GI Flashcards

Question

[GI Pharmacology] I. Drugs that treat acid-peptic disease 1. H2 receptor antagonists A. MOA B. Clinical indications C. Adverse effects

Answer 1

I. Acid-peptic disease - peptic ulcers, GERD, stress-related mucosal injury due to imbalance between factors that are aggressive (acid, pepsin, bile) vs defensive (blood flow, mucous, HC03-, prostaglandins) 1. H2 receptor antagonists - "-dines" eg ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), cimetidine (Tagamet) A. MOA - competitive inhibitors of histamine on H2 receptors - most effective at reducing nocturnal acid secretion - famotidine is most potent and no drug interactions B. Clinical indications - being replaced by PPIs but OTC versions heavily used i. GERD - for <3x week ii. Gastric and duodenal ulcers (Peptic ulcer disease) - bedtime administration C. Adverse effects - generally safe, most side effects with cimetidine (anti-androgenic --> galactorrhea, impotence, gynecomastia) - GI effects - lipophilic - cross placenta and breast milk --> do not use in pregnancy

Answer 2

2. Proton Pump Inhibitors (PPIs) - "azoles" eg omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid) * other -azoles are antifungals eg ketoconazole A. MOA - prodrug that is activated via protonation in acid --> forms covalent disulfide bond with the proton pump --> noncompetitive, irreversible inhibitor - suppress fasting and meal-stimulated acid secretion better than H2 antagonists B. Clinical indications - once daily dosing i. GERD - first line - most effective for tx of GERD ii. peptic ulcer disease - heal duodenal (and to lesser extent gastric) ulcers, faster healing and symptom relief than H2 antagonists iii. H. pylori associated ulcers - heal ulcer and eradicate organism (triple therapy with amoxicillin + clarithromycin; quadruple therapy with metronidazole) iv. NSAID-associated ulcers eg ibuprofen (Advil), naproxen (Aleve) C. Adverse effects - generally safe, some GI side effects - low bioavailability when taken with food - eat on empty stomach - suppresses gastric acid barrier --> ↑ gastric bacterial concentrations --> ↑ risk of enteric infections (eg C. difficile), respiratory infections - decreased Ca2+ absorption (needs acidic environment) --> worsens osteoporosis and bone fractures

Answer 3

3. Antacids A. MOA - weak bases - Mg(OH)2, Al(OH)3, CaC03 (Tums) - that react with gastric HCl --> salt + water - reduce gastric acidity as well as pepsin, which is inactive in pH>4 - work fast but weak in neutralizing ability B. Clinical indications i. intermittent heartburn ii. duodenal ulcers - but no gastric iii. GERD - antacid + alginic acid (Gaviscon) C. Adverse effects - gassy, bloated

Answer 4

4. Sucralfate - sucrose + Al(OH)3 A. MOA - viscous substance that is insoluble in water and has weak buffering action --> selectively binds necrotic ulcer tissue --> acts as a barrier to acid, pepsin, bile --> reestablish pH gradient in mucous layer B. Clinical indications - duodenal ulcers - prevention and healing; traveler's diarrhea C. Adverse effects - requires acidic conditions --> cannot be taken with PPIs, H2 antagonists, or antacids 5. Colloidal bismuth compounds - Pepto-Bismol A. MOA - same as sucralfate B. Clinical indications - H. pylori ulcers -direct antimicrobial activity, esp when combined with tetracycline and metronidazole 6. Misoprostol A. MOA - PGE1 analog --> ↑ production of mucous barrier and ↓ acid production B. Clinical indications - NSAID-induced ulcers - off label to induce labor C. Adverse effects - don't give to women of childbearing age (abortifacient), dose-dependent diarrhea

Answer 5

1. Metoclopramide (Reglan) A. MOA - blocks dopamine D2 receptors in area postrema (chemoreceptor trigger zone) --> increases esophageal clearance, raises LES pressure, and accelerates gastric emptying B. Clinical indications i. antiemetic - main use ii. prokinetic - symptomatic relief in pts with post-op gastric motor failure or diabetic gastroparesis iii. treats refractory heartburn - in combo with antisecretory agents (H2 antagonist, PPI) C. Adverse effects - many CNS effects --> extrapyramidal sx (Parkinsonism), anxiety, depression

Answer 6

*NOT ON STEP 1* 2. Lubiprostone (Amitiza) A. MOA - fatty acid from PGE1 that activates Type 2 Cl- channels in GI epithelial cells --> chloride-rich fluid secretion --> softens stool, increases motility, promotes BMs B. Clinical indication i. chronic idiopathic constipation ii. IBS with constipation C. Adverse effects - not for use in children (under 16) - nausea, diarrhea, headache 3. Linaclotide (Linzess) A. MOA - peptide agonist of guanylate cyclase that activates CFTR Cl- channel in GI epithelial cell --> chloride-rich fluid secretion --> softens stool, increases motility, promotes BMs - reduces pain by decreased activation of colonic sensory neurons B. Clinical indications i. chronic idiopathic constipation ii. IBS with constipation C. Adverse effects - not for use in children (under 16) - most common is diarrhea

Answer 7

1. Visceral pain - arises from irritation of visceral peritoneum, hollow viscera, and mesentery * visceral peritoneum - peritoneal covering over mesentery and solid organs A. Development - derived from splanchnic layer of lateral plate mesoderm B. Innervation - autonomic; visceral pain afferents travel with splanchnic SNS nerves and do not lateralize --> visceral pain perceived in midline - nerves run along blood vessels in mesentery - can associate location of pain with blood supply e.g. foregut (celiac), midgut (SMA), hindgut (IMA) C. Triggers - sense mechanical (tension, overdistension, mesenteric traction, visceral muscle spasm) and chemical (ischemia, inflammation) D. Characteristics -midline - poorly localized (low density of pain receptors, convergence onto same level of spinal cord) - not evoked equally from all organs (hollow>solid) E. Clinical - dull, deep-seated discomfort, crampy/colicky, aching - accompanied by autonomic sx (pain afferents run with autonomic nerves) --> diaphoresis, changes in HR and BP, nausea, diarrhea F. Referred pain - visceral pain perceived in superficial somatic structures due to convergence --> visceral afferents synapse onto same neurons in spinal cord as somatic afferents - diffuse (midline) --> then referred

Answer 8

2. Somatic pain - arises from irritation of parietal peritoneum (peritoneal lining of abdominal wall, pelvis, diaphragm) A. Development - derived from somatic layer of lateral plate mesoderm B. Anatomy - somatic; parietal pain afferents are spinal afferent nerves - skin, muscle and parietal peritoneum of abdominal wall innervated by the same T7-L1 spinal nerves --> pain lateralizes C. Triggers - detects peritonitis - inflammation of peritoneum secondary to illness in viscera (e.g. perforation) - fluid in abdomen common D. Characteristics - lateralized to specific quadrant - many sensory nerves with dense meshwork of free nerve endings - precise mapping of spinal nerves to spinal cord and cortex (not multiple organs coming to same level like the viscera) E. Clinical features - severe, sharp, knife-like pain - constant (not colicky), well-localized, worsens with movement F. Rigidity --> involuntary guarding due to reflex arc --> pain afferents come into spinal cord and synapse onto motor neurons going to abdominal wall musculature - differentiate from voluntary guarding bc patient cannot maintain that on inspiration

Answer 9

1. GI inflammation A. Luminal obstruction (eg stone, lymph node) --> response is secretion of fluid into lumen (distension) and reflex contraction --> increased pressure --> venous congestion and thrombosis of capillaries --> barrier disrupted and bacteria invade --> ischemia and inflammation --> focal abscess --> gangrenous necrosis and perforation B. Dull, periumbilical pain and nausea with luminal obstruction --> increasingly severe pain with venous congestion / ischemia --> constant, sharp, localized pain when inflamed organ perforates --> leads to parietal peritoneum inflammation "peritonitis" - appendicitis - RLQ - diverticulitis (usually in sigmoid colon) - LLQ

Answer 10

Bowel obstruction - cessation of BM and passage of gas, high pitched tinkling bowel sounds, colicky/crampy abdominal pain + nausea/vomiting 1. Small bowel obstruction - Causes, in order of likelihood: A- adhesions (from prior surgery), B- bulges (hernia), C- cancer B. Symptoms - obstruction leads to secretion of fluid into lumen and reflex contraction of smooth muscle to overcome obstruction --> abdominal distension 2. Large bowel obstruction - Cause - MCC is malignancy. most common benign cause is sigmoid volvulus (sigmoid colon twists on itself), more common in elderly

