Statin treatment associated hepatotoxicity

• ALT > 3 x normal limit
  • placebo-controlled outcome trials where 10-40 mg doses of simvastatin, lovastatin, fluvastatin, atorvastatin, and pravastatin were compared with placebo, the incidence of ALT elevation >3 times ULN was found to be 1.3% with test drugs and 1.1% with placebo with no case of liver failure (1)
    
    
• incidence of serious hepatotoxicity
  • serious hepatotoxicity is rare, a few cases of liver failure associated with statin use have been reported to the FDA between 1987 and 2000, the rate of about one case per million person-years of use
    • however the occurrence of acute liver failure (ALF) thought to be caused by statins is well below what is now understood as the background rate of idiopathic ALF in the general population - estimated that idiopathic ALF rate to be from 0.5 to 1.0 case per million, and the incidence of possible statin-induced ALF to be 0.2 cases per million in United States (2)
      • no consistent liver biopsy picture from possible statin-related drug injury has emerged, and there are no reports of chronic carriers of drug-induced liver damage from statins
        
        
• use of statins in liver disease
  • decompensated cirrhosis, acute liver failure and worsening obstructive biliary disease remain contraindications for statin therapy - however low doses of statins can be used with careful monitoring in compensated cirrhosis, chronic liver disease and partial obstructive biliary disease (2)
    • statins can be used safely in patients with either non-alcoholic fatty liver disease or NASH and even, mild to moderate alcohol consumption (up to 1-2 drinks/d) is not a contraindication for their use
    • hepatitis C
      • there is evidence of the safe use of statins in in hepatitis C patients (3)
        • it has been sown that ffluvastatin has an anti-HCV activity in chronic carriers of HCV in whom treatment with peginterferon/ribavirin had failed (4)

Liver toxicity with respect to different statins (5)

• atorvastatin
  • atorvastatin-related hepatotoxicity has been associated with a mixed pattern of liver injury typically occurring several months after the initiation of the medication (6)
  • been a case report of underlying autoimmune hepatitis apparently revealed by atorvastatin(6)
  • there has prolonged cholestasis reported after atorvastatin use (5,6)
• simvastatin
  • simvastatin hepatotoxicity is hypothesized to occur due to drug-drug interactions
    • several case reports involving amiodarone
    • also been case reports describing hepatotoxicity when simvastatin is used in conjunction with flutamide and diltiazem
• pravastatin, rosuvastatin, and fluvastatin
  • pravastatin
    • reported to cause acute intrahepatic cholestasis
      • liver toxicity occurred within 2 months after initiating the drug and it resolved within 2 months after its discontinuation
      • there is a perception that pravastatin is less hepatotoxic than other statins
        • attributed to its non-CYP based metabolism and its hydrophilic nature
  • rosuvastatin
    • been shown to trigger an autoimmune-type hepatitis similar to atorvastatin
  • fluvastatin, as opposed to many other statins, is metabolized by cytochrome P450 2C9 instead of CYP3A4
    • incidence of elevations in hepatic biochemistries is similar to the class as a whole although initial studies revealed a lower rate of hepatic enzyme elevation in the control population

Reference:

• 1) Law MR et al.Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003 Jun 28;326(7404):1423
• 2)Sikka P et al. Statin Hepatotoxicity: Is it a Real Concern? Heart Views. 2011 Jul;12(3):104-6.
• 3) Madhoun MF, Bader T. Statins improve ALT values in chronic hepatitis C patients with abnormal values. Dig Dis Sci 2010;55:870-1.
• 4) Bader T et al. Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008;103:1383-9.
• 5) Bhardwaj SS, Chalasani N.Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis. 2007 Aug;11(3):597-613, vii.
• 6) Merli M et al. Atorvastatin-induced prolonged cholestasis with bile duct damage.Clin Drug Investig. 2010;30(3):205-9.