PEPTIC ULCER DISEASE (basal and nocturnal gastric and stimulated) – normal or

acid secretion); H. pylori decreased

o Active inflammation disrupts the mucosal integrity of the might cause this  Prepyloric Gus or those in
stomach and/or duodenum local defect or excavation.  Decreased bicarb secretion body – same pathogenesis
o Chronic in nature; most patients are asymptomatic in duodenal bulb; H. pylori with DU
might also cause this)  Impairment of mucosal
PATHOPHYSIOLOGY defense factors – GU in
minimal acid levels
o Encompasses both gastric and duodenal ulcers
o Ulcers: breaks in the mucosal surface, >5mm, depth: to the  Classified by location:
submucosa o Type I – gastric body; low
o Most common cause risk factors for PUD: H. pylori and gastric acid production
NSAIDs o Type II – antrum; gastric
o Ff by (decreasing order) acid normal – low
o COPD o Type III – within 3cm of
o chronic renal insufficiency pylorus; commonly c DUs;
o cirrhosis normal – high gastric acid
o nephrolithiasis production
o current tobacco use o Type IV – cardia; low
o older age gastric acid prod
o former tobacco use
o 3 or more doctor visits
o Coronary heart dse
o Former alcohol use
o African – American race
o Obesity
o Diabetes
o Accounts for majority of PUD
o Also in gastric mucosa –assoc lymphoid tissue
EPIDEMIOLOGY
lymphoma and gastric adenocarcinoma
Duodenal ulcers Gastric ulcers Bacterium
 6 – 15% of western  Occur later in life (60s)
population  Most cases are males o Before – Campylobacter pyloridis
 Rate has declined because  Less common than DUs o Gram –negative microaerophilic rod but can transform to
of decreasing frequency of (s/sx are silent and coccoid form – dormant state)
H. pylori – caused present only after o S- shaped (0.5 – 3 um)
occurrence complications develop) o Contains multiple sheathed flagellla
o Most commonly found in deeper portions of mucuous gel
which coats gastric mucosa or between mucous layer and
PATHOLOGY gastric epithelium
o Initially resides in antrum but migrates to more proximal
Duodenal ulcers Gastric ulcers segments of stomach
 Mostly occurs in first  Mostly: distal jxn between o May attach to gastric epithelium but does not invade cells
o Designed for the aggressive envi of stomach
portion of duodenum antrum and acid secretory
o Hop proteins, urease, vacuolating cytotoxin (Vac A) –
(>95%) mucosa
determinant of org’s pathogenesis and colonization
 Also: within 3 cm of the  GUs assoc with H. pylori
o Contains genomic fragment that codes for cag –pathogenicity
pylorus also assoc with antral
island (cag-PAI)
 Usually ≤1 cm diameter but gastritis
o Cag – A: translocated by components of cag-PAI into host
can reach 3 – 6 cm  NSAID –related GU: (-)
cells
 Ulcers: sharply demarcated, chronic gastritis but (+) o Activates series of cellular events for cell growth and
depth reaching the chemical gastropathy, cytokine production
muscularis propria (foveolar hyperplasia, o Urease – produces ammonia from urea (alkalinizes
 Base of ulcer: zone of edema of lamina propria, surrounding pH)
eosinophilic necrosis with epithelial regeneration in (-) o First step of infection depends of production of this and
surrounding fibrosis of H. pylori) its motility
 Malignant DUs – ext rare  Pangastritis and normal/low o Catalase, lipase, adhesins, platelet-activating factor, and
 Increased acid production, gatric acid secretion pic B – induces cytokines
duodenal acid, mucosal o With extensive genetic diversity which enhances ability to
injury promote dse