Answer 11

Congenital defects 1. Gastroschisis - full thickness abdominal wall defect that occurs to the right of umbilicus - due to abnormal folding of anterior abdominal wall during development (closes by 4 wks) --> exposure of abdominal contents / viscera (not covered by peritoneal sac) - emergency, needs immediate closure; higher survival rate (even with poorer GI function) bc not associated with other anomalies 2. Omphalocele - persistent herniation of bowel into umbilical cord --> covered by peritoneum and amnion lining, usually larger than gastroschisis - physiological herniation during development at 6 wks that allows bowels to develop then rotate and go back into the gut at 10 wks - worse prognosis bc of high risk of associated anomalies e.g. neuploidy, structural anomalies eg VACTERL --> Vertebral, Anal, Cardiac, TE fistula, Renal, Limb

Answer 12

3. Meckel diverticulum - most common congenital anomaly of GI tract; true diverticulum - outpouching of all 3 layers of bowel wall due to incomplete obliteration of vitelline duct (connects umbilicus to terminal ileum in utero) Rule of 2's: -2" long - found in distal ileum, within 2 ft of ileocecal valve - 2% of pop - presents at 2 yrs of age - 2 main presentations: A) acute appendicitis or B) hematochezia --> copious brick-red painless rectal bleeding - 2 epithelial types (pancreatic + gastric) 4. Diaphragmatic hernia - due to congenital defect of pleuroperitoneal membrane, more commonly occurs on left side where pericardioperitoneal canal is larger and closes later - hypoplastic lung on affected side with pulmonary HTN and hypoxemia - diagnosed on prenatal US, present at birth with respiratory distress (tachypnea, grunting, nasal flaring), cyanosis, absent bowel sounds, and scaphoid abdomen

Answer 13

1. Indirect inguinal hernia - goes through deep inguinal ring, superficial inguinal ring, and into scrotum --> covered by all three layers of spermatic fascia - lateral to inferior epigastric vessels - more common in younger males, due to patent processus vaginalis 2. Direct inguinal - goes through superficial inguinal ring and bulges through abdominal wall at Hesselbach's triangle (inferior epigastric vessels, rectus abdominus, inguinal ligament) - medial to inferior epigastric vessels - more common in older men, due to weakness in transversalis fascia 3. Femoral - protrudes through femoral canal inferior to inguinal ligament, and medial to femoral vein - more common in women, but most common hernia overall in women are inguinal - more likely to present with hernia or strangulation * (NAVEL from lateral to medial - nerve, artery, vein, empty lymphatic space)

Answer 14

1. Ventral mesentery - suspensory ligaments of liver (falciform, coronary, and triangular) + lesser omentum (hepatogastric + hepatoduodenal ligaments) - all others are dorsal 2. Pringle Maneuver - compress hepatoduodenal ligament (which contains portal triad - portal vein, common bile duct, and proper hepatic artery) to control bleeding

Answer 15

Crohn's 1. Epi - peak incidence in 20s, higher risk in smokers, genetic predisposition - linked to Th1 immune response (cell mediated immunity via IgG, IFNgamma, TNFalpha) 2. Pathology - transmural inflammatory disease that affects ANY part of GI tract from mouth to anus; terminal ileum most common site; rectum is spared 3. Appearance A. Macroscopic - skip lesions with cobblestone mucosa; creeping fat; strictures with "string sign" on imaging - Aphthous ulcers in mouth (i.e. canker sores) B. Microscopic - noncaseating granulomas throughout all three layers 4. Clinical - systemic symptoms, pain, abdominal mass, and large bowel obstruction more common than with UC A. Ileocolitis - RLQ pain with non-bloody diarrhea B. Jejunocolitis - malabsorption --> steatorrhea, nutritional deficiency eg B12 deficiency C. Colonic - large bowel diarrhea (tenesmus, bleeding, frequent small stools) D. Perianal - fistula, fissure, abscesses around anus 5. Complications - fistula (due to persistent inflammation), small bowel obstruction (due to strictures) 6. Extraintestinal - calcium oxalate kidney stones - normally oxalate in lumen combines with calcium to be excreted in stool - in Crohn's, unbound FFAs take up the Ca2+, so oxalate is reabsorbed in the colon --> hyperoxaluria --> kidney stones 7. Treatment - corticosteroids (e.g. prednisone, budesonide), antimetabolite (azathioprine), antibiotics (metronidazole, cipro), anti-TNF Abs (infliximab / Remicade, adalimumab / Humira)

Answer 16

Ulcerative colitis 1. Epi - peak incidence in 20s, smoking is protective, genetic predisposition - linked to Th2 (humoral immunity via IgE, IL-4,5,10,13) 2. Pathology - chronic inflammation of the mucosa (epithelium, lamina propria, and muscularis mucosa) and occasionally submucosa --> continuous and superficial - starts in rectum and extends proximally throughout colon 3. Appearance A. Macroscopic - continuous, symmetric lesions (NO skip lesions) ONLY in colon; pseudopolyps (regenerated mucosa); loss of haustra with "lead pipe" sign on X-ray B. Microscopic - crypt abscesses with neutrophils 4. Clinical - bloody diarrhea more common than with Crohn's - exacerbations and remissions; LLQ pain with bloody diarrhea [Crohn's is RLQ without blood in stool] - large bowel diarrhea with frequent small stools, tenesmus, and urgency - severe disease - diffuse abdominal tenderness + systemic symptoms 5. Complications - toxic megacolon - sudden onset fever, abdominal distension, no bowel function + severe bloody diarrhea, low BP and increased HR - colorectal cancer - increased risk with extent (entire colon) and duration (10+ years of disease) 6. Extraintestinal - primary sclerosing cholangitis (inflammation of bile ducts), associated with p-ANCA Treatment - 5-aminosalicylates (mesalamine), antimetabolite (6-MP), anti-TNF Abs (infliximab / Remicade)

Answer 17

Common Extraintestinal Manifestations A. Dermatologic i. Erythema nodosum - tender subcutaneous nodules on lower extremities (eg knees); due to IC depositions in fat venules with vasculitis ii. Pyoderma gangrenosum - neutrophil infiltrate of all layers of skin; inflammatory pustule that forms ulcer B.. Ocular i. Episcleritis - redness, burning ii. Uveitis - inflammation of choroid and retina; floaters C. Arthritis - nondestructive migratory arthritis; affects large joints

Answer 18

1. Appendicitis A. Causes: obstruction of appendix due to fecalith, tumor, ascaris hookworm - most common tumor of appendix is carcinoid tumor - DDx for young children should include Meckel diverticulum B. Clinical - obstruction --> dull visceral periumbilical pain (inflammation) --> ischemia, necrosis, perforation --> localized pain at RLQ McBurney point (peritonitis with guarding/rebound tenderness) with fever and nausea 2. Mesenteric lymphadenitis A. Cause - Yersinia enterocolitica (Gram negative encapsulated bacteria with bipolar safety-pin staining) --> invades M cells to spread to lymph nodes and terminal ileum B. Clinical - mimics appendicitis --> RLQ pain and bloody diarrhea - commonly seen in toddlers if transmitted through puppy poop and milk products

Answer 19

3. Angiodysplasia A. Cause - AV malformation of submucosal vessels - connection between artery and vein with no capillary bed --> dilated, tortuous submucosal veins - most commonly in cecum and right (ascending) colon - associated with ESRD, vWD disease B. Clinical - rupture of veins --> hematochezia (painless bright red blood in stool) in older adults 4. Colonic diverticula A. Cause - outpouching of only mucosa and submucosa through muscularis propria and serosa (false diverticulum) - due to wall stress (constipation, straining, low-fiber diet) - most commonly in sigmoid colon at weak point of vasa recta perforation B. Clinical - usually painless and asymptomatic, complications: i. diverticular (arterial) bleeding --> painless copious hematochezia, can stop spontaneously ii. diverticulitis - due to obstructing fecalith - inflamed diverticulum can cause microperforation of colonic wall --> appendicitis symptoms (peritonitis) but in LLQ iii. colovesicular fistula - inflamed diverticulum ruptures and attaches to bladder--> pneumaturia (air in urine) lower GI bleeding can also be due to vascular ectasias in patients 70+ years

