An assessment by the Statin Liver Safety Task Force: 2014 update

      Highlights

      • 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.

      Abstract

      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.

      Keywords

      Tabled 1Evidence grading: Strength of recommendation
      The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines1 and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.2
      GradeStrength of recommendation
      AStrong recommendation

      There is high certainty based on the evidence that the net benefit
      Net benefit is defined as benefits minus risks/harms of the service/intervention.
      is substantial
      BModerate recommendation

      There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate
      CWeak recommendation

      There is at least moderate certainty based on the evidence that there is a small net benefit
      DRecommend against

      There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits
      EExpert opinion

      There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends
      NNo recommendation for or against

      There is insufficient evidence or evidence is unclear or conflicting
      The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines
      • Stone N.J.
      • Robinson J.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].
      and adapted from the original Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence rating.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ∗∗ Net benefit is defined as benefits minus risks/harms of the service/intervention.
      Tabled 1Evidence grading: Quality of evidence
      Permission to reuse table granted from the American Medical Association.
      Type of evidenceQuality rating
      The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement.
      Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomesHigh
      Well-conducted meta-analyses of such studies
      Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect
      RCTs with minor limitations affecting confidence in, or applicability of, the resultsModerate
      Well-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studies
      Well-conducted meta-analyses of such studies
      Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate
      RCTs with major limitationsLow
      Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results
      Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports)
      Physiological studies in humans
      Meta-analyses of such studies
      Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate.
      RCT, randomized controlled trial.
      This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines
      • Stone N.J.
      • Robinson J.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].
      that were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint National Committee.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members Appointed to the Eighth Joint National Committee (JNC 8).
      Taken from James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2013 Dec 18. http://dx.doi.org/10.1001/jama.2013.284427 [Epub ahead of print].
      The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement.
      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).
      • Stein E.A.
      • Bays H.
      • O'Brien D.
      • Pedicano J.
      • Piper E.
      • Spezzi A.
      Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia.
      Although mainly used in drug development, an illustrative metric that may be conceptually useful for clinicians is Hy's Law (Table 1).

      US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation 2009. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf. Accessed March 14, 2014.

      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.
      • Stein E.A.
      • Bays H.
      • O'Brien D.
      • Pedicano J.
      • Piper E.
      • Spezzi A.
      Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia.
      Table 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.

      Update on 2006 Statin Safety Task Force report questions

      Statins are the most common drugs used in treatment of hypercholesterolemia and among the most commonly used pharmaceuticals in clinical practice. As acknowledged by the hepatologist experts in the 2006 National Lipid Association Statin Safety Task Force Report, statins can increase liver-associated enzymes.
      • Cohen D.E.
      • Anania F.A.
      • Chalasani N.
      National Lipid Association Statin Safety Task Force Liver Expert Panel
      An assessment of statin safety by hepatologists.
      Table 2 lists the questions and answers addressed by these hepatology experts in 2006 as well as the list of questions and answers from this 2014 Task Force. The following are six follow-up questions addressed by the current 2014 expert panel.
      Table 2Questions addressed by liver experts in the 2006 and 2014 National Lipid Association Statin Safety Task Force Report
      • Cohen D.E.
      • Anania F.A.
      • Chalasani N.
      National Lipid Association Statin Safety Task Force Liver Expert Panel
      An assessment of statin safety by hepatologists.
      2006 National Lipid Association Statin Safety Task Force QuestionsAnswer
      Are elevations in serum aminotransferase levels associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, or statin, therapy?Yes
      Are statin-associated elevations in aminotransferase levels indicative of liver damage or dysfunction?No
      Are statin-associated elevations in aminotransferases a class effect?Yes
      Does statin therapy increase the incidence of liver failure, liver transplants, or death associated with liver failure in the general population?Yes
      Should liver enzymes and liver function tests be monitored in patients receiving long-term statin therapy?No
      Are any of the following conditions a contraindication for statin therapy?
      • Chronic liver disease
      No
      • Compensated cirrhosis
      No
      • Decompensated cirrhosis or acute liver failure
      Yes
      Can statins be used in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis?Yes
      2014 National Lipid Association Statin Safety Task Force Questions
      Have any unexpected safety concerns arisen since the regulatory recommendation that liver enzymes need not be measured after initiating statin therapy?No
      Should baseline liver enzymes be obtained before initiating statin therapy?Yes
      Are statins safe to use in patients with nonalcoholic fatty liver disease?Yes
      Do statins have drug interactions with medications used to treat infections (eg, hepatitis B, C) that require change in statin, change in statin dosing, or change in antiviral regimen dosing?Yes
      Can statins safely be used in liver transplant recipients?Yes
      Can statins safely be used in patients with autoimmune hepatitis?Yes

