TouroCOM OMS2

Gastrointestinal Module
OMM (Section Done)
101019-Approach to the Esophagus
● Describe the effects of hypersympathetic tone on the functioning of the esophagus
● Name the stages of swallowing and identify the related CN’s and their associated
foramina, and physiologic function
○ Phases of swallowing:
■ “Voluntary” Stage
● Moving bolus to back of pharynx
● Tongue function crucial
● CN XII Hypoglossal nerve (CN XII):
○ Influence of Somatic Dysfunction within Hypoglossal Canal
or nerve route
○ Position of occiput
● Upper cervical fascia
○ Myofascial structures
○ Tongue, Hyoid, Neck
○ Dr. Edgar Miller’s treatment
■ Pharyngeal stage
● Pharyngeal constrictors
● Upper esophagus = skeletal muscle
● CN IX, X
■ Esophageal stage
● CN X
● Peristalsis
● Sympathetics play a role here too.
● T3-8 for esophagus
○
● Describe the effects of altered parasympathetic tone on the functioning of the esophagus
● Describe the anatomic relationships of the entire esophagus to surrounding structures
including the diaphragm
○ Jugular Foramen
■ Between Petrous portion of temporal bone and basi-occiput
■ Passes CN’s IX, X, XI; Internal jugular vein
■ Influence of Somatic Dysfunction (eg. An Internally rotated temporal
bone) affecting passage through the Jugular Foramen
● Describe the physiology of esophageal functioning with swallowing
○ Dysphagia
■ Esophagus
● Mechanical lesions obstructing the esophagus or motility
disorders.
● Patients with mechanical obstruction experience dysphagia,
primarily for solids. This is recurrent, predictable, and, if the
lesion progesses, will worsen as the lumen narrows.
● Patients with motility disorders have dysphagia for both solids
and liquids. It is episodic, unpredictable, and nonprogessive.
● Osteopathically: Fascial strain, Vagus, Sympathetic input
 altering peristalsis
■ Oropharynx
● Complex process elevation of tongue, closure of the
nasopharnyx, relaxation of the upper esophageal sphincter,
closure of the airway, and pharyngeal peristalsis.
● A variety of mechanical and neuromuscular conditions can disrupt
this process.
● From an Osteopathic view - Evaluate Tongue, Myofascial
connections, interruptions to CN’s XII, IX, (X)
■
● Describe the physiologic functioning of the Lower Esophageal Sphincter (LES)
○ Lower esophageal sphincter (LES)
○ Thickening of muscular layers
○ Functional sphincter
○ Normally contracted
○ Opens to allow passage of food bolus
○
● Describe the key structures to assess with OMM for a patient with GERD and explain the
rationale for these structures
● Identify the structures, attachments, and associations for the posterior diaphragm
○ Diaphragm has close relationship to Lower Esophagus
■ Phrenico-esophageal ligaments
■ Allows for movement with respiration and swallowing
○ Right crus of diaphragm
○ Medial arcuate ligament
■ Fascial connection to Psoas muscle
■ Influences Crus
■ Lateral arcuate ligament
■ Quadratus Lumborum
○ Median arcuate ligament
● Consider the impact of diet, lifestyle choices, stress on GERD
○ Diet
○ Food sensitivities
■ Gluten, soy, corn, etc…
● Inflammation
■ Coffee
○ Eating habits
○ Add HCL?
○ Breathing
○ Stress…
● Describe the potential influence of somatic dysfunction as highlighted in the presented
case
● Identify the levels for Viscero-somatic reflexes and Chapman Points with regards to the
organs discussed
○

○ Pancreatitis will tend to produce Viscero-somatic reflexes on both sides: T

5-9 L + R
○ Other organs tend to lateralize – Stomach: Left; Liver, GB: Right)
○
○

○ Ganglion Release
■ Assess with fingers midline over ganglia
■ Objective tissue resistance
■ Subjective tenderness
■ Feel similar to facilitated segment
■ Treatment involves gentle posterior pressure until release is perceived.
 ■

○
● Describe the effect of sympathicotonia on the patient’s disease process for the organs
covered
○ Stomach
■ Mucous:
● Protective mucosal layer
● Influenced by blood supply
● Food or irritation stimulates mucus secretion
● Pyloric glands - mucus (and gastrin)
■ Acid secretion:
● Under both hormonal + nervous control
● (primarily vagus and ENS)
● Oxyntic glands (chief and parietal cells) produce HCl (and
pepsinogen, intrinsic factor)
■ Also physical grinding of food…
■ TX:
● Normalize vagal tone
● Remove SD
● Acid secretion
● Remove irritation – waste products (lymph, venous drainage)
● Normalize increased sympathetic tone:
○ Inhibits Brunner’s glands
○ Decreases blood supply – effect?
○ Duodenum
■ Proximal duodenum - Glandular contribution in order to change pH
■ Extensive mucous Brunner’s glands mainly between pylorus and ampulla
of vater
■ Secretes alkaline mucus in response to:
● Tactile or irritating stimuli on the duodenal mucosa
● Vagal impulses
● GI hormones, mainly secretin
○ Pancreaus
■ Two main GI contributions:
● Sodium Bicarbonate
 ○ Neutralizes acidity
● Digestive Enzymes
○ Trypsin, Chymotrypsin
■ Primarily regulated through parasympathetics, CCK, and secretin
■ Through papilla of vater surrounded by the sphincter of Oddi
■ Sphincter contracts with sympathetic stimulation
○ Gall Bladder
■ Stores and concentrates bile
■ Release of bile from GB takes contractions of GB wall and relaxation of
Sphincter of Oddi
■ CCK stimulates GB contractions
■ Also stimulated by vagus and ENS fibers
○ Liver
■ Coronary ligaments
■ Falciform ligament
■ Parenchyma innervated by both PNS, SNS
● Abundant supply of visceral afferent located in walls of biliary
system, responsive to stretch
■
● Identify the location of cell bodies for the various neurons discussed
○ Myenteric plexus:
■ Located between Circular and Longitudinal muscle layers
■ Regulates muscular contraction and therefore peristalsis
○ Meissner’s plexus:
■ Located in the submucosa
■ Regulates absorption and glandular secretion
○ Autonomics
■ AFFERENT:
● Called visceral afferents and travel with autonomic fibers
● Both:
○ Sympathetic (T1-L2)
■ Cell bodies in DRG
○ Parasympathetic (Medulla - C2 and S2-S4)
■ ganglion
● Superior ganglion (jugular)
● Inferior ganglion (nodose)
● Ganglia located within and just inferior to
jugular foramen respectively
■ EFFERENT:
● For sub-diaphragmatic organs:
○ Travel through para-vertebral ganglion to synapse in the
PRE- vertebral ganglia
○ UPPER GI = Celiac Ganglion
● For Intra-thoracic organs (eg. The esophagus)
○ Synapse in Paravertebral ganglia
 ○

● Know the route that sympathetic impulses travel to reach the intended organ (Abdominal
v. Thoracic)
● Be familiar with the reviewed physiology of each of the organs mentioned
● Be able to articulate the influence of respiration on venous flow in the liver
○

○ Liver Flip Procedure: With posterior pressure applied to right anterior rib margin
the motion of the liver will be altered with descent of the diaphragm during
inspiration. A sudden withdrawal of this pressure will ‘snap’ liver and readjust its
relationship to the diaphragm allowing freer motion.
○
● Describe techniques and expected outcome from their administration with regards to
physiological changes
101026- Approach to the GI Tract
● Identify the anatomy of the lower GI tract
 ○

● identify how to support any functional bowel problems with OMM

○ Example: OMM Tx of IBS
■ Sympathetics:
● Treat T10-L2 for intestines and colon
■ Treat superior and inferior mesenteric ganglia
■ Chapman’s reflexes of the small intestines
● anterior intercostals between ribs 8-10,
● Posterior L3- L4-L5 paravertebrals
● Anterior Chapman’s also iliotibial band of the right and left
thigh
■ Treat the parasympathetics especially if having constipation by treating
the sacrum, and the vagus-OA-C1-C2
■ Treat the lymphatics to reduce congestion
● Thoracic inlet
● Doming the diaphragm
● Lymphatic pump
● Mesenteric lift
● visceral manipulation
○ Manipulative medicine directed toward improving:
■ circulatory
■ lymphatic flow
 ●

● Congestion leads to accumulation of:

○ Waste products
○ Reduced oxygenation
○ Decreased nutrition to cells
○ Increased likelihood of fibrosis-scarring
○ Worsens the prognosis of Ulcerative colitis and Crohn’s
disease
● Vessels travel via mesenteries-easily affected by dysfunction in
surrounding tissue
● Drains to Cisterna Chyli(L1-L2 area) drains to the thoracic duct
● Drainage may be affected by
● Poor efficiency of the diaphragms
● Torsion of fascias around lymphatic channels
● Congestion in the bowel channels will interfere in medical
treatment of disease processes
● Thoraco-lumbar diaphragm main pump for the abdominal
diaphragm
● Pelvic diaphragm needs to function with and not against the
thoracic diaphragm
●
■ balancing autonomics
● Treat the sympathetics- to reduce sympathetic facilitation
○ Fight or flight reduces normal peristaltic movement of the
gut
○ The sympathetics relax the lumen, contract the the
sphincters and decreases secretions and motility
 ■ Spinal cord level T10-T11
● Middle GI tract-small intestines, ascending
colon
● proximal 2/3 of the transverse colon(right
colon)
● Corresponding nerve and ganglion
○ Lesser Splanchnic Nerve
○ Superior Mesenteric Ganglion
■ Spinal cord level T12-L2
● distal 1/3 of the transverse colon
● descending colon and sigmoid colon(left
colon),rectum
● Appendix-T12
● Corresponding Nerve and Ganglion
○ Least Splanchnic nerve
○ Inferior Mesenteric Ganglion
● The parasympathetics contract the lumen,relax the sphincters and
increases secretions and motility (rest and relax!)
○ Vagus Nerve- all the viscera above the diaphragm
■ treat OA,C1,C2
■ Entire small intestine - Vagus
■ Large intestine- first half ascending and transverse
colon - Vagus nerve
○ pelvic splanchnic nerve-treat sacrum and pelvic
diaphragm
■ second half of large intestine
■ descending
■ rectosigmoid
○
● describe the clinical approach to diagnosing GI illnesses
○ Getting a good History
○ Review of systems
○ Labs
■ Stool for ova and parasites and bacterial cultures
● describe the role of the lymphatics on GI function
● Identify Chapman’s reflexes in diagnosis and treatment of the lower GI tract.
○ Example: irritable bowel syndrome can be reduced by treating the iliotibial band
and/or the lumbosacral paraspinal tissues and their associated reflexes
○ Small intestines diagnoses and treatment are the intercostal spaces between
ribs 8-9, ribs 9-10, ribs 10-11- anterior chapman’s reflexes
■ Helpful in treating abdominal distention and bowel spasticity
○ Helpful in diagnosing appendicitis- tip of the right 12th rib
 ○ Colon reflexes are on the anterior aspect of the iliotibial band to within 1” of the
patella-seen commonly in IBS and chronic constipation
○ Reflexes may not be present in Cancer patients
○