Answer 20

5. Microscopic colitis - collagenous colitis + lymphocytic colitis A. Cause - biopsy shows increased intraepithelial lymphocytes or subepithelial collagen band B. Clinical - chronic, non-bloody watery diarrhea in middle-aged female; colonscopy, images normal 6. IBS A. Cause - disturbed intestinal motility; tests will be normal --> clinical diagnosis (can be confused with celiac disease); related to stress B. Clinical - young adult female with relapsing abdominal pain with bloating, flatulence and changes in bowel habits (diarrhea alternating with constipation)

Answer 21

7. C. difficile associated colitis (nosocomial) A. Cause - Clostridium difficile (spore-forming Gram-positive obligate anaerobic); use of clindamycin B. Clinical i. Exotoxin A - binds to intestinal brush border --> cell death, inflammation --> watery diarrhea (toxin in stool) ii. Exotoxin B - depolymerizes actin --> disrupts cytoskeleton --> pseudomembranous colitis (yellow-gray exudate) - treat with oral vancomycin or metronidazole --- 8. Ischemic colitis / bowel ischemia A. Cause i. mucosal - generalized hypoperfusion (SMA watershed areas - splenic flexure, sigmoid colon), shock/dehydration (low CO) ii. transmural - acute vascular occlusion via embolus (afib) or thrombosis, atherosclerosis (superior mesenteric artery) B. Clinical - severe, diffuse pain with pain out of proportion to physical findings; crampy abdominal pain + bloody diarrhea - usually on left side (more likely to be obstruction bc of narrowing of lumen) * benign physical exam --> no signs of peritonitis bc it takes time for damage to be transmural and affect parietal peritoneum - ischemia --> infarction --> necrosis / perforation --> sepsis

Answer 22

1. Familial adenomatous polyposis (FAP) A. Cause - AD mutation in APC (chromosome 5) --> ↑ beta catenin activity --> cell proliferation - MYH gene mutation if AR, fewer polyps B. Clinical - hundreds of adenomatous polyps throughout colon and rectum - need to be removed or will develop colorectal carcinoma (but can develop cancers elsewhere) C. Gardner Syndrome - FAP + fibromatosis + osteomas (benign skull tumor) D. Turcot Syndrome - FAP + CNS tumors (medulloblastoma + glial) 2. Juvenile Polyposis syndrome - multiple polyps in the stomach and polyp < 18 yo - 2/3 develop colorectal carcinoma - differentiate from sporadic, solitary hamartomas in kids <5 which are benign * harmartoma - benign growths which contain all tissue elements but are disorganized 3. Peutz-Jeghers Syndrome A. Cause - AD mutation B. Clinical - hamartomatous polyps throughout GI tract + mucocutaneous hyperpigementation (Freckle-like spots) on lips, oral mucosa, and genital - ↑ risk intussusception - increased risk of colorectal and breast cancer

Answer 23

Colorectal carcinoma (colon cancer) - 3rd MCC of cancer death, 3rd most common site of cancer 1. HNPCC - Hereditary non-polyposis colon cancer (Lynch Syndrome) A. Cause - AD inherited mutations in DNA mismatch repair enzymes --> microsatellite instability B. Clinical - de novo colorectal carcinoma, usually right sided (raised lesion) and in proximal colon; iron deficiency anemia - increased risk for other malignancies eg ovarian *typical presentation: elderly patient with change in bowel habits or new onset iron deficiency anemia* 2. Adenoma carcinoma sequence - second molecular pathogenesis pathway (first is mismatch repair) - APC mutations (first and second hits) - increase risk of polyp formation - K-RAS mutation - polyp formation - additional cancer suppressor mutations (p53, DCC) + COX overexpression - progression of adenoma to carcinoma; aspirin protective 3A. Right-sided (ascending colon) - raised lesion; presents with iron deficiency anemia (occult bleed bc blood mixes with stool) + fatigue; metastases to liver (isolated ↑ in ALP and GGT imply liver involvement) *IDA microcytic anemia is a red flag in men and postmenopausal women* B. Left-sided (descending colon) - napkin-ring lesion, presents with LLQ pain and bloody stool (hematochezia); more likely to have obstruction bc of narrowing of the lumen

Answer 24

1. Impaction - Hardened stool stuck in the rectum or lower colon A. Cause - Due to fecal retention (children) or neuromuscular disorders eg Parkinson's, ALS or chronic constipation (older adults) B. Clinical - incontinence, rectal bleeding or itching; stool can be palpated on DRE 2. Anal fissure A. Cause - tear in anal mucosa below pectinate line on posterior aspect of anal canal (area is poorly perfused) - low fiber diets, constipation B. Clinical - pain while pooping 3. Hemorrhoids - swollen and inflamed veins A. External - below pectinate line, arterial supply from inferior rectal artery (branch of interior pudendal artery) - somatic innervation from inferior rectal branch of pudendal nerve --> painful - lymphatics - superficial inguinal nodes B. Internal - above pectinate line, arterial supply from superior rectal artery (branch of IMA) - visceral innervation --> not painful - lymphatics - internal iliac nodes

Answer 25

1. Midgut volvulus A. Cause - twisted bowel due to malrotation around SMA axis during fetal development B. Clinical - presents few days after birth, rapid deterioration - bilious vomiting + "apple peel"/corkscrew spiral sign on imaging *sigmoid volvulus more common in elderly (large bowel obstruction) 2. Intussusception A. Cause - telescoping of proximal segment of bowel forward into distal segment (usually at ileocecal junction) --> obstruction and disruption of blood supply - kids - idiopathic, possibly viral infection (Rotavirus) --> lymphoid/Peyer's patch hyperplasia --> lead point (Meckel diverticulum is pathologic lead point) - adults - uncommon, due to lead point / tumor (malignant) B. Clinical - intermittent, colicky abdominal pain with currant jelly stools and palpable abdominal mass - bulls-eye on ultrasound 3. Necrotizing enterocolitis A. Cause - unknown, seen in premature, formula fed babies with immature immune system B. Clinical - necrosis of intestinal mucosa --> abdominal distension, vomiting, bloody stools - perforation --> pneumatosis intestinalis (air gas cysts in bowel wall), air in portal vein

Answer 26

1. Bowel obstruction in newborn - surgical emergency Cardinal signs: i. polyhydramnios ii. bilious vomiting iii. failure to pass meconium in first day iv. abdominal distension 2. Hirschsprung Disease A. Cause - congenital failure of neural crest ganglion cells to descend into Meissner (submucosal) plexus and Auerbach (myenteric) plexus --> bowel cannot relax - associated with Down syndrome - always involves rectum B. Clinical - failure to pass meconium within 48 hours, bilious vomiting - empty rectal vault on DRE - abdominal distension + megacolon dilated with feces and gas *meconium ileus is first manifestation of cystic fibrosis Layers of GI tract: mucosa - muscularis mucosa - submucosa (Meissner submucosal plexus) - muscularis propria (Auerbach myenteric plexus) - serosa

Answer 27

Acute pancreatitis 1. Diagnosis: A. Labs - high serum lipase (more specific) and amylase > 3x normal B. Clinical - acute epigastric pain radiating to the back (pancreas is retroperitoneal) C. Imaging - pancreas surrounded by edema (fluid in abdomen) --> body's response to try to temper the pancreatic enzymes 2. Pathogenesis - autodigestion of pancreas by pancreatic enzymes due to trypsin activation - reduced intracellular protective mechanisms to prevent trypsinogen activation (low Ca2+, SPINK1 inhibitor) - obstruction of of pancreatic duct due to tumor, mucus plugs due to CFTR mutation 3. Clinical - - severe epigastric pain radiating to back - nausea, vomiting, fever - pain aggravated by food - pain relieved by sitting up and leaning forward (relieves pressure on pancreas)

