Pravastatin 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.
Pravastatin (pra" va stat' in) is an 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”), pravastatin lowers total serum cholesterol and low densitylipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke. Pravastatin was approved for use in the United States in 1991 and continues to be widely used with more than 9 million prescriptions filled yearly. Current indications are for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease. Pravastatin is available in tablets of 10, 20, 40 and 80 mg in several generic forms and under the brand name of Pravachol. The recommended dose in adults is 40 to 80 mg once daily. Common side effects include muscle cramps, joint aches, headache and weakness.
Pravastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in 3% to 15% of patients; but levels above 3 times the upper limit of normal (ULN) occurred in only 0.7% of pravastatin treated compared to 0.3% of placebo recipients. These elevations were more common with higher doses of pravastatin, being 2.3% with 80 mg daily. Most of these elevations were self-limited and did not require dose modification. Pravastatin has been only rarely associated with clinically apparent hepatic injury with symptoms or jaundice at a rate estimated to be 1 per 100,000 users. In the case reports, latency varied from 2 to 9 months and the pattern of serum enzyme elevations from cholestatic to hepatocellular. Recovery was complete within a few months. Rash, fever and eosinophilia were uncommon as were autoantibodies, but few cases have been reported and the full clinical syndrome not well defined. Pravastatin appears to be less likely to cause clinically apparent liver injury than atorvastatin, simvastatin and rosuvastatin.
Likelihood score: B (likely cause of clinically apparent liver injury).
Mechanism of Injury
The cause of hepatic injury from pravastatin is unknown. Pravastatin has only minimal hepatic metabolism and most is excreted unchanged in the urine. The mild, self-limited ALT elevations may be due to production of a minor toxic intermediate of metabolism and the reversal of these elevations due to adaptation. The idiosyncratic, clinically apparent liver injury associated with pravastatin may be due to failure of adaptation.
Outcome and Management
The mild ALT elevations associated with pravastatin therapy are usually self-limited and do not require dose modification, although pravastatin 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 pravastatin, recovery is usually complete within 1 to 2 months. In view of the wide scale use of pravastatin, clinically apparent and severe liver injury is extraordinarily rare. Recurrence of injury with rechallenge has been reported and should be avoided. Switching therapy to another statin after pravastatin induced injury can lead to recurrence and should be done with careful monitoring.
Case 1. Acute cholestatic hepatitis attributed to pravastatin therapy.
[Modified from: Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pravastatin. Am J Gastroenterol 1999; 94:1388-90. PubMed Citation]
A 57 year old man developed abdominal pain and nausea followed by fever and jaundice 6 weeks after starting pravastatin (20 mg daily) for long standing hypercholesterolemia. He had a history of coronary artery disease and had been treated with beta blockers and various cholesterol lowering drugs, including fenofibrate and simvastatin in the past. At the time of presentation, he was taking only pravastatin and metoprolol, both of which were discontinued promptly. He denied alcohol use and had no risk factors for viral hepatitis. Physical examination showed jaundice and hepatic tenderness but no rash, fever or signs of chronic liver disease. Laboratory results showed a cholestatic pattern of serum enzyme elevations and hyperbilirubinemia (Table). Tests for hepatitis A, B and C were negative as were autoantibodies. Ultrasound and CT of the abdomen showed no evidence of biliary obstruction and ERCP was normal. A liver biopsy showed intrahepatic cholestasis compatible with drug induced liver injury. He was treated with ursodiol (750 mg daily). Once pravastatin was stopped, symptoms and liver test abnormalities improved rapidly and were completely normal 7 weeks later.
|Medication:||Pravastatin (20 mg daily)|
|| Mixed (R=2.8)
||3+ (jaundice, hospitalization)|
|Time After Starting
||Time After Stopping
||Alk P* (U/L)
||Outpatient follow up
* Some values estimated from Figure 1.
The onset of injury within 2 months of starting pravastatin and resolution within 2 months of stopping is supportive evidence that this represented drug-induced liver disease due to pravastatin. All other causes of acute liver injury were satisfactorily excluded. Metoprolol had been used for a longer period and, like other beta-blockers, is a rare cause of drug induced liver injury. The pattern of serum enzyme elevations was considered “mixed” but the clinical presentation, symptoms and liver histology were more cholestatic. This patient had previously tolerated simvastatin without obvious liver injury. Cross susceptibility to cholestatic hepatitis from the statins is frequent but not invariable.
