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  7th International Workshop
on HIV and Aging
September 26-27, 2016
Washington, DC
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An assessment by the Statin Liver Safety Task Force: 2014 update
  Download the PDF here
Provider recommendations to patients
It is not uncommon to find media, Internet, and book-promoting sources that warn against the use of statins because of concerns of liver toxicity (among other reported reasons). It is true that statins may potentially cause very rare hepatic adverse experiences. However, these extremely rare occurrences should not detract from the potential benefit of proven reduction in CHD risk, which has far greater health implications than the possibility of serious liver injury. The objective evidence strongly suggests that for patients at risk for CHD, the risks of not taking the statin outweigh the risks of taking the statin. Patients should appreciate that based on data from objective, large-scale clinical trials, statins are not only remarkably safe, but, most of all, statins reduce the chances of CHD events, including myocardial infarction (heart attack), stroke, and revascularization procedures among patients with and without manifest vascular disease. Statins have been shown to reduce deaths from these diseases.21, 22
⋅In statin-treated patients, an increase in liver enzymes may be due to different etiologies, which the clinician should consider before assuming the increase in liver enzymes is due to the statin.
⋅Mild to modest increases in liver enzymes are not necessarily a contraindication to either initiation or continued use of statins, especially if the clinical presentation and subsequent assessment suggests non-alcoholic fatty liver disease as the reason for the liver enzyme elevation.
⋅Patients with elevated liver enzymes are best evaluated using an organized, systematic approach (such as the recommended algorithms in this publication), whether found before initiation of statin therapy, or discovered while treated with statin therapy.
In the 2006 Report of the National Lipid Association's Statin Safety Task Force, a panel of experts in hepatology published their findings on specific questions related to the liver blood testing during statin therapy. Among their recommendations was that regulatory agencies reconsider the statin-labeling recommendation at that time, which required post-statin liver enzyme testing. Since then, the Food and Drug Administration altered statin labeling such that unless clinically indicated for other reasons, after a pre-statin therapy baseline evaluation, follow-up liver enzyme testing was not uniformly required after statin initiation. This 2014 report provides an update on interim issues relevant to statins and liver safety. Some of the points discussed include the value of baseline liver enzymes before initiating statin therapy, safety of statin use in patients with nonalcoholic fatty liver disease, potential drug interactions between statins and drugs used to treat hepatitis, the use of statins in liver transplant recipients, and the use of statins in patients with autoimmune liver disease. Finally, this panel provides diagnostic and algorithmic approaches when evaluating statin-treated patients who experience elevations in liver enzymes.
Because of the frequency of routine blood testing of a "panel" of various laboratory parameters, elevated liver enzymes are commonplace in the day-to-day management of patients. The challenge to clinicians is to have a reasonable and effective approach toward diagnosing various etiologies of elevated liver enzymes, and then to determine their clinical meaning in making treatment decisions. Although many clinicians recognize that mild-to-moderate elevations in liver enzymes may not always represent hepatotoxicity, other clinicians may have concerns that any elevation in liver enzymes might represent harm to patients.
In the clinical development and use of pharmaceuticals, relatively common early safety signals that prevent further development or withdrawal of a drug after approval include prolongation of the QT interval on electrocardiogram. Hepatotoxicity is also among the most common causes of discontinuation of drug development or drug withdrawal from the market (both early and late).4 Although mainly used in drug development, an illustrative metric that may be conceptually useful for clinicians is Hy's Law (Table 1).5 Hy's law is a term often used by regulatory agencies to assign high risk for significant liver injury in patients with persistent and substantial alanine aminotransferase (ALT) elevations (greater or equal to 3 times the upper limits of normal [ULN] in the presence of hyperbilirubinemia [more than 2 times the ULN]) without elevated alkaline phosphatase and without other causes of liver injury. In the 1970s, Hyman Zimmerman described how drug-induced liver injury (DILI) was associated with a high rate (10% to 50%) of mortality caused by acute liver failure in the pretransplantation era. For every 10 patients meeting the Hy's law, it was estimated that 1 patient would progress to acute liver failure, and for every 10 patients who experience ALT >5 to >10 times the ULN, it was estimated that 1 patient would meet Hy's law. Because Hy's law cases are thought to represent hepatocellular injury sufficient to impair bilirubin excretion, only a few cases are needed to suggest to regulatory agencies (eg, the US Food and Drug Administration [FDA]) that the drug is likely to cause severe, if not fatal, DILI. The occurrence of Hy's law cases in a drug development program almost invariably results in cessation of drug development.4
able 1Hy's law criteria must meet each of the following
⋅Elevations in alanine or aspartate aminotransferase ≥3 times the upper limit of normal
⋅Increases in total bilirubin >2 times the upper limit of normal
⋅No other demonstrable cause, such as cholestasis (as might be suggested by an increase in alkaline phosphatase); viral hepatitis A, B, or C; preexisting or acute hepatobiliary disease; or another drug capable of causing the observed injury (see Table 3)
But although the profile defining Hy's law is potentially concerning for DILI, mild to moderate elevations in liver enzymes alone (ie, without an increase in bilirubin) may not always reflect a true "toxicity" because increases in hepatic aminotransferases are not technically abnormal "liver function tests." Elevations in hepatic transaminases represent a release of enzymes from hepatocytes and are not a specific finding related to liver function. More accurate assessments of "liver function" would include albumin, prothrombin time, and perhaps direct bilirubin. This distinction is important because elevations in ALT and/or aspartate aminotransferase (AST) alone may not be of clinical significance. Conversely, elevations in ALT and/or AST associated with elevated bilirubin levels may suggest clinically significant acute liver injury (with the caveat that elevated blirubin levels can sometimes be due to benign causes of hyperbilirubinemia, such as Gilbert's syndrome).
