 100 g of protein, 2 L of fluid, and the required sodium, potassium, chloride, calcium, vitamins, and other elements. Salivary, gastric, intestinal, hepatic, and pancreatic secretions add an
additional 7–8 L of protein-, lipid-, and electrolyte-containing fluid to intestinal contents. This massive load is reduced by the small and large intestines to less than 200 g of stool that contains less than 8 g of fat, 1–2 g of
nitrogen, and less than 20 mmol each of Na+, K+, Cl–, HCO3–, Ca2+, or Mg2+.

If the abnormality involves a single step in the absorptive process, as in primary lactase deficiency, or if the disease process is limited to the proximal small intestine SELECTIVE MALABSORPTION of only a single
nutrient may occur.
However, GENERALIZED MALABSORPTION of multiple dietary nutrients develops when the disease process is extensive, disturbing several digestive and absorptive processes, as occurs in COELIAC DISEASE with
extensive involvement of the small intestine.

Topic!#15.!Malabsorption:!classification,!symptoms:!
We will discuss !
- enzyme deficiency
- coliac
Malabsorption:!defective!crossing!through!intestinal!wall!by!products!of!normal!
- CD digestion.!Disruption!of!digestion!and!nutrient!absorption.!!
- SBS !
- Circulation
• Selective!malabsorption:!involve!only!specific!substrates!
- Alterations due to microorgs
others • Global!malabsportion:!generalized! multiple dietary nutrients
• Malapsorption!syndrome:!complex!of!symptoms!secondary!to!maldigestion!
and/or!malabsorption,!realizing!when!the!extension!of!the!disease!exceeds!
the!ability!of!intestine!compensation.!!
Classification:!!
1. Alteration!of!digestive!process!
2. Alteration!of!uptake!and!transport!caused!by!damage!or!reduction!of!
absorption!surface!
3. Miscellaneous!
!

1.

2.

!
Signs!and!symptoms!in!general:!
• Modification!of!the!luminal!content!with!persistence!of!nutrients!in!the!
tympanites - ab distension
lumen.!Can!lead!to!diarrhea,!steatorrhea,!meteorism,!abdominal!discomfort!
• Decreased!tissue!utilization!of!nutrients!with!deficiency!manifestations.!Can!
lead!to!paleness,!asthenia,!and!loss!of!weight,!delay!or!stop!of!growth,!
edemas,!mucosal,!skin!and!adnexal!dystrophy,!amenorrhea,!tetany,!bone!
pain,!hemorrhagic!and!neurological!manifestations,!hemeralopia,!recurrent!
infections.!!
!
o Steatorrhea!(triglycerides,!phospholipids,!vitamins!(ADEK),!cholesterol!
etc.!is!malabsorbed)!
o Diarrhea!(increased!fecal!water)!
o Weight!loss,!muscle!wasting!!
o Microcytic!anemia!(iron!is!malabsorbed)!
o Macrocytic!anemia!(vitamin!B!or!folic!acid!malabsorbed)!

! 57!
 Trousseau sign is a sign observed in patients with low calcium. To elicit the sign, a blood pressure cuff is placed around the arm and
inflated to a pressure greater than the systolic blood pressure and held in place for 3 minutes. This will occlude the brachial artery. In
the absence of blood flow, the patient's hypocalcemia and subsequent neuromuscular irritability will induce SPASM OF THE
MUSCLES OF THE HAND AND FOREARM.

Chvostek's sign is the twitching of the facial muscles in response to tapping over the area of the facial nerve.

o Paresthesia,!tetany,!positive!trousseau!and!chvostek!signs!(calcium,!
vitamin!D,!Mg!malabsorbed)!
o Bone!pain,!pathological!fracture,!skeletal!deformities!(Ca!and!vitamin!
D!malaborbed)!
o Bleeding!tendency!(ecchymoses,!epistaxis,!due!to!vitamin!K!
deficiency)!
o Edema!(protein!malabsorption)!
o Milk!intolerance!(cramps,!bloating,!diarrhea)!
Enzymatic!deficits:!!
1. Impaired!lactose!digestion:!!
Lactose!is!a!disaccharide!and!the!principal!carbohydrate!in!mammalian!milk.!It!is!the!
most!important!source!of!energy!during!the!1st!year!of!human!life.!Lactose!promotes!
absorption!of!Ca,!P,!Mg!and!Mn.!Lactase!is!a!brush!boarder!enzyme!that!hydrolyzes!
lactose!into!glucose!and!galactose.!!
Malabsorbed!lactose!is!fermented!by!intestinal!bacteria,!producing!gas!and!organic!
acid.!The!nonmetabolized!lactose!and!organic!acids!result!in!an!increased!stool!
osmotic!load!and!obligatory!fluid!loss.!!
!
1. Human!lactase!deficiencies:!!
These!conditions!have!low!lactase!enzyme!activity!due!to!molecular!distinct!
conditions,!however!they!represent!strikingly!different!phenotypes.!!
In!general!the!symptoms!are:!diarrhea,!bloating,!flatulance!and!abdominal!pain!after!
ingestion!of!milkQcontaining!products.!Diagnosis!is!made!on!symptomatic!
improvement!on!lactose!free!diet.!!
!
a. Lactase!nonMpersistence!(LNP)!=!adult!type!hypolactasia!or!primary!lactase!
deficiency!or!wild!type!pattern.!There!are!two!types!of!primary!lactase!
deficiency.!
a. In!70%!of!the!cases:!This!is!in!fact!a!normal!developmental!
phenomenon,!where!the!lactase!receptors!are!down!regulated!after!
weaning.!!
b. In!30!%!of!the!cases!it!is!due!to!mutation!in!lactase!gene!(2q21Q22)!
which!results!in!retaining!high!lactase!activity!throughout!life!(lactase!
persistence).!
c. Symptoms:!diarrhea,!bloating,!excessive!flatus,!abdominal!cramping!
and!sometimes!nausea!and!vomiting.!!
b. Secondary!or!acquired!lactase!deficiency!
a. Loss!of!lactase!activity!in!people!with!lactase!persistence!
b. For!example!due!to!gastrointestinal!disorder!that!affect!the!proximal!
small!intestinal!mucosa,!Crohn’s!disease,!viral!gastroenteritis,!
giardiasis,!short!bowel!syndrome,!malnutrition.!
c. Congenital!form!of!lactase!deficiency!(CLD)!
a. Severe!GI!disorder!of!newborns.!!
b. Symptoms:!watery!diarrhea!which!can!lead!to!dehydration,!acidosis!
and!failure!to!thrive!first!days!or!weeks!of!life.!!

Bile contains bile acids, which are critical for digestion and absorption of fats and fat-soluble vitamins in the small intestine.
Many waste products, including bilirubin, are eliminated from the body by secretion into bile and elimination in feces.
As!amphipathic molecules with hydrophobic and hydrophilic regions, conjugated bile salts form micelles and solubilize lipids. 58!
Bile acid-containing micelles aid lipases to digest lipids and bring them near the intestinal brush border membrane, which results
in fat absorption.
 Due to infective agents
Due to structural defects
Due to surgical structural changes
Due to enzyme deficiencies
Due to digestive failure
Due to other systemic diseases affecting GI tract
!
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1.
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2. !
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3. !
!
2. Celiac!disease:!!
It’s!one!of!the!most!common!disorders!in!Europe!(1%)!which!is!associated!with!
severe!morbidity.!It!is!an!autoimmune!disorder!which!is!precipitated!by!ingestion!of!
gluten!(storage!protein!of!wheat,!barley,!rye)!in!a!genetically!predisposed!person,!
which!have!alleles!that!encode!for!HLAQDQ2!and!DQ8.!90%!of!the!cases!are!
unrecognized!in!childhood,!however!autoimmune!processes!are!ongoing.!
Autoantibodies!against!transglutaminase!develop!and!appear!in!the!circulation!
during!the!course!of!the!disease.!These!antibodies!are!detectable!by!laboratory!
methods.!This!results!in!diffuse!damage!to!the!proximal!small!intestinal!mucosa!with!
malabsorption!of!nutrients.!
!
Signs!and!symptoms:!!
Typical!symptoms"!weight!loss,!chronic!diarrhea,!abdominal!distention,!growth!
retardation!(infants!<!2!years!old):!
• Iron!deficiency!anemia,!! Anti-endomysium ab
• Dyspepsia! Anti gliadin ab

• Flatulance! What are the two most important clinical signs in coeliac disease?
• Lactose!intolerance,!! diarrhoea X
• Failure!to!thrive,!! malnutrition X

• Short!stature,!!
• Delay!of!puberty,!!
• Hair!loss,!!
• Dry!skin,!!
• Eye!and!tongue!redness,!!
• Problems!with!menstruation,!!
• Headache!(iron),!!
• Neurosis,!depression,!chronic!fatigue.!!
• Dermatitis!herpetiformis:!!cutaneous!variant!of!celiac!disease.!It’s!a!skin!rash!
consisting!of!pruritic!papulovesicles!over!the!extensor!surfaces!of!the!
extremities!and!over!the!trunk,!scalp!and!neck.!It!occurs!in!<!10%!of!patients!
with!celiac!disease.!!

! 59!
Irreversible!complications:!!
• Short!stature,!!
• Face!deformity,!!
• Osteoporosis!(compression!of!vertebra),!!
• Ataxia!cerebellaris,!!
• Dementia,!!
• Endocrine!deficiency!(diabetes!mellitus,!hypothyreosis),!!
• Liver!failure,!!
• Ulcerative!jejunitis,!!
• Mesenterial!cavitation!syndrome,!!
• Refracture!spure,!!
• EnteropathyQassociated!TQcell!lymphoma.!!
Lab!findings!are!nonspecific!but!may!raise!the!suspicion!of!malabsorption!and!celiac!
disease.!Serologic!tests!should!be!done,!and!test!for!IgA!tissue!transglutaminase!
(IgA!tTG)!which!has!95%!sensitivity!and!specificity!for!the!diagnosis!of!celiac!disease.!
IgA!levels!should!be!obtained!in!patients!with!a!negative!IgA!tTG!antibody!when!
celiac!disease!is!strongly!suspected,!because!up!to!3%!of!patients!with!celiac!disease!
have!IgA!deficiency.!You!can!also!measure!IgG!antibodies!to!deaminated!gliadin!
which!has!excellent!specificity!and!sensitivity!as!well.!The!levels!of!all!antibodies!
become!undetectable!after!3Q12!months!of!dietary!gluten!withdrawal.!
!
Endoscopic!mucosal!biopsy!of!proximal!and!distal!duodenum!is!the!standard!method!
for!confirmation!of!the!diagnosis.!Atrophy!and!scalloping!of!the!duodenal!folds!may!
be!observed.!Histology!reveals!abnormalities!ranging!from!intraepithelial!
lymphocytosis!alone!to!extensive!infiltration!of!the!lamina!propria!with!lymphocytes!
and!plasma!cells!with!hypertrophy!of!the!intestinal!crypts!and!blunting!or!complete!
loss!of!intestinal!villi.!!
!
Treatment:!GlutenMfree!diet!is!an!effective!treatment!of!the!disease!and!prevent!
complications.!Many!celiac!disease!patients!also!have!lactose!intolerance!and!should!
therefore!avoid!dairy.!!
!
Celiac!disease!may!be!associated!with!other!autoimmune!disorders!such!as!Addisons!
disease,!Graves!disease,!DM!type!1,!myasthenia!gravis,!scleroderma,!sjögren!
syndrome,!atrophic!gastritis!and!pancreatic!insufficiency.!!
!

! 60!
 3. Crohn’s!disesase:!check!topic!19!!
4. “Short!bowel!syndrome”:!!
In!patients!that!have!undergone!a!large!surgical!resection!of!the!small!bowel!(f.ex!
due!to!Crohn!disease,!mesenteric!infarction,!radiation!enteritis,!volvulus,!tumor!
resection,!trauma).!Clinical!manifestations!are!various!and!depend!on!localization!
and!extension!of!resection.!!
!
Causes!of!malabsorption!are:!loss!of!absorption!surface,!impaired!synthesis!of!GI! Absorption of the
majority of nutrients
tract!hormones,!accelerated!intestinal!transit,!possible!loss!of!the!ileocecal!valve! takes place in the
(retrograde!bacterial!migration!–!small!intestinal!bacterial!overgrowth).!! JEJUNUM, with the
! following notable
exceptions:
Resection!of!terminal!ileum:!
# Results!in!malabsorption!of!bile!salts!and!vitamin!B12!which!are!normally! Iron is absorbed in the
absorbed!in!this!region.! DUODENUM.

# Patient!require!monthly!injection!of!IM!vit!B12.! Vitamin B12 and bile

# Malabsorption!of!bile!salts!stimulates!fluid!secretion!from!the!colon!"! salts are absorbed in the
watery!diarrhea!or!steatorrhea.!Can!be!treated!by!salt!binding!resins! TERMINAL ILEUM.

(cholestyramine!or!colesevelam)! Water and lipids are

absorbed by passive
Extensive!small!bowel!resection:! diffusion
# Resection!up!to!40Q50%!of!small!bowel!is!well!tolerated.!If!more,!resection! THROUGHOUT the
may!result!in!“short!bowel!syndrome”!which!is!characterized!by!weight!loss! small intestine.
and!diarrhea!due!to!nutrient,!water!and!electrolyte!malabsorption.!!
# If!colon!is!also!removed,!at!least!200cm!of!proximal!jejunum!is!required!to!
maintain!oral!nutrition.!
# Patients!with!<!100Q200!cm!of!proximal!jejunum!almost!always!need!
parenteral!nutrition.!!
Teduglutide!is!a!glucagonQlike!peptideQ2!analogue!that!stimulates!small!bowel!
growth!and!absorption!and!was!approved!2012!for!the!treatment!of!short!bowel!
syndrome.!It!results!in!a!reduced!need!for!parenteral!nutrition.!Small!intestine!
transplantation!is!now!being!performed!with!reported!5!year!graft!survival!rates!of!
40%.!!
!
5. Circulatory!alterations:!
Mucosal!ischemic!injury!can!lead!to!atrophy!of!the!enterocytes.!This!leads!to!global!
malabsorption!with!diarrhea,!steatorrhea,!and!loss!of!proteins,!weight!loss!and!other!
signs!of!malnutrition.!!
The!main!alterations!are:!!
• Chronic!mesenteric!ischemia!(arteriosclerosis,!vasculitis,!infective!arteritis,!
connective!tissue!diseases,!extrinsic!compressions,!anatomic!abnormalities)!!
• Venous!mesenteric!insufficiency!(phlebitis,!thrombosis,!thromboembolism,!
portal!stasis,!compressions,!infiltrations,!trauma)!!
• Secondary!lymphatic!obstructions!(lymphatic!infiltrations,!lymphomas,!solid!
tumors,!traumas,!thoracic!duct!damages)!
• Chronic!heart!failure!(‘cardiac!cahexia’):!Hematic!stasis!in!splanchnic!district!
→!edema!or!congestion!→!hypoxia!of!mucosa!!

! 61!
 • EndMstage!liver!disease:!Inadequate!absorption!of!micoQ!and!macronutrients!
and!impaired!digestion!–!malnutrition!is!a!bad!prognostic!factor,!common!~!
80%!(even!in!Child!A!~!25%!)!–!associated!to!severity!of!liver!disease!and!
presence!of!portal!hypertension!(portal!hypertensive!enteropathy:!mucosal!
congestion,!villous!atrophy,!compromised!gut!barrier!function)!!
– small!intestinal!bacterial!overgrowth!!
– cholestasis!→!↓!intraluminal!bile!salt!concentration!→!↓!absorption!
of!fatQsoluble!vitamins!–!pancreatic!insufficiency!is!also!common!
!
6. Alteration!caused!by!microbial!agents:!!Small!intestinal!bacterial!
overgrowth!(SIBO):!
Unlike!in!the!colon!which!is!rich!with!bacteria,!the!small!bowel!normally!has!fewer!
than!10,000!organisms!per!ml.!thus,!overgrowth!of!bacteria!in!the!small!intestine!
may!cause!malabsorption!via!number!of!mechanisms.!Bacteria!can!cause!damage!to!
small!bowel,!deconjugate!bile!acids,!uptake!of!nutrients!(vit!B12,!carbs!etc.)!and!
more.!Conditions!that!predispose!to!small!bowel!bacterial!overgrowth:!!
!
# Old!age!(particularly!with!physical!disability)!
# Hypochlorhydria!or!gastric!achlorhydria!(endogenous!or!induced!by!PPI’s!or!
H2!blockers)!!
# Short!bowel!syndrome!
# Resection!of!ilealQcecal!valve!
# Surgical!blind!loops!(end!to!side!anastomosis)!
# Anatomical!disruptions!leading!to!intestinal!dysmotility!and!stasis!(following!
massive!bowel!resection;!bowel!strictures!or!adhesions)!
# Partial!or!total!gastrectomy!
# Crohn’s!disease!–!bacterial!translocation!
# Celiac!sprue!–!bacterial!translocation!
# Intestinal!diverticular!disease!
# Enterocutaneous!fistulae!
# Impaired!peristalsis!caused!by!above!GI!conditions!or!chronic!intestinal!
pseudoQobstruction:!DM,!Parkinson’s,!neuropathy,!myopathy,!infectious,!
autoimmune!or!metabolic!diseases.!!
# Hepatic!cirrhosis!–!bacterial!translocation!
# Malnutrition!or!illnessQassociated!immunodeficiency!
Signs!and!symptoms:!!
# Many!are!asymptomatic!!
# Symptoms!are!nonspecific:!flatulence,!weight!loss,!abdominal!pain,!diarrhea,!
sometimes!steatorrhea.!
# Deconjugation!of!bile!acids,!leads!to!fat!and!soluble!vitamin!(ADEK)!
malabsorption!and!steatorrhea!
# !production!of!toxic!metabolites!and!injury!to!the!enterocytes!!
# Competition!with!the!host!for!nutrients!(B12!deficiency)!
# Carbohydrate!malabsorption!(lactose!intolerance)!!
# Protein!malabsorption!

! 62!
A!specific!diagnosis!can!be!achieved!only!by!aspirate!and!culture!of!proximal!jejunal!
secretion!that!demonastrates!over!105!organisms/mL.!hwoever,!this!is!an!invasive!
and!laborious!test.!Noninvasive!breath!tests!are!easier!to!perform!and!have!
sensitivity!of!60Q90%!and!specificity!of!85%!(breath!hydrogen!test,!breath!methane!
test,!with!glucose!and!lactose).!
!
Treatment!"!correct!the!anatomical!defect!which!predisposed!the!bacterial!growth!
(if!possible),!otherwise,!treatment!with!oral!broadQspectrum!antibiotics!effective!
against!enteric!aerobes!and!anerobes!for!1Q2!weeks!(ciprofloxacin,!norfloxacin,!
amoxicillin!clavulanate,!or!a!combination!of!metronidazole!and!TMX/SMP)!!
Trimethoprim/sulfamethoxazole
!
7. Miscellaneouse!disease!that!can!cause!malabsorptions:!!
• Amyloidosis!
o Autonomic!neuropathy!of!enteric!nervous!system!and!myopathy!
which!lead!to!alterations!of!intestinal!transit!and!SIBO.!Amyloid!
deposits!–!barrier!disruption!and!ischemia.!
• Systemic!sclerosis!
o Common!(50Q90%)!and!affects!many!sites!of!GI!tract.!Typically!restuls!
from!the!fibrosis!(collagen!deposition)!which!results!in!impaired!
intestinal!motility,!digestion,!absorption!and!excretion.!Reduce!
hematic!flow,!lymphatic!obstruction!
• Autonomic!neuropathy:!typical!of!DM!(poor!blood!glucose!control)!
o Gastroparesis!(postprandial!gastric!statis)!5Q12%!(female>male)!
o Intestinal!enterophathy!(small!bowel!stasis)!4Q22%!(diarrhea,!
constipation,!fecal!incontinency)!
o Its!important!to!exclude!drug!related!causes,!check!thyroid!hormonal!
function!
• Zollinger!Ellison!syndrome!(gastrinoma)!
o Hypergastrinemia!Q>!acid!hypersecretion!Q>!reduction!in!gastric!pH!Q>!
enzyme!inactivation!(pancreatic!lipase)!
• Atrophic!gastritis!(H.pylori!or!autoimmune)!
o Achlorhydria:!can!cause!ironQdeficiency!anemia!(conversion!of!ferric!
iron!into!ferrous!form!–!reducing!iron!absorption)!
o SIBO!
o Decreased!availability!of!intrinsic!factor:!megaloblastic!anemia!and!
possible!neurological!dysfunction!(B12!deficiency)!
• Medicines:!!
o Acarbose!(selective!inhibition!of!alpha!glucosidase)!
o Colchicine!(damage!of!intestinal!mucosa!which!results!in!villous!
atrophy,!reversible!deficit!of!lactase)!
o Orlistat!(selective!inhibition!of!pancreatic!lipase)!
• Hyperthyroidism!!
o Accelerated!intestinal!transit!–!inadequate!mixing!among!nutrients!
and!digestive!juices,!reduces!time!of!contact!with!intestinal!mucosa!
(diarrhea,!steatorrhea)!
!
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 • Aging!
o Reduced!absorption!(carbs!and!amino!acids)!without!typical!
histological!small!bowel!alteration.!!
o Decreaed!number!of!sugar!and!amino!acid!transporters,!reduced!
enzyme!activity!(lactase,!sucrase),!increased!risk!of!SIBO!(atrophic!
gastritis,!PPI!use,!GI!motility!disorders),!vascular!alterations!(chronic!
mesenteric!ischemia,!chronic!heart!failure)!
• Neurofibromatosis!
o Periampullary,!duodenal,!pancreatic!cancer!(pancreatic!insufficiency,!
biliary!obstruction)!
o Mesenteric!infiltration!–!vascular!and!lymphatic!obstructions!
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 Maldigestion is a disorder of the enzymatic
cleavage of the food. The causes may range of
the stomach ( gastrectomy ), the pancreas ,
the liver and the bile ducts are and congenital
enzyme defects as in lactose intolerance be.

Topic!#16.!Malabsorption:!diagnostics!and!treatment.!Maldigestion:!
!
Maldigestion:!defective*hydrolysis*of*nutrients.!Digestion!is!the!process!by!which! CAUSES OF MALDIGEST
Mastication
food!is!broken!down!into!simpler!substances!so!that!it!can!be!absorbed!by!the! stomach and SI motility
alimentary!tract.!It!is!both!a!mechanical!and!chemical!process!that!starts!from!the! GI motility
time!food!enters!the!mouth.!Problems!with!digestion!(maldigestion)!may!arise!in! Mechanical digestion
Enzyme deficiency
any!part!of!the!alimentary!tract.!A!disruption!in!one!part!of!the!tract!will! Bile acid deficiency
inadvertently!affect!digestion!and!absorption!in!neighboring!sections!thereby!
eliciting!a!wide!range!of!signs!and!symptoms.!
!
Disorders!affecting!mastication!(chewing),!as!well!as!stomach!and!small!intestine!
motility,!impairs!mechanical!digestion.!Gastrointestinal!motility!does!not!only!affect!
the!movement!of!food!through!the!gut,!it!is!also!play!a!major!role!in!mechanical!
digestion.!When!mechanical!digestion!is!affected,!food!in!the!stomach!and!small!
intestine!may!not!be!adequately!exposed!to!the!digestive!enzymes.!Therefore!
mechanical!digestion!can!upset!chemical!digestion.!
!
Most!of!the!common!causes!of!maldigestion!are!conditions!that!impair!chemical!
digestion,!f.ex!enzyme!deficiency!or!bile!deficiency.!Maldigestion!can!be!due!to!
lactase!deficiency,!pancreatic!insufficiency,!bile!salt!deficiency.!
!
Difference!between!maldigestion!and!malabsorption.!Maldigestion!is!when!there!is!
failure!of!the!chemical!processes!of!digestion.!Malabsorption!is!when!the!intestnial!
mucosa!fails!to!absorb!the!digested!nutrients.!
!
Malabsorption:!diagnosis!and!treatment:!!
!
Diagnosis!of!lactose!intolerance:!!
1. Hydrogen!breath!test:!patient!ingests!25g!of!lactose.!If!rise!in!H2!og!CH4!in!
breath!then!a!positive!result.!!
2. Mucosal!biopsy!to!check!for!lactase!activity!in!mucosa!
3. Genetic!testing!!
4. Lactose!absorption!test:!monitoring!of!blood!glucose!0,!60,!120!min!after!
ingestion!of!50g!of!lactose!(which!is!equivalent!of!1L!of!milk).!If!<1,1mM!
increase!in!blood!glucose,!it!indicates!lactose!intolerance!
Treatment!of!lactose!intolerance!is!sometimes!to!decrease!or!stop!intake!of!lactose!
(milkQproducts),!however!patients!that!choose!to!restrict!or!eliminate!milk!products!
may!have!increased!risk!of!osteoporosis.!Calcium!supplementation!is!recommended!
for!those!susceptible!patients.!Lactase!enzyme!replacement!therapy!is!commercially!
available!as!nonprescription!formulas!(Lactaid,!Lactrase,!Dairy!Ease).!!
! effects of deficiency of the malabsorbed nutrients (such as anaemia with vitamin B12 malabsorption).
There is no single, specific test for malabsorption. Investigation is guided by symptoms and signs. A range of different conditions can produce malabsorption and it is necessary to look for each of these specifically. Tests are
also needed to detect the systemic

BLOOD TESTS: reveal anaemia,! high CRP or low albumin. In this setting, microcytic anaemia usually implies iron deficiency and macrocytic can be caused by impaired folic acid or B12 absorption or both.
Low cholesterol or triglyceride may give a clue toward fat malabsorption. Low calcium and phosphate may give a clue toward osteomalacia from low vitamin D.
!
Specific vitamins like vitamin D or micro nutrient like zinc levels can be checked. Fat soluble vitamins (A, D, E & K) are affected in fat malabsorption. Prolonged prothrombin time can be caused by vitamin K deficiency.

SEROLOGICAL STUDIES: IgA Anti-transglutaminase antibodies or IgA Anti-endomysial antibodies for Coeliac disease, IgG against Gliadin
!
STOOL STUDIES: Microscopy is particularly useful in diarrhoea, may show protozoa like Giardia, ova, cyst and other infective agents. Fecal fat study to diagnose steatorrhoea is rarely performed nowadays.
!
Low fecal pancreatic elastase is indicative of pancreatic insufficiency. Chymotrypsin can be assessed as well.

!
RADIOLOGICAL STUDIES: BARIUM follow through is useful in delineating small intestinal anatomy. Barium enema may be undertaken to see colonic or ileal lesions.

CT abdomen is useful in ruling out structural abnormality, done in pancreatic protocol when visualising pancreas.

MAGNETIC RESONANCE CHOLANGIOPANCREATOGRAPHY (MRCP) to complement or as an alternative to ERCP.

INTERVENTIONAL STUDIES: BIOPSY of small bowel showing coeliac disease manifested by blunting of villi, crypt hyperplasia, and lymphocyte infiltration of crypts.
ENDOSCOPY to detect duodenal pathology and obtain D2 biopsy (for coeliac disease, tropical sprue, Whipple's disease, abetalipoproteinaemia etc.)
!
Enteroscopy for enteropathy and jejunal aspirate and culture for bacterial overgrowth
CAPSULE ENDOSCOPY is able to visualise the whole small intestine and is occasionally useful. 65!
COLONOSCOPY is necessary in colonic and ileal disease.
ERCP will show pancreatic and biliary structural abnormalities.

Other investigations: Glucose hydrogen breath test for bacterial overgrowth, Lactose hydrogen breath test for lactose intolerance, Bile salt breath test (14C-glycocholate) to determine bile salt malabsorption.
SCHILLING test to establish cause of B12 deficiency.
Diagnosis!of!SIBO:!!
# Hydrogen!breath!test:!the!patient!ingests!glucose!(50Q75g),!you!will!see!a!
baseline!H2!or!CH4!>20ppm!or!rise!in!H2!or!CH4!by!12Q15!ppm.!
# Gold!standard:!culture!of!jejenum!aspirate!for!bacterial!count.!If!>!104!or!106!
CFU/ml!then!it!is!positive!for!SIBO.!Colonic!type!bacteria.!The!problem!with!
this!though!is!that!it!is!invasive,!time!consuming,!there!can!be!technical!
difficulties,!contamination,!missing!distal!SIBO.!!
!
Treatment!of!SIBO:!!
# Treatment!of!predisposing!conditions!
# Correct!nutritional!state!and!vitamin!deficiency!
# Suppression!of!abnormal!colonization!(broad!spectrum!antibiotics!are!
effective!against!Gram!negative!and!anaerob!bacteria)!

!
!
Hydrogen!breath!test:!after!ingestion!of!50g!of!lactose,!a!rise!in!hydrogen!of!>!
20ppm!within!90!minutes!is!a!positive!test,!indicative!of!bacterial!carbohydrate!
metabolism.!
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! 66!
The Rome Criteria is a system developed to classify the functional
gastrointestinal disorders, disorders in which symptoms cannot be
explained by the presence of structural or tissue abnormality

Topic!#17.!Irritable!bowel!syndrome.!Diverticulosis:!!
The!ROME!III!classification!classifies!Irritable!bowel!syndrome!(IBS)!in!group!C1.!
Group!C!stands!for!functional!bowel!disorders.!Symptoms!usually!begin!in!late!teens!
to!early!twenties!and!it!is!a!chronic!condition.#The#symptoms#are#not#explicable#by#
the#presence#of#structural#or#biochemical#abnormalities.!They!may!be!continuous!or!
intermittent.!Consensus!definition!of!irritable!bowel!syndrome!is!abdominal!
discomfort!or!pain!that!has!two!of!the!following!three!features:!!
!
1. Relived!with!defecation!
2. Onset!associated!with!a!change!in!frequency!of!stool!
3. Onset!associated!with!a!change!in!form!(appearance)!of!stool!
ROME!criteria!for!diagnosis!of!IBS:!! Irritable bowel syndrome (IBS) is a group of symptoms—including abdominal pain
and changes in the pattern of bowel movements without any evidence of underlying
• Abdominal!pain/discomfort!! damage. These symptoms occur over a long time, often years. It has been classified
into four main types depending on if diarrhea is common, constipation is common,
o Relieved!With!defecation!! both are common, or neither occurs very often (IBS-D, IBS-C, IBS-M, or IBS-U
respectively). IBS negatively affects QoL. Disorders such as anxiety, major
o Relieved!With!defecation!and/or!! depression, and chronic fatigue syndrome, are common among people with IBS.

o With!change!in!stool!frequency!and/or!!
The causes of IBS are not clear. Theories include gut–brain axis problems, SIBO,
genetic factors, food sensitivity, and gut motility problems. Onset may be triggered
o With!change!in!stool!consistency!! by an intestinal infection, or stressful life event. IBS is a functional gastrointestinal
disorder. Diagnosis is based on signs and symptoms in the absence of worrisome
• Two!or!more!at!least!25%!of!the!time!! features. Worrisome features include onset at greater than 50 years, weight loss,
blood in the stool, or a family history of inflammatory bowel disease. Other
o Change!in!stool!frequency!! conditions that may present similarly include celiac disease, microscopic colitis,
inflammatory bowel disease, bile acid malabsorption, and colon cancer.
o Change!in!stool!consistency!!
There is no cure for IBS. Treatment is carried out to improve symptoms. This may
o Difficult!stool!passage!! including dietary changes, medication, probiotics, and counselling. Dietary
measures include increasing soluble fiber intake, a gluten free diet, or a diet low in
o Sense!of!incomplete!evacuation!! fermentable oligosaccharides, disaccharides, monosaccharides, and polyols
(FODMAP).
o Presence!of!mucus!in!stool!! Loperamide may be used to help with diarrhea while laxatives may be used to help
with constipation. Antidepressants may improve overall symptoms and pain.
• Symptoms!should!be!present!for!>3!months!
About 10 to 15% of people in the developed world are believed to be affected by
IBS. It is 2x as common in women as men and typically occurs before age 45. The
Clinical!features!irritable!bowel!syndrome:!! condition appears to become less common with age. IBS does not affect life
expectancy or lead to other serious diseases.
• Altered!bowel!habits!
o Constipation!alternating!with!diarrhea!(one!predominant)!
o Constipation:!episodic!Q>!continuous!!
o Stools:!hard,!narrowed!caliber!(dehydration,!retention,!spasm!
o Incomplete!evacuation!
o Diarrhea:!small!volumes,!mucus!!
o NEVER!at!NIGHT,!NEVER!BLOOD!!
• Abdominal!pain!
o Variable!in!intensity:!mild!to!interferes!with!daily!activities!
o Location:!hypogastrium,!right!side,!left!side,!epigastrium!
o Episodic,!crampy,!consistent!
o Exacerbated!by!eating,!emotional!stress!
o Flatus!or!stool!
! Abdominal!distention,!belching!or!flatulence!–!can!be!due!to!
larger!amount!of!gas?,!impaired!transit!of!gas!–!retention.!Or!
reduced!tolerance.!!
• Absence!of!detectable!structural!abnormalities!
• Usually!young!patients!(<45)!

! 67!
 • Female:male!=!2Q3:1!
• Keep!in!mind!when!examining!the!patient!that!there!is!no!progression!of!
symptoms,!no!fever,!no!weight!loss,!normal!amount!of!stool,!no!evidence!of!
blood!in!stool.!Stress!and!emotional!upset!can!lead!to!increased!symptoms.!!
• Patients!may!also!have!other!somatic!or!psychological!complaints!such!as!
dyspepsia,!heartburn,!chest!pain,!headaches,!fatigue,!myalgias,!urologic!
dysfunction,!gynecological!symptoms,!anxiety!or!depression.!!
• The!diagnosis!is!established!in!the!presence!of!tests!to!exclude!organic!
disease.! The causes of IBS are not clear. Theories include gut–brain axis problems,
! SIBO, genetic factors, food sensitivity, and gut motility problems.
Pathophysiology!of!IBD!is!poorly!understood.!Could!be!due!to!increased!motor!
reactivity,!altered!visceral!sensation,!lowered!sensation!thresholds!or!cortical!pain!
modulation!"!enteric!nervous!system!dysregulation.!!
!
• Altered!motor!activity!could!have!some!affect:!!
o Unstimulated!conditions!–!normal,!!
o Stimulated!conditions!–!abnormal!due!to:!!
! Increased!rectoQsigmoid!motor!activity!after!eating,!provoked!
stimuli!leading!to!exaggerated!colonic!motor!responses!
(inflation!of!rectal!balloons!–!contractile!activity!increases)!!
• Exaggerated!sensory:!
o Visceral!stimulation!–!postprandial!pain!(food!into!the!cecum),!rectal!
balloon!inflation!leading!to!sensations.!!
o Visceral!afferent!dysfunction!–!increased!organ!sensitivity!
(mechanoreceptor!activated!stimuli),!spinal!hyperQexcitability,!cortical!
modulation.!!
o Patient!often!have!lower!visceral!pain!threshold,!reporting!abdominal!
pain!at!lower!volumes!of!colonic!gas!insufflation!or!colonic!balloon!
inflation!than!controls.!
• CNS:!
o Emotional!disorders!(Stress)!lead!to!exacerbation!of!symptoms!
o Therapeutic!response!!
o PET:!increase!of!blood!flow!in!different!cortical!region.!!
• Symptoms!compatible!with!irritable!bowel!syndrome!develop!within!1!year!in!
up!to!10%!of!patients!after!an!episode!of!bacterial!gastroenteritis!compared!
with!<2%!of!controls.!Patients!with!increased!stressors!at!the!onset!of!
gastroenteritis!appear!to!be!at!increased!risk!for!developing!“postQinfectious”!
irritable!bowel!syndrome.!Increased!inflammatory!cells!have!been!found!in!
mucosa!and!submucosa!of!patients!with!irritable!bowel!syndrome,!but!their!
importance!is!unclear.!Chronic!inflammation!is!postulated!by!some!
investigators!to!contribute!to!alterations!in!motility!or!visceral!
hypersensitivity.!
!
!

! 68!
 • Abnormal!psychiatric!features:!!
o More!than!50%!of!patients!with!IBS!who!seek!medical!attention!have!
underlying!depression,!anxiety!or!somatization.!
o No!single!psychiatric!diagnosis!
o Chronic!stress!may!alter!motility!or!modulate!pathways!that!affect!
central!and!spinal!processing!of!visceral!afferent!sensation.!!
!
Differential!diagnosis:!!
• Abdominal!pain!!
–!Biliary!tract!disease!Biliary!tract!disease,!peptic!ulcer,!ischemia,!peptic!ulcer,!
ischemia,!cc,!diverticular!disease,!IBD!iverticular!disease,!IBD!!
–!Acute!intermittent!porphyria!!
• Pain,!bloating,!vomiting!!
–!Intest.!Intest.!obstruction,!inf.!Giardia!bstruction,!inf.!Giardia!!
• Diarrhea!–!Lactase!deficiency,!laxative!abuse,!malabsorbtion!Lactase!
deficiency,!laxative!abuse,!malabsorbtion,!hyperthyroidism,!IBD,!infection!
hyperthyroidism,!IBD,!infection.!!
• Constipation!!
–!Drugs:!antichol,!antihypertensive,!antidepr.!antichol,!antihypertensive,!
antidepr.!!
–!Endocr:!hypothyr,!hypoparathyr.!
Diagnosis:!!
• Typical!symptoms!!
• Exclusion!diseases!with!similar!symptoms!!!
–!Certain!tests:!!
Complete!blood!count,!!
Sedimentation!sigmoidoscopy!!
Stool!(blood,!parasites)!!
–!>40!years:!Ba!enema!or!colonoscopy!!
Q!Lactase!deficiency:!H2!breath!test,!lactose!free!diet!
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 There is no cure for IBS. Treatment is carried out to improve symptoms.
- Dietary changes, medication, probiotics, and counselling.
- Dietary measures include increasing soluble fiber intake, a gluten free
diet, or a diet low in oligosaccharides, disaccharides, monosaccharides,
and polyols (FODMAP).
! - Loperamide may be used to help with diarrhea while laxatives may be
Treatment:!! used to help with constipation. Antidepressants may improve overall
symptoms and pain.
• Diet!
o Avoid!obvious!food!(coffee,!disaccharides,!legumes,!cabbage)!!
o Stool!bulking!agents!(fiber,!bran,!hydrophilic!colloid)!
! Effect:!speeds!colonic!transit!(delay),!binds!water!(good!for!
excessive!hydration!of!dehydration.!Visceral!afferent!function.!!
o 20%!aggravates!bloating!and!distention!
• Drug!therapy!should!be!reserved!for!patients!with!moderate!to!severe!
symptoms!that!do!not!respond!to!conservative!measures.!!
• Antispasmotics!(relax!smooth!muscle!of!the!gut,!reduce!its!contractility)!
o Anticholinergic!drugs!! Musculotropics, such as mebeverine
o Can!be!combined!with!sedatives!(benzodiazepine!or!barbiturate).!It!
reduces!the!CNS!component!of!intestinal!contractility!and!the!
intestinal!motor!response.!!
o Side!effects!are!common:!urinary!retention,!constipation,!tachycardia,!
dry!mouth!etc.!
• Antidiarrheal!agents!(before!anticipated!stressful!events)!
o Paregoric,!codeine,!tincture!of!opium!(can!lead!to!addiction!),!
loperamide!
o Diphenoxylate!(less!addictive)!
• Anticonstipation!agents!
o Oral!osmotic!laxatives,!! laxatives such as polyethylene glycol, sorbitol, and lactulose
o Polyethylene!glycol,!lubiprostone,!linaclotide.!
• Antidepressants!
o TCA’s:!believed!to!have!effect!on!motility,!visceral!sensitivity!and!
central!pain!perception!independent!on!their!psychotropic!effects!"!
Slow!jejunal!migrating!motor,!complex!transit!propagation,!delay!
whole!gut!transit.!Might!have!motor!inhibitory!effect!and!alter!
visceral!afferent!neural!function.!Due!to!their!anticholinergic!effect,!
these!agents!might!be!more!suitable!in!patients!with!diarrheaQ
predominant!symptoms!(rather!than!constipation!predominant).!!
o SSRI!are!less!effective!that!TCA’s!
o SerotoninM3!receptor!antagonist:!increases!intestinal!motility,!
cilansetron secretion!and!sensation.!F.ex!Alosetron.!Side!effects:!ischemic!colitis!
(1/700).!It!should!not!be!used!in!patients!with!constipation.!
o SerotoninM4!receptor!antagonist:!prokinetic!effects.!F.ex!Tegaserod.!!
o Probiotics:!it!is!hypothesized!that!changes!in!gut!flora!may!reduce!
symptoms!through!suppression!of!inflammation!or!reduction!of!
bacterial!gas!production,!resulting!in!reduced!distention,!flatulus!and!
visceral!sensitivity.!F.ex!Bifidobacterium!infantis!(1!tablet!x2!daily)!
have!shown!modest!benefit!in!small!studies!
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! 70!
 • Psychological!therapies:!
o CognitiveQbehavioral!therapies,!relaxation!techniques!and!
hypnotherapy!appear!to!be!beneficial!in!some!patients.!!
Diverticular!disease:!
Diverticular!disease!can!be!congenital!or!acquired!in!small!or!large!intestine.!Colonic!
These are outpockets of the diverticulosis!increase!with!age,!ranging!from!5%!in!those!under!age!40,!to!30%!at!
colonic mucosa and
submucosa through age!60,!to!more!than!50%!over!age!80!years!in!Western!societies.!Most!are!
weaknesses of muscle layers
in the colon wall.
asymptomatic!and!discovered!incidentally!at!endoscopy!or!on!barium!enema.!
Diagnosis is often during
Complications!occur!in!<5%,!including!GI!bleeding!and!diverticulitis.!!
routine colonoscopy or as an !
incidental finding during CT
scan Colonic!diverticulosis!are!herniation!of!the!mucosa!through!the!muscularis!at!the!
RF point!of!nutrient!artery!penetrates.!Colonic!diverticula!may!vary!in!size!from!a!few!
increasing age
constipation mm!to!several!cm!and!in!number!from!one!to!several!dozen.!
a diet that is low in dietary
fiber (although this claim is
!
controversial)
connective tissue disorders
Location!is!usually!sigmoid!colon!(decrease!in!frequency!in!the!proximal!colon).!Exact!
(such as Marfan syndrome mechanism!is!unknown.!Might!be!due!to!increased!intraluminal!pressure,!thickening!
and Ehlers Danlos Syndrome)
that may cause weakness in of!mucosal!coat!(contractions)!or!deficiency!in!dietary!fibers:!fecal!bulk!decreases,!
the colon wall
hereditary or genetic narrowing!of!colon!(recent!studies!challenge!this!theory).!
predisposition,[15]
extreme weight loss !
heavy meat consumption
Small!intestinal!diverticula:!!
Duodenum:!medial!surface!of!the!second!portion,!no!symptoms.!Rarely!acute!
diverticulitis!(abdominal!pain,!fever,!GI!bleeding,!perforation)!develops.!!
!
Jejenum:!less!common,!inflammation,!bleeding,!perforation,!peritonitits.!Bacterial!
overgrowth!–!malabsorption.!!
!
!
!
Meckel’s!diverticulum:!persistent!
omphalomesenteric!duct.!Within!100cm!of!
ileocecal!valve!(ileal,!gastric,!colonic!mucosa).!
Complications:!hemorrhage!(peptic!ulcer),!
mimic!acute!appendicitis,!mechanical!
obstruction!(intussusception).!!
!
!
!
!
!
!
Depending upon which layers of the structure are involved, they are described as being either TRUE or FALSE.
!
TRUE diverticula involve ALL layers of the structure, including muscularis propria and adventitia, such as Meckel's
!
diverticulum.
!
!
FALSE diverticula (also known as "pseudodiverticula") do not involve muscular layers or adventitia. False diverticula
involve only the submucosa and mucosa.
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! 71!
Diverticulitis:!!
Diverticulitis!is!an!inflammation!in!or!around!a!
diverticular!sac.!More!than!90%!of!patients!with!
diverticulosis!have!uncomplicated!and!no!
specific!symptoms.!Diverticulitis!can!happen!due!
to!retention!of!undigested!food!residue!and!
bacteria!(fecalith)!in!the!diverticulosis!sac.!This!
hampers!the!blood!supply!which!leads!to!
invasion!of!bacteria.!Intramural!or!pericolic!
abscess!can!form,!which!can!lead!to!peritonitis!
and!stricture.!!
!
Perforation!of!colonic!diverticulum!resulst!in!an!
intraQabdominal!infection!that!may!vary!from!
microperfection!(most!common)!to!
macroperforation!with!either!abscess!or!
generalized!peritonitits.!
!
!
!
Acute!colonic!diverticulitis:!!
Fever,!left!lower!quadrant!pain,!peritoneal!irritation,!bleedings.!Nausea!and!vomiting!
are!frequently!present.!Sometimes!mass!can!be!palpated.!Stool!occult!blood!is!
common,!but!hematochezia!is!rare.!Mild!to!moderate!leukocytosis!is!present.!
!
Diagnosis:!no!sigmoidoscopy!!No!barium!enema!!The!increased!pressure!can!lead!to!
rupture.!!
!
Treatment!of!acute!diverticulitis:!bowel!rest,!IV!fluds,!broad!spectrum!antibiotics.!If!
patient!don’t!respond!to!empirical!therapy!abdominal!CT!can!be!done!to!exclude!
other!causes!or!evaluate!the!diverticulitis.!
!
If!repeated!attacks:!intermittent!antibiotic!therapy!(norfloxacin,!ciprofloxacin,!
rifaximin),!mesalazin?,!surgical!resection!if!peritonitis,!large!undrainable!abscess,!and!
clinical!deterioration!despite!medical!management!and!percutaneous!drainage.!!
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UC is one of the IBD - long-term condition with inflammation of the mucosal surface of the colon and rectum. The primary symptom is abdominal pain and diarrhea with
blood. Weight loss, fever, and anemia may also occur. Often symptoms come on slowly and can range from mild to severe. Symptoms or flares typically occur intermittently
with periods of no symptoms. Complications may include megacolon, inflammation of the eye, arthritis, or liver, and colon cancer.
The cause is unknown. It could be immune system dysfunction, genetics, changes of normal gut bacteria, and environmental factors.
It could be the result of less exposure to intestinal infections, or a Western diet and lifestyle.
It is a kind of inflammatory bowel disease (IBD) along with Crohn's disease and microscopic colitis. Diagnosis is by colonoscopy with biopsies.

Topic!#18.!Diagnostics!and!treatment!of!ulcerative!colitis:!
This!is!an!idiopathic!inflammatory!condition!that!involves!the!mucosal!surface!of!
colon,!resulting!in!diffuse!friability!and!erosions!with!bleeding.!!
• 1/3!of!cases!is!confined!to!rectosigmoidal!region!
• 1/3!of!cases!extend!to!splenic!flexure!
• 1/3!of!cases!extend!more!proximally!(extensive!colitis)!
No!correlation!with!symptom!severity!and!disease!extent.!The!disease!is!more!
common!in!nonQsmokers!and!former!smokers.!Disease!severity!may!be!lower!in!
active!smokers!and!may!worsen!in!patients!who!stop!smoking.!If!a!patient!has!had!
appendectomy!<!age!of!20,!there!is!reduced!risk!of!developing!ulcerative!colitis.!!
!
Signs!and!symptoms:!highly!variable!clinical!profile!
• Bloody!diarrhea!is!the!hallmark!of!the!clinical!profile!
• Cramps!!
• Abdominal!pain!
• Fecal!urgency!
• Tenesmus!(continual!or!recurrent!inclination!to!evacuate!the!bowels)!
• Physical!examination!should!focus!on!orthostatic!hypotension!and!pulse!
(volume!status),!and!nutritional!status.!!
From!the!signs!and!symptoms!it!is!clinically!useful!to!classify!patient!as!having!mild,!
moderate!or!severe!disease:!!
!
1. Mild!to!moderate:!gradual!onset!of!infrequent!diarrhea!(<4!bowel!
movements!per!day),!with!infrequent!rectal!bleeding!and!mucus.!Due!to!
rectal!inflammation!there!is!fecal!urgency!and!tenesmus.!Left!lower!quadrant!
cramps!relieved!by!defecation!are!common,!but!no!significant!abdominal!
tenderness.!There!may!be!mild!fever,!anemia!and!hypoalbuminemia!
2. Severe!disease:!>6!bowel!movements!per!day,!resulting!in!severe!anemia,!
hypovolemia!and!impaired!nutrition!with!hypoalbuminemia.!Abdominal!pain!
and!tenderness!are!present.!“fulminant!colitis”!is!a!subset!of!severe!disease!
characterized!by!rapidly!worsening!symptoms!with!signs!of!toxicity.!!
Lab!findings:!abnormality!in!hematocrit,!ESR!and!serum!albumin!–!reflects!disease!
Stool culture, to rule out parasites and infectious causes.
severity! CRP
Electrolyte studies and renal function tests are done, as chronic diarrhea may be associated with hypokalemia,
! hypomagnesemia and pre-renal failure.

