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Pathways underlying iron accumulation in human nonalcoholic fatty liver disease^1,2,3

¹ From the Department of Internal Medicine, General Hospital Oberndorf, Oberndorf, Austria (EA, DL, and CD); the Department of General Internal Medicine, Department of Immunology and Infectious Diseases, Medical University of Innsbruck, Austria (IT, MT, and GW); the Department of Pathology (HH and OD) and the First Department of Medicine (MS), Paracelsus Private Medical University Salzburg, Austria

Background: Mild iron overload is frequently observed in nonalcoholic fatty liver disease (NAFLD).

Objective: We aimed to study putative pathways underlying iron accumulation in NAFLD.

Design: Hepatic and duodenal expression of critical iron molecules in NAFLD patients with (n = 32) and without (n = 29) iron overload, hereditary hemochromatosis (n = 10), and controls (n = 20) were investigated. Phlebotomy treatment was performed in 14 NAFLD patients.

Results: The hepatic expressions of the iron-export protein ferroportin-1 (FP-1) and of the iron-sensing molecule hemojuvelin (HJV) were significantly lower in NAFLD patients. The mRNA expression of the iron-regulatory peptide hepcidin was increased in NAFLD patients with iron overload, which was paralleled by low duodenal FP-1 expression. Hepatic mRNA and serum protein concentrations of tumor necrosis factor- (TNF-) were increased in NAFLD patients and were inversely correlated with both liver FP-1 and HJV mRNA and positively associated with body mass index and hepatic hepcidin mRNA. Accordingly, TNF- inhibited the FP-1 and HJV mRNA formation in HepG2 cells. Phlebotomy treatment of NALFD patients reduced serum ferritin, transferrin saturation, and TNF- concentrations and improved liver function tests.

Conclusions: Iron accumulation in NAFLD may result from an impaired iron export due to down-regulation of FP1 and ineffective hepatic iron sensing, as indicated by low HJV expression. TNF- appears to play a role in exerting these regulatory changes. Increased hepcidin formation in iron-overloaded NAFLD patients, however, results in decreased duodenal FP-1 expression, whereas a reduction in liver FP-1 may perpetuate hepatic iron retention. Phlebotomy offers a safe and efficient therapy for these metabolic disturbances.