Mild-to-moderate elevations in liver transaminases, with no increase in bilirubin levels may reflect liver inflammation (eg, hepatitis). It is also possible these findings are reflective of a noninflammatory hepatic steatosis (as opposed to an inflammatory steatohepatitis). These are histiological diagnoses. An increase in liver enzymes with statin therapy has no specific hepatic histiopathologic findings, as is true with other potential etiologies such as celiac disease. Hence, whether it is an increase in liver enzymes before statin therapy or an increase in liver enzymes while being treated with statin therapy, patients benefit when clinicians have a logical diagnostic plan in place to determine the cause and clinical implications of elevated liver enzymes.


2014 Questions
⋅1.Have any unexpected safety concerns arisen since the regulatory recommendation that liver enzymes need not be measured after initiating statin therapy?
EXPLANATION: The initial 2006 National Lipid Association Statin Safety Task Force Expert Liver Panel recommended that routine liver enzyme testing not be required.6 Subsequently, in 2012, the FDA issued a communication regarding "Important safety label changes to cholesterol-lowering statin drugs," wherein they stated7:
"Labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. The labels now recommend that liver enzyme tests should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury."7
This decision was based on the FDA's comprehensive review of the statin class of drugs. In its description of the Data Summary, the FDA stated:7
"FDA reviewed current monitoring guidelines, including the National Lipid Association's Liver Expert Panel and Statin Safety Task Force recommendations. The Liver Expert Panel stated that the available scientific evidence does not support the routine monitoring of liver biochemistries in asymptomatic patients receiving statins. The Panel made this recommendation because (1) irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic in nature, and (2) no data exist to show that routine periodic monitoring of liver biochemistries is effective in identifying the very rare individual who may develop significant liver injury from ongoing statin therapy. The Panel believed that routine periodic monitoring will instead identify patients with isolated increased aminotransferase levels, which could motivate physicians to alter or discontinue statin therapy, thereby placing patients at increased risk for cardiovascular events.1 The National Lipid Association's Statin Task Force also stated that routine monitoring of liver function tests is not supported by the available evidence."
"FDA reviewed post-marketing data to evaluate the risk of clinically serious hepatotoxicity associated with statins. FDA had conducted several post-marketing reviews of statins and hepatotoxicity between years 2000 and 2009 by searching the Agency's Adverse Event Reporting System (AERS) database. Those reviews consistently noted that reporting of statin-associated serious liver injury to the AERS database was extremely low (reporting rate of ≤2 per one million patient-years). FDA's updated review focused on cases of severe liver injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury Network (DILIN) liver injury severity scale, which were reported to AERS from marketing of each statin through 2009. Cases meeting those criteria were further assessed for causality. Seventy-five cases (27 cases with a severity score of 4, and 48 cases with a severity score of 5 (37 deaths and 11 liver transplants) were assessed for causality. Thirty of the 75 cases (14 deaths, 7 liver transplantations, and 9 severe liver injury) were assessed as possibly or probably associated with statin therapy. No cases were assessed as highly likely or definitely associated with statin therapy. FDA concluded that, despite a rising use of statins as a class since the late 1990s, there has not been a detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use."
"FDA also reviewed cases from the DILIN and Acute Liver Failure Study Group (ALFSG), organizations that have been submitting reports to FDA of drug-associated liver injury in their liver injury outcome studies. As of January 1, 2011, DILIN had submitted 25 reports of statin-associated liver injury to FDA, 12 of which gave hospitalization as an outcome. A 2010 article from ALFSG included 133 prospectively identified cases of idiopathic drug-induced liver injury resulting in acute liver failure.3 Of these 133 patients, 15 were taking statins, and in six of these 15 individuals a statin was identified as the only potential drug to cause drug-induced liver injury."
