CONSENSUS INITIATIVE FOR THE DEFINITION OF PHENOTYPIC DIAGNOSTIC CRITERIA FOR HEMOCHROMATOSIS

Maria Rosina TROPPMAIR¹, Yelena GINZBURG¹⁰, Fabiana BUSTI⁶, Michaela PLAIKNER¹, Benjamin HENNINGER¹, Yves GANDON³, Heinz ZOLLER¹, Herbert TILG¹, Graca PORTO², Edouard BARDOU-JACQUET³, Jeremy SHEARMAN⁴, John D. RYAN⁵, Domenico GIRELLI⁶, Elena CORRADINI⁷, Bill GRIFFITHS⁸, Luca VALENTI⁹

¹Medical University of Innsbruck, Innsbruck, Austria
¹⁰Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States
²Center for Predictive and Preventive Genetics/IBMC , i3S-University of Porto and University Hospital Center of Santo António, Porto, Portugal
³CHU de Rennes - Université de Rennes, Rennes, France
⁴Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwickshire, United Kingdom
⁵Beaumont Hospital, Dublin, Ireland
⁶Department of Medicine, University of Verona and Integrated University Hospital of Verona, Verona, Italy
⁷Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, and Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
⁸Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
⁹Department of Pathophysiology and Transplantation, Universita Degli Studi Di Milano, and Biological Resource Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milano, Italy

Background

The finding that hemochromatosis is caused by a dysregulation of the hepcidin-ferroportin axis has promoted an update in disease nomenclature without providing practical diagnostic criteria. Iron overload in hemochromatosis is progressive in the liver, while sparing the spleen. R2* Magnetic Resonance Imaging (MRI) has replaced liver biopsy for iron quantification. R2* is directly proportional to liver iron and linearly increases with magnetic field strength.

Aims

The aim of this initiative is to establish phenotypic diagnostic criteria for hemochromatosis and develop thresholds for liver and spleen R2*/T in patients with iron overload and homozygosity for the C282Y variant to develop diagnostic criteria applicable for patients with suspected non HFE-hemochromatosis .

Methods

In this ongoing multi-center retrospective study, we collect liver and spleen MRI (R2*/Tesla) and serum iron parameters in patients homozygous for C282Y. In the study cohort, hemochromatosis was defined by homozygosity for C282Y and transferrin saturation (TSAT) > 50% in males and > 45% in females.

Results

In 143 C282Y homozygous patients who met the inclusion criteria, median ferritin was 738.5mg/l (460.8; 1679.0) and median TSAT 83% (69.3; 87.0). Median liver R2*/Tesla was 120.6s-1*T-1 (54.5;228.6), median spleen R2*/Tesla 24.0s-1*T-1 (17.5; 32.3).

Conclusion

We propose 2 out of 3 of the following criteria for the phenotypic hemochromatosis diagnosis: (i) C282Y homozygosity, (ii) elevated TSAT and (iii) liver R2* >100s-1T-1 with spleen R2* <50s-1T-1. If appropriately validated, these criteria could be used as thresholds for treatment indication and for referral to 2nd level genetic testing in patients with suspected non-HFE hemochromatosis.