Drug Induced Liver Disease (Hepatotoxicity)-Chapter 11-HISTOLOGICAL PATTERN IN DRUG-INDUCED LIVER DISEASE Part-2

Differential diagnosis

     The histological features can be indistinguishable from other causes of acute hepatitis such as acute viral hepatitis, initial presentation of autoimmune hepatitis and Wilson disease. The presence of bile duct injury, prominent eosinophilic infiltrate, granulomas, sharply defined perivenular necrosis, or cholestasis out of proportion to hepatocellular injury, favours adverse drug reaction, but none of these features is specific.

Acute liver failure (fulminant hepatitis)

         Acute liver failure (ALF) is defined as the onset of hepatic encephalopathy within 8 weeks of onset of symptoms.

Based on morphological features, ALF can be subdivided into three categories.

·         Extensive microvesicular steatosis. This pattern is rare and has been observed with tetracycline and nucleoside analogues such as zidovudine.

·         Necrosis with marked inflammatory activity. It is similar to the acute hepatitis pattern discussed above except that the confluent necrosis involves most of the liver parenchyma (massive/submassive hepatic necrosis). The most commonly implicated drugs are isoniazid, other antimicrobial agents (sulfonamides, cotrimoxazole, ketoconazole), monoamine oxidase inhibitors, and anticonvulsants (phenytoin, valproate). Any drug that causes acute hepatitis can potentially cause ALF.

·         Necrosis with little or no inflammation. This pattern is seen with acetaminophen (fig 4), recreational drugs such as cocaine and 3,4-methylenedioxymethylamphetamine (MDMA; ecstasy), industrial organic compounds such as carbon tetrachloride, and some herbal preparations. Necrosis can be accompanied by steatosis.

Acetaminophen

Acetaminophen toxicity is the leading drug-related cause, implicated in nearly 40% of ALF, the remaining being attributed to idiosyncratic drug reactions. 

Chronic hepatitis

Chronic liver disease typically refers to persistent biochemical abnormalities beyond 6 months. In some series, the cut-off of 3 months has been used for hepatocellular injury and 6 months for cholestatic or mixed injury. Progression to chronicity has been reported in 5–10% of adverse drug reactions and is higher for the cholestatic/mixed injury pattern. Histologically proven drug-induced chronic hepatitis with fibrosis is a rare phenomenon. Some specific patterns and clinicopathological situations are discussed below.

Chronic hepatitis with negative autoimmune markers

The histological features are indistinguishable from chronic viral hepatitis, and progression to fibrosis and even cirrhosis can occur. The features of acute hepatitis may be seen to a variable degree. Drugs associated with this pattern include lisinopril (antihypertensive), sulfonamide (antibiotic), trazodone (antidepressant), and

chemotherapeutic agents such as uracil, 5-fluorouracil prodrug tegafur and tamoxifen.

 Isolated case reports implicate numerous other drugs including phenytoin and the Chinese herb Jin bu huan. 

Autoimmune hepatitis

Several drugs can cause chronic hepatitis that is serologically and morphologically indistinguishable from de novo autoimmune hepatitis (AIH). The hepatic disease may be accompanied by features of hypersensitivity such as rash, arthralgia and peripheral eosinophilia.

Minocycline

Long-term use of minocycline, a synthetic tetracycline for treatment of acne, can lead to hepatitis that can mimic lupus-related hepatitis, AIH or overlap syndrome. Autoimmune disease can develop within days of starting the drug or may be delayed for many years. High titres of antinuclear antibodies (ANAs) are common, but smooth muscle (SMA) and other autoantibodies often are negative. Autoimmune markers may be elevated in chronic hepatitis due to drugs (drug-induced autoimmune hepatitis). Inflammatory activity can be minimal to mild, and eosinophils are typically inconspicuous (fig 5). Marked fibrosis and cirrhosis are rare, and patients often improve after drug withdrawal. 

Nitrofurantoin

Nitrofurantoin is used to treat urinary tract infections. The hepatic injury can manifest as self-limited acute hepatitis, chronic hepatitis, and rarely as hepatic failure. Chronic hepatitis can be indistinguishable from de novo AIH and is often associated with ANA and SMA.

Others

Other drugs implicated in AIH include methyldopa (antihypertensive) and clometacin non-steroidal anti-inflammatory drug (NSAID). Antibodies to liver-kidney-microsomal antibodies, akin to type 2 AIH, have been described in hepatitis related to hydralazine (antihypertensive) and tienilic acid (ticrynafen, a diuretic withdrawn from the American market), but this association is not clearly defined.

Methotrexate

Methotrexate is a folate antagonist that is used for long-term treatment of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The histological features of methotrexate-related toxicity range from minor fatty change, hepatocyte anisonucleosis, mild portal-based inflammation, and focal necrosis to more severe hepatocellular necrosis, fibrosis and cirrhosis (fig 6).

Acute cholestatic injury

       Drug-induced cholestatic injury can manifest clinically with jaundice, pruritus, dark urine and pale stools. Liver enzyme studies typically reveal elevation of alkaline phosphatase and γ-glutamyl transferase. Transaminases can be variably elevated. A Danish study of 1100 cases of drug-associated injury reported 16% with the acute cholestatic pattern.

The histological patterns of injury can be divided into two forms. Pure (bland) cholestasis in which bile plugs are seen in hepatocytes or canaliculi and are most prominent in zone 3. Inflammation and hepatocellular injury are not observed. This pattern is typically observed with anabolic steroids (fig 7) and oral contraceptives. Other drugs that have been incriminated include prochlorperazine, thiabendazole and warfarin. Cholestatic hepatitis can result from a wide variety of drugs; it is the classic pattern seen with toxicity due to macrolide antibiotics such as erythromycin (fig 8) and the antipsychotic agent chlorpromazine.