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ACUTE RESPONSES TO HEPATIC INJURY

ACUTE RESPONSES TO HEPATIC INJURY. Richard T Miller GlaxoSmithKline. OUTLINE. Chronology of injury Types of injury (a few definitions) - Patterns/Cells Responses to injury - regeneration - fibrosis - cellular and biochemical. CHRONOLOGY OF HEPATIC INJURY.

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ACUTE RESPONSES TO HEPATIC INJURY

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  1. ACUTE RESPONSES TO HEPATIC INJURY Richard T Miller GlaxoSmithKline

  2. OUTLINE Chronology of injury Types of injury (a few definitions) - Patterns/Cells Responses to injury - regeneration - fibrosis - cellular and biochemical

  3. CHRONOLOGY OF HEPATIC INJURY • Acute (single exposure) • Chronic (repeat exposure)

  4. HEPATIC DEGENERATION AND NECROSIS • Hepatocellular • Endothelial • Bile duct

  5. HEPATOCELLULAR DEGENERATION • Ballooning degeneration • Enlarged, clear cells • Dilated RER • Reversible

  6. TYPES OF HEPATIC INJURY • Degenerative • Vacuolar hydropic = dilated ER fat = cytoplasmic accumulation glycogen = cytoplasmic accumulation • Enzyme induction (?)

  7. TYPES OF HEPATIC INJURY • Liver enlargement • degenerative responses • hepatocellular hypertrophy? • > cell size increase due to increased • organelle (e.g., SER)

  8. HEPATIC MORPHOLOGY Normal Centrilobular Hypertrophy - PP

  9. HEPATIC MORPHOLOGY Normal Centrilobular Hypertrophy - PB

  10. LIPOFUSCIN • Pigment accumulation • Lysosomal, pericanalicular • Partially digested cellular remnants

  11. Lipofuscin Accumulationin the Liver of Rats * 5 4 3 2 1 0 WYHD WYLD CA Control * Lipofuscin (%) * 0 1 2 5 11 22 WEEKS

  12. PATTERNS OF ACUTE HEPATOCELLULAR NECROSIS • Centrilobular* • Periportal • Midzonal • Random • Massive *Most common pattern in toxicity

  13. P Focal injury P P C P P P

  14. P Multifocal injury P P C P P P

  15. P Diffuse injury P P P P P

  16. APOPTOSIS • Single cell death • Morphologically distinct • condensed chromatin • uptake by adjacent cells • Counterbalance hyperplasia • chemically induced • proliferative lesions

  17. REPAIR OF HEPATIC INJURY • Regeneration • Scarring

  18. HEPATIC REGENERATION Tightly controlled, multi-step process - determined by functional mass Steps - priming (TNFa, IL-6) - cell cycle progression G0 > G1 ---S-----G2-----M

  19. HEPATIC REGENERATION Cell cycle progression - Transcription factors (NFkB, STAT3; both induced by TNFa). - Growth Factors (TGFa, HGF, VEGF(?)) - Cell cycle genes (P53, P21). - DNA replication/Mitosis [Cyclin D1 (determines GF autonomy), other cyclins]. - Coordinated matrix (collagen) production, degradation. - Biliary, vascular components. Fausto N (2005). Mechanisms of Liver Regeneration and Their Clinical Implications Journal of Hepatobiliary Pancreatic Surgery 12(3):181-9.

  20. PLOIDY

  21. PLOIDY

  22. MEGALOCYTOSIS • Nuclear and cytoplasmic enlargement • Inhibition of mitosis (not DNA synthesis) • Chronic toxicity (ex., pyrrolizidine alkaloids)

  23. OVAL CELL PROLIFERATION • Rodent most common • Derivation from terminal ductule cells • “Facultative stem cell” concept • Progenitor of hepatocytes and biliary epithelial cells • RLE cells in vitro

  24. FEATURES OF CHRONIC HEPATOCELLULAR INJURY • Nodule formation • Fibrosis • Bile duct response • Inflammation

  25. HEPATIC FIBROSIS • Stellate cells activation • Loss of retinoid droplets • Proliferation • Expression of collagen, “matrix” genes • Actin filaments • Mechanism • Kupffer cell cytokines • TGF-b1 • Inflammation

  26. NORMAL LIVER Hepatocytes Stellate Cell Endothelial cells Macrophage RBCs Friedman, SL (2004). Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 1(2):98-105. 81.9

  27. EARLY HEPATIC FIBROSIS Hepatocytes Activated Stellate Cells Friedman, SL (2004). Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 1(2):98-105. 81.9

  28. PATTERNS OF BILIARY SYSTEM INJURY • Acute necrosis • Unique agents • Intrahepatic vs. Extrahepatic

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