Statin treatment and use in liver disease

Use of Statins in Liver Disease

• liver disease and statins
  • results from studies of statin therapy in patients with elevated liver enzyme levels, nonalcoholic fatty liver disease, hepatitis C, cirrhosis, liver transplants, and hepatocellular carcinoma show benefit without increased risk of adverse effects. Thus, based on available evidence, statin therapy should not be withheld in this patient population; however, more robust, prospective clinical trials are needed to confirm the safety and efficacy (1)
• Use of statins in Non-alcoholic steohepatitis (NASH):
  • clinical studies contribute additional support to the safe use of statins in NAFLD patients
    • controlled, prospective study of maximum-dose pravastatin therapy in a variety of clinically diagnosed chronic liver diseases, including 64% with NAFLD, showed equal effectiveness in lowering LDL cholesterol, with no difference in aminotransferase elevation incidence (2)
    • retrospective study by Ekstedt et al (3)
      • histological outcomes from 17 NAFLD patients who received statins for up to 16 years were compared to those from 51 NAFLD patients without statin exposure. After a comparable period of follow-up, no change in fibrosis score was seen in 11 of 17 (64%) statin-treated patients versus only 18 of 51 (37%) non-statin-treated patients
        • 5 of 17 (29%) statin-treated patients had bridging fibrosis or cirrhosis at the end of observation versus only 6 of 51 (12%) non-statin-treated patients, despite similar baseline levels of the fibrosis stage between groups
          • this may be because there was a subgroup with severe lipotoxicity and progressive fibrosis despite therapeutic measures such as statins
            • an alternative hypothesis is there is a subgroup at risk for progressive fibrosis as a result of long-term statin therapy via an undetermined mechanism
    • there is evidence that statins are safe in patients with persistent aminotransferase elevation because of NASH (5)
      • study indicates that statins may have a positive effect on hepatic histology in patients with NASH
• Use of statins in patients with hepatitis C
  • statins have equivalent efficacy in lipid lowering and similar rates of aminotransferases elevation in HCV infection in comparison with patients without known liver disease (based on a study using pravastatin) (2)

Effects of Statins on the Liver

• a small percentage of patients experience an increase in liver enzymes (in particular, alanine and aspartate transaminases) (4)
  • typically, with standard doses, little or no effect is seen on gamma glutamyl transferase, alkaline phosphatase, or bilirubin
  • increases in transaminases with statins are generally seen in the first 6 months of treatment, are asymptomatic, and reverse on stopping the statin treatment or with dose reduction
    • transaminases also may return to normal with continuation of the statin
    • it is unclear whether the effect on transaminases indicates hepatotoxicity or rather some sort of hepatic reaction to reduction of lipid levels. Other cholesterol-lowering agents, including fibrates, resins (which are not systemically absorbed), niacin, and ezetimibe, all increase liver enzymes
      • suggests these changes could be a hepatic response to lipid-lowering rather than hepatotoxicity
      • isolated elevations of aminotransferases in the absence of increased bilirubin levels have not been linked clinically or histologically with evidence of acute or chronic liver injury (3)
        • other mechanisms have been proposed that could explain commonly observed aminotransferase elevations in individuals treated with statins, including a transient pharmacologic effect secondary to cholesterol reduction in hepatocytes, comorbid conditions such as diabetes mellitus and obesity, and the consumption of alcohol or nonstatin medications

Notes:

• Qresearch prospective cohort study analysis (6)
  • this 6 year study investigated the use of statins and moderate or serious liver dysfunction
    • moderate or severe liver dysfunction, defined as an alanine transaminase concentration >120 IU/l (that is, more than three times the upper limit of normal) among patients without diagnosed chronic liver disease, as this is the severity at which guidelines recommend treatment is discontinued
    • overall, statins were associated with an increased risk of liver dysfunction in both men and women
      • in women there was some indication of differences between the effects of individual statins (overall test P=0.058)
        • highest risk was associated with fluvastatin (2.53, 1.84 to 3.47), which was significantly higher than that with simvastatin (1.52, 1.38 to 1.66)
      • in men, differences between the effects of individual statins were significant (overall test P=0.0045)
        • highest risk was associated with fluvastatin (1.97 1.43 to 2.72) and the lowest with pravastatin (1.21, 0.93 to 1.58)
    • a dose-response effect was evident
    • risk of liver dysfunction was highest within the first year of treatment with any statin: the adjusted hazard ratio for women was 2.38 (2.11 to 2.70) and for men was 2.32 (2.07 to 2.59). The hazard ratio in the 1-3 years after starting treatment for women was 1.39 (1.23 to 1.57) and for men was 1.35 (1.21 to 1.51). After stopping statins the risks returned to normal between one and three years in women and from three years in men
    • the number needed to harm (NNH) was 136 (109 to 175)

Reference:

• (1) Onofrei MD et al. Safety of statin therapy in patients with preexisting liver disease. Pharmacotherapy. 2008 Apr;28(4):522-9
• (2) Lewis JH et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease. Hepatology 2007; 46: 1453-1463
• (3) Ekstedt M et al.Statins in patients with elevated liver enzymes because of non-alcoholic fatty liver disease (NAFLD): A clinical and histopathological follow-up study. J Hepatology 2006(44): S254-S25
• (4) Armitage J. The safety of statins in clinical practice The Lancet, Volume 370, Issue 9601, 24 November 2007-30 November 2007, Pages 1781-1790
• (5) Ekstedt M et al.. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007 Jul;47(1):135-41. Epub 2007 Mar 8
• (6) Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010;340:c2197