Answer 28

``` 1. I GET SMASHED I-idiopathic G- gallstones *MCC E- ethanol T- trauma S- steroids M- mumps A- autoimmune disease S- scorpion sting H- hypercalcemia/hypertriglyceridemia E- ERCP endoscopy procedure D- drugs causing violent abdominal distress --> Didanosine (HIV antiviral), Corticosteroids, Valproic acid, Azathioprine (6MP), Diuretics (furosemide, HCTZ) ``` 2. Gallstones (MCC) - due to gallstones that block common bile and pancreatic ducts --> ascending cholangitis + biliary pancreatitis alcohol - 2nd MCC (majority of acute pancreatitis is gallstones + alcohol) 3. Hyperlipidemia - when TG levels > 1000 mg/dL - eruptive xanthomas filled with chylomicrons with inflamed base (red ring); on extensor surfaces 4. Divisum - dorsal and ventral pancreatic ducts fail to fuse at 8 weeks - most common congenital anomaly of pancreas - usually asymptomatic but can cause pancreatitis

Answer 29

1. Forms A. Interstitial (80%) - swelling of cells, which are perfused --> diffuse enlargement and homogenous enhancement on imaging B. Necrotizing (20%) - bv are squeezed and no perfusion --> non-enhancing - can be sterile (70%) or infected (30%) 2. Markers of disease severity - older age - alcoholic pancreatitis - ↑ risk necrosis - obesity - ↑ BUN - signs of systemic inflammation (organ failure) - signs of fat necrosis and bleeding --> bruises 3A. Markers of organ failure: ↑ activation trypsin --> ↑ coagulation, complement --> vascular abnormalities - shock - systolic BP < 90 - pulmonary insufficiency - Pa02 < 60 mmHg --> ARDS - renal failure - Cr > 2 mg/Dl - GI bleeding > 500 mL/24 hr B. Pseudocyst - complication of acute pancreatitis; fluid collection surrounded by granulation tissue (not epithelium) --> persistently elevated amylase or early satiety

Answer 30

Chronic pancreatitis 1. Causes - alcohol (60%), idiopathic (25%), autoimmune, obstructive, genetic - in kids - most likely to be cystic fibrosis 2. Pathogenesis - chronic inflammation, atrophy, and calcification of the pancreas --> irreversible impairment of function; amylase and lipase may not be elevated 3. Clinical A. Early manifestation - recurrent epigastric pain associated with nerve involvement and/or dilatation of the duct B. Late manifestations - - steatorrhea (due to lack of lipase) + weight loss - diabetes mellitus - pancreatic calculi (dystrophic calcifications in pancreatic duct)

Answer 31

``` Pancreatic adenocarcinoma 1. Risk factors: A. Tobacco use B. Chronic pancreatitis C. Diabetes D. Age > 50 ``` 2. K-RAS, p16, p53, and DPC4/SMAD4 - precursor lesion with neoplasia and progression, similar to adenoma-carcinoma sequence in colon cancer - associated with CA 19-9 tumor marker - predicts course of disease - pancreatic carcinomas like to invade nerves 3. Clinical - persistent, aching abdominal radiating to back; increased by eating or lying supine (like acute pancreatitis) - pancreatic head tumor --> obstructive jaundice with dark urine, clay stools - extreme weight loss due to malabsorption + anorexia - Trousseau syndrome - migratory thrombophlebitis (blood clot in vein) with redness and tenderness on palpation of extremities due to hypercoagulable state - Courvoisier's law - distended/palpable, nontender gallbladder + obstructive jaundice --> cancer of gallstone or pancreas 4. Treatment - Whipple surgery, chemo, radiation

Answer 32

1. Neuroendocrine tumors (NET) - originate from multipotential cells in gut crypts (Kulchitsky and ECL cells), can be GI or pancreatic - small cells in sheets - positive silver stain - positive markers: neuron-specific enolase, chromogranin A, synaptophysin ``` 2. Syndrome - Manifestations Carcinoid - diarrhea, flushing, wheezing ZE - severe PUD, diarrhea Insulinoma - hypoglycemia VIPoma - secretory diarrhea Gucagonoma - diabetes, migratory necrolytic erythema Somatostatinoma - diabetes, gallstones GRFoma - acromegaly Non-functioning - nothing ```

Answer 33

1. Insulinoma - most common pancreatic NET A. Cause - tumor of pancreatic beta cells B. Clinical - overproduction of insulin --> hypoglycemia - ↑ insulin and C-peptide levels with glucose < 40 - Whipple's triad: hypoglycemia sx (sweating, tachycardia, weakness), low plasma glucose, sx relief when glucose increased C. Treatment - surgical resection 2. Zollinger-Ellison syndrome A. Cause - gastrin secreting tumor (gastrinoma) of pancreas or duodenum - associated with MEN1 B. Clinical - chronic unexplained diarrhea (malabsorption) + intractable ulcer disease + abdominal pain (due to recurrent ulcers) - positive secretin stimulation test --> gastrin levels are paradoxically elevated after giving secretin (gastrin inhibitor) C. Treatment - PPIs; side effects are fractures (need H+ for osteoclast activity and bone turnover) and B12 deficiency (parietal cells make IF)

Answer 34

3. VIPoma A. Cause - excessive release of VIP from pancreatic tumor B. Clinical - WDHA Watery Diarrhea Hypokalemia Achlorhydria (no stomach acid production) 4. Glucagonoma A. Cause - tumor of pancreatic alpha cells --> glucagon overproduction; pulling AA out of tissue to make glucose B. Clinical - dermatitis (migratory necrolytic erythema), diabetes (hyperglycemia), DVT, declining weight, depression 5. Somatostatinoma A. Cause - tumor of pancreatic delta cells --> somatostatin overproduction --> inhibition of cholecystokinin, glucagon, insulin, exocrine pancreas secretion - duodenal somatostatinoma associated with NF1 B. Clinical - gallstones, diabetes, diarrhea (due to steatorrhea) C. Treatment (for all) - surgery, octreotide (somatostatin analog)

Answer 35

Carcinoid syndrome A. Cause - due to carcinoid tumor - slow-growing malignant tumor of neuroendocrine cells --> secrete serotonin (5-HT) - in ileum (most common malignancy in small intestine) - associated with hypergastrinemia (seen in ZE or autoimmune gastritis) --> Gastrin stimulates neuroendocrine ECL cells --> dysplasia B. Clinical i. only local tumor effects (bleeding, pain, obstruction) if tumor is limited to GI tract --> serotonin has first pass metabolism in liver ii. if serotonin reaches systemic circulation --> carcinoid syndrome --> stimulates intestinal secretion and motility, inhibits absorption --> - recurrent diarrhea - facial flushing - right-sided valvular heart disease (tricuspid regurg, pulmonic stenosis) - increases with inspiration - bronchospasm --> difficulty breathing + asthmatic wheezing - tryptophan depleted to make serotonin --> niacin deficiency --> pellagra (diarrhea/dementia/C3-4dermatitis) - ↑ 5-HIAA in urine C. Treatment - somatostatin analog (octreotide), surgery

Answer 36

1. Bile - composed of bile salts (water soluble bc bile acids are conjugated to glycine or taurine), phospholipids e.g. lecithin, cholesterol, conjugated bilirubin, water, and ions - bile acid synthesis in hepatocyte: RLS is catalyzed by CYP7A1, primary bile acids conjugated to glycine and taurine to become hydrophilic, polar, better detergents 2. Bile functions A. Cholesterol excretion (body's only mechanism) B. Intestinal absorption of lipids and fat-soluble vitamins C. Controlling bacterial overgrowth (via membrane disruption) D. Hormone to regulate enterohepatic circulation 3. Gallbladder- concentrates hepatic bile - micelles allow bile to stay isotonic to plasma despite increased concentration - gallbladder is derivative of embryonic foregut; blood supply is cystic artery, branch of right hepatic

Answer 37

1. Cholesterol gallstones (80%) - mostly composed of crystalline cholesterol, also some bile pigments; radiolucent A. Pathophysiology - cholesterol supersaturation --> nucleation --> growth B. Risk factors: - female - ↑ estrogen ↑ hepatic secretion of biliary cholesterol; ↑ progesterone ↓ gallbladder motility - fat - ↑ HMG CoA reductase activity - forty - fertile (pregnant) - or multiparity + - too much cholesterol (diet, dyslipidemia, obesity) - reduced bile salt and phospholipids (lecithin) - rapid weight loss - Native American

Answer 38

2. Pigment stones A. Brown stones (18%) i. Location - bile ducts (Eg common bile duct); radiolucent - form in infected bile ii. Cause - biliary stasis, deconjugated bilirubin (insoluble and precipitates as calcium bilirubinate, the main component of brown stones) iii. Risk factors - biliary infections --> chronic parasitic infection e.g. Clonorchis, Ascaris - which produces beta-glucoronidase (deconjugates bilirubin) B. Black stones (2%) i. Location - exclusively in gallbladder; radiopaque - form in sterile bile ii. Cause - hyperbilirubinemia iii. Risk factors - - chronic liver disease (e.g. cirrhosis, Crohn's) - ineffective erythropoiesis (Vit B12/folate deficiency) - hemolysis (e.g sickle cell, thalassemias) - increased risk among patients with disease affecting terminal ileum (e.g. Crohn's ileal resection)