Endoscopy:!in!acute!colitis!the!diagnosis!can!be!established!by!sigmoidoscopy.!The!
mucosa!is!edemic,!friable,!mucus!and!erosive.!Endoscopy!should!not!be!performed!
in!patients!with!fulminant!colitis!due!to!risk!of!rupture.!! Pseudopolyps.
! internal surface of the colon is blotchy and broken in places.
The
Imaging:!plain!abdominal!x!ray!is!performed!to!look!for!significant!colonic!dilation.!!
!
Diagnosis:!Correct!diagnosis!of!inflammatory!bowel!disease!(IBD)!depends!on!
clinicalQpathologic!correlation.!!
!
Biopsies of the mucosa can definitively diagnose UC and differentiate it from Crohn's disease.
The pathology in ulcerative colitis typically involves:
- distortion of crypt structure
- inflammation of crypts (cryptitis)
! - crypt abscesses 73!
- hemorrhage or inflammatory cells in the lamina propria.
- Pseudopolyps due to atrophy of the mucosa, no cobblestones
 Pseudopolyps due to atrophy of the mucosa, no cobblestones

Gross!findings:!mucosa!is!erosive!and!ulcerations!may!be!seen.!Generally!the!colon!is!
diffusely!involved!up!to!the!point!where!the!mucosa!transitions!to!normal!regions.!
Microscopic!findings:!Alteration!of!crypt!architecture.!Increased!chronic!
inflammatory!cells!in!the!lamina!propria,!Neutrophilic!inflammation,!including!
neutrophilic!infiltration!of!the!surface!epithelium!and!neutrophilic!cryptitis,!crypt!
abscesses,!erosions!and!ulcers.!!
!
Differential!diagnosis:!initially!ulcerative!colitis!is!indistinguishable!from!other!colitis!
f.ex!infectious!colitis!(campylobacter,!shigella,!salmonella,!Ecoli!O157,!C.diff).!Biopsy!
can!therefore!be!good!to!distinguish!the!cause.!CMV!colitis!occurs!in!
immunocompromised!patients.!In!elderly!patients!ischemic!colitis!may!involve!the!
rectosigmoid.!Crohns!disease!involving!the!colon!but!not!small!intestine!could!be!
mistaken!for!ulcerative!colitis!(sometimes!distinction!between!these!2!diseases!may!
not!be!possible).! Pseudomembranous colitis
Radiation colitis
! Infectious colitis
Treatment:!!
!
!Two!main!treatment!objectives:!
!
1. To!terminate!the!acute,!symptomatic!attack!
2. To!prevent!recurrence!of!attacks!
Mild!to!moderate!colitis:!
!
• Topical!mesalamine!(this!drug!is!a!5QASA,!which!are!antiQinflammatory!drugs.!
Preferred!in!most!cases,!and!can!be!use!in!remission,!dose!is!2,4Q4,8g!daily)!
• Other!5Maminosalicylates!(5QASA)!oral!or!topical!(balsalazide!or!sulfasalazine).!
Oral!is!better!if!the!disease!extends!above!sigmoid!colon.!!!
• Topical!corticosteroids!(do!not!help!to!maintain!remission,!only!in!acute!
episodes,!prednisolone!and!methylprednisolone!is!most!commonly!used!if!4!
weeks!of!5QASA!does!not!work,!and!rapid!improvement!is!usually!achieved!in!
2!weeks.)!
• Approximately!3%!of!patient!do!not!respond!to!steroids!(develop!steroid!
dependency)!or!5QASAs!and!will!need!immunomodulating!agents!"!
Thiopurine!(mercaptopurine,!Azathioprine),!methotrexate!(not!known!if!it!is!
effective),!antiMTNF!(infliximab,!adalimumab,!golimumab,!are!usually!quite!
effective).!!
• Probiotics!(2!packets!2x!daily)!containing!8!different!nonpathogenic!strains!of!
lactobacilli,!Bifidobacterium!and!streptococci!(has!shown!benefits!vs!placebo!
in!trials).!!
!
!
!
!

! 74!
 Severe!colitis!(about!15%!of!patients!have!more!severe!courses!of!the!disease,!may!
progress!to!fulminant!colitis!or!toxic!megacolon,!hospitalization!is!usually!required):!!
!
• General!measures:!!
o Discontinue!all!oral!intake!for!24Q48!hours!or!until!the!patient!
demonstrates!clinical!improvement.!!
o Discontinue!all!opioids!or!anticholinergic!agents.!!
o Restore!circulating!volume!with!fluids,!correct!electrolyte!
abnormalities!and!consider!transfusion!for!significant!anemia.!!
o Abdominal!examination!should!be!repeated!to!look!for!evidence!of!
worsening!distention!or!pain,!can!also!order!a!plain!x!ray!to!see!
colonic!dilation.!!
o Send!stool!for!bacterial!culture!(C.diff!,!ova!and!parasite!examination,!
CMV!superinfection!should!be!considered!in!patients!on!long!term!
immunosuppressive!therapy),!!
o Give!prophpylaxis!for!DVT!(since!the!patient!is!at!bed!rest).!
• Corticosteroids!(methylprednisolone!or!hydrocortisone!IV!and!then!oral!
when!patient!is!erady)!
• AntiMTNF!therapy!if!steroids!do!not!improve!symptoms!(infliximab)!
• Ctyclosporine!IV!
• Surgical!therapy!is!recommended!if!none!of!these!medical!therapies!work,!
because!patient!is!unlikely!to!respond!to!further!medical!therapy!anyway.!If!
there!is!fulminant!colitis!or!toxic!megacolon!that!does!not!improve!in!48Q72!
Iron supplementation
hours.!Also!absolute!indication!if!there!is!severe!hemorrhage,!perforation!of!
carcinoma!is!documented.!
o After!surgery!the!patient!may!have!ileostomy!or!ileal!pouchQanal!
anastomosis.!

Fulminant!colitis:!is!when!patient!rapidly!gets!worse!over!a!course!of!1Q2!weeks,!and!
the!chance!of!toxic!megacolon!is!high.!The!patient!must!be!monitored!closely!as!they!
often!have!fever,!prominent!hypovolemia,!hemorrhage!and!abdominal!distention.!
Broad!spectrum!antibiotics!should!be!administered.!
!
Toxic!megacolon:!is!when!the!colon!is!>6cm!in!diameter!on!plain!films.!Along!with!
the!antibiotics,!patient!should!be!advised!to!roll!from!side!to!side!and!onto!the!
abdomen!in!effort!to!decompress!the!distended!colon.!In!cases!where!there!is!no!
improvement!in!48Q72!hours!need!surgery!to!prevent!perforation.!!
!
Risk!of!colon!cancer!in!patients!with!ulcerative!colitis!is!markedly!increased.!The!risk!
might!be!reduces!in!patients!treated!with!5QASA!therapy.!Ingestion!of!folic!acid!also!
seems!to!help.!Colonoscopies!is!recommended!every!1Q2!years!in!patients!with!
ulcerative!colitis!where!multiple!random!biopsies!are!taken!throughout!the!colon.!
Colectomy!is!recommended!if!dysplasia!is!detected.!Spraying!the!mucosa!with!
methylene!blue!or!indigo!carmine!enhance!the!detection!of!subtle!mucosal!lesions.!!
!

! 75!
 Ulcerative!colitis!vs!Crohns!disease:!
!
To!distinguish!ulcerative!colitis!from!Crohn!disease,!a!number!of!factors!are!
considered.!Ulcerative!colitis!is!typically!a!disease!that!is!limited!to!the!colon!(with!
the!exception!of!backwash!ileitis).!This!condition!generally!involves!the!entire!colon!
diffusely,!including!the!rectum,!and!inflammation!may!become!worse!as!it!
progresses!from!the!right!side!of!the!colon!to!the!left.!Perianal!disease!is!uncommon,!
and!mesenteric!adenopathy!is!only!occasionally!seen.!
Despite!its!name,!ulcerative!colitis!often!does!not!present!with!macroscopic!ulcers!
(although!histologic!evidence!of!erosions!and!ulcers!is!common!in!untreated!
disease),!and!fissuring!disease!is!typically!absent.!In!contrast,!Crohn!disease!is!overtly!
ulcerative,!with!characteristic!fissures.!
Unlike!Crohn!disease,!ulcerative!colitis!does!not!exhibit!transmural!inflammation,!
and!serositis!is!absent,!except!in!the!setting!of!fulminant!colitis!or!toxic!megacolon.!
Instead,!the!inflammation!in!ulcerative!colitis!is!typically!limited!to!the!mucosa!and!
submucosa.!Granulomas!are!not!a!characteristic!feature!of!this!disease,!although!
granulomas!may!be!seen!with!mucous!extravasation!in!sites!of!crypt!abscess!or!crypt!
destruction.!The!muscularis!mucosa!is!usually!thickened,!and!mucosal!atrophy!may!
be!seen.!
!
!
!
pseudopolyps are the! non-atrophied mucosa
Colon haustration is! lost
Crypts are distorded
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
Crohn's disease Ulcerative colitis
!
Terminal ileum involvement Commonly Seldom
Colon involvement ! Usually Always
Rectum involvement Seldom Usually
Involvement around the anus Common Seldom
Bile duct involvement No increase in rate of primary sclerosing cholangitis Higher rate of PSC
Distribution of disease skip lesions Continuous area
Endoscopy ! Deep serpiginous (snake-like) ulcers Continuous ulcer 76!
Depth of inflammation May be transmural, deep into tissues Shallow, mucosal
Stenosis Common Seldom
Granulomas on biopsy May have non-necrotizing non-peri-intestinal crypt granulomas Non-peri-intestinal crypt granulomas not seen[
Topic!#19.!Diagnostics!and!treatment!of!Crohn’s!disease:!!
Crohn’s!disease!is!a!transmural!involvement!that!can!result!in!mucosal!inflammation!
and!ulceration,!structuring,!fistula!development!and!abscess!formation.!Cigarette!
smoking!is!strongly!associated!with!the!development!of!Crohn’s!disease,!resistance!
to!medical!therapy!and!early!disease!relapse:!!
• 1/3!involve!small!bowel,!most!commonly!the!terminal!ileum!!
• ½!involve!small!bowel!and!colon,!most!often!terminal!ileum!and!adjacent!
proximal!ascending!colon!
• 20%!colon!alone!is!affected.!!
• <5%!have!symptomatic!involvement!of!upper!GI!tract!
Signs!and!symptoms:!due!to!variable!location!of!the!disease!there!can!be!variable!
symptoms.!
!
• Chronic!inflammatory!disease!is!the!most!common!presentation.!!
o Malaise!
o Weight!loss!
o Loss!of!energy!
o Diarrhea!(if!ileocolitis),!nonbloody!and!often!intermittent!
o Bloody!diarrhea!if!crohn’s!disease!involves!the!colon!–!may!mimic!
symptoms!of!ulcerative!colitis.!!
o Cramping!or!steady!lower!quadrant!periumbilical!pain!is!common!
o Tenderness!on!abdominal!palpitation,!usually!in!right!lower!quadrant!
• Intestinal!obstruction!!
o Narrowing!of!small!bowel!due!to!inflammation,!spasm!or!fibrotic!
stenosis!
o Postprandial!bloating!and!cramping!pains!
o This!may!occur!in!patients!with!active!inflammatory!symptoms!
• Penetrating!disease!and!fistulae!
o Sinus!tracts!that!penetrate!the!bowel,!wehre!they!may!be!contained!
to!form!fistulas!to!adjacent!structures.!!
o Fistulas!can!be!asymptomatic,!but!can!also!have!symptoms!such!as!
diarrhea,!weight!loss,!bacterial!overgrowth!and!malnutrition,!
recurrent!infections!etc.!!
• Perianal!disease!
o Large!painful!skin!tags,!anal!fissures,!perianal!abscesses,!fistulas!
• Extraintestinal!manifestations:!
o Arthralgia,!!
o Arthritis,!!
o Iritis!or!uveitis,!!
o Pyoderma!gangrenosum,!!
o Erythema!nodosum,!!
o Oral!apthous!lesions,!!

! 77!
 o Increased!prevalence!of!gallstones!due!to!malabsorption!of!bile!salts!
from!terminal!ileum.!!
o Nepthrolitiasis!with!urate!or!calcium!oxalate!stones!may!occur.!!
Lab!findings!are!not!that!specific.!They!may!show!inflammatory!activity!or!nutritional!
complications.!!
!
In!most!cases!the!initial!diagnosis!of!Crohn´s!disease!is!based!on!a!compatible!clinical!
picture!with!supporting!endoscopic,!pathologic!and!radiographic!findings.!
!
• Colonoscopy!with!mucosal!biopsy:!usually!performed!first.!Apthoid,!linear!or!
stellate!ulcers,!strictures,!segmental!involvement!with!areas!of!normalQ
appearing!mucosa!adjacent!to!inflamed!mucosa.!In!10%!of!cases!it!is!difficult!
to!distinguish!ulcerative!colitis!from!Crohn’s.!Granulomas!may!also!be!
present!which!are!highly!suggestive!of!Crohn’s.!!
• CT!or!MR!enterography!or!barium!upper!gastrointestinal!series!with!small!
bowel!follow!through!often!is!obtained!in!patients!with!small!bowel!
involvement.!Findings:!ulcerations,!strictures!and!fistulas,!it!may!also!identify!
bowel!wall!thickening!and!vascularity,!mucosal!enhancement!and!fat!
stranding.!!
• Capsule!imaging!may!help!establish!a!diagnosis!when!clinical!suspicion!for!
small!bowel!involvement!is!high!but!radiography!is!normal!or!nonQdiagnostic.!!
Complications:!!
• Abscess!"!tender!abdominal!mass!with!fever!and!leukocytosis.!Emergent!CT!
is!needed!to!confirm!diagnosis.!Give!broad!spectrum!antibiotics.!
Percutaneous!drainage!or!surgery!is!usually!required!
• Obstruction!"!give!patient!IV!fluid!and!nasogastric!suction.!Systemic!
corticosteroid!therapy!is!indicated!in!patients!with!symptoms!or!signs!of!
active!inflammation!but!is!unhelpful!in!patients!with!inactive,!fixed!disease.!
Sometimes!surgery!is!required!if!everything!else!fails.!!
• Abdominal!and!rectovaginal!fistulas!
o If!no!symptoms,!no!therapy!is!required!
o Medical!therapy!sometimes!is!enough!in!outpatients!who!are!
otherwise!stable!
! Total!IV!therpy!may!close!the!fistula!temporarily!but!when!oral!
feeding!are!resumed!they!may!open!again!
! Anti!TNT!agents!may!promote!closure!
o Most!symptomatic!fistulas!require!surgical!therapy,!especially!those!
who!do!not!respond!to!medical!therapy!or!if!abscess!is!involved.!!
• Perianal!disease!"!pelvic!MRI!and!endoscopic!ultrasonography!are!the!best!
noninvasive!studies!for!evaluating!perianal!fistulas.!Patient!should!be!advised!
proper!perianal!skin!care,!gentle!wiping!and!use!baby!wipes.!Oral!antibiotics!
(metronidazole!or!ciprofloxacin)!may!promote!symptom!improvement!or!

! 78!
 healing!in!patients!with!fissures!or!uncomplicated!fistulas.!If!fever!and!much!
pain,!suspect!abscess.!!
• Carcinoma!"!patients!with!Crohn’s!disease!are!at!increased!risk!of!
developing!colon!carcinoma.!Annual!screening!is!recommended.!!
• Hemorrhage!"!unlike!ulcerative!colitis,!risk!of!hemorrhage!is!low!in!Crohn´s!
disease.!!
• Malabsorption!"!may!arise!after!extensive!surgical!resection!of!small!
intestine!and!from!bacterial!overgrowth!in!patients!with!fistulas,!strictures!
and!stasis.!!
Differential!diagnosis:!!
• Irritable!bowel!syndrome!
• Celiac!disease!
• Infectious!colitis!or!other!types!of!colitis!
!
Treatment!of!active!disease:!!
1. Nutrition!
a. Well!balanced!diet,!!
b. Eat!smaller!amounts!at!a!time!but!more!often!over!the!day,!!
c. Avoid!fatty!foods!
d. If!obstructive!symptoms!advise!patient!not!to!eat!raw!fruit!or!
vegetables,!nuts!or!popcorn!etc.!!
e. Enteral!therapy!via!nasogastric!tube!may!be!required!for!children!and!
adolescent!with!poor!intake!and!growth!retardation!
f. Total!parenteral!nutrition!(only!IV!nutrition)!may!be!required!short!
term!in!patients!who!are!waiting!for!surgery,!have!severe!obstruction,!
high!output!fistulas,!severe!diarrhea!or!abdominal!pain!
2. Symptomatic!medication!
a. If!diarrhea!is!due!to!poor!absorption!of!bile!acids:!cholestyramine!2Q
4g,!colestipol!5g!or!colesvelam!625mg!1!or!2!times!daily!before!meals!
to!bind!to!the!malabsorbed!salts.!!!
b. If!diarrhea!is!due!to!active!Crohn’s!disease:!may!respond!to!empirical!
treatment!of!corticosteroids!or!immunosuppressive!agents.!They!may!
also!benefit!of!broadQspectrum!antibiotics!due!to!risk!of!bacterial!
overgrowth.!!
c. Other!reasons!for!diarrhea:!!
i. Lactase!deficiency!
ii. Short!bowel!syndrome! sulfasalazine
3. Specific!drug!therapy! balszalazine
a. 5MASA!(Mesalamine)!has!for!a!long!time!been!used!as!initial!therapy!
for!treatment!of!milk!to!moderate!Crohn’s!disease,!however!current!
guidelines!recommend!against!it!due!to!little!efficacy.!
b. Antibiotics!because!they!may!reduce!inflammation!through!alteration!
of!gut!flora,!reduction!of!bacterial!overgrowth!or!treatment!of!

! 79!
 microperforations.!Oral!metronidazole!or!ciprofloxacin!or!rifaximin!
are!commonly!administered!for!6Q12!weeks.!
c. Corticosteroids!dramatically!decrease!active!symptoms!but!have!little!
effect!on!the!underlying!disease.!Budesonide!preaparation!(Entocort)!
is!used!for!8Q16!weeks!for!patients!with!mild!to!moderate!Crohn´s.!
however!prednisone!or!methylprednisone!is!used!for!patients!with!
Immunomodulation severe!Crohn’s.!!
thiopurine
d. Immunomodulatory!drugs!are!given!if!1:!for!maintenenace!of!
6mercaptopurine
azathioprine remission!after!induction!with!corticosteroids,!or!2:!induction!of!
mtx remission,!in!combination!with!antiQTNF!therapy.!These!drugs!are!
Azathioprine,!mercaptopurine!or!methotrexate.!
antiTNF e. AntiMTNF!therapy!(infliximab,!adalimumab,!certolizumab)!are!used!to!
adalimumab induce!and!maintain!remission!in!patients!with!moderate!to!severe!
infliximab Crohn’s,!including!fistulizing!disease,!also!to!treat!extraintestinal!
golimumab manifestation!of!Crohn´s!(except!optic!neuritis).!!
f. AntiMintegrins!(natalizumab,!vedolizumab)!are!an!option!for!patients!
Anti-integrin
natalizumab who!do!not!respond!to!antiQTNF!agents.!!
Surgery:!Main!indications!are!intractability!to!medical!therapy,!intraQabdominal!
abscess,!massive!bleeding,!symptomatic!refractory!internal!or!perianal!fistulas,!and!
intestinal!obstruction.!!
!
Prognosis:!with!proper!medical!and!surgical!treatment,!the!majority!of!patients!are!
able!to!cope!with!this!chronic!disease!and!its!complications!and!lead!productive!
lives.!!
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! 80!
 Polyps are fleshy growths occurring on the lining of the colon or rectum. Untreated colorectal polyps can develop into
colorectal cancer. They may have a stalk (pedunculated) or be sessile or flat.
Colorectal polyps are classified by their behaviour (i.e. benign vs. malignant) or etiology (e.g. as a consequence of
inflammatory bowel disease). They may be benign (e.g. hyperplastic polyp), pre-malignant (e.g. villous, tubular adenoma)
or malignant (e.g. colorectal adenocarcinoma).

Topic!#20.!Colorectal!polyposis:!
Polyps!are!discrete!mass!lesions!that!protrude!into!the!intestinal!lumen.!Most!are!
sporatic,!however!they!may!be!inherited!as!a!part!of!familial!polyposis!syndrome.!
The 4 most common Polyps!can!be!divided!into!4!main!categories:!!
types of colon
polyps are
1. Mucosal!adenomatous!polyps!(tubular,!tubulovillous!and!villous).!Of!polyps!
1. inflammatory, removed!in!colonoscopy!70%!are!adenomatous,!most!remainder!are!
2. adenomatous
serrated.!!
(adenoma),
3. hyperplastic 2. Mucosal!serrated!polyps!(hyperplastic,!sessile!serrated!polyp!and!traditional!
4. villous serrated!adenomas)!
(tubulovillous)
polyps. 3. Mucosal!nonMneplastic!polyps!(juvenile!polyps,!hamartomas,!inflammatory!
In addition to these, polyps)!
2 less common types
include 4. Submucosal!lesions!(lipomas,!lymphoid!aggregates,!carcinoids,!pneumatosis!
5. lymphoid, which cystoides!intestinalis)!
are considered rare
and benign Adenomas!and!serrated!polyps!may!be!flat,!sessile!or!pedunculated!(containing!a!
6. juvenile
stalk).!They!are!present!in!30%!of!adults!over!50!years!of!age.!Over!95%!of!cases!f!
adenocarcinoma!of!colon!are!believed!to!arise!from!these!lesions.!Sequence!of!
nonQfamilial!adenomatous!and!serrated!polyps!to!carcinoma!has!been!proposed.!The!
APC gene majority!of!cancers!arise!in!adenomas!after!inactivation!of!APC!gene,!which!leads!to!
chromosomal!instability!and!inactivation!or!loss!of!other!TSG.!By!contrast,!most!
Kras or BRAF
cancers!arising!from!a!serrated!polyps!appear!to!have!Kras!or!BRAF!oncogene!
oncogenes activation!with!methylation!of!CpGQrich!promoter!regions!that!leads!to!inactivation!
methylation of of!TSG!or!mismatch!repair!genes!(MLH1)!with!microsatellite!instability.!!
CpG rich regions
Mismatch repair
!
gene inactivation

!
*
Adenoma*to*carcinoma*sequence*
*
Most!adenomas!are!small,!<1cm,!and!have!low!risk!of!becoming!malignant;!<5%!of!
these!enlarge!with!time.!Adenomas!and!serrated!polyps!are!classified!as!“advanced”!
if!they!are!>1cm,!or!contain!villous!features!of!high!grade!dysplasia.!!
!
!

! 81!
Signs!and!symptoms:!!
• Most!patients!are!completely!asymptomatic!
• Chronic!occult!blood!loss!may!lead!to!iron!deficiency!anemia!
• Large!polyps!may!ulcerate,!resulting!in!intermittent!hematochezia!
Testing:!!
• Fecal!occult!blood!test!(FOBT)!
• Fecal!blood!immunochemical!test!for!hemoglobin!(FIT)!
• Radiologic!tests:!!
o Barium!enema!
o CT!colonography!
o Abdominal!CT!
o Colonoscopy!–!the!best!means!of!detecting!and!removing!
adenomatous!and!serrated!polyps.!It!should!be!performed!in!all!
patients!with!positive!FOBT,!FIT!or!DNA!test,!or!iron!deficiency!
anemia.!!
o Capsule!endoscopy!is!also!a!possibility!but!it!is!not!as!sensitive!and!
specific!as!colonoscopy.!!
Treatment:!!
• Colonoscopic!polypectomy!–!polyps!are!removed!during!colonoscopy!via!
biopsy!forceps!or!snare!cautery.!Complications!include!perforation!(0,2%)!
and!clinically!significant!bleeding!(0,3Q1%).!!
• Postpolyectomy!surveillance!–!when!polyps!have!been!detected!and!
removed,!the!patient!needs!surveillance!colonoscopy!within!3Q5!years.!It!also!
depends!on!how!many!polyps!were!found!and!if!the!biopsy!shows!dysplasia,!
how!frequent!the!surveillance!needs!to!be.!!!
Hereditary!colorectal!cancer!and!polyposis!syndrome!
!
Up!to!4%!of!all!colorectal!cancers!are!caused!by!germline!genetic!mutations!that!
impose!on!carriers!as!high!lifetime!risk!of!developing!colorectal!cancer.!There!are!3!
main!familial!mutations!that!are!important,!and!distinguishing!them!from!each!other!
is!important!for!the!patient!regarding!treatment.!!
!
1. Familial!adenomatous!polyposis!(FAP)!
a. Genetic!testing!confirms!mutation!of!APC!gene!(90%)!or!MYH!gene!
(8%).!Incidence!1:10,000!people.!!
b. Prophylactic!colectomy!is!recommended!to!prevent!otherwise!
inevitable!colon!cancer,!it!should!be!done!before!age!of!20.!!
c. Colorectal!polyps!develop!at!a!mean!age!of!15,!and!cancer!at!40!years!
of!age.!Colorectal!cancer!is!inevitable!at!the!age!of!50.!!
d. Extraintestinal!manifestations:!soft!tissue!tumors!of!skin,!desmoid!
tumors,!osteomas,!congenital!atrophy!of!retinal!pigment.!
Malignancies!of!CNS!and!thyroid!may!also!develop.!
!

! 82!
 2. Hamartomatous!polyposis!syndrome!
benign disorganised mass of tissue hamartomatous!polyps!and!lipomas!are!throughout!the!GI!tract,!
3. Lynch!syndrome!(=hereditary!nonpolyposis!colon!cancer!(HNPCC))!
other cancers including
endometrial cancer (second
most common), ovary,
stomach, small intestine,
hepatobiliary tract, upper
urinary tract, brain, and
skin. The increased risk for
these cancers is due to
inherited mutations that
impair DNA mismatch
repair. It is a type of cancer
syndrome.
! 83!
a. Rare,!accounts!for!<!0,1%!of!colorectal!cancers!
b. PeutzQjegher!syndrome!(AD)!–!hamartomatous!polyps!throughout!the!
GI!tract,!most!notably!in!the!small!intestine.!Hamartomas!may!
become!large,!and!although!they!are!not!malignant,!GI!malignancies!
(stomach,!bowel!and!colon)!develop!in!40Q60%!of!cases,!breast!in!30Q
50%!as!well!as!a!host!of!other!malignancies!(gonads,!pancreas)!
c. Familial!juvenile!polyposis!(AD)!–!several!juvenile!hamartomatous!
polyps!located!most!commonly!in!the!colon.!There!is!up!to!50%!more!
risk!of!developing!adenocarcinoma.!
d. PTEN!multiple!hamartoma!syndrome!(Cowden!disease)!–!
trichilemmomas!and!cerebellar!lesions.!Increased!rate!of!malignancy!
is!demonstrated!in!thyroid,!breast!and!urogenital!tract!
!
a. AD!condition.!Caused!by!a!mutation!in!a!gene!that!detects!and!repairs!
DNA!baseQpair!mismatches,!resulting!in!DNA!microsatellite!instability!
and!inactivation!of!tumor!suppressor!genes.!!
b. If!a!patient!has!this!mutation!he/she!needs!to!be!screened!every!year!
at!the!beginning!of!age!of!25!years!(or!at!age!5!years!younger!than!the!
age!at!diagnosis!of!the!youngest!affected!family!member)!
c. Increased!lifetime!risk!of!colorectal!cancer!is!50Q80%,!endometrial!
cancer!30Q60%!and!other!cancers!that!may!develop!in!young!age.!!
d. Unlike!familial!adenomatous!polyposis,!HNPCC!patients!develop!only!
a!few!adenomas,!which!may!be!flat!or!more!often!contain!villous!
features!or!high!grade!dysplasia.!These!adenomas!are!belived!to!
undergo!rapid!transformation!over!1Q2!years!from!normal!tissue!"!
adenoma!"!cancer.!!
e. Bethesda!criteria!(patient!has!increased!likelihood!of!harboring!a!
germline!mutation)!–!identifies!approximately!70%!of!mutant!positive!
HNPCC!families.!
f. If!cancer!is!detected!subtotal!colectomy!with!ileorectal!anastomosis!
should!be!performed.!
!
!
 !
!
RF of polyps in the colon: overweight, smokers, a personal or family history of colon polyps

The most common ! general classification is: adenomatous (tubular, tubulovillous, villous), serrated (pedunculated, sessile, hyperplastic), non
!
neoplastic (inflammatory, hamartomas, juvenile) and submucosal lesions
hyperplastic - benign
!
neoplastic (adenomatous & malignant),
hamartomatous!and,
inflammatory.
!
! no malignant potential. Hyperplastic polyps are serrated polyps.
Hyperplastic polyp:
Hyperplastic polyps have 3 histologic patterns of growth: microvesicular, goblet cell and mucin poor.
!
Neoplastic polyp:! cells have lost its normal differentiation. They can be either benign or malignant growths.
!
Adenomas: Neoplastic polyps of the bowel are often benign hence called adenomas. An adenoma is tumor glandular tissue, that has not (yet) gained
the properties of! a cancer. The common adenomas of the colon (colorectal adenoma) are the tubular, tubulovillous, villous, and sessile serrated
(SSA).
!
!
The villous subdivision are associated with the highest malignant potential because they generally have the LARGEST SURFACE AREA.
!
(This is because the villi are projections into the lumen and hence have a bigger surface area.)

Hamartomatous! polyp: They are normally made up of a mixture of tissues. They contain mucus-filled glands, with retention cysts, abundant
!
connective tissue, and a chronic cellular infiltration of eosinophils. rarely cause problems such as compression. Hamartomatous polyps are often
found by chance; occurring in syndromes such as Peutz-Jegher Syndrome or Juvenile Polyposis Syndrome.
!
!
Peutz-Jeghers syndrome is associated with polyps of the GI tract. People are often diagnosed with Peutz-Jegher after presenting at around the age of
9 with an intussusception. The polyps themselves carry little malignant potential but because of potential coexisting adenomas there is a 15% chance
!
of colonic malignancy.
!
Juvenile polyps are hamartomatous polyps which often become evident before twenty years of age, but can also be seen in adults. They are usually
! in the rectum which most commonly present with rectal bleeding. People with juvenile polyposis have an increased risk of
solitary polyps found
colon cancer. !

! These are polyps which are associated with inflammatory conditions such as Ulcerative Colitis and Crohns disease.
Inflammatory polyp:
!
Malignant potential is associated with
!
- degree of dysplasia
! villous adenoma):
- Type of polyp (e.g.
- Tubular Adenoma: 5% risk of cancer
!
- Tubulovillous adenoma: 20% risk of cancer
!
- Villous adenoma: 40% risk of cancer
Size of polyp:
<1 cm =<1% risk of cancer
1 cm=10% risk of cancer
2 cm=15% risk of cancer
! 84!
Loss of APC tumor suppressor gene – both copies of the gene must be lost; APC protein promotes the degradation of β-catenin => accumulation of β-catenin leads to activation the transcription of
genes such as cyclin D1 and MYC that promote cell proliferation

Mismatch repair pathway (microsatellite instability)

Inactivation of mismatch repair genes
Mutations occur in one of 5 specific genes => MSH2, MSH6, MLH1, PMS1, and PMS2
Loss of mismatch repair => hyper-mutable state => microsatellites are unstable during replication => alterations occur => microsatellite instability => HNPCC

Topic!#21.!Symptoms!and!diagnostics!of!colorectal!cancer!(CRC):!
CRC!is!the!second!most!frequently!diagnosed!tumor!in!both!men!and!women,!in!
male!patients!following!pulmonary!cancer,!in!women!following!breast!cancer.!70%!of!
the!tumors!are!found!in!the!left!colon!!!
!
• 5!year!survival!depending!on!the!stage!of!the!disease!is!between!90%!Q!9%.!!
• 90!%!of!the!patients!is!older!than!50!years.!
• 80Q85%!of!the!cases!is!considered!as!sporadic!CRC.!!
• Accumulations!in!the!family!is!well!known,!among!first!line!relatives!CRC!is!3x!
more!frequent.!5%!of!CRC!are!caused!by!inherited!germ!line!mutations.!!
Colorectal!cancers!are!almost!all!adenocarcinomas!and!the!majority!of!them!arise!
from!malignant!transformation!of!adenomatous!polyps.!10Q20%!of!CRC!arise!from!
serrated!polyps!(they!are!predominantly!in!the!proximal!colon,!poor!differentiation!
and!more!favorable!prognosis).!Polyps!smaller!<1cm!may!develop!into!CRC!roughly!
in!10!years.!Advanced!polyps!(bigger!than!1!cm!and/or!have!dysplasia)!develop!
quicker!into!CRC.!!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
Risk:!
• Age!"!risk!increases!sharply!after!the!age!of!45!years.!90%!of!CRC!occur!after!
age!of!50.!!
• family!history!of!neoplasia!(very!important!risk!factor),!!
• inflammatory!bowel!disease!"!5Q10%!after!20!years!and!20%!after!30!years,!
treatment!with!5QASA!agents!and!folate!is!associated!with!lower!risk!of!
cancer!in!patients!with!ulcerative!colitis.!
• dietary!and!lifestyle!factors!"!diet!rich!in!fats!and!red!meat!are!associated!
with!increased!risk!of!colorectal!adenomas!and!cancer,!whereas!diet!high!in!
fruits,!vegetables!and!fiber!are!associated!with!decreased!risk!(this!diet!is!not!
associated!with!decrease!in!recurrence!of!polyps).!
• NSAIDs!and!aspirin!taken!per!day!have!been!suggested!to!reduce!risk!(80Q
325mg!Aspirin!per!day).!However!because!long!term!aspirin!therapy!is!
associated!with!GI!hemorrhagic!and!stroke!risk,!it!is!not!suggested!to!patients!

! 85!
 to!take!Aspirin!as!a!chemopreventive!agent!in!people!without!polyps!or!with!
small!adenomas!unless!there!are!other!medical!indications.!
• Physical!activity!has!been!shown!to!reduce!CRC!specific!mortality!and!allQ
cause!mortality.!
• Incidence!of!CRC!is!higher!in!blacks!than!whites,!not!known!why.!!
• Higher!risk!in!patients!with!DM,!metabolic!syndrome,!obesity!and!cigarette!
smoking.!!
• Low!(general)!risk:!!
o Age!above!50!high!!
o Intake!of!fat/low!fibers!!
o Smoking,!obesity,!alcoholQabuse!!
• Medium!risk:!!
o Colorectal!adenoma!in!the!own!history,!!
o CRC!and/or!colorectal!polyps!in!the!family!!
• High!risk:!!
o Previous!CRC!in!the!history,!!
o Hereditery!disease!forms!(HNPCC,!FAP,!Gardner!sy,!PQJ!sy,!chronic!IBD!
etc)!
!
Maintaining#a#healthy#body#weight,#a#healthy#diet#and#physically#active#life#style#
is#recommended#to#CRC#survivors.#
!
Signs!for!early!diagnosis:!!
• Bleeding:!macroscopic!or!microscopic!!
• Rapid!new!development!of!hemorrhoids!
right colon
• Iron!deficiency!of!unknown!origin!–!can!manifest!as!fatigue!and!weakness!
Left colon • Changes!in!stoolQhabits!
Lesions!of!proximal!colon:!chronic!blood!loss!can!cause!iron!deficiency!anemia,!
patient!is!then!fatigued!and!weak.!Obstruction!is!uncommon!due!to!large!diameter!
of!proximal!colon!and!liquid!consistency!of!fecal!material.!!
!
Lesions!of!left!colon:!obstruction!can!develop!because!the!left!colon!is!smaller!in!
diameter,!colicky!abdominal!pain!and!change!of!bowel!habits!are!common.!
Constipation!may!alternate!with!periods!of!increased!frequency!and!loose!stools.!
Marked!bleeding!is!unusual.!!
!
Rectal!cancer!(tumor!arising!<!12!cm!proximal!to!the!anal!verge):!tenesmus!
(continuous!or!recurrent!inclination!to!evacuate!bowel),!urgency!and!hematochezia.!
!
Late!signs:!palpable!abdominal!mass,!loss!of!bodyweight,!dull!pain,!loss!of!appetite!
!
!
!
!
!
!

! 86!
 Detection and diagnosis is based on several test:
CEA: - DRA
reduction of CEA level following operative treatment is a good
- Fecal testing for blood.
prognostic sign
- Barium enema – barium sulfate fills the colon to give an X-ray
re-elevation of CEA after operative treatment is suggestive of disease
progression - Sigmoidoscopy and colonoscopy.
- Biopsy for confirmation.
Laboratory!signs:!! - Radiographic studies (CT) to assess metastatic spread.

• Check!for!evidence!of!anemia!(also!blood!in!stool)!
• Elevated!liver!enzymes,!particularly!alkaline!phosphatase!(suspicious!for!
metastatic!cancer)!
• CEA!tumor!marker!(they!should!normalize!after!complete!surgical!resection,!
if!persistent!further!evaluation!is!needed)!
Colonoscopy!is!the!diagnostic!procedure!of!choice!and!it!also!permits!biopsy!for!
pathologic!confirmation!of!malignancy.!If!a!full!long!colonoscopy!is!not!possible!in!a!
patient!for!some!reason,!barium!enema!or!CT!colonography!examination!should!be!
performed.!Rectal!digital!examination!can!reveal!up!to!25%!of!tumors.!!
!
Imaging:!chest,!abdominal!and!pelvic!CT!scans!are!required!for!preoperative!staging.!
CT!scans!may!demonstrate!distal!metastasis!but!are!less!accurate!in!the!
determination!of!the!level!of!local!tumor!extention!(T!stage)!or!lymphatic!spread!(N!
stage).!In!rectal!cancer!pelvic!MRI!or!US!is!recommended!to!determine!the!depth!of!
penetration!of!the!cancer!through!rectal!wall!and!perirectal!lymph!nodes.!PET!scan!is!
not!routinely!used!to!stage!or!surveillance!of!CRC.!!
!
TNM!staging!is!most!commonly!used.!Staging!is!important!because!it!correlates!with!
the!patients!long!term!survival!and!tells!us!which!patients!should!receive!adjuvant!
therapy!(surgery,!chemo,!radiation?).!!
! TNM, DUKES, ASTLER-COLLER, FULL DUKES
! common staging system is the TNM system, from the American Joint Committee on Cancer (AJCC).
The most
!
"T" extent, "N" lymph node, and "M" metastasis. I, II, III, IV: a higher number indicates a more advanced cancer and worse prognosis.

AJCC! stage TNM stage

Stage !0 Tis N0 M0 Tis: Tumor confined to mucosa; cancer-in-situ
Stage I T1 N0 M0 T1: Tumor invades submucosa
!
Stage I T2 N0 M0 T2: Tumor invades muscularis propria
Stage !II-A T3 N0 M0 T3: Tumor invades subserosa or beyond (without other organs involved)
!
Stage II-B
Stage III-A
T4 N0 M0
T1-2 N1 M0
T4: Tumor invades adjacent organs or perforates the visceral peritoneum
N1: Metastasis to 1 to 3 regional lymph nodes. T1 or T2.
Stage !III-B T3-4 N1 M0 N1: Metastasis to 1 to 3 regional lymph nodes. T3 or T4.
!
Stage III-C
Stage IV
any T, N2 M0
any T, any N, M1
N2: Metastasis to 4 or more regional lymph nodes. Any T.
M1: Distant metastases present. Any T, any N.
!
Dukes! classification
In 1932 the British pathologist Cuthbert Dukes devised a famous classification system for colorectal cancer. This system has largely been
! by the more detailed TNM staging system and is no longer recommended for use in clinical practice.
replaced
Dukes'! A: Invasion into but not through the bowel wall
Dukes' B: Invasion through the bowel wall penetrating the muscle layer but not involving lymph nodes
Dukes'! C: Involvement of lymph nodes
Dukes'! D: Widespread metastases

!
Astler-Coller classification
Stage !A: Limited to mucosa
Stage B1: Extending into muscularis propria but not penetrating through it; nodes not involved
Stage !B2: Penetrating through muscularis propria; nodes not involved
Stage !C1: Extending into muscularis propria but not penetrating through it. Nodes involved
Stage C2: Penetrating through muscularis propria. Nodes involved
!
Stage D: Distant metastatic spread
! gives valuable information for the prognosis and management of the particular cancer.
The stage
!
Full Dukes' classification
! modification of the original Dukes classification was made in 1935. This subdivided stage C. This staging system was noted to be
Another
!
prognostically relevant to rectal and colonic adenocarcinoma. Stage D was added by Turnbull to denote the presence of liver.
Stage A: Limited to muscularis propria; nodes not involved
Stage B: Extending beyond muscularis propria; nodes not involved
Stage C: Nodes involved but highest (apical) node spared
Stage D: Distant metastatic spread
! 87!
 Familial!Adenomatous!Polyposis!(FAP):!
This!Autosomal!dominant!disorder!is!caused!by!the!inherited!mutation!and!
inactivation!of!APC!(adenomatosus!polyposis!coli)!gen!(5q21),!which!is!responsible!
for!the!degradation!of!βQcatenin.!This!plays!a!role!Q!together!with!EQcadherin!Q!in!the!
cellular!adhesion,!and!connected!to!TCFQ4!(T!cell!factor)!also!activates!different!
proliferating!gens!(cQMyc,!cyclin!D1,!PPARδ).!
The!mutation!of!the!oncoprotein!KQRAS!(12p)!that!plays!a!role!in!the!intracellular!
signalQtransduction!can!be!shown!in!half!of!the!tumours.!Following!its!binding!to!the!
membraneQreceptor!of!the!epithelial!growth!factor!(EGF)!the!RASQGDP!turns!into!
RASQGTP,!that!will!induce!proliferating!gens.!The!mutant!form!of!RAS!is!unable!to!
detach!from!the!GTP,!thus!the!induction!goes!on.!These!events!are!accompanied!by!
the!activation!of!COXQ2,!then!gastrin,!DNAQmethyltransferase!upregulation,!and!
finally!the!mutation!of!p53!(17p)!and!DCC!supressor!gens!occur.!The!mutation!of!p53!
is!characteristic!for!the!later!phase!of!the!adenomacarcinoma!progression!and!can!
be!detected!in!about!half!of!the!cases!of!CRC.!
!
!
FAMILIAL POLYPOSIS !
SYNDROMES !
Uncommon, autosomal dominant
!
disorders with malignant potential.
! polyposis
Familial adenomatous
develops 500-2500 !adenomas that
carpet the mucosal surface, most of
!
which are tubular adenomas.
The risk of colonic!cancer is nearly
! prophylactic
100% by midlife unless
colectomy is done.
!
The genetic defect in FAP is mutation
in APC gene located! on chromosome 5.
!
!
!
HNPCC:!
The!HNPCC!is!caused!by!the!inactivation!of!the!DNA!mismatch!repair!system!(MMR).!
In!the!process!the!mutation!of!about!6!gens!(hMSH2,!hMSH3,!hMSH6!Q!2p21;!hMLH1!
Q!3p21;!hPMS1!Q!2q31Q33,!hPMS2!Q!7p22)!plays!a!role.!Therefore!the!soQcalled!
microsatellite!instability!(MSI)!can!be!detected,!in!about!15!%!of!the!tumours.!This!
process!can!involve!such!inportant!regulating!and!supressor!gens,!like!TGFQβ!II!
receptor,!InsulinQlike!GF!II!receptor,!TCFQ4,!BAX!etc.!The!accumulating!mutations!lead!
to!uncontrolled!cellQproliferation.!
!
!an AD genetic condition. The hallmark of HNPCC is defective DNA mismatch repair, which leads to
!microsatellite instability, also known as MSI-H.
!The following are the AMSTERDAM criteria in identifying high-risk candidates for molecular genetic
!testing
!LYNCH SYNDROME
!An autosomal dominant disorder, known as hereditary non-polyposis colorectal cancer syndrome
!(HNPCC).
Has a high risk of develop into colon cancer, as well as other cancers => endometrium, ovary, stomach,
!small intestine, hepatobiliary tract, upper urinary tract, brain, and skin.
Caused by mutation of DNA mismatch repair genes.

! 88!
Topic!#22.!Colorectal!cancer:!therapy,!prevention!and!screening:!
!!
Surgical!resection!of!primary!colonic!or!rectal!cancer!is!the!treatment!of!choice!for!
almost!all!patients!who!have!resectable!lesions!and!can!tolerate!general!anesthesia.!
Multiple!studies!have!revealed!that!laparoscopic!approach!demonstrates!similar!
outcomes!as!open!colectomy.!Regional!dissection!of!at!least!12!lymph!nodes!should!
be!done!to!determine!staging,!which!guides!decisions!about!adjuvant!chemotherapy.!!
!
Rectal!cancer:!!
Compared!with!colon!cancer,!rectal!cancer!has!lower!longQterm!survival!rates!and!
significantly!higher!rates!of!local!tumor!recurrence!with!surgery!alone.!
!
In!case!of!rectal!cancer!perioperative!irradiation!(5!x!4Gy!or!20!x!1,8!Gy)!and/or!
chemoradiotherapy!(5Mfluorouracil)!is!performed!before!the!surgery!in!all!node!
positive!tumors!and!in!T3!and!greater!tumors!due!to!increased!risk!of!local!
recurrence.!!
!
In!patients!with!small,!mobile!T1!or!T2!rectal!tumors,!that!are!<8cm!from!anal!verge,!
transanal!excision!may!be!considered,!which!spares!the!rectum!and!anal!sphincter.!!
!
Systemic!chemotherapy!for!colon!cancer:!!
Chemotherapy!and!radiotherapy!have!been!demonstrated!to!improve!overall!and!
tumorQfree!survival!in!selected!patients!with!CRC!depending!on!stage.!!
!
Stage!I!"!no!adjuvant!chemotherapy!is!recommended!due!to!excellent!5!year!
survival!rate!(90Q100%)!
!
Stage!II!(node!negative!disease)!"!5!year!survival!is!about!80%.!Benefit!from!
adjuvant!chemotherapy!has!not!been!demonstrated!in!most!controlled!trials.!!
!
Stage!III!(nodeMpositive!disease)!"!surgical!resection!5!year!survival!rate!is!30Q50%.!
However!postoperative!adjuvant!chemotherapy!significantly!increases!diseaseQfree!
survival!as!well!as!overall!survival!up!to!30%!and!is!recommended!for!all!fit!patients.!
FOLFOX!(combination!of!oxaliplatin,!5QFU!and!leucovorin)!is!better!than!FL!(5QFU!and!
leucovorin),!however!there!are!worse!side!effects!with!FOLFOX!(diarrhea,!
myelosuppression,!peripheral!sensory!neuropathy!(all!reversible!side!effects).!!
!
Stage!IV!(metastatic!disease)!"!in!some!cases!the!metastasis!is!resectable!(in!liver),!
if!not!radiofrequency!or!microwave!coagulation,!embolization!or!hepatic!intraQ
arterial!chemotherapy!may!be!done.!This!can!increase!survival!rate!and!provide!long!
term!tumor!control.!However!the!majority!of!patients!with!Stage!IV!CRC!do!not!have!
resectable!tumors!and!median!survival!approaches!24!months.!The!goal!of!therapy!
in!these!cases!is!to!slow!tumor!progression!while!maintaining!a!reasonable!quality!of!
life!for!as!long!as!possible.!!
!
!

! 89!
 • Currently!FOLFOX!or!FOLFIRI!(5QFU,!folinic!acid!and!irinotectan)!is!preferred!
as!a!first!line!therapy!for!stage!IV.!
• Adding!biological!agent!has!been!proven!to!improve!response!rate!and!
overall!survival!and!is!recommended!as!a!first!line!treatment!for!suitable!
patients.!One!of!these!drugs!is!called!Bevacizumab!(a!monoclonal!Ab!
targeting!VEGF)!and!combination!of!Bevacizumab!with!FOLFOX!or!FOLFIRI!
prolongs!mean!survival!2Q5!months!compared!with!either!regimen!alone.!
Bevacizumab!can!cause!serious!side!effects:!thromboembolic!events,!bowel!
perforation!or!serious!bleeding!in!up!to!5%!of!patients.!!
• Patients!with!wild!type!kQras!mutations!addition!to!first!line!therapy!"!
cetuximab!or!panitumumab!(monoclonal!Ab!targeting!EGFR)!in!combination!
with!FOLFOX!or!FOLFIRI,!prolonges!survival!of!approximately!4!months.!!Side!
effects!of!EGFR!drugs!are!acneiform!rash!in!the!majority!ofpatietns.!
Cetuximab!can!cause!serious!infusion!reaction!in!2Q5%!of!patients.!!
• Second!line!therapy:!When!patient!becomes!unresponsibe!to!FOLFOX!or!
FOLFIRI!(+Bevacizumab!or!Cetuximab!or!panitumumab),!therapy!is!switched!
to!alternate!regimen,!which!may!increase!survival!to!>!20!months.!This!is!
antiQangiogenic!agent!=!Aflibercept,!in!combination!with!FOLFIRI.!
In!case!of!liver!metastases:!!
• local!chemotherapy!or!chemoembolisation!via!arteria!hepatica,!using!
floxuridine!(FUDR)!and!adriamycin!and!mitomycin!and/or!systemic!
administration!of!5FU/leucovorin!(neoadjuvant!chemotherapy!followed!by!
resection!of!the!liver!resulted!in!prolongation!of!survival)!!
• RFA!treatment,!cryotherapy,!ethanol!infiltration!
Follow!up!after!surgery:!!
• Patients!should!be!evaluated!every!3Q6!months!for!5!years!with!history,!
physical!examination!and!laboratory!surveillance,!including!CEA!levels.!!
• It’s!also!recommended!to!take!CT!of!chest,!abdomen!and!pelvis!annually!up!
to!5!years!postQresection!in!high!risk!stage!II!and!III!patients.!!
• Colonoscopy!should!be!done!1!year!after!surgery,!and!they!should!be!
repeated!every!3Q5!years.!!
• When!patient!has!rising!CEA!levels,!but!unrevealing!CT,!PET!scan!may!be!
more!sensitive!for!the!detection!of!occult!metastatic!disease.!!
Screening!for!colorectal!neoplasms:!!
• Fecal!occult!blood!testing!"!most!CRC!and!some!large!adenomas!result!in!
increased!chronic!blood!loss.!Many!different!tests!exist!to!evaluate!fecal!
blood!with!different!sensitivity!and!specificity.!
• Multitarget!DNA!assay!"!stool!DNA!testa!measure!a!variety!of!mutated!
genes!and!methylated!gene!markers!from!exfoliated!tumor!cells.!Most!
currently!available!tests!are!not!practical!for!population!based!screening!due!
to!high!cost!and!cumbersome!requirements!for!stool!colelctions!and!mailing.!!
!