● Identify the levels of the parasympathetic and sympathetic nervous system of the lower
GI tract
○ Sympathetics Assessment
■ Access with fingers midline over the ganglion
● Objective tissue resistance
● Subjective tenderness
● Feel similar to facilitated segment
● Treatment involves gentle posterior pressure until release is
perceived.
●
 ●
● Identify the collateral sympathetic ganglion that are used to treat lower GI tract.
○ collateral ganglion may have self-contained mechanisms which controls function
locally without reporting to the spinal cord

PATH (Half Done)

101019- Esophagus and Salivary Glands
● Hematemesis: bright red blood
○ coffee ground emesis (trauma, mallor weiss tear, esoph. varices, oropharyngeal
origin)
○ -gastric HCl degrades free heme (peptic ulcer, malignant ulcer)
● Gastroesophogeal Reflux Disorder (Gastric contents, Biliary reflux- i.e. small bowel
obstruction)
● Diarrhea (Watery, bloody, mucusy- “clear rice water”)
○ ask frequency, amount, what stims, any travel history
● Steatorrhea (malabsorption)
○ fatty diarrhea, stool
○ may have assoc. fat-dependant vitamin def.
● Hematochezia
 ○ aka Bright red blood per rectum
○ (anal fissures, hemorrhoids, colorectal carcinoma, angiodysplasia (colon))
● Melena (upper GI bleed, peptic ulcer, tumor, trauma)
○ aka Black tarry stools
○ degradation of hemoglobin in colon
● Guiac test
○ aka fecal occult blood test
○ checks for small bleeds in GI tract not visible to eye
○ pt. should not eat meat or have vit C, cause may cause false positivity
Lab Sheet
● Categorize the pathogenesis, morphology, and clinical manifestation of benign and
malignant salivary gland disorders
● Associate the pathogenesis of Barrett esophagus and esophageal carcinoma
● Discuss the environment, genetic, and physiologic factors, morphology, and
complications of peptic ulcers
● Explain the role of H. pylori in the pathogenesis of duodenal ulcers
● List the pathogenesis, morphology, and clinical manifestations of celiac disease
Lecture
● Be able to classify the different kinds of malabsorption/floating stools/diarrhea
● Work out a diagnostic road map for the different kinds of malabsorption/floating stools/
diarrhea

101026- Liver Lab

● Define hyperbilirubinemia, jaundice, icterus, and cholestasis
○ hyperbilirubinemia: An elevated level of the pigment bilirubin in the blood. A
sufficient elevation will produce jaundice. Some degree of hyperbilirubinemia is
very common in babies right after birth, especially premies.
○ jaundice: Jaundice is the yellowish staining of the skin and sclerae (the whites
of the eyes) that is caused by high levels in blood of the chemical bilirubin. The
color of the skin and sclerae vary depending on the level of bilirubin. When the
bilirubin level is mildly elevated, they are yellowish. When the bilirubin level is
high, they tend to be brown.
○ icterus: At least one medical dictionary defines icterus as the presence of
jaundice seen in the sclera of the eye. This is incorrect. Icterus is synonymous
with jaundice. They are one and the same thing.
○ cholestasis: Cholestasis is any condition in which the flow of bile from the liver is
blocked
● Review the pathophysiologic mechanism of hyperbilirubinemia and jaundice
○ Circulating bilirubin is tightly bound to albumin. Elimination of bilirubin
requires conversion to water-soluble conjugates by the hepatocytes
through the action of uridine diphosphate (UDP)-glucuronyl transferase
(glucuronidation) and secretion into the bile.
○ Conjugated bilirubin, along with bile salts, is then excreted via the biliary
system into the duodenum and deconjugated by bacterial enzymes in the
terminal ileum and colon.
○ Twenty percent of deconjugated bilirubin (urobilinogen) is reabsorbed and
re- excreted in bile.
○ Unconjugated bilirubin is mostly bound to albumin and is not filtered by the
 kidney; conjugated bilirubin, however, may be filtered and reabsorbed in
the kidney, with a small fraction excreted in the urine.
○ A significant amount of conjugated bilirubin in the urine suggests
cholestasis and hepatobiliary dysfunction.
● Recognize and evaluate laboratory liver function tests and radiographic images utilized
for hyperbilirubinemia and pancreatitis
○

○ Billirubin Level
■ Determine whether hyperbilirubinemia is predominantly conjugated
or unconjugated (direct fraction, less than 15%). Up to 30% of
total bilirubin is in conjugated form. Normal total serum bilirubin
concentrations are between 0.2 and 0.9 mg/dL.
○ Liver Enzymes
■ In general, if the cause of jaundice is cholestasis, the serum
alkaline phosphatase (ALP) and γ-glutamyl peptidase (GGT) levels
will be predominantly elevated.
■ If the cause is global hepatocellular dysfunction, the serum
alanine aminotransferase (ALT) and aspartate aminotransferase
 (AST) will be predominantly elevated.
● Hemolytic disorders, such as spherocytosis or sickle cell anemia, are suggested
by unconjugated hyperbilirubinemia in conjunction with other laboratory
anomalies. Gilbert syndrome, which is characterized by impaired bilirubin
conjugation, is a benign condition that does not produce jaundice.
● Alcoholic hepatitis is often suggested by the history. In patients with this
condition, the serum aspartate aminotransferase/alanine aminotransferase ratio
(AST:ALT) is often greater than 2:1, and the aminotransferase levels rarely
exceed 300 U/L.
● Autoimmune hepatitis, whether an acute episode or an acute relapse of chronic
disease, may present with markedly elevated serum ALT and AST levels. An
appropriate autoimmune screen includes antinuclear antibodies, anti-smooth
muscle antibodies, and protein electrophoresis to determine whether gamma
globulin levels are elevated.
● In patients with suspected cholestatic hepatobiliary disease, abdominal
ultrasonography can help determine whether the intrahepatic or extrahepatic
biliary ducts are obstructed. The absence of biliary dilatation suggests
intrahepatic cholestasis; the presence of biliary dilatation indicates extrahepatic
cholestasis from mechanical obstruction.
● Primary sclerosing cholangitis is characterized by fibrosing inflammation in the
intrahepatic and extrahepatic bile ducts. Most patients are asymptomatic at
the time of presentation. Consider this diagnosis in patients with a history of
inflammatory bowel disease who have abnormal liver function test results.
● Explain the pathophysioloic mechanism, morphology, and clinical manifestations
associated with “gallstone pancreatitis” and hepatitis
○ Gallstone pancreatitis
■ Evidence suggests that pancreatic duct outflow obstruction is the initial
event. Several possible sequelae of duct obstruction, including:
● refluxed biliary-pancreatic secretions
● pancreatic duct hypertension
● aberrant acinar cell secretion
■ may result in pancreatic duct injury and release of pancreatic enzymes
into the glandular interstitium, thus triggering a bout of acute pancreatitis
○ Hepatitis
■ Hepatitis Virus seeks out liver cells and destroys them after making
copies of itself
■ Liver cells regenerate eventually, usually
● Discuss the risk factors, pathogenesis, morphology, and clinical manifestations of
cholelithiasis, and acute and chronic cholecystitis
○ Cholelithiasis is the presence of stones in the gallbladder.
○ Cholecystitis is acute or chronic inflammation of the gallbladder.
○ Choledocholithiasis is the presence of stones in the common bile duct.
○ Risk Factors:
■ Women are more likely to develop gallstones than men, with a ratio
of 2:1.
■ Classically, gallstones occur in obese, middle-aged women, which
leads to the popular mnemonic, fat fertile forties.
■ Oral contraceptive pills with high estrogen content increase the
 incidence of gallstones.
■Incidence increases with age.
○ Pathogenesis:
■ Pigmented gallstones are composed of calcium bilirubinate and
appear in 2 major forms: black and brown. Hemolysis and liver
disease are associated with the black stones; the brown, earthy
stones more frequently are formed outside the gallbladder and
often are associated with bacterial infections of the biliary tract.
○ Morphology & Clinical Manifestations:
■ Approximately 15% of gallstones are radiopaque and can be visualized
on plain x-ray.
■ Ultrasound (US) is the most sensitive and specific test for the detection of
gallstones.
● US provides information about the size of the common bile duct
and hepatic duct and the status of liver parenchyma and the
pancreas.
● Thickening of the gallbladder wall and the presence of
pericholecystic fluid are radiographic signs of acute cholecystitis.
■ The cholecystitis signs and symptoms during an attack include a severe,
steady pain in the upper right abdomen. The pain worsens with deep
breathing and may extend to the lower right shoulder blade. The pain
becomes agonizingly unbearable and the patient may suffer from nausea
and vomiting. The acute cholecystitis signs and symptoms include pain
in the upper right quadrant of abdomen, jaundice, fever, nausea and
vomiting.
■ The cholecystitis pain lasts for about 12 hours or more and the muscles
on the right side of the abdomen become rigid. In few patients,
cholecystitis symptoms may include fever. Patients with chronic
cholecystitis may suffer from mild cholecystitis signs and symptoms as
compared to those with acute cholecystitis.
■ The cholecystitis signs and symptoms subside after two to three days.
These cholecystitis symptoms disappear totally after about a week. If the
cholecystitis symptoms do not fade away even after a week, you should
seek medical help. This pain may be due to development of an abscess,
a perforation or even gangrene. The signs and symptoms due to these
causes will include fever, chills, high blood cell count and lack of sounds
from the intestine.
○ Acute vs. Chronic
■ Acute:
■ Chronic:
● The chronic cholecystitis signs and symptoms are vague, not very
severe abdominal pain.
● Chronic indigestion and belching are also seen as chronic
cholecystitis symptoms.
● Discuss the epidemiology, pathogenic mechanism, and morphology of hepatocellular
carcinoma
○ Epidemiology:
■ Hepatocellular carcinoma accounts for most liver cancers. This type of
 cancer occurs more often in men than women.
■ It is usually seen in people ages 50 - 60.
■ The disease is more common in parts of Africa and Asia (via Hep B) than
in North or South America and Europe.
■ 5% of all cancers
○ Pathology:
■ Any chronic inflammatory liver disease has the potential to induce
hepatocellular carcinoma, but the pathophysiologic process most
commonly associated next to the disease is cirrhosis, found in up to 80%
of cases.
■ However, culture of all possible sources is key, considering that 20%
of cases are due to noncirrhotic, nonviral causes. Whether cirrhosis
itself or the workings underlying cirrhosis is responsible for malignant
transformation of hepatocytes is not known.
○ Symptoms:
● Abdominal pain or tenderness, especially in the upper-right part
● Easy bruising or bleeding
● Enlarged abdomen
● Yellow skin or eyes (jaundice)
○ Morphology:
■ Ultrasound and determination of a-fetoprotein every 6 months contained
by patients at risk
● Nodules > 1cm need diagnostic work-up.
● Nodules < 1cm: increase screening frequency to every 3 months
● Ultrasound have a sensitivity, specificity and positive predictive
value of 71, 93 and 14 %, respectively. The corresponding
information for a-fetoprotein are 39, 76 and 9 %.
■ The tumor may consist of only one mass lesion, but often times may be
multiple masses within the liver. There are a number of different changes
seen on liver biopsy of these tumors, the most common of which is the
formation of liver cell cords lined by endothelial cells (refer to image),
the cords thicker than seen in normal non-tumor liver. When the
tumor is well-differentiated, the neoplastic cells often show features that
can be seen in normal hepatocytes such as fat and bile; however, in the
poorly differentiated tumors, the cells may also be quite pleomorphic with
giant cells and may be difficult to differentiate from certain metastatic
tumors.
 ■

