1 / 55

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.

coby-riley
Download Presentation

ACUTE RESPONSES TO HEPATIC INJURY

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related