! 90!
 • Endoscopic!examination!of!the!colon:!
o Flexible!sigmoidoscopy!(rectosigmoid!and!descending!colon),!
requires!no!sedation.!Chief!disadvantage!is!that!is!does!not!evaluate!
proximal!colon.!Prevalence!of!proximal!vs!distal!neoplasia!is!higher!in!
people!over!age!of!65,!blacks!and!women.!!
o Colonoscopy!(examines!the!entire!colon)!
! Suggestion!of!ACS:!colonoscopy!once!in!10!years!enough.!
! Prolonged!history!of!IBD!(both!CU!and!MC)!(in!case!of!
pancolitis!after!8!years,!in!left!side!colitis!after!15!years)!
colonoscopy!is!indicated!in!each!1Q3!years,!together!with!
mapping!biopsies.!Real!polyps!should!be!treated!as!in!nonQIBD!
patients.!
! If!CRC!in!the!patients’!own!history,!increased!risk!for!
metachron!tumors,!therefore!total!colonoscopy!within!6!
months!following!the!operation!is!compulsory.!!!
! If!preoperative!total!colonoscopy!was!performed,!after!
curative!resection!first!control!after!1!year!and!subsequently!
every!3!years.!!!
! Following!successful!complete!polypectomy!with!stalk,!control!
colonoscopy!once!in!3!years.!!!
! Following!!removal!of!big,!sessile!polyps,!control!endoscopy!is!
indicated!after!6!and!12!months.!If!residuum!remained,!that!
cannot!be!removed!by!endoscopy,!surgery!is!needed!!
! In!familial!accumulation!of!CRC,!especially!if!there!were!
cancer!or!adenoma!cases!below!the!age!of!60,!close!relatives!
should!be!screened!once!in!5!years,!starting!at!minus!10!years!
of!the!age!of!the!earliest!detected!CRC.!
• Amsterdam!criteria:!3!relatives!have!tumors,!2!of!them!
must!be!first!grade!relatives!2!generations!have!to!be!
involved,!and!at!least!one!tumor!has!to!be!detected!
under!the!age!of!50.!
! In!HNPCC!families!from!the!age!of!25!biannual!endoscopy!
should!be!done,!or!at!least!it!should!be!started!5!years!earlier,!
than!the!onset!of!the!earliest!tumor.!From!the!age!of!40,!
annual!investigation!is!indicated.!
! In!genetically!proven!FAP!annual!endoscopy!is!indicated!from!
the!age!of!12,!when!polyps!are!detected,!total!colectomy!is!
indicated!and!if!the!rectum!was!preserved,!the!residual!rectum!
remnant!has!to!be!controlled!every!6!months!!If!no!polyps!are!
detected!at!the!age!of!40,!subsequently!endoscopy!in!every!3!
years!is!enough.!
!
!
!

! 91!
 • Radiograophic!examination!
o CT!colonography!
o Barium!enema!"!Double!contrast!enema!once!in!5!years!may!
replace!endoscopy,!as!alternative,!sensitivity!83!%!vs.!95%.!
Prevention:!Maintaining#a#healthy#body#weight,#a#healthy#diet#and#physically#
active#life#style#are#recommended#to#CRC#survivors.#
!
• Dietary!and!lifestyle!factors!"!diet!rich!in!fats!and!red!meat!are!associated!
with!increased!risk!of!colorectal!adenomas!and!cancer,!whereas!diet!high!in!
fruits,!vegetables!and!fiber!are!associated!with!decreased!risk!(this!diet!is!not!
associated!with!decrease!in!recurrence!of!polyps).!
• NSAIDs!and!aspirin!taken!per!day!have!been!suggested!to!reduce!risk!(80Q
325mg!Aspirin!per!day).!However!because!long!term!aspirin!therapy!is!
associated!with!GI!hemorrhagic!and!stroke!risk,!it!is!not!suggested!to!patients!
to!take!Aspirin!as!a!chemopreventive!agent!in!people!without!polyps!or!with!
small!adenomas!unless!there!are!other!medical!indications.!
• Physical!activity!has!been!shown!to!reduce!CRC!specific!mortality!and!allQ
cause!mortality.!
• Treatment!with!5QASA!agents!and!folate!is!associated!with!lower!risk!of!
cancer!in!patients!with!ulcerative!colitis.!
Diet!instructions:!!
• More!fibers!(min!30g/day)!
• More!calcium!intake!
• More!vegetables!
• More!vitamin!C!and!E!
• More!physical!activity!
• Less!animal!fat!and!less!alcohol!!

!
!
!

! 92!
 Acute pancreatitis is the sudden inflammation of the pancreas. It has severe complications and high mortality despite treatment.
Mild cases are often treated with conservative measures, such as Null diet and aggressive IV fluid rehydration.
Severe cases require admission to the ICU or even surgery to deal with complications.
To predict the prognosis, there are several scoring criteria that have been used as predictors of survival.
Two such scoring systems are the Ranson criteria and APACHE II (Acute Physiology And Chronic Health Evaluation) criteria.

Topic!#23.!Diagnostics!of!acute!pancreatitis:!!
!
Regulation!of!pancreatic!secretion:!!
• Gastric!acid!(pH!<!4,5)!"!secretin!
increases!"!water!and!electrolyte!rich!
juice.!!
• Long!chain!fatty!acids,!essential!amino!
acids,!gastric!acids!"!CCK!increases!"!
enzyme!rich!secretion!!
• Parasympathetic!nervous!system!
(Vagus)!has!significant!control!
Acute!pancreatitis:!!
Acute!pancreatitis!is!an!inflammation!of!the!pancreas!with!the!damage!of!the!
surrounding!tissues!and!systemic!complications.!There!is!abrupt!onset!of!deep!
belt shaped pain, scapula
epigastric!pain,!often!with!radiation!to!the!back.!Often!there!is!history!of!previous!
episodes.!Most!cases!of!acute!pancreatitis!are!related!to!biliary!tract!disease!(a!
passed!gallstone,!usually!<5mm!in!diameter),!it’s!often!related!to!heavy!alcohol!
intake!(see!etiology).!The!exact!pathogenesis!is!not!known,!however!autodigestion,!
free!radicals,!disorders!of!microcirculation!and!bacterial!endotoxins!may!be!
connected!to!it.!
!
1. Edematous!pancreatitis!
a. Structure!of!the!organ!is!intact,!there!is!edema,!no!acinar!cell!
necrosis.!Peripancreatic!fat!necrosis!can!occur.!!
2. Necrotizing!pancreatitis!
a. Parenchymal!necrosis,!hemorrhage,!intra!and!extra!pancreatic!fat!
necrosis.!Often!infection.!!
Etiology:!!
• Biliary!tract!disease!(gallstones)!
Small gallbladder
o 20x!higher!incidence.!Usually!occurs!with!other!causes!like!alcohol,!
stones: biliary tract
pancreatitis hyperlipidemia,!fatty!foods.!!
• Disorders!of!sphincter!of!Oddi!
o Tumor,!dyskinesis,!stenosis!
• Pancreas!divisum!congenital anomaly in the ducts of the pancreas in which a single pancreatic duct is not
formed, but rather remains as two dorsal and ventral ducts.
• Alcohol!!
Alcoholic pancreatitis
o Not!too!often!in!alcholics!
o Secretin,!CCK!metabolism!decreases!which!leads!to!increase!in!
pancreatic!secretions.!Spasm!of!sphincter!of!Oddi.!Fatty!foods.!!
• Iatrogenic!causes:!
o ERCP,!sphincter!of!oddi!manometria!
o Biopsy!
o Operation!
!
CCK - synthesized and secreted by endocrine cells located in duodenum. Its secretion is strongly stimulated by the presence of partially digested proteins and fats in the SI. CCK is
released into blood and binds to receptors on pancreatic ACINAR cells > secrete large quantities of digestive enzymes.

Secretin: This hormone is also a product of endocrinocytes located in the epithelium of the DUODENUM. Secretin is secreted (!) in response to acid in the duodenum, which of course
occurs when acid-laden chyme from the stomach flows through the pylorus. The predominant effect of secretin on the pancreas is to stimulate DUCT cells to secrete water and
bicarbonate. ! 93!
Gastrin: This hormone, which is very similar to cholecystokinin, is secreted in large amounts by the stomach in response to gastric distention and irritation.
In addition to stimulating acid secretion by the parietal cell, gastrin stimulates pancreatic acinar cells to secrete digestive enzymes. (CCK and gastrin same effect)
 • Drugs:!!
o Azathioprine,!sulfonamides,!thiazide,!diuretics,!furosemide,!estrogens!
• Metabolic!causes:!!
o Hypertriaglyceridemia,!hypercalcemia,!renal!failure,!acute!fatty!liver!
of!pregnancy!
• Ischemia!
• Trauma!(seat!belt)!
• Infections:!! Infectious pancreatitis
o Virus:!mumps,!coxsackie,!echo,!CMV!
o Bacteria:!mycoplasma,!campylobacter,!mycobacterium!avium!
• Ulcus!duodeni:!penetrating!to!the!pancreas!
• Tumors!
Clinical!features:!
• Abdominal!pain!(deep!epigastric!pain)!
o Mild/severe!
o Steady!and!boring!
o Location:!epigastric,!umbilical!
o Radiation:!around!as!a!belt,!to!the!back!or!the!chest!(“beltQlike!pain”),!
it!may!radiate!to!the!right!or!left.! 34. What of the following symptoms is most
characteristic for acute pancreatitis ?
• Nausea,!vomiting,!weakness!and!sweating.!! deep pain in the umbilical region, subileus,
• Mild!jaundice!may!be!seen.! vomitus, hypocalcaemia X

• Abdominal!distension,!and!fever.!
On!physical!examination:!
• Patient!is!distressed!and!anxious!
• Low!grade!fever!
• Tachycardia,!hypotension!
o Hypovolemia!–!exudation!of!blood!an!plasma!proteins!to!the!
retroperitoneal!space!(increased!permability)!or!due!to!vomiting.!!
o Vasodilation!–!release!of!kinin!peptides!(systemic!effect!of!proteolytic!
and!lipolytic!enzymes)!
• Pulmonary!findings:!!
o Basilar!rales,!atelectasis,!pleural!effusion!(left!sided)! Dyspnea
• Abdominal!findings:!!
o Tenderness,!tenderness,!guarding,!rigidity!or!rebound,!
o Bowel!sounds!diminished!or!absent!
o Cullen!sign:!blue!discoloration!around!the!umbilicus,!indicates!
hemiperitoneum!!
o Upper!abdominal!mass!due!to!the!inflamed!pancreas!or!a!pseudocyst!
may!be!palpated.!
• Erythematous!skin!nodules!!
• Subcutaneous!fat!necrosis!
!
Grey-Turner's sign (hemorrhagic discoloration of the flanks)
Cullen's sign (hemorrhagic discoloration of the umbilicus)
Pleural effusions (fluid in the bases)
Grünwald sign (appearance of ecchymosis around the umbilicus due to local toxic lesion of the vessels)
! sign (pain or resistance in the zone where the head of pancreas is located (in epigastrium, 6–7 cm above the
Körte's 94!umbilicus))
Kamenchik's sign (pain with pressure under the xiphoid process)
 The normal level for amylase is 0-137 U/L
Laboratory!data:!Enzymes:!! The normal lipase level is 12-70 U/L
• Amylase!elevation!(3fold!above!normal)!!
o It!is!not!specific,!it!is!also!elevated!in!salivary!gland!disease,!in!gut!
perforation!or!academia!
o No!definite!correlation!between!severity!and!degree!of!serum!
amylase!
• Lipase!elevation!
o It’s!elevated!with!amylase,!elevation!up!to!7Q14!days.!It!is!slightly!
more!accurate!for!the!diagnosis!of!lipase.!
• Trypsin! The normal range is 115-350 ng/ml
o Specific!and!sensitive,!but!expensive.!!
• Phospholipase!A2! Blood urea nitrogen (BUN), creatinine, and electrolytes
• Leukocytosis!(15Q20!G/L)! lack of a gold standard diagnostic test

o Inflammation,!hemoconcentration!
• Hyperglycemia!
o Insulin!decreases,!glucagon!increases,!adrenal!glucocorticoids!and!
catecholamins!increase.!! stress
• Hypocalcemia!–!may!reflect!severity!of!the!disease.!
o Due!to!intraperitoneal!soapification!
o Levels!lower!than!7mg/dL!and!normal!albumin,!are!associated!with!
tetany!and!unfavorable!prognosis.!
• Hyperbilirubinemia!(rare)! Tetany is seen in severe hypocalcemia (ionized Ca level lower than 1.1 mmol/L).

• AP,!AST!and!LDH!elevation,!ALT!>!150!units/L!suggest!pancreatitis!
• Hypertriglyceridemia!(underlying!disease)!
• An!early!rise!in!hematocrit!value!above!44%!suggest!hemoconcentration!and!
predicts!pancreatic!necrosis! men is 40 to 54%; for women it is 36 to 48%.
• Hypoxemia!(due!to!pulmonary!effects)!
• Proteinuria,!granular!casts,!glycosuria!
Diagnosis:!!
• EKG! Nonspecific ST-T changes - we do ECG to exclude Acute coronary syndromes
o ST!segment,!T!abnormalities!–!simulating!myocardial!ischemia!
• X!ray!
o Excluding!of!other!diseases!(perforation)!
o Fleischner’s!atelectasia! thin, linear densities in the lung bases oriented parallel to the diaphragm
o Pleural!effusion!
o They!may!show!gallstones!if!calcified!
o Colon!cutoff!sign!–!gasQfilled!segment!of!transverse!colon!abruptly!
ending!at!the!area!of!pancreatic!inflammation! Colon cut-off sign describes gaseous distension seen in
proximal colon associated with narrowing of the splenic
• Ultrasonography!is!often!unnecessary! flexure in cases of acute pancreatitis.

o Meterorism:!undetectable!pancreas!
o Enlargement,!peritoneal!fluid!
• CT!(more!sensitive!if!diagnosis!of!pancreatitis!is!unsure)!
o Enlarged!pancreas!can!be!seen!

! 95!
 Indicators!of!severe!attack:!hypotension!(<90)!or!tachycardia!(>130),!hypoxia!
(<60mmHg),!oliguria!(<50ml/h)!or!BUN!increased!Creatinine.!Metabolic!indicators:!
Ca!<1,9!and!Albumin!<32g/L.!
!
Differential!diagnosis:!!
Perforations!(peptic!ulcer),!Acute!cholecystitis,!biliary!colic,!Acute!intestinal!
obstruction,!Mesenterial!vascular!occlusion,!Renal!colic,!AMI,!Dissecting!aorta!
aneurysm,!Vasculitis,!Diabetic!ketoacidosis.!
!
Complications!of!acute!pancreatitis:!
!
Local:!
• Necrosis!(sterile,!infected)!!
• Pancreatic!fluid!collections!!
• Abscess!
• Pseudocyst!(!pain,!rupture!hemorrhage,!infection!obstr.!Of!GI!tract)!!
• Pancreatic!ascites!–!Disruption!of!pancreatic!duct!Disruption!of!pancreatic!
duct!–!Leaking!pseudocyst!!
• Involvement!of!contiguous!organ!by!necrotizing!pancreatitis!–!Massive!
intraperitoneal!hemorrhage!–Thrombosis!of!vessels!(splenic,!portal!vein)!–!
Bowel!infarction!–!Obstructive!jaundice!
Systemic:!!
• Pulmonary!–!Pleural!effusion,!atelectasis,!mediastinal!abscess!Pleural!
effusion,!atelectasis,!mediastinal!abscess,!pneumonitis,!Acute!Respiratory!
Distress!Syndrome!
• Cardiovascular!–!RR↓,STQT!changes,!pericardial!effusion!T!changes,!
pericardial!effusion!!
• Hematological!–!DIC!!
• GI!hemorrhage!–!Peptic!ulcer,!erosion!into!major!blood!vessels!
• Renal!–!Oliguria!azotemia,!renal!vein!thrombosis,!Oliguria!azotemia,!renal!
vein!thrombosis,!acute!tubular!necrosis!!
• Metabolic!–!gyc↑,!Tg!↑,!Ca↓,!encephalopathy!!
• CNS!–!Psychosis,!fat!emboli,!!
• Fat!necrosis!
Prognostic criteria: 2 scoring systems are the Ranson criteria (alcohol) and APACHE II (Acute Physiology And Chronic Health Evaluation) criteria.
!
Only the APACHE-II can be fully calculated upon admission. Also Balthazar, Glasgow (gallstone and alcohol induced)

!
Ranson criteria is a clinical prediction rule for predicting the severity of acute pancreatitis.
At admission: age > 55 years, WBC count > 16000 cells/mm3, blood glucose > 10 mmol/L, serum AST (aspartate transaminase or GOT) > 250 IU/L, serum LDH > 350 IU/L
At 48 hours: Calcium < 2.0 mmol/L, Hematocrit fall >10 mmol/l, Oxygen (hypoxemia PO2 < 60 mmHg), BUN increased after IV fluid hydration, Base deficit (negative base excess) > 4 mEq/L, Sequestration of fluids
>6L
!
!
Ranson's score of ≥ 8 Organ failure Substantial pancreatic necrosis (at least 30% glandular necrosis according to contrast-enhanced CT)

Interpretation If the score ≥ 3, severe pancreatitis likely. If the score < 3, severe pancreatitis is unlikely.
!
APACHE: score > 8 points predicts 11% to 18% mortality
! (<8.0 mg/dL) or serum albumin <33 g/L (<3.2.g/dL)>
Indicators of organ failure: Hypotension (SBP <90 mmHG) or tachycardia > 130 beat/min, PO2 <60 mmHg, Oliguria (<50 mL/h) or increasing BUN and creatinine
Serum calcium < 1.90 mmol/L

! used to determine the severity of acute pancreatitis. maximum of 10 points.

Balthazar scoring: grading system

Grade A Normal CT !
Balthazar Grade: Appearance on CT
0 points
Grade B Focal or diffuse enlargement of the pancreas 1 point
Grade C Pancreatic gland!abnormalities and peripancreatic inflammation 2 points
Grade D Fluid collection in a single location 3 points
!
Grade E Two or more fluid collections and / or gas bubbles in or adjacent to pancreas 4 points

Necrosis Score
Necrosis Percentage Points
No necrosis 0 points
0 to 30% necrosis 2 points
30 to 50% necrosis 4 points
Over 50% necrosis ! 6 points 96!
Glasgow criteria: both gallstone and alcohol induced pancreatitis, whereas the Ranson score is only for alcohol induced pancreatitis.
If a patient scores 3 or more it indicates severe pancreatitis. It is scored through the mnemonic, PANCREAS:

P - PaO2 <8kPa
A - Age >55-years-old
 AGRESSIVE FLUID!!!!!!
BOWEL REST!!!
PAIN RELIEF!!!
NUTRITIONAL SUPPORT - PARENTERAL OR NASOJEJENAL

Topic!#24.!Treatment!of!acute!pancreatitis:!
!!
Mild!edematous!pancreatitis:!
!
• Rest!the!pancreas!by!no!oral!alimentation!(no!food!and!liquids!by!mouth),!
bed!rest.!!
• Decrease!gastric!fluid!with!H2!receptor!blockers.!!gastric acid reaching duodenum causes CCK and secretin to stimulate pancreas
• Give!analgesics!for!the!pain!(novamiasophen,!paracetamol,!spasmolytics,!
pethidine).!Morphine!has!been!thought!to!cause!sphincter!of!Oddi!spasm.!
• IV!fluid!(due!to!vomiting!and!intravascular!fluid!loss),!lactate!Ringer!solution!
is!preferable!to!normal!saline.!
• Patient!can!start!eating!again!after!4Q7!days!(tea!and!carbohydrates),!when!
patient!is!largely!free!of!pain!and!has!bowel!sounds.!Clear!liquids!are!given!
first,!then!start!with!low!fat!diet.!
• You!don’t!need!to!give!antibiotics!!
Volume replacement, antibiotics, nasojejunal feeding, PPI
Severe!acute!necrotizing!pancreatitis:!
!
• Artificial!nutrition!is!needed!because!the!patient!needs!to!fast!for!weeks,!thus!
the!energy!supply!will!go!down.!You!can!either!give!nutrition!by!total!
parenteral!route!or!via!enteral!route!(not!tolerated!in!patients!with!ileus).!
• You!also!need!to!give!the!patient!fluids!(6Q8!L)!due!to!fluid!loss!and!
impairment!of!microcirculation!(pancreatic!necrosis!and!multiple!organ!
failure).!!
• Treatment!of!pain!is!necessary!(NSAIDs,!local!anesthetics,!opioids).!It!limits!
the!pancreatic!stimulation!and!improves!abdominal!distension.!You!cannot!
give!analgesics!by!oral!route.!Be!careful!when!using!morphine!because!it!
might!contract!sphincter!of!Oddi.!!
• You!need!to!give!antibiotics!(broad!spectrum!which!penetrates!into!
pancreatic!tissue),!imipenem!or!meropenem,!ciprofloxacin!and!
metronidazole.!In!rare!cases!antifungal!therapy!is!needed.!
• Maintain!metabolic!balance!(hyperglycemia!and!hypocalcemia!needs!to!be!
corrected).!!
• If!needed!gallstones!have!to!be!removed.!!
• Sometimes!surgery!is!needed!to!remove!the!necrotic!tissue!and!stop!the!
progression!of!the!disease.!!
o Total!parenteral!nutrition!can!predispose!the!patient!to!catheter!
related!infections,!metabolic!disturbances,!effects!of!gut!permeability!
and!it!is!more!expensive.!!
o Enteral!nutrition!is!when!the!patient!has!a!nasojejenal!tube!w.!
continuous!infusion.!It!maintains!gut!barrier!and!maintains!better!
mesenterial!circulation.!It!has!negative!feedback!on!pancreas!and!
analgesic!effects.!Less!complications!and!it!is!cheaper.!!

! 97!
Mortality!rates!of!acute!pancreatitis!have!declined!from!at!least!10%!to!around!5%!
since!the!1980s,!but!mortality!rate!for!severe!acute!pancreatitis!remains!at!least!
20%.!Half!of!the!deaths!occur!in!the!first!2!weeks,!usually!from!multiorgan!failure.!
Multiorgan!failure!is!associated!with!mortality!rate!of!at!least!30%!and!if!it!persists!
beyond!the!first!48!hours,!the!mortality!rate!is!>50%.!Later!deaths!occur!due!to!
complications!of!infected!necrosis.!!
!
Recurrences!are!common!in!alcoholic!pancreatitis!but!can!be!reduced!by!regularly!
scheduled!interventions!to!eliminate!alcohol!consumption!after!discharge!from!the!
hospital.!!
!
The!risk!of!chronic!pancreatitis!following!an!episode!of!acute!alcoholic!pancreatitis!is!
13%!in!10!years,!and!16%!in!20!years.!!
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! 98!
Among the causes of chronic pancreatitis are the following:
long-standing inflammation of the pancreas
Alcohol Autoimmune disorders Intraductal obstruction
Idiopathic pancreatitis Tumors Ischemia chronic damage with persistent pain and
Calcific stones Cystic fibrosis malabsorption
smoking may be a high-risk factor to develop chronic pancreatitis.
persistent abdominal pain
Obstruction of the pancreatic duct because of either a benign or malignant process may result in chronic pancreatitis. steatorrhea from malabsorption of the fats
Significant weight loss
Topic!#25.!Chronic!pancreatitis:!
Chronic!pancreatitis!is!an!irreversible!destruction!of!parenchyma!of!the!pancreas!
with!decreased!exocrine!and!endocrine!functions.!It!increases!the!amount!of!
connective!tissue,!there!are!signs!of!inflammation!and!regeneration.!There!is!chronic!
or!intermittent!epigastric!pain,!steatorrhea,!weight!loss!and!abnormal!pancreatic!
imaging!can!be!seen.!It!occurs!most!frequently!in!patients!with!alcoholism!(45Q80%!
of!cases).!!
!
There!are!2!forms!of!chronic!pancreatitis:!
1. Obstructive!chronic!pancreatitis:!
In!this!type!of!chronic!pancreatitis!there!is!diffuse!atrophy!and!fibrosis.!
Removing!of!obstruction!improves!the!histological!picture!and!function.!
2. Calcifying!pancreatitis!(metabolic!disorder):!
In!this!type!there!is!focal!atrophy!and!fibrosis,!segmental!dilation!of!
pancreatic!duct,!and!protein!plugs!and!intraductal!stones.!!
!
Etiology:!!
• Alcohol!!
o Long!term!alcohol!abuse!(men!80g,!women!40Q50g/day!for!10Q15!
Problems when the immune system attacks the body.
years)!
Fatty!food,!coffee,!smoking,!concentrated!form!of!alcohol!–!provoke!
Blockage of the tubes (ducts) that drain enzymes from
the pancreas.
Cystic fibrosis.
o
High levels of a fat, called triglycerides, in the blood.
Overactive parathyroid gland. progression!
Use of certain medicines (especially sulfonamides,
thiazides, and azathioprine) o Smoking!is!also!a!risk!factor!for!idiopathic!chronic!pancreatitis!and!has!
been!reported!to!accelerate!progression!of!alcoholic!chronic!
pancreatitis.!!
o Effect!of!alcohol:!spasm!in!sphincter!of!Oddi!which!leads!to!ductal!
destruction!(decrease!in!HCO3Q!cc!and!volume!and!increased!
permeability.!Ca!gets!into!the!ducts.!Now!protein!plugs!and!stones!
can!form,!with!irregular!inflammation!and!fibrosis.!increase!of!protein!
secretion!increases!the!viscocity!of!the!fluid!in!the!ducts.!There!is!also!
defect!of!biosynthesis!of!lithostatis!(protein!matrix!of!stones)!
o Toxic!metabolic!hypothesis:!fatty!degeneration!of!acinar!cells!(defect!
of!lipid!metabolism!Q>!intracellular!deposits!of!lipid!Q>!stimulation!of!
resting!fibroblasts).!Increased!membrane!lipid!peroxidation!Q>!acinar!
cell!injury.!!
o Theory!of!necrosis!fibrosis!sequence:!interstitial!fat!necrosis!Q>!
perilobular!fibrosis!Q>!distort!of!intralobular!ducts!(stenosis!and!
dilation)!Q>!hamper!the!normal!flow!Q>!protein!plugs!Q>!acinar!cell!
necrosis!
• Hereditary!form!of!chronic!pancreatitis!(AD,!incomplete!penetration)!
o Lack!of!lithostatis,!cystic!fibrosis!(CFTR),!pancreatic!secretory!trypsin!
inhibitory!gene!(PSTI)!(serine!protease!inhibitor!(SPINK1)),!CLDN2!x!
linked!gene,!PRSS1!gene!on!chromosome!7!etc.!
!

! 99!
 • Obstructive!chronic!pancreatitis!
o Stenosis!of!papilla!of!Vater!(tu,!scars,!pancreas!divisum),!stricture,!
stone!or!tumor!which!obstructs.!!
• Autoimmune!pancreatitis!
o Antibodies,!Immunoglobulins,!Lymphocyte!infiltration,!association!
with!other!autoimmune!diseases!(Sjögren,!PBC,!IBD)!
primary biliary cholangitis
• Idiopathic!chronic!pancreatitis!
o 15Q20%!of!all!cases!
o Slow!appearance!of!exocrine!and!endocrine!dysfunction!
o Pain!is!not!common!
o Atherosclerosis?!Genetical!abnormality?!
• Tropical!–!related!to!malnutrition!(in!Africa!and!Asia)!
o Serin!protease!inhibitor!Kazal!type!1!mutation!
• Drug!induced!chronic!pancreatitis! (especially sulfonamides, thiazides, and azathioprine)
o Phenacetin,!antihypertensive!drugs,!anticonvulsant!
• Hyperparathyroidism!(2%)!

MNEMONIC!for!predisposing!factors!of!chronic!pancreatitis:!TIGARMO!!
# T:!Toxic!metabolic!
# I:!Idiopathic!
# G:!Genetic!
# A:!Autoimmune!
# R:!Recurrent!and!severe!acute!pancretitis!
# O:!Obstructive!
Clinical!manifestations:!!
• Pain!dominates!first!(dull!and!girdle!like!pain)!"!pain!results!in!part!from!
impaired!inhibitory!pain!modulation!by!the!CNS.!During!attacks!tenderness!
over!the!pancreas,!mild!muscle!guarding!and!ileus!may!be!noted.!Attacks!may!
last!a!few!hours!to!2!weeks.!!
o Recurring!pain!
! Consumption!of!alcohol!"!new!foci!of!necrosis!"!edema!"!
increased!pancreatic!pressure!
! Postprandial!stenosis!+!secretion!"!swelling!"!increased!
pancreatic!pressure!
o Permanent!pain!
! Stenosis!of!duct!(stones)!=!obstruction,!swelling,!increased!
tissue!pressure!and!decreased!microcirculation.!!
! Damage!of!neurilemmal!of!neurons!
! Fibrosis!around!neurons!
!
!
!
!

! 100!
 • Later!symptoms!of!exocrine!and!endocrine!insufficiency!will!become!
dominant!
o Exocrine!functions!decreased!"!maldigestion!and!weight!loss!
! In!alcoholics!the!lipase!activity!decreases!first!
! Steatorrhea!!
! Lack!of!fat!soluble!vitamins!
! Long!chain!triglyceride!maldigestion!
! Due!to!maldigestion!there!is!weight!loss,!postprandial!pain!and!
diabetes!mellitus!
! Over!80%!of!adults!develop!diabetes!mellitus!within!25!years!
after!the!clinical!onset!of!chronic!pancreatitis.!!
• Anorexia,!nausea,!vomiting,!constipation,!flatulence!and!weight!loss!are!
common.!!
Diagnosis:!
• Lab!tests:!!
o Serum!lipase!and!amylase!may!be!elevated!during!acute!attacks,!
however,!normal!values!do!not!exclude!the!diagnosis.!!
o Serum!AP!and!bilirubin!may!be!elevated!(compression!of!bile!duct).!!
o Glycosuria!may!be!present.!!
• Tests!of!exocrine!pancreas!function!
o Indirect!or!Direct!tests!(Secretin!stimulation!test,!Lund)!
Lundh's test is a test of function of the exocrine pancreas gland. The
• Ultrasound! exocrine involves release of various digestive enzymes, including lipase and
proteases, such as trypsin, in response to hormonal stimulation after eating.

o Less!invasive,!less!expensive! involves placing a tube with multiple channels in to the duodenum. This
tube has holes in the stomach and in the duodenum. A meal consisting of
proteins, carbohydrates and fats is injected into the stomach. A sample of the

o Irregular!echo!pattern! duodenal juice is taken at the 30 minute mark, and then every 30 minutes
until the two hour mark. The activity of trypsin is measured and averaged

o Dilated!duct,!enlargement,!pseudocysts!
among the 4 collections. A positive test is defined by low trypsin activity on
the average of the samples, and is suggestive of decreased exocrine function.

o Not!sensitive:!early!stages!of!chronic!pancreatitis!or!cancer!not!
detected!
• CT!
o Sensitivity!and!specificity!higher!
o Meteriorism!doesn’t!disturb!
o Differential!diagnosis:!is!it!chronic!pancreatitis!or!cancer!
• ERCP!
o Most!specific!and!most!sensistive!(not!in!early!stages)! Endoscopic retrograde cholangiopancreatography (ERCP) is

o Duct!changes,!stones,!calcification!protein!plugs,!pseudocysts.! a technique that combines the use of endoscopy and

fluoroscopy, can see the inside of the stomach and duodenum,
and inject a contrast medium into the ducts in the biliary
o Differential!diagnosis:!chronic!pancreatitis!or!cancer! tree and pancreas so they can be seen on radiographs.

o MRCP!"!less!invasive!alternative! magnetic resonance cholangiopancreatography

• Endoscopic!US!
o Hyperechoinc!foci!with!shadowing!indicative!of!calculi!in!the!main!
pancreatic!duct!and!lobularity!with!honeycombing!of!the!pancreatic!
parenchyma.!
o Detection!of!cancer!in!early!stages!
!
!

! 101!
 collection of fluid rich in pancreatic
enzymes, blood, and necrotic tissue, typically
Complications:! located in the lesser sac of the abdomen.

• Pseudocyst:!more!frequently!in!alcoholics.!Spontaneous!resolution!is!rare.!
The!main!sign!is!pain.!Infections!are!rare.!Complications!are!that!they!can!
rupture!and!fistula.!Therapy!is!surgical!or!endoscopic!drainage!(CystoQ
gastrotomy!or!cystoduodenostomy)!
• Ascites:!leakage!from!a!pseudocyst!or!disruption.!Diagnosis!is!made!by!
finding!amylase!or!lipase!concentration!in!the!ascites!fluid.!!
o Therapy:!feeding!by!nasoenteral!tube,!somatostatis,!pancreatic!
drainage,!resection!
• Fistula:!percutan!drainage!in!the!skin,!hyperemic!opening!with!erosion,!
colorless!fluid.!Can!also!leak!into!pleural!space!and!cause!pleural!effusion!or!
into!the!peritoneal!space!and!cause!ascites.!
• Splenic!vein!thrombosis!
• Opioid!addiction!is!common!!
• Diabetes!mellitus!
• Pancreatic!abscess!
• Steatorrhea,!malnutrition,!peptic!ulcer!
• Pancreatic!cancer!(develops!in!4%!of!patients!after!20!years,!risk!may!relate!
to!tobacco!and!alcohol!use)!
Treatment!
• Treat!the!pain!!
o Opioids!should!be!avoided!if!possible.!
o Preferred!agents!are:!acetaminophen,!NSAIDs,!tramadol!along!with!
painQmodifying!agents!such!as!TCA’s,!SSRI’s,!gabapentin!or!pregabalin.!!
• Conservative!treatments!
o Dietary!recommendations!
! Alcohol!abstinence!and!small!doses!of!food!with!restriction!of!
fat!
! Inhibition!of!pancreatic!secretion!
Pancreatin
o Steatorrhea!is!treated!with!pancreatic!supplements!(high!lipase!
activity).!Capsules!are!given!with!each!meal!(during!and!after).!!
cimetidine,
famotidine, o H2!receptor!blockers,!PPI’s!or!sodium!bicarbonate!are!given!orally!
nizatidine and
ranitidine before!and!after!meals!to!decrease!the!inactivity!of!lipase!by!acid!and!
may!thereby!further!decrease!the!steatorrhea!
o Proteolytic!inactivation:!chymotrypsin!and!trypsin!inhibitor!(?),!
protein!rich!food!and!mix!with!the!food!micropellet.!Trypsin!
inactivates!colipase!(connects!lipase!to!micellar!bile!salts).!
o Promoting!of!pancreatic!juice!excretion!
! Spasmolytics,!nitrates!
! Papillotomy,!dilation!of!pancreatic!duct!
• Medical!management!of!hyperlipidemia!
• Treatment!of!diabetes!mellitus!
• Treatment!of!pseudocyst!by!endoscopy!or!surgical!

! 102!
 • Autoimmune!pancreatitis!is!treated!with!steroids!orally!for!1Q2!months!and!
then!taper!of!5mg!every!2Q4!weeks.!Azathioprine!reduces!the!risk!of!relapse!
• Celiac!plexus!blockade!–!infiltration!with!alcohol!
• Endoscopic!and!surgical!treatment!
o Indicated!to!treat!underlying!biliary!tract!disease!
o Ensure!free!flow!of!bile!into!duodenum!
o Drain!persistent!pseudocyst!
o Treat!other!complications!
o Eliminate!obstruction!of!pancreatic!duct!
o Attempt!to!relieve!pain!
o Exclude!pancreatic!cancer.!!
Chronic!pancreatitis!often!leads!to!disability.!Prognosis!is!best!in!patients!with!
recurrent!acute!pancreatitis!caused!by!remediable!condition,!such!as!cholelithiasis,!
choleductolithiasis,!stenosis!of!sphincter!of!Oddi!or!hyperparathyroidism!(basically!
something!that!is!fixable),!and!those!with!autoimmune!pancreatitis.!!
The!quality!of!life!is!poorer!in!patients!with!constant!pain!than!with!intermittent!
pain.!
!
Surgery to treat chronic pancreatitis tends to be divided into 2 areas – resectional and
!
drainage procedures.
!
Among the reasons to opt for surgery are if there is a pseudocyst, fistula, ascites, or a fixed
!
obstruction.
The annual incidence of chronic pancreatitis is 5 to 12 per 100,000 persons, the prevalence is
! per 100,000 persons.
50
!
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! 103!
There are a number of types of pancreatic cancer. The most common, pancreatic adenocarcinoma, accounts for about 85% of cases. 1-2% of cases of pancreatic cancer are
neuroendocrine tumors, which arise from the hormone-producing cells of the pancreas. These are generally less aggressive than pancreatic adenocarcinoma.

Signs and symptoms of the most common form of pancreatic cancer may include yellow skin, abdominal or back pain, unexplained weight loss, light-colored stools, dark urine and loss
of appetite. There are usually no symptoms in early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not develop until the disease has reached an
advanced stage. RF: smoking, obesity, diabetes, and certain rare genetic conditions. 5–10% are linked to inherited genes. Pancreatic cancer is usually diagnosed by a combination of
medical imaging techniques such as US, CT, blood tests, and biopsy. The disease is divided into stages, from early (stage I) to late (stage IV). Screening is not effective.

Topic!#26.!Pancreatic!cancer:!!
Carcinoma!is!the!most!common!neoplasm!of!the!pancreas.!Pancreatic!cancer!
accounts!for!2%!of!death!of!all!cancers!and!5%!of!cancers.!Neuroendocrine!tumors!
account!for!1Q2%!of!pancreatic!cancers!and!may!be!functional!producing!gastrin,!
insulin,!glucagon,!vasoactive!intestinal!peptide,!somatostatin,!growth!hormone!
releasing!hormone,!adrenocorticotropic!hormone!and!others,!or!nonQfunctional.!
Cystic!neoplasms!account!for!only!1%!of!pancreatic!cancers,!but!they!are!important!
to!distinguish!from!pseudocyst.!!
!
• 90%!of!pancreatic!cancer!originate!from!ductal!epithelial!cells,!!
• 5%!from!acinar!cells!and!5%!from!other!sources.!!
• 2/3!of!the!cancers!originate!in!the!head!region!of!pancreas,!!
• The!other!1/3!from!the!body!and!tail.!
Risk!factors:!!
• Age! Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic adenocarcinoma occur in those over 70.
• Tobacco!use!(thought!to!cause!20Q25%!of!cases)!
• Heavy!alcohol!use!
• Obesity! diabetes
• Chronic!pancreatitis!
• Prior!abdominal!radiation!
• Family!history!
• Possibly!gastric!ulcer!and!exposure!to!arsenic!and!cadmium!
Main!symptoms:!!
• New!onset!diabetes!mellitus!after!age!of!45!years!occasionally!heralds!the!
onset!of!pancreatic!cancer.!Metformin!use!may!reduce!the!risk!of!pancreatic!
cancer!slightly,!but!insulin!use!and!glucagonQlike!peptide!1!based!therapy!can!
increase!the!risk!
• Pain!is!present!in!>70%!of!the!cases!
o Upper!abdominal!pain!often!with!radiation!to!back,!often!vague!and!
diffuse!and!located!in!the!epigastrium!or!left!upper!quadrant!when!
the!lesion!is!in!the!tail.!
o Sitting!up!and!leaning!forward!may!afford!some!relief,!and!ususally!
indicates!that!the!lesion!has!spread!beyond!the!pancreas!and!is!
inoperable!
• Diarrhea,!perhaps!due!to!maldigestion,!is!an!occasional!early!symptom!
• Weight!loss!
• Migratory!thrombophlebitis!is!a!rare!sign! Trousseau’s sign
• Obstructive!jaundice!(may!be!painless)!usually!due!to!tumor!in!pancreatic!
head!
• Enlarged!gallbladder!(may!be!painful)!and!palpable!in!some!cases,!indicative!
of!obstructive!neoplasm!=!Courvoisier!sign!
• Hard!periumbilical!nodule!may!be!palpable!=!Sister!Josephs!nodule! palpable nodule bulging into the
umbilicus as a result of
metastasis of a malignant cancer
in the pelvis or abdomen.

Jaundice accompanied by a painlessly swollen gallbladder

(known as Courvoisier's sign) may also raise suspicion, and
! can help differentiate pancreatic cancer from gallstones. 104!
 Medical imaging techniques, such as CT and endoscopic US are used both to confirm the diagnosis and to
help about the resectability. MRI and PET may also be used and magnetic resonance
cholangiopancreatography may be useful in some cases.
Abdominal US is less sensitive and will miss small tumors, but can identify cancers that have spread to
the liver and ascites. It may be used for a quick and cheap first examination before other techniques.

A biopsy by fine needle aspiration, often guided by endoscopic ultrasound, may be used where there is
uncertainty over the diagnosis.

Laboratory!differences:!! Liver function tests can show bile duct obstruction (raised conjugated bilirubin, γ-glutamyl
transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker.
• Mild!anemia! However, it lacks sensitivity and specificity. It has a sensitivity of 80% and specificity of 73% and is
Alkaline Phosphatase USED FOR FOLLOWING KNOWN CASES RATHER THAN DIAGNOSIS.
• AP,!Bilirubin,!LDH,!elevated!
• Glycosuria,!hyperglycemia!and!impaired!glucose!tolerance!due!to!DM!
• Serum!amylase!and!lipase!is!sometimes!elevated.!
Tumor!markers:!!
• Ca19Q9,!sensitivity!70%!and!specificity!87%!(not!for!early!pancreatic!cancers)!
• CEA!
• Plasma!chromogranin!A!levels!are!elevated!in!88Q100%!of!patients!with!
pancreatic!neuroendocrine!tumors.!
Diagnosis!is!made!by!endoscopic!ultrasound!(hypoechoic),!and!CT.!!
!
Doctors!need!to!be!careful!with!US!because!it!may!be!interfered!with!intestinal!gas.!
CT!also!identifies!metastasis!and!delineates!the!extent!of!the!tumor.!MRI!is!an!
alternative!to!CT.!PETQCT!can!also!be!used.!Endoscopic!US!is!more!sensitive!than!CT!
for!detecting!pancreatic!cancer!and!equivalent!to!CT!for!detecting!nodal!involvement!
and!resectability.!It!can!also!be!used!to!guide!FNA!for!tissue!diagnosis.!
!
Staging!is!done!by!TNM!classification.!!
!
Treatment:!!
• Surgical:!palliative!surgery!
o Whipple!procedure!(pancreaticoduodenal!resection)!if!the!cancer!is!
strictly!limited!to!the!head!of!pancreas,!periampullary!area!and!
duodenum!(T1,!N0!and!M0)!
• Curative!endoscopic!intervention!
o Stent!obstructive!bile!duct!to!relieve!jaundice.!A!plastic!stent!if!
patient’s!anticipated!survival!is!<!6months,!metal!stent!if!>6!months.!!
• Chemotherapy!adjuvant!or!neoadjuvant:!gemcitabine!or!5QFU!or!both.!Can!
also!be!combined!with!radiation!therapy.!Chemotherapy!has!been!
disappointing!in!metastatic!cancer!although!improved!response!have!been!
reported!using!FOLFIRINOX!(oxaliplatin,!irinotecan,!fluorouracin,!leucovorin)!
• Irradiation!(surrounding!organs!are!sensitive!to!radiation)!
• Additional!therapy:!nutrition!and!pain!relief.!!
o Celiac!plexus!nerve!block!or!thoracoscopic!splanchnicectomy!may!
improve!pain!control!
!
Carcinoma!of!pancreas,!especially!in!body!or!tail!has!poor!prognosis;!80Q85%!of!
patients!present!with!advanced!unresectable!disease,!and!reported!5!year!survival!
rates!range!from!2%!to!5%.!Tumors!of!the!ampulla!have!better!prognosis,!with!
reported!5!year!survival!rates!of!20Q40%!after!resection.!Jaundice!and!lymph!node!
involvement!are!adverse!prognostic!factors.!!
!

! 105!
Acute viral hepatitis involves 3 phases:
- prodromal phase (preceding): non-specific and flu-like symptoms common to many acute viral infections. fatigue, NV, poor appetite, joint pain, and headaches. Fever in hepatitis A and E.
Later, liver-specific symptoms, including choluria (dark urine) and clay-colored stools.

- Yellowing of the skin and sclera follow the prodrome after about 1–2 weeks and can last for up to 4 weeks, also hepatosplenomegaly, weight loss and RU abdominal pain. The non-specific
symptoms seen in the prodromal typically resolve by this time.

- The recovery phase is characterized by resolution of the clinical symptoms with persistent elevations in liver lab values and a persistently enlarged liver. All cases of hepatitis A and E are
expected to fully resolve after 1–2 months. Most hepatitis B cases are also self-limiting and become chronic and will resolve in 3–4 months. Few cases of hepatitis C will resolve completely.

Topic!#27.!Acute!viral!hepatitis:!
Hepatitis!simply!means:!inflammation!of!the!liver.!Acute!hepatitis!is!classified!as!less!
then!6!months!of!liver!inflammation.! Acute viral hepatitis is inflammation of the liver caused by infection with one of the 5 hepatitis
viruses. In most people, the inflammation begins suddenly and lasts only a few weeks.
!
There!are!many!nonQinfectious!types!of!hepatitis:!
Metabolic: Alcoholic hepatitis
• Alcoholic!hepatitis! Toxic and drug-induced hepatitis
• DrugQinduced!hepatitis! Non-alcoholic steatohepatitis NASH
• Autoimmune!hepatitis! Genetic hepatitis
Ischemic hepatitis
• Many!hereditary!diseases!that!can!cause!hepatitis!
!
Viral!hepatitis:!
There!are!5!wellQunderstood,!main!categories!of!viral!hepatitis:! five unrelated hepatotropic viruses
• Hepatitis!A:!
o Transmitted!via!the!fecalQoral!route! Faecal HAV : 2–4 weeks : Early detection
o More!prevalent!in!the!developing!countries! Ig M anti HAV : 4–12 weeks : During Acute Illness
Ig G anti HAV : 5 weeks – persistent : Old infection or Reinfectio
o Usually!causes!more!mild!form!of!hepatitis!
o Does!NOT!become!chronic!
• Hepatitis!B:! Hep B surface antigen (HBsAg) is most frequently
o Transmitted!parenterally!(IV,!IM,!SC),!sexually!or!perinatally! used to screen for the presence of this infection.
o Can!present!with!serum!sicknessQlike!illness! IgM specific to the hepatitis B core antigen (anti-
HBc IgM) may be the only serological evidence of
disease.
o Can!progress!to!chronic!disease!–!see!picture!below! Therefore, most hepatitis B diagnostic panels
contain HBsAg and total anti-HBc (both IgM and

• Hepatitis!C:! IgG).

o Its!main!route!of!transmission!is!parenterally!and!is!therefore!more! presence of antibodies to the HCV.

using an enzyme immunoassay.
prevalent!in!IV!drug!users.!Sexual!or!perinatal!transmission!is!not! confirmatory test is then performed If this test is positive, a

common.!
to verify the immunoassay and to
determine the viral load. A
recombinant immunoblot assay is
o Does!not!cause!significant!acute!illness! used to verify the immunoassay
and the viral load is determined by

o Can!progress!to!chronic!disease!–!see!pictures!below! an HCV RNA polymerase chain

reaction.

