THE NATURAL HISTORY OF FERROPORTIN DISEASE - RESULTS OF THE INTERNATIONAL, MULTICENTER EASL NON-HFE

Heinz ZOLLER^1,20, Mayka SANCHEZ⁸, Hansi WEISSENSTEINER⁹, Sebastian SCHÖNHERR⁹, Lukas FORER⁹, Florian KRONENBERG⁹, Lorenz M PAMMER², Christian KREMSER¹⁰, Benjamin HENNINGER¹⁰, Paulo C J L SANTOS¹¹, An PENG¹², Benedickt SCHAEFER², Fudi WANG¹², De Gobbi MARCO¹³, Sule UNAL¹⁴, Yamakawa NORIYUKI¹⁵, Hal DRAKESMITH¹⁶, Herbert TILG², Edouard BARDOU-JACQUET¹⁷, Domenico GIRELLI⁷, Alberto PIPERNO¹⁸, Antonello PIETRANGELO¹⁹, Maria TROPPMAIR², Elena CORRADINI¹⁹, Massimo FIORINI³, Stefania SCARLINI³, Sara PELUCCHI⁴, Raffaella MARIANI⁵, Graça PORTO⁶, Fabiana BUSTI⁷

¹Medical University of Innsbruck, Innsbruck, Austria
¹⁰Medical University of Innsbruck, Department of Radiology, Anichstrasse 35, 6020, Innsbruck, Austria
¹¹Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of Sao Paulo,, Sao Paulo, Brazil
¹²Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University,, Beijing 100083, China
¹³University of Torino, Department of Clinical and Biological Sciences, AOU San Luigi Gonzaga, Orbassano,, Torino, Italy
¹⁴Hacettepe University, Division of Pediatric Hematology, 06100, Ankara, Turkey
¹⁵Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
¹⁶Medical Research Council Translational Immune Discovery Unit MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington,, Oxford OX3 9DS, United Kingdom
¹⁷Department of Liver Diseases CHU de Rennes, Rennes 1 University, Pontchaillou Hospital, 35033, Rennes, France
¹⁸17Centre for Rare Disease-Disorders of Iron Metabolism, Fondazione IRCCS, San Gerardo dei Tintori, European Reference Network-EuroBloodNet, 20900, Monza, Italy
¹⁹Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, University Hospital of Modena, 41125,, Modena, Italy
²Medical University of Innsbruck, Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology, Anichstrasse 35, 6020,, Innsbruck, Austria
²⁰Christian Doppler Laboratory for Iron and Phosphate Biology, Medical University of Innsbruck,, Innsbruck, Austria
³Internal Medicine Unit and Centre for Hemochromatosis and Heredometabolic Liver Diseases, EuroBloodNet Referral Center for Iron Disorders, Policlinico, Azienda Ospedaliero-Universitaria di Modena, , Modena, Italy
⁴School of Medicine and Surgery, University of Milano-Bicocca, 20900, Monza, Italy
⁵SSD Rare Diseases, Fondazione IRCCS-San Gerardo dei Tintori, European Reference Network-EuroBloodNet, 20900 , Monza, Italy
⁶Hemochromatosis and Iron Metabolism Unit, Serviço de Imuno-hemoterapia, CHUdSA - Centro Hospitalar Universitário de Santo António, , Porto, Portugal
⁷Department of Medicine, Section of Internal Medicine, University of Verona and EuroBloodNet Referral Center for Iron Disorders, Azienda Ospedaliera Universitaria Integrata of Verona, , Verona, Italy
⁸Iron Metabolism: Regulation and Diseases, Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), 08195, Sant Cugat del Vallès, Spain
⁹Medical University of Innsbruck, Institute of Genetic Epidemiology,, Innsbruck 6020, Austria

Background and Aims: Ferroportin (FPN) disease and SLC40A1-related hemochromatosis (former type 4B) are phenotypically distinct diseases caused by mutations in SLC40A1. Transferrin saturation and splenic/macrophage iron overload distinguish FPN disease from hemochromatosis. Prognosis and management of patients with SLC40A1 mutations has been inferred from HFE hemochromatosis, despite differences in phenotypic presentation. We aim to define the clinical characteristics and management of patients with SLC40A1mutations in comparison to HFE hemochromatosis.

Methods: The EASL non-HFE registry study collected structured clinical data from 95 patients with SLC40A1 mutations and was expanded by 339 published cases from a systematic literature search. Data were compared with an age and sex matched cohort of patients diagnosed with HFE C282Y homozygous hemochromatosis.

Results: Individuals with FPN disease had significantly lower serum iron, ferritin, and transferrin saturation when compared with hemochromatosis patients. Thirty-three percent of patients presented with a SLC40A1-related hemochromatosis phenotype. Median hepatic and splenic iron concentration was higher in individuals with FPN disease as compared to the HFE hemochromatosis group (p<0.001). Mean survival after diagnosis was 32.6 years in individuals with SLC40A1 mutations as compared to 24.4 years in HFEhemochromatosis patients (p=0.509). In the SLC40A1 group, 74% of patients received phlebotomies (median: 0.7/month) which was not associated with survival.

Conclusion: Higher ferritin and hepatic iron concentrations indicate more severe iron overload in patients with FPN disease compared to hemochromatosis patients, but both groups show comparable survival. In individuals with FPN disease treated with phlebotomy no survival benefit was observed.