Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype

Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles.


Introduction
Although guidelines are available for hereditary hemochromatosis (HH), a high percentage of the recommendations within them are not shared between the different guidelines [1]. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training.
The final version of these recommendations was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles.

Whom to treat and when to start
Patients with HFE p.Cys282Tyr (C282Y/C282Y) homozygous genotype and biochemical evidence of iron overload, i.e., increased serum ferritin ([ 300 lg/L in male and postmenopausal female and [ 200 lg/L in premenopausal female) and increased fasting transferrin saturation (C 45%) [2,3].

Considerations
• A judgement has to be made for each individual patient taking into account their ferritin level (according to local reference value), age, gender, and co-morbidities. • Patients with other genotypes should be referred for further advice. • Recent studies observed a beneficial effect of early and sustained management of patients with iron excess, even when iron load is mild or moderately elevated serum ferritin [4,5].

Treatment
Phlebotomy (venesection therapy) is the standard treatment for patients with HH having been used for more than 60 years. It is effective in reducing morbidity and mortality of HH [6]. Iron overload leads to tissue injury mainly through the production of reactive oxygen species which damage cell membranes and organelles, ending up with cellular death. Thus, to start the treatment is important.
Each 500 mL phlebotomy withdraws approximately 250 mg of iron which is subsequently released, in a compensatory process, from overloaded tissues (especially the liver), ending up, with phlebotomy repetition, to the total removal of body iron excess.

Initial or induction phase
A phlebotomy schedule of the order of 400-500 mL, considering body weight, weekly or every 2 weeks has been proposed [2,7].
The objective in this phase is usually to reach serum ferritin at 50 lg/L provided that there is no anemia.
Serum ferritin should be checked once a month until the values reach the upper normal limits, and every 2 weeks thereafter, until the final goal of serum ferritin is reached [2,3,5].

Considerations
• The volume and frequency of the phlebotomies should be adapted to the clinical characteristics and (individual) tolerance of the patient. • Tolerance: clinical data (general tolerance and blood pressure); hemoglobin (levels should not decrease below 11 g/dL) [7]. • Phlebotomies can be performed in a clinic, hospital, transfusion/blood donor centers or in certain circumstances at home (by a nurse under medical supervision). • Patients should be well hydrated and fed.

Maintenance phase
The maintenance phase follows the induction phase.
The patient with HH needs lifelong follow-up. One phlebotomy every 1-4 months, depending on the patient's iron status [2,7].

Considerations
• The frequency of maintenance phlebotomy varies among individuals, ranging from one per month to one per year [3]. • Hemoglobin levels should not be \ 11 g/dL.
• Hemoglobin value, typically, should be assessed preceding phlebotomy, especially in older patients, who are more susceptible to anemia and chronic blood losses. • Serum ferritin should be checked at every other phlebotomy (at the same time as hemoglobin), at least yearly. • Fasting transferrin saturation should also be checked, at least once a year. • In certain countries, a growing number of patients with uncomplicated hemochromatosis donate blood or qualify as blood donors. Blood removed from therapeutic phlebotomy may be used at the discretion of the blood service [8].

When to stop
Patients who have had iron overload should never stop having their iron status monitored and their treatment planned in the light of their iron status, general condition, and age.

Additional considerations
Diet A healthy varied diet should be eaten, avoiding foods with iron fortification such as breakfast cereals. Iron and vitamin C supplementation and high alcohol consumption should also be avoided [3]. In certain geographical regions (especially subtropical), HH patients should avoid raw shellfish and undercooked pork because of the risk of severe infections. Dietary restriction should not replace phlebotomy therapy.

Chelation therapy
Iron chelation is usually indicated for iron overload related to chronic anemias that need repeated transfusions. However, iron chelators are an alternative treatment (or adjuvant) only used in rare and special cases of HH, when phlebotomies are medically contraindicated, simply impossible owing to poor vein conditions, or the efficacy was not achieved with phlebotomies.

Possible future of HH therapeutics
Hepcidin-based therapies might, in future, become a potential adjunct treatment to phlebotomy in the induction phase or a replacement for the phlebotomy maintenance phase. The possibility of using hepcidin is based on the diminishing of hepcidin levels in HH patients, which is responsible for increased serum iron and transferrin saturation, and subsequently to tissue iron overload [9]. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creative commons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 3 Inserm Unit 1241, University Hospital Pontchaillou, Rennes, France 4 HI -Haemochromatosis International, London, UK 5 European Federation of Associations of Patients with Haemochromatosis, Seine, France