Acute hepatic injury with atorvastatin: an unusual occurrence.

Atorvastatin, a commonly used and well-tolerated hypolipidemic drug, belongs to the class of statins or hydroxymethylglutaryl-coenzyme A reductase inhibitors. Use of atorvastatin may be associated with minor asymptomatic elevations in serum aminotransferases, but clinically significant hepatotoxicity is usually infrequent. Here we present a case of self-limiting clinically apparent acute hepatic injury attributable to atorvastatin occurring at recommended daily dose of 20 mg once a day. This case was postulated to be an unusual idiosyncratic reaction of the drug.

Introduction

Atorvastatin is known to decrease the incidence of consequences of atherosclerosis such as coronary artery disease, ischemic cerebrovascular disease and peripheral vascular disease. The effect of this drug is exerted through a mevalonic acid like moiety that blocks the conversion of hydroxymethylglutaryl-coenzyme A (HMG-CoA) to mevalonate (a precursor of cholesterol) by competitively inhibiting HMG-CoA reductase enzyme, a rate limiting step in cholesterol biosynthesis. The drug is generally well-tolerated with some non-serious side-effects such as gastrointestinal disturbances. Asymptomatic, transient elevations in serum aminotransferases are frequent in the initial weeks of atorvastatin therapy, but clinically apparent acute hepatic damage is a rare occurrence.[1] We report a case of clinically obvious acute hepatic injury in atorvastatin with therapeutic doses.

Case Report

This was a case of a 63-year-old, hypertensive male, presented in an emergency with a chief complaint of sudden onset of weakness on the left side of limbs for 6 h. Patient was well-oriented to time and place at the time of admission. There was no history of unconsciousness, vomiting and seizures. The computed tomography scan brain was normal. Patient showed marked improvement and regained full power of the left side of the limbs within 14 h of admission. His laboratory investigations including liver function tests were within normal limits except the lipid profile, which was reported as total serum cholesterol-285.60 mg/dl, high-density lipoprotein-57.12 mg/dl, triglycerides-150 mg/dl, low-density lipoprotein-197.28 mg/dl respectively.

The patient was diagnosed a case of transient ischemic attack (TIA) with hypertension and hyperlipidemia and was discharged with metoprolol 50 mg, atorvastatin 20 mg and aspirin 75 mg once a day.

The patient was followed-up after 1 month and his laboratory investigations were found to be normal at this visit except slightly raised levels of aminotransferase enzymes. But on 2nd follow-up (about 2 months after the TIA), the patient presented with the complaints of loss of appetite, nausea, fatigue, abdominal discomfort and yellowish discoloration of skin and eyes. His laboratory investigations revealed elevated serum aminotransferases (alanine aminotransferase [ALT]-1124 IU/L), (aspartate aminotransferase [AST]-1049 IU/L) along with serum alkaline phosphatase (214 IU/L), total bilirubin (5.2 mg/dl) and conjugated bilirubin (1.72 mg/dl).

Serological screening tests for acute viral hepatitis (hepatitis A virus, hepatitis B virus [HBV], hepatitis C virus [HCV] an hepatitis E virus, cytomegalo virus and Epstein-Barr virus) were negative. HBV deoxyribonucleic acid and HCV ribonucleic acid were not detected in peripheral blood. Antinuclear antibody test for autoimmune hepatitis was also negative. Ultrasound abdomen was normal. Patient did not consent for a liver biopsy. There was no history of excessive alcohol use and the ratio of AST/ALT was less than two, thereby ruling out the possibility of alcoholic liver diseases. There was no past history of chronic liver disease or no recent episodes of shock, hypoxia and heart failure, thereby excluding ischemic hepatitis. Looking into the above facts, atorvastatin induced hepatotoxicity was suspected. Atorvastatin was hence withdrawn and replaced by rosuvastatin 10 mg once a day. Other drugs were continued as prescribed earlier. Serum aminotransferase levels returned to near normal within a month after withdrawal of atorvastatin followed by a gradual disappearance of symptoms. A Naranjo's score of 6 suggested “probable relationship” between atorvastatin and the acute hepatic injury. This idiosyncratic hepatic injury was defined as hepatocellular by Roussel Uclaf Causality Assessment Method (RUCAM). The RUCAM score of this idiosyncratic event was 7, which indicates a probable link between hepatotoxicity and atorvastatin.[2]

Discussion

There have been a few case reports of acute hepatic injury associated with statins including atorvastatin. A review by Russo et al. concluded that only 40 cases of statin induced hepatotoxicity have been reported in the literature.[3] A recent research article by Björnsson et al. revealed that 73 cases of statin induced liver injury (with a possible link between the drug and hepatotoxicity) were reported to Swedish adverse drug reaction advisory committee from 1988 to 2010.[4] Around 109 cases of atorvastatin induced acute hepatitis were reported to Food and Drug Administration from January 2004 to October 2012.[5]

Our case represents an idiosyncratic form of acute hepatic injury with atorvastatin. Occurrence of hepatitis is usually infrequent (1 in 1000-1 in 10,000) and unpredictable in idiosyncratic drug reactions. The response is not dose dependent and the injury may occur at any time during or shortly after exposure to drug.[6] Our case showed an unusual and unpredictable acute hepatic injury within 2 months after administration of atorvastatin at a prescribed dose of 20 mg daily.

Any type of hepatic cell injury can cause modest elevations in the serum aminotransferases. However, strikingly elevated serum transferases (>1000 IU/L) occur almost exclusively in diseases associated with extensive hepatocellular injury such as viral hepatitis, ischemic liver injury (due to prolonged hypotension or acute heart failure) or drug induced liver injury.[7] In this case investigations revealed serum transferases levels >1000 IU/L and a history of atorvastatin ingestion.[8] A similar pattern of hepatic injury with atorvastatin was also reported by Bhardwaj and Chalasani.[9]

The patient was also on concomitant medications such as metoprolol and aspirin. Aspirin may be associated with direct dose dependent hepatotoxicity (rather than idiosyncratic form). This occurs at anti-inflammatory doses and is uncommon with anti-platelet doses.[8] Metoprolol is also not linked with clinically significant idiosyncratic hepatotoxicity. An extensive Medline search yielded only a single case report of hepatotoxicity with metoprolol.[10] Thus atorvastatin induced acute hepatic injury was suspected in our case and the drug was withdrawn resulting in near normal aminotransferases levels within a month after discontinuation. A cross reactivity with rosuvastatin was not reported in this case.

The temporal association between administration of drug in usual therapeutic doses and the onset of abnormal serum aminotransferases within 2 months after administration, the resolution of symptoms and near normal transferase levels within 1 month after withdrawal and absence of alternative explanations strongly suggests that atorvastatin was the causal drug for this idiosyncratic form of self-limited, acute liver injury.

Conclusion

Our report attempts to highlights that atorvastatin may be associated with an idiosyncratic hepatic injury, which is uncommon but sometimes may lead to acute liver failure that is difficult to manage. Therefore, physician should be vigilant when prescribing atorvastatin and liver function tests should be performed if symptoms arise.