Association between iron metabolism and non-alcoholic fatty liver disease: results from the National Health and Nutrition Examination Survey (NHANES 2017–2018) and a controlled animal study

Abstract

Background Iron metabolism may be involved in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). The relationship between iron metabolism and NAFLD has not been clearly established. This study aimed to clarify the relationship between biomarkers of iron metabolism and NAFLD. Methods Based on the National Health and Nutrition Examination Survey (NHANES), restricted cubic spline models and multivariable logistic regression were used to examine the association between iron metabolism [serum iron (SI), serum ferritin (SF), transferrin saturation (TSAT), and soluble transferrin receptor (sTfR)] and the risk for NAFLD. In addition, stratified subgroup analysis was performed for the association between TSAT and NAFLD. Moreover, serum TSAT levels were determined in male mice with NAFLD. The expression of hepcidin and ferroportin, vital regulators of iron metabolism, were analyzed in the livers of mice by quantitative real-time PCR (qRT-PCR) and patients with NAFLD by microarray collected from the GEO data repository. Results Patients with NAFLD showed decreased SI, SF, and TSAT levels and increased STfR levels based on the NHANES. After adjusting for confounding factors, TSAT was significantly negatively correlated with NAFLD. Of note, the relationship between TSAT and NAFLD differed in the four subgroups of age, sex, race, and BMI (P for interaction < 0.05). Consistently, mice with NAFLD exhibited decreased serum TSAT levels. Decreased hepcidin and increased ferroportin gene expression were observed in the livers of patients and mice with NAFLD. Conclusion Serum TSAT levels and hepatic hepcidin expression were decreased in both patients and mice with NAFLD. Among multiple biomarkers of iron metabolism, lower TSAT levels were significantly associated with a higher risk of NAFLD in the U.S. general population. These findings might provide new ideas for the prediction, diagnosis, and mechanistic exploration of NAFLD.

Associations between higher plasma ferritin and hepcidin levels with liver stiffness in patients with type 2 diabetes: An exploratory study

“…In a small single‐centre study involving 51 patients with NAFLD, 30 patients with chronic viral hepatitis and 20 control subjects, Ryan et al found that higher plasma ferritin levels were associated with advanced histological features of NAFLD (especially higher liver fibrosis stages), whereas circulating hepcidin levels and hepatic iron deposition were the strongest predictors of plasma ferritin levels 15 . Studies examining the association between circulating hepcidin levels and advanced NAFLD have provided conflicting results 24–28 . For instance, in a case–control study of 88 patients with biopsy‐proven NAFLD and 88 control subjects, Senates et al reported that patients with NAFLD had significantly higher circulating hepcidin levels than control subjects 25 .…”

“…15 Studies examining the association between circulating hepcidin levels and advanced NAFLD have provided conflicting results. [24][25][26][27][28] For instance, in a case-control study of 88 patients with biopsy-proven NAFLD and 88 control subjects, Senates et al reported that patients with NAFLD had significantly higher circulating hepcidin levels than control subjects. 25 However, in that study the association between hepcidin levels and histological features of NAFLD became nonsignificant after adjusting for potential confounding factors.…”

“…9,23 Although there are still conflicting results, higher circulating hepcidin levels seem to be also associated with advanced NAFLD in some studies. 20,[24][25][26][27][28] To our knowledge, however, it is currently unknown whether an association also exists between circulating levels of ferritin and hepcidin with liver fibrosis among patients with T2DM and NAFLD.…”

“…It is thought that tissue (hepatic) iron deposition may also trigger low‐grade inflammation and oxidative stress, thus promoting the development of NASH and liver fibrosis 9,23 . Although there are still conflicting results, higher circulating hepcidin levels seem to be also associated with advanced NAFLD in some studies 20,24–28 …”

Iron Metabolic Biomarkers and the Mortality Risk in the General Population: A Nationwide Population-Based Cohort Study

“…Serum ferritin (SF) and transferrin saturation (TSAT) are 2 commonly measured biomarkers of iron metabolism in clinical settings [ 11 ], which reflects iron storage [ 12 ] and iron availability, respectively [ 13 ]. The abnormal range of SF and TSAT are used to indicate iron metabolism abnormalities [ 14 ].…”