"Based on all available data, FDA has determined that all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury in association with statins."7
Data since the this FDA position continue to support a favorable benefit:risk ratio with a strategy of obtaining liver enzymes at baseline and then as clinically indicated afterwards. Data published since 2006 continue to demonstrate that the risk of statin-promoted liver failure is very rare.8
⋅2. Should baseline liver enzymes be obtained before initiating statin therapy?
EXPLANATION: The current prescribing information of statins generally state: "Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter."9 As noted previously, no clinical trial data support a favorable benefit:risk ratio for liver enzyme testing performed after baseline values in statin-treated patients, unless clinically indicated. With regard to obtaining liver enzyme testing before initiating statin therapy, no randomized clinical trial evidence is available to support or refute obtaining liver enzyme testing at baseline. Therefore, a natural question may be: Why get them? Routine liver enzyme screening in the general population is not generally recommended. Obtaining liver enzyme testing requires the procedure of phlebotomy (which is a procedure not without risk). Obtaining liver enzyme testing in asymptomatic patients may also increase cost and, if abnormalities are found, may (sometimes) result in unnecessary liver testing and even potential liver biopsies. Finally, obtaining baseline liver enzyme testing may enhance the patient's fear of liver damage (especially when recommended in direct-to-consumer advertisements), which may adversely affect statin compliance.
Nonetheless, it is the consensus of this liver expert panel that obtaining baseline liver enzymes is optimal in the care of statin-treated patients. First, in many locations of clinical practice, liver enzymes are included in a battery of generalized blood testing when evaluating patients (which may also include glucose, electrolytes, and kidney blood testing) with no or minimal additional cost. Second, should future liver enzymes (or glucose levels) be found to be abnormal in a statin-treated patient, it may be useful to have a baseline value to compare. Finally, patients in need of statin therapy are typically those at risk for atherosclerotic coronary heart disease (CHD). Often such risks are in the form of increased body fat (adiposity), especially with dysfunctional fat (adiposopathy), diabetes mellitus, and metabolic syndrome-each that may contribute to or be associated with fatty liver (Table 3).
⋅3. Are statins safe to use in patients with nonalcoholic fatty liver disease?
EXPLANATION: The 2006 National Lipid Association Statin Safety Task Force indicated that although decompensated cirrhosis or acute liver failure was a contraindication for statin use, other chronic liver diseases (presumably including uncomplicated chronic hepatitis B and C) and compensated cirrhosis were not contraindications for statin use. The current question expands upon this topic by specifically addressing nonalcoholic fatty liver disease (NAFLD), which is the most common cause of chronic liver disease in Western nations, especially among patients with adiposopathy (dysfunctional adipose tissue) and dyslipidemia.10, 11, 12 The challenge is that it is difficult to clinically distinguish between the subset of NAFLD patients with the more benign nonalcoholic fatty liver (hepatic steatosis), and the more serious nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and liver cancer.11 In other words, the distinction between hepatic steatosis and NASH is a histopathologic one. Although some published data support that statins may improve hepatic steatosis,13, 14, 15, 16 little data exist to support statins as an effective treatment for steatohepatitis. The totality of evidence suggests that, at a minimum, statin therapy can be used safely in dyslipidemic individuals with NAFLD and that weight loss in overweight or obese patients is often an effective treatment modality in NAFLD.
⋅4. Do statins have drug interactions with medications used to treat infections (hepatitis B, C, etc.) that require change in statin, change in statin dosing, or change in antiviral regimen dosing?
STRENGTH OF RECOMMENDATION: A (strong) (depending on the medication used).
EXPLANATION: Examples of drugs used to treat infectious hepatitis C include interferons (eg, pegylated interferon), nucleoside/nucleotide analogues (eg, ribavirin), protease inhibitors (eg, boceprevir, telaprevir, and simeprevir), and nucleotide analogue inhibitors (eg, sofosbuvir). This is an evolving therapeutic area, with the potential that agents such as boceprevir and telaprevir will be less prescribed (at least in the United States) in the near future. With regard to hepatitis B, examples of therapeutic agents include interferon-alpha, pegylated interferon-alpha, entecavir, tenofovir, and sometimes adefovir, lamivudine and telbivudine. Even without specific mention in drug labeling, clinicians should be aware of potential drug interactions with statins, as might be applicable via similar cytochrome P450 metabolism of these agents and statins. If a drug interaction is possible, then consideration should be given to change the statin to one without a potential drug interaction or to limit the statin to lower doses.