Epidemiology
PATHOPHYSIOLOGY
o Developing countries – 80% are with H. pylori by 20yo
DU GU o Industrialized – 20-50% “ “ “
 Most cases: H. pylori and  Most cases: H. pylori and o Improved sanitation decreased transmission of H. pylori
NSAIDs NSAIDs o Poor socioeconomic status and less education – higher
 Acid secretory abnormalities  Gastric acid output (basa colonization rates
o Others: (1) birth or residence in developing countries, (2)
domestic crowding, (3) unsanitary conditions, (4) unclean
food or water, (5) exposure gastric contents of infected indvdl
o Transmission: person –person, oral –oral, fecal –oral
Pathophysiology
o Almost always assoc with chronic gastritis
o End result of infxn: by complex interplay between bacterial
and host factors
Bacterial factors
o Cag-PAI (+) – higher risk of PUD, premalignant gastric
lesions, and gastric cancer
H. pylori: gastric residence, induce
mucosal injury, avoid host defense
(different strains-different virulence factors:
y-glutamyl transpeptidase, cytotoxin-assoc
gene A (cagA) product, Vac A + pathogen-
assoc molecular patterns (PAMPs) such as
flagella and lipopolysaccharides (LPS)
special area (cag-PAI) encodes Cag A and pic
B 2. Apoptosis r/t T cell and IFN-y interaction
Virulence factors + bacterial constituents
= mucosal damage and target host
immune cells
Vac A:
CD4 T cells (inhibit proliferation)
B cells, CD8, macrophages, mast cells
(disrupt normal functions)
Cag A-dependent mech:
Inhibit parietal cell H+, K+-ATPase
activity -> low acid production
Urease:
Generates NH3 – damaging epithelial
cells
Surface factors:
Chemotaxis for neutrophils and
monocytes – epithelial cell injury
Proteases and phospholipases:
Break down glycoprotein lipid complex
of mucous gel – reducing first line
mucosal defense efficacy
Adhesins (OMPs – BabA)
Attachment to gastric epithelial cells
LPS
Promote smoldering chronic
inflammation
Host factors
o May be genetic predisposition to acquire H. pylori
o Local injury and mucosal and systemic humoral response
Inflammatory process: recruitment of
neutrophils, lymphocytes (T, B),
macrophages, plasma cells
Local injury by binding to class II major
histocompatibility complex (MHC)
molecules on gastric epithelia cells
Cell death (apoptosis)
Cag A:
Further cell injury and activation of cellular
pathways (cytokine production and
repression of tumor-suppressor genes
Cytokines: IL – 1α/β, 2, 6, 8
TNFα, interferon
Cell injury:
1. Activated neutrophils-mediated production of reactive
oxygen or nitrogen species and enhanced epithelia cell
turnover
H. pylori and DUs
o Mechanism is unclear
o Strain may be more virulent – those that cause DU
o (+) DU –promoting gene A (dupA)
o H. pylori infxn in the antrum – increased acid production,
increased duodenal acid, and mucosal injury
Acid secretion – direct and indirect action of org +
proinflammatory cytokines (IL-8, TNF, and IL-1) on
G, D, and parietal cell
o Basal and stimulated gastrin release increased in H plyori –
infected idvls and somatostatin –secreting D cells
decreased
o Decreased duodenal mucosal bicarbonate production
SUMMARY: H pylori on GI tract is dependent on host and microbial
factors. The type and distribution of gastritis correlates with what ulcer
will develop
o Antral –predominant: DU
o Primarily the corpus: GU, gastric atrophy, gastric carcinoma
NSAID INDUCED
Epidemiology
o SE and complications d/t NSAIDs are considered the
most common drug –related toxicities in the US
o (low dose users) H pylori can increase the risk of GI
bleeding; +++ smoking and alcohol consumption
o RF for GI bleeding to occur in NSAID users: advanced
age, history of ulcer, concomitant use of
glucocorticoids, high –dose NSAID, multiple NSAID,
concomitant use of anticoagulants, clopidogrel, serious
multisystem dse
Pathophysiology
PG: critical role in maintaining gastroduodenal mucosal integrity
and repair
 - Interruption in PG synthesis: impair mucosal defense
Acid –induced activation of chemical receptors in the
duodenum, enhanced duodenal sensitivity to bile acids,
or gastroduodenal motility

Pain worsened by meals, N/V of undigested food –

gastric outlet obstruction

o (NSAID-induced) bleeding, perforation, obstruction

without prior symptoms; bleeding and perforation – common
in elders
o Epigastric pain - gnawing or burning (DU and GU); ill –
defined, aching sensation or hunger pain
 DU – 90 min to 3h p meal; relieved by antacids or
food
o Awakens pt from sleep (12AM – 3AM)
 GU – precipitated by food
o Nausea and weight loss – GU
o Sudden onset severe, generalized abdl pain – perforation
o Tarry stools, coffee-ground emesis – bleeding
o Dyspepsia constant, (-) relief with food or antacids, radiates
and repair – mucosal injury to back – penetrating ulcer (pancreas)

