Pathology of the Small Intestine

1. Pathology of the Small Intestine Aiman Zaher, MD

2. Objectives At the end of this segment, when given a clinical presentation, gross specimen, and/or photomicrograph students will be able to: Compare and contrast the clinical presentations, etiologies, pathogenesis, and gross and microscopic changes found in developmental, inflammatory, circulatory, mechanical, and neoplastic disorders of the small intestine.

3. Objectives At the end of this segment, when given a clinical presentation, gross specimen, and/or photomicrograph students will be able to: Predict the clinical complications associated with diseases of the small intestine. Define the words in the glossary

4. Glossary Adhesions Ileus Intussusception Volvulus

5. Structure and Function

6. Gross ~6 meters long Duodenum (retroperitoneal), jejunum, ileum Blood supply Blood supply to duodenum Superior pancreaticoduodenal artery (branch of gastroduodenal artery). Inferior pancreaticoduodenal artery (branch of superior mesenteric artery). Blood supply to remainder of small intestine is from superior mesenteric artery

7. The purpose of the small intestine is for terminal digestion & absorption of foodstuffs. Histology Lined with many villi Villi have three cell types: Columnar absorptive cells with microvilli Mucin-secreting goblet cells Endocrine cells Between the villi are the crypts of Lieberk�hn Contain stem cells, goblet cells, endrocrine cells, and Paneth cells (contain antimicrobial proteins) Duodenum contains numerous submucosal glands, called Brunner�s glands

8. Congenital Anomalies

9. Congenital Anomalies Heterotopia Usually pancreas, but can be gastric mucosa appearing as small nodules in the mucosa or intestinal wall Atresia and Stenosis Duodenal atresia is most common, followed by jejunum and ileum Stenosis can also be acquired e.g. intussusceptions

10. Congenital Anomalies Meckel Diverticulum Failure of the vitelline duct (connects the developing gut to the yolk sac) to involute Found on the anti-mesenteric side of gut within two feet of ileocecal valve Contains all three layers of normal bowel wall (true diverticulum) Heterotopic rests of gastric or pancreatic tissue found in 50% ? peptic ulceration ? bleeding Complications include intussusception, incarceration or perforation, but most are incidental findings

12. Enterocolitis

13. Diarrhea & Dysentery Diarrhea An increase in stool mass, frequency or fluidity in most patients Characterized by pain, urgency, perianal discomfort and incontinence Dysentery Low-volume, painful, bloody diarrhea

14. Diarrhea & Dysentery - Mechanisms Secretory diarrhea Passage of >500 ml/day of watery stools, isotonic with plasma e.g. rotavirus, E. coli, V. cholaerae, villus adenomas and excessive laxative use Osmotic diarrhea Passage of > 500 ml/day of stools, osmolality exceeds that of plasma by > 50 mOsm. e.g. lactase deficiency and antacids Exudative diseases Passage of frequent purulent, bloody stools e.g. Shigella, Salmonella

15. Malabsorption bulky stools with excess fat that floats on the water (steatorrhea) and increased osmolality e.g. Celiac Sprue and Crohn disease Deranged Motility Improper gut neuromuscular function ? variable patterns of increased stool volume e.g. surgical reduction of bowel length, diverticula Diarrhea & Dysentery - Mechanisms

16. Infectious Enterocolitis Intestinal diseases of microbial origin Characterized by diarrhea and in some instances ulceration of the bowel Causes >12,000 deaths per day among children in developing countries and equals � of all deaths before age 5 worldwide

17. Infectious Enterocolitis Viruses Acute, self-limited infectious diarrhea is most frequently caused by enteric viruses. Rotavirus � outbreaks in infants Norwalk viruses � outbreaks in school children and adults; Norwalk virus is responsible for the majority of cases of nonbacterial food-borne epidemic gastroenteritis in all age groups. Adenoviruses � outbreaks in infants Astroviruses � outbreaks in children

18. Infectious Enterocolitis Bacteria E. coli (food borne; invasive & non-invasive forms) Vibrio cholerae (water borne; enterotoxin ? secretory diarrhea) S. aureus (food poisoning; preformed toxin) Salmonella and Shigella (invasive bloody diarrhea; toxins) MAI (AIDs associated) Clostridium difficile (antibiotic associated colitis) Parasites e.g. Giardia lamblia, Entamoeba histolytica