Answer 39

1. Biliary colic A. Cause - gallstone becomes impacted in cystic duct during gallbladder contraction - pain goes away when gallbladder relaxes and obstruction is relieved B. Clinical - sporadic episodes of epigastric or RUQ pain that radiates to right scapular tip + nausea/vomiting + diaphoresis - postprandial, esp consumption of fatty food - intense, dull, constant - not relieved by anything 2. Acute cholecystitis A. Cause - inflammation of gallbladder due to gallstone obstructing cystic duct - gallbladder wall thickening B. Clinical - constant, severe RUQ pain with radiation to scapula + nausea/vomiting + fever - Murphy's sign - inspiratory arrest on RUQ palpation due to pain - use ultrasound or HIDA scan to diagnose - thick walls and pericholecystic fluid 3. Porcelain gallbladder A. Cause - chronic cholecystitis B. Clinical - incidental finding on imaging --> calcified gallbladder --> associated with gallbladder cancer

Answer 40

1. Ascending / Acute cholangitis A. Cause - Choledocholithiasis (gallstone in the common bile) --> cholestasis --> dilatation and bacterial overgrowth (usually E. coli) --> ascending cholangitis (infection of the bile duct) B. Clinical - Charcot's triad with fever, RUQ pain, and jaundice - increased WBCs, and LFTs - hypotension, altered mental status (due to systemic infection) *emergency! can kill patients quickly 2. Gallstone pancreatitis A. Cause - gallstone in distal common bile duct that obstructs common channel Ampulla of Vater --> bile reflux into pancreatic duct --> inflammatory process B. Clinical - MCC of pancreatitis --> acute epigastric pain often radiating to the back, ↑ serum amylase/lipase 3. Gallstone ileus A. Cause - chronic impaction of stone --> inflammation --> biliary-enteric fistula (gallbladder to duodenum) --> gallstone erodes into GI tract and obstructs ileocecal valve B. Clinical - air in biliary tree *pathognomonic* - mechanical bowel obstruction

Answer 41

[Not on Step1] 1. Acalculous cholecystitis A. Cause - unclear; related to prolonged fasting or parenteral nutrition B. Clinical --> pigment stone 2. Empysematous cholecystitis A. Cause - Clostridia or E. coli B. Clinical - rapidly progressive gangrene with gallbladder perforation; surgical emergency! 3. Gallbladder cancer A. Cause - chronic inflammation due to gallstone, chronic infection due to Salmonella typhi, hereditary syndromes (eg Lynch), chemical exposures, calcification of gallbladder, primary sclerosing cholangitis 4. Mirizzi syndrome - gallstone in cystic duct compresses common hepatic duct --> obstructive jaundice (but common bile duct is normal)

Answer 42

1. Cleft lip and palate A. Cause - holoprosencephaly (failure of left and right hemispheres to separate), vitamin A teratogenicity B. Clinical - distinct midline facial defects that can occur together or alone, unilateral or bilateral - cleft lip: failure of fusion of maxillary and median nasal processes (formation of primary palate); more common, M>F - cleft palate: failure of fusion of lateral palatine shelves (formation of secondary palate); F>M 2. TEF A. Cause - most common type --> esophageal atresia with blind esophageal pouch + distal fistula (connection) between esophagus and trachea - due to failure of canalization - associated with cardiac anomalies B. Clinical - polyhydramnios in utero - 3C's: coughing, choking, cyanosis - neonates drool and vomit with first feeding - unable to pass nasogastric tube into stomach

Answer 43

1. Kwashiorkor A. Cause - protein deficiency, most common in toddlers bc they require high protein intake for growth - occurs in developing countries B. Clinical - soft, pitting painless edema with abdominal distension 2. Marasmus A. Cause - caloric and protein deficiency B. Clinical - muscle wasting, bradycardia, hypothermia, hypotension

Answer 44

1. Laxatives A. Bulk-forming laxatives (methyl cellulose, psyllium) - indigestible, hydrophilic colloids (plant fibers) that absorb water and form bulky gel --> distend colon and promote peristalsis B. Stool softeners (eg docusate, glycerin suppository) -lubricate stool and prevent absorption of water from stool --> reduces straining and promotes passage C. Osmotic laxatives (magnesium compounds e.g. Milk of Magnesia, lactulose, polyethylene glycol e.g. MiraLAX) - nonabsorbable substances that draw water into intestinal lumen --> distension --> peristalsis --> bowel movement - used for colonic cleansing prior to GI endoscopic procedures D. Stimulant cathartic laxatives (Senna, aloe vera) - stimulate enteric nervous system + secretion of colonic electrolytes + fluid into bowel --> induce BMs - can cause melanosis coli

Answer 45

2. Antidiarrheal agents *contraindicated in pts with inflammatory diarrhea (treat underlying cause) A. Opioid agonists - diphenoxylate (Lomotil) - prescription, cross BBB so CNS effects at high doses and must be prescriped with atropine - loperamide (Imodium) - OTC, does not cross BBB i. MOA: activate mu-opioid receptors in the GI tract --> increased colonic phasic segmenting activity and colonic transit time ii. Indications - diarrhea iii. Adverse effects - constipation (increase hydration and fiber) B. Somatostatin analog - octreotide i. MOA - inhibits secretion of hormones: - gastrin --> ↓ acid and pepsinogen secretion - CCK --> ↓ pancreatic secretions, gallbladder contraction - secretin --> ↓ pancreatic HC03- secretion - motilin --> ↓ peristalsis --> slowed GI motility - VIP --> ↓ intestinal fluid secretion and relaxation + inhibits GIP, GH, TSH, and prolactin ii. Indications - secretory diarrhea due to VIPoma or carcinoid tumor iii. Adverse effects - flatulence, abdominal pain, nausea - impaired pancreatic secretion --> steatorrhea, ADEK deficiency - inhibition of gallbladder contractility --> gallstones - long term --> hypothyroidism

Answer 46

3. IBS drugs A. Altered bowel habits i. predominant diarrhea --> opioid agonists to reduce frequency and urgency ii. predominant constipation --> increased dietary fiber + Cl- channel activators (linaclotide), osmotic laxatives (PEG), bulk-forming laxatives (psyllium) to soften stool and reduce straining B. Pain and severe IBS - chronic abdominal pain --> low doses TCAs without altering mood - severe diarrhea --> 5HT3 receptor antagonist (alosetron) to treat visceral pain bloating, nausea

Answer 47

4. IBD drugs A. 5-aminosalicylates (mesalamine) e.g. olsalazine i. MOA - work topically on diseased GI mucosa ii. Indication - first-line for UC B. Glucocorticoids (type of corticosteroid) - prednisone, prednisolone, budesonide (oral) - hydrocortisone (enema, foam, suppository) - to minimize systemic absorption i. MOA - suppresses immunity and inflammation ii. Indication - Crohn's iii. Adverse effect - Cushingoid C. Antimetabolites A. MOA - purine antimetabolites i. Indication - 6-MP for UC, azathioprine for Crohn's ii. Adverse effect - can cause hepatotoxicity D. Anti-TNF therapy i. MOA - inhibit TNF, key pro-inflammatory cytokine ii. Indication - infliximab (Remicade) for both severe Crohn's and UC - adalimumab (Humira) for severe Crohn's iii. Adverse effect - opportunistic infection from suppression of helper T cells --> fungal (Candida, Aspergillus)

Answer 48

A. 5-HT3 antagonists - "setron" --> ondansetron, granisetron, dolasetron, palonestron i. MOA - inhibits activation of 5HT3 receptors on vagal afferents by serotonin --> decreased vagal stimulation of nucleus tractus solitarius (medullary vomiting center) ii. Indications - chemo-induced vomiting, post-op vomiting - can cause constipation, headache, dizziness, or serotonin syndrome B. NK1R antagonists - aprepitant i. MOA - inhibit neurokinin 1 receptors in area postrema (chemoreceptor trigger zone) ii. Indication - chemo-induced vomiting C. H1 antihistamines - diphenhydramine (Benadryl), dimenhydrinate (Dramamine) i. MOA - inhibit histamine H1 receptors; first generation - vestibular system responsible for vertigo, motion sickness and contains H1 and M1 receptors ii. Indications - motion sickness

