Serum Hepcidin Levels Correlate with Phenotypes of the Metabolic Syndrome At Population Level
Authors: Martinelli Nicola , Traglia Michela , Campostrini Natascia , Biino Ginevra , Previtali Sara , Corbella Michela , Sala Cinzia , Busti Fabiana , Masciullo Corrado , Manna Daniele , Buetti Iwan , Pistis Giorgio , Olivieri Oliviero , Toniolo Daniela , Camaschella Clara , Girelli Domenico 
Published: October 2019

Abstract
Abstract 348

Background and Aims:
Hepcidin is a 25 amino acid hormone mainly produced by the liver in response to increased plasma or tissue iron to homeostatically down-regulate absorption and recycling of the metal from duodenum and macrophages, respectively. Hepcidin expression is also upregulated by inflammation. Dysmetabolic hyperferritinemia is among the commonest causes of increased serum ferritin levels encountered in clinical practice, but its pathophysiology remains unclear. Indeed, the Metabolic Syndrome (MS) that affects near 20–25% of western adults, is characterized by subclinical inflammation, which hampers the interpretation of serum ferritin as a marker of body iron stores. We recently measured serum hepcidin levels in the large Val Borbera (VB) population to evaluate their genetic determinants (Traglia et al. J Med Genet 2011). Taking advantage of this survey, we investigated for the first time the relationships between hepcidin, ferritin, C-Reactive Protein (CRP) and MS phenotypes at population level.

Subjects and Methods:
Serum hepcidin-25 levels measured by Mass Spectrometry were analyzed in 941 subjects for whom complete data allowing classification of MS according to NLHBI criteria (fasting glucose ≥100 mg/dl or antidiabetes medication; blood pressure ≥135/85 mmHg or antihypertensive medication; triglycerides ≥150 mg/dl; HDL cholesterol <40 mg/dl in men and < 50 mg/dl in women; and obesity) and CRP levels were available. MS was defined by having ≥3 of the above criteria. Due to the known important gender differences in hepcidin levels (Traglia M et al. J Med Genet 2011), multivariate analyses were done separately in males (n=400, 21.8% with MS) and females (n=541, 18.5% with MS).

Main Results:
Serum hepcidin-25 levels increased linearly with the increasing number of MS traits in males (ANOVA: F=6.8, P=0.009) and, even more strongly, in females (ANOVA: F=35.2, P<0.001). This trends paralleled those of serum ferritin levels in both genders. In multivariate analyses adjusted for age and SNP rs1800562 (C282Y mutation in the HFE gene), the inclusion of ferritin in males abolished but in females only reduced the association of hepcidin with MS. On the contrary, CRP did not influence the same association in both genders. Regarding the single MS criteria, the strongest association of hepcidin were observed with body mass index, triglycerides, and fasting blood glucose (P<0.001 for all three) in females.

Conclusions:
Hepcidin levels are strongly associated with MS features at population level, independently of subclinical inflammation. This association appears to reflect a response to increasing iron stores in males, while in females some MS traits may directly influence hepcidin levels.

Disclosures:
No relevant conflicts of interest to declare.