101026- Genetics
● Hemochromatosis (iron)
● Wilson’s disease (copper)
● α1-antitrypsin deficiency
● Celiac disease
● Cystic fibrosis

CS
101020CS- Esophagus, Stomach, Intestines
● Esophageal Symptoms: Heartburn, Dysphagia, Odynophagia, bleeding, respiratory
symptoms,globus
● Know etiology, pathophysiology ,risks, clinical manifestation, diagnostic modalities,
differential diagnosis, treatment and complications for each disorder:
● Disorders of Motility: Achalasia, Chaga’s disease, GERD
 ● Disorders of Structure: Diverticulae, Zenker’s, midesophageal, distal esophageal
● Mucosal disease: esophagitis, esophageal erosions, esophageal ulcer, Barrett’s
● Disorders of Structure: Boerhave’s syndrome, Mallory-Weiss tear, Varices
● Understand strictures- benign and malignant
● Understand definition and clinical manifestation of esophageal webs Schatzki Ring,
Plummer-Vinson Syndrome
● Know etiology and risks for esophageal carcinoma
● Congenital disorders: tracheoesophageal fistula
● Know etiology, pathophysiology ,risks, clinical manifestation, diagnostic modality,
differential diagnosis, treatment and complications for each disorder or symptom:
● Gastric symptoms: dyspepsia, hematemesis, melena
● Disorders of Function: delayed gastric emptying (DM, post-operative atony) and
accelerated gastric emptying (Dumping syndrome)
● Disorders of Structure: PUD, gastric ulcer, H.pylori, hemorrhagic gastritis, stress ulcers,
chronic gastritis, erosions, tumors, polyps, carcinoma, hypertrophic gastropathy,
Menetier disease, Zollinger Ellison syndrome, carcinoid, lymphoma, stromal tumor
● Congenital disorders: pyloric stenosis, diaphragmatic hernia
● Know etiology, pathophysiology ,risks, clinical manifestation, diagnostic modality,
differential diagnosis, treatment and complications for each disorders:
● Duodenal tumors, adenoma, adenocarcinoma, Hamartomatous polyps, Peutz Jagger,
carcinoid and lymphoma

101022-Malabsorbtion
101027-Gall Bladder
● Know Cholelithiasis, types of stones, clinical presentation, workup and complications
● Know clinical presentation, diagnosis, complications and treatment of cholecystitis
● Understand acute andchronic cholecystitis, and ascending cholangitis,
cholesterolosis, and hydrops of the gall bladder
● Understand unconjugated versus conjugated bilirubinemia, physiologic jaundice;
Gilbert syndrome, Crigler-Najjar, Dubin-Johnson, Rotor syndrome, biliary tract
obstruction, primary biliary cirrhosis, primary sclerosing cholangitis
● Know clinical presentation of gall bladder and bile duct cancer
101027-Pancreas
● Know acute and chronic pancreatitis, etiology, presentation, complications, prognosis
(Ranson criteria), and management
○ etiology
○ presentation
○ complications
○ prognosis (Ranson criteria)
○ management
● Know tumors of the pancreas, clinical presentation, complications, and treatment
○ clinical presentation
○ complications
○ treatment
101027-Liver Disease
● To gain knowledge in the evaluation and management of patients with liver disease
○ History
■ Duration of abnormal LFTS
■ Chronic > 6months
 ■ Risk factors for viral hepatitis
■ Family history of liver disease
■ Alcohol or drug use
■ Meds
■ Age
■ Gender
■ Psychological state
■ Comorbid diseases
■ Travel history
○ Physical
■ Jaundice, arthralgias, myalgias, rash, anorexia, weight loss,
abdominal pain, fever, pruritis, change in urine or stool
■ Stigmata of liver diseases
○ Chemistry/Lab Changes
■ Alanine aminotransferase (ALT)
● Hepatocellular damage
● Hepatic ALT predominant (< 5x Normal)
○ Chronic hepatitis C
○ Chronic hepatitis B
○ Acute viral hepatitis (A–E, EBV,CMV
○ Steatosis/steatohepatitis
○ Hemochromatosis
○ Medications/toxins
○ Autoimmune hepatitis
○ Alpha1-antitrypsin deficiency
○ Wilson's disease
○ Celiac disease
■ Aspartate aminotransferase (AST)
● Hepatocellular damage
● < 5x Normal
○ Liver
■ Alcohol-related liver injury
■ Steatosis/steatohepatitis
■ Cirrhosis
○ Heart, Skeletal muscle, Blood
■ Hemolysis
■ Myopathy
■ Thyroid disease
■ Strenuous exercise
■ Macro-AST
■ Bilirubin
● Cholestasis, impaired conjugation, or biliary obstruction
● Conjugated hyperbilirubinemia
○ Direct
○ Decreased excretion into bile ductules or backward leak
○ Hepatobiliary disease
○ Not bound to album -> infiltered throught the kidney ->
bilirubinuria
○ Causes:
 ■ Bile duct obstruction
■ Hepatitis
■ Cirrhosis
■ Medications/toxins
■ Primary biliary cirrhosis
■ Primary sclerosing cholangitis
■ Sepsis
■ Total parenteral nutrition
■ Intrahepatic cholestasis of pregnancy
■ Benign recurrent cholestasis
■ Vanishing bile duct syndromes
■ Dubin-Johnson syndrome
■ Rotor syndrome
● Unconjugated Hyperbilirubinemia
○ Indirect
○ Bound to albumin -> Not filtered through the urine
○ Overproduction
■ Extravascular or intravascular hemolysis
■ Hematoma
■ dyserythropoiesis
○ impaired uptake
■ CHF
■ Portosystemic shunts
■ Gilbert’s
■ Drugs-rifampin, probenecid,
○ impaired conjugation
■ Crigler-Najjar syndrome type I and II
■ Gilbert’s
■ Neonates
■ Hyperthyroidism
■ Ethinyl estradiol
■ AIH, Wilson’s disese, Cirrhosis
○ Causes of isolated unconjugated hyperbilirubinemia
■ Gilbert's syndrome
■ Neonatal jaundice
■ Hemolysis
■ Blood transfusion (hemolysis)
■ Resorption of a large hematoma
■ Shunt hyperbilirubinemia
■ Crigler-Najjar syndrome
■ Ineffective erythropoiesis
■ Alkaline phosphatase
● Cholestasis, infiltrative disease, or biliary obstruction
● Fractionate
● 5’ nucleotidase
● GGT
○ Alcoholism, pancreatic diseases, MI, CRF, COPD, DM,
phenytoin, barbituates
■ Prothrombin time
 ● Synthetic function
■ Albumin
● Synthetic function
■ Gamma-glutamyltransferase
● Cholestasis or biliary obstruction
■ Bile acids
● Cholestasis or biliary obstruction
■ 5'-Nucleotidase
● Cholestasis or biliary obstruction
■ Lactate dehydrogenase
● Hepatocellular damage, not specific for hepatic disease
○ Extrahepatic Cholestasis
■ CBD obstruction
■ Stricture after invasive procedures
■ Malignancy
● pancreatic, ampullary, gallbladder, cholangiocarcinoma
■ PSC
■ Acute and Chronic pancreatitis
■ AIDS cholangiopathy
● CMV, cryptosporidium
■ Parasitic infections
● Ascaris, lumbricoides, liver flukes
○ Intrahepatic Cholestasis
■ Viral hepatitis
■ Alcoholic hepatitis (transaminases <500IU/l)
■ NASH
■ PBC
■ Vanishing bile duct syndrome
■ TPN
■ Sepsis/ Hypoperfusion
■ Paraneoplastic Syndromes (Stauffer’s syndrome)
■ Post op patient
■ Following organ transplant
■ Hepatic crisis in sickle cell
■ Pregnancy
■ ESLD
■ Drugs and toxins- alkylated steroids chlorpromazine, bush tea, arsenic
■
○ Mild Elevation of serum aminotransferases (< 250U/L)
■ Step 1
● Review possible link to medications, herbal therapies, illicit drugs
● Screen for alcohol abuse
● Screen for HBV and HCV
● Screen for hemochromatosis
● Evaluate for fatty liver
■ Step 2:
● Exclude non hepatic causes
● Exclude Muscle disorders
● Exclude Thyroid disease
 ● Consider Celiac disease
● Consider Adrenal insufficiency
■ Step 3
● Consider autoimmune hepatitis
● Consider Wilson’s disease
● Consider Alpha 1 antitrypsin
■ Step 4
● If aminotransferases are less than 2 fold observe
● if aminotransferases are more than 2 fold Liver biopsy
○ Evaluation of elevated alkaline phosphatase
■ Step 1
● Rule out physiologic causes
■ Step 2
● Determine the source by fractionation of alk phos, GGT, and
5’nucleotidase
■ Step 3
● If negative for liver source, test for bone disease
● If positive for liver source, check AMA and RUQ U/S
■ Step 4
● If AMA is positive and U/S normalLiver biopsy
● If AMA is negative and U/S abnormalLiver biopsy
● If alkphos is > 50% elevated and AMA is negative and U/S normal
Liver biopsy/ERCP/MRCP
● If alkphos is <50% elevated and AMA is negative and U/S normal
observe
● If U/S has dilated ducts ERCP
○ Elevation of bilirubin
■ Step 1
● H/P and labs
■ Step 2
● Unconjugated bilirubin with normal AP, ALT,AST Hemolysis work
up and review medications
● Conjugated bilirubin with abnormal AP, ALT, AST RUQ U/S
■ Step 3
● If dilated ducts ERCP/MRCP
● If no dilation but has abnormal ALT review work up for abnormal
ALT, review meds, AMA, ERCP/MRCP, and liver biopsy
■
● Understand the diagnosis and management of viral, metabolic, autoimmune, alcohol,
toxic hepatitis
○ viral
■ diagnosis
■ management
○ metabolic
■ diagnosis
■ management
○ autoimmune
■ diagnosis
■ management
 ○ alcohol
■ diagnosis
■ management
○ toxic hepatitis
■ diagnosis
■ management

