Unit 1 Flashcards

Question

paneth cells

Answer 1

contain large eosinophilic granules that have defensins, antibacterial peptides, lysozyme and phosophlipase.

Answer 2

only found in duodenum and release large quantities of bicarbonate into the crypts in order to neutralize the acid arriving from the pyloric sphincter. they also secrete mucins.

Answer 3

contain loose lamina propria core containing small blood vessels and capillaries, lymphocytes, and series of small lymphatic spaces that connect to the lacteal, a larger lymphatic vessel in the center, which transports fluid entering from lumen and chylomicrons (lipoprotein droplets) that are exocytosed by enterocytes on the side facing the lamina propria. enterocytes take up fatty acids and monoglycerides from the lumen of the gut and resynthesizes them into di and triglycerides to be released by exocytosis on the opposite side. nutrients taken up of capillaries are transported to the liver via the hepatic portal system; lacteals enter larger lymphatics and proceed to the bloodstream via the thoracic duct.

Answer 4

lymphoid tissue is present both as scattered individual cells and as lymphatic nodules and peyer's patches, groups of nodules, in the mucosa of the intestine.

Answer 5

specialized epithelial cells that take up antigen cells and phagocytose luminal contents and present these antigens to underlying lymphocytes and macrophages.

Answer 6

release IgA, which bind to receptors on epithelial cells and then are transcytosed to the lumenal surface where they act as antibacterial agents by discouraging pathogenic bacterial colonization and adherence (mucus production also aids in this)

Answer 7

the gland is organized into acini, which are clusters of pancreatic acinar cells arranged at the end of a common duct (like a cul de sac). the basal portion of these cells have RER that synthesizes proteins for secretion and stored in zymogen granules (secretory granules). most secreted enzymes are initially released as zygomens than partial degraded to become enzymatically active. such enzymes include trypsin, chymotrypsin, elastase, carboxypeptidase, and triacylglycerol lipase. amylase (which degrades starch to glucose and maltose) and ribonuclease (which cleaves RNA) are synthesized by the pancreas in their active forms. zygomens prevent autodigestion. (98% of pancreas is dedicated to exocrine function but the pancreas also houses endocrine islets of langerhans cells).

Answer 8

trypsinogen is the zygomen, which is activated by enterokinase, which is not secreted but is a membrane anchored enzyme in the apical plama membrane of duodenal digestive/absorptive cells. trypsin activates other zymogens through proteolysis

Answer 9

where larger ducts join together to join the common bile duct than join the bile duct to form the sphincter of oddi.

Answer 10

also found in acini of the pancreas, represent the beginning of the duct system and secrete much of the pancreatic juice, including water and bicarb to help the brunner's glands to neutralize the chyme arriving from the stomach. secretin and cholycystokinin control secretion.

Answer 11

composed of the cecum and appendix, transverse and descending colons and rectum. compared to the small intestine, it is smooth and lacks plicae and villi. it has many straight tubular glands or crypts and the epithelial layer has two cell types, abundant mucous-producing cells and absorptive cells. the main function of the large intestine is recovery of water and salt during concentration of fecal material. the lamina propria and submucosa contain numerous lymphocytes, scattered and in large aggregates and nodules. 2/3 of wall is muscular, with large bands of circular muscles. the longitudinal layer has muscular specializations, mostly consisting ob bands called taeniae. segmented contraction of these bands causes sacculation of the bowel, which compresses and segments fecal material. at the anus, the circular layer is thickened to form the internal anal sphincter and downstream is circular striated muscle, the external anal sphincter.

Answer 12

longitudinal structural folds of the mucosa in the distal region of the rectum.

Answer 13

contains three main salivary glands including paired submandibular glands, sublingual and the paired parotid glands, which secrete serous (parotid), mucous (sublingual), or mixed (submandibular). they are all based on the acinar design with circumferential myoepithelial cells. contraction of myoepithelial cells propel salivary secretions from the acini. serous secretions are watery with amylase, DNase, RNase. Mucous secretions are lubricative and protective. serous epithelial cells also transport IgA that, in combination with lysozyme and peroxidase, provide antibacterial action. Ducts modify the ionic contents of saliva as they move towards major ducts.

Answer 14

manifests in 80-90% of pts. The principal pathological abnormalities of the GI tract consist of smooth muscle atrophy and gut wall fibrosis. smooth muscle atrophy in esophagus leads to weak peristalsis and dysphagia, also leads to weak LES and GERD. chronic GERD can lead to esophagitits and strictures. esophageal manometry is diagnostic.

Answer 15

Receptive relaxation (vagally mediated inhibition of body tone. Liquid emptying by tonic pressure gradient. Solid emptying by vagally-mediated contractions. Residual solids emptied during non-fed state by MMC every 90-120 minutes

Answer 16

dyspepsia is discomfort or pain related to eating. organic causes includePUD, atypical GERD, gastric/esophageal caner, pancreaticobiliary disorders, food drug (NSAIDs) intolerance.

Answer 17

no organic etiology. pathophysiology may involve alterations in gastric motility, 40% of pts have impaired gastric accommodation.

Answer 18

stomach paralysis leading to impaired transit of food from stomach to duodenum. need to exclude gastric outlet obstruction. clinical manifestations include N/V, early satiety, portprondial abdominal distention and pain. causes include idiopathic (post-infectious?), post sugical (vagal nerve injury due to gastric esophageal, thoracic surgical procedures, ie lung transport), diabetes (neuropathy), medication (opiates), paraneoplastic, rheumatologic, neurologic, myopathic (scleroderma). diagnosed with gastric emptying study. management includes lifestyle and diet measures (small meals, low fat, glucose control), medications (prokinetic and antiemetics), gastric electric stimulation, and surgery.

Answer 19

Signs and symptoms of mechanical obstruction of the small bowel without a lesion obstructing flow of intestinal contents. Characterized by the presence of dilation of the bowel on imaging. Major Manifestation of Small Intestinal Dysmotility. Small Intestinal Bacterial Overgrowth a complication of CIPO, stasis leads to bacterial overgrowth, fermentation, and malabsorpbtion. Symptoms include N/V, abdominal pain, distention, constipation, diarrhea, urinary symptoms. Neuropathic causes include degenerative neuropathies (parkinson's), paraneoplastic atuoimmune (anti-Hu Ab), changas diases (parasite Trypanosoma cruzi), diabetes. Mixed myopathic and neuropathic causes includes infiltrative conditions such as scleroderma, amyloidosis, eosinophillic gastroenteritis. And idiopathic. In children it is mostly congenital, mostly primary condition (visceral neuropathy with myopathy). Absent MMC predicts need for IV nutrition. One third of infants born die in 1st year of life.

Answer 20

The anorectal junction is formed by the longitudinal muscle of the rectum, the sling fibers of the puborectalis muscle, the attachments of the levator ani muscle, and the proximal margins of the internal and external anal sphincters. this is the approximately 90 degree anorectal angle formed by the puborectalis. The puborectalis and levator ani muscles are straited muscles that form part of the pelvic floor. They are in a state of constant tone pulling the rectum anteriorly and elevating the rectum, thereby reducing the anorectal angle. The IAS is a thickened band of circular smooth muscle with high tone that is in continuity with the circular smooth muscle of the rectum. It is innervated thru the pelvic plexus by lumbar sympathetics and sacral parasympathetic nerves. It receives powerful inhibitory innervation from enteric inhibitory motor neurons, the cell bodies of which are in the enteric ganglia. It contributes approximately 75% of the resting sphincter pressure and is primarily responsible for maintaining anal continence at rest. The EAS is a striated muscle that is an expansion of the levator ani muscle and is distal to but partly overlapping the IAS and also has high resting tone. But unlike the IAS, its tone can be influenced by voluntary effort to help maintain continence. The EAS and other pelvic floor muscles are innervated thru the pudendal nerve (S3-S4) by motor neurons within cell bodies in the spinal cord.

Answer 21

Hirschsprung’s is a congenital absence of myenteric neurons of the distal colon. As a result, there is no reflex inhibition of the IAS following rectal distention. It is more common in Males compared with female and occurs in 1 in 5000 births. There is a characteristic pattern on anal manometry, showing megarectum/megacolon on defecography (no relazation of IAS with pressure), and the diagnosis is confirmed by a deep rectal biopsy which shows no myenteric neurons.

Answer 22

Bowel evacuation is facilitated by coordinated activity of the abdominal and the pelvic floor muscles. At rest, the puborectalis and internal and external anal sphincter muscles are tonically contracted. Propagated HAPC motor activity propels undigested residue from the colon into the rectum, resulting in rectal distention and triggering the urge to defecate. When the time is right for defecation, the internal and external anal sphincters and the puborectalis muscle relax during the bear down maneuver (which also involves coordination with abdominal muscle activity) leading to pelvic floor descent, an increase (widening) of the anorectal angle, and thus, an open and straighter canal through which stool can pass. Certain defecation disorders, such as pelvic floor dyssynergia (inadvertent contraction or failure to relax of the pelvic floor muscles with bearing down) can result in a relative obstruction to outflow of contents (not shown) and symptoms of constipation. Significant risk factors for constipation in older women are failure of the anorectal angle to open or excessive perineal descent, which represent disturbances of pelvic floor function and rectal evacuation.

Answer 23

Inability to coordinate the abdominal, rectoanal and pelvic floor muscles during defecation, due to Anismus (high anal resting pressure), Incomplete anal relaxation, Paradoxical contraction of the pelvic floor and external anal sphincters (dyssynergia), Rectal hyposensitivity, Excessive perineal descent, Rectocoele. Causes include Bad toilet habits, Painful defecation, Obstetric or back injury, Brain gut dysfunction

Answer 24

Abnormal anorectal manometry, showing paradoxical contraction of the pelvic floor and external anal sphincters. Treatment: Biofeedback therapy is effective

Answer 25

Triple Therapy: Clarithromycin-Amoxicillin or Metronidazole-PPI. Quadruple Therapy: Bismuth subsalicylate-Metronidazole-Tetracycline-PPI or H2 Antagonist. Sequential Therapy: Amoxicillin-PPI (5 days) then Clarithromycin-Tinidazole-PPI (5 days)

Answer 26

[PPIs] (Omeprazole [Prilosec] / Esomeprazole [Nexium], Lansoprazole [Prevacid], Rabeprazole [Aciphex], Pantoprazole (Protonix]). Omeprazole is available OTC.

Answer 27

administered as prodrug, than absorbed into systemic system where it diffuses into parietal cell where the proton catalyzed formation of the active sulfenamide the drug in the acidic secretory canniculi. Covalent linkage of sulfenamide form to sulfhydryl groups of H+-K+-ATPase irreversibly inactivates enzyme. Since 18 hours are required for synthesis of new enzyme this action results in an 80-95% reduction in daily acid production despite a plasma half-life of only 0.5-2 hours. Maximal suppression of acid secretion may require several doses of PPIs (not all pumps are active simultaneously), thus it may take 2-5 days to reach steady state level of 80% inhibition. Efficacy of the 5 available PPIs is equivalent at comparable doses

Answer 28

Rapidly absorbed, highly protein bound. Best to give on empty stomach 1 hour ac (before meals) so peak plasma concentration occurs with maximal proton pump secretion. Rapid first pass metabolism via CYP450 enzymes (2C19 and 3A4); consider dosage reduction in patients with severe hepatic disease (esomeprazole, lansoprazole). No drug accumulation in chronic renal failure with once-daily dosing

Answer 29

GERD. Most effective agent for nonerosive and erosive reflux disease and complications (85-90% with QD dosing, 15% require BID dosing). Peptic ulcer disease. More rapid symptom relief and faster healing than H2 antagonists [90% for duodenal (4 weeks) and gastric ulcers (6-8 weeks)]. H. pylori associated ulcers also require therapy with antibiotic combination. NSAID-induced ulcers. Effective for treatment (healing impaired if NSAID not stopped) or prevention of ulcers and ulcer-related complications. Prevention of stress gastritis. Increasing use in critically ill patients to reduce mucosal bleeding, despite any clear demonstration of efficacy at present time. Zollinger-Ellison syndrome. Higher doses provide complete symptomatic relief and ulcer healing.

Answer 30

very safe. Mild side effects (1-5%). Headache, abdominal pain, nausea, constipation, diarrhea Minor reduction in oral cyanocobalamin (B12) absorption and levels. Hypergastrinemia resulting from chronic PPI use (5-10%) does NOT result in tolerance (as with H2 antagonists) but may contribute to rebound increases in gastric acidity upon discontinuation. Drug-drug interactions due to actions on CYP450 enzymes: omeprazole may inhibit conversion of antiplatelet agent clopidogrel to active form

Answer 31

(Ranitidine [Zantac], Cimetidine [Tagamet], Famotidine [Pepcid], Nizatidine [Axid]). All agents are available OTC for acute gastritis (lower dosage strengths).

Answer 32

Mechanism of action is reversible, competitive block at parietal cell H2 receptors on basolateral membrane. Less efficacious than PPIs but still suppress 24 hour acid secretion by 70%. Better at blocking nocturnal (basal, H2-mediated) acid secretion (90%) than meal-stimulated (ACh- and gastrin-mediated, 60-80%). Since suppression of nocturnal acidity is key to duodenal ulcer healing, evening dosing of H2 antagonists is usually adequate therapy.

Answer 33

All are rapidly absorbed from the GI tract; some enhancement with food, small decrease if given with antacids. Less protein binding than PPIs. Some hepatic metabolism (10-35%), but no dosage adjustment for liver disease Major route of elimination is renal excretion; half-lives of 1-4 hours with duration of action dependent on dose given. Dosage reduction required if impaired renal function (especially in elderly patients).

Answer 34

GERD. Infrequent heartburn can be managed with OTC antacids (more rapid onset) or intermittent H2 antagonists. Frequent heartburn generally requires BID H2 antagonists. Proton pump inhibitors (PPIs) preferred in severe erosive esophagitis. Peptic ulcer disease. H2 antagonists largely replaced by PPIs. Still useful in suppressing nocturnal acid secretion (given at bedtime) for acute uncomplicated ulcers (6-8 week duration, 80-90% healing rate). Stress-related gastritis. Reduced bleeding when given IV.

Answer 35

Generally well tolerated (side effects in 8 weeks and in high doses): Gynecomastia, galactorrhea, decreased sperm count. Rare: Blood dyscrasias with cimetidine; liver toxicity (reversible), seen with all agents.

Answer 36

Cimetidine inhibits cytochrome P450 oxidative metabolism (CYP1A2, 2C9, 2D6, 3A4) that can increase the effects or toxicity of number of drugs (theophylline, warfarin, phenytoin, carbamazepine, ketoconazole, itraconazole, benzodiazepines). All antisecretory agents can decrease ketoconazole absorption by causing an increase in gastric pH.

Answer 37

Mucosal Protective Agents. When acid-induced damage occurs, pepsin will hydrolyze mucosal proteins causing erosion and ulcerations. This process is inhibited by this sulfated disaccharide aluminum salt that selectively binds to necrotic ulcer tissue to form protective barrier (single dose up to 6 hrs) Also decreases back diffusion of H+ ions and binds to pepsin and bile acids. Possible action to stimulate prostaglandin and epidermal growth factor production. Activated by acid pH

Answer 38

Prostaglandin (PGE1) analog. Prostaglandins have physiological action in gastric parietal cells to inhibit cAMP formation that results in decreased H+ secretion (most important clinical effect); they also stimulate acid neutralizing HCO3− formation and cytoprotective mucus formation. Major indication is alleviation of NSAID-induced GI ulceration. Side effects include diarrhea (promote fluid secretion) and/or uterine stimulation (cramping) in up to 30% of patients. Contraindicated during pregnancy because of increase in uterine motility.

Answer 39

Primary use is pain relief (healing?) due to peptic ulceration and acute gastritis. Should rapidly raise pH of stomach contents to 4-5 (above the pH optimum of pepsin); if raised to pH 7 can cause rebound acid secretion (via increased gastrin release). Should be nonabsorbable. Antacids vary in extent of systemic absorption. NaHCO3 results in the highest levels of systemic actions and its use is generally avoided.

Answer 40

Adverse effects include constipation (Ca++ and Al+++ antacids) or diarrhea (Mg++ antacids) is common. Fixed combinations of Mg and Al antacids (e.g., Mylanta® and Maalox®) used to theoretically counteract the adverse effects of each other.

Answer 41

General rule is to space drug dosing around antacid dosing to minimize potential for interactions. Decreased absorption due to binding or adsorption interactions in gut (chelation with Al+++ - Ca++ - Mg++): Tetracycline, fluoroquinolones, digoxin, chlorpromazine, indomethacin. Altered absorption due to effect on gastric emptying. Altered excretion due to alkaline urine: Aspirin (increased), quinidine (decreased). Reduced bioavailability of H2 antagonists and ketoconazole via increased gastric pH

Answer 42

Tums. Exerts rapid, prolonged neutralization of acid, but can see rebound secretion due to Ca++ effect on gastrin release. Safe, generally non-systemic, not recommended for chronic use (but OK as Ca++ supplementation). Constipation can occur; hypercalcemia / renal calculi possible if prolonged use

Answer 43

(hydroxide [Amphojel], carbonate [Basaljel], phosphate [Phosphojel]). Very widely used, binds phosphate in gut (also used in chronic renal failure to treat hyperphosphatemia). Main side effect is constipation. Chronic intake may lead to CNS toxicity (encephalopathy)

Answer 44

Magnesium (as oxide, hydroxide [Milk of Magnesia], carbonate). Major side effect is osmotic diarrhea; often added to antacid preparations to counteract Al+++ or Ca++-induced constipation. Avoid use if renal disease present (retention of Mg++ ions can occur)

Answer 45

Potent and effective, evolution of CO2. Contraindicated for prolonged therapy due to systemic effects: Na+ overload and alkalosis. Avoid if: Pregnant, CHF, hypertension, edema, renal failure (i.e., conditions exacerbated by fluid retention)

Answer 46

agonist at excitatory neuronal and smooth muscle motilin receptors

Answer 47

agonist at excitatory neuronal 5-HT4 receptors on enteric nervous system cholinergic motor neurons. Tegaserod (Zelnorm), Cisapride (Propulsid) act as agonists at postsynaptic 5HT4 receptors to directly increase ACh release. Stimulates motility and increases transit in esophagus, stomach, small intestine and ascending colon. Reduces bloating associated with irritable bowel syndrome. Cisapride may cause life-threatening arrhythmias from prolongation of QT interval (especially if its metabolism by cytochrome P450 is inhibited). This side effect has led to its use being severely restricted.

Answer 48

Dopamine antagonist that blocks presynaptic inhibition of ACh release by dopamine at D2 receptors. Will produce coordinated contractions that enhance transit of luminal contents. As a dopamine antagonist, metoclopramide has additional advantageous effect to relieve nausea and vomiting by block of dopamine receptors in chemoreceptor trigger zone. Metoclopramide (as a dopamine receptor antagonist) may cause somnolence, dystonic reactions, and tardive dyskinesia.

Answer 49

inhibits (-) hydrolysis of acetylcholine by acetylcholinesterase (AChE)

Answer 50

acts directly as an agonist (+) at excitatory (+) M3 smooth muscle receptors

Answer 51

Direct activation of M3 muscarinic receptors in the gut (as with older cholinergic agents such as direct receptor agonists [bethanechol] or cholinesterase inhibitors [neostigmine]) will increase GI motility BUT will NOT do so in a coordinated manner that will be NO net increase in propulsive activity and will also tend to increase gastric and pancreatic secretions. The mechanism of action common to most prokinetic agents is an “upstream” effect on the motor neuron itself rather than a postsynaptic action. They act to increase gastric motility by increasing release of acetylcholine from cholinergic neurons in the enteric nervous system. This allows maintenance of the coordinated activity among gut segments that is necessary for propulsion of luminal contents.

Answer 52

Vomiting center / solitary tract nucleus coordinate complex actions, contain high concentrations of muscarinic, H1, and serotonin receptors. Afferent input includes chemoreceptor trigger zone / area postrema (dopamine, 5-HT3, muscarinic, and mu opioid receptors), vestibular apparatus (muscarinic and H1 receptors), vagal / enteric afferents (5-HT3), and higher CNS centers.

Answer 53

Block of serotonin (5-HT3) receptors at chemoreceptor trigger zone (CTZ in CNS), solitary tract nucleus, and on visceral afferents (GI tract). All agents well absorbed from GI tract with metabolism via CYP enzymes. Parenteral formulations available. Biologic half-life exceeds pharmacologic half-life, i.e., anti-emetic effects remain after disappearance of parent drug from plasma. Well tolerated, occasionally headaches, constipation, drowsiness. Associated with QT prolongation so caution if underlying heart condition-hypomagnesemia-hypokalemia. Particularly effective in prevention and treatment of vomiting caused by cytotoxic drugs. Also used for emesis and nausea and vomiting associated with post-operative use of opioid analgesics.

Answer 54

Blockade of dopamine receptors in CTZ (high dose metoclopramide used to treat nausea/vomiting of cancer chemotherapy probably also block 5HT3 receptors). Side effects are largely due to block of dopamine receptors at other sites including extrapyramidal symptoms (movement disorders), restlessness, fatigue, drowsiness, diarrhea. Phenothiazines are generally not effective against emetic stimuli in gut (mediated via 5HT3 receptors); also have some blocking actions at muscarinic and histamine receptors which increases their utility in other forms of nausea such as that associated with motion sickness.

Answer 55

(meclizine [Bonine], hydroxyzine [Vistaril], diphenhydramine as dimenhydrinate [Dramamine], cyclizine [Marezine], promethazine [Phenergan]). First generation agents with good CNS penetration and additional muscarinic receptor blocking actions. Available orally; promethazine also parenterally and rectally. Primary use for motion sickness and postoperative emesis

Answer 56

(scopolamine [Transderm-Scop transdermal patch]). Primary use is prevention and treatment of motion sickness; some efficacy in post-operative nausea and vomiting. Most commonly administered transdermally with duration of action of 72 hours

Answer 57

Useful as prophylactic agent against emesis in patients receiving cancer chemotherapy that have not responded to other anti-emetic therapy. Mechanism of action is unknown, probably related to stimulation of CB1 cannabinoid receptors on neurons in and around area postrema. Highly lipid soluble compound that is rapidly absorbed orally with extensive first pass metabolism (bioavailability is 10-20%). Large volume of distribution contributes to persistence of metabolites for several weeks after a single dose.

Answer 58

central sympathomimetic actions include tachycardia, palpitations, hypotension, vasodilation. Behavioral actions include euphoria, somnolence, detachment, nervousness, panic. Use with caution in patients with history of substance abuse (Controlled Substance - Schedule III). Reports of abstinence syndrome (irritability, insomnia, restlessness) following abrupt withdrawal

Answer 59

Substance P receptor antagonist. Specific indication for the delayed phase emesis (2-5 days later) associated with the highly emetogenic cisplatin. Given for 3 days at start of therapy. Block the actions of the neurotransmitter substance P at the neurokinin 1 (NK1) receptor that are mediated via vagal afferent fibers to the solitary tract nucleus and the area postrema. Administered orally, extensive binding to plasma proteins, primarily eliminated by hepatic metabolism with half-life of 9-13 hours. Metabolism by CYP3A4 has potential for drug-drug interactions with other 3A4 substrates such as methylprednisolone, warfarin, and dexamethasone (may require their dosage to be reduced)

Answer 60

Anti-inflammatory glucocorticoids. Possible anti-emetic action via mechanism to suppress peritumoral inflammation and prostaglandin production

Answer 61

Benzodiazepines. Sedative, anti-anxiety, and amnestic properties can reduce the anticipatory component of nausea and vomiting

Answer 62

Nausea is common in early pregnancy - severe vomiting with dehydration and weight loss (hyperemesis gravidum) has a lower rate of occurrence. Nonpharmacologic treatment approaches include: dietary manipulations, avoidance of triggers, acupuncture and acupressure, and hypnosis. Pharmacologic treatment if nonpharmacologic measures fail. Addition of pharmacotherapy is reasonable with use of drugs reported to be effective and with the best maternal-fetal side effect profile. Trials of 3-4 days can be used to observe for improvement in nausea and vomiting symptoms - if no improvement add a second drug - if side effects occur use another drug. Ginger improves nausea but does not decrease episodes of vomiting. Pyridoxine (vitamin B6) is effective against mild to moderate nausea, but no effect on vomiting. H1 antagonists, Doxylamine is first-line agent-and most commonly used and acts on the vestibular system to decrease stimulation of the vomiting center. Dopamine antagonists are second line agents due to less favorable safety profile. Oral-IV routes Ondansetron most commonly used agent - greater efficacy in reducing both nausea and vomiting than pyridoxine-doxylamine.

Answer 63

Stomach acid facilitates absorption of iron, calcium, and vitamin B-12. The four anatomical regions of the stomach are the cardia, fundus, body, and antrum. The mucosa of each of these regions contains gastric pits into which several types of glands empty. Cardiac glands consist of mucous cells, which secrete mucus and small amounts of pepsinogen. Oxyntic glands are in the fundus and body. They contain mucous cells, parietal cells, chief cells, endocrine cells and enterochromaffin cells. The gastric antrum contains pyloric glands with mucous cells and endocrine cells, most importantly G cells that produce gastrin and D cells, which produce somatostatin.

Answer 64

food enters the proximal stomach triggering receptive relaxation occurs, which is vagally mediated inhibition of fundic and body tone. Vagally mediated segmental contractions originating in the mid-body of the greater curve mix the food. Non-digestible retained gastric solids (those larger than 1 mm) are emptied in the fasting state by the interdigestive migrating motor complex (MMC). The MMC occurs every 1 ½ to 2 hours in the non-fed state and consists of contractions, which begin in the stomach, moving the residual particulate matter through an open pylorus, and then into and through the small bowel. Gastric contents in the duodenum and upper small intestine stimulate receptors, which respond to low pH, high osmolality (osmoreceptors), fatty acids, and caloric density. Activation of these receptors, in turn, triggers enterogastric reflexes that slow gastric emptying. Hormones such as secretin, CCK, and GIP may play a role in these reflexes. The purpose of these inhibitory mechanisms is to prevent the small intestine from being overwhelmed by rapid entry of nutrients from the stomach.

Answer 65

Hydrochloric acid is bactericidal to most microorganisms. Thus, the stomach serves as a gatekeeper to the small intestine, keeping out most potential pathogens. The stomach itself, because of its acidic milieu coupled with gastric motility, is usually sterile. Only micro-aerophilic spiral organisms (i.e., Helicobacter pylori and Helicobacter Heilmannei) are found in the healthy human subject. Gastric juice is a combination of parietal (acid) and non-parietal secretions. Parietal cells secrete intrinsic factor and hydrochloric acid at a concentration of 160 mmol/L (pH~0.8) and a volume determined by the number of actively secreting parietal cells. Non-parietal secretions include electrolytes and mucus. The relative proportions of parietal and non-parietal secretions determine the volume and acidity of gastric juice produced during any given period.

Answer 66

Because of their constant exposure to high concentrations of hydrochloric acid, gastro-duodenal epithelial cells would appear to be at risk of auto-digestion. However, under normal circumstances mucosal protective factors prevent such self-destruction. These factors involve prostaglandin E2 and prostacyclin. The means by which prostaglandins protect gastroduodenal mucosa include the secretion of mucus, stimulation of bicarbonate secretion, and maintenance of mucosal blood flow during periods of potential injury. Bicarbonate secretion is enhanced in the duodenum at pH levels below three.

Answer 67

Symptoms of delayed gastric emptying include early satiety (86%), epigastric fullness, pain or bloating (90%), nausea (93%), and/or vomiting (68%). Before attributing symptoms to a motility disorder, it is imperative to exclude mechanical obstruction like gastric outlet obstruction (e.g. from a chronic duodenal ulcer) by upper endoscopy or an oral contrast study radiology study. A radionuclide scan diagnoses gastroparesis using a radio labeled meal, usually an egg salad sandwich; the amount of radionuclide remaining at multiple time points is measured. Greater than 10 percent remaining at 4 hours or greater than 70 percent remaining at 2 hours defines gastroparesis. Causes of delayed emptying include post-surgical states, endocrine disorders (e.g. diabetes, hypothyroidism), muscular disorders, systemic sclerosis, and drugs. Vagal nerve dysfunction or destruction leads to failure of receptive relaxation, causing early satiety and failure of antral grinding, leading to delayed emptying. Gastroparesis secondary to autonomic nerve damage from long standing diabetes is the most common. Post viral (Norwalk, Rotavirus) gastroparesis occurs and usually resolves in 1-12 months. A variety of medications like narcotics, tricyclic antidepressants, and clonidine slow gastric emptying.

Answer 68

a microaerophilic, gram-negative rod that produces abundant urease which produces ammonia and raises the local pH. The organism is also able to escape the effects of acidic gastric juice, by burrowing through the mucus layer and colonizing the surface epithelium of the gastric mucosa, where the pH is near neutral. H. pylori possess a wide variety of virulence factors, including adhesins, phospholipases, cytotoxins, cytokines and urease, permit the organism to avoid destruction by gastric acid, colonize the gastric epithelium, damage epithelial cells, and incite an inflammatory response. It virtually never penetrates the epithelium but does inject proteins like CagA that causes numerous cellular effects including the activation of NFkB and are linked to the development of gastric cancer. H. pylori elicits a robust inflammatory response (active and chronic gastritis-see below), which persist throughout life unless the organism is eradicated. Whether H. pylori are pathogenic (causes disease) relates to both H. pylori related pathogenic factors (e.g. bacterial strain). H. pylori may increase suppressive regulatory T cells. T regs, in part, may explain how the bacterium elicits inflammation without clearance of infection. Both oral-oral and fecal-oral mechanisms of transmission are believed to occur.

Answer 69

Mucosal biopsies are used for histological demonstration of the organism or the presence of urease (CLO test). Urease will split urea into ammonia and carbon dioxide. The ammonia will raise the pH of the test medium and change the color of a pH sensitive indicator (i.e. phenol red from yellow to red). Culture is the least sensitive of the direct techniques, perhaps because of the fastidious growth characteristics of the organism. Noninvasive methods include blood antibody tests, urea breath tests, and a stool antigen test. Chronic H. pylori infection produces a circulating antibody response readily detected by ELISA tests. Most antibody tests have 85% sensitivity and 79% specificity (due to prior cleared infection). Antibody tests cannot be used acutely for confirming eradication. Other non-invasive means of detecting H. pylori are the urea breath tests (UBT). A stool antigen test has performance characteristics similar to that of the UBT and is the most commonly used test in the outpatient setting to confirm eradication.

Answer 70

urea labeled with either 13C or 14C is ingested with a liquid meal. If urease is present, labeled carbon dioxide will be split off and absorbed into the circulation where its presence can be determined by analysis of expired breath. This test has virtually 100% positive predictive value and about 95% negative predictive value. As with the rapid urease test, proton pump inhibitors or high doses of H2 receptor antagonists may result in falsely negative tests.

Answer 71

H. pylori infection is always accompanied by infiltration of the gastric mucosa with neutrophils (active gastritis) and/or lymphocytes (chronic gastritis). The presence of chronic active gastritis (CAG) is considered by many to be a surrogate marker of H. pylori infection even when the organism is not specifically identified. This inflammatory response is associated with release of cytokines and increased cellular proliferation of the mucosa, which may be an important initiating factor in the minority of H. pylori, infected patients who will develop an ulcer, gastric cancer, or gastric lymphoma.

Answer 72

Most infected subjects have a mild, diffuse chronic active superficial gastritis unassociated with symptoms or disease states. A second group has antral predominant gastritis, with relative sparing of the gastric body. Such individuals tend to have high levels of acid secretion and may develop duodenal ulcer. The third group has multifocal atrophic gastritis. Because the gastric body is atrophic, acid secretion tends to be low. This group of patients is at risk for gastric ulceration or, through the pathway of metaplasia and dysplasia, gastric adenocarcinoma. While all patients infected with H. pylori should be offered treatment, infection should be sought only in selected situations, including peptic ulcer disease, low-grade gastric B – cell lymphoma, and a family history of gastric adenocarcinoma.

Answer 73

The most often used regimen consists of a proton pump inhibitor (because the antibiotics work better at a more neutral pH), amoxicillin 1 gm, and clarithromycin 500 mg each given twice daily for 7-14 days. Patients who fail first line therapy are often treated with “classsical” quadruple therapy consisting of a PPI, bismuth, tetracycline, and metronidazole. Recently, sequential therapy has been touted as better than triple therapy.

Answer 74

With the exception of H. pylori gastritis, infectious causes of gastritis are very uncommon. Bacterial causes include syphilis and tuberculosis. Fungal diseases include Candidiasis, Aspergillosis, Histoplasmosis and Mucormycosis. Parasitic diseases include Giardiasis, Cryptosporidiosis, Anisakiasis, and Stongyloidiasis. Viruses (e.g., CMV) are rare causes of gastritis and ulceration and occur in the immuno-compromised host (e.g. AIDS, chemotherapy).

Answer 75

Endoscopically, lymphocytic gastritis may appear with normal gastric folds, mucosal nodularity with erosions, volcano-like (varioliform gastritis), or with giant gastric folds (hypertrophic lymphocytic gastritis). Biopsies show extensive lymphocytic infiltration. H.pylori infection must be ruled out first. The cause is unknown. Symptoms include vague abdominal pain, anorexia, weight loss, occult bleeding, and hypoalbuminemia. An association with celiac spruce has been noted. The most important aspect of management is to exclude lymphoma or other specific forms of gastritis. There is no proven therapy, although case reports note efficacy with anti-ulcer therapy, sodium cromoglycate, or corticosteroids.

Answer 76

This entity is associated with infiltration of the gastric wall with eosinophils. Depending upon the layers involved, there may be mucosal ulceration or luminal obstruction, producing symptoms of delayed gastric emptying (i.e., early satiety, nausea, and vomiting). There is associated peripheral eosinophilia. Parasitic infestation should be excluded. Treatment of eosinophilic gastritis is with corticosteroids and, occasionally, surgery. The cause is unknown.

Answer 77

Crohn’s disease and sarcoidosis, may be associated with granulomatous inflammation. Patients with AIDS, or immunosuppressed following organ transplantation, are at risk of infection with opportunistic organisms such as CMV.

Answer 78

includes menetier disease, H. pyolri, Z-E syndrome, gastric lymphoma and gastric adenocarcinoma.

Answer 79

This rare disease has hyptertrophic rugal folds, often sparing the antrum, and histologic features of massive foveolar hyperplasia with cystic dilation, which may penetrate into the submucosa. Symptoms include abdominal pain, weight loss, and bleeding. Hypoalbuminemia occurs frequently. When the process is extensive, there may be replacement of parietal cells and resultant hypochlorhydria. There is relatively little inflammation and H. pylori are usually absent.

Answer 80

A Menetrier’s-like syndrome with large gastric folds and protein-losing gastropathy may be one manifestation of H. pylori gastritis. Histologically, there is foveolar hyperplasia and chronic active gastritis. Eradication of infection usually leads to resolution of the syndrome.

Answer 81

Acid hypersecretory states resulting from a large parietal cell mass can be associated with large gastric folds. Zollinger-Ellison syndrome is when a gastrin secreting neuroendocrine tumor stimulates parietal cells and increases acid secretion.

