Lipid-Lowering Agents That Cause Drug-Induced Hepatotoxicity

Clin Liver Dis 11 (2007) 597–613

Lipid-Lowering Agents That CauseDrug-Induced Hepatotoxicity

Sidharth S. Bhardwaj, MD, Naga Chalasani, MD*Division of Gastroenterology and Hepatology, Indiana University School of Medicine,

1001 West 10th Street, WD OPW 2005, Indianapolis, IN 46202, USA

Cardiovascular disease remains the leading cause of death in the UnitedStates and Europe, according to American Heart Association and BritishHeart Foundation data [1,2]. Hyperlipidemia is one of the major risk fac-tors, and its treatment has come to the forefront of primary and subspecialtycare as a preventative strategy against cardiovascular morbidity and mortal-ity [1]. The newest Adult Treatment Panel guidelines of the National Cho-lesterol Education Program (ATP III) identify an optimal low-densitylipoprotein (LDL) level lower than stated in previous reports and recom-mend even more aggressive management in patients at risk of coronaryheart disease [3]. Despite their widespread use, clinically significant hepaticinjury caused by lipid-lowering medications remains rare [4–6]. The antihy-perlipidemic drug with the highest potential for hepatic injury is the sus-tained-release (SR) formulation of niacin [4]. 3-Hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, otherwise known as ‘‘sta-tins,’’ rarely cause clinically significant liver injury, although asymptomaticelevation in aminotransferase levels is common [4]. The notion that ezeti-mibe may carry less risk of hepatotoxicity has been challenged recently,and it may not be a safe alternative to statins in patients who have pre-ex-isting liver disease [7].

The pattern of liver injury from antihyperlipidemics is typically hepato-cellular or mixed in nature with rare instances of a purely cholestatic picture[4,5]. The proposed mechanisms of hepatotoxicity are varied, depending onthe drug or drug class, and include effects on the cytochrome P-450 system,

This work is supported in part by K24 069290 (NC). Dr. Chalasani has consulting agree-

ments with Abbott Pharmaceuticals, Merck Pharmaceuticals, Ortho-McNeil, Metabasis, and

Advanced Life Sciences. He has received speaking honoraria from Roche Pharmaceuticals.

* Corresponding author.

E-mail address: [email protected] (N. Chalasani).

1089-3261/07/$ - see front matter � 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.cld.2007.06.010 liver.theclinics.com

mailto:[email protected]

598 BHARDWAJ & CHALASANI

impairment of bile acid transport proteins, immune-mediated inflammatoryresponse to the medication or its metabolites, immune-mediated apoptosisby tumor necrosis factor, and oxidative stress caused by intracellular dam-age [6]. Fig. 1 provides the chemical structures of commonly prescribedlipid-lowering medications with known hepatotoxicity, and Table 1 providesa concise overview of patterns of hepatotoxicity and recovery, as well ashepatotoxicity potential.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins)

Statins competitively inhibit HMG-CoA reductase, an enzyme necessaryfor cholesterol biosynthesis; they also act in several ways to decrease thelevel of LDL and increase the stability of atherosclerotic plaques [8,9]. These

Fig. 1. Chemical structures of commonly prescribed lipid-lowering medications with known

hepatotoxicity.

Table

Hepa

Lipid

agent

vg. length

f use

efore injury

Avg.

recovery

time

Hepatotoxicity

potential

Statin ften within

first several

months

2–3 months

(but

usually

within

10 weeks)

Serious liver

injury is very

rare

Niaci

(es

for

week–48

months

1–2 months Common with

SR

formulation

but rare with

IR or ER

Fibra

(es

fen

D ND Serious liver

injury is very

rare

Ezeti D ND Very low, but

seen in higher

frequency than

previously

thought

A lipoprotein; n/a, data not available; ND, inadequate

patie protein. 599

LIPID

LOWERIN

GAGENTS

1

totoxicity of various anti-hyperlipidemic agents

-lowering

or class

Mechanism

of action

Typical pattern

of biochemical

derangement

Typical histologic

appearance of injury

A

o

b

s Inhibits HMG-CoA

reductase

(involved in

cholesterol

synthesis)

Hepatocellular

(although cholestatic

and mixed injury are

seen as well)

Few cases have shown

inflammation of

portal tracts with mild

piecemeal necrosis

and mild, focal

periportal fibrosis

O

n

pecially SR

mulation)

Decreases hepatic

TG esterification

and LDL/VLDL

production

Mostly hepatocellular

but may be mixed

injury

Generally varying

patterns of necrosis,

but may also include

centrilobular

cholestasis or steatosis

1

tes

pecially

ofibrate)

Inhibits hepatic TG

synthesis;

decreases hepatic

FFA extraction

(gemfibrozil)

Hepatocellular injury

(especially with

gemfibrozil) but

mixed pattern of

injury seen with

fenofibrate

Fenofibrate can cause

ductopenia, chronic

hepatitis, and fibrosis

(especially in

combination with

statin medications)

N

mibe Inhibits absorption

of cholesterol at

small intestine

Rare cholestatic

hepatitis or acute

autoimmune hepatitis

n/a N

bbreviations: ER, extended release; FFA, free fatty acid; IR, intermediate release; LDL, low-density

nt data to reliably quantify; SR, sustained release; TG, triglyceride; VLDL, very low-density lipo


medications are effective is reducing cardiovascular mortality and are widelyprescribed [8]. More than 145 million prescriptions were written for statinsin the United States in 2005, and more than 10,000 prescriptions were writ-ten for lovastatin, the first generic statin available in the United States (a40% increase from the previous year) [10]. The use of these drugs is likelyto increase, given their effectiveness and relative safety, especially if any ofthem were to become available over-the-counter.