⋅5. Can statins safely be used in liver transplant recipients?
EXPLANATION: Cardiovascular complications are common among patients undergoing liver transplantation, with an increase in NASH being an additional cardiovascular risk factor beyond other more traditional cardiovascular risk factors.17 No cardiovascular outcome study exists to support reduction in cardiovascular events with statin therapy in this patient population. Nonetheless, it seems appropriate to consider the use of statin therapy in clinically appropriate liver transplant recipients having a reasonable mid- to long-term prognosis.
⋅6. Can statins safely be used in patients with autoimmune hepatitis?
EXPLANATION: The published data report rare cases of statin-induced autoimmune hepatotoxicity.18, 19, 20 Although these few case reports of suspected statin-induced autoimmune hepatitis exist, no conclusive findings have yet suggested an "at-risk" patient population or provided a potential mechanism of action. Given the sporadic nature of this association, the very rare cases of autoimmune hepatotoxicity occurring in statin treated patients are likely to be idiosyncratic associations. However, a more common clinical challenge is the patient having both a systemic autoimmune disease (eg, rheumatoid arthritis, multiple sclerosis, antiphospholipid syndrome, systemic lupus erythematosus) along with hypercholesterolemia, but with or without autoimmune liver disease. Little to no evidence exists that statins are unsafe when administered to patients with (non-statin) autoimmune liver disease, as long as the autoimmune liver disease is not associated with substantial liver dysfunction or damage. If autoimmune diseases are to be treated with pharmacotherapy, then drugs potentially used to treat such disorders should be investigated for potential interactions regarding the catabolism and excretion of statins.
Recommendations from the 2014 Statin Liver Safety Task Force
Recommendations to clinicians

Table 1 provides clinicians a summary of Hy's law, which represents the constellation of liver blood abnormalities with the highest potential for liver toxicity (eg, DILI). Table 2 provides a summary of recommendations made by the 2006 and 2014 Liver Safety Panels. Table 3 provides clinicians an "at-a-glance" summary of illustrative diagnoses for the patient with elevated liver enzymes, with or without statin use. The intended utility of Table 3 is to emphasize that when a statin-treated patient experiences elevated liver enzymes, the first inclination should not be to assume the elevated liver enzymes are due to the statin. Rather, onset of increased liver enzymes should prompt the clinician to engage in a careful and systematic evaluation (history and physical examination), with a consideration of all potential etiologies.
Figures 1 and 2 represent algorithmic approaches to statin considerations in the patient with elevated liver enzyme blood testing. Mild-to-modest elevations in liver enzymes (<3 times the ULN), are very common in clinical practice. As such, perhaps the 2 most important diagnostic approaches include repeating the values for confirmation and the use of sound clinical judgment. As noted in Figure 1, if the clinical presentation is most likely NAFLD, then the next step is usually lifestyle interventions (eg, appropriate nutrition and physical activity, management of potential secondary causes). Clearly, for the majority of patients with mild elevations in liver enzymes, investments in a large battery of diagnostic procedures (specialized blood testing, imaging studies, biopsies) are best reserved for situations wherein other causes are suspected (Table 3), the presentation is atypical, or if the patient does not respond as anticipated. Especially for the nonspecialist in hepatology, these algorithms may provide a reasonably cost-effective approach. If these algorithms were followed before referral to a liver specialist, then this panel believes it is less likely that the patient with elevated liver enzymes would require additional testing by the liver specialist before diagnostic decisions, implementation of therapy, or recommendation for more unique or invasive procedures (such as specialized imaging procedures or liver biopsy). Conversely, a lack of such a diagnostic workup may result in the liver specialist spending the first patient encounter ordering these same tests, with a request that the patient return at a later date for an additional medical evaluation. Streamlining the diagnostic process may allow for earlier diagnosis and treatment of patients with elevated liver enzymes and may perhaps avoid prolonged discontinuance of medical therapies, such as statins.
Provider recommendations to patients
It is not uncommon to find media, Internet, and book-promoting sources that warn against the use of statins because of concerns of liver toxicity (among other reported reasons). It is true that statins may potentially cause very rare hepatic adverse experiences. However, these extremely rare occurrences should not detract from the potential benefit of proven reduction in CHD risk, which has far greater health implications than the possibility of serious liver injury. The objective evidence strongly suggests that for patients at risk for CHD, the risks of not taking the statin outweigh the risks of taking the statin. Patients should appreciate that based on data from objective, large-scale clinical trials, statins are not only remarkably safe, but, most of all, statins reduce the chances of CHD events, including myocardial infarction (heart attack), stroke, and revascularization procedures among patients with and without manifest vascular disease. Statins have been shown to reduce deaths from these diseases.21, 22