• Hepatitis!D:!
o It!requires!the!outer!envelope!of!the!HbsAg!(surface!antigen!of!
hepatitis!B!virus)!for!replication!and!therefore!can!be!transmitted!only!
as!a!coQinfection!with!HBV!or!as!a!superinfection!in!a!chronic!HBV!
carrier.!!
o Can!progress!to!chronic!disease!–!and!since!it!always!requires!HBV,!its!
progression!will!be!the!same!as!for!HBV!–!see!picture!below!
• Hepatitis!E:!
o Transmitted!via!the!fecalQoral!route!
o More!prevalent!in!the!developing!countries!–!mostly!in!India,!
Pakistan,!SEQAsia!and!parts!of!Africa!
o Usually!causes!more!mild!form!of!hepatitis!
o Does!NOT!become!chronic!
• Other!viruses!that!can!cause!one!form!or!another!of!hepatitis:!EBV,!CMV,!HSV!
!
!Hepatitis B, hepatitis C, and hepatitis D are transmitted when blood or mucous membranes are exposed
!to infected blood and body fluids, such as semen and vaginal secretions.
!Fulminant hepatitis is a rare and life-threatening complication of acute hepatitis that can occur in cases of hepatitis
!B, D, and E (pregs), in addition to drug-induced and autoimmune hepatitis.
!The complication more frequently occurs in instances of hepatitis B and D co-infection and in pregnant women with
hepatitis E. In addition to the signs of acute hepatitis, people can also demonstrate signs of coagulopathy (easy
bruising and bleeding) and encephalopathy (confusion, disorientation, and sleepiness).
!Mortality due to fulminant hepatitis is typically the result of various complications including cerebral edema,
106!
gastrointestinal bleeding, sepsis, respiratory failure, or kidney failure.
 !
Acute!hepatitis!has!a!wide!spectrum!of!clinical!presentations,!ranging!from!almost!
asymptomatic!to!fulminant!liver!failure:!
• Jaundice:!look!first!in!the!sclera!since!this!may!be!the!first!place!that!jaundice!
prodromal stage
jaundice can!be!detected.!
resolution • DarkQcolored!urine:!due!to!conjugated!hyperbilirubinemia!
• RUQ!pain!
• Nausea!and!vomiting!
• Fever!and!malaise!–!sometimes!these!are!the!only!symptoms!of!acute!
hepatitis!
• Hepatomegaly!may!also!be!present!
!
In!severe!cases,!acute!hepatitis!may!result!in!liver!failure!and!its!complications!–!this!
is!known!as!fulminant!hepatitis.!Its!uncommon!but!may!be!lifeQthreatening.!It!occurs!
more!commonly!in!hepatitis!B,!D!and!E!than!in!other!types.!The!complications!
include:!
• Hepatic!encephalopathy:!neuropsychiatric!abnormalities!in!patients!with!
liver!dysfunction,!characterized!by!personality!changes,!intellectual!
impairment!and!a!depressed!level!of!consciousness.!The!main!signs!are!
asterixis!(tremor!of!the!hand!when!the!wrist!is!extended)!and!palmar!
erythema!(reddening!of!the!skin!on!the!palmar!aspect!of!the!hands!–!mainly!
over!the!hypothenar!eminence).!!
• Hepatorenal!syndrome:!it’s!the!endQstage!of!reductions!in!renal!perfusion!
induced!by!increasingly!severe!hepatic!injury.!It’s!a!diagnosis!of!exclusion!and!
is!associated!with!a!poor!prognosis.!
• Bleeding!diathesis:!unusual!susceptibility!to!bleeding!(hemorrhage)!mostly!
due!to!a!defect!in!the!coagulation!system.!This!occurs!only!when!liver!
function!is!very!compromised.!
!

! 107!
Acute hepatitis B infections become less likely to progress to chronic forms as the patient gets older.

Most patients who get Hep D at the same time as Hep B (co-infection) recover without developing a chronic infection;
however, in people with Hep B who later acquire Hep D (superinfection), chronic infection is much more common at 80-90%, and liver disease progression is accelerated.

Chronic hepatitis C progresses towards cirrhosis, with estimates of cirrhosis prevalence of 16% at 20 years after infection.
While the MAJOR CAUSES OF MORTALITY IN HEPATITIS C IS END STAGE LIVER DISEASE, hepatocellular carcinoma is an important additional long term complication and
cause of death in chronic hepatitis.

Topic!#28.!Classification!and!diagnosis!of!chronic!viral!hepatitis:!
Chronic!viral!hepatitis!is!classified!as!longer!than!6!months!of!persistant!liver!
inflammation.!It!has!a!wide!variety!of!presentations.!
• Some!patients!are!asymptomatic!–!or!so!called!“chronic!carriers”.!These!
patients!may!only!present!with!late!complications!of!hepatitis,!such!as!
cirrhosis!(see!topic!#32)!or!hepatic!cell!carcinoma!(see!topic!#38).!
• Chronic!hepatitis!can!only!be!the!result!of!acute!hepatitis!B,!C!or!D!–!
therefore!these!patients!might!have!had!any!of!the!acute!hepatitis!symptoms!
described!in!topic!#27.!
• Its!categorized!based!on!the!grade!of!inflammation,!stage!of!fibrosis!and!the!
etiology!of!the!disease.!
• It!occurs!after!acute!HBV!in!5Q10%!of!patients!
• It!occurs!after!actue!HCV!in!over!80%!of!patients!!!
• The!risk!of!developing!cirrhosis!or!HCC!is!25Q40%!in!patients!with!chronic!HBV!
and!10Q25%!in!patients!with!chronic!HCV.!! Faecal HAV : 2–4 weeks : Early detection
Ig M anti HAV : 4–12 weeks : During Acute Illness
! Ig G anti HAV : 5 weeks – persistent : Old infection or Reinfection
Diagnosis!(of!both!acute!and!chronic!hepatitis):! Antigen, antibody and immunoglobulins IgG, IgM
1) Serum!serology:!the!presence!of!serum!antigens!and!immunoglobulins!is!the!
most!important!factor!for!diagnosing!viral!hepatitis.!These!are!helpful!to!
determine!the!acuity!or!chronicity!of!the!illness!and!also!the!adequate!
immunity.!
o Hepatitis!A:!Hep!A!antibody!(antiQHAV)!is!detectable!during!the!acute!
infection!and!persists!for!life!–!so!its!presence!does!not!distinguish!
between!active!diesase!or!immunity.!IgMQspecific!antibody!denotes!
acute!infection.!
o Hepatitis!B:!!
$ Hep!B!surface!antigen!(HbsAg):!is!present!in!both!acute!and!
chronic!infection.!Its!detectable!in!1Q2!weeks!after!the!
infection.!It!persists!in!chronic!hepatitis!even!though!there!are!
no!symptoms!present.!If!the!virus!is!cleared,!HbsAg!becomes!
undetectable.!!
$ Hep!B!e!antigen!(HbeAg):!it!reflects!active!viral!replication!and!
indicates!infectivity.!It!appears!shortly!after!HbsAg.!!
$ AntiMHbsAg!antibody!(antiMHBs):!present!after!vaccination!or!
after!the!clearance!of!HbsAg.!Detectable!1Q3!months!after!
infection!and!in!most!cases,!its!presence!indicates!immunity!to!
HBV.!This!is!what!they!look!for!each!year!we!have!a!bloodtest!
in!unideb!%!!
$ Hep!B!core!antibody!(antiMHBc):!assay!of!IgM!and!IgG!
combined.!Its!useful!because!it!may!be!the!only!serological!
marker!of!HBV!infection!during!the!“window!period”!in!which!
HbsAg!is!disappearing!but!antiQHbsAg!is!not!yet!detectable.!It!
does!not!distinguish!between!acute!or!chronic!infection!and!its!
presence!does!not!indicate!immunity.!
$ Viral!load:!HBV!DNA!measured!by!PCR!–!if!it!persists!for!more!
than!6!weeks,!patient!is!likely!to!develop!chronic!disease.!
!

! 108!
 presence of antibodies to the HCV. using an
enzyme immunoassay.
If this test is positive, a confirmatory test is
then performed to verify the immunoassay
and to determine the viral load. A
recombinant immunoblot assay is used to
verify the immunoassay and the viral load is
o Hepatitis!C:!! determined by an HCV RNA polymerase
chain reaction.
$ Hep!C!antibody:!it’s!the!key!marker!of!HCV!infection.!
Sometimes!not!detectable!until!months!after!the!infection!so!
its!absence!does!not!rule!out!infection.!
$ Viral!load:!HCV!RNA!measured!by!PCR.!Detectable!1Q2!weeks!
after!the!infection!so!its!more!sensitive!than!HCV!antibody.!!
o Hepatitis!D:!Hep!D!antibody!(antiQHDV)!presence!indicates!HDV!
superinfection.!The!antibody!may!not!be!present!in!acute!illness,!so!
repeat!testing!may!be!necessary.!
o Hepatitis!E:!Hep!E!antibody!IgM!(antiQHEV)!usually!starts!to!rise!4!
weeks!after!infection!and!remains!detectable!for!2!months!after!the!
onset!of!illness.!!
!
2) PCR:!used!to!detect!viral!RNA!to!diagnose!HCV.!!
3) Liver!function!tests:!
o ALT!is!typically!elevated!more!than!AST!for!all!forms!of!viral!hepatitis!–!
the!opposite!of!alcoholic!hepatitis!
o In!acute!hepatitis,!ALT!is!usually!>1000.!
o In!chronic!HBV,!ALT!can!also!be!>1000!
o In!chronic!HCV,!ALT!is!generally!lower!than!in!chronic!HBV.!

!
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! 109!
Topic!#29.!Treatment!of!chronic!viral!hepatitis:!
Treatment!is!important!to!reduce!the!risk!of!liver!disease!and!to!prevent!the!patient!
from!passing!the!infection!to!others.!
!
Chronic!HBV:!
• Treat!with!interferon!alpha:!!
& Antiviral!actions:!they!activate!the!host!cell!ribonuclease!that!will!
degrade!viral!mRNA.!They!also!promote!the!formation!of!natural!killer!
cells!that!destroy!infected!liver!cells.!
& Conventional!forms!are!administered!daily!or!3x!a!week!due!to!slow!
absorption!from!IM!or!SC!injections.!
& Pegylated!forms!can!be!given!only!1x!a!week.!Its!when!polyethylene!
glycol!has!been!added!to!make!the!interferon!last!longer!in!the!body.!
& Side!effects:!GI!irritation,!fluQlike!symptoms,!hair!loss,!reversible!
hearing!loss,!mental!confusion,!severe!depression!etc.!!
!
• Alternative!treatment:!lamivudine!(nucleoside!analog).!!
& It’s!a!nucleoside!reverse!transcriptase!inhibitor!(NRTIs)!
& It!prevents!the!“newly!formed!DNA”!from!integrating!into!the!host!
genome!to!cause!an!infection!
& NRTIs!are!inactive!prodrugs!that!need!the!host!kinases!to!
phosphorylate!them!–!after!that,!they!can!inhibit!the!DNA!polymerase!
enzyme,!needed!in!the!replication!and!synthesis!of!DNA.!They!will!
cause!a!DNA!chain!termination!and!therefore!the!DNA!chain!being!
formed!cannot!grow!anymore.!(Remember!the!antiviral!topics!from!
pharm!last!year?!Yes?!No?!Then!look!it!up!%)!
& Side!effects:!headache,!GI!distress!and!insomnia.!
& Lamivudine!is!the!least!toxic!of!all!of!the!NRTIs!!
!
Chronic!HCV:!
Treat!with!interferon!alpha!and!ribavirin.!If!used!earlier!in!the!diesase,!this!
combination!can!reduce!the!progression!from!acute!to!chronic!HCV.!
& Ribavirin´s!precise!antiviral!mechanism!is!not!100%!known!
& But!its!known!that!it!can!inhibit!the!replication!of!wide!ranges!of!RNA!and!
DNA!viruses!including!HCV,!influenza!A!and!B,!HIV!etc.!
& Side!effects:!bone!marrow!suppression,!upper!airway!irritation!and!
teratogenicity!
!
Extra!knowledge!of!hepatitis!treatments:!
• Active!(vaccine)!and!passive!(immunoglobulin)!immunization!are!available!for!
both!hepatitis!A!and!B.!It’s!the!standard!of!care!for!infants!and!health!care!
workers!to!be!vaccinated!for!HBV.!
• Travelers!often!receive!vaccinations!for!HAV.!Passive!immunization!can!be!
given!for!people!who!are!exposed!to!the!virus.!
• Treatment!for!hepatitis!A!and!E!is!supportive:!relieve!the!symptoms!of!
nausea,!vomiting!and!abdominal!pain!and!maintain!adequate!intake!of!fluids.!
• Consider!liver!transplant!in!advanced!disease,!although!recurrence!can!occur.!

! 110!
Overlapping presentation with primary biliary cirrhosis and primary sclerosing cholangitis has been observed.

Classification: 4 subtypes are recognised

- positive ANA and SMA, elevated IgG (classic form, responds well to low dose steroids);
- positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3;
- positive antibodies against soluble liver antigen (this group behaves like group 1) (anti-SLA, anti-LP)
- no autoantibodies detected

Topic!#30.!Characteristics!and!treatment!of!autoimmune!hepatitis!(AH):!
Autoimmune!hepatitis!is!liver!inflammation!that!occurs!when!your!body´s!immune!
system!turns!against!liver!cells!–!meaning!that!our!immune!system!mistakes!our!liver!
cells!for!foreign!pathogens!and!creates!antibodies!to!attack!them.!The!exact!cause!of!
autoimmune!hepatitis!is!unclear!but!its!thought!that!it!could!be!caused!by!the!
interaction!of!genes!controlling!immuneQsystem!function!and!exposure!to!particular!
viruses!or!drugs.!!
!
Untreated!autoimmune!hepatitis!can!lead!to!scarring!of!the!liver!(cirrhosis)!and!
eventually!to!liver!failure!since!it’s!a!chronic!condition.!When!diagnosed!and!treated!
early,!it!often!can!be!controlled!with!drugs!that!suppress!the!immune!system.!
!
There!are!two!main!forms!of!autoimmune!hepatitis:!
& Type!1:!This!is!the!most!common!type!and!it!can!occur!at!any!age.!About!half!
of!the!people!that!have!type!1!have!other!autoimmune!diseases,!like!celiac!
disease,!rheumatoid!arthritis!or!ulcerative!colitis.!
& Type!2:!This!type!is!most!common!in!children!and!young!people,!even!though!
adults!can!also!develop!type!2.!Other!autoimmune!diseases!may!also!
accompany.!
!
There!are!few!risk!factors!that!might!increase!the!risk!of!autoimmune!hepatitis:!
• Being!female:!Although!men!can!also!develop!AH,!its!more!common!in!
women.!
• History!of!certain!infections:!AH!may!develop!after!infections!with!the!
measles,!HSV!or!EBV.!AH!is!also!linked!to!hepatitis!A,!B!or!C!infection.!
• Heredity:!Your!chances!increase!if!AH!runs!in!your!family.!
• Having!an!autoimmune!disease:!Have!some!other!autoimmune!disease!will!
increase!your!chances!of!developing!AH.!Also,!other!autoimmune!diseases!
can!cause!symptoms!of!liver!disease!and!are!therefore!associated!with!the!
development!of!AH.!Example!of!these!diseases:!
o Ulcerative!colitis!
o Graves!disease!
o Rheumatoid!arthritis!
o Inflammatory!bowel!disease!
o Sjögren!syndrome!
o Etc….!
!
Signs!and!symptoms!of!AH!can!range!from!minor!to!severe!and!they!may!include:!
• Fatigue!
• Abdominal!discomfort! depends on whether it is
acute: Jaundice, fever, RUQ pain, fatigue, hepatomegaly
• Jaundice!! chronic: arthralgia, skin rash

• Enlarged!liver!
• Abnormal!blood!vessels!on!the!skin!(spider!angiomas)!
• Skin!rashes!
• Joint!pains!
• In!women:!loss!of!menstruation!!
!

! 111!
 (antinuclear antibody (ANA)
anti-smooth muscle antibody (SMA)
liver/kidney microsomal antibody (LKM-1, LKM-2, LKM-3)
anti soluble liver antigen and liver–pancreas antigen (SLA/LP)
anti-mitochondrial antibody (AMA)).
However, the diagnosis of autoimmune hepatitis always requires a liver biopsy.

Diagnosis:! exclude viral, drug induced, toxic, alcoholic

AH!can!easily!be!confused!with!other!illnesses,!for!example!viral!hepatitis.!Therefore!
its!important!to!make!a!proper!diagnosis!to!rule!out!viral!hepatitis,!determine!the!
type!of!AH!and!to!check!the!liver!function.!
1) Blood!tests!are!used!to!measure!the!antibody!levels!in!the!blood.!Those!
antibodies!that!are!associated!with!AH!are:!!
o AntiQnuclear!antibody!
o AntiQsmooth!muscle!antibody!
2) Liver!biopsy!can!confirm!the!diagnosis!and!determine!the!type!and!severity!of!
the!liver!damage!and!inflammation.!
!
Treatment:!
Whatever!the!type!is,!the!goal!of!treatment!is!to!slow!or!stop!the!immune!system!to!
attack!the!liver.!
Treatment: immunosuppressive • Prednisone!(corticosteroid):!is!generally!used!initially.!For!the!first!months!its!
glucocorticoids such as
prednisone, azathioprine, and taken!at!high!doses!and!then!to!reduce!the!risk!of!side!effects,!the!dose!is!
remission can be achieved.
Budesonide : fewer adverse
gradually!reduced!over!the!course!of!few!months!until!reaching!the!lowest!
effects. possible!dose!that!controls!the!disease.!Most!people!need!to!continue!taking!
Those with autoimmune prednisone!for!at!least!18Q24!months!and!many!remain!on!it!for!life!to!
hepatitis who do not respond to
glucocorticoids and prevent!AH!from!recurring.!Unfortunately,!prednisone,!especially!when!taken!
azathioprine may be given
other immunosuppressives like long!term,!can!cause!wide!range!of!serious!side!effects!like:!diabetes,!
mycophenolate, ciclosporin, thinning!of!bones,!high!blood!pressure,!cataracts,!glaucoma!and!weight!gain.!
tacrolimus, MTX.
• Immunosuppressant!drugs:!may!be!recommended!in!addition!to!prednisone,!
Liver transplantation may be
required if patients do not
however!taking!these!drugs!may!compromise!the!body´s!ability!to!fight!other!
respond to drug therapy or
when patients present with
infections.!
fulminant liver failure. o Azathioprine:!becomes!6QMercaptopurine!–!6MP!is!metabolized!by!
xanthine!oxidase!(XO)!but!XO!inhibitors!are!for!example!allopurinol!so!
beware!when!treating!gout!at!the!same!time.!Side!effects!of!6MP:!
bone!marrow!suppression!
• Liver!transplant:!last!chance!if!the!medications!don’t!halt!the!progress!of!the!
disease.!
!
Complications!of!AH:!
• Liver!failure!
• Scarring!of!the!liver!(cirrhosis)!
• Liver!cancer!
• Increased!blood!pressure!in!the!portal!vein,!which!supplies!blood!to!the!liver!
• Enlarged!veins!in!the!stomach!and!esophagus!(esophageal!varices)!
• Fluid!accumulation!in!the!abdomen!(ascites)!
!
70%*of*AH*patients*go*into*remission,*however*the*remission*can*take*up*to*3*years.*
*
Even*though*some*patients*have*had*a*liver*transplant,*the*disease*can*sometimes*
recur*again.!
!
!
!

! 112!
Topic!#31.!Alcoholic!liver!disease:!
Excessive!alcohol!intake!can!lead!to!fatty!liver,!hepatitis!and!cirrhosis.!Alcoholic!
hepatitis!is!often!a!reversible!disease!but!it’s!the!most!common!precursor!of!cirrhosis!
–!hepatitis!C!being!the!2nd!most!common!cause!of!cirrhosis.!The!frequency!of!
alcoholic!cirrhosis!is!estimated!to!be!10Q15%!among!persons!who!consume!over!50g!
of!alcohol!daily!for!over!10!years.!The!risk!of!cirrhosis!is!lower!(5%)!in!the!absence!of!
other!cofactors!such!as!chronic!viral!hepatitis!and!obesity.!Genetic!factors!may!also!
play!a!role!in!susceptibility!and!severity!of!liver!disease.!Women!are!for!example!
more!susceptible!than!men.! so if you are fat, have HBV or HCV and drink alcohol, you will get cirrhosis

REVERSIBLE REVERSIBLE

IRREVERSIBLE

Mallory body/Mallory's hyaline, is an

inclusion found in the cytoplasm of
liver cells. Mallory bodies are damaged
intermediate filaments within the
hepatocytes.

!
Signs!and!symptoms:!
The!clinical!picture!can!vary!from!asymptomatic!hepatomegaly!to!a!rapidly!fatal!
acute!illness!or!endQstage!cirrhosis.!The!most!common!signs!and!symptoms!are:!
• Recent!period!of!heavy!drinking!
• Anorexia!and!nausea!
• Hepatomegaly!
• Jaundice!
• Abdominal!pain!(right!upper!quadrant)!+!tenderness!
• Splenomegaly!!
• Ascites!!
• Fever!!
• Encephalopathy!!
• Infection!–!invasive!aspergillosis!is!common!in!patients!with!severe!alcholic!
hepatitis.!
!
!
!

! 113!
 MILD ABNORMAL LFT
Laboratory!findings:!
• In!patients!with!fatty!liver:!mild!liver!enzyme!elevations!may!be!the!only!
laboratory!abnormality!
• Anemia!–!usually!macrocytic!(RBCs!are!larger!than!their!normal!volume)!
• Leukocytosis!is!common!in!patients!with!severe!alcoholic!hepatitis!–!its!when!
WBCs!are!above!the!normal!range!in!blood,!indicating!an!inflammatory!
response!
• Leukopenia!(lower!than!normal!WBCs)!is!sometimes!seen!but!resolves!after!
cessation!of!drinking!
• AST!elevation!but!usually!not!above!300!units/L!(Normal!is!10Q40!units/L)!
• AST!is!greater!than!ALT!–!usually!by!a!factor!of!2!or!more!–!meaning!that!its!
usually!twoQtimes!greater!than!ALT!
• Serum!alkaline!phosphate!is!elevated!
• Serum!bilirubin!increased!by!60Q90%!in!alcoholic!hepatitis!
!
The!effect!of!alcohol!in!humans:!
• Alcohol!induced!liver!
disease!
• Upper!GI!tract!
problems:!stomatitis,!
carcinoma!of!the!oral!
cavity!and!esophagus,!
gastritis,!reflux.!
• Pancreatitis!
• Dilated!
cardiomyopathy!
• Nervous!system!
problems:!epilepsy,!
dementia,!
polyneuropathy!
• Immunodeficiencies!
• Malnutrion/undernouri
shment!
!
Differential!diagnosis:!
Alcoholic!hepatitis!can!mimic!cholecystitis,!cholelithiasis!and!drug!toxicity.!A!formula!
based!on!the!AST/ALT!ratio,!BMI!index,!MCV!value!(mean!corpuscular!volume!–!the!
size!of!the!RBCs)!and!sex!can!distinguish!alcoholic!liver!disease!from!nonalcoholic!
fatty!liver!disease.!!
!
!
!
!
!
!
!

! 114!
General!measures!of!treatment:!
Abstinence!from!alcohol!is!essential.!Fatty!liver!is!quickly!reversible!with!abstinence.!
Nutritional!support!improves!liver!disease!but!not!necessarily!survival!in!patients!
with!malnutrition.!Administration!of!micronutrients,!particularly!folic!acid,!thiamine!
and!zinc!is!indicated,!especially!when!deficiencies!are!noted.!
& Wernicke<Korsakoff*syndrome*can*result*due*thiamine*deficiency.*It’s*the*
combined*presence*of*Wernicke´s*encephalopathy*and*Korsakoff´s*psychosis*–*
but*can*also*manifest*separately.*The*syndrome*can*cause*vision*changes,*
ataxia*and*impaired*memory.*!
& Naltrexone*or*baclofen*may*be*considered*in*combination*with*counseling*to*
reduce*the*likelihood*of*starting*drinking*again.!
!
Pharmacologic!measures!of!treatment:!
• Methylprednisolone:!32!mg/day!orally!for!1!month!may!reduce!shortQterm!
mortality!in!patients!with!alcoholic!hepatitis!and!encephalopathy.!
• Pentoxifylline:!400!mg!orally!3x!daily!for!4!weeks!may!reduce!1!month!
mortality!rates!in!patients!with!severe!alcoholic!hepatitis,!mainly!by!
decreasing!the!risk!of!hepatorenal!syndrome.! Steroid: 30-40mg/day for 4-6 weeks in acute alcohol hepatitis
• Antioxidants:!vitamin!E! pentoxyphilline: 3x400mg anti TNF effect
S-adenosylmethionine: lack of glutathion, methyl group donor
• AntiMTNF!(infliximab):!in!alcoholic!hepatitis! Anti TNF: Infliximab
• Silymarin! Zinc: inhibits formation of free radicals
Silymarin
! Antioxidants vit E
Prognosis:!
• Unfavorable!prognostic!factors!are:!old!age,!a!serum!bilirubin!greater!than!10!
mg/dL,!hepatic!encephalopathy,!coagulopathy,!azotemia,!leukocytosis,!sepsis!
and!other!infections!and!lack!of!response!to!corticosteroid!therapy.!
• Complications!of!portal!hypertension!(ascities,!variceal!bleeding,!hepatorenal!
syndrome),!coagulopathy!and!severe!jaundice!suggest!a!poor!longQterm!
prognosis.!
• Alcoholic!cirrhosis!is!also!a!risk!factor!for!hepatocellular!carcinoma!–!
especially!in!carriers!of!the!C282Y!mutation!for!hemochromatosis!or!those!
with!increased!hepatic!iron.!!
• The!most!important!prognostic!factor!is!the!abstinence!of!alcohol!drinking.!
!
Extra!info!about!alcohol!consumption!from!the!lecture!slides:!
& “The!French!paradox”:!10Q20g!daily!alcohol!consumption!(mainly!red!wine)!
can!be!protectice!against!cardiovascular!effects!
& Significant!liver!damage!can!result!after!10!years!of!drinking!40Q50!g/day!for!
females!and!60Q80!g/day!for!males.!!
& Metabolism!of!alcohol!starts!in!the!stomach!but!is!mainly!metabolized!in!the!
liver!via:!
o AlcoholQdehydrogenase:!forms!acetaldehyde!which!is!very!toxic!
o AldehydeQdehydrogenase:!forms!acetic!acid!then!CO2!and!water!
o Microsomal!ethanol!oxidation!system!(MEOS)!of!the!endoplasmic!
reticulum!
o Only!7Q10!g!are!metabolized!per!one!hour!
!

! 115!
 Alcoholic!fatty!liver:!
• It’s!a!reversible!condition!upon!abstinence!from!alcohol!
• Most!patients!are!asymptomatic!but!can!feel!pressure!in!the!right!upper!
quadrant,!nausea!or!abdominal!dyscomfort.!!
• The!most!common!sign!is!hepatomegaly!with!tenderness!on!pressure.!
• Lab!findings:!!
o GGT!(gammaQglutamyl!transferase)!is!significantly!elevated!or!200Q
4000!IU/mL!
o GOT!is!higher!than!GPT!(a.k.a!AST!is!higher!than!ALT)!
o RBC!volume!(MCV)!is!larger!than!100!fl!
• On!sonography!the!liver!appears!large!and!white! HYPERECHOIC
!
Alcoholic!hepatitis:!
• Mortality!is!about!10%!
• Can!transit!to!cirrhosis!–!
sometimes!difficult!to!
distinguish!those!two!
• Lab!findings:!
o Bilirubin!elevation!
(mostly!conjugated!
direct)!
o ESR,!WBC!and!CRP!
elevated!
o GGT!é!
o AST/ALT!>!2!
o Low!albumin!
o MCV!>!100!fl!
• Histological!findings:!granulocyte!infiltration!in!the!fatty!liver!with!progressive!
fibrogenesis!that!can!lead!to!cirrhosis.!
!
Alcoholic!cirrhosis:!
• Caused!by!continued!alcohol!abuse!–!to!the!stage!of!being!IRREVERSIBLE!!
• The!clinical!findings!vary!from!asymptomatic!to!severe!states!of!portal!
hypertension,!splenomegaly,!ascites,!edema,!hepatic!encephalopathy.!
• Can!lead!to!feminization!due!to!estrogen!overload!è!palmar!erythema,!
gynecomastia,!female!type!body!hairs,!atrophy!of!testies.! DECREASED FERTILITY
!
Non-alcoholic fatty liver
Primary: type!2 DM, obesity, hyperlipidaemia
Secondary: !
- drug: glucocorts, synthethic estrogen, amiodarone, nsaids
!
- surgery: small bowel resection, biliopancreatic diversion, jejenoileal bypass
Other !
!
abeta, hypobetalipoprotenaemia, parenteral nutrition, wilson’s, toxins, IBD

!
!
!
!
!

! 116!
Metabolic syndrome.
Most people who have NASH are 40 to 50 years old

As NASH progresses and liver damage gets worse, you may start to have symptoms such as: Fatigue, Weight loss for no clear reason, General
weakness, RUQ pain. It may take many years for NASH to become severe enough to cause symptoms.

Topic!#32.!Clinics!and!diagnosis!of!liver!cirrhosis:!
Cirrhosis is a late stage of hepatic fibrosis that has
resulted in widespread distortion of normal hepatic !
architecture. Cirrhosis is characterized by regenerative
nodules surrounded by dense fibrotic tissue. ... Late !
manifestations include portal hypertension, ascites, and,
when decompensation occurs, liver failure. !
There are 2 primary ingredients: !
Hepatic fibrosis
!
Regenerating liver cells !
In response to injury and loss, growth regulators induce !
hepatocellular hyperplasia (producing regenerating
nodules) and arterial growth (angiogenesis). Among the !
!
growth regulators are cytokines and hepatic growth
factors (eg, epithelial growth factor, hepatocyte growth
factor, transforming growth factor-α, tumor necrosis
factor). !
Angiogenesis produces new vessels within the fibrous
!
sheath that surrounds nodules. These vessels connect the
hepatic artery and portal vein to hepatic venules,
!
restoring the intrahepatic circulatory system. Such !
interconnecting vessels provide low-volume, high-
pressure venous drainage that cannot accommodate as !
much blood volume as normal. As a result, portal vein
pressure increases. Such distortions in blood flow causes !
portal hypertension, which increases because the
regenerating nodules compress hepatic venules. !
!
Cirrhosis!is!a!chronic!liver!disease!characterized!by!fibrosis,!disruption!of!the!liver!
architecture!(vascular!and!parenchymal!changes)!and!widespread!nodules!in!the!
liver.!The!fibrous!tissue!replaces!damaged!or!dead!hepatocytes.!Its!generally!
irreversible!when!advanced!but!at!early!stages,!specific!treatment!of!the!cause!of!
cirrhosis!may!improve!or!reverse!the!condition.!The!point!at!which!the!disease!
becomes!irreversible!is!not!clear.!!
!
The!distortion!of!liver!anatomy!causes!two!major!events:!
1) Decreased!blood!flow!through!the!liver!è!leading!to!hypertension!in!the!
portal!circulation!=!portal!hypertension.!This!has!widespread!manifestations,!
including:!
o Ascites!
o Peripheral!edema!
o Splenomegaly!!
o Varicosity!of!veins!in!the!circulation!(gastric!varices,!esophageal!
varices,!hemorrhoids)!
2) Hepatocellular!failure!that!leads!to!impairment!of!biochemical!functions!like!
decreased!albumin!and!clotting!factor!synthesis!
!
Causes!of!cirrhosis:!
• Alcoholic!liver!disease!–!THE!MOST!COMMON!CAUSE!OF!CIRRHOSIS!
• Chronic!hepatitis!B!and!C!infections!–!2nd!MOST!COMMON!CAUSES! primary biliary cholangitis (PBC),
• Drugs:!acetaminophen!toxicity,!methotrexate!! Isoniazid is an autoimmune disease of the
liver. It is marked by slow
• Autoimmune!hepatitis! progressive destruction of the
• Primary!biliary!cirrhosis,!secondary!biliary!cirrhosis! small bile ducts of the liver, with
the intralobular ducts and the
• Inherited!metabolic!diseases:!hemochromatosis,!Wilon´s!disease! Canals of Hering (intrahepatic
• Hepatic!congestion!secondary!to!RQsided!heart!failure! ductules) affected early in the
disease.
• α1QAntitrypsin!(AAT)!deficiency!
!
Rumack-Matthew nomogram is an acetaminophen toxicity nomogram plotting serum concentration of acetaminophen against the time since
ingestion in an attempt to prognosticate possible liver toxicity as well as allowing a clinician to decide whether to proceed with N-Acetylcysteine
(NAC) treatment or not. It is a logarithmic graph starting not directly from ingestion, but from 4 hours post ingestion
! 117!
 Caput medusae, also known as palm tree sign, is
the appearance of distended and engorged
superficial epigastric veins, which are seen
radiating from the umbilicus across the abdomen.

Clinical!features:!
Some!patients!have!no!obvious!clinical!findings,!especially!early!in!the!disease.!
Patients!may!have!signs!or!symptoms!suggestive!of!one!or!more!of!the!complications!
of!cirrhosis!(see!next!section).!But!the!most!common!signs!of!chronic!liver!disease!is:!
• Ascites!
In liver disease there is an • Varices! Clinically,*cirrhosis*is*considered*to*progress*through*3*
increased production of
• Gynecomastia! stages:*compensated*(can*be*asymptomatic*or*show*signs*
androstenedione by the
adrenal glands, increased • Testicular!atrophy! of*spidernevi,*hairloss,*hepatosplenomegaly,*
aromatisation of
• Palmar!erythema! gyneacomastia,*muscle*atrophy*or*palmar*erythema),*
androstenedione to
oestrogen, loss of clearance • Spider!angiomas!on!the!skin! compensated*with*varices*and*decompensated*(ascites,*
of adrenal androgens by
• Hemorrhoids! variceal*bleeding,*encephalopathy*or*jaundice)*that*
the liver and a rise in
SHBG, resulting in • Caput!medusae! correlates*with*the*thickness*of*the*fibrous*septa.*Once*a*
gynaecomastia and test patient*develops*complications*of*cirrhosis,*they*have*
atrophy. • Weight!loss!
“decompensated”*disease.*
• Muscle!cramps!!
• Abdominal!pain:!can!be!due!to!
the!hepatic!enlargement,!stretching!of!the!Glisson!capsule!or!the!presence!of!
ascites!
!
Complications:!
1) Portal!hypertension!
o Clinical!features:!see!above!
o Bleeding!secondary!to!esophageal!varices!is!the!most!common!lifeQ
threatening!complication!of!portal!hypertension.!The!bleeding!can!be;!
hematemsis,!melena,!hematochezia.!
o Treatment:!if!no!varices!then!no!treatment.!If!varices!then!give!nonQ
selective!βQblockers!!
o To!prevent!hemorrhages,!endoscopical!treatments!are!used:!TIPS!
(transjugular!intrahepatic!portosystemic!shunt).!
!
2) Varices:!
a) Esophageal/gastric:!
o Esophageal!is!much!more!common.!It!accounts!for!90%!of!the!
varices!while!the!gastric!only!10%.!
o Clinical!features:!massive!hematemesis,!melena!and!the!
worsening!of!hepatic!encephalopathy!
o Upper!GI!endoscopy!used!for!diagnosis!and!to!treat!the!
hemorrhage!with!variceal!ligation!or!sclerotherapy!
o Other!treatments:!hemodynamic!stabilization!with!fluids!to!
maintain!BP,!antibiotics!as!prophylatics,!octreotide!and!βQ
blockers!as!a!longQterm!treatment!to!prevent!rebleeding.!
b) Rectal!hemorrhoids!
c) Caput!medusae:!distension!of!the!abdominal!wall!veins!
!
!
!
!
!

! 118!
 3) Ascites:!
o Accumulation!of!fluid!in!the!
peritoneal!cavity!due!to!portal!
hypertension!(éhydrostatic!
pressure)!and!
hypoalbuminemia!(êoncotic!
pressure).!
o It’s!the!most!common!complication!of!cirrhosis!
o Clinical!features:!abdominal!distension!and!pain,!shifting!dullness!and!
fluid!wave,!dyspnea.!
o Diagnosed!with!abdominal!ultrasound!(that!can!detect!fluid!as!little!as!
30!mL)!and!paracentesis.!Its!important!to!examine!the!cell!count,!
ascites!albumin!and!do!gram!stain!and!culture!to!rule!out!infection,!
for!example!spontaneous!bacterial!peritonitis.!
o Treatment:!bed!rest,!low!sodium!diet!and!diuretics!(furosemide!and!
spironolactone).!Perform!therapeutic!paracentesis!if!tense!ascites,!
shortness!of!breath!or!early!satiety!is!present.!Peritoneovenous!
shunts!are!also!a!possibility.!
!
4) Hepatic!encephalopathy:!
o Toxic!metabolites!that!are!normally!detoxified!or!removed!by!the!liver!
accumulate!and!reach!the!brain.!There!are!many!toxic!substances!that!
can!cause!this,!but!ammonia!is!the!most!important.!
o It!occurs!in!50%!of!all!cirrhosis!cases!–!severity!varies!
o Clinical!features:!decreased!mental!function,!confusion,!stupor,!coma,!
asterixis!(“flapping!tremor”!–!when!you!ask!the!patient!to!extend!the!
arms!and!dorsiflex!the!hands),!rigidity,!“fetor!hepaticus”!(musty!odor!
of!breath).!
o Treatment:!Lactulose!is!a!nonQabsorbable!sugar!that!when!
metabolized!by!our!colon!bacterias,!it!favours!the!formation!of!NH+,!
which!is!poorly!absorbed!from!the!GI!tract,!thereby!promoting!the!
excretion!of!ammonia.!Neomycin!is!an!antibiotic!that!kills!the!bowel!
flora,!decreasing!the!ammonia!production!by!intestinal!bacteria.!Its!
also!good!to!limit!protein!intake!to!30Q40!g/day.!
!
! !
! !
! !
! !
!

! 119!
 5) Hepatorenal!syndrome!–!indicates!endMstage!liver!disease:!
o Progressive!renal!failure!secondary!to!renal!hypoQperfusion!resulting!
from!vasoconstriction!of!renal!vessels.!It’s!a!functional!renal!failure!–!
meaning!that!the!kidneys!are!morphologically!normal,!therefore!this!
condition!does!not!respond!to!volume!expansion.!
o Clinical!features:!azotemia!(abnormally!high!levels!of!nitrogenQ
containing!compounds),!oliguria,!hyponatremia,!hypotension,!low!
urine!sodium.!
o Treatment:!liver!transplantation!is!the!only!cure!(according!to!the!
book)!but!according!to!the!lecture!slides:!fluid!+!diuretics!+!albumin!!
!
6) Spontaneous!bacterial!peritonitis:!
The diagnosis of SBP requires o Its!when!the!ascitic!fluid!gets!infected!and!is!most!common!in!patients!
paracentesis (aspiration of fluid
with a needle) from the with!ascites!caused!by!endQstage!liver!disease.!
abdominal cavity. If the fluid o Mortality!rate!is!high!or!20Q30%!
contains bacteria or large
numbers of neutrophil
o E.coli!is!the!most!common!cause,!followed!by!Klebsiella!and!
granulocytes (>250 cells/µL). S.pneumoniae!
All people with cirrhosis might
benefit from antibiotics (oral
o Clinical!features:!abdominal!pain,!fever,!vomiting,!rebound!
fluoroquinolone norfloxacin) tenderness,!êBowel!sounds.!
o Diagnosis!made!by!paracentesis!and!examination!of!the!fluid!
o Treatment:!broadQspectrum!antibiotics.!Give!specific!antibiotics!once!
organism!is!identified.!
o People*with*cirrhosis*are*also*more*susceptible*to*infections*in*general*
(not*only*peritonitis)*due*to*malnutrition*and*alteration*of*the*immune*
system*caused*by*decreased*function*of*the*liver.*These*infections*are*
usually*urinary*tract*infections,*pneumonias*and*endocarditis.!
! Decompensated*phase:*gram*neg*infections!
! Compensated*phase:*gram*pos*infections*!
!
7) Hyperestrinism!–!excess!estrins!in!the!body:!
o Spider!angiomas!–!dilated!cutaneous!arterioles!with!
central!red!spot!and!reddish!extensions!that!radiate!
outward!like!a!spider´s!web!(see!picture)!
o Palmar!erythema!
o Gynecomastia!!
o Testicular!atrophy!
!
8) Coagulopathy:!
o Occurs!secondary!to!decreased!synthesis!of!clotting!factors!
o This!leads!to!prolonged!prothrombin!time!and!vitamin!K!becomes!
ineffective!because!it!cannot!be!used!by!the!liver.!
o Treatment:!fresh!frozen!plasma!
! In addition, poor factor VII synthesis (due to liver disease) or
increased consumption (in disseminated intravascular
9) Hepatocellular!carcinoma! coagulation) may prolong the PT.
o 10Q25%!of!patients!with!cirrhosis!!
the Child-Pugh score is used to assess the prognosis of chronic
o See!more!details!in!topic!#38! liver disease, mainly cirrhosis. Although it was originally used
! to predict mortality during surgery, it is now used to
determine the prognosis, as well as the required strength of
treatment and the necessity of liver transplantation.
Total bilirubin, Serum albumin, Prothrombin time,
prolongation, Ascites, Hepatic encephalopathy.
! 5-6 A 100% 120!
7-9 B 81%
10-15 C 45%
Laboratory!findings:!
• During!the!compensated!phase,!the!lab!results!are!usually!normal!
• During!the!decompensated!phase:!!
o Low!WBC!count!due!to!hypersplenism!or!high!due!to!infection!
o Thrombocytopenia!due!to!alcoholic!bone!marrow!suppression!
o Folate!deficiency!
o Prolonged!prothrombin!time!due!to!reduced!levels!of!clotting!factors!
(except!for!factor!8)!
o éBilirubin!
o éGammaQglobulin!
o AST!and!alkaline!phosphate!modestly!elevated!
o Vitamin!D!deficiency!
!
Diagnostic!procedures:!
1) Imaging:!Ultrasound!can!assess!the!liver!size,!detect!ascites,!hepatic!nodules!
and!small!hepatocellular!carcinomas.!Hepatic!nodules!can!then!be!further!
characterized!by!contrastQenhanced!CT!or!MRI.!
2) Liver!biopsy:!Nodules!suspicious!for!malignancy!may!be!biopsied!under!
ultrasound!or!CT!guidance.!General!liver!biopsy!may!be!performed!by!
laparoscopy!or!in!patients!with!coagulopathy!and!ascites,!by!a!transjugular!
approach.!
3) FibroSure!test:!Biomarker!test!that!uses!the!results!of!six!blood!serum!tests!
to!generate!a!score!that!is!correlated!with!the!degree!of!liver!damage!in!
people!with!liver!disease.!It!has!the!same!prognostic!value!as!a!liver!biopsy.!
4) Routine!blood!test:!For!example!AST!and!platelet!count!
5) Physical!examination:!enlarged,!palpable!and!firm!liver!with!sharp!or!nodular!
edges.!
!
Assessment!of!hepatic!functional!reserve:!
Child´s!classification!estimates!hepatic!reserve!in!liver!failure.!Its!used!to!measure!
disease!severity!and!is!a!predictor!of!morbidity!and!mortality.!Class!C!indicates!the!
most!severe!disease!and!class!A!the!milder!disease.!!

!
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! 121!
!
Treatment!of!cirrhosis:!
a) Treat!the!underlying!cause:!abstinence!from!alcohol,!give!interferons!for!
hepatitis!B!and!C!
b) Avoid!all!agents!that!may!cause!liver!injury!like!acetaminophen!and!alcohol!
c) Once!cirrhosis!develops,!aim!the!treatment!at!managing!any!complications!
that!arise.!The!most!serious!complications!are!variceal!bleeding,!ascites!and!
hepatic!encephalopathy.!
d) Liver!transplant!is!the!only!hope!for!a!complete!cure.!Abstincence!from!
alcohol!for!more!than!6!months!is!required!before!a!patient!is!eligible!for!
transplantation.!
e) Histological!changes!cannot!be!turned!back!but!Colchicine!causes!slower!
fibrosis!formation.!
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! 122!
 The portal venous system refers to the vessels involved in the drainage of the capillary beds of the GI tract and
spleen into the capillary bed of the liver. Blood flow to the liver is unique in that it receives both oxygenated and
deoxygenated blood. Inferior mesenteric joins splenic vein and they both join superior mesenteric forming the
portal vein. Gastric vein joins.

Topic!#33.!Portal!hypertension,!causes,!treatment,!complications:!
Portal!hypertension!is!an!increase!in!the!blood!pressure!within!a!system!of!veins!
called!the!portal!venous!system.!Veins!coming!from!the!stomach,!intestine,!spleen!
and!pancreas!merge!into!the!portal!vein,!which!then!branches!into!smaller!vessels!
and!travels!through!the!liver.!!
!
The!causes!of!portal!hypertension!can!be!multiple!–!divided!into!cirrhotic!and!
noncirrhotic!portal!hypertension.!
!
fibrous septa and regenerative nodules
Cirrhosis!leads!to!distortion!of!liver!anatomy,!resulting!in!decreased!blood!flow!
through!the!liver!Q!leading!to!hypertension!in!the!portal!circulation!=!portal!
hypertension.!!
!
The!rest!of!this!topic!is!only!about!noncirrhotic!portal!hypertension!since!all!the!info!
about!symptoms,!complications!and!treatment!are!to!be!found!in!topic!#32!about!
cirrhosis!in!general.!
!

!
!
Budd–Chiari syndrome is caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites,
!
and liver enlargement. The formation of a blood clot within the hepatic veins can lead to Budd–Chiari syndrome.
The acute syndrome presents with rapidly progressive severe upper abdominal pain, yellow discoloration of the skin and whites of the eyes, liver
enlargement, enlargement of the spleen, fluid accumulation within the peritoneal cavity, elevated liver enzymes, and eventually encephalopathy.

! syndrome (75%): thrombosis of the hepatic vein

Primary Budd–Chiari 123!
Hepatic vein thrombosis is associated with the following in decreasing order of frequency:
Polycythemia vera, Pregnancy, Postpartum state, Use of oral contraceptives, Hepatocellular carcinoma, Lupus anticoagulants
Secondary Budd–Chiari syndrome (25%): compression of the hepatic vein by an outside structure (e.g. a tumor)
 Possible!causes!of!noncirrhotic!portal!hypertension:!
1) Extrahepatic!portal!vein!obstruction:!
o Portal!vein!thrombosis!–!often!with!cavernous!transformation!(portal!
cavernoma).!Its!when!the!normal!single!channel!portal!vein!is!
replaced!with!numerous!tortuous!venous!channels.!An!underlying!
Eggs can also become lodged
in the liver, leading to high hypercoagulable!state!is!found!in!many!patients!with!portal!vein!
blood pressure through the thrombosis!–!for!example!factor!V!Leiden!mutation,!Protein!C!and!S!
liver, enlarged spleen, the
buildup of fluid in the deficiency,!antiphospholipid!syndrome!etc.!
abdomen - abdominal fluid o Splenic!vein!obstruction!–!presents!as!gatric!varices!without!
and portal hypertension due
to schistosomiasis esophageal!varices!
2) Schistosomiasis!
3) Nodular!regenerative!hyperplasia:!usually!presents!with!unexpected!onset!of!
signs!or!symptoms!of!portal!hypertension!in!a!patient!with!little!evidence!of!
chronic!liver!disease.!The!diagnosis!is!made!by!liver!biopsy,!showing!absence!
of!significant!fibrosis!and!presence!of!nodularity.!NRH!is!associated!with!
collagen!vascular!disease,!myeloproliferative!disorders!and!drugs!–!mainly!
immunosuppressants!like!azathioprine!and!HIV!drugs.!
4) ArterialQportal!vein!fistula:!represents!the!abnormal!flow!between!the!portal!
venous!system!and!the!hepatic!arterial!system!within!the!liver.!
5) It!can!also!be!idiopathic! idiopathic portal hypertension
!
Risk!factors!for!noncirrhotic!portal!hypertension:!
• Oral!contraceptives!
• Pregnancy!
• Chronic!inflammatory!disease!
• Injury!to!the!portal!venous!system:!accidents,!surgery!etc!
• Malignancies!!
! diseases of hypercoagulation
Clinical!findings!of!noncirrhotic!PH:!
Its!important!to!understand!that!these!are!all!symptoms!that!are!similar!to!other!
liver!diseases!but!these!are!symptoms!of!patients!without!liver!disease.!
• Splenomegaly!
• Upper!GI!bleeding!from!esophageal!or!gastric!varices!
• Acute!portal!vein!thrombosis!causes!abdominal!pain!
• Ascites!in!only!25%!of!the!cases!
• Minimal!hepatic!encephalopathy!is!reported!to!be!common!in!patients!with!
noncirrhotic!portal!vein!thrombosis!
• Aside!from!these!symptoms,!the!physical!findings!are!not!remarkable!
!
Diagnosis:!
Color!Doppler!ultrasound!and!contrast!enhanced!CT!are!usually!the!initial!diagnostic!
tests!for!portal!vein!thrombosis!–!Magnetic!resonance!angiography!(MRA)!of!the!
portal!system!is!generally!confirmatory.!Needle!biopsy!of!the!liver!is!needed!to!
diagnose!schistosomiasis,!nodular!regenerative!hyperplasia!and!noncirrhotic!portal!
fibrosis.!
The diagnosis of portal hypertension can be done via HVPG (hepatic venous pressure gradient)
!
measurement has been accepted as the gold standard for assessing the severity of portal hypertension.
!
Portal hypertension is defined as HVPG greater than or equal to 5 mm Hg and is considered to be
clinically significant when HVPG exceeds 10 to 12 mm Hg.

