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Gastrointestinal disorders 2
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Gastrointestinal disorders 2

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  • Dear doctor you have written that small bowel more likely to have ishcemic changes than large bowel...can you give a reference for this statement...as in other places i read that colonic ishcemia is most common
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  • 1. GASTROINTESTINAL DISORDERS Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University
  • 2. Signs & Symptoms of Small Bowel Disease
    • Colicky pain
      • Pain followed by a pain-free interval; accompanied by constipation and inability to pass gas
      • Symptom of bowel obstruction
    • Diarrhea
      • Sign of infection, malabsorption, osmotic diarrhea
      • If bloody – may be a sign of infarction or dysentery
    • Anemia
      • Malabsorption of iron, folate or B12
  • 3. Signs & Symptoms of Large Bowel Disease
    • Diarrhea
      • Infection, laxative abuse, inflammatory bowel disease
      • If bloody  infarction or dysentery
    • Pain
      • Inflammatory bowel disease, ischemic colitis, diverticulitis, AP, peritonitis
    • Iron deficiency
      • Polyps or colorectal cancer
    • Hematochezia – massive loss of whole blood per rectum
      • Sigmoid diverticulosis or angiodysplasia
  • 4. Meckel Diverticulum
    • Most common type of true diverticulum in the alimentary tract
    • Due to failed involution of the vitelline duct
    • Small pouch extending from the anti-mesenteric side of the bowel
    • “ Rule of 2s”
      • 2% of population
      • Within 2 feet (85 cm) of ileocecal valve
      • Approx. 2 inches (5 cm) long
      • 2x as common in males
      • Most often symptomatic by age 2
  • 5. Meckel Diverticulum
    • Mucosal lining resembles normal small intestines
    • Ectopic pancreatic or gastric tissue may be present  result in peptic ulceration of adjacent small intestinal mucosa
      • Present with occult bleeding or abdominal pain
  • 6. Meckel Diverticulum The specimen is a portion of small intestine with a diverticulum protruding out 25 mm in length.
  • 7. Meckel Diverticulum Meckel diverticulum. Photomicrograph (original magnification, ×16; hematoxylin-eosin [H-E] stain) shows the diverticulum composed of all layers of the intestinal wall. Normal small intestinal mucosa and a focus of gastric mucosa (arrow) line the diverticulum.
  • 8. Large Bowel Pulsion Diverticulum
    • Sigmoid colon most common site
    • Due to a low-fiber diet with increased constipation
    • Area of weakness is where vessels penetrate the muscularis propria  diverticulum is juxtaposed to a b.v.
    • Most common cause of fistulas  colovesical fistula  connection between large bowel and the bladder
  • 9. Large Bowel Pulsion Diverticulum
    • Most common cause of hematochezia
    • Most common complication is diverticulitis
      • Caused by stool impacted in diverticulum sac  produce ulceration and ischemia
      • Presents as “left-sided appendicitis”
      • Increased risk for perforation and abscess formation
  • 10. Extensive diverticulosis of sigmoid colon with segmentation and shortening of bowel. Openings of diverticula can be clearly seen. Circular muscle is thick and corrugated.
  • 11. Whole mount of colon with diverticular disease. Whole-mount view of colonic diverticulosis. One of the diverticula shows marked chronic peridiverticulitis. Note hypertrophy of the muscle wall.
  • 12. Hirschsprung Disease
    • 1 of 5000 live births
    • Congenital aganglionic megacolon
    • Results when:
      • Normal migration of neural crest cells from cecum to rectum is arrested, OR
      • Ganglion cells undergo premature death
    • Distal intestinal segment lacks both Meissner submucosal and Auerbach myenteric plexus
  • 13. Hirschsprung Disease
  • 14. Hirschsprung Disease
    • Absence of coordinated peristaltic contractions  functional obstruction occurs  (+) dilation proximal to affected segment
    • Heterozygous loss-of-function mutations in receptor tyrosine kinase (RET) account for majority of familial cases
    • Males affected preferentially
    • Disease more extensive in females
  • 15. Hirschsprung Disease
    • Diagnosis requires documenting absence of ganglion cells within the affected segment
    • Rectum always affected  most cases limited to rectum and sigmoid colon
    • (+) megacolon  stretch and thin the colonic wall to the point of rupture (usually cecum)
  • 16. Hirschsprung Disease Gross specimen of Hirschsprung's disease. The proximally dilated segment of bowel has been resected. Colonic mucosa stained for acetylcholinesterase from a patient with Hirschsprung's disease. There is a marked increase in the number of nerve fibers in the lamina propria.
  • 17. Hirschsprung Disease
    • Neonate with failure to pass meconium in the immediate post-natal period
    • Obstructive constipation follows
    • Major threats to life
      • Enterocolitis
      • Fluid and electrolyte disturbances
      • Perforation
      • Peritonitis
  • 18. Intestinal Obstruction
    • Occur at any level
    • Small intestine most often involved due to narrow lumen
    • Clinical manifestations include:
      • Abdominal pain and distention
      • Vomiting
      • Constipation
  • 19. Intestinal Obstruction: Hernias
    • Weakness or defect in the wall of the peritoneal cavity  protrusion of a serosa-lined pouch of peritoneum  hernial sac
    • Acquired hernia
      • Most commonly occurs anteriorly via:
        • Inguinal canal
        • Femoral canal
        • Umbilicus
        • Sites of surgical scars
  • 20.  
  • 21. Intestinal Obstruction: Hernias
    • Direct hernia
    • Single layer of transversalis is stretched in the floor of Hesselbach triangle
    • Hernia bulges through floor of Hesselbach triangle; bulge disappears when patient reclines
    • Small bowel can not enter scrotal sac  no obstruction or incarceration
  • 22. Route of a direct hernia. The hernia sac passes directly through Hesselbach's triangle and may disrupt the floor of the inguinal canal.
  • 23. Intestinal Obstruction: Hernias
    • Femoral hernia
    • Most common in women
    • Bulge located below inguinal ligament
    • Highest rate of incarceration of small bowel
  • 24. Intestinal Obstruction: Hernias
    • Indirect hernia
    • Most common hernia
    • Pathogenesis in children: persistence of peritoneal connection between inguinal canal and tunica vaginalis
    • Pathogenesis in adults: protrusion of new peritoneal process into inguinal canal
    Route of an indirect hernia. Note that the hernia sac passes outside of the boundaries of Hesselbach's triangle and follows the course of the spermatic cord.
