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380 SEC TION III Gastrointestinal   gastrointestinal—Physiology Locations of gastrointestinal secretory cells Vagus nerve Fundus Cardia ACh ACh Parietal D cells HCl cells Somato- Antrum Body Histamine statin Intrinsic Mucus factor ECL cells Pyloric Pepsinogen ACh sphincter Chief CCK cells I cells S cells GRP Gastrin G cells (to circulation) Secretin Duodenum Mucous GIP cells K cells Gastrin  acid secretion primarily through its effects on enterochromaffin-like (ECL) cells (leading to histamine release) rather than through its direct effect on parietal cells. Pancreatic secretions Isotonic fluid; low flow Ž high Cl−, high flow Ž high HCO3−. ENZYME ROLE NOTES α-amylase Starch digestion Secreted in active form Lipases Proteases Fat digestion Trypsinogen Protein digestion Includes trypsin, chymotrypsin, elastase, carboxypeptidases Secreted as proenzymes also called zymogens Dipeptides and tripeptides degraded within intestinal mucosa via intracellular process Converted to active enzyme trypsin Converted to trypsin by enterokinase/ Ž activation of other proenzymes and cleaving enteropeptidase, a brush-border enzyme on of additional trypsinogen molecules into active duodenal and jejunal mucosa trypsin (positive feedback loop) Carbohydrate SGLT-1 Na+/K+- Only monosaccharides (glucose, galactose, absorption ATPase fructose) are absorbed by enterocytes. Glucose and galactose are taken up by SGLT1 (Na+ Na+ 3 Na+ GLUT-2 dependent). Fructose is taken up via facilitated Glucose or 2 K+ diffusion by GLUT5. All are transported to galactose Basolateral blood by GLUT2. GLUT-5 membrane Fructose d-xylose test: simple sugar that is passively Apical Enterocyte absorbed in proximal small intestine; blood membrane and urine levels  with mucosal damage, normal in pancreatic insufficiency.

Gastrointestinal   gastrointestinal—Physiology SEC TION III 381 Vitamin and mineral Vitamin and mineral deficiencies may develop absorption in patients with small bowel disease, bowel resection, intestinal failure (also called short Salivary R B12 P Animal bowel syndrome), or bariatric surgery (eg, R-protein protein vitamin B12 deficiency after terminal ileum resection). HCI Intrinsic IF factor Iron absorbed as Fe2+ in duodenum. Folate absorbed in small bowel. Duodenum B12 P Vitamin B12 absorbed in terminal ileum along Pepsin B12 R with bile salts, requires intrinsic factor. P Iron fist, Bro IF Pancreatic IF protease B12 B12 IF R R Ileum B12 IF B12 IF B12 IF Colon Terminal ileum Peyer patches Unencapsulated lymphoid tissue A found in Think of IgA, the Intra-gut Antibody A lamina propria and submucosa of ileum. Contain specialized Microfold (M) cells that sample and present antigens to iMmune cells. B cells stimulated in germinal centers of Peyer patches differentiate into IgA-secreting plasma cells, which ultimately reside in lamina propria. IgA receives protective secretory component and is then transported across the epithelium to the gut to deal with intraluminal antigen. uploaded by medbooksvn

382 SEC TION III Gastrointestinal   gastrointestinal—Physiology Bile Composed of bile salts (bile acids conjugated to  absorption of enteric bile salts at distal ileum Bilirubin glycine or taurine, making them water soluble), (as in short bowel syndrome, Crohn disease) phospholipids, cholesterol, bilirubin, water, prevents normal fat absorption and may cause and ions. Cholesterol 7α-hydroxylase catalyzes bile acid diarrhea. rate‑limiting step of bile acid synthesis. Calcium, which normally binds oxalate, binds Functions: fat instead, so free oxalate is absorbed by gut ƒ Digestion and absorption of lipids and fat- Ž  frequency of calcium oxalate kidney soluble vitamins stones. ƒ Bilirubin and cholesterol excretion (body’s 1° means of elimination) ƒ Antimicrobial activity (via membrane disruption) Heme is metabolized by heme oxygenase to biliverdin (green), which is subsequently reduced to bilirubin (yellow-brown). Unconjugated bilirubin is removed from blood by liver, conjugated with glucuronate, and excreted in bile. Direct bilirubin: conjugated with glucuronic acid; water soluble (dissolves in water). Indirect bilirubin: unconjugated; water insoluble. Bloodstream Conjugated (direct) Liver bilirubin RBC 90% Kidney UDP- Macrophage glucuronosyl- Enterohepatic Excreted in urine Heme transferase circulation as urobilin Unconjugated Gut 10% ( yellow color (indirect) of urine) bilirubin Gut 20% bacteria Albumin Urobilinogen 80% Unconjugated bilirubin-albumin Excreted in feces as stercobilin ( brown color of stool)

Gastrointestinal   gastrointestinal—Pathology SEC TION III 383 `  GASTROINTESTINAL — PAT H OLOGY Oral pathologies Also called canker sores. Common oral lesions that appear as painful, shallow, round to oval ulcers Aphthous ulcers covered by yellowish exudate A . Recurrent aphthous stomatitis is associated with celiac disease, IBD, SLE, Behçet syndrome, HIV infection. Squamous cell carcinoma Most common malignancy of oral cavity. Usually affects the tongue. Associated with tobacco, Sialolithiasis alcohol, HPV-16. Presents as nonhealing ulcer with irregular margins and raised borders. Leukoplakia (white patch B ) and erythroplakia (red patch) are precursor lesions. Sialadenitis Salivary gland tumors Stone formation in ducts of major salivary glands (parotid C , submandibular, or sublingual). Associated with salivary stasis (eg, dehydration) and trauma. Presents as recurrent pre-/periprandial pain and swelling in affected gland. Inflammation of salivary gland due to obstruction, infection (eg, S aureus, mumps virus), or immune-mediated mechanisms (eg, Sjögren syndrome). Usually benign and most commonly affect the parotid gland. Submandibular, sublingual, and minor salivary gland tumors are more likely to be malignant. Typically present as painless mass/ swelling. Facial paralysis or pain suggests malignant involvement. ƒ Pleomorphic adenoma (benign mixed tumor)—most common salivary gland tumor D . Composed of chondromyxoid stroma and epithelium and recurs if incompletely excised or ruptured intraoperatively. May undergo malignant transformation. ƒ Warthin tumor (papillary cystadenoma lymphomatosum)—benign cystic tumor with germinal centers. May be bilateral or multifocal. Typically found in people who smoke. “Warriors from Germany love smoking.” ƒ Mucoepidermoid carcinoma—most common malignant tumor. Mucinous and squamous components. AB CD Achalasia Failure of LES to relax due to degeneration Manometry findings include uncoordinated or of inhibitory neurons (containing NO and absent peristalsis with  LES resting pressure. A VIP) in the myenteric (Auerbach) plexus of Dilated esophageal wall. Barium swallow shows dilated esophagus with esophagus area of distal stenosis (“bird’s beak” A ). 1° achalasia is idiopathic. 2° achalasia may arise from Chagas disease (T cruzi infection) Treatment: surgery, endoscopic procedures (eg, or extraesophageal malignancies (mass effect botulinum toxin injection). or paraneoplastic). Chagas disease can cause achalasia. Presents with progressive dysphagia to solids and liquids (vs obstruction—primarily solids). Associated with  risk of esophageal cancer. uploaded by medbooksvn

