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Liver and intrahepatic bile ducts-nontumor

Hepatitis - noninfectious

Drug / toxin induced hepatitis


Reviewers: Komal Arora, M.D. (see Reviewers page)
Revised: 6 May 2012, last major update May 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General,† acetaminophen,† amiodarone,† anabolic steroids,† atorvastatin,† carbon tetrachloride,† chlorpromazine,† cresol,† erythromycin,† halothane,† isoniazid,† methotrexate,† oral contraceptives,† phenothiazines,† phenylbutazone,† phenytoin,† ramipril,† sulfa drugs,† terbinafine,† tetracycline

General
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● Occurs through hepatic conversion of drug/toxin to active toxin or via immune mechanisms (drug or metabolite acts as hapten)
● Either predictable (intrinsic) or unpredictable (idiopathic)
● Either hepatocellular (cytotoxic) or cholestatic

Predictable: dose related, affects virtually everyone (acetaminophen, tetracycline, anti-neoplastic agents, Amanita phalloides toxin, carbon tetrachloride, alcohol)
● Either direct effect of drug or via interference with a metabolic pathway

Unpredictable: depends on hostís propensity to metabolize a drug/toxin or mount an immune response
● Not dose related
● Either hypersensitivity related or toxic metabolite related

● Can mimic any pattern of primary liver disease; need thorough clinical history, including exposure to herbal and over the counter drugs and toxins, plus a literature search, to diagnose (
J Clin Pathol 2009;62:481, Semin Liver Dis 2009;29:364)
● Most common pattern is acute hepatitis, with or without cholestasis; acetaminophen is most common cause of acute liver failure in US
● Drug induced chronic hepatitis is rare, but fibrosis and cirrhosis occur with methotrexate; autoimmune hepatitis-like disease occurs with minocycline
● Drug related cholestatic injury may be prolonged and lead to ductopenia
● Drug-induced steatohepatitis is rare, but occurs with amiodarone and irinotecan; tamoxifen, estrogens and nifedipine, can precipitate or exacerbate steatohepatitis in presence of other risk factors

Tables
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Consensus criteria for terminology in drug-induced liver injury


Overview of drug-induced liver injury patterns


Herbal products with known hepatotoxicity

Micro description
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● Mixed macro- and microvesicular steatosis
● May have eosinophils if allergic, lymphocytes if immune-mediated, neutrophils with phenothiazines
● Epithelioid granulomas with phenylbutazone, sulfonamides, sulfonylureas
● Centrilobular necrosis with carbon tetrachloride, acetaminophen
● Periportal necrosis with yellow phosphorus
● Microvesicular steatosis with intravenous tetracycline, cholestasis with anabolic steroids and oral contraceptives, cholestatic hepatitis with phenothiazines

Micro images
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Resolving hepatitis:
Left-parenchymal infiltrate is diminished compared to acute hepatitis; hepatocellular injury is minimal; prominent pigment accumulation in sinusoidal macrophages
Right-sinusoidal macrophages are evident with PAS+ diastase resistant cytoplasmic contents



Prolonged cholestasis: persistence of canalicular bile plugs accompanied by feathery degeneration of periportal hepatocytes (cholate stasis)


Microvesicular steatosis: numerous small lipid droplets are present in hepatocyte cytoplasm


Sinusoidal obstruction syndrome: endothelial injury in small hepatic venules leads to luminal occlusion due to endothelial swelling and thrombosis, and results in sinusoidal dilatation and congestion


Peliosis: the hepatic parenchyma contains blood-filled cavities that lack an endothelial lining


Stellate (Ito) cell lipidosis: fat-laden stellate cells with multiple lipid vacuoles that indent the nucleus; Ito cells are along sinusoids in space of Disse


Ground-glass hepatocytes: with cyanamide (used for alcohol abuse), diazepam, barbiturates, insulin, IV glucose


Acetaminophen

General
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● Discrete centrilobular coagulative necrosis

Micro images
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Marked hepatocellular necrosis in zonal, centrilobular pattern; inflammatory infiltrate is minimal; residual viable hepatocytes show some steatosis


Amiodarone

General
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● Dose related liver toxicity if > 200 mg daily

Micro description
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● Alcohol-like changes with periportal Mallory bodies and late periportal fibrosis

