Liver is the major site for drug metabolism, it is not surprising, therefore, that drug toxicity and
adverse drug reactions frequently affect the liver. Drug-induced liver disease represents an important
problem. More than 1100 drugs have been implicated in causing liver disease at least in rare occasion.1
Drug-induced liver injury appears to account for about 10% of hepatitis in adults, and more than
40% of cases of hepatitis among patients over 50 years of age.2,3 Most forms of drug injury are less
common in children compared to adults. Some forms of drug-induced liver disease, however, are more
common in children, e.g. valproic acid and aspirin-induced injury. Up to 25% of cases of fulminant
hepatic failure and 20-50% of cases of non-viral chronic hepatitis may be drug-induced.4-9
Spectrum of Drug-Induced Liver Disorder
Hepatic manifestations of drug-induced liver injury can mimic almost the entire spectrum of liver
diseases.9-10 The predominant clinical presentations, however, resemble either acute hepatitis (from
hepatocellular injury) or cholestatic liver disease. Hepatocellular injury may be manifested as minimal
biochemical abnormalities occuring in patients in whom there is no evidence of liver disease, or it may
present as acute hepatitis, acute liver failure (fulminant hepatic failure), chronic hepatitis, and
cirrhosis.11 Hepatocellular injury is of grave significance as the mortality approximates 10%
irrespective of the specific drug.1 In addition to hepatocellular necrosis, in some drugs
hepatotoxicity is manifested as acquired phospholipidosis (e.g. amoidarone), steatohepatitis (e.g.
amiodarone, tamoxifen), microvesicular steatosis (e.g. valproate, tetracyclin, aspirin).12-15
Drug-induced cholestatic liver disease and other forms of drug-induced liver disorders are discussed
Classification of Hepatotoxic Agents
The type of liver cell injury may be intrinsic and dose dependent or may be idiosyncratic and
dose-independent. The mechanism of intrinsic hepatotoxins may relate either to formation of free
radicals or electrophilic intermediates, or to production of reactive oxygen species, which like free
radicals, leads to lipid peroxidation.16,17 On the other hand, idiosyncratic hepatotoxins are
dose-independent, their toxicity is non-predictable, and they produce hepatic injury in a small
proportion of exposed individuals with unique susceptibility, and may be either immunologically or
metabolically mediated.1,18 This host susceptibility may be affected by age, gender, nutritional
factors, systemic disease, exposure to other drugs, and by genetic predisposition.
Histopathology of Drug-Induced Hepatocellular Necrosis
Most drugs generally produce one type of injury in exposed or susceptible individuals, although some
drugs are known to cause more than one type of injury.
Acute Hepatocellular Injury
The pattern of hepatocellular injury resembles the typical or classic viral hepatitis. In which the
hepatocellular injury is non-zonal, but occurs diffusely throughout all acinar zones. The injury
consists of ballooning or acidophilic degeneration, or both. Areas of focal necroses, prominent Kupffer
cells, inflammatory cells and clusters of macrophages containing ceroid pigment (lipofuscin and iron in
resolving acute hepatitis) are distributed haphazardly in the acini. Mitotic figures may be observed in
hepatocytes. Portal and acinar inflammation is variable. Eosinophils and cholestasis may be present.
This pattern of injury is seen with the idiosyncratic type of drug-induced hepatitis, and cannot be
separated from viral hepatitis by morphology alone.
Examples: methyldopa, disulfiram, isoniazid, iproniazid, PAS, papaverine, sulfonamides, disulfiram,
This type of liver cell injury is usually related to direct effects of the drug itself or its metabolites.5
The hepatocyte injury is usually coagulative in type, where the injured hepatocytes become shrunken
with eosinophilic cytoplasm and pyknotic nuclei. Inflammatory cells in the area of necrosis are minimal
and mostly consist of neutrophils and later on macrophages. The borders between the effected and the
viable hepatocytes are often distinct. Cholestasis may be observed. Small droplet steatosis frequently
is seen in the surviving hepatocytes, especially in acetaminophen, carbon tetrachloride and phosphorous
Most frequently the injury is perivenular or involving zone 3, but some drugs may effect other zones.5,19
Acinar zone 3 hepatocellular necrosis is characteristic of specific drugs or toxins such as
acetaminophen, carbon tetrachloride, phalloidin, mushrooms, aflatoxin, halothane, enflurane, etc. This
pattern of injury may mimic that is seen in ischemic injury.
Acinar zone 1 necrosis is seen in cocaine toxicity, phosphorous and iron poisoning.
Confluent / Massive Necrosis
Drugs causing zonal necrosis or pan-acinar spotty necrosis, in the more severe forms, may lead to more
extensive liver cell injury, i.e. bridging, submassive or massive necrosis, and fulminant hepatic
failure. The necrosis involves several adjacent acini in massive necrosis. Regenerative activity in the
forms of ductular hepatocytes or neocholangioles in the collapsed areas and the viable hepatocytes
forming two cell thick plates occur early, but the incidence of recovery is usually minimal. Portal and
acinar inflammation is variable. Cholestasis, ballooning or fatty degeneration is frequently noted in
remaining liver cells.
In massive necrosis, it may be difficult to determine whether the injury starts as pan-acinar spotty
necrosis or zonal necrosis. A rim of surviving hepatocytes around portal areas suggests zonal necrosis.
Chronic Hepatocellular Injury
Drug-induced chronic hepatitis is morphologically indistinguishable from autoimmune chronic hepatitis.
Some of the cases may have clinical, biochemical and serologic similarities to autoimmune hepatitis.
