Clinical Gastroenterology and Hepatology 2014;-:-–-

Management of Dyslipidemia as a Cardiovascular Risk Factor inIndividuals With Nonalcoholic Fatty Liver Disease

Kathleen E. Corey* and Naga Chalasani‡

*Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts; and ‡Department ofMedicine, Indiana University School of Medicine, Indianapolis, Indiana

Abbreviations used in this paper: CV, cardiovascular; CVD, cardiovasculardisease; DM, diabetes mellitus; FRS, Framingham Risk Score; HDL, high-density lipoprotein; HDL-C, HDL-cholesterol; LDL, low-density lipoprotein;MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease;NASH, nonalcoholic steatohepatitis; NCEP, National Cholesterol Educa-tion Program; OSA, obstructive sleep apnea.

© 2014 by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2013.08.014

Nonalcoholic fatty liver disease (NAFLD) is the mostfrequent cause of liver disease in the United States and isassociated with an increased risk of cardiovascular disease(CVD) and cardiovascular (CV) mortality, independent oftraditional cardiovascular risk factors. CVD is one of themost common causes of death among individuals withNAFLD and management of NAFLD must extend beyondliver disease to include CVD risk modification. Cliniciansshould assess CVD risk with the Framingham Risk Scoreand screen for CVD risk factors including dyslipidemia,diabetes mellitus, hypertension, tobacco use, and themetabolic syndrome. CVD risk factors, particularly dysli-pidemia, require aggressive medical management toreduce the high risk of CVD events and death in individualswith NAFLD.

Keywords: Dyslipidemia; Nonalcoholic Fatty Liver Disease;Cardiovascular Disease.

Nonalcoholic fatty liver disease (NAFLD) impacts30% to 40% of Americans.1 Nonalcoholic stea-

tohepatitis (NASH), the progressive form of NAFLD,impacts 2% to 12% of Americans.2 NASH can lead to thedevelopment of cirrhosis and it is predicted that by theyear 2020, NASH cirrhosis will be the leading indicationfor liver transplantation in the United States.3

Although NASH can result in end-stage liver disease,steatosis and NASH are associated with an increased riskof CVD events and death both independently and by theirfrequent association with the metabolic syndrome(MetS), insulin resistance, and dyslipidemia.4 A meta-analysis assessing the natural history of NAFLD foundthat although NASH was associated with increased liver-related mortality when compared with steatosis, therewas no difference in the risk of CVD-related deathbetween NASH and steatosis.4 Currently, cardiovasculardisease (CVD) is the leading cause of death in individualswith NAFLD.5 Modification of CVD risk factors, particu-larly dyslipidemia, is necessary to decrease CVDmorbidity and mortality in individuals with NAFLD. Inthis review, we address the need for CVD risk stratifi-cation and outline methods for CVD risk management inindividuals with NAFLD. Although the breadth of data onCVD risk management in NAFLD is expanding, limitationsremain. Where data are unavailable for NAFLD specif-ically, we have drawn from the CVD literature in the

general population and in individuals with other CVDrisk factors.

Dyslipidemia in Nonalcoholic Fatty LiverDisease

Dyslipidemia is frequent in individuals with NAFLD. Asubstudy from the Multi-Ethnic Study of Atherosclerosisassessed the relationship between radiographicallydiagnosed NAFLD and dyslipidemia.6 NAFLD was asso-ciated independently with increased triglyceride levels,increased low-density lipoprotein (LDL) particle con-centration, decreased LDL particle size, and decreasedhigh-density lipoprotein (HDL) levels after controllingfor insulin resistance. These findings have been repli-cated in individuals with NAFLD from other communitycohorts and in individuals with NAFLD and diabetesmellitus (DM).7,8 In addition, non–HDL-cholesterol(non–HDL-C) is increased in individuals with NASH.9

Non–HDL-C is a measure of all atherogenic lipoproteinsincluding very-low-density lipoproteins, LDLs,intermediate-density lipoproteins, and lipoprotein a.10

Non–HDL-C is calculated from a standard lipid panel(non–HDL-C ¼ total cholesterol–HDL) and guidelinescite non–HDL-C values of less than 150 mg/dL as asecondary target for lipid-lowering therapy.11,12

