11.1 Gastrointestinal, Hepatic, Biliary & Pancreatic Pathology

Why this area matters

The TOS lists:

• congenital GIT abnormalities;
• diseases of the esophagus (achalasia, reflux, varices, Barrett esophagus, tumors);
• diseases of the stomach (gastritis, H. pylori, GERD, peptic ulcer, Zollinger-Ellison syndrome, tumors);
• diseases of the small intestine and colon (hernias, volvulus, intussusception, malabsorption, diarrhea, infectious enterocolitis, irritable bowel, IBD, polyps, appendicitis, hemorrhoids, tumors);
• diseases of the liver, biliary tract and pancreas.

Liver cancer and gastrointestinal infections are major causes of death in the Philippines.

Congenital anomalies

Esophagus

• Achalasia: loss of inhibitory myenteric neurons. The lower esophageal sphincter fails to relax, giving dysphagia to solids and liquids and a "bird's beak" on barium swallow. Chagas disease causes a secondary form.
• Reflux esophagitis: basal cell hyperplasia, elongated papillae and eosinophils. Long-standing reflux leads to Barrett esophagus, discussed below.
• Esophageal varices: dilated submucosal veins from portal hypertension. Rupture causes massive hematemesis.
• Mallory-Weiss tears: longitudinal mucosal tears at the gastroesophageal junction after retching.
• Carcinoma: squamous cell carcinoma in the upper and middle thirds (smoking, alcohol, very hot drinks, nitrosamines) versus adenocarcinoma in the distal third (from Barrett esophagus). Both cause progressive dysphagia and weight loss.

Stomach

• Acute gastritis and stress ulcers: caused by NSAIDs, alcohol, burns (Curling ulcers), intracranial injury (Cushing ulcers) and shock.
• Chronic gastritis:
  • H. pylori gastritis is antral, with neutrophils and plasma cells and curved rods in the mucus. It is the most common form.
  • Autoimmune gastritis affects the body and fundus. Antibodies against parietal cells and intrinsic factor cause achlorhydria, high gastrin and pernicious anemia.
• Peptic ulcer disease:
  • Duodenal ulcers are about four times as common as gastric ulcers. They sit in the first part of the duodenum and are tied to H. pylori and high acid.
  • Gastric ulcers sit on the lesser curvature. They are punched out with clean bases, and must be biopsied to exclude cancer.
  • Zollinger-Ellison syndrome (a gastrin-secreting tumor, sometimes part of MEN1) causes multiple, distal and refractory ulcers.
  • Complications are bleeding, perforation and obstruction.
• Gastric tumors:
  • Intestinal-type adenocarcinoma forms a mass or ulcer and follows H. pylori, atrophy and intestinal metaplasia.
  • Diffuse-type (signet-ring cell) adenocarcinoma (E-cadherin loss) infiltrates the wall and causes linitis plastica (leather-bottle stomach).
  • Metastatic signs include the Virchow node (left supraclavicular), Sister Mary Joseph nodule (umbilical) and Krukenberg tumor (bilateral ovarian).
  • MALT lymphoma is linked to H. pylori and may regress after eradication.
  • GIST arises from interstitial cells of Cajal and is c-KIT (CD117) positive.

Small intestine and colon

• Obstruction:
  • Adults: adhesions and hernias.
  • Infants and young children: intussusception (ileocolic; red currant-jelly stools; a lead point such as a Meckel diverticulum or enlarged Peyer patches).
  • Older adults: sigmoid volvulus.
• Malabsorption:
  • Celiac disease (gluten sensitivity): villous atrophy, crypt hyperplasia, intraepithelial lymphocytes; anti-tissue transglutaminase antibodies.
  • Lactase deficiency and pancreatic insufficiency are other causes.
• Infectious enterocolitis:
  • Cholera causes secretory "rice-water" diarrhea with an intact mucosa.
  • Shigellosis and amebiasis cause dysentery with mucosal ulcers.
  • Typhoid ulcerates Peyer patches.
  • Clostridioides difficile forms pseudomembranes after antibiotics.
• Irritable bowel syndrome: a functional disorder with no structural lesion.
• Polyps:
  • Hyperplastic polyps are small, rectosigmoid and serrated, with almost no malignant risk.
  • Adenomas are dysplastic. Risk rises with size (over 2 cm), villous architecture (villous adenomas carry the highest risk) and high-grade dysplasia.
  • Juvenile and Peutz-Jeghers (hamartomatous) polyps also occur.
• Appendicitis: usually from luminal obstruction by a fecalith or lymphoid hyperplasia. There is transmural neutrophilic infiltration, with risk of perforation and abscess.
• Hemorrhoids: dilated anal and perianal venous plexuses. Internal hemorrhoids lie above the dentate line and are painless; external ones lie below it and are painful when thrombosed.

