1. LIVER HISTOLOGY & PHYSIOLOGY Structural Units - Lobule : Hexagonal structure with a central vein in the middle and portal triads at the periphery. - Acinus :
1. LIVER HISTOLOGY & PHYSIOLOGY Structural Units - Lobule : Hexagonal structure with a central vein in the middle and portal triads at the periphery. - Acinus : Functional unit based on microcirculation. - Portal Triad : Contains a bile duct, hepatic artery branch, and portal vein branch. - Central Vein : Tributary of the hepatic vein. Acinar Zones Zone Location Oxygenation Affected by --- --- --- --- Zone 1 Periportal Best Phosphorus poisoning, eclampsia Zone 2 Midzonal Intermediate Yellow fever Zone 3 Centrilobular Worst Alcohol, CCl4, ischemia, shock, right heart failure Liver Functions - Bilirubin metabolism and excretion. - Bile acid synthesis (12-36g/day): Cholic acid and chenodeoxycholic acid. - Secreted as taurine and glycine conjugates. - 10-20% deconjugated in ileum (enterohepatic circulation). - Functions of bile : 1. Elimination of water-insoluble bilirubin, excess cholesterol, and xenobiotics. 2. Emulsification of dietary fat in the gut. 2. BILIRUBIN METABOLISM Pathway - Aging RBCs → Heme → (Heme oxygenase) → Biliverdin → (Biliverdin reductase) → Bilirubin. - Bilirubin binds to albumin → liver → conjugated with glucuronic acid (UDP-glucuronosyltransferase). - Bilirubin glucuronides → excreted in bile → gut → urobilinogen → stercobilin (stool). - Some urobilinogen is reabsorbed via enterohepatic circulation and excreted in urine. Jaundice - Bilirubin 2 mg/dl results in jaundice (icterus). - Kernicterus : Unconjugated bilirubin accumulation in the brain; highly toxic. Causes of Jaundice 1. Excessive production (hemolysis). 2. Reduced hepatocellular uptake. 3. Impaired conjugation (Gilbert's, Crigler-Najjar syndromes). 4. Decreased hepatocellular excretion. 5. Impaired bile flow (cholestasis). Types of Bilirubin Feature Unconjugated Conjugated --- --- --- Water solubility Insoluble Soluble Albumin binding Tight Loose Urine Absent Present (tea-colored) Toxicity Toxic (kernicterus) Nontoxic Lab Total minus direct Direct bilirubin Cause Hemolysis, impaired conjugation Cholestasis, hepatocellular disease 3. LIVER FUNCTION TESTS (LFTs) Category Tests --- --- Hepatocyte integrity AST (SGOT), ALT (SGPT), LDH Biliary excretory function Serum bilirubin, Alkaline phosphatase (ALP), GGT Hepatocyte synthetic function Albumin, Prothrombin time (PT), Ammonia Key Clinical Correlations - ALT is more specific for liver injury than AST. - AST:ALT 2:1 suggests alcoholic liver disease. - Isolated elevation of Alkaline phosphatase suggests cholestasis or biliary obstruction. - Low Albumin + prolonged PT indicates severe hepatocellular dysfunction. 4. HISTOLOGIC PATTERNS OF HEPATIC INJURY Pattern Description Associated with --- --- --- Steatosis Fat (TG) in hepatocytes Alcohol, NAFLD, obesity, drugs Ballooning degeneration Hydropic swelling Alcoholic/viral hepatitis Councilman bodies Acidophilic apoptotic hepatocytes Acute viral hepatitis Mallory bodies Eosinophilic cytokeratin inclusions Alcoholic hepatitis, Wilson's, NASH Piecemeal necrosis Periportal necrosis Chronic hepatitis Bridging necrosis Portal-portal or portal-central Severe hepatitis Massive necrosis Entire lobules Fulminant hepatitis Fibrosis Collagen deposition Chronic liver disease Cirrhosis Regenerative nodules + fibrosis End-stage liver disease 5. CHOLESTASIS Definition Systemic retention of bilirubin and other solutes (bile salts, cholesterol) due to hepatocellular dysfunction or biliary obstruction. Clinical Features - Jaundice and dark urine. - Pruritis (bile salt deposition in skin). - Skin xanthomas (cholesterol deposits). - Malabsorption of fat-soluble vitamins (A, D, E, K). - Pale/clay-colored stools. Laboratory Findings - Elevated conjugated bilirubin. - Significantly elevated Alkaline phosphatase (ALP) and GGT. 6. HEPATIC FAILURE Definition Loss of 80-90% of hepatic functional capacity. Causes 1. Chronic liver disease : Cirrhosis. 2. Massive hepatic necrosis : Viral hepatitis, drugs (Acetaminophen, Halothane, Rifampicin), or mushroom toxins (Amanita phalloides). 3. Dysfunction without necrosis : Reye's syndrome, acute fatty liver of pregnancy. Clinical Consequences - Encephalopathy : Due to hyperammonemia; characterized by Asterixis (flapping tremor). - Portal Hypertension : Ascites, splenomegaly, esophageal varices, and caput medusae. - Synthetic Failure : Hypoalbuminemia (edema), coagulopathy (bleeding), and hypoglycemia. - Endocrine : Gynecomastia and palmar erythema (impaired estrogen metabolism). - Hepatorenal Syndrome : Renal failure secondary to severe liver disease without intrinsic kidney pathology; characterized by low urinary sodium. 7. CIRRHOSIS Histologic Features 1. Bridging fibrous septa (Collagen types I & III). 2. Disruption of the entire liver architecture. 3. Parenchymal regenerative nodules. Pathogenesis - Key cell: Ito cell (hepatic stellate cell) . - Stimulated by TGF-β, TNF, and IL-1 to produce collagen. Classification - Micronodular ( 3mm) : Classically associated with Viral Hepatitis. 8. VIRAL HEPATITIS Feature HAV HBV HCV HDV HEV --- --- --- --- --- --- Type RNA DNA RNA RNA RNA Transmission Fecal-oral Parenteral/Sexual Parenteral Parenteral Fecal-oral Chronicity Never 5-10% (adults) 85% Yes Never HCC Risk No Yes Yes No No Special - HBx protein Lymphoid aggregates Needs HBV High mortality in pregnancy HBV Serology - HBsAg : Indicates active infection. - Anti-HBs : Indicates immunity (recovery or vaccination). - HBeAg : Indicates high infectivity/active replication. - Anti-HBc IgM : Marker of acute infection. - Window Period : Only Anti-HBc IgM is positive; HBsAg and Anti-HBs are negative. 9. ALCOHOLIC LIVER DISEASE Three Stages 1. Hepatic Steatosis : Soft, yellow, greasy liver. Reversible with abstinence. 2. Alcoholic Hepatitis : Characterized by ballooning degeneration, Mallory bodies, and neutrophilic infiltration. 3. Alcoholic Cirrhosis : Micronodular shrunken liver; end-stage. Pathogenesis - Excess NADH production shifts metabolism toward lipid biosynthesis. - Acetaldehyde causes direct lipid peroxidation and cytoskeletal disruption. 10. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) - Most common metabolic liver disease. - Associated with Type 2 Diabetes, Obesity, and Insulin Resistance . - Histology may be identical to alcoholic steatohepatitis (NASH) but occurs in non-drinkers.