19. Miscellaneous Intestinal Inflammatory Disorders AIDS Diarrheal illness in 50% of AIDS patients in developed countries Some malbsorption, some ulcerative colitis, infections with other organisms; possibly due to HIV mucosal damage, itself Complications of Transplantation (particularly bone marrow) Pre-transplant: Blunted villi, degeneration and flattening of crypt cells with decreased mitosis due to direct toxic injury Graft versus host: focal crypt cell necrosis: severe, watery diarrhea Drug-induced intestinal injury Focal ulceration when a pill sticks to the mucosa or enterocolitis (most commonly NSAIDs) Radiation endothelial cell injury ? ischemic fibrosis & stricture Acute radiation enteritis: anorexia, cramping, and malabsorption Chronic radiation enteritis: inflammatory enteritis Neutropenic colitis (typhlitis)

20. Malabsorption Syndromes

21. Malabsorption Syndromes Malabsorption - Definition Characterized by suboptimal absorption of fats, fat-soluble and other vitamins, proteins, carbohydrates, electrolytes and minerals, and water

22. Pathogenesis - Malabsorption Syndromes Defective Intraluminal Digestion Pancreatic insufficiency Zollinger-Ellison Syndrome Bacterial overgrowth Primary Mucosal Cell Abnormalities Defective terminal digestion (lactose intolerance) Defective epithelial transport (abetalipproteinemia) Reduced Small Intestinal Surface Area Crohn Disease Celiac Sprue Lymphatic Obstruction TB Lymphoma Infection Whipple disease Tropical Sprue Iatrogenic Gastrectomy Distal ileal resection

23. Malabsorption Syndromes Clinical Presentation Chronic diarrhea and steatorrhea: Pass bulky, frothy, greasy, yellow, or gray stools weight loss, anorexia and abdominal pain In US pancreatic insufficiency, Celiac Sprue and Crohn disease are most important Multiple systems involved; if prolonged leads to: Anemia, petechiae, hemorrhages, dermatitis, bone pain, peripheral neuropathy, latent tetany, menstrual and reproductive disturbances, among other symptoms Symptoms due to vitamin deficiencies

24. Celiac Disease AKA Celiac Sprue and Gluten-Sensitive enteropathy Definition Chronic disease with characteristic mucosal lesion of the small intestine and impaired nutrient absorption that improves on withdrawal of wheat gliadins and related grain proteins from diet Epidemiology Almost exclusively Caucasians

25. Celiac Disease Etiology Hypersensitivity to wheat gluten and gliadin associated with HLA-DQ2 and DQ8 Pathogenesis T-cell-mediated hypersensitivity

26. Celiac Disease Morphology Grossly, mucosa appears flat or scalloped, or even normal Microscopically, diffuse enteritis with marked atrophy or total loss of villi Epithelial cells degenerated with loss of microvilli and increased intraepithelial lymphocytes Crypts exhibit increased mitotic activity. Morphology mimics other diseases, like tropical sprue Mucosa will revert back to normal when stimulus taken away.

29. Celiac Disease Clinical Features Diarrhea & failure to thrive in infants, but adults might not present with malabsorption syndromes till their 50s Anti-gliadin or �anti-endomysial� antibodies favors diagnosis Definitive diagnosis requires Clinical documentation of malabsorption Small bowel biopsy results Improvement of symptoms upon gluten withdrawal Clinical Complications Risk of neoplasia e.g. non-Hodgkin lymphoma, small intestinal adenocarcinoma, and esophageal SCC (50-100X risk)

30. Tropical Sprue (Postinfectious Sprue) Celiac-like malabsorption syndrome, seen in people of the tropics or visiting the tropics, including the Caribbean. No specific causal agent found, but enterotoxigenic organisms implicated Responds to antibiotic therapy Changes similar to those of Celiac disease, but is seen at all levels of the small intestine and not associated with lymphoma

31. Whipple Disease A rare systemic disease of primarily the intestines, joints, and CNS, caused by gram-positive actinomycete, Tropheryma whippelii Pathogenesis unknown Patients are usually white, M:F = 10:1, 40-50 years of age Lamina propria is laden with distended macrophages, containing tiny, rod-shaped bacilli that are PAS positive

33. Whipple Disease Clinical Presents with malabsorption syndrome, sometimes of years� duration Arthropathy is often the initial presentation Lymphadenopathy & hyperpigmentation >50% Also, polyarthritis, cardiac, and neurologic signs and symptoms Responds to broad spectrum antibiotics

34. Disaccharidase (Lactase) Deficiency Disaccharidase is an apical membrane enzyme that cleaves lactose.

35. Pathogenesis Incomplete breakdown of disaccharide (lactose) into glucose and galactose Leads to osmotic diarrhea Bacterial fermentation of unabsorbed sugar ? increased hydrogen production and gaseous symptoms Disaccharidase (Lactase) Deficiency

