Liver & intrahepatic bile ducts

Drug / toxin induced hepatitis

Drug / toxin induced hepatitis (DILI)-general

Author: Anthony W.H. Chan, M.B.Ch.B.

Topic Completed: 1 June 2016

Minor changes: 25 June 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

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

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Table of Contents

Cite this page: Chan A. Drug / toxin induced hepatitis (DILI)-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverdrugtoxingeneral.html. Accessed September 21st, 2021.

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

Leading cause of acute liver failure and one of major reasons for liver transplantation in the US (Hepatology 2010;52:2065)
Incidence in general population is 20/100,000 (Mayo Clin Proc 2014;89:95)

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

42 year old man with cresol ingestion as suicide attempt (Arch Pathol Lab Med 2003;127:364)
72 year old man with amiodarone induced cirrhosis (Hepatology 2012;55:325)
73 year old man with amiodarone induced acute liver failure (BMJ Case Rep 2012 Dec 18;2012)
80 year old woman with amiodarone induced submassive necrosis in background of cirrhosis (ACG Case Rep J 2015;2:116)
3 men ages 51 - 59 years with hepatitis due to ramipril (Arch Pathol Lab Med 2003;127:1493)

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:
- Acute hepatic necrosis due to acetaminophen, carbon tetrachloride
- Acute hepatitis, due to isoniazid (JAMA 1961;176:877)
- Granulomatous hepatitis, due to phenytoin (Aust N Z J Med 1981;11:539)
Neoplasm and mimics:
- Focal nodular hyperplasia, due to oral contraceptives (Hepatology 1995;22:1674)
- Hepatocellular adenoma, due to oral contraceptives (Hepatology 1995;22:1674), anabolic steroids (J Gastroenterol 2000;35:557)
- Hepatocellular carcinoma, due to aflatoxin (Lancet 1991;338:1356)
- Angiosarcoma and cholangiocarcinoma, due to thorotrast (Cancer 1982;49:2161)
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:
- Due to amiodarone, methotrexate (J Gastroenterol Hepatol 2001;16:1395)
Sulfa drugs:
- Granulomas, often epithelioid
Terbinafine:
- Marked centrilobular cholestasis, severe bile duct damage
Tetracycline:
- Microvesicular steatosis
Vascular lesion:
- Sinusoidal obstruction syndrome, due to antineoplastic cytotoxic agents (Paediatr Drugs 2010;12:277)
- Budd-Chiari syndrome, due to oral contraceptives, dacarbazine (Postgrad Med J 2015;91:692)
- Nodular regenerative hyperplasia, hepatoportal sclerosis, due to azathioprine (Hepatol Res 2013;43:999)
- Sinusoidal dilatation and peliosis, due to oral contraceptives (Dig Liver Dis 2015;47:e10)