  • 25. Intestinal Obstruction: Hernias
    • Indirect hernia
    • Small bowel passes through internal inguinal ring  may enter scrotal sac  bowel directly hits examining finger
    • Complications: incarceration or strangulation
    Route of an indirect hernia. Note that the hernia sac passes outside of the boundaries of Hesselbach's triangle and follows the course of the spermatic cord.
  • 26. Intestinal Obstruction: Hernias
    • Umbilical hernia
    • Most common in adults with ascites, pregnancy, or obesity
    • Most common in black American NBs
    • Peritoneal protrusion extends into fascial defect containing remnants of umbilical cord
    • Majority close spontaneously by the 2 nd year
    • Incarceration more likely in adults than children
  • 27. Umbilical hernia exacerbated by refractory ascites. Advanced liver disease precluded operative repair in this case.
  • 28. Intestinal Obstruction: Hernias
    • Ventral hernia
    • Incisional hernia
    • Hernia develops in weakened area of previous surgical excision
    • Obesity most common cause
  • 29. Intestinal Obstruction: Hernias
    • External herniation - protrusion of viscera, usually in inguinal hernias; small bowel loops usually involved
    • Incarcerated hernia – impaired venous drainage of entrapped viscus  stasis and edema  increased bulk of herniated loop  permanent entrapment of viscus
    • Strangulated hernia - arterial and venous compromise results in infarction of the entrapped viscus
  • 30.  
  • 31. Incarcerated umbilical hernia Strangulated inguinal hernia
  • 32. Intestinal Obstruction: Adhesions
    • Develop in the background of surgical procedures, infection, or other causes of peritoneal inflammation
    • Adhesions may develop between bowel segments, the abdominal wall, and operative sites
    • Can create closed loops through which other viscera may slide and become entrapped  internal herniation
  • 33.  
  • 34. Intestinal Obstruction: Volvulus
    • Complete twisting of a loop of bowel about its mesenteric base of attachment
    • Produce both luminal and vascular compromise
    • Occurs most often in large redundant loops of sigmoid colon  followed in frequency by the cecum, small bowel, stomach or transverse colon
  • 35. A volvulus is a twisting of the bowel on itself. It is one cause of intestinal obstruction.
  • 36. Intestinal Obstruction: Intussusception
    • Occurs when a segment of intestine, constricted by a wave of peristalsis, telescopes into the immediately distal segment
    • Invaginated segment propelled by peristalsis and pulls the mesentery along
    • May lead to compression of mesenteric vessel and infarction
  • 37.  
  • 38. Intestinal Obstruction: Intussusception
    • Older children and adults  intraluminal mass or tumor serves as the point of traction
    • Barium enema can reduce the intus-susception in infants and young children
    • Surgical intervention in older patients
  • 39. Ischemic Bowel Disease
    • Small bowel more likely than large bowel to have ischemic damage
      • Most of small bowel supplied by superior mesenteric artery (SMA)
        • Areas supplied by SMA include:
          • Small bowel
          • Ascending and transverse colon
      • SMA and IMA overlap at the splenic flexure  splenic flexure is a watershed area  susceptible to ischemia
  • 40. Ischemic Bowel Disease
      • Intestinal capillaries from crypt to surface before emptying into the post-capillary venules  surface epithelium vulnerable to ischemic injury
        • Surface epithelial atrophy, necrosis and sloughing, with normal hyper-proliferative crypts  morphologic signature of IBD
  • 41. Ischemic Bowel Disease
    • Types of infarctions:
      • Transmural
        • Full-thickness hemorrhagic infarction  usually involves all or part of the small bowel
        • Usually due to occlusion of SMA
      • Mural
        • Involves mucosa and submucosa
      • Mucosal
        • No deeper than muscularis mucosa
    • Mural & mucosal infarctions usually occur in hypoperfusion states (eg shock)
  • 42. Ischemic Bowel Disease
    • Causes of acute ischemia involving SI:
      • Acute mesenteric ischemia (50%)
        • Embolism from L side of heart to SMA – atrial fibrillation is the most common predisposing arrhythmia
        • Thrombosis of the mesenteric artery (usually SMA)
      • Non-occlusive ischemia (25%)
        • Hypotension due to CHF most common
        • Shock, patient taking digitalis, vasospasm (?)
  • 43. Ischemic Bowel Disease
    • Causes of acute ischemia involving SI:
      • Mesenteric vein thrombosis (25%)
        • Thrombosis states
          • Polycythemia vera, anti-phospholipid syndrome
        • Extension of renal cell carcinoma into vena cava
  • 44. Ischemic Bowel Disease
    • Pathogenesis:
    • Initial Phase – Hypoxic injury
      • Onset of vascular compromise
      • Epithelial lining cells of intestines relatively resistant to transient hypoxia
  • 45. Ischemic Bowel Disease
    • Pathogenesis:
    • Second Phase – Reperfusion injury
      • Initiated by restoration of the blood supply
      • Greatest damage occurs
      • Involve free radical production, neutrophil infiltration, release of inflammatory mediators, activation of HIF-1 and NF- κβ
  • 46. Ischemic Bowel Disease
    • Major variables in IBD include:
    • Severity of vascular compromise
    • Time frame during which compromise develops
    • Vessels affected
  • 47. Ischemic Bowel Disease
    • Morphology:
      • Mucosal and mural infarction may involve any level of the gut
      • Lesions usually segmental and patchy
      • Mucosa hemorrhagic and may be ulcerated and dark red or purple
      • Bowel wall thickened by edema
  • 48. Ischemic Bowel Disease
    • Morphology:
      • Transmural infarction due to acute arterial obstruction may involve substantial portions of the bowel  splenic flexure site at greatest risk
        • Coagulation of the muscularis propria within 1 – 4 days
        • Perforation may occur
      • Microscopic: atrophy or sloughing of surface epithelium + neutrophilic infiltrates
  • 49.  
  • 50.  
  • 51.  