Answer 82

non-inflammatory of epithelial cell injury. The entities frequently produce dramatic visual damage to gastroduodenal epithelium. Includes injury due to NSAIDs, ethanol, and stress related.

Answer 83

Ulceration, defined as a lesion greater than 5mm in diameter with depth and breaches the muscularis mucosa, is believed to be the result of prostaglandin depletion, since even NSAIDs administered intravenously, with enteric coatings, or as rectal suppositories, can cause upper gastrointestinal ulcers. Patients with prior ulcer disease and perhaps the elderly are at an increased risk of developing NSAID ulcer complications. Duodenal ulcers also occur because of NSAID use, but less often than gastric ulcers. NSAID-induced ulceration is important only if associated with dyspepsia or, more ominously, bleeding or perforation.

Answer 84

is with PPIs, healing usually occurs even if the NSAID is continued. H2-receptor antagonists may heal duodenal ulcers in the NSAID user, but are much less effective with the more commonly seen NSAID gastric ulcers. Misoprostol was used as a treatment for NSAID-induced ulcers but causes diarrhea. H2-receptor antagonists in standard ulcer healing doses will effectively prevent the formation of NSAID-induced duodenal ulcers but not gastric ulcers. More potent H2 receptor antagonists or proton pump inhibitors will prevent gastric ulcers as well. Misoprostol, reduces the development of NSAID-induced gastric ulcers. prophylaxis with misoprostol or PPIs reduces the incidence of ulcer complications, but the absolute benefit is small.

Answer 85

Another area of interest was development of NSAIDs which are less damaging to gastro-duodenal mucosa. Approaches include the development of COX-2 specific NSAIDs. Examples include celecoxib, rofecoxib, and valdecoxib. They inhibit only cyclooxygenase-2, they do not inhibit prostaglandin formation in the stomach and duodenum. As a result, fewer gastroduodenal ulcers develop and fewer ulcer complications occur as well. Dyspepsia occurs as often with COX-2 selective agents as with non-selective NSAIDs. However, most COX-2 selective NSAIDs except celecoxib were removed from the marked because they increase the risk of myocardial infarction.

Answer 86

The ingestion of ethanol will produce lesions that are similar to acute NSAID-induced lesions (i.e., erythema, erosions, and subepithelial hemorrhages). The clinical importance of such lesions has been greatly over-emphasized, as there is poor correlation with symptoms and serious bleeding is rare. There is little to no associated histologic inflammation.

Answer 87

Hemorrhage and erosions of the stomach and duodenum occur in patients who are under “physiologic stress.” These include patients with CNS injury, prolonged mechanical ventilation, coagulopathy, and burns, but not patients admitted to coronary care units. The pathogenesis of these lesions is probably multifactorial but may involve elements of mucosal ischemia in the presence of gastric acid. While most such patients are not acid “hypersecretors,” it appears that acid is an essential permissive factor, since reduction of gastric acidity will prevent the lesions. Exceptions to the rule regarding acid secretion include patients with CNS injuries, burns, or sepsis. Such patients may hypersecrete acid and are at risk for the development of peptic ulcers (e.g., Cushing’s ulcer, Curling’s ulcer) with the attendant complications of bleeding or perforation.

Answer 88

Peptic ulcers (and accompanying symptoms) occur when gastroduodenal mucosal defenses are unable to protect the epithelium from the corrosive effects of acid and proteases, such as pepsin. it is primarily a disease of failed mucosal integrity, not of excess acid/pepsin secretion. While a certain minimal level of gastric acid and pepsin are necessary for the formation of an ulcer, their presence alone (with the exception of Zollinger-Ellison Syndrome) is not sufficient to produce an ulcer. most patients with ulcer disease secrete normal amounts of acid. The most important factors predisposing to failure of mucosal integrity are H. pylori infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs). Duodenal ulcers most often occur in areas of inflamed gastric metaplasia in the duodenal bulb and gastric ulcers in antral mucosa, often near the junction of oxyntic and antral epithelium.

Answer 89

The lifetime prevalence of peptic ulcer is a 5-10% with prevalence in men and women being about equal for gastric ulcer but with men predominating for duodenal ulcer. The incidence increases with age, a phenomenon that may be explained by a higher prevalence of H. pylori and the increased use of NSAIDs in the elderly. The incidence of non-NSAID associated ulcers has declined substantially, likely due to the declining prevalence of H. pylori. Other ulcer risk factors include smoking and certain diseases (chronic lung disease, cirrhosis, chronic renal failure).

Answer 90

While many ulcers may be asymptomatic, they most often present with burning epigastric pain. The pain is typically relieved with food or antacids and may often awaken a patient from sleep. Nocturnal pain relieved with antacids may be the most specific symptom of peptic ulcer. The pain of peptic ulcers, as with the ulcers themselves, comes and goes. With therapy, ulcer pain generally subsides quickly, long before healing of the ulcer.

Answer 91

An episode of bleeding occurs in as many as 30% of patients with peptic ulcer disease in their lifetimes. Factors associated with a poor outcome from a bleeding ulcer include hemodynamic instability following the bleed, continuation, or recurrence of bleeding in hospital, and age/concomitant diseases. Large, deep ulcers high on the lesser gastric curve or posterior duodenal bulb are more likely to erode major vessels and result in substantial bleeding. Ulcers which initially cease bleeding but in which endoscopic examination discloses a visible vessel will re-bleed in hospital up to 50% of the time and therefore warrant prophylactic therapy.

Answer 92

The least common complication of ulcer disease is obstruction, leading to nausea, vomiting, and early satiety. While the edema surrounding an acute ulcer may produce transient obstruction, which resolves with ulcer healing, chronic obstruction is the result of repeated bouts of acute ulceration, leading to the formation of scar tissue and narrowing.

Answer 93

Ulcer medications speed the rate of healing of an ulcer and relieve ulcer symptoms faster. The most frequently used approach to treat an ulcer is with anti-acid secretory medications. Liquid antacids like Maalox are of historical interest only in terms of ulcer healing. The most important factors determining the speed of ulcer healing with antisecretory agents are the duration of time that gastric pH is above 3.0 (rather than the degree which pH is raised above 3.0) and the number of weeks of therapy. Proton pump inhibitor treatment and H. pylori eradication are the cornerstones of therapy. In severe acute bleeds PPI “drips” are used in the ICU to tightly control pH.

Answer 94

Adenocarcinomas are classified histologically as “diffuse” or “intestinal”. This type of cancer has become less common in the United States. Could reflect changes in H. pylori prevalence, diet, sanitation. There is a close association between gastric adenocarcinoma of both types and chronic H. pylori gastritis. Other factors include carcinogenesis, since only a small proportion of patients infected with H. pylori will develop cancer. Early gastric cancer is limited to the mucosa or submucosa (regardless of lymph node involvement) and has a much better 5-year survival than advanced gastric cancer involving disease that has penetrated the muscular layer. Unless there is evidence of distant metastasis or the patient is a poor operative candidate, surgical or endoscopic resection is usually attempted, but only about half of the patients undergoing surgery are potentially curable. the overall 5-year survival is 10%. chemotherapeutic regimens can be used as adjuvant therapy or as primary therapy in patients with unresectable disease; however, survival has not been significantly prolonged.

Answer 95

The diffuse type is less common, is relatively undifferentiated, and may be associated with signet-ring cells and excess mucin production. The diffuse form of cancer is believed to evolve from non-atrophic gastritis.

Answer 96

The intestinal type forms glands, is found in association with atrophic gastritis, intestinal metaplasia, and dysplasia, and is the type that occurs in regions with a high incidence of gastric adenocarcinoma. H. pylori superficial gastritis evolves in some patients through atrophic gastritis to intestinal metaplasia, dysplasia, and the intestinal type of gastric adenocarcinoma.

Answer 97

adenoma, hyperplastic and fundic gland.

Answer 98

Hyperplastic polyps are proliferations of gastric foveolar cells (mucus producing) and arise from chronic inflammation and are found in gastric body autoimmune gastritis and in H. Pylori infection with chronic atrophic gastritis. Polyps larger than 1cm have an increased risk of harboring dysplasia or adenocarcinoma.

Answer 99

Gastric adenomas arise from dysplastic epithelial cells and have a risk of progressing to adenocarcinoma. They should be removed endoscopically with subsequent surveillance. There is an especially high incidence of adenomatous polyps, sometimes multiple polyps, in patients with familial adenomatous polyposis (FAP). Additionally, FAP patients have a predilection for adenomas in the region of the duodenal papilla.

Answer 100

Fundic gland polyps consist of dilated oxyntic glands lined by flattened parietal and mucus cells. They are the most common (74% of gastric polyps, seen at 6% EGDs) type of gastric polyp and usually result from long term PPI therapy. They are unrelated to H. pylori infection and have no malignant potential. Fundic gland polyps also arise in patients with FAP but usually number >20, occur in the antrum, and are found with duodenal adenomas (above) which helps differentiate the cause.

Answer 101

Benign gastric tumors arising from the supporting tissues (stromal tumors) include leiomyomas and lipomas. These tumors may be submucosal, bulging into the gastric lumen; subserosal, extending extraluminally; or both. Small stromal tumors are usually asymptomatic, but larger ones may present with abdominal pain or gastrointestinal bleeding. Malignant counterparts of these tumors are leiomyosarcoma or liposarcoma. The larger the tumor, the more likely it is to be malignant, but the only definitive means of differentiating benign from malignant tumors is by evidence of invasion or metastasis. Treatment is with surgical resection. Stromal tumors can be found in the duodenum but account for only about 5% of duodenal tumors.

Answer 102

Gastrointestinal stromal tumors or GISTs are a specific subtype of stromal tumor that has a different prognosis (based on size and number of mitoses per 50 high power fields) and treatment implications vs. the other stromal tumors. GISTs express c-KIT (CD117), a transmembrane receptor tyrosine kinase (identified with immunostaining) and show a dramatic clinical response to therapy with imatinib, a receptor tyrosine kinase inhibitor. They arise from the interstitial cells of Cajal, the GI pacemaker cells. They are often removed surgically and treated with adjuvant or neoadjuvant imatinib

Answer 103

Tumors of neuro-endocrine cell origin have various names depending on their location (i.e., gut-carcinoid tumors; pancreas-islet cell tumors) or, if appropriate, by the peptide secreted. If the peptide is present in high levels in the circulation, there may be an associated clinical syndrome (e.g., gastrinoma, insulinoma, VIPoma) as well. Histologically these tumors are composed of nests of small, rather bland looking cells. Carcinoid tumors are included in this category.

Answer 104

Carcinoid tumors usually arise from enterochromaffin or enterochromaffin-like cells of the intestinal tract. Most intestinal carcinoids are endocrinologically silent. If hepatic metastasis of intestinal carcinoid occurs, high circulating level of vasoactive amines can produce the carcinoid syndrome. Carcinoid tumors of the stomach are relatively rare, they occur primarily in the fundus and body. There are two types of carcinoid tumor. The first is the sporadic type, usually single or few in numbers. They may metastasize and in general, surgical resection is recommended, especially if they are large. The second type, often smaller and more numerous, is found primarily in patients with achlorhydria secondary to atrophic gastritis of the type in which the antrum is spared (autoimmune atrophic gastritis). Here, achlorhydria results in high levels of gastrin, which is trophic for ECL cells of the proximal stomach. If a carcinoid tumor is found in achlorhydric patients with hypergastrinemia, antrectomy has been reported to lead to regression of the tumor. Carcinoid tumors may be the second most common duodenal tumor after adenocarcinoma. As in the stomach, surgical resection may be possible depending upon the size of the tumor and the operative suitability of the patient.

Answer 105

Gastric lymphoma accounts for less than 5% of all gastric neoplasms. Evidence shows a strong association between H. pylori infection and primary gastric B-cell lymphoma. The likely sequence of events is development of a low-grade clonal proliferation of B-cells in H. pylori induced gastric MALT (mucosa associated lymphoid tissue). This lesion (low-grade B cell MALToma), which accounts for about 10% of primary gastric lymphomas, resolves about 70% of the time after successful eradication of H. pylori. If not treated in the low-grade stages, the lesion may progress to high-grade lymphoma, which is no longer amenable to antimicrobial therapy and requires conventional surgical treatment and/or radiation and chemotherapy. It is imperative with suspected MALT tumors that high-grade lymphoma is excluded. Thus, CT scan and EUS staging of the lesion should be performed in all cases of suspected MALT to avoid missing “hidden” high-grade lymphoma. High-grade lymphoma is treated with systemic chemotherapy.

Answer 106

The pancreas is a lobulated organ situated posterior to the stomach and anterior to the thoracic spine and ribs in the retroperitoneum. It transverses the abdomen from left to right infero-diagonally, with the tail situated immediately medial to the splenic hilum and the head sandwiched within the C-loop of the duodenum. Its blood supply is derived from branches of the superior pancreatoduodenal and splenic arteries (off the celiac axis) and the inferior pancreatoduodenal artery (off the SMA). It lies immediately anterior to the SMV-PV confluence and the SMA, and immediately inferior/anterior to the splenic artery and vein.

Answer 107

Over 80% of pancreatic cells are epithelial in origin and comprise the acinar glands. These cells form the exocrine component. Acinar cells produce a multitude of digestive pro-enzymes that are secreted across the apical cell membrane into a tiny ductule at the center of each acinus. These ductules coalesce into the larger exocrine duct system of the pancreas that ultimately leads to the main (ventral) duct and the ampulla of Vater. In 5-10% of individuals the dominant route of exocrine flow (main duct) is the dorsal duct which empties into the duodenum via the minor papilla. A small minority of the enzymes produced, specifically amylase and lipase, are metabolically active when secreted, though they typically cause no pathology in humans under physiologic conditions. Most of the enzymes are produced and secreted into pancreas ducts as inactive pro-enzymes or zymogen forms. These pro-enzymes are packaged and secreted into the ducts of the pancreas. They will later require activation within the duodenal lumen in order to provide digestive function.

Answer 108

the precursor form or zymogen of the pancreatic enzyme trypsin. It is found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is activated by enteropeptidase, which is found in the intestinal mucosa, to form trypsin. Once activated, the trypsin can activate more trypsinogen into trypsin. Trypsin cleaves the peptide bond on the carboxyl side of basic amino acids such as arginine and lysine.

Answer 109

a proteolytic enzyme and a precursor (zymogen) of the digestive enzyme chymotrypsin. It is synthesized in the acinar cells of the pancreas and stored inside membrane-bounded granules at the apex of the acinar cell. The cell is then stimulated by either a hormonal signal or a nerve impulse and the contents of the granules spill into a duct leading into the duodenum. It is activated into its active form by another enzyme called trypsin. Chymotrypsin preferentially cleaves peptide amide bonds where the carboxyl side of the amide bond (the P1 position) is a large hydrophobic amino acid (tyrosine, tryptophan, and phenylalanine). These amino acids contain an aromatic ring in their sidechain.

Answer 110

the main proteases include proteases such as trypsinogen, chymotrypsinogen, and carboxypeptidases A/B, which get slightly modified when activated in the duodenum. Acinar and ductal epithelial cells also produce large amounts of bicarbonate and water. These ingredients form the bulk of pancreas juice volume. They maintain flow throughout the ducts and keep zymogens inactive with a high pH. Besides providing an aqueous medium for digestive enzymes, the role of bicarbonate and water is to neutralize gastric acid within the duodenum. Without pancreatic HCO3 and water, the duodenum and jejunum would be damaged by low-pH gastric secretions. Also, bile acids and pancreatic enzymes require a neutral pH in order to maintain structure and function. Thus, pancreatic HCO3 and water also help maintain pancreatic and biliary digestive function. Within the pancreas under normal conditions, trypsin inhibitor deactivates any trypsin that is prematurely activated. Also, basal pancreatic juice flow, maintained by water and bicarbonate secretion, continually flushes out any activated enzymes.

Answer 111

Pancreatic islet cells make up the endocrine function of the pancreas. They contain specialized cells that produce insulin, somatostatin, VIP, glucagon, and others. Their role in health and disease will be addressed elsewhere.

Answer 112

Acute pancreatitis is a relatively common condition that varies from mild to severe. In severe cases (5-10%), it can be fatal. Acute pancreatitis occurs when pancreatic enzymes are inappropriately and prematurely activated resulting in autolysis of the gland. This may result in severe inflammation and/or necrosis of pancreatic tissue. It most commonly occurs when the pancreatic duct becomes obstructed, which results in stagnation of pancreas enzymes within the duct lumen and activation of the enzyme activation cascade. Premature activation of enzymes occurs to a small extent in normal individuals, but peristalsis of the duct, sphincter of Oddi relaxation, bicarbonate/water secretion and flow, and trypsin inhibitor function within normal duct keep this process from getting out of control. Alternatively, ethanol may cause pancreatitis via several mechanisms including a direct toxic effect on pancreatic acinar cells and ductal epithelium, which causes both premature release and activation of trypsinogen and stagnant flow of pancreas juice.

Answer 113

The most common cause of pancreatitis in western countries is a gallstone. Gallstone pancreatitis occurs when a stone (even if small or transient) lodges in the distal common bile and/or ampulla. This may result in obstruction of the ventral duct (of Wirsung) and/or bile reflux into the pancreas, which reinforces zymogen activation. The second most common cause of acute pancreatitis is alcohol abuse. Abusers of alcohol typically develop acute pancreatitis within 3-5 days of a binge. Acute pancreatitis has been linked to other causes of duct obstruction including tumors or procedures that cause swelling of the duodenum and/or ampulla, e.g. balloon enteroscopy or endoscopic retrograde cholangiopancreatography (ERCP). Congenital ductal abnormalities (e.g. pancreas divisum, annular pancreas) may occasionally cause a functional duct obstruction and pancreatitis, and such abnormalities increase the risk of acute pancreatitis when other risk factors (e.g. ETOH abuse) are present. Sphincter of Oddi dysfunction types 2 or 3 may result in recurrent acute pancreatitis. Severe hyperlipidemia may precipitate acute pancreatitis. Blunt or penetrating trauma to the abdomen may cause pancreatitis by direct ductal injury and enzyme release. Less common causes of acute pancreatitis include drugs (thiazide diuretics, azathioprine, anti-retroviral drugs), hypercalcemia states, infections (Mumps, Coxsackievirus), and cystic fibrosis.

Answer 114

The typical symptoms of acute pancreatitis are severe pain in the upper abdomen, sometimes radiating to the back, and nausea/vomiting. Low-grade fevers may accompany this. The pain is usually intolerable, prompting an urgent visit to the ER or doctor’s office.

Answer 115

Lipase released from dying acinar cells breaks down fat, liberating free fatty acids which precipitate with calcium and form insoluble soaps. In severe pancreatitis, there may be frank coagulation necrosis of the gland and/or hemorrhage into the retroperitoneum. Microscopically, necrosis of pancreatic tissue is associated with intense infiltrates of neutrophils and apoptosis of epithelial cells.

Answer 116

The diagnosis of acute pancreatitis is usually suggested by the history and physical exam, typically a female with risk factors of gallstones or individual with known alcohol abuse. The diagnosis requires confirmation by serum blood tests (lipase and amylase) or imaging. Other diagnostic tests include ultrasound or CT scan of the abdomen. Ultrasound is cheap, noninvasive, and readily available. It is very good (90% accurate) at detecting gallstones but less effective at imaging the pancreas or bile ducts. When severe cases are suspected or the diagnosis remains questionable, a contrast CT scan should be considered. CT will show inflammatory changes within and surrounding the pancreas - gland edema, fat stranding, fluid - and may occasionally reveal a cause such as a tumor. CT may also detect complications such as necrosis, pseudocyst, or hemorrhage.

Answer 117

A diagnostic blood test is a serum level of amylase and lipase elevated greater than 3 times the upper limit of normal. When the pancreas is inflamed, enzymes leak out into the bloodstream and the elevated levels will be detected in serum. Lipase is more specific for pancreatitis and equally to slightly more sensitive than serum amylase, since it rises within 1-2 hours and decreases over the following week. Serum amylase rises and falls within 24-48 hours but its specificity is imperfect since amylase may be elevated in non-pancreatitis diseases including Mumps, Sjogrens syndrome, penetrating peptic ulcer, intestinal trauma or ischemia, and ectopic pregnancy.

Answer 118

Treatment of acute pancreatitis involves admission to the hospital, making the patient NPO (nothing to eat or drink), intravenous pain medications, and time. The vast majority of patients with uncomplicated acute pancreatitis will improve with these supportive measures alone. Avoidance of alcohol is pivotal in preventing disease recurrence or progression to chronic pancreatitis. Patients with gallstones who are otherwise fairly healthy will need cholecystectomy (gallbladder surgery) at a later date to remove the source of the stones. Most offending bile duct stones will pass into the duodenum spontaneously. But in cases where the stone does not pass (based on blood tests or imaging studies), the persistent bile duct stone requires extraction. This is typically done via ERCP but can also be done surgically (a longer, more complicated procedure than gallbladder removal alone).

Answer 119

Chronic pancreatitis (CP) is a condition that develops after repeated bouts of acute pancreatitis. It most commonly occurs as a result of chronic alcohol abuse. Macroscopically, it is characterized by replacement of healthy pancreatic tissue by hard fibrous tissue. There may also be atrophy of the gland. Pancreas juice may become viscous, and calcifications (stones) may develop within the duct if these clumps of protein precipitate with into calcium salts. Microscopically, broad bands of scar tissue replace lost lobular tissue. Sometimes, moderate numbers of lymphocytes and/or plasma cells are present. There is relative sparing of the islets cells. Fibrous tissue may result in narrowings (strictures) of the duct. Calcified pancreatic duct stones, sometimes large, may also contribute to obstruction, particularly when lodged above a stricture. Along with gland destruction/loss and atrophy, these factors contribute to the symptoms of malabsorption, pain, and malnutrition.

Answer 120

The most common cause of CP in western countries is chronic alcohol abuse. Cigarette smoking also contributes significantly to fibrosis, particularly in those who abuse alcohol. In a growing number of patients, familial (inherited) causes are identified. Genetic conditions that predispose to CP include CFTR gene mutations and/or cystic fibrosis, mutations in the trypsinogen (PRSS) or trypsin inhibitor (SPINK) genes, and familial hypertriglyceridemia. In some equatorial countries (e.g. Saharan Africa), over 25% of CP cases have been attributed to an idiopathic variant that occurs at a young age with extensive calcifications, so-called tropical pancreatitis.

Answer 121

Several pathologic factors have been proposed in the development of CP, especially the variant caused by alcohol: Intraductal plugs may form as the result of changes in protein secretion or pH conditions of the pancreatic duct. Oxidative and non-oxidative metabolites of ethanol may have a role in injury. Cigarette smoking may promote pancreatic fibrosis through oxidative pathways. It has also been proposed that episodes of necrosis may lead to pancreatic fibrosis. The importance of each mechanism is unclear. Pancreatic stellate cells have a central role in the generation of pancreatic fibrosis, although the stimulating factors are still being determined. When stimulated, stellate cells proliferate and transform into collagen-synthesizing cells.

Answer 122

Pancreatic lipase secretion must decrease to a level less than 10% of normal before a person eating a regular diet will develop excess fecal fat excretion (steatorrhea). In healthy individuals, some fat (~ 10g or less daily) is excreted into the stool. Similar reserves are found for the endocrine pancreas. The fact that the pancreas has large reserves means that much of the pancreas can be removed or damaged before endocrine or exocrine insufficiency occurs. In CP, once more than 90% of the gland has been destroyed, fat malabsorption may occur. Protein and carbohydrate malabsorption generally occurs even later (after 95% gland destruction) since salivary amylase and gastric pepsin can provide a digestive function reserve.

Answer 123

symptoms of pain and/or malabsorption in the form of steatorrhea. Abdominal pain is the most frequent presenting symptom. It usually waxes and wanes but never entirely disappears. The pain is typically epigastric and radiates directly to the back, or it may be present with back pain alone. Pain is multifactorial and results from an obstructed duct (stones or strictures), chronic inflammation within the pancreas or surrounding nerves, and/or pseudocysts that impinge on adjacent structures. Patients may eventually develop diarrhea, weight loss, or anemia related to malabsorption of carbohydrates and proteins. A normocytic or macrocytic anemia may also occur because of Vitamin B12 deficiency. Pancreatic proteases are required to cleave the R-protein-cobalamin complex, allowing for intrinsic factor to bond to B12. Thus, pancreatic duct obstruction or atrophy in CP may lead to B12 malabsorption and eventually a macrocytic anemia. Bleeding diathesis may develop as result of fat-soluble vitamin malabsorption, specifically vitamin K.

Answer 124

The dominant malabsorbed nutrient is lipid, thereby causing the distinct form of diarrhea knows as steatorrhea. Steatorrhea – frequent, oily, foul-smelling, and/or buoyant stools which increase in frequency after meals – flatulence (gas), and weight loss are the cardinal symptoms of pancreatic malabsorption. Another specific feature of steatorrhea is the presence of (oil-like) lipid droplets in the toilet water. Malabsorption does not occur until later stages of chronic pancreatitis since only 10-20% of acinar cells are required for maintaining lipase reserve, as described above. This is illustrated in the graph below.

Answer 125

A thorough history and physical is paramount in importance and nearly always suggestive. A plain x-ray of the abdomen may showed calcifications scattered over the epigastrium in patients (20-30%) with severe/calcific disease. A rapid fat (Sudan) stool stain (qualitative) is a quick, useful test that may be diagnostic if the appearance of the stool and patient’s history are also compatible. Otherwise, the definitive test for fat malabsorption is a 72-hour quantitative stool collection for fat analysis. While the patient ingests a high-fat diet (e.g.> 100 g fat/day), a 72-hour stool collection should show > 10-20% fecal fat excretion or 50g fat in the stool. Though rarely used nowadays, the gold standard diagnosing pancreatic insufficiency is the secretin stimulation test.

Answer 126

The test is performed using two aspiration tubes. One is placed in the stomach to remove gastric acid and prevent acid-related secretin release. The second tube is placed just distal to the major papilla within the duodenal lumen. After a 1-hr basal collection period, secretin is given intravenously and the collections are continued for 1-2 hrs. A duodenal bicarbonate response to secretin, specifically a [HCO3] less than 80mEq/L after 2 hours is diagnostic of pancreatic exocrine failure. This test is non-specific and abnormal results may also be found in patients with pancreatic duct tumors, previous pancreatic surgery, or cystic fibrosis.

Answer 127

Following acute or chronic pancreatitis, focal auto-digestion of the pancreas and/or leakage of pancreas enzymes outside the duct may allow for fluid collections to develop. These are organized collections of liquefied/auto-digested pancreatic parenchyma, containing a mixture of pancreas juice and clumps of semi-solid, necrotic tissue. Since these fluid collections line a true epithelial lining characteristic of a cyst, they are called “pseudocysts.” Over time pseudocysts usually resolve as the pancreatitis improves (provided the cause is addressed), but sometimes (particularly in alcoholics who continue to drink), they may persist, grow, and/or push on adjacent structures and cause various symptoms. In these cases, patients may require surgical or endoscopic drainage.

Answer 128

Pancreatic adenocarcinoma (PA) is a major (4th-leading) cause of cancer mortality among adult men and women in the US. The vast majority of these tumors (90-95%) arise from ductal epithelial cells and the remaining 5-10% arise from acinar cells. Both cells types carry a similar prognosis. A typical PA develops from ductal epithelial cells along the following histologic sequence: normal, atypia, low-grade dysplasia, high-grade dysplasia, invasive cancer. The cancer cells usually form primitive, mucin-positive, gland-like structures. The tumor cells elicit a strong, fibrotic reaction known as “desmoplasia,” which makes their texture very hard and the cancer cells less permeable to chemotherapy drugs. Additionally, the tumors often grow with microscopic tentacles that are not visible on imaging studies.

Answer 129

A typical PA develops from ductal epithelial cells. Other types of pancreatic adenocarcinoma include mucinous cystadenocarcinomas, and intraductal papillary mucinous tumors (IPMTs). These cancers arise from cystic lesions in the pancreas and are much less common than ductal adenocarcinoma. They may cause symptoms or be detected on imaging while still at an early, benign, (adenomatous) cystic stage. Hence they carry a more favorable prognosis.

Answer 130

The risk of pancreatic adenocarcinoma (PA) is increased by a positive family history, tobacco abuse, chronic pancreatitis, obesity, and occasionally a genetic syndrome (e.g. Peutz-Jeghers, Von Hippel-Lindau). The various mechanisms of carcinogenesis are still poorly understood.

Answer 131

The most common presenting symptoms are vague abdominal or back pain and weight loss. Pain typically indicates invasion of the pancreatic capsule or nerve invasion and a later stage of disease. Because most PAs originate in the head of the pancreas, patients may also present with symptoms of bile duct obstruction, including jaundice, choluria (dark color of the urine caused by bilirubinuria), acholic stools, or pruritus (from bile acid retention). Head of pancreas (HOP) cancers that present with jaundice are typically at an earlier stage than body or tail cancers that present with abdominal/back pain, so most patients who undergo surgery have disease confined to the HOP and obstructive jaundice. Occasionally, PA causes acute pancreatitis by obstructing the main pancreatic duct. Patients with PA have an increased risk for developing blood clots because of an associated hyper-coaguable state known as Trousseau’s syndrome and because of physical inactivity.

Answer 132

Because of the location of the pancreas deep within the retroperitioneum and the difficulty imaging or palpating the organ, there is no cheap, noninvasive, accurate and readily available, universal screening test for PA. Unfortunately, most patients present with locally advanced or metastatic disease after the onset of symptoms. The diagnosis of PA is usually made by contrast abdominal CT scan (80-90%), which shows the pancreas, bile ducts, and pancreatic duct very well. CT can also demonstrate for liver and other distant metastases. Abdominal ultrasound is less accurate (

Answer 133

The five-year survival of pancreatic adenocarcinoma is dismal, around 2-4%.

Answer 134

In the unusual cases where the disease appears localized to the pancreas and the patient is healthy enough to tolerate a major surgery, resection (usually a Whipple’s procedure, which involves surgical removal of the pancreas head, gallbladder, bile duct, and duodenum) provides the only chance for cure. Unfortunately, even in patients who undergo surgery, the tumor is usually found to be more advanced in the operating room or recurs shortly thereafter. Neoadjuvant (pre-operative) chemotherapy, sometimes with radiation, may increase the yield of surgery but is still a topic of debate. In patients with metastases, recurrent disease, or high surgical risk, palliative measures may be offered. The most common palliative procedure is ERCP with placement of a stent across the bile duct stricture. This will relieve cholestasis symptoms. EUS-guided injection of the celiac nerve, known as celiac plexus neurolysis, helps relieve pain and reduces narcotic use in many patients. Palliative chemotherapy may also be offered to some patients, but this carries side effects and at best only increases the lifespan by 3-6 months.

Answer 135

Neuroendocrine tumors (NETs) arise from the enterochromaffin cells of the lung, GI tract, or the pancreatic islets. These were previously called carcinoids (carcinoma-like) because of their histologic appearance mimicking carcinoma but relatively benign clinically course compared to gastric or rectal carcinomas. Now it generally only applies to metastatic NETs that produce serotonin by products resulting in the carcinoid syndrome. Most pancreatic NETs are clinically silent and are detected on routine imaging when still small. Others may cause pain (when very large or metastatic) or produce symptoms via hormone secretion such as insulin, glucagon, gastrin, VIP, or somatostatin.

Answer 136

produce symptoms via hormone secretion such as insulin, glucagon, gastrin, VIP, or somatostatin. The type of hormone produced by the tumor differentiates determines the cell type and thus the tumor name – insulinoma, glucagonoma, gastrinoma, VIPoma, or somatistatinoma. Insulinomas cause recurrent hypoglycemia. Glucagonomas cause hyperglycemia/diabetes, weight loss, and diarrhea. Gastrinomas cause GERD or peptic ulcers, diarrhea, and fat malabsorption from deactivation of pancreatic enzymes. VIPomas produce severe, chronic, secretory-type diarrhea with hypokalemia and weight loss. Somatistatinomas are rare but cause weight loss, malabsorption, and acalculous cholecystitis by decreasing GI motility and exocrine secretion.

Answer 137

The diagnosis of NET is made by cross-sectional imaging, CT or MRI, and confirmed by fine-needle aspiration (FNA), octreotide scanning (for gastrinoma or VIPoma), or surgical resection.

Answer 138

Somatostatin is secreted at several locations in the digestive system: Delta cells in the pyloric antrum, the duodenum and the pancreatic islets. In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion. Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin, secretin and histamine which effectively slows down the digestive process.

Answer 139

All NETs carry a risk of malignant degeneration and metastasis, with the risk increasing directly with size of the lesion and the cell type (glucagonoma and somatistatinoma are almost always malignant whereas insulinomas are almost always benign). The differentiation between benign and malignant cannot be made histologically; it is made based on the presence of metastases, usually by imaging studies. Because all NETs carry some risk, surgical resection is indicated for nearly all NETs in surgically fit patients. Small (

Answer 140

Autoimmune pancreatitis (AIP) is a chronic, inflammatory condition that results in a particular set of symptoms. The underlying trigger is unknown, but in AIP, IgG-4 + plasma cells and lymphocytes infiltrate the pancreas and its vessels resulting in localized or diffuse enlargement of the pancreatic parenchyma and narrowing of the pancreatic duct and/or bile duct. Glandular atrophy, ductal dilation, calcifications, and steatorrhea are features of chronic pancreatitis but NOT features of AIP.

Answer 141

Patients with AIP are typically males aged 45-70 without a history of alcohol or hyperlipidemia or a family history of pancreatitis. Associated autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, lupus, or sjogren’s syndrome (among others) occur in ~ 25%.

Answer 142

AIP produces symptoms more like cancer than chronic pancreatitis or recurrent acute pancreatitis. Most patients present with chronic epigastric or diffuse abdominal pain, and nearly half also develop cholestasis (jaundice, dark urine, and/or itching) from an associated BBS.

Answer 143

Serum IgG-4 is elevated in ~ 80% of patients and is > 70% specific for the disease. IgG-total, ANA, and rheumatoid factor are elevated in a minority. CT, US, or MRI show a focally or diffusely enlarged pancreas with decreased enhancement and loss of the lobular contour. ERCP and EUS show a focally or diffusely narrowed pancreatic duct and, in about half of cases, a bile duct stricture. In cases where malignancy cannot be ruled out, a definitive diagnosis can be made by EUS-guided or percutaneous biopsy of the pancreas with IgG-4 staining or endoscopic biopsy of the ampulla.

Answer 144

Treatment of AIP with a 6-week course of PO corticosteroids is prompt and effective. Patients with jaundice or pruritus may benefit from ERCP with placement of a temporary biliary stent. Immunomodulators can be used in rare, refractory cases.

Answer 145

inability to initiate a swallow or transfer food bolus into esophagus.May occur with obstruction or neuromuscular disease (leading to dysfunction of oropharyngeal musculatire causing a propulsive/motility disorder). Nasal regurgitation may occur. Aspiration, food or liquids passing into airway or lungs, may occur.

