Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin

Abstract

Background & Aims Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines IL6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin and IL6 and IL1β, and other risk factors in patients with non-alcoholic fatty liver disease (NAFLD) with iron deficiency. Methods We collected data on 675 adult subjects (>18 y old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation <20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, as well as serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency. Results One third of patients (231/675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P<.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61±45 vs 81±51 ng/mL; P<.0001). Iron deficiency was significantly associated with female sex, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, Black or American Indian/Alaska Native race (P≤.018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal; P≤.0001 and 0.45 vs 0.32 for iron normal; P≤.005). Conclusion Iron deficiency is prevalent in patients with NAFLD and associated with female sex, increased body mass index, and non-white race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiological response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

“…Rodent data have shown that a high‐fat diet leads to a redistribution of iron from the liver to adipose tissue with a 4‐fold increase in adipocyte iron concentration and a 2‐fold reduction in HIC 32. Human studies demonstrate that obesity is associated not only with iron deficiency but paradoxically also with increased subcutaneous and visceral adipose tissue iron 33, 34, 35. Furthermore, increased adipocyte iron leading to a reduction in adiponectin expression has been demonstrated in a variety of mouse and adipocyte culture models 9.…”

Non-Alcoholic Steatohepatitis: Clinical and Translational Research

“…Iron deficiency (transferrin saturation <20%) was observed in 34.2% of subjects included in a large sample of 675 NAFLD patients. It was observed predominantly among subjects with MS. Iron deficiency was correlated with lower serum hepcidin levels, a phenomenon believed to result from lower circulating iron levels (52). Obesity but not NAFLD were associated with elevated serum hepcidin levels in a large sample of patients undergoing bariatric surgery (49).…”

Interactions between iron and fat in non-alcoholic fatty liver disease

“…However, Hamp1 expression was markedly decreased in these mice suggesting appropriate Hamp1 response to reduced hepatic iron stores and is consistent with previous studies [24,125,147,154]. These findings are also in keeping with the established association between iron deficiency and obesity in humans [111,112].…”

“…Further complexity in these relationships arises when one considers that iron deficiency has been shown to be associated with obesity and in women with obesity and NAFLD. [111,112] Iron-related genetic polymorphisms, such as those of the HFE gene, may contribute to NAFLD pathogenesis, although it would appear that, other than for individuals with hereditary hemochromatosis, the effect of these polymorphisms, is likely to be small. The complexity of these relationships between iron and NAFLD is further increased when one considers the possibility that NAFLD itself is likely to have a number of effects on iron metabolism.…”