HFE hemochromatosis: an overview about therapeutic recommendations

Cancado, Rodolfo D; Alvarenga, Aline Morgan; Santos, Paulo Caleb JL

doi:10.1016/j.htct.2021.06.020

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Hematology, Transfusion and Cell Therapy

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Special article • Hematol., Transfus. Cell Ther. 44 (1) • Jan-Mar 2022 • https://doi.org/10.1016/j.htct.2021.06.020 copy

HFE hemochromatosis: an overview about therapeutic recommendations

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Hemochromatosis is currently characterized by the iron overload caused by hepcidin deficiency. Large advances in the knowledge on the hemochromatosis pathophysiology have occurred due to a better understanding of the protein of the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype. In the present review, the main aims are to show updates on hemochromatosis and to report a practical set of therapeutic recommendations for the human factors engineering protein (HFE) hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, elaborated by the Haemochromatosis International Taskforce.

Keywords
Hemochromatosis; Iron overload; Iron metabolism; HFE

	Involved gene	Inheritance	Function of protein encoded by the gene	Values of iron parameters and main clinical aspects for differential diagnosis
Hemochromatosis types
Type 1	HFE	Autosomal recessive	HFE protein, homeostatic iron regulator, is involved in hepcidin synthesis interacting with transferrin receptor.	Iron overload and known manifestation of classical hemochromatosis (HFE type)^* ⁎ See main clinical manifestations in the “clinical aspects” section. .
Type 2A	HJV (also known as HFE2)	Autosomal recessive	Hemojuvelin, a BMP co-receptor, is involved in hepcidin synthesis.	Severe iron overload and juvenile form of hemochromatosis ^* ⁎ See main clinical manifestations in the “clinical aspects” section. .
Type 2B	HAMP	Autosomal recessive	Hepcidin, produced mainly in hepatocytes, downregulates iron efflux from enterocytes via ferroportin.	Severe iron overload and juvenile form of hemochromatosis ^* ⁎ See main clinical manifestations in the “clinical aspects” section. .
Type 3	TFR2	Autosomal recessive	Transferrin receptor 2, mediates cellular uptake of transferrin-bound iron and is involved in hepcidin synthesis.	The phenotypes can be from mild hemochromatosis- like type 1 to severe juvenile- like form.
Type 4 ^⁎⁎ ⁎⁎ Hemochromatosis type 4: when SLC40A1 mutation leads to hepcidin resistance (previously called hemochromatosis type 4B).	SLC40A1 (also known as FPN1)	Autosomal recessive	Ferroportin is an iron exporter in the duodenal.	The phenotypes can be from mild hemochromatosis-like type 1 to severe juvenile-like form.
Other diseases
Ferroportin disease ^⁎⁎⁎ ⁎⁎⁎ Ferroportin disease: when SLC40A1 mutation leads to ferroportin loss of function (previously called hemochromatosis type 4A).2, 3, 5, 17, 18	SLC40A1 (also known as FPN1)	Autosomal dominant	Ferroportin is an iron exporter in the duodenal.	Increased ferritin and normal/decreased transferrin saturation. Iron magnetic resonance imaging: strong signal in spleen.
BMP6-related iron overload	BMP6	Autosomal dominant	Bone morphogenetic protein 6 is a regulatory molecule of the hepcidin expression.	Increased ferritin and transferrin saturation. Low level of plasma hepcidin. Moderate iron overload.
Hereditary aceruloplasminemia	CP	Autosomal recessive	Ceruloplasmin is involved in the peroxidation of Fe²⁺ transferrin to Fe³⁺ transferrin.	Increased ferritin and normal/decreased transferrin saturation. Microcytic anemia. Iron magnetic resonance imaging: strong signal in the liver. Low levels of ceruloplasmin.
Hereditary atransferrinemia	TF	Autosomal recessive	Transferrin is the iron transporter.	Iron overload and microcytic anemia. Iron magnetic resonance imaging: strong signal in liver and weak signal in spleen.
Hereditary hyperferritinemia with or without cataract	FTL	Autosomal dominant	Light subunit of the ferritin protein, which is the major intracellular iron storage protein.	Hyperferritinemia with or without cataract. Normal serum iron and transferrin saturation.

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH) R. Dr. Diogo de Faria, 775 cj 133, 04037-002, São Paulo / SP - Brasil - São Paulo - SP - Brazil
E-mail: htct@abhh.org.br

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[1] *Corresponding author at: Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, EPM/Unifesp. