LIVER FUNCTION TESTS AND STATINS

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1 LIVER FUNCTION TESTS AND STATINS Philippe J. Zamor and Mark W. Russo Current Opinion in Cardiology 2011,26:

2 SUMMARY Purpose of review: To discuss recent data on statins in patients with elevated liver tests. Recent findings: As a result of the obesity epidemic in Western societies, conditions associated with metabolic syndrome are increasing NAFLD. Because most patients with metabolic syndrome have indications for statins, clinicians will be confronted with prescribing statins to patients with elevated liver tests. Statins are associated with elevations in aminotransferases in up to 3% of treated patients, but statins rarely lead to serious DILI, chronic liver disease, or acute liver failure. Data have emerged demonstrating that not only are statins well tolerated to use in most patients with elevated liver tests but also they may have a beneficial therapeutic effect in treating the underlying liver disease. Studies demonstrate that statins may increase response rates of antiviral therapy for hepatitis C. In a study of 437 patients with moderate elevations in baseline aminotransferases, patients on statins were more likely to have a decline in aminotransferases compared with untreated patients. Summary: Data support using statins in patients with elevated liver tests, especially patients with NAFLD, who may be at particularly high risk for cardiovascular disease.

3 Introduction Statins are among the most widely prescribed classes of medications, with > 130 million written in the USA in Obesity epidemic Hyperlipidemia & use of statins NAFLD: The most common cause of abnormal LFT in the western world. Have higher all-cause mortality than the general population. Frequently have other conditions associated with metabolic syndrome, including DM risk for cardiovascular disease. Diabetic + NAFLD High risk for cardiovascular disease and benefit from statins More likely to have elevated aminotransferases from NAFLD.

4 Introduction NAFLD + hyperlipidemia and other indications for lipidlowering therapy, clinicians are often faced with a perceived dilemma: Prescription of statins if the patient has elevated liver tests. The assumption that patients with underlying liver disease and elevated liver tests are predisposed to DILI may leave clinicians reluctant to prescribe statins when otherwise indicated. This review will focus on DILI associated with statins in patients with chronic liver disease. Data are compelling that not only are statins well tolerated to use in patients with chronic liver disease, but also in some types of chronic liver disease statins may have a beneficial effect on the underlying liver disease

5 Statins and drug-induced liver injury Aminotransferase elevations up to 3xULN Severe DILI is rare. The mechanism of DILI is not fully understood in rats given supratherapeutic doses of simvastatin (125 mg/kg / day) a suggested mechanism of toxicity is inhibition of the HMG-CoA reductase and mevalonate synthesis.

6 Serious DILI Jaundice (total BIL> 2xULN) after aminotransferase elevations. Hepatocellular jaundice from a drug had a 10% fatality rate. Severe DILI from statins are case reports or case series. In a systematic review of the literature, 40 cases of DILI from statins were identified among 26 Articles. The most common dose was 20mg daily, and time from initiation of therapy to DILI ranged from 1 week to 48 months. There were two cases of death, in which DILI from statins may have played a role.

7 Serious DILI Patterns of DILI of statins: Hepatocellular (The most common pattern) Cholestatic (can be seen) Mimicking autoimmune liver disease with the presence of autoantibodies, such as ANA. A retrospective study of the United Network for Organ Sharing (UNOS) database: Among patients who underwent liver transplant between in the United States, three cases were identified as having liver transplant for acute liver failure from statins. Two related to the use of cerivastatin, which has been subsequently withdrawn from the market (not for hepatotoxicity) One related to the use of simvastatin. These studies were retrospective analyses, and formal causality assessment of DILI and confirmation that cases were bona-fide cases of DILI from statins were not performed.

8 Serious DILI DILIN: Severe DILI is the focus of the DILI Network (DILIN), a multicenter prospective study of severe DILI from drugs other than acetaminophen. DILIN prospectively evaluates cases with formal causality assessment by expert hepatologists. Severe DILI: Aminotransferases > 5xULN or ALP > 2xULN or Total BIL >2.5 mg/dl associated with elevations in aminotransferases. Among 300 cases included in DILIN, 6 cases of statins were implicated as the single causative agent and in 5 cases statins were among multiple drugs implicated as a cause of DILI. Spanish Registry : Support that severe DILI from statins is rare. Given the vast number of prescriptions written for statins and the relatively small number of cases of DILI reported in these studies, severe DILI from statins appears to be an exceedingly rare event.