MMI (Almost Done)

101021- GI Immunity
● Describe the innate immune components of the intestinal epithelial barrier (villi and
crypts). Describe their role in preventing spread/infection of the host by commensal
bacteria.
○ Innate immune components of the intestinal epithelium:
■ Intestinal Epithelial Cell
■ (IEC) barrier
● Tight junctions
○ forms a barrier against the penetration of microorganisms.
● Antimicrobial Proteins
■ Mucus Layers
● The mucosa are continually bathed in a thick layer of mucus.
● Goblet cells produce mucin, that forms a protective layer of gel-
like mucus over the surface epithelium.
● There are 2 layers of mucus:
○ 1st layer is colonized by bacteria, which becomes trapped
in the mucus and is pushed out by intestinal peristalsis.
○ 2nd layer contains high concentrations of antimicrobial
proteins (produced by IECs), making it resistant to
bacterial growth, thus, keeping bacteria away from
epithelial surface.
■ IgA
● essential in maintaining luminal compartmentalization of intestinal
bacteria, as shown by the fact that IgA deficiency leads to
increased penetration of symbiotic bacteria into the host tissues.
■ gamma-delta Intestinal Epithelial Lymphocytes (IELs)
● contribute to epithelial repair by secreting:
○ epithelial growth factors
○ produce a number of pro-inflammatory
○ antimicrobial factors.
● represent an important bridge between innate and adaptive
immunity
● do not recognize MHC-associated peptide antigens and are not
MHC restricted
● A working hypothesis for the specificity of γδ T cells is that
they may recognize antigens that are frequently encountered
 at epithelial boundaries between the host and the external
environment
■ Macrophages
● quickly phagocytose bacteria that pass across the mucosal barrier
■ Commensal Bacteria
● The beneficial properties endowed by commensal bacteria on
host physiology underlie the requirement for immune hypo-
responsiveness to these microbial communities.
● On the other hand, the symbiotic nature of the intestinal
host-microbial relationship is dependent on limiting bacterial
penetration of host tissues by the immune system, as
demonstrated by:
○ the increased penetration of symbiotic bacteria into the
tissues of individuals with an IgA deficiency,
○ and by the increased translocation of bacteria into he host
tissues of experimental animals with compromised innate
immunity in the gut.
● Describe the significance of the expression pattern of pathogen recognition receptors on
the luminal vs. the baso-lateral surface of intestinal epithelial cells.
○ express an array of PRRs, the engagement of which promotes a cascade of
signaling events that result in expression of pro-inflammatory cytokines and anti-
microbial proteins
○ IECs express little or no cell surface TLR2 or TLR4, thus minimizing the
recognition of ubiquitous gram negative bacterial LPS.
○ Basolateral and intracellular localization of PRRs (TLR3, 4, 7, 8 and 9) would
engage only pathogenic bacteria that actively invade the epithelial-cell barrier
(Commensal bac don’t seem to have the virulence factors necessary to penetrate
the epithelium).
○ Repeated contact with bacterial components induce downregulation of TLRs,
and inhibition of intracellular signaling though TLRs, suggesting a mechanism by
which inflammatory responses induced by commensal bacteria are inhibited to
maintain tolerance.
● Describe the roll of NOD-1/NOD-2.
 ○

○ NOD1 or NOD2 activate RIP2. RIP2 activates IKK gamma alpha beta. IKK
complex activates NF kappa B. NF Kappa B goes to the nucleus to produce
proinflammatory cytokines and and chemokines like:
■ Production of anti-microbial proteins (eg. defensins, cathelicidins, and C-
type lectins)
○ Paneth cell sit at the base of small intestinal crypts.
■ They produce various anti-microbial proteins, such as the defensins (a
and b), which interact with and lyse gram positive and gram negative
bacterial membranes.
■ The crypt is kept sterile to protect stem cells
■ bacteria in an infected crypt will stimulate the release of anti-microbial
proteins by bacterial engagement of PRRs,
● cell surface TLR 2 binds peptidoglycan
● TLR 4 binds LPS
● NOD 1 binds muramyl tripeptides from gram negative bact,
● NOD 2 binds peptidoglycan from gram positive and negative,
respectively
● Appraise the significance of the inhibition of NF-kB signaling by commensal bactreria.
● Compare and contrast the process of antigen presentation and T and B cell activation
in the Peyer’s Patches and Mesenteric lymph nodes during the steady state (in the
absence of infection/inflammation) with antigen presentation and T and B cell activation
in the presence of an infection.
○ The GALT includes:
■ peyer’s patches
■ solitary lymphoid follicles of the intestine
■ appendix
■ tonsils
■ adenoids
■ mesentric lymph nodes
○ The GALT can be divided into
 ■ a) organized tissues that are responsible for the induction phase of the
adaptive immune response to gut antigens
■ b) effector sites, which consist of activated lymphocytes scattered
throughout the epithelium and lamina propria of the mucosa.
○ Peyer’s Patches
■ The peyer’s patches are aggregates of lymphoid cells built into the
intestinal wall. They are made up of a large B cell follicle an interfollicular
T cell region, and numerous intervening macrophages and dendritic cells
■ Overlying the lymphocytes and separating them from the gut lumen
is a layer of follicle-associated epithelium (FAE), that contains both
conventional absorptive intestinal epithelial cells (enterocytes), and a
smaller number of specialized epithelial cells called microfold cells (M
cells).
● Unlike enterocytes, M cells do not secrete digestive enzymes or
mucus, and lack the thick surface glycocalyx. This enables M
cells to take up intact microorganisms and particulate antigens
from the gut lumen.
○ The M cells of the Peyer’s patches are specialized for the
uptake of pathogens from the intestinal lumen and their
transcytosis across the epithelium and into underlying the
lymphoid tissue.
○ In this way, these cells are continuously sampling luminal
antigens, which get taken up by DCs (on the basal
surface), and presented to naïve T and B cells in the
Peyer’s patches or mLN.

● Dendritic cells resident in the lamina propria outside of the

organized lymphoid tissues can also capture luminal antigens
independently of M cells. The DC then move into the T-cell area
of a mesenteric lymph node, to stimulate antigen specific T cells.
○ DCs can extend processes between the cells of the
epithelium.
● List the factors suppressing DC activation during the steady state, with the factors
contributing to DC activation during an infection.
○ The type of adaptive immune response generated in the Peyers Patches and
mLymph Nodes is dependent upon the signals that the dendritic cells receive
from the local environment:
○ In the presence of commensal bacteria, there is constitutive production by gut
epithelial cells of:
■ TGF-b
■ prostaglandin E2 (PGE2)
■ both of which tend to maintain local DCs in a quiescent state with low
levels of costimulatory molecules.
○ The result is the production of local IgA antibodies, together with the generation
of Tregs that inhibit effector T cells that could cause inflammation.
○

○ The presence of invasive bacteria results in complete dendritic cell activation.

○ When pathogens are encountered, local inflammation caused by bacterial
penetration and PAMP recognition cause DCs to mature completely after taking
up antigen.
○ As a result, DCs express IL-12 and high levels of costimulatory molecules
(CD80/CD86).
○ These DCs induce CD4 T cells to differentiate Into effector Th1 and Th2 cells.
 ○

● Appraise the role of dendritic cell activation in the establishment of oral tolerance.
○ As we previously saw for B cells activated in the mucosa, T cells activated by
DCs in Peyer’s patches have been imprinted with gut homing properties.
● Describe the function of CTLA-4.
○ CTLA-4 is structurally homologous to CD28, but CTLA-4 is expressed on recently
activated CD4+ and CD8+ T cells
○ its function is to inhibit T cell activation by counteracting signals delivered by
the TCR complex and CD28. Thus, CTLA-4 is involved in terminating T cell
responses.
● Describe the significance of CCR9 and a4b7 in the circulation of GALT-activated
lymphocytes. (Compare and contrast with the expression of CCR7 and L selectin
expressed by naïve cells)
○ The expression of L-selectin and CCR7 allow naïve T cells circulating throughout
the bloodstream to home to peripheral lymphoid organs, such as the Peyer’s
Patches, or lymph nodes draining the skin.
○ Activation in the GALT changes adhesion molecule expression. Cells lose L-
selectin, and gain the integrin a4b7 and the chemokine receptor CCR9.
○ Lymphocytes activated in the Peyer’s patches or mLN drain back into the blood
via the thoracic duct, and are drawn back to the mucosal tissue as a result of
expression of the a4:b7 integrin and the CCR9 chemokine receptor.
○ Priming of lymphocytes in one mucosal tissue can induce protective
immunity at other mucosal surface
○ MAdCAM-1 (the GALT ligand for a4b7) is not restricted entirely to the
blood vesseles of the intestine
■ also found on the vasculature in the other mucosal surfaces
■ lymphocytes primed in GALT migrate to other sites within the
 common mucosal immune system
● Describe the constituent cells of the lamina propria and intestinal epithelium.
○ The lymphocytes that enter the mucosa redistribute into distinct compartments:
■ B cell blasts mature into IgA producing plasma cells and remain in the
lamina propria.
● Secretory IgA produced by B cells (the best characterized
effector molecule in the gut) acts to prevent luminal antigens,
microorganisms, and other foreign proteins from penetrating the
intestinal surface, and can neutralize toxins and infectious agents.
■ CD4 T cells are distributed through out the LP of the villus and crypt.
● Most of the T cells of the lamina propria have a memory
phenotype, indicating that they have been previously exposed to
antigen. These are present with or without infection.
● Lamina propria CD4 T cells are of particular importance to local
immune regulation, and produce large amounts of cytokines,
including IFNg, IL-4 and IL-10. Many may provide help for B cell
production of IgA.
● Many of the properties of LP CD4 T cells are similar to those
of “anergic” regulatory T cells.
■ CD8 T cells migrate preferentially to the epithelium.
● Lamina propria CD8 T cells can exhibit potent cytotoxic T
lymphocyte (CTL) activity.
● Describe the etiology, pathogenesis, diagnosis and treatment of Celiac disease.
○ Celiac Disease: also referred to as “celiac sprue” or gluten-sensitive enteropathy,
results from from immunological hypersensitivity to ingested gluten-containing
cereals, such as wheat, rye, or barley in genetically predisposed individuals.
○ Etiology and Pathogenesis:
■ In susceptible individuals, Celiac disease is triggered by Gluten, the major
storage protein of wheat and similar grains.
● 1. Gluten contains a 33-amino acid α-gliadin peptide that is
resistant to degradation by digestive enzymes.
● 2. This peptide undergoes deamination in the small intestine by
the enzyme Tissue transglutaminase (tTG), and is then processed
into three epitopes that preferentially bind HLA-DQ2 or HLA –
DQ8, that are sub-sequently recognized by CD4 T cells.
● 3. These activated T cells generate IFNg and other cytokines
believed to cause the villous atrophy and crypt hyperplasia
characteristic of this disease. Celiac is a Th1 disease.
 ●

