Liver & intrahepatic bile ducts
Drug / toxin induced hepatitis
Drug / toxin induced hepatitis-general


Topic Completed: 1 June 2016

Minor changes: 22 September 2020

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PubMed Search: Drug[TI] OR toxin[TI] "induced hepatitis"[TI] full text[sb]

Anthony W.H. Chan, F.R.C.P.A.
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Cite this page: Chan A. Drug / toxin induced hepatitis-general. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/liverdrugtoxingeneral.html. Accessed October 20th, 2020.
Definition / general
  • Drug / toxin reactions can be intrinsic or predictable, where they are dose dependent (e.g. acetaminophen); or idiosyncratic and unpredictable, where they are dose independent (e.g. isoniazid)
Epidemiology
Pathophysiology
  • Underlying mechanisms include direct / indirect toxicity, aberrant metabolism producing toxic metabolites and immune mediated hypersensitivity

  • Risk factors (J Hepatol 2015;63:503)
    • Drug properties (e.g. threshold dosage, lipophilicity, toxic metabolite, oxidative stress, mitochondrial liability, inhibition of hepatobiliary transporters)
    • Host factors (e.g. age, gender, underlying liver or other disease, genetic factors)
    • Drug - host interaction
Diagrams / tables

Images hosted on other servers:

Consensus criteria
for terminology
in drug induced
liver injury

Overview of drug induced liver injury patterns

Herbal products with known hepatotoxicity

Clinical features
  • Very wide range of clinical and pathological presentations can result; the time of onset after drug exposure varies from hours to months
  • Clinical manifestations range from asymptomatic deranged liver function to fulminant hepatic failure and death
  • Mimic all forms of acute, chronic, vascular or neoplastic liver diseases that are caused by other etiologies
  • LiverTox, which is produced by NLM (National Library of Medicine) and NIDDK (National Institute of Diabetes and Digestive and Kidney Disease), provides up to date, accurate and easily accessed information on drug induced liver injury

  • Amiodarone
    • Class III antiarrhythmic medication used in virtually all forms of supraventricular and ventricular tachycardia (Vasc Health Risk Manag 2010;6:465)
    • Dose related liver toxicity if > 200 mg daily
    • Associated with hepatotoxicity (odds ratio of 5.5, 95% CI: 1.3 - 21.2) (Br J Clin Pharmacol 2015;79:988)
    • Asymptomatic hepatic dysfunction is common in patients receiving longterm amiodarone (15 - 30%) (JAMA 2007;298:1312)
    • Symptomatic hepatotoxicity is less common: 0.5 - 2.9% have clinically overt hepatitis (Hepatology 1989;9:679)
    • Fulminant acute liver failure and cirrhosis are rare
    • Longterm users should be monitored by serum alanine transaminase or aspartate transaminase every 6 months (JAMA 2007 Sep 19;298:1312)

  • Anabolic steroids:
    • Elevation of liver enzymes, cholestatic jaundice, liver tumors (benign and malignant), peliosis hepatitis

  • Chlorpromazine:
    • Slow metabolizers have cholestasis and jaundice 1 - 5 weeks after treatment
    • Good prognosis

  • Halothane:
    • Rare, fatal immune mediated hepatitis

  • Isoniazid:
    • Hepatocellular inflammation

  • Methotrexate:
    • Related to duration of therapy

  • Ramipril:
    • Inhibitor of angiotensin converting enzyme
    • May cause prolonged cholestatic hepatitis and biliary cirrhosis; other ACE inhibitors rarely cause cholestasis

  • Terbinafine:
    • Antifungal drug for 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)
Diagnosis
  • Diagnosis of drug or toxin induced liver injuries requires clinical, biochemical and pathological correlation
  • LiverTox, which is produced by NLM (National Library of Medicine) and NIDDK (National Institute of Diabetes and Digestive and Kidney Disease), provides up to date, accurate and easily accessed information on drug induced liver injury
Case reports
Microscopic (histologic) description
  • Morphological patterns can be categorized into:
    • Necroinflammatory injury: acute hepatic necrosis, acute hepatitis and granulomatous hepatitis
    • Cholestatic injury: bland cholestasis, acute cholestatic hepatitis and chronic cholestatic injury
    • Steatosis and steatohepatitis
    • Vascular lesion: sinusoidal obstruction syndrome, Budd-Chiari syndrome, nodular regenerative hyperplasia, hepatoportal sclerosis, sinusoidal dilatation and peliosis
    • Neoplasm and neoplasm-like lesion
    • Adaptive change

  • Amiodarone
    • Steatosis, both macrovesicular and microvesicular, is most frequent finding; may be accompanied by ballooning degeneration and Mallory-Denk bodies (Hum Pathol 1990;21:59)
    • Variable degree of fibrosis and even cirrhosis may be found
    • Panacinar necrosis is seen in fulminant acute liver (ACG Case Rep J 2015;2:116)

  • Carbon tetrachloride:
    • Centrilobular necrosis

  • Chlorpromazine:
    • Cytoplasmic and canalicular cholestasis, portal inflammation with eosinophils
    • Minimal necrosis

  • Cholestatic injury:
    • Bland cholestasis, due to oral contraceptives
    • Acute cholestatic hepatitis, due to amoxicillin / clavulanate (Gut 1992;33:368)
    • Chronic cholestatic injury, due to chlorpromazine (Hepatology 1994;20:1437)

  • Methotrexate:
    • Steatosis, ballooning degeneration and necrosis, cholestasis, portal inflammation, progressive fibrosis, cirrhosis

  • Necroinflammatory injury:
  • Neoplasm and mimics:
  • Oral contraceptives:
    • Pure canalicular cholestasis with normal portal tracts

  • Phenothiazines:
    • Neutrophils, cholestatic hepatitis

  • Phenylbutazone:
    • Epithelioid granulomas

  • Phenytoin (Dilantin):
    • Multiple histiocytic granulomas
    • Also cholestasis, multifocal necrosis, lymphocyte beading in sinusoids (similar to infectious mononucleosis)

  • Ramipril:
    • Cholestasis, duct necrosis, extravasation of bile, ductular proliferation, portal inflammation

  • Steatosis and steatohepatitis:
  • Sulfa drugs:
    • Granulomas, often epithelioid

  • Terbinafine:
    • Marked centrilobular cholestasis, severe bile duct damage

  • Tetracycline:
    • Microvesicular steatosis

  • Vascular lesion:
Microscopic (histologic) images

Images hosted on other servers:

Resolving hepatitis

Prolonged cholestasis

Microvesicular steatosis


Sinusoidal obstruction syndrome

Peliosis

Stellate (Ito) cell lipidosis

Ground glass hepatocytes


Anabolic steroid induced pure cholestasis

Atorvastatin induced acute hepatitis

Erythromycin related cholestatic hepatitis

Methotrexate toxicity


Methotrexate: advanced
lesion with ballooning
degeneration and necrosis,
cholestasis, early fibrosis

Phenytoin (Dilantin):
cytoplasmic cholestasis
and lymphocyte beading
in sinusoids

Tetracycline:
minocycline induced
autoimmune hepatitis


Phenytoin (Dilantin): histiocytic granuloma

Sulfa drugs: granuloma

Microvesicular steatosis

Electron microscopy description
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