Cardiovascular Disease andNonalcoholic Fatty Liver Disease

CVD events are a frequent cause of morbidity andmortality in individuals with NAFLD (Table 1). Threecommunity-based studies have shown that individualswith radiographically diagnosed NAFLD have anincreased risk of CVD events and mortality compared

Table 1. Studies of CV Risk in NAFLD

Study Cohort

Numberof

subjects

Modality ofNAFLD

Diagnosis

Follow-up

period, y Risk or incidence of CVD events Comments

Hamaguchiet al16

Japanesecommunitycohort

1637 Ultrasound 5 CVD events: NAFLD, 5.2%; non-NAFLD, 1.0% (P < .001)

Independent of MetS and CVrisk factors

Targheret al13

US diabeticcohort

2103 Ultrasound 6.5 Increased fatal and nonfatal CVDevents: OR, 1.87 (CI, 1.2–2.6)

Independent of MetS and CVrisk factors, DM

Haringet al81

Germancommunitycohort

4160 Ultrasound 7.3 Increased CVD mortality in men withNAFLD: HR, 6.22 (CI, 1.22–31.62)

Independent of CV risk factors;no difference seen inwomen

Adamset al14

US community-basedcohort

420 Ultrasound 7.6 Percentage of deaths from CVDevents, 25%

Soderberget al17

Swedish tertiarycare cohort

118 Biopsy 24 Increased total mortality in NAFLD,mainly CVD-related: SMR, 1.69(CI, 1.24–2.25)

Matched controls

Ekstedtet al18

Swedish tertiarycare cohort

129 Biopsy 13.7 Increased mortality, primarily CVDin NASH patients: RR, 1.38(P ¼ .006)

Matched controls

Schwimmeret al82

Children atautopsy

817 Biopsy NA Increased coronary and aorticatherosclerosis in NAFLD: OR,1.8 (P < .001)

Independent of obesity

Dam-Larsenet al83

Danishpopulation-basedcohort

170 Biopsy 20.4 Percentage of deaths from CVDevents, 38%

Only steatosis included

Rafiq et al84 US tertiaryreferral-basedcohort

173 Biopsy 18.5 Percentage of deaths from CVDevents, 12.7%

CI, confidence interval; HR, hazard ratio; NA, not applicable; OR, odds ratio; RR, risk ratio; SMR, standardized mortality ratio.

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with individuals without NAFLD.13–15 Hamaguchi et al16

assessed 1637 subjects in a community-based cohortfrom Japan for NAFLD by ultrasonography. Nineteenpercent of the cohort was found to have NAFLD.Cardiovascular (CV) events occurred in 5.2% of NAFLDsubjects and 1.0% of non-NAFLD individuals over 5years (P < .01). This difference remained statisticallysignificant after adjustment for the MetS. Adams et al14

found a high incidence of CV mortality in a US-basedcohort. A total of 420 individuals with NAFLD werefollowed up for a median of 7.6 years. Individuals withNAFLD had significantly increased mortality whencompared with the general population, with astandardized mortality ratio of 1.34 (95% confidenceinterval, 1.003–1.76). Targher et al13 found that CVDevents and mortality also were more common amongdiabetic individuals with NAFLD than diabetic patientswithout NAFLD (odds ratio, 1.87; 95% confidenceinterval, 1.2–2.60).

Histologically defined NAFLD also is associated withan increased CVD risk. Soderberg et al17 performed liverbiopsies in 256 subjects, 118 of whom had NAFLD, whichwere blindly scored for steatosis and NASH. Individualswith NAFLD (both steatosis and NASH) had a 69%increased mortality rate compared with the overallpopulation. Ekstedt et al18 also found that individuals

with NASH had increased mortality compared with thegeneral population, a difference not seen in individualswith steatosis only. Again, CVD was the most commoncause of death among individuals with NASH. Thus,individuals with both radiographically and histologicallydefined NAFLD are at increased risk for CVD andmortality.

