Copyright ©The Author(s) 2022.
World J Hepatol. Nov 27, 2022; 14(11): 1931-1939
Published online Nov 27, 2022. doi: 10.4254/wjh.v14.i11.1931
Table 1 Review about therapeutic recommendations
Who to start treatmentPatient with homozygous genotype HFE p.Cys282Tyr (C282Y/C282Y) and with biochemical indication of iron overload, namely, fasting transferrin saturation increase (≥ 45%) together with serum ferritin increase (> 300 μg/L for men and postmenopausal women, and > 200 μg/L in premenopausal women).
Initial phase or intensive (of induction)Phlebotomies of 400-500 mL (according to body weight) weekly or every 2 wk (depending on the amount of initial iron excess). Objective: to reach a serum ferritin value of 50 μg/L, in the absence of anaemia.
Maintaining phaseOne phlebotomy every 1-4 mo, depending on iron parameters.Objective: to maintain ferritin levels around 50 μg/L (without anaemia; haemoglobin levels should not be < 11 g/dL). Plasma ferritin should be verified prior to each phlebotomy, and transferrin saturation approximately twice a year.
When to stopPatients presenting iron overload should never stop checking their iron parameters, and their treatment must be planned according to their iron parameters, general health condition, and age.
Table 2 Previous classification of haemochromatosis
Haemochromatosis typesGene LocationInheritanceGene product functionMain clinical manifestations
1HFE6p21.3ARInvolved in hepcidin synthesis via BMP6, interaction with TFR1.Iron overload and known manifestation of classical haemochromatosis (HFE type). Arthropathy, skin hyperpigmentation, liver damage, diabetes, endocrine dysfunction, cardiomyopathy, hypogonadism.
2AHJV1p21ARInvolved in hepcidin synthesis, BMP co-receptor.Type 2: earlier onset, < 30 yr. Severe iron overload and juvenile form of haemochromatosis.
2BHAMP19q13ARHepcidin, produced mainly in hepatocytes, downregulates iron efflux from enterocytes via ferroportin.Hypogonadism and cardiomyopathy more prevalent. Severe iron overload and juvenile form of haemochromatosis.
3TFR27q22ARTransferrin receptor 2, mediates cellular uptake of transferrin-bound iron and is involved in hepcidin synthesis.Phenotypes can range from moderate to severe form of haemochromatosis.
4A SLC40A12q32ADFerroportin is an iron exporter in duodenal.Lower tolerance to phlebotomies with risk of anaemia. The phenotype strongly differs from newly defined haemochromatosis (mild clinical symptoms, major spleen iron overload, major hyperferritinemia without transferrin saturation increase).
4B SLC40A1ADFerroportin acting a hepcidin receptor.Very rare; in general, clinically similar to HFE-haemochromatosis.
Table 3 New classification of haemochromatosis proposed by the working group
New classification
Molecular pattern
HFE-relatedp.Cys282Tyr homozygosity or compound heterozygosity of p.Cys282Tyr with other rare HFE pathogenic variants or HFEdeletion.Low penetrance; consider presence of host-related or environmental cofactors for iron overload. In subjects with other HFE genotypes (p.Cys282Tyr/His63Asp compound heterozygosity or p.His63Asp homozygosity) consider second-line genetic testing for rarer variants.
Non HFE-relatedRare pathogenic variants in non-HFE genes: - HJV-related; - HAMP-related; - TFR2-related; - SLC40A1 (very rare gain-of-function variant)-related.Potentially, variants in any hepcidin-regulatory gene may be causative (the effects of novel mutations should be confirmed through functional and epidemiological studies). Molecular subtypes characterization only at specialized canters, but diagnosis of non-HFE related haemochromatosis is sufficient to start phlebotomies at nonspecialized centres1.
Digenic2Double heterozygosity and/or double homozygosity/heterozygosity for variants in two different genes involved in iron metabolism (HFE and/or non-HFE).More commonly, p.Cys282Tyr variants in HFE gene might coexist with variants in other genes; rarely, both variants involve non-HFE genes.
Molecularly undefinedMolecular characterization (still) not available after sequencing of known genes (provisional diagnosis).Patients should be referred (or DNA should be sent) to specialized centers.