Physical examination

 Direct injury Important in discovering ulcer complication

- NSAID remains unionized lipophilic form in the acid
o Epigastric tenderness – most frequent finding; right of the
environment of stomach
midline
- Migrate across lipid membranes of epithelial cells o Tachycardia or orthostasis – DHN sec to vomiting or active
becomes ionized and trapped therefor leading to cell GI blood loss
injury o Severely tender, board –like abdomen – perforation
 Alter surface mucous layer o Succession splash – retained fluid in stomach (gastric outlet
- Permits back diffusion of H and pepsin leading to obstruction)
further epithelia damage
PUD –related complications
 GI bleeding
o Most common complication
o Occur mostly in >60yo
Other factors o In elders, bc of NSAID use
o Most mortality cases are of nonbleeding cause –
Smoking multiorgan failure, pulmonary complications, malignancy
o >50% present with bleeding without warning s/sx
- Decrease healing rate, impair response to therapy,
and increase ulcer –related complication (perforation)  Perforation
- CAUSE: altered gastric emptying, decreased proximal o Second most common
duodenal bicarbonate production, increased risk for H. o Ulcer bed tunnels into adjacent organs
pylori infection, and smoking –induced generation of o Elders – NSAID use
noxious mucosal free radicals o DU – penetrate posteriorly into pancreas -> pancreatitis
Genetic o GU – hepatic lobe; gastrocolic fistulas
- First –degree relatives with DU are 3x as likely to
 Gastric outlet obstruction
develop an ulcer o Least common
- Blooc type O o Secondary to inflammation and edema
Psychological stress o Also: fixed, mechanical obstruction sec to scar formation in
Diet peripyloric areas
Others o s/sx: onset of early satiety, N/V, increase postprandial
- Advanced age abdominal pain, weight loss
- Chronic pulmonary o Often resolves with ulcer healing
o Tx: endoscopic balloon dilation or surgical intervention