Cardiovascular Risk Stratification inNonalcoholic Fatty Liver Disease

Several different methods are used in the generalpopulation to estimate CVD risk including the Framing-ham Risk Score (FRS). The FRS is a validated measure ofCV risk in the general population. Incorporating age, sex,cholesterol, HDL, smoking status, and hypertension, theFRS predicts an individual’s 10-year risk of myocardialinfarction or CVD death. Furthermore, the FRS has beenvalidated as a predictor of CVD in NAFLD and should beused to risk-stratify individuals and guide treatment ofrisk factors including dyslipidemia.19

The MetS is frequent in individuals with NAFLD andis associated with increased CVD and all-cause mortal-ity.20,21 Therefore, assessment for the MetS is an im-portant component of CVD risk stratification. Several

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definitions for MetS exist.22 The MetS as defined by theNational Cholesterol Education Program (NCEP) requiresthe presence of 3 or more of the following components:(1) increased triglyceride levels (�150 mg/dL); (2) lowHDL level (<40 mg/dL in men, <50 mg/dL in women);(3) increased fasting glucose level (�110 mg/dL); (4)hypertension (�130/85 mm Hg or on antihypertensivemedication); and (5) abdominal obesity (waistcircumference: >102 cm in men, >88 cm in women).

In addition to evaluation for the MetS, individualsshould be evaluated for other CVD risk factors includingDM, which can be diagnosed using fasting glucose orglycosylated hemoglobin levels.23

Cardiac stress testing, carotid artery intima-mediathickness assessment, and the coronary artery calciumscore also can add to CVD risk stratification. These mo-dalities can be used to detect subclinical atheroscleroticdisease and to predict future CV events.23–25 Individualswith NAFLD and increased CVD risk have been found tohave increased mean carotid artery intima-mediathickness levels and increased coronary artery calciumscores, suggesting the utility of these tests for riskstratification in individuals with NAFLD.26–28

Management of Dyslipidemia andCardiovascular Disease Risk inNonalcoholic Fatty Liver Disease

Lifestyle modification, encompassing weight loss andincreased physical activity, is the cornerstone of dyslipi-demia management in NAFLD. However, for groups withincreased CVD risk, lifestyle modification should beaccompanied by lipid-lowering therapy. Guidelines setforth by the NCEP Adult Treatment Panel III provideguidance on which groups should be targeted for lip-id-lowering therapy and outline treatment goals(Figure1).12Theseguidelineswerenotdesignedspecificallyto address dyslipidemia in individuals with NAFLD. How-ever, they can be applied safely to individuals with NAFLD.

Figure 1. Evaluation andmanagement of cardio-vascular risk in NAFLD.FH, family history; HbA1C,glycosylated hemoglobin.Adapted from the NCEPprogram Adult TreatmentPanel III guidelines.12

Dietary Modification

Little data are available for the preferred diet forindividuals with NAFLD. Two small studies have sug-gested that diets low in carbohydrates may result in areduction in intrahepatic triglyceride concentration andan improvement in histologically defined NAFLD.29,30

Low carbohydrate diets have a beneficial effect onserum lipid levels.31 For LDL lowering, the NCEPrecommends a diet low in saturated fat (<7% of totalcalories) and cholesterol (<200 mg/d). Plant sterolsand stanols as well as increased intake of soluble fiberalso can be used for dietary lipid lowering.12

Recently, a large randomized controlled trial foundthat subjects who consumed a Mediterranean diet had areduction in the incidence of cardiac events comparedwith those following a low-fat diet.32 Limited data existon the benefit of the Mediterranean diet in NAFLD. A trialof 12 subjects with biopsy-proven NAFLD assessed theimpact of a Mediterranean diet on hepatic steatosis asassessed by magnetic resonance spectroscopy.33 Subjectsundertook, in random order, 6 weeks of a low-fat, high-carbohydrate diet and a Mediterranean diet, separatedby a 6-week wash-out period. Magnetic resonancespectroscopy steatosis decreased significantly in thegroup following the Mediterranean diet compared withthe low-fat, high-carbohydrate diet (39% reduction vs7% reduction; P ¼ .012), with no difference in weightloss between groups. This study suggests that inindividuals with NAFLD, the Mediterranean diet mayhave benefits beyond the management of dyslipidemia.However, further studies are needed before this diet canbe routinely recommended.

Fructose consumption, present in processed foodsand beverages, is associated with NAFLD development.34

The impact of fructose avoidance has yet to be evaluatedrigorously but individuals should be advised to limitfructose consumption. The United States Dietary Guide-lines for 2010 classify fructose as an added sugar andrecommends limiting added sugars to 3 servings or

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fewer per day for persons on less than a 2000-calorie-per-day diet and to 5 servings or fewer per day for thoseon a 2000-calorie-per-day or higher diet.