Although liver toxicity has been a concern since the introduction of thesedrugs, several clinical trials have shown that statins are safe to use for theprevention of coronary disease and death, even in the setting of chronic liverdisease [11]. Irreversible liver damage leading to death or liver transplanta-tion seems to be extremely uncommon with statins [11]. In fact, the inci-dence of liver enzyme elevations in the statin-treated population has notbeen consistently different from that in placebo-treated patients [9,11–14].Concern surrounding the safety of this class of medications increased signif-icantly in 2001 after cerivastatin was withdrawn from the market because ofthe high incidence of rhabdomyolysis in patients taking the drug [15]. Sincethat time, new drug applications for statin medications have been scruti-nized closely [15]. Rosuvastatin required a greater number of patients inthe initial studies as well as more extensive postmarketing data [15]. Thischange was caused more by concern about myotoxicity and renal toxicitythan about hepatotoxicity.

Initial studies of statins performed on animals revealed that very highdoses of statins may cause hepatotoxicity, but typical therapeutic doses ofthe drug were not associated with significant liver injury [16,17]. High dosesof lovastatin caused significant hepatocellular necrosis in rabbits [16]. Thispattern of injury also was seen in a guinea pig model exposed to high dosesof simvastatin [17]. Hepatocellular necrosis from statins is exceptionally rarein humans, however. Asymptomatic elevations in aminotransferase levelsare common with statins, but they do not necessarily indicate hepatic dam-age, especially when bilirubin levels are normal. The degree of elevation intransaminase levels, however, does not reflect the amount, or even the pres-ence, of liver injury [15]. The increase in transaminase levels is a dose-relatedphenomenon, with higher statin doses leading to a greater frequency of ami-notransferase elevations [15].

Atorvastatin

Atorvastatin-related hepatotoxicity has been associated with a mixed pat-tern of liver injury typically occurring several months after the initiation ofthe medication [18–21]. There also has been a recent case report of underly-ing autoimmune hepatitis apparently revealed by atorvastatin [22]. Afterbroad experience with this medication (hundreds of thousands of treated pa-tients), significantly increased transaminase levels greater than three timesthe upper limit of normal (ULN) were seen in only 0.7% of cases [18].

601LIPID LOWERING AGENTS

One case report described hepatocellular and cholestatic injury that oc-curred 12 weeks after the initiation of drug therapy and resolved within 2months after discontinuation of the drug [19]. Liver histology in this caserevealed portal inflammation with presence of eosinophils in addition tomild piecemeal necrosis. This case did not show any evidence of cross-reac-tivity across drug class, because simvastatin subsequently was introducedwithout recurrence of liver injury. A few other case reports have describedacute cholestatic hepatitis attributed to the use of atorvastatin [18–21].These cases seem to be associated with advanced age or chronic illnesses.For example, cholestatic hepatitis has been reported in a young womanwho had systemic lupus erythematosus [18]. Liver function studies and jaun-dice improved immediately with cessation of therapy and normalized withina month. Two case reports have described cholestatic injury in patients overthe age of 70 years [20,21]. Both cases improved rapidly with cessation of thedrug, and hepatitis recurred with reinitiation of therapy.

Lovastatin

Mixed hepatic injury in hepatocellular and cholestatic patterns also hasbeen noted with the use of lovastatin [23]. Elevations in hepatic enzymelevels are dose-related and resolve with discontinuation of therapy[13,23,24]. Although mild elevations in hepatic enzymes (alanine amino-transferase [ALT] ! three times ULN) have been shown to occur in upto 5% of patients receiving higher doses of therapy (80 mg/d), reversal ofliver enzyme levels has occurred spontaneously even with continuation ofthe medication [13]. As with other statin medications, clinically significantdisease, in the rare cases when it occurs, is seen within several months ofthe initiation of the drug and resolves within 2 months after discontinuation[23,24]. One reported case in which a liver biopsy was done revealed histo-logic findings of centrilobular necrosis and cholestasis with a mixed inflam-matory infiltrate [23]. Based on 232 cases of acute liver injury potentiallyassociated with lovastatin, the risk of fulminant liver failure attributableto lovastatin was estimated to be 2 in 1 million patients against a backgroundof 1 in 1 million in the general population [13,14].

Simvastatin

Drug–drug interactions are hypothesized to be the cause of simvastatinhepatotoxicity [25,26]. Several case reports involving amiodarone are of po-tential importance because these medications often are used together in a pa-tient who has known cardiovascular disease [25]. There also have been casereports describing hepatotoxicity when simvastatin is used in conjunctionwith flutamide, troglitazone, and diltiazem [26–28]. The addition of diltia-zem probably increased the serum simvastatin level significantly by inhibit-ing cytochrome P3A4 (CYP3A4) [26]. Troglitazone (no longer commerciallyavailable) is an inducer of CYP3A4, and thus hepatotoxicity cannot be


attributed to potentiation of simvastatin in this case [27]. Additionally, tro-glitazone itself is known to be hepatotoxic. As with other statin medications,mixed injury is seen at least as often as hepatocellular injury [27,28]. Recov-ery within weeks to a few months after discontinuation of the drug is thegeneral rule, although a much longer course of recovery is seen sometimes[25–28].

Pravastatin, rosuvastatin, and fluvastatin

Pravastatin has been reported to cause acute intrahepatic cholestasis [29].In this case, liver toxicity occurred within 2 months after initiating the drugand resolved within 2 months after its discontinuation [29]. Although neverstudied rigorously, there is a perception that pravastatin is less hepatotoxicthan other statins because of its non-CYP–based metabolism and its hydro-philic nature [30,31].

Rosuvastatin is the most recently approved drug in this class, and exten-sive clinical experience is lacking, although it has been the most carefullyscrutinized statin to date [32]. Rosuvastatin, like atorvastatin, has beenshown to trigger autoimmune-type hepatitis [32]. A case report publishedin 2005 noted a mixed pattern of liver injury and delayed recovery (O 6months from drug discontinuation to hepatic enzyme normalization) [32].Fluvastatin, unlike many other statins, is metabolized by cytochromeP-450 2C9 instead of CYP3A4 [30]. The incidence of elevations in hepaticbiochemistries is similar to that for the class as a whole, although initialstudies found a lower rate of hepatic enzyme elevation in the control popu-lation [30].