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
Pravastatin – Generic, Pravachol®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 05 August 2017
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Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol 2007; 99: 379-81. PubMed Citation (Analysis of MedWatch reports of adverse events found no excess in liver related adverse event reports per million prescription due to lovastatin alone [2.3] vs niacin alone [2.5] vs the combination [3.2], but slightly higher rates with atorvastatin [4.5], simvastatin [5.7] and pravastatin [4.9], but data relied upon spontaneous reporting).
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Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury including 2 due to atorvastatin, 2 simvastatin and 2 cerivastatin, but none to pravastatin).
Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012; 56:374-80. PubMed Citation (Between 1988 and 2010, the Swedish registry received 217 adverse event reports possibly related to statins, 124 [57%] being liver related, 73 of which could be evaluated: 2 were fatal and one led to liver transplant; 3 had positive rechallenge; 43 [59%] were hepatocellular, 22 [30%] cholestatic and 8 [11%] mixed; 30 were due to atorvastatin, 28 simvastatin, 11 fluvastatin, 2 pravastatin and 2 rosuvastatin, arising after 30-248 days; atorvastatin injury was more likely to be cholestatic and was estimated to occur in 2.9 per 100,000 person years).
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monitoring is not necessary and that statins can be safety used in patients with
nonalcoholic liver disease, and are probably safe in other forms of chronic
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of 90 studies of 48 different "unintended effects" of statins with evidence of
an increased risk of myopathy [Odds Ratio: OR=2.6] and raised liver enzymes
for lipids. Treat Guidel Med Lett 2014; 12 (137): 1-6. PubMed Citation (Concise
recommendations on management of hyperlipidemia mentions that 1-2% of patients
on high doses of statins develop ALT elevations [above 3 times ULN], but that
there is not always cross sensitivity to this side effect and that patients with
mild-to-moderate ALT elevations can tolerate statins; no discussion of
clinically apparent liver).
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47 [5.5%] were attributed to statins [16 atorvastatin, 13 simvastatin, 12
fluvastatin, 4 lovastatin and 2 pravastatin], usually with a hepatocellular
pattern of injury, 8.5% with autoimmune features, chronic injury in 19%, and no
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for use of high doses of rosuvastatin [adjusted odds ratio of
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899 cases of drug induced liver injury enrolled in a US prospective study
between 2004 and 2013, 31 cases [3.4%] were attributed to statins, including 8
to atorvastatin, 8 simvastatin, 7 rosuvastatin, 4 pravastatin, 2 fluvastatin
and 2 lovastatin).
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hepatotoxicity? J Hepatol 2015; 62: 751-2. PubMed Citation (85 year old woman
on atorvastatin for more than a year developed jaundice after increasing dose
from 40 to 80 mg daily [bilirubin 4.1 mg/dL, ALT 909 U/L, Alk P 415 U/L, CK 4753
U/L, INR 1.71], with transient worsening, but ultimate improvement and
CH, Chang YC, Lee YC, Liu YC, Chuang LM, Lin JW. Severe hepatic injury
associated with different statins in patients with chronic liver disease: a
nationwide population-based cohort study. J Gastroenterol Hepatol 2015; 30:
155-62. PubMed Citation (Among 37,929
Taiwanese persons with chronic liver diesase started on statin therapy for
hyperlipidemia between 2005 and 2009, there were 912 incident cases of
hospitalization for liver injury, rates being similar for the 6 different
statins used [1.94-2.95 per 100,000 person-days], but higher in those on high
doses of atorvastatin [40 or 80 mg daily]).
HS, Lee SH, Kim H, Lee SH, Cho JH, Lee H, Yim HW, et al. Statin-related
aminotransferase elevation according to baseline aminotransferases level in real
practice in Korea. J Clin Pharm Ther 2016; 41: 266-72. PubMed Citation (Among 21,233 Korean
patients starting statin therapy between 2009 and 2013, abnormal ALT or AST
values above 3 times ULN were more frequent among those with mild baseline
ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver
2017; 37: 173-8. PubMed Citation (Review of the
hepatotoxicity of statins mentions that atorvastatin has been the most
frequently implicated statin [accounting for 30-40% of cases] in drug induced
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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