Answer 146

neurologic propulsive/ motility diseases include stroke, ALS, parkinson's, MS, and polio. Muscular propulsive/ motility diseases include myasthenia gravis, muscular dystrophy, and muscle injury due to surgery or radiation therapy. Benign structural diseases includes zenker’s diverticulum (outpouching of esophagus leading to food regurgitation or bacterial colonization (halitosis)), crycopharyngeal bar, or other (thyromegaly, fibrosis (e.g. radiation)). Malignant structural diseases include squamous cell carcinoma of tongue, oropharynx, soft palate, or upper larynx (Head and Neck Cancers)

Answer 147

symptoms include dysphagia to both solids and liquids and chest pain. Etiology includes achlasia (abnormal peristalsis, failure of LES relaxation), spastic disorder, peak peristalsis, and scleroderma. Must first excluding structural lesions (with upper endoscopy or barium esophagram) then diagnosis with esophageal manometry.

Answer 148

Loss of peristalsis in distal esophagus. Failure of LES to relax with swallowing. Age of incidence is 25-60, equal M:F ration. Most common symptoms include dysphagia to solids and liquids, weight loss, regurgitation. Other symptoms include chest pain, difficulty belching, heartburn, and hiccups. 98% are primary and idiopathic. Secondary (pseudoachalasia) achalasia includes direct mechanical obstruction of LES, infiltrative submucosal invasion (either a primary esophageal or gastric malignancy or infiltrative metastatic malignancy (pancreatic, breast, neurofibromatosis, bladder, prostate, etc)), paraneoplastic syndrome (such as small cell lung cancer, pancreatic, prostate), and chagas disease. With paraneoplastic syndrome, tumors expresses neuronal antigen, which is also expressed in neuron, this leads to T cells attacking neurons of the myenteric plexus.

Answer 149

Types I (classic) shows no significant change in esophageal pressurization with swallowing. Type II shows simultaneous pressurization spanning entire esophagus length with swallowing. Treatments target the LES and include botox injections, pneumatic dilation, surgical myotomy with good outcomes. Type III (spastic) shows abnormal, lumen obliterating contractions and spasms. Botox injections, pneumatic dilation, surgical myotomy have poor outcomes.

Answer 150

Normally, LES pressure & relaxation is regulated by excitatory and inhibitory neurotransmitters. With achalasia, selective loss of inhibitory neurons in the myenteric plexus results in relatively unopposed excitatory (cholinergic) neurons leading to hypertensive nonrelaxed esophageal sphincter

Answer 151

medical treatments include nitrates (stimulates guanylate cyclase, decreasing intracellular Ca and causing SMC relaxation), calcium channels, slidenafil. Endoscopic therapy is much more effective, which includes GC injections of botulinum toxin (causing inhibition of ACh release from nerve endings), pneumatic ballon dilation (which tears LES muscle fibers), and per-oral endoscopic myotomy (POEM). Surgical (Heller) myotomy is usually laparoscopic, 70-85% remission at 10 years, and complications include reflux (unless combined with fundoplication) and perforation.

Answer 152

Multisystem disorder characterized by obliterative small vessel vasculitis and connective tissue proliferation with fibrosis of multiple organs. GI manifestations in 80-90%. The principal pathological abnormalities of the GI tract consist of smooth muscle atrophy and gut wall fibrosis. Smooth muscle atrophy and gut wall fibrosis is predominantly a myopathic process and leads to weak peristalsis causing dysphagia and weak LES causing GERD. Unrepentant GERD causes esophagitis and stricture.

Answer 153

Conditions of uncertain etiology. Peristalsis preserved. Symptoms usually chest pain and dysphagia. Postulated pathophysiology related to overactivity of excitatory nerves or overreactivity of the smooth muscle response

Answer 154

are caused by luminal narrowing and obstruction. symptoms include dysphagia to solids and liquids only much later, weight loss, and sometimes heartburn. Benign causes include strictures (GERD related or due to caustic ingestions), schatzki's ring, and eosinophilic esophagitis (leading to extrinsic compression). Malignant causes include esophageal cancer (adenocarcinoma or squamous cell cancer), metastsis (rare, includes melanoma, breast cancer, renal cell carcinoma, lung cancer), and direct invasion. Treatment of benign esophageal strictures is endoscopic dilation using balloons or sequential commercial dilators.

Answer 155

Chronic immune/antigen-mediated esophageal disease. Clinicopathologic diagnosis is based on symptoms of esophageal dysfunction, eosinophilic infiltrate in the esophagus, and absence of other potential causes of esophageal eosinophilia. Increasing incidence and prevalence. 0.2-4/1000 in general population. In adults & adolescents, it causes dysphagia (25-100%) and is about 50% of cases of acute food impaction. Other clinical features include food avoidance and maybe heartburn. In children, it is more non-specific (feeding intolerance, failure to thrive, abdominal pain). It is most common in those over 40 years of age, white males (but being diagnosed more frequently in minority populations), and is commonly associated with other allergic diseases (asthma, atopic dermatitis, seasonal allergies, food allergies). With endoscope, one can see ringed esophagus with linear furrow. Microscopically, there are many eosinophils.

Answer 156

Treatment includes dilation, diet changes, and medical treatments, including topical steroid. Asthma preparations are swallowed. Elemental Diet (allergen-free) is effective in children. More practical is the 6 food elimination diet (SFED), which includes eliminates 6 most common food allergens such as milk, eggs, wheat, soy, seafood, nuts

Answer 157

Pathologic reflux of gastric juice Acid) into esophagus. Classic symptoms include heartburn and regurgitation with acidic taste (postitional). Heartburn presents as burning sensation, substernal or epigastric, rises in chest and is often post-prandial (after meals) and may be positional (lying down/nocturnal). Less Classic Symptoms include water brash, throat clearing, cough, and rare symptoms, such as wheezing, stridor, hoarseness. Relieved by antacids or anti-secretory medications

Answer 158

Acid in the esophagus or airway causing symptoms and/or esophageal damage. Esophagus lacks defenses (mucous secretion, alkalinity) against acid. Can be caused by inappropriate LES relaxation, hiatal hernia, gastric or esophageal surgery, dysmotility, or obstruction and rarely Zollinger-Ellison, Sjogren’s, Scleroderma

Answer 159

Males = females, Obesity, Alcohol? (Minimally if at all) Tobacco, Medications, Pregnancy, and Other medical illnesses (scleroderma, ZE, gastroparesis)

Answer 160

an abnormal change (metaplasia) in the cells of the lower portion of the esophagus. It is characterized by the replacement of the normal stratified squamous epithelium lining of the esophagus by simple columnar epithelium with goblet cells (which are usually found lower in the gastrointestinal tract). It is a consequence of GERD. Risk factors include being male, white, having central adiposity, advancing age (plateau in 60s), and chronic GERD. It is a significant in risk of developing esophageal adenocarcinoma. Previously thought to be higher risk, currently estimated at ~ 0.1-0.5% per year. Patients may benefit from endoscopy with biopsies every 3-5 years to assess for dysplasia. Presence of dysplasia is a much greater risk for the development of esophageal cancer. Low-grade dysplasia merits even closer surveillance. High-grade dysplasia is ominous and merits treatment. Endoscopic treatments are used for HGD and early esophageal adenocarcinomas and include ablation of Barrett’s tissue and endoscopic resection of visible lesions

Answer 161

Symptoms include progressive dysphagia from solids to liquids, weight loss, sometimes profound. Rare symptoms include hemoptysis, chest pain, or anemia. Does not cause symptoms until advanced. Preferred treatment is surgical resection, if detected early. Chemotherapy/radiation initially in advanced cases (most). Metal stent placement or feeding tube for palliation. Types include squamous cell carcinoma (risk factors are older age, alcohol/tobacco use, caustic injuries) and adenocarcinoma (risk factors include older age, smoking, obesity, GERD, and Barrett’s esophagus and nearly always in distal esophagus or gastric cardia).

Answer 162

Hyperplasia of pyloric muscularis propria leading to obstruction of gastric outflow. M:F = 4:1. Presents in 2-3rd week of life with regurgitation and persistent projectile non-bilious vomiting. Firm ovoid abdominal mass. Treatment includes surgical splitting of muscularis propria (“myotomy”)

Answer 163

Morphologically resembles acute gastritis. Injury is mediated by vasoconstriction/ischemia. Erosion and ulceration may be widespread. Occurs in 75% of critically ill patients. Trauma, shock, or sepsis (stress ulcers). Burns (Curling ulcers). Intracranial disease (Cushing ulcers)

Answer 164

Helicobacter pylori infection. Autoimmune gastritis. Eosinophilic gastropathy, an allergic disease [e.g. cow’s milk] and parasitic infection. Lymphocytic gastropathy, which is associated with celiac disease. Granulomatous gastropathy, such as crohn’s disease, sarcoidosis, infection

Answer 165

Corpus restricted chronic atrophic gastritis. Anti-parietal cell and anti-intrinsic factor antibodies, with or without pernicious anemia. Common in scandinavian and northern european descent. Lymphocyte and plasma cell infiltrate in the body of stomach and glandular atrophy. There is also intestinal metaplasia.

Answer 166

Rare progression to cancer; associated with Helicobacter and other chronic gastritides. Microscopic findings include mucosal inflammation and edema and cystically dilated foveolae.

Answer 167

Very rare progression to cancer (in FAP patients); FAP associated and sporadic (usually PPI associated). Microscopic findings show cystically dilated oxyntic gland

Answer 168

Common progression to cancer; increased incidence in FAP, Helicobacter gastritis, and other chronic gastritides. Microscopic findings include dark, atypical cells.

Answer 169

Types include intertinal type with an ulcerating pattern and diffuse type (signet ring cell) with linitis plastica pattern.

Answer 170

Wnt signalling pathway activation is common in intestinal type cancers and can occur with loss of APC (as in FAP). Loss of CDH1 (mutation or methylation) is common in diffuse type cancers. There are germline loss of CDH1 in familial gastric cancer. Amplification of Her2/neu occurs in a minority of tumors (intestinal > diffuse). This is important because of susceptibility to tyrosine kinase inhibitor trastuzumab

Answer 171

Microscopic findings include diffuse infiltrate of B-cells and disruption of gastric glands (lymphoepithelial lesions).

Answer 172

they are well differentiated. They are associated with gastric atrophy and type 1 multiple endocrine neoplasia (MEN-1), an autosomal dominant disorders. Microscopic findings include nests and trabeculae of monomorphic cells.

Answer 173

Most contain a mutation in the c-kit oncogene, which is used as diagnostic aid on tissue and is targeted with therapy with tyrosine kinase inhibitor imatinib. Microscopic findings include spindle cell proliferation and c-kit staining.

Answer 174

Located in the uppermost portion of the esophagus. Symptoms include regurgitation, halitosis, and aspiration (clinical: gurgling). It is associated with reduced UES compliance

Answer 175

Acid secretion is stimulated by the parasympathetic neurotransmitter acetylcholine (ACh), the hormone gastrin, and the paracrine substance histamine. ACh binds to muscarinic receptors on the basolateral membrane, which leads to the activation of a G-protein intermediate and a rise in intracellular Ca2+. Gastrin is also thought to act by increasing intracellular Ca2+. Histamine binding to histaminergic H2 receptors leads to the activation of a different G-protein that turns on adenylate cyclase. This enzyme catalyzes the synthesis of cyclic AMP (cAMP). Ca2+ and cAMP activate distinct protein kinases that phosphorylate H+/K+-ATPase. ACh and gastrin potentiate acid secretion as a result of their stimulation of histamine release from enterochromafﬁn-like (ECL) cells. Thus, in the direct pathway, ACh, gastrin and histamine directly stimulate the parietal cell, triggering the secretion of H+ into the lumen. In the indirect pathway, ACh and gastrin stimulate the ECL cells, resulting in secretion of histamine. This histamine then acts on the parietal cell.

Answer 176

There are 4 phases of gastric acid secretion, a basal phase and 3 phases associated with eating. The rate of acid secretion between meals is low. The basal (inter-digestive) phase follows a circadian rhythm: the rate of acid secretion is lowest in the morning before awakening and highest in the evening. The resting pH can range from 3 to 7. The rate of acid secretion is enhanced several-fold by eating. The smell, sight, taste and swallowing of food initiate the cephalic phase, which is primarily mediated by the vagus nerve. Stimulation of the vagus nerve results in release of ACh, triggering of the histamine release from ECL cells, release of gastrin-releasing peptide (GRP) from the vagal and enteric neurons (ENS); and inhibition of somatostatin release from the delta cells (D cells) in the stomach. The cephalic phase accounts for 30% of total acid secretion. Entry of food into the stomach initiates the gastric phase of acid secretion. First, the food distends the gastric mucosa, which activates a vagovagal reﬂex as well as local ENS reﬂexes. Second, partially digested proteins stimulate antral gastrin (G) cells, which release gastrin. The gastric phase accounts for about 50% to 60% of total acid secretion. In the intestinal phase, the presence of amino acid and partially digested peptides in the proximal portion of the small intestine stimulates acid secretion by stimulating duodenal gastrin (G) cells to secrete gastrin. Approximately 5% to 10% of total acid secretion is a result of the intestinal phase.

Answer 177

Plant starch, amylopectin, is the largest single source of carbohydrates in most human diets. It is a polymer of glucose containing both α-1,4 and α-1,6 linkages. In contrast, cellulose is a β-1,4 linked polymer that cannot be digested by intestinal enzymes. It is the major component of dietary "fiber". Amylase catalyzes only the hydrolysis of internal α-1,4 linkages to generate maltose, maltotriose (3 glucose monomers) and α-limit dextrin. Because of the enzyme's specificity, free glucose is never the product of amylase digestion. The other major carbohydrates in the diet are the disaccharides sucrose and lactose.

Answer 178

Mucosal sucrase-isomaltase (SI) activity represents the last stage of small-intestinal digestion of branch points of starch to glucose.

Answer 179

serves as the ﬁnal step in small-intestinal digestion of linear forms of starch to glucose

Answer 180

Intestinal sugar transporters are responsible for transporting the monosaccharides (glucose, galactose and fructose) from the intestinal lumen to the blood. The Na+-dependent glucose transporter SGLT1 is located in the brush-border or apical membrane of enterocytes. SGLT1 transports glucose and galactose, along with Na+, from the intestinal lumen into the cytosol. The Na+-independent fructose transporter GLUT5 is also apical, a unique member of the facilitative glucose transporter family, and transports fructose from the lumen into the cytosol. The Na‘-independent fructose transporter GLUT2 is basolateral and transports all three monosaccharides from the cytosol to the blood.

Answer 181

Lactose intolerance is caused by the absence of the brush border enzyme lactase. Unabsorbed lactose draws water into the intestinal lumen, producing an osmotic diarrhea. In addition, the gut bacterial ﬂora metabolize the unabsorbed lactose, forming gases such as hydrogen, methane and carbon dioxide. Genetic absence of Na+/glucose co-transporter SGLT1 in the intestinal brush-border causes glucose-galactose malabsorption in humans. These patients have diarrhea when they ingest dietary sugars. This diarrhea results from reduced small intestinal Na+ and fluid absorption as well as fluid secretion secondary to the osmotic effects of non-absorbed monosaccharide. Diarrhea associated with glucose-galactose malabsorption is rectified by replacing dietary glucose with fructose because fructose is absorbed by a distinct carrier (GLUT5). The genetic mutations of human SGLT1 result in the potentially fatal neonatal condition of glucose-galactose malabsorption.

Answer 182

The secreted endopeptidases hydrolyze the interior peptide bonds: Pepsin - aromatic amino acids, Trypsin - arginine (R) and lysine (K), Chymotrypsin - aromatic amino acids, Elastase - neutral aliphatic amino acids

Answer 183

The secreted exopeptidases (carboxypeptidases) hydrolyze one amino acid at a time from the C-(carboxy)-terminus of proteins and peptides: Carboxypeptidases A and Carboxypeptidases B

Answer 184

an exoprotease that removes one amino acid at a time from the N(amino)-terminus. brush border protease

Answer 185

removes dipeptides from the N-terminus. brush border protease

Answer 186

converts dipeptides to amino acids. brush border protease

Answer 187

1. Activation of trypsinogen to trypsin by the brush border protease enterokinase. 2. Activation of all other precursors by trypsin. 3. Trypsin, chymotrypsin, elastase, carboxypeptidase A & B all hydrolyze protein to amino acids and di-, tri- and oligopeptides. 4. The brush border proteases hydrolyze oligopeptides to amino acids. 5. Pancreatic proteases digest themselves and each other.

Answer 188

Absorption of the products of protein digestion occurs by Na+-dependent co-transport . Unlike carbohydrate absorption (in which only monomers are absorbed), di- and tripeptides are absorbed intact. In fact, it is estimated that up to 70% of protein is absorbed in this way. Four different amino acid carriers have been identified with the following specificities: neutral, basic, acidic, and a special carrier that efficiently transports proline and glycine across the enterocyte brush border. Within the enterocytes, di- and tripeptides are hydrolyzed to amino acids by cytoplasmic peptidases. Amino acids exit the basolateral membrane of the enterocyte by facilitated diffusion and enter blood capillaries.

Answer 189

Conditions exist in which deficiency of pancreatic enzymes occur, e.g. in chronic pancreatitis. The absence of trypsin alone makes it appear as if all of the pancreatic enzymes are missing. Conditions also exist in which specific transporters are missing, e.g. in cysteinuria, Hartnup disease and cystic ﬁbrosis. Cysteinuriajs a genetic absence/defect of the Na+-amino acid transporters. It is called cysteinuria because in these patients the same Na+-amino acid transporter is also missing from the kidneys. These patients lack the capacity for renal or intestinal absorption of cystine, lysine, arginine and ornithine amino acids. The intestinal defect results in the excretion of amino acids in feces. The renal defect results in excretion of the amino acids in urine (Cysteinuria means excess cystine urinary excretion). Hartnup disease is a genetic absence/defect of the neutral amino acid transporter. Cystic fibrosis is a genetic absence/defect in the Cl- channel called the CFTR or cystic fibrosis transmembrane receptor.

Answer 190

a protein that helps to anchor lipase to the surface of the droplets.

Answer 191

a neutral fat. The most abundant storage form of fat in animals and plants, and hence the most important dietary lipid. A molecule of triglyceride is composed of a molecule of glycerol in which each of the three carbons is linked through an ester bond to a fatty acid. Triglycerides cannot be efficiently absorbed, and are enzymatically digested by pancreatic lipase into a 2-monoglyceride and two free fatty acids, all of which can be absorbed.

Answer 192

Fat droplets are emulsified by bile salts and lecithin to form particles on the order of 1 µm in diameter. This process increases the surface area for subsequent digestion by lipase and colipase, a protein that helps to anchor lipase to the surface of the droplets. The products of lipase digestion are 2'-monoglycerides and fatty acids, which are solubilized in bile-salt micelles. Inside the enterocytes, triglycerides are re-synthesized from monoglycerides and fatty acids. They are then packaged into lipoprotein particles called chylomicrons.

Answer 193

are cylindrical structures about 10 nm across, with hydrophilic groups oriented toward the aqueous phase and hydrophobic groups associating in the interior. Micelles are required to transport the products of fat digestion through the unstirred water layer near the surface of enterocytes.

Answer 194

The abundance of hydrophilic glycoproteins protruding from the brush border membrane, as well as mucus are responsible for the unstirred layer. Lipids move in and out of the micelles, and when they strike the cell surface they are able to diffuse passively through the membrane and into the cells.

Answer 195

lipoprotein particles synthesized from triglycerides in the enterocyte. In addition to containing triglycerides, chylomicrons contain phospholipids, cholesterol (also absorbed from micelles), and apolipoproteins. In the Golgi they are incorporated into secretory vesicles. Vesicles migrate to the basolateral membrane, and the chylomicrons are released into the interstitial space by exocytosis. They then enter the lacteals because they are too large for capillaries. Fat-soluble vitamins (A, D, E, K) are absorbed by precisely the same route as fat digestion products and cholesterol.

Answer 196

Inadequate triglyceride digestion results in steatorrhea (excessive loss of fat in the stool). This is a hallmark of a diverse group of digestive disorders that cause fat malabsorption. Along with fat malabsoption comes fat-soluble vitamin malabsorption. Fat malabsorption digestive disorders include: Liver disease with bile salt deficiency: patients with chronic liver disease cannot make micelles. Pancreatic insufficiency: patients with chronic pancreatitis and cystic ﬁbrosis lack enzymes to digest fat. Weight loss medication: new anti-obesity drugs inhibit lipase activity resulting in fat malabsorption and so-called “anal leakage”.

Answer 197

1) H2O readily moves across the intestinal epithelium. A consequence of this is that chyme entering the duodenum is rapidly brought into isotonic equilibrium with the blood. 2) H2O absorption follows the absorption of solutes and is therefore said to be absorbed isotonically. In the duodenum and jejunum, the absorption of sugars and amino acids in co-transport with Na+ causes Cl- to follow for electrical reasons, and H2O to follow for osmotic reasons. Cl- and H2O move across the epithelium by paracellular pathways. the primary active transport process that drives all subsequent absorption processes is the Na+/K+-ATPase. In addition, Na+ can be absorbed in exchange for H+ via the apical Na+/H+ exchanger. the vast volume of the extracellular fluid does not instantly dilute absorbed solutes. Solutes are deposited in the confined regions between cells, and diffusion is slowed somewhat by a basement membrane that exists between the cells and the capillaries. This sets up a standing osmotic gradient that provides the driving force for H2O absorption.

Answer 198

In the ileum, the mechanisms of water and electrolyte absorption are very similar to those in the upper small intestine. Under normal circumstances the vast majority of nutrients have already been absorbed by the time digested chyme reaches the ileum. Other than specialized absorption tasks (bile salts and vitamin B12), the main job left to the ileum is to continue to absorb H2O. Most Cl- is absorbed by a transcellular pathway involving Cl-/HCO3- exchange in the apical membrane, and facilitated diffusion across the basolateral membrane.

Answer 199

In the colon, no sugars or amino acids are absorbed. An important mechanism for Na absorption is via the apical Na+ channels (epithelial sodium channel, ENaC). Any stimulus that brings about an increase in plasma aldosterone levels causes very similar changes in colonic epithelia cells of the GI tract to those that occur in epithelial cells of the distal nephron of the kidneys. The colon, along with the kidneys, is instructed to absorb more Na+, and consequently more H2O. Another similarity is that increased Na+ absorption by this pathway leads to increased K+ secretion across the apical membrane. In the colon there is net K+ secretion when the lumenal concentration drops below 25 mM. Normally K+ ions secreted in the colon are of little consequence for electrolyte balance because the volume of fluid flowing through these regions is quite small. In severe diarrhea, however, the fluid loss is substantial, and can lead to hypokalemia. For this reason potassium is included in fluids given to patients with severe diarrhea. Water soluble vitamins (B vitamins, vitamin C, niacin, folic acid, pantothenic acid, and biotin) are absorbed either by co-transport with Na+, or by passive diffusion. As with other solutes, their absorption is virtually complete in the upper small intestine. An important exception is vitamin B12

Answer 200

is absorbed in the distal ileum in a complex with intrinsic factor. The brush border membrane of ileal enterocytes contains a specific receptor for the B12-IF complex. Impaired absorption of B12 leads to a disease called pernicious anemia.

Answer 201

Slow waves generally consist of an upstroke depolarization, a partial repolarization, and a plateau potential that can last for several seconds. Slow waves are an intrinsic property of muscle cells in a given region (i.e. no external stimulation is required). Another way of saying this is that the BER is myogenic or muscle-derived. each depolarization does not cause contraction (measured as an increase in tension, T). Contraction only occurs when the depolarization exceeds a specific membrane potential. In many parts of the GI tract a sufficient depolarization is reached during one or more action potentials (or spike potentials) that fire at the peak of a slow wave. The addition of acetylcholine to the preparation causes action potentials to fire at each peak, and the muscle contracts at the frequency set by the BER. The force of each contraction is proportional to the number of action potentials. The entry of Ca2+ ions during the action potentials, due to opening of voltage-dependent Ca2+ channels on the smooth muscle cell membrane, triggers a contraction.

Answer 202

The contractile apparatus of most of the Gl tract is made up of smooth muscle cells. Actin and myosin are the major contractile proteins. Actin is polymerized into thin ﬁlaments, and myosin is arranged in thick ﬁlaments, with cross-bridges extending to make contact with the thin ﬁlaments. The ratio of thin to thick ﬁlaments is about 10:1 (2:1 in skeletal muscle). Contraction of smooth muscle cell occurs when myosin interacts with actin, triggered by the entry of Ca+ ions into the cell. Formation of a complex between Ca2+ and calmodulin activates myosin light chain kinase, which phosphorylates myosin and allows cross-bridge formation (cycling) to occur. Nerve axons run through the bundles of smooth muscle cells and release neurotransmitters, which also induce Ca2+ entry and therefore can initiate contraction.

Answer 203

is the predominant motor activity in the intestines, helping to ensure proper digestion and absorption. contractions are isolated and not coordinated with movement above and below, it propels contents in both directions. When the contracting area relaxes, the contents flow back into the original segment with the result that mixing has occurred without net propulsion.

Answer 204

contractions of adjacent segments are coordinated in a proximal to distal manner, resulting in net propulsion of contents. The contractile ring moves towards the bolus, pushing it distally. At the same time, the intestine relaxes distal to the bolus (called receptive relaxation, produced by the pressure of the proximal bolus). This facilitates properly polarized propulsion. This coordination requires nerves of the myenteric plexus. In the stomach, peristalsis occurs when the BERs are coordinated by vagal input in such a way that contraction of a distal segment follows just after contraction of the immediately preceding segment. following a vagotomy, BERs are still observed, but they become disorganized and coordinated peristaltic movements are abolished.

Answer 205

The upper third of the esophagus consists of skeletal muscle, and the remainder consists of smooth muscle. A peristaltic wave of contraction pushes the bolus ahead to the lower esophageal sphincter (LES) in about 5 sec (liquids plummet to the LES much faster than the peristaltic wave). Just before the bolus arrives, the LES relaxes, and the bolus is propelled into the stomach. The peristaltic wave is controlled by the vagus nerve, which receives its signals from the swallowing center. However, if the vagus nerve is severed, a local myenteric complex can maintain swallowing. Note that the primary function of LES is to prevent reﬂux of acid gastric contents into the esophagus, whose epithelium (above distal 2-3 cm) is not adequately protected against this material.

Answer 206

storage, mixing and slow controlled emptying of the food. In synchrony with relaxation of the LES, the stomach undergoes the process of receptive relaxation. The fundus and the body of the stomach can accommodate volume increases as large as 1.5 L without a marked increase in intra-gastric pressure. This process is also regulated by the vagus nerve.

Answer 207

(1) After eating, contractions start around mid-stomach at the frequency of slow waves (~3/min). Peristaltic waves push a bolus toward the antrum, (2) The contractions become stronger and faster in the antrum and begin to outrun the bolus. Since pyloric opening small, most content reﬂected backward toward the body of the stomach. This process is called retropulslon. It serves to break up the food into smaller particles and mix it with digestive juices so that absorption can take place later in the gut. The digestive juice mixture is called chyme. (3) Transient opening of the pylorus allows smaller particles and chyme to leave the stomach and enter the duodenum. No movement of the gastric contents occurs between contractions.

Answer 208

is controlled by the pyloric sphincter, which is normally under the high tone. Intense waves force a few mls of chyme through the sphincter into the duodenum. Rate of emptying is increased by distension. Increased stretch leads to increased peristalsis through vagal and myenteric reﬂexes and decreases pyloric tone. Gastrin is a hormone secreted in response to the presence of food in the stomach. Gastrin also increases peristaltic contraction and decreases pyloric tone. Thus, the combination of distension and gastrin increase the rate of gastric emptying.

Answer 209

Arrival of food into the duodenum causes distention and irritation by acidity and solutions of high osmolarity. Detection of food in the duodenum leads to the reﬂex inhibition of gastric peristalsis and an increase in pyloric tone. Thus, the duodenum controls delivery rate so that it is not overwhelmed. Additionally, arrival of fats in the duodenum leads to secretion of cholecystokinin (CCK) by enteric endocrine cells. CCK decreases gastric motility providing a further method whereby the actions in the duodenum decrease the rate of gastric emptying to prevent overwhelming of the intestinal absorptive capacity.

Answer 210

Contraction of the small intestine during digestion consists of segmentation and peristalsis. The rhythm of the segmentation is the same as that of the BER. During segmentation the chyme is mixed with digestive enzymes and kneaded so that the intestine’s absorptive surfaces are constantly being exposed to new contents. Peristaltic movements occur over short distances to propel the digestive chyme at ~1cm/min in an aboral (distal) direction, so it takes 3-5 hrs to transit the intestine. Between meals a process known as migrating myoelectric motor complexes (MMC) sweep down the gastric antrum and along the small intestines. This process occurs about every 90 min, and performs a housekeeping role to remove bacteria and indigestible material. A long wave of peristalsis begins in the stomach, travels to the ileocecal sphincter and then repeats. At any one time 40cm of intestine is involved. Involvement of a region lasts 10-15 minutes, during which ~50 peristaltic waves occur. The region involved changes slowly, moving towards the ileum. When it arrives (~2 hrs), new activity begins in the stomach. Each wave is preceded by a rise in the plasma concentration of the hormone motilin, which is released from the small intestine and appears to initiate the process. Note that eating terminates the MMC, which only occur during fasting.

Answer 211

Distension in the ileum causes relaxation of the ileocecal sphincter, and contents pass into the cecum of the large intestine. In the colon, segmentation contractions mix and dry the chyme, so that only 100-200 ml of ﬂuid is lost daily in the feces. These contractions are quite prominent in some species, forming sacculatlons in the colon known as hausta (the haustratlons). Most forward propulsion in the colon takes place during a process known as a mass movement. Mass movements constitute a type of motility not seen elsewhere in the digestive tract. Known also as giant migrating contractions, this pattern of motility is like a very intense and prolonged peristaltic contraction that strips an area of large intestine clear of contents. During these movements segmental activity temporarily ceases and there is a loss of haustration. Thus, most prominent patterns of motility observed in the colon are segmentation movements, which are responsible for haustrations of the colon, and forward propulsions, known as mass movements.

Answer 212

In periods between meals, the colon is generally quiescent. Following a meal, colonic motility increases significantly, due to signals propagated through the enteric nervous system - the so-called gastrocolic and duodenocolic reﬂexes, manifestations of enteric nervous system control. Additionally, distension of the colon is a primary stimulator of contractions. Several times each day, mass movements push feces into the rectum, which is usually empty. The gastrocolic reflex is a stimulus for this. Feces enter the rectum, leading to distension of the rectum and stimulation of the defecation reflex. This is largely a spinal reflex mediated via the pelvic nerves, and results in reflex relaxation of the internal anal sphincter followed by voluntary relaxation of the external anal sphincter and defecation. The external anal sphincter consists of striated muscle. The urge to defecate accompanies distension of the rectum. In humans and "house-trained" animals, defecation can be prevented by voluntary constriction of the external sphincter. In order for defecation to proceed, the sphincter must be released voluntarily. If the external sphincter is not released, defecation reflex will ultimately be inhibited. In babies and in people with damaged spinal cords, the defecation reflex is sufficient to empty lower bowel without voluntary input.

Answer 213

Mucins, large glycoproteins that lubricate food and facilitate swallowing; The enzymes Amylase and lingual lipase which begin the digestion of starches and fats; NaHCO3, which helps to maintain an optimal pH for enzyme activity and also to reduce Ca2+ solubility. When the pH > 7.0, teeth do not lose Ca2+ to oral ﬂuids; The antibacterial agents immunoglobulin A (lgA), lysozyme which destroys bacterial cell walls, and Iactoferrln which chelates iron thus preventing the growth of bacteria that require iron.

Answer 214

The acini of the submaxillary and sublingual glands contain two types of cells, serous and mucous. Serous acinar cells are responsible for the secretion of fluid, electrolytes, and enzymes; mucous acinar cells secrete mucins. Proteins are released from acinar cells by exocytosis of secretory granules, a process triggered by a rise in intracellular Ca2+. From the acinus, saliva passes relatively unchanged through a short intercalated duct and into a striated duct. The striated duct is lined by epithelial cells that function like renal tubule cells to modify the inorganic ion composition.

Answer 215

At high flow rates, saliva is slightly hypotonic and rich in bicarbonate, while at low flow rates it becomes quite hypotonic. At low flow rates there is time for the ducts to modify the secretion. Na+ and Cl- ions are transported out of the lumen of the duct. The HCO3- and K+ ions are secreted into the lumen of the ductd. Because the ductal cells are quite impermeable to water, the modified saliva becomes hypotonic. Salivary secretion is under the control of the autonomic nervous system. Interestingly, both parasympathetic and sympathetic stimulation increase secretion, parasympathetic input being the more profound influence.

Answer 216

Pancreatic exocrine secretion consists of enzymatic components and aqueous components. Acinar cells produce and secrete digestive enzymes. An important feature is that each cell produces the full complement of pancreatic enzymes. Active enzymes, and in some cases enzyme precursors, are packaged into secretory granules and released by exocytosis. Unlike the enzymes of saliva and gastric juice, the pancreatic enzymes are essential for normal digestion and absorption, 95% of acinar cell protein synthesis is secretory enzymes (zymogens): Trypsinogen, Chymotrypsinogen, RNase/amylase/lipase, etc., Zymogens, so not enzymatically active until activated by proteolytic cleavage, Enterokinase (produced by small intestinal mucosa) activates trypsin, which activates the rest by proteolytic cleavage. In normal circumstances, these enzymes are inactive, however if even a small amount becomes active while still in the pancreas, this sparks a chain reaction - autodigestion (acute pancreatitis).

Answer 217

When chyme (i.e. fat-containing digestion products) arrives in the small intestine, it stimulates release of cholecystokinin (CCK). CCK is a 33 amino acid peptide (last 4 amino acid residues are the same as those of gastrin). The 8-carboxy terminal amino acid residues are necessary for activity. CCK is most important stimulus for aclnar cell secretion. Inositol triphosphate (IP¬3) and Ca2+ are probably the most important 2nd messengers for CCK. ACh is also stimulatory for secretion, as is gastrin, again through lP¬3/Ca2+ pathways. This shows once again how digestive phases are coordinated, since gastric mediators also impact on pancreatic secretion.

Answer 218

The aqueous component consists mostly of water and bicarbonate, and is produced by duct cells. This component neutralizes acid in the duodenum, preventing injury to the duodenal mucosa and bringing the pH to an optimum level for enzymatic digestion of chyme to proceed. Thus, this HCO3 rich solution serves two purposes: Solvates enzymatic secretions - keeps them moving down duct; Alkalinity necessary to neutralize gastric acid dumped from stomach into small intestine. Presence of acid in small intestine leads to secretion from duodenal endocrine cells of secretin. Secretin is most important stimulus for NaHCO3 ~ thus, the presence of acid in the intestine leads to the secretion of a neutralizing solution; Secretin and CCK both inhibit gastric acid/fluid production and delay gastric emptying until the intestine is ready for more.