9 Statins and chronic liver disease NAFLD: The most common cause of abnormal LFT in the western world Present in up to 33% of American and European populations. The rise of NAFLD mirrors the obesity epidemic and overlaps with metabolic syndrome and DM. The spectrum of NAFLD: Hepatic steatosis only (not associated with significant progression of liver disease) Portal inflammation, sinusoidal fibrosis, and ballooning hepatocytes containing Mallory s hyaline (similar to alcoholic liver disease). Cirrhosis : Ballooning hepatocytes and fibrosis risk for cirrhosis. Cirrhosis and its complications (ascites, varices, and HCC) Risk for cardiovascular disease (particularly + DM). 69% higher all-cause mortality than the general population, (mainly due to cardiovascular disease.) Thus, NAFLD derive a significant clinical benefit from statin therapy.

10 Recent studies A recent post-hoc analysis of the Greek Atorvastatin and CHD Evaluation (GREACE) study : Atorvastatin in NAFLD + CAD cardiovascular events Elevated baseline aminotransferases 68% relative risk reduction of cardiovascular events in those who received a statin: 3.2 events per 100 patient years (statin group) versus 10.0 (nonstatin group), P= Reduction from baseline ALT, AST, and GGT in the statin group: 35, 47, and 46%, respectively. 10 patients on statins had ALT or AST levels > 3times the ULN 3 cases Normal with statin dose reduction from 80 40mg, suggesting a dose response relationship. 7 cases withdrew from the study due to DILI attributed to statin use, but there was no evidence of cholestatic (rise in BIL and/or ALP) liver injury None of the liver test elevations led to liver biopsy. Aminotransferases not exceed 3times the ULN in the GREACEstudy so the results may not be generalizable to patients with higher elevations in aminotransferases.

11 Recent studies Further evidence of the safety and efficacy of statins in patients with chronic liver disease was demonstrated in a RCT of pravastatin versus placebo. In a prospective double-blind study of 326 patients randomized to placebo or pravastatin 80mg daily, investigators examined the efficacy and safety of pravastatin in patients with well compensated liver disease. The cause of liver disease was NAFLD and HCV in 64 and 23% of patients, respectively. Fewer patients in the pravastatin group had elevations in ALT compared with the placebo group, 7.5 and 12.5%, respectively (P=0.13). No patient had to discontinue pravastatin due to elevations in liver tests. Pravastatin was effective in lowering total cholesterol and LDL with 16 and 25% reductions by week 36 of therapy.

12 Recent studies In a separate study of 68 patients with NAFLD, initiated statins reduction in the amount of steatosis in the statin group on serial liver biopsies: Statin group: 20% steatosis on baseline liver biopsy compared with 11% on follow-up liver biopsy, P= No statins group: not significant reduction in steatosis between baseline and follow-up liver biopsies. 24% of in the statin cohort had hepatic fibrosis progression compared with 45% in the no statin group. Noninvasive modalities that measure fat content in the liver, such as MRI with magnetic resonance spectroscopy, may facilitate future studies of the association between statins and hepatic steatosis.

13 Statins inhibit HCV replication and improve treatment response rates Sustained viral response undetectable HCV RNA in the serum 6 months after completion of antiviral therapy and considered a cure. In-vitro evidence : statins have antiviral properties against HCV by inhibiting HCV replication. (by disrupting host protein geranylgeranylation) Statin + PEG-IFN and ribavirin SVR rates SVR = 53% (statins + antiviral therapy ) SVR= 39% (antiviral only) P < Rao and Pandya analyzed data from the Veterans Affairs medical system Statin + Diabetic HCV patients Statistically significantly improved outcomes. On multivariate analysis 1.5 times more likely to have a SVR [OR 1.52 (95% CI ), P=0.0124] despite having higher viral loads, a negative predictor of response to therapy.