  • 52. Ischemic Bowel Disease
    • Clinical:
      • Older individuals with co-existing cardiac or valvular disease
      • Acute transmural infarction:
        • sudden, severe abdominal pain and tenderness
        • sometimes with diarrhea or melena
        • Blood loss  shock and vascular collapse
        • Decreased or absent bowel sounds (ileus)
        • Mucosal breakdown  bacterial infection and sepsis
  • 53. Ischemic Bowel Disease
    • Clinical:
      • Mucosal and mural infarctions may progress to more extensive infarction if blood supply is not restored
      • Chronic ischemia – may manifest as inflammatory bowel disease
  • 54. Ischemic Bowel Disease
    • Clinical:
      • Ischemic colitis
        • Involves splenic flexure of large bowel
        • Atherosclerotic narrowing of SMA or IMA  (+) mesenteric angina
          • Severe pain in splenic flexure shortly after eating
          • Weight loss due to fear of eating
          • Accompanied by bloody diarrhea due to mucosal or mural infarction
        • Common site of strictures and obstruction
  • 55. Ischemic colitis. The lesion is typically located in the splenic flexure. The mucosa is markedly hyperemic and covered by a fibrinopurulent exudate. Ischemic colitis with hyalinized lamina propria and gland dropout
  • 56. Ischemic Bowel Disease
    • Clinical:
      • Necrotizing enterocolitis (NEC)
        • Most common acquired GI emergency of neonates (premature and LBW)
        • Acute disorder of small & large intestines
        • Occurs most often at time of feeding
  • 57. Autopsy of infant showing abdominal distension, intestinal necrosis and hemorrhage, and peritonitis due to perforation.
  • 58. Necrotizing enterocolitis. Gross appearance. The mucosa is necrotic. Numerous small gas-filled cysts are present in the wall. Low-power microscopic appearance showing extensive ulceration, necrosis, and hemorrhage.
  • 59. Angiodysplasia
    • Malformed submucosal and mucosal blood vessels  ectatic nests of tortuous veins, venules, and capillaries
    • Cecum or right colon  increased wall stress stretches the venules
    • After 6 th decade of life
    • Accounts for 20% of major episodes of lower intestinal bleeding  (+) hematochezia
    • Hemorrhage may be acute and massive OR chronic and intermittent
  • 60. An angiodysplasia in the cecum, explaining the patients iron deficiency anaemia
  • 61. Angiodysplasia
    • Pathogenesis:
      • Undefined but can be associated with:
        • Intermittent occlusion of submucosal veins associated with normal distention and contraction  focal dilation and tortuosity of overlying submucosal and mucosal vessels
        • Degenerative vascular changes due to aging
        • Calcific aortic stenosis and Meckel diverticulum – possible developmental component
  • 62. Malabsorption
    • Defective absorption of fats, fat- and water-soluble vitamins, proteins, carbohydrates, electrolytes and minerals, and water
    • Presents most commonly as chronic diarrhea accompanied by weight loss, anorexia, abdominal distention, borborygmi, and muscle wasting
    • Hallmark is steatorrhea
  • 63. Malabsorption
    • General symptoms include:
      • Diarrhea
      • Flatus
      • Abdominal pain
      • Weight loss
      • Others:
        • Vitamin deficiencies
        • Osteopenia – calcium, Mg, or vit. D deficiency
        • Peripheral neuropathy – vit. A or B12 deficiency
        • Endocrine and skin disturbances
  • 64. Malabsorption: Cystic Fibrosis Absent epithelial cystic fibrosis transmembrane conductance regulator Defective intestinal chloride ion secretion Impaired bicarbonate, sodium, and water secretion Defective luminal hydration Formation of intraductal concretions in pancreatic ducts Exocrine pancreatic insufficiency Failure of intraluminal phase of nutrient absorption
  • 65. Malabsorption: Celiac Disease
    • Also known as celiac sprue or gluten-sensitive enteropathy
    • Immune-mediated triggered by ingestion of gluten-containing cereals (eg, wheat, rye, or barley) in genetically-predisposed individuals
      • Gliadin – alcohol-soluble fraction of gluten; contains the disease-producing components
  • 66. Malabsorption: Celiac Disease Some gliadin peptides Induce epithelial cell expression of IL-15 Activation and proliferation of NKG2D+ CD8+ intra-epithelial T lymphocytes No recognition of gliadin Cross the epithelium Deaminated by tissue trans-glutaminase Interact with HLA-DQ2 or HLA-DQ8 on APCs Presented to CD4+ T cells (+) Immune reaction
  • 67. Malabsorption: Celiac Disease
    • Associated with other immune diseases
    • Second portion of duodenum or proximal jejunum  exposed to highest concentration of dietary gluten  biopsy specimens diagnostic
      • Intraepithelial lymphocytosis (CD8+ T cells)
      • Crypt hyperplasia
      • Villous atrophy
      • Inc. plasma cells, mast cells, and eosinophils within upper part of the lamina propria
  • 68. This is an endoscopic biopsy of celiac disease that shows total crypt hyperplastic villous atrophy with complete flattening of the mucosal surface.  Note the intense lymphoplasmacytic inflammation in the lamina propria.
  • 69. The surface epithelium of this biopsy contains numerous intraepithelial lymphocytes.