384 SEC TION III Gastrointestinal   gastrointestinal—Pathology Other esophageal pathologies Gastroesophageal Transient decreases in LES tone. Commonly presents as heartburn, regurgitation, dysphagia. May reflux disease also present as chronic cough, hoarseness (laryngopharyngeal reflux). Associated with asthma. Complications include erosive esophagitis, strictures, and Barrett esophagus. Esophagitis Inflammation of esophageal mucosa. Presents with odynophagia and/or dysphagia. Types: ƒ Reflux (erosive) esophagitis—most common type. 2° to GERD. ƒ Medication-induced esophagitis—2° to bisphosphonates, tetracyclines, NSAIDs, ferrous sulfate, potassium chloride. ƒ Eosinophilic esophagitis—chronic, immune-mediated, eosinophil-predominant. Associated with atopic disorders (eg, asthma). Esophageal rings and linear furrows on endoscopy. ƒ Infectious esophagitis—Candida (most common; white pseudomembranes A ), HSV-1 (punched-out ulcers), CMV (linear ulcers). Associated with immunosuppression. ƒ Corrosive esophagitis—2° to caustic ingestion. Plummer-Vinson Triad of dysphagia, iron deficiency anemia, esophageal webs.  risk of esophageal squamous cell syndrome carcinoma (\"Plumber dies\"). May be associated with glossitis. Mallory-Weiss Partial thickness, longitudinal lacerations of gastroesophageal junction, confined to mucosa/ syndrome submucosa, due to severe vomiting. Often presents with hematemesis +/– abdominal/back pain. Usually found in patients with alcohol use disorder, bulimia nervosa. Esophageal varices Dilated submucosal veins (red arrows in B ) in lower 1/3 of esophagus 2° to portal hypertension. Common in patients with cirrhosis, may be source of life-threatening hematemesis. Distal esophageal Formerly called diffuse esophageal spasm. Spontaneous, nonperistaltic (uncoordinated) spasm contractions of the esophagus with normal LES pressure. Presents with dysphagia and anginalike chest pain. Barium swallow may reveal “corkscrew” esophagus. Manometry is diagnostic. Treatment includes nitrates and CCBs. Scleroderma Esophageal smooth muscle atrophy Ž  LES pressure and distal esophageal dysmotility Ž acid esophageal reflux and dysphagia Ž stricture, Barrett esophagus, and aspiration. Part of CREST syndrome. involvement Esophageal Most commonly iatrogenic following esophageal instrumentation. Noniatrogenic causes include perforation spontaneous rupture, foreign body ingestion, trauma, malignancy. May present with pneumomediastinum (arrows in C ). Subcutaneous emphysema may be due to dissecting air (signs include crepitus in the neck region or chest wall). Boerhaave syndrome—transmural, usually distal esophageal rupture due to violent retching. ABC

Gastrointestinal   gastrointestinal—Pathology SEC TION III 385 Barrett esophagus Specialized intestinal metaplasia (arrow in A )—replacement of nonkeratinized stratified A squamous epithelium with intestinal epithelium (nonciliated columnar with goblet cells [arrows in B ]) in distal esophagus. Due to chronic gastroesophageal reflux disease (GERD). Associated with  risk of esophageal adenocarcinoma. Esophagus Squamocolumnar (epithelial) junction B (SCJ or Z line) Lower esophageal sphincter Stomach Esophageal cancer Typically presents with progressive dysphagia (first solids, then liquids) and weight loss. Aggressive course due to lack of serosa in esophageal wall, allowing rapid extension. Poor prognosis due to CANCER advanced disease at presentation. Squamous cell PART OF ESOPHAGUS AFFECTED RISK FACTORS PREVALENCE carcinoma Upper 2/3 Alcohol, hot liquids, caustic More common worldwide Adenocarcinoma strictures, smoking, achalasia, nitrosamine-rich foods Lower 1/3 Chronic GERD, Barrett More common in America esophagus, obesity, tobacco smoking uploaded by medbooksvn