      2014 Questions

      • 1.
        Have any unexpected safety concerns arisen since the regulatory recommendation that liver enzymes need not be measured after initiating statin therapy?
      ANSWER: No.
      STRENGTH OF RECOMMENDATION: A (strong).
      QUALITY OF EVIDENCE: Low.
      EXPLANATION: The initial 2006 National Lipid Association Statin Safety Task Force Expert Liver Panel recommended that routine liver enzyme testing not be required.
      • Cohen D.E.
      • Anania F.A.
      • Chalasani N.
      National Lipid Association Statin Safety Task Force Liver Expert Panel
      An assessment of statin safety by hepatologists.
      Subsequently, in 2012, the FDA issued a communication regarding “Important safety label changes to cholesterol-lowering statin drugs,” wherein they stated

      US Food and Drug Administration. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed January 29, 2014.

      :“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.”

      US Food and Drug Administration. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed January 29, 2014.

      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:

      US Food and Drug Administration. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed January 29, 2014.

      “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.
      • Stone N.J.
      • Robinson J.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [e-pub ahead of print].
      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.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members Appointed to the Eighth Joint National Committee (JNC 8).
      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.”

      US Food and Drug Administration. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed January 29, 2014.

      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.
      • Reuben A.
      • Koch D.G.
      • Lee W.M.
      Acute Liver Failure Study Group
      Drug-induced acute liver failure: results of a U.S. multicenter, prospective study.
      • 2.
        Should baseline liver enzymes be obtained before initiating statin therapy?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: E (expert opinion).
      QUALITY OF EVIDENCE: Low.
      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.”

      Pfizer. LIPITOR® (atorvastatin calcium) prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Revised February 2013.