Answer 49

1. Causes of jaundice A. Prehepatic e.g. hemolytic anemia - ↑ indirect bilirubin, normal ALT/AST, normal ALP *B-E have ↑ unconjugated AND conjugated bilirubin (no value in fractionating)* B. Hepatocellular inflammation e.g. acute viral hepatitis - ↑ bilirubin, ↑ ALT/AST (>500), ALP moderately high (<300) * the only times AST/ALT ~ 1000 are acute viral hepatitis, ischemic hepatitis, and acetaminophen overdose C. Hepatocellular failure e.g. chronic liver disease - ↑ bilirubin, ALT/AST moderately high (<300), ALP moderately high (<300) D. Cholestasis (intrahepatic e.g. congenital or extrahepatic e.g. obstruction) - ↑ bilirubin, normal or moderately high AST/ALT, ↑ ALP (>300 or 3xnormal) *ALP v high (>300) in liver infiltration e.g. tumor, TB while AST/ALT are normal 2. Jaundice - clinical, seen when bilirubin > 3 mg/dL A. yellowing of skin, sclera, mucous membranes (due to conjugated and unconjugated bilirubin) - sclera detected first due to high elastin content B. dark cola-colored urine (due to soluble conjugated bilirubin in the urine; obstructive jaundice) - urine color changes precede yellowing of sclera C. clay-colored stools (due to absence of stercobilin; obstructive jaundice)

Answer 50

1. Transaminases - preformed enzymes produced by hepatocytes; released into plasma with hepatocellular necrosis and inflammation ALT - most specific for liver; upper limit normal (ULN) 40 AST - found in liver but also muscle and RBC; ULN 40 LDH - much less specific; ULN 200 - usually ALT >> AST (AST>ALT in alcoholic disease) 2. AST and ALT elevations A. Mild elevation (<150) - nonalcoholic fatty liver disease, chronic hepatitis, cirrhosis B. Moderate (150+) - acute hepatitis, drugs, alcohol C. Severe (800+) - acetaminophen, shock, fulminant liver failure - in acute hepatic illness/injury -- can go into the thousands 3. Zone 1: closest to portal triad (portal vein, hepatic artery, bile duct - where bile drains) - viral hepatitis, ingested toxins e.g. cocaine Zone 2: intermediate - yellow fever Zone 3: closest to central vein (where blood drains) - first affected by ischemia - contains CYP450 --> acetaminophen toxicity - alcoholic hepatitis, metabolic toxins

Answer 51

1. Unconjugated (indirect) hyperbilirubinemia A. Hemolytic anemia eg Beta thalassemia B. Physiologic in newborns due to immature UDP glucoronyltransferase (UGT1A1) --> phototherapy to make UCB more soluble to be excreted C. Crigler-Najjar syndrome (AR) - Type I - no UGT --> UCB is toxic and goes to brain (kernicterus) --> jaundice, lethargy, poor feeding, hearing loss, neurodevelopmental delays, paralysis of upwards gaze --> die in few years - Type II - less severe, responds to phenobarbital to increase bilirubin --> survive but jaundiced D. Gilbert syndrome (AR) - mildly decreased UGT; mild jaundice with stress and fasting, totally benign - -- 2. Conjugated (direct) hyperbilirubinemia A. Dubin Johnson (AR) - defective excretion of conjugated bilirubin from the hepatocyte into bile canaliculus; benign but grossly black liver B. Rotor (AR) - same as Dubin-Johnson but liver is NOT black

Answer 52

1. Cholestasis - deficient bile transit, can be complete or partial, macroscopic (due to obstruction) or microscopic (due to impairment of transport) --> biochemical markers identical 2. Biochemical markers of cholestasis A. ↑ alkaline phosphatase (ALP) - measured first; then gamma-glutamyl transpeptidase (GGT) --> ↑ in both suggests cholestasis - alk phos sources: liver, bone, kidney, placenta - GGT: sensitive indicator of alcohol use B. Bile components - bilirubin ↑ --> jaundice *can have cholestasis w/out jaundice* - bile salts ↑ --> pruritus, can be first presenting symptom - cholesterol ↑ - excretory products - copper ↑, higher drug levels - water and electrolytes - renally compensated 3. Hepatic infiltration - due to granuloma, abscess, or tumor --> similar to cholestasis but lacks elevated bilirubin, cholesterol, bile salts, or pruritus - elevated alk phos and GGTP - normal transaminases (~40) - normal bilirubin (~1)

Answer 53

Biliary tract disease - presents with cholestatic pattern of LFTs (↑ ALP, ↑ CB) and jaundice 1. Primary sclerosing cholangitis A. Cause - p-ANCA (+); ↑ IgM; "onion-skin" concentric bile duct fibrosis with beading ("beads on a string") due to strictures/dilation of bile ducts --> obliteration of bile ducts --> cirrhosis B. Clinical - in middle-aged men with ulcerative colitis - ↑ risk cholangiocarcinoma and gallbladder cancer 2. Primary biliary cirrhosis A. Cause - IgM anti-mitochondrial Ab (+) - autoimmune reaction --> lymphocytic infiltrate + granulomas in portal tract--> destruction of intrahepatic bile ducts (which are part of portal triad in liver acinus) B. Clinical - in middle aged women, associated with other autoimmune conditions (esp Sjogren, thyroid) - RUQ pain, fatigue, pruritis, jaundice + ↑ ALP/GGT, lipid, cholesterol (xanthoma) - cirrhosis --> ↑ risk hepatocellular carcinoma - treat with Ursodiol (ursodeoxycholic acid) - bile acid that enterohepatic recirculation --> lowers hepatic cholesterol secretion and delays progression of PBC 3. Secondary biliary cirrhosis A. Cause - extrahepatic biliary obstruction --> ↑ pressure in intrahepatic ducts --> injury/fibrosis and bile stasis B. Clinical - seen in patients with known obstructive lesions (gallstones, biliary strictures, pancreatic cancer)

Answer 54

Nonalcoholic fatty liver disease (NAFLD) - most common liver disease 1. Progression - reversible before cirrhosis - healthy --> NAFLD (25% of US population) --> nonalcoholic steatohepatitis NASH (25% of them) --> cirrhosis (25% of NASH pts) --> hepatocellular carcinoma - diagnosis of exclusion - need to biopsy 2. Two hit hypothesis A. First hit - fat accumulation --> NAFLD - metabolic syndrome: 3+ more of the following - hyperglycemia (>110 mg/dL), visceral/central obesity, dyslipidemia (>150 TAGs, <50 HDL), hypertension (>130/85) - diet - hypercalorific, fatty diet B. Second hit - inflammation --> NASH - mitochondrial dysfunction - omega-6 fatty acids and fructose --> pro-inflammatory (omega-3 is anti-inflammatory)

Answer 55

1. Acute viral hepatitis - systemic infection that predominantly affects liver A. Causes - Hepatitis viruses (A-E), other viruses (EBV, CMV, Coxsackie), IVDU, alcohol, ischemia, biliary tract disease B. Clinical - subclinical --> malaise, nausea/vomiting, low-grade fever, diarrhea --> dark urine, jaundice, hepatomegaly - pruritus due to cholestasis - elevated AST and ALT levels (ALT >> AST) 2. Serological markers A. HAV - IgM Ab for acute hepatitis A infection; IgG Ab indicates prior infection or vaccine and is protective B. HBV - in order of appearance HBsAg - surface antigen; indicates infection HBeAg - marker of active viral replication and infectivity, high HBV DBA in serum anti-HBc - IgM (active infection) - seen during window period; IgG (prior exposure/chronic) anti-Hbe - low transmitability, low HBV RNA anti-Hbs - recovery / immunity C. HCV - diagnose via anti-HCV Ab in serum, but most sensitive marker is HCV RNA in serum (v expensive test)

Answer 56

1. HAV (Acute, asymptomatic) A. Virus type - (+) sense, naked, SS RNA picornavirus - naked --> acid-stable (not destroyed by the gut) B. Transmission - fecal oral - developing countries - contaminated water supplies --> endemics - developed countries - shellfish; outbreaks in daycare centers C. Clinical - often asymptomatic - acute viral hepatitis: low-grade fever, nausea/vomiting, hepatomegaly, jaundice - no jaundice in kids D. Sequelae - no chronic carrier state E. Treatment - inactivated vaccine for high risk patients