14 Table 1- Recent studies demonstrating safety and/or beneficial effect of statins in patients with chronic liver disease Study Purpose Statin Findings Athyros et al. [8] Rao and Pandya [9] Henderso n et al. [10] Hippisley- Cox and Coupland [11] Post-hoc analysis of 437 patients with elevated baseline liver tests enrolled in a randomized trial of atorvastatin Retrospective study VA database to evaluate HCV response rates in patients on statins Retrospective single center study of effect of statins on ALT in HCV patients Retrospective analysis of new statin users from large databases from England and Wales Mostly atorvastatin, simvastatin, pravastatin, fluvastatin Simvastatin (89%) Simvastatin, lovastatin SimvastatinA torvastatin, pravastatin, rosuvastatin fluvastatin Significant reduction in cardiovascular events in statin group versus no statin group, 10 versus 30%, P<0.0001, 35% reduction in ALT in statin group versus 12% increase in no statin group Diabetic patients on statins were 1.5 times more likely to have treatment response to antiviral therapy for hepatitis C, P= Although statin group had ALT 1.4 times higher than nonstatin group,65% had decline in ALT compared with 58% in no statin group ALT>120 IU/l was more commonly seen among smokers, DM, RA, corticosteroid users. Severe DILI not reported

15 Statin in cirrhosis Statins portal HTN and HCC. A double-blind RCT of simvastatin versus placebo: Simvastatin significantly decreased hepatic venous pressure gradient by a mean of 89.3% in cirrhosis. (independent of beta blocker use.) Because this was a proof-of concept study, it was not designed to assess overall liver mortality data. Simvastatin improved liver perfusion(assessed by measurement of hepatic wedged pressure and free hepatic venous measurements) There was no increase in statin-related hepatotoxicity in the treatment group as compared with the placebo group. Statin in cirrhosis Portal HTN morbidity and mortality from variceal hemorrhage

16 Statin and HCC HCC has been increasing in incidence worldwide, especially in patients with cirrhosis. A matched case control study: Nested within a cohort of diabetic patients A significant reduction in the incidence of HCC was seen in the group of patients who used statins versus in those who were not on statin therapy. Although there is not enough evidence to support the use of statins to prevent HCC, this large trial highlights the potential role of statins in cancer chemoprevention.

17 When statins should be avoided Avoided in : Acute viral hepatitis (such as acute hepatitis A and B) Autoimmune hepatitis flares If statins are indicated they should be initiated after resolution of the acute infection or control and remission of the underlying autoimmune disease. Alcoholic hepatitis, who may experience profound elevations in total bilirubin. Statins in cirrhosis: may require lower doses because may have greater exposure to the drug. Typically, advanced cirrhotics develop low cholesterol as their liver disease progresses.

18 Conclusion Statins were once thought to be contraindicated in patients with chronic liver disease but are now recommended. Given the overlap between chronic liver disease and cardiovascular risk factors, the indication for lipid-lowering therapy often arises. There is a lack of data to support serial monitoring of liver tests while on statin therapy, but typically patients with chronic liver disease have liver test monitoring for their underlying liver condition. Elevations in serum transaminases up to 3times the ULN or baseline are acceptable. Elevations in BIL> 2mg/dl may indicate potential severe liver dysfunction and should prompt the clinician to discontinue the statin. Recommend starting statins at lower doses, and titrating to the desired dose. Concomitant use of other medications that are metabolized by the CYP3A4 system should be prescribed cautiously. As the adage states, the benefits of statins clearly outweigh the risks in patients with chronic liver disease.

19 Key points Baseline liver tests should be obtained in patients with known chronic liver disease or risk factors for NAFLD before starting a statin. Statins are well tolerated to use in patients with elevations in aminotransferases. Statins may lower aminotransferases and improve liver histology in patients with NAFLD and may improve response rates to antiviral therapy for hepatitis C. Patients with acute hepatitis, alcoholic hepatitis, or decompensated cirrhosis may not be candidates for statins until the active condition resolves.

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