386 SEC TION III Gastrointestinal   gastrointestinal—Pathology Gastritis Erosions can be caused by: Especially common among patients with Acute gastritis ƒ NSAIDs— PGE2 Ž  gastric mucosa alcohol use disorder and those taking daily protection NSAIDs (eg, for rheumatoid arthritis) Chronic gastritis ƒ Burns (Curling ulcer)—hypovolemia H pylori Ž mucosal ischemia Burned by the Curling iron Autoimmune ƒ Brain injury (Cushing ulcer)— vagal Always Cushion the brain stimulation Ž  ACh Ž  H+ production Ménétrier disease Affects antrum first and spreads to body of A Mucosal inflammation, often leading to atrophy stomach (hypochlorhydria Ž hypergastrinemia) and intestinal metaplasia ( risk of gastric cancers) Affects body/fundus of stomach Most common.  risk of peptic ulcer disease, MALT lymphoma Autoantibodies (T-cell induced) to the H+/K+-ATPase on parietal cells and to intrinsic factor.  risk of pernicious anemia Hyperplasia of gastric mucosa Ž hypertrophied rugae (“wavy” like brain gyri A ). Causes excess mucus production with resultant protein loss and parietal cell atrophy with  acid production. Precancerous. Presents with Weight loss, Anorexia, Vomiting, Epigastric pain, Edema (due to protein loss; pronounce “WAVEE”). Gastric cancer Most commonly gastric adenocarcinoma; Virchow node—involvement of left A lymphoma, GI stromal tumor, carcinoid supraclavicular node by metastasis from (rare). Early aggressive local spread with node/ stomach. liver metastases. Often presents late, with Weight loss, Early satiety, Abdominal Pain, Krukenberg tumor—metastasis to ovaries Obstruction, and in some cases acanthosis (typically bilateral). Abundant mucin-secreting, Nigricans or Leser-Trélat sign (WEAPON). signet ring cells. ƒ Intestinal—associated with H pylori, dietary nitrosamines (smoked foods common in Sister Mary Joseph nodule—subcutaneous East Asian countries), tobacco smoking, periumbilical metastasis. achlorhydria, chronic gastritis. Commonly on lesser curvature; looks like ulcer with Blumer shelf—palpable mass on digital rectal raised margins. exam suggesting metastasis to rectouterine ƒ Diffuse—not associated with H pylori; most pouch (pouch of Douglas). cases due to E-cadherin mutation; signet ring cells (mucin-filled cells with peripheral nuclei) A ; stomach wall grossly thickened and leathery (linitis plastica).

Gastrointestinal   gastrointestinal—Pathology SEC TION III 387 Peptic ulcer disease Gastric ulcer Duodenal ulcer Can be greater with meals—weight loss Decreases with meals—weight gain PAIN ~ 70% ~ 90% H PYLORI INFECTION  mucosal protection against gastric acid MECHANISM NSAIDs  mucosal protection or  gastric acid secretion OTHER CAUSES Zollinger-Ellison syndrome RISK OF CARCINOMA  Generally benign Biopsy margins to rule out malignancy Not routinely biopsied Ulcer complications Gastric, duodenal (posterior > anterior). Most common complication. Hemorrhage Ruptured gastric ulcer on the lesser curvature of stomach Ž bleeding from left gastric artery. An ulcer on the posterior wall of duodenum Ž bleeding from gastroduodenal artery. Obstruction Perforation Pyloric channel, duodenal. A Duodenal (anterior > posterior). Anterior duodenal ulcers can perforate into the anterior abdominal cavity, potentially leading to pneumoperitoneum. May see free air under diaphragm (pneumoperitoneum) A with referred pain to the shoulder via irritation of phrenic nerve. Acute gastrointestinal Upper GI bleeding—originates proximal to bleeding ligament of Treitz (suspensory ligament of duodenum). Usually presents with hematemesis and/or melena. Associated with peptic ulcer disease, variceal hemorrhage. Lower GI bleeding—originates distal to ligament of Treitz. Usually presents with hematochezia. Associated with IBD, diverticulosis, angiodysplasia, hemorrhoids, anal fissure, cancer. uploaded by medbooksvn

388 SEC TION III Gastrointestinal   gastrointestinal—Pathology Malabsorption Can cause diarrhea, steatorrhea, weight loss, weakness, vitamin and mineral deficiencies. Screen for syndromes fecal fat (eg, Sudan stain). Celiac disease Also called gluten-sensitive enteropathy, celiac Associated with dermatitis herpetiformis,  bone A sprue. Autoimmune-mediated intolerance of density, moderately  risk of malignancy (eg, gliadin (gluten protein found in wheat, barley, T-cell lymphoma). rye). Associated with HLA-DQ2, HLA-DQ8, northern European descent. d-xylose test: abnormal. Serology: ⊕ IgA anti-tissue transglutaminase Primarily affects distal duodenum and/or proximal jejunum Ž malabsorption and (IgA tTG), anti-endomysial, and anti- steatorrhea. deamidated gliadin peptide antibodies. Histology: villous atrophy, crypt hyperplasia A , Treatment: gluten-free diet. intraepithelial lymphocytosis. Healthy Villous Gliadin villus atrophy G Gluten Villous atrophy Deamidated Tissue Intraepithelial gliadin transglutaminase (tTG) lymphocytes Intraepithelial G IFN-γ,IL-21 lymphocytes Crypt APC G T cell B cell hyperplasia HLA DQ 2/8 Anti-tTG Anti-deamidated gliadin Anti-endomysial Lactose intolerance Lactase deficiency. Normal-appearing villi, Lactose hydrogen breath test: ⊕ for lactose except when 2° to injury at tips of villi (eg, viral malabsorption if post-lactose breath hydrogen Pancreatic enteritis). Osmotic diarrhea with  stool pH value increases > 20 ppm compared with insufficiency (colonic bacteria ferment lactose). baseline. Tropical sprue Due to chronic pancreatitis, cystic fibrosis,  duodenal bicarbonate (and pH) and fecal obstructing cancer. Causes malabsorption of elastase. Whipple disease fat and fat-soluble vitamins (A, D, E, K) as well B as vitamin B12. d-xylose test: normal. Similar findings as celiac sprue (affects small  mucosal absorption affecting duodenum and bowel), but responds to antibiotics. Cause is jejunum but can involve ileum with time. unknown, but seen in residents of or recent Associated with megaloblastic anemia due to visitors to tropics. folate deficiency and, later, B12 deficiency. Infection with Tropheryma whipplei PASs the foamy Whipped cream in a CAN. (intracellular gram ⊕); PAS ⊕ foamy macrophages in intestinal lamina propria B filled with PAS ⊕ material. Cardiac symptoms, Arthralgias, and Neurologic symptoms are common. Diarrhea/steatorrhea occur later in disease course. Most common in older males.

