Background & Aims: Pathogenic variants in the cellular iron exporter ferroportin (SLC40A1) cause hepatic and splenic iron overload. Low to normal transferrin saturation (TSAT) and iron accumulation in Kupffer cells with high splenic iron distinguish ferroportin disease (FD) from SLC40A1-related hemochromatosis (SLC40A1-HC), which are both caused by variants in SLC40A1. The aim of our study was to describe pathogenic mutations in SLC40A1, phenotypic variability in affected patients and compare outcomes with HFE-related hemochromatosis (HFE-HC). Methods: The international EASL non-HFE hemochromatosis patient registry prospectively collected clinical, radiological, biochemical, and genetic data for 95 patients with SLC40A1 variants from six centers. Additionally, 363 patients were identified by a systematic literature review. As a comparator, 603 patients diagnosed with HFE-HC were included. Results: The FD phenotype presented in 65.5% of affected individuals. Patients with FD were younger at diagnosis and more often female than those with SLC40A1-HC. SLC40A1 variants were associated with higher hepatic and splenic iron concentrations compared to the HFE-HC group. Variability in phenotypic presentation was high among patients with SLC40A1 variants, and a genotype-to-phenotype correlation could only explain a small proportion of this variation. Variants that directly affect the metal binding site in ferroportin more likely presented with high TSAT. Patients with the SLC40A1-HC phenotype (TSAT >45%) had a higher risk of fibrosis. Life expectancy was similar between patients with SLC40A1 variants and matched patients with HFE-HC. Most individuals with SLC40A1 variants (73.2%) received regular phlebotomies, which were not associated with differences in life expectancy. Conclusions: Mutations in SLC40A1 cause a highly variable disease spectrum with hepatic and splenic iron overload. Fibrosis risk is higher in patients with elevated TSAT. Clinical Trial number: Not applicable. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Characterization of ferroportin disease and SLC40A1-related hemochromatosis – Results from the EASL non-HFE registry
Busti, Fabiana;Girelli, Domenico;Corradini, Elena;
2026-01-01
Abstract
Background & Aims: Pathogenic variants in the cellular iron exporter ferroportin (SLC40A1) cause hepatic and splenic iron overload. Low to normal transferrin saturation (TSAT) and iron accumulation in Kupffer cells with high splenic iron distinguish ferroportin disease (FD) from SLC40A1-related hemochromatosis (SLC40A1-HC), which are both caused by variants in SLC40A1. The aim of our study was to describe pathogenic mutations in SLC40A1, phenotypic variability in affected patients and compare outcomes with HFE-related hemochromatosis (HFE-HC). Methods: The international EASL non-HFE hemochromatosis patient registry prospectively collected clinical, radiological, biochemical, and genetic data for 95 patients with SLC40A1 variants from six centers. Additionally, 363 patients were identified by a systematic literature review. As a comparator, 603 patients diagnosed with HFE-HC were included. Results: The FD phenotype presented in 65.5% of affected individuals. Patients with FD were younger at diagnosis and more often female than those with SLC40A1-HC. SLC40A1 variants were associated with higher hepatic and splenic iron concentrations compared to the HFE-HC group. Variability in phenotypic presentation was high among patients with SLC40A1 variants, and a genotype-to-phenotype correlation could only explain a small proportion of this variation. Variants that directly affect the metal binding site in ferroportin more likely presented with high TSAT. Patients with the SLC40A1-HC phenotype (TSAT >45%) had a higher risk of fibrosis. Life expectancy was similar between patients with SLC40A1 variants and matched patients with HFE-HC. Most individuals with SLC40A1 variants (73.2%) received regular phlebotomies, which were not associated with differences in life expectancy. Conclusions: Mutations in SLC40A1 cause a highly variable disease spectrum with hepatic and splenic iron overload. Fibrosis risk is higher in patients with elevated TSAT. Clinical Trial number: Not applicable. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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