Description. Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis are well documented but rare forms of drug induced liver injury. In addition, fatty liver disease is more often chronic than acute even when drug induced. Drug induced fatty liver is characterized by mild to moderate serum enzyme elevations, generally with a hepatocellular pattern arising in a patient with fatty liver, as shown by liver biopsy or imaging tests, usually ultrasound. The clinical presentation resembles nonalcoholic fatty liver disease and may sometimes merely represent exacerbation of an underlying NAFLD caused by the medication or weight gain triggered by the medication.

Latency to Onset. The time to onset of NAFLD is typically 3 to 12 months, but may occur up years after starting medication.

Symptoms. Symptoms are usually absent or mild and nonspecific. The diagnosis is usually made based upon laboratory or imaging test results done routinely or for an independent reason. Dark urine, jaundice, and pruritus are uncommon and immunoallergic features are rarely present.

Serum Enzyme Elevations. Serum enzymes are usually only mildly elevated, typically in a hepatocellular pattern, more suggestive of chronic rather than acute hepatitis. Serum bilirubin is rarely elevated and the INR is preserved unless cirrhosis is present.

Drugs. Medications commonly implicated in causing fatty liver include corticosteroids, antidepressant and antipsychotic medications and, most commonly, tamoxifen. In many instances, it is unclear whether the fatty liver disease is a direct result of the medication on the liver or a consequence of weight gain triggered by the medication (as occurs with many antidepressant or antipsychotic medications). Amiodarone and methotrexate are also capable of causing fatty liver disease and hepatic injury that resembles alcoholic hepatitis with fat, lobular disarray, inflammation, Mallory bodies and fibrosis. With these two agents, however, the inflammation and fibrosis generally overshadows the degree of steatosis. Both of these agents can cause fibrosis and cirrhosis.

Differential Diagnosis. The finding of serum enzyme elevations with fat on liver biopsy or imaging suggests nonalcoholic fatty liver, and the role of medications should be suspect if an agent associated with fatty liver is being taken.

Definition. The diagnosis of NAFLD requires the finding of serum enzyme elevations and fat in the liver as shown by imaging tests or liver biopsy:

1.

Hepatocellular pattern of serum enzyme elevations (R value >5) with minimal alkaline phosphatase elevations

2.

Latency of 3 to 12 months after starting the medication

3.

Nonspecific symptoms (if present) of nausea, fatigue, or abdominal pain

4.

Fat in the liver as shown by ultrasound, computerized tomography or magnetic resonance imaging

5.

If liver biopsy is obtained, changes of steatosis, inflammation and ballooning degeneration

6.

Resolution or lessening of evidence of liver injury and fatty liver with stopping the medication.

Because nonalcoholic fatty liver is so frequent in the general population, the finding of serum enzyme elevations and fat in the liver by imaging tests is not uncommon, particularly in patients who are overweight or have hyperlipidemia or diabetes - patients who are also likely to be taking medications. Thus, the diagnosis of drug induced NAFLD is challenging, and should rest upon the de novo appearance of liver enzyme elevations or hepatic fat in a patient known to be free of these findings before starting the drug; or, alternatively, the resolution of these findings with stopping the medication. Some cases of drug induced NAFLD actually represent an underlying propensity to this metabolic liver disease in a patient on a medication that causes weight gain or disturbances in lipid or glucose metabolism. The most clearly defined cause of drug induced NAFLD is tamoxifen which is typically given long term (up to five years) in postmenopausal women, many of whom may already have risk factors for NAFLD, such as obesity, diabetes or hyperlipidemia. The presence of steatosis and ballooning degeneration, inflammation and variable degrees of fibrosis is generally referred to as nonaclcoholic steatohepatitis (NASH) and is considered a more severe part of the spectrum of NAFLD, being potentially progressive and leading to advanced fibrosis or cirrhosis. Amiodarone and methotrexate are two other agents that can cause NAFLD and NASH and often present at a more advanced stage accompanied by inflammation and fibrosis.