Summary 1. LIVER HISTOLOGY & PHYSIOLOGY Key Points - Structural Units - Lobule = hexagonal, central vein in middle, portal triads at periphery - Acinus = functi
Summary 1. LIVER HISTOLOGY & PHYSIOLOGY Key Points - Structural Units - Lobule = hexagonal, central vein in middle, portal triads at periphery - Acinus = functional unit based on microcirculation - Portal triad contains: bile duct + hepatic artery + portal vein branch - Central vein = tributary of hepatic vein - Acinar Zones (CRITICAL FOR EXAMS) ⭐ 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 & excretion - Bile acid synthesis (12-36g/day): cholic acid + chenodeoxycholic acid - Secreted as taurine & glycine conjugates - 10-20% deconjugated in ileum → enterohepatic circulation - Functions of bile: 1. - Elimination of water-insoluble bilirubin, excess cholesterol, xenobiotics 2. - Emulsification of dietary fat in gut - Pathway - Aging RBCs → Heme → (Heme oxygenase) → Biliverdin → (Biliverdin reductase) → Bilirubin - Bilirubin bound to albumin → liver → conjugated with glucuronic acid (UDP-glucuronosyltransferase) - Bilirubin glucuronides → excreted in bile → gut → urobilinogen → stercobilin (stool) - Some urobilinogen reabsorbed → enterohepatic circulation → excreted in urine Detailed Notes Structural Units - Lobule = hexagonal, central vein in middle, portal triads at periphery - Acinus = functional unit based on microcirculation - Portal triad contains: bile duct + hepatic artery + portal vein branch - Central vein = tributary of hepatic vein Acinar Zones (CRITICAL FOR EXAMS) ⭐ 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 & excretion - Bile acid synthesis (12-36g/day): cholic acid + chenodeoxycholic acid - Secreted as taurine & glycine conjugates - 10-20% deconjugated in ileum → enterohepatic circulation - Functions of bile: 1. Elimination of water-insoluble bilirubin, excess cholesterol, xenobiotics 2. Emulsification of dietary fat in gut 2. BILIRUBIN METABOLISM Pathway - Aging RBCs → Heme → (Heme oxygenase) → Biliverdin → (Biliverdin reductase) → Bilirubin - Bilirubin bound to albumin → liver → conjugated with glucuronic acid (UDP-glucuronosyltransferase) - Bilirubin glucuronides → excreted in bile → gut → urobilinogen → stercobilin (stool) - Some urobilinogen reabsorbed → enterohepatic circulation → excreted in urine Jaundice - Bilirubin 2 mg/dl → jaundice (yellowish skin + sclera = icterus) - Kernicterus = unconjugated bilirubin accumulation in brain → toxic ⭐ Causes of Jaundice 1. Excessive production (hemolysis) 2. Reduced hepatocellular uptake 3. Impaired conjugation (Gilbert's, Crigler-Najjar) 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 urine) Toxicity Toxic (kernicterus) Nontoxic Lab Total minus direct Direct bilirubin Cause Hemolysis, impaired conjugation Cholestasis, hepatocellular disease 3. LIVER FUNCTION TESTS Category Tests --- --- Hepatocyte integrity AST (SGOT), ALT (SGPT), LDH Biliary excretory function Serum bilirubin, Alkaline phosphatase, GGT Hepatocyte synthetic function Albumin, Prothrombin time, Ammonia Key Points ⭐ - ALT more specific for liver than AST - AST:ALT 2:1 = alcoholic liver disease ⭐ - ↑↑ Alkaline phosphatase = cholestasis/biliary obstruction - ↓ Albumin + ↑ PT = severe hepatocellular dysfunction - Aminopyrine breath test + galactose elimination = hepatocyte function 4. HISTOLOGIC PATTERNS OF HEPATIC INJURY Pattern Description Associated with --- --- --- Steatosis Fat (neutral fat/TG) in hepatocytes Alcohol, NAFLD, obesity, drugs Ballooning degeneration Hydropic swelling of hepatocytes Alcoholic hepatitis, viral hepatitis Councilman bodies Acidophilic apoptotic hepatocytes Acute viral hepatitis ⭐ Mallory bodies Eosinophilic cytokeratin inclusions Alcoholic hepatitis ⭐ (also