Answer 219

In a number of respects, it is the reverse of acid secretion by parietal cells, with HCO3- being transported into the lumen and H+ being transported into the interstitial fluid. Some differences are that the primary active transport process is the Na+/K+-ATPase in the basolateral membrane, and H+ is transported into the plasma by secondary active transport using the energy of the inward Na+ gradient. The low H+ concentration leads to high OH- and consequently high HCO3-, which is transported, into the lumen by CI-/HCO3- exchange. Much of the CO2 used to produce bicarbonate appears to come not from cellular metabolism, but from the blood. The H+ transported into the plasma combines with HCO3- in the plasma to produce CO2, which is free to diffuse into the cell. Na+ is transported from the plasma to the lumen by a paracellular pathway. The driving force for Na+ movement is the negative potential of the lumen with respect to the plasma. In part this is created by the electrogenic action of the Na+/K+-ATPase, which transports 3 Na ions into the plasma in exchange for 2 K ions. H2O then follows the net movement of NaHCO3 into the duct lumen. When stimulated, the epithelial cells of pancreatic duct secrete an isotonic NaHCO3 solution. Secretin (via cAMP) and ACh (via Ca2+) both stimulate HCO3- secretion by the pancreatic duct.

Answer 220

At low ﬂow rates, HCO3- is exchanged for Cl- as the solution moves down the duct — thus, the final concentration of bicarbonate is low and Cl- is relatively high. At high flow rate, fluid moves through duct too fast to allow for significant exchange, so HCO3- is high, Cl- is relatively low. The secretion consists primarily of NaCl at low flow rates and NaHCO3 at high flow rates. As you might expect, mechanisms similar to those invoked to explain the ionic composition of gastric juice also account for the variations in pancreatic juice. In this case the two-component theory of secretion states that there is a basal secretion from acinar cells (mostly NaCl), and a duct cell secretion (mostly NaHCO3) superimposed on the basal secretion that varies with the level of stimulation. As the rate of secretion increases, the bicarbonate dilutes the small amount of Cl. There is also evidence that as H2O moves down the ducts it can be exchanged for Cl. At low secretory rates there is time for exchange to occur, helping to make Cl the predominant anion.

Answer 221

The primary stimulant of enzyme secretion from acinar cells is the hormone cholecystokinin (CCK). While the main stimulant of bicarbonate-rich ﬂuid secretion from duct cells is the hormone secretin. The parasympathetic transmitter acetylcholine (vagal ACh) stimulates enzyme secretion, with little or no effect on juice. Neural influences on juice secretion are probably mediated primarily by peptidergic pathways, i.e. VIP (vasoactive intestinal peptide) It is interesting to note here that CCK, while not a stimulator of duct cells on its own, is known to potentiate the effect of secretin on duct cells. Both CCK and ACh are thought to activate the enzyme phospholipase C (PLC) via a G-protein intermediate. PLC catalyzes an increase in the messenger inositol trisphosphate (IP3), which releases Ca2+ from intracellular stores. The increase in Ca2+ triggers exocytosis of secretory granules. Secretin is known to act by increasing cAMP, although how this potentiates Ca2+-dependent exocytosis is unclear.

Answer 222

1) Cephalic phase accounts for 25-50% of secretion. 2) Gastric phase accounts for 10% of secretion. 3) Intestinal phase is most important, accounting for 50-100% of secretion. The cephalic phase is stimulated by sight/thought/smell/taste of food. These stimuli lead to increased vagal release of ACh (and possibly VIP). These secretagogues increase pancreatic enzyme secretion. The gastric phase is stimulated by distention, which activates vago-vagal reflexes. During the intestinal phase, food in the intestine leads to increased CCK, and acid in the intestine results in secretin secretion with a vagal reflex component here also.

Answer 223

stool osmotic gap=290- 2(stool Na + stool K), Osmotic (gap >50mOsm due to unmeasured Osm), such as lastose intolerance, sorbitol, fructose, magnesium containing laxatives. Secretory (gap

Answer 224

due to malabsorption, with causes including celiac, whipple's disease, small bowel bacterial overgrowth, or short gut (small bowel) from surgery. can also be due to maldigestion such as with pancreatic insufficiency or billary obstruction

Answer 225

causes include crohn's disease, ischemia, or invasive infections in the colon (C. difficile, EHEC, Amebiasis, Shigella)

Answer 226

Due to irritable bowel syndrome. It is usually watery diarrhea. It is a diagnosis of exclusion.

Answer 227

Abnormal absorption leads to malabsorption, a syndrome of disordered or inadequate absorption of nutrients. It is caused by a host of intestinal diseases, medications or dietary products that impair nutrient digestion, absorption, or delivery. Symptoms depend on the nutrient malabsorbed, but patients often experience weight loss, diarrhea, foul-smelling stools and vitamin deficiencies. Steatorrhea is a hallmark sign of generalized malabsorption. It is a manifestation of dysfunctional lipid absorption from decreased pancreatic and biliary secretions, abnormal enterocyte processing, or lymphatic obstruction.

Answer 228

Impaired lipolysis can occur from various causes, but the most common is pancreatic insufficiency from chronic pancreatitis. Protein malabsorption occurs because of the marked decrease in secretion of trypsinogen, chymotrypsinogens, proelastase, and porcaroxypeptidases A and B. Steatorrhea occurs because of the decreased activity of lipase and colipase, which leads to lipid maldigestion. Carbohydrate malabsorption is rare because of the reserves of amylase.

Answer 229

Chronic liver disease leads to fewer hepatocytes with decreased function leading to decreased bile formation, bile being necessary for the absorption of lipids. Examples include alcoholic cirrhosis, primary biliary cirrhosis, biliary obstruction.

Answer 230

Impaired mixing can occur after surgical alteration of the GI tract as in post-gastrectomy operations (Bilroth II, Roux-en-Y). In addition, inadequate mixing of ingested food with biliary and pancreatic secretions occurs because the ingested food may precede the arrival of pancreatic and bile, leading to maldigestion.

Answer 231

A number of diseases damage the small intestinal mucosa. The main mechanism of malabsorption in these conditions is the decrease in absorptive surface area. These conditions are characterized by: 1. Intestinal inflammation and villus flattening (celiac sprue, infection, tropical sprue, graft vs host disease, Whipple’s disease). 2. Ulceration NSAIDs (non-steroidal anti-inflammatory drugs), Crohn’s Disease. 3. Ischemia (radiation enteritis, mesenteric ischemia from arterial embolus, arterial thrombosis, venous thrombosis). 4. Infiltration (amyloidosis, collagenous sprue, lymphoma). 5. Other (byapass, extensive small intestine resection)

Answer 232

Celiac sprue (gluten-sensitive enteropathy, celiac disease) is an inflammatory disease of the small intestine. It occurs because of an immune response to peptides of gluten, a protein found in wheat, rye, barley, and to a lesser extent in oats. It often appears when weaning a child from breast milk and when cereal is introduced in the diet, but can presents in adults. It is characterized by loss of villi due to the presence of increased intraepithelial lymphocytes, and crypt hyperplasia leading to malabsorption. The degree of malabsorption may predict the severity of mucosal involvement. Carbohydrate, fat, and protein malabsorption occur because of villus destruction. Celiac disease affects the proximal small intestine so malabsorption of iron and folate also occur.

Answer 233

Commonly patients present with symptoms of malabsorption-steatorrhea including diarrhea, weight loss, bloating and abdominal pain. Unexplained iron deficiency anemia in adults should make one think of celiac disease.

Answer 234

Diagnosis is made by intestinal biopsy (villous flattening, intraepithelial lymphocytes, crypt hyperplasia) and use of serologic tests for anti-endomysial antibodies (sensitivity 90%, specificity 99%) anti-tissue transgluatminases (tTg) IgA antibodies (90% sensitive, specificity 99%) and anti-gliadin IgA and IgG antibodies (sensitive but not specific).

Answer 235

Patients with celiac disease require a lifelong gluten free diet. Adherence to the diet will reverse villous flattening within a few weeks and show a decrease in antitissue transglutaminase IgA antibody titer.

Answer 236

There is an association of T-cell lymphoma in patients with long standing disease. Adenocarcinomas of the small intestine have been reported. Refractory ulcerative jejunitis occurs rarely.

Answer 237

Tropical sprue is a disease that occurs in residents or visitors to the tropics, particularly Southeast Asia, the Caribbean, and India. It can occur years after an individual returns from the tropics. The cause is unclear, but thought to be from bacterial toxins or colonization of aerobic coliform bacteria in the small intestine. Intestinal biopsy shows mucosal changes similar to that of celiac sprue, however villous atrophy is patchy. Tropical sprue can affect the proximal and distal small bowel. The classic presentation is with a megaloblastic anemia due to vitamin B12 and folate deficiency accompanied with diarrhea. Diagnosis made by travel history to tropics, vitamin B12 and folate deficiency, and characteristic intestinal biopsy. Treatment includes vitamin B12 and folate supplementation and prolonged course of antibiotics (6 months to 1 year).

Answer 238

Ischemic bowel disease results from impaired organ perfusion. Ischemia can result in injury to the small intestine as well as the colon depending on the affected vessel. A portion of the duodenum, entire small intestine and half of the colon receive arterial blood from the superior mesenteric artery (SMA). The inferior mesenteric artery (IMA) supplies the left colon and rectum. Collateral circulation exists between the SMA and IMA via the marginal arteries and Arc of Riolan. Chronic mesenteric ischemia occurs when 2 of the 3 major vessels are occluded. The mucosa layer is the most vulnerable but injury can range through the submucosa, deep muscularis and serosa. Usually transmural infarction (all layers involved) implies embolus or thrombosis of one the major vessels whereas partial thickness injury implies hypoperfusion. The hallmark symptom is abdominal angina, post-prandial abdominal pain. This can be accompanied by weight loss due to fear of eating (sitophobia).

Answer 239

The appendix attaches to the cecum and was originally thought to be a vestigial organ, an evolutionary remnant of the large cecum that animals use to bacterially ferment and digest plants (e.g. horse). Evolution to a fruit based diet was thought to result in the appendix shrinking due to a lack of selective pressure. One recent theory proposes that the appendix evolved individually 32 times in mammals and may serve as a reservoir to replenish normal gut bacteria. Small retrospective studies (low quality of evidence) have suggested that not having an appendix is a risk factor for recurrent Clostridium difficile infection, supporting the notion that “good” bacteria live there.

Answer 240

The most common disease of the appendix is appendicitis and is covered elsewhere. The classic presentation is mid abdominal pain that migrates to the RLQ once peritonitis starts to develop. Nausea and vomiting are frequent symptoms. High fever, WBC count and severe pain suggest perforation. IV fluids, IV antibiotics and surgical resection are the treatment. Remember that the appendix can be found in multiple orientations and therefore cause pain in a variety of locations.

Answer 241

Tumors of the appendix are rare and are frequently found when the appendix is removed for other reasons. About half of the tumors are carcinoid, a neuroendocrine tumor. Metastasis of carcinoid to the liver can produce serotonin syndrome characterized by episodic flushing, diarrhea, wheezing and right sided valvular heart disease. Epithelial tumors of the appendix are rarer still and show the same range from dysplasia (villous adenoma) to adenocarcinoma as colon polyps and cancers. Rare mucinous tumors called cystadenomas can obstruct the appendix leading to rupture. Seeding of mucus secreting cells creates a condition called pseudomyxoma peritonei characterized by diffuse collections of gelatinous mucinous material throughout the abdomen.

Answer 242

Inflammatory bowel disease (IBD) is a common GI disorder of disorderly immune function involving the small and large intestines comprised of 2 main variants, Crohn’s disease and ulcerative colitis (UC). Approximately 15-20% of cases will have features of both categories and cannot be further differentiated, so-called indeterminant colitis. The cause of inflammatory bowel disease is still a bit of a mystery, but certain factors clearly contribute. There is a genetic component, since certain genes (HLA-B27) are more common in patients with IBD and approximately 1/4 of patients have a positive family history. Environmental triggers, such as tobacco exposure, bacterial infection, diet, or climate, may also contribute. Immune dysregulation is clearly a dominant feature, one that is targeted with various therapies that inhibit the systemic or GI immune systems. For unclear reasons, tobacco use (not just nicotine) aggravates Crohn’s disease and ameliorates UC. UC is very unusual in smokers. In both Crohn’s and UC, autoimmune dysregulation leads to chronic inflammation of the mucosa and submucosa.

Answer 243

Crohn’s disease may occur anywhere from the distal oropharynx to the anus (“from tongue to bung”), whereas UC is limited to the colon. Because of disease location, UC may be cured by surgical resection (colectomy) but Crohn’s may only be modified by it. Crohn’s occurs most commonly in the terminal ileum and right colon but also may occur in the left colon. Jejunal involvement is infrequent and duodenal, gastric, and esophageal involvement is rare. UC occurs usually involves the rectosigmoid (>90%) and occurs throughout the colon (pan-colonic) in nearly half of cases. When only the rectum is involved (ulcerative proctitis), the prognosis and risk of cancer are favorable.

Answer 244

Crohn’s disease is clearly exacerbate by tobacco use, whereas UC tends to improve with tobacco use. In fact symptomatic UC is rare in smokers. Patients with Crohn’s disease should discontinue tobacco use. Although tobacco (not just nicotine) is protective against UC, neither smoking or nicotine supplements are not advocated as therapy for UC because of carcinogenesis and overall health risks.

Answer 245

In Crohn’s disease, the inflammation is often transmural, i.e. extends to the muscle and serosa. In UC, the inflammation is confined to the mucosa and sometimes the submucosa. Transmural inflammation in Crohn’s may lead to the spread of disease outside the lining of the GI tract, and “creeping fat,” aka visible inflammation of the mesentery, may be seen during laparoscopy or open surgery. Fistulae are pathologic connections between the GI tract and other structures, with the name dependent on structures involved (e.g. colocutaneous, enterocolonic, colovaginal, cologastric, colovesical, etc…). Fistula formation is unique to Crohn’s diseas. Colocutaneous fistulas involving the perianal region are the most common. As a result of transmural disease, the wall of the small bowel (and less commonly, the colon) may become fibrotic and narrowed, leading to the formation of focal strictures. Such strictures can predispose patients to obstruction.

Answer 246

Another distinguishing feature is the appearance and extent of disease within the intestinal lumen. Crohn’s disease generally causes patchy inflammation or ulceration with relative sparing of mucosa in between, the so-called “skip lesions.” UC causes diffuse inflammation characterized by friability, edema, bleeding, and punctate ulcerations. Crohn’s is associated with linear or focal ulceration of the mucosa whereas UC has circumferential ulceration. Within an area of UC-related ulceration, islands of spared mucosa may be present, with the appearance of a polyp. These are called pseudopolyps.

Answer 247

Distinguishing histologic features of Crohn’s and UC will be covered in detail in a separate lecture and will not be addressed here. Of note, a disgtinguishing histologic feature of Crohn’s disease is the presence of granulomas, but they are only identified in ~ 20% of cases. Despite the clinical, microscopic, and macroscopic differences between UC and Crohn’s, approximately 20% of patients with IBD have clinical, endoscopic, or histologic features of both entities and cannot be differentiated into one subtype or another. In such cases the disease is termed indeterminant colitis and this managed according to the more dominant features.

Answer 248

Both Crohn’s and UC may present with diarrhea or abdominal pain. Crohn’s disease may cause lower abdominal pain consistent with colitis or mid-abdominal (periumbilical) pain more consistent with small bowel disease. The pain with UC is almost always localized to the lower quadrants, LLQ more frequently than RLQ, which is consistent with sigmoid and rectal involvement. With colitis, the diarrhea in Crohn’s and UC is usually small-volume, 4-6 times per day, and often associated with tenesmus (extreme urgency to defecate) or a sense of incompete evacuation after defecation. With severe Crohns ileitis or jejunitis, the diarrhea may occasionally be large-volume, foul smelling, and/or associated with steatorrhea, which could indicate malabsorption. Weight loss is common with either disorder, both from increased GI catabolism, loss of nutrients in the stool, and/or decreased PO intake because of abdominal pain, nausea, or generalized malaise. Nausea and vomiting are more common with Crohn’s than UC. Hematochezia and anemia are generally indicative of UC or severe Crohn’s colitis. UC may also cause visible mucus in the stool. Crohn’s may lead to signs or symptoms or small bowel obstruction, particulary if the patient has had previous GI surgery. Fistula formation (see below) only occurs with Crohn’s disease.

Answer 249

The management of inflammatory bowel disease is relatively complex and depends on the type, severity, and location of disease and the type of previous therapy used. It will not be covered in detail. Glucocorticoids may help induce remission in those presenting with new disease or experiencing an acute flare, but these are unsafe and ineffective over the long-term. Medications for chronic disease control include sulfasalazine, 5-aminosalicylates, topical steroids (Budesonide), immunomodulators (Azathioprine and 6-mercaptopurine), and TNF-alpha antagonists (e.g. Infliximab, Adalimumab, Certolizumab). Antibiotics sometimes help with healing of fistulas and distal colitis. Surgery, including subtotal colectomy, partial small bowel or colon resection, or stricturoplasty, is used for refractory disease, particularly in young patients with UC who frequently require sterioids for disease flares. In such patients, surgery may be curative. Nowadays, in the ands of skilled colorectal surgeons, a permanent ileostomy can usually be avoided by constructing a J-shaped pouch out of ileum, which serves as the new rectum.

Answer 250

Patients with longstanding IBD, particularly those with UC or Crohn’s involving the colon, who still have a colon carry a 5 to 7-fold relative risk of colorectal cancer compared to controls and should undergo cancer screening. The risk of cancer increases significantly with disease duration, such that after 8-10 years of disease, a yearly colonoscopy with random biopsy is recommended. Patients with high-grade dyplasia or cancer generally should undergo total colectomy instead of segmental colon resection.

Answer 251

IBD patients, particularly those requiring chronic or frequent use of corticosteroids, should be screened for osteoporosis. IBD is associated with osteopenia and osteoporosis independent of steroid use. Patients with malabsorption should be screened for fat-soluble vitamin deficiency (K, A, D, E) and Vitamin B12 deficiency. Patients taking immunomodulators have an increased risk of infection and pancytopenia and sometimes need to be screened for this. Patients taking biologics carry an increased risk of lymphoma, fungal and mycoplastic infections, and CNS disease. A TB skin test (PPD) is mandatory prior to starting therapy. There is a slightly increased risk of IBD exacerbation during pregnancy and/or teratogenic effects of medications. Thus women of childbearing age with IBD, particularly those taking biologics or immunomodulators, should use birth control or consult with their gastroenterologist/OB-Gyn prior to attempted conception.

Answer 252

an autoimmune, inflammatory condition of the colon associated with mild to moderate diarrhea. The presumed cause is inflammation in the colonic mucosa with associated malabsorption of water and sodium. Although intraluminal bacteria or dietary components are presumed to “trigger” the illness, the definite underlying causes and mechanisms are unknown. Bile acid-related irritation of the colon, which may be “sensitized” in select individuals, is another proposed mechanism. Patients (females > males) present after age 50 with chronic, watery, non-bloody diarrhea. The diarrhea is generally mild, but occasionally moderate, in severity but rarely causes dehydration or requires hospitalization. Mortality is not increased. The diarrhea is usually improved in the fasting state, suggesting that the mechanism for diarrhea relates to colonic salt and malabsorption of NaCl/water. Weight loss, constipation, bleeding, and non-GI symptoms are rare.

Answer 253

Imaging studies and endoscopic findings are almost always normal. Fecal leukocytes may be present on stool analysis, which is otherwise negative. Subtle endoscopic abnormalities may suggest the diagnosis, but this is not the norm. The diagnosis is made by endoscopic biopsy. There is an association with celiac sprue (5-40% of patients), so testing for sprue is appropriate. Other causes of colitis can be ruled out with the history and endoscopic exam.

Answer 254

There are 2 variants of microscopic colitis, lymphocytic colitis (LC) and collagenous colitis (CC), which can only be differentiated by histology. The histologic findings and similarities/differences between LC and CC will be addressed separately in a separate lecture.

Answer 255

Treatment of LC and CC is the same. Antidiarrheals (Imodium, Lomotil) and Bismuth subsalicylate are used first for symptom control, especially in mild cases. Patients who do not improve with these medications may improve with topical steroids (Budesonide), aminosalicylates, or bile acid binders (Cholestyramine). Immunomodulators are occasionally used. Although symptoms may be troublesome, there is minimal mortality or morbidity related to MC. The risk of colon cancer is not increased.

Answer 256

Ischemic colitis (IC) is an inflammatory condition of the colon that develops as a result of severely impaired regional blood flow. Many patients with IC have predisposing conditions such as peripheral vascular disease or congestive heart failure. Others may have an identifiable predisposing trigger (recent dehydration, cocaine use, abdominal surgery with cross-clamping of the aorta). But over 50% of patients with IC have no antecedent GI disease and no identifiable risk factors. Vasospasm is the presumed mechanism for ischemia in these cases. The disease occurs most commonly in watershed areas of the colon (i.e. areas where there may be relative sparing of vascular supply) such as the splenic flexure, sigmoid, and rectum, but any region may be affected.

Answer 257

IC usually presents with the sudden-onset of crampy lower abdominal pain, diarrhea, and/or hematochezia in patients over 60 years old. There may be tenesmus. Weight loss or severe bleeding suggests an alternative diagnosis. Patients who have had recent surgery may have nausea and/or vomiting from associated adynamic ileus. The diagnosis is suspected based on the history and physical. A KUB x-ray may also suggest IC if it shows “thumbprinting” of the colonic mucosa, but this is not a sensitive test. Contrast CT of the abdomen, if ordered, may also suggest IC when there is colonic wall thickening, pericolonic inflammation (fat stranding), and/or decreased perfusion.

Answer 258

The gold standard for diagnosis is colonoscopy or flexible sigmoidoscopy with biopsy. Endoscopic findings include mucosal edema, friability, ulceration, or hemorrhage. In severe cases, there may be a dusky, cyanotic color to the mucosa or decreased bleeding noted after taking a biopsy. The abnormalities are usually limited to vascular region of the colon, with the remaining parts of the colon appearing normal. Biopsy shows acute inflammation, intravascular thrombi, and/or mucosal necrosis.

Answer 259

Treatment of IC is supportive, with intravenous hydration and correction of any predisposing factors (arrhythmia, CHF, myocardial infarction). Vascular interventions, either by angioplasty or surgical bypass, are rarely necessary but may be considered in patients with known vascular disease and persistent symptoms. Most patients will recover from an episode of IC spontaneously within 5-10 days and have no recurrence.

Answer 260

Intestinal gangrene (IG) is a separate from ischemic colitis, more severe entity usually involving the small bowel. It results from complete absence of blood flow to the bowel such as that occurring with mesenteric thrombosis or embolism or trauma involving the abdominal vessels. Patients are usually in severe pain and hemodynamically compromised with obvious peritoneal signs on physical exam. This condition is a surgical emergency, and patients who do not undergo surgery have nearly 100% mortality from abdominal sepsis. Because of the distribution of mesenteric vessels and collateral blood flow, intestinal gangrene involving the colon is uncommon.

Answer 261

Infectious colitis (InC) is a relatively common cause of acute diarrhea. Unlike most infections of the small intestine (Cholera, Cryptosporidia, Giardia), infectious colitis usually presents with an inflammatory diarrhea caused by invasion or destruction of the mucosa by the microbe. The presenting symptoms are usually crampy lower abdominal pain and diarrhea, which is typically small-volume, frequent, and may be bloody or mucoid but without caloric malabsorption. The diarrhea can be frequent and severe enough to cause dehydration or anemia.

Answer 262

InC should be considered in all patients with acute diarrhea, particularly those with the following risk factors: travel, usually outside the US, to endemic areas; contacts with diarrhea; recent hospitalization or antibiotic use; or ingestion of undercooked beef. Antibiotic use is the strongest and most prevealent risk factor for Clostridium Difficile (C. Diff) colitis. Anal intercourse is a risk factor for sexually transmitted infectious proctitis or rectal ulcers (GC, herpes, Syphillis) and should be addressed.

Answer 263

A positive leukocyte stain of the stool strengthens the diagnosis of InC, however this finding is nonspecific as fecal leukocytes may also be present in UC or IC. Stool cultures are > 90% sensitive for most bacterial pathogens (E. Coli, Shigella, Salmonella, Yersinia), and stool toxin assays are > 90% sensitive for C.Difficile when repeated 2-3 times. Amebiasis may be ruled out with a negative serology but this is non-specific. In cases where stool analysis is negative despite a persistent clinical suspicion for InC, colonoscopy with biopsy should be performed, because this is extremely sensitive; for certain pathogens (C. Diff, Entamoeba histolitica) it is specific as well. Venereal proctitis (Gonorrhea, syphilis, Chlamydia, Herpes) can be assessed by tissue gram stain, culture, PCR, or immunofluorescence of a rectal ulcer specimen. In persistent or prolonged (> 3 weeks) cases, colonoscopy with biopsy may be necessary to rule out IBD and C.Diff colitis. C.Diff colitis, otherwise known as pseudomembranous colitis, results in the formation of necrotic, mucupurulent debris adherent to inflamed colonic mucosa. The endoscopic finding of pseudomenbranes is diagnostic of C.Diff.

Answer 264

Colitis may be also be caused by medications, most notably nonsteroidal anti-inflammatory drugs (NSAIDs). Other offending medications include gold salts (rarely used nowadays) or penicillamine. The endoscopic findings and clinical presentation may mimic UC, or there may be single or scattered, focal ulcers of the colon. Colonoscopy may be necessary to assist with diagnosis, particularly when there is rectal bleeding. The key to treating drug-induced colitis is identifying and withdrawing the offending agent. Prognosis is generally good when the disease is recognized early.

Answer 265

Radiation-induced colitis most commonly involves the rectum, where it is known as radiation proctitis (RP) as a result of therapy for prostate, cervical, or bladder cancer. RP may occur anywhere from several months to at least a decade from the time of pelvic radiation. The dose and duration of XRT is not necessarily relevant to the incidence of RP, but RP is more frequent in patients who have had high-dose pelvic XRT more than once. RP typically causes painless rectal bleeding. Tenesmus and mild diarrhea may also occur. Fecal incontinence is less common. Whereas the history is usually suggestive, the diagnosis is readily confirmed by proctoscopy or colonoscopy. Typical endoscopic findings include mucosal cobblestone-like edema and scattered telangiectasias, which may be actively oozing during the exam. Initial treatment of RP includes oral or suppository medications such as anti-diarrheals or aminosalicylates. In cases where medication does not control symptoms, endoscopy with topical therapy (heat or argon gas-based ablation) may be tried. Rarely, surgical proctectomy or segmental resection is needed.

Answer 266

Diverticulosis is the term used for outpouchings of the colon wall. These diverticula are composed of mucosa and submucusal layers, which herniate outward through the muscularis propria but are contained by serosa. The diverticula form and subsequently grow, within the muscular gap created by penetrating vasa recta that penetrate the colon wall.

Answer 267

Diverticulosis is very common in western countries but essentially non-existent in rural Africa and Asia. There may be environmental factors, but the low-fiber western diet is certainly a risk factor. Diverticulosis occurs more commonly in patients who consume a diet low in fiber (5g per day or less). Dietary fiber intake improves overall colonic motility (which is why fiber supplements are used to treat constipation) but decreases peristaltic squeeze pressure and intra-colonic pressure. Thus, a low-fiber diet increases peristaltic squeeze pressure and intra-colonic pressure, increasing the risk of diverticulogenesis. This is presumed to be the leading factor in the high incidence of diverticulosis in western countries. Age is another strong risk factor. In the US, the prevalence of asymptomatic diverticulosis detected on routine colonoscopy ranges from 10-15% in patients 50% in patients over 80 years-old.

Answer 268

In 80% of patients, diverticulosis is a benign condition and patients remain asymptomatic throughout their lifetime. In 20-25% of patients, complications occur which include infection and/or perforation and abscess formation (diverticulitis) or hemorrhage.

Answer 269

Diverticula are constantly filling and emptying of stool. A large stool or food particle may occasionally lodge within a diverticulum and become impacted. Because all diverticula contain bacteria, if impaction is not relieved within due time, the bacteria will multiply, expand, form gas, and eventually rupture the diverticulum. When this occurs, the term acute diverticulitis is applied. The perforation may be contained with minimal abscess formation around the colon wall (uncomplicated diverticulitis), or there may be free perforation, a large abscess may develop with, or the bowel may be become obstructed (complicated diverticulitis). Sigmoid diverticula are the most common location. Diverticulitis usually presents with the relatively quick (within hours) onset of lower abdominal pain (usually LLQ), fever, nausea, and/or vomiting. Mild diarrhea may also occur, presumably from associated colonic dysmotility.

Answer 270

Uncomplicated diverticulitis may be treated with oral or IV antibiotics alone. Complicated diverticulitis requires percutaneous drainage and sometimes surgery. If pre-operative drainage cannot be performed and surgery is required (e.g. perforation with frank peritonitis or sepsis), this may involve a 3-stage operation. Otherwise, an abscess can usually be drained by placing a tube through the skin or the rectal wall into the cavity, and surgery can be simplified, delayed, and sometimes avoided. After resolution of acute diverticulitis, patients who do not undergo surgery carry an increased risk of colonic stricture formation and obstruction. Diverticular hemorrhage occurs when the mucosa of the diverticulum erodes into the adjacent, penetrating vasa recta (usually from pressure necrosis) and intraluminal bleeding ensues. Diverticular hemorrhage will be included in the following section.

Answer 271

Lower GI bleeding (LGIB) refers to intraluminal GI bleeding whose source is located distal to the ligament of Treitz. Colonic bleeding, i.e. bleeding from a site within the colon, is the most common cause of LGIB, but clinically significant lower GI bleeding is much less common than upper GI bleeding. Thus, LGIB usually refers to colonic bleeding since small bowel pathology is much less prevalent.

Answer 272

LGIB typically presents as hematochezia (passage of red or maroon blood per rectum). Less commonly, bleeding from the right colon can present as melenic stools (black, foul-smelling, partially digested blood). Others, such as those with cancer, may present with symptomatic anemia (pallor, fatigue) but deny visible blood in the stool. When colitis is present, crampy lower abdominal pain may be present. Patients who have lost more than 10% of their blood volume may report dizziness (particularly when standing) or have syncope (passing out) from hypotension or severe anemia. Whatever the source, acute LGIB usually ceases on its own. If the source is not identified, it can recur.

Answer 273

The differential diagnosis for LGIB includes, in decreasing order of prevalence, the following: diverticulosis, arteriovenous malformations (AVMs), neoplasia, colitis (IBD, IC, InC, RP), iatrogenic (post-polypectomy is the most common), anorectal disease (hemorrhoids, fissure), and miscellaneous etiologies (Dieulafoy’s lesion, solitary rectal ulcer). Some clues in the history may suggest a particular etiology. In patients with diverticulosis, the classic presentation is sudden-onset, painless, large-volume hematochezia which stops 2-3 days later. In patients with neoplasia, there is often a history of weight loss, changes in stool caliber or frequency (if the lesion is obstructive), a personal or family history of polyps or cancer, or microcytic anemia with iron deficiency. With bloody diarrhea (dysentery) related to InC, there may be a history of travel, ill contacts who shared the same meal recently or a known outbreak, or antibiotic use. Patients with drug-induced colitis may report NSAID use.

Answer 274

The diagnosis of LGIB is usually made clinically, but the underlying etiology is identified during colonoscopy. This is the test of choice unless unusual circumstances (nausea/vomiting/distention suggestive of obstruction, peritoneal signs) suggest additional pathology which should be investigated with cross-sectional imaging.

Answer 275

The initial treatment of LGIB involves stabilizing the patient with intravenous fluids or transfusions if necessary, correcting anemia or clotting disorders (if relevant), and avoiding PO intake. Hospitalization is usually indicated. The subsequent treatment depends on the cause and may involve supportive care (e.g. IC), medications (e.g. for IBD, InC, or RP), endoscopic or angiographic therapy (diverticulosis, AVMs), or surgery (neoplasia, recurrent diverticular bleeding, refractory bleeding from any cause).

Answer 276

Colonic obstruction (CO) may result from numerous causes. 90% of CO cases are casused by the following: adenocarcinoma of the colon or rectum, volvulus, and benign strictures resulting from acute diverticulitis. Obstructive colon cancer (20% of colon cancers) is usually left sided and preceded by a prodrome of change in stool frequency or caliber. Volvulus typically involves the cecum or sigmoid colon, where a colonic loop twists around on its mesentery, resulting in strangulation and luminal obstruction). Volvulus usually occurs in elderly (> 65 YO) patients, often those with chronic constipation or polypharmacy. Surgical adhesions or foreign bodies (swallowed or inserted per rectum) are less common causes of CO. Consider the latter scenario in homosexual patients, prisoners, rape victims, and drug smugglers. The latter group (“mules”) may ingest packets of drugs which can rupture (often causing overdose), obstruct, or both.

Answer 277

CO typically presents with diffuse or upper abdominal discomfort, distension, and nausea/vomiting. The emesis may be feculent. Absence of stool passage (obstipation) may also be reported, although some patients, typically those with a distal CO, may experience low-grade diarrhea and/or incontinence as liquid stool passes around an obstructive lesion.

Answer 278

The diagnosis can usually be made clinically and with the help of plain abdominal radiographs (abdominal series x-rays). X-rays show dilated loops of colon and/or small intestine proximal to the obstructing lesion, with decompression and/or absence of gas distally. CT scan is usually not necessary for diagnosis but is helpful to clarify the exact location and extent and type of obstructing lesion, particularly before surgery begins.

Answer 279

Patients should be admitted to the hospital, made nil-per-os (NPO or nothing by mouth) and a nasogastric tube (NGT) inserted for decompression of gastric distension. This helps significantly with nausea and vomiting. Colonoscopy may be appropriate pre-operatively for confirming the diagnosis and location of cancer but usually does not change the need for an operation. A sigmoid volvulus may be diagnosed and relieved by colonoscopy with endoscopic rotation of the twisted segment; however there is a > 50% chance of subsequent recurrence. Thus, younger or healthier patients should have segmental colon resection. Foreign bodies, particularly those involving drugs or those large enough to obstruct, should be extracted manually by a general surgeon during laparotomy. Chronically ill patients with obstructive colon cancer and poor short-term prognosis may benefit from a colonoscopy with (palliative) metal stent placement across the tumor instead of surgery.

Answer 280

Fiber/ bulk forming. Usually recommended first. Recommended because they approximate physiological mechanism (facilitate passage and stimulate peristalsis via absorption of water and subsequent bulk expansion). Effective in 12-24 hrs to 3 days; always take with 8 oz water/juice. May combine and interact with other drugs (digoxin / salicylates), so space dosing

Answer 281

Saline (osmotically active agents) Cathartics. Added to fiber as second step. High volume solutions (4 liters of Golytely or Colyte) widely used for bowel cleansing prior to radiologic, surgical, or endoscopic procedures. Contain sodium and potassium salts to prevent net transfer of electrolytes into lumen. Smaller volume solutions (250-500 ml of Miralax®) now used for difficult to treat constipation; given as daily dose for treatments of less than 2 weeks duration. Prolonged, frequent, or excessive use may lead to electrolyte depletion.

Answer 282

Nondigestable sugars. Dissacharide metabolized by colonic bacteria to low molecular weight acids leading to osmotic diarrhea and increased colonic peristalsis. Alternative for acute constipation; particularly useful in elderly patients

Answer 283

Try if fiber / saline fail. Thought to act via increase in peristaltic activity by inducing low-grade inflammation (local irritation) in bowel to promote accumulation of water and electrolytes and stimulation of intestinal motility. Proposed mechanisms include activation of prostaglandin-cAMP and NO-cGMP pathways. Usually active within 6-10 hrs orally or 15-60 min rectally. Effective, but potentially dangerous side effects (electrolyte / fluid deficiencies, severe cramping). Safe for chronic use in recommended doses, but most widely abused class. May be a 4-8-fold variation in the effective dose in individual patients, thus recommended doses may result in a lack of effect in some, but may produce cramping and fluid loss side effects in others

Answer 284

Castor oil contains a triglyceride that is hydrolyzed in the gut to ricinoleic acid, which then acts primarily in the small intestine to stimulate fluid/electrolyte secretion and speed intestinal transit. [The castor bean also contains ricin, an extremely toxic glycoprotein.]