Differential diagnosis
Clinical features
 Dyspepsia
o Essential dyspepsia
History o Most commonly encountered dx with upper abdl pain
o Group of disorders typified by upper abdominal pain in (-)
o Abdl pain (common but poor predictive factors for GU and ulcer
DU); less likely among elders  Other ulcer –like symptoms
 o Proximal GI tymors
o Gastroesophageal reflux
o Vascular dse
o Pancreaticobiliary dse (biliary colic, chronic pancreatitis)
o Gastroduodenal Crohn’s dse
Diagnostic evaluation
o Endoscopy
o Most sensitive and specific approach to UGI examination
o Direct visualization of mucosa and photographic
documentation any mucosal defects and tissue biopsy to
r/o malignancy
o Identification of lesions too small for radiograph to detect
o Evaluation of atypical radiographic abn
o Source of blood loss
o Radiographic (Barium study) or endoscopic procedure
o Required for the documentation of ulcer
o Single contrast barium meals (double –contrast)
o Detection of DU
DU: well –demarcated crater; most often in the bulb
GU: benign or malignant; may appear as a crater with radiation
mucosal folds from the ulcer margin
TREATMENT
A. Acid –neutralizing/ inhibitory drugs
A.1. Antacids
o Given to pts with symptomatic relief of dyspepsia
o Most common: aluminum hydroxide and magnesium
hydroxide
o Aluminum – constipation and phosphate depletion
Should not be used in CRF – chronic neurotoxicity
o Mg OH – loose stools
Should not be used in pts with CRF - hypermagnesemia
o Combination of both (Maalox, Mylanta) – prevent side effects
o Calcium carbonate – (long term use) Ca carbonate -> CaCl -
> milk –alkali syndrome (hypercalcemia, hyperphosphotemia,
renal calcinosis progressing to renal insufficiency)
o NaHCO3 – systemic alkalosis
A.2. H2 receptor antagonists
o Inhibits basal and stimulated acid secretion
o Often used for tx of active ulcers (4 – 6 weeks) + abx for H.
pylori
o Cimetidine, Ranitidine, Famotidine, Nizatidine
o Cimetidine – first of its kind to be used for tx of acid peptic
disorders
- Weak antiandrogenic S/E -> reversible gynecomastia and
impotence
- Inhibits cytochrome P450 -> monitor if with warfarin,
phenytoin, theophylline
- Other rare reversible effects: confusion, elevated serum
aminotransferases, creatinine, se prolactin
o Ranitidine, famotidine, nizatidine
- More potent H2 RB
o Cimetidine, ranitidine – bind to hepatic cytochrome P450 (not
famotidine and nizatidine)
o Other rare, reversible S/E
- Pancytopenia
- Neutropenia
- Anemia
- Thrombocytopenia
A.3. Proton Pump (H+K+ ATPase) Inhibitors
o Inhibit all phases of gastric acid secretion
o Rapid onset
o Maximum acid inhibitory effect between: 2 – 6h p
administration
o Duration of inhibitory effect: 72 – 96h
o Rptd daily dosing – progressive acid inhibitory effects
o T ½: ~18h (it takes 2 – 5 days for gastric acid secretion to
return to normal lvls once d/c)
o Best administered: pre –meal (pumps need to be activated
first except immediate –release formulation of omep)
o Se gatrin return to normal lvls within 1 – 2wks p cessation
o Rebound gastric acid hypersecretion p d/c; may last for 2
mos
o May interfere with drug absorption (ketoconazole, ampicillin,
iron, digoxin)
o Caution: drug –drug interaction: theophylline, warfarin,
diazepam, atazanavir, phenytoin; clopidogrel (competition
with the same cytochrome P450)
o Long –term use: CAP, community and hospital –acquired C.
difficile dse; hip fx in older women; iron and vit B12 and Mg
deficiency
Pt ≥65 yo: higher risk for long term effects of PPI use
o Esomeprazole
o Omeprazole and Lansoprazole
- Acid –labile
- Administered as enteric –coated granules in sustained –
release capsule wc dissolves in the SI at pH 6
A.4. Others
o Potassium –competitive acid pump antagonists (P-CABs)
- Inhibit gastric acid secretion via potassium competitive
binding of the H+K+ATPase
- Revaprazan, venoprazan
B.Cytoprotective agents
B.1. Sucralfate
o Serves as a physiochemical barrier, promotes trophic action
by binding growth factors (EGF
o Enhances PG synthesis, stimulates mucus and bicarb
secretion
o Enhances mucosal defense and repair
o Most common S/E: constipation
o C/I: avoided with CRF (avoid aluminum –induced
neurotoxicity)
o Standard dose: 1 g qid
B.2. Bismuth –containing preparations
o Induce ulcer healing
o A/E: black stools, constipation, darkening of tongue
o Long –term, high dose: neurotoxicity
o One of the agents for anti –H pylori regimen
B.3. Prostaglandin analogues
o Maintains and enhances mucosal injury and repair
o Most common toxicity: diarrhea (others: uterine bleeding and
contractions,
o Standard dose: 200µg qid
 Therapy for H. Pylori

Goal: provide relief of symptoms (pain or dyspepsia), promote

ulcer healing, and prevent ulcer recurrence and complications

o H pylori eradication for pts with documented PUD

o Eradication when:
- First-degree relatives of family members with gastric cancer
- Pts with previous gastric neoplasm treated by endoscopic or
subtotal resection
- Idvls risk for gastritis or severe atrophy
- With gastric inhibition for >1 yr
- With strong environmental risk factors for gastric cancer
- HP-positive patients fearing gastric cancer
- Unexplained IDA and idiopathic thombocytonpenic purpura

o Dual therapy – 2 abx + either PPI, H2 blocker, or bismuth

compound (comparable success)
o Triple therapy – effective; potential for poor compliance and
drug –induced effects
o Prevpac (lansoprazole, clarithromycin, amoxicillin); Helidac
(PPI or H2 blocker) QID x 14 days
o Side effects of treatment
- Bismuth: black stools, constipation, darkening of tongue
- Amoxicillin: abx –assoc diarrhea, N/V, skin rash, allergic
rxn
- Tetracycline: rashes, hepatotoxicity and anaphylaxis
(rare)