  • 70. Malabsorption: Celiac Disease
    • Clinical:
    • Adults
      • 30 – 60 yrs old; 2-3x more common in women; three forms:
        • Silent disease – (+) serology plus villous atrophy without symptoms
        • Latent disease – (+) serology without villous atrophy
        • Symptomatic disease : anemia, chronic diarrhea, bloating, or chronic fatigue
  • 71. Malabsorption: Celiac Disease
    • Clinical:
    • Pediatric celiac disease
      • Males = females
      • Malabsorption or atypical symptoms affecting almost any organ
      • Classic symptoms:
        • Begins between 6 – 24 mos. after introduction of gluten to diet
        • Irritability, abdominal distention, anorexia, chronic diarrhea, failure to thrive, weight loss, or muscle wasting
  • 72. Malabsorption: Celiac Disease
    • Clinical:
    • Pediatric celiac disease
      • Non-Classic symptoms:
        • Older age
        • Abdominal pain, nausea, vomiting, bloating, or constipation
        • Extra-intestinal: arthritis, seizure disorders, aphthous stomatitis, iron deficiency anemia, pubertal delay, and short stature
  • 73. Malabsorption: Celiac Disease
    • Clinical:
    • Dermatitis Herpetiformis
      • Itchy, blistering skin lesion; 10% of patients
    • Lymphocytic gastritis and lymphocytic colitis
      • Increased incidence
  • 74. Dermatitis herpetiformis on the forearm
  • 75. Malabsorption: Celiac Disease
    • Clinical:
    • Long-term complications
      • Anemia
      • Female infertility
      • Osteoporosis
      • Cancer
        • Enteropathy-associated T-cell lymphoma – intraepithelial T cells
        • Small intestinal adenoCA – more frequent in patients with celiac dse
  • 76. Malabsorption: Celiac Disease
    • Diagnosis:
      • Serologic tests
        • Presence of IgA Ab to tissue trans- glutaminase or IgA or IgG Ab’s to deaminated gliadin – most sensitive
        • Presence of HLA-DQ2 or HLA-DQ8 – high negative predictive value
  • 77. Whipple Disease
    • Rare, multivisceral chronic disease
    • Caused by gram (+) Tropheryma whippelii
    • Triad of diarrhea, weight loss and malabsorption
    • Morphologic hallmark: distended, foamy macrophages in small intestinal lamina propria
      • (+) villous expansion due to dense macrophage infiltrates  shaggy gross appearance to mucosal surface
  • 78. Whipple Disease Outer aspect of mesenteric lymph nodes massively involved by Whipple's disease. Cut surface of mesenteric lymph nodes massively involved by Whipple's disease.
  • 79. Whipple Disease Jejunal mucosa in Whipple's disease. The lamina propria is packed with histiocytes and empty round spaces. The latter contained lipid material that has been extracted during tissue processing.
  • 80. Celiac Disease Whipple Disease Characteristic Clinical Autoimmune: Abs vs gliadin Female dominant; usually begins in infancy Primarily involves duodenum & jejunum Flattened villi Hyperplastic glands w/ chronic inflammation Strong association with dermatitis herpetiformis (autoimmune vesicular disease) May produce T-cell lymphoma of stomach and/or small intestines Restrict or eliminate gluten from diet Best screening test: anti- gliadin antibodies Male dominant disease Caused by Tropheryma whippelii bacilli (only visible by EM) Blunting of villi Foamy PAS-positive macrophages in lamina propria  obstruct lymphatics & reabsorption of chylomicrons Fever, recurrent polyarthritis, generalized LAD, increased skin pigmentation Treat with antibiotics
  • 81. Malabsorption: Tropical Sprue
    • Occurs almost exclusively in people living in or visiting the tropics
    • Generally endemic disease
    • Histologic changes similar to celiac but villous atrophy uncommon
    • Involvement of distal small bowel  with vitamin B12 deficiency
    • Malabsorption within days or few weeks of an acute diarrheal enteric infection
  • 82. Tropical sprue showing lymphoplasmacytic infiltrate and villous blunting
  • 83. Malabsorption: Lactase Deficiency
    • Types of lactase deficiency
      • Congenital lactase deficiency
        • Due to mutation in gene encoding lactase
        • Autosomal recessive; rare
        • Explosive diarrhea with watery, frothy stools + abdominal distention upon milk ingestion
  • 84. Malabsorption: Lactase Deficiency
    • Types of lactase deficiency
      • Acquired lactase deficiency
        • Due to down-regulation of lactase gene expression
        • Native Americans, African-Americans, Chinese population
        • After childhood; associated with enteric or bacterial infections
        • Abdominal fullness, diarrhea, and flatulence  due to fermentation of unabsorbed sugars by colonic bacteria
  • 85. Diarrhea
    • Increase in stool mass, frequency, or fluidity, typically greater than 200 g/day
    • Types:
      • Secretory
        • Isotonic stool and persists during fasting
        • High-volume diarrhea
        • No inflammation in bowel mucosa
        • Causes: laxative use, enterotoxins (eg, cholera toxin), ETEC, increased serotonin (carcinoid syndrome)
  • 86. Diarrhea
    • Increase in stool mass, frequency, or fluidity, typically greater than 200 g/day
    • Types:
      • Osmotic
        • Due to excessive osmotic forces exerted by unabsorbed luminal solutes  draws hypotonic salt solution out of the bowel
        • High volume diarrhea; no inflammation in bowel mucosa
        • Causes: lactase deficiency, ingestion of poorly absorbed solutes
  • 87. Diarrhea
    • Increase in stool mass, frequency, or fluidity, typically greater than 200 g/day
    • Types:
      • Malabsorptive
        • Follows generalized failures of nutrient absorption
        • Associated with steatorrhea
        • Relieved by fasting
  • 88. Diarrhea
    • Increase in stool mass, frequency, or fluidity, typically greater than 200 g/day
    • Types:
      • Exudative
        • Due to inflammatory disease  pathogens enter enterocytes
        • Purulent, bloody stools  invasive
        • Continue during fasting
        • Low-volume diarrhea
  • 89. Infectious Enterocolitis
    • Bacterial infections
      • ETEC – most common
      • Most common pathogens vary with age, nutrition, host immune status, and environmental influences
    • Pediatric infectious diarrhea
      • Result in severe dehydration and metabolic acidosis
      • Most commonly caused by enteric viruses
  • 90. Infectious Enterocolitis: Cholera Cholera Toxin B subunit A subunit Binds GM1 ganglioside (surface of epithelial cells) Carried to ER (retrograde transport) Endocytosis Reduced by protein disulfide isomerase in ER Cytosol Unfolding Refolding Interact with cytosolic ADP ribosylation factors Activate G protein Stimulate adenylate cyclase Inc. cAMP Open CFTR Cl released in lumen; secretion of HCO 3 , Na + & water MASSIVE DIARRHEA