Answer 285

Acts as stool-softener (facilitates admixture of aqueous and fatty substances). Role is primarily prevention. Used in patients with cardiovascular disease / hernia / postpartum patients. Often used in combination with stimulant laxative when initiating opioid analgesic therapy.

Answer 286

Lubricant (mineral oil, olive oil) that coats fecal contents preventing colonic absorption of fecal water. Use with caution in very young / elderly due to potential for aspiration into lungs.

Answer 287

Peripherally acting opioid antagonists. Option for patients taking opioids for non-cancer pain that have failed laxative therapy. Given SC, doesn’t cross BBB. Expensive ($700 per day)

Answer 288

Peripherally acting opioid antagonists. Option for patients taking opioids for non-cancer pain that have failed laxative therapy. New pegylated derivative of naloxone given orally ($10 per day). Extensive first-pass metabolism - primarily binds opioid receptors in GI tract only

Answer 289

Drugs that can be associated with diarrhea as a side effect - misoprostol, antibiotics (esp. broad spectrum), muscarinic agonists, SSRIs, colchicine, NSAIDs, and digoxin.vProducts are available to treat the symptoms, cause (bacteria), or effects (loss of fluids and electrolytes) of diarrhea. Many patients with sudden onset of diarrhea have a benign, self-limiting illness that requires no treatment or evaluation. In severe cases involving infants, children, and the elderly, the principal concern is extreme fluid and electrolyte loss. Primary treatment is oral rehydration therapy. Agents discussed below do NOT generally address the underlying pathophysiology of diarrhea, but provide symptomatic relief of mild cases of acute diarrhea. The majority of these products are available over-the-counter.

Answer 290

Several different mechanisms that are mediated via opioid receptors, including effects on intestinal motility (μ), intestinal secretion (δ), and absorption (μ and δ). Loperamide also has anti-secretory activity against cholera toxin. Loperamide is effective against traveler’s diarrhea, alone or in combination with antimicrobial agents. Use should be discontinued if no improvement in 48 hours. Side effectsz: Low addiction liability due to low water solubility (difficult to dissolve and then inject); Few adverse effects but overdosage can cause CNS depression (esp. in children) and paralytic ileus; May worsen Shigella infections

Answer 291

Recognized by FDA as safe and effective (marked capacity to bind free fecal water). Useful in diarrhea (absorbs 60X weight in H2O) and constipation (prevents fecal desiccation).

Answer 292

Kaolin, pectin, attapulgite, charcoal, bismuth subsalicylate (Pepto Bismol, Kaopectate). Rationale is to adsorb “toxins” that cause irritation (of doubtful value); can also adsorb drugs, nutrients, digestive enzymes. Generally, take after each loose bowel movement until diarrhea controlled. Can usually manage mild to moderate diarrhea (promote “formed stools” and perception of decreased fluidity, but small effect on fluid volume excreted). Avoid use of bismuth subsalicylate in children under 12 (salicylate risk for Reye’s syndrome)

Answer 293

IBS is an idiopathic, chronic relapsing disorder characterized by abdominal discomfort (pain, bloating, distention, or cramps) along with alterations in GI motility (diarrhea, constipation, or both).

Answer 294

Aimed at relieving abdominal pain and discomfort (low dose tricyclic antidepressants) and improving bowel function (antidiarrheal agents [loperamide] if diarrhea or fiber supplements / osmotic laxatives if constipation) plus two classes of agents specifically for IBS.

Answer 295

Block of 5-HT3 receptors on sensory and motor neurons reduces pain and inhibits colonic motility. Low oral bioavailability (10%), should be taken on empty stomach. Renal excretion (66%) and hepatic metabolism (33%); should not be given to patients with severe renal or hepatic dysfunction. Use is now restricted (as is alosetron) to women under 55, approved for treatment of IBS patients with predominant constipation or chronic idiopathic constipation who haven’t responded to other treatments. Adverse reactions includes some diarrhea (10%) early in therapy that resolves within first few days of treatment. Linked with heart attacks, strokes, and unstable angina leading to restricted use.

Answer 296

Gluten (wheat, barley, rye) digested by luminal and brush-border enzymes exposure to α-gliadin peptide results in autoantibody formation, resulting in inflammation ( increased T-lymphocytes) leads to villous atrophy creating tissue damage and loss of mucosal and brush-border surface area causing malabsorption, diarrhea

Answer 297

Class II HLA-DQ2 or HLA-DQ8 allele. Association with other autoimmune diseases: Type 1 DM, thyroiditis, Sjögren syndrome

Answer 298

CLASSICAL: Bulky fatty diarrhea, flatulence, weight loss, anemia, nutritional deficiencies, growth failure in children. ATYPICAL: Minor gastrointestinal complaints but other stuff: anemia, dental enamel defects, infertility, arthritis. Celiac disease often presents with extra-intestinal complaints: Fatigue, Iron deficiency anemia, Pubertal delay, short stature, Aphthous stomatitis. Associated with dermatitis herpetiformis blistering skin disease. Increased incidence of lymphocytic gastritis, lymphocytic colitis. Celiac-disease associated malignancies include enteropathy-associated T-cell lymphoma (EAT Lymphoma), and small intestinal adenocarcinoma

Answer 299

endoscopy will show loss of surface villi. Serology will show IgA antibodies to tissue transglutaminase and anti-edumysial antibodies. Tissue biopsy will show villous blunting, increased intraepithelial lymphocytes, lymphoplasmacytosis of lamina propria.

Answer 300

Caused by gram-positive bacilli Tropheryma whippelii. Bacilli absorbed by lamina propria macrophages, which can be stained with PAS stain. Organism-laden macrophages accumulate within the small intestinal lamina propria and mesenteric lymph nodes causing lymphatic obstruction. Impaired lymphatic transport causes malabsorptive diarrhea. Tissue biopsy demonstrates the presence of the organisms

Answer 301

Triad of diarrhea, weight loss, malabsorption. Other common symptoms: arthritis, lymphadenopathy, neurologic disease. Typically presents in middle-aged or elderly white males

Answer 302

causes parasitic enterocolitis. Protozoan parasite causing sporadic or epidemic diarrhea, waterborne and foodborne. In US, water is a major source of transmission. Cysts are resistant to chlorine (filter necessary). 7-14 day incubation period. Chronic diarrhea, malabsorption, flatulence, weight loss, may cause intermittent symptoms. Flagellated protozoan decreases brush border enzymes. Can persist for years

Answer 303

Duodenal biopsy: identification of organisms in lumen Tear-drop shaped with two nuclei on each side of axoneme . Cyst in stool by immunofluorescence. Micro findings show Villous blunting but no ulceration; Intraepithelial lymphocytes; Numerous protozoa bound to brush border, but no invasion. Most often in duodenum, schools of fish

Answer 304

Mostly related to ingestion of contaminated water, food, or foreign travel. These infections typically create an acute self-limited colitis (except for cholera, typhoid, yersinia, and mycobacteria). Patients typically present several weeks after onset of symptoms, therefore tissue biopsy rarely shows classic acute infectious findings. Pathogens include Cholera, Campylobacter spp, Shigellosis, Salmonellosis, Enteric (typhoid) fever, Yersinia spp., Escherichia coli, Mycobacterial infection

Answer 305

Gram-negative bacteria; major cause of diarrhea worldwide. A leading cause of bacterial foodborne illness in US. Produces a watery diarrhea +/- blood. Found in contaminated meat (poultry), water and unpasteurized dairy. C. jejuni commonly associated with food-borne gastroenteritis. C. fetus more often seen in immunosuppressed patients

Answer 306

Gram-negative bacilli transmitted through food and water. Important cause of food poisoning and traveler’s diarrhea. Causes Typhoid (enteric) Fever (S. typhimurium). Symptoms include abdominal pain, headache, fever; abdominal rash and leukopenia; diarrhea (not until 2nd week of infection) initially watery then bloody; characteristic pathology most commonly seen in the ileum, colon, appendix and Peyer’s patches; perforation and toxic megacolon possible. Non-Typhoid Salmonella species are mild self-limited gastroenteritis. Endoscopy shows mucosal redness, ulceration and exudates

Answer 307

Non-invasive, therefore nonbloody diarrhea. Enterotoxigenic E. coli is a major cause of traveler’s diarrhea. Enteropathogenic E. coli is an infection of infants and neonates

Answer 308

Invasive (similar to Shigella) with symptoms of non-bloody diarrhea, dysentery-like illness, bacteremia. Transmitted via contaminated cheese, water, person-to-person contact. A cause of traveler’s diarrhea

Answer 309

Non-invasive, toxin-producing, contaminated hamburgers. Bloody diarrhea, severe cramps, mild or no fever, sometimes renal failure (HUS). On endoscopy: edema, erosions, ulcers, hemorrhage (right colon mostly) . Deadly outbreaks

Answer 310

Non-invasive, therefore nonbloody diarrhea. Similar to enteropathogenic E. coli, with chronic diarrhea and wasting in AIDS. Form a coating of adherent bacteria on surface epithelium of enterocytes

Answer 311

Most often caused by Clostridium difficile. Colitis often occurs after course of antibiotic therapy (“antibiotic-associated colitis”). Most frequently implicated antibiotics are third-generation cephalosporins. Common in hospitalized patients (up to 30%). Presents with fever, leukocytosis, abdominal pain, cramps, watery diarrhea.

Answer 312

Disruption of normal colonic flora by antibiotic allows C. difficile overgrowth and release toxins causing disruption of epithelial cytoskeleton, tight junction barrier loss, cytokine release and apoptosis

Answer 313

Pseudomembranes is adherent layer of inflammatory cells and mucinous debris at sites of colonic mucosal injury. Surface epithelium denuded, mucopurulent exudates. Microscopic findings show a “volcano-like” eruption of neutrophils and mucinous debris attached to the surface epithelium

Answer 314

Cytomegalovirus (mouth – anus), Herpesvirus (esophagus and anorectum), Enteric Viruses, Rotavirus

Answer 315

Most common cause of severe childhood diarrhea and diarrheal mortality worldwide. Children between 6 – 24 months are most vulnerable. Selectively infects and destroys mature enterocytes, causing the villus surface repopulated by immature secretory cells, leading to loss of absorptive function, allowing net secretion of water and electolytes, leading to osmotic diarrhea and DEHYDRATION. Two vaccines now available, previous vaccine increased risk of intussusception

Answer 316

Prevalent pathogens in tropic and subtropical countries. Diagnosis is primarily by examination of stool samples. Microscopic findings show flask-shaped ulcers with organisms in the mucous/fecal material

Answer 317

10% of world’s population is infected with E. histolytica parasite. Associated with a severe dysentery-like, fulminant colitis. Can disseminate to other sites (liver). Cecum most commonly affected; “flask-shaped” ulcers in mucosa. Microscopic findings show flask-shaped ulcers with organisms in the mucous/fecal material

Answer 318

Most common method of diagnosing is by examination of stool for ova and parasites. Worldwide distribution, many people multiply infected. Cause of serious disease in nations with deficient sanitation systems, poor socioeconomic status and hot, humid climates. Seen in immigrants, patients who travel to endemic areas. Nutritional problems can be severe or life-threatening, especially in children

Answer 319

One of most common parasites in humans. Most common in tropics. Ingested from soil contaminated with feces. Obstruction, perforation, growth retardation. Giant worms (up to 20cm) can be identified

Answer 320

withered, atrophic crypts and lamina propria fibrosis

Answer 321

collagenous colitis shows thickened subepithelial collagen layer. Lymphocytic colitis show increased intraepithelial lymphocytes.

Answer 322

Neither CD nor UC is considered to be an autoimmune disease. Colitis results from a combination of defects: Host interactions with intestinal microbiota; Intestinal epithelial dysfunction (Defects in intestinal epithelial tight junction barrier function); Aberrant mucosal immune responses. The mucosal immune response is T-cell mediated and Dysregulation of immunoregulation: pro- and anti-inflammatory cytokines

Answer 323

With active IBD, there is cryptitis and crypt abscess. With chronic IBD, there is crypt architectural distortion. With crohn's disease there is transmural chronic inflammation and transmural lymphoid aggregates. UC shows chronic inflammation restricted to mucosa. Distinguishing features with crohn's disease includes granulomas and fissuring ulcers.

Answer 324

Diverticular outpouching lined by mucosa, submucosa, and variable amounts of muscularis propria = diverticulosis. Mucosa is compressed/flattened. In diverticulitis the diverticulum becomes infiltrated with acute, then chronic inflammatory cells, and as the inflammation extends, the mucosa ulcerates and pericolonic abscesses, or sometimes fistula form.

Answer 325

Luminal obstruction by stone-like mass of stool “fecalith”, causing ischemic injury and stasis of luminal contents, leading to inflammatory response. Most common in adolescents and young adults. Lifetime risk for appendicitis is 7%. M>F. Classic finding is McBurney’s sign, tenderness located 2/3 of the distance from the umbilicus to the right anterior superior iliac spine. Often presents as an acute abdomen. Appendectomy is treatment of choice; often laparoscopic.

Answer 326

Mucosal ulceration. Transmural acute and chronic inflammation. Extension of inflammation into the mesoappendix

Answer 327

a yellow liquid with amphopathic properties that contributes to excretion of various compounds (cholesterol, copper, medications) and lipid digestion within the small bowel. It contains water, bile acids, cholesterol, phospholipids, lecithin, and electrolytes. Bile acids are the main active ingredient and contribute most to lipid digestion. Bile is synthesized by hepatocytes and secreted into the cannaliculi, which drain into the peripheral intrahepatic bile ducts. These eventually coalesce into the right and left hepatic ducts, which fuse to form the common hepatic duct. During the fasting state, parasympathetic vagal tone and cholecystokinin levels are decreased. Thus, the sphincter of Oddi remains closed, and gallbladder and bile duct peristalsis are inhibited. During this state bile will flow proximally up the cystic duct and into the gallbladder.

Answer 328

The gallbladder serves as a bile reservoir. It is a bag-like structure composed of columnar epithelium, a thin fibromuscular layer, and serosa. Gallbladder bile becomes 5-10x more concentrated during fasting. Sodium is actively transported from the lumen into the bloodstream, and water follows passively. As a result, the composition of bile changes after it is synthesized but before it passes out of the bile duct. In the fed state, cholecystokinin levels and vagal tone increase, resulting in gallbladder and bile duct peristalsis, which results in transport of bile into the duodenal lumen where it is used in lipid digestion.

Answer 329

Gallstones form when there is too much cholesterol in bile, too little water, or both. Supersaturation of bile with cholesterol first results in formation of cholesterol crystals (microlithiasis) and eventually clinically significant stones. Numerous pathogenic factors contribute to lithogenesis including gallbladder or bile duct dysmotility (stasis), hereditary mutations in cholesterol chain structure, or inflammation in the gallbladder. In an individual patient with stones, multiple mechanisms are usually present.

Answer 330

cholesterol stones, brown stones, or pigment stones. Most stones have mixed features of more than one type. Cholesterol stones are composed mainly of cholesterol, bile acids, phospholipids, and lecithin. They are typically white or yellow in color and soft and greasy in consistency. They always develop within the gallbladder but may later spill into the bile duct or duodenum. They develop as a result of cholesterol and bile salt super-saturation, which occurs under various situations: genetic mutations in cholesterol side chains, bile acid hypersecretion, gallbladder stasis, or a combination. The risk factors for cholesterol stones include obesity, rapid weight gain or weight loss, female gender, age over 30, Latin American or Native American ethnicity, or estrogen/contraceptive use.

Answer 331

Pigment stones are composed predominantly of calcium bilirubinate salts which coalesce around a mucin nidus. They develop in patients with increased concentrations of bilirubin in the bile, especially those with hemolytic states such as sickle cell anemia. They are more common in Asian populations. They may develop de novo within the gallbladder or bile duct. They are typically black and hard in consistency. As with all types of stones, they may develop within an obstructed gallbladder (or bile duct) as a result of stasis. In Asia, they may also develop when there is chronic inflammation within the biliary tree, as in parasitic infections (e.g. clonorchis) or a condition in those from Southeast Asia known as oriental cholangiohepatitis.

Answer 332

Pure brown stones usually develop de novo within the bile duct as a result of infection in patients with prostheses (tubes or stents) or downstream obstruction, and these are often a hybrid of cholesterol and pigment stone crystals. These will not be discussed in this lecture.

Answer 333

the best initial diagnostic study for gallstones is abdominal ultrasound, which is cheap, safe, and readily available. It is very accurate (>90%) for gallbladder stones or cholecystitis. It is also extremely sensitive for assessing the bile duct diameter and thus detecting ductal dilation, which may or may not indicate a ductal stone. Its accuracy for visualizing bile duct stones is weaker, around 50%. CT scan may be considered if the cause of abdominal pain is unclear or if additional organs, particularly the pancreas or bowel, need to be evaluated. More expensive and invasive tests are available to assess or remove stones in the bile ducts. These include MRI of the biliary tree (magnetic resonance cholangiopancreatography or MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). Because it requires sedation and a small risk (5%) of pancreatitis, ERCP is usually reserved for those patients with frank cholangitis or a high probability of bile duct stones based on preliminary studies. However, the benefit of ERCP is its ability to treat disease effectively, e.g. removal of stones or placement of stents, in place of open or more invasive surgery.

Answer 334

Once a gallstone forms, it usually remains in the gallbladder as an innocent bystander and causes no complications or symptoms. A significant minority of stones, however, will move downstream and obstruct the gallbladder neck, cystic duct, or common bile duct. If a stone occludes the gallbladder intermittently, such as when a patient consumes a meal (particularly a fatty meal, which triggers cholecystokinin release), then symptoms of biliary colic may occur. Biliary colic is usually a dull or crampy pain in the epigastrium or right upper quadrant which occurs within an hour of eating and resolves spontaneously, typically within 3-5hours, corresponding to the time that cholecystokinin tone declines and/or offending stone/s moves back proximally.

Answer 335

Alternatively, a stone may lodge in the cystic duct and become impacted. If bacterial superinfection of the gallbladder lumen also occurs, this may result in acute (calculous) cholecystitis, which is severe inflammation and/or ischemia of the gallbladder, usually associated with infection. Patients with acute cholecystitis usually report severe pain localized to the right upper quadrant, which may radiate to the right flank or shoulder. On physical exam, this commonly results in a focal tenderness to deep palpation of the right upper quadrant, and when the examiner performs this palpation during exhalation the patient will stop exhalation suddenly. This finding is known as the Murphy’s sign and is strongly suggestive of acute cholecystitis.

Answer 336

Like acute pancreatitis, cholecystitis usually requires hospitalization for pain control. Patients are treated with intravenous fluids, nothing-by-mouth (gallbladder rest), intravenous antibiotics, and pain medications. Unless the patient is too ill or unstable for surgery, surgical removal of the gallbladder (cholecystectomy, usually done via a laparoscopic approach) is the treatment of choice and should be performed within 1-2 weeks. Cholecystitis or gallbladder stones do not typically results in significant elevations in liver chemistries or biliary obstruction. A rare exception, however, is the phenomenon known as Mirizzi’s syndrome. In Mirizzi’s, a stone lodged in the cystic duct causes severe, localized edema and inflammation to develop in the region, which leads to benign obstruction of the common bile duct or common hepatic duct. Alternatively, when cholecystitis leads to severe, gaseous distention (hydrops) of the gallbladder and the gallbladder sits over or immediately adjacent to the bile duct, the enlarged gallbladder may lead to extrinsic compression of the common bile duct or common hepatic duct. These complications of cholecystitis resolve after cholecystectomy.

Answer 337

a condition similar to calculous cholecystitis, however there is no obstructive stone and usually no infection. Rather, inflammation and/or necrosis of the gallbladder develop as a result of ischemia (vascular insufficiency). Most commonly this occurs in states of generalized hypoperfusion such as sepsis, severe trauma or burns, myocardial infarction. It may also occur in patients with vasculitis involving the cystic artery, with polyarteritis nodosa being the classic example.

Answer 338

Gallstones may also migrate through the cystic duct and into the common bile duct, a phenomenon known as choledocholithiasis. If they are too large to pass through the ampulla, they may cause bile duct obstruction, acute pancreatitis, or both. Symptoms of choledocholithiasis without pancreatitis usually include epigastric or right upper quadrant pain, jaundice, and dark urine.

Answer 339

If bacterial infection develops within the bile duct above an obstructing stone, ascending cholangitis may occur. This is a life-threatening condition, and patients are at risk of developing sepsis very quickly. The typical symptoms of ascending cholangitis comprise Charcot’s triad: right upper quadrant pain, jaundice, and fever. If it progressed, sepsis may develop and result in hypotension, confusion, kidney failure, or death (Reynold’s pentad = Charcot’s triad plus confusion and hypotension). Ascending cholangitis is an emergency and requires admission to the hospital and intravenous antibiotics. Urgent endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction or stent placement is usually necessary.

Answer 340

Over time, gallstones may produce chronic inflammation in the gallbladder, a condition known as chronic cholecystitis. This is usually clinically silent and follows repeated episodes of mild cholecystitis. This increases the risk of gallbladder cancer. Nearly all patients with chronic cholecystitis have gallstones (>90%). Chronic cholecystitis causes marked thickening and fibrosis of the wall of the gallbladder. Histologically, there are numerous chronic inflammatory cells (lymphocytes, plasma cells, macrophages), with few if any PMNs, in the submucosa.

Answer 341

a gland-forming epithelial cancer that usually develops in patients with gallstones and chronic cholecystitis, which are the two well-established risk factors. In Asia, the risk of gallbladder carcinoma is also linked to super-injection with parasites (liver flukes). The 5-year survival is less than 10%. Some exhibit a pattern of exophytic growth and fill the lumen of the gallbladder. Others will lead to prompt obstruction of the gallbladder neck or cystic duct and get diagnosed earlier, after the gallbladder is removed because of cholecystitis. Most cases of gallbladder cancer present late because the tumors do not obstruct a critical duct. They may cause symptoms late by invading the liver inferiorly, the duodenum laterally, or the colon inferiorly. Like pancreatic carcinoma, gallbladder cancers commonly produce a thick stroma of connective tissue known as “desmoplasia.”

Answer 342

Ideally, treatment of gallbladder cancer involves surgical resection of the gallbladder and surrounding lymph nodes. A partial liver resection may sometimes be necessary. Because many patients present late, with advanced disease, surgery is typically non-curative or ineffective. Palliative measures should be offered to these patients, including pain control and possibly ERCP with stent placement.

Answer 343

Rarely, a large gallbladder stone may cause chronic obstruction and inflammation of the gallbladder, then adhesion of the inflamed gallbladder to adjacent small bowel, fistulization (abnormal connection) between the gallbladder and small bowel, migration of the stone into the small intestine, and subsequent obstruction of the ileocecal valve by the stone. This is a rare scenario known as gallstone ileus.

Answer 344

Benign biliary strictures (BBS) are caused by edema and fibrosis (scarring). They may be single or multiple, short or long, and may occur anywhere in the biliary tree. Differentiating benign from malignant is critical since the treatment and prognoses are usually different.

Answer 345

BBS are often associated with chronic choledocholithiasis. Chronic inflammation of the bile duct wall adjacent to a stone is the presumed pathogenesis in this situation. Conversely, strictures can also predispose to stone formation upstream as a result of cholestasis. BBS may be iatrogenic (caused by surgical procedure misadventures), typically during a laparoscopic cholecystectomy when cautery injury damages the bile duct or a surgical clip is indadvertently placed over a duct other than the cystic duct. BBS may also be caused by radiation. Another common cause of BBS is chronic pancreatitis (CP). In severe CP, the distal common bile duct may be narrowed as a result of severe fibrosis in the surrounding pancreatic head. These mainly occur in the setting of severe, calcific CP with pancreatic duct stones, when the pancreas is severely fibrotic, hard, and shrunken. CP-related strictures are usually refractory to standard endoscopic treatment (ERCP with dilation or stents) because of their rigidity and prompt referrals to Surgery. Autoimmune pancreatitis may cause BBS. Rare causes of BBS include AIDS cholangiopathy (which can mimic PSC), oriental cholangiohepatitis, and biliary parasites. These will not be discussed further.

Answer 346

an unusual cause of BBS that can occur when there is an impacted stone in the cystic duct or severe gallbladder distension (hydrops), both of which are associated with acute cholecystitis.

Answer 347

Primary sclerosing cholangitis (PSC) is an idiopathic, intra- and extrahepatic inflammatory disorder causing numerous BBS throughout the biliary tree. It predominantly affects Caucasian males ages 30-60. The gallbladder is usually spared, for unclear reasons. Most cases of PSC are associated with inflammatory bowel disease (IBD), usually ulcerative colitis. The course of PSC is independent and often different from the course of IBD. Strictures are typically multifocal and progressive. Patients with PSC have a high risk of developing cholangiocarcinoma within the affected areas. About half of patients with PSC will have some progression in their strictures and will develop liver fibrosis and/or cirrhosis. There is no effective medical therapy that affects the natural history of PSC although ursdodeoxycholic acid may alleviate pruritus and other symptoms.

Answer 348

Typically, when BBS are severe enough to result in symptoms, they cause bile stasis or cholestasis: jaundice, dark (bilirubin-rich) urine (also known as choluria), pruritis (itching) from the systemic retention of bile acids, and occasionally acholic (gray or white-colored, from absence of bilirubin) stools. They may also cause RUQ abdominal pain or recurrent cholangitis, with attacks of pain, fever, and/or jaundice. Cholangitis is most common in the setting of multiple strictures, PSC in particularly, particularly after ERCP or when the biliary tree has been instrumented. Occasionally, BBS are found incidentally on imaging studies performed for other (non-biliary) reasons, when a dilated biliary tree or segment of the bilary tree is seen. BBS may also be detected incidentally on blood tests (liver chemistries, particularly GGT or alkaline phosphatase).

Answer 349

The diagnosis of BBS may be suggested by non-invasive imaging such as ultrasound or CT scan, which illustrate dilation of the bile duct/s proximal to the stricture. Occasionally, the stricture itself is seen on CT. The diagnosis is confirmed by MRCP or ERCP, with ERCP also being able to test for cholangiocarcinoma at the same time by biopsy of the stricture/s. Liver biopsy is sometimes performed to assess the degree of liver damage (fibrosis); in ~ 25-30% of cases, the classic finding of concentric fibrosis around the bile ducts (“onion-skinning”) may be seen.

Answer 350

The treatment of benign biliary strictures usually involves ERCP. Dilation of the BBS (with a balloon or tapered dilator) or stent placement across the stricture may be performed during ERCP, and biopsies also be taken to help differentiate BBS from malignancy. If the stricture responds to these therapies, stents can usually be upgraded and eventually removed and the patients may have no further symptoms. In patients who have had gastric surgery or are otherwise not candidates for ERCP for whatever reason, percutaneous transhepatic cholangiography (PTC, which is performed by Interventional Radiology) may provide diagnosis and therapy similar to an ERCP but with the downside of higher procedural risk (since the skin and liver are punctured), and patients have to wear a plastic tube/bag that exits the skin and is clipped to the waist. Patients with severe, refractory BBS may need to be referred for surgery or undergo repeated stent changes indefinitely. Surgery involves either a resection of the stricture or, more commonly, bypass of the obstructed segment. In PSC, the same treatments apply, but there is also a need to rule out cholangiocarcinoma for any dominant or worsening strictures. Patients with PSC and cirrhosis who develop liver failure should be evaluated for liver transplantation as this is the only effective treatment. In addition to these therapies, patients with BBS may need medicine to control pruritus (H1-antagonists, cholestyramine, opiate antagonists, or ursodeoxycholic acid), but there is no benefit of medicines on the BBS itself.

Answer 351

Malignant biliary strictures (MBS) include adenocarcinoma of the ampulla (of Vater), pancreatic head cancer (discussed previously), cancer of the biliary epithelium (cholangiocarcinoma), gallbladder carcinoma (discussed above), metastases to the liver or hilum, and occasionally hepatocellular carcinoma.

Answer 352

The most common symptoms of MBS include cholestasis, i.e. jaundice, choluria, pruritus, and acholic (white or gray-colored) stools. Abdominal pain may develop later in the course as a result of nerve invasion, capsule distension, or visceral obstruction. Pancreatic cancers rarely cause acute pancreatitis.

Answer 353

Except for ampullary carcinoma, MBS usually present late in their course, after they have become unresectable. Early MBS, particularly ampullary cancer, may be effectively treated with surgery, which involves a Whipple’s resection (surgical removal of the head of the pancreas, duodenum, common bile duct, gallbladder, and sometimes pylorus) or transduodenal excision. ERCP with palliative metal stent placement is offered to the remaining majority. When ERCP fails because of a large or severely obstructive tumor, percutaneous drainage of the bile duct may also alleviate cholestasis. Chemotherapy and radiation are offered to patients with MBS with regionally advanced or metastatic tumors, either for palliation or, occasionally, to reduce the tumor burden to a surgically resectable stage. With rare exceptions, chemotherapy and/or radiation alone may give 3-6 months of survival to the patient but do not result in a cure or long-term remission.

Answer 354

The sphincter of Oddi is the muscular sphincter that regulates opening and closing of the biliary orifice. It is comprised of 3 parts: a 3-4mm common sphincter, 2-3mm biliary sphincter, and a 1-2mm pancreatic sphincter. Under normal conditions the sphincter relaxes (under nitric oxide and beta-adrenergic control) during the fed state and contracts (under cholinergic control) in the fasting state.

Answer 355

For unclear reasons, the sphincter may contract episodically and lead to various complications in patients at risk. Patients with SOD are usually (> 80%) females ages 20-55. Complications include episodic epigastric or RUQ pain, elevations in liver or pancreatic chemistries, recurrent pancreatitis, and dilation of the bile or pancreatic duct by imaging. The diagnosis is suspected after a careful history (symtoms mimic biliary colic), usually in patients who have had a cholecystectomy. The diagnosis is supported by dynamic elevations in the liver chemistires (usually during attacks of pain) or dilation of the bile duct by ultrasound.

Answer 356

There are 3 types (type I, type II, type III) depending on the severity of obstruction but these will not be discussed further. The diagnosis can be confirmed during ERCP by measuring the pressure within the sphincter with sphincter of Oddi manometry (see image below), however the accuracy of this test between attacks of pain is variable. Otherwise, the treatment is ERCP-guided biliary, pancreatic, or combined sphincterotomy. This carries a risk of post-ERCP pancreatitis of ~ 10-20% in these patients and the benefits of the procedure should be weighed carefully against the risks, given that SOD does not lead to death or liver failure. Biliary (or pancreatic) stents, medications, and surgery are rarely used nowadays because of poor efficacy, side effects, and/or uncertain duration of treatment.

Answer 357

Site: Upper small bowel. Pathogens: Norwalk, Rotavirus, Giardia, Cholera, ETEC

Answer 358

Site: Colon. Pathogens: C. jejuni, Shigella, Salmonella, E. coli O157:H7, C. difficile, E. histolytica,

Answer 359

Vibrio cholerae, Enterotoxigenic E. coli, Rotavirus, Norwalk virus, Giardia lamblia

Answer 360

cases are sporadic, usually in the winter, occasionally epidemic. Common in infants and young children. Transmitted through fecal-oral route. Duration of illness usually lasts 5-8 days.

Answer 361

Commonly seen as family and community epidemics, often seen in winter. Affects older children and adults. transmitted through fecal-oral route, contaminated shellfish and water. illness lasts 1-2 days.

Answer 362

Causes vast majority of hemorrhagic colitis (and HUS) in U.S. Illness lasts 2-4 days (

Answer 363

Verotoxin Shiga-like toxin (SLT-I/II). Binds especially to human renal endothelial cells. Inhibits protein synthesis. Antibiotics may increase toxin release.

Answer 364

C. difficile is the leading, and virtually the only, cause of nosocomial infectious diarrhea. Culturing for other agents in this setting is not indicated. Most commonly associated with antibiotic use. Symptoms may be mild diarrhea, watery or bloody, or may have fever, leukocytosis with severe colitis

Answer 365

Site: Nodes; Blood;Gallbladder Pathogens: Salmonella typhi, S. paratyphi, ±Yersinia

Answer 366

Histopathologic term for inflammation and fibrosis of the gallbladder with poor correlation to clinical symptoms. Pathogenesis is not well established but 95% are associated with gallstones

Answer 367

Congenital dilatation of the common bile duct.

Answer 368

Stones (gallstones, kidney stones) in the abdomen have characteristic locations. They can also have distinctive radiographic structures in their shadows. Calcified gallstones are typically laminated due to forming over long periods of time and faceted due to being multiple and rubbing against one another with the contractions of the gallbladder. Only about 10% of gallstones are shown to be calcified and visible on plain films.

Answer 369

Calcifications in the wall or capsule of an organ usually have an eggshell appearance and are denser peripherally where they are caught tangential to the x-ray beam. Plaque in the walls of arteries can also calcify and have appearances which can be interrupted parallel lines or tubular and serpiginous depending on the course of the vessel. Phleboliths are round calcifications with lucent centers often seen in the pelvis. They are calcifications within a vein and generally of no clinical significance but can sometimes be difficult to differentiate from a ureteral stone.

Answer 370

Gas or air can be seen in the stomach, small and large intestine. The stomach air bubble (if present) is usually seen in the left upper quadrant (LUQ). It can also be seen above the diaphragm if the patient has a hiatal hernia. On a supine film, the air rises into the more anterior body of the stomach whereas it rises to the posterior fundus on a prone film. Small bowel and colon can be differentiated by location with the colon be typically more peripheral. However, that is not always reliable especially if the patient has had surgery or if malrotation or a volvulus is present.

Answer 371

The small bowel often contains fluid and it is not uncommon to have scattered air-fluid levels. The presence of an air-fluid level by itself is not pathologic. Small bowel has valvulae conniventes, which have a characteristic fold pattern that can be differentiated from the appearance of the haustral indentations/folds present in the colon. Valvulae conniventes are more numerous, more narrowly spaced, and cross the lumen from one side to the other. Sacculations of the colon (formed by the longitudinal muscles (taenia coli) and circular muscles) = haustra of the colon. Haustral markings should not cross the entire diameter of the lumen.

Answer 372

With a bowel obstruction, the bowel proximal to the site of the obstruction will distend and dilate. The hallmark of obstruction is dilatation of the bowel. If the bowel is dilated all the way to the anorectal junction, the obstruction is functional. In a mechanical obstruction, a compensatory increase in peristalsis will develop and eventually result in the clearing of air distal to the point of obstruction. In an early small bowel obstruction, not enough time might have occurred for the air to clear distal to the obstruction or from the colon and hence there might be dilated loops of small and large bowel.