Clinically significant hepatotoxicity caused by statins remains extremelyrare, although, as a class, asymptomatic elevations in transaminases lessthan three times ULN are common [33,34]. The incidence of ALT threetimes ULN or higher associated with the use of statins is less than 3%,and a minor increase in incidence is seen related to dose (Table 2) [33,34].There have been rare reports of significantly higher transaminase levels;

Table 2

Rates of aminotransferase elevation and drug discontinuation for available statins

Statin

No. of prescriptions

written in 2004

(in millions)

Incidence of AST or

ALT level O 3 times

ULN (%)

Rate of

discontinuation (%)

Atorvastatin 62.5 0–0.7 n/a

Fluvastatin 1.9 1.2 0.6

Lovastatin 7.4 0.6 0.2

Pravastatin 12.0 1.3 0.1

Rosuvastatin 6.3 0 0

Simvastatin 23.8 1.8 0.5

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; n/a, data

not available; ULN, upper limit of normal.


however, even these cases were not associated with clinical or histologic ev-idence of liver dysfunction [35]. Statins have no signature biochemical orhistologic pattern for liver injury in patients who actually have developedliver toxicity. Hepatocellular, cholestatic, and mixed patterns of liver injuryhave been reported in the literature (Table 3) [4,5,13,14,36]. A few case re-ports have noted an autoimmune-type reaction attributed to or unmaskedby the use of statins [22,37,38]. The risk of fulminant liver failure remainsextremely low; Merck’s World-wide Adverse Event Database estimatedthe risk of fulminant liver failure attributable to lovastatin was 2 in 1 millionpatients based on 232 cases of acute liver injury potentially associated withlovastatin [13,14]. Of the few cases of actual hepatotoxicity from statins,liver biopsy data show chronic inflammation of the portal tracts with mildpiecemeal necrosis and, on rare occasion, mild focal periportal fibrosis [13].

Asymptomatic elevation in transaminase levels associated with statin useshould not be considered ongoing liver disease or injury. Increased amino-transferase levels have been theorized to represent a pharmacodynamic ef-fect of lipid lowering, although the mechanism of the elevation remainsunknown [14]. There has been some suggestion that the elevation in aspar-tate aminotransferase (and, to a lesser extent, ALT) levels may result frommuscle cell damage [14]. Clinically significant liver injury may result fromidiosyncratic mechanisms or the immunoallergic mechanisms noted earlier[5,36]. There does seem to be a class effect with some evidence of cross-tox-icity [5]. Like other classes of medications, the statins have been linked tovarious tumors in rodent models that have not been noted in humans[39,40]. The Scandinavian Simvastatin Survival Study, however, reportedno difference in cancer incidence between the simvastatin and the placebogroups during a 10-year follow-up period [41]. Furthermore, a previouslypublished meta-analysis of five large clinical trials demonstrated no associ-ation between statin use and the risk of cancer during a 5-year period [39].

The current recommendation to monitor liver function tests before andduring statin therapy is controversial because of the lack of evidence-based

Table 3

Types of liver injury associated with statin use

Finding Frequency Comment

Asymptomatic elevations in

aminotransferases

0.1–3% Dose dependent; class effect;

clinically not significant

Clinically significant acute

liver injury

Very rare May be seen in combination with

other medications (eg,

ezetimibe)

Fulminant hepatic failure Extremely rare (isolated

case reports)

Estimated risk of fulminant liver

failure is 2 in 1 million

Autoimmune hepatitis Case reports Statins may induce autoimmune

hepatitis in genetically

susceptible individuals


supporting data, with some experts in the field calling for its re-examination[8,16,42–44]. The existing guidelines state that liver enzymes should bechecked before starting statin therapy and periodically evaluated thereafter[8]. The package inserts continue to state that liver function tests should beassessed before and 12 weeks after initiating therapy with statins and alsoafter each dose escalation. The Statin Safety Task Force Meeting conductedby the National Lipid Association (2005), however, has argued against rou-tine monitoring of liver biochemistries before starting or during treatmentwith statins (Box 1) [9].

Niacin

Niacin, or nicotinic acid, is used primarily to increase high-density lipo-protein (HDL) through a mechanism that is not entirely clear. A reductionin LDL is seen also and apparently occurs because of an inhibition of he-patic very low-density lipoprotein and triglyceride secretion and thus a re-duction in the substrate needed to make LDL particles [45]. The SRpreparation is easily available over-the-counter and may be used by patientsseeking a perceived naturopathic solution to their high cholesterol or by pa-tients seeking a cheaper option to treat themselves. Patients may use poten-tially toxic doses without their physicians’ knowledge. This unsupervised useof the SR formulation often leads to the dose-related toxicity of niacin andshould be discouraged [4,46–48]. The onset of hepatotoxicity generally

Box 1. Summary of recommendations of the liver expert panelto the National Lipid Association on statin safety

� Asymptomatic increases in aminotransferases are a classeffect of 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 shouldnot be considered a contraindication for statin use.

� Current evidence supports the use of statins to treathyperlipidemia in patients who have nonalcoholic fatty liverdisease and nonalcoholic steatohepatitis.

From Vuppalanchi R, Chalasani N. Statins for hyperlipidemia in patients withchronic liver disease: are they safe? Clin Gastroenterol Hepatol 2006;4(7):838–9;with permission. Copyright � 2006, American Gastroenterological Society.


appears anywhere from 1 week to 48 months after the initiation of the drugand usually subsides with discontinuation [49–51]. Recovery usually is seenin 1 to 2 months [47,49]. Fulminant hepatic failure has been reported but isvery rare [50,52,53]. Combination therapy with statins does not increase theincidence of adverse effects of either medication [54].

