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:
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.
- Hepatocellular pattern of serum enzyme elevations (R value >5) with minimal alkaline phosphatase elevations
- Latency of 3 to 12 months after starting the medication
- Nonspecific symptoms (if present) of nausea, fatigue, or abdominal pain
- Fat in the liver as shown by ultrasound, computerized tomography or magnetic resonance imaging
- If liver biopsy is obtained, changes of steatosis, inflammation and ballooning degeneration
- Resolution or lessening of evidence of liver injury and fatty liver with stopping the medication.
Case 1. Nonalcoholic steatohepatitis induced by tamoxifen.
[DILIN Case #105-3016]
A 37 year old woman was found to have abnormal serum enzymes during long term tamoxifen therapy. Two years previously, she had been found to have bilateral breast cancers and underwent bilateral mastectomies followed by reconstructive breast surgery. The breast cancer tissue was human estrogen receptor negative. She was started on long term tamoxifen (20 mg daily) and goserelin (3.6 mg implant monthly) therapy. Before starting therapy, her serum enzymes were normal (Table), but one year later they were found to be elevated. She had no symptoms of liver disease and specifically denied fatigue, nausea and abdominal pain. She had no history of liver disease and denied alcohol use. She had no risk factors for viral hepatitis and was not taking other medications. Physical examination showed no fever, rash, abdominal tenderness or enlargement of liver or spleen. She was mildly overweight (body mass index 28.5), but had not gained weight in the previous year. Laboratory results showed moderate elevations in serum aminotransferase levels (ALT 150 U/L, AST 138 U/L), with normal alkaline phosphatase, bilirubin (0.3 mg/dL), albumin (4.5 g/dL) and prothrombin time (INR 1.1). Fasting blood glucose and lipids were normal. Tests for hepatitis A, B and C were negative as were autoantibodies. Serum ceruloplasmin was normal (34.4 mg/dL). Ultrasound of the abdomen suggested fatty liver. A liver biopsy showed severe macrovesicular steatosis with lobular hepatitis, and mild pericellular fibrosis without Mallory bodies, compatible with steatohepatitis. The combination of ursodeoxycholic acid, vitamin C and vitamin E were started and tamoxifen continued. Serum enzymes remained elevated and six months later began to rise reaching a peak of an ALT 770 U/L, AST 810 U/L, despite minimal or no rise in alkaline phosphatase and bilirubin levels. At this point, the patient began to complain of fatigue, nausea, vague abdominal discomfort, dark urine and itching. Tamoxifen and goserelin were discontinued. A repeat liver biopsy showed less steatosis, but increased lobular inflammation, ballooning degeneration and fibrosis with multiple Mallory bodies. Over the next several months, serum aminotransferases decreased minimally.
|| Tamoxifen (20 mg daily)
|Pattern:|| Hepatocellular (R=15)|
|Severity:|| 1+ (serum enzyme elevations only with symptoms)|
|Latency:|| 2 years|
|Recovery:|| Incomplete after 2 months|
|Other medications:|| Goserelin|
|Time After Starting
||Time After Stopping
|Pre||Pre||24||55||0.7||1 month before surgery|
|20 months||189||75||0.3||Liver biopsy|
|21 months||143||67||0.3||Vitamin E and ursodiol|
|29 months||0||770||112||0.5||Tamoxifen stopped|
|30 months||1 month||567||103||0.5||Liver biopsy|
|31 months||2 months||418||102||0.4|
Fatty liver develops in up to one third of women treated with tamoxifen, but is usually benign and not associated with serum enzyme elevations, symptoms or progressive liver disease. In a proportion of patients, however, the accumulation of fat is associated with appearance of inflammation and cell injury (steatohepatitis), which can lead to progressive fibrosis and ultimately to cirrhosis. Serum aminotransferase levels are usually minimally elevated. In this case, ALT elevations were moderate and persistent, leading to liver biopsy and attempts to treat the fatty liver injury using ursodiol and vitamin E while continuing tamoxifen. These interventions appeared to have no effect, and serum enzymes continued to rise. A follow up liver biopsy showed worsening of the injury and progressive fibrosis. Stopping tamoxifen led to improvements in serum enzyme elevations but the improvement was slow and incomplete.
Case 2. Nonalcoholic steatohepatitis after long term corticosteroid therapy.
[Modified from: Itoh S, Igarashi M, Tsukada Y, Ichinoe A. Nonalcoholic fatty liver with alcoholic hyaline after long-term glucocorticoid therapy. Acta Hepato-Gastroenterologica 1977; 24: 415-8. PubMed Citation]
A 34 year old woman with systemic lupus erythematosis was treated with betamethasone with good clinical response with improvements in rash, fatigue and laboratory tests. Over a 6 month period, the daily dosage was gradually decreased from 5 to 1.25 mg daily. Initially, her liver tests were normal, but with corticosteroid therapy, ALT and AST were mildly elevated (Table). However, after 16 months of therapy, serum aminotransferase levels were more than 5 fold elevated (ALT 256 U/L, AST 272 U/L) and she was readmitted for evaluation. Her weight had risen by 11 kilograms and she had firm hepatomegaly. Laboratory tests showed elevations in serum aminotransferase levels, but normal serum bilirubin, albumin, and prothrombin time. She had an abnormal glucose tolerance test (fasting 118 mg/dL, 2 hour postprandial glucose 248 mg/dL). Testing for HBsAg was negative. She was known to be positive for antinuclear antibody (1:128). She denied alcohol use which was confirmed by family and friends. A liver biopsy showed marked steatosis with inflammation including neutrophils, occasional Mallory bodies and mild central sinusoidal and portal fibrosis. Weight loss led to slight decreases in serum ALT levels.
|| Betamethasone (1.25 mg daily)
|Pattern:|| Hepatocellular or mixed (R=~4.6)|
|Severity:|| Mild (serum enzyme elevations only)|
|| Several months
|Recovery:|| Not mentioned|
|Other medications:|| None mentioned|
|Months After Starting
|16||58.2||256||131||4.0||Protime 10.4 sec|
This is an early but well documented report of nonalcoholic steatohepatitis arising during corticosteroid therapy. The patient was evidently asymptomatic of liver disease, but the height of the serum aminotransferase elevations led to a hospital admission and liver biopsy. An issue is whether the liver disease was due to corticosteroid therapy directly or was the result of weight gain and insulin resistance caused by the therapy, the latter being more likely. Betamethasone is a synthetic, high potency glucocorticoid; 1.25 mg of betamethasone is roughly equivalent to 15 mg of prednisone.
Hepatic Histology of Drug Induced Fatty Liver Disease