  • 91. Infectious Enterocolitis: Shigellosis
    • Shigella spp one of the most common causes of bloody diarrhea
    • Infective dose < several hundred organisms
    • Most infections and deaths occur in children < 5 y/o
    • All Shigella organisms carry virulence plasmids
    • S. dysenteriae type I – (+) Shiga toxin
  • 92. Infectious Enterocolitis: Shigellosis MOT M (microfold) cells Intracellular proliferation Escape into lamina propria Phagocytosed by macrophages Induce apoptosis and inflammation
  • 93. Infectious Enterocolitis: Shigellosis
    • Infection most prominent in left colon
    • Mucosal hemorrhage and ulceration
    • Pseudomembranes may be present
  • 94. Infectious Enterocolitis: Shigellosis
    • Self-limited  6 days diarrhea, fever, and abdominal pain
      • Diarrhea initially watery  dysenteric phase (50%)
      • Constitutional symptoms can persist for as long as 1 month
    • Complications uncommon
      • Reiter syndrome - sterile arthritis, urethritis, conjunctivitis in HLA-B27 (+) men 20 – 40 y/o
      • Hemolytic Uremic Syndrome
  • 95. Infectious Enterocolitis: Salmonellosis
    • Salmonella typhi – typhoid fever
    • Non-typhoid Salmonella – usually due to Salmonella enteritidis
    • Infection most common in young children and the elderly
    • MOT: ingestion of contaminated food, particularly raw or undercooked meat, poultry, eggs, and milk
  • 96. Infectious Enterocolitis: Salmonellosis Salmonella Virulence genes Encode type III secretion system Transfer of bacterial proteins into M cells and enterocytes Activation of host cell Rho GTPases (+) actin rearrangement and bacterial uptake Bacterial growth within phagocytes
  • 97. Infectious Enterocolitis: Salmonellosis Salmonella Induce epithelial release of eicosanoid hepoxilin A3 Attract neutrophils into intestinal lumen Mucosal damage
  • 98. Infectious Enterocolitis: Salmonellosis Salmonella Flagellin Activation of TLR4 in host cells Bacterial LPS Acute Inflammation + ulceration PG synthesis Enterotoxins Cytokines Activation of adenyl cyclase Inc. cAMP Fluid production (SI and LI) DIARRHEA
  • 99. Infectious Enterocolitis: Typhoid Fever Salmonella typhi Small intestines Engulfed by mononuclear cells in underlying lymphoid tissue M cells Blood and lymphatic dissemination Reactive hyperplasia of phagocytes and lymphoid tissue
  • 100. Infectious Enterocolitis: Typhoid Fever
    • Hallmark histologic finding:
      • Infiltration of tissues by macrophages (typhoid cells) that contain bacteria, erythrocytes, and degenerated lymphocytes
      • Aggregates called typhoid nodules
  • 101. Infectious Enterocolitis: Typhoid Fever Seen here: Salmonella, isolated from infected macrophages. (Mildly color-enhanced.)
  • 102. Infectious Enterocolitis: Typhoid Fever
    • Four classic pathologic stages in the intestines
      • Hyperplastic changes
      • Necrosis of the intestinal mucosa
      • Sloughing of the mucosa
      • Development of ulcers  may perforate
  • 103. Infectious Enterocolitis: Typhoid Fever Histopathology of a lymph node in a case of Typhoid Fever. Typhoid nodules (microgranulomas) in ileal wall.
  • 104. Infectious Enterocolitis: Escherichia coli – ETEC
    • Principal cause of traveller’s diarrhea
    • Toxins:
      • Heat-labile (LT) – similar to cholera toxin  activate adenylate cyclase
      • Heat-stable (ST) – homologous to mammalian regulatory protein guanylin  stimulate guanylate cyclase
    • Secretory, non-inflammatory diarrhea, dehydration, shock (in severe cases)
    • Usually no histologic changes
  • 105. Infectious Enterocolitis: Escherichia coli – EHEC
    • E. coli O157:H7
    • Consumption of inadequately cooked ground beef, contaminated milk and vegetables
    • Shiga-like toxins
    • Morphology and clinical symptoms similar to S. dysenteriae
    • Large outbreaks of bloody diarrhea, and HUS
  • 106. Infectious Enterocolitis: Escherichia coli – EHEC Lethal enterohemorrhagic E. coli O-157 infection (8 y-o F). Massive and diffuse hemorrhage in the autopsied colon (gross findings)
  • 107. Infectious Enterocolitis: Escherichia coli – EHEC Lethal enterohemorrhagic E. coli O-157 infection (8 y-o F). Marked hemorrhagic destruction of the autopsied colonic mucosa (HE)
  • 108. Infectious Enterocolitis: Escherichia coli – EIEC
    • Bacteriologically similar to Shigella
    • Invade epithelial cells  non-specific features of acute self-limited colitis
    • Most common among young children in developing countries
    • Contaminated cheese, water, or person-to-person spread
    • Bacterial invasion and destruction of colonic mucosa
  • 109. Infectious Enterocolitis: Escherichia coli – EAEC
    • Enteroaggregative E. coli
    • Can also be a cause of traveller’s diarrhea
    • Attach to enterocytes via adherence fimbriae
      • Aided by dispersin – bacterial surface protein  neutralizes the negative surface charge of LPS
    • Non-bloody diarrhea – prolonged in individuals with AIDS
  • 110. Infectious Enterocolitis: Escherichia coli – EAEC Numbers of rods attached to the crypt epithelium in the region of active inflammation (HE, high power) Numbers of rods attached to the crypt epithelium (HE, oil immersion)
  • 111. Pseudomembranous Colitis
    • Antibiotic-associated colitis or antibiotic-associated diarrhea
    • Generally caused by Clostridium difficile but may also be caused by Salmonella, C. perfringens type A or S. aureus
    • Any antibiotic may be responsible  most commonly implicated are 3 rd generation cephalosporins
  • 112. Pseudomembranous Colitis Antibiotic intake Disruption of normal colonic flora Overgrowth of C. difficile Toxin release Ribosylation of small GTPAses (Rho) Disruption of epithelial cytoskeleton Tight junction barrier loss Cytokine release Apoptosis
  • 113. Pseudomembranous Colitis
    • Pseudomembranes made up of an adherent layer of inflammatory cells and debris at sites of colonic mucosal injury
    • Histopathology:
      • Denuded surface epithelium
      • Dense neutrophilic infiltrates in lamina propria
      • Occasionally with fibrin thrombi in capillaries
  • 114. Pseudomembranous Colitis There are multiple, discrete white plaques of purulent exudate on the mucosal surface. The patient was taking ampicillin. (Courtesy of Dr. RA Cooke, Brisbane, Australia; from Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology. Edinburgh, Churchill Livingstone, 2004).