● 4. An additional component to the pathogenesis of this disease

may include that some gliadin peptides induce epithelial cells to
express IL-15, which in turn triggers activation and proliferation of
CD8+ intraepithelial lymphocytes (IELs).
● 5. These CD8+ IELs are induced to express NKG2D, a natural
killer cell marker.
● 6. These lymphocytes become cytotoxic and kill enterocytes with
surface MIC-A, an HLA class I-like protein expressed in response
to stress and reocognized by NKG2D.
● 7. Thus, unlike the CD4+ T cells, these NKG2D+ CD8+ T cells do
not recognize gliadin.
● 8. Autoabs present: IgA against tTG and endomysium; IgA and
IgG against gliadin.
■ Genetics:
● Host factors determine susceptibility to disease
● HLA proteins seem to be critical, since almost all people with
celiac disease carry the class II HLA-DQ2 or HLA-DQ8 allele.
● However, the HLA locus accounts for less than half of the genetic
component of celiac disease.
● Remaining genetic factors may include polymorphisms of
immune-regulatory genes, such as those encoding IL-2, IL-21,
CCR3, and genes that determine epithelial polarity.
● There is also an association of celiac disease with other immune
diseases including type 1 diabetes, thyroiditis, and Sjögren
syndrome, as well as ataxia, autism, depression, some forms
of epilepsy, IgA nephropathy, Down syndrome, and Turner
syndrome.
■ Clinical Features:
● The onset of disease varies from infancy through old age
● Symptomatic adult celiac disease is often associated with anemia,
chronic diarrhea, bloating or chronic fatigue.
● In those patients with pediatric celiac disease, classic symptoms
typically begin between 6 and 24 months and include irritability,
 abdominal distention, anorexia, chronic diarrhea, failure to thrive,
weight loss, and muscle wasting.
● A characteristic itchy, blistering skin lesion, dermatitis
herpetiformis, can be present in as many as 10% of patients.
○ Involved skin shows deposition of IgA and C3 below
epithelial basement membrane. Likely the result of the
deposition of IgA immune complexes originating in the
intestinal mucosa following gluten ingestion.
■ Morphology:
● The major site of tissue injury in celiac disease is the proximal
small intestine.
● Biopsy specimens show the classical lesion characterized by:
○ increased numbers of intraepithelial T lymphocytes,
particularly gd T cells.
○ blunting and flattening of the mucosal surface,
○ with villi either absent, or broad and short, elongated crypts
(a sign of marked increase in epithelial cell turnover),
○ inflammatory cell infiltrate in the lamina propria, including
plasma cells (IgA, and IgG producing), CD4 T cells,
macrophages, mast cells and basophils.
○ Cuboidal rather than columnar epithelial cells are observed
● Histological lesions regress with gluten free diet.
○

■ Diagnosis and Treatment:

● A jejunal biopsy is the essential diagnostic test for Celiac disease.
● Noninvasive serologic tests are generally performed prior to
biopsy.
○ The most sensitive tests are the presence of IgA
antibodies to tissue transglutaminase or IgA or IgG
antibodies to deamidated gliadin.
○ Anti-endomysial antibodies are highly specific but less
sensitive than other antibodies.
○ In cases with negative IgA tests, IgA deficiency, which is
more common in celiac patients, should be ruled out.
● The absence of HLA-DQ2 or HLA-DQ8 is useful for its high
negative predictive value, but the presence of these alleles is not
helpful in confirming the diagnosis.
● Treatment: life long elimination of gluten from wheat, rye and
 barley from the diet.
101022- GI Infectious Disease
● Be able to identify organisms that cause bloody and/or watery diarrhea.

Bloody: Hemming Yer Shi Invasive Salmon Enta Camps is Historically Difficult
Watery: Rotating Toxic Nordic Salmon Adds Clostrophic Vibes to Giant Crypts
● List the hallmark signs and symptoms of diarrheal gastrointestinal infectious diseases
& List typical organisms causing the highlighted diseases and relate the infective
properties of the organism to the characteristics of disease pathologies.
○ Helicobacter Pylori
■ Gastritis
■ Gastric and Duodenal Ulcers
■ Treatment is 7-10 day combination of:
● a proton pump inhibitor (e.g., omeprazole),
● a macrolide (e.g., clarithromycin)
● a beta-lactam (e.g., amoxicillin)
○ E. Coli
○ Salmonella
■ Typhoid fever
● Patients present with abdominal pain, fever, chills.
● Rose spots can develop: a rash consisting of faint pink macules
on the trunk and abdomen.
● Hepatosplenomegaly, intestinal bleeding and/or perforation
caused by erosions of Peyer’s patches.
■ Enterocolitis/ gastroenteritis
● S. enteritidis, S. typhimurium
● 6-48 incubation period, nausea, vomiting abdominal pain.
● Watery or Bloody diarrhea.
● Symptoms may be prolonged with antibiotics.
○ Shigella
■ S. dysenteriae
● Causes enterocolitis/ shigellosis
● Bloody diarrhea
● Fever, abdominal pain
 ● Antibiotics
● Fluid and electrolyte replacement
○ Yersinia enterocolitica
■ Enterocolitis
● Incubation period 1-10 days.
● Bloody diarrhea, fever, abdominal pain.
● Can mimic Crohn’s disease or appendicitis.
● Manifestations in adults can include arthritis and septicemia
○ Campylobacter jejuni
■ Gastroenteritis
● Inflammatory diarrhea, fever, and abdominal pain (mimicking
acute appendicitis).
● 10 or more bowel movements a day, stools may be bloody .
● Generally self-limited.
● May be confused with Crohn’s or ulcerative colitis.
● Complications:
● reactive arthritis
■ Guillain-Barré syndrome
● an autoimmune disorder of the peripheral nervous system
characterized by development of symmetrical weakness over
several days and recovery requiring months or longer.
● Pathogenesis related to antigenic cross-reactivity between
the surface lipopolysaccharides of bacteria and peripheral nerve
gangliosides of host.
○ Vibrio cholera
■ Abrupt onset of watery diarrhea and vomiting about 2 to 3 days after
ingestion of the bacteria.
■ "rice-water" stools feces-streaked stool specimens become colorless
and odorless, free of protein, and speckled with mucus.
■ The resulting severe fluid and electrolyte loss can lead to dehydration.
■ Treatment:
● Fluid and electrolyte replacement
● Antibiotic resistance has been reported
○ Giardia
■ Incubation period is about 10 days before symptoms appear.
■ Disease onset is sudden with foul-smelling, watery diarrhea, abdominal
cramps, and flatulence, and steatorrhea.
■ Ventral sucking disks attach to lining of duodenal wall, causing a fatty,
foul-smelling diarrhea.
■ Metronidazole
○ Cryptosporidium parvum
■ Immunocompetent
● 1-2 weeks after exposure, patient has profuse, explosive watery
diarrhea.
● Lasts about 5 days, then rapidly clears.
● Abdominal cramps, anorexia, nausea, weight loss and vomiting.
■ Severe diarrhea in immunocompromised
● fulminant cholera-like illness which requires intravenous
rehydration therapy.
 ○ Rotavirus
■ Shortens microvilli in duodenum and proximal jejunun, causing decreased
absorptive surface coupled with decreased enzymatic function.
■ Can destroy intestinal cells.
■ Malabsorption and defective handling of fats and carbs.
■ Incubation- 1-3 days
■ Abrupt onset of vomiting followed by frequent copious watery brown
stools.
■ May have low-grade fever
■ Major complication is dehydration
■ ROTA (Right Out The Anus)
○ Norwalk Virus
■ Low infectious dose required for infection.
■ Damage to the intestinal brush border prevents proper absorption of
water and nutrients and causes a watery diarrhea.
■ Diagnosis (for patient and source) is usually PCR on stool samples.
■ Acute gastroenteritis
● Watery
● Bloody stools do not occur
● Nausea, vomiting, diarrhea
● 60% of all nonbacterial gastroenteritis in US.
● Outbreaks of viral gastroenteritis on cruise ships are commonly
attributed to Norwalk virus.
● The incubation period is usually 24 to 48 hours, and the illness
resolves within 12 to 60 hours without problems.
● Immunity is short-lived
● Identify the diagnostic properties of each organism in the context of the disease in which
it is presented.
○ Helicobacter Pylori
■ Breath Test
● Urease test relatively sensitive and highly specific; urea breath
test is a noninvasive test.
○ E. Coli
■ MacConkey Agar
● Lactose Fermentor
■ EMB Agar
● E. coli produces dark, blue-black colonies with a metallic green
sheen
● EMB helps in differentiating lactose fermenting E.coli (green) and
Enterobacter (pink)
■ Indole positive
● Positive Indole: Bacteria that contain tryptophanase can
hydrolyse tryptophan to its metabolic products(indole, pyruvic
acid, ammonia)
● Indole accummulates
● Add Kovac’s reagent to change to red color
 ■