Answer 57

2. Hepatitis B Virus (Blood, birthing, baby-making) A. Virus type - circular, partially dsDNA virus with envelope, surface coat (HBsAg), inner core (HBcAg) - host RNA polymerase transcribes mRNA --> HBV DNA polymerase reverse transcribes the RNA to dsDNA B. Transmission - blood (needlesticks), birthing (during delivery), baby-making (sexual) - endemic in SSA and SE Asia C. Clinical i. Most people are subclinical - mild serum sickness-like illness with fever, arthralgia, rash ii. polyarteritis nodosa (type 3 HSN) - medium vessel "beads on a string" vasculitis iii. membranous nephropathy - BM thickening with subepithelial "spike and dome" deposits iv. MPGN - Type I with subendothelial IC deposits and "tram-track" appearance due to BM splitting (more likely with HCV) D. Sequelae - adults: 90% recover without sequelae (Anti-HBs) - those that don't get chronic/carrier hepatitis (HBsAg, no Ab) --> cirrhosis --> hepatocellular carcinoma - fulminant hepatitis v rare - babies: 90% progress to chronic infection E. Treatment - recombinant hepatitis B vaccine to high risk groups and all children - neonates / exposed people - HBIg (immunoglobulin) + vaccine - pregnant women / chronic infection - NRTIs eg lamivudine, IFNalpha (treatment does not get rid of carrier state, only suppresses)

Answer 58

3. Hepatitis C Virus (Cirrhosis, Cancer, Carrier) A. Virus type - (+) sense, enveloped RNA flavivirus - lack of 3'-->5' exonuclease proofreading activity --> genetic heterogeneity in HCV envelope proteins B. Transmission - primarily blood (IVDU, blood transfusions) - HCV RNA in serum indicates infection C. Clinical - mild presentation, majority asymptomatic - acute viral hepatitis - jaundice, RUQ pain, ↑ ALT - chronic - ALT normalizes, lymphocyte aggregates in portal tract - fatigue D. Sequelae - >50% become chronic HCV --> cirrhosis --> small % get hepatocellular carcinoma Extraintestinal manifestations: - hematologic: Idiopathic thromboctopenic purpura, essential cryoglobulinemia (cryoglobulins of anti-HCV IgM that precipitate out in cooler temperatures) - renal: MPGN (subendothelial tramtrack deposits) - autoimmune: Sjogren's - dermatologic: lichen planus, porphyria cutanea tarda E. Treatment - ribavirin + IFNalpha, protease inhibitors (can eradicate/cure carrier state) - throw out any donated blood with anti-HCV

Answer 59

4. Hepatitis D Virus (Defective dependent) A. Virus type - enveloped, circular (-) sense RNA deltavirus B. Transmission - defective virus that requires HBV HBsAg (surface antigen) for infection; via IVDU, transfusion, or MSM - anti-HDV in serum C. Clinical - co-infection of HBV and HDV - similar to HBV - superinfection with HBV and then HDB --> worse prognosis; enhances severity of HBV with acceleration of chronic hepatitis --> cirrhosis --> hepatocellular carcinoma D. Sequelae - N/A E. Treatment - prevent in non-carriers with HBV vaccine (so HDV cannot be transmitted either)

Answer 60

5. Hepatitis E Virus (Enteric, Epidemic, Expectant) A. Virus type - naked, circular RNA hepevirus - naked --> acid-stable (not destroyed by the gut) B. Transmission - fecal oral (like HAV) - waterborne epidemics in developing countries C. Clinical - short incubation period - acute viral hepatitis - jaundice, nausea/vomiting, low-grade fever D. Sequelae - no carrier state - high mortality rate in pregnant women due to fulminant hepatitis (massive hepatic necrosis in absence of preexisting liver disease) E. Treatment - self-limited

Answer 61

1. Hepatic steatosis - can lead to cirrhosis A. Macrovesicular - more common, big fat lipid droplets due to obesity (NAFL), diabetes, alcoholism - more likely to be reversible B. Microvesicular - small intracytoplasmic fat vacuoles --> foamy cytoplasm - due to fatty liver of pregnancy, Reye's syndrome, HCV 2. Alcoholic hepatitis - long-term consumption; swollen and necrotic hepatocytes with neutrophilic infiltration; Mallory bodies - intracytoplasmic eosinophilic inclusions (damaged keratin filaments) - AST>>ALT (2:1) 3. Alcoholic cirrhosis - irreversible - shrunken liver with hobnail appearance - sclerosis around central vein in zone 3 - chronic liver disease --> jaundice, hypoalbuminemia

Answer 62

1. Budd-Chiari syndrome A. Cause i. pills and pregnancy - thrombophilic disorders, also Factor V Leiden ii. platelets (essential thrombocytosis) and polycythemia vera - myeloproliferative disorders iii. protein C deficiency and prothrombin mutations - hypercoagulable state - associated with hepatocellular carcinoma B. Pathophys - obstruction, congestion, necrosis --> hepatic veins are thrombosed or compressed C. Clinical - congestive liver disease "Budd Chiari syndrome" --> sudden onset RUQ pain, ascites, and hepatomegaly +/- varices - but no JVD (as in right heart failure) - nutmeg liver (blood backing up) - can be seen in right heart failure or Budd-Chiari

Answer 63

2. Reye syndrome A. Cause - in children with viral infection (VZV, Influenza B) given aspirin B. Pathophys - aspirin metabolites reversibly inhibit mitochondrial enzymes --> impairs oxidative phosphorylation and fatty acid beta oxidation in the liver C. Clinical - rapidly progressive encephalopathy (confusion, seizures, hypoglycemia, vomiting) with hepatic dysfunction (hepatomegaly due to microvesicular fatty change - can lead to coma and death - only children with Kawasaki disease (most common childhood vasculitis) should be given aspirin

Answer 64

Wilson disease A. Cause - AR mutation ATP7B gene --> in copper-transporting ATPase in hepatocytes B. Pathophys - inadequate excretion from liver into bile --> copper accumulates in liver, kidneys, brain, cornea, joints - ↓ ceruloplasmin (primary copper-carrying protein in the blood), ↑ urinary copper C. Clinical - presents in young adulthood, <40 yo i. liver disease - acute liver failure, cirrhosis ii. neurologic - parkinsonism (essential tremor) iii. Kayser-Fleischer rings (deposits in cornea) iv. renal - Fanconi syndrome (no reabsorption in PCT), hemolytic anemia

Answer 65

4. Fulminant hepatic failure A. Cause - drugs/toxins (acetaminophen), Budd-Chiari, Wilson's, microvesicular fat syndrome (e.g. Reye) - hepatitis viruses (A-E) -- most cases due to HBV B. Pathophys - massive hepatic necrosis in absence of preexisting liver disease - low AST and ALT bc no hepatocytes to dump out the preformed enzymes - prolonged PT, increased bilirubin, shrinking liver C. Clinical - confusion, disorientation, ascites, edema, jaundice - high mortality

Answer 66

1. Embryology - Bile ducts form from ductal plate 2. Choledochal cysts (bile duct cyst) A. Cause - congenital cystic dilatations of biliary tree B. Clinical - baby (~6 months) presents with cholestasis (↑ bilirubin, ↑ALP, ↑ GGTP) and RUQ pain, fever, jaundice, palpable mass - associated with cholangiocarcinoma (due to chronic inflammation) 3. Biliary atresia A. Cause - fibroproliferative obliteration of the extrahepatic biliary system (bile ducts) --> then affects intrahepatic - MCC of surgically correctible cholestasis and MCC of liver transplant in newborns B. Clinical - presents from birth to 8 weeks --> newborn with persistent jaundice (scleral icterus, dark urine) - usually isolated, can be associated with splenic malformation 4. Caroli's disease - saccular dilatation of the intrahepatic bile ducts - associated with ARPKD

Answer 67

1. Cavernous hemangioma - discrete red nodules in liver (abnormal proliferation of blood vessels in a bed of fibrous connective tissue) - most common benign incidental finding, usually in younger women - solitary, asymptomatic, growth static - biopsy contraindicated bc of risk of hemorrhage 2. Focal nodular hyperplasia - anomalous arterial structure in liver becomes hyperperfused --> hyperplasia of hepatic parenchyma containing biliary components and and subdivided into nodules by dense fibrous tissue - asymptomatic, solitary, in women - central stellate scar 3. Hepatic adenoma - uncommon benign epithelial tumor in otherwise normal liver; solitary, in right lobe - typical presentation: young woman with h/o of OCP use - risk factors: OCPs, anabolic steroids, pregnancy - pathology: large, non-functional cells with loss of normal architecture (no bile ductules) - clinical: incidental, but can rupture --> RUQ abdominal pain, hemorrhage + shock --> emergency! - risk of malignancy - remove all