Exercise

Regular exercise is associated with decreased triglyc-eride and LDL levels and increased HDL levels.35,36 TheNCEP recommends at least 30 minutes of moderateactivity most days of the week as part of dyslipidemiamanagement.12 Exercise is associated independentlywith a reduction in aminotransferase levels and hepatictriglyceride content. Sixty minutes per week of aerobicexercise decreases aminotransferase levels in subjectswith NAFLD.37 A trial of subjects with NAFLDrandomized to no exercise or three 30- to 45-minutecycling sessions weekly found that the cycling grouphad a significant decrease in hepatic triglyceride contentand visceral adipose content without a change in overallbody weight.38 Individuals with NAFLD should beadvised to participate in regular, aerobic exercise.

Cigarette Smoking and Alcohol Use

Cigarette smoking is associated with increased CVDand all-cause mortality. The American College of Cardi-ology recommends that individuals who use tobaccoreceive counseling regarding smoking cessation and, ifneeded, referral to tobacco cessation support pro-grams.23 Moderate alcohol intake, defined as 1 unit ofalcohol daily for women and 2 units daily for men, mayincrease HDL and apolipoprotein AI levels and decreasedrisk.12 Therefore, moderate alcohol use may be helpful inreducing CVD risk.

Several studies have suggested that mild to moderatealcohol use may be protective against NAFLD develop-ment.39,40 However, no data exist to determine theimpact of alcohol use on existing NAFLD or NASH orthe impact of alcohol use on CVD risk in individualswith NAFLD. Therefore, it is premature to recommendregular alcohol use in individuals with NAFLD.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is characterized byperiods of apnea during sleep resulting in oxygen desa-turation. Chronically, OSA increases the risk of the MetS,CVD, and sudden death whereas treatment of OSAimproves the MetS and decreases CVD mortality.41–46

Several studies have suggested a relationship be-tween OSA and NAFLD. Animal models have shown thatmice exposed to chronic intermittent hypoxia are morelikely to develop steatosis and hepatic inflamma-tion.47,48 In human beings, several studies have shown arelationship between OSA and NAFLD. A study ofsubjects with OSA and NASH found that the oxygendesaturation index, a measure of OSA severity, was

correlated directly with the NASH activity score andfibrosis stage even after adjustment for insulinresistance and obesity.49 In addition, a prospectivestudy of individuals with radiographically definedNAFLD and OSA found that the initiation of contin-uous positive airway pressure lead to an improvementin radiographic steatosis.50 Thus, a potential linkbetween NAFLD and OSA may exist and requiresfurther evaluation. It would be premature to suggestthat OSA treatment will improve NAFLD. However,because treatment of OSA does improve the MetS andCVD risk, screening for OSA should be considered inindividuals with NAFLD.

Diabetes Mellitus

DM is associated with an increased risk of CVD.Because DM is highly prevalent among individuals withNAFLD, comprehensive management is essential for CVDrisk reduction. A detailed discussion of the managementof DM in individuals with NAFLD is beyond the scope ofthis review. However, primary and secondary preventionof CVD events in individuals with DM should focus onmultifactorial risk reduction, including treatment of hy-pertension and dyslipidemia.51 In addition, specifictreatments of DM including metformin may decreaseCVD events.52

Lipid-Lowering Medications

3-hydroxy-3-methylglutaryl–coenzyme A reductaseinhibitors. Treatment of dyslipidemia should not bewithheld in individuals with NAFLD. 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors, orstatins, have a well-established role in the primary andsecondary prevention of CVD and individuals withNAFLD can benefit from risk reduction.12 A post hocanalysis of the Greek Atorvastatin and Coronary HeartDisease Evaluation study showed not only that statinsare safe in individuals with abnormal liver function testspresumably as a result of NAFLD, but that individualswith NAFLD who received statins had a significantreduction in CV events when compared with those withNAFLD not on statins (10% vs 30%; P < .0001).53 Thus,statins significantly reduce CV events in individuals withNAFLD and should be used for individuals who requirelipid-lowering therapy.