The typical pattern of injury involves an elevation in aminotransferaselevels, although a mixed pattern of hepatocellular and cholestatic injurycan be seen [47,55]. Histologic findings usually consist of liver necrosis tovarious degrees and in varying patterns, but centrilobular cholestasis andsteatosis simulating the radiographic appearance of hepatobiliary neoplasiahave been seen [56,57]. A history of nausea and vomiting as well as signs andsymptoms of acute liver failure provide clinical clues to niacin toxicity[58,59]. Other clinical indicators of niacin hepatotoxicity include a sharp re-duction of serum lipid levels preceding the liver injury and a presentationsimilar to acute abdomen with a cholestatic pattern of liver disease in thesetting of fatty infiltration of the liver [58,60].

Almost any formulation of niacin can cause hepatotoxicity in doses thatexceed 2 to 3 g/d, but the SR formulation is significantly more hepatotoxic[61,62]. The immediate-release (IR) formulations of niacin in usual thera-peutic doses almost never cause serious liver injury [63,64]. The over-the-counter SR formulation of the drug is not approved by the Food andDrug Administration for the treatment of dyslipidemia but is still availableto patients for this purpose as a supplement or ‘‘neutraceutical.’’ Half thepatients who take niacin SR develop a symptomatic elevation in transami-nase levels [48,63,65].

The hepatotoxicity of niacin is related to drug metabolism by a high-af-finity, low-capacity amidation pathway that leads to toxic nicotinomide andpyrimidine metabolites; thus, the more slowly released SR formulation canlead to higher levels of toxic metabolites (Table 4) [63,64,66]. The alternative

Table 4

Pathways and potential of niacin toxicity by formulation

Toxicity potential

Formulation

Primary

metabolic

pathway

Toxic metabolites

produced or toxic

process initiated Hepatotoxicity

Cutaneous

flushing

Immediate

release

Conjugation Prostaglandins Extremely low High

Extended

release

Conjugation

O amidation

Prostaglandins

O nicotinomide

and pyrimidine

metabolites

Low Low

Sustained

release

Amidation Nicotinomide and

pyrimidine

metabolites

High Very low


metabolic pathway is a low-affinity, high-capacity conjugation pathway thatleads to prostaglandin-mediated vasodilation and subsequent cutaneousflushing [63,64,66]. The rapidly released IR formulation overwhelms thehigher-affinity amidation pathway, and the majority is metabolized usingthe high-capacity conjugation pathway, leading to a much lower rate of hep-atotoxicity [66]. Extended-release niacin has an intermediate rate of dissolu-tion and can be associated with both flushing and hepatotoxicity [63].

Fibrates

Several studies have linked clofibrate and gemfibrozil to hepatomegaly,hepatocyte apoptosis, and hepatocarcinogenesis in rodent models [67–69].This increased cancer risk has not been seen in humans, however, nor hasthe hepatomegaly or apoptosis [70]. There is a case report in the Spanish lit-erature of gemfibrozil leading to cholestatic hepatitis, and there are otherrare reports of hepatocellular injury [70–74]. Fenofibrate very rarely may in-stigate an autoimmune hepatitis-type reaction with resultant ductopenia,chronic hepatitis, and fibrosis, especially when used in combination with sta-tin medications [70,75].

Ezetimibe

Ezetimibe lowers cholesterol by inhibiting its intestinal absorption at thebrush border of the small intestine [76]. This medication does not induce orinhibit enzyme systems in the liver but undergoes enterohepatic circulationand is exposed to the liver and bile [7]. Therefore, although systemic expo-sure to ezetimibe is limited, the exposure is not limited solely to the lumen,and ezetimibe is, in fact, a systemic drug. Much of the previous data aboutthe hepatotoxicity of ezetimibe came from the manufacturer’s prereleaseclinical trials that showed ezetimibe to be generally well tolerated with an in-cidence of adverse events similar to placebo [77]. Recent studies, however,have noted that ezetimibe, rarely, may cause hepatotoxicity in the form ofsevere cholestatic hepatitis and acute autoimmune hepatitis [7]. The mecha-nism of toxicity may be related to the metabolism of the drug; it is absorbedrapidly and glucuronidated, yielding an active metabolite, and there is signif-icant enterohepatic recirculation [76]. The frequency of increased transami-nase levels was noted to be slightly higher in patients receiving ezetimibeadministered with HMG-CoA reductase inhibitors than in patients treatedwith HMG-CoA reductase inhibitors alone, but whether this increase willtranslate into a higher rate of toxicity remains to be seen [77–80].

Bile acid–binding resins

Bile acid–binding resins lower cholesterol indirectly by increasing theconversion of cholesterol into bile acids in the hepatocytes [81]. These agents


bind bile acids in the intestine, causing a subsequent reduction in the enter-ohepatic recirculation of bile acids [81–83]. Furthermore, the decrease in in-trahepatic cholesterol increases LDL receptor expression [81]. Drugs in thisclass are noted to be mostly safe for the liver, and cholestyramine actuallyhas been noted to be hepatoprotective [81,84]. There is a case report of hep-atotoxicity from colestipol in a patient who developed asymptomatic eleva-tion in his transaminase levels to 10 times ULN [82]. The hepatocellularinjury occurred 3 months after the initiation of the drug and resolved within4 weeks of discontinuation of the medication. Rechallenge was not attemp-ted in this case. The exact mechanism of the hepatotoxicity of bile acid–binding resins is unknown [84].

