Gastrointestinal and Liver Pathology Review

Cirrhosis

• Architectural change in the liver.
• Characterized by diffuse bridging fibrosis and regenerative nodules.
• Most common cause of portal hypertension.

Serum Ascites Albumin Gradient (SAAG)

• Used to differentiate between portal hypertension and other causes of ascites (fluid buildup in the abdomen).
• Calculated by subtracting the albumin concentration in ascitic fluid from the serum albumin concentration: SAAG = Serum Albumin - Ascites Albumin
• If SAAG > 1.1, the ascites is likely due to portal hypertension.
• If SAAG < 1.1, the ascites is due to other causes.
• Other causes of ascites:
  • Nephrotic syndrome
  • Heart failure
  • Chronic Kidney Disease (CKD)
  • Malignancy
  • Infection
  • Conditions affecting vascular permeability

Clinical Manifestations of Cirrhosis and Portal Hypertension

• Neurological:
  • Hepatic encephalopathy
  • Asterixis (flapping tremor)
• Gastrointestinal:
  • Dull abdominal pain
  • Nausea, vomiting
  • Fetor hepaticus (foul-smelling breath)
    • Caused by volatile organic compounds (VOCs) that the liver cannot detoxify.
    • Odor often described as smelling like garlic or rotten eggs.
    • VOCs include trimethylamine and methylmarcaptan.
• Hematological:
  • Laryngocytopenia
  • Splenomegaly (very important)
• Renal: hepatorenal syndrome
• Metabolic: hyponatremia
• Cardiovascular: peripheral edema
• Reproductive:
  • Testicular atrophy
  • Gynecomastia (due to increased estrogen)
• Skin:
  • Spider angiomas (common on USMLE)
  • Palmar erythema
  • Jaundice
  • Pruritus
• Esophageal and Gastric Varices:
  • Esophageal varices (hematemesis)
  • Gastric varices (melena)

Spontaneous Bacterial Peritonitis (SBP)

• Also called primary bacterial peritonitis.
• A common and potentially fatal infection in patients with cirrhosis and ascites.
• Treated with ceftriaxone (third-generation cephalosporin).
• Diagnosis: Paracentesis with ascitic fluid analysis.
• Absolute Neutrophil Count (ANC) > 250 cells/mm3.

Liver Pathology Serum Markers

• AST and ALT (Aminotransferases):
  • Included in most liver disease assessments.
  • ALT is typically more elevated than AST in most liver diseases.
  • In alcoholic liver disease, AST is more elevated than ALT (AST > ALT).
    • Mnemonic: AST in "School" (Alcohol is not allowed in school).
    • Ratio of AST to ALT > 2:1 suggests alcoholic liver disease.
  • AST is also known as SGOT (Serum Glutamic Oxaloacetic Transaminase).
    • Mnemonic: Go to School (G-O S-GOT).
    • Normal value: 9-40 U/L
  • ALT is also known as SGPT (Serum Glutamic Pyruvic Transaminase).
    • Normal value: 7-56 U/L
• ALP (Alkaline Phosphatase):
  • Increased in biliary diseases, bone diseases, and cholestasis.
  • Normal value: 45-115 U/L

Functional Biomarkers

• Bilirubin:
  • Elevated in liver diseases (biliary obstruction, cirrhosis, alcoholic hepatitis, viral hepatitis).
  • Normal value: < 1 mg/dL
• Albumin:
  • Decreased in advanced liver diseases (marker of liver's biosynthetic function).
  • Normal value: 3.5-5.5 g/dL
• Prothrombin Time (PT):
  • Increased in advanced liver diseases.
  • Normal value: 10-13 seconds
• Platelets:
  • Decreased in advanced liver disease due to decreased thrombopoietin production and increased splenic sequestration.
  • Normal value: 150,000-450,000 /microliter

Reye Syndrome

• Rare but fatal childhood hepatic encephalopathy.
• Associated with aspirin use during viral infections.
• Aspirin metabolites decrease beta-oxidation by reversible inhibition of mitochondrial enzymes.
• Histological findings:
  • Microvesicular fatty changes
  • Mitochondrial abnormalities

Alcoholic Liver Disease

• Hepatic Steatosis (Fatty Liver):
  • Macrovesicular fatty changes.
• Alcoholic Hepatitis:
  • Mallory bodies.
• Alcoholic Cirrhosis:
  • Sclerosis around the central vein.
• AST > ALT (2:1 ratio).