○ Salmonella
■ Motile (H antigen flagella)
■ Non-lactose fermenting (vs E.coli)
■ Produces H2S (vs Shigella)
● Hektoen-enteric agar differentiates Salmonella and Shigella
because only Salmonella produces H2S, which makes colonies
light green with black centers.
■ Oxidase negative
■ Sensitive to acid
○ Shigella
■ Gram negative rods
■ Non-lactose fermenters
■ Nonmotile
■ Oxidase negative
■ Stool culture
● Does not ferment lactose (vs. E.coli)
● Does not produce H2S (vs. Salmonella)
● Non-motile (vs. Salmonella)
○ Yersinia enterocolitica
■ Gram-negative rods
■ Non-lactose fermenter
■ oxidase negative
■ Motile at 25C, not at 37C
■ Cefsulodin-irgasan-novobiocin (CIN) agar is a highly selective medium
for this organism. characteristic deep red center with a transparent
margin, or "bull's-eye”.
●

○ Campylobacter jejuni
■ Comma-shaped, gram-negative rods
■ Motile
■ Microaerophilic
 ■ Growth Campylobacter Agar (Skirrow) at 42C
○ Vibrio cholera
■ Gram-negative
■ Facultative anaerobe
■ Do not ferment lactose
■ Positive oxidase
■ Polar flagella, motile
■ Curved rods
■ TCBS: thiosulfate citrate bile salt sucrose medium.
■ Virulence:
○ Giardia
■ Trophozoite:
● tear-drop shape ranging from 12-15 micronmeters.
● Has 2 nuclei with central karyosomes.
● Adhesion disk occupies the ventral side.
● 4 flagella
■ Cyst:
● Newly formed- 2 nuclei
● Older- 4 nuclei
● Thick wall
● Internal fibers
■ Specimen stool on multiple days
■ With negative result with stool specimen in conjunction with continued
suspicion of giardiasis, duodenal aspiration or biopsy of small intesting
■ Microscopy
■ Commercially available test for fecal antigen
○ Cryptosporidium parvum
■ Obligate intracellular
■ Cysts: acid fast stain, immunofluoresence
■

○ Rotavirus
■ Family reoviridae
■ Non-enveloped, ds RNA viruses
■ Double-capsid structure
○ Norwalk Virus
■ Calciviridae
■ Naked, icosahedral
 ■ Positive-sense ssRNA
■ Transmission is via fecal-oral route,
■ contaminated food and water.
● Know pathogenic mechanisms associated with toxins.
○ Helicobacter Pylori
○ E. Coli
■ ETEC
■ EIEC
■ EPEC
■ EHEC
○ Salmonella
■ LPS, Capsule
■ Facultative intracellular replication (replicate in vacuoles).
○ Shigella
■ Shiga toxins- Disrupts proteins synthesis, cleaves 60S ribosome
■ Type III secretion system
■ Invade M-cells located in Peyer’s patches
● Replication occurs in the cytoplasm where Shigella will polymerize
actin filaments to propel through cytoplasm.
● Cell-to-cell passage
○ Yersinia enterocolitica
■ Endotoxin
○ Vibrio cholera
■ Cholera A-B toxin- toxin ADP ribosylates Gs, keeping adenylate cyclase
active and increasing cAMP (turns the on on).
■ Encodes on a lysogenic bacteriphages.
101029-GI Inflammatory Disease
● Identify organisms associated with different types of food poisoning.
○ S. aureus
■ Meats, mayonnaise, custard
○ B. cereus
■ Reheated rice
○ Clostridium perfringens
■ Reheated meat dishes
○ Vibrio parahaemolyticus and V. vulnificus
■ Contaminated seafood
○ Clostridium botulinum
■ Improperly canned food
■ 1 to 3 days after consuming ; weak, dizzy, blurred vision with fixed,
dilated pupils, dry mouth; flaccid paralysis, + /- vomiting.
■ Infants: “floppy baby syndrome”
○ E. coli O157:H7
■ Undercooked meat
○ Salmonella
■ Poultry, meat, eggs
○ Trichinella spiralis
■ pork
 ○

● List virulence factors associated with organisms that cause food poisoning.
○ S. aureus
■ Heat-stable toxin (Enterotoxin, SE-A)
■ Bacteria release toxin in foods (e.g. custards).
■ Self-limiting, 5-24hr nausea, vomiting, diarrhea, abdominal pain.
○ B. cereus
■ Gram positive rods
■ Spore-forming
■ Ubiquitous
■ Enterotoxins
● Heat-stable, emetic form: associated with fried rice
● Ingestion of enterotoxin, not bacteria.
● Incubation period is short (1-6 hours) after eating, illness is short
also (~24 hrs).
● Vomiting, nausea, abdominal cramps (disease like that in S.
aureus).
● Heat-labile, diarrheal form: stimulates the adenylate cyclase-
cyclic adenosine monophosphate (cAMP) system in intestinal
epithelial cells, leading to profuse watery diarrhea.
○ True infection
○ Contaminated meat and sauces
○ Enterotoxin is heat-liable (mechanism like ETEC LT)
 ○ Clostridium perfringens
○ Vibrio parahaemolyticus and V. vulnificus
○ Clostridium botulinum
■ Obligate anaerobic rods, spore-forming, motile
■ Found in the soil and dust.
○ E. coli O157:H7
○ Salmonella
○ Trichinella spiralis
● Identify symptoms associated with different types of food poisoning.
● List typical organisms causing the highlighted hepatic diseases and relate the infective
properties of the organism to the characteristics of disease pathologies.
○ Hepatitis viruses
■ Hepatitis A
● Picornavirus
● Spread by fecal oral route
● Non-enveloped, Positive-sense, ss RNA virus
● Associated with shellfish
● 2-4 week incubation period
● Viral replication does not appear to be cytotoxic; liver damage
may result from T-cell-mediated injury.
● Diagnosis: detection of serum IgM antibodies
● Prevention: Hepatitis A vaccine
■ Hepatitis B
● Hepadnavirus
● Spread parenterally by blood or needles, by sexual contact, and
perinally
● Small, enveloped
● Unusually stable
● DNA is circular and partly double stranded
● Reverse transcriptase and replicates through RNA intermediate
● HBsAg (Hepatitis B surface Antigen)- containing particles
○ Released into the serum of infected people and outnumber
the actual virions
● Pathology:
○ Detection of both the HBsAg and the HBeAg components
of the virion in the blood indicates the existence of an
ongoing infection
■ HBsAg
● Found during acute disease and persistant
infections.
● See antigen past 6-months suggest chronic
● HBsAb- antibody
■ HBeAg
● Active viral production/ infectious.
● HBeAb- antibody; indicates virus is no
longer detectable and suggests lower risk of
transmission.
■ HBcAb
● First antibody to appear
 ● IgM important screening for recent infection.
■ Liver Enzymes:
● Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) leak from
damaged cells; thus, these enzymes are
sensitive indicators of liver injury.
○ Can cause acute or chronic, symptomatic or asymptomatic
disease
■ HBsAg and HBeAg are secreted into the blood
during viral replication
■ Chronic- continued presence of HBsAg and/or
HBeAg and a lack of detectable antibody
■
● Virus replication (incubation period can be~75 days).
○ Noncytopathic; Infection without causing liver damage (i.e.,
elevation of liver enzyme levels) or symptoms
○ Intracellular build-up of filamentous forms of HBsAg-
ground-glass hepatocyte cytopathology
● Immunopathology causes symptoms by eliminating infected
hepatocytes.
○ Cell mediated and inflammation - Insufficient T-cell
response can result in mild symptoms, an inability to
resolve infection, and chronic hepatitis.
● Antibody (vaccination) can neutralize, but large amounts of
HBsAg in serum can block this.
○ Immune complexes can lead to type III hypersenstivity
reactions- vasculitis, arthralgia, rash and renal damage.
● Morphology: Ground Glass Hepatocyte
○

● Fever, malaise, anorexia followed by nausea, vomiting, abdominal

discomfort and chills.
 ● Icteric symptoms: jaundice, dark urine, and pale stools.
● Chronic Persistent can lead to extrahepatic disease like:
○ 5% - 10% of HBV infections
○ polyarteritis nodosum
○ glomerulonephritis
○ May become infected with HDV
○ Association with primary hepatocellular carcinoma (PHC)
■ 80% can be attributed to HBV infection
■ Genome is integrated and cells express antigens
■ Usually fatal
■ The latency period between HBV infection and
PHC may be as short as 9 years or as long as 35
years.
● Chronic Treatment-
○ lamivudine (targets polymerase)
○ Adefovir dipivoxil, famciclovir (nucleoside analogues)
○ Interferon alpha
● Vaccination
○ Only part of virus in vaccine is HBsAg, response to vaccine
can be easily measured by quantifying the anti- HBs in the
vaccinee ~6-8 weeks after last dose.
■ Hepatitis C
● Flavivirus
○ Ss (+) RNA genome
○ 30-60nm in diameter
○ Enveloped
○ 2 glycoproteins: Site for mutations and antigenic variability
● Binds CD81 (tetraspanin)
○ Expressed on hepatocytes and B-lymphocytes
● Can also coat itself with low-density lipoprotein, or very low-
density lipoprotein and then use the lipoprotein receptor for uptake
into hepatocytes .
● Spread parenterally by blood or needles, by sexual contact, and
perinally
● High incidence of chronic asymptomatic infections.
○ Especially prevalent in southern Italy, Spain, Central
Europe, Japan, and parts of Middle East. ~20% of
Egyptian blood donors are HCV+.
● Highest risk
○ IVDU
○ Transfusion and organ recipients
○ Hemophiliacs
● Pathology:
○ Persistent infection is facilitated by ability to prevent host
cell death & remain cell associated.
○ Binds the tumor necrosis factor receptor and to protein
kinase R
○ Inhibits apoptosis
○ Attenuates IFN-alpha activity
 ○ Viremia lasts 4-6 months in people with acute infection and
longer than 10 years in those with persistent.
○ HCV induced liver damage may be exacerbated by
alcohol, certain medications, and other hepatitis viruses to
promote cirrhosis.
○ Promotes development of hepatocullar carcinoma.
● Diagnosis
○ ELISA for anti-HCV
○ Also used to screen blood supply
○ RT-PCR
○ Especially in seronegative people
○ Seroconversion 7-31 weeks
● Treatment
○ Recombinant interferon alpha or pegylated interferon
○ Ribavirin
●
■ Hepatitis G
● Flavivirus
● Transmitted in blood
■ Hepatitis E
● Calciviruses
○ non-enveloped, positive-sense,
○ single-stranded RNA virus
● Spread by fecal oral route
● Fecal-oral transmission
● Associated with water-borne epidemics
● Incubation period- 4-5 weeks
● Not associated with chronic liver disease
● Selectively high morbidity in pregnant women
■ Hepatitis D
● Helper virus; Spread in blood, semen, and vaginal secretions
● Delta hepatitis, is unique in that it requires actively replicating
HBV as a "helper virus" and occurs only in patients who have
active HBV infection. HBV provides an envelope for HDV RNA
and its antigens. Delta agent exacerbates the symptoms caused
by HBV.
○ Entamoeba histolytica
■ Flask-shaped ulcerations
■ Extraintestinal amebiasis is associated with trophozoites
■ Amebiasis
■ May be asymptomatic, but still pass organisms
■ Symptoms reflect the localized tissue destruction
■ in the large intestine.
● Abdominal pain, cramping, colitis with diarrhea
● Severe disease: numerous bloody stools per day.
○ extraintestinal amebiasis can occur in lungs, brain
● Liver involvement: hepatomegaly and abscess formation-
trophozoites in the blood are removed as they pass through liver
■ Cyst and trophozoite forms can be found in patients stool.
 ■ Extraintestinal amebiasis is sometimes diagnosed using scanning
procedures for the liver and other organs.
■ Adequate sanitation measures
■ Chlorination and filtration of water supplies
○ Leishmania donovani
■ Protozoa: Leishmania donovani
■ Transmitted by sandfly
■ Parts of India, Bangladesh, Nepal, Sudan, and Brazil
■ Protozoa engulfed by macrophages
■ Division eventually destroys infected cell
■