PBC, Wilson's, NASH) Piecemeal necrosis Periportal necrosis Chronic hepatitis Bridging necrosis Portal-portal or portal-central Severe hepatitis Massive necrosis Entire lobules Fulminant hepatitis Coagulative necrosis Mummified hepatocytes, poorly staining Lytic necrosis Hepatocytes swell and rupture Fibrosis Portal, central, bridging Chronic liver disease Cirrhosis Regenerative nodules + fibrosis End-stage 5. CHOLESTASIS Definition - Systemic retention of bilirubin and other solutes eliminated in bile (bile salts, cholesterol) - Results from hepatocellular dysfunction OR intra/extrahepatic biliary obstruction Clinical Features - Jaundice - Pruritis (bile salts deposited in skin) ⭐ - Skin xanthomas (cholesterol deposits) - Malabsorption (fat-soluble vitamins A, D, E, K) - Pale/clay-colored stools - Dark urine Lab - ↑ Bilirubin (conjugated) - ↑↑ Alkaline phosphatase ⭐ - ↑ Lipids - ↑ GGT Biopsy Findings - Bile pigment accumulation within hepatic parenchyma - Hepatocyte swelling + foamy degeneration - Bile duct distension + proliferation - Bile lakes (rupture of bile ducts) - Portal tract fibrosis - Cholangitis + cholangiolitis Types - Intrahepatic : hepatocellular dysfunction - Extrahepatic : mechanical obstruction of bile ducts 6. HEPATIC FAILURE Definition - Loss of 80-90% of hepatic functional capacity Causes 1. Chronic liver disease (cirrhosis) — progressive 2. Massive hepatic necrosis (fulminant failure): - Viral hepatitis - Drugs: acetaminophen, halothane, rifampicin, MOI antidepressants, CCl4 - Amanita phalloides mushroom toxins 3. Hepatic dysfunction without necrosis : - Reye's syndrome - Tetracycline toxicity - Acute fatty liver of pregnancy Clinical Consequences Hepatic dysfunction signs: - Jaundice + cholestasis - Hypoalbuminemia → edema, ascites - Hyperammonemia → encephalopathy - Hypoglycemia - Fetor hepaticus (musty odor) - Palmar erythema - Spider angiomas - Hypogonadism + gynecomastia (↓ estrogen metabolism) - Weight loss + muscle wasting - Coagulopathy (↓ clotting factors) Portal hypertension from cirrhosis: - Ascites - Splenomegaly - Hemorrhoids - Caput medusae (abdominal skin) - Esophageal varices Life-threatening complications: - Hepatic failure → multiple organ failure - Coagulopathy - Hepatic encephalopathy - Hepatorenal syndrome - Esophageal varices → rupture → massive GI bleed - Hepatocellular carcinoma Prognosis - 80% mortality ⭐ 7. HEPATIC ENCEPHALOPATHY - Metabolic disorder of CNS + neuromuscular system - Associated with severe hepatocellular dysfunction + portosystemic shunting - Pathogenesis : ammonia → neuronal dysfunction + generalized brain edema ⭐ - Asterixis = flapping tremor = hallmark sign ⭐ Clinical Spectrum - Subtle behavioral changes - Confusion → stupor → deep coma → death - Other: rigidity, hyperreflexia, EEG changes, seizures - Minor morphologic changes in brain 8. HEPATORENAL SYNDROME - Renal failure in severe liver disease WITHOUT intrinsic kidney disease - Excluded: concomitant liver + kidney damage, ATN secondary to circulatory collapse - Pathogenesis: vasoconstriction → decreased renal blood flow - Urine : hyperosmolar, protein-negative, low Na⁺ ⭐ - Lab: ↑ blood urea + creatinine - Px: may hasten death or persist for months 9. CIRRHOSIS Definition - Irreversible end-stage chronic liver disease → parenchymal injury + fibrosis 3 Histologic Features ⭐ 1. Bridging fibrous septa 2. Disruption of entire liver architecture 3. Parenchymal nodules Types Type Nodule size Associated with --- --- --- Micronodular Uniform, 3mm Viral hepatitis ⭐ Mixed Both Etiologic Classification ⭐ Cause % --- --- Alcoholic liver disease 60-70% Viral hepatitis 10% Biliary diseases 5-10% Primary hemochromatosis 5% Wilson's disease Rare α1-antitrypsin deficiency Rare Cryptogenic 10-15% Others: drugs (α-