Cholesteryl ester transfer protein inhibitors

Trials were underway to evaluate the first drug in the class of cholesterylester transfer protein (CETP) inhibitors but were cut short because of in-creased mortality in patients taking a combination of the first drug in thisclass, torcetrapib, with atorvastatin [85–87]. Torcetrapib binds to CETPand blocks the transfer of lipids and phospholipids from HDL to other lipo-proteins [88]. Because it has been established that low HDL cholesterol is aspowerful a predictor for coronary heart disease as elevated LDL cholesterol,this medication was highly anticipated, especially as a complementary med-ication to the statins. Indeed, initial studies found that the combination ofatorvastatin and torcetrapib yielded striking improvements in the choles-terol profiles of study subjects, and in initial studies combination therapyseemed safe and well tolerated [85,86]. Unfortunately, the phase III trialwas suspended because of a significant increase in mortality in patients re-ceiving the combination compared with those receiving atorvastatin alone[87,89]. Increased rates of hypertension are suspected to be involved andhad been reported previously in patients randomly assigned to torcetrapib,although it is unknown whether this effect definitively led to the mortalityfindings [87,89]. Little is known at present about the potential hepatotoxicityof this class of medications.

Use of lipid-lowering medications in patients

who have pre-existing liver disease

Because current recommendations state that statins should not be used inpatients who have active liver disease, practicing physicians typically avoidstatins in patients who have elevated liver enzyme levels. This practice isproblematic, because hyperlipidemic patients have a significant prevalenceof underlying nonalcoholic fatty liver disease. Patients who have nonalco-holic fatty liver disease would benefit tremendously from statins becauseof their heightened risk of cardiovascular disease [42,90].


Several recent studies examined whether patients who have underlyingliver disease are at increased risk for statin hepatotoxicity [90–95]. In onestudy, the incidence of statin hepatotoxicity over a 6-month period in 342hyperlipidemic patients who had elevated liver enzyme levels and who re-ceived statins was compared with 1437 hyperlipidemic patients who hadnormal aminotransferase levels and received statins (statin controls) andwith 2245 patients who had elevated liver enzyme levels who did not receivestatins (liver disease controls) [91]. Elevations in liver biochemistries duringa 6-month follow-up were categorized into mild–moderate or severe basedon predefined criteria. Compared with the statin controls, patients whohad elevated liver enzyme levels had higher incidence of mild–moderate el-evations (4.7% versus 1.9%; P ¼ .002) but not severe elevations (0.6% ver-sus 0.2%, P ¼ ns) [91]. Patients who had elevated liver enzyme levels andwho received statins, however, did not show a higher incidence of mild–moderate elevations (4.7% versus 6.4%; P ¼ ns) or severe elevations(0.6% versus 0.4%; P ¼ ns) than the liver disease controls who did not re-ceive statins [91]. These data point out that some individuals who have ele-vated baseline liver enzyme levels have increases in their liver biochemistries,whether they receive statins or not. Because most patients in this study re-ceived either atorvastatin or simvastatin, in a subsequent study of similar de-sign, the same group examined whether patients who have elevated liverenzymes are more likely than persons who have normal liver enzymes tohave hepatotoxicity from lovastatin (a first-generation statin) [24]. Thisstudy also showed that hyperlipidemic individuals who have elevated base-line liver enzyme levels did not have higher frequency of lovastatin hepato-toxicity than those who had normal liver enzyme levels, as definedbiochemically [24]. More recently, investigators from the Palo Alto VeteransAdministration Medical Center have shown that patients who have chronichepatitis C are not at higher risk for statin hepatotoxicity than hyperlipi-demic patients who do not have hepatitis C [92]. Similarly, a recent reportfrom Dallas showed that statin use was not associated with hepatic steatosisor ALT levels in patients participating in the Dallas Heart Study [93]. A re-cent randomized, controlled study showed that pravastatin, 80 mg/d, is safein patients who have compensated chronic liver disease [94].

Emerging data suggest that statins actually are of benefit in patients whohave underlying liver disease [95]. A retrospective cohort study conducted inadult members of the Northern California Kaiser Permanente Medical CareProgram also suggested that lovastatin may be beneficial in patients whohave pre-existing liver disease [94]. In this study, 13,492 patients with lova-statin exposure had better clinical outcomes, with no evidence of increasedhepatotoxicity, when compared with 79,628 patients without lovastatinexposure [95].

All these data indicate that it is reasonable to conclude that patients whohave chronic liver disease and compensated cirrhosis should not be pre-cluded from receiving statins to treat hyperlipidemia. The authors believe


that that these observations can be extended cautiously to other lipid-lower-ing agents (eg, fibrates and niacin), although they have not been studied spe-cifically. The Statin Safety Task Force of the National Lipid Associationrecently recommended that chronic liver disease or compensated cirrhosisshould not be considered a contraindication for statins (see Box 1) [9].

Summary

Cardiovascular disease is the leading cause of death is the Western world,and the effort to reduce cardiovascular risk factors, including hyperlipid-emia, has led to the increased use of lipid-lowering agents. Hyperlipidemicpatients often have underlying fatty liver disease, however, and thus mayhave elevated and fluctuating liver biochemistries. Therefore, caution shouldbe applied before attributing elevated liver tests to lipid-lowering agents.

Although the statins are the most publicized lipid-lowering medicationsin the arena of drug-induced liver injury, their potential to cause clinicallysignificant liver injury is quite minimal. SR niacin, in fact, is the onlydrug in this category that causes clinically significant hepatotoxicity. Ezeti-mibe recently has been considered a safe alternative to statin therapy in thesetting of pre-existing liver disease, but recent evidence calls this belief intoquestion. There has been a widespread perception that statins are deleteri-ous for patients who have underlying chronic liver disease. Several recentstudies and expert opinion, however, currently fully endorse statin use in pa-tients who have nonalcoholic fatty liver disease and other chronic liver dis-ease if clinically indicated.

References

[1] American Heart Association. Cardiovascular disease statistics. 2006. Available at: http://

www.americanheart.org/presenter.jhtml?identifier¼4478. Accessed January 1, 2007.

[2] British Heart Foundation statistics website. CVD mortality in Europe. 2005. Available at:

http://www.heartstats.org/topic.asp?id¼753. Accessed January 1, 2007.

[3] Grundy SM, Cleeman JI, Merz CN, et al. Coordinating Committee of the National Choles-

terol Education Program. Implications of recent clinical trials for the National Cholesterol

Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44(3):

720–32.

