Description. The course of illness resembles chronic viral hepatitis with serum aminotransferase elevations without jaundice and with mild if any symptoms. Serum aminotransferase levels may fluctuate over time and intermittently fall into the normal range.

Latency to Onset. The first onset of aminotransferase elevations may be within weeks or months of starting the medication, but the diagnosis of chronic hepatitis requires that elevations are present for several months or a liver biopsy showing typical features of chronic hepatitis. Sometimes the duration of the elevations is not known, but biochemical and clinical characteristics suggest chronic injury.

Symptoms. Usually minimal if present at all and include nonspecific symptoms of weakness, fatigue, intermittent nausea and abdominal discomfort.

Serum Enzyme Elevations. A hepatocellular pattern of serum enzyme elevations with ALT that persists in being above the ULN, with some values at least 2 times ULN over a period of at least 6 months. Alkaline phosphatase and serum bilirubin may be mildly elevated, but are rarely >2 times ULN. Autoantibodies are common particularly if the injury is severe.

Drugs. Medications that can cause a chronic hepatitis include isoniazid, propylthiouracil, nitrofurantoin, minocylcine, fibrates, statins, hydralazine and methyldopa. These medications can also cause acute hepatitis or an autoimmune hepatitis like syndrome, so that chronic hepatitis due to medications may be a mild form of acute drug induced hepatitis in which the medication is continued so that the injury becomes chronic. Drug induced chronic hepatitis usually occurs in patients while on a medication chronically. The persistence of chronic hepatitis after stopping a medication is very uncommon and probably represents an unrelated process or autoimmune hepatitis triggered by the medication.

Differential Diagnosis. Other causes of chronic hepatitis include autoimmune hepatitis and hepatitis B, C and D and hepatitis E (due to genotype 3 HEV and usually in immunosuppressed patients). Clinical features of chronic hepatitis can also accompany celiac disease and inflammatory bowel disease. Nonalcoholic and alcoholic liver disease can cause serum aminotransferase elevations typical of chronic hepatitis, but imaging of the liver and liver biopsy demonstrate steatosis and a different pattern of liver injury (zone 3 ballooning degeneration).

Criteria for Definition. Elements important in the diagnosis are exclusion of other causes (hepatitis A, B, C and E) and features of chronic hepatitis as shown by:

1.

Persistent ALT levels above the ULN on at least 3 occasions

2.

Alkaline phosphatase levels of less than 2 times ULN

3.

Minimal and nonspecific symptoms

4.

Mild or minimal bilirubin elevations

5.

Liver biopsy changes of chronic hepatitis with portal inflammation and spotty lobular inflammation and necrosis with variable decrees of interface hepatitis and portal fibrosis.

It is often difficult to distinguish between a mild, anicteric case of drug induced acute hepatitis and drug induced chronic hepatitis, but the time to onset and insidious nature of the presentation can help to distinguish the two. The mild, transient ALT elevations that occur with many medications are usually benign and nonprogressive, and can resolve even with continuation of the drug. In contrast, the ALT elevations that occur with chronic hepatitis induced by medications usually indicate significant liver injury that can lead to fibrosis and even cirrhosis. The importance of making this distinction is important both for differential diagnosis and management. The differential diagnosis of chronic hepatitis includes idiopathic autoimmune hepatitis which can present an identical fashion. The management is to discontinue the medication, but corticosteroid therapy may be appropriate if the hepatitis is slow to resolve or severe.