■ Spread through reticuloendothelial system (takes months)

■ Damage to spleen, liver, bone marrow
● Splenomegaly, thrombocytopenia, and anemia
● fever, weight loss, and an enlarged spleen and liver
● (typically, the spleen is bigger than the liver)
■ Also causes cutaneous form of disease
■ Diagnosis
● Biospy look for non-flagellated protozoan within macrophages
● Serology
○ Echinococcus granulosus
■ Hydatidosis, or hydatid disease
■ Cestodes (tapeworms)
■ Reservoirs
■ Adults in intestines of canines.
■ cyst stage is present in the viscera of herbivores.
■ Human accidentally ingest eggs, hatch into oncosperes in human
intestine, oncosphere penetrates the human intestinal wall and enters
the circulation to be carried to various tissue sites, primarily the liver and
lungs.
■ Larvae form a unilocular hydatid cyst, which is a slow-growing, tumor-
like, and space-occupying structure enclosed by a laminated germinative
membrane.
■ hydatidosis, or hydatid disease
● Cysts and daughter cysts accumulate fluid as they grow. This fluid
is potentially toxic; if spilled into body cavities, anaphylactic shock
and death can result.
● 5 to 20 years may pass before any symptoms appear.
 ● The pressure of the expanding cyst in an organ is usually the first
sign of infection.
● cyst may exert pressure on both bile ducts and blood vessels and
create pain and biliary rupture
● Diagnosis is difficult
● Biopsy is risky because of potential for anaphylactic shock.
● Surgical resection of the cyst
●

■ Schistomsomas
■ Yellow fever
○ Pathology:
■ Hepatic damage is occurs in all types of viral hepatitis, but extent of cell
injury or necrosis varies
■ Virus injures or kills hepatocytes
■ Inflammatory response further injures or destroys hepatocytes by lysing
the infected or neighboring cells
■ Later, direct antibody attack against viral antigens causes further
destruction of infected cells
■ Edema and swelling of the interstitium lead to collapse of capillaries,
 decreased blood flow, tissue hypoxia, scarring, and fibrosis
● Identify the diagnostic properties of each organism in the context of the disease in which
it is presented
101030-Liver Infections
● Describe the inflammatory injury that occurs during autoimmune gastritis, and relate this
injury to the underlying mechanism of vitamin B12 deficiency and megaloblastic anemia.
● Describe the most likely immunologically mediated mechanism of injury during
autoimmune gastritis.
● Describe the potential role of antibodies directed against intrinsic factor in the
development of autoimmune gastritis.
○ Chronic gastritis
■ inflammation of the gastric mucosa
■ is relatively common, and is associated with atrophy of gastric glands and
loss of specialized secretory cells, including parietal cells and chief cells
■ Two main types:
● Type B gastritis is caused by Helicobacter pylori infection
● Type A is the result of an Autoimmune response.
○ Diffuse atrophic gastritis in the body and fundus of the
stomach, with lack of, or minimal involvement of the
antrum.
○ Antibodies to parietal cells and intrinsic factor that can be
detected in serum and gastric secretions.
○ Defective secretion of gastric acid and intrinsic factor (due
to loss of parietal cells).
○ Increased serum gastrin, owing to G cell hyperplasia.
○ Vitamin B12 deficiency
○ Reduced serum pepsinogen I concentration (produced by
chief cells)
○ Pathogenesis:
■ Autoimmune associated loss of the parietal cells
compromises the production of intrinsic factor
■ Chronic lymphocytic infiltration of the gastric body
leads to eventual atrophy of gastric parietal cells
and loss of intrinsic factor production.
■ The absorption of dietary vitamin B-12 requires
intrinsic factor produced by the parietal cells.
■ Lack of intrinsic factor disables ileal vitamin B12
absorption, leading to B12 deficiency and a slow
onset of megaloblastic anemia (pernicious anemia).
■ The absence of acid production by parietal cells
drives increased gastrin release, resulting in
hypergastrinemia and hyperplasia of antral gastrin-
producing G cells.
■ Over 90% of patients with pernicious anemia are
found to produce the Gastric Parietal Cell Antibody
(GPC Ab), which targets the gastric proton pump
(H+/K+ ATPase) of parietal cells.
■ These antibodies are unlikely to be pathogenic
in vivo because the pump is not accessible to
 circulating autoantibodies.
■ In addition, in animal models, the transfer of these
autoantibodies alone does induce gastritis.
■ Rather, it is more likely that CD4+ T cells directed
against parietal cell components,including the
H+,K+-ATPase, are the principal agents of injury.
■ This is supported by the observation that transfer
of H+,K+-ATPase-reactive CD4+ T cells into naive
mice results in gastritis and production of H+,K+-
ATPase autoantibodies.
○ Absorption of Vit B12 may further be impaired during
autoimmune gastritis by the production of antibodies
directed against intrinsic factor itself.
○ Two types of autoantibodies to intrinsic factor are common
in pernicious anemia:
■ Two thirds of patients have an antibody to intrinsic
factor that impedes its binding to vitamin B12,
preventing formation of the complex that is
absorbed in the ileum.
■ About half of patients with this antibody also have
an antibody against the intrinsic factor–vitamin B12
complex that interferes with its absorption
■ Antibodies to parietal cells and to intrinsic factor are
present early in the disease course. Progression
to gastric atrophy probably occurs over 2 to 3
decades, and anemia is seen in only a few patients.
■ A genetic component to the disease is suggested
by the observation that pernicious anemia and
autoimmune gastritis are often associated with
other autoimmune diseases including Hashimoto
thyroiditis, insulin-dependent (type I) diabetes
mellitus, Addison disease, primary ovarian failure,
primary hypo-parathyroidism, Graves disease,
vitiligo, myasthenia gravis, and Lambert-Eaton
syndrome.
■ Despite this strong genetic influence, autoimmune
gastritis stands apart from other autoimmune
diseases in that there is little evidence of linkage to
specific HLA alleles.
○ Diagnosis and Treatment:
■ Based upon: Low serum vitamin B12
■ Presence of anti-parietal cell antibodies
■ Treatment: Lifelong vitamin B12 replacement
therapy.
● Assess the relationship between FoxP3, regulatory T cells and the development of
autoimmune enteropathy.
○ AUTOIMMUNE ENTEROPATHY
■ Autoimmune enteropathy is an X-linked disorder characterized by severe
persistent diarrhea and autoimmune disease that occurs most often in
 young children.
■ A particularly severe familial form, termed IPEX, an acronym denoting:
● Immune dysregulation
● Polyendocrinopathy
● Enteropathy
● X-linkage, is due to a germline mutation in the FOXP3 gene,
which is located on the X chromosome.
■ FOXP3 is a transcription factor expressed in CD4+ regulatory T cells, and
individuals with IPEX and FOXP3 mutations have defective T-regulatory
function.
■ Other defects in regulatory T cell function have also been linked to less
severe forms of autoimmune enteropathy.
■ Autoantibodies to enterocytes and goblet cells are common, and some
patients may have antibodies to parietal or islet cells. Within the small
intestine intraepithelial lymphocytes may be increased, but not to the
extent seen in celiac disease, and neutrophils are often present.
■ Therapy includes immunosuppressive drugs such as cyclosporine and, in
rare cases, bone marrow transplantation
● Compare and contrast the pathologenesis, clinical symptoms and tissue injury of
Crohn’s Disease and Ulcerative Colitis.
○ The distinction between UC and CD is based, in large part, on the distribution of
affected sites and the morphologic expression of disease at those sites.
■ Ulcerative colitis is a severe ulcerating inflammatory disease that is
limited to the colon and rectum and extends only into the mucosa and
submucosa.
■ In contrast, Crohn disease, which has also been referred to as regional
enteritis (because of frequent ileal involvement) may involve any area of
the GI tract and is typically transmural.
■

■ Both CD and UC are more common in females and frequently present in

the teens and early 20s.
■ IBD is found most commonly in developed countries.
■ In western, industrialized nations IBD is most common among
Caucasians and, in the United States, occurs 3 to 5 times more often
among eastern European (Ashkenazi) Jews.
■ However, IBD incidence worldwide is on the rise, possibly as a result
of the reduced frequency of enteric infections, which has resulted in
inadequate development of regulatory processes to limit mucosal immune
responses. (Hygiene hypothesis)
■ Chrohn’s Disease
● Crohn’s Disease (CD) is a syndrome of unknown cause
characterized by chronic, relapsing and remitting, focal,
transmural inflammation of the GI tract.
● CD can occur in any area of the GI tract, but most typically in the
terminal ileum, ileocelcal valve and cecum.
● The presence of multiple, separate, sharply delineated areas
of disease, resulting in skip lesions, is characteristic of Crohn
disease
●