Answer 373

Gas in dilated small and large bowel is also the appearance of a generalized ileus. How do you tell the difference? History might help as generalized adynamic or paralytic ileus occurs in post-operative patients. Bowel sounds should also be absent or hypoactive. Time is also an important factor as x-rays capture a snapshot in time. Serial films should help to clarify the clinical picture. With a large bowel obstruction, usually there is only dilated colon. However, if the ileocecal valve is incompetent, it can allow air to decompress backwards into the small bowel.

Answer 374

Gas or air can also be seen in the bowel wall (pneumatosis), biliary system (pneumobilia), and in the portal vein. While the presence of air in these locations is abnormal, some causes can be benign. The most common cause of pneumobilia is prior surgical or endoscopic intervention.

Answer 375

on x-rays, you are able to see differences and interfaces/contours/silhouettes when you have two different densities next to one another. Fat distributions in the abdomen help you visualize the structures they invest. For example the intra-abdominal fat can be seen as a dark band outlining the inferior margin of the liver (soft tissue density) or the psoas muscle (soft tissue density). These fat planes can disappear due to pathology, which can cause inflammation resulting in edema/fluid (soft tissue density). Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) can sometimes be identified on plain films. Mass effect is the displacement of structures such as bowel away from their normal locations. This can be caused by tumors or enlarged organs.

Answer 376

GI fluoroscopy studies include: Barium swallow, Esophagram, Upper GI, Small bowel follow through (SBFT), Enteroclysis, and Barium enema

Answer 377

Contrast agents are used to opacify the lumen and include air, thin (low density) and thick (high density) barium, and water-soluble contrast. Barium should not be used or given orally upstream of a colon obstruction as it can become impacted. The small amounts of barium that enter the larynx and lungs with swallowing dysfunction do no harm as barium is not inherently toxic to lung tissue. The major indication for iodinated water-soluble contrast is possible gut perforation. Extravasation of water-soluble agents into the peritoneum and retroperitoneum is safer than barium. Iodinated water-soluble contrast is either high osmolality or low osmolality. Avoid use of high osmolality (Gastrografin® and Gastroview) in patients with proximal GI obstruction as aspiration can lead to life-threatening pulmonary edema.

Answer 378

Barium swallow is a general term for fluoroscopic-radiographic contrast exam of oral, pharyngeal, and/or esophageal swallowing. There are different types of exams (pharynx dynamic and static imaging, modified barium swallow, biphasic esophagram) that can be tailored to the patient depending on the indication and clinical setting. As a single test, a barium swallow can evaluate the 3 phases of swallowing: oral, pharyngeal, and esophageal and structural and functional abnormalities of the oral cavity, pharynx, and esophagus. For retrosternal dysphagia, the symptom might result from esophageal motility disorders or from structural abnormalities such as esophagitis, rings, strictures, or tumors. The barium swallow study performed on these patients is a biphasic esophagram. Upright views using a double-contrast technique of air and high density barium assess for mucosal disease and prone single contrast views with low density barium assess for distensibility, motility, and the presence of a hiatal hernia.

Answer 379

Upper GI is the fluoroscopic-radiographic contrast exam that examines the esophagus, stomach, and duodenum using both single contrast and double contrast (air + contrast [barium]) techniques. Air is usually introduced by having the patient swallow carbon-dioxide producing crystals. The various parts of the esophageal, gastric, and duodenal anatomy are best evaluated in different views and the patient must change positions in order to move the air and barium to coat these areas and produce optimal visualization.

Answer 380

Evaluation of the jejunum, ileum, and terminal ileum can be performed with a small bowel follow through (SBFT) and enteroclysis. A SBFT is often combined with the upper GI. In the SBFT portion, spot or supine abdomen radiographs are obtained at timed intervals (15-30 mins.) until the barium reaches the colon. Areas of interest or concern can be evaluated fluoroscopically with a compression paddle to try to separate areas of overlapping loops of bowel.

Answer 381

Enteroclysis is the gold standard of small bowel imaging but is not as well tolerated by patients, is more costly, and has a higher radiation exposure than SBFT. It allows for double contrast examination of the jejunum and much of the ileum. A tube must be placed into the jejunum and after barium is injected, methylcellulose or air is then instilled. The routine exam for the small bowel is SBFT and enteroclysis is reserved for situations when superior anatomic information is needed.

Answer 382

Contrast or barium enema (BE) is the fluoroscopic-radiographic test to evaluate the colon and rectum. An enema tube with a rectal tip and balloon is inserted into the rectum. In a single contrast exam, only barium is instilled into the patient. For a double contrast study, the colon is distended with both barium and air. While holding in the barium, the patient moves in various positions in order for the barium and air to travel retrograde to the cecum and obtain optimal x-ray images to evaluate all portions of the large intestine. Adequate bowel prep is needed as stool can mimic or obscure pathology. If there is a risk for perforation, water-soluble contrast can be used. Contrast enemas should not be performed immediately after an endoscopic biopsy or in toxic megacolon due to the danger of perforation or in a patient with suspected acute perforation.

Answer 383

Ultrasound in the GI system is typically used to evaluate the abdominal organs and biliary system. Except for suspected appendicitis and specific pediatric indications, ultrasound is not widely used in the United States to evaluate the GI tract. Ultrasound uses sound waves to create images rather than ionizing radiation that is used to obtain x-ray and CT images. Air is not a good window for ultrasound and usually produces “dirty shadowing” and poor/no visualization of structures posterior to air or air-filled structures. Ultrasound is also operator dependent and more dependent on body habitus than CT or MRI.

Answer 384

Computed tomography (CT) of the abdomen and/or pelvis is widely used to evaluate causes of abdominal pain and indications related to the GI system. Conventional barium examinations remain superior to CT (and MRI) for evaluating motility, intraluminal, and mucosal disease of the GI tract but advancements are continuing to be made with techniques such as CT enterography (enteric contrast administered orally) and CT enteroclysis. CT is better for evaluating the intramural component of the bowel and allows evaluation of the adjacent mesentery, omentum, retroperitoneum, peritoneal cavity, and viscera.

Answer 385

Intravenous (IV) contrast improves evaluation of the bowel wall, solid organs, and vascular structures. However in certain circumstances it can mask abnormalities such as identification of renal stones, subtle calcifications, or hemorrhage. Thus it is extremely important to provide the radiologist with pertinent history and information about the clinical question so the study can be appropriately protocoled. If you have any questions, ask the radiologist! There are risks associated with the administration of IV contrast as it is nephrotoxic and patients can have allergic reactions. Depending on the type/severity of the contrast reaction and the necessity for IV contrast, patients can be premedicated for a contrast CT scan. A baseline serum creatinine and glomerular filtration rate (GFR) should be available or obtained before the injection of contrast medium in patients at risk for nephrotoxicity (see below).

Answer 386

MRI is another cross-sectional imaging modality used to evaluate the GI system but has mainly been used to evaluate the solid organs and biliary tract. MRI use for the GI tract and peritoneum continues to increase as advances in MR imaging hardware and software overcome the challenges presented by motion artifact and long examination times. Enterography and enteroclysis techniques optimize bowel distention. CT and MRI enterography/enteroclysis are not limited by overlapping bowel loops as occurs with fluoroscopic-radiographic contrast exams.

Answer 387

MR (and CT) cholangiopancreatography are employed in the assessment of the hepatobiliary and pancreatic ductal systems for evaluation of strictures, stones, and neoplasms.

Answer 388

IV contrast agents used in MRI are gadolinium-based. According to the ACR Contrast Manual, gadolinium agents are considered to have no nephrotoxicity at approved dosages for MR imaging however there is a risk of nephrogenic systemic fibrosis (NSF) in patients with severe renal dysfunction.

Answer 389

Nuclear medicine imaging has been used in the evaluation of practically every GI problem but improvements and widespread use of endoscopy, manometry, and other imaging techniques (US, CT, MRI) have limited their application to specific clinical problems. Nuclear medicine studies involve injection of a radioactive dose or swallowing of a substance followed by imaging. Spatial resolution is low and imaging times can be long, sometimes up to 1 hour or more.

Answer 390

Angiography/Interventional radiology is used for numerous indications related to the GI system. Its use is more widespread for therapeutic purposes but in some instances it is used for diagnosis. These include: GI bleeding, Biliary obstruction, Image-guided biopsy, Abscess drainage, Feeding tubes, Portal hypertension, IR oncology

Answer 391

This congenital lesion is present in roughly 1 in 3000 live births and manifests most commonly as a connection of distal esophagus and trachea that occurs in the setting of esophageal atresia. The result is that the proximal esophagus ends in a blind pouch and the distal esophagus is open into the trachea. The majority of these infants have other congenital abnormalities including cardiac defects (e.g. ventricular septal defect), genitourinary anomalies (e.g. renal agenesis), gastrointestinal malformations (e.g. imperforate anus), or musculoskeletal abnormalities (e.g. polydactyly). During intrauterine life, polyhydramnios is very common and lack of stomach gas on prenatal ultrasound is an indication of this abnormality. The clinical presentation is typically soon after birth. Infants have episodes of coughing and choking with symptoms worsening at feeding. Feeding may lead to aspiration and infection (pneumonia). Surgical correction is usually required during the first days of life although some patients with very small fistulae may occasionally present later in childhood or even as adults.

Answer 392

This lesion is more common in male than female infants and can occur in up to 1 in 200 live male births. Although a familial tendency has been noted, both hereditary and environmental factors are thought to be important in the etiology. Structurally, there is hypertrophy and hyperplasia of the smooth muscle in the gastric wall at the level of the pylorus that leads to narrowing of the antrum that can cause near complete obstruction. The proximal stomach is typically secondarily dilated. The typical clinical presentation is with projectile vomiting that generally occurs at approximately 3 weeks of age.

Answer 393

This is the most common congenital malformation of the small intestine and can occur in up to 4% of the population (most references site 2% as the incidence). The lesion is usually asymptomatic. Structurally, it arises due to partial persistence of the vitelline (omphalomesenteric) duct or yolk stalk. A small blind pouch forms that protrudes from the terminal ileum and typically measures 2 to 3 cm in length and width. Sometimes persistence of the duct occurs with a thin sinus tract or fibrous band extending to the umbilicus that may cause small bowel obstruction. The wall of a Meckel Diverticulum often contains gastric mucosa which may undergo such typical gastric diseases as peptic ulceration.

Answer 394

This rare malformation is caused by a failure of the intestines to return from the extraembryonic celom to the abdominal cavity at 10 weeks of gestation. An omphalocele consists of a defect in the abdominal wall at the attachment site of the umbilical cord. A large sac composed of amnionic membranes is filled with loops of bowel. Gastroschisis is superficially similar (bowel protruding from the abdomen), but occurs by a different mechanism. In gastroschisis, the cause of the bowel protrusion is a paraumbilical defect in the abdominal wall.

Answer 395

This important anomaly of the large intestine occurs during development when the intestines are prevented from assuming their normal position inside the abdomen. This usually occurs as the intestines are returning to the abdominal cavity just after 10 weeks gestation. Most patients are asymptomatic, but the typical presentation is with volvulus of the large bowel.

Answer 396

These lesions are saccular or tubular portions of bowel that recapitulate normal histological relationships. They present as cystic mass lesions or may lead to intestinal obstruction. These cysts may or may not retain a communication with the lumen of the bowel.

Answer 397

Stenosis refers to congenital narrowing of the bowel whereas atresia refers to complete failure of development causing a blind ending. These lesions are uncommon and generally occur along with other malformations as part of a malformation syndrome or in the setting of cystic fibrosis. Usually, only a segment of bowel is involved and vascular insufficiency during development is a likely cause.

Answer 398

This malformation occurs with a spectrum of severity ranging from a thin membrane of tissue covering the anus to the worst disease which is complete agenesis of the rectum. More severe forms are often associated with other cloacal or urogenital abnormalities.

Answer 399

This disease is also referred to as congenital megacolon due to the massive dilatation of the intestinal lumen which is the most prominent clinical feature. Usually children are detected by a failure to pass meconium soon after birth. When only short segments of bowel are involved, presentation may be delayed until later in life occasionally due to perforation of a distended megacolon. The disease occurs more commonly in male infants with a sex ratio of M:F=4:1. The disease is caused by a number of mutations most of which are in RET receptor or ligand genes that control development of the nervous plexi of the colon. Endothelin 3 and endothelin receptor genes are also important regions of mutation. These mutations lead to failure of the bowel nerve plexi (both Auerbach and Meissner) to form in a segment of the bowel wall with a resulting absence of ganglion cells. Usually, there is a constricted segment of bowel lacking ganglion cells that begins in the rectum and extends a variable distance proximally. The normally innervated bowel upstream of the aganglionic segment is typically dilated. Treatment is by surgical resection of the abnormal segment of bowel.

Answer 400

NEC mainly occurs as a complication of prematurity that develops in the first week to 10 days of life and is manifested by abdominal distension and bloody stools. Generally occurrence is associated with hypoxemia (such as in RDS) where blood is shunted away from the intestine to provide scarce oxygen resources to more important organs. Ishcemic damage to the bowel wall leads to invasion of organisms, formation of gas gangrene within the bowel wall (pneumatosis intestinalis) with subsequent perforation and peritonitis. Any part of the bowel may be affected although the most commonly involved areas are the terminal ileum, cecum, and right colon. Medical therapy includes bowel rest and antibiotics; if this fails, surgical resection of the involved bowel is performed.

Answer 401

Kids get many of the same gastrointestinal disease as adults, including inflammatory bowel disease and celiac disease; these are covered in other lectures. A common pediatric GI disease is esophagitis, of which most cases fall into two diagnostic categories. One is reflux esophagitis, which is most commonly caused by inadequate gastroesophageal sphincter function. Reflux esophagitis is accompanied by abnormal esophageal pH probe testing due to reflux of gastric acid, and responds to treatment with acid blocking drugs. The other diagnostic category is allergic, or so-called “eosinophilic”, esophagitis, which is caused by an immune reaction to dietary allergens. pH probe testing is normal in allergic esophagitis, and patients do not respond to acid blockade. Rather, this condition requires treatment with inhaled or oral steroids, and/or dietary modification if the allergen can be identified. Histologically, reflux esophagitis shows a mild intraepithelial infiltrate with eosinophils and associated reactive epithelial changes. The findings in eosinophilic esophagitis are similar, but the infiltrate is more severe, shows superficial epithelial accentuation and often extends into the submucosa where it may also be accompanied by fibrosis. Not surprisingly, the distribution of pathology in the esophagus is also different in these two diseases: reflux esophagitis is predominantly a distal esophageal process, whereas eosinophilic esophagitis usually involves the length of the esophagus with relative uniformity; this is a diagnostically helpful finding.

Answer 402

Non-Neoplastic Polyp. Often present with bleeding. Often due to mucosal prolapse (very common in the rectum). Cycles of injury and healing result in “polyp” formation = inflamed colonic mucosa with ulceration/erosion, epithelial hyperplasia

Answer 403

Non-Neoplastic Polyp. "Hamartomatous" polyps are a distinct subset of polyps, most occurring in childhood (pre-pubertal). Hamartoma are "tumor-like" over-growth / mature tissue / developing where it is normally present (e.g. colonic tissue developing in the colon). Types include Juvenile (sporadic and syndromic) and Peutz-Jeghers (syndromic). Polyps can be in variable locations in lower GI system. Benign features histologically but syndromic juvenile polyps often have foci of dysplasia. May portend: Risk of future GI carcinoma (increase frequency of screening), Both Peutz-Jeghers and Juvenile polyposis = 40% cumulative risk for CA; Extra-GI manifestations; Need to consider familial screening (genetic counseling) in some cases

Answer 404

present around ages 10-15. mutated gene is LKB1/STK11. Gastrointestinal lesions are arborizing polyps. Location in order of frequency: small intestine > colon > stomach; colonic adenocarcinoma. Extra-gastrointestinal manifestations include mucocutaneous pigmented lesions; increased risk of thyroid, breast, lung, pancreas, gonadal, and bladder cancers

Answer 405

presents under the age of 5. Mutated genes are SMAD4, BMPR1A. Gastrointestinal lesions include juvenile polyps; risk of gastric, small intestinal, colonic, and pancreatic adenocarcinoma. Extra GI manifestations are pulmonary arteriovenous malformations, digital clubbing

Answer 406

Usually appear in the left colon. Frequency increases with age. Histology shows delayed maturation with overgrowth of superficial epithelium resulting in serrated architecture. There is no dysplasia but need to distinguish from “sessile serrated polyp/adenoma” (SSP) which are pre-malignant. The lesion abuts muscularis mucosa (arrow) and does not have a stalk. It is composed of mixed absorptive and goblet cells; cells are crowded, possibly due to delayed shedding of epithelium  “hyperplastic.” A serrated architecture results. This is a benign, usually non-neoplastic lesion to be distinguished from SSPs

Answer 407

Sessile Serrated Polyps/Adenoma, leading to alternate pathways to carcinoma than the usual adenomatous polyp. Microsatellite Instability pathway. DNA hypermethylation pathway (CpG island methylation). More commonly affects right side presenting as a solitary, sessile, and flat. Cytology may or may not show dysplastic epithelium. Are pre-neoplastic

Answer 408

Size is variable – range from a few mm to several cm (10 cm or more). Present in nearly 50% of Western adults by age 50. Present throughout the colon. Have epithelial cytologic dysplasia ranging from low grade to high grade (carcinoma in situ). Villous adenomas contain foci of invasion more frequently than tubular adenomas but SIZE MATTERS (size is the most important characteristic that correlates with risk of malignancy overall in the patient). Presence of high grade dysplasia increases risk of malignant transformation in that polyp but not in the rest of the colon

Answer 409

1. Cells: Piling up on each other (no respect!). 2. Nuclei are darker (hyperchromasia) and there is progressive loss of basal-orientation 3. Cytoplasm is reduced compared to nucleus (increased N:C ratio). There is also reduced mucin production. 4. Mitotic Figures: increased mitotic activity

Answer 410

Villi are finger shaped, with fibrovascular core underlying epithelial layer and increased surface area. Lesions are sessile. Architecture shows multiple, slender villi (finger-like projections). Cross-section shows no evidence of thickening of the bowel wall to suggest an invasive component. Epithelium show adenomatous / dysplastic changes

Answer 411

First one copy of APC on chromosome 5 is lost, first hit (either somatic or germline). Next methylation abnormalities is the second hit of APC. Beta catenin is often mutated. Other mutations include K-RAS on chromosome 12, p53 on chromosome 17. This all leads to additional mutations and gross chromosomal alterations occur as lesion becomes cancer. There is no increase in the rate of cell proliferation in the early stage of polyp formation. Polyps represent an increase in the size of the proliferating crypt compartment.

Answer 412

WNT/APC/beta-catenin – classical adenoma-carcinoma sequence. K-Ras/MAP kinase/PI3 kinase signaling pathways—activating mutations. Microsatellite Instability – defects in mismatch repair proteins. Also, epigenetic events such as methylation-induced gene silencing, which enhances progression along these pathways

Answer 413

Wnt protein ligands are critical for development. Animals lacking Wnt homologs fail to develop entire organs. The fly homolog of human wnt-1 is wingless. Wnt ligands drive proliferation of their target tissues/organs. The Wnt pathway regulates the levels of cytoplasmic -catenin

Answer 414

it binds β- catenins in the cytoplasm, that have dissociated from adherens contacts between cells. With the help of casein kinase 1 (CK1), which carries out an initial phosphorylation of β-catenin, GSK-3β is able to phosphorylate β-catenin a second time. This targets β-catenin for ubiquitination and degradation by cellular proteasomes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes.

Answer 415

APC mutations can run in families, producing Familial Adenomatous Polyposis (FAP). FAP patients have increased risk of colon cancer, but these account for a small fraction of the total cases of colon cancer (~5%). Most people who acquire colon cancer without FAP acquire spontaneous somatic mutations in APC. Treatments include (1) surveillance colonoscopy and (2) colectomy are often ultimately performed. 100% will develop invasive adenocarcinoma, often before age 30.

Answer 416

Overall, the extracellular mitogen binds to the membrane receptor. This allows Ras (a GTPase) to swap its GDP for a GTP. It can now activate MAP3K (e.g., Raf), which activates MAP2K, which activates MAPK. MAPK can now activate a transcription factor, such as myc.

Answer 417

an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. Cetuximab is indicated for the treatment of patients with EGFR expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy

Answer 418

Develop colon cancer at an earlier age than sporadic forms. Tend to be right-sided. Inherit mutation of mismatch repair gene allele, acquire the second allele mutation over time leading to microsatellite instability

Answer 419

No symptoms most often. Nonspecific findings include fatigue, weight loss, and anemia

Answer 420

Change in bowel habits and indicators, including constipation or urgency. Narrowing of stool. Cramping / pain. Blood Loss showing up as blood in stool or bleeding from rectum (BBBPR) and can lead to anemia (iron-deficiency). Unexplained weight loss

Answer 421

visualization via colonoscopy with or without biopsy, barium enema. blood detection in stool revealing hemorrhage of ulcerated lesion. DNA/ mutation detection in shed, due to shed neoplastic cells vs. normal colonic epithelial cells.

Answer 422

Invasion of dysplastic epithelial cells into and beyond the lamina propria. Adenomas at risk: 4 cm: high risk (~40% in one study) of identification of invasive component within lesion.

Answer 423

Most colon adenocarcinomas have the appearance of well defined “gland” formation. A variable amount of mucin is produced by the cells. Neoplastic glands (adenocarcinoma) invading into muscularis propria, inciting a “desmoplastic” (fibrotic) response. There is “dirty necrosis” in the lumen of some of the glands (arrow), a fairly common finding in colon carcinoma. Neoplastic glands invading into adipose with an associated desmoplastic response (stage II). Lymph node metastasis is stage III. Distant metastasis is stage IV. Colon cancer most commonly metastasizes to the liver.

Answer 424

The liver is engaged in a number of metabolic roles that are important in the regulation and production of blood components and the production of bile. The liver is divided into four lobes and is surrounded by a fibrous connective tissue capsule (Glisson’s capsule). Due to its location as the first organ receiving blood on-line from the digestive system, it is the first to receive nutrients and any toxic substances. It synthesizes most of the blood proteins, glycoproteins, and lipoproteins, stores glucose from the gut temporarily in the form of glycogen, metabolizes many lipid-soluble molecules and toxins, and is involved in urea formation. As so many of the functions of the liver relate to its intimate association with the blood, a key point to keep in mind is that the microstructural arrangement of hepatocytes maximizes their area of contact with the blood. At the same time, the biliary secretion is completely separated from the blood supply, essentially “sealed off” by tight junctions between hepatocytes.

Answer 425

It receives the majority (70- 75%) of its blood supply from the hepatic portal vein and about 25-30% from the hepatic artery which branches from the celiac trunk. The hepatic veins drain the liver, emptying into the inferior vena cava. These vessels and the bile duct enter and leave the liver in a hilar region called the porta hepatis.

Answer 426

Repeated branching of the hepatic portal vein and the hepatic artery leads to the smallest individual functional units within the liver: the liver lobules. These can be defined, as indicated below, according to the function under consideration, into the classical lobule, the portal lobule, and the acinar lobule.

Answer 427

The classic lobule is an approximately hexagonal-shaped arrangement of anastomosing plates of hepatocytes arranged radially around a central vein. At the six vertices of the lobule run the interlobular vessels (2 types) carrying incoming blood from both the hepatic portal vein (largely deoxygenated) and the hepatic artery (oxygenated). In these vessels, the blood is not yet mixed. Also at each vertex runs a bile duct, and lymphatic space called the space of Mall. The interlobular vessels and the bile duct form the portal triad, which is surrounded by a loose connective tissue stroma. Branches from the interlobular vessels (distributing or perilobular branches) extend peripherally around the edges of the lobules, distributing blood into the sinusoids between the plates of hepatocytes. Blood percolates through the narrow sinusoids between the plates, en route to the central vein. It flows over both surfaces of the plates, which are usually one hepatocyte cell thick, hence two sides of most hepatocytes are exposed to the plasma. The bile secretion system is separated from the blood supply. A network of tiny bile canaliculi run within the plates of hepatocytes, sealed from exposure to the blood by zonulae occludens between hepatocytes. The network of canaliculi is peripherally connected to the bile ducts running along each vertex of the lobule.

Answer 428

The “portal lobule” is merely a way of defining the same basic structure of the liver in a different way. It is not a totally different structure. Rather than defining a lobule as the roughly hexagonal zone around each central vein, as the classic lobule does, the portal lobule is defined as the roughly triangular shape drawn between three central veins. This area defines a zone of tissue around a bile duct into which a group of bile canaliculi feed, hence defines a basic “bile secretory” functional unit.

Answer 429

The acinar lobule is again just another structural definition based on function. The “short axis” of this lobule lies between two portal triads (one edge of the “border” of a classic lobule). The “long axis” of this lobule lies between two central veins. The acinar lobule defines liver tissue in terms of blood delivery. The distributing branches of the interlobular vessels run along the “edges” of a classic lobule, but run along the short axis of the acinar lobule. Medically, it is relevant because exposure to toxins leads to degeneration nearest the distributing vessels, but lack of oxygenation or nutrients affects hepatocytes nearest the central vein. Also, glycogen tends to accumulate more efficiently in hepatocytes of the central zone of the acinar lobule, which is nearest the blood supply. Different “zones” have been described (zones 1, 2, and 3 and below), which are affected differently under different pathological conditions.

Answer 430

Hepatocytes are polyhedral in shape and are arranged in anastomosing plates or sheets with two sides facing the blood sinusoids. They are metabolically very versatile and every hepatocyte is capable of performing all their functions, there being no division of labor. Hepatocytes take up glucose after a meal and store it as glycogen which prevents large oscillations of glucose concentrations. During fasting periods, glycogen is converted to glucose which reenters the blood. Hepatocytes also take up various lipid-soluble toxins that arrive from the intestine, bilirubin from the spleen (from the splenic vein which joins the hepatic portal system), and can detoxify such substances by biochemically conjugating them, for example, with glucuronic acid. Excess cholesterol is eliminated in bile.

Answer 431

Hepatocytes produce the major blood proteins: albumin, various clotting glycoproteins including fibrinogen and prothrombin, among others, and the lipoproteins (categorized as very low density, low density, intermediate density, and high density ipoproteins-VLDL, LDL, IDL, and HDL-hepatocytes produce mainly VLDL).

Answer 432

The surface area of the hepatocyte plasma membrane facing the sinusoids are increased ~5-10 fold through extensive microvilli, which aids in absorptive processes. The arrangement of the hepatocyte plates ensures that every hepatocyte is exposed to plasma components. The hepatocyte contains a number of organelles typical of secretory cells; rough and smooth endoplasmic reticulum, a Golgi network, and secretory vesicles. Lysosomes and peroxisomes are also abundant, as well as lipid droplets. The smooth endoplasmic reticulum, in particular, hypertrophies upon exposure to various toxins, or alcohol. Inducible enzymes in the smooth E.R. and other enzymes in peroxisomes are involved in detoxification processes. Many administered drugs are conjugated or otherwise modified by hepatocytes, often leading to less active (or more highly active!) metabolic byproducts.

Answer 433

Outside the microvillar surface of hepatocytes facing the sinusoids is a fenestrated layer of endothelial cells. The fenestrae, which can be between or within endothelial cells, are large enough to permit all plasma components and lipoproteins to freely pass, but do not permit red blood cells to contact the hepatocyte surface.

Answer 434

The space between the endothelial cells and the hepatocyte is called the perisinusoidal space, or space of Disse. This space is also occupied by a fine meshwork of reticular fibers (collagenous) which can be observed with certain silver staining procedures. Presumably, the reticular fibers provide support for the sheets of hepatic cells, the endothelial cells on top of them, and the Kupffer cells

Answer 435

derived from the monocyte lineage, that also form part of the fenestrated endothelial layer adjacent to the hepatocytes (as opposed to residing on top of the endothelial cells). They are readily distinguished from the standard endothelial cells in having larger nuclei, and rapidly phagocytose particulate materials (such as small carbon particles) which can be easily observed microscopically. As enteric venous blood may contain bacteria, Kupffer cells in the liver play a crucial role in defense, as well as in general removal of particulate material from the blood (also recall that the spleen is directly involved in adaptive immune responses to systemic infections within blood).

Answer 436

The bile canaliculi result from apposed grooves in adjacent hepatocytes, and form a circumferential belt around each hepatocyte, forming a network of tubules running entirely within the hepatocyte plates. They are surrounded by the plasma membranes of adjacent hepatocytes, and have microvilli extending into the lumen. Along the margins of the canaliculi the plasma membranes of hepatocytes are closely apposed and tight junctions prevent leakage of bile. Nearer the portal triad, bile canaliculi lead to small bile ductules (canals of Hering), still within the liver lobule, which are surrounded by a cuboidal layer of epithelial cells having microvillar projections into the lumen.

Answer 437

Bile is composed primarily of bile salts which are typically cholate derivatives. Smaller amounts of cholesterol, phospholipids, bilirubin glucuronides, and proteins are also present, in addition to electrolytes. Polymeric IgA is a major protein in bile that is transcytosed by hepatocytes. All these molecules are secreted into the bile canaliculi by mechanisms (other than the proteins) that are thought not to involve vesicular fusion. Bile salts are largely recycled; after passage through the intestine, they are reabsorbed by the intestinal mucosa and taken up by the liver. About half a liter of bile is produced daily.

Answer 438

From the canals of Hering, ductules lead to the interlobular bile ducts of the portal triad. The epithelial lining of the ducts is initially cuboidal but becomes columnar as the ducts fuse toward the porta hepatis to form the lobar ducts which connect to form the common hepatic duct. All the epithelial cells have numerous microvilli and are involved in electrolyte transport and absorption of water. The bile ducts, toward the hilum of the liver, run through a dense connective tissue having elastic fibers; smooth muscle cells appear within the fibrous matrix.

Answer 439

The gall bladder is a distensible pouch, attached to the liver surface, which is connected to the common hepatic duct via the cystic duct. The ducts fuse to form the common bile duct that in most individuals joins the pancreatic duct and enters the duodenum. Two sphincters control bile release into the duodenum, one before entry of the pancreatic duct (the sphincter choledochus or sphincter of Boyden) and one after entry of the pancreatic duct (the sphincter of Oddi). Cholecystokinen released by enteroendocrine cells of the intestine induce gall bladder contraction and sphincter relaxation, leading to bile secretion.

Answer 440

The gall bladder stores and concentrates bile. The mucosal layer is extensively folded. The columnar epithelium adjacent to the lumen has numerous microvilli and tight junctions at the apical surface, numerous mitochondria, and folded basolateral surfaces which actively transport salt into the basolateral spaces between cells. Water follows the salt by osmosis, and is taken up by the extensive capillary system within the loose connective tissue of the lamina propria. Numerous lymphocytes and plasma cells are also evident in the lamina propria. A muscularis externa of randomly arranged smooth muscle fibers lies external to the lamina propria, and an outer adventitia is comprised of large blood vessels embedded in connective tissue rich in elastic fibers and, on the side near the liver, adipose tissue.

Answer 441

Hepatocytes have two main mechanisms of death, ballooning degeneration and necrosis/apoptosis. Ballooning Degeneration is hepatocyte swelling with clumping of hepatocyte organelles and keratin filaments with clearing of the cytoplasm. This is most often seen in steatohepatitis. Necrosis and apoptosis is characterized by decreasing cell size with increased eosinophillia of the cytoplasm and a small dark nucleus. This is often seen in ischemia and chronic viral hepatitis. When these cells are seen singly in the hepatic parenchyma, they are variably called acidophils, Councilman bodies, or single necrotic hepatocytes. Wide spread ischemia is typically shows confluent zone 3 ischemic necrosis. Autoimmune hepatitis and viral hepatitis often show acidophils at the interface zone.

Answer 442

All types of inflammatory cell infiltrate may be seen in the hepatic parenchyma. The type of infiltrate is never specific for a particular diagnosis, but a predominance of a particular type makes certain etiologies more likely. Common inflammation/etiology associations: Neutrophils – Steatohepatitis, Eosinophils – drug reaction, Plasma cells – autoimmune hepatitis. The location of the infiltrate is also important and may suggest a particular etiology. Inflammation in the lobule is a major contributor to lobular disarray. Common location/etiology associations: Portal based – biliary disease, Interface inflammation – autoimmune and viral hepatitis, Zone 3 – autoimmune hepatitis or acute cellular rejection (transplant patients)

Answer 443

Choelstasis is the accumulation of bile within the hepatic parenchyma. Bile may accumulate in hepatocytes, bile caniliculi, Kupffer cells, and bile ducts. Cytoplasmic bile often leads to ballooning degeneration. Cholestasis can result from both obstructive and non-obstructive causes.

Answer 444

In obstructive cholestasis bile outflow is impaired and bile begins to build up in the caniliculi of zone 1 hepatocytes. Hepatocytes undergo metaplasia to become similar to bile duct cells to take care of the increased bile. The result is the appearance of many bile duct like structures at the interface zone, usually with edema and neutrophilic inflammation.

Answer 445

The development of fibrosis is the common end result of inflammation/injury within the hepatic parenchyma. The fibrosis originates from collagen deposition by activated stellate in the space of Disse. With progressive fibrosis, cirrhosis develops.

Answer 446

Using the previously described pathologic patterns of liver injury and correlating these changes with clinical and serologic evidence of disease allows classification into clinicopathologic patterns of liver disease. For viral liver disease, acute and chronic hepatitis are the most common patterns. Cholestatic liver disease is also an important clinicopathologic pattern.

Answer 447

Acute hepatitis is the new onset of symptomatic disease that has lasted less than 6 months and is associated with laboratory evidence of hepatocyte injury with elevations of AST and ALT. Common causes of acute hepatitis include acute viral hepatitis, autoimmune hepatitis, and adverse drug reaction, as well as idiopathic cases. The liver usually shows marked lobular disarray and inflammation, with numerous single necrotic hepatocytes, and cholestasis. The background architecture of the liver should not contain significant fibrosis (which would suggest more chronic disease).

Answer 448

Chronic hepatitis is clinical, serologic, or pathologic evidence of hepatic injury/inflammation for greater then 6 months. Common etiologies include viral hepatitis, autoimmune hepatitis, and adverse drug reaction, as well as idiopathic cases. Liver specimens usually show less impressive lobular disarray, less prominent inflammation, rare single necrotic hepatocytes, and the slow progression of fibrosis over time. Chronic hepatitis is a major cause of morbidity and mortality and results in the majority of the hepatopathology.

Answer 449

To standardize the pathologic reporting of liver biopsies with chronic hepatitis, several systems have been developed to assess the necroinflammatory activity (GRADE) and the degree of fibrosis (STAGE). The most commonly used systems use a 0-4 scale for both grade and stage. Grade refers with the current liver injury/damage while stage refers to the amount of fibrosis and the cumulative result of injury over time.

Answer 450

Cirrhosis is the end stage of chronic liver disease from any cause and is defined pathologically, however, there are also many clinical and laboratory features as well. Pathologically it shows bridging fibrous septa with distortion of the architecture and regenerative nodules. Clinical/laboratory features of portal hypertension and poor synthetic function. Patients with cirrhosis are at increased risk for hepatocellular carcinoma.

Answer 451

Cholestatic liver disease is identified by either acute or chronic jaundice with primarily elevations of alkaline phospahtase, gamma glutamyl transpeptidase, and bilirubin. Cholestatic liver disease has a broad differential diagnosis and includes both obstructive and non-obstructive causes. Liver specimens usually show cholestasis with an interface ductular reaction, edema, and neutrophilic inflammation, along with other more specific pathology, based on the etiology.