Early data suggest that statins also may have a spe-cific role in the treatment of NAFLD, although this re-quires confirmation before it can be widely applied.54 Aretrospective trial of statin use in 68 individuals withhistologically defined NAFLD found that those who usedstatins had a reduction in steatosis, despite a highermean BMI and prevalence of DM, than those not onstatins.55 In addition, the rate of fibrosis developmentwas unexpectedly low in individuals on statin therapy.In individuals with radiographically defined NAFLD,

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atorvastatin has been shown in several studies to beassociated with NAFLD regression.54,56,57 However, arandomized controlled trial of simvastatin in NASHtherapy did not result in any histologic benefit.58 Thus,the impact of statin therapy on NAFLD remainsuncertain. Importantly, however, statin hepatotoxicitywas not reported in any study, reinforcing that statinsare safe in individuals with NAFLD.

In addition to the role of statins in managementof dyslipidemia, statins also may play a role in the pre-vention of hepatocellular carcinoma.59 By using a com-munity-based cohort of individuals with DM, a nestedcase-control study found that significantly fewer cases(individuals with hepatocellular carcinoma) were pre-scribed statins when compared with controls, suggestinga preventive role for statins in hepatocellular carcinomadevelopment. Although this study was not designed toassess hepatocellular carcinoma prevention in those withNAFLD, its findings may be applicable to those withNAFLD.

Statin hepatotoxicity. Concern for hepatotoxicityassociated with statins has led to reluctance on the partof clinicians to treat dyslipidemia in individuals withNAFLD.60 However, the incidence of statin-inducedhepatotoxicity in those with NAFLD is rare and notgreater than that experienced in the general pop-ulation.61–64 Chalasani et al64 evaluated the incidence ofaminotransferase increases in individuals with baselineincreases in aminotransferases (presumably secondaryto NAFLD) on statins, and individuals with increasedliver enzyme levels who did not receive statins. Whencompared with those with increased liver enzymelevels not receiving statins, individuals with increasedbaseline liver enzyme levels on statins did not have ahigher incidence of either mild-moderate increases(4.7% vs 6.4%; P ¼ .2) or severe increases (0.6% vs0.4%; P ¼ .6). These findings have been replicated in arandomized controlled trial of high-dose pravastatin inindividuals with chronic liver disease, predominantlyfrom NAFLD.65

Omega-3 fatty acids. If additional lipid-loweringtherapy is needed beyond statins, omega-3 fatty acidscan be given safely in individuals with NAFLD. Omega-3fatty acids reduce serum triglyceride levels by reducingvery-low-density lipoprotein secretions from hepato-cytes. Omega-3 fatty acids in doses of 3 to 4 g/d areassociated with a decrease in triglyceride levels (25% to35%) and a small increase in HDL levels (1%–3%).66,67

Early studies have suggested that omega-3 fatty acidsmay improve aminotransferase levels and radiographicsteatosis in individuals with NAFLD and dyslipidemia,and, thus, are attractive for dyslipidemia managementin individuals with NASH.68–70

Fibrates. Fibrates act to lower serum triglyceridelevels while simultaneously increasing HDL levels.Although fibrates reduce CV mortality among individualswith increased triglyceride levels, they do not decreaseCV mortality among individuals with normal triglyceride

levels. Statins carry a risk of muscle toxicity. When sta-tins are taken in combination with fibrates the risk isincreased. This risk can be reduced by using hydrophilicstatins (ie, pravastatin, rosuvastatin, fluvastatin, andatorvastatin), which have less muscle penetration thanhydrophilic statins, when combination therapy withfibrates is needed.71,72

Fenofibrate has been studied in individuals withNAFLD.73 In a trial of 16 individuals with biopsy-provenNAFLD, fenofibrate 200 mg/d for 48 weeks decreasedtriglyceride, glucose, gamma-glutamyl transpeptidase,and alkaline phosphatase levels. In addition, a decreasein hepatocyte ballooning was seen. However, there wasno significant change in steatosis grade, NASH activityscore, lobular inflammation, or fibrosis. However, a sec-ond trial of using clofibrate did not show a change inaminotransferase levels or histology.74 No hepatotoxicitywas reported from fibrates in any of the earlier-described trials. Therefore, although fibrates have notbeen shown to consistently improve NAFLD histologi-cally, they do offer an effective treatment for hyper-triglyceridemia and can be used safely in individualswith NAFLD.