  • 115. Pseudomembranous Colitis Fully developed pseudomembrane
  • 116. Pseudomembranous Colitis
    • Risk factors:
      • Advanced age
      • Hospitalization
      • Antibiotic treatment
    • Clinical presentation:
      • Fever, leukocytosis, abdominal pain, cramps, hypoalbuminemia, watery diarrhea, dehydration
  • 117. Viral Gastroenteritis: Norovirus
    • Previously known as Norwalk-like virus
    • Common cause of non-bacterial infectious gastroenteritis
    • Contaminated food or water, person-to-person spread
    • Abnormalities most evident in SI
      • Mild villous shortening
      • Epithelial vacuolization
      • Loss of microvillus brush border
      • Crypt hypertrophy
      • Lymphocytic infiltration of lamina propria
  • 118. Viral Gastroenteritis: Rotavirus
    • Most common cause of severe childhood diarrhea and diarrheal mortality worldwide
    • Children 6 – 24 months of age
    • Selectively infects and destroys mature enterocytes in SI  villus surface repopulated by immature secretory cells  loss of absorptive function + net secretion of water and electrolytes
  • 119. Viral Gastroenteritis: Rotavirus Marked infiltration of lymphoid cells both in the lamina propria and within the surface epithelium (HE)
  • 120. Irritable Bowel Syndrome (IBS)
    • Chronic, relapsing abdominal pain, bloating, and changes in bowel habit
    • Interplay between psychologic stressors, diet, and abnormal GI motility
      • Impairment of signaling in the brain-gut axis  disturbances in intestinal motility & enteric sensory function
    • 20 – 40 y/o; female > male
    • Gross and microscopic evaluation normal
  • 121. Irritable Bowel Syndrome (IBS)
    • Diagnosed using clinical criteria:
      • Abdominal pain or discomfort at least 3 days per month over three months
      • Improvement with defecation
      • Change in stool frequency or form
  • 122. Inflammatory Bowel Disease: UC and CD
    • Chronic condition resulting from inappropriate mucosal immune activation
    • Two conditions:
      • Crohn’s disease
        • Regional enteritis
        • May involve any area of GIT; typically transmural
      • Ulcerative colitis
        • Severe ulcerating inflammatory disease
        • Limited to colon and rectum  extends into mucosa and submucosa
  • 123. Fever Ulcerative colitis Crohn’s disease Epidemiology Whites > black Americans No sex predilection Young adults Whites > black Americans; Jews > non-Jews Women > men Young adults Extent Mucosal & submucosal Transmural Location Mainly rectum Extends continuously into left colon (may involve entire colon) Does not involve other areas of GIT 30% - terminal ileum alone 50% - ileum and colon 20% - colon alone Involves other areas of GIT (mouth to anus) Gross feature Bowel region Distribution Stricture Wall appearance Colon only Diffuse Rare Thin Ileum + colon Skip lesions Yes Thick
  • 124. Fever Ulcerative colitis Crohn’s disease Microscopic Inflammation Pseudopolyps Ulcers Lymphoid rxn Fibrosis Serositis Granulomas Fistula/sinus Limited to mucosa Marked Superficial, broad-based Moderate Mild to none Mild to none No No Transmural Moderate Deep, knife-like Marked Marked Marked Yes (~35%) Yes Clinical findings Perianal fistula Malabsorption Malignant potential Recurrence after surgery Toxic megacolon No No Yes No Yes Yes (in colonic disease) Yes With pancolitis, early age onset, duration > 10 years Common No Radiography “ Lead pipe” appearance in chronic disease “ String” sign in terminal ileum from luminal narrowing by inflam-mation, fistulas
  • 125. Ulcerative colitis. Chronic form, showing mucosal ulceration with residual foci of elevated and hyperemic mucosa. Ulcerative colitis. Acute form with marked hyperemia.
  • 126. Pseudopolyps in ulcerative colitis.
  • 127.  
  • 128. Gross appearance of Crohn's disease. Note the segmental nature of the inflammation, and rigidity of the wall, and flattening of the mucosa are characteristic. So-called ‘aphthous ulcers’, an early feature of Crohn's disease.
  • 129. Gross appearance of Crohn's disease. Example of cobblestone appearance.
  • 130. Whole mount specimen of Crohn's disease showing transmural inflammation with predominance of the inflammation in the mucosa and submucosa. Crohn's disease showing marked inflammatory changes and the formation of a fissure.
  • 131. Inflammatory Bowel Disease: Diverticulitis
    • Inflammatory changes due to obstruction of diverticulae
    • Increased pressure within an obstructed diverticulum can lead to perforation
      • Because wall of diverticulum is supported only by the muscularis mucosa and a thin layer of subserosal adipose tissue
  • 132. Inflammatory Bowel Disease: Diverticulitis
    • Sequelae:
      • Perforation
        • Lead to pericolonic abscesses, sinus tracts, and peritonitis
      • Segmental diverticular disease
        • Lead to colitis, fibrotic thickening in and around the colonic wall, or stricture formation
  • 133. Acute inflammatory infiltrates near the base of the diverticulum Acute diverticulitis
  • 134. Small and Large Bowel Polyps
    • Sigmoid colon – most common site for GI polyps; may occur in esophagus, stomach, or small intestine
    • Begin as small elevations of the mucosa  sessile polyps
    • As sessile polyps enlarge  proliferation of cells adjacent to the mass + traction on the luminal protrusion  create a stalk  pedunculated polyps
  • 135.  
  • 136. Small and Large Bowel Polyps: Types
    • Non-neoplastic Polyps
    • Inflammatory Polyps
      • Underlying cause: imparied relaxation of anorectal sphincter  create a sharp angle at ant. rectal shelf  recurrent abrasion and ulceration overlying rectal mucosa
      • Clinical triad of:
        • Rectal bleeding
        • Mucus discharge
        • Inflammatory lesion of the anterior rectal wall
  • 137. Gross appearance of inflammatory fibroid polyp. Inflammatory fibroid polyp showing myofibroblast-like cells, eosinophils, and other inflammatory cells in a sclerotic background.