Nonalcoholic Fatty Liver Disease (NAFLD)

• Cellular ballooning and eventual necrosis.
• May cause cirrhosis and hepatocellular carcinoma.
• Histopathology: Ballooning of cells with central necrosis.

Autoimmune Hepatitis

• Chronic inflammatory liver disease, more common in females.
• May be asymptomatic or present with nausea, fatigue, pruritus.
• Increased AST and ALT.
• Positive antinuclear, anti-smooth muscle, and anti-microsomal antibodies.
• Increased bilirubin causes pruritus.

Hepatic Encephalopathy

• Liver cirrhosis leads to decreased metabolism of substances like ammonia.
• Ammonia causes neuropsychiatric dysfunction.
• Asterixis (flapping tremor) is a key sign.
• Portosystemic shunts bypass the liver, allowing toxins to reach the brain.
• Shunt: abnormal connection between portal vein and systemic veins

Alpha-1 Antitrypsin Deficiency

• Misfolded genetic protein aggregates in hepatocytes.
• Associated with panacinar emphysema (especially in the lower lobes).

Jaundice

• Yellowing of skin and sclera due to bilirubin deposition.
• Caused by increased bilirubin production or decreased clearance.
  • Causes: Hemolysis, Obstruction, Tumors, Liver disease
• Types:
  • Conjugated (direct) hyperbilirubinemia: Biliary tract obstruction (gallstones, liver/pancreatic cancer), excretion defects (Dubin-Johnson, Rotor syndrome).
  • Unconjugated (indirect) hyperbilirubinemia: Too much hemolysis.Crigler-Najjar, Gilbert syndrome (decreased UDP-glucuronosyltransferase).
  • Mixed

Benign Neonatal Hyperbilirubinemia (Physiological Jaundice of Newborn)

• Unconjugated hyperbilirubinemia.
• Increased fetal RBC turnover and increased hematocrit level.
• Decreased conversion of urobilinogen.
• Increased beta-glucuronidase activity.
• Treatable with phototherapy.

Cholangiocarcinoma

• Malignant tumor of bile duct epithelium.
• Presents with fatigue, weight loss, abdominal pain, jaundice, and biliary tract obstruction.

Pancreatitis

• Acute Pancreatitis: auto digestion of pancreas by pancreatic enzymes
  • Causes: gallstones, alcohol, trauma, hyperlipidemia, mumps, autoimmune, drugs. Two of three criteria:
    • Acute epigastric pain radiating to the back
    • Increased serum amylase or serum lipase.(Lipase is more specific)
  • Complications: Pseudocyst in the head of the pancreas (made of granulation tissue).
    • Abscess/necrosis, hemorrhage, infection, organ failure
• Chronic Pancreatitis: atrophy and calcification of pancreas
  • Risk factor: alcoholic abuse.
  • Diagnostic: steatorrhea due to fat soluble vitamin deficiency, AMS and lipase may or may not be elevated.
    • Stool elastase test & D-Xylose tests (normal, differentiates from lactose intolerance or celiac disease).
      • Abdominal CT Scan

Acute Cholangitis

• Charcot's Triad: Right upper quadrant pain, Jaundice and Fever.
• Reynolds Pentad: Charcot's triad, Confusion and Shock.