! 124!
 Treatment:!
If!splenic!vein!thrombosis!is!the!cause!of!variceal!bleeding,!splenectomy!is!curative.!
For!other!causes!of!noncirrhotic!portal!hypertension:!
• Endoscopic!variceal!ligation!can!be!used!to!prevent!the!recurrence!of!variceal!
hemorrhage!
• Sclerotherapy!can!also!be!used!to!prevent!the!recurrence!–!it’s!the!injection!
of!solution!(usually!salt!solution)!directly!into!the!vein.!It!will!irritate!the!lining!
of!the!blood!vessel,!causing!it!to!collapse!and!stick!together!and!the!blood!to!
clot.!
• These!procedures!are!followed!by!betaQblockers!to!reduce!portal!pressure.!
Most!commonly!propranolol!and!nadolol!are!used.!
• Portosystemic!shunting!(TIPS)!is!reserved!for!failures!of!the!endoscopic!
therapy!
!
Its!rare!that!noncirrhotic!causes!of!PH!lead!to!liver!dysfunction!and!therefore!is!liver!
transplantation!as!a!treatment!option!rare.!!
!
Anticoagulation,!mainly!with!LMWH!or!thrombolytic!therapy!may!be!indicated!for!
isolated!acute!portal!vein!thrombosis!and!possibly!for!acute!splenic!vein!thrombosis.!
The!use!of!enoxaparin!to!prevent!portal!vein!thrombosis!and!hepatic!
decompensation!in!patients!with!cirrhosis!has!shown!promise.!!
!
! treatment of portal hypertension is divided into:
The
!
1. Portosystemic shunts
!
Selective shunts allow non-intestinal flow to be shunted to the systemic venous drainage while leaving the
!
intestinal venous drainage to continue to pass through the liver. For example: splenorenal shunt. This connects
! splenic vein to the left renal vein thus reducing portal system pressure. In an H-shunt, which could be
the
mesocaval (from the superior mesenteric vein to the inferior vena cava) or could be, portocaval (from the
!
portal vein to the inferior vena cava) a graft, either synthetic or the preferred vein harvested, is connected
!
between the superior mesenteric vein and the inferior vena cava. (splenic to renal, SMV to IVC or PV to IVC)
!
Now transjugular intrahepatic portosystemic shunting (TIPS) are performed.
! has the advantage of being easier to perform and doesn't disrupt the liver's vascularity.
TIPS
!
2.! Prevention of bleeding
Both pharmacological (non-specific β-blockers, nitrate isosorbide mononitrate, vasopressin such as
!
terlipressin) and endoscopic (banding ligation) are done.
! (transjugular intrahepatic portosystemic shunting) is effective at reducing the rate of rebleeding.
TIPS
!
The management of active variceal bleeding includes administering vasoactive drugs (somatostatin,
!
octreotide), endoscopic banding ligation, balloon tamponade and TIPS, sclerotherapy.
!
!
Ascites
This should be drained SLOWLY to avoid sudden changes in systemic volume status which can precipitate
!
hepatic encephalopathy, renal failure and death.
! management includes salt restriction, spironolactone, paracentesis, and TIPS.
The
!
Hepatic encephalopathy
!
Lactulose, enemas, and use of antibiotics such as neomycin, vancomycin, and the quinolones.
! maintenance of adequate nutrition is advocated.
the
!
!
!

! 125!
 Stages
Stage 1 – PORTAL STAGE: Normal sized triads; portal inflammation, small bile duct damage. Granulomas are often detected.
Stage 2 – PERIPORTAL STAGE: Enlarged triads; periportal inflammation. proliferation of small bile ducts.
Stage 3 – SEPTAL STAGE: Active and/or passive fibrous septa.
Stage 4 – BILIARY CIRRHOSIS: Nodules present; garland or jigsaw puzzle pattern.

Antimitochondri
al antibodies and
serum IgM levels
Topic!#34.!Primary!biliary!cirrhosis.!Symptoms,!signs!and!treatment:!
are elevated. The Primary!biliary!cirrhosis!is!a!chronic!disease!of!the!liver!
diagnosis is based characterized!by!autoimmune!destruction!of!small!
on these resulting in
increased
intrahepatic!bile!ducts!and!cholestasis!(reduced!or!
markers. stoppage!of!bile!flow).!Bile,!which!is!produced!in!the!
liver,!plays!a!major!role!in!digesting!food!and!helps!to!
ursodeoxycolic
acid
get!rid!of!the!body´s!worn!out!RBCs,!cholesterol!and!
toxins.!When!bile!ducts!are!damaged!as!in!PBC,!
harmful!substances!can!build!up!in!the!liver!and!
sometimes!lead!to!irreversible!scarring!of!the!liver!
(cirrhosis).!! Elevated alkaline phosphatase and elevated gamma
! glutamin transpeptidase levels are characteristic

The!disease!develops!slowly,!occurs!usually!in!women!
aged!40Q60!years!and!is!often!detected!by!accidental!
findings!of!elevated!alkaline!phosphatase!levels.!
!
The!frequency!of!the!disease!among!firstQdegree!
relatives!of!affected!person!is!1Q6%!and!the!
concordance!rate!in!identical!twins!is!high!–!suggesting!
genetical!along!with!environmental!triggers.!The!
disease!may!also!be!associated!with!other!
autoimmune!diseases!like!Sjögren,!Raynaud,!
Scleroderma!etc.!!
!
Other!possible!risk!factors:!
• History!of!UTI!caused!by!E.coli!or!Lactobacilli!
• Smoking!
• Hormone!replacement!therapy!
• Usage!of!hair!dye!
!
Clinical!findings:!
Many!patients!are!asymptomatic!for!years!after!the!diagnosis.!The!onset!of!clinical!
illness!is!gradual,!with!the!first!symptoms!as:!
• Fatigue!–!excessive!daytime!somnolence!
• Pruritus!–!itchy!skin!
• Dry!eyes!and!mouth! xerosconjunctiva, xerostomia
!
With!progression!of!the!disease,!later!symptoms!are:!
• Hepatosplenomegaly!–!due!to!the!portal!hypertension! due to cirrhosis
• Xanthomatous!lesions!on!the!skin,!tendons!and!around!the!eyelids!–!
yellowish!deposits!of!fat!underneath!the!skin.!
• Jaundice!
• Steatorrhea!
• Vitamin!deficiencies!–!because!with!a!lack!of!bile,!the!digestive!system!cannot!
absorb!fats!and!fatQsoluble!vitamins;!A,!D,!E,!K.!
• Signs!of!portal!hypertension!
• Orthostatic!hypotension!

! 126!
 • Cognitive!dysfunction!
• Gallstones!and!bile!duct!stones:!because!bile!cannot!flow!through!the!bile!
ducts,!it!may!harden!into!stones!–!causing!pain!and!infection!
• Increased!risk!of!low!bone!density,!osteoporosis!and!fractures!!
• Increased!risk!of!hepatocellular!carcinoma!
!
Diagnosis:!
Elevated alkaline & Blood!tests:!shows!normal!results!early!in!the!disease.!Liver!tests!show! PBC is characterized by
interlobular bile duct
phosphatase and
elevated gamma elevated!alkaline!phosphatase,!cholesterol!and!in!later!stages,!bilirubin.! destruction. Histopathologic
glutamin Antimitochondrial!antibodies!and!serum!IgM!levels!are!elevated.!The! findings of PBC include the
following:
transpeptidase levels
are characteristic
diagnosis!is!based!on!these!increased!markers.! Inflammation of the bile
& Liver!biopsy:!not!essential!for!diagnosis!but!allows!for!histological!staging.! ducts
intraepithelial lymphocytes,
! and
Treatment:! Periductal epithelioid
granuloma.
Since!there!is!no!cure!for!PBC,!treatment!focuses!on!slowing!the!progress!of!the!
disease,!relieving!symptoms!and!preventing!complications.!
!
Treatment!of!the!disease!itself:!
& Ursodeoxycholic!acid!(Ursodiol):!is!the!only!FDA!approved!medical!treatment!
for!PBC.!It’s!a!bile!acid!that!helps!move!bile!through!the!liver.!It!slows!the!
progression!of!the!disease!Q!especially!in!the!earlyQstage,!it!stabilizes!
histology,!improves!longQterm!survival,!reduces!the!risk!of!developing!
esophageal!varices!and!delays!(and!possibly!prevents)!the!need!for!liver!
transplantation.!Side!effects:!weight!gain!and!rarely!loose!stools.!
Ursodeoxycholic!acid!has!improved!the!survival!rate!of!the!disease.!
& Liver!transplant:!When!treatments!no!longer!control!PBC!and!the!liver!begins!
to!fail,!a!liver!transplant!may!help!prolong!life.!The!downside!is!that!PBC!
often!recurs!in!transplanted!liver!–!but!it!may!take!several!years!to!develop.!
& New!medications:!Immunosuppressants!like!methotrexate!and!colchicine!
have!been!reported!to!benefit!in!improving!symptoms!and!serum!levels!of!
alkaline!phosphatase!and!bilirubin.!
! (a bile acid sequestrant) may be
prescribed to absorb bile acids in
Treatment!of!symptoms:! the gut and be eliminated, rather
than re-enter the blood stream.
& To!treat!the!pruritus,!give!4g!of!Cholestyramine!in!water!or!juice!3x!daily.!
Rifampin!(antibacterial)!and!opioid!antagonists!like!naloxone!also!show!
promising!results.!
& Modafinil!may!improve!daytime!somnolence!
& Pilocarpine!and!artificial!tears!and!saliva!to!treat!dry!eyes!and!mouth.!
& Calcium!and!Vitamin!D!supplements!to!prevent!osteoporosis!
& Vitamin!A,!D,!E,!K!to!improve!any!vitamin!deficiencies.!!!
!
!
Without*liver*transplant*the*survival*rate*is*7<10*years*once*symptoms*develop.*
!
!
!
!

! 127!
 Ceruloplasmin is a ferroxidase (iron II to iron III) enzyme that is encoded
by the CP gene.

Ceruloplasmin is the major copper-carrying protein in the blood, and in

addition plays a role in iron metabolism. Hephaestin, is noted for its
homology to ceruloplasmin, and also participates in iron metabolism.

The Wilson's disease gene (ATP7B) on chromosome 13 and is expressed

primarily in the liver, kidney, and placenta. The gene codes for a cation
Topic!#35.!Wilson´s!disease!and!haemochromatosis:! transport enzyme ATPase that transports copper into bile and incorporates
it into ceruloplasmin. Mutations can be detected in 90% of cases.
Wilson´s!disease:!
Its!an!autosomal!recessive!disease!of!copper!metabolism.!Normally,!excess!copper!is!
excreted!by!the!liver,!but!the!livers!of!patients!with!Wilson´s!disease!cannot!do!so!
because!there!is!usually!a!deficiency!of!ceruloplasmin!–!a!copperQbinding!protein!
that!is!necessary!for!copper!excretion.!Therefore,!copper!accumulates!in!liver!cells.!
As!hepatocytes!die,!copper!leaks!into!the!plasma!and!accumulates!in!various!organs!
–!like!the!kidney,!cornea!and!brain.!The!disease!is!most!often!apparent!during!
childhood/adolescence!(after!the!age!of!5)!and!the!majority!of!cases!present!
between!ages!5!and!35.!!

Copper is needed as a cofactor for a number of enzymes such as

cytochrome c oxidase, dopamine-hydroxylase, superoxide dismutase
and tyrosinase.

Copper enters the body through the digestive tract. A transporter

protein on the cells of the small bowel, copper membrane transporter
1 (CMT1), carries copper inside the cells. Here, in response to rising
concentrations of copper, an enzyme called ATP7A releases copper
into the portal vein to the liver.

ATP7B that links copper to ceruloplasmin and releases it into the

bloodstream, as well as removing excess copper by secreting it into
bile. Both functions of ATP7B are impaired in Wilson's disease.
Copper accumulates in the liver tissue; ceruloplasmin is still secreted,
but in a form that lacks copper (APOCERULOPLASMIN).

Copper causes oxidative damage through Fenton chemistry; this

damage eventually leads to chronic active hepatitis, fibrosis and
cirrhosis. The liver also releases copper into the blood. This free
copper precipitates throughout the body but particularly in the
kidneys, eyes and brain.
cardiomyopathy and HF

!
Clinical!features!–!due!to!copper!deposition!in!various!organs:!
• Liver!disease:!it’s!the!most!common!initial!manifestation!of!the!disease.!The!
manifestations!vary!and!may!include!acute!hepatitis,!cirrhosis!and!fulminant!
hepatic!failure.!
• Eyes:!KayserQFleischer!rings.!Yellowish!rings!in!the!cornea!that!do!NOT!
interfere!with!vision.!
• CNS:!!
o Extrapyramidal!signs:!parkinsonian!symptoms!(resting!tremor,!rigidity,!
bradykinesia),!chorea,!drooling,!incoordination!due!to!copper!
deposition!in!the!basal!ganglia.!
o Psychiatric!disturbances:!depression,!neuroses,!personality!changes,!
psychosis.!
• Kidney:!aminoaciduria,!nephrocalcinosis!

Kidneys: renal tubular acidosis (Type 2), a disorder of bicarbonate handling by the proximal tubules leads to nephrocalcinosis, a
weakening of bones (due to calcium and phosphate loss), and occasionally aminoaciduria.

! 128!
Hormones: hypoparathyroidism (failure of the parathyroid glands leading to low calcium levels), infertility, and habitual abortion.
Diagnosis:!
Its!made!by!determining!the!following!–!patients!may!have!few!or!many!of!these!
findings.!If!diagnosed,!firstQdegree!relatives!must!be!screened!as!well.!
• Hepatic!disease:!elevated!aminotransferase,!impaired!synthesis!of!
coagulation!factors!and!albumin!
• Serum!ceruloplasmin!levels:!usually!decreased!but!normal!levels!do!not!
exclude!the!diagnosis!
• Liver!biopsy:!will!show!significantly!elevated!copper!concentrations!
!
Treatment:!
1) Chelating!agents:!for!example!DQpenicillamine!–!which!removes!and!
detoxifies!the!excess!copper!deposits.!
2) Zinc:!it!prevents!uptake!of!dietary!copper.!Its!given!alone!as!presymptomatic!
drug!or!in!conjuction!with!chelating!agents!to!symptomatic!patients.!
3) Liver!transplantation:!if!unresponsive!to!therapy!or!fulminant!liver!failure!
4) Monitor!patient´s!copper!levels,!urinary!copper!excretion,!ceruloplasmin!and!
liver!function.!Physical!examination!for!signs!of!liver!or!neurological!disease.!
!
!
Haemochromatosis:!
iron is generally only lost during bleeding or slughing off of the small intestine cells.

Its!an!autosomal!recessive!disease!of!iron!absorption.!Excessive!iron!absorption!in!
the!intestine!leads!to!increased!accumulation!of!iron!(as!ferritin!and!hemosiderin)!in!
various!organs.!Over!many!years,!fibrosis!in!involved!organs!occurs!secondary!to!
hydroxyl!free!radicals!that!are!generated!by!the!exceess!iron.!The!affected!organs!
are:!
& Liver!(primary!organ)!
& Pancreas!!
& Heart!!
& Joints!!
& Skin!!
& Thyroid!glands!
& Gonadas!!
& Hypothalamus!!
!
Its!important!as!soon!as!diagnosis!is!made,!to!
screen!the!patient´s!siblings.!Early!diagnosis!and!
treatment!before!development!of!complications!
(primarily!cirrhosis,!heart!disease!and!diabetes)!
improve!survival.!!
!
Clinical!features:!
Most!patients!are!asymptomatic!initially.!Findings!may!include!signs!of!liver!disease,!
fatigue,!arthritis,!impotence/amenorrhea,!abdominal!pain!and!cardiac!arrhythmias.!
!
!
!
!

! 129!
 Complications:!
• Cirrhosis:!it!increases!the!risk!of!hepatocellular!carcinoma!200Qfold!!The!
presence!of!liver!disease!is!a!primary!factor!in!determining!the!prognosis.!
• Cardiomyopathy:!CHF,!arrhythmias!!
• Diabetes!mellitus:!due!to!iron!deposition!in!the!pancreas! bronze diabetes
• Arthritis:!most!common!sites!are!the!2nd!and!3rd!metacarpoQpharyngeal!
joints,!hips!and!knees!
• Hypogonadism:!impotence,!amenorrhea,!loss!of!libido!
• Hypothyroidism!!
• Hyperpigmentation!of!skin!
!
Diagnosis:!
• Markedly!elevated!serum!iron!and!ferritin!
• Elevated!iron!saturation!(transferrin!saturation)!
• Decreased!total!ironQbinding!capacity!
• Genetic!testing!for!chromosomal!abnormalities!
• Liver!biopsy!to!determine!hepatic!iron!concentration!is!required!for!
diagnosis!!
• Quick*hit:*early*in*the*disease*course,*mild*elevation*of*ALT*and*AST*levels*
may*be*the*only*abnormalities*that*are*noted*because*the*patient*is*usually*
asymptomatic.*Obtain*iron*studies*–*if*its*levels*are*elevated,*order*a*liver*
biopsy*to*confirm*the*diagnosis.!
!
Treatment:!
The!treatment!of!choice!is!repeated!phlebotomies!–!draw!blood!from!the!patient!
repeatedly.!It!improves!survival!dramatically!if!initiated!early!in!the!course!of!the!
disease.!Also!treat!complications!if!there!are!any.!Consider!liver!transplantation!in!
advanced!cases.!!
!
!
!
! can be distinguished between PRIMARY (HEREDITARY) and SECONDARY (ACQUIRED).
The causes
- Mutations in HFE: "classical" haemochromatosis.
!
- Mutations in Haemojuvelin, hepcidin antimicrobial peptide (HAMP), transferrin receptor-2 (TFR2), ferroportin,
!
caeruloplasmin, transferrin
! of hereditary haemochromatosis have AR inheritance.
Most types
!
Secondary haemochromatosis
! chronic haemolysis, including intravascular haemolysis and ineffective erythropoiesis (haemolysis in bone marrow)
- Severe
! frequent blood transfusions, which are usually needed either by individuals with hereditary anaemias (such as
- Multiple
beta-thalassaemia major, sickle cell anaemia) or by older patients with acquired anaemias such as in myelodysplastic
!
syndromes
! parenteral iron supplements, such as what can acutely happen in iron poisoning
- Excess
! dietary iron
- Excess
!
Diagnosis
! several methods available for diagnosing and monitoring iron loading including:
There are
Serum !ferritin: In males and postmenopausal females, a serum ferritin value of over 300 ng/mL indicates iron overload.
In premenopausal females, a serum ferritin value of over 150-200 ng/mL indicates iron overload.
!
Liver biopsy
HFE !
MRI

! 130!
 Topic!#36.!Liver!transplantation:!
!
!
The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced
! treatment
by the donor organ in the same anatomic location as the original liver. Liver transplantation is a viable
option for END-STAGE LIVER DISEASE and ACUTE LIVER FAILURE. !
The first human liver transplant was performed in 1963 by Dr. Thomas Starzl of Denver, USA. !
!
Transplantation can be done in any acute or chronic condition resulting in irreversible liver dysfunction, provided
that the recipient does not have other conditions such as: metastatic cancer outside liver, active drug! or alcohol abuse
!
and active septic infections are absolute contraindications. HIV infection was once considered an absolute
contraindication, this has been changing recently.
!
Advanced age and serious heart, lung, or other disease may also prevent transplantation (relative contraindications).
Most liver transplants are performed for chronic liver diseases that lead to irreversible cirrhosis of !the liver.
MILAN criteria to select patients with liver cancers for liver transplantation. !
Most liver transplant recipients receive corticosteroids plus a calcineurin inhibitor such as tacrolimus or ciclosporin
plus a purine antagonist such as mycophenolate mofetil for organ rejection. !
40 percent to 60 percent of a donor's liver is removed. !
Liver!transplantation!is!indicated!in!selected!cases!of!irreversible,!progressive!chronic!
liver!diseases,!acute!liver!failure!and!in!certain!metabolic!diseases!in!which!the!
metabolic!defect!is!in!the!liver.!Its!a!surgical!procedure!that!removes!a!liver!that!no!
longer!functions!properly!and!replaces!it!with!a!healthy!liver!from!a!living!or!
deceased!donor.!The!human!liver!regenerates!and!returns!to!its!normal!size!within!
couple!of!months!after!surgical!removal!of!part!of!the!organ!–!meanwhile,!the!
transplanted!portion!grows!and!restores!normal!liver!function!in!the!recipient.!This!
makes!livingQdonor!liver!transplant!an!alternative!to!waiting!for!a!deceasedQdonor!
liver!to!become!available.!
!
To!be!considered!for!a!livingQdonor!liver!transplant,!both!the!donor!and!recipient!
must!undergo!a!thorough!health!and!psychological!evaluation.!Matching!of!livingQ
donor!livers!with!recipients!is!based!on!age,!blood!type,!organ!size!and!other!factors.!!
!
!Liver!transplantation!should!be!considered!in!patients!with:!
• Worsening!functional!status!
• Rising!bilirubin!
• Decreasing!albumin!
• Worsening!coagulopathy!
• Refractory!ascites!
• Recurrent!variceal!bleeding!
• Worsening!encephalopathy!
!
Liver!transplantation!is!more!often!used!to!treat!chronic!liver!failure!–!occuring!
slowly!over!months!or!years.!The!most!common!cause!of!chronic!liver!failure!is!
scarring!of!the!liver!(cirrhosis)!Q!where!scar!tissue!replaces!normal!liver!tissue!and!
impairs!liver!function.!Major!causes!of!cirrhosis!leading!to!liver!failure!and!therefore!
liver!transplant!include:!Hepatitis!B!and!C,!alcoholic!liver!disease,!nonalcoholic!fatty!
liver!disease,!genetic!diseases!affecting!the!liver!(hemochromatosis!and!Wilson´s!
disease),!primary!biliary!cirrhosis,!biliary!atresia!etc.!(see!more!details!on!cirrhosis!in!
topic!#32).!
!

! 131!
Absolute!contraindications!include:!
Q!Malignancy! metastatic cancer outside liver
active drug or alcohol abuse
Q!Advanced!cardioQpulmonary!disease! active septic infections
Q!Sepsis! HIV infection (changing recently)

!
Relative!contraindications!include:!
Q!Age!over!70!years!
Q!Morbid!obesity!
Q!Portal!and!mesenteric!vein!thrombosis!
Q!Active!alcohol!or!drug!abuse!–!at!least!6m!of!abstinence!of!alcohol!is!required!!
Q!Severe!malnutrition! Advanced age and serious heart, lung, or other disease may also prevent
Q!Lack!of!patient!understanding! transplantation (relative contraindications)
and compliance
!
Complications!of!the!procedure:!
• Bile!duct!complications:!bile!duct!leaks!or!shrinkage!
• Bleeding/blood!clot!–!like!in!all!other!surgeries!!
• Failure!of!the!donated!liver!to!work!in!the!recipient!
• Rejection!of!donated!liver!
• Infection!!
• Neurologic!disorders:!mental!confusion,!seizures!
!
The!major!impediment!to!more!widespread!use!of!liver!transplantation!is!a!shortage!
of!donor!organs.!Hepatocellular!carcinoma,!hepatitis!B!and!C,!some!cases!of!BuddQ
Chiari!syndrome!and!autoimmune!liver!disease!may!recur!in!the!transplanted!liver.!
The!incidence!of!recurrence!of!hepatitis!B!can!be!reduced!by!preoperative!and!
postoperative!treatment!with!a!nucleoside!or!nucleotide!analog.!
!
Immunosuppression!is!important!to!prevent!rejection!of!the!donor!liver!after!the!
transplant.!This!is!achieved!with!combinations!of:!
• Cyclosporine!
Patients!taking!these!drugs!are!
• Tacrolimus!or!Sirolimus!
at!risk!for!obesity,!diabetes!
• Corticosteroids!
mellitus!and!hyperlipidemia.!
• Axathioprine!
• Mycophenolate!mofetil!
!
5<year*survival*rates*are*now*as*
high*as*80%.**
*
People*who*receive*a*living<donor*
liver*ofter*have*better*short<term*
survival*but*comparing*long<term*
results*is*difficult*because*people*
who*got*a*living<donor*liver*usually*
had*to*wait*for*a*shorter*time*for*
the*transplant.*
*
!

! 132!
 Acetaminophen (Paracetamol)
Nonsteroidal anti-inflammatory drugs
Glucocorticoids
Isoniazid, rifampin
Other hydrazine derivative drugs
Natural products: amanita mushrooms, aflatoxin, herbal
Industrial toxin: arsenic, carbon tetrachloride, and vinyl chloride

Topic!#37.!Drug!induced!and!toxic!liver!diseases,!causes!and!clinics!of!acute!liver!
failure:!
Many!therapeutic!agents!may!cause!drugQinduced!liver!injury!and!upto!10%!of!these!
patients!die!or!undergo!liver!transplantation!within!6!months!of!onset.!The!
medications!most!commonly!implicated!are!NSAIDS!and!antibiotics!because!of!their!
widespread!use.!!
!!
Clinicians!must!inquire!carefully!about!the!use!of!many!widely!used,!potentially!
hepatotoxic!drugs!or!exposure!to!hepatotoxins,!including!overQtheQcounter!“natural”!
and!herbal!products,!in!any!patient!with!liver!disease.!!
!
In!some!cases,!coadministration!of!a!second!agent!may!increase!the!toxicity!of!the!
first!–!like!using!isoniazid!and!rifampin!together!or!acetaminophen!and!alcohol.!
Except!for!drugs!used!to!treat!TB!and!HIV,!the!risk!of!hepatotoxicity!is!not!increased!
in!patients!with!preexisting!cirrhosis.!!
!
DrugQinduced!liver!disease!can!mimic!viral!hepatitis,!biliary!tract!obstruction!or!other!
types!of!liver!disease.!Drug!toxicity!may!be!categorized!on!the!basis!of!pathogenesis!
or!predominant!histologic!appearance.!
!
Categorization!by!pathogenesis:!
1) Direct!hepatotoxicity:!Liver!toxicity!caused!by!this!group!of!drugs!is!
characterized!by!doseQrelated!severity,!a!latent!period!following!exposure!
and!susceptibility!in!all!individuals.!Examples!of!drugs!that!can!lead!to!direct!
hepatotoxicity!are:!
o Acetaminophen!–!toxicity!is!enhanced!by!fasting!and!chronic!alcohol!
use!because!of!depletion!of!glutathione!and!induction!of!cytochrome!
P450!2E1!
o Alcohol!! NAPQI

o Chloroform!!
o Heavy!metals!!
o Mercaptopurine!!
o Niacin!!
o Plant!alkaloids!
o Tetracyclines!!
o Valproic!acid!
o Vitamin!A!
!
!
!
!
!
!
!
!
!

! 133!
 Patient susceptibility

2) Idiosyncratic!reactions:!Except!for!acetaminophen,!most!severe!
hepatotoxicity!is!idiosyncratic.!Reactions!of!this!type!are!spordiac,!not!related!
to!dose!above!a!general!threshold!of!100mg/day!and!occasionally!associated!
with!features!suggesting!an!allergic!reaction!–!such!as!fever!and!eosinophilia.!
In!many!cases,!the!drug!is!lipophilic!and!toxicity!results!directly!from!a!
metabolite!that!is!produced!in!these!individuals!on!a!genetic!basis.!DrugQ
induced!liver!injury!may!be!observed!only!during!postQmarketing!surveillance!
and!not!during!preclinical!trials.!Example!of!these!drugs!include:!
o Amiodarone!
o Fluoroquinolones! it can lead to jaundice, liver failure, or even death.
o Isoniazid! Antimicrobials and herbal and dietary
o Ketoconazole! supplements are among the most common
therapeutic classes to cause
o Lamotrigine!
o Methyldopa!
o Phenytoin!
o Streptomycin!
o Statins,*like*all*cholesterol<lowering*drugs,*may*cause*serum*
aminotransferase*elevations*but*rarely*cause*true*hepatitis*–*are*
therefore*no*longer*considered*contraindicated*in*patients*with*liver*
disease.!
!
Categorization!by!histopathology:!
1) Cholestasis!(reduced!or!stopped!bile!flow):!
a) Noninflammatory:!This!kind!of!cholestasis!is!caused!by!inhibition!or!
genetic!deficiency!of!hepatobiliary!transporter!systems.!Drugs!that!can!
cause!this:!azathioprine,!cyclosporine,!estrogens!etc.!
b) Inflammatory:!These!drugs!cause!inflammation!of!portal!areas!with!bile!
duct!injury:!Augmentin!(among!the!most!common!causes!of!drugQinduced!
liver!injury),!azathioprine,!cephalosporins,!etc.!
!
2) Acute!or!chronic!hepatitis:!These!drugs!result!in!hepatitis!that!is!
histologically!and!sometimes!clinically!similar!to!autoimmune!hepatitis.!
Asprin,!isoniazid,!methyldopa,!NSAIDS!etc.!Hepatitis!can!also!occur!in!patients!
taking!cocaine,!MDMA!(ecstasy)!as!well!as!a!variety!of!alternative!remedies!
like!green!tea!extracts,!Herbalife!products,!Hydroxycut!and!other!dietary!
supplements.!
!
3) Other!reactions:!
a) Macrovesicular!fatty!liver:!alcohol,!amiodarone,!corticosteroids!etc!
b) Microvesicular!fatty!liver:!resulting!from!mitochondrial!injury!–!caused!by!
for!example!valproic!acid,!tetracyclines!etc!
c) Granulomas:!allopurinol,!phenytoin!etc!
d) Fibrosis!and!cirrhosis:!methotrexate!and!Vitamin!A!
e) Sinusoidal!obstruction!syndrome:!this!disorder!may!result!from!
treatment!with!antiQneoplastic!agents!like!oxaliplatin!
f) Neoplasms:!hepatic!adenoma!or!angiosarcoma!
!

Aflatoxin is a potent human carcinogen. It is a naturally occurring toxic metabolite produced by certain fungi
(Aspergillus flavis), a mold found on food products such as corn and peanuts, peanut butter.
! 134!
 Drug-induced liver damage (hepatotoxicity) results not from paracetamol itself, but from one of its metabolites,
N-acetyl-p-benzoquinoneimine (NAPQI). ecommended maximum daily dose for healthy adults is 3 grams. Higher
doses lead to increasing risk of toxicity. In adults, single doses above 10 grams

Acute!liver!failure:!
Acute!liver!failure!is!the!appearance!of!severe!complications!rapidly!after!the!first!
signs!of!liver!disease!(for!example!jaundice)!and!indicates!that!the!liver!has!sustained!
severe!damage!–!or!80Q90%!loss!of!function!of!liver!cells.!Acute!liver!failure!can!be!
either:!
& Fulminant:!characterized!by!the!development!of!hepatic!encephalopathy!
within!8!weeks!after!the!onset!of!acute!liver!disease.!Coagulopathy!(INR!1,5!
or!higher)!is!invariably!present.!
& Subfulminant:!it!occurs!when!the!above!stated!findings!appear!between!8!
weeks!and!6!months!after!the!onset!of!acute!liver!disease!and!carries!an!
equally!poor!prognosis!as!fulminant!liver!failure.!!
!
Causes:!
• Acetaminophen!toxicity!is!the!most!common!cause,!accounting!for!at!least!
45%!of!cases.!These!cases!are!usually!either!suicide!attempts!or!unintentional!
overdose!(“therapeutic!misadvantures”),!which!are!often!a!result!of!a!
decrease!in!the!threshold!toxic!dose!because!of!chronic!alcohol!use!or!
fasting.!!
• Idiosyncratic!drug!reactions!are!the!2nd!most!common!cause!–!with!antiQTB,!
antiepileptics!and!antibiotics!being!the!most!common!drugs.!!
• Poisonous!mushrooms!(Amanita!phalloides)! Most deaths are due to Amanita phalloides (death cap mushroom).
Delayed toxicity occurs with Amanita phalloides.
• Shock!! Amanita phalloides poisoning causes vomiting and profuse watery diarrhoea after a
latent period of 6-12hrs, followed by hepatic and renal failure.
• Hyperthermia!or!hypothermia! For most toxic mushrooms only symptomatic treatment is required. Activated charcoal
may decrease absorption of given within 1hr.
Initially, symptoms are gastrointestinal in nature and include colicky abdominal pain,
• BuddQChiari!syndrome! with watery diarrhea and vomiting, which may lead to dehydration, and, in severe
cases, hypotension, tachycardia, hypoglycemia, and acid–base disturbances. These first
• Malignancy!–!most!commonly!lymphomas! symptoms resolve two to three days after the ingestion. A more serious deterioration
signifying liver involvement may then occur—jaundice, diarrhea, delirium, seizures,
and coma due to fulminant hepatic failure and attendant hepatic encephalopathy
• Wilson´s!diease!! caused by the accumulation of normally liver-removed substance in the blood. Renal
failure (either secondary to severe hepatitis or caused by direct toxic renal damage) and

• Reye!syndrome!
coagulopathy may appear during this stage. Life-threatening complications include
increased intracranial pressure, intracranial hemorrhage, pancreatitis, acute renal
failure, and cardiac arrest. Death generally occurs six to
!
The!risk!of!acute!liver!failure!is!increased!in!patients!with!diabetes!mellitus!and!
outcome!is!worsened!by!obesity.!Viral!hepatitis!now!accounts!for!only!12%!of!all!
cases!of!acute!liver!failure.!The!decline!of!viral!hepatitis!as!the!principal!cause!of!
acute!liver!failure!is!due!to!universal!vaccination!of!infants!and!children!against!
hepatitis!B!and!the!availability!of!the!hepatitis!A!vaccine.!!
!
!
!
!
!
!
!
Acute
! liver
failure has
!
several systemic
!
manifestations
!
such as:
!
!
!

! 135!
 Clinical!findings:!
• GI!symptoms,!systemic!inflammatory!response!(SIRS!criteria),!renal!
dysfunction!and!hemorrhagic!phenomena!are!common.!
• Jaundice!may!be!absent!or!minimal!early!!
• Lab!tests!show!severe!hepatocellular!damage!
• In!acetaminophen!toxicity:!serum!aminotransferase!elevations!are!towering!
(greater!than!5000units/L).!
• 10%!have!elevated!serum!amylase!due!to!renal!dysfunction!
• Blood!ammonia!level!is!elevated!and!correlates!with!the!development!of!
encephalopathy!and!intracranial!hypertension!
!
Treatment:!!
Its!directed!towards!achieving!metabolic!and!hemodynamic!stability.!
& Intravascular!volume!should!be!preserved!but!large!volume!infusions!of!
hypotonic!fluids!should!be!avoided!
& To!preserve!muscle!mass!and!immune!function,!protein!administration!is!
advised!
& Cerebral!edema!and!sepsis!are!the!leading!cause!of!death!–!prophylatic!
antibiotic!therapy!decreases!the!risk!of!infection!but!has!no!effect!on!survival!
so!its!not!routinely!recommended!
& Despite!adrenal!insufficiency,!corticosteroids!may!lower!overall!survival!
& Acetylcystine!is!given!for!acetaminophen!toxicity!up!to!72!hours!after!
ingestion!–!for!massive!overdose,!give!it!IV!to!extend!its!duration!until!the!
serum!aminotransferase!levels!are!declining!and!serum!acetaminophen!
levers!are!undetectable.!Acetylcystine!improves!cerebral!blood!flow!and!
oxygenation.!
& Penicillin!G!is!given!for!mushroom!poisoning!
& Nucleoside!analogs!for!patients!with!fulminant!hepatitis!B!
& Its!important!to!elevate!the!patients!head!to!30!degrees!and!use!extradural!
sensors!to!monitor!intracranial!pressure!for!impending!cerebral!edema!with!
the!goal!of!maintaining!the!IC!pressure!below!20mmHg!and!the!cerebral!
perfusion!pressure!above!70mmHg.!
& Mannitol!may!decrease!cerebral!edema!
& IV!hypertonic!saline!to!induce!hypernatremia!may!reduce!intracranial!
hypertension!
!
With*earlier*recognition*of*acute*liver*failure,*the*frequency*of*cerebral*edema*has*
declined*and*overall*survival*has*improved*steadily*and*is*now*75%.*
*
The*survival*rate*in*fulminant*liver*failure*with*severe*encephalopathy*is*as*low*as*
20%.!
!
!
Toxic hepatitis is an inflammation of the liver caused by chemicals. Many chemicals that are intentionally or unintentionally consumed can have toxic effects on the liver.
!
Among these chemicals are drugs, industrial solvents and pollutants. Toxins can occasionally cause chronic liver disease and even cirrhosis.

!
Toxins that can damage the liver have been divided into two groups:
Direct hepatotoxicity/Predictable, those that are known to cause toxic hepatitis and liver damage with large exposure. Examples of chemicals found in this group are cleaning
solvents, carbon!tetrachloride and acetaminophen.
Idiosyncratic/ Unpredictable, those toxins that damage the liver in a very small proportion of individuals exposed to the chemical. Unpredictable injury produced by most drugs
!
is very poorly understood but recent data suggest that a toxic response to a drug probably depends on the kind of enzyme a person inherits to metabolize the drug.

unstable highly toxic bi-products are sometimes produced; these highly toxic bi-products can attack and injure the liver.
Regular alcohol consumption, DM, Obesity will likely enhance the chance of drug toxicity especially in the case of acetaminophen.

!
Symptoms such as nausea, vomiting, fever, jaundice, abnormal liver blood tests and liver biopsy findings are often identical to viral hepatitis. 136!
On the other hand, symptoms like fever, abdominal pain and jaundice can mimic other liver conditions, such as stones blocking the bile ducts.
 The most common types are hepatocellular carcinoma (HCC) which makes up 80%.
More rare primary forms of liver cancer include cholangiocarcinoma, mixed tumors,
sarcoma and hepatoblastoma; a rare malignant tumor in children.
Topic!#38.!Hepatocellular!carcinoma!(HCC):!
HCC!is!the!most!common!malignant!liver!tumor!along!with!cholangiocarcinoma.!It!
accounts!for!more!than!80%!of!primary!liver!cancers!and!accounts!for!most!deaths!
due!to!cancers!worldwide.!There!are!two!pathologic!types:!
& Nonfibrolamellar!(most!common):!
o Usually!associated!with!hepatitis!B!or!C!and!cirrhosis!
o Usually!unresectable!with!very!short!survival!time!(months)!
& Fibrolamellar:!
o Usually!NOT!associated!with!hepatitis!B!or!C!or!cirrhosis!
o More!often!resectable,!with!relatively!longer!survival!time!
o Seen!most!commonly!in!adolescents!and!young!adults!!
!
Risk!factors!of!HCC:!
• Cirrhosis!–!especially!in!association!with!alcohol!or!hepatitis!B!or!C!but!HCC!
develops!in!10%!of!cirrhotic!patients!
Alcoholism
Hepatitis B • Chemical!carcinogens:!aflatoxins,!vinyl!
Hepatitis C (25%)
Aflatoxin chloride!etc!
Cirrhosis
Nonalcoholic steatohepatitis (if
• AAT!deficiency! Alpha-1 antitrypsin
progression to cirrhosis)
Hemochromatosis
• Hemachromatosis,!Wilson´s!disease!
Alpha 1-antitrypsin deficiency •
Wilson's disease
Schistosomiasis!
Type 2 diabetes (probably • Hepatic!adenoma!(10%!risk!of!becoming!
aided by obesity)
Hemophilia malignant)!
Steroids
• Cigarette!smoking!
• Glycogen!storage!disease!type!1!
!
Clinical!features:!
• Abdominal!pain!–!due!to!painful!
HCC may present with
yellow skin, ascites, easy hepatomegaly!
bruising from • Weight!loss,!anorexia,!fatigue!
coagulopathy, loss of
appetite, weight loss,
• Signs!and!symptoms!of!chronic!liver!disease:!portal!hypertension,!ascites,!
abdominal pain jaundice,!splenomegaly!
especially in the right • Paraneoplastic!syndromes:!erythrocytosis,!thrombocytosis,!hypercalcemia,!
upper quadrant, nausea,
vomiting, or feeling
carcinoid!syndrome.!!
tired. !
Diagnosis:!
• Liver!biopsy!–!required!for!definitive!diagnosis!
• Lab!tests:!hepatitis!B!and!C!serology,!liver!function!tests!and!coagulation!tests!
• Imaging!studies:!ultrasound,!CT!scan!(of!chest,!abdomen!and!pelvis!),!MRI!or!
MRA!if!surgery!is!an!option!(because!they!provide!more!detail!about!the!
anatomy!of!the!tumor)!
• Tumor!marker!elevation:!AFP!(alpha!fetoprotein)!is!useful!as!a!screening!tool.!
AFP!may!be!elevated!in!40Q70%!of!patients!with!HCC!and!is!also!helpful!in!
monitoring!response!to!therapy.!
!
!
!

! 137!
 Treatment:!
In!the!10%!of!patients!who!have!resectable!tumors,!liver!resection!is!the!main!
treatment.!Liver!transplantation!is!a!possibility!only!if!the!diagnosis!is!made!early.!
!
HCC*is*a*likely*diagnosis*in*a*patient*with*cirrhosis*who*has*a*palpable*liver*mass*and*
elevated*AFP!*
*
Prognosis:!
In!the!cancer!is!unresectable!then!its!less!than!1!year.!If!its!rescetable:!5Qyear!survival!
rate!is!25%.!
!
!
!
!
Treatment options for HCC and prognosis are dependent on tumour size, staging, and extent of liver injury.
!
Tumour grade is also important; high-grade tumors will have a poor prognosis.
!
The aflatoxin from Aspergillus species of fungus is a carcinogen and aids carcinogenesis.
!
!
BARCELONA CLINIC LIVER CANCER (BCLC) staging classification to select people for treatment.
!
Important features that guide treatment include: -
size
!
spread (stage)
!
involvement of vessels
!
presence of a tumor capsule
presence of extrahepatic metastases
!
presence of daughter nodules
!
vascularity of the tumor
!
MRI is the best imaging method to detect the presence of a tumor capsule.
!
!
A !receptor tyrosine kinase inhibitor, Sorafenib, approved by the US FDA in December 2005 and in Europe in
July 2006, may be used in patients with advanced hepatocellular carcinoma.
!
!
Sorafenib is a small molecule that inhibits tumor-cell proliferation and tumor angionesis.
!
!
Liver transplant

!
resection
!
!
!
!
!
!
!
!
!
!
!
!
!
!

! 138!
2 types of Acute cholecystitis:
1. Acute calculous cholecystitis: Gallstones blocking the flow of bile account for 90% of cases of cholecystitis. Blockage of bile flow leads to thickening and buildup of bile causing an
enlarged, red, and tense gallbladder. The gallbladder is initially sterile but often becomes infected by bacteria, predominantly E. coli, Klebsiella, Streptococcus, and Clostridium.
Inflammation can spread to the outer covering of the gallbladder and surrounding structures such as the diaphragm, causing referred right shoulder pain.

2. Acalculous cholecystitis: no stone is in the biliary ducts. It accounts for 5–10% of all cases of cholecystitis and is associated with high morbidity and mortality rates. Acalculous
cholecystitis is typically seen in people who are hospitalized and critically ill. following surgery in the absence of trauma. It is associated with many causes including vasculitis, chemotherapy,
major trauma or burns.
Jaundice, CT or US. Treatment involves immediate antibiotics and cholecystectomy within 24–72 hours.

Topic!#39.!Acute!and!chronic!cholecystitis:!
Acute!cholecystitis:!
Its!an!obstruction!of!the!cystic!duct!(NOT!
infection)!that!induces!acute!inflammation!of!the!
gallbladder!wall.!Its!most!commonly!caused!by!
gallstones!arising!from!the!gallbladder!but!10%!of!
patients!with!gallstones!develop!acute!
cholecystitis.!Uncomplicated!cholecystitis!has!an!
excellent!prognosis!but!the!development!of!
complications!such!as!perforation!or!gangrene!
renders!the!prognosis!less!favorable.!
!
Clinical!features:!
• Symptoms:!
a) Pain!is!always!present!and!is!located!in!RUQ!or!epigastrium.!It!may!
radiate!to!the!right!shoulder!or!scapula.!!
b) Nausea!and!vomiting!
c) Anorexia!!
• Signs:!
a) RUQ!tenderness!and!rebound!tenderness!
b) Murphy´s!sign!is!pathognomonic!(meaning!its!characteristic!for!this!
particular!disease)!–!inspiratory!arrest!during!deep!palpation!of!the!
RUQ.!Not!always!present.! Murphy’s sign: patient is asked to inhale while the examiner's fingers are
hooked under the liver border at the bottom of the rib cage. The
c) Hypoactive!bowel!sounds! inspiration causes the gallbladder to descend onto the fingers, producing
pain if the gallbladder is inflamed.
d) LowQgrade!fever!and!leukocytosis!
!
Continuation!or!progression!of!RUQ!abdominal!pain,!tenderness,!muscle!guarding,!
fever!and!leukocytosis!after!24Q48!hours!suggests!severe!inflammation!and!possible!
gangrene!of!the!gallbladder,!resulting!from!ischemia!due!to!splanchnic!
vasoconstiction!and!intravascular!coagulation.!Necrosis!may!occasionally!develop!
without!specific!signs!in!the!obese,!diabetic,!elderly!or!immunosuppressed!patient.!
Gangrene!may!lead!to!gallbladder!perforation,!usually!with!formation!of!a!
pericholecystic!abscess!but!rarely!to!generalized!peritonitis.!
!
Other!serious!acute!complications!include!emphysematous!cholecystitis!–!secondary!
infection!with!gasQforming!organism.! Emphysematous cholecystitis or clostridial cholecystitis, is an acute infection of the
gallbladder wall caused by gas-forming organisms (eg, Clostridium or E. coli) that
! is considered a surgical emergency.

Diagnosis:!
• RUQ!ultrasound!is!the!test!of!choice.!It!has!a!high!sensitivity!and!specificity.!It!
findings!include!thickened!gallbladder!wall,!pericholecystic!fluid,!distended!
gallbladder!and!gallstones.!
• CT!scan!is!as!accurate!as!ultrasound!but!its!more!sensitive!in!identifying!
complications!of!acute!cholecystitis!like!perforation!or!abscess.!
hepatobiliary • Radionuclide!scan!with!HIDA!is!used!when!the!ultrasound!results!are!
imidoacetic inconclusive.!If!its!normal!than!acute!cholecystitis!can!be!ruled!out!!If!the!
gallbladder!is!not!visualized!4!hours!after!injection!of!HIDA,!diagnosis!of!acute!
acid
cholecystitis!is!confirmed.!!

! 139!
 Treatment:!
Conservative!measures!are!the!main!approach!in!uncomplicated!cases.!It!includes!
hydration!with!IV!fluids,!bowel!rest,!IV!antibiotics!(cephalosporin!with!the!addition!of!
metronidazole)!and!correction!of!electrolyte!abnormalities.!Morphin!or!meperidine!
may!be!given!for!pain.!Cholecystectomy!is!indicated!in!most!patients!with!
symptomatic!gallstones!and!to!prevent!recurrance.!Its!preferred!that!the!surgery!is!
performed!within!24Q48!hours!to!reduce!the!risk!of!major!bile!duct!injury!and!death.!
In!highQrisk!patients!for!recurrence,!ultrasoundQguided!aspiration!of!the!gallbladder!
or!endoscopic!insertion!of!stent!may!postpone!or!even!avoid!the!need!for!surgery.!
Immediate!cholecystectomy!is!mandatory!if!there!are!evidences!of!gangrene!or!
perforation.!
!
Chronic!cholecystitis:!
It!results!from!repeated!episodes!of!acute!cholecystitis!or!chronic!irritation!of!the!
gallbladder!wall!by!stones!and!is!characterized!pathologically!by!varying!degrees!of!
chronic!inflammation!of!the!gallbladder.!Gallstones!are!usually!present.!
!
In!about!4Q5%!of!cases,!the!villi!of!the!gallbladder!undergoes!
polypoid!enlargement!due!to!deposition!of!cholesterol!that!
may!be!visible!to!the!naked!eye!–!so!called!“strawberry!
gallbladder”!cholesterolosis!–!these!cholesterol!depositions!
will!look!like!the!seeds!on!strawberries!(see!picture).!In!
other!cases,!hyperplasia!of!all!or!part!of!the!gallbladder!wall!
may!be!so!marked!as!to!give!the!appearance!of!a!myoma!
(adenomyomatosis).!
!
excessive accumulation of serous fluid
Hydrops!of!the!gallbladder!results!when!acute!
cholecystitis!subsides!but!cystic!duct!obstruction!
persists,!producing!distention!of!the!gallbladder!
with!a!clear!mucoid!fluid.!Occasionally!a!stone!in!
the!neck!of!the!gallbladder!may!compress!the!
common!hepatic!duct!and!cause!jaundice!(so!called!
Mirizzi!syndrome!–!see!lower!picture).!!
!
mimics gallbladder cancer Xanthogranulomatous!cholecystitis!is!a!rare!variant!

of!chronic!cholecystitis!–!characterized!by!grayishQ
yellow!nodules!or!streaks,!representing!lipidQladen!
macrophages!in!the!wall!of!the!gallbladder.!!
!
Treatment:!
It’s!the!same!as!for!acute!cholecystitis.!!
!
!
!
!
!
!

