Gt4_07 v7_gt4_07_v7

Gastroenterology Today 2007; 17(4)
Metformin induced cholestatic hepatitis
Dr. Emma Nixon1, Dr. A Simon2, Dr. G Lipscomb3, Dr. S Wells4
Introduction
Figure 1. Liver Biopsy
Hepatic adverse drug reactions are common in everydayclinical practice. Most oral hypoglycaemic agents havebeen implicated in hepatotoxicity . While the sulphonureas,glucosidase inhibitors and the thiazolodineodines arecommonly reported to cause adverse reactions in the formof liver toxicity [1], there have been only three welldocumented reports of metformin induced hepatic injury[2-4]. This report describes a case of metformin inducedacute cholestatic hepatitis.
Case report
A 58-year-old female was referred by her General Practi-tioner for investigation of jaundice. She gave a three week Histological examination of the 1.9cm long core biopsy showed a history of flu like symptoms, general fatigue and painless normal lobular architecture with no fibrosis or portal inflammation.
jaundice. One week prior to the onset of symptoms she There were small clusters of chronic inflammatory cells in the lobules, had been started on metformin 500mg twice daily for newly mild Kupffer cell hyperplasia and minimal macrovesicular fatty change.
Eosinophils were not prominent in the infiltrate. No spotty necrosis or piecemeal necrosis was seen. There was no evidence of excess haemosiderin, granulomata, alpha-one-antitrypsin bodies, excess She was on no other regular medications. She had no copper associated protein, bile stasis, bile ductile proliferation or Mallory’s hyalin. The appearances were of mild lobular inflammation significant past medical history. She reported no alcohol and were thought to possibly represent resolving hepatitis. There were excess, previous liver disease or jaundice, blood transfu- no diagnostic features of autoimmune hepatitis.
sions, tattoos or travel abroad. Clinical examination wasunremarkable except for jaundice.
Laboratory investigations revealed a bilirubin of 52 Discussion
(normal <17umol/L), an aspartate aminotransferase (AST)level of 303 (normal <40U/L ), an alanine aminotrans- This case represents one of the few reported incidents of ferase (ALT) of 716 (normal <50U/L) and an alkaline phos- metformin induced hepatitis. The time scale from the intro- phatase (ALP) of 101 (normal <160IU/L). Her albumin was duction of metformin to the onset of jaundice was four 42 and international normalised ratio 1.1. Serology for hep- weeks. This is consistent with a drug reaction. The other atitis A, B, C, E, CMV and EBV was negative. Autoimmune reported cases documented hepatic injury occurring from screen including anti-mitochondrial antibodies, anti-smooth two to six weeks following institution of metformin. The liver muscle antibodies, and anti-liver kidney microsomes was biopsy showed normal liver architecture and features of cholestasis and lobular inflammation. The histologicalfeatures were non specific and consistent with a drug Results of abdominal ultrasonography revealed only mild induced hepatitis. The patient was not taking any other splenomegaly. A percutaneous liver biopsy showed medications and other causes of acute hepatitis were cholestasis with lobular inflammation, consistent with a excluded. In previous reports the patients involved were also taking other medications known to cause hepaticinjury, however in one of the three cases the metformin Metformin was withdrawn and her liver function gradually was reintroduced at a later date with a recurrence of the improved. Her transaminitis resolved within three months The reason for acute liver injury by metformin remainsunclear. Although metformin accumulates within the liver,it does not undergo hepatic metabolism and has not been 1. Clinical Fellow – Gastroenterology
shown to cause dose-dependent hepatotoxicity [5,6]. It 2. Staff Grade – Gastroenterology
3. Consultant – Gastroenterology
appears therefore to represent a rare idiosyncratic drug 4. Consultant – Histopathology
reaction, with resolution of hepatitis on its discontinuation.
Royal Bolton Hospital , Bolton BL4 0JR
Gastroenterology Today 2007; 17(4)
The high prevalence of NASH related liver abnormalities in 2. Babich M, Pike J. Metformin induced acute hepatitis. Am J patients with type 2 diabetes mellitus means that minor Med. 1998; 104: 490-92.
elevation of liver enzymes are not uncommon in this 3. Desilets DJ, Shorr AF. Cholestatic jaundice associated with population. This case highlights the importance of recog- the use of metformin. Am J Gastroenterol. 2001;9 6: 2257-8.
nising drug induced hepatoxiticy in this group of patients, 4. Deutch M, Kountouras D. Metformin hepatotoxicity. Ann Int in particular regard to metformin which is in wide clinical . 2004; 140: 2025.
use and previously thought not to cause hepatic injury. 5. Wilcock C, Wyre ND. Subcellular distribution of metformin in rat liver. J Pharmacol. 1991; 43(6): 442-4.
6. Scheen AJ. Clinical Pharmacokinetics of metformin. Clin References
Pharmacokinet. 1996 May; 30(5): 359-71. Review.
1. Chittaii S, George J. Hepatatoxicity of commonly used drugs; nonsteroidal anti-inflammatory dugs, antihypertensives,
antidiabetic agents, anticonvulsants, lipid lowering agents,
psychotropic drugs. Semin Liver Dis. 2002; 22: 169-83.
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