Consensus Statement on the definition and classification of metabolic hyperferritinaemia

Abstract

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes. Sections MethodologyGiven the high prevalence of hyperferritinaemia in clinical practice, combined with a growing understanding of the underlying pathophysiology and clinical implications, an updated definition and grading system is warranted. The overall goal of this Consensus Statement was therefore to provide a proposal for a more accurate diagnosis and classification of MHF, to be validated by prospective studies, to provide suggestions on the design of these studies and to highlight some of the main unmet research needs in the field. Owing to the current absence of robust evidence to support the recommendation to screen for and diagnose MHF and then to treat this condition with a specific approach (such as iron depletion), the current Consensus Statement is mainly directed at clinicians who work in tertiary referral centres and clinical and basic researchers. The updated MHF definition will enable larger collaborative studies on the clinical implications, pathophysiology and therapy of this condition, although it will still require prospective validation and further refinement. The long-term goal is the improvement of clinical management of patients with MHF. On the basis of current evidence, we also provide expert recommendations for clinicians on the diagnosis, management, follow-up and treatment of this condition (presented in the Supplementary material).Consensus was reached by a multidisciplinary global panel of expert researchers with an interest in MHF from five continents and 14 countries working in the fields of iron metabolism, clinical endocrinology, ...

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

“…9 Circulating ferritin levels are also increased in obesity-related metabolic disorders. 9 The iron-regulatory hormone hepcidin regulates iron influx into the bloodstream from duodenal enterocytes and macrophages, but low-grade inflammation may promote hepcidin synthesis. 9,21 Excess fatty acid levels, which happens during diets rich in fat, sugar or processed foods, may reduce the hepcidin's ability to limit intestinal iron absorption.…”

“…9 The iron-regulatory hormone hepcidin regulates iron influx into the bloodstream from duodenal enterocytes and macrophages, but low-grade inflammation may promote hepcidin synthesis. 9,21 Excess fatty acid levels, which happens during diets rich in fat, sugar or processed foods, may reduce the hepcidin's ability to limit intestinal iron absorption. 9 As a result, there is an increased hepcidin production, and iron accumulates in cells expressing ferroportin, especially macrophages and hepatocytes.…”

“…9,21 Excess fatty acid levels, which happens during diets rich in fat, sugar or processed foods, may reduce the hepcidin's ability to limit intestinal iron absorption. 9 As a result, there is an increased hepcidin production, and iron accumulates in cells expressing ferroportin, especially macrophages and hepatocytes. 9 In the presence of systemic insulin resistance and low-grade inflammation, iron accumulates not only in hepatocytes, but also in Kupffer and hepatic stellate cells, thus leading to hepatocellular damage, ferroptosis, inflammation and hepatic fibrosis.…”

“…9 Ferritin is an iron storage protein reflecting body iron stores. 9 Ferritin is also an acutephase protein, and its circulating levels may be increased in cardiometabolic disorders, such as obesity, metabolic syndrome and cardiovascular disease, 9 which are conditions often observed in people with NAFLD. In the last years, accumulating evidence suggested that higher plasma ferritin levels are also associated with more severe liver fibrosis, [10][11][12][13][14][15][16][17] vascular damage 18 and increased all-cause mortality 19 in cohorts of patients with biopsy-proven NAFLD.…”

“…22 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][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.…”