      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).
      Table 3Illustrative causes of elevated liver enzymes in adolescents and adults
      Increases in aspartate aminotransferase (AST) and to a lesser extent, alanine aminotransferase (ALT) may be derived from other body tissues, such as muscle and red blood cells that, although not liver related, should also be evaluated when AST and ALT blood levels are increased. Also, the list in this table is not all-inclusive because many other possible causes of elevated liver enzymes exist.
      • Celiac disease
      • Congestive cardiomyopathy
      • Endocrine diseases
        • Adiposity resulting in adiposopathy
        • Diabetes mellitus and insulin resistance syndromes
        • Hyperthyroidism and hypothyroidism
        • Metabolic syndrome
      • Excessive ethanol intake (with or without alcoholic hepatitis)
        • In patients without underlying liver disease, ethanol intake that is more likely to cause increases in liver enzymes include >2 units a day for men and 1 unit per day for women (unit = generally defined as 12 oz of beer, 5 oz of wine, 1.5 oz for 80 proof mixed drinks)
      • Fatty liver
        • Nonalcoholic fatty liver disease
        • Nonalcoholic steatohepatitis
      • Gallbladder disease (eg, cholelithiasis with obstruction)
      • Genetic diseases
        • Alpha 1 antitrypsin deficiency
        • Cystic fibrosis
        • Hemochromatosis (excessive iron storage)
        • Hepatic porphyrias
        • Wilson's disease (excessive copper storage)
      • Infections
        • Viral infection
          • Adenovirus
          • Cytomegalovirus
          • Coxsackievirus
          • Echovirus
          • Epstein-Barr (eg, mononucleosis)
          • Hepatitis A, B, C, and E
          • Herpes simplex virus
          • Human immunodeficiency virus
          • Rubella
        • Bacterial infection, especially with sepsis
          • Chlamydia
          • Rickettsia
          • Spirochetes
          • Tuberculosis and other mycobacteria
        • Fungal infection
          • Candidiasis
          • Histoplasmosis
        • Parasitic infections (protozoa and helminthes)
          • Schistosomiasis
          • Leptospirosis
          • Toxoplasmosis
          • Visceral larva migrans
      • Malignancies
        • Primary liver cancer
        • Metastatic cancer
        • Leukemia and lymphoma
      • Other liver diseases
        • Autoimmune hepatitis (eg, idiopathic, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus)
        • HELLP syndrome in pregnancy (Hemolysis, ELevated liver enzymes, Low Platelet count)
        • Primary biliary cirrhosis
        • Primary sclerosing cholangitis
        • Thrombotic occlusion of the hepatic veins (Budd-Chiari syndrome)
      • Selected medications
        • Antibiotics
          • Amoxicillin
          • Amphotericin
          • Azole antifungal agents (eg, fluconazole, ketoconazole)
          • Ciprofloxacin
          • Erythromycin
          • Isoniazid
          • Nitrofurantoin
          • Protease inhibitors
          • Rifampin
          • Sulfonamide antibiotics (eg, sulfamethoxazole)
          • Tetracycline
          • Trimethoprim
        • Cardiovascular disease medications
          • Amiodarone
          • Ezetimibe when combined statins
          • Fibrates (gemfibrozil, fenofibrate)
          • Hydralazine
          • Labetalol
          • Methyldopa
          • Niacin (especially over-the-counter slow-release preparations at doses greater than 1500 mg/d)
          • Quinidine
          • Statins
        • Herbal supplements
          • Chaparral
          • Ephedra
          • Gentian
          • Germander
          • Jin Bu Huan
          • Kavakava
          • Ma-huang
          • Scutellaria
          • Senecio/crotalaria (bush teas)
          • Senna
          • Shark cartilage
        • Hormones
          • Anabolic steroids (eg, testosterone)
          • Estrogens
          • Excessive thyroid hormone
          • Systemic corticosteroids
          • Tamoxifen
        • Illicit drugs
          • Anabolic steroids
          • Cocaine
          • Methylenedioxymethamphetamine (MDMA or ecstasy)
          • Phencyclidine (PCP)
        • Neurologic and psychiatric medications
          • Carbamazepine
          • Chlorpromazine
          • Phenobarbital
          • Phenytoin
          • Trazodone
          • Valproic acid
        • Pain medications
          • Acetaminophen
          • Aspirin
          • Nonsteroidal anti-inflammatory drugs
        • Other medications
          • Dantrolene
          • Disulfiram
          • Etretinate
          • Halothane
          • Heparin
          • Orlistat
          • Propylthiouracil
          • Sulfonylureas
          • Vitamin A and derivatives
          • Zafirlukast
      • Toxins
        • 2-Nitropropane
        • Carbon tetrachloride
        • Chloroform
        • Dimethylformamide
        • Hydrazine
        • Hydrocarbons
        • Hydrochlorofluorocarbons
        • Hypervitaminosis A
        • Insecticides
        • Mushrooms
        • Organophosphates
        • Toluene
        • Trichloroethylene
      • “Weight loss” or “workout” or “body building” supplements