  • 138. Small and Large Bowel Polyps: Types
    • Non-neoplastic Polyps
    • Hamartomatous Polyps
      • Sporadic occurrence
      • In the context of genetically determined or acquired syndromes
      • With associated intestinal and extra-intestinal manifestations
      • Possibility of other family members being affected
  • 139. Small and Large Bowel Polyps: Types
    • Non-neoplastic Polyps
    • Hamartomatous Polyps
      • Juvenile polyps
        • Most common polyp in children (< 5 yrs old)
        • Located in the rectum  may prolapse out of the rectum and bleed
          • Sporadic – usually solitary; called retention polyps
          • Syndromic – juvenile polyposis; autosomal dominant; (+) pulmonary A-V malformations
        • Pedunculated, char. cystic spaces (dilated glands filled with mucin & inflammatory debris
  • 140. Small and Large Bowel Polyps: Types
    • Non-neoplastic Polyps
    • Hamartomatous Polyps
      • Juvenile polyps
        • Mucosal hyperplasia the initiating event
        • Juvenile polyposis syndrome – mutation of SMAD4 most common; associated with increased risk of colonic adenocarcinoma
        • Dysplasia may occur
  • 141. Juvenile polyposis. The markedly hyperemic quality is a characteristic feature of these lesions. Whole-mount view of a juvenile (retention) polyp.
  • 142. Small and Large Bowel Polyps: Types
    • Non-neoplastic Polyps
    • Hamartomatous Polyps
      • Peutz-Jeghers Syndrome
        • Autosomal dominant
        • Multiple GI hamartomatos polyps + muco- cutaneous hyperpigmentation
        • Can initiate intussusception
        • Increased risk of malignancies (colon, pancreas, breast, lung, ovaries, uterus, and testicles
        • Loss-of-function mutations in the gene LKB1/STK11 (tumor suppressor gene)
  • 143. Duodenal polyp in a Peutz-Jeghers syndrome patient. Medium power microscopic view of a PJS-type jejunal polyp with pseudo-invasion. Arrows indicate hamartomatous small intestine mucosa in the intestinal wall.
  • 144. Small and Large Bowel Polyps: Types
    • Non-neoplastic Polyps
    • Hyperplastic Polyps
      • Most common type in adults (6 th and 7 th decades); majority in sigmoid
      • Result from decreased epithelial cell turnover & delayed shedding of surface epithelial cells  “piling up” of goblet cells and absorptive cells
      • No malignant potential or polyposis syndromes
      • Histologic: “sawtooth” appearance
  • 145. Gross appearance of multiple hyperplastic polyps. The lesions are characteristically small, sessile, and pale. Microscopic appearance of hyperplastic polyp. The individual glands show a typical serration of their mid portion.
  • 146. Small and Large Bowel Polyps: Types
    • Neoplastic Polyps: Adenomas
      • Colonic adenomas – most common and clinically important; precursor of colorectal adenocarcinoma
      • Intraepithelial neoplasms  small, pedunculated to large sessile lesions
      • No gender preference; increase with age
      • Characterized by presence of epithelial dysplasia
  • 147. Small and Large Bowel Polyps: Types
    • Neoplastic Polyps: Adenomas
      • Risk factors for malignancy:
        • Adenomas > 2 cm size (40% risk)
        • Multiple polyps
        • Polyps with increased villous component
        • High grade dysplasia
      • Size is the most important characteristic that correlates with risk  40% of lesions > 4 cm contain foci of cancer
  • 148. Small and Large Bowel Polyps: Types
    • Neoplastic Polyps: Adenomas
      • Classification:
        • Tubular (adenomatous polyps)
          • Most common (60% of polyps)
          • Sigmoid colon most common site
          • Small, pedunculated – looks like a mushroom; section shows complex branching of glands (adenomatous change)
  • 149. A small adenomatous polyp (tubular adenoma) is seen here. This lesion is called a &quot;tubular adenoma&quot; because of the rounded nature of the neoplastic glands that form it. It has smooth surfaces and is discreet. Such lesions are common in adults. Small ones are virtually always benign. Those larger than 2 cm carry a much greater risk for development of a carcinoma, having collected mutations in APC, DCC, K-ras, and p53 genes over the years.
  • 150. A microscopic comparison of normal colonic mucosa on the left and that of an adenomatous polyp (tubular adenoma) on the right is seen here. The neoplastic glands are more irregular with darker (hyperchromatic) and more crowded nuclei. This neoplasm is benign and well-differentiated, as it still closely resembles the normal colonic structure.
  • 151. Small and Large Bowel Polyps: Types
    • Neoplastic Polyps: Adenomas
      • Classification:
        • Tubulovillous adenoma
          • 20 – 30% of polyps
          • Usually pedunculated
          • Adenomatous and villous change (similar to small bowel villi)
  • 152. Tubulovillous adenoma
  • 153. Small and Large Bowel Polyps: Types
    • Neoplastic Polyps: Adenomas
      • Classification:
        • Villous adenoma
          • 10% of polyps
          • Sessile with a primarily villous component
          • Rectosigmoid location
          • Greatest risk for developing colon cancer (30% - 40% risk)
          • May cause hypoproteinemia and hypo- kalemia
  • 154. Gross appearance of villous adenoma. The lesion is characteristically large and flat and has an arborescent architecture. Low-power microscopic appearance of villous adenoma. Long villi are arranged in parallel, perpendicularly to the mucosa.
  • 155. Familial Syndromes
    • Familial Adenomatous Polyposis (FAP)
      • Clinical findings:
        • Malignant transformation between 35 – 40 years of age  prophylactic colectomy recommended
        • Associated with congenital hypertrophy of retinal pigment epithelium
        • Associated with a variety of extra-intestinal manifestations
  • 156. Familial Syndromes
    • Familial Adenomatous Polyposis (FAP)
    • Variants:
      • Gardner’s syndrome
        • Additional findings of benign osteomas, epidermal cysts, desmoid tumors, thyroid tumors, and dental abnormalities
      • Turcot’s syndrome
          • Intestinal adenomas + tumors of CNS
          • 2/3 – APC mutation  develop medulloblastomas
          • 1/3 – mutation in DNA repair genes  develop glioblastomas
  • 157. Familial polyposis The colon is covered in a carpet of adenomatous polyps.
