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tatins for Hyperlipidemia in Patientsith Chronic Liver Disease: Are Theyafe?

ver the past several years, it has become clear thataggressive lowering of serum lipid levels is essen-

ial to reduce cardiovascular morbidity and mortality.ipid-lowering agents are among the most widely pre-cribed class of medications worldwide, with more than45 million prescribed in the United States alone in005.1 Although statins are the most widely used lipid-

owering agents, ezetimibe has garnered significant mar-et share since its approval in 2002, and it is the thirdost commonly prescribed lipid-lowering agent in thenited States (�19 million prescriptions in 2005).1

Although not evidence based, current recommenda-ions discourage the use of statins in patients with pre-xisting liver disease.2,3 If prescribers complied with thisecommendation, nearly 25% of US adults will be ineli-ible to receive statins; 20% of US adults are estimated toave nonalcoholic fatty liver disease and another 5%ave other types of liver diseases such as hepatitis C andholestatic liver diseases.4 Therefore, there has beenignificant interest in investigating the safety of statins inatients with pre-existing liver disease. Two previouslyublished studies have shown that patients with in-reased liver enzyme levels are not at higher risk fortatin hepatotoxicity than those with normal liver en-yme levels.5,6 These studies have shown that clinicallyignificant liver injury from statins is very rare in clinicalractice, and no relation exists between the type oftatin and the occurrence of liver test abnormalities.urthermore, it was shown that patients with increasedaseline liver enzyme levels have fluctuations in their

iver biochemistries regardless of exposure to statins. Toocus on patients with potential fatty liver disease, those

studies have excluded patients with hepatitis C fromheir analyses. In retrospect, this exclusion is an impor-ant issue because in certain patient populations (eg, USeterans) the prevalence of co-existing hepatitis C andyperlipidemia is quite high, and thus these studies haveot addressed the safety of statins in patients with hep-titis C. However, in a study published in this issue oflinical Gastroenterology and Hepatology, investiga-

ors from the Stanford Veterans Administration Hospitalonducted a database study to address if statins can berescribed safely in patients with hepatitis C.7 Biochem-

cal evidence of statin hepatotoxicity over a 12-montheriod was assessed in 166 hepatitis C antibody–positiveeterans who received statins as compared with 332epatitis C–positive veterans who did not receive statinsnd 332 veterans without hepatitis C who did receive

tatins. They found no association between hepatitis N

CLIN

–antibody positivity and biochemical evidence of statinepatotoxicity, and based on their results it was con-luded that statin therapy is safe in hepatitis C patientsith hyperlipidemia. Not withstanding some limitations

hat the authors elaborate in their discussion, this studyrovides further reassurance that clinically significantepatotoxicity from statins is very rare in clinical prac-ice, and the patients with underlying liver disease doot necessarily have increased risk from statin use. This

s consistent with recent recommendations made to theational Lipid Association by a liver expert panel thatndorsed statin use in patients with chronic liver diseasend Child’s A cirrhosis (Table 1).8 In fact, investigatorsrom the Kaiser Permanente group recently have re-orted in abstract form that in patients with chronic

iver disease, lovastatin was associated with a large andignificant decrease in adverse hepatic end points suchs liver failure and Hy’s rule (Hy Zimmerman’s rule stateshat if drug-induced hypertransaminasemia and jaundiceccur at the same time without biliary obstruction, aortality rate of at least 10% is to be expected).9,10

Because of the prevailing but exaggerated perceptionf risk of hepatotoxicity from statins when used in pa-ients with pre-existing liver disease, some cliniciansrescribe luminal agents such as ezetimibe based on thessumption that the luminal agents’ lack of systemicharmacologic effects would be much less likely toause hepatotoxicity. However, in this issue of Clinicalastroenterology and Hepatology, Stolk et al11 report 2ases of clinically significant liver injury likely associatedith ezetimibe arguing against a lack of systemic effectsith ezetimibe. The first case was a 52-year-old womanho developed cholestatic hepatitis 16 weeks after add-

ng ezetimibe to atorvastatin (40 mg/day), which she hadeen taking for 1 year. The second case was a 58-year-oldan who developed clinically significant liver diseaseithin weeks after adding ezetimibe to atorvastatin (80

able 1. A Summary of Recommendations of the LiverExpert Panel to the National Lipid Association onStatin Safety

Asymptomatic increases in transaminase levels are a class effectof statins and they do not indicate liver dysfunction

Liver failure causing death or hospitalization or requiring livertransplantation is very rare from statins

Current evidence does not support routine monitoring of liverenzyme levels and liver biochemistries in patients receivingstatins

Presence of chronic liver disease and Child’s A cirrhosis should notbe considered a contraindication for statin use

Current evidence supports the use of statins to treat hyperlipidemiain patients with nonalcoholic fatty liver disease and nonalcoholicsteatohepatitis

OTE. See Cohen et al8 for full report of the recommendations.

ICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:838–839

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July 2006 STATINS IN CHRONIC LIVER DISEASE 839

g/day), which was taken for 3 years. Based on the rapidherapeutic response to prednisone, the authors specu-ated that ezetimibe may have precipitated an acuteutoimmune hepatitis in the second case. There is also aublished report of a 50-year-old woman who developedutoimmune hepatitis 3 months after ezetimibe wasdded to atorvastatin (80 mg/day), which she had takenor 18 months.12 It is not possible to establish causality inhat case because of the concomitant use of diclofenac,hich is known to cause autoimmune-type liver injury.e recently encountered a patient who developed re-

ersible jaundice (peak total bilirubin level, �5 mg/dL)ithin several weeks of adding ezetimibe to simvastatin,hich was taken for several years (this case has been

eported to Food and Drug Administration MedWatch).ased on these reports, it is tempting to speculate anssociation between hepatotoxicity and ezetimibe whent is given in combination with statins. However, cautionhould be exercised in overinterpreting these very rareases of hepatotoxicity with an agent that otherwiseeems to be very safe and effective. Nonetheless, theeport by Stolk et al11 shows that, similar to most otheredications, luminal agents very rarely may cause idio-

yncratic drug-induced liver disease. It is worth pointingut that a similar phenomenon was noted with somether luminal agents such as acarbose and orlistat.13–16

In summary, based on the available literature, it ap-ears safe to conclude that patients with pre-existinghronic liver disease are not at higher risk for statinepatotoxicity, and thus should receive statins as indi-ated for their hyperlipidemia and cardiovascular dis-ase. The fact that ezetimibe is a luminal agent shouldot assure the prescriber or patient that it is entirely freerom hepatotoxicity. As with some other luminal agents,t appears that ezetimibe very rarely can cause clinicallyignificant hepatotoxicity.

RAJ VUPPALANCHI

NAGA CHALASANI

Division of Gastroenterology and Hepatology,Indiana University School of Medicine, Indianapolis,

Indiana

eferences1. Available at: http://www.drugtopics.com/drugtopics. Accessed:

April 6, 2006.2. Pasternal RC, Smith SC, Bairez-Merz C, et al. ACC/AHA/NIHLBI

clinical advisory on the use and safety of statins. Circulation2002;106:1024–1028.

3. Chalasani N. Statin hepatotoxicity: focus on statin usage in non-alcoholic fatty liver disease. Hepatology 2005;41:690–695.

4. The Physician Desk Reference. 59th ed. Montvale, NJ: ThompsonHealthCare, 2005.

5. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with ele-vated liver enzymes are not at higher risk for statin hepatotoxicity.Gastroenterology 2004;128:1287–1292.

6. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated base-line liver enzymes do not have higher frequency of hepatotoxicityfrom lovastatin than those with normal baseline liver enzymes.Am J Med Sci 2005;329:62–65.

7. Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hep-atotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol2006;4:902–907.

8. Cohen D, Anania F, Chalasani N. Report of the liver expert panel.Statin Safety Task Force, National Lipid Association Am J Cardiol2006;97(Suppl):77C–81C.

9. Avins AL, Manos MM, Levin TR, et al. Lovastatin is not hepato-toxic to patients with pre-existing liver disease (abstr). Gastroen-terology 2006;130:A595.

0. Senior JR. Regulatory perspective. In: Kaplowitz N, DeLeve LD,eds. Drug induced liver disease. New York: Marcel Dekker, Inc,2003:739–754.

1. Stolk MFJ, Becx MCJM, Kuypers KC, et al. Severe hepatic sideeffects of ezetimibe. Clin Gastroenterol Hepatol 2006;4:908–911.

2. van Heyningen C. Drug-induced acute autoimmune hepatitis dur-ing combination therapy with atorvastatin and ezetimibe. Ann ClinBiochem 2005;42:402–404.

3. Andrade R, Lucena M, Vega J, et al. Acarbose-associated hepa-totoxicity. Diabetes Care 1998;21:2029–2030.

4. Fujimoto Y, Ohhira M, Miyokawa N, et al. Acarbose-induced he-patic injury. Lancet 1998;351:340.

5. Kim DH, Lee EH, Hwang JC, et al. A case of acute cholestatichepatitis associated with Orlistat. Taehan Kan Hakhoe Chi 2002;8:317–320.

6. Lau G, Chan CL. Massive hepatocellular [correction of hepatocul-lular] necrosis: was it caused by Orlistat? Med Sci Law 2002;42:309–312.

Supported in part by NIH grant K24 DK 069290 (to N.C.).