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 separately.

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

Pan-Acinar Spotty Hepatitis
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, etc.

Zonal Necrosis
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 induced toxicity.

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 drugs.

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 injury.

References

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