Gastrointestinal   gastrointestinal—Pathology SEC TION III 389 Inflamm tory bowel diseases Crohn disease Ulcerative colitis LOCATION Any portion of the GI tract, usually the terminal Colitis = colon inflammation. Continuous ileum and colon. Skip lesions, rectal sparing. colonic lesions, always with rectal involvement. GROSS MORPHOLOGY Transmural inflammation Ž fistulas. Mucosal and submucosal inflammation only. Cobblestone mucosa, creeping fat, bowel Friable mucosa with superficial and/or wall thickening (“string sign” on small bowel deep ulcerations (compare normal B with follow-through A ), linear ulcers, fissures. diseased C ). Loss of haustra Ž “lead pipe” appearance on imaging. MICROSCOPIC MORPHOLOGY Noncaseating granulomas, lymphoid aggregates. Crypt abscesses/ulcers, bleeding, no granulomas. COMPLICATIONS Malabsorption/malnutrition, colorectal cancer ( risk with pancolitis). Fistulas (eg, enterovesical fistulae, which can Fulminant colitis, toxic megacolon, perforation. cause recurrent UTI and pneumaturia), phlegmon/abscess, strictures (causing obstruction), perianal disease. INTESTINAL MANIFESTATION Diarrhea that may or may not be bloody. Bloody diarrhea (usually painful). EXTRAINTESTINAL MANIFESTATIONS Rash (pyoderma gangrenosum, erythema nodosum), eye inflammation (episcleritis, uveitis), oral ulcerations (aphthous stomatitis), arthritis (peripheral, spondylitis). Kidney stones (usually calcium oxalate), 1° sclerosing cholangitis. Associated with MPO- gallstones. May be ⊕ for anti-Saccharomyces ANCA/p-ANCA. cerevisiae antibodies (ASCA). TREATMENT Glucocorticoids, azathioprine, antibiotics (eg, 5-aminosalicylic acid preparations (eg, ciprofloxacin, metronidazole), biologics (eg, mesalamine), 6-mercaptopurine, infliximab, infliximab, adalimumab). colectomy. DISEASE ACTIVITY Fecal calprotectin used to monitor activity and distinguish from noninflammatory diseases (irritable bowel). ABC Microscopic colitis Inflammatory disease of colon that causes chronic watery diarrhea. Most common in older females. Colonic mucosa appears normal on endoscopy. Histology shows lymphocytic infiltrate in lamina propria with intraepithelial lymphocytosis or thickened subepithelial collagen band. uploaded by medbooksvn

390 SEC TION III Gastrointestinal   gastrointestinal—Pathology Irritable bowel Recurrent abdominal pain associated with ≥ 2 of the following: syndrome ƒ Related to defecation ƒ Change in stool frequency ƒ Change in form (consistency) of stool No structural abnormalities. Most common in middle-aged females. Chronic symptoms may be diarrhea-predominant, constipation-predominant, or mixed. Pathophysiology is multifaceted. May be associated with fibromyalgia and mood disorders (anxiety, depression). First-line treatment is lifestyle modification and dietary changes. Appendicitis Acute inflammation of the appendix (blue arrow in A ), can be due to obstruction by fecalith (in A adults) or lymphoid hyperplasia (in children). Proximal obstruction of appendiceal lumen Ž closed-loop obstruction Ž  intraluminal pressure Ž stimulation of visceral afferent nerve fibers at T8-T10 Ž initial diffuse periumbilical pain Ž inflammation extends to serosa and irritates parietal peritoneum. Pain localized to RLQ/ McBurney point (1/3 the distance from right anterior superior iliac spine to umbilicus). Nausea, fever; may perforate Ž peritonitis. May elicit psoas, obturator, and Rovsing (severe RLQ pain with palpation of LLQ) signs; guarding and rebound tenderness on exam. Treatment: appendectomy. Diverticula of the GI tract Diverticulum Blind pouch A protruding from the alimentary “True” diverticulum—all gut wall layers tract that communicates with the lumen of outpouch (eg, Meckel). the gut. Most diverticula (esophagus, stomach, duodenum, colon) are acquired and are “False” diverticulum or pseudodiverticulum— termed “false diverticula.” only mucosa and submucosa outpouch. Occur especially where vasa recta perforate Diverticulosis Many false diverticula of the colon B , muscularis externa. Diverticulitis commonly sigmoid. Common (in ~ 50% of people > 60 years). Caused by  intraluminal Often asymptomatic or associated with vague pressure and focal weakness in colonic wall. discomfort. Associated with obesity and diets low in fiber, high in total fat/red meat. Complications include diverticular bleeding (painless hematochezia), diverticulitis. Inflammation of diverticula with wall thickening (red arrows in C ) classically Complications: abscess, fistula (colovesical causing LLQ pain, fever, leukocytosis. Treat fistula Ž pneumaturia), obstruction with supportive care (uncomplicated) or (inflammatory stenosis), perforation (white antibiotics (complicated). arrows in C ) (Ž peritonitis). Hematochezia is rare. AB C Serosa Muscularis layer Submucosa Mucosa True diverticulum False diverticulum

Gastrointestinal   gastrointestinal—Pathology SEC TION III 391 Zenker diverticulum Pharyngoesophageal false diverticulum A . Thyropharyngeus A Esophageal dysmotility causes herniation of muscle mucosal tissue at an area of weakness between Killian triangle the thyropharyngeal and cricopharyngeal parts Cricopharyngeus of the inferior pharyngeal constrictor (Killian muscle triangle). Presenting symptoms: dysphagia, Zenker obstruction, gurgling, aspiration, foul breath, diverticulum neck mass. Most common in older males. Trachea Meckel diverticulum True diverticulum. Persistence of the vitelline The rule of 2’s: (omphalomesenteric) duct. May contain 2 times as likely in males. Umbilicus ectopic acid–secreting gastric mucosa and/or 2 inches long. Meckel pancreatic tissue. Most common congenital 2 feet from the ileocecal valve. diverticulum anomaly of GI tract. Can cause hematochezia/ 2% of population. melena (less common), RLQ pain, Commonly presents in first 2 years of life. intussusception, volvulus, or obstruction near May have 2 types of epithelia (gastric/ terminal ileum. pancreatic). Diagnosis: 99mTc-pertechnetate scan (also called Meckel scan) for uptake by heterotopic gastric mucosa. Hirschsprung disease Congenital megacolon characterized by lack Risk  with Down syndrome. of ganglion cells/enteric nervous plexuses Explosive expulsion of feces (squirt sign) Nerve plexus (Auerbach and Meissner plexuses) in distal segment of colon. Due to failure of neural crest Ž empty rectum on digital exam. Enlarged cell migration. Associated with loss of function Diagnosed by absence of ganglion cells on rectal colon mutations in RET. suction biopsy. No nerves Presents with bilious emesis, abdominal Treatment: resection. distention, and failure to pass meconium RET mutation in the REcTum. within 48 hours Ž chronic constipation. Collapsed Normal portion of the colon proximal to the rectum aganglionic segment is dilated, resulting in a “transition zone.” uploaded by medbooksvn

