Haemochromatosis revisited

Table 1 Review about therapeutic recommendations

Who to start treatment	Patient 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 phase	One 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 stop	Patients 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 types	Gene	Location	Inheritance	Gene product function	Main clinical manifestations
1	HFE	6p21.3	AR	Involved 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.
2A	HJV	1p21	AR	Involved in hepcidin synthesis, BMP co-receptor.	Type 2: earlier onset, < 30 yr. Severe iron overload and juvenile form of haemochromatosis.
2B	HAMP	19q13	AR	Hepcidin, produced mainly in hepatocytes, downregulates iron efflux from enterocytes via ferroportin.	Hypogonadism and cardiomyopathy more prevalent. Severe iron overload and juvenile form of haemochromatosis.
3	TFR2	7q22	AR	Transferrin 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	SLC40A1	2q32	AD	Ferroportin 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	SLC40A1		AD	Ferroportin acting a hepcidin receptor.	Very rare; in general, clinically similar to HFE-haemochromatosis.

TFR2: Transferrin receptor 2; HFE: Encodes HFE protein; HJV: Encodes hemojuvelin; HAMP: Encodes hepcidin; TFR2: Encodes transferrin receptor 2; SLC40A1: Encodes ferroportin; BMP6: Bone morphogenetic protein 6, AR: Autosomal recessive; AD: Autosomal dominant.

Table 3 New classification of haemochromatosis proposed by the working group

New classification	Molecular pattern	Note
HFE-related	p.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-related	Rare 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.
Digenic2	Double 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 undefined	Molecular characterization (still) not available after sequencing of known genes (provisional diagnosis).	Patients should be referred (or DNA should be sent) to specialized centers.

¹Providing that iron overload is confirmed by magnetic resonance imaging (MRI). If MRI is not accessible, close monitoring of haemoglobin level is needed to avoid occurrence of anaemia.

²Caution is needed to interpret as digenic inheritance results from next generation sequencing outputs reporting several variants in gene panels. Whenever possible, strict criteria for defining pathogenic variants should be adopted, and corroborated by family segregation and/or functional studies.