15.2 Glomerulonephritis, Inflammatory Bowel Disease, and Hepatorenal Disease Pathophysiology

15.1 Glomerulonephritis, Inflammatory Bowel Disease, and Hepatorenal Disease Pathophysiology

1. Renal Pathology: Nephrotic vs. Nephritic Syndromes

Renal glomerular diseases present along a pathophysiological spectrum categorized primarily as nephrotic syndrome (podocyte breakdown leading to severe proteinuria) or nephritic syndrome (inflammatory basement membrane disruption leading to hematuria).

Nephrotic Syndrome Spectrum

Nephrotic syndrome is characterized by heavy proteinuria (> 3.5 g/24 hours), hypoalbuminemia (< 3.0 g/dL), generalized peripheral and periorbital edema (due to reduced plasma oncotic pressure), hyperlipidemia, lipiduria, and oval fat bodies or fatty casts in the urine. Loss of antithrombin III in urine creates a hypercoagulable state with risk of renal vein thrombosis.

Nephritic Syndrome Spectrum

Nephritic syndrome is an inflammatory process causing glomerular capillary wall rupture. It presents with hematuria with dysmorphic red blood cells (RBCs) and RBC casts, hypertension (fluid retention), oliguria, azotemia (elevated BUN and creatinine), and mild-to-moderate proteinuria (< 3.5 g/day).

• Post-Streptococcal Glomerulonephritis (PSGN):
  • Pathophysiology: Type III hypersensitivity reaction occurring 1\u20133 weeks after Group A beta-hemolytic Streptococcus pharyngitis or impetigo. Immune complexes (streptococcal pyrogenic exotoxin B) deposit in glomeruli.
  • Diagnostics: Immunofluorescence demonstrates a "starry sky" granular IgG and C3 deposition along the GBM and mesangium. EM reveals diagnostic subepithelial "humps". Laboratory testing shows low serum C3 levels and elevated anti-streptolysin O (ASO) or anti-DNase B titers.
• IgA Nephropathy (Berger Disease):
  • Pathophysiology: Most common primary glomerulonephritis worldwide. IgA immune complex deposition in the glomerular mesangium following a mucosal upper respiratory tract infection (URI) or gastroenteritis.
  • Diagnostics: Immunofluorescence demonstrates mesangial IgA deposits. Presents as synpharyngitic hematuria (recurrent gross hematuria occurring simultaneously with or within 1\u20132 days of an upper respiratory infection).
• Rapidly Progressive Glomerulonephritis (RPGN):
  • Pathophysiology: Severe, fulminant glomerular injury causing rapid loss of renal function over days to weeks. Characterized histologically by crescents in Bowman's space composed of proliferating parietal epithelial cells, macrophages, and fibrin.
  • Subtypes:
    1. Type I (Anti-GBM Disease / Goodpasture Syndrome): Autoantibodies against alpha-3 chain of Type IV collagen. Linear IgG deposition along GBM on IF. Presents with pulmonary hemorrhage (hemoptysis) and glomerulonephritis.
    2. Type II (Immune Complex RPGN): Granular IF deposition; progression of PSGN, Lupus Nephritis, or Henoch-Sch\u00f6nlein Purpura.
    3. Type III (Pauci-Immune RPGN): Minimal immune complex deposition on IF. Strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA): PR3-ANCA/c-ANCA positive in Granulomatosis with Polyangiitis (Wegener); MPO-ANCA/p-ANCA positive in Microscopic Polyangiitis and Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss).

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2. Gastrointestinal Pathology: Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) encompasses Crohn's Disease and Ulcerative Colitis, two distinct chronic relapsing inflammatory disorders of the gastrointestinal tract.

Comparative Pathophysiology of IBD

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3. Liver Pathology: Cirrhosis, Etiologies, and End-Stage Complications

Pathophysiology of Cirrhosis

Cirrhosis represents the final common pathway of chronic liver injury. It is characterized by diffuse architecture reorganization featuring bridging fibrous septa and regenerative parenchymal nodules.

• Cellular Mechanism: Chronic hepatocyte injury and inflammation activate resident hepatic stellate cells (Ito cells) located in the Space of Disse. Activated stellate cells transdifferentiate into myofibroblast-like cells that secrete massive amounts of Transforming Growth Factor-beta (TGF-beta) and collagen (Types I and III), obliterating sinusoid fenestrations and impairing hepatocyte-blood exchange.

Specific Etiologies of Chronic Liver Disease

• Alcoholic Liver Disease: Steatosis (fatty liver) -> Alcoholic Hepatitis (hepatocyte ballooning, neutrophilic infiltrate, and Mallory-Denk bodies composed of damaged cytokeratin intermediate filaments) -> Alcoholic Cirrhosis.
• Non-Alcoholic Fatty Liver Disease (NAFLD / NASH): Associated with metabolic syndrome and insulin resistance. Steatosis without alcohol excess; NASH features ballooned hepatocytes and fibrosis.
• Chronic Viral Hepatitis: Chronic Hepatitis B (ground-glass hepatocytes filled with HBsAg) and Hepatitis C (lymphoid follicles in portal tracts) are major global causes of cirrhosis and hepatocellular carcinoma (HCC).
• Hereditary Hemochromatosis: Autosomal recessive mutation in the HFE gene (C282Y), causing unregulated intestinal iron absorption. Excess iron accumulates in tissues (Fenton reaction ROS generation). Classic triad: Bronze diabetes (hyperpigmentation + diabetes mellitus) and micronodular cirrhosis. Increased risk of HCC.
• Wilson Disease: Autosomal recessive mutation in ATP7B gene, impairing copper excretion into bile and copper incorporation into ceruloplasmin. Excess copper accumulates in liver, brain (basal ganglia/lenticular nucleus), and cornea (Kayser-Fleischer rings in Descemet's membrane). Lab test reveals low serum ceruloplasmin and elevated 24-hour urinary copper.
• Alpha-1 Antitrypsin (AAT) Deficiency: Autosomal codominant mutation (PiZZ allele) causing misfolding of AAT protein in the endoplasmic reticulum of hepatocytes. Histology shows Periodic acid-Schiff (PAS)-positive, diastase-resistant eosinophilic globules in hepatocytes. Causes panacinar emphysema and hepatic cirrhosis.

Pathophysiology of End-Stage Cirrhosis Complications

1. Portal Hypertension: Increased resistance to portal blood flow through fibrotic sinusoids leading to opening of portosystemic collateral vessels:
   • Esophageal Varices: Left gastric vein to esophageal veins; rupture causes catastrophic hematemesis.
   • Caput Medusae: Umbilical vein re-cannulation to paraumbilical veins.
   • Rectal Varices: Superior rectal vein to middle/inferior rectal veins.
   • Splenomegaly & Ascites: Hypoalbuminemia + splanchnic arterial vasodilation + portal hypertension drive fluid into peritoneal cavity.
2. Hepatic Encephalopathy: Impaired hepatic detoxifying capacity and portosystemic shunting allow neurotoxins, predominantly ammonia (NH3), to cross the blood-brain barrier. Ammonia causes astrocyte swelling (via glutamine accumulation), presenting with asterixis (flapping tremor), confusion, somnolence, and coma.
3. Hepatorenal Syndrome: Severe portal hypertension induces massive splanchnic arterial vasodilation mediated by nitric oxide. This triggers intense compensatory renal vasoconstriction, causing profound renal hypoperfusion, oliguria, and acute renal failure with unremarkable renal histology and low urine sodium (< 10 mEq/L).