392 SEC TION III Gastrointestinal   gastrointestinal—Pathology Malrotation Anomaly of midgut rotation during fetal Liver Stomach A development Ž improper positioning of bowel dd bands (small bowel clumped on the right side) A , formation of fibrous bands (Ladd bands). La Can lead to volvulus, duodenal obstruction. Small bowel Colon Intussusception Telescoping of a proximal bowel segment into Intussuscipiens A a distal segment, most commonly at ileocecal Intussusceptum junction. Typically seen in infants; rare in Volvulus adults. Sigmoid A colon Usually idiopathic in children, less frequently due to an identifiable lead point. Idiopathic form is associated with recent viral infections (eg, adenovirus), rotavirus vaccine Ž Peyer patch hypertrophy may act as a lead point. Common lead points: ƒ Children—Meckel diverticulum, small bowel wall hematoma (IgA vasculitis). ƒ Adults—intraluminal mass/tumor. Causes small bowel obstruction and vascular compromise Ž intermittent abdominal pain, vomiting, bloody “currant jelly” stools. Physical exam—sausage shaped mass in right abdomen, patient may draw their legs to chest to ease pain. Imaging—ultrasound/CT may show “target sign” A . Twisting of portion of bowel around its mesentery; can lead to obstruction and infarction. Can occur throughout the GI tract. ƒ Gastric volvulus more common with anatomic abnormalities (paraesophageal hernia), and presents with severe abdominal pain, dry heaving, and inability to pass nasogastric tube ƒ Midgut volvulus more common in infants and children (minors) ƒ Sigmoid volvulus (coffee bean sign on x-ray A ) more common in older adults (seniors)

Gastrointestinal   gastrointestinal—Pathology SEC TION III 393 Other intestinal disorders Acute mesenteric Critical blockage of intestinal blood flow (often embolic occlusion of SMA) Ž small bowel ischemia necrosis A Ž abdominal pain out of proportion to physical findings. May see red “currant jelly” stools. Risk factors: atrial fibrillation, peripheral arterial disease, recent MI, CHF. Angiodysplasia Tortuous dilation of vessels Ž hematochezia. Most often found in the right-sided colon. More common in older patients. Confirmed by angiography. Associated with end-stage renal disease, von Willebrand disease, aortic stenosis. Chronic mesenteric “Intestinal angina”: atherosclerosis of celiac artery, SMA (most commonly affected), or IMA ischemia Ž intestinal hypoperfusion Ž postprandial epigastric pain Ž food aversion and weight loss. Colonic ischemia Crampy abdominal pain followed by hematochezia. Commonly occurs at watershed areas (splenic flexure, rectosigmoid junction). Typically affects older adults. Thumbprint sign on imaging due to mucosal edema/hemorrhage. Ileus Intestinal hypomotility without obstruction Ž constipation and  flatus; distended/tympanic abdomen with  bowel sounds. Associated with abdominal surgeries, opiates, hypokalemia, sepsis. No transition zone on imaging. Treatment: bowel rest, electrolyte correction, cholinergic drugs (stimulate intestinal motility). Necrotizing Seen in premature, formula-fed infants with immature immune system. Necrosis of intestinal enterocolitis mucosa (most commonly terminal ileum and proximal colon), which can lead to pneumatosis intestinalis (arrows in B ), pneumoperitoneum, portal venous gas. Proctitis Inflammation of rectal mucosa, usually associated with infection (N gonorrhea, Chlamydia, Campylobacter, Shigella, Salmonella, HSV, CMV), IBD, and radiation. Patients report tenesmus, rectal bleeding, and rectal pain. Proctoscopy reveals inflamed rectal mucosa (ulcers/vesicles in the case of HSV). Rectal swabs are used to detect other infectious etiologies. Small bowel Normal flow of intraluminal contents is interrupted Ž fluid accumulation and intestinal dilation obstruction proximal to blockage and intestinal decompression distal to blockage. Presents with abrupt onset of abdominal pain, nausea, vomiting, abdominal distension. Compromised blood flow due to excessive dilation or strangulation may lead to ischemia, necrosis, or perforation. Most commonly caused by intraperitoneal adhesions (fibrous band of scar tissue), tumors, and hernias (in rare cases, meconium plug in newborns Ž meconium ileus). Upright abdominal x-ray shows air-fluid levels C . Management: gastrointestinal decompression, volume resuscitation, bowel rest. Small intestinal Abnormal bacterial overgrowth in the small intestine (normally low bacterial colony count). Risk bacterial overgrowth factors: altered pH (eg, achlorhydria, PPI use), anatomical (eg, small bowel obstruction, adhesions, fistula, gastric bypass surgery, blind loop), dysmotility (eg, gastroparesis), immune mediated (IgA deficiency, HIV). Presents with bloating, flatulence, abdominal pain, chronic watery diarrhea, malabsorption (vitamin B12) in severe cases. Diagnosis: carbohydrate breath test or small bowel culture. ABC uploaded by medbooksvn