● Symptoms:
○ In most patients disease begins with intermittent attacks
of relatively mild diarrhea, fever, and abdominal pain.
However, the clinical manifestations and patient history of
CD are highly variable, and relate to the anatomical sites
involved in the disease.
○ Diarrhea
○ Abdominal pain
○ Fatigue
○ Weight loss
○ Rectal pain
○ Hematochezia (passage of blood tinged stool)
○ Fever
○ Growth failure in children
○ Nauseau
○ Vomiting
○ Dyspepsia
○ Arthralgias
○ Skin lesions
○ Aphthous mouth ulcers
○ Visual changes
○ Extra-intestinal manifestations of CD include: uveitis,
migratory
■ Polyarthritis,
■ sarcolitis,
■ ankylosing spondylitis
■ erythema nodosum
■ clubbing of the fingertips.
● Tissue Injury
○ The characteristic early lesions of CD consists of ulcer-like
lesions that occur in a focal fashion in the gut. Mulitple
lesions often coalesce into elongated ulcers. Sparing of
uninvolved mucosa results in a cobblestone appearance.
○ Inflammatory cells include lymphocytes, plasma cells,
eosinophils and abundant neutrophils that infiltrate and
damage crypt epithelium. CD4 T cells and macrophages
that can aggregate into noncaseating granulomas.
 ○ Fissures frequently develop between mucosal folds and
may extend from the intestinal lumen into the deeper levels
of the gut wall.
● Pathology:
○ Evidence suggests that the disease is the result of an
abnormal interaction between:
■ multiple host susceptibility genes
● Early evidence for genetic influence of
the development of CD came from the
observation that the concordance rate for
the disease in monozygotic twins is 50%.
● More recently, genome-wide scans of
affected families identified NOD2 as a
susceptibility gene in Crohn’s disease.
● Recall that NOD2 encodes a cytoplasmic
pattern recognition receptor that binds
bacterial peptidoglycan and subsequently
activates NF-kB.
● Disease associated NOD2 variants may be
less effective at recognizing and combating
lunimal microbes, which are then able
to enter the lamina propria and trigger
inflammation.
● Other data suggest that NOD2 actively
regulates mucosal immune responses to
prevent excessive activation by luminal
microbes.
● In either case inflammation arises from
abnormal immune reactions to bacterial
flora.
● Be aware that NOD2 is one of many genetic
factors contributing to disease: only 10% of
people with NOD2 variant are positive for
CD.
■ the mucosal immune system
● CD patients have increased titers of anti-
bacterial antibodies, particularly to gut flora,
suggesting a component of the disease is
loss of tolerance to enteric flora.
● Polarization of involved CD4 T cells to
produce Th1 cytokines is well recognized in
CD.
● More recent evidence suggests that
Th17 cells may also contribute to disease
pathogenesis:
○ This is based upon the observation
that certain polymorphisms in the
receptor for IL-23 confer protection
from CD.
 ○ Recall that IL-23 is required for the
development and maintenance of
Th17 cells.
○ This suggests that the protective
IL-23 receptor polymorphisms may
attenuate proinflammatory Th17
responses in CD.
○ TH17 cells produce the cytokines
IL-17, which induces production of
chemokines and other cytokines
from various cells, and these recruit
neutrophils (and monocytes, not
shown) into the site of inflammation.
Some of the cytokines made by
TH17 cells, notably IL-22, function to
maintain epithelial barrier function in
the intestinal tract and other tissues.
■ GI epithelium with the microbial environment of the
gut
● CD lesions are most typically found in
locations with high bacterial counts, namely
the cecum and the terminal ileum.
● Surgical diversion of the fecal stream
ameliorates disease
● Most patients have at least a temporary
response to antibiotic therapy.
● One interpretation of these data is that
enteric organisms might contribute to the
pathogenesis of disease, although
● their precise role in the disease has yet to
be defined.
● Epithelial defects: dis-function of the
epithelial cell barrier is thought to be a
critical component of IBD pathogenesis.
● Defects in intestinal epithelial tight junction
barrier function are present in CD patients,
and this barrier dysfunction appears to be
associated with NOD2 polymorphisms.
● In addition, the Paneth cell granules, which
contain antibacterial peptides termed
defensins, are abnormal in some CD
patients. This suggests that defective
epithelial anti-microbial function contributes
to IBD.
■ Environmental Trigger
● Periods of active disease are typically
interrupted by asymptomatic periods that
last for weeks to many months.
● Disease re-activation can be associated
 with a variety of external triggers, including
physical or emotional stress, specific dietary
items, and cigarette smoking.
● Smoking is a strong exogenous risk factor
for development of Crohn disease and, in
some cases, disease onset is associated
with initiation of smoking. Unfortunately,
smoking cessation does not result in
disease remission.
○ Diagnosis
■ tests with highest specificity are GI endoscopy with
biopsy.
■ Required to differentiate CD from UC:
■ gross appearance of the lesions and their location
and distribution
■ serologic testing for ANCAs (To help rule out UC.)
○ Treatment:
■ Includes immunosuppressive drugs such as
corticosteroids, cyclosporine, and purine synthesis
blockers.
■ Infliximab: blocks TNFalpha and has shown to
improve remission for active disease, and to heal
fistulae.
● Ulcerative Colitis
○ Ulcerative colitis (UC) is closely related to CD. However,
intestinal disease in UC is limited to the colon and rectum.
○ Common extra-intestinal manifestations of ulcerative
colitis overlap with those of CD and include migratory
polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, skin
lesions, pericholangitis, and primary sclerosing cholangitis.
○ Characterized as a relapsing disorder with attacks of
bloody diarrhea with stringy, mucoid material, lower
abdominal pain, and cramps that are temporarily relieved
by defecation.
■ These symptoms may persist for days, weeks, or
months before they subside, and, occasionally, the
initial attack may be severe enough to constitute a
medical or surgical emergency.
○ More than half of patients have clinically mild disease,
although almost all experience at least one relapse
during a 10-year period, and up to 30% require colectomy
within the first 3 years after presentation because of
uncontrollable symptoms.
○ Pathology:
■ The characteristic pathological features of UC
consist of superficial mucosal inflammation and
ulceration of the rectal and colonic mucosa, which
occurs in a continuous pattern, typically most
severe in the rectum, and decreasing progressively
 in severity in more proximal areas of the colon.
■ UC may be very limited involving only a few cm
of rectum, may involve only the distal colon and
rectum, or may involve the entire colon.
■ Microscopically, the mucosa has intense infiltration
of the colonic crypts with neutrophils, resulting
in destruction of the crypts and ulceration.
Lymphocytes and plasma cells are also found.
■ Granulomas are not present in UC.
○ Disregulation of mucosal immune responses
■ The concordance of monozygotic twins for UC is
only 16%, suggesting that genetic factors are less
dominant than in CD. NOD2 mutations are not
associated with UC.
■ In contrast to CD, data suggest that ulcerative
colitis is a TH2-mediated disease, and this is
consistent with observations of increased mucosal
IL-5 and 13 in ulcerative colitis patients.
■ However, the same IL-23 receptor polymorphisms
that conferred protection from CD, do so as well for
UC, which seems to support roles for TH17 cells in
some cases of UC.
■ Antineutrophil cytoplasmic antibodies (ANCAs) are
found in 80% of patients with ulcerative colitis.
● However, these abnormalities are not
unique for ulcerative colitis, nor are they
a prerequisite for the development of the
disease.
● It is, therefore, possible that some or all of
these immune features are, the result, not
the cause, of mucosal damage.
○ Environmental Triggers
■ The factors that trigger ulcerative colitis are not
known, but infectious enteritis precedes disease
onset in some cases.
■ In other cases the first attack is preceded by
psychologic stress, which may also be linked to
relapse during remission.
■ The initial onset of symptoms has also been
reported to occur shortly after smoking cessation in
some patients, and smoking may partially relieve
symptoms.
○ Diagnosis
■ The distinction between ulcerative colitis and Crohn
colitis is based on different anatomical localization
and histopathology.
■ Ulcerative colitis is a diffuse process, usually more
severe distally, while Crohn colitis is patchy or
segmental and often spares the rectum.
 ■ The inflammation in ulcerative colitis is superficial
(i.e., usually limited to the mucosa) and is
characterized by an acute inflammatory infiltrate,
with neutrophils and crypt abscesses.
■ By contrast, Crohn colitis is transmural and
involves all layers, with granulomas in some of the
specimens.
● Discuss the significance of the NOD2 PRR in the development of Crohns disease.
● Describe the evidence connecting the pathogenesis of IBD and Th17 cells.
● Describe the potential roll for Th17 cells in the development of IBD.
● Describe the environmental triggers for CD and UC.
● Appraise the role of Th1 and Th2 subsets in the pathogenesis of CD and UC.
● Describe the known immunopathogenesis of eosinophilic gastroenteritis and
autoimmune liver disease.
○ Eosinophilic Gastroenteritis (EG) refers to a clinically heterogeneous disorder
characterized by infiltration of the GI tract by eosinophils.
● Most common areas of involvement are the stomach and small
intestine.
● Tissue involvement is variable and may involve the mucosa,
muscle, or serosal layers in varying degrees.
■ Pathogenesis:
● roll of allergy is uncertain, since removal of potential allergens
does not lead to clinical improvement.
● Likely roll for eosinophil chemoattractants, which include IL-3, IL-5
and GM-CSF.
○ Autoimmune Hepatitis
■ Autoimmune hepatitis is a chronic and progressive hepatitis of unknown
etiology.
■ The pathogenesis is attributed to T cell-mediated autoimmunity, in
which hepatocyte injury is caused by IFN-γ produced by CD4+ and
CD8+ T cells and by CD8+ T-cell-mediated cytotoxicity. This reaction is
potentially fueled by aberrant HLA expression by hepatocytes, triggered
by genetic factors, viral infection or drugs.
■ A defect in regulatory T-cells may underlie the uncontrolled activation of
pathogenic, self-reactive lymphocytes.
■ Autoimmune hepatitis commonly affects middle aged women, and may
occur concurrently with other autoimmune disorders, such as celiac
disease, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis,
Sjögren syndrome, and ulcerative colitis
■ The salient features include the absence of serologic markers of viral
infection, elevated serum IgG and γ-globulin levels (1.2 to 3.0 times
normal), and high serum titers of autoantibodies.
■ Autoimmune hepatitis is classified into types 1 and 2, based on the
patterns of circulating antibodies.
● Type 1 is characterized by the presence of antinuclear (ANA),
anti-smooth muscle (SMA), anti-actin (AAA), and anti-soluble liver
antigen/liver-pancreas antigen (anti-SLA/LP) antibodies.
● The main antibodies detected in Type 2 autoimmune hepatitis
are anti-liver kidney microsome-1 (ALKM-1) antibodies, which are
 mostly directed against CYP2D6, and anti-liver cytosol-1 (ACL-1).
● Type 1 is much more common than Type 2 in the United States
and is associated with the HLA-DR3 serotype.
■ Treatment is aimed at suppressing the immunological effector
mechanisms, and the corticosteroid, and trials with Predinsolone induces
clinical remission and prolongs life.

Pharm
101020Pharm- Intro to GI