Answer 68

Hepatic Cysts - most are incidental and benign, can be associated with ADPKD 1. Echinococcus granulosus (sheep worm) - humans ingest eggs from dog feces; MCC worldwide - solitary hydatid cyst with eggshell calcification - rupture --> anaphylaxis and acute abdomen (sudden, severe abdominal pain) 2. Entamoeba histolytica (protozoa parasite) - amoebic liver abscess with fever and dull RUQ pain, pus smells like anchovy - plus there are flask-shaped ulcers in the colon, fecal-oral transmission 3. S. bovis (Gram + cocci) --> colon cancer --> pyogenic hepatic abscess - fatal if untreated 4. Klebsiella (Gram - rod) - can cause liver abscesses as sole presenting clinical manifestation - "currant jelly" sputum, urease positive, nosocomial pneumonia 3A's - aspiration, alcoholics, abscesses

Answer 69

1. Hepatocellular carcinoma - most common malignant tumor in adults; 3rd leading cause of cancer deaths worldwide; M>F A. Causes i. in areas with high chronic HBV infection, high carrier rates (due to vertical transmission) ii. due to cirrhosis - HCV - alcohol - metabolic diseases of liver --> hemochromatosis, alpha-1 antitrypsin deficiency, Wilson, NASH iii. carcinogens - aflatoxin (aspergillus) - risk is peanuts B. Spread - spreads hematogenously (most carcinomas spread via lymphatics) and invades vessels - can lead to Budd-Chiari syndrome (block hepatic vein) C. Fibrolamellar type - genetic, in younger patients (<35yo), single hard "scirrhous" tumors, cells rich in mitochondria D. Clinical - vague (malaise, fatigue, anorexia, fullness), jaundice, hepatomegaly (RUQ pain) - ↑ alpha fetoprotein E. Metastatic disease - most common tumor in liver is metastatic disease from another site --> multiple tumors - in peritoneal cavity: colorectal, pancreas/stomach/ esophagus - breast, lung, melanoma

Answer 70

2. Hepatoblastoma - most common childhood liver tumor - associated with APC and beta catenin activity gene mutations - tumor marker is alpha fetoprotein 3. Cholangiocarcinoma - malignant tumor of biliary tree, from bile duct cells A. can be intrahepatic, perihilar (called "klatskin" tumor), distal - painless jaundice (Courvoisier) ddx - pancreatic cancer, cholangiocarcinoma B. Risk factors - liver fluke infestation (opisthorchis, clonorchis, ascaris) - primary sclerosing cholangitis - chronic choledocholithiasis - HBV, HCV - NASH 4. Angiosarcoma - malignant tumor of endothelial origin - associated with vinyl chloride (in PVC) and arsenic

Answer 71

Cirrhosis - liver fibrosis 1. Symptoms - general (nausea/vomiting, weakness, fatigue, anorexia) - diarrhea, abdominal distension, vague RUQ pain - pruritus - due to deposition of bile salts - signs of GI bleed --> hematemesis (bleeding from esophageal varices), hematochezia (bleeding from rectal varices) - confusion, sleep disturbance (mild hepatic encephalopathy) - women - amenorrhea - men - impotence, infertility 2. Lab findings - ↑ AST, ALT, ALP, GGT, bilirubin A. Anemia - microcytic (blood loss), macrocytic (folate deficiency in alcoholics) B. Pancytopenia due to hypersplenism (trapped in spleen) - especially low platelet count (thrombocytopenia) C. Hyponatremic, hypokalemic alkalosis (due to RAAS) D. Prolonged PT/INR (decrease in coagulation factors) --> 80% of liver has to be dead E. Hypoalbuminemia (produced by hepatocytes) --> 80% of liver has to be dead 3. Varices - esp esophageal, due to portal hypertension - prevent bleeding with non-selective beta blockers e.g. propanolol, nadolol - treat acute hemorrhage with ADH/vasopressin (constricts mesenteric arteries) and octreotide (splanchnic vasoconstriction)

Answer 72

3. Physical findings A. Vitals - splanchnic arteriolar vasodilation --> hyperdynamic circulation --> ↑ resting HR and CO, ↓ SVR and BP B. Dermatologic - jaundice - scleral icterus - spider angiomata (telangiectasia) C. fetor hepaticus - sweet pungent smell to breath due to ↑ dimethyl sulfide (indicates portal system shunting) D. men - gynecomastia due to ↑SHBG (higher affinity for testosterone than estrogen), ↑ androstenedione synthesis (↑ aromatization to E1/E2), spironolactone, testicular atrophy (alcohol is direct toxin) - altered sex hormone metabolism also causes palmar erythema

Answer 73

E. ascites - due to portal hypertension (also leads to varices) and plasma volume expansion --> decreased intravascular volume --> activates RAAS --> edema - treat with Na+ restriction, spironolactone, paracentesis - suspect spontaneous bacteria peritonitis if patient with cirrhotic ascites develops fever, increased PMN count * portal HTN can also be caused by schistosoma F. caput medusae - portal blood shunted to periumbilical veins --> umbilical vein --> abdominal wall veins - DDx includes IVC obstruction, where veins are more lateral G. hepatic encephalopathy - triggered by ↑ NH3 production (protein, GI bleeding, constipation) or ↓ clearance (renal failure, diuretics) --> confusion, memory loss, asterixis - treat with lactulose (increased conversion to NH4+) and neomycin or rifaximin (kills bacteria) [NOT ON STEP] - Cruveilhier-Baumgarten murmur - epigastrium venous hum caused by collateral connections between portal system and remnant of umbilical vein - Duputryen's contracture - pinky and ring finger, due to tenseness of tendon

Answer 74

Hemochromatosis 1. Cause - AR point mutation in HFE gene (C282Y in chromosome 6) - can also be secondary to chronic transfusion therapy 2. Pathogenesis - abnormal iron sensing due to ↓ hepcidin (main iron regulator) --> ↑ ferroportin (export into blood) and ↑ intestinal absorption --> ↑ serum iron, ↑ ferritin (storage form), ↑ transferrin saturation (iron / TIBC) --> iron accumulates in liver, skin, heart, pituitary, joints, pancreas 3. Clinical - presents after 40 yo - triad: skin hyperpigmentation, bronze diabetes, cirrhosis - dilated cardiomyopathy (reversible) --> mitral regurgitation (holosystolic murur at apex) - hypogonadism --> fertility problems e.g. loss of libido, impotence, amenorrhea - arthropathy (due to calcium pyrophosphate deposition) - hepatomegaly --> cirrhosis --> hepatocellular carcinoma (cause of death) 4. Treatment - hemosiderin on prussian blue stain - phlebotomy, chelation with deferoxamine, deferasirox *people with hemochromatosis at risk of infection with iron-eating bacteria: A) Listeria monocytogenes, B) Yersinia enterocolitica, C) Vibrio vulnificus

Answer 75

Alpha antitrypsin deficiency 1. Cause - ↓ apha antitrypsin; autosomal codominant disorder (PiMM normal, PiZZ is most common mutant) 2. Pathogenesis - - liver: misfolded gene product protein aggregates in hepatocyte ER - lungs: ↓ alpha antitrypsin --> uninhibited elastase in alveoli --> ↓ elastic tissue 3. Clinical - liver + lung disease at a young age - hepatic: fatigue, PAS (+) globules in liver --> cirrhosis * Whipple disease uses PAS stain to visualize macrophages in the villi - pulmonary: cough, dyspnea --> panacinar emphysema in lungs

Answer 76

1. Hepatorenal syndrome - liver causes damage to kidneys - poor blood flow to liver bc of fibrosis --> vasodilators released (prostaglandins and NO) --> dilation of splanchnic arterial beds --> worsens ascites and ↓ intravascular volume --> RAAS activated --> ↑ Ang II --> constricts BOTH efferent AND afferent arteriole --> ↓ GFR --> kidney failure - treat with midodrine (alpha agonist) and octreotide 2. Hepatopulmonary syndrome - PGs and NO also dilate pulmonary circulation --> create shunts --> V/Q mismatch (perfusion > ventilation) --> dyspnea, hypoxemia, and platypnea (SOB on standing, relieved by lying down; opposite of orthopnea)