Novel pathway for iron deficiency in pediatric non-alcoholic steatohepatitis

Background & aims: Iron may be an important factor in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it catalyzes the production of potent reactive oxygen species. We aim to examine iron status in pediatric NASH. Methods: Serum indices of NASH patients (N=36) were compared to those in the U.S. National Health and Nutrition Examination Survey database (N=802). Iron related gene expression was examined in NASH livers and normal livers, using microarray and quantitative real-time PCR (10 NASH livers and 6 controls). Transferrin and catalase expression were also examined in hydrogen peroxide treated HepG2 cells. Results: Serum iron concentration (P<0.01) and soluble transferrin receptor 1 (P<0.0001) were decreased while serum ferritin was elevated in NASH patients (P<0.01). No detectable iron was observed in NASH liver by Perls' Prussian blue staining. Transferrin (P<0.01) and transferrin receptor 2 (P<0.01) mRNA were elevated in NASH patients. Of particular interest, transferrin mRNA was positively correlated with catalase mRNA (r=0.9338, P<0.0001). H₂O₂ treatment of HepG2 cells induced mRNA expression of transferrin and catalase. Conclusions: Pediatric NASH patients exhibited decreased serum iron concentration and no detectable iron was observed in any NASH liver by Perls' Prussian blue staining. These changes are consistent with the facts that most NASH patients are obese and exhibit chronic inflammation. In line with a status of iron deficiency, gene expression studies suggested decreased expression of transferrin and transferrin receptor 2 in NASH livers. Induction of transferrin by H₂O₂, and consequently, decreased iron absorption, suggests a novel mechanism for iron deficiency in NASH patients.