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.

Fig. 1. Pathophysiology of metabolic hyperferritinaemia and associated iron accumulation.

Hepatic lipid accumulation (steatosis) and alterations of lipid metabolism in the liver are conditions associated with systemic insulin resistance, and they lead to lipotoxicity and local inflammation, inducing the synthesis of ferritin, a molecule with antioxidant activity. Within this context, excess levels of lipids and iron in the diet lead to increased circulating levels of iron (Fe), especially in male individuals with a permissive genetic background. Owing to the presence of subclinical inflammation downregulating ferroportin 1, iron is accumulated not only in hepatocytes, but also in Kupffer cells and hepatic stellate cells, triggering hepatocellular damage, ferroptosis, inflammation and fibrogenesis. This process triggers progressive liver disease, but spillover of iron from the liver might also worsen insulin resistance in adipose tissue and impair the secretion of appetite-controlling peptides, thereby facilitating the progression to type 2 diabetes mellitus and its complications. The figure represents the main pathophysiological pathways leading to metabolic hyperferritinaemia in patients with metabolic dysfunction (not all the extrahepatic and intrahepatic interactions between lipid, glucose and iron metabolism are depicted).

Fig. 2. Clinical management of metabolic hyperferritinaemia.

The diagnosis, based on the evaluation of inclusion and exclusion criteria, is followed by staging of iron accumulation (by ferritin and if available by MRI) and of organ damage. In addition to the current therapy for metabolic dysfunction, iron depletion therapy can be considered for patients with the most severe iron stores or within clinical trials. Iron stores are then monitored non-invasively.