Serologic tests for viral hepatitis B and C are crucial in differentiating chronic viral hepatitis from
drug-induced chronic hepatitis. Ground glass hepatocytes and the demonstration of HBsAg and HBcAg by
immunostains are diagnostic features of chronic hepatitis B. Chronic hepatitis C has characteristic, but
not diagnostic features, which are lymphoid aggregates or lymphoid follicles in portal tracts, scattered
hepatocytes containing fat droplets, and bile duct damage. Chronic drug-induced hepatitis may lead to
fibrosis and cirrhosis. In addition to chronic hepatitis, other drug-induced parenchymal lesions such as
non-alcoholic steatohepatitis, phospholipidosis may also progress to cirrhosis. These chronic lesions
most likely result from mild but continued or repeated injury of prolonged exposure to the hepatotoxic
Examples: alpha-methyldopa,20 oxyphenisatin,21 amiodarone,12 perhexilene maleate,22
Coralgil,13 valproic acid 14,15 , nitrofurantoin.23,24 Knowledge of these drugs with appropriate
follow-up has prevented development of advanced liver disease in most patients.
Diagnosis of Drug-Induced Liver Disease
A detailed and complete history is crucial. If a certain drug is suspected as the cause of liver
dysfunction, a history of the dosage, duration of treatment, route of administration, and temporal
relationship between the onset of symptoms or signs of liver injury and the beginning of drug exposure
should be obtained.
Other causes of liver disease should be ruled out, e.g. serologic tests for viral hepatitis can
exclude hepatitis A, B and C.
Most drugs produce similar lesions in exposed or susceptible individuals, therefore morphologic
findings may in some cases be useful in confirming the diagnosis of drug-induced liver disease. This is
even more so in individuals who are exposed to more than one drug or have pre-existing liver disease.
Use of the offending drug has to be immediately discontinued if clinicopathologic correlation points
that a drug is a possible or probable cause of a liver injury. This in most cases is followed by prompt
improvement in the clinical and biochemical picture, providing further confirmation of a drug-induced
- Zimmerman HJ. Drug Hepatotoxicity. 2nd Ed. Philadelphia: Lippincott, 1999.
- Biour M, Poupon R, Grange JD, Chazouilleres O. Hepatotoxicite des medicaments. Gastroenterol Clin
- Benhamou JP. Drug-induced hepatitis: Clinical aspects. In: Fillastre JP, Ed. Hepatotoxicity of
drugs. Rouen: University de Rouen, 1985: pp 22-30.
- Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure:summary of a workshop.
- Zimmerman HJ, Ishak KG. Hepatic injury due to drugs and toxins. In: MacSween RNM, Burt AD,
Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, Eds. Pathology of the Liver. Churchill Livingstone 2002:
- Dossing M, Sonne J. Drug-induced hepatic disorders. Incidence, management and avoidance. Drug
- Farrell GC. Drug-induced chronic active hepatitis. In: GC Farrell, Ed. Drug-Induced Liver
Disease. Edinburgh: Churchill-Livingstone, 1994: pp 413- 430.
- Lee WM. Drug-induced hepatotoxicity. N Engl J Med 995;333:1118-1127.
- Ishak KG, Zimmerman HJ. Morphologic spectrum of drug-induced hepatic disease. Gastroenterol Clin
North Am 1995;24:759-786.
- Larrey D. Drug-induced liver diseases. J Hepatol 2000;32 (suppl 1):77-88.
- Maddrey WC. Clinicopathological patterns of drug-induced liver disease. In: N. Kaplowitz and
LD.Deleve, Eds. Drug-Induced Liver Disease. New York, Marcel Dekker, Inc, 2003, pp 227-242.
- Lewis JH, Ranard RC, Caruso A, Jackson LK, MullickF, Ishak KG, Seeff LB, Zimmerman HJ. Amiodarone
hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology
- Zimmerman HJ, Ishak KG. Non-alcoholic steatohepatitis and other forms of pseudoalcoholic liver
disease. In: Hall P, Ed. Alcoholic Liver Disease. Pathology and Pathogenesis. Second Edition.
London, Edward Arnold, pp175-198.
- Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury: analyses of 23 fatal cases. Hepatology
- Eadie MJ, Hooper WD, Dickinson RG. Valproate-associated hepatotoxicity and its biochemical
mechanisms. Medical Toxicology 1988;3:85-106.
- Deleve LD, Kaplowitz N. Mechanism of drug-induced liver disease. Gastroenterol Clin North Am
- Pessayre D. Role of reactive metabolites in drug-induced hepatitis. J Hepatol 1995;23 (Suppl
- Neuberger J. Immune mechanisms in drug hepatotoxicity. Clin Liver Dis 1998;2:471-482.
- Kanel GC: Histopathology of drug-Induced Liver Disease. In: N Kaplowitz and LD Deleve, Eds.
Drug-Induced Liver Disease. New York: Marcel Dekker, Inc. 2003, pp243-286.
- Maddrey WC, Boitnott JK. Severe hepatitis from methyldopa. Gastroenterology 1975;68:351-360.
- Reynolds TB, Peters RL, Yamada S. Chronic active and lupoid hepatitis caused by a laxative,
oxyphenisatin. N Engl J Med 1971;280:813-820.
- Pessayre D, Bichara M, Degott C, et al. Perhexiline maleate-induced cirrhosis. Gastroenterology
- Schattner A, Von Der Walde J, Kozak N, Sokolovskaya N, et al. Nitrofurantoin-induced immune-mediated
lung and liver disease. Am J Med Sci 1999;317:336-340.
- Sharp JR, Ishak KG, Zimmerman HJ. Chronic active hepatitis and severe hepatic necrosis associated
with nitrofurantoin. Ann Intern Med 1980;92:14-19.