Mechanism of action of metformin in nonalcoholic steatohepatitis: authors’ reply

Abstract

Sirs, Mascitelli and colleagues1 speculate that metformin acts by reducing iron overload causing decreases in serum ferritin and improved insulin resistance. Current evidence suggests that metformin leads to improvement in insulin resistance not by altering iron metabolism but by activating the LKB1 receptor in liver leading to upregulation of AMP kinase, a master regulator of glucose metabolism.2 There is scant evidence to suggest that metformin reduces iron absorption or hepatic iron content. Persons with insulin resistance and nonalcoholic steatohepatitis often have high serum ferritin levels,3, 4 but this association does not prove causality. To address these issues, we have analysed results of iron staining from the 26 patients who were treated with metformin in this study.5 Liver biopsy tissue was stained using Perl’s iron stain and graded from 0 to 4 with 0 = no iron seen; trace = rare speck of iron staining; 1+ to 4+ according to published criteria.6 No patient had more than 2+ iron staining and a majority (60%) had no stainable iron (Table 1). The distribution of iron staining scores did not change with therapy, the average being 0.40 before and 0.42 at the end of 48 weeks of metformin treatment. Among 18 nonresponders, the average iron score decreased slightly from 0.39 to 0.32; among the eight responders, the average increased slightly, from 0.43 to 0.63, but no patient increased by more than 1 point and the changes were not statistically significant. Iron staining is only a semi-quantitative means of assessing hepatic iron, but these results suggest that metformin had little or no effect on iron absorption or liver iron accumulation. Declaration of personal interests: None. Declaration of funding interests: This paper was supported by the intramural research program of National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.