Answer 452

Hepatitis A and E are extremely similar viruses. They are ssRNA viruses that are spread via the fecal-oral route, never lead to chronic disease, and are tested for by looking for IgM and IgG specific antibodies. HEV has a high mortality in pregnant women.

Answer 453

Hepatitis C is becoming an increasing problem as about 80% people exposed develop chronic liver disease. Transmission is via blood and body fluids as well as vertical. Anti-HCV antibodies indicate exposure and are positive in 97% of people exposed by 6 months. PCR testing for HCV RNA indicates ongoing infection. HCV rarely present as acute hepaitits. The histology of HCV is non-specific and includes interface and lobular necroinflammatory activity with progressively increased fibrosis. Nodular aggregates of lymphocytes in portal areas are a common finding.

Answer 454

Hepatitis B has been steadily decreasing as more people and treated for it and clear the virus while others are being immunized to it. HBV is the only DNA virus of the hepatotropic viruses and can integrate into host genome. HBV is transmitted by blood and body fluids as well as vertically. Only about 10% of exposed patients do not clear the virus completely and about 5% progress to chronic hepatitis B infection. Histologically, it is similar to HCV except for the presence of ground glass hepatocytes and sanded nuclei which represent viral particles within the hepatocytes. See the figures below for serologic testing of HBV. Immunization for HBV using non-infectious HBsAg results in a positive anti-HBs.

Answer 455

Hepatitis D can not replicate without concurrent HBV infection, but can augment the effects of HBV. The histology may show increased plasma cells.

Answer 456

Non-hepatotropic viruses that may infect the liver include HSV, CMV, and adenovirus. These infections are usually associated with more systemic viral infection and show characteristic viral cytopathic effect within the hepatic parenchyma. They are usually associated with immunosuppression (CMV especially) but may be seen in immune competent patients as well (HSV).

Answer 457

Autommune hepatitis is an autoimmune disease characterized by hepatic inflammation and damage usually associated with prominent plasma cells on histology. AIH often presents with an acute flare (acute hepatitis pattern on histology) and then settles into a chronic hepatitis. Females account for 78% of the disease. Liver function testing usually shows increased AST and ALT with normal ALP. Serologic testing usually shows a profile of as least one positive autoantibody (ANA, ASMA, Anti-LKMB) in 80% of cases and an elevated IgG level. Treatment is usually with steroids. On histology, if the disease is active, there will be ongoing interface and centrolobular necroinflammatory with zones of confluent hepatocyte necrosis and a prominent plasma cell component. The histology may be indistinguishable from viral hepatitis.

Answer 458

PBC is an autoimmune disease primarily involving the intrahepatic bile ducts with inflammatory bile duct destruction. The presentation of PBC is usually insidious with pruritus often appearing before jaundice. Females account for over 85% of cases. Liver function testing usually shows elevated ALP, GGT, and bilirubin with normal to only slightly increased AST and ALT. Serologic testing results in a positive AMA (90%) and elevated IgM. Both acute and chronic histologic changes may be seen. Acute changes include lymphohistiocytic and plasma cell rich inflammation of the portal areas with active lymphocytic cholangitis and bile duct destruction, a constellation of findings termed a florid duct lesion. Cholestasis in the lobule is also common. Chronically, the histology shows bile duct loss (ductopenia) with a ductular reaction and periportaql copper accumulation. Over time, fibrosis begins to develop in the periportal regions with eventual bridging fibrosis and cirrhosis.

Answer 459

PSC is an idiopathic disease characterized by patchy inflammation and eventual obliterative fibrosis of the bile ducts. The disease usually affects the extrahepatic bile ducts but may also involve the intrahepatic ducts. The most common presentation is with a persistently elevated alkaline phosphatase and no other signs/symptoms. Over time, as the disease progresses patients experience increasing fatigue, pruritus, and jaundice. Male are twice as likely as females to be affected (male to female ratio 2 to 1). There is a strong association with inflammatory bowel disease (67% of PSC patients have IBD) and specifically ulcerative colitis (70%). The chronic injury to the biliary tree markedly increases risk for cholangiocarcinoma. Liver function testing usually shows increased ALP, GGT, and bilirubin. There are no solid serologic associations. As opposed to other hepatic diseases where the diagnosis is based on clinicopathologic correlation, PSC is diagnosed on clinicoradiologic correlation, which is obtained either endoscopically (by endoscopic retrograde cholangiopancreatography, ERCP) or by MR scanning (MRCP). Cholangiography shows beading of the extra- and intrahepatic bile ducts with multiple biliary strictures alternating with areas of dilation (string of pearls). Histologically, PSC shows lymphocytic periductular inflammation around the larger bile ducts with progressive fibrosis. The peri-ductular fibrosis is concentric around the ducts creating an onion skin pattern, hence the terminology “onion skin fibrosis”. In severe disease the lobules show prominent cholestasis. As the disease progresses, smaller intrahepatic bile ducts become sclerotic resulting in ductopenia.

Answer 460

Several diseases processes (including cholelithiasis, biliary atresia, choledochal cysts, and cystic fibrosis) can result in sclerosis/fibrosis of the biliary tree. At the end stage primary and secondary sclerosing cholangitis may be indistinguishable with the exception of the clinical history.

Answer 461

A wide variety of drugs have been reported to cause liver injury and elevated liver function testing. Of all adverse drug reactions, 10% involve the liver. Presentations can be are extremely varied from asymptomatic elevations of liver function tests to acute hepatitis to cholestatic changes. Injury may be dose related (usually a direct hepatotoxin) or idiosyncratic. Histologic changes may show necrosis, cholestasis, biliary injury, autoimmune-like hepatitis, acute hepatitis, or chronic hepatitis. Acetaminophen is the most common cause of drug induced liver injury and represents a large proportion of cases of acute liver failure leading to liver transplant in US. Acetaminophen in an intrinsic hepatotoxin which causes confluent coagulative necrosis, beginning in zone 3 (centrolobular) and progressing to pan-lobular necrosis depending on the dose.

Answer 462

The four main metabolic liver diseases include steatosis/steatohepatitis, hereditary hemochromatosis, Wilson’s disease, and alpha-1-antitrypsin deficiency. The latter three are all inherited genetic diseases that are autosomal recessive.

Answer 463

Steatohepatitis is defined by the histologic triad of steatosis, lobular inflammation, and hepatocyte ballooning degeneration. These changes are non-specific and are seen in a variety of conditions. Clinically, steatohepatitis is separated into alcoholic and non-alcoholic forms. Non-alcoholic steatohepaitits (NASH) is usually seen in patients with diabetes, metabolic syndrome, obesity, or adverse drug reaction. Regardless of the cause, steatohepatitis leads to hepatic fibrosis over time and a 20% risk of cirrhosis. The fibrosis begins in the centrolobular region (zone 3) and shows a prominent sinusoidal pattern (chicken-wire). The cirrhosis pattern most often seen in steatohepaitits is a micronodular pattern secondary to the fine sinusoidal fibrosis.

Answer 464

Alcoholic steatohepatitis is defined by a clinical history of alcohol exposure and the histologic triad on liver biopsy. Laboratory findings associated with alcoholic steatohepatitis include an AST to ALT ratio of greater than 2 as well as a normal ALP with increased GGT. Mallory hyaline and a prominent neutrophil component of the infiltrate are two histologic features more often seen in alcohol than in NASH.

Answer 465

NASH is commonly seen in obesity, diabetes, hypertriglyceridemia, and adverse drug reaction. As obesity and diabetes are becoming more common, the prevalence of NASH has also increased.

Answer 466

HH is a genetic disease of iron overload secondary to a mutation in HFE gene on chromosome 6. The most common genetic mutations are C282Y and H63D. Inheritance is autosomal recessive and the incidence is approximately 5/1000 in people of Northern European descent. Males are more likely to suffer the effects of iron overload than females (ratio of 5-7:1). The mutated HFE gene results in abnormal regulation of iron absorption in the small intestine. The result is excess iron absorption and deposition of iron in tissues. The clinical manifestations usually occur in middle age and are characterized by a triad of liver disease, diabetes, and heart failure. Histologically there is progressive iron deposition within the cytoplasm of hepatocytes, beginning in the periportal region first. Over time, iron acts as an oxidant and results in hepatocyte injury and fibrosis. Diagnosis is now primarily based on genetic testing. In the past, hepatic biopsy tissue was tested for quantitative levels of iron.

Answer 467

Primary hepatic hemosiderosis, what is seen in HH, must be differentiated from secondary hemosiderosis. Secondary causes include excessive ingestion, repeated transfusions, hemolysis, and underlying liver disease. In secondary causes of hemosiderosis most of the hemosiderin is in Kupffer cells rather than in the hepatocytes.

Answer 468

Wilson’s disease is a genetic disease of copper overload secondary to mutations in the ATP7B gene on chromosome 13. Inheritance is autosomal recessive with and incidence of 1 in 30,000. ATP7B encodes a copper transport protein that is involved in the biliary excretion of copper. Over 30 different mutations have been described and most patients are compound heterozygotes. Laboratory studies usually show low to normal serum ceruloplasmin levels. Patients often show neurologic symptoms and have Kayser-Fleischer rings by ophthalmologic examination. Histologically there is patchy copper accumulation in hepatocytes. The rest of the parenchyma may show steatosis and acute/chronic hepatitis like changes.

Answer 469

A1A is a genetic disease characterized by decreased production of a protease inhibitor. Inheritance is autosomal recessive. The protease inhibitor normally prevents the actions of proteases released by neutrophils and thus limits tissue damage. PiMM is normal genotype; PiMZ is heterozygote; and PiZZ is most common disease genotype. Lab studies show protease inhibitor levels less than 10% of normal. Most patients show pulmonary Emphysema and only about 10% have liver disease. Histologically there is intracytoplasmic accumulation of PAS positive, diastase resistant hyaline globules with progressive fibrosis. These globules represent abnormally folded A1A.

Answer 470

Due to the dual blood supply to the liver (hepatic artery and portal vein), true ischemic infarcts are rare. However, if hepatic artery thrombosis occurs suddenly, it is possible. Portal vein thrombosis is an important cause of non-cirrhotic portal hypertension. About 50% of cases are idiopathic. Acute portal vein thrombosis often shows prominent congestion of the sinusoids with associated hepatocyte atrophy.

Answer 471

Sub-optimal hepatic blood outflow may be secondary to a number of causes and shows marked centrolobular sinusoidal dilation, congestion, and hemorrhage. Grossly the liver is enlarged and tense. Diagnostic considerations include hepatic vein thrombosis/stricture, inferior vena cava thrombosis/stricture, and heart failure.

Answer 472

Budd-Chiari syndrome is defined by liver enlargement, pain, and ascites with main hepatic vein occlusion. Over time, regardless of the cause, these changes may result in subsinusoidal fibsosis and cirrhosis if not corrected. In heart failure patients, this has been termed cardiac sclerosis.

Answer 473

HCC is the most common primary malignant tumor of the liver and occurs almost exclusively in patients with chronic liver disease (HCV, HBV, NASH, alcohol) and a cirrhotic liver (90%). The prognosis of HCC is based on size, presence of macroscopic and microscopic vascular invasion, focality, and invasion of adjacent structures. Histologically, HCC is defined by abnormally thickened hepatic plates (greater then 3 cells thick), endothelialization of the sinusoids, invasion of the fibrosis, unpaired arteries, and vascular invasion. A wide variety of histologic patterns may be encountered. Treatment is usually with trans-arterial chemoembolization if resection or transplantation is not an option.

Answer 474

Distinct mass in a cirrhotic liver. Invasion of main branch of portal vein or hepatic artery. May have green-yellow color (bile). Microscopically, thickened hepatic plates, endothelialization of sinusoids, invasion of fibrous tissue/vessels, unpaired arteries, no true portal areas

Answer 475

May be intra- or extrahepatic. PSC is a major risk factor. Usually presents at an advance stage. 1 and 2 year survival 25% and 13% respectively. Grossly, densely fibrotic mass in the hilar region with infiltrative edges and tan-white in color. Microscopically, invasive gland forming tumor with abundant desmoplastic response

Answer 476

Grossly, very well circumscribed with no other liver disease. Microscopic findings depends on primary.

Answer 477

Benign neoplasm of dilated vascular spaces. Most common primary hepatic tumor. Incidence of 2%. More common in females (1:4). Most common presentation is vague RUQ pain, early satiety, nausea, vomiting. Grossly, well circumscribed mass in a non-cirrhotic liver, spongy hemorrhagic cut surface with areas of infarction and thrombosis. Microscopically, dilated thin walled vascular spaces, infarction, thrombosis, and benign appearing endothelial cells

Answer 478

Second most common primary hepatic mass. Presumed hyperplastic parenchyma due to a vascular anomaly. Commonly found in association with hemangiomas. More common in women than men (4:1). Diagnosed in the 3rd - 4th decade of life. Usually asymptomatic. Grossly, shows central stellate scar. Microscopically, abarrent malformed vascular stuctures, ductular reaction, no true portal areas

Answer 479

Occurs in women of child-bearing age. 1:9 Male to female ratio. Associated with oral contraceptive use. Present with RUQ pain, most are asymptomatic. Risk is of rupture into abdomen with hemorrhage. Low risk of malignant transformation (5%). Gross appearance shows well circumscribed mass in a non-cirrhotic liver and soft fleshy cut surface. Microscopic appearance shows proliferation of benign hepatocytes, normal hepatocyte plate thickness, numerous unpaired arteries, no bile ducts or portal areas. May be difficult to distinguish between adnoma and well differentiated HCC

Answer 480

Hepatic agenesis is rare and incompatible with life. It is often associated with other severe congenital anomalies in stillborn fetuses. The liver, its vascular and peritoneal connection, and the gallbladder usually have a mirror image configuration in situs inversus totalis. In the asplenia/polysplenia syndromes, the liver may be midline and the lobes symmetrical.

Answer 481

The biliary tree can demonstrate a variety of structural abnormalities. One of the most common is choledochal cyst, which is a dilation of the biliary tree. Most cases present before the age of 10 years with jaundice and abdominal pain. The classic triad of presenting symptoms, seen in 40% of patients, is jaundice, abdominal pain, and a right upper quadrant mass.

Answer 482

Jaundice (icterus) refers to yellowish pigmentation of the skin and sclerae, and is due to abnormally high levels of bilirubin in the blood (hyperbilirubinemia). Jaundice is a common finding in the newborn period. The differential diagnosis of neonatal jaundice is long, and includes both completely innocuous causes and serious disorders requiring prompt recognition and therapy. Thus, the correct diagnosis of neonatal jaundice is very important.

Answer 483

Many newborns experience a period of physiologic jaundice, which is related to an inability to adequately conjugate bilirubin. These infants have an elevated level of unconjugated bilirubin. The mechanism for conjugation of bilirubin is not mature until approximately 2 weeks of age. Additionally, during this time, increased bilirubin production occurs because of the breakdown of fetal red blood cells. Large hematomas from birth trauma, sepsis, hypoxia, prematurity, and medications can worsen physiologic jaundice. Additionally, breast milk contains beta-glucuronidases, which deconjugate bilirubin glucuronides in the gut, also contributing to increased jaundice. Physiologic jaundice is usually self-limited but phototherapy can be used. Phototherapy transforms bilirubin into isomers, which can be excreted in bile and urine.

Answer 484

Elevated levels of conjugated bilirubin in the neonate occur in approximately 1 in 2500 live births. Etiologies to be excluded include infection (viral and bacterial), metabolic disorders (including alpha-1 antitrypsin deficiency, cystic fibrosis and metabolic storage disorders), bile duct obstruction (especially extrahepatic biliary atresia), and medication effects. Once these etiologies have been excluded, patients may fall into the category of idiopathic neonatal hepatitis; this classification is continually diminishing as specific etiologies are identified and defined.

Answer 485

Biliary Atresia is an important cause of neonatal cholestasis. The incidence is 1 in 8,000-12,000 live born infants. Two forms are described. The perinatal form is more common and accounts for 65-90% of cases. In this disorder, the extrahepatic biliary tree is normal at birth and undergoes progressive destruction. Patients are usually of normal birth weight and have normal post birth weight gain; however, they develop late onset jaundice with progressively acholic stools. Most commonly, atresia of the entire extrahepatic biliary system is present. Proposed etiologies include infection, toxin, autoimmune destruction, and underlying genetic lesions. Histological findings on liver biopsy include: cholestasis in hepatocytes, canaliculi, and bile ducts; portal fibrosis with prominent bile duct proliferation; variable inflammation. These histologic findings are suggestive of BA; however, definitive diagnosis requires a cholangiogram to assess the patency of the biliary tree.

Answer 486

Treatment includes hepatoportoenterostomy, also known as the Kasai Procedure. In this procedure, the extrahepatic biliary system is excised and a loop of small bowel in connected to the hepatic hilum to allow for bile drainage. The success of this procedure decreases after day of life 60. Therefore bile duct obstruction should be considered and excluded in all infants with persistent neonatal cholestasis. The success of the procedure is limited by intrahepatic progression of disease and infection. Patients often progress to cirrhosis and require liver transplantation for long-term survival. Biliary atresia is the number one pediatric disorder requiring liver transplantation. The less common embryonic/fetal form of biliary atresia (10-35% of cases) probably represents a congenital structural anomaly of the biliary tree, and is usually associated with other congenital anomalies. In this form, infants develop progressive jaundice immediately after birth.

Answer 487

25-40% of infants with conjugated hyperbilirubinemia continue to have an undiagnosed etiology and may be categorized as having idiopathic neonatal hepatitis. Over 85% of cases are sporadic and 10-15% familial. Patients usually exhibit hepatomegaly and conjugated hyperbilirubinemia without a definable etiology. Findings on liver biopsy show cholestasis, prominent giant cell transformation of hepatocytes, minimal inflammation, and normal bile ducts.

Answer 488

TPN (Total Parenteral Nutrition) hepatopathy is seen in the context of disease requiring more than short-term administration of TPN. The most common contexts are gastrointestinal diseases, such as congenital anatomic defects of the GI tract and necrotizing enterocolitis. The risk and severity are roughly proportional to duration of TPN therapy. Biopsy findings are similar to, and can be indistinguishable from, those in biliary atresia. The majority of cases will resolve once TPN is discontinued, but some patients can progress to cirrhosis.

Answer 489

Unconjugated hyperbilirubinemia. A genetic mutation leads to lack of (Type I) or decrease in (Type II) UDP-glucuronyltransferase (UGT1A1), which normally conjugates bilirubin to glucuronic acid, thus making water-soluble bilirubin glucuronides, which are excreted in bile. Bile contains only trace amount of unconjugated bilirubin. Serum unconjugated bilirubin levels are extremely high. Type I is fatal without liver transplantation. Patients with Type II have jaundice, but are otherwise asymptomatic, and can have a normal life expectancy.

Answer 490

Unconjugated hyperbilirubinemia. Patients have mild, benign fluctuating levels of serum bilirubin due to a decrease in UGT1A1 activity. Patients experience episodic jaundice, often during periods of physiologic stress such as illness.

Answer 491

Conjugated hyperbilirubinemia. Results from hereditary defect in excretion of bilirubin glucuronides across the canalicular membrane due to absence of multidrug resistance protein 2. Patients may have episodic jaundice, but most have normal life expectancy.

Answer 492

Conjugated hyperbilirubinemia. Defect unknowm; clinically similar to Dubin-Johnson Syndrome.

Answer 493

The liver is affected in a number of genetic disorders, most of which (eg: alpha-1-antitrypsin disease) are discussed in other lectures. An additional genetic disease of children affecting the liver that is not discussed elsewhere is cystic fibrosis (CF). The incidence of liver disease in patients with CF is increasing as life expectancy of these patients increases. Of CF patients, 1-4% will develop liver dysfunction and 5-10% of affected individuals will develop cirrhosis. The hepatic lesion of CF is termed Focal Biliary Cirrhosis and consists of patchy, irregular areas of fibrosis with bile duct proliferation. The bile ducts contain inspissated secretions. Centrilobular steatosis and variable chronic inflammation are also commonly present.

Answer 494

The liver is involved in many metabolic disorders. These include disorders of iron and copper metabolism (hemochromatosis and Wilson disease, respectively, discussed in other lectures), and the more rare pediatric diseases of carbohydrate metabolism, lipid metabolism, lysosomal storage and amino acid metabolism.

Answer 495

Enzyme defects result in abnormal accumulation of glycogen in hepatocytes and other organs. These are classified by enzyme defect and location of accumulated glycogen. The liver is involved in Types I, III, IV, VI, and IX. Other disorders of carbohydrate metabolism include galactosemia and fructosemia.

Answer 496

Lipid: Wolman Disease, defect in cholesterol ester storage. Sphingolipidoses: Niemann Pick Disease (sphingomyelin) and Gaucher Disease (glucosyl ceramide). Oligosaccharidoses: abnormal glycoprotein degradation, including Farber and Fabry Diseases (ceramide accumulation)

Answer 497

Defects in fatty acid oxidation may clinically resemble Reye Syndrome, resulting in rapid childhood death from seemingly innocuous febrile illness. Examples include carnitine deficiency, and defects in acyl-CoA-dehydrogenases.

Answer 498

Reye Syndrome is a now rare disorder related to mitochondrial dysfunction. Most cases were seen in association with salicylate use in children with viral infection and fever. Initial fever and upper respiratory illness with initial recovery were followed by acute onset vomiting, delirium and progression to coma and death. Mechanism of disease was related to mitochondrial injury, especially in liver, brain, and skeletal muscle. Patients accumulated fat in liver, kidneys, myocardium and skeletal muscle. Cerebral edema was common. Treatment included supportive measures, hydration, and monitoring of intracranial pressure. This disorder is now rare, probably do to decreased salicylate use in children.

Answer 499

Bengin pediatric neoplasm. Benign infantile neoplasm with 85% presenting at

Answer 500

Hepatoblastoma accounts for 27% pediatric liver tumors and 47% of malignant pediatric liver tumors. 90% of cases present before age 5 yrs. A male to female ratio of 2:1 is reported. The tumor recapitulates hepatogenesis and, unlike hepatocellular carcinoma, arises in an otherwise normal liver (ie: not in the context of underlying chronic liver disease). Histological subtypes include epithelial and mesenchymal histology. Symptoms include an enlarged abdomen, anorexia, weight loss, nausea, vomiting, and pain. Most cases (90%) have an elevated alpha-fetoprotein level (tumor marker); beta-hCG may be elevated as well. Activation of the Wnt/Beta catenin pathway is present in. There is an increased incidence in Beckwith-Wiedemann Syndrome and Familial Adenomatous Polyposis, and 80% of cases show activation of the Wnt/beta-catenin signaling. Treatment consists of preoperative chemotherapy and surgical resection. The most important prognostic factor is stage at time of resection.

Answer 501

Hepatocellular Carcinoma is primarily a malignancy of adults but also occurs in children, usually at an older age than hepatoblastoma (> 5 yrs). It usually presents in the background of chronic liver disease, such as congenital hepatitis B infection or metabolic disease. As in hepatoblastoma, serum alpha-fetoprotein is elevated.

Answer 502

Undifferentiated/Embryonal Sarcoma is an aggressive malignancy, which may arise in the setting of mesenchymal hamartoma. Serum alpha fetoprotein is not elevated. The tumor can have a misleading cystic appearance on imaging.

Answer 503

Serum liver chemistry tests are often referred to as liver function tests (“LFTs”). This is a misnomer in that most of these tests do not actually assess liver function. The term liver chemistry tests imply that these tests are solely of hepatic origin, but in fact, these tests are not specific for the liver and encompass numerous hepatic biochemical processes that reflect hepatocellular injury, intra- or extrahepatic cholestasis, infiltrating diseases of the liver, impairment of hepatic synthesis, and alterations in liver metabolism. Additionally normal values do not exclude underlying liver disease. Liver chemistries are often checked when a liver disorder is suspected, during periodic health screening and for insurance physicals and during hospitalizations unrelated to hepatic disorders. Common liver chemistry tests include aspartate aminotransferases (AST), alanine aminotransferase (ALT), bilirubin (total and conjugated), alkaline phosphatase, and albumin. The prothrombin time is also a useful test in assessing liver synthetic dysfunction.

Answer 504

The AST and ALT are abundant hepatic enzymes that catalyze the transfer of amino groups to form the hepatic metabolites pyruvate and oxaloacetate, respectively. The ALT is found in the cytosol of hepatocyts, whereas two AST isoenzymes are located in the cytosol and mitochondria, respectively. Both the ALT and AST are released from damaged hepatocytes into the blood after hepatocellular injury or death. The AST also is abundantly expressed in several nonhepatic tissues including heart, skeletal muscle, and blood. The ALT is found in low concentrations in tissues other than liver, so it is frequently considered specific for hepatocellular injury. However, this specificity is not absolute because serum ALT elevations can occur in nonhepatic conditions such as myopathic diseases. Both the ratio and absolute elevation of the AST and ALT can provide important information regarding the extent and etiology of liver disease.

Answer 505

The ratio of AST & ALT is approximately 0.8 in normal subjects. In some settings, this ratio changes in characteristic ways that may suggest a diagnosis. In particular, the AST is greater than the ALT in alcoholic hepatitis and a ratio greater than 2:1 is highly suggestive of this disorder. The relatively lower elevation of serum ALT has been ascribed to hepatic deficiency of pyridoxal-6-phosphate in alcoholics, which is a cofactor for the enzymatic activity of ALT. According to this hypothesis, the altered ratio reflects a failure to appropriately increase the ALT rather than a disproportionate elevation in AST. Preferential alcohol-induced injury to mitochondria enriched in AST may also contribute to the 2:1 ratio.

Answer 506

There are numerous causes of increased serum ALT and AST levels in both symptomatic and asymptomatic patients. Both the magnitude and relative level of elevation of the ALT and AST may be useful in narrowing the differential diagnosis for the cause of the liver injury, especially when the level of elevation is either mild or severe. Therefore, a useful paradigm to categorize elevated serum ALT and AST levels involves ALT and AST elevations of less than 5 times normal, with either a predominant ALT or AST elevation; and ALT and AST elevations greater than 15 times normal.

Answer 507

Acute viral hepatitis (A-E, herpes), medications/toxins, ischemic hepatitis, wilson's disease, acute budd-chiari syndrome, hepatic artery ligation or thrombosis.

Answer 508

The alkaline phosphatase family of enzymes are present in nearly all tissues and responsible for removing phosphate groups from nucleotides, proteins and alkaloids. In liver, the enzyme is isolated to the microvilli of the bile canaliculus. Under normal conditions, serum alkaline phosphatase is predominantly derived from the liver and bone isoenzymes, with intestinal enzymes contributing a minor component. Serum alkaline phosphatase levels can be elevated by cholestatic or infiltrative diseases of the liver and by diseases causing obstruction to the biliary system, as well as by bone diseases, numerous medications, and tumors of hepatic and nonhepatic origin. When evaluating serum liver chemistries, the important clinical issue is the determination of whether the alkaline phosphatase abnormality is of hepatobiliary or nonhepatic origin. Liver alkaline phosphatase is more heat stable than bone, and isoenzyme determination can be made based on heat sensitivity. Serum assays of 5’-nucleotidase or γ-glutamyltransferase (GGT) activity can be used to confirm the liver-specific origin for an elevation of the alkaline phosphatase. Serum levels of GGT also may be elevated after alcohol consumption (presumably because of enzyme induction) and in almost all types of liver disease, so elevations of this enzyme are therefore less useful for determining the cause of liver disease.

Answer 509

Isolated hepatic alkaline phosphatase isoenzyme elevations may be the sole abnormality in primary biliary cirrhosis (PBC) or other cholestatic and infiltrative diseases of the liver. Cholestatic conditions may cause a conjugated hyperbilirubinemia, and elevated serum bilirubin levels may occur before the development of frank jaundice. When a serum alkaline phosphatase elevation is detected, it must be interpreted in the clinical setting of the patient’s historical findings and physical examination. If medications are suspected, the initial evaluation may involve discontinuation of medications and repetition of the serum liver chemistries. However, patients with persistently elevated serum alkaline phosphatase levels of hepatic origin must be evaluated for cholestatic and infiltrative liver diseases (granulomatous diseases including sarcoidosis, lymphoma, metastatic disease) and for biliary obstruction. The initial evaluation should include ultrasonography to assess the hepatic parenchyma and biliary system. If extrahepatic obstruction is evident, an endoscopic retrograde cholangiopancreatography should be considered. If extrahepatic obstruction is not evident, an antimitochondrial antibody (AMA) should be obtained. A positive result is diagnostic for PBC. Because potentially treatable cholestatic and infiltrative liver diseases (i.e., PBC, sarcoidosis, primary sclerosing cholangitis, etc.) may have long asymptomatic periods characterized solely by mild, asymptomatic elevations of the serum alkaline phosphatase, the continued presence of persistent hepatic alkaline phosphatase elevations (typically greater than 6 months’ duration) of unknown origin typically warrants further evaluation, often with imaging of the biliary tree and liver biopsy.

Answer 510

Bilirubin is a normal heme degradation product that is excreted from the body predominately via secretion into bile. Bilirubin is insoluble in water and requires conjugation (glucuronidation) into the water-soluble bilirubin mono- and di-glucuronide forms before biliary secretion. To secrete bilirubin into bile, unconjugated bilirubin must be taken up into the hepatocyte and conjugated into the glucuronide form by the endoplasmic reticulum enzyme bilirubin UDP-glucuronyltransferase (bilirubin-UGT), and the water-soluble bilirubin glucuronides must be secreted across the canalicular membrane into bile. Bilirubin-UGT, the enzyme that conjugates bilirubin, is expressed shortly after birth. However, once enzyme expression occurs, it continues to be highly expressed and active even in severe liver disease and cirrhosis. Diminished expression of this enzyme is one of the defects causing Gilbert’s syndrome, a benign, unconjugated hyperbilirubinemia occurring in up to 5% of the normal population. Unconjugated hyperbilirubinemia also may result from hemolysis (increased heme breakdown) or in rare genetic diseases such as the Crigler-Najjar syndrome.

Answer 511

After the neonatal period, most hepatic conditions that result in a conjugated hyperbilirubinemia are caused by either extrahepatic obstruction of bile flow, intrahepatic cholestasis, hepatitis, or cirrhosis, with a resultant impairment of hepatocellular bilirubin secretion into bile. Because bilirubin-UGT expression and bilirubin conjugation typically are well preserved, these pathophysiological states usually result in a conjugated hyperbilirubinemia. Cholestatic diseases are often associated with elevations in alkaline phosphatase and can be categorized as either anatomic obstructions to bile flow (extrahepatic cholestasis) or as functional impairments of bile formation by the hepatocyte (intrahepatic cholestasis). Disorders causing hyperbilirubinemia, however, may not always be associated with abnormalities of the serum alkaline phosphatase or other serum liver chemistries. In fact, hyperbilirubinemia is relatively common with many forms of liver disease and does not necessarily imply the presence of either cholestatic or hepatocellular liver disease, nor even indicate that hepatic disease is present (especially unconjugated hyperbilirubinemias due to Gilbert’s syndrome).

Answer 512

The initial evaluation of an elevated isolated serum bilirubin level is, thus, a determination of whether the bilirubin elevation is caused by conjugated (direct) or unconjugated (indirect) bilirubin. In asymptomatic, healthy individuals a presumptive diagnosis of Gilbert’s syndrome can be made if mild (

Answer 513

The serum albumin and prothrombin time may be essential in the evaluation of hepatic function, although not specific for evaluating liver function. Albumin levels may be diminished due to poor nutritional status, severe illness with protein catabolism, nephrosis, malabsorption, and other abnormalities of the gastrointestinal tract, whereas prothrombin time elevations may occur with malabsorption and with several acquired or genetic hematologic abnormalities. Nonetheless, in the proper clinical scenario these tests may be important indicators of hepatic synthetic function. The liver synthesizes both albumin and many of the blood coagulation factors that are required to be in adequate concentrations in order for the prothrombin time to be normal. Thus, in the absence of other nonhepatic etiologies for abnormalities in the albumin or prothrombin time, these laboratory tests can be useful in assaying hepatic synthetic function. The half-life of serum albumin normally is 19–21 days, whereas the half-life of blood coagulation factors may be less than a day, so these tests often can be used in tandem to assess both acute and chronic components of hepatic function or impairment. Unlike serum liver chemistry tests like the serum ALT, AST, and alkaline phosphatase (which are not true indicators of hepatic function), serum albumin levels and prothrombin time, along with physical examination findings such as encephalopathy, are important clinical parameters of hepatic function that are essential in the context of interpreting abnormal serum liver chemistry tests, especially in clinical scenarios of impending hepatic failure.

Answer 514

The diagnosis of chronic HBV is determined by the presence of hepatitis B surface antigen (HBsAg) for >6 months. The treatment of chronic HBV reduces the risk of progressive chronic liver disease and long-term complications of cirrhosis and hepatocellular carcinoma (HCC). Treatment is most often considered in patients with chronic hepatitis: 1) HBsAg positive >6 months, 2) serum HBV DNA >105 copies/mL and 3) persistent or intermittent elevation in ALT and AST levels. Patients not meeting these criteria may benefit from liver biopsy with treatment offered to those with histologically active or advanced liver disease. Patients with cirrhosis and positive HBV DNA should be offered treatment regardless of ALT and AST elevation to prevent decompensation of liver disease (development of jaundice, ascites, variceal bleeding). Although treatment can lead to viral suppression in HBeAg positive patients with normal ALT, the likelihood of HBeAg seroconversion (loss of HBeAg and developemend of HBeAb) is low. Treatment options for patients with chronic HBV include interferon (standard and pegylated) and nucleoside/tide analogs (lamivudine, adefovir, entecavir or tenofovir). The advantage of interferon is its finite duration of treatment, absence of resistant mutants and more durable response. On the other hand interferon has many side effects. Interferon should not be used in patients with advanced liver disease. Nucleoside/tide analogs have fewer side effects. The goal of treatment is to achieve HBeAg seroconversion, which is associated with negative HBV DNA when treatment is stopped. The goal of treatment is not to achieve loss of HBsAg, which occurs rarely.

Answer 515

The diagnosis of chronic HCV infection is presence of HCV RNA in the blood, which over many years to decades can ultimately lead to cirrhosis and hepatocellular carcinoma. The goal of antiviral therapy is to eradicate HCV RNA and to remain HCV RNA negative 12 weeks after antiviral therapy is stopped. This is termed a sustained virological response (SVR) and is considered a cure. The benefits of SVR include halting progression of liver disease and reducing HCC (although patients with cirrhosis may develop HCC after SVR and still need to be screened). The current standard of care for treating HCV genotype 1 has been pegylated interferon, ribavirin and an NS3/4a protease inhibitor (boceprevir or telaprevir) for 24-48 weeks. Patients with other genotypes are currently treated with pegylated interferon and ribavirin.

Answer 516

Many new therapies for HCV are under development that target the HCV-encoded proteins that are vital to the replication and life cycle of the virus. These include NS5A protein, NS5B RNA dependent RNA polymerase, NS3 RNA helicase and NS2/3 autoprotease. It is anticipated that in the near future interferon free regimens will be available and that within the next 5 years >90% of patients with HCV will be able to achieve SVR with treatment.

