Transcript ACUTE RESPONSES TO HEPATIC INJURY Richard T Miller GlaxoSmithKline OUTLINE • Chronology of injury • Types of injury (a few definitions) - Patterns/Cells • Responses to 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
• Acute (single exposure)
• Chronic (repeat exposure)
HEPATIC DEGENERATION
AND NECROSIS
• Hepatocellular
• Endothelial
• Bile duct
HEPATOCELLULAR
DEGENERATION
• Ballooning degeneration
– Enlarged, clear cells
– Dilated RER
– Reversible
TYPES OF HEPATIC INJURY
• Degenerative
– Vacuolar
hydropic = dilated ER
fat = cytoplasmic accumulation
glycogen = cytoplasmic accumulation
– Enzyme induction (?)
TYPES OF HEPATIC INJURY
• Liver enlargement
– degenerative responses
– hepatocellular hypertrophy?
> cell size increase due to increased
organelle (e.g., SER)
HEPATIC MORPHOLOGY
Normal
Centrilobular Hypertrophy - PP
HEPATIC MORPHOLOGY
Normal
Centrilobular Hypertrophy - PB
LIPOFUSCIN
• Pigment accumulation
• Lysosomal, pericanalicular
• Partially digested cellular remnants
PATTERNS OF ACUTE
HEPATOCELLULAR NECROSIS
•
•
•
•
•
Centrilobular*
Periportal
Midzonal
Random
Massive
*Most common pattern in toxicity
APOPTOSIS
• Single cell death
• Morphologically distinct
– condensed chromatin
– uptake by adjacent cells
• Counterbalance hyperplasia
– chemically induced
– proliferative lesions
REPAIR OF HEPATIC INJURY
• Regeneration
• Scarring
HEPATIC REGENERATION
• Tightly controlled, multi-step process
- determined by functional mass
• Steps
- priming (TNFa, IL-6)
- cell cycle progression
G0 > G1 ---S-----G2-----M
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.
PLOIDY
PLOIDY
MEGALOCYTOSIS
• Nuclear and cytoplasmic enlargement
• Inhibition of mitosis (not DNA
synthesis)
• Chronic toxicity (ex., pyrrolizidine
alkaloids)
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
FEATURES OF CHRONIC
HEPATOCELLULAR INJURY
• Nodule formation
• Fibrosis
• Bile duct response
• Inflammation
HEPATIC FIBROSIS
• Stellate cells activation
– Loss of retinoid droplets
– Proliferation
– Expression of collagen, “matrix”
genes
– Actin filaments
• Mechanism
– Kupffer cell cytokines
– TGF-b1
– Inflammation
Fausto N (2005). Mechanisms of Liver Regeneration and Their Clinical
Implications Journal of Hepatobiliary Pancreatic Surgery 12(3):181-9.
Fausto N (2005). Mechanisms of Liver Regeneration and Their Clinical
Implications Journal of Hepatobiliary Pancreatic Surgery 12(3):181-9.
PATTERNS OF BILIARY
SYSTEM INJURY
• Acute necrosis
• Unique agents
• Intrahepatic vs. Extrahepatic
SUMMARY – RESPONSE TO
HEPATIC INJURY
•
Liver response is dependent upon nature,
extent and chronicity of injury. Regenerative
capacity of liver is enormous.
•
Response to acute injury is rapid, well
coordinated and dynamic.
•
Mixture of response modalities often seen.
•
Liver fibrosis/cirrhosis is likely to have
deleterious consequences on liver function.