394 SEC TION III Gastrointestinal   gastrointestinal—Pathology Colonic polyps Growths of tissue within the colon A . Grossly characterized as flat, sessile, or pedunculated on the basis of protrusion into colonic lumen. Generally classified by histologic type. HISTOLOGIC TYPE CHARACTERISTICS Generally nonneoplastic Hamartomatous Solitary lesions do not have significant risk of transformation. Growths of normal colonic tissue polyps with distorted architecture. Associated with Peutz-Jeghers syndrome and juvenile polyposis. Hyperplastic polyps Most common; generally smaller and predominantly located in rectosigmoid region. Occasionally evolves into serrated polyps and more advanced lesions. Inflammatory Due to mucosal erosion in inflammatory bowel disease. pseudopolyps Mucosal polyps Small, usually < 5 mm. Look similar to normal mucosa. Clinically insignificant. Submucosal polyps May include lipomas, leiomyomas, fibromas, and other lesions. Potentially malignant Adenomatous polyps Neoplastic, via chromosomal instability pathway with mutations in APC and KRAS. Tubular B histology has less malignant potential than villous C (“villous histology is villainous”); tubulovillous has intermediate malignant potential. Usually asymptomatic; may present with occult bleeding. Serrated polyps Neoplastic. Characterized by CpG island methylator phenotype (CIMP; cytosine base followed by guanine, linked by a phosphodiester bond). Defect may silence mismatch repair gene (eg, MLH1) expression. Mutations lead to microsatellite instability and mutations in BRAF. “Saw-tooth” pattern of crypts on biopsy. Up to 20% of cases of sporadic CRC. AB C Sessile Pedunculated Polyposis syndromes Autosomal dominant mutation of APC tumor suppressor gene on chromosome 5q21-q22. 2-hit Familial adenomatous hypothesis. Thousands of polyps arise starting after puberty; pancolonic; always involves rectum. polyposis Prophylactic colectomy or else 100% progress to CRC. Gardner syndrome FAP + osseous and soft tissue tumors (eg, osteomas of skull or mandible), congenital hypertrophy of retinal pigment epithelium, impacted/supernumerary teeth. Turcot syndrome Peutz-Jeghers FAP or Lynch syndrome + malignant CNS tumor (eg, medulloblastoma, glioma). Turcot = Turban. syndrome Autosomal dominant syndrome featuring numerous hamartomatous polyps throughout GI tract, Juvenile polyposis along with hyperpigmented macules on mouth, lips, hands, genitalia. Associated with  risk of syndrome breast and GI cancers (eg, colorectal, stomach, small bowel, pancreatic). MUTYH-associated polyposis syndrome Autosomal dominant syndrome in children (typically < 5 years old) featuring numerous hamartomatous polyps in the colon, stomach, small bowel. Associated with  risk of CRC. Autosomal recessive disorder of the MUTYH gene responsible for DNA repair. Associated with significantly  risk of CRC, polyps (adenomatous; may be hyperplastic or serrated), and serrated adenomas. Also associated with duodenal adenomas, ovarian and bladder cancers.

Gastrointestinal   gastrointestinal—Pathology SEC TION III 395 Lynch syndrome Also called hereditary nonpolyposis colorectal cancer (HNPCC). Autosomal dominant mutation of mismatch repair genes (eg, MLH1, MSH2) with subsequent microsatellite instability. ∼ 80% Colorectal cancer progress to CRC. Proximal Colon is always involved. Associated with Endometrial, Ovarian, and Skin cancers. Merrill Lynch has CEOS. EPIDEMIOLOGY RISK FACTORS Most patients are > 50 years old. ~ 25% have a family history. PRESENTATION Adenomatous and serrated polyps, familial cancer syndromes, IBD, tobacco use, diet of processed DIAGNOSIS meat with low fiber. A Rectosigmoid > ascending > descending. Most are asymptomatic. Right side (cecal, ascending) associated with occult bleeding; left side B (rectosigmoid) associated with hematochezia and obstruction (narrower lumen Ž  stool caliber). Ascending—exophytic mass, iron deficiency anemia, weight loss. Descending—infiltrating mass, partial obstruction, colicky pain, hematochezia. Can present with S bovis (gallolyticus) bacteremia/endocarditis or as an episode of diverticulitis. Iron deficiency anemia in males (especially > 50 years old) and postmenopausal females raises suspicion. Screening: ƒ Average risk: screen at age 45 with colonoscopy (polyp seen in A ); alternatives include flexible sigmoidoscopy, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), FIT-fecal DNA, CT colonography. ƒ Patients with a first-degree relative who has colon cancer: screen at age 40 with colonoscopy, or 10 years prior to the relative’s presentation. ƒ Patients with IBD: screen 8 years after onset. “Apple core” lesion seen on barium enema x-ray B . CEA tumor marker: good for monitoring recurrence, should not be used for screening. Molecular Chromosomal instability pathway: mutations in APC cause FAP and most sporadic cases of CRC pathogenesis of (commonly right-sided) via adenoma-carcinoma sequence. colorectal cancer Microsatellite instability pathway: mutations or methylation of mismatch repair genes (eg, MLH1) cause Lynch syndrome and some sporadic CRC via serrated polyp pathway. Overexpression of COX-2 has been linked to CRC, NSAIDs may be chemopreventive. Chromosomal instability pathway Loss of tumor suppressor Loss of APC gene KRAS mutation gene(s) (TP53, DCC) Normal colon Colon at risk Adenoma Carcinoma Intercellular adhesion Unregulated Tumorigenesis Proliferation intracellular signaling uploaded by medbooksvn

396 SEC TION III Gastrointestinal   gastrointestinal—Pathology Cirrhosis and portal Cirrhosis—diffuse bridging fibrosis (via stellate Serum ascites albumin gradient (SAAG)— hypertension cells) and regenerative nodules disrupt normal difference between albumin levels in serum architecture of liver;  risk for hepatocellular and ascitic fluid. A carcinoma. Can lead to various systemic changes A . Etiologies include alcohol, SAAG = albuminserum – albuminascites nonalcoholic steatohepatitis, chronic viral Used to evaluate the etiology of ascites. hepatitis, autoimmune hepatitis, biliary SAAG ≥ 1.1 = portal hypertension. disease, genetic/metabolic disorders. SAAG < 1.1 = consider other causes. Portal hypertension— pressure in portal Neurologic venous system. Etiologies include cirrhosis Hepatic encephalopathy (most common cause in developed countries), Asterixis (”flapping tremor”) vascular obstruction (eg, portal vein thrombosis, Budd-Chiari syndrome), schistosomiasis. Gastrointestinal Anorexia Integumentary Nausea, vomiting Jaundice Dull abdominal pain Fetor hepaticus Spider angiomas* Palmar erythema* Hematologic Thrombocytopenia Purpura Anemia Petechiae Coagulation disorders Splenomegaly E ects of portal hypertension Renal Hepatorenal syndrome Esophageal and gastric varices Metabolic Hyperbilirubinemia ( hematemesis/ Hyponatremia melena) Cardiovascular Vascular Cardiomyopathy Caput medusae Peripheral edema Anorectal varices Ascites Spontaneous bacterial peritonitis Reproductive Testicular atrophy* Gynecomastia* Amenorrhea *Due to estrogen