Niacin. Niacin (nicotinic acid) decreases lipids byinhibiting the hepatic production of lipoproteins. Niacindecreases triglyceride levels and is associated withreduced CV mortality.75 However, niacin should be usedwith caution in DM because it can worsen glucoseintolerance. Because glucose intolerance may be asso-ciated with the development and progression ofNAFLD, it should not be the first-line therapy forhypertriglyceridemia.

Lipid treatment goals. LDL targets designed to reduceCVD risk have been established by the NCEP AdultTreatment Panel III. These guidelines provide individu-alized LDL goals based on the assessment of anindividual’s CVD risk factors (Figure 1).

Fatty Liver and Newly ApprovedLipid-Lowering Agents

Statins are effective LDL-lowering agents; however, inan important subset of individuals, statins cannot lowerLDL to goal treatment levels. Therefore, the search formedications to improve LDL lowering is ongoing. Twonew lipid-lowering agents recently were approved.Mipomersen, an anti-sense oligonucleotide, binds toand degrades hepatic apolipoprotein B messengerRNA, decreasing circulating LDL levels. Mipomersenis effective at LDL lowering in individuals with hyper-lipidemia, homozygous familial hypercholesterolemia,and statin intolerance.76–78 However, 11% to 33% ofsubjects receiving mipomersen developed increases inaminotransferase levels greater than 3 times the upperlimit of normal. Of the 14 individuals who developedincreases in aminotransferase levels, steatosis assessedby magnetic resonance spectroscopy was found in 12.

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Two of these individuals underwent liver biopsy. Bothpatients were found to have NASH, 1 patient withoutfibrosis and 1 patient with stage 1 fibrosis. Thesefindings suggest an association between mipomersenuse and fatty liver.

A second mechanism for lipoprotein reduction isthrough microsomal triglyceride transferase proteininhibition. Microsomal triglyceride transferase proteincatalyzes the formation of apolipoprotein-B–containingproteins in the liver. Lomitapide, a microsomal triglyc-eride transferase protein inhibitor, has been shown inindividuals with hypercholesterolemia and homozygousfamilial hypercholesterolemia to lower LDL levels.However, similar to mipomersen, lomitapide is associ-ated with frequent increases in aminotransferase levelsand radiographic steatosis.79,80 As a result, lomitapide isapproved for homozygous familial hypercholesterolemiabut comes with a black box warning for hepatotoxicity.Thus, although mipomersen and lomitapide arebeneficial in decreasing LDL levels, they are associatedwith hepatotoxicity, possible NASH development, andcannot currently be recommended for lipid-loweringtherapy in individuals with NAFLD.

Future Directions

NAFLD is an increasing epidemic in the United Statesand is associated with CV mortality. Many individualswith NAFLD will die of CVD before the development ofend-stage liver disease. Thus, the careful managementof CVD risk factors including dyslipidemia in individualswith NAFLD is essential to reduce CVD-related mortal-ity. Gastroenterologists and hepatologists should playan active role in comprehensive CVD risk assessmentincluding screening for dyslipidemia, DM, the MetS,cigarette smoking, and alcohol use. Management of CVDrisk factors should be grounded in counseling of life-style modification including weight loss, dietarychanges, and increased physical activity. When needed,this should be accompanied by lipid-lowering medica-tion with treatment goals set by the NCEP. Compre-hensive evaluation and aggressive management of CVDrisk factors in individuals with NAFLD could decreaseCVD events and deaths significantly.

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Reprint requestsAddress requests for reprints to: Naga Chalasani, MD, Professor of Medicineand Cellular and Integrative Physiology, Chief, Division of Gastroenterologyand Hepatology, Indiana University School of Medicine, 1050 Wishard Boule-vard, RG 4100, Indianapolis, Indiana 46202. e-mail: nchalasa@iupui.edu;fax: (317) 278-1949.

Conflicts of interestThis author discloses the following: Dr Chalasani has served as a consultant inthe past 12 months to Lilly, Salix, Aegerion, Merck, Abbott, and Mochida in thearea of drug hepatotoxicity. He has also received research grant support fromGilead, Genfit, Takeda, Cumberland Pharmaceuticals, Intercept pharmaceuti-cals, and Enterome. The remaining author discloses no conflicts.

FundingSupported in part by a National Institutes of Health grant (K24 DK069290A toN.C.) and an AASLD Clinical and Translational Research Award (K.E.C.).