  • 158. Familial Syndromes
    • Hereditary Non-polyposis Colorectal Cancer
      • Lynch syndrome
      • Colon cancers occur at younger age; often located in the right colon
      • Due to inherited mutations in genes that encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication
        • Majority involve mismatch repair genes MSH2 and MLH1  (+) microsatellite instability
  • 159. Small Bowel Malignancy
    • Small bowel is the LEAST common site for primary malignancy in the GIT
    • Primary adenocarcinoma
      • Duodenum most common site
    • Carcinoid tumor
      • Most common small bowel malignancy
      • Neuroendocrine tumor
      • Malignant
      • Foregut and hindgut tumors  invade but rarely metastasize
      • Midgut tumors  invade & metastasize
      • Tip of vermiform appendix most common site
      • Terminal ileum – metastasize to liver
      • (+) production of serotonin
  • 160.  
  • 161. This low power section shows the typical histologic appearance of a submucosal carcinoid tumor. Histologically, carcinoids typically grow as multiple solid nests of tumor cells.
  • 162. Colon Cancer
    • Risk Factors:
      • Age older than 50 years
      • Low fiber/high saturated fat diet
      • Cigarette smoking
      • Familial polyposis syndrome, family history, ulcerative colitis
    • Carcinogenesis of colon cancer:
      • Adenoma-carcinoma sequence
        • Sequential mutations of different genes ( APC, RAS, TP53 )
        • Accounts for 80% of sporadic colon cancers
        • Inactivation of DNA mismatch genes
  • 163.  
  • 164. The malignant transformation is evident through different grades of cellular alterations (dysplasia).
  • 165. Colon Cancer
    • Locations:
      • Rectosigmoid – 50% of cases
      • Ascending colon – 15% of cases
      • Descending colon – 15% of cases
      • Transverse colon & cecum – 10% each
    • Screening Tests:
      • Fecal occult blood test – not very sensitive or specific
      • Colonoscopy – gold standard
      • Barium enema
  • 166. Colon Cancer
    • Clinical Findings:
      • Left-sided cancers tend to obstruct
        • Bowel diameter smaller than right colon
        • Lesions with annular, “napkin-ring” appearance
        • Change in bowel habits – constipation and diarrhea with or without bleeding; change in caliber, change in consistency; stools with mucus
  • 167.  
  • 168.  
  • 169. Colon Cancer
    • Clinical Findings:
      • Right-sided cancers tend to bleed
        • Bowel diameter greater than left colon
        • Tumors are more polypoid in appearance
        • Blood in the stool and iron deficiency are more likely
        • Anemia, with symptoms such as dizziness, malaise, and palpitations
        • Anorexia, asthenia, unexplained weight loss
  • 170.  
  • 171. Colon Cancer
    • Clinical Findings:
      • Symptoms due to metastasis
        • Sites of metastasis: liver (most common), lungs, bone, and brain
        • Shortness of breath (lung metastasis)
        • Jaundice (liver metastasis)
  • 172. Duke’s Staging: Stage A tumors - limited to the wall (not extending beyond muscularis propria), stage B - extending through the wall (into subserosa and/or serosa, or extra-rectal tissues), and stage C - those having lymph node metastasis (C1 when only perirectal nodes were positive and C2 when nodes at the point of mesenteric blood vessel ligature, called apical nodes, were involved.
  • 173. Astler-Coller Staging: The original scheme had five stages, A was limited to the mucosa, B1 involved muscularis propria but did not penetrate it, B2 penetrated the muscularis propria, and C1 and C2 were counterparts of B1 and B2 with nodal metastases. Since then, later modifications have added three more stages. B3 represents involvement of adjacent structures, C3 is B3 with nodal metastasis, and D signifies presence of distant metastasis. 6
  • 174.  
  • 175. Acute Appendicitis
    • Pathogenesis in children: lymphoid hyperplasia (60% of cases) often secondary to a viral infection
      • Examples: adenovirus, measles virus or immunization
    • Pathogenesis in adults:
      • Fecalith obstructs proximal lumen  inc. intraluminal pressure  mucosal injury and bacterial invasion
      • Other causes: seeds, pinworm
    • Primary pathogens are E. coli (most common) and Bacteroides fragilis
  • 176. Acute Appendicitis
    • Clinical findings in sequence:
      • Initial colicky periumbilical pain
        • Irritation of unmyelinated afferent C fibers on visceral peritoneal surface
        • Refer pain to midline
      • Nausea, vomiting, and fever
        • Pain precedes nausea and vomiting
      • Pain shifts to RLQ
        • Irritation of A δ fibers on parietal peritoneum  localizes pain to exact location
        • Rebound tenderness at McBurney’s point (Bloomberg’s sign)
  • 177. Acute Appendicitis
    • Complications:
      • Peri-appendiceal abscess with or without perforation
        • Most common complication
        • May develop subphrenic abscess usually due to Bacteroides fragilis
      • Pyephlebitis
        • Infection of the portal vein  danger of portal vein thrombosis
        • Radiograph: gas in portal vein
  • 178. Swollen appendix due to acute appendicitis
  • 179.  
  • 180. Signs and Symptoms of Anorectal Disease
    • Bleeding
      • Internal hemorrhoids (painless), anorectal cancer, infection, fissure
    • Pain
      • Anal fissure, thrombosed external hemorrhoids
    • Pruritus
      • E.g. Pinworm infection
    • Anal fistula
      • Crohn’s disease
  • 181. Internal hemorrhoids
    • Dilated superior hemorrhoidal veins in mucosa and submucosa
    • Causes:
      • Straining at stool (most common)
      • Pregnancy, portal hypertension
    • Clinical findings:
      • Often prolapse out of the rectum
      • Commonly pass bright red blood with stool – blood coats the stool
      • Anal pruritus and soiling of underwear
  • 182.  
  • 183. External hemorrhoids
    • Dilated inferior hemorrhoidal veins
    • Painful thrombosis
  • 184. Anal Carcinoma
    • Basaloid (epidermoid or cloacogenic) Carcinoma
      • Most common type
      • Located in the transitional zone above the dentate line
      • Female dominant
    • Squamous cell carcinoma
      • Located in the anal canal
      • Majority are in homosexual men (HPV association)
  • 185. Gross appearance of carcinoma of anal canal. The tumor involves the dentate line and is exophytic with a central ulceration.
  • 186. Invasive well-differentiated squamous cell carcinoma of the anal canal. Low-power view of basaloid carcinoma of the anal canal.

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