Gastrointestinal   gastrointestinal—Pathology SEC TION III 397 Spontaneous bacterial Also called 1° bacterial peritonitis. Common and potentially fatal bacterial infection in patients peritonitis with cirrhosis and ascites. Often asymptomatic, but can cause fevers, chills, abdominal pain, ileus, or worsening encephalopathy. Commonly caused by gram ⊝ organisms (eg, E coli, Klebsiella) or less commonly gram ⊕ Streptococcus. Diagnosis: paracentesis with ascitic fluid absolute neutrophil count (ANC) > 250 cells/mm3. Empiric first-line treatment is 3rd generation cephalosporin (eg, ceftriaxone). Serum markers of liver pathology ENZYMES RELEASED IN LIVER DAMAGE Aspartate  in most liver disease: ALT > AST aminotransferase  in alcoholic liver disease: AST > ALT (ratio usually > 2:1, AST does not typically exceed 500 U/L and alanine aminotransferase in alcoholic hepatitis). Make a toAST with alcohol AST > ALT in nonalcoholic liver disease suggests progression to advanced fibrosis or cirrhosis  aminotransferases (>1000 U/L): differential includes drug-induced liver injury (eg, acetaminophen toxicity), ischemic hepatitis, acute viral hepatitis, autoimmune hepatitis Alkaline phosphatase  in cholestasis (eg, biliary obstruction), infiltrative disorders, bone disease γ-glutamyl  in various liver and biliary diseases (just as ALP can), but not in bone disease (located in transpeptidase canalicular membrane of hepatocytes like ALP); associated with alcohol use FUNCTIONAL LIVER MARKERS  in various liver diseases (eg, biliary obstruction, alcoholic or viral hepatitis, cirrhosis), hemolysis Bilirubin Albumin  in advanced liver disease (marker of liver’s biosynthetic function) Prothrombin time  in advanced liver disease ( production of clotting factors, thereby measuring the liver’s biosynthetic function) Platelets  in advanced liver disease ( thrombopoietin, liver sequestration) and portal hypertension (splenomegaly/splenic sequestration) Reye syndrome Rare, often fatal childhood hepatic Avoid aspirin (ASA) in children, except in encephalopathy. KawASAki disease. Associated with viral infection (especially VZV Salicylates aren’t a ray (Reye) of sunSHINE for and influenza) that has been treated with kids: aspirin. Aspirin metabolites  β-oxidation Steatosis of liver/hepatocytes by reversible inhibition of mitochondrial Hypoglycemia/Hepatomegaly enzymes. Infection (VZV, influenza) Not awake (coma) Findings: mitochondrial abnormalities, Encephalopathy fatty liver (microvesicular fatty changes), hypoglycemia, vomiting, hepatomegaly, coma.  ICP  morbidity and mortality. Renal and cardiac failure may also occur. Requires expert review. uploaded by medbooksvn

398 SEC TION III Gastrointestinal   gastrointestinal—Pathology Alcoholic liver disease Macrovesicular fatty change A that may be reversible with alcohol cessation. Hepatic steatosis Alcoholic hepatitis Requires sustained, long-term consumption. Swollen and necrotic hepatocytes with neutrophilic infiltration. Mallory bodies B (intracytoplasmic eosinophilic inclusions of damaged keratin Alcoholic cirrhosis filaments). Final and usually irreversible form. Sclerosis around central vein may be seen in early disease. Regenerative nodules surrounded by fibrous bands (red arrows in C ) in response to chronic liver injury Ž portal hypertension and end-stage liver disease. ABC Nonalcoholic fatty Associated with metabolic syndrome (obesity, insulin resistance, HTN, hypertriglyceridemia, liver disease  HDL); obesity Ž fatty infiltration of hepatocytes A Ž cellular “ballooning” and eventual necrosis. Steatosis present without evidence of significant inflammation or fibrosis. May persist or A even regress over time. Nonalcoholic steatohepatosis—associated with lobular inflammation and hepatocyte ballooning Ž fibrosis. May progress to cirrhosis and HCC. Autoimmune hepatitis Chronic inflammatory liver disease. More common in females. May be asymptomatic or present with fatigue, nausea, pruritus. Often ⊕ for anti-smooth muscle or anti-liver/kidney microsomal-1 antibodies. Labs:  ALT and AST. Histology: portal and periportal lymphoplasmacytic infiltrate. Hepatic Cirrhosis Ž portosystemic shunts Ž  NH3 metabolism Ž neuropsychiatric dysfunction (reversible) encephalopathy ranging from disorientation/asterixis to difficult arousal or coma. Triggers: ƒ  NH3 production and absorption (due to GI bleed, constipation, infection). ƒ  NH3 removal (due to renal failure, diuretics, bypassed hepatic blood flow post-TIPS). Treatment: lactulose ( NH4+ generation) and rifaximin ( NH3-producing gut bacteria).