[4] Parra JL, Reddy KR. Hepatotoxicity of hypolipidemic drugs. Clin Liver Dis 2003;7(2):

415–33.

[5] Chitturi S, George J. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflamma-

tory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents,

psychotropic drugs. Semin Liver Dis 2002;22(2):169–83.

[6] Bertolami MC. [Mechanisms of hepatotoxicity]. Arq Bras Cardiol 2005;85(5):25–7 [in Por-

tuguese] Available at: http://www.scielo.br/scielo.php?script¼sci_arttext&;;pid¼S0066-782X2005002400007&lng¼en&nrm¼iso. Accessed January 8, 2007.

[7] StolkMF, BecxMC,KuypersKC, et al. Severe hepatic side effects of ezetimibe. ClinGastro-

enterol Hepatol 2006;4(7):908–11.

[8] Talbert RL. Safety issues with statin therapy. J Am Pharm Assoc (2003) 2006;46(4):479–88.

http://www.americanheart.org/presenter.jhtml?identifier=4478

http://www.americanheart.org/presenter.jhtml?identifier=4478

http://www.heartstats.org/topic.asp?id=753

http://www.scielo.br/scielo.php?script=sci_arttext&;;pid=S0066-782X2005002400007&lng=en&nrm=iso

http://www.scielo.br/scielo.php?script=sci_arttext&;;pid=S0066-782X2005002400007&lng=en&nrm=iso


[9] Cohen DE, Anania FA, Chalasani N. National Lipid Association Statin Safety Task Force

Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006;

97(8A):77C–81C.

[10] Drug Topics. Pharmacy facts and figures. 2006. Available at: http://www.drugtopics.com/

drugtopics/article/articleList.jsp?categoryId¼7604. Accessed December 5, 2006.

[11] Vuppalanchi R, Chalasani N. Statins for hyperlipidemia in patients with chronic liver dis-

ease: are they safe? Clin Gastroenterol Hepatol 2006;4(7):838–9.

[12] RussoMW,Galanko JA, Shrestha R, et al. Liver transplantation for acute liver failure from

drug induced liver injury in the United States. Liver Transpl 2004;10(8):1018–23.

[13] Tolman KG. The liver and lovastatin. Am J Cardiol 2002;89(12):1374–80.

[14] TolmanKG.Defining patient risks from expanded preventive therapies. Am J Cardiol 2000;

85(12A):15E–9E.

[15] Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J

Cardiol 2006;97(8A):44C–51C.

[16] MacDonald JS, Gerson RJ, Kornbrust DJ, et al. Preclinical evaluation of lovastatin. Am J

Cardiol 1998;62(15):16J–27J.

[17] Horsmans Y, Desager JP, Harvengt C. Biochemical changes and morphological alterations

of the liver in guinea-pigs after administration of simvastatin (HMG CoA reductase-inhib-

itor). Pharmacol Toxicol 1990;67(4):336–9.

[18] Jimenez-Alonso J, Osorio JM, Guierrez-Cabello F, et al. Atorvastatin-induced cholestatic

hepatitis in a young woman with systemic lupus erythematosus. Arch Intern Med 1999;

159(15):1811–2.

[19] Nakad A, Bataille L, Hamoir V, et al. Atorvastatin-induced acute hepatitis with absence of

cross-toxicity with simvastatin. Lancet 1999;353(9166):1763–4.

[20] de Castro ML, Hermo JA, Baz A, et al. [Acute cholestatic hepatitis after atorvastatin rein-

troduction] [in Spanish; Case Report]. Gastroenterol Hepatol 2006;29(1):21–4.

[21] Gershovich OE, Lyman AE. Liver function test abnormalities and pruritis in a patient

treated with atorvastatin: case report and review of the literature. Pharmacotherapy 2004;

24(1):150–4.

[22] Pelli N, Setti M, Ceppa P, et al. Autoimmune hepatitis revealed by atorvastatin. Eur J Gas-

troenterol Hepatol 2003;15(8):921–4.

[23] Grimbert S, Pessayre D, Degott C, et al. Acute hepatitis induced by HMG-CoA reductase

inhibitor, lovastatin. Dig Dis Sci 1994;39(9):2032–3.

[24] Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not

have higher frequency of hepatotoxicity from lovastatin than those with normal baseline

liver enzymes. Am J Med Sci 2005;329:62–5.

[25] Ricaurte B, Guirguis A, Taylor HC, et al. Simvastatin-amiodarone interaction resulting in

rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006;40(4):

753–7.

[26] KanathurN,MathaiMG,ByrdRP Jr, et al. Simvastatin-diltiazemdrug interaction resulting

in rhabdomyolysis and hepatitis. Tenn Med 2001;94(9):339–41.

[27] Caldwell SH,Hespenheide EE, vonBorstel RW.Myositis, microvesicular hepatitis, and pro-

gression to cirrhosis from troglitazone added to simvastatin. Dig Dis Sci 2001;46(2):376–8.

[28] Ashar U, Desai D, Bhaduri A. Flutamide-induced hepatotoxicity with possible potentiation

by simvastatin. J Assoc Physicians India 2003;51:75–7.

[29] Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pra-

vastatin. Am J Gastroenterol 1999;94(5):1388–90.

[30] de Denus S, Spinler SA, Miller K, et al. Statins and liver toxicity: a meta-analysis. Pharma-

cotherapy 2004;24(5):584–91.

[31] KubotaT, FujisakiK, ItohY, et al. Apoptotic injury in cultured human hepatocytes induced

by HMG-CoA reductase inhibitors. Biochem Pharmacol 2004;67(12):2175–86.

