Reply to: “Statin hepatotoxicity and the dilemma of causality in rare hepatic adverse drug reactions”
Authors: Ted Bader
Journal: Journal of Hepatology (2012)

Yes! Statins can be given to liver patientsJournal of HepatologyVol. 56Issue 2PreviewStatins are given to 10–20% of adults in developed countries. Statins increase alanine aminotransferase (ALT) concentrations in 10% of patients without liver disease, and this increase can exceed more than three times the upper limit of normal in 1% of such patients. In contrast, we will note that this ALT escalation does not appear to occur when statins are initiated in patients with fatty liver or hepatitis C. Full-Text PDF Open AccessStatin hepatotoxicity and the dilemma of causality in rare hepatic adverse drug reactionsJournal of HepatologyVol. 57Issue 3PreviewIn his editorial, Bader [1] highlights the problems associated with assessing statin-induced hepatotoxicity, a rare hepatic adverse drug reaction (ADR). However, the definitions of hepatotoxicity and idiosyncratic reactions are used by Bader in a confusing way. With the appraisal "Yes! Statins can be given to liver patients" Bader also creates the impression that statins are withheld from patients with liver disease [1]. At least outside the US, however, mainstream physicians including hepatologists never had a problem prescribing statins to their liver patients; uncertainty exists only how to proceed in cases of decompensated liver cirrhosis. Full-Text PDF Open Access It is gratifying that since the publication of my editorial review on statins and the liver (February 2012 issue of the Journal), the USA Food and Drug Administration (FDA) announced on 28 February 2012, a marked relaxation of package insert language on all statins [[1]FDA. Statin drugs – drug safety communication: class labeling change; 2012. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm293670.htm> [accessed 24/4/2012].Google Scholar]. Since pharmaceutical safety boards of many countries closely follow the insert language of the FDA, these revisions will be of interest to a worldwide audience. What was previously a hodge-podge of comments about the liver that differed for each statin, the discussion has been greatly redacted and made uniform. Briefly, the statin labels no longer recommend ALT monitoring after starting a statin. Should acute liver disease develop, the statin should be withheld until the cause is ascertained. This would imply that the patient should be told before treatment about possible signs of drug-induced liver injury and urged to inform the physician if these symptoms occur. The label reminds the reader that an ALT elevation can also occur from muscle injury. These changes represent a seismic shift in policy. The FDA clearly agrees that an elevated ALT after initiating a statin is not a sign of hepatotoxicity. Instead, the shift in monitoring for symptoms follows the same successful approach as for isoniazid monitoring. I have advocated these changes for some time [2Bader T. The myth of statin-induced hepatotoxicity.Am J Gastroenterol. 2010; 105: 978-980Crossref PubMed Scopus (66) Google Scholar, 3Bader T. Liver tests are irrelevant when prescribing statins.Lancet. 2010; 376: 1882-1883Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 4Bader T. Yes! Statins can be given to liver patients.J Hepatol. 2012; 56: 305-307Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Still, the labels advise that liver tests be checked prior to initiating a statin, and that statins should not be given to patients with "active liver disease." The phrase "active liver disease" is not defined on the label nor anywhere else I am aware of. The correspondents and I both agree that statins can be given to patients with chronic liver disease. There is reasonable disagreement over use in decompensated liver patients simply due to a lack of data. However, data are starting to appear. In Spain, Abraldes et al. gave 40 mg of simvastatin or placebo to 60 cirrhotics with portal hypertension (proved by WHVP) in a randomized controlled fashion over 30 days. The intervention group experienced a significant decrease in portal hypertension that was additive to the effects of propranolol. Moreover, liver tests increased more often with placebo than simvastatin [[5]Abraldes J.G. Albillos A. Bañares R. Turnes J. González R. García-Pagán J.C. et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.Gastroenterology. 2009; 136: 1651-1658Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar]. The correspondents generalize, without support, that non-USA physicians have no trouble giving statins to patients with liver disease. In the editorial, I cite an international HCV treatment study where the majority of authors are not from the USA [[6]Bacon B.R. Gordon S.C. Lawitz E. Marcellin P. Vierling J.M. Zeuzem S. et al.Boceprevir for previously treated chronic HCV genotype 1 infection.NEngl J Med. 2011; 364: 1207-1217Crossref PubMed Scopus (1513) Google Scholar]. Only 3% of the 403 patients were on statins; whereas, given the customary age range for participants in HCV studies, one would expect 30% or more of these latter study patients to need a statin. These data would seem to indicate a bias by hepatologists worldwide not to give statins to patients who have at least hepatitis C disease. The problem the correspondents fail to apprehend with RUCAM methodology is its extremely low positive predictive value (PPV). With RUCAM, the probability of a statin being correctly identified as the "true" cause of idiopathic test abnormalities is less than 1% [[4]Bader T. Yes! Statins can be given to liver patients.J Hepatol. 2012; 56: 305-307Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. That is, if the RUCAM determines the statin is the culprit, 99 out of a 100 times it is wrong. Not the type of certainty one would want in a court of law, for example. While this level of uncertainty may be sufficient to withdraw a drug from a patient, it is not compelling enough to conclude scientifically that statins cause idiosyncratic reactions. Thus, there remains legitimate doubt as to whether statins are responsible for rare instances of idiosyncrasy. All of the cases presented by Bjornsson et al. could easily be counted as background noise [[7]Bjornsson E. Jacobsen E. Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing.J Hepatol. 2012; 56: 374-380Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Nevertheless, until we become more scientific and settle the issue with proteomics and microarray testing, we are stuck with clinical opinion; the variations of RUCAM represent only attempts to score clinical judgment with numbers. The terminology for the subject is critical otherwise the reader will confuse what the message of statin mythology has been all about. The letter writers use the term "hepatotoxicity" both as a general term, and for predictable dose-dependent reactions. I believe universal practice is to now use "DILI" or "drug-induced liver injury" as a general term, and restrict hepatotoxicity to the predictable, dose-dependent setting [[8]Schiff E.R. Sorrell M. Maddrey W. Schiff's diseases of the liver. Lipincott, Philadelphia, London2003Google Scholar]. The remaining concerns of the correspondents have become moot since the revisions of 28 February 2012 by the FDA. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.