36. Disaccharidase (Lactase) Deficiency Congenital form Presents in infants on exposure to milk or milk products Explosive, watery diarrhea and abdominal distension that stops when taken off milk Acquired form More common Adults, blacks & native americans > whites; sometimes related to viral or bacterial enteric infection No morphologic changes

37. Abetalipoproteinemia Deficiency of betalipoprotein that is required for intestinal transport of chylomicrons Chylomicrons Chylomicrons

38. Circulatory Disorders

39. Ischemic Bowel Disease General Can be restricted to either the small or large intestine, or both Infarctions seen with acute occlusion of celiac, superior and inferior mesenteric arteries Insidious loss of one vessel may go unnoticed due to rich anastomoses Etiology Arterial thrombosis Arterial embolism Venous thrombosis Nonocclusive ischemia; e.g. cardiac failure, shock, etc. Miscellaneous Radiation injury Volvulus Stricture

40. Ischemic Bowel Disease Types of lesions Transmural Infarction All layers due to sudden occlusion of major vessels Bowel swollen, gangrenous and perforates in few days Mural & Mucosal Infarction Most commonly due to hypoperfusion in watershed areas Necrosis of mucosa only; mucosa hemorrhagic; serosa normal Chronic Ischemia Mucosal atrophy; ulcerations; mural fibrosis Can lead to stricture

44. Ischemic Bowel Disease Clinical Features Uncommon, but grave. 50-75% death rate Short time between symptoms and perforation Transmural infarcts sudden severe abdominal pain and tenderness; sometimes nausea, vomiting and bloody diarrhea or melena shock and vascular collapse in hours peristalsis is diminished Mucosal and mural infarcts may not be fatal if cause corrected nonspecific abdominal complaints and intermittent bloody diarrhea, but may progress to extensive infarction & sepsis Chronic ischemic infarcts insidious with intermittent bloody diarrhea, resembling inflammatory bowel disease

45. Obstructions/ Dilatations

46. Hernias Etiology Usually weakness in wall of peritoneal cavity may permit protrusion of a pouch-like, serosa-lined sac of peritoneum Most common sites inguinal and femoral canals umbilicus surgical scars Clinical Significance Segments of viscera protrude and become trapped e.g. small bowel ? Ischemia Incarceration = permanent trapping of bowel loop due to edema from impaired venous drainage Strangulation = compromised arterial supply & venous drainage ? infarction

48. Adhesions Etiology Inflammation (peritonitis) e.g. surgery, infection, radiation and endometriosis As healing occurs, get adhesions between bowel loops, bowel wall, & surgical site Complications Twisting of bowel loops around peritoneal fibrous bands, strangulating & obstructing the bowel

51. Intussusception Etiology One segment of bowel, constricted by a wave of peristalsis, telescopes into another more distal segment Once in peristalsis, wedges in further Mesentery pulled in, and ischemia ensues Pathogenesis Infants � usually no underlying cause, but can be associated with rotavirus infection Adults � usually an intralumenal mass or neoplasm

53. Volvulus Definition Complete twisting of a bowel loop about its mesenteric base. Produces obstruction & infarction Most often occurs in large redundant loops of sigmoid colon and small intestine.

55. Neoplasms of the Small Intestines 3-6% of GI Tumors Adenomas and mesenchymal tumors most frequent benign tumors Malignant tumors rare �Only ~1% of GI tumors e.g. adenocarcinomas and carcinoids followed by lymphomas and sarcomas

56. Adenomas Epidemiology 25% of benign tumors Most in Ampulla of Vater region Higher incidence in patients with familial polyposis Clinical Occult blood in stool Rarely, obstruction and intussuseption Morphology Tumors resemble those seen in colon Those that extend into ampular orifice render themselves difficult to remove surgically short of pancreatoduodenectomy to remove entire ampullary region

57. Adenocarcinoma Epidemiology Age - 40-70 years Majority in duodenum Major risk factor is inflammation from CD Clinical Features Weight loss, cramping, nausea, vomiting Obstructive jaundice if located in Ampulla Fatigue if blood loss Clinical Complications Most neoplasms ? penetrates wall ? invade mesentery ? metastasized to regional nodes ? ? liver by time diagnosis is made 70% survival at 5 years with surgery

59. References Kumar, Abbas, and Fausto: ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE, 7th Edition, pp.828-870.