Gastrointestinal & Hepatic Pathology

Barrett Esophagus & Carcinogenesis

Complication of chronic gastroesophageal reflux disease (GERD). The normal non-keratinizing stratified squamous epithelium of the distal esophagus undergoes metaplasia to non-ciliated columnar epithelium containing mucin-secreting goblet cells. Barrett esophagus is the definitive precursor lesion for esophageal adenocarcinoma (in contrast to esophageal squamous cell carcinoma, which arises in the middle/upper third from alcohol and tobacco use).

Inflammatory Bowel Disease (IBD): Crohn Disease vs. Ulcerative Colitis

Colorectal Carcinogenesis: The Adenoma-Carcinoma Sequence

The classical Chromosomal Instability (CIN) pathway accounts for 80% to 85% of sporadic colorectal cancers:

1. APC Inactivation (First & Second Hit): Loss or mutation of both alleles of the APC tumor suppressor gene on chromosome 5q21. Loss of the APC destruction complex permits beta-catenin to accumulate in the nucleus, activating c-MYC and cyclin D, producing a hyperproliferative epithelium and early tubular adenoma.
2. KRAS Mutation: Activating mutation of the KRAS oncogene on chromosome 12p promotes unregulated intracellular growth signaling, leading to adenoma enlargement and architectural dysplasia.
3. TP53 & SMAD4 Inactivation: Inactivation of tumor suppressor genes on chromosome 18q (SMAD4) and chromosome 17p (TP53). Loss of p53 eliminates the G1/S DNA repair and apoptosis checkpoint, enabling malignant transformation into an invasive adenocarcinoma.

Alternative Pathway (Microsatellite Instability / MSI, 15%): Caused by defective DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). Seen in hereditary Lynch syndrome (HNPCC) and sporadic cancers with MLH1 promoter hypermethylation.

Hepatic Cirrhosis & Steatotic Liver Disease

• Cirrhosis: The end-stage irreversible consequence of chronic diffuse liver injury, defined by a pathognomonic triad:
  1. Bridging Fibrous Septa: Dense bands of collagen extending between portal tracts and central veins. Fibrogenesis is mediated by hepatic stellate cells (Ito cells) in the space of Disse, which transform into proliferative myofibroblasts under TGF-$\beta$ stimulation, depositing Type I and Type III collagen.
  2. Parenchymal Regenerative Nodules: Proliferating hepatocyte clusters encircled by fibrous bands, lacking normal central venous architecture. Classified as micronodular ($< 3\text{ mm}$, classic for alcohol) or macronodular ($> 3\text{ mm}$, classic for chronic hepatitis B or C).
  3. Disruption of Vascular Architecture: Sinusoidal capillarization causes resistance to portal blood flow, resulting in portal hypertension (esophageal varices, splenomegaly, ascites, caput medusae).
• Metabolic Dysfunction-Associated Steatohepatitis (MASH / NASH): Defined by macrovesicular steatosis ($> 5\%$ of hepatocytes) plus hepatocyte ballooning degeneration, lobular inflammation, and pericellular "chicken-wire" fibrosis in zone 3. Ballooned hepatocytes frequently exhibit Mallory-Denk bodies (tangled, eosinophilic cytoplasmic inclusions of cytokeratins 8 and 18).

Liver, gallbladder and pancreas: more key lesions

• Viral hepatitis:
  • Acute: lobular disarray, hepatocyte ballooning, apoptotic (Councilman) bodies, portal mononuclear inflammation.
  • Chronic: portal and interface hepatitis leading to fibrosis. Hepatitis B shows ground-glass hepatocytes.
• Alcoholic liver disease: steatosis, then alcoholic hepatitis (ballooning, Mallory-Denk bodies, neutrophils, perivenular fibrosis), then micronodular cirrhosis.
• Hepatocellular carcinoma: arises in cirrhotic or HBV-infected livers. It raises alpha-fetoprotein, invades the portal veins and is highly vascular. Risk factors in the Philippines are hepatitis B, aflatoxin, alcohol and hepatitis C. The fibrolamellar variant occurs in young people without cirrhosis.
• Gallstones:
  • Cholesterol stones, the most common, are associated with female sex, obesity, pregnancy, estrogen, rapid weight loss and clofibrate.
  • Pigment stones: black from chronic hemolysis (sickle cell disease, thalassemia) and cirrhosis; brown from biliary infection and parasites (Ascaris, Clonorchis).
  • Complications are acute cholecystitis, choledocholithiasis with ascending cholangitis (Charcot triad), gallstone pancreatitis and gallstone ileus.
• Gallbladder carcinoma: associated with gallstones and porcelain gallbladder.
• Pancreas:
  • Acute pancreatitis is mostly from gallstones and alcohol. It causes enzymatic fat necrosis with calcium soaps (hypocalcemia), hemorrhage and pseudocysts.
  • Chronic pancreatitis causes fibrosis, calcifications, exocrine and endocrine insufficiency.
  • Pancreatic ductal adenocarcinoma (KRAS) in the head of the pancreas causes painless jaundice with a palpable gallbladder (Courvoisier sign), Trousseau migratory thrombophlebitis and a raised CA 19-9.