Answer 517

Hereditary hemochromatosis (HH) is an inherited disorder in which mutations in the HFE gene (i.e., C282Y, H63D) or other genes (e.g., hemojevulin, hepcidin, ferroportin) result in increased intestinal iron absorption. Early detection and treatment can prevent major causes of death in HH including decompensated cirrhosis, hepatocellular carcinoma, diabetes and cardiomyopathy. Survival is normal in patients in whom treatment is initiated before the development of cirrhosis or diabetes. The simplest and cheapest and most effective way to remove accumulated iron in non-anemic patients is therapeutic phlebotomy. Each 500 mL of whole blood removed contains 200-250 mg of iron. For a typical patient with HH, the estimated iron stores is 10 grams. One phlebotomy per week for one year should fully deplete the patient of accumulated iron. The endpoint of treatment is a serum ferritin of 50 ng/mL. Maintenance phlebotomy every 2-4 months should be done to maintain serum ferritin between 50-100 ng/mL. For anemic patients who would not tolerate phlebotomy, chelation therapy can be performed with desferoxamine.

Answer 518

Autoimmune hepatitis (AIH) is a chronic hepatitis characterized by immunologic and autoimmune features. The decision to treat is determined by degree of elevation in serum transaminases and/or histologic findings. The primary treatment is to suppress an overactive immune system. Treatment is typically with corticosteroids (initially prednisone 40-60 mg daily, lowered to 10-20 mg daily as disease is controlled. Azathioprine is also used to treat autoimmune hepatitis. Treatment can begin with both azathioprine and prednisone. The use of azathioprine allows for either no or lower doses prednisone to be used. The main side effect of azathioprine is reduction in the white blood cell count, nausea and rarely pancreatitis. Side effects of corticosteroids are many including weight gain, anxiety, osteoporosis, diabetes, high blood pressure and cataracts. Autoimmune hepatitis is a chronic disease and stopping therapy after normalization of serum transaminases typically results in a flair of AIH. There is a about a 50% chance of a flair of AIH with cessation of therapy after achieving a 2 year remission.

Answer 519

Primary sclerosing cholangitis (PSC) is an inflammatory disease of the intra- and extrahepatic bile ducts leading to bile duct strictures and obstruction and can ultimately lead to cirrhosis. There is no effective medical therapy for PSC. Treatment is focused on management of complications of biliary obstruction with stenting of strictures with endoscopic retrograde cholangioscopy and treating cholangitis with antibiotics. Liver transplantation is the only long-term treatment for the condition.

Answer 520

Wilson Disease is an autosomal recessive disorder leading to decreased hepatocellular excretion of copper into bile resulting in hepatic copper accumulation and injury. Eventually copper is released into the bloodstream and deposited into other organs such as the brain, kidney and cornea. Treatment consists of general chelators that induce cupria (loss of copper in the urine) such as D-penicillamine and trientine. Measuring 24-hour urinary copper excretion while on treatment monitors adequacy of treatment. With chronic (maintenance) treatment, urinary copper excretion should run in the vicinity of 200-500 mcg per day on treatment. Values of urine copper excretion

Answer 521

Non-alcoholic steatohepatitis (NASH) is the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. It can progress to cirrhosis and liver failure and rarely liver cancer. Its treatment largely revolves around modifying risk factors for NASH: 1) Obesity, 2) Type II diabetes mellitus, and 3) Dyslipidemia. Investigational therapies have included use of diabetes drugs (even if not associated with diabetes) and vitamin E – an antioxidant.

Answer 522

Type 1 Helper T cells, Th1, recognize antigen and make a lymphokine that attracts thousands of macrophages, the heavy-duty phagocytes, to the area where antigen has been recognized. The cytokines Th1 make are IFNγ, which attracts and activates M1 (inflammatory, destructive, “angry”) macrophages; and IL-2, which helps CTL get activated when they recognize antigen.

Answer 523

Th17 Helper T cells, Th17, are similar to Th1 in that their main role is to cause focused inflammation, although they are more powerful than Th1. Important in resistance to some tough organisms like Listeria, and to Candida. They have been implicated in some serious forms of autoimmunity, usually along with Th1. They make IL-17. Dendritic cells can make the IL-23 that pushes differentiation into Th17; a new monoclonal antibody (tildrakizumab) specific for IL- 23 is, in Phase 2 studies, remarkable effective in psoriasis. IBD will be next, as IL-23 is considered a central cytokine in Crohn Disease and possibly also ulcerative colitis.

Answer 524

Type 2 Helper T cells, Th2, stimulate macrophages to become M2 ‘alternatively activated,’ able to function in walling-off pathogens and promoting healing, a process that usually takes place after the pathogen-killing Th1 response. They are very important in parasite immunity if the Th1’s M1 macrophages can’t kill the invader. Th2 make IL-4 which attracts not only macrophages but also eosinophils.

Answer 525

Follicular Helper T cells, Tfh, are stimulated by antigen and migrate from T cell areas of lymph nodes into the B cell follicles, where they help B cells get activated and make the IgM, IgG, IgE and IgA antibody subclasses.

Answer 526

Regulatory T cells, Treg, make cytokines (IL-10, TGFβ) that suppress the activation and function of Th1, Th17, and Th2 cells, so they keep the immune response in check. They are part of the Th family.

Answer 527

Cytotoxic or killer T cells, CTL for short, destroy any body cell they identify as bearing a foreign or abnormal antigen on its surface, presented on Class I MHC. They can also make IFNγ which attracts macrophages to eat the cells in which they induce apoptosis.

Answer 528

Th1, Th2, Th17, Tfh, and Treg have a molecular marker, called CD4, on their surface, which increases their affinity for antigen, helps get them activated, and also serves us as a convenient tag for their identification. They all look for antigen on MHC class II (on macrophages, dendritic cells, and B cells).

Answer 529

Killers (CTL) have a related marker, CD8. They look for antigen on MHC Class I, on all nucleated cells.

Answer 530

Pre-T cells in the thymus begin proliferating rapidly and express a randomly assembled (from T-cell receptor V(D)J libraries) T cell receptor (TCR). They then examine the surfaces of stromal cells. Three fates are possible: non-selection, negative selection, and positive selection

Answer 531

If there is essentially no affinity between the TCR and the MHC on the stromal cells (which are always loaded with a self-peptide of some sort).

Answer 532

If there is high affinity for a self-peptide in MHC, the developing T cell is autoimmune, and dies by apoptosis. A significant proportion of these cells can turn into Tregs! They are called tTreg, and they serve to suppress Th1/2/17 as well as CTL that are mistakenly recognizing self tissues. If they are selectively knocked out in mice, generalized multi-organ autoimmunity results. But they don’t get inflammatory bowel disease.

Answer 533

If there is low affinity (above a certain threshold, but not high enough to activate the T cell) it is selected to mature and become part of the T cell repertoire. Positive selection takes place usually when the CDR 1s and CDR2s of both the TCR α and β chains interact adequately with amino acid residues on the alpha-helical sides of the peptide-binding MHC groove. This is not enough binding energy to activate the T cell, but enough for selection. In the periphery, if the peptide that loads into MHC makes appropriately strong contacts with the CDR3s of the α and β TCR chains, the total binding energy is now sufficient, and the T cell will be stimulated. Most of the variability of a TCR is in its CDR3s, especially the one on the beta chain, which is coded for by a bit of the V segment, the whole D and the whole J, as well as the 2 “N regions” between them where the “sloppiness” occurs.

Answer 534

Most helpers begin as an undecided precursor: Th0 (zero). These cells are found in the paracortex of lymph nodes, and corresponding positions in other secondary lymphoid tissues. When their correct antigen is brought to them by dendritic cells (DC), they begin to divide and differentiate, becoming either Th1, Th17, Th2, Tfh, or Treg cells. The previous experience of the DC—the conditions in the periphery when it was stimulated, what TLR were engaged, what cytokines and chemokines predominated—is the main determinant of the Th0’s ultimate progeny (this is an area we’re mostly guessing about). For most antigens, you end up with some of each; it’s the relative proportions that matter in deciding the functional outcome of the antigen exposure.

Answer 535

There is normally abundant TGFβ in the submucosal Peyer’s patches, and that favors the differentiation of Th0 cells into Treg. The resident dendritic cells here make IL-10, and that also favors Treg development. Thus these sites are rich in Treg cells, which is desirable considering the constant bombardment with bacteria- and food-derived, non-pathogenic, potential immunogens coming through the M cells of the gut epithelium. If a peptide comes in unaccompanied by damage or inflammation, you probably don’t want to make an immune response to it, so it’s good to make Tregs. Also very common in Peyer’s patches are Tfh that specifically drive B cells towards making IgA, so that the mucus layer nearest the epithelial cells that line the gut is, surprisingly, almost sterile. More than one group has suggested the Tregs can differentiate easily into such Tfh, and vice versa; a nice touch, as they’d both prevent harmful responses and help protective ones.

Answer 536

the combination of TGFβ and IL-6 has been shown to downregulate Treg and upregulate Th1 and Th17 (the CD4+ Th that makes IL-17 and is expanded by IL-23; both these cytokines are also common in areas of inflammation.1) IL-6 is produced by epithelial and other cells in response to stress or damage. This model links a lot of disparate observations. Normal commensal gut organisms have evolved to live in the lumen and not try to invade; the innate response to them, producing mostly TGFβ, would be at a low, steady level to which we have adapted by setting a cut-off, above which we switch from Treg production to the defensive Th1, Th17, or Th2.

Answer 537

The recognition of normal organisms is mostly carried out by innate immunity via PRR (pattern- recognition receptors) that bind various PAMPs. These include the TLRs we discussed right at the beginning last year, and several other PRR systems, including one called NOD2. NOD2 detects muramyl dipeptide, a component of bacterial cell walls, and triggers cytokine production by activating NF-κB.

Answer 538

The Treg in the gut are demonstrably different from those generated in the thymus, so they’re called iTreg (induced, by exposure to normal flora). They prevent chronic inflammation that would result from Th1/2/17 recognizing normal commensal flora; if they are knocked out in mice, IBD results, but not systemic autoimmunity (which we presume is still prevented by tTreg.)

Answer 539

Mice infected with Toxoplasma get sick, then recover. They make a strong Th1 response to Toxo (this might seem odd, because immunity to parasites is thought of as Th2-mediated; but this reminds us that Th1 come first, because if you can kill it, no necessity for last-ditch reliance on Th2 cells.) Histology showed that during the Toxo infection, commensal bacteria readily penetrate the gut and can be seen between and beyond the epithelial cells. The mice, their Treg suppressed by the serious infection, also make a very strong Th1 response to their own commensals. Now, this must be a decision point: if the mice are lucky, the Toxo resolves, Treg again become dominant, and the Th1 against commensals decrease, leaving behind a gut rich in memory cells; but these do not normally get activated. However, if you were an unlucky mouse with enough of the risk alleles, you might be unable to suppress (or might later reactivate) those Th1 cells against commensals, and then you’d be on the way to IBD. The authors suggest that a bout of serious gut infection (Listeria? E. coli?) might set susceptible people up for later IBD development.

Answer 540

This is seen almost exclusively in people who have the HLA-DQ2 or -DQ8 allele. These Class II MHC are uniquely able to present immunodominant peptides derived from gliadin (one of two kinds of gluten proteins) to Th1/Th17 cells. These peptides, with their chain-kinking prolines and bulky glutamine and glutamic acid side chains, are too awkward to fit into most MHC antigen- presenting grooves. Since up to a third of people have one of these alleles, it’s not surprising that celiac disease is common, but it’s not that common; bad luck must play a part, as well as other risk alleles. Increased gluten content in food? No, hasn’t happened. Too-early exposure of infants to gluten? No, say two 2014 studies reported in NEJM.

Answer 541

Probably not much in most people, though antibody to TTG2 can result in chronic skin inflammation (dermatitis herpetiformis) by cross- reaction with skin-associated TTG3. How is the antibody induced? Probably this way: when TTG2 is trying to cleave the highly branched and charged molecule gliadin, it may get “stuck” and become unable to release its substrate. Then you have a foreign molecule linked essentially covalently to a self-molecule. As you remember, this is the setup for “illicit help:” A B cell that’s anti-TTG2 (that never normally gets helped) takes up the complex, and presents foreign gliadin peptides to Tfh (specific for gliadin on DQ2 or DQ8), which then help the B cell make antibody to TTG2. Because this is happening in the gut, the class of the diagnostically-useful antibody is commonly IgA. Eventually, by epitope spreading, cross-reactivity to TTG3 appears. Note that celiac disease itself is not autoimmune, but dermatitis herpetiformis, if it appears, is. Also recall that these 2 HLA-DQ alleles also confer risk for Type 1 diabetes.

Answer 542

The essential requirements for diagnosis of non-celiac gluten sensitivity: Negative blood tests for celiac disease and no sign of damage on an intestinal biopsy. Symptom improvement when gluten is removed from the diet. Recurrence of symptoms when gluten is reintroduced. No other explanation for the symptoms.

Answer 543

It seems that there are people who suddenly develop intolerance to red meat. IgE antibody specific to galactose-α-1,3-galactose (alpha-gal) can be detected, and symptoms are those of delayed mild to severe anaphylaxis. Avoiding mammalian meat will prevent symptoms, and avoiding ticks leads to gradual loss of the sensitivity.

Answer 544

Galactose-α-1,3-galactose part of cell membranes of many organisms, but not of primates. The tick is a tiny hypodermic, and the Lone Star tick apparently makes a lot of alpha-gal in its drool (a different tick causes this syndrome in South America). Since it’s a parasite, the typical response to it will the Th2 cells, and the Th2-like Tfh that direct B cells to switch to making IgE. The IgE can then react against alpha-gal coming in with a load of meat.

Answer 545

Cirrhosis represents the end histological stage of chronic liver disease characterized by regenerative nodules surrounded by fibrous tissue. Generally it is irreversible. Initially, cirrhosis is compensated. The transition to a decompensated stage is marked by the development of variceal hemorrhage, ascites, hepatic encephalopathy and/or jaundice. Once decompensation occurs, the patient is at risk of dying. The complications of cirrhosis are largely the result of portal hypertension and/or liver insufficiency. Development of variceal hemorrhage and ascites are the direct consequence of portal hypertension, while jaundice occurs as a result of a compromised liver function. Encephalopathy is the result of both portal hypertension (portosystemic shunting) and liver dysfunction (decreased ammonia metabolism). Ascites in turn can become complicated by infection (spontaneous bacterial peritonitis) and by the development of a functional renal failure (hepatorenal syndrome).

Answer 546

Any patient with chronic liver disease is at risk for developing cirrhosis. Although the definitive diagnosis of cirrhosis is histological, various clinical features in the setting of chronic liver disease, may suggest the presence of cirrhosis. If these features are present, the diagnosis of cirrhosis can be confirmed non-invasively by imaging studies. However, the absence of these features does not rule out the presence of cirrhosis.

Answer 547

Commonly seen physical exam findings of cirrhosis include jaundice, spider angiomata, enlargement of the left lobe of liver, caput medusae, ascites, muscle wasting and splenomegaly.

Answer 548

With liver dysfunction there is hypoalbuminemia, a prolonged prothrombin time and hyperbilirubinemia. The presence of these findings, in the presence of chronic liver disease, indicates the possibility of cirrhosis. However, an even earlier more sensitive finding suggestive of cirrhosis is a low platelet count that occurs as a result of portal hypertension and hypersplenism.

Answer 549

Abdominal imaging (CT scan, ultrasound or MRI) can reveal a nodular liver with caudate lobe hypertrophy, ascites, splenomegaly, venous collaterals, recanulization of the umbilical vein and hepatocellular carcinoma. Liver biopsy is not necessary to diagnose cirrhosis if a patient with chronic liver disease presents with complications of cirrhosis or if abdominal imaging is diagnostic of cirrhosis. Liver biopsy is only necessary in confirming cirrhosis in a patient with chronic liver disease who lacks complications of liver disease or physical exam, laboratory or radiological findings consistent with cirrhosis. Liver biopsy is not required for liver transplantation evaluation.

Answer 550

Once cirrhosis has been diagnosed, there are a couple commonly used scoring systems to characterize the severity of one’s liver disease. One is the Child-Turcotte-Pugh (CTP) score. This scoring system was developed to predict the risk of mortality after surgical shunt surgery for variceal bleeding. The score is based on five parameters: encephalopathy, ascites, bilirubin, albumin and the prothrombin time. Each parameter is graded from 1 to 3, therefore the minimal score is 5 and the maximal score is 15. The minimal listing criterion for liver transplantation is a CTP score of 7. Another scoring system is the Model for End-Stage Liver Disease (MELD) score. This is a mathematical model that was originally developed to predict risk of death after placement of a transjugular portosystemic shunt (TIPS; see below). It has been shown to estimate the 3-month mortality in patients with cirrhosis and is used to rank patients on the liver transplant list. It is derived from total bilirubin, creatinine, and INR (prothrombin time).

Answer 551

Most complications of cirrhosis are the result of portal hypertension. In fluid mechanics, Ohm’s law states that pressure (P) is dependent upon flow (F) and resistance to flow (R). Therefore, portal hypertension can result from an increase in portal venous inflow, an increase in resistance to portal flow or an increase in both flow and resistance.

Answer 552

In cirrhosis, the initial mechanism leading to portal hypertension is an increase in intrahepatic vascular resistance. The increase in intra-hepatic vascular resistance has both static (structural) and dynamic (vasoactive) components. The deposition of fibrous tissue and the formation of nodules disrupt the architecture of the liver, leading to an increased resistance to portal blood flow. The vascular component is due to active vasoconstriction within the liver. Nitric oxide (NO), an endothelial-derived vasodilator, has been shown to be an important regulator of the vascular tone in various vascular beds including the intrahepatic vasculature. Normally, increases in flow and subsequent shear stress lead to an increase in perfusion pressure that in turn leads to a flow-dependent increase in NO production that serves to limit the increase in perfusion pressure. In cirrhosis, there is a reduction in endothelial NO release leading to further vasoconstriction and increased resistance.

Answer 553

Portal hypertension as a result of increased intrahepatic resistance leads to increased shear stress in the splanchnic vasculature which results in increase production of NO, resulting in splanchnic vasodilation and subsequently increased portal blood inflow, leading to further increases in portal hypertension. In more advanced cirrhosis (when ascites is present) there is an increase in translocation of bacteria from the gut that further increases NO production. The overall result is portal hypertension (P) from increased intrahepatic resistance (R) and increased portal venous inflow (F) from splanchnic vasodilation.

Answer 554

Although cirrhosis is the most common cause of portal hypertension, it is not the only one. Portal hypertension is classified according to the site of increased resistance. In cirrhosis, the site of increased resistance is sinusoidal.

Answer 555

The definitive method to establish the diagnosis of portal hypertension is to measure portal pressure. Since the portal system is not easily accessible given its location between two capillary beds measuring pressure directly either percutaneously or transhepatically are cumbersome and may be associated with complications. Hepatic vein catheterization with measurement of wedged and free pressures is the simplest, safest, most reproducible and most widely used method to indirectly measure portal pressure. It is customary to express measurements of portal pressure as the gradient between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP), the so called hepatic venous pressure gradient (HVPG). The systemic venous pressure (FHVP) is used as an internal zero reference point. It corrects for extraportal, intra-abdominal effects on portal pressure (e.g. ascites). The normal HVPG ranges from 3 to 6 mmHg. Table 3 summaries HVPG in differential diagnosis of portal hypertension.

Answer 556

Cirrhosis, through an increased intrahepatic resistance and an increased portal blood inflow, leads to portal hypertension and the subsequent formation of portal-systemic collaterals. Some of the most important collaterals are those that form through the dilatation of the coronary and gastric veins that then constitute gastroesophageal varices. Both development of varices and growth of small varices occur at a rate of 7-8% per year. Although there are no identified clinical predictors for the development of varices, factors associated with variceal growth are Child B/C cirrhosis, alcoholic etiology and presence of red wale marks on initial endoscopy. Factors other than pressure, such as volume of blood flow and local anatomic factors may contribute to the formation of varices.

Answer 557

The most important predictor of variceal hemorrhage is variceal size. The incidence of first variceal hemorrhage in patients with small varices is very small, at ~5% per year, while large varices bleed at a rate of ~15% per year. Rupture of a vessel occurs when the expanding force exceeds its maximal wall tension. The higher the tension, the greater the possibility of rupture. Tension in the varix (T) is directly proportional to transmural pressure (difference between the intravariceal and the intraluminal esophageal pressure) and to variceal radius (r) and is inversely proportional to variceal wall thickness. A large varix has a large radius and a thin wall and therefore a larger tension and a greater propensity to rupture.

Answer 558

As portal pressure results from both an increase in intrahepatic resistance and an increase in portal inflow, the three types of therapy for varices and variceal hemorrhage (pharmacotherapy, endoscopic therapy, shunt therapy) can be analyzed in this context. Vasoconstrictors (e.g., octreotide) act by causing splanchnic vasoconstriction thereby reducing portal blood inflow. As they decrease flow through collaterals, resistance at this level is slightly increased, resulting in a moderate reduction in portal pressure. Vasodilators theoretically act by causing intrahepatic vasodilatation thereby reducing intrahepatic resistance. Since the dynamic component of the increased intrahepatic resistance is not substantial, the expected decrease in portal pressure is moderate. Combining a vasoconstrictor with a venodilator theoretically will have a combined effect reducing both flow and resistance, thereby resulting in a more marked decrease in portal pressure. Endoscopic therapy (band ligation or sclerotherapy) is a local therapy that does not act on the mechanisms that lead to portal hypertension. Shunt surgery or TIPS (see below), by bypassing the liver (the site of increased resistance) maximally reduces resistance, leading to normalization of portal pressure. However, by bypassing the liver this therapy can lead to other complications such as encephalopathy and liver failure.

Answer 559

Portal hypertension can be corrected by creating a communication between the hypertensive portal system and low-pressure systemic veins, bypassing the liver (i.e., the site of increased resistance). This communication can be created surgically or by the transjugular placement of an intrahepatic stent that connects a branch of the portal vein with a branch of a hepatic vein, a procedure designated transjugular intrahepatic porto-systemic shunt (TIPS). TIPS is performed by advancing a catheter introduced through the jugular vein into a hepatic vein and into a main branch of the portal vein (Fig. 3). An expandable stent is then introduced connecting hepatic and portal systems, and blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein. The procedure is highly effective in correcting portal hypertension but can be associated with complications related to diversion of blood flow away from the liver, namely portal-systemic encephalopathy and liver failure.

Answer 560

Cirrhosis is the most common cause of ascites, accounting for 80% of cases. Peritoneal malignancy, heart failure and peritoneal tuberculosis are also common, accounting for another 15% of the cases. Less common causes of ascites include pancreatitis, hemodialysis and Budd-Chiari syndrome (hepatic vein thrombosis). Of the most common causes, cirrhosis and heart failure are portal sinusoidal hypertensive causes of ascites, while peritoneal malignancy and tuberculosis are non-portal hypertensive causes.

Answer 561

Elevated portal pressure gives rise to increase in NO production both in the splanchnic and systemic circulations. NO is a potent vasodilator that leads to splanchnic and systemic vasodilatation, decreased effective arterial blood volume, activation of neurohumoral systems (renin, angiotensin, aldosterone) and sodium and water retention, a key element in the pathogenesis of ascites. Additionally, in more advanced cirrhosis there is an increase in translocation of bacteria from the gut that leads to a further increase in NO production.

Answer 562

A diagnostic paracentesis should be performed in every patient who develops new ascites. Diagnostic paracentesis is a safe procedure that can be performed even in cirrhotic patients with coagulopathy. In patients in whom ascites cannot be localized by percussion or in whom a first attempt does not yield fluid, paracentesis should be performed under ultrasonographic guidance. It should also be routinely performed if and when a cirrhotic patient with ascites is hospitalized, because up to half the episodes of spontaneous bacterial peritonitis (SBP, see below) are community-acquired and may be asymptomatic. Diagnostic paracentesis is essential in patients with signs and symptoms of abdominal or systemic infections (fever, abdominal pain) or in those with renal dysfunction or encephalopathy as these may be the only evidence of spontaneous bacterial peritonitis.

Answer 563

For diagnostic paracentesis, 20-50 cc of ascites fluid is obtained. In patients with new onset ascites, the fluid should be routinely evaluated for albumin (with simultaneous estimation of serum albumin, total protein, polymorphonuclear (PMN) cell count and bacteriological cultures. Protein and the serum ascites albumin gradient (see below) are used for the differential diagnosis of ascites. Ascites PMN count and cultures are performed to determine the presence of infection (e.g. SBP). The following tests should be performed depending on individual circumstances: glucose and lactic dehydrogenase or LDH (if secondary peritonitis is suspected), amylase (if pancreatic ascites is suspected) and cytology (to exclude malignant ascites) acid-fast bacilli smear and culture and adenosine deaminase determination (to exclude peritoneal tuberculosis), triglycerides (if the fluid has a milky appearance, i.e. chylous ascites) and red blood cell count in cases in which the appearance of the fluid is unusually bloody.

Answer 564

The serum-ascites albumin gradient (SAAG) is based on the fact that, per Starling forces, oncotic-hydrostatic balance is the major controlling force determining the protein concentration of fluid in the peritoneal cavity. Calculating the SAAG involves measuring the albumin concentration of serum and ascitic fluid specimens and subtracting the ascitic fluid value from the serum value. The SAAG is a reflection of sinusoidal pressure, having been shown to directly correlate with HVPG. The SAAG cutoff value that best distinguishes patients in whom ascites is secondary to liver disease and those with malignant neoplasm is a SAAG of 1.1 g/dL. Interestingly, the SAAG value of 1.1 g/dL roughly corresponds to an HVPG of 11-12 mmHg, the threshold pressure that has been described as being necessary for the development of ascites in cirrhotic patients. The three main causes of ascites, cirrhosis, peritoneal pathology (malignancy or tuberculosis) and heart failure, can be easily distinguished by combining the results of both the SAAG and ascites total protein content. A SAAG ≥1.1 g/dL indicates ascites that is the result of sinusoidal hypertension. A SAAG 2.5 g/dL due to the loss of protein through a normal “leaky” sinusoid as oppose to the “capillarized” sinusoid seen in cirrhosis.

Answer 565

includes diuretics and sodium restriction, large volumen paracentosis, and TIPS

Answer 566

As ascites results from both an increased sinusoidal pressure and sodium retention, the different therapies for ascites can be analyzed in this context. Diuretics act at the level of sodium retention by increasing sodium excretion. Together with dietary sodium restriction they promote a negative sodium balance. Refractory ascites occurs in ~10% of cirrhotic patients. It can be either diuretic-intractable or diuretic-resistant. Diuretic intractable ascites is that in which diuretic-related complications prevent achieving a maximal dose of diuretics. Diuretic-resistant ascites is defined as that in which no response is achieved despite maximal diuretic therapy. The most common type, present in 80% of patients with refractory ascites is diuretic-intractable ascites.

Answer 567

Large volume paracentesis (LVP) is a local therapy that does not act on the mechanisms that lead to ascites formation. It consists of the direct removal of ascitic fluid from the peritoneal cavity through a needle. It is performed in association with albumin as a plasma volume expander in order to increase the effective arterial blood volume.

Answer 568

TIPS acts by decompressing the hepatic sinusoids and also increases the effective arterial blood volume by shunting portal venous blood into the systemic circulation. However, by bypassing the liver this therapy can lead to other complications such as encephalopathy and liver failure.

Answer 569

Hepatorenal syndrome (HRS) occurs in patients with advanced cirrhosis. As liver disease worsens, further reductions in systemic vascular resistance occur, leading to a further drop in effective arterial blood volume and increased activation of the neurohumeral systems which in addition to further sodium and water retention, leads to worsening ascites formation and renal vasoconstriction leading to renal dysfunction and if severe HRS from reduced glomerular filtration rate. It is a functional renal failure in that the kidneys of these patients have no significant histological abnormalities. HRS has been divided in 2 types based on clinical characteristics and prognosis. Type 1 HRS is a rapidly progressive renal failure, in which a doubling of serum creatinine (or halving of creatinine clearance) occurs within a 2–week period. Type 2 HRS is more slowly progressive and is associated with refractory ascites. Although survival is poor in all patients with HRS, the cumulative probability of survival is significantly worse in patients with HRS type 1 than in those with HRS type 2. Median survival in HRS type 2 is 6 months compared to only 2 weeks in HRS type 1.

Answer 570

The diagnosis of HRS is largely a diagnosis of exclusion. Any condition that leads to worsening of the hemodynamic status of the cirrhotic patient can lead to renal failure (NOT necessarily HRS). Factors that worsen vasodilatation are infection (particularly gram-negative infections), the use of nitrates alone (or other vasodilators such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) and large volume paracentesis without albumin infusion. Factors that decrease the effective arterial blood volume are blood loss (e.g. gastrointestinal hemorrhage), fluid losses through over diuresis or diarrhea (often induced by overdoses of lactulose). Factors that induce renal vasoconstriction are the use of non-steroidal anti-inflammatory drugs (NSAIDs) and factors that cause nephrotoxicity such as the use of aminoglycosides. Correctable conditions that lead to worsening of the hemodynamic status of the cirrhotic patient, that is, factors that worsen vasodilatation, factors that lead to decreased effective arterial blood volume and factors that lead to renal vasoconstriction, must be ruled out and treated before a diagnosis of HRS can be established. Major criteria in the diagnosis are outlined in Table 5.

Answer 571

HRS is a functional renal failure that results from hemodynamic abnormalities due to end-stage liver disease and severe portal hypertension. Therefore, the mainstay of therapy of HRS is liver transplantation. Liver transplantation for HRS is curative, if transplantation is performed within 4-6 weeks before irreversible ischemic damage occurs. Therapies that can “bridge” a patient to transplant are the combination of vasoconstrictors (that will act by ameliorating the vasodilatory state) combined with albumin (that will increase effective arterial blood volume). Terlipressin (not yet FDA approved) is a vasopressin analogue that has recently been shown to improve renal function from HRS. Its exact role in management of HRS remains to be determined.

Answer 572

Spontaneous bacterial peritonitis (SBP) is an infection of ascitic fluid that occurs in the absence of a hollow viscus perforation and in the absence of an intra-abdominal inflammatory focus such as an abscess, acute pancreatitis or cholecystitis. Any cirrhotic patient with ascites (uncomplicated or refractory) is at risk of developing SBP, a potential precipitating factor of the HRS.

Answer 573

Bacteria can migrate from the intestinal lumen to mesenteric lymph nodes and other extraintestinal sites, a process called bacterial translocation (BT). This process increases in various conditions commonly associated with Gram-negative infections such as burn, trauma or shock. Since Gram-negative bacteria are the most frequently isolated bacteria in SBP, BT has been proposed as the main mechanism in the pathogenesis of SBP. In experimental animals, BT is increased in cirrhotic animals with ascites but not in rats with pre-hepatic portal hypertension.

Answer 574

The most frequent presentations of SBP are fever, jaundice and abdominal pain. However, patients with SBP can present atypically with only encephalopathy or with evidence of shock. Importantly, up to one-third of the patients may be entirely asymptomatic. A high index of suspicion and early diagnosis are key in the management of SBP. A diagnostic paracentesis should be performed in any patient that presents with any symptom (abdominal pain) or sign (fever, abdominal tenderness) of SBP. Since encephalopathy and/or renal dysfunction may be the only evidence of bacterial infection in a cirrhotic patient, diagnostic paracentesis (and blood cultures) should also be performed in this setting. Since SBP is often asymptomatic and is often community-acquired, a diagnostic paracentesis should be performed promptly in any cirrhotic patient admitted to the hospital, regardless of cause for admission. The diagnosis of SBP is established with an ascitic fluid polymorphonuclear count (PMN) greater than 250/mm3.

Answer 575

Bacteria can be isolated from ascites in 40-50% of the cases even with sensitive methods (i.e. inoculation into blood culture bottles). Bacteria implicated in SBP are mostly gram-negative enteric organisms, accounting for 70-80% of cases. Gram-positive organisms are found in 20-30% of cases. SBP is mostly a monobacterial infection and the most commonly isolated organism is E. coli. Anaerobes and fungi very rarely cause SBP. Their presence should raise the suspicion of a secondary bacterial peritonitis.

Answer 576

Appropriate empiric antibiotic therapy is based on the administration of a safe antibiotic that will cover the most likely causative pathogens and should be initiated as soon as the diagnosis of SBP is established (ascites PMN count >250/mm3). Based on controlled and uncontrolled trials, the recommended antibiotics are third-generation cephalosporins (cefotaxime and ceftriaxone have been the most utilized) or amoxicillin-clavulanic acid, administered intravenously. In patients with uncomplicated SBP, oral ofloxacin has been shown to be as useful as intravenous cefotaxime, however the use of quinolones depends on the local prevalence of quinolone-resistant organisms. Aminoglycosides, however, should be avoided as they are associated with high incidence of renal toxicity in cirrhotic patients. The minimal duration of therapy should be at least 5 days although, in clinical trials, the median duration of therapy needed for a reduction in ascites PMN below 250/mm3 is 7 days.

Answer 577

Patients who have recovered from an episode of SBP have a 70% chance of developing another episode within the first year. Secondary prophylaxis is therefore justified in these patients. The only predictor of the development of SBP is the ascitic fluid protein concentration.

Answer 578

Hepatic encephalopathy (HE) is defined as the neuropsychiatric manifestations of cirrhosis of the liver. In cirrhosis, hepatic encephalopathy results from a combination of portosystemic shunting and failure to metabolize neurotoxic substances. Astrocytes are the only cells in the brain that can metabolize ammonia and, in hepatic encephalopathy, changes in the astrocytes are seen (Alzheimer’s type II astrocytosis). Ammonia, which crosses the blood-brain barrier, results in up-regulation of astrocytic peripheral-type benzodiazepine receptors which are the most potent stimulants of neurosteroid production. Neurosteroids are the major modulators of GABA, which results in cortical depression and hepatic encephalopathy.

Answer 579

The diagnosis of hepatic encephalopathy is based on history and physical exam findings. Ammonia levels are unreliable, and there is a poor correlation between the stage of encephalopathy and blood level of ammonia. Therefore, measurements of ammonia are not necessary. Psychometric tests such as the number connection test and the EEG are typically used in research studies and not for clinical diagnosis

Answer 580

Precipitating factors for hepatic encephalopathy include a high protein load, gastrointestinal bleeding or constipation, as well as infection and over diuresis (leading to azotemia and hypokalemia). Narcotics and sedatives by directly depressing brain function further contribute to hepatic encephalopathy. A commonly seen cause of chronic encephalopathy is the placement of the TIPS.

Answer 581

The mainstay of HE is lactulose (despite data lacking supporting its use). Lactulose acts by several mechanisms. The acidic pH decreases urease-producing bacteria which produce ammonia. The proton H+ produced combines with NH3 to give NH4+, which is non-absorbable, and results in ammonia excretion in stool. The cathartic effect of lactulose is also helpful. Reducing ammonia producing bacteria in the gut by using non-absorbable antibiotics (neomycin or rifaximin) is also useful. Change in dietary protein from an animal source to a vegetable source may also be beneficial. L-ornithine L-aspartate and benzoate may increase ammonia fixation in the liver. In patients who have a large portosystemic shunt in the absence of liver disease, occlusion of the shunt may be carried out.