[32] Wolters LMM, Van Buuren HR. Rosuvastatin-associated hepatitis with autoimmune fea-

tures. Eur J Gastroenterol Hepatol 2005;17(5):589–90.

http://www.drugtopics.com/drugtopics/article/articleList.jsp?categoryId=7604




[33] PasternakRC, Smith SC Jr, Bairey-Merz CN, et al. American College of Cardiology. Amer-

ican Heart Association. National Heart, Lung and Blood Institute. ACC/AHA/NHLBI

Clinical advisory on the use and safety of statins. Circulation 2002;106(8):1024–8.

[34] Farmer JA, Torre-Amione G. Comparative tolerability of the HMG-CoA reductase inhib-

itors. Drug Saf 2000;23(3):197–213.

[35] Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of pravastatin in long-term

clinical trials: Prospective Pravastatin Pooling (PPP) project. Circulation 2002;105(20):

2341–6.

[36] Perger L, Kohler M, Fattinger K, et al. Fatal liver failure with atorvastatin. J Hepatol 2003;

39(6):1095–7.

[37] Graziadei IW,ObermoserGE, SeppNT, et al.Drug-induced lupus-like syndrome associated

with severe autoimmune hepatitis. Lupus 2003;12(5):409–12.

[38] Alla V,AbrahamJ, Siddiqui J, et al. Autoimmune hepatitis induced by statins. J ClinGastro-

enterol 2006;40(8):757–61.

[39] Guallar E, Goodman SN. Statins and cancer: a case of meta-uncertainty. Am J Med 2001;

110(9):738–40.

[40] NewmanTB,Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA1996;275(1):55–60.

[41] Strandberg TE, PyoralaK, Cook TJ, et al. 4SGroup.Mortality and incidence of cancer dur-

ing 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet 2004;

364(9436):771–7.

[42] Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;

41(4):690–5.

[43] Marzoa-Rivas R, Crespo-Leiro MG, Paniagua-Marin MJ, et al. Safety of statins when re-

sponse is carefully monitored: a study of 336 heart recipients. Transplant Proc 2005;37(9):

4071–3.

[44] Patel DN, Pagani FD, Koelling TM, et al. Safety and efficacy of atorvastatin in heart trans-

plant recipients. J Heart Lung Transplant 2002;21(2):204–10.

[45] McCormack PL, Keating GM. Prolonged-release nicotinic acid: a review of its use in the

treatment of dyslipidaemia. Drugs 2005;65(18):2719–40.

[46] Vogt A, Kassner U, Hostalek U, et al, NAUTILUS Study Group. Evaluation of the safety

and tolerability of prolonged-release nicotinic acid in a usual care setting: the NAUTILUS

study. Curr Med Res Opin 2006;22(2):417–25.

[47] Dalton TA, Berry RS. Hepatotoxicity associated with sustained-release niacin. Am J Med

1992;93(1):102–4.

[48] Etchason JA, Miller TD, Squires RW, et al. Niacin-induced hepatitis: a potential side effect

with low-dose time-release niacin. Mayo Clin Proc 1991;66(1):23–8.

[49] Henkin Y, Johnson KC, Segrest JP. Rechallenge with crystalline niacin after drug-induced

hepatitis from sustained-release niacin. JAMA 1990;264(2):241–3.

[50] HodisHN.Acute hepatic failure associatedwith the use of low-dose sustained-release niacin.

JAMA 1990;264(2):181.

[51] Reimund E, Ramos A. Niacin-induced hepatitis and thrombocytopenia after 10 years of

niacin use. J Clin Gastroenterol 1994;18(3):270–1.

[52] Mullin GE, Greenson JK, Mitchell MC. Fulminant hepatic failure after ingestion of sus-

tained-release nicotinic acid. Ann Intern Med 1989;111(3):253–5.

[53] Clementz GL, Holmes AW.Nicotinic acid-induced fulminant hepatic failure. J Clin Gastro-

enterol 1987;9(5):582–4.

[54] Moon YS, KashyapML. Niacin extended-release/lovastatin: combination therapy for lipid

disorders. Expert Opin Pharmacother 2002;3(12):1763–71.

[55] American Society of Health-System Pharmacists. ASHP Therapeutic Position Statement on

the safe use of niacin in the management of dyslipidemias. Am J Health Syst Pharm 1997;

54(24):2815–9.

[56] Scheer MS, Perlmutter S, Ross W, et al. Ultrasonographic findings in niacin-induced hepa-

titis. J Ultrasound Med 1999;18(4):321–3.


[57] Kristensen T, Olcott EW. Effects of niacin therapy that simulate neoplasia: hepatic steatosis

with concurrent hepatic dysfunction. J Comput Assist Tomogr 1999;23(2):314–7.

[58] Coppola A, Brady PG, Nord HJ. Niacin-induced hepatotoxicity: unusual presentations.

South Med J 1994;87(1):30–2.

[59] Lavie CJ, Milani RV. Safety and side effects of sustained-release niacin. JAMA 1994;272(7):

513–4.

[60] Gray DR, Morgan T, Chretien SD, et al. Efficacy and safety of controlled-release niacin in

dyslipoproteinemic veterans. Ann Intern Med 1994;121(4):252–8.

[61] Capuzzi DM, Guyton JR, Morgan JM, et al. Efficacy and safety of an extended-release

niacin (Niaspan): a long-term study. Am J Cardiol 1998;82(12A):74U–81U.

[62] Rader JI, Calvert RJ, Hathcock JN. Hepatic toxicity of unmodified and time-release prep-

arations of niacin. Am J Med 1992;92(1):77–81.

[63] Pieper JA. Overview of niacin formulations: differences in pharmacokinetics, efficacy, and

safety. Am J Health Syst Pharm 2003;60(13 Suppl 2):S9–14.

[64] McKenney J. Niacin for dyslipidemia: considerations in product selection. Am JHealth Syst

Pharm 2003;60(10):995–1005.

[65] Lawrence SP. Transient focal hepatic defects related to sustained-release niacin. J Clin Gas-

troenterol 1993;16(3):234–6.

[66] McKenney JM, Proctor JD, Harris S, et al. A comparison of the efficacy and toxic effects of

sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA1994;271(9):

672–7.