Gastrointestinal   gastrointestinal—Pathology SEC TION III 399 Liver tumors Hepatic hemangioma Also called cavernous hemangioma. Most common benign liver tumor (venous malformation) A ; typically occurs at age 30–50 years. Biopsy contraindicated because of risk of hemorrhage. Focal nodular Second most common benign liver tumor; occurs predominantly in females aged 35–50 years. hyperplasia Hyperplastic reaction of hepatocytes to an aberrant dystrophic artery. Marked by central stellate scar. Usually asymptomatic and detected incidentally. Hepatic adenoma Rare, benign tumor, often related to oral contraceptive or anabolic steroid use; may regress spontaneously or rupture (abdominal pain and shock). Hepatocellular Also called hepatoma. Most common 1° malignant liver tumor in adults B . Associated with HBV carcinoma (+/− cirrhosis) and all other causes of cirrhosis (including HCV, alcoholic and nonalcoholic fatty liver disease, autoimmune disease, hemochromatosis, Wilson disease, α1-antitrypsin deficiency) and specific carcinogens (eg, aflatoxin from Aspergillus). Findings: anorexia, jaundice, tender hepatomegaly. May lead to decompensation of previously stable cirrhosis (eg, ascites) and portal vein thrombosis. Spreads hematogenously. Diagnosis: ultrasound (screening) or contrast CT/MRI C (confirmation); biopsy if diagnosis is uncertain. Hepatic angiosarcoma Rare, malignant tumor of endothelial origin; associated with exposure to arsenic, vinyl chloride. Metastases Most common malignant liver tumors overall; 1° sources include GI, breast, lung cancers. Metastases are rarely solitary. A BC Budd-Chiari syndrome Hepatic venous outflow tract obstruction IVC (eg, due to thrombosis, compression) with Budd-Chiari syndrome centrilobular congestion and necrosis hepatosplenomegaly Ž congestive liver disease (hepatomegaly, ascites, varices, abdominal pain, liver vs portal vein thrombosis failure). Absence of JVD. Associated with no hepatomegaly unless hypercoagulable states, polycythemia vera, preexisting liver disease postpartum state, HCC. May cause nutmeg liver (mottled appearance). Portal vein thrombosis—thrombosis in portal vein proximal to liver. Usually asymptomatic in the majority of patients, but associated with portal hypertension, abdominal pain, fever. May lead to bowel ischemia if extension to superior mesenteric vein. Etiologies include cirrhosis, malignancy, pancreatitis, and sepsis. uploaded by medbooksvn

400 SEC TION III Gastrointestinal   gastrointestinal—Pathology α1-antitrypsin Misfolded gene product protein aggregates in In lungs,  α1-antitrypsin Ž uninhibited elastase deficien y hepatocellular ER Ž cirrhosis with in alveoli Ž  elastic tissue Ž panacinar A PAS ⊕ globules A in liver. Codominant trait. emphysema. Often presents in young patients with liver damage and dyspnea without a history of tobacco smoking. Jaundice Abnormal yellowing of the skin HOT Liver—common causes of  bilirubin A and/or sclera A due to bilirubin deposition. level: Hyperbilirubinemia 2° to  production Hemolysis or  clearance (impaired hepatic uptake, Obstruction conjugation, excretion). Tumor Liver disease Conjugated (direct) Biliary tract obstruction: gallstones, cholangiocarcinoma, pancreatic or liver cancer, liver fluke. hyperbilirubinemia Biliary tract disease: 1° sclerosing cholangitis, 1° biliary cholangitis Excretion defect: Dubin-Johnson syndrome, Rotor syndrome. Unconjugated Hemolytic, benign (neonates), Crigler-Najjar, Gilbert syndrome. (indirect) hyperbilirubinemia Both direct and indirect hyperbilirubinemia. Mixed Hepatitis, cirrhosis. hyperbilirubinemia Benign neonatal Formerly called physiologic neonatal jaundice. Mild unconjugated hyperbilirubinemia caused by: hyperbilirubinemia ƒ  fetal RBC turnover ( hematocrit and  fetal RBC lifespan). ƒ Immature newborn liver ( UDP-glucuronosyltransferase activity). ƒ Sterile newborn gut ( conversion to urobilinogen Ž  deconjugation by intestinal brush border β-glucuronidase Ž  enterohepatic circulation). β-glucuronidase—lysosomal enzyme for direct bilirubin deconjugation. Also found in breast milk. May lead to pigment stone formation. Occurs in nearly all newborns after first 24 hours of life and usually resolves without treatment in 1–2 weeks. Exaggerated forms: Breastfeeding failure jaundice—insufficient breast milk intake Ž  bilirubin elimination in stool Ž  enterohepatic circulation. Breast milk jaundice— β-glucuronidase in breast milk Ž  deconjugation Ž  enterohepatic circulation. Severe cases may lead to kernicterus (deposition of unconjugated, lipid-soluble bilirubin in the brain, particularly basal ganglia). Treatment: phototherapy (non-UV) isomerizes unconjugated bilirubin to water-soluble form.

Gastrointestinal   gastrointestinal—Pathology SEC TION III 401 Biliary atresia Most common reason for pediatric liver transplantation. Fibro-obliterative destruction of bile ducts Ž cholestasis. Associated with absent/abnormal gallbladder on ultrasonogram. Often presents as a newborn with persistent jaundice after 2 weeks of life, darkening urine, acholic stools, hepatomegaly. Labs:  direct bilirubin and GGT. Hereditary All autosomal recessive. hyperbilirubinemias Mildly  UDP-glucuronosyltransferase conjugation. Asymptomatic or mild jaundice usually with Gilbert syndrome stress, illness, or fasting.  unconjugated bilirubin without overt hemolysis. Crigler-Najjar Relatively common, benign condition. syndrome, type I Absent UDP-glucuronosyltransferase. Presents early in life, but some patients may not have Dubin-Johnson neurologic signs until later in life. syndrome Rotor syndrome Findings: jaundice, kernicterus (unconjugated bilirubin deposition in brain),  unconjugated bilirubin. Treatment: plasmapheresis and phototherapy (does not conjugate UCB; but does  polarity and  water solubility to allow excretion). Liver transplant is curative. Type II is less severe and responds to phenobarbital, which  liver enzyme synthesis. Conjugated hyperbilirubinemia due to defective liver excretion. Grossly black (Dark) liver due to impaired excretion of epinephrine metabolites. Benign. Phenotypically similar to Dubin-Johnson, but milder in presentation without black (Regular) liver. Due to impaired hepatic storage of conjugated bilirubin. Endothelial cells HEPATIC SINUSOID Kup er cell Hemoglobin circulating bilirubin (macrophage) (albumin bound, unconjugated, water insoluble) Space of Disse BILIRUBIN UPTAKE Unconjugated bilirubin CONJUGATION UDP-glucuronosyl- Q transferase R Conjugated bilirubin (bilirubin diglucuronide, water soluble) INTRACELLULAR S TRANSPORT T Obstructive jaundice Bile flow (downstream) Bile canalicular Hepatocyte lumen uploaded by medbooksvn