! 140!
 Risk factors for cholesterol gallstones is the 5 F's: Fat (overweight), Forty ( above
40), female, fertile (premenopausal- increased estrogen increase cholesterol levels in
bile and decrease gallbladder contractions), and fair (more common in Caucasians).

Topic!#40.!Gallstones:!
Gallstones!are!more!common!in!women!and!increase!in!incidence!in!both!sexes!and!
all!races!with!age!but!gallstone!disease!is!associated!with!increased!overall,!
cardiovascular!and!cancer!mortality.!There!are!three!types!of!stones,!classified!
according!to!their!predominant!chemial!composition:!
1) Cholesterol!stones:!they!are!yellow!to!green!and!are!associated!with!the!
following:!
o Obesity,!diabetes,!hyperlipidemia,!rapid!weight!loss!
o Multiple!pregnancies!(especially!in!obese!women),!oral!contraceptive!
use!
o Chron´s!disease,!ileal!resection!
o Advanced!age!
o Cirrhosis!
o Cystic!fibrosis!
2) Pigment!stones:!they!are!either!black!or!brown!and!contain!calcium!bilirubin!
o Black!stones:!usually!found!in!the!gallbladder!and!are!associated!with!
either!hemolysis!(e.g.!due!to!sickle!cell!disease!or!thalassemia)!or!
alcoholic!cirrhosis.!
o Brown!stones:!usually!found!in!bile!ducts!and!are!associated!with!
biliary!tract!infection.!
3) Mixed!stones:!have!components!of!both!cholesterol!and!pigment!stones!and!
account!for!the!majority!of!stones.!!
!
Protecting!factors!of!gallstone!formation:!low!carbohydrate!diet,!physical!activity,!
cardiorespiratory!fitness,!consumption!of!caffeinated!coffee,!diet!high!in!fiber!and!
rich!in!fruits!and!vegetables!–!so!basically!healthy!eating!and!exercise!does!the!trick!
%!
!
Clinical!features:!
Most!cases!are!asymptomatic!but!the!majority!of!patients!found!to!have!incidental!
gallstones!will!remain!asymptomatic.!Biliary!colic!is!the!primary!clinical!symptom!of!
gallstones!and!is!due!to!temporary!obstruction!of!the!cystic!duct!by!a!gallstone.!Pain!
occurs!as!the!gallbladder!contracts!against!this!obstruction:!
• Pain!is!typically!located!in!the!RUQ!or!epigastrium!and!may!be!mild,!
worse after meals,
moderate!or!severe.! colicky type of pain
• Patients!clasically!report!pain!after!eating!and!at!night.! or could feel like cramps
• Boas´sign!–!referred!right!subscapular!pain!of!biliary!colic!
• 1/3!of!patients!with!biliary!colic!develop!acute!cholecystitis!within!2!years.!
! A positive Murphy's sign is a common finding on physical examination during a gallbladder attack.
Gallstone!complications:! Mirizzi sign when stone in the cystic duct compress the common hepatic duct and causes jaundice

• Cholecystitis!(acute!or!chronic)!with!prolonged!obstruction!of!cystic!duct!
• Choledocholithiasis!with!its!associated!complications!–!its!bile!duct!stones!or!
gallstones!in!the!bile!duct.!It!can!lead!to!obstructive!jaundice!and!acute!
pancreatitis.!
• Gallstone!ileus!–!small!bowel!obstruction!caused!by!gallstones!
• Malignany!!
!
Small gallstones are at risk of passing into the cystic duct and causing impaction and obstruction
and pancreatitis and other complication of bile stasis : choledocholithiasis

! Bigger gallstones - elective cholecystectomy - may cause gall bladder cancer after years 141!
Diagnosis:!
RUQ!ultrasound!has!high!sensitivity!and!specificity!for!stones!larger!than!2mm.!CT!
scan!and!MRI!are!alternatives.!!
!
Treatment:!
• If!the!patient!is!asymptomatic!–!then!NO!treatment!is!needed.!!
• NSAIDS!can!relieve!biliary!cholic!pain!
• Laparoscopic!cholecystectomy!is!the!treatment!of!choice!for!symptomatic!
gallbladder!disease.!Patients!may!go!home!within!1!day!of!the!procedure!and!
return!to!work!within!days.!
• Conversion!to!open!cholecystectomy!may!be!necessary!in!some!cases,!but!
mainly!in!acute!cholecystitis.!
• Ursodeoxycholic!acid!is!a!bile!salt!that!when!given!orally!for!up!to!2!years!
dissolve!some!cholesterol!stones!and!may!be!considered!in!occasional,!
selected!patients!who!refuse!cholecystectomy.!!
!

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! 142!
 Topic!#41.!Neoplasms!of!bile!ducts:!
Cholangiocarcinoma:!
It’s!a!tumor!of!intrahepatic!or!extrahepatic!bile!ducts!–!most!of!them!are!
adenocarcinomas.!The!mean!age!of!diagnosis!is!70!years.!These!tumors!can!be!
located!in!three!different!regions:!
1) Proximal!third!of!the!common!bile!duct.!
This!is!the!most!common!location,!also!
called!Klatskin´s!tumor:!it!involves!the!
junction!of!the!right!and!left!hepatic!
ducts!or!the!so!called!perihilar!area.!Has!a!
very!poor!prognosis!because!they!are!
unresectable!(see!picture).!
2) Distal!extrahepatic!–!here!is!the!best!
chance!of!resectability!
3) Intrahepatic!–!least!common.!
!
Risk!factors:!
• Primary!sclerosing!cholangitis:!it’s!a!
major!risk!factor.!It’s!a!chronic!idiopathic!
disease!of!intrahepatic!and/or!
extrahepatic!bile!ducts!characterized!by!
thickening!of!bile!duct!walls!and!narrowing!of!their!lumens.!It!can!lead!to!
cirrhosis,!portal!hypertension!and!liver!failure.!!
• Other!risk!factors:!ulcerative!colitis,!choledochal!cysts!and!Clonorchis!sinensis!
infestation!(but!only!in!Hong!Kong).!
• Most!cases!of!cholangiocarcinoma!are!spordiac!–!meaning!its!not!hereditary!
!
Clinical!features:!
Weight!loss!and!obstructive!jaundice!with!its!associated!symptoms;!dark!urine,!clayQ
colored!stools!and!pruritius!(itchy!skin).!Fistula!formation!between!the!biliary!system!
and!adjacent!organs!may!also!occur.!
!
Courvoisier!sign!is!said!to!signify!malignant!disease!–!its!when!the!gallbladder!is!
palpable,!nontender,!with!obstructive!jaundice.!The!downside!of!this!sign!is!that!its!
clinical!generalization!has!been!proved!to!be!accurate!in!only!about!50%!of!the!time.!
!
Diagnosis:! Endoscopy and fluoroscopy - endoscopic retrograde cholangiopancreatography
1) Cholangiography!(PTC!or!ERCP):!for!diagnosis!and!assessment!of!
resectability.!
2) Stent!placement:!If!the!patinet!has!an!uresectable!tumor,!stent!placement!is!
an!option!during!either!PTC!or!ERCP!and!may!relieve!biliary!obstruction.!!
3) Lab!findings:!in!biliary!obstruction!it!will!show!predominantly!conjugated!
hyperbilirubinemia,!with!total!serum!bilirubin!values!ranging!from!5Q30!
mg/dL!(normal!values!are!0,3Q1,9!mg/dL).!Alkaline!phosphatase!and!AST!is!
Family history of congenital
fibrosis or cysts
usually!minimally!elevated.!Serum!CA!19Q9!is!elevated!in!most!cases!and!may!
Parasitic infestations help!distinguish!cholangiocarcinoma!from!a!benign!biliary!stricture.!
Gallstones and hepatolithiasis!
Primary sclerosing cholangitis
(PSC)
Ulcerative colitis, with or
without PSC ! 143!
Toxic materials
Drugs
 Treatment:!
Most!patients!do!not!have!resectable!tumors!at!diagnosis!–!therefore!surgery!is!not!
indicated!in!those!cases.!The!survival!rate!is!low!depsite!aggressive!chemotherapy,!
stenting!or!biliary!drainage.!!
!
The!prognosis!of!cholangiocarcinoma!is!bad!–!survival!is!less!than!1!year!after!the!
diagnosis!with!rapid!detoriation.!Usually!death!occurs!within!few!months.!!
!
!

bile duct cancer is a form of cancer that is composed of malignant epithelial cells that originate in the hepatic bile ducts.

Other biliary tract neoplasms: gallbladder cancer and cancer of the ampulla of Vater.

Cholangiocarcinoma is a rare neoplasm that is classified as an adenocarcinoma (a cancer that forms glands or secretes significant
amounts of mucins).

It has an annual incidence rate of 1–2 cases per 100,000 in the Western world.
Prominent signs and symptoms of cholangiocarcinoma include abnormal liver function tests, abdominal pain, jaundice, and weight
loss, generalized itching, fever, and changes in color of stool or urine.
The disease is diagnosed through a combination of blood tests, imaging, endoscopy, and sometimes surgical exploration, with
confirmation obtained with BIOPSY.

Known risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts),
infection with the parasitic liver flukes Clonorchis sinensis, some congenital liver malformations, and exposure to Thorotrast
(thorium dioxide), a chemical formerly used in medical imaging. However, most people with cholangiocarcinoma have no !identifiable
risk factors -!SPORADIC
!
Cholangiocarcinoma is considered to be an incurable and rapidly lethal cancer unless both the primary tumor and any metastases
!
can be fully removed by surgery. No potentially curative treatment exists except surgery, but most people have advanced stage
!
disease at presentation and are inoperable at the time of diagnosis.
People with cholangiocarcinoma are generally managed - though not cured - with chemotherapy, radiation therapy, and other
!
palliative care measures.
!
If the tumor !can be removed surgically, patients may receive adjuvant chemotherapy or radiation therapy after the operation to
improve the chances of cure.
!
Carcinoma ! of the ampulla of Vater is a rare malignant tumor arising within 2 cm of the distal end
!
of the common bile duct, where it passes through the wall of the duodenum and ampullary
papilla. !
The common ! bile duct merges with the pancreatic duct of Wirsung to form a common channel
that exits !through the ampulla into the duodenum. The most distal portion of the common bile
!
duct is dilated (ie, forms the ampulla of Vater) and is surrounded by the sphincter of Oddi, which
!
spirals upward around the terminal portion of the duct.
Carcinoma ! of the ampulla of Vater tends to manifest early due to biliary outflow obstruction, as
opposed to pancreatic neoplasms that often are advanced at the time of diagnosis.
Surgical resection with curative intent is the only option for long-term survival. Surgical,
endoscopic,! or radiologic biliary decompression; relief of gastric outlet obstruction; and
144!
adequate pain control may improve the quality of life but do not affect overall survival rate.
 Type 2 diabetes makes up about 85-90% of all cases. Increases in the overall diabetes prevalence rates reflect
an increase in risk factors for type 2, greater longevity and being overweight or obese.
There were 694.700 cases of diabetes in Hungary in 2015.

Topic!#42.!Classification!and!epidemiology!of!diabetes!mellitus:!
Epidemiology:!
An!estimated!25,8!million!people!(8,3%)!in!the!USA!have!diabetes!mellitus,!of!which!
about!1!million!have!type!1!and!most!of!the!rest!have!type!2.!A!third!group!
designated!as!“other!specific!types”!are!only!in!the!thousands.!
!
Globally,!an!estimated!422!million!adults!are!living!with!DM,!according!to!the!latest!
2016!data!from!WHO.!DM!prevalence!is!incresing!rapidly!and!the!number!is!
projected!to!almost!double!by!2030.!Increases!in!the!overall!DM!prevalance!rates!
largely!reflect!an!increase!in!risk!factors!for!type!2!DM,!notably!greater!longevity!and!
being!overweight!or!obese.!
!
DM!occurs!throughout!the!world!but!is!more!common!(espescially!type!2)!in!the!
more!developed!countries.!This!increase!follows!the!trend!of!urbanization!and!
lifestyle!changes,!including!increasingly!sedentary!lifestyles,!less!physically!
demanding!work!and!the!global!nutrition!transition,!marked!by!increased!intake!of!
foods!that!are!high!energyQdense!but!nutrientQpoor.!
!
The!WHO!estimates!that!DM!resulted!in!1,5!million!deaths!in!2012,!making!it!the!8th!
leading!cause!of!death.!
!
Classification:!
DM!is!a!syndrome!with!disordered!metabolism!and!inappropriate!hyperglycemia!due!
to!either!a!deficiency!of!insulin!secretion!or!to!a!combination!of!insulin!resistance!
and!inadequate!insulin!secretion!to!compensate!for!the!resistance.!!
!

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! 145!
Type!1!Diabetes!Mellitus!–!5%!of!all!diabetic!patients:!!
• Its!characterized!by!a!severe!deficiency!of!insulin!due!to!pancreatic!islet!B!cell!
destruction.!The!rate!of!destruction!is!variable,!being!rapid!in!some!
individuals!and!slow!in!others.!
• These!patients!require!exogenous!insulin!to!live!–!since!they!have!virtually!
no!circulating!insulin,!elevated!plasma!glucose!and!the!pancreatic!B!cells!fail!
to!respond!to!all!insulinogenic!stimuli.!
• The!onset!is!typically!in!youth!(before!age!20),!but!can!occur!at!any!age!
• This!type!is!NOT!related!to!obesity!
• Is!usually!associated!with!ketosis!in!its!untreated!state!–!raised!levels!of!
ketone!bodies!in!the!body.!
• There!are!2!subtypes!of!Type!1!DM:!
a) ImmuneMmediated!type!1!DM!(type!1A):!This!type!is!when!the!DM!is!due!
to!pancreatic!islet!B!cell!destruction!caused!by!an!autoimmune!process.!
This!is!the!case!in!95%!of!Type!1!DM.!The!cause!is!both!environmental!
and!genetic!–!but!most!of!these!patients!possess!either!HLAQDR2!or!HLAQ
DR4!genes.!A!child!whose!mother!has!type!1!DM!has!a!3%!risk!of!
developing!the!disease!and!6%!risk!if!the!child´s!father!has!it.!Some!
patients!with!a!milder!expression!of!type!1!DM!initially!retain!enough!B!
cell!function!to!avoid!ketosis!but!as!their!B!cell!mass!diminshes!later!in!
life,!dependance!on!insulin!therapy!develops.!
! Type!1A!DM!develops!in!genetically!suceptible!individuals!
who!are!exposed!to!an!environmental!factor!that!triggers!the!
autoimmune!respone!and!B!cell!destruction!ensues.!
! Type!1A!DM!does!not!appear!until!about!90%!of!B!cells!are!
destroyed!!
! Its!thought!that!some!people!with!type!2!DM!may!actually!
have!this!mild!form!of!type!1!DM!–!then!its!called!“latent!
autoimmune!diabetes!of!adulthood”.!
! Evidence!for!environmental!factors!playing!a!role!in!the!
development!of!type!1!DM!include!the!observation!that!the!
disease!is!more!common!in!Scandinavian!countries.!But!which!
environmental!factor!is!responsible!for!the!increased!risk!is!
not!known!–!there!have!been!many!different!hypothesis!
including!infections!with!certain!virusus!(mumps,!rubella)!and!
consumption!of!cow´s!milk.!!
! Hygiene!hypothesis:!in!the!developed!countries,!childhood!
infections!have!become!less!frequent!and!so!perhaps!the!
immune!system!becomes!dysregulated!with!development!of!
autoimmunity!and!condtions!such!as!asthma!and!DM.!
b) Idiopathic!type!1!DM!(type!1B):!these!are!the!5%!of!DM!1!patients!that!
have!no!evidence!of!pancreatic!B!cell!autoimmunity!to!explain!their!
disease.!
!
!
!
!

! 146!
People with insulin resistance, also known as impaired insulin sensitivity, have built up a tolerance to insulin, making the hormone less effective. As a result, more
insulin is needed to persuade fat and muscle cells to take up glucose and the liver to continue to store it.
In response to the body's insulin resistance, the pancreas makes greater amounts of the hormone to keep blood glucose levels under control. (This is why people with
type 2 diabetes tend to have elevated levels of circulating insulin.) The ability of the pancreas to increase insulin production means that insulin resistance alone won't
have any symptoms at first. Over time, though, insulin resistance tends to get worse, and the pancreatic beta cells that make insulin can wear out. Eventually, the
pancreas no longer produces enough insulin to overcome the cells' resistance. The result is higher blood glucose levels (prediabetes) and, ultimately, type 2 diabetes.

Type!2!Diabetes!Mellitus!–!more!then!90%!of!all!diabetic!patients:!
• Insulin!levels!are!usually!normal!to!high!but!may!diminsh!over!many!years!of!
having!diabetes!–!this!is!the!reason!why!people!that!have!DM!2!first!start!by!
taking!metformin!(most!often)!but!with!time!have!to!take!both!metformin!
and!insulin!like!people!with!type!1!DM.!
• Insulin!resistance!!
• This!type!of!DM!often!goes!undiagnosed!for!many!years!
• Lack!of!compensation!in!these!patients!–!normally,!the!pancreas!secretes!
more!insulin!in!response!to!free!fatty!acids,!thus!neutralizing!the!excess!
glucose.!In!type!2!DM!patients,!free!fatty!acids!fail!to!stimulate!pancreatic!
insulin!secretion.!Therefore,!compensation!does!not!occur!and!
hyperglycemia!develops.!B!cells!become!desensitized!to!glucose,!leading!to!
decreased!insulin!secretion.!
• Circulating!endogenous!insulin!is!sufficient!to!prevent!ketoacidosis!but!
inadequate!to!prevent!hyperglycemia!in!the!face!of!increased!needs!owing!it!
to!tissue!insensitivity.!!
• Genetic!and!environmental!factors!combine!to!cause!both!the!insulin!
resistance!and!beta!cell!loss.!Many!studies!indicate!strong!genetic!influences,!
since!in!monozygotic!twins!over!40!years!of!age,!concordance!develops!in!
over!70%!of!cases!within!a!year!whenever!type!2!diabetes!develops!in!one!
twin.!Obesity!is!the!most!important!environmental!factor.!!
• Risk!factors:!
o Obesity!–!plays!a!major!role.!Its!associated!with!increased!plasma!
levels!of!free!fatty!acids,!which!make!muscles!more!insulin!resistant,!
reducing!glucose!uptake.!Also,!in!the!liver,!free!fatty!acids!increase!
the!production!of!glucose.!!
o Genetics!!
o Age!–!insulin!production!decreases!with!age!!
!
Other!specific!types!of!Diabetes!Mellitus:!
& MaturityMonset!diabetes!of!the!young!(MODY):!nonQinsulinQdependant!
diabetes!with!autosomal!dominant!inheritance!with!the!age!of!onset!around!
25!years!or!younger.!Patients!are!not!obese.!
& Diabetes!due!to!mutant!insulins!
& Diabetes!due!to!mutant!insulin!receptors:!defect!in!one!of!the!insulin!
receptor!genes!with!acanthosis!nigricans!(dark!discoloration!of!the!axilla!and!
nape!of!the!neck).!
& Diabetes!associated!with!a!mutation!of!mitochondrial!DNA:!therefore!only!
the!mother!transmits!this!gene.!DM!usually!develops!in!these!patients!in!
their!late!30s!and!often!they!have!hearling!loss!also.!!
& Wolfram!syndrome:!autosomal!recessive!neurodegenerative!disorder.!It!
consists!of!DM,!diabetes!insipidus,!optic!atrophy!and!deafness.!
& Diabetes!secondary!to!other!causes:!endocrine!tumors!secreting!growth!
hormones,!glucocorticoids,!catecholamines,!glucagon!or!somatostatin!can!
cause!glucose!intolerance.!
Random blood!sugar test. A blood sample will be taken at a random time. Blood sugar values are expressed in millimoles per liter (mmol/L). Regardless of when you
last ate, a random blood sugar level of 11.1 mmol/L or higher suggests diabetes, especially when coupled with any of the signs and symptoms of diabetes, such as
!
polyuria and polydipsia.

Fasting blood sugar test. A blood sample will be taken after an overnight fast. A fasting blood sugar level less than 5.6 mmol/L is normal.
A fasting blood sugar level from 5.6 to 6.9 mmol/L is considered prediabetes. If it's 7 mmol/L or higher on two separate tests, you have diabetes. FBG: 5.6 or lower

! 147!
Oral glucose tolerance test. Fasting overnight, and the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested
periodically for the next two hours.

A blood sugar level less than 7.8 mmol/L is normal. A reading between 7.8 mmol/L and 11.0 mmol/ indicates prediabetes. A reading of 11.1 mmol/L or higher after two
hours may indicate diabetes.
 Topic!#43.!Metabolic!XMsyndrome:!
25%!of!the!general!nonQobese,!nondiabetic!population!has!insulin!resistance!of!a!
magnitude!similar!to!that!seen!in!type!2!DM.!These!individuals!are!at!much!higher!
risk!for!developing!type!2!DM!than!insulinQsensitive!persons.!In!addition!to!diabetes,!
these!individuals!have!increased!risk!for!elevated!plasma!triglycerides,!lower!HDLs!
and!higher!blood!pressure!–!a!cluster!of!abnormalities!termed!syndrome!X!or!
metabolic!syndrome!–!so!basically!a!multiplex!risk!factors!that!arise!from!insulin!
resistance!accompanying!abnormal!adipose!deposition!and!function.!
!
These!associations!have!been!expanded!to!include!LDL,!hyperuricemia,!abdominal!
obesity,!prothromic!state!with!increased!levels!of!PAI!type!1!(plasminogen!activator!
inhibitor)!and!proinflammatory!state.!These!clusters!of!abnormalities!significantly!
increase!the!risk!of!atherosclerotic!disease.!!
!
The!main!value!of!grouping!these!disorders!as!a!syndrome!is!to!remind!clinicians!that!
the!therapeutic!goals!are!not!only!to!correct!hyperglycemia!but!also!to!manage!the!
elevated!blood!pressure!and!dyslipidemia!that!result!in!increased!cerebrovascular!
and!cardiac!morbidity!and!mortality!in!these!patients.!!
!
When!these!clusters!of!conditions!occur!
To!make!it!simple:!
together,!it!will!increase!the!risk!of!heart!
• Increased!blood!pressure! disease,!stroke!and!diabetes.!Having!just!
• High!blood!sugar! one!of!them!doesn’t!mean!you!have!
• Excess!body!fat!around!the!waist! metabolic!syndrome!–!it!will!just!increase!
• Abnormal!cholesterol!or!triglyceride! the!risk!of!serious!diseases!and!having!
! more!than!one!will!increase!the!risk!even!
! more.!
!
Symptoms:!
Most!of!the!disorders!associated!with!metabolic!syndrome!have!no!symptoms,!
although!large!waist!circumference!is!a!visible!sign.!If!the!blood!sugar!is!very!high,!
signs!and!symptoms!of!diabetes!might!result!–!thirst,!urination,!fatigue!and!blurred!
vision.!
!
Diagnosis!according!to!the!American!Heart!Association!–!patient!has!at!least!3!of!the!
following!5!condtions:!
• Fasting!glucose!>!100!mg/dL!(or!receiving!drug!therapy!for!hyperglycemia)! 150 mg/dL = 8.3 mmol/L
• Blood!pressure!>!130/85!mmHg!(or!receiving!drug!therapy!for!HT)! 100 mg/dL = 5.5 mmol/L
• Triglycerides!>!150!mg/dL!(or!receiving!drug!therapy!for!hyperTG)! 50 mg/dL = 2.7 mmol/L
40 mg/dL = 2.2 mmol/L
• HDL!<!40!mg/dL!in!men!or!<!50!mg/dL!in!women!(or!receiving!threapy!for!
reduced!HDL!levels)!
• Waist!circumference!>!102!cm!in!men!or!>!88!cm!in!women!
Metabolic syndrome! is a clustering of AT LEAST 3 OF THE 5 following medical conditions:
!
Central obesity (cf. TOFI)
!
elevated blood pressure
elevated fasting plasma glucose
!
high serum triglycerides
!
low high-density lipoprotein (HDL) levels

Metabolic syndrome is associated with the risk of developing cardiovascular disease and type 2 diabetes.
Most patients are older, obese, sedentary, and have a degree of insulin resistance.
Stress can also be a contributing factor. The most important risk factors are diet (particularly sugar-sweetened beverage consumption), genetics,
!
aging, sedentary behavior 148!
or low physical activity, disrupted sleep, mood disorders/psychotropic medication use, and excessive alcohol use

• Waist Circumference
Males: <94cm = normal, 94-102cm= cardiovascular risk, >109cm= high risk
!
Treatment:!
Lifestyle!change!and!weight!loss!are!the!most!important!initial!steps!in!treating!
metabolic!syndrome.!The!following!medications!can!be!used!to!treat!some!of!the!
manifestations:!!
& Statins:!for!elevated!LDL!levels!
& Niacin:!for!decreased!HDL!levels!
& Niacin!or!fibrates:!for!elevated!triglycerides!
& Metformin!or!other!insulinMsensitizing!agents:!for!hyperglycemia!
!
Complications:!
• Cardiovascular:!CHD,!a.fib,!heart!failure,!aortic!stenosis!
• Ischemic!stroke!
• Nonalcoholic!fatty!liver!disease!
• Obstructive!sleep!apnea!
• Cancers:!breast,!colon,!gallbladder,!kidney!and!prostate!
• Neurocognitive!performance!!
!PCOS, Dementia, atherosclerosis

!
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! 149!
 The classical symptoms of type 1 diabetes include: polyuria,
polydipsia, dry mouth, polyphagia, fatigue, and weight loss.
Topic!#44.!Symptoms!and!signs!of!diabetes!mellitus:!
Many type 1 diabetics are diagnosed when they present with
Type!1!DM:! diabetic ketoacidosis. The signs and symptoms of DKA are
• Symptoms!develop!quickly!over!days!to!weeks! dry skin, rapid deep breathing, drowsiness, polydipsia,
polyuria, abdominal pain, and vomiting.
• Sometimes!symptoms!appear!after!an!illness!
• Patients!often!present!with!acute!diabetic!ketoacidosis!–!see!below!
!
Type!2!DM:!
• This!is!usually!discovered!on!screening!urinanalysis!or!blood!sugar!
measurement.!Sometimes!the!diagnosis!is!made!during!evaluation!for!other!
diseases!like!heart,!kidney,!neurologic!or!infection.!
• Symptomatic!patients!may!present!with!polyuria,!polydispsia,!polyphagia,!
fatigue,!blurred!vision,!weight!loss!and/or!candidal!vaginitis.!
• Patients!who!have!not!routinely!sought!medical!attention!may!present!with!
complications!such!as!MI,!stroke,!intermittent!claudication,!impotence,!
peripheral!neuropathy,!proteinuria!or!retinopathy.!

!
!
!
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!
!
!
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!

! 150!
 Signs/acute!complications!of!DM:!
Diabetic!ketoacidosis!(DKA):!
• Its!an!acute,!lifeQthreatening!medical!emergency!that!can!occur!in!both!type!1!
and!2!diabetic!patients!–!but!more!common!in!type!1.!
• Its!secondary!to!insulin!deficiency!and!glucagons!excess!–!both!of!which!
contribute!to!accelerated!severe!hyperglycemia!and!accelerated!ketogenesis.!
• Severe!hyperglycemia!leads!to!osmotic!diuresis,!which!causes!dehydration!
and!volume!depletion.!
• Consequences!of!DKA!include!hyperglycemia,!ketonemia!(abnormally!high!
concentration!of!ketone!bodies!in!the!blood),!metabolic!acidosis!and!volume!
depletion.!
• Any!type!of!stress!or!illness,!like!infections!or!trauma!or!just!inadequate!
administration!of!insulin!can!precipitate!DKA.!
• Clinical!features!of!DKA:!
o Symptoms!occur!rapidly!–!typically!in!less!than!24!hours!
o Nausea!and!vomiting!
metabolic
o Kussmaul´s!breathing!–!rapid,!deep!breathing!due!to!the!acidosis! compensatory respiratory alkalosis
o Fruity!(acetone)!breath!odor!
o Abdominal!pain!
o Marked!dehydration,!orthostatic!hypotension,!tachycardia!–!due!to!volume!
depletion!
o Polydipsia,!polyuria,!polyphagia,!weakness!
o Altered!consciousness,!drowsiness!and!frank!coma!may!occur!if!not!treated!
• Treatment:!!
o Give!insulin!immediately!after!the!diagnosis!is!established!–!start!with!
a!priming!dose!of!0,1!units/kg!IV!and!then!give!infusion!of!0,1!units/kg!Metabolic acidosis: ABG
insulin causes further hypokalemia
which will cause arrthymias
per!hour.!Be!certain!that!the!patient!is!not!hypokalemic!before! is essential for the
giving!insulin!!Continue!the!insulin!until!the!metabolic!acidosis!is! diagnosis. If the pH is low
(under 7.35) and the
corrected,!then!begin!to!decrease!the!insulin.!Give!SC!insulin!when! bicarbonate levels are
the!patient!starts!eating!again.! decreased (<24 mmol/l),
metabolic acidemia is
o Fluid!replacement!with!normal!saline!–!add!5%!glucose!once!the! present, and metabolic
blood!glucose!reaches!250!mg/dL!to!prevent!hypoglycemia.! acidosis is presumed. Due
to respiratory
o Replace!potassium!prophylatically!with!IV!fluids! compensation
o Monitor!potassium,!magnesium!and!phosphate!levels!very!closely! (hyperventilation),
carbon dioxide is
o ATH!#Cerebral#edema#can#result#if#glucose#levels#decrease#too# decreased and conversely
rapidly!# oxygen is increased

#
!
DKA arises due to lack of insulin. The lack of insulin and corresponding elevation of glucagon leads to increased release of glucose by the liver
(normally! suppressed by insulin) from glycogen via glycogenolysis and gluconeogenesis. High glucose levels go into the urine, taking water and
! as Na and K) along : OSMOTIC DIURESIS. This leads to polyuria, dehydration, and compensatory thirst and polydipsia.
solutes (such

! of insulin also leads to the RELEASE OF FREE FATTY ACIDS FROM ADIPOSE TISSUE (LIPOLYSIS), WHICH ARE
The absence
CONVERTED ! THROUGH A PROCESS CALLED BETA OXIDATION, AGAIN IN THE LIVER, INTO KETONE BODIES (acetoacetate and β-
hydroxybutyrate). β-Hydroxybutyrate can serve as an energy source in the absence of insulin-mediated glucose delivery. The ketone bodies, however,
have a low! pKa and therefore cause metabolic acidosis. The body initially buffers the change with the bicarbonate buffering system, but this system
is quickly! overwhelmed and other mechanisms must work to compensate for the acidosis. One such mechanism is hyperventilation to lower the
blood CO2 levels (compensatory respiratory alkalosis): Kussmaul respiration.
!
In various! situations such as infection, insulin demands rise but are not matched by the failing pancreas.
!
Blood sugars rise, osmotic diuresis and dehydration occurs, and resistance to the normal effects of insulin increases further by way of a vicious circle.

As a result of the above mechanisms, the average adult with DKA has a 6L water shortage, shortages in Na, K, Cl, Phosphate, Mg and Ca.
Glucose levels usually exceed 13.8 mmol/L.

! 151!
 Hyperosmolar!hyperglycemic!nonketotic!syndrome!(HHNS):!
• It’s!a!state!of!severe!hyperglycemia,!hyperosmolarity!and!dehydration!that!is!
typically!seen!in!elderly!type!2!DM!patients.!
• Ketosis!and!acidosis!are!typically!absent!or!minimal!since!ketogenesis!is!
minimal!because!small!amount!of!insulin!is!released!to!blunt!
counterregulatory!hormone!release!(glucagons).!
• Severe!dehydration!is!due!to!continued!hyperglycemic!diuresis!and!the!
patient!is!unable!to!drink!enough!fluids!either!due!to!lack!of!access!in!
elderly/bedridden!patients!or!due!to!inadequate!thirst!drive.!
• Precipitating!events!are!similar!to!those!of!DKA!
• Clinical!features!of!HHNS:! Any type of stress or illness, like infections or trauma or just
o Thirst,!polyuria! inadequate administration of insulin can precipitate DKA

o Hypotension,!tachycardia!–!due!to!extreme!dehydration!and!volume!
depletion!
o CNS!findings!and!focal!neurologic!signs!are!common!(for!example!seizures)!
due!to!the!hyperosmolarity.!
o Lethargy!and!confusion!may!develop,!leading!to!convulsions!and!coma!
• Treatment:!
o Fluid!replacement!is!most!important!–!give!normal!saline,!1L!in!the!first!
hour,!another!liter!in!the!next!2!hours!and!then!switch!to!half!normal!saline!
once!the!patient!stabilizes!
o Glucose!levels!are!lowered!as!the!patient!is!rehydrated!but!the!patient!still!
requires!insulin!!–!give!bolus!of!5Q10!units!IV,!followed!by!continous!lowQ
dose!infusion!of!2Q4!units/hour.!
o When!glucose!levels!reach!250!mg/dL,!add!5%!glucose!!
o Very!rapid!lowering!of!blood!glucose!can!lead!to!cerebral!edema!in!
children!–!just!as!in!DKA!!
!
!
Diagnosis!of!Diabetes!Mellitus:!
Screen!all!adults!over!the!age!of!45!years!every!3!years!–!for!those!with!risk!factors!
like!obesity!and!positive!family!history,!start!screening!earlier.!Perform!any!one!of!
the!following!tests!on!two!separate!days:!
1) Fasting!plasma!glucose:!the!criteria!for!DM!is!glucose!>126!mg/dL.!If!its!
between!100Q126!mg/dL!then!recheck!fasting!glucose.!
2) Random!plasma!glucose:!the!criteria!for!DM!is!glucose!>200!mg/dL!in!a!
person!with!diabetic!symptoms.!
3) Two!hour!postprandial!plasma!glucose!level:!the!criteria!for!DM!is!glucose!
>200!mg/dL!after!administration!of!the!equivalent!of!a!75g!glucose!load!
4) Hemoglobin!A1c:!criteria!for!DM!is!A1c!>6,5!
!
!
1. Random blood sugar test. A blood sample will be taken at a random time. Blood sugar values are expressed in millimoles per liter
(mmol/L).! Regardless of when you last ate, a random blood sugar level of 11.1 mmol/L or higher suggests diabetes, especially when
!
coupled with any of the signs and symptoms of diabetes, such as polyuria and polydipsia.

! blood sugar test. A blood sample will be taken after an overnight fast. A fasting blood sugar level less than 5.6 mmol/L is
2. Fasting
normal.!
A fasting blood sugar level from 5.6 to 6.9 mmol/L is considered prediabetes.
If it's 7!mmol/L or higher on two separate tests, you have diabetes. FBG: 5.6 or lower

3. Oral glucose tolerance test OGTT. Fasting overnight, and the fasting blood sugar level is measured. Then you drink a 75g sugar, and
blood sugar levels are tested periodically for the next two hours.
! 152!
A blood sugar level less than 7.8 mmol/L is normal. A reading between 7.8 mmol/L and 11.0 mmol/ indicates prediabetes. A reading of
11.1 mmol/L or higher after two hours may indicate diabetes.
 Other!diagnosis:!
• Hyperglycemia:!serum!glucose!>450!mg/dL!and!<850!mg/dL!
• Metabolic!acidosis:!blood!pH!<7,3!and!serum!bicarbonate!<15!mEq/L!
• Ketonemia:!serum!levels!of!acetoacetate,!acetone!and!betaQhydroxybutyrate!
are!greatly!increased!
!
!
!
!
!
!
!
!
!
!
!
!
!
Hyperosmolar hyperglycemic state (HHS) is a complication of DM (type 2) in which high blood sugars cause severe dehydration,
increases in osmolarity (relative concentration of solute) and a high risk of complications, coma and death. It is diagnosed with blood
!
tests. It is related to DKA but they are differentiated with measurement of ketone bodies and acidosis, not detectable in HHS.
!
!
The treatment of HHS consists of correction of the dehydration with IV fluids, reduction of the hyperglycaemia with insulin, and
management of any underlying conditions that might have precipitated the illness, such as an acute infection.
!
!
According to the consensus statement published by the American Diabetes Association, diagnostic features of HHS may include the
following:
!
Plasma glucose level (>30 mmol/L)
!
Serum osmolality >320 mOsm/kg
Profound dehydration(polydipsia))
Serum pH ! >7.30
! >15 mEq/L or >24mmol/L
Bicarbonate
Small ketonuria (~+ on dipstick) and absent-to-low ketonemia (<3 mmol/L)
!
Some alteration in consciousness
Neurologic! signs including focal signs such as sensory or motor impairments or focal seizures or motor abnormalities, including
flaccidity, depressed reflexes, tremors or fasciculations.
!
Hyperviscosity and increased risk of blood clot formation
!
Nonketotic coma is usually precipitated by an infection, MI, stroke or another acute illness. A relative insulin deficiency leads to a
!
serum glucose that is usually higher than 33 mmol/L (600 mg/dL), and a resulting serum osmolarity that is greater than 320 mOsm.
This leads! to excessive Osmotic diuresis, which, in turn, leads to volume depletion and hemoconcentration that causes a further
!
increase in blood glucose level.
Ketosis is absent because the presence of some insulin inhibits hormone-sensitive lipase mediated fat tissue breakdown.
!
!
!
!
!
!
!
!
!
!
!
!
!

! 153!
Topic!#45.!LongMterm!complications!of!diabetes!mellitus:!
Macrovascular!complications:!
The!main!problem!is!accelerated!atherosclerosis,!which!puts!patients!at!increased!
risk!of!stroke,!MI!and!CHF.!The!accelerated!atherosclerosis!in!diabetics!is!the!reason!
the!target!BP!is!lower!in!diabetics!than!in!the!general!population!and!the!target!LDL!
levels!are!also!lower.!The!cause!of!accelerated!atherosclerosis!is!not!known,!
although!glycation!of!lipoproteins!and!increased!platelet!adhesiveness/aggregation!
are!thought!to!be!two!potential!causes.!In!addition,!the!process!of!fibrinolysis!may!
be!impaired!in!diabetic!patients.!The!manifestation!of!atherosclerosis!include!the!
following:!
1) Coronary!artery!disease!(CAD):!
o The!risk!of!CAD!is!2Q4x!greater!in!diabetics!
o It’s!the!most!common!cause!of!death!in!diabetics!
o Silent!MI!are!common!
o The!risk!of!coronary!events!is!greatly!reduced!if!the!patient!can!
eliminate!or!reduce!other!major!cardiovascular!risk!factors!like!
smoking,!HTN!and!obesity.!
narrowing of the arteries other than those that supply the
2) Peripheral!vascular!disease:!in!up!to!60%!of!diabetics! heart or the brain. Peripheral artery disease most
3) Cerebrovascular!disease!(strokes)! commonly affects the legs. The classic symptom is
intermittent claudication. Other symptoms including skin
! ulcers, bluish skin, cold skin, or poor nail and hair growth
Microvascular!complications:!
All!of!these!complications!can!be!markedly!reduced!by!achieving!tight!glucose!
control!–!however*if*it*can*reduce*the*risk*of*macrovascular*disease*remains*
unknown.*It’s*the*macrovascular*complications*that*cause*death*in*the*majority*of*
type*2*diabetics.!
1) Diabetic!nephropathy:!most!important!cause!of!endQstage!renal!disease.!The!
pathologic!types!of!diabetic!neuropathy!are:!
o Nodular!glomerular!sclerosis!(KimmelstielQWilson!syndrome)!–!with!
hyaline!deposition!in!one!are!of!the!glomerulus!
o Diffuse!glomerular!sclerosis!–!hyalin!deposition!is!global!
o Isolated!glomerular!basement!membrane!thickening!
!
Microalbuminura/proteinuria:!if!microalbuminuria!is!present,!strict!glycemic!
control!is!critical!to!limit!the!progression!to!clinical!proteinuria!and!
hypertension.!Persistant!HTN!and!proteinuria!cause!a!decrease!in!GFR,!
leading!to!renal!insufficiency!and!eventually!endQstage!renal!disease.!Due!to!
this,!its!very!important!to!control!the!BP!aggressively!with!ACE!inhibitors!or!
ARB!immediately.!
o Microalbuminuria!is!the!screening!test!!–!If!you!wait!for!the!dipstick!
to!be!positive!for!proteinuria,!you!have!waited!too!long!!
o Definition!of!microalbuminuria:!30Q300!mg/day!
o It!takes!1Q5!years!for!mircoalbuminuria!to!advance!to!fullQblown!
proteinuria!–!but!with!proper!treatment!of!BP,!its!prolonged.!
!
!
!

! 154!
 2) Diabetic!retinopathy:!prevalence!is!75%!
after!20!years!of!diabetes!–!so!annual!
screening!of!all!diabetics!by!an!
opthalmologist!is!recommended!since!
this!is!the!leading!cause!of!blindness!in!
the!USA.!
o Ocular!problems!in!diabetics:!
cataracts,!glaucoma!
o Nonproliferative!retinopathy!
accounts!for!the!majority!of!
cases!
o Fundoscopic!examination!shows!hemorrhage,!exudates,!
microaneurysms!and!venous!dilation!
o These!patients!are!usually!asymptomatic!unless!retinal!edema!or!
ischemia!involves!the!central!macula!
o Edema!of!the!macula!is!the!leading!cause!of!visual!loss!in!diabetic!
patients!
o Hypertention!and!fluid!retention!worsen!this!condition!
o Proliferative!retinopathy!is!when!scarring!and!new!vessels!form!
(neovascularization)!–!can!lead!to!vitreal!hemorrhage!and!retinal!
detachment!=!leading!to!blindness!
o Possible!treatment!with!photocoagulation!
!
3) Diabetic!neuropathy:!!
o Peripheral/distal!symmetric!neuropathy:!affects!sensory!nerves!in!a!
“stocking/glove”!pattern.!Usually!begins!in!feet,!later!involves!hands.!
Numbness!and!paresthesias!are!common.!
o Loss!of!sensation!can!lead!to!ulcer!formation!–!patients!don’t!feel!the!
pain!so!there!is!no!shift!in!their!weight!to!protect!the!area!that´s!
ulcerized!–!with!the!subsequent!ischemia!of!pressure!point!areas.!
o Painful!diabetic!neuropathy:!hypersensitivity!to!light!touch!–!severe!
burning!pain,!especially!at!night!that!can!be!difficult!to!tolerate.!
Treatment:!gabapentin,!TCA!
o CN!complications,!secondary!to!nerve!
infraction:!most!often!involves!CN!3!
(oculomotor).!Diabetic!3rd!nerve!palsy:!eye!
pain,!diplopia,!ptosis,!inability!to!adduct!the!eye!
but!the!pupils!are!spared.!!
o Mononeuropathies:!median!nerve!neuropathy,!
ulnar!neuropathy,!common!peroneal!
neuropathy.!Diabetic!lumbosacral!plexopathy!is!
severe,!deep!pain!in!the!thigh!–!leading!to!
atrophy!and!weakness!in!the!thigh!and!hip!muscles.!
o Autonomic!neuropathy:!impotence!in!men,!neurogenic!bladder!with!
retention!or!incontinence,!gastroparesis!(chronic!nausea!and!
vomiting,!early!satiety),!constipation!or!diarrhea,!postural!
hypotension.!

! 155!
 microangiopathy plus polyneuropathy - ulcers on sole
4) Diabetic!foot:!caused!by!combination!of!artery!disease!(ischemia)!and!nerve!
disease!(neuropathy).!It!can!lead!to!ulcers/infections!and!may!require!
amputation.!With!neuropathy,!the!patient!doesn’t!feel!pain,!so!repetitive!
injuries!go!unnoticed!and!ultimately!lead!to!nonQhealing.!!
!
5) Increased!susceptibility!to!infection:!this!results!from!impaired!WBC!
function,!reduced!blood!supply!and!neuropathy.!Wound!healing!is!impaired!
in!diabetics,!increasing!the!risk!for!cellulitis,!candiditis,!pneumonia,!
osteomyelitis!and!polymicrobial!foot!ulcers.!Infections!of!ischemic!foot!ulcers!
may!lead!to!osteomyelitis!and!may!require!amputation.!
!
!

All forms of diabetes has risks of long-term complications. These typically

develop after 10-20 years but may be the first symptom in those who have
not received a diagnosis.

Diabetes 2x the risk of cardiovascular disease and about 75% of deaths in

diabetics are due to coronary artery disease. Other "macrovascular"
diseases are cerebrovascular stroke, and peripheral vascular disease.

The primary complications of diabetes due to damage in small blood vessels

include damage to the eyes, kidneys, and nerves. Diabetic retinopathy is
caused by damage to the blood vessels in the retina of the eye, and can result
in gradual vision loss and blindness. Diabetic nephropathy, can lead to tissue
scarring, urine protein loss, and eventually chronic kidney disease,
sometimes requiring dialysis or kidney transplant. Diabetic neuropathy, is
the most common complication of diabetes. The symptoms can include
numbness, tingling, pain, and altered pain sensation, which can lead to
damage to the skin. Diabetes-related foot problems (such as diabetic foot
ulcers) may occur, and can be difficult to treat, requiring amputation.
Additionally, PROXIMAL diabetic neuropathy causes painful muscle
wasting and weakness.

The damage to small blood vessels leads to a microangiopathy, which can

cause one or more of the following:
Diabetic cardiomyopathy leads to impaired diastolic dysfunction and heart
failure.
Diabetic nephropathy can lead to chronic renal failure, requiring dialysis.
DM is the most common cause of adult kidney failure.
Diabetic neuropathy, abnormal and decreased sensation, usually in a 'glove
and stocking' distribution starting with the feet, later often and hands. When
combined with damaged blood vessels this can lead to diabetic foot.

Other forms of diabetic neuropathy may present as autonomic neuropathy.

Diabetic amyotrophy is muscle weakness due to neuropathy.
Diabetic retinopathy: blood vessels in the retina as well as macular edema,
which can lead to severe vision loss or blindness.
Retinal damage (from microangiopathy) makes it the most common cause of
blindness among non-elderly adults in the US.
Diabetic encephalopathy is the increased cognitive decline and risk of
dementia. Various mechanisms are proposed, including alterations to the
vascular supply of the brain and the interaction of insulin with the brain.

Macrovascular disease leads to cardiovascular disease, to which accelerated

atherosclerosis is a contributor:
Coronary artery disease, leading to angina or MI
!
Diabetic myonecrosis ('muscle wasting')
! Peripheral vascular disease, which contributes to intermittent claudication
as well as diabetic foot.
Stroke (mainly the ischemic type)

! 156!
Moderation is advised with consuming alcohol and using some drugs. Alcohol inhibits glycogenesis in the liver and some drugs inhibit hunger
symptoms. This, with impaired judgment, memory and concentration caused by some drugs can lead to hypoglycemia. People with diabetes
who take insulin or tablets such as sulphonylureas should not, therefore, consume alcohol on an empty stomach but take some starchy food
(such as bread or potato crisps) at the same time as consumption of alcohol.
The type of fats in the diet is also important, with saturated fats and trans fatty acids increasing the risk and polyunsaturated and
monounsaturated fat decreasing the risk.

Topic!#46.!Dietary!in!diabetes!mellitus:!
A!wellQbalanced,!nutritious!diet!and!exercise!remains!a!fundamental!element!of!
therapy,!especially!in!type!2!diabetics.!The!ADA!recommends!that!the!percentage!of!
total!daily!calorie!intake!should!be:!
• 45Q65%!carbohydrates!
• 25Q35%!fat!
• 10Q35%!protein!
!
In!patients!with!type!2!DM,!limiting!the!carbohydrates!intake!and!substituting!some!
of!the!calories!with!monosaturated!fats!like!olive!oil,!nut!and!avacados,!can!lower!
triglycerides!and!increase!HDL!cholesterol.!In!those!patients!with!obesity!and!type!2!
DM,!weight!reduction!by!caloric!restriction!is!an!important!goal!of!the!diet.!!
!
Patients!with!type!1!or!2!DM!who!take!insulin!should!be!taught!“carbohydrate!
counting”,!so!they!can!administer!their!insulin!bolus!for!each!meal!based!on!its!
carbohydrate!content.!
!
The!current!recommendations!for!both!types!of!diabetes!continue!to!limit!
cholesterol!to!300!mg!daily!and!individuals!with!LDL!cholesterol!more!than!100!
mg/dL!should!limit!dietary!cholesterol!to!200!mg!daily.!
!
High!protein!intake!may!cause!progression!of!kidney!disease!in!patients!with!diabetic!
nephropathy!–!for!these!individuals,!a!reduction!in!protein!intake!to!0,8kg/day!(or!
about!10%!of!total!calories!daily)!is!recommended.!
!
Soluble!fibers!such!as!gums!and!pectins,!found!in!beans,!oatmeal!or!apple!skin,!tend!
to!retard!nutrient!absorption!rates!so!that!glucose!absorption!is!slower!and!
hyperglycemia!may!be!slightly!diminshed.!Due!to!this,!ADA!recommends!food!high!in!
soluble!fibers!as!a!stable!component!of!the!diet!in!diabetics.!!
!
The!glycemic!index:!
Its!an!index!of!a!carbohydrate!containing!food!and!its!determined!by!comparing!the!
glucose!excursions!after!consuming!50g!of!test!food,!with!glucose!excursions!after!
consuming!50g!of!reference!food.!