[67] Chen H, Huang CY, Wilson MW, et al. Effect of the peroxisome proliferators ciprofibrate

and perfluorodecanoic acid on hepatic cell proliferation and toxicity in Sprague-Dawley

rats. Carcinogenesis 1994;15(12):2847–50.

[68] Cornwell PD, De Souza AT, Ulrich RG. Profiling of hepatic gene expression in rats treated

with fibric acid analogs. Mutat Res 2004;549(1–2):131–45.

[69] Dix KJ, ColemanDP, Jeffcoat AR. Comparative metabolism and disposition of gemfibrozil

in male and female Sprague-Dawley rats and Syrian golden hamsters. Drug Metab Dispos

1999;27(1):138–46.

[70] Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol

2004;94(7):935–8.

[71] Bustamante Balen M, Plume Gimeno G, Bau Gonzalez I, et al. [Acute hepatitis caused by

gemfibrozil]. Gastroenterol Hepatol 1998;21(8):419–20 [in Spanish].

[72] de Diego Lorenzo A, Catalina V, Garcia Sanchez A, et al. [Cholestatic hepatitis caused by

gemfibrozil]. Rev Esp Enferm Dig 2001;93(9):610–1 [in Spanish].

[73] Grubisic-Cabo F, Vrdoljak E. Drug-induced hepatitis in a patient withmalignantmelanoma

treated with interferon alfa 2b adjuvantly who had been administered gemfibrozil in therapy.

Med Oncol 2006;23(1):121–4.

[74] Ho CY, Kuo TH, Chen TS, et al. Fenofibrate-induced acute cholestatic hepatitis. J Chin

Med Assoc 2004;67(5):245–7.

[75] Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-

term statin-fibrate combinations in patients with refractory familial combined hyperlipid-

emia. Am J Cardiol 1997;80(5):608–13.

[76] Landmesser U, Bahlmann F,MuellerM, et al. Simvastatin versus ezetimibe: pleiotropic and

lipid-lowering effects on endothelial function in humans. Circulation 2005;111(18):2356–63.

[77] Cruz-Fernandez JM, BedaridaGV,Adgey J, et al. Efficacy and safety of ezetimibe co-admin-

istered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in pa-

tients with hypercholesterolemia and coronary heart disease. Int J Clin Pract 2005;59(6):

619–27.

[78] Goldman-Levine JD, Bohlman LG. Ezetimibe/simvastatin (Vytorin) for hypercholesterol-

emia. Am Fam Physician 2005;72(10):2081–2.

[79] Reyderman L, Kosoglou T, Cutler DL, et al. The effect of fluvastatin on the pharmacokinet-

ics and pharmacodynamics of ezetimibe. Curr Med Res Opin 2005;21(8):1171–9.


[80] van Heyningen C. Drug-induced acute autoimmune hepatitis during combination therapy

with atorvastatin and ezetimibe. Ann Clin Biochem 2005;42(Pt 5):402–4.

[81] Armani A, Toth PP. Colesevelam hydrochloride in the management of dyslipidemia. Expert

Rev Cardiovasc Ther 2006;4(3):283–91.

[82] Sirmans SM,Beck JK, BanhHL, et al. Colestipol-induced hepatotoxicity. Pharmacotherapy

2001;21(4):513–6.

[83] Hofmann AF. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepato-

toxicity. Drug Metab Rev 2004;36(3–4):703–22.

[84] Graf D, Kohlmann C, Haselow K, et al. Bile acids inhibit interleukin-6 signaling via gp130

receptor-dependent and -independent pathways in rat liver.Hepatology 2006;44(5):1206–17.

[85] Thuren T, LongcoreA, Powell C, et al. Torcetrapib combinedwith atorvastatin raises HDL-

C, lowers LDL-C, and is well tolerated: results from a phase 2 dose-ranging clinical trial.

Circulation 2005;112(17 Suppl):II-179 [Abstract: 942].

[86] Davidson M, McKenney J, Revkin J, et al. Efficacy and safety of a novel cholesteryl ester

transfer protein inhibitor torcetrapib when administered with and without atorvastatin to

subjects with a low level of high-density lipoprotein cholesterol [abstract 802]. In: Program

and abstracts from the American College of Cardiology Annual Scientific Sessions 2005.

Orlando (FL), March 6–9, 2005.

[87] Daley J. Pfizer scraps drug trial after deaths. The Independent [serial online]. December 4,

2006. Available at: http://news.independent.co.uk/business/news/article2037520.ece. Ac-

cessed December 4, 2006.

[88] Brewer HB Jr. High-density lipoprotein: a new potential therapeutic target for the preven-

tion of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24:387–91.

[89] FDA Statement. Pfizer stops all torcetrapib clinical trials in interest of patient safety. Avail-

able at: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01514.html. Accessed December

4, 2006.

[90] Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic

and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol

2004;99(8):1497–502.

[91] Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated liver enzymes are not at

higher risk for statin hepatotoxicity. Gastroenterology 2004;126:1287–92.

[92] Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with

hepatitis C. Clin Gastroenterol Hepatol 2006;4(7):902–7.

[93] Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hep-

atology 2006;44:466–71.

[94] Lewis JH, Fusco MJ, Medoff JR, et al. Safety and efficacy of pravastatin 80 mg/day in 320

hypercholesterolemic patients with compensated chronic liver disease (CLD): results of

a prospective, randomized, double-blind, placebo-controlled study. Gastroenterology

2006;130:A–65.

[95] Avins AL, Manos MM, Levin TR, et al. Lovastatin is not hepatotoxic to patients with pre-

existing liver disease. Gastroenterology 2006;130:A–595.

http://news.independent.co.uk/business/news/article2037520.ece

http://www.fda.gov/bbs/topics/NEWS/2006/NEW01514.html

Documents

Lipid-Lowering Agents That Cause Drug-Induced Hepatotoxicity