A Rare Case Series Demonstrating the Mixed Pattern of Metformin-Induced Hepatotoxicity

Abstract

Introduction: Metformin is one of the most commonly prescribed medications in the management of type 2 Diabetes Mellitus (DM). It is not known to be hepatotoxic, as it is not metabolized by the liver. However, very few case reports of metformin-induced hepatotoxicity have been reported to date. Here in, we report a case series of two patients with clinical presentations consistent with metformin-induced hepatotoxicity. Methods: Case 1: A 56 y/o male presented with a one-week history of right-sided abdominal discomfort and jaundice. A month prior to presentation he was placed on metformin for his type II DM. Laboratory work up revealed aspartate transaminase (AST) of 4422 U/L, alanine transaminase (ALT) of 4701 U/L, total bilirubin (TB) of 20.7 mg/dl, direct bilirubin (DB) of 17mg/dl and alkaline phosphatase of 192 U/L. Serological work up for hepatitis A, B and C were negative. Case 2: A 61 y/o male presented with worsening pruritus and jaundice. Patient had a medical history of chronic hepatitis C and type II DM for which he was prescribed metformin 2 months prior to admission. Laboratory tests revealed TB of 25.6 mg/dl with direct bilirubin of 20 mg/dl, alkaline phosphatase 916 U/L, AST of 916 U/L, ALT of 1269 U/L consistent with a mixed hepatocellular and cholestatic pattern of liver injury. Hepatitis C viral load by PCR revealed a titer of 7 IU/ml, which was unlikely to be the etiology of his acute presentation. Both patients denied any contributing social and family history. Results: Diagnostic workup ruled out autoimmune and metabolic disease in both patients. Imaging showed normal liver parenchyma, ductal architecture and normal gall bladder in both patients. Liver biopsy was performed. In case one liver biopsy was consistent with markedly active lobular and portal hepatitis. There were no viral inclusions identified. Biopsy in case two revealed a cholestatic hepatitis unlikely to be secondary to a viral etiology and suggestive of a drug induced hepatitis. Metformin induced hepatotoxicity was thought to be the most probable diagnosis and metformin was held. Rapid resolution of signs and symptoms with normalization of liver enzymes was noted during hospital stay and subsequent follow up Conclusion: Metformin induced hepatotoxicity is a rare drug induced idiosyncratic reaction. As metformin is a widely used drug, physicians should be aware of this potential adverse reaction. Early recognition and cessation of medication is crucial in reversal of this adverse effect.