        Specific supplements are not listed in the table because dietary supplements are not regulated by the Food and Drug Administration before being marketed. Thus, evidence of the potential to definitively cause liver injury is mainly via case and media reports, and not through the rigors of controlled clinical trials. This makes it challenging to definitively confirm a specific supplement causes any safety adverse outcomes. Also, as noted in the table, liver injury due to supplements may not only be the result of the supplement itself, but may also be due to an added ingredient to the supplement, or an unintended toxin introduced into a batch of the supplement during processing.
        • Liver injury from the supplement itself
        • Liver injury from other toxic ingredients
        • Liver injury from a bad batch of the supplement
      Increases in aspartate aminotransferase (AST) and to a lesser extent, alanine aminotransferase (ALT) may be derived from other body tissues, such as muscle and red blood cells that, although not liver related, should also be evaluated when AST and ALT blood levels are increased. Also, the list in this table is not all-inclusive because many other possible causes of elevated liver enzymes exist.
      Specific supplements are not listed in the table because dietary supplements are not regulated by the Food and Drug Administration before being marketed. Thus, evidence of the potential to definitively cause liver injury is mainly via case and media reports, and not through the rigors of controlled clinical trials. This makes it challenging to definitively confirm a specific supplement causes any safety adverse outcomes. Also, as noted in the table, liver injury due to supplements may not only be the result of the supplement itself, but may also be due to an added ingredient to the supplement, or an unintended toxin introduced into a batch of the supplement during processing.
      • 3.
        Are statins safe to use in patients with nonalcoholic fatty liver disease?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: B (moderate).
      QUALITY OF EVIDENCE: Moderate.
      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.
      • Torres D.M.
      • Williams C.D.
      • Harrison S.A.
      Features, diagnosis, and treatment of nonalcoholic fatty liver disease.
      • Chatrath H.
      • Vuppalanchi R.
      • Chalasani N.
      Dyslipidemia in patients with nonalcoholic fatty liver disease.
      • Bays H.E.
      • Toth P.P.
      • Kris-Etherton P.M.
      • et al.
      Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association.
      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.
      • Chatrath H.
      • Vuppalanchi R.
      • Chalasani N.
      Dyslipidemia in patients with nonalcoholic fatty liver disease.
      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,
      • Foster T.
      • Budoff M.J.
      • Saab S.
      • Ahmadi N.
      • Gordon C.
      • Guerci A.D.
      Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial.
      • Athyros V.G.
      • Tziomalos K.
      • Gossios T.D.
      • et al.
      Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • Holmqvist M.
      • Bodemar G.
      • Kechagias S.
      Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
      • Nelson A.
      • Torres D.M.
      • Morgan A.E.
      • Fincke C.
      • Harrison S.A.
      A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial.
      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?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: A (strong) (depending on the medication used).
      QUALITY OF EVIDENCE: High.
      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?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: C (weak).
      QUALITY OF EVIDENCE: Low.
      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.
      • Vanwagner L.B.
      • Bhave M.
      • Te H.S.
      • Feinglass J.
      • Alvarez L.
      • Rinella M.E.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      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?
      ANSWER: Yes.
      STRENGTH OF RECOMMENDATION: E (expert opinion).
      QUALITY OF EVIDENCE: Low.
      EXPLANATION: The published data report rare cases of statin-induced autoimmune hepatotoxicity.
      • Alla V.
      • Abraham J.
      • Siddiqui J.
      • et al.
      Autoimmune hepatitis triggered by statins.
      • Russo M.W.
      • Scobey M.
      • Bonkovsky H.L.
      Drug-induced liver injury associated with statins.
      • John S.G.
      • Thorn J.
      • Sobonya R.
      Statins as a Potential risk factor for autoimmune diseases: a case report and review [e-pub ahead of print].
      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.
      Figure thumbnail gr1
      Figure 1Comprehensive approach to patients with elevated liver blood testing (transaminases <3 times the upper limits of normal).
      • Davern T.J.
      • Chalasani N.
      • Fontana R.J.
      • et al.
      Drug-Induced Liver Injury Network (DILIN)
      Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury.
      • D'Agata I.D.
      • Balistreri W.F.
      Evaluation of liver disease in the pediatric patient.
      Figure thumbnail gr2
      Figure 2Comprehensive approach to patients with elevated liver blood testing (transaminases >3 times the upper limits of normal).

       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.
      • Taylor F.
      • Huffman M.D.
      • Macedo A.F.
      • et al.
      Statins for the primary prevention of cardiovascular disease.
      • Lardizabal J.A.
      • Deedwania P.C.
      Benefits of statin therapy and compliance in high risk cardiovascular patients.

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