Rosuvastatin is a commonly used cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy, and rarely with clinically apparent acute liver injury.
Rosuvastatin (roe soo" va stat' in) is a potent, orally available inhibitor of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase the major rate-limiting enzyme in cholesterol synthesis. Like other members of its class (the “statins”), rosuvastatin lowers total serum cholesterol and low density lipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke. Rosuvastatin was approved for use in the United States in 2003 and currently several million prescriptions are filled yearly. Rosuvastatin is indicated for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease. Rosuvastatin is available in tablets of 5, 10, 20 and 40 mg generically and under the trade name Crestor. Rosuvastatin is one of the more potent statins available and is typically used in a comparably lower dose. The recommended dose in adults is 5 to 40 mg once daily, based upon tolerability and lipid levels. Common side effects include muscle cramps, joint aches, headache and weakness.
Rosuvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 3% of patients, but levels above 3 times the upper limit of normal (ULN) occur no more frequently among rosuvastatin treated [0.2%] as placebo [0.3%] recipients. Serum enzyme elevations are more common with higher doses of rosuvastatin, being 2.2% with 40 mg daily. Most of these elevations are self-limited and do not require dose modification. Rosuvastatin is also associated with frank, clinically apparent hepatic injury but this is rare, occurring in less than 1:10,000 patients. The onset is typically after 2 to 4 months and the pattern of serum enzyme elevations is usually hepatocellular, although cholestatic cases have also been reported. Rash, fever and eosinophilia are uncommon. Several of the statins including rosuvastatin have been linked to hepatitis with autoimmune features including elevated immunoglobulin levels, ANA positivity and a clinical response to corticosteroids. Such features are not, however, invariable (Case 1).
Likelihood score: B (likely cause of clinically apparent liver injury).
Mechanism of Injury
The cause of hepatic injury from rosuvastatin is unknown. Rosuvastatin is minimally (~10%) metabolized in the liver (via CYP 2C9). The mild, self-limited ALT elevations may be due to a toxic intermediate of drug metabolism and the reversal of these elevations due to adaptation. The idiosyncratic, clinically apparent liver injury associated with rosuvastatin is often accompanied by autoimmune features and may, therefore, be caused by immune mechanisms.
Outcome and Management
The mild ALT elevations associated with rosuvastatin therapy are usually self-limited and do not require dose modification; rosuvastatin should be stopped if ALT levels rise above 10-fold the ULN, or persist in being above 5-fold elevated or are associated with symptoms. In the clinically apparent liver injury attributed to rosuvastatin, recovery is usually complete within 1 to 2 months. Recurrence of injury with rechallenge has been reported and should be avoided. Cases of chronic hepatitis, but no instances of acute liver failure or vanishing bile duct syndrome, attributable to rosuvastatin have been reported. In cases of autoimmune hepatitis-like injury, corticosteroids have been used when recovery does not occur promptly. If corticosteroids are used, the dose and duration of treatment should be kept to a minimum, and careful followed up after stopping is essential. Switching therapy to another statin after rosuvastatin induced injury is apparently safe, but few instances have been reported, and it should be done with careful monitoring for recurrence.
Case 1. Acute self-limited hepatitis during rosuvastatin therapy.
[Modified from: Famularo G, Miele L, Minisola G, Grieco A. Liver toxicity of rosuvastatin therapy. World J Gastroenterol 2007; 13: 1286-8. PubMed Citation]
A 64 year old man developed jaundice approximately 15 weeks after starting rosuvastatin (10 mg daily) for hypercholesterolemia. He had a history of acute myocardial infarction four months previously, which was treated with angioplasty and stenting. Discharge medications included clopidogrel, aspirin, metoprolol, ramipril and atorvastatin. One week later, rosuvastatin was substituted for atorvastatin because of skin rash and minor ALT elevations (55 U/L). Subsequently, he felt well until he developed malaise, anorexia and upper abdominal discomfort followed by jaundice slightly over 3 months later. On examination, he had no fever, rash or signs of chronic liver disease. Laboratory results showed elevations in serum bilirubin and aminotransferase levels, but normal alkaline phosphatase and GGT (Table). Tests for hepatitis A, B, C, and E were negative as were routine autoantibodies. Ultrasonography of the liver and biliary tree was normal. Rosuvastatin was stopped while blood pressure and antiplatelet medications were continued. Liver test abnormalities improved promptly and were normal two weeks later.
|Medication:||Rosuvastatin (10 mg daily)|
|Pattern:|| Hepatocellular (aminotransferase elevations only)|
||3+ (jaundice, hospitalization)|
|Other medications:||Clopidogrel, aspirin, metoprolol, ramipril, atorvastatin|
|Time After Starting
||Time After Stopping
||Alk P* (U/L)
||Discharge after heart attack
|Atorvastatin stopped and rosuvastatin started
||Admission: rosuvastatin stopped
* Some values estimated from Figure 1.
The onset of injury approximately 3 months after starting rosuvastatin and the rapid recovery with stopping therapy makes the diagnosis of rosuvastatin induced acute hepatitis highly likely. Other diagnoses were approximately ruled out and there was documentation of normal liver tests before starting statin therapy. Acute, clinically apparent liver injury is rare with rosuvastatin therapy (~1:10,000 patients treated) and is rapidly reversible with prompt discontinuation of therapy. Rechallenge with rosuvastatin is inadvisable, but other statins might be initiated with careful monitoring of serum enzymes.
Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from
the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared
of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.
REPRESENTATIVE TRADE NAMES
Rosuvastain – Crestor®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 05 August 2017
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liver injury estimated to arise in 1 in 17,000 users, cholestatic in 56% and
with autoimmune features in 10% and rarely fatal).
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