Statins and Liver Injury

Aim Atorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia Atorvastatin is generally safe but may induce cholestasis The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice Methods Adult male mice were given atorvastatin (10, 30, and 100 mg/kg, po) daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined Results Repeated administration of atorvastatin did not affect animal body weight gain or liver weights Serum enzyme activities were in the normal range Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1 Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ The most dramatic change was the 30-fold induction of Cyp7a1 Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression Conclusion Repeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes

Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

Since their introduction in 1987, hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, more commonly known as statins, have become some of the most widely prescribed medications in the world. Though generally considered to be safe and well tolerated, statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases. Rarely, statins have been noted to induce more serious hepatic injury, including liver injury with autoimmune features. Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns, though with the former being the prevailing pattern of injury. Fortunately, severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation. When evaluating cases of suspected statin-induced liver injury, a complete medical history, laboratory tests including a complete metabolic panel, autoimmune markers, and viral panel, as well as hepatic imaging, are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method. The aim of this review is to review the current evidence for statin-induced liver injury and cholestasis.

Statin-induced Liver Injury Patterns: A Clinical Review

Statins are the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, revolutionizing the treatment of hypercholesterolemia and the management of patients with increased cardiovascular risk. Using statins for primary and secondary prevention of cardiovascular diseases has become commonplace and lipid-lowering therapies have become more intense in compliance with the more aggressive targets set by the trials demonstrating their safety and efficacy in high-risk patients, such as: HPS(Heart Protection Study of cholesterol lowering with simvastatin) [1], AVERT (Atorvastatin versus Revascularization Treatment) [2], PLANET I and II (renal effects of atorvastatin and rosuvastatin in proteinuric patients with and without diabetes) [3]. Although the beneficial effect of the statins is a fact, one cannot ignore their side-effects, ranging from benign and asymptomatic to severe and organ-threatening (jeopardizing especially liver and kidney function). Serious adverse reactions associated with statin treatment include: muscle damage, renal failure, liver dysfunction, and polyneuropathy.

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Ahmed Sawah

Papers

Statin Induced Cholestatic Hepatitis: Confirmed on Re-Challenge