Pharmacology of the Gastrointestinal System

• H2 Blockers (Cimetidine, Famotidine, Nizatidine):
  • Used for GERD, gastritis, peptic ulcer disease.
  • Mnemonic: Table for two (H2) before you dine.
  • Adverse Effects:
    • Cimetidine: Potent inhibitor of cytochrome P450, antiandrogenic effects (gynecomastia, impotence, decreased libido).
• Proton Pump Inhibitors (PPIs) (Omeprazole, Lansoprazole):
  • Used for GERD, stress ulcer prophylaxis, reflux esophagitis, gastritis.
  • Adverse Effects:
    • Increased risk of bloodstream infections.
    • Vitamin B12 malabsorption.
    • Disrupt normal bacterial balance in gut.
• Antacids (Aluminum Hydroxide, Calcium Carbonate, Magnesium Hydroxide):
  • Aluminum hydroxide: Causes constipation.
  • Calcium carbonate: Can chelate and decrease effectiveness of other drugs (e.g., tetracyclines), iron should not be given as it causes chelation, leading to hyperchromatosis
  • Magnesium hydroxide: Causes diarrhea.
• Misoprostol:
  • Prostaglandin E1 analog.
  • Decreases acid production and protects gastric mucosa.
  • Used as an abortifacient (ripens the cervix).
  • Decreases cyclic AMP
• Bismuth and Sucralfate:
  • Increases healing of ulcers.
  • Given in traveler's diarrhea and H. pylori quadruple therapy (Tetracycline, Metronidazole, Bismuth, PPI).
  • H. pylori triplet therapy: Amoxicillin, Clarithromycin and PPI
• Octreotide:
  • Long-acting somatostatin analog.
  • Used for acute variceal bleeding (also propranolol).
• Sulfasalazine:
  • Causes reversible oligospermia.
• Loperamide:
  • Poor CNS penetration (low addictive potential).
  • Naloxone alternate which has poor CNS penetration
  • Adverse effect: constipation.
• Antiemetics:
  • Ondansetron and Granisetron (5-HT3 receptor antagonists):
    • Used for nausea and vomiting after chemotherapy or surgery.
    • Safe in pregnancy (morning sickness).
    • Adverse effects: Constipation, headache, QT prolongation.
  • Prochlorperazine and Metoclopramide (D2 receptor antagonists):
    • Adverse Effects:
      • Extrapyramidal symptoms, hyperprolactinemia, anxiety, drowsiness.
  • Aprepitant and Fosaprepitant (Neurokinin-1 receptor antagonists):
    • Used for chemotherapy-induced nausea and vomiting (when ondansetron fails).
• Orlistat:
  • Inhibits gastric and pancreatic lipase.
  • Decreases breakdown and absorption of dietary fats.
  • Causes flatulence, abdominal pain, bowel urgency.

Malabsorption Syndromes

• General features: Diarrhea, steatorrhea, weight loss.
• Celiac Disease (Gluten-Sensitive Enteropathy):
  • Gliadin intolerance.
  • Associated with Human Leukocyte Antigen (HLA) DQ2 and DQ8.
  • Primarily affects distal duodenum and proximal jejunum.
  • Causes steatorrhea and malabsorption due to villous atrophy and crypt hyperplasia.
  • Treatment: Gluten-free diet.
  • D-xylose test: Abnormal.
  • Serology: Positive IgA anti-tissue transglutaminase.
  • Histology: Villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis.
  • Intussusception
• Lactose Intolerance:
  • Lactase deficiency.
  • Villi are normal.
  • Causes osmotic diarrhea (watery) with low stool pH.
  • Lactose hydrogen breath test is positive.
• Pancreatic Insufficiency:
  • Due to chronic pancreatitis.
    • D-xylose test is normal.
  • Steatorrhea.
  • Fecal elastase is decreased.
• Tropical Sprue:
  • Unknown cause.
  • Is a condition where intestine is struggling to absorb nutrients.
  • Associated with megaloblastic anemia due to folate deficiency and B12 deficiency.
• Whipple Disease:
  • Caused by Tropheryma whipplei.
  • PAS positive with foamy macrophages.
    • Glycogen accumulation.
  • Cardiac symptoms, joint pain, neurological symptoms.
  • More common in older males.