Micro images
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Hydropic swelling, inflammation, acidophil bodies, cytoplasmic cholestasis


Periportal Mallory bodies


Amiodarone steatohepatitis: marked hepatocyte ballooning, numerous Mallory hyaline bodies and minimal steatosis

Electron microscopy images
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Mallory bodies


Giant mitochondria


Myelin figures


Phospholipidosis: formation of lysosomal inclusion bodies due to accumulation of amiodarone

Additional references
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Histopathology 1993;22:80, Curr Vasc Pharmacol 2008;6:228


Anabolic steroids

General
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● Elevation of liver enzymes, cholestatic jaundice, liver tumors, both benign and malignant, and peliosis hepatis

Micro images
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Anabolic-steroid-induced pure cholestasis. Prominent bile plugs are present in hepatocytes and canaliculi without inflammation or hepatocellular damage

Additional references
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Mini Rev Med Chem 2011;11:430


Atorvastatin

Micro images
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Atorvastatin-induced acute hepatitis: mixed parenchymal inflammation with lymphocytes, plasmahistiocytic cells, neutrophils; no bile duct damage or fibrosis


Carbon tetrachloride

Micro description
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● Centrilobular necrosis


Chlorpromazine

General
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● Slow metabolizers have cholestasis and jaundice 1-5 weeks after treatment
● Good prognosis

Micro description
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● Cytoplasmic and canalicular cholestasis, portal inflammation with eosinophils
● Minimal necrosis


Cresol

Case reports
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● Case history of 42 year old man with ingestion as suicide attempt (Arch Pathol Lab Med 2003;127:364)

Micro images
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Focal hepatocyte dropout and regeneration


Erythromycin

Micro images
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Erythromycin-related cholestatic hepatitis: has features similar to acute hepatitis, plus bile plugs in hepatocytes and canaliculi


Halothane

General
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● Rare, fatal immune-mediated hepatitis

Gross images
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Soft friable liver due to massive necrosis


Isoniazid

General
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● Hepatocellular inflammation


Methotrexate

General
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● Related to duration of therapy

Micro description
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● Steatosis, ballooning degeneration and necrosis, cholestasis, portal inflammation, progressive fibrosis, cirrhosis

Micro images
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Methotrexate toxicity: prominent macrovesicular steatosis and periportal fibrosis


Advanced lesion with ballooning degeneration and necrosis, cholestasis, early fibrosis


Oral contraceptives

Micro description
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● Pure canalicular cholestasis with normal portal tracts


Phenothiazines

Micro description
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● Neutrophils, cholestatic hepatitis


Phenylbutazone

Micro description
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● Epithelioid granulomas


Phenytoin (Dilantin)

Micro description
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● Multiple histiocytic granulomas
● Also cholestasis, multifocal necrosis, lymphocyte beading in sinusoids (similar to infectious mononucleosis)

Micro images
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Cytoplasmic cholestasis and lymphocyte beading in sinusoids


Histiocytic granuloma


Ramipril

General
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● An inhibitor of angiotensin-converting enzyme
● Case reports of hepatitis in 3 men ages 51-59 years (
Arch Pathol Lab Med 2003;127:1493)
● May cause prolonged cholestatic hepatitis and biliary cirrhosis; other ACE inhibitors may rarely cause cholestasis

Micro description
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● Cholestasis, duct necrosis, extravasation of bile, ductular proliferation, portal inflammation

Micro images
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Necrotic bile ducts


Sulfa drugs

Micro description
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● Granulomas, often epithelioid

Micro images
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Granuloma


Terbinafine

General
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● Anti-fungal drug for treating onychomycosis and chronic subcutaneous mycosis
● May cause persistent cholestasis (even after drug withdrawal), liver failure and death
● Histologic changes resemble acute cellular rejection (
Hum Pathol 2003;34:187)

Micro description
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● Marked centrilobular cholestasis, severe bile duct damage


Tetracycline

Micro description
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● Microvesicular steatosis

Micro images
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Minocycline-induced autoimmune hepatitis: marked necroinflammatory activity with numerous plasma cells


Microvesicular steatosis

End of Liver and intrahepatic bile ducts-nontumor > Hepatitis - noninfectious > Drug / toxin induced hepatitis


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