Eating!low!glycemic!index!foods!results!in!lower!glucose!levels!after!meals.!Low!
glycemic!index!foods!have!values!of!55!or!less!and!include!fruits,!vegetables,!grainy!
bread!and!pasta.!High!glycemic!index!foods!have!values!of!70!or!greater!and!include!
baked!potato,!white!bread!and!white!rice.!Even!though!its!may!not!be!possible!to!
accurately!predict!the!glycemic!index!of!a!particular!food!in!the!context!of!a!meal,!its!
resonable!to!choose!foods!with!low!glycemic!index.!

! 157!
Artifical!sweeteners!like!aspartame,!sacharin,!sucralose!and!rebiana!have!a!sweet!
taste!and!don’t!raise!blood!glucose!levels!–!and!therefore!better!to!choose!food!
containing!these!products!instead!of!sucrose.!
!
Fructose!represents!a!“natural”!sugar!substance!that!is!highly!effective!sweetener!
and!induces!only!slight!increase!in!plasma!glucose!levels!and!does!not!require!insulin!
for!its!metabolism.!However,!because!of!potential!adverse!effects!of!large!amounts!
of!fructose!on!raising!serum!cholesterol,!triglycerides!and!LDL,!it!does!not!have!any!
advantage!as!a!sweetening!agent!in!the!diabetic!diet.!
!
Sugar!alcohols!are!commonly!used!as!sweeteners!and!bulking!agents.!They!occur!
naturally!in!a!variety!of!fruits!and!vegetable!but!are!also!commercially!made!from!
sucrose,!glucose!and!starch!–!like!sorbitol,!mannitol!and!xylitol.!They!are!not!as!easily!
absorbed!as!sugar,!so!they!do!not!raise!blood!glucose!levels!as!much.!Therefore!
sugar!alcohols!are!often!used!in!food!products!that!are!labeled!as!“sugar!free”!such!
as!chewing!gum!and!candy.!
!
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! 158!
 Topic!#47.!Insulin!therapy!of!diabetes!mellitus.!DCCT!study!and!its!results:!
Insulin!therapy!is!mostly!for!type!1!diabetics!but!with!the!progression!of!type!2!DM!
and!with!increased!age,!people!with!type!2!DM!often!require!insulin!therapy!aswell.!
• Insulin!is!usually!selfQadministered!by!SC!injection!into!the!abdomen,!
buttocks,!arms!or!legs!but!given!IV!for!emergency!ketoacidosis.!
• Most!type!1!diabetics!require!0,5Q1,0!unit/kg!per!day!to!achieve!acceptable!
glycemic!control.!Start!with!a!conservative!dose!and!adjust!the!regiment!
according!to!the!patient´s!glucose!levels!
• Many!different!regimens!exist!and!every!patient!has!unique!need:!
Types of insulins depend on the time taken for onset and duration of action. It depends on the patient’s need

isophane

!
Intensive!insulin!therapy:!
• LongQacting!insulin!is!given!once!daily!in!the!evening!
• Regular!insulin!is!given!30Q45min!before!each!meal!and!should!be!adjusted!
according!to!preprandial!home!glucose!measurements!
• These!more!aggressive!therapies!have!been!shown!to!significantly!decrease!
the!incidence!of!diabetes!complications!such!as!retinopathy!and!
microalbuminuria!when!compared!to!prior!regimens.!!
• Continuous!SC!infusion!of!insulin!can!be!given!via!an!insulin!pump.!
Preprandial!boluses!are!given!in!addition!to!the!basal!infusion.!
• ATH!#With#intensive#insulin#therapy,#the#risk#for#hypoglycemia#is#a#serious#
concern!!
#
If!the!patient!is!unable/unwilling!to!carry!out!an!intensive!insulin!program:!
• Give!70/30!units!before!breakfast!and!before!the!evening!meal!for!basal!
coverage!
• Give!a!shortQacting!insulin!(regular)!for!prandial!control!if!necessary!
• Adjust!doses!according!to!fasting!and!4pm!glucose!determinations#
!
Inpatient!management!of!diabetic!patients:!
• An!insulin!sliding!scale!(SSI)!of!regular!insulin!doses!given!according!to!
bedside!fingerQstick!glucose!determinations!is!helpful!in!controlling!blood!
glucose!levels!in!the!hospital!setting.!SSI!should!be!used!as!an!addition!to!
regimens!of!intermediateQacting!insulin!because!if!SSI!is!given!alone,!
hyperglycemia!usually!results.!

The general principles of sliding scale therapy are: The amount of carbohydrate to be eaten at each meal is
pre-set. The basal (background) insulin dose doesn't change. You take the same long-acting insulin dose no
matter what the blood glucose level.

! 159!
 • Monitor!blood!glucose!4x!per!day!–!before!meals!and!at!bedtime!!
!
Modifying!insulin!doses:!
• Physical!activity:!depending!on!the!intensity!of!the!activity!–!decrease!insulin!
dosage!1Q2!units!per!20Q30!minutes!of!activity!
• During!illness:!administer!all!of!the!routine!insulin.!Episodes!of!DKA!can!occur!
during!the!illness.!
• Stress!and!diet!changes:!both!need!dosing!adjustments!
• Patients!undergoing!surgery:!they!should!get!1/3!to!1/2!of!the!usual!daily!
insulin!requirements!that!day!–!with!frequent!monitoring!and!adjustments!if!
necessary.!
!
Monitoring!glucose!levels!in!DM:!
HbA1C!gives!an!estimate!of!the!degree!of!glucose!over!2Q3!months.!The!ADA!
recommends!a!treatment!goal!of!HbA1C!<7,0%!
& >10%!is!poor!control!
& 7,0Q8,5%!is!good!control!
& <7,0%!is!ideal!
! <7.2mmol/L
The!ADA!also!recommends!keeping!fasting!blood!glucose!level!<130!mg/dL!and!peak!
postprandial!blood!glucose!<180!mg/dL.! <10.0mmol/L
!
Pictures:!
These!are!graphic!depictions!of!3!different!insulin!dosing!regimens,!illustrating!time!
of!injection!(30min!before!each!meal)!and!the!insulin!effect.!Note!that!many!
different!regimens!exist!and!each!patient!has!unique!needs:!
!
!
!
!
!
!
!
!
!
!
!
!
!

! 160!
 to test the glucose hypothesis and determine whether the complications of type 1 diabetes (T1DM) could be prevented or delayed.

DCCT!study!and!its!results:!
The!Diabetes!Control!and!Complications!Trial!(DCCT)!was!a!major!clinical!study!
conducted!from!1983!to!1993.!The!study!showed!that!keeping!blood!glucose!levels!
as!close!to!normal!as!possible!slows!the!onset!and!progression!of!eye,!kidney!and!
nerve!damage!caused!by!diabetes.!In!fact,!it!demonstrated!that!any!sustained!
lowering!of!blood!glucose,!helps!even!if!the!person!has!a!history!of!poor!control.!
!
The!DCCT!involved!1441!volunteers,!ages!13Q39,!with!type!1!DM.!The!volunteers!had!
to!have!had!diabetes!for!at!least!1!year!but!no!longer!than!15!years.!They!also!were!
required!to!have!no,!or!only!early!signs!of!diabetic!eye!disease.!
!
The!study!compared!the!effects!of!standard!control!of!blood!glucose!versus!intensive!
control!on!the!complications!of!diabetes.!Intensive!control!meant!keeping!HbA1C!
levels!as!close!as!possible!to!the!normal!value!of!6%!or!less.!Volunteers!were!
randomly!assigned!to!each!treatment!group.!
!
Affect!on!diabetic!eye!disease:!
Study!results!showed!that!intensive!therapy!reduced!the!risk!for!developing!
retinopathy!by!76%.!In!participants!who!had!some!eye!damage!at!the!beginning!of!
the!study,!intensive!management!slowed!the!progression!of!the!disease!by!54%.!
!
Affect!on!diabetic!kidney!disease:!
Findings!showed!that!intensive!treatment!prevented!the!development!and!slowed!
the!progression!of!diabetic!kidney!disease!by!50%.!
!
Affect!on!diabetic!nerve!disease:!
Study!results!showed!the!risk!of!nerve!damage!was!reduced!by!60%!in!people!on!
intensive!treatment.!
!
Affect!on!diabetesQrelated!cardiovascular!disease:!
People!with!type!1!DM!have!a!tenfold!greater!risk!of!heart!disease!compared!with!
nondiabetic!patients!because!high!blood!glucose!can!damage!the!heart!and!blood!
vessels.!That!damage!can!lead!to!heart!attacks!and!strokes!–!the!leading!cause!of!
death!for!people!with!diabetes.!When!the!initial!findings!of!the!DCCT!were!
announced!in!1993,!it!was!too!early!to!detect!the!effects!of!the!therapies!on!
cardiovascular!disease!because!patient!were!so!young!when!the!trials!started.!In!
2005,!however,!EDIC!researchers!reported!that!the!risk!of!any!heart!disease!was!
reduced!by!42%!in!people!who!had!been!in!the!intensive!treatment!group.!
Volunteers!in!the!intensive!treatment!group!also!cut!their!risk!of!nonfatal!heart!
attack,!storke!or!death!from!cardiovascular!causes!by!57%.!
!
Elements!of!intensive!management!in!the!DCCT:!
• Testing!blood!glucose!levels!4x!or!more!per!day!
• Injecting!insulin!at!least!3x!daily!or!using!an!insulin!pump!
• Adjusting!insulin!doses!according!to!food!intake!and!exercise!
• Making!monthly!visits!to!a!health!care!team!composed!of!a!physician,!nurse!
educator,!dietitian!and!behavioral!therapist!

! 161!
 Topic!#48.!Oral!antidiabetics:!
Optimal!treatment!for!type!2!diabetic!patients:!
& Glycemic!control!
& BP!control!–!goal!is!<130/85!mmHg!–!the!lower!the!better,!as!long!as!the!
patient!tolerates!it.!
& Optimization!of!serum!lipids!–!goal!is:!LDL!<100!and!HDL!>40.!
& Smoking!cessation!
& Daily!aspirin,!if!not!contraindicated!
!
Type!2!diabetic!patients!require!exercise!and!diet!as!the!initial!steps!as!well!as!oral!
hypoglycemic!drugs!if!diet!and!exercise!isn´t!enough!to!lower!the!blood!glucose!
levels.!The!current!emphasis!is!to!treat!aggressively!and!move!quickly!to!insulin!if!
needed!to!optimize!HbA1C.!The!oral!hypoglycemic!drugs!are!used!in!type!2!diabetics!
when!conservative!therapy!fails:!
• Start!with!one!agent!(metformin!is!the!best!initial!drug!therapy)!–!if!
monotherapy!fails,!use!two!agents!from!different!classes!in!combination.!
• Each!agent!has!advantages!and!disadvantages!–!so!clinical!judgement!is!
required!in!selecting!the!initial!agent.!
• Do!not!give!it!to!patients!who!cannot!eat!(for!example!because!of!illness!or!
surgery)!–!could!lead!to!serious!hypoglycemia!!
• In!patients!with!relatively!mild!disease,!use!of!these!drugs!(alone!or!in!
combination)!can!bring!glucose!levels!to!normal,!but!patients!with!severe!
disease!often!do!not!respond!adequately!–!therefore!many!type!2!diabetics!
eventually!require!insulin.!
o Oral*hypoglycemic*agents*are*effective*in*type*2*diabetes*with*
7.7 - 13
moderate*hyperglycemia*–*fasting*glucose*between*140<240*mg/dL!
o If*the*patient*has*severe*hyperglycemia*–*fasting*glucose*is*above*240*
mg/dL*then*insulin*typically*is*the*agent*if*choice*–*whether*its*type*1*
or*2.!
Drugs is used in diabetes to treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, liraglutide and pramlintide, all
are administered orally and are thus also called oral antihyperglycemic agents. Their selection depends on the nature of the diabetes, age and situation of the
person, as well as other factors.

1. BIGUANIDES reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Metformin is a biguanide, has become
the most commonly used agent for type 2 diabetes. Among common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.

Reduction in glycated hemoglobin (A1C) values for metformin is 1.5–2.0%

Metformin (Glucophage): usually the first-line medication used for treatment of type 2 diabetes. In general, it is prescribed at initial diagnosis in conjunction with
exercise and weight loss.
There is an immediate release as well as an extended-release formulation, typically for patients experiencing GI side-effects.

2. THIAZOLIDINEDIONES: also known as "glitazones," bind to PPARγ (peroxysome proliferator activated receptor gamma, a regulatory protein involved in
gene transcription. PPARs act on peroxysome proliferator responsive elements (PPRE). The PPREs influence insulin-sensitive genes, which enhance production of
insulin-dependent enzymes. The final result is better use of glucose by the cells.
Typical reductions in glycated hemoglobin (A1C) values are 1.5–2.0%.
Some examples are: rosiglitazone, pioglitazone

3. SULFONYLUREAS are insulin secretagogues, triggering insulin release by inhibiting the K/ATP channel of the pancreatic beta cells. First and Second
generation. All cause weight gain.
Typical reductions in glycated hemoglobin (A1C) values for second-generation sulfonylureas are 1.0–2.0%.
First-generation agents: acetohexamide, chlorpropamide
Second-generation agents: glipizide, glimepiride,, glycopyramide

4. NONSULFONYLUREA: MEGLITINIDES
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at
a different binding site. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.
Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.
repaglinide
nateglinide
Adverse reactions include weight gain and hypoglycemia.

5. ALPHA-GLUCOSIDASE INHIBITOR they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small
intestine. helpful in combination with other agents in type 2 diabetes.

!
Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%. 162!
miglitol, acarbose, voglibose
These medications are rarely used in the United States because of the severity of their side-effects (flatulence and bloating).
Little!bit!more!info!about!these!drugs:!
• Sulfonylureas:!they!block!the!K+!channels!of!the!BQcell,!keeping!it!
depolarized.!That!will!cause!Ca2+!influx!=!insulin!release!!Since!these!drugs!
are!working!24/7!–!but!(most)!people!are!not!eating!24/7,!they!can!lead!to!
fasting!hypoglycemia.!That’s!why!people!taking!these!drugs!are!
recommended!to!eat!more!often!during!the!day!but!in!smaller!doses.!These!
drugs!also!increase!FA!synthesis!and!storage!=!leading!to!weight!gain.!
• Metformin:!it!mimics!the!response!like!it!was!insulin!working!but!since!DM!2!
people!have!less!sensitive!insulin!receptors,!this!drug!will!“bypass”!the!
receptor!and!go!straight!into!the!cell!and!cause!the!same!intracellular!effects!
as!if!it!was!insulin!working.!The!good!thing!about!metformin!is!that!it!doesn’t!
cause!hypoglycemia!or!weight!gain!–!that’s!the!reason!why!metformin!is!so!
often!used,!since!almost!all!people!with!DM!2!are!overweight.!Metformin!
also!blocks!gluconeogensis!and!is!contraindicated!in!patients!with!renal!
failure.!!
• Other!oral!hypoglycemics,!not!mentioned!in!table!4Q6:!!
o Incretins:!augments!glucoseQdependant!insulin!secretion.!
o Pramlintide:!analog!of!amylin!–!hormone!produced!by!the!BQcells!and!
it!contributes!to!glycemic!control!by!decreasing!glucagon!release.!
o Repaglinide/nateglinide:!work!like!sulfonylureas!but!have!rapid!onset!
and!short!duration!of!action.!
!
!

! 163!
Topic!#49.!Hyperglycemic!ketoacidosis,!nonMketoacidotic!coma.!Therapy:!
!
ATH!*This*is*almost*the*same*as*I*wrote*in*topic*44*but*with*little*extra*info*so*DON’T*
SKIP*IT!*!**
!
Diabetic!ketoacidosis!(DKA)!–!also!called!hyperglycemic!ketoacidosis:!
• Key!features!of!DKA:!hyperglycemia,!positive!serum!or!urine!ketones!and!
metabolic!acidosis.!
• Its!an!acute,!lifeQthreatening!medical!emergency!that!can!occur!in!both!type!1!
and!2!diabetic!patients!–!but!more!common!in!type!1.!
through lipolysis induced by
• Its!secondary!to!insulin!deficiency!and!glucagons!excess!–!both!of!which! glucagon
contribute!to!accelerated!severe!hyperglycemia!and!accelerated!ketogenesis.!
• Severe!hyperglycemia!leads!to!osmotic!diuresis,!which!causes!dehydration!
and!volume!depletion.!
• Consequences!of!DKA!include!hyperglycemia,!ketonemia!(abnormally!high!
concentration!of!ketone!bodies!in!the!blood),!metabolic!acidosis!and!volume!
depletion.!
• Any!type!of!stress!or!illness,!like!infections!or!trauma!or!just!inadequate!
administration!of!insulin!can!precipitate!DKA.!
!
Clinical!features!of!DKA:!
• Symptoms!occur!rapidly!–!typically!in!less!than!24!hours!
• Nausea!and!vomiting!
compensatory respiratory alkalosis
• Kussmaul´s!breathing!–!rapid,!deep!breathing!due!to!the!acidosis!
• Fruity!(acetone)!breath!odor!
• Abdominal!pain!
• Marked!dehydration,!orthostatic!hypotension,!tachycardia!–!due!to!volume!
depletion!
• Polydipsia,!polyuria,!polyphagia,!weakness!
• Altered!consciousness,!drowsiness!and!frank!coma!may!occur!if!not!treated!
!
Diagnosis:! >25 but <47

1) Hyperglycemia:!serum!glucose!typically!>450!mg/dL!and!<850!mg/dL!
2) Metabolic!acidosis:!
o Blood!pH!<7,3!
o Serum!HCO3Q!<15!mEq/L! <24mmol/L
o Increased!anion!gap!due!to!production!of!ketones!
3) Ketonemia!(serum!positive!for!ketones)!and!ketonuria:!serum!levels!of!
acetoacetate,!acetone!and!betaQhydroxybutyrate!are!all!greatly!increased.!!
4) Ketonemia!and!acidosis!are!required!for!the!diagnosis!of!DKA!
!
Differential!diagnosis!of!DKA:!
• Alcoholic!ketoacidosis!
• HHNS!
• Hypoglycemia!–!altered!mental!status,!abdominal!pain!and!acidosis!!
• Sepsis!or!intoxications!–!like!methanol,!ethanol!or!ethylene!glycol!!

! 164!
Treatment:!
& Give!insulin!immediately!after!the!diagnosis!is!established!–!start!with!a!
priming!dose!of!0,1!units/kg!IV!and!then!give!infusion!of!0,1!units/kg!per!
hour.!Be!certain!that!the!patient!is!not!hypokalemic!before!giving!insulin!!
Continue!the!insulin!until!the!anion!gap!closes!and!metabolic!acidosis!is!
corrected,!then!begin!to!decrease!the!insulin.!Give!SC!insulin!when!the!
patient!starts!eating!again.!
! As*insulin*is*given,*it*causes*a*shift*of*potassion*into*cells,*resulting*in*a*
hypokalemia,*which*can*happen*very*rapidly.*That’s*the*reason*why*
we*have*to*be*certain*that*the*patient*is*not*hypokalemic*before*
giving*the*insulin*!!
& Fluid!replacement!with!normal!saline!–!add!5%!glucose!once!the!blood!
glucose!reaches!250!mg/dL!to!prevent!hypoglycemia.!
& Replace!potassium!prophylatically!with!IV!fluids!
& Monitor!potassium,!magnesium!and!phosphate!levels!very!closely!
& ATH!#Cerebral#edema#can#result#if#glucose#levels#decrease#too#rapidly!!
#
Hyperosmolar!hyperglycemic!nonketotic!syndrome!(HHNS)!–!can!also!be!called!
nonQketoacidotic:!
HHNS!has!a!higher!mortality!rate!than!DKA!but!its!less!common!than!DKA.!This!may!
be!because!many!HHNS!patients!are!elderly!with!other!comorbid!conditions!for!
example!heart,!renal!or!pulmonary!disease.!! >33
• Key!features:!severe!hyperosmolarity!(>320!mOsm/L),!hyperglycemia!(>600!
mg/dL),!dehydration!and!acidosis!and!ketosis!are!absent!(unlike!DKA).!
• It’s!a!state!of!severe!hyperglycemia,!hyperosmolarity!and!dehydration!that!is!
typically!seen!in!elderly!type!2!DM!patients.!
• Low!insulin!levels!lead!to!hyperglycemia.!Severe!hyperglycemia!causes!an!
osmotic!diuresis,!leading!to!dehydration.!
• Ketosis!and!acidosis!are!typically!absent!or!minimal!since!ketogenesis!is!
minimal!because!small!amount!of!insulin!is!released!to!blunt!
counterregulatory!hormone!release!(glucagons).!
• Severe!dehydration!is!due!to!continued!hyperglycemic!diuresis!and!the!
patient!is!unable!to!drink!enough!fluids!either!due!to!lack!of!access!in!
elderly/bedridden!patients!or!due!to!inadequate!thirst!drive.!
• Precipitating!events!are!similar!to!those!of!DKA!
!
Clinical!features!of!HHNS:!
• Thirst,!polyuria!
• Hypotension,!tachycardia!–!due!to!extreme!dehydration!and!volume!
depletion!
• CNS!findings!and!focal!neurologic!signs!are!common!(for!example!seizures)!
due!to!the!hyperosmolarity.!
• Lethargy!and!confusion!may!develop,!leading!to!convulsions!and!coma!
!
!
!
!

! 165!
Diagnosis:! >50
1) Hyperglycemia:!serum!glucose!typically!higher!than!DKA!and!frequently!>900!
mg/dL.!
2) Hyperosmolarity:!serum!osmolarity!>320!mOsm/L!
3) Serum!pH:!>7,3!(NO!acidosis!)!
4) Serum!HCO3M:!>15!
5) BUN!(blood!urea!nitrogen)!is!usually!elevated!and!prerenal!azotemia!is!
common!!
!
Treatment:!
• Fluid!replacement!is!most!important!–!give!normal!saline,!1L!in!the!first!hour,!
another!liter!in!the!next!2!hours!and!then!switch!to!half!normal!saline!once!
the!patient!stabilizes!
• Glucose!levels!are!lowered!as!the!patient!is!rehydrated!but!the!patient!still!
requires!insulin!!–!Give!initial!bolus!of!5Q10!units!IV,!followed!by!continous!
lowQdose!infusion!of!2Q4!units/hour.!
14
• When!glucose!levels!reach!250!mg/dL,!add!5%!glucose!!
• In!patients!with!cardiac!disease!or!renal!insufficiency,!avoid!volume!overload!
–!can!lead!to!CHF.!But!its!still!needed!to!give!fluids.!!
• Very!rapid!lowering!of!blood!glucose!can!lead!to!cerebral!edema!in!children!
–!just!as!in!DKA!!
!

>25
50

!
!
!
!
!
!
!
!

! 166!
 Topic!#50.!Hypoglycemia:!
Physiologic!responses!to!hypoglycemia:! 5.0 5.5
1) When!glucose!levels!approach!80!mg/dL!(normal!value!is!100!mg/dL),!insulin!
levels!decrease.!This!decrease!is!normally!enough!to!prevent!hypoglycemia.!
2) As!glucose!levels!decrease!further,!glucagon!levels!increase!but!glucagon!is!
the!first!line!of!defense!against!more!severe!hypoglycemia.!
3) Epinephrine!is!the!next!hormone!to!combat!hypoglycemia.!Cortisol!and!other!
catecholamines!also!play!a!role.! 2.8
4) As!glucose!levels!decrease!to!50!mg/dL!and!below,!symptoms!begin.!
!
In!diabetic!patients,!if!severe!neuropathy!is!present,!the!autonomic!response!
(epinephrine)!to!hypoglycemia!is!not!activated.!This!leads!to!neuroglycopenic!
symptoms.!Its!common!for!diabetic!patients!to!become!hypoglycemic!with!
conventional!therapy!(insulin!or!oral!hypoglycemics).!With!longstanding!disease!in!
which!they!lose!their!neurogenic!symptom!response!to!hypoglycemia,!patients!do!
not!recognize!the!impeding!hypoglycemia!and!may!even!have!a!seizure!or!enter!a!
coma.!
!
General!characteristics!of!hypoglycemia:!
• The!primary!organ!at!risk!in!hypoglycemia!is!the!brain.!The!brain!uses!glucose!
as!its!main!source!of!energy,!except!when!using!ketone!bodies!during!fasting.!
Unlike!other!tissues,!the!brain!cannot!use!free!fatty!acids!as!an!energy!
source.!
• Hypoglycemia!is!really!due!to!an!imbalance!between!glucagon!and!insulin.!
• If!there!is!no!correlation!between!the!symptoms!and!low!glucose!levels!(for!
example!patient!has!symptoms!when!glucose!levels!are!normal),!an!
underlying!disorder!of!glucose!metabolism!is!unlikely!–!i.e.!the!patient!does!
not!have!true!hypoglycemia.!
!
Causes:!
• Drug!induced:!taking!too!much!insulin!is!a!common!problem!in!diabetic!
patients!attempting!tight!control!of!their!disease.!
• Factitious!hypoglycemia!(“artificially!made”!hypoglycemia):!if!the!patient!
took!insulin!surreptitiously,!there!will!be!a!high!blood!insulin!level!and!a!low!
blood!CQpeptide!levels,!because!exogenous!insulin!does!not!contain!CQ
peptide.!Patients!taking!exogenous!insulin!will!also!develop!antiQinsulin!
antibodies,!which!can!be!measured.!If!the!patient!took!sulfonylurea,!check!
urine!or!serum!for!levels!of!this!drug.!
• Insulinoma:!tumor!of!the!pancreas!that!produces!excessive!amounts!of!
insulin.! elevated insulin, elevated C-peptide
• Ethanol!ingestion!
• Postoperative!complications:!after!gastric!surgery!due!to!rapid!gastric!
emptying!
• Reactive/idiopathic!hypoglycemia:!symptoms!occur!2Q4!hours!after!a!meal,!
rarely!indicates!a!serious!underlying!disorder.!!
Not enough cortisol, such as in Addison's disease, not enough glucagon, or not enough epinephrine can result in hypoglycemia.
The most common cause of hypoglycemia is medications used to treat DM such as insulin, sulfonylureas, and biguanides. Risk is greater in diabetics who
have eaten less than usual, exercised more than usual, or drunk alcohol.
Serious illness may result in hypoglycemia. Severe disease of nearly all major organ systems can cause hypoglycemia as a symptoms.
Hospitalized persons, in ICU or those prevented from eating, can develop hypoglycemia.
Other causes of! hypoglycemia include kidney failure, tumors, liver disease, hypothyroidism, starvation, inborn errors of metabolism,
167!
severe infections,
reactive hypoglycemia, and a number of drugs including alcohol.
Inborn errors of metabolism may include the lack of an enzyme to make glycogen (glycogen storage type 0).
Clinical!features:! 2.5-2.8 mmol/L
• Symptoms!occur!at!a!blood!glucose!level!of!40Q50!mg/dL!
• Elevated!epinephrine!levels!cause:!
o Sweating!
o Tremors!
o Increased!BP!and!pulse!
o Anxiety!!
o Palpitations!
• Neuroglycopenic!symptoms:!decreased!glucose!for!the!brain!(CNS!
dysfunction)!results!in:!
o Irritability!
o Behavioral!changes!
o Weakness!
o Drowsiness!
o Headache!
o Confusion!
o Convulsions!
o Coma!and!even!death!!
!
Diagnosis:!
• Blood!glucose!levels:!symptoms!usually!begin!when!its!below!50!mg/dL!
• Whipple´s!triad:!its!used!to!diagnose!true!hypoglycemia,!for!example!due!to!
underlying!disease!like!insulinoma:!
a) Hypoglycemic!symptoms!are!brought!on!by!fasting!
b) Blood!glucose!<50!mg/dL!during!symptomatic!attack!
c) Glucose!administration!brings!relief!of!symptoms!!
• Lab!tests:!measure!serum!insulin,!CQpeptide!and!glucose!when!symptoms!
occur!–!an!overnight!fast!may!be!sufficient!to!produce!symptoms.!
• 72!hour!fast:!used!to!diagnose!insulinoma!if!its!suspected!!
!
!
!
!
!
!
!

! 168!
 Reactive hypoglycemia, or postprandial hypoglycemia, is a term describing recurrent episodes of
symptomatic hypoglycemia occurring within 4 hours after a high carbohydrate meal in people who do not
have diabetes.

Treatment:! glucagon injection

1) If!the!patient!can!eat,!give!sugarQcontaining!foods.!If!not!then!give!½!to!2!
ampules!of!D50W!(50%!Dextrose!in!water)!IV.!
2) Repeat!administration!of!D50W!as!necessary!but!switch!to!D10W!as!clinical!
condition!improves!and!glucose!level!is!approximately!>100!mg/dL.!
3) Appropriate!management!of!underlying!cause!–!for!example!diabetes!or!
insulinoma!
4) If!reactive/idiopathic!hypoglycemia!is!suspected,!dietary!interventions!are!
appropriate!
5) If!the!patient!is!an!alcoholic,!give!thiamine!before!administering!glucose!to!
avoid!Wernicke´s!encephalopathy.!
!
!

!
!
!
!
! with diabetes levels below 3.9 mmol/L (70 mg/dL) is diagnostic. In adults without diabetes, symptoms related to low blood
In people
sugar, low blood sugar at the time of symptoms, and improvement when blood sugar is restored to normal confirm the diagnosis.
!
Otherwise a level below 2.8 mmol/L (50 mg/dL) after not eating or following exercise may be used.
!
Other tests that may be useful in determining the cause include insulin and C peptide levels.

! people with diabetes, prevention is by matching the foods eaten, with the amount of exercise, and the medications used. When
Among
! feel their blood sugar is low, testing with a glucose monitor is recommended. Some people have few initial symptoms of low
people
blood sugar and frequent routine testing in this group is recommended. Treatment of hypoglycemia is by eating foods high in simple
! or taking dextrose. If a person is not able to take food by mouth, an injection of glucagon may help.
sugars
!
!
The term "hypoglycemia" is sometimes incorrectly used to refer to idiopathic postprandial syndrome, a controversial condition with
similar symptoms that occur following eating but with normal blood sugar levels
!
!
!
!
!
!
!
!
!
!
!
!
!
!

! 169!
Topic!#51.!Gout:!
Gout!is!a!metabolic!disease!of!a!heterogenous!nature,!often!familial!(if!parent!has!it,!
7Q9%!chance!of!the!child!to!get!gout!as!well).!It’s!due!to!abnormal!amounts!of!urates!
(hyperuricemia,!serum!uric!acid!levels!>!6,8!mg/dL!=!404,5!mcmol/L)!in!the!body.!
Why!does!it!happen,!either!1!or!2,!sometimes!both,!or!3:!
1. Primary!gout!=!Overproduction!of!uric!acid!
2. Primary!gout!=!Underexcretion!of!uric!acid!
3. Secondary! gout! =! related! to! medication! use! (diuretics,! low! dose! aspirin,!
cyclosporine! and! niacin),! myeloproliferative! disorders,! multiple! myeloma,!
hemoglobinopathies,! chronic! kidney! disease,! hypothyroidism,! psoriasis,!
sarcoidosis! and! lead! poisoning.! Alcoholic! ingestion! promotes! hyperuricemia!
by!increasing!urate!production!and!decreases!renal!excretion!of!uric!acid.!!
The! acute! inflammation! is! beleved! to! be! initiated! by! ingestion! of! uncoated! urate!
crystals!by!monocytes!and!synoviocytes.!Once!inside!the!cells!the!gout!crystals!are!
processes! via! receptors! and! inflammasomes! that! in! turn! release! a! variety! of!
cytokines!capable!of!mediating!inflammation.!!
Uric! acid! kidney! stones! are! present! in! 5Q10%! of! the! population! with! gouty! arthritis!
and!it!correlates!highly!with!level!of!hyperuricemia.!!
Dramatic!therapeutic!response!to!NSAIDs!
Signs!and!symptoms:!
• About!90%!of!patients!with!primary!gout!are!men,!usually!over! 30! years!of!
age.!In!women!the!onset!is!usually!postmenopausal!
• Acute!onset,!usually!monoMarticular!and!often!occurs!at!night!(nocturnal).!!
• The! attacks! are! usually! recurrent! and! often! involving! the! first! MTP! joint.!
Feet,!ankle!and!knees!are!also!commonly!affected.!!
• Gouty!attacks!may!also!develop!in!periarticular!soft!tissues!such!as!the!arch!
of!the!foot.!
• Distribution!is!usually!asymmetrical!
• PolyMarticular! involvement! is! more! common! in! patients! with! long! standing!
disease.! With! chronicity,! urate! deposits! and! subcutaneous! tissue,! bone,!
cartilage,!joints!and!other!tissues.!!
• Intense!pain!
• Swollen!joint!and!very!tender!
• Skin!is!tense,!warm!and!dusky!red!
• Fever!is!common!(39°C)!
• Local!desquamation!and!pruritus!during!recovery!(not!always!present)!
• Characteristic!lesion!is!tophus!=!a!nodular!monosodium!urate!monohydrate!
crystal!with!an!associated!foreign!body!reaction.!Tophi!are!found!in!cartilage,!
subcutaneous! tissue! and! periarticular! tissue! "! external! ears,! feet,!
olecranon,!prepatellar!bursae!and!hands.!Urates!have!been!demonstrated!in!
synovial! tissues!(and! fluid)! during! acute! gout! attack.!Tophi!usually!develop!
years!after!the!initial!attack.!
• May! develop! without! apparent! precipitating! factors! or! may! follow! rapid!
increases!or!decreases!in!serum!urate!levels.!It!may!be!related!to!medication!

! 170!
 change!(diuretics,!low!dose!aspirin,!cyclosporine!and!niacin)!or!alcohol!excess!
(particularly!beer)!or!in!a!fasting!patient!(changes!in!metabolism!etc.).!!
• Asymptomatic!periods!of!months!or!years!commonly!follow!the!initial!acute!
attack!
• If!there!are!repeated!attacks!through!years!of!gouty!arthritis!and!untreated!
hyperuricemia,! gout! can! evolve! into! a! chronic,! deforming! polyarthritis! of!
upper!and!lower!extremities!that!mimics!rheumatoid!arthritis.!!
Laboratory!findings:!
• Serial! measurements! of! serum! uric! acid! detect! hyperuricemia! in! 95%! of!
patients,! however! a! single! determination! during! an! acute! flair! of! gout! is!
normal! in! up! to! 25%! of! the! cases.! Thus,! a! normal! serum! uric! acid! level!
tophus: a deposit of uric therefore!does!not!exclude!gout.!
acid crystals, in the form of
monosodium urate crystals, • During!an!attack!the!leukocyte!count!is!usually!elevated!
in people with longstanding
hyperuricemia. Tophi are • Identification# of# sodium# urate# crystals# in# joint# fluid# or# material# aspirated#
pathognomonic for the
disease gout. Most people from#a#tophus#establishes#the#diagnosis.#
with tophi have had
previous attacks of acute o The! crystals! which! may! be! extracellular! or! found! within! neutrophils!
arthritis, eventually leading
to the formation of tophi. are! needleQlike! and! negatively! birefringent! when! examined! by!
Chronic tophaceous gout is
known as Harrison polarized!light!microscopy.!!
Syndrome.
!

!
!
Imaging:!!
Early! in! the! disease! radiographs! show! no! changes.! Later,! punchedQout! lesions! with!
an!overhangin!rim!of!cortical!bone!(“rat!bite”)!develop.!When!they!are!adjacent!to!a!
soft!tissue!tophus,!they!are!diagnostic!of!gout.!!
Differential!diagnosis:!!
• Cellulitis! Calcium pyrophosphate dihydrate (CPPD) crystal
deposition disease, also known as pseudogout is a
• Acute!pyogenic!arthritis! rheumatologic disorder with varied symptoms and
signs arising from the accumulation of crystals of
• Pseudogout! calcium pyrophosphate dihydrate in the connective
tissues.
• Rheumatoid!arthritis!(when!chronic)!

! 171!
 Treatment:! remember! that! asymptomatic! hyperuricemia! does! NOT! need! to! be!
treated!!
Acute!attacks:!
• NSAIDs! "! Naproxen! 500mg! x2! daily! or! Indomethacin! 25Q50! mg! every! 8!
hours,! should! be! continued! until! the! symptoms! have! resolved! (usually! 5Q10!
Colchicine inhibits microtubule days).!
polymerization by binding to
• Colchicine!"!this!is!good!in!acute!attacks!provided!the!duration!of!the!attack!
tubulin. Availability of tubulin
is essential to mitosis, so is!less!than!36!hours.!It!should!be!administered!orally!–!first!a!loading!dose!
colchicine functions as a
"mitotic poison" or spindle 1.2mg! followed! by! a! dose! of! 0.6mg! 1! hour! later! and! then! dosing! for!
poison.
prophylaxis!0.6mg!1Q2x!per!day,!beginning!12!hours!later.!
colchicine also inhibits • Corticosteroids! "! mostly! used! in! patients! with! contraindications! to! use!
neutrophil motility and
activity, leading to a net anti- NSAIDs!(peptic!ulcer,!impaired!kidney!function,!allergies!etc.).!corticosteroids!
inflammatory effect. may! be! given! IV! (methylprednisolone! 40mg/day)! or! orally! (prednisone! 40Q
This has proven useful in the
treatment of acute gout flares. 60mg/day).! These! steroids! can! be! given! for! 5Q10! days! and! then! discontinue!
(no!need!to!taper!down).!Or!give!the!full!dose!for!2Q5!days,!and!then!tapered!
over! 7Q10! days.! You! can! also! inject! the! affected! joint! with! steroids!
(triamcinolone! 10Q40mg,! depending! on! the! size! of! the! joint).! You! should!
check!for!bacteria!in!synovial!joint!before!doing!this!!Because!gout!and!septic!
arthritis!can!coexist.!
• InterleukinM1! inhibitors! "! anakinra! (interleukin! receptor! antagonist),!
canakinumab! (monoclonal! antibody! against! interleukin! 1! beta),! rilonacept,!
have! high! efficacy! for! management! of! gout,! however! have! not! yet! been!
approved!by!FDA!in!USA!for!this!indication.!!
Between!attacks:!
• Diet! "! avoid! alcohol! (especially! beer),! moderation! eating! foods! with! high!
Red meat and organ meats (liver)
Refined carbohydrates (white purine,!avoid!organ!meats!and!beverages!sweetened!with!high!fructose!corn!
bread, white rice, pasta, sugar) syrup.!High!liquid!intake!is!important!(a!daily!urinary!output!of!2L!or!more),!it!
Processed foods (chips, snack
foods, frozen dinners) will! aid! urate! excretion! and! minimize! the! urate! precipitation! in! the! urinary!
Sugary beverages
Alcohol
tract.!
• Avoidance! of! hyperuricemic! medications! "! thiazide,! loop! diuretics,! niacin,!
low!dose!aspirin.!
• Colchicine! prophylaxis! "! can! be! used! long! term! in! patient! who! have! mild!
hyperuricemia!and!few!gout!attacks.!It!can!also!be!used!when!urate!lowering!
therapy!(see!drugs!below)!is!started,!to!suppress!the!attacks!precipitated!by!
abrupt!changes!in!the!serum!acid!level.!
• Reduction!of!serum!uric!acid!"!when!a!person!has!frequent!attacks!(<2!per!
year),!tophaceous!deposits,!or!chronic!kidney!disease.!Goal!is!to!maintain!uric!
acid!levels!at!or!below!6mg/dL!or!357!mcmol/L.!!
o Xanthine! oxidase! inhibitor! (allopurinol! or! febuxostat)! "! first! line!
treatment.!This!drug!blocks!the!final!enzymatic!step!in!the!production!
of!uric!acid.!!
Side! effects! of! allopurinol:! hypersensitivity! (2%)! which! can! be! life!
threatening,! may! progress! to! epidermal! necrolysis,! vasculitis,! and!

! 172!
 hepatitis.!If!rash!develops!patient!should!stop!immediately!taking!the!
drug.!Usually!allopurinol!is!titrated!up!to!300mg!per!day,!max!dose!is!
800mg.!
o Uricosuric! drugs! (probenecid)! "! second! line! treatment.! They! block!
the! tubular! reabsorption! of! filtered! urate! in! kidney,! thereby!
increasing!uric!acid!excretion!by!the!kidney.!Probenecid!should!not!be!
used!if!creatinine!clearance!is!<!50ml/min.!To!reduce!risk!of!uric!acids!
kidney! stone,! patient! is! adviced! to! increase! their! fluid! intake! and!
some! clinicians! should! consider! prescribing! alkalizing! agent,! to!
maintain!urine!pH!>!6,0.!! because acidic urine precipitate uric acid stones
!
o Uricase! (pegloticase)! "! must! be! administered! IV! (8mg! every! 2!
weeks)! and! is! indicated! for! the! rare! patient! with! refractory! chronic!
tophaceous!gout.!This!drug!has!a!“black!box!warning”!and!should!only!
be! administered! by! health! care! professionals! prepared! to! manage!
anaphylactic!shock!and!other!serious!infusion!reaction.!!

!
!
!
Medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of
kidney ! stones, and for the high uric acid levels that can occur with CHEMOTHERAPY.
It is taken by mouth or IV.
!
Allopurinol is a purine analog; it is a isomer of hypoxanthine and is an inhibitor of the xanthine oxidase. XO is
!
responsible for the oxidation of hypoxanthine and xanthine, resulting in the production of uric acid.
!
In addition to blocking uric acid production, inhibition of XO causes an increase in hypoxanthine and xanthine. While
xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and
!
guanosine monophosphates (AMP and GMP). Increased levels of these may cause feedback inhibition of the first and
!
rate-limiting enzyme of purine biosynthesis.
!
Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.

! 173!
 Porphyria is a group of rare hereditary disease in which porphyrins build up, affecting the skin or nervous system.

Symptoms of acute porphyria: abdominal pain, chest pain, vomiting, confusion, constipation, fever, and seizures. These symptoms
typically come and go with attacks that last for days to weeks. Attacks may be triggered by alcohol, smoking, stress, or certain
medications. If the skin is affected, blisters or itching may occur with sunlight exposure.
Porphyria is due to a mutation in one of the genes that makes heme. Some types are AD and some are AR.

Aquired - Porphyria cutanea tarda may also be due to increased iron in the liver, hepatitis C, alcohol, or HIV/AIDS. The underlying
Topic!#52.!Porphyria:! mechanism results in a decrease in the amount of heme produced and a build up of porphyrins involved in making heme.
Porphyria!refers!to!a!group!of!disorders!that!result!from!a!buildup!of!natural!
chemicals!that!produce!porphyrin,!which!is!essential!for!the!production!of!heme,!
component!of!hemoglobin.!A!shortage!of!any!of!those!enzymes,!needed!for!heme!
production!can!create!an!excess!buildup!of!certain!compounds!but!the!specific!type!
of!porphyria!is!determined!by!which!enzyme!is!lacking.!Porphyria!mainly!affects!the!
nervous!system!and!skin!but!can!also!affect!other!organs.!The!signs!and!symptoms!
can!vary,!depending!on!the!specific!type!and!severity.!High!levels!of!porphyrins!can!
cause!significant!problems.!!
!
There!are!two!general!categories!of!porphyria!–!acute,!which!mainly!affects!the!
nervous!system!and!cutaneous,!which!mainly!affects!the!skin.!Some!types!of!
porphyria!have!both!nervous!system!symptoms!and!skin!symptoms,!and!others!have!
mainly!one!or!the!other.!
Non-acute porphyrias are X-linked dominant
! protoporphyria (XLDPP), congenital erythropoietic
ACUTE porphyrias are acute intermittent porphyria porphyria (CEP), porphyria cutanea tarda (PCT), and
(AIP), variegate porphyria (VP), amino levulinic acid erythropoietic protoporphyria (EPP).
dehydratase deficiency (ALAD) and hereditary
coproporphyria (HCP). None of these are associated with acute attacks; their
primary manifestation is with skin disease. For this reason,
They primarily affect the nervous system, resulting in these 4 porphyrias — along with two acute porphyrias, VP
acute attacks. The major symptom of an acute attack is and HCP, that may also involve skin manifestations — are
abdominal pain, vomiting, hypertension and called cutaneous porphyrias. Skin disease is encountered
tachycardia. The most severe neurological where excess porphyrins accumulate. Porphyrins are
complications: motor neuropathy (dysfunction of the photoactive, and exposure to light results in promotion of
peripheral nerves that innervate muscle), which leads to electrons to higher energy levels. When these return to the
muscle weakness and quadriplegia and CNS symptoms resting energy level or ground state, energy is released
such as seizures and coma. (fluorescence) . This causes local skin damage.

!
!
Porphyria!cutanea!tarda:!
• It’s!the!most!common!type!of!porphyria!
• Cases!are!spordiac!or!hereditary!
• The!disease!is!associated!with!ingestion!of!certain!medications!like!estrogens!
and!liver!disease!from!alcoholism,!hemochromatosis!or!hepatitis!C.!
• Prevention:!barrier!sun!protection!with!clothing!is!required!
• Pseudoporphyria:!It´s!when!people!have!skin!lesions!identical!to!those!of!
porphyria!cutanea!tarda!and!biopsy!results!will!also!be!the!same.!In!these!
patients!the!urine!porphyrins!are!normal.!This!is!seen!in!patients!undergoing!
dialysis!and!in!those!taking!certain!medications!like!tetracyclins!and!NSAIDS;!
especially!naproxen.!
!
! Inherited mutations in the UROD gene cause about 20% of cases (the other
80% are sporadic).
!
UROD makes an enzyme called uroporphyrinogen decarboxylase.
!

! 174!
Clinical!findings:!
• Painless!blistering!and!fragility!of!the!skin!of!the!
dorsal!surface!of!the!hands!
• Facial!hypertrichosis!–!abnormal!hair!growth!
• Hyperpigmentation!!
! blisters on the sun exposed areas, skin fragility, erosions, scars, milia,
hyperpigmentation, hypertrichosis
Diagnosis:!
• Urine:!urinary!uroporphyrins!are!elevated!twoQ!to!fivefold!above!
coproporphyrins!
• Liver!function!tests:!they!are!abnormal,!with!evidence!of!hepatitis!C!
infection,!increased!liver!iron!stores!and!hemochromatosis!gene!mutations.!
!
Treatment:!
& Stop!all!triggering!agents!like!medications!and!alcohol!
& Phlebotomy!without!oral!iron!supplementation!will!improve!it!!
& Very!lowQdose!antimalarial!medication;!hydroxychloroquine!will!increase!the!
excretion!of!porphyrins!
& Deferasirox,!iron!chelator!can!also!improve!this!disease!
& Treatment!is!continued!until!the!patient!is!asymptomatic!
!
Acute!intermittent!porphyria:!
This!type!of!porphyria!has!the!most!serious!consequences,!usually!presents!in!
adulthood!and!is!inherited!in!an!autosomal!dominant!way!–!even!though!it!remains!
clinically!silent!in!most!patients!who!carry!the!mutation.!Its!caused!by!a!partial! porphobilinogen deaminase.
deficiency of the enzyme

deficiency!of!hydroxymethylbilane!synthase!activity,!leading!to!increased!excretion!
of!aminolevulinic!acid!and!porphobilinogen!in!the!urine.!
• Clinical!illness!usually!develops!in!women!
• Symptoms!begin!in!the!teens!but!can!begin!after!menopause!in!rare!cases!
• Cutaneous!photosensitivity!is!ABSENT!
• Attacks!are!precipitated!by!many!factors,!like!drugs!(sulfonamides,!
barbiturates)!or!infections!
• Prevention:!avoid!precipitating!factors!like!drugs.!Starvation!diets!or!
prolonged!fasting!can!also!cause!attacks!and!must!be!avoided.!
!
Clinical!findings:!
Severe and poorly localized abdominal pain
• Intermittent!(unexplained)!abdominal!pain!of!varying!severity!–!the!
abdominal!pain!is!neurologic,!it!may!be!due!to!abnormalities!in!autonomic!
innervation!in!the!gut.!But!since!its!neurologic!in!origin,!fever!and!
leukocytosis!is!absent.!
• Any!part!of!the!nervous!system!may!be!involved!–!with!evidence!for!
autonomic!and!peripheral!neuropathy.!
• Peripheral!neuropathy!can!be!symmetric!or!asymmetric,!mild!or!severe!–!if!
severe,!it!can!even!lead!to!quadriplegia!with!respiratory!paralysis.!
• Other!CNS!manifestations:!seizures,!altered!consciousness,!psychosis.!
!
Autonomic neuropathy: Urinary symptoms such as painful urination, urinary retention, urinary incontinence, or dark urine
!
Psychiatric signs and symptoms of AIP: anxiety, agitation, hallucinations, delirium, or depression.
!
Signs that suggest dysfunction of the autonomic nervous system may be evident including tachycardia, hypertension, sweating,
restlessness, and tremor. Other neurologic signs and symptoms of AIP include peripheral neuropathy and abnormal sensations.
Proximal muscle weakness typically beginning in the arms is characteristic; the muscle weakness seen in AIP can progress to
! include the muscles of breathing and can be fatal.
175!
Diagnosis:!
Electrolyte disturbances such as low blood sodium may be seen due to SIADH when the
• Hyponatremia! HYPOTHALAMUS is involved in the disease process.
• Urine!analysis:!increased!amount!of!porphobilinogen!in!the!urine!during!an!
acute!attack.!Freshly!voided!urine!is!of!normal!color!but!may!turn!dark!upon!
standing!in!light!and!air.!
!
Treatment:!
& HighQcarbohydrate!diet!diminishes!the!number!of!attacks!in!some!people!
& Acute!attacks!may!be!lifeQthreatning!and!require!prompt!diagnosis,!
withdrawal!of!the!inciting!agent!if!possible!and!treatment!with!analgesics!and!
IV!glucose!in!saline!and!hematin.!!
& Liver!transplantation!for!patients!with!poorly!controlled!disease!by!medical!
therapy!
!
Erythropoietic!porphyria:! ferrochelatase
uroporphyrinogen III decarboxylase
• Its!primarily!a!disorder!of!bone!marrow!heme!synthesis.!Deficient!activity!of!
the!enzyme!uroprophyrinogen!III!synthase!in!erythrocyte!precursor!cells!
causes!a!shift!of!the!pathway!of!heme!synthesis.!
• The!accumulated!porphyrinogens!are!spontaneously!oxidized!to!their!
corresponding!porphyrins,!which!are!waterQsoluble!photosensitizers!with!a!
reddish!hue.!These!porphyrins!are!released!from!the!maturing!erythrocytes!
into!the!plasma!and!are!excreted!by!renal!mechanism!–!producing!a!portQ
wine!colored!urine.!
• Autosomal!recessive!trait!
• Clinical!features!are!cutaneous!photosensitivity!problems:!blisters,!erosions!
and!scarring!of!lightQexposed!skin.!Other!clinical!manifestations:!
o Damage!of!cartilage!and!bones!
o Hypertrichosis!!
o ReddishQcolored!urine!
o Hemolytic!anemia!can!be!mild!or!severe.!It!can!cause!hypersplenism!
in!more!serious!cases.!Also,!hypertrophy!of!the!bone!marrow!in!such!
cases!can!lead!to!osseous!fragility!and!pathologic!fractures.!
• Treatment:!absolute!avoidance!of!sun!exposure!is!crucial.!
!
Variegate!porphyria:!
• Inherited!as!an!autosomal!dominant!trait!
• Manifestations!may!include!cutaneous!photosensitivity,!systemic!symptoms!
arising!from!neurologic!dysfunction!or!both.!
• Since!most!attacks!are!drug!induced,!minimizing!exposure!to!these!drugs!is!
important.!
!
Many people with this disorder never experience symptoms. When symptoms occur: skin damage, abdominal
! pain, vomiting, diarrhoea and constipation. During an attack, a person may also experience muscle weakness,
! seizures, and mental changes such as anxiety and hallucinations: BOTH CNS AND CUTANEOUS
! SYMPTOMS

! These signs and symptoms are triggered by nongenetic factors such as certain drugs, dieting or fasting, certain
! hormones and stress.

! 176!
Copro!porphyria:!
• Inheritance!is!autosomal!dominant.!deficiency of the enzyme coproporphyrinogen oxidase
• Many!persons!with!this!disorder!remain!asymptomatic!
• Attacks!may!be!triggered!by!drugs!or!by!fasting,!which!boosts!heme!synthesis!
–!this!is!the!reason!why!the!management!of!attacks!is!to!eat!highQ
carbohydrate!diet!–!to!decrease!heme!synthesis.!
• Clinical!features:!abdominal!pain,!neuropathies,!constipation!and!skin!
changes!–!but!neurologic!problems!are!more!common.!The!etiology!of!the!
skin!disease!may!be!the!deposition!of!formed!porphyrins!in!the!skin!that!
react!with!sunlight!and!lead!to!skin!damage.!
!
Treatment!approaches!for!porphyria:!
1) The!goal!in!managing!an!acute!attack!is!to!decrease!heme!synthesis!and!to!
reduce!the!production!of!porphyrin!precursors.!
2) For!mild!attacks!–!high!carbohydrate!diet!containing!a!lot!of!glucose!and!
energy!is!adviced!along!with!supporting!measures!for!up!to!48!hours.!Also,!
high!oral!dose!of!glucose!can!inhibit!heme!synthesis.!IV!glucose!solutions!can!
be!used!in!patients!who!cannot!eat.!
3) Severe!attacks,!especially!those!involving!severe!neurologic!symptoms!–!give!
hematin!4mg/kg/day!for!4!days!–!this!drugs!causes!heme!biosynthesis!to!
decrease.!Patients!with!severe!attacks!should!be!hospitalized!for!symptom!
control!and!monitoring!of!fluid!and!electrolyte!balance!–!as!well!as!
cardiovascular,!respiratory!and!neurologic!functions.!
4) Pain!control!is!best!achieved!with!narcotics,!high!doses!are!typically!required.!
5) For!seizure!control,!give!gabapentin.!Most!of!the!classic!antiseizure!drugs!are!
contraindicated!in!acute!attacks!of!porphyria!but!IV!diazapam!is!considered!
to!benefit!and!outweights!the!risk!in!this!acute!situation.!
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 abnormally elevated levels of any or all lipoproteins in the blood.
Hyperlipidemias are divided into primary and secondary subtypes. Primary
hyperlipidemia is usually due to genetic causes (such as mutation in a recepto),
while secondary hyperlipidemia arises due to other underlying causes such as
Topic!#53.!Hyperlipoproteinaemias:! diabetes.
Hyperlipidemia!is!one!of!the!most!important!(and!modifiable)!risk!factors!for!CAD!
since!it!causes!accelerated!atherosclerosis.!Hyperlipidemia!may!be!a!primary!
disorder!such!as!a!familial!dyslipidemia!syndrome!or!secondary!to!another!cause.!
!
Familial hyperlipidemias are classified according to the Fredrickson classification, which is
Dyslipidemia!syndromes:!based on the pattern of lipoproteins on electrophoresis or ultracentrifugation.

deficiency of lipoprotein lipase (LPL)

mutation either in the LDL

receptor gene or the ApoB gene

due to overproduction of
substrates, including triglycerides

high chylomicrons and IDL

Type!IIA,!IIB!and!IV!account!for!over!80%!of!all!of!familial!dyslipidemias.!
!
Secondary!causes!of!hyperlipidemia:!
• Endocrine!disorders:!hypothyroidism,!DM,!Cushing´s!syndrome!
• Renal!disorders:!nephrotic!syndrome,!uremia!!
• Chronic!liver!disease!
• Medications:!glucocorticoids,!estrogen,!thiazide!diuretics!and!beta!blockers!
• Pregnancy!!
!
Risk!factors!of!developing!hyperlipidemias:!
• Diet:!
o Saturated!fatty!acids!and!cholesterol!cause!elevation!in!LDL!and!total!
cholesterol.!!
o High!calorie!diet!increase!TG!levels.!
o Alcohol!increases!TG!levels!and!HDL!levels.!
• Age:!cholesterol!levels!increase!with!age!until!about!65!years.!The!increase!is!
greatest!during!early!adulthood.!
• Inactive!lifestyle!
• Abdominal!obesity!

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 • Positive!family!history!
• Gender:!men!have!higher!cholesterol!levels!than!women!–!but!after!
menopause,!cholesterol!levels!become!equal!and!may!even!become!higher!in!
women!than!in!men!after!that.!
• Medications:!
o Thiazides!–!increase!LDL,!total!cholesterol,!TG!levels!
o Beta!blockers!(propranolol)!–!increase!TGs!and!lower!HDL!
o Estrogens!–!increase!TG!levels!
o Corticosteroids!!
o HIV!protease!inhibitors!
Genetic!mutation!that!predisposes!to!the!most!severe!hyperlipidemias!
•
!
Clinical!features:!
Most!patients!are!asymptomatic!but!these!symptoms!can!manifest!in!severe!
hyperlipidemia:!
& Xanthelasma:!yellow!plaques!on!eyelids!
& Xanthoma:!hard,!yellowish!masses!found!on!tendons! xanthomas in tendons, skin, palm
& Pancreatitis!
!
Diagnosis:!
• Lipid!screening!–!measure!total!cholesterol!and!HDL!levels.!If!either!is!
abnormal!then!order!a!full!fasting!lipid!profile;!which!includes!TG!and!LDL!
levels.!
• Consider!checking!lab!tests!to!exclude!secondary!causes!of!hyperlipidemia:!
o TSH!–!hypothyroidism!!
o Liver!function!tests!–!chronic!liver!disease!
o BUN,!Creatine!and!urinary!proteins!–!nephrotic!syndrome!
o Glucose!levels:!diabetes!
!
Treatment:!
The!longQterm!goal!is!to!reduce!coronary!heart!disease!(CHD)!risk.!The!shortQterm!
goal!is!to!reduce!LDL!levels.!
• If!the!patient!has!no!established!CHD!–!target!LDL!level!is!<130!mg/dL!
• If!the!patient!has!established!CHD!or!is!diabetic!–!target!LDL!level!is!<100!
mg/dL!
!
!
!
LDL Cholesterol
!
Optimal: Less than 2.60 mmol/L

!
With known disease (CHD or diabetes), less than 1.80 mmol/L

Total Cholesterol
!
Desirable: Less than 5.2 mmol/L
!
High: 6.22 mmol/L or higher

HDL Cholesterol !
Average level, average risk: 1.0-1.3 mmol/L for men and 1.3-1.5 mmol/L for women
!
Fasting TAG !
!
Desirable: Less than 1.7 mmol/L

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 Therapy!for!high!LDL!cholesterol:!
• Diet:!lowering!fat!intake!(especially!saturated!fats)!reduces!serum!cholesterol!
more!than!lowering!cholesterol!intake.!Eat!food!rich!in!omegaQ3!fatty!acids,!
like!fish.!
• Exercise!and!weight!loss:!it!will!increase!HDL!and!reduce!the!risk!of!CAD.!
• Drug!therapy:!statins,!niacin,!bileQacid!sequestrants!and!gemfibrozil.!Statins!
can!reduce!relative!cardiovascular!risk!by!20Q30%!regardless!of!baseline!LDL!
levels!! cholestyramine, colestipol, and colesevelam are medications for lowering LDL cholesterol in conjunction with diet modification
o ATH!*All*patients*on*statins*should*have*their*AST*and*ALT*monitored*
even*if*asymptomatic.*About*1%*of*patients*on*statins*will*develop*
such*elevations*in*AST*and*ALT*that*the*statin*will*need*to*be*
discontinued.!
!
Therapy!for!high!TG!levels:!
• First!line!therapy!is!weight!loss,!exercise,!glycemic!control!in!diabetics!and!
lowQfat!diet.!
• Medications:!fibrates,!nicotinic!acid!and!fish!oil!
• Statins!should!be!considered!even!in!patients!with!high!TG!levels!because!of!their!
cardioprotective!effects.!
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 LDL Cholesterol
Optimal: Less than 2.59 mmol/L
With known disease (CHD or diabetes), less than 1.81 mmol/L

Total Cholesterol
Desirable: Less than 5.2 mmol/L
High: 6.2 mmol/L or higher

HDL Cholesterol
Average level, average risk: 1.0-1.3 mmol/L for men and 1.3-1.5 mmol/Lfor women

The!role!of!lipids!in!CAD!risk:! Fasting Triglycerides

LDL!cholesterol:!
Desirable: Less than 1.7 mmol/L

• It!accounts!for!2/3!of!total!cholesterol!
• CAD!risk!is!primarily!due!to!the!LDL!component!because!LDL!is!thought!to!be!
the!most!atherogenic!of!all!lipoproteins!
• Levels!above!160!mg/dL!significantly!increase!CAD!risks!
• LDL!levels!are!not!directly!calculated:!Total!cholesterol!–!HDL!–!TG/5!=!LDL!
• The!LDL!goal!in!diabetic!patients:!100!mg/dL!or!lower!
• If!patient!has!CAD!and!DM:!goal!is!70!mg/dL!or!less!
!
Total!cholesterol:!
• Levels!less!than!200!are!desirable!
• The!risk!of!CAD!increases!sharply!when!total!cholesterol!is!above!240!
!
HDL!cholesterol:!
• It!has!protective!effects!by!removing!excess!cholesterol!from!arterial!walls.!
This!protective!effect!is!at!least!as!strong!as!the!atherogenic!effect!of!LDL.!
• For!every!10!mg/dL!increase!in!HDL!levels,!CAD!risk!decreases!by!50%.!
• Low!HDL!(<40)!is!a!major!independent!risk!factor!for!CAD!
!
Triglycerides:!
Elevated!TGs!are!associated!with!coronary!risk!but!its!unknown!whether!this!
association!is!casual.!Its!uncertain!whether!lowering!TG!levels!reduces!coronary!risk.!
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Acid–base balance means the appropriate balance between chemical acids and bases, called body pH. The body is very sensitive to its
extracellular pH level, so strong mechanisms exist to maintain it. Outside the acceptable range of pH, proteins are denatured and digested,
enzymes lose their ability to function, and death may occur. The body's acid–base balance is normally tightly regulated by buffering agents,
the respiratory system, and the renal system, keeping the arterial blood pH between 7.36 and 7.42.
Extracellular buffers include bicarbonate and ammonia, whereas proteins and phosphate act as intracellular buffers;

Topic!#54.!AcidMbase!balance,!disorders!of!waterM!and!salt!metabolism.!(Metabolic!
and!respiratory!alkalosisMacidosis,!hyperM!and!hypocalcemia,!hyperM!and!
hyponatremia,!volume!depletion):!
!
Metabolic!acidosis:!
Its!characterized!by!decreased!blood!pH!and!a!decreased!
plasma!bicarbonate!concentration.!!
!
Example:!When!fixed!acid!(lactate)!is!added,!the!H+!from!
the!acid!must!be!buffered!by!the!bicarbonate!system!–!
therefore,!decreasing!the!HCO3−!levels.!When!this!
happens,!CO2!is!formed!and!removed!by!the!lungs:!
!
H+!+!HCO3−!↔!H2CO3−!↔!H2O!+!CO2!
!
HCO3−!levels!will!decrease!in!ECF!and!the!kidneys!will!need!to!reabsorb!more!HCO3−!
(new!HCO3−)!to!maintain!normal!pH.!So!by!looking!at!this!picture,!you!can!see!that!
when!we!increase!lactate,!HCO3−!levels!decrease.!!
!
Effects!of!acidosis:!
• Right!shift!in!oxygenQhemoglobin!dissociation!curve!diminshes!the!affinity!of!
hemoglobin!for!oxygen!–!so!increases!oxygen!delivery!to!tissues.!
• Depresses!CNS!
• Decreased!pulmonary!blood!flow!
• Arrhythmias!!
• Impairs!myocardial!function!
• Hyperkalemia!!
!
Anion!gap:!
AG!=!([Na+]!+![K+])!−!([Cl−]!+![HCO3−])!
!
The!anion!gap!is!the!difference!between!measure!cations!and!anions!in!serum!–!
normal!values!are!5Q15!mEq/L.!Its!used!to!help!distinguish!between!anionQgap!and!
nonQanionQgap!metabolic!acidosis.!!
!
Causes!of!increased!AG!acidosis:!
Its!characterized!by!high!anion!gap!–!or!higher!than!11!mEq/L.!This!kind!of!metabolic!
acidosis!is!generally!cauesd!by!the!body!producing!too!much!acid!or!not!producing!
enough!bicarbonate.!
• Ketoacidosis!–!due!to!DM,!prolonged!starvation!or!prolonged!alcohol!abuse!
• Lactic!acidosis!–!due!to!low!tissue!perfusion!(decreased!oxygen!delivery!to!
tissues),!shock!states!(septic,!cardiogenic,!hypovolemic)!or!excessive!
expenditure!of!energy,!e.g.!seizures.!
• Renal!failure!–!decreased!NH4+!excretion,!thus!decreased!net!acid!–!
decreased!excretion!of!organic!anions,!sulfate!and!phosphate!increases!the!
anion!gap.!!
• Intoxication!–!aspirin,!methanol,!ethylene!glycol!

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Causes!of!normal!AG!acidosis!(“nonQanion!gap”!acidosis):!
This!kind!of!acidosis!will!not!increase!the!anion!gap!–!because!low!HCO3−!levels!are!
associated!with!high!ClQ,!so!that!the!AG!remains!normal.!That’s!why!its!also!called!
hyperchloremic!metabolic!acidosis.!
• Renal!loss!of!bicarbonate:!
o Proximal!tubular!acidosis:!due!to!decreased!HCO3−!reabsorption.!
Causes!include!multiple!myeloma!and!Wilson´s!diseaes.!
o Distal!tubular!acidosis:!due!to!the!inability!to!make!HCO3−.!Causes!
include!SLE!and!Sjögren´s.!
• GI!loss!of!HCO3−:!most!common!cause!is!diarrhea.!Other!causes!can!be!
pancreatic!fistula!but!pancreatic!secretions!contain!high!HCO3−!levels,!small!
bowel!fistulas!and!ureterosigmoidostomy!where!the!colon!secretes!HCO3−!in!
urine!in!exchange!for!ClQ.!
!
Clinical!features!of!metabolic!acidosis:!
1) Hyperventilation:!deep!rhythmic!breathing,!also!known!as!Kussmaul´s!
respiration.!It’s!a!typical!compensation!(i.e.!response)!for!a!metabolic!acidosis!
and!the!primary!clinical!sign.!Usually!seen!in!severe!metabolic!acidosis!(pH!
<7,20).!
2) Decreased!cardiac!output!and!tissue!perfusion:!occurs!in!severe!metabolic!
acidosis.!Acidosis!diminishes!tissue!responsiveness!to!catecholamines.!This!
can!lead!to!an!undesirable!chain!of!events:!poor!tissue!perfusion!→!lactic!
acidosis!→!decreased!cardiac!output!→!hypotension!→!further!decrease!in!
tissue!perfusion.!
!
Diagnosis!of!metabolic!acidosis:!
• History!
• Calculate!the!anion!gap!
• Winter´s!formula:!Expected!PaCO2!=!1,5*(measured!HCO3−)!+!8!+/Q!2.!
o This!formula!predicts!the!expected!respiratory!compensation!(or!the!
PaCO2!levels;!pressure!of!CO2!dissolved!in!arterial!blood)!to!metabolic!
acidosis!–!In*metabolic*acidosis,*PaCO2*should*DECREASE!!
o If!the!actual!PaCO2!is!higher!than!the!calculated!PaCO2,!then!the!patient!
has!metabolic!acidosis!with!respiratory!acidosis.!This!is!a!serious!finding!
because!this!failure!of!compensation!can!be!a!sign!of!impending!
respiratory!failure.!The!classic!example!is!an!asthmatic!child!who!has!a!
PaCO2!that!goes!from!abnormal!to!normal!with!no!treatment.!This!is!a!
bad!sign,!and!it!probably!means!the!child!will!need!emergent!intubation!
shortly!!
o If!the!actual!PaCO2!is!lower!than!the!calculated!PaCO2,!then!the!patient!
has!metabolic!acidosis!with!respiratory!alkalosis.!
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Treatment!–!varies!depending!on!the!cause!of!metabolic!acidosis:!
• Sodium!bicarbonate!is!sometimes!needed,!especially!in!normal!AG!acidosis.!
When!correcting!metabolic!acidosis,!it!takes!24!hours!for!the!HCO3−!to!get!to!
the!brain.!During!this!time,!hyperventilation!continues.!
• Mechanical!ventilation!may!be!required!if!the!patient!is!fatigued!from!
prolonged!hyperventilation.!
!
Metabolic!alkalosis:!
Its!characterized!by!an!increased!blood!pH!and!plasma!HCO3−!levels.!Uncomplicated!
metabolic!alkalosis!is!typically!transient,!because!kidneys!can!normally!excrete!the!
excess!HCO3−.!Its!useful!to!distinguish!between!two!things:!metabolic!alkalosis!with!
volume!contraction!due!to!fluid!loss!or!metabolic!alkalosis!with!volume!expansion!
usually!due!to!pathology!of!the!adrenal!glands.!An!easy!way!to!make!this!distinction!
is!via!the!chloride!concentration!in!the!urine.!
!
Causes:!
ECF!contraction:!
• Vomiting!or!nasogastric!suction!–!when!HCl!is!lost,!gastric!HCO3−!generation!
occurs,!causing!alkalosis.!
• Diuretics!–!they!decrease!the!ECF!volume.!The!body!HCO3−!levels!remain!
normal!but!plasma!HCO3−!levels!increase!because!of!the!ECF!contraction.!
• Urine!chloride!<10!mEq/L!
• Characterized!by!hypokalemia!
!
ECF!expansion:!
• Most!are!secondary!to!adrenal!disorders.!Increased!mineralcorticoid!
secretion!leads!to!increased!tubular!reabsorption!of!Na+!and!HCO3−!and!an!
excessive!loss!of!ClQ!in!the!urine.!Since!water!will!follow,!the!result!is!
metabolic!alkalosis!and!ECF!expansion.!
• Other!causes:!Cushings!and!diuretics!abuse.!
• Urine!chloride!>20!mEq/L!
• Characterized!by!hypertension!–!due!to!increased!mineralcorticoids!
!
Clinical!features:!
There!are!no!characteristic!signs!or!symptoms.!Medical!history!is!the!most!helpful.!
Look!for!vomiting,!gastric!drainage!or!diuretic!therapy.!
!
Diagnosis:!
1) Elevated!HCO3−!levels!and!blood!pH!
2) Hypokalemia!is!common!–!due!to!renal!loss!of!K+!
3) Hypoventilation!–!PaCO2!is!elevated!as!a!compensatory!mechanism!
4) Urine!chloride!!
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Treatment:!
For!volume!contraction!give!normal!saline!with!potassium!to!restore!the!ECF!
volume.!For!volume!expansion,!treat!the!underlying!cause.!
!
Respiratory!acidosis:!
Its!defined!as:!reduced!blood!pH!and!PaCO2!>!40mmHg.!Renal!compensation!by!
increasing!HCO3−!reabsorption!to!compensate!the!acidic!state!begins!within!12Q24!
hours!and!takes!up!to!5!days!to!complete.!Any!disorder!that!reduces!CO2!clearance,!
i.e.!inhibits!adequate!ventilation!can!lead!to!respiratory!acidosis.!
& Acute!respiratory!acidosis:!
o Due!to!abrupt!failure!of!ventilation,!like!CNS!disease,!drugQinduced!
respiratory!depression!or!airway!obstruction!
o PaCO2!is!elevated!with!acidemia!(pH!<7,35)!
o Immediate!compensatory!elevation!of!HCO3−!!
o There!is!an!increase!of!1mmol/L!for!every!10mmHg!increase!in!PaCO2!
& Chronic!respiratory!acidosis:!
o It!may!be!secondary!to!many!disorders,!like!COPD!and!neuromuscular!
disorders!like!ALS.!
o PaCO2!is!elevated!with!a!normal!or!nearQnormal!pH!secondary!due!to!
renal!compensation!and!increased!serum!HCO3−!levels.!
o Renal!adaptation!occurs!and!HCO3−!increases!by!4mmol/L!for!every!
10mmHg!increase!in!PaCO2.!
!
Clinical!features:!
• Somnolence,!confusion!and!myoclonus!with!asterixis!
• Headaches,!confusion!and!papilledema!–!signs!of!acute!CO2!retention.!
• Increased!PaCO2!è!increased!cerebral!blood!flow!è!increased!CSF!pressure!è!
results!in!generalized!CNS!depression!
!
Treatment:!
1) Verify!patency!of!the!airway!
2) If!PaO2!is!low!(<60mmHg)!–!give!oxygen!
o Caution!*In*patients*who*are*“CO2*retainers”*e.g.*COPD*patients,*
oxygen*can*exacerbate*the*respiratory*acidosis,*so*administer*oxygen*
with*caution.*(If*I*remember*correctly,*I*think*3L*of*oxygen*is*the*
maximum*for*CO2*retainers).!
3) Improve!alveolar!ventilation!–!remove!obstruction,!if!its!drugQinduced!
hypoventilation!then!clear!the!agent!(e.g.!naloxone),!give!bronchodilators!
etc.!!
4) Intubation!and!mechanical!ventilation!may!be!necessary!in!these!cases:!
severe!acidosis,!PaCO2!>!60!or!inability!to!increase!PaO2!with!supplemental!
oxygen,!if!patient!shows!detoriation!in!mental!status.!!
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Respiratory!alkalosis:!
Its!characterized!by!an!increased!blood!pH!and!decreased!PaCO2.!In!order!to!
maintain!blood!pH!within!the!normal!range,!HCO3−!must!decrease!–!for!that!to!
happen,!the!kidneys!must!excrete!more!HCO3−.!This!happens!over!the!course!of!
several!hours.!
!
Causes:!
Any!disorder!that!increases!the!respiratory!rate!inappropriately!can!lead!to!
respiratory!alkalosis.!
1) Anxiety!
2) Pulmonary!embolism,!pneumonia,!asthma!
3) Sepsis!!
4) Hypoxia!–!leads!to!increased!respiratory!rate!
5) Mechanical!ventilation!
6) Pregnancy!–!increased!serum!progesterone!can!cause!hyperventilation!
7) Medication!–!aspirin!toxicity!
!
Clinical!features:!
• Symptoms!are!mostly!related!to!decreased!cerebral!blood!flow!=!
lightheadedness,!dizziness,!anxiety!and!paresthesias!
• Tetany!!
• Arrhythmias!–!in!severe!cases!
!
Treatment:!
• Correct!the!underlying!cause!
• Sometimes!this!does!not!need!to!be!treated,!like!in!the!case!of!pregnancy!
• Breathing!into!a!paper!bag!
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 Hyponatremia is a low sodium level in the blood. Mild symptoms include a decreased ability to think, headaches, nausea, and poor
balance. Severe symptoms include confusion, seizures, and coma.
Normal serum sodium levels are 135–145 mmol/L. Hyponatremia is generally defined as a serum sodium level of less than 135 mmol/L
and is considered severe below 120 mmol/L.
Low volume hyponatremia can occur from diarrhea, vomiting, diuretics, and sweating.
Normal volume hyponatremia is divided into cases with dilute urine and concentrated urine. Cases in which the urine is dilute include
adrenal insufficiency, hypothyroidism, and drinking too much water or too much beer. Cases in which the urine is concentrated include
syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Hyponatremia:! High volume hyponatremia can occur from heart failure, liver failure, and kidney failure.

This!refers!to!too!much!water!in!relation!to!sodium!in!the!serum.!Its!defined!as!a!
plasma!Na+!concentration!<135!mmol/L!and!symptoms!usually!begin!when!the!levels!
fall!below!120.!It!very!important!to!keep!serum!Na+!levels!normal!or!slightly!high!in!
people!with!increased!intracranial!pressure!–!since!in!decreased!ECF!osmolarity,!
water!shifts!into!brain!cells,!further!increasing!the!ICP.!
!
Causes!and!classification!–!based!on!serum!osmolality:!
1) Hypotonic!hyponatremia!–!its!the!“true!hyponatremia”!with!serum!
osmolality!<280!mOsm/kg:!
a)!Hypovolemic:!!
o Low!urine!sodium!–!due!to!sodium!retention!by!the!kidneys!to!
compensate!for!extrarenal!losses!like!diarrhea!or!vomiting.!
o High!urine!sodium!–!due!to!e.g.!diuretic!excess!
b)!Euvolemic:!!
o No!evidence!of!ECF!expansion!or!contraction!
o Possible!causes:!SIADH,!psychogenic!polydipsia,!intake!of!excess!of!
free!water;!fluid!replacement!with!hypotonic!solution!or!water!alone!
is!consumed!aftr!intensive!exertion!with!profuse!sweating!
c) Hypervolemic:!due!to!waterQretaining!states!–!due!to!e.g.!CHF!!
2) Isotonic!hyponatremia!(pseudohyponatremia):!An!increase!in!plasma!solids!
lowers!the!plasma!sodium!concentration!but!the!amount!of!sodium!in!plasma!
is!normal.!!
3) Hypertonic!hyponatremia:!Caused!by!osmotic!substances!that!cause!an!
osmotic!shift!of!water!out!of!cells!–!these!substances!cannot!cross!the!cell!
membrane!and!therefore!create!osmotic!gradient.!These!substances!include:!
glucose,!mannitol,!sorbitol!and!radiocontrast!agents.!
!
Clinical!features:!
• Neurologic!symptoms!predominate!–!caused!by!“water!intoxication”!–!
osmotic!water!shifts,!leading!to!increased!ICF!volume,!specifically!brain!cell!
swelling!or!cerebral!edema!=!headache,!delirum,!muscle!twitching,!weakness,!
hyperactive!deep!tendon!reflexes.!
• Increased!ICP,!seizures,!coma!
• GI!–!nausea,!vomiting,!diarrhea!
• Hypertension!due!to!increased!ICP!
• Increased!salivation!and!lacrimation!
• Oliguria!progressing!to!anuria!–!may!not!be!reversible!if!therapy!is!delayed!!
!
Diagnosis:!
• Plasma!osmolality!
• Urine!osmolality!
• Urine!sodium!concentration:!should!be!low!in!hyponatremia!
!
!
!
!

! 187!
 Rapid partial correction with 3% normal saline is only recommended in those with significant symptoms and occasionally
those in whom the condition was of rapid onset.

Low volume hyponatremia is typically treated with intravenous normal saline.

SIADH is typically treated with fluid restriction

high volume hyponatremia is typically treated with both fluid restriction and a diet low in salt.

Treatment!of!hypotonic!hyponatremia:!
a) Mild!(Na+!120M130!mmol/L):!withould!free!water!and!allow!the!patient!to!reQ
equilibrate!spontaneously.! Loop diuretics act on the Na+-K+-2Cl− symporter (cotransporter)
in the thick ascending limb of the loop of Henle to inhibit sodium,
+
b) Moderate!(Na !110M129!mmol/L):!loop!diuretics! chloride and potassium reabsorption. This is achieved by competing
for the Cl− binding site: Furosemide, Ethacrynic acid, Torsemide
c) Severe!(Na+!<100!mmol/L):!give!hypertonic!saline!to!increase!serum!sodium!
by!1Q2!mEq/L/hour!until!symptoms!improve.!!
d) Beware*of*increasing*serum*sodium*too*rapidly!*It*can*produce*central*
pontine*demyelination.!
!

!
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!

! 188!
Hypernatremia:!
Its!defined!as!plasma!Na+!concentration!>145!mmol/L.!It!refers!to!excess!sodium!in!
relation!to!water!–!can!result!from!water!loss!or!sodium!infusion.!Its!important!to!
assess!the!ECF!volume!clincally:!
!
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!
Clinical!features:!
• Neurologic!symptoms!predominate:!They!are!secondary!to!osmotic!effects!
on!the!brain!when!water!shifts!out!of!the!brain!cells,!leaving!them!
dehydrated!=!altered!mental!state,!restlessness,!weakness.!Can!lead!to!
confusion,!seizures!and!coma.!
• Tissues!and!mucous!membranes!are!dry,!salivation!decreases!
!
Diagnosis:!
Urine!volume!should!be!low!if!the!kidneys!are!responding!correctly.!Urine!osmolality!
should!be!>800!mOsm/kg.!
!
!Treatment:!
• Hypovolemic:!give!isotonic!NaCl!to!restore!hemodynamics!and!when!that’s!
corrected,!replace!with!free!water!
• Isovolemic:!oral!fluids!
• Hypervolemic:!give!diuretics!(furosemide)!and!D5W!to!remove!excess!
sodium!
• Too*rapid*correction*can*lead*to*cerebral*edema*as*water*shifts*into*brain*
cells*–*so*correction*should*be*made*slowly.!

! 189!
Hypocalcemia:!
Its!low!calcium!levels!in!the!blood!serum!–!or!levels!lower!than!2,1!mmol/L.!Normal!
values!are!2,1Q2,6!mmol/L.!
!
Causes:!
• Hypoparathyroidism!–!it’s!the!most!common!cause.!Usually!due!to!surgery!on!
the!thyroid!gland.!
• Acute!pancreatitis!
• Renal!insufficiency!!
• Hyperphosphatemia!Q!PO43−!precipitates!with!Ca2+!resulting!in!calcium!
phosphate!deposition.!
• Hypomagnesemia!–!results!in!decreased!PTH!secretion!
• Vitamin!D!deficiency!
• Malabsorption!–!problems!in!the!bowels!
• Hypoalbuminemia!–!but!ionized!fraction!is!normal!so!hypoalbuminemia!is!
clinically!irrelevant!
!
Clinical!feastures:!
1) Asymptomatic!
2) Rickets!and!osteomalacia!
3) Increased!neuromuscular!irritability:!numbness,!tingling!in!fingers!and!toes,!
tetany!with!hyperactive!deep!tendon!reflexes!
4) Arrhythmias,!prolonged!QT!interval!in!ECG!–!hypocalcemia!should!always!be!
in!the!differntial!diagnosis!for!a!prolonged!QT!interval!
!
Diagnosis:!
• Obtain!BUN,!Cr,!magnesium,!albumin!and!ionized!calcium!
• Serum!PO43−:!its!high!in!renal!insufficiency!and!hypoparathyroidism!but!low!in!
vitamin!D!deficiency!
• PTH!
!
Treatment:!
• If!symptomatic,!provide!IV!calcium!gluconate!
• For!longQterm!management,!use!oral!calcium!supplements!and!vitamin!D!
• For!PTH!deficiency:!vitamin!D!+!high!oral!calcium!intake!
• Correct!hypomagnesemia!–!its!difficult!to!correct!the!calcium!level!if!the!
magnesium!is!not!replaced!first.!
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! 190!
Hypercalcemia:!
It’s!a!condition!in!which!the!calcium!levels!in!the!blood!are!above!normal.!
!
Causes:!
1) Endocrinopathies:!
o Hyperparathyroidism!–!increased!Ca2+,!low!PO43Q!!
o Renal!failure!–!usually!results!in!hypocalcemia!but!sometimes!
secondary!hyperparathyroidism!elevates!PTH!levels!enough!to!cause!
hypercalcemia!
o Paget´s!disease!of!bones!–!due!to!osteoclastic!bone!resorption!
2) Malignancies:!
o Metastatic!cancer!–!bony!metastases!result!in!bone!destruction!due!
to!osteoclastic!activity!
o Multiple!myeloma!–!lysis!of!bone!by!tumor!cells!
o Tumors!that!release!PTHQlike!hormone!–!e.g.!lung!cancer!
3) Pharmacologic:!
o Vitamin!D!intoxication!=!increased!GI!absorption!of!calcium!
o Drugs!–!thiazide!diuretics,!which!inhibit!calcium!excretion!
4) Other:!
o Sarcoidosis!–!increased!GI!absorption!of!calcium!
o Familial!hypocalciuric!hypercalcemia!
!
Clinical!features:!Q!MEMONIC:!“Stones,!bones,!grunts!and!groans,!psychiatric!
overtones”:!
1) Stones:!kidney!stones!!
2) Bones:!bone!aches!and!pains,!osteitis!fibrosa!cystica!(“brown!tumors”);!
predisposes!to!pathologic!fractures!
3) Grunts!and!groans:!muscle!pain!and!weakness,!pancreatitis,!peptic!ulcers,!
gout,!constipation!
4) Psychiatric!overtones:!depression,!fatigue,!anorexia,!sleep!disturbances,!
anxiety,!lethargy!
5) Other!findings:!polydipsia,!polyuria,!hypertension,!shortened!QT!interval!
6) Some!patients!are!asymptomatic!
! Obtain BUN, Cr, magnesium, albumin and ionized calcium
Diagnosis:! • Serum PO43−: its high in renal insufficiency and hypoparathyroidism but low in vitamin D deficiency
• PTH
Same!lab!tests!as!in!hypocalcemia.!Other!tests:!bone!scan!to!identify!lytic!lesions,!
radioimmunoassay!of!PTH;!which!is!elevated!in!primary!hyperparathyroidism!but!low!
in!occult!malignancy!and!urinary!cAMP;!which!is!also!elevated!in!primary!
hyperparathyroidism.!
!
Treatment:!
• Increase!urinary!excretion:!IV!fluids!–!its!the!first!step.!Give!furosemide,!it!
will!further!inhibit!calcium!reabsorption.!
• Inhibit!bone!resorption:!give!bisphosphonates!or!calcitonin!
• Give!glucocorticoids:!if!vitamin!DQrelated!mechanism!and!multiple!myeloma!
are!the!causes.!
• Hemodialysis:!in!renal!failure!patients!

! 191!
Volume!depletion:!
Causes:!
1) GI!losses!due!to!vomiting,!nasogastric!suction,!diarrhea,!fistula!drainage!etc!
2) ThirdQspacing!due!to!ascites,!effusions,!bowel!obstruction,!burns!
3) Inadequate!intake!
4) Polyuria!–!for!example!due!to!DKA!
5) Sepsis,!intraQabdominal!and!retroperitoneal!inflammatory!processes!
6) Trauma,!open!wounds!
7) Insensible!losses!–!via!the!skin!and!respiration!
!
Clinical!features:!
• CNS!findings:!mental!state!change,!sleepiness,!coma!
• Cardiovascular!findings:!orthostatic!hypotension,!tachycardia,!decreased!
pulse!pressure!
• Skin:!hypothermia,!pale!extremities,!dry!tongue!
• Oliguria!!
• Ileus,!weakness!
• Acute!renal!failure!
!
Diagnosis:!
• Monitor!urine!output!and!daily!weights!
• Elevated!serum!sodium,!low!urine!sodium!and!a!BUN/Cr!ratio!of!>20:1!–!
suggesting!hypoperfusion!to!the!kidneys!
• Increased!hematocrit!(RBC!ratio!to!the!total!volume!of!blood)!
• Concentration!of!formed!elements!in!the!blood!(RBCs,!WBCs,!platelets,!
plasma!proteins)!increase!with!an!ECF!deficit!
!
Treatment:!
• Correct!the!volume!deficit:!
o Use!bolus!–!begin!with!isotonic!solution!
o Monitor!HR,!BP,!urine!output!and!weight!
o Maintain!urine!output!at!0,5Q1!mL/kg/hour!
o Replace!any!blood!loss!with!crystalloid!at!a!3:1!ratio!
• Maintenance!fluid:!D51/2NS!–!5%!dextrose!in!half!amount!of!normal!saline!
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! 192!
Topic!#55.!Metabolic!bone!disorder:!
The!term!“metabolic!bone!disorder”!denotes!those!conditions!producing!diffusely!
decreased!bone!density!and!diminished!bone!strength.!It!is!categorized!by!histologic!
appearance;!osteoporosis!and!osteomalacia!–!both!of!which!can!coexist!in!the!same!
patient.!
!
Osteoporosis:!
Its!when!the!bone!mass/quality!is!decreased,!causing!increased!bone!fragility!and!
fracture!risk.!In!osteoporosis,!the!bone!mineral!density!is!at!least!2,5!standard!
deviations!below!that!of!young,!normal!individuals.!Most!of!these!patients!are!
postmenopausal!women!and!elderly!men.!
!
Mechanism:!
Failure!to!attain!optimal!(peak)!bone!mass!before!the!age!of!30,!or!the!rate!of!bone!
resorption!exceeds!the!rate!of!bone!formation!after!peak!bone!mass!is!attained.!
Osteoporosis!is!a!“silent”!disease!–!meaning!its!asymptomatic!until!a!fracture!occurs.!
This!is!why!its!SO!important!to!exercise!and!take!calcium!and!vitamin!D!supplements!
to!prevent!this!disease!–!and!this!needs!to!be!done!at!a!young!age!to!attain!the!
optimal!bone!mass!before!the!age!of!30.!!
!
Classification:!
& Primary:!
o Type!1:!most!common!in!postmenopausal!women.!Excess!loss!of!
trabecular!bone,!vertebral!compression!fractures!and!colles!fractures!
are!common.!
o Type!2:!most!common!in!men!and!women!over!70!years!of!age.!Equal!
loss!of!both!cortical!and!trabecular!bone.!Fractures!of!femoral!neck,!
proximal!humerus!and!pelvis!are!common.!
& Secondary:!an!obvious!cause!is!present,!such!as!excess!steroid!
therapy/Cushings,!vitamin!D!deficiency!etc.!
!
Risk!factors:!
• Estrogen!depletion:!postmenopausal!state!or!history!of!athletic!amenorrhea!
or!eating!disorder.!
• Female!gender!–!women!have!lower!peak!bone!mass!
• Calcium!deficiency!or!vitamin!D!deficiency!
• Decreased!peak!bone!mass!
• Heritable!risk!factors!!
• Decreased!physical!activity!
• Smoking!and!alcohol!abuse!
!
Clinical!features:!
1) Vertebral!body!compression!fractures:!most!common!in!thoracic!and!lumbar!
spine.!Can!lead!to!pain,!deformity!and!kyphosis!formation!w/restricted!
movement!and!loss!of!height!
2) Colles!fracture:!distal!radius!fracture!due!to!fall!on!outstretched!hand!
3) Hip!fractures!and!long!bone!fractures!

! 193!
 Diagnosis:!
• DEXA!scan:!it’s!the!gold!standard.!It!measures!bone!density,!by!comparing!
the!density!of!the!patient!with!a!standard!control,!which!is!the!bone!density!
of!a!healthy!30!year!old!person.!
• Rule!out!secondary!causes!by!checking:!calcium,!phosphate,!alkaline!
phosphatase,!TSH,!vitamin!D,!free!PTH,!creatinine!and!CBC.!
!
Nonpharmacologic!treatment:!
a) Diet:!adequate!calorie!intake,!avoid!malnutrition.!Take!supplemental!calcium!
and!vitamin!D!daily.!
b) Exercise:!weightQbearing!exercise!for!30min,!at!least!3x!a!week,!to!stimulate!
bone!formation.!!
c) Don’t!smoke:!smoking!accelerates!bone!loss!
d) Eliminate!or!reduce!alcohol!intake!
!
Pharmacologic!therapy:!
Its!indicated!in!postmenopausal!women!with!established!osteoporosis!(TQscore!2,5!
or!less)!and!highQrisk!postmenopausal!women!with!TQscore!between!Q1,0!and!Q2,5.!
Bone and joint pain. a) Bisphosphonates:!inhibit!bone!resorption!and!are!firstQline!treatment.!They!
Constipation or diarrhoea.
decrease!osteoclastic!activity!and!therefore!decrease!the!risk!of!fractures.!!
b) PTH!therapy:!increases!bone!mineral!density!and!reduces!fracture!risk.!Due!
to!high!cost!and!longQterm!safety!concerns,!its!not!a!firstQline!drug.!Only!
indicated!in!patients!with!severe!osteoporosis!who!cannot!tolerate!
bisphosphonates.!Maximum!duration!of!treatment!is!2!years!due!to!concern!
for!osteosarcomas.!
c) Calcitonin:!useful!as!shortQterm!therapy!in!elderly!women!with!vertebral!
compression!fractures.!LongQterm!benefits!are!minimal!and!therefore!its!not!
commonly!used.!
!

!
!
! Osteopenia : a medical condition in which the protein and mineral content of bone tissue is
! reduced, but less severely than in osteoporosis.
!
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! 194!
 Osteomalacia:!
Defective!mineralization!of!the!growing!skeleton!in!childhood!causes!permanent!
bone!deformities!(rickets).!Defective!skeletal!mineralizaton!in!adults!is!known!as!
osteomalacia!and!is!caused!by!any!condition!that!results!in!inadequate!calcium!or!
phosphate!mineralization!of!bone!osteoid.!
!
Causes:!
1) Vitamin!D!deficiency:!it’s!the!most!common!cause!of!osteomalacia!and!its!
incidence!is!increasing!worldwide!due!to!diminshed!exposure!to!sunlight,!
caused!by!urbanization,!public!transportations,!modest!clothing!and!
sunscreen!use.!Patients!who!develop!severe!osteomalacia,!have!had!chronic!
severe!vitamin!D!deficiency!or!serum!25OHD!under!25!nmol/L.!Deficiency!of!
vitamin!D!may!arise!from:!
o Insufficient!sun!exposure!
o Malnutrition!
When the plasma ionized o Malabsorption:!can!be!due!to!pancreatic!insufficiency,!IBD,!
calcium level is low or falls
the opposite happens. gastrectomy!etc.!
Calcitonin secretion is 2) Calcium!intake!deficiency:!the!total!daily!consumption!should!be!at!least!
inhibited and PTH secretion
is stimulated, resulting in 1000!mg.!Patients!who!have!deficient!calcium!intake!develop!rickets!
calcium being removed from (children)!or!osteomalacia,!despite!sufficient!vitamin!D.!This!is!common!in!
bone to rapidly correct the
plasma calcium level. elderly,!since!intestinal!calcium!absorption!declines!with!age.!
3) Phosphate!deficiency:!chronic!hypophosphatemia!can!cause!bone!pain!and!
Foods that are high in oxalic
acid such as spinach, chard affect!bone!integrity.!
and chocolate, reduce 4) Aluminum!toxicity:!aluminum!inhibits!bone!mineralization!
absorption. Oxalic acid
binds with the calcium to
5) Hypophosphatasia:!this!should!not!be!confused!with!hypophosphatemia!!
form an insoluble salt Hypophosphatasia!is!a!severe!deficiency!of!bone!alkaline!phosphatase.!It’s!a!
crystal.
rare!genetic!cause!of!osteomalacia!that!is!often!misdiagnosed!as!
This vitamin works in the osteoporosis.!At!its!mildest!it!presents!with!premature!loss!of!teeth,!foot!
digestive tract to absorb
calcium into the blood
pain,!thigh!pain!or!arthritis.!No!treatment!exists.!
stream from the walls of!the
duodenum Clinical!findings:!
The!clinical!manifestation!of!defective!bone!mineralization!depends!on!the!age!of!
onset!and!the!severity.!In!adults,!its!typically!asymptomatic!at!first!but!eventually!
results!in!bone!and!joint!pain!along!with!reduced!muscle!strength.!Pathologic!
fractures!may!occur.!
!
Diagnosis:!
• Serum!is!obtained!for!calcium,!albumin,!phosphate,!alkaline!phosphatase,!
PTH!and!25OHD3!
• Bone!densitometry:!can!help!to!document!the!degree!of!the!disease!
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 Prevention!and!treatment:!
• Obtain!adequate!sunshine!vitamin!D!–!in!order!to!do!so,!the!face,!arms,!
hands!or!back!must!be!exposed!to!the!sun!without!sunscreen!for!15min!at!
least!2x!weekly!
• Eat!natural!food!sources!of!vitamin!D:!fish,!cod!liver!oil,!sardines,!tuna,!cow´s!
milk!
• Recommened!daily!dose!of!vitamin!D3!is!1000!IU!for!people!that!are!deprived!
of!sunlight.!PlantQderived!vitamin!D2!has!less!biologic!availability.!
• Addition!of!calcium!supplements!to!vitamin!D!is!not!necessary!for!the!
prevention!of!osteomalacia!in!otherwise!wellQnourished!patients!but!is!
recommended!in!patients!with!malabsorption!or!poor!nutrition.!
!
!
!
Metabolic bone disease is an umbrella term referring to abnormalities of bones caused by a metabolic disorders. Most commonly these disorders are
!
caused by abnormalities of minerals such as calcium, phosphorus, magnesium or vitamin D leading to dramatic disorders that are reversible once the
! has been treated.
underlying defect

Rickets is defective mineralization or calcification of bones before epiphyseal closure in children due to deficiency or impaired metabolism of vitamin D,
phosphorus or calcium, potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing
countries. The predominant cause is a vitamin D deficiency, but lack of adequate calcium in the diet may also lead to rickets.

Osteomalacia is a similar condition occurring in adults, generally due to a deficiency of vitamin D but occurs after epiphyseal closure.

Signs and symptoms of rickets include:

Bone tenderness
Dental problems
Skeletal deformity: Toddlers: Bowed legs and double malleoli (genu varum), Older children: Knock-knees (genu valgum)

Types: Vitamin D deficiency: Type 1 (25-Hydroxyvitamin D3 1-alpha-hydroxylase deficiency), Type 2 (calcitriol receptor mutation)
Hypocalcemia-related rickets: Hypocalcemia, Chronic renal failure (CKD-BMD)
Hypophosphatemia-related rickets: Congenital
___
Paget's disease of bone is caused by the excessive breakdown and formation of bone, followed by disorganized bone remodeling. This causes bone to
weaken, resulting in pain, misshapen bones, fractures and arthritis. Paget's disease may be caused by a slow virus infection (i.e., paramyxoviridae)
present for many years before symptoms appear. There is a hereditary factor in the development of Paget's disease of bone.
The pathogenesis of Paget's disease is described in 4 stages:
Osteoclastic activity
Mixed osteoclastic - osteoblastic activity
Osteoblastic activity
Malignant degeneration

Paget's disease may be diagnosed using one or more of the following tests: appearance on X-rays.
An elevated level of alkaline phosphatase in combination with normal calcium, phosphate, and aminotransferase levels in an elderly patient are
suggestive of Paget's disease.
Elevated levels of serum and urinary hydroxyproline are also found.
Bone scans are useful in determining the extent and activity of the condition.
If a bone scan suggests Paget's disease, the affected bone(s) should be X-rayed to confirm the diagnosis.

Bisphosphonates: Pamidronate disodium , Alendronate sodium, Etidronate disodium

Calcitonin
Surgery, Diet, Exercise

! 196!