Mechanisms of Hepatic Injury

What is immune-mediated liver injury?

Idiosyncratic, host-dependent hypersensitivity liver injury

Major immune mechanisms of hepatotoxicity?

Antibody/complement lysis; cell-mediated cytotoxicity; immune-complex inflammation

What acts as the hapten in immune-mediated hepatotoxicity?

Covalently bound xenobiotic-protein adduct

What cytokine is implicated in apoptosis in immune-mediated injury?

TNF

How is immune-mediated toxic hepatitis different from classic autoimmune disease?

Requires ongoing xenobiotic exposure; less self-perpetuating

What severe anesthetic-associated immune hepatitis is classic?

Halothane hepatitis

What reactive halothane metabolite forms hepatoprotein adducts?

Trifluoroacetyl chloride

Which drugs are most classically linked to autoimmune-type liver injury?

Nitrofurantoin; minocycline

Which drugs with hypersensitivity commonly present with hepatitis?

Halothane; TMP-SMX; antiepileptics; allopurinol

Which drugs with hypersensitivity commonly present with cholestasis?

Chlorpromazine; erythromycin estolate; penicillins; rifampin; sulfonamides

Typical time to onset for hypersensitivity liver injury?

1 to 8 weeks

Which drugs may take up to ~20 weeks to cause hypersensitivity liver injury?

Isoniazid; dantrolene

What happens on rechallenge with a hypersensitivity hepatotoxin?

Earlier onset

Classic hypersensitivity clues in DILI?

ANA; SMA; eosinophilia; atypical lymphocytosis; fever; rash

Can absence of rash/eosinophilia exclude immune-mediated DILI?

No

What liver lesion can result from hypersensitivity reactions?

Hepatic granulomas

How do xenobiotics cause cholestasis mechanistically?

Tight-junction injury; transport failure/blockade; ↓ membrane fluidity; ↓ canalicular contractility

What is vanishing bile duct syndrome?

Irreversible bile duct/canalicular injury

How do estrogens cause intrahepatic cholestasis?

Alter membrane lipid composition + inhibit bile secretion

How does rifampin cause cholestatic jaundice mechanistically?

Impairs bilirubin uptake into hepatocytes

How do methyltestosterone and C-17 alkylated anabolic steroids cause cholestasis?

Impair bilirubin secretion into canaliculi

How does cyclosporine cause cholestasis?

Blocks bile salt uptake and canalicular transport

Which drug is noted for cholestasis with minimal inflammation or hepatocellular injury?

Floxacillin

What does ANIT injure?

Tight junctions near canaliculi

What does ANIT-induced tight-junction injury cause?

Reflux of bile into sinusoids

What defines mitochondrial hepatotoxicity?

Impaired respiration → fat accumulation, ↓ ATP, lactic acidosis

How do nucleoside analogs cause mitochondrial injury?

Inhibit mitochondrial DNA synthesis

How do activated Kupffer cells worsen toxicity?

Generate free radicals + promote autoimmune injury

What do activated stellate cells ultimately cause?

Fibrosis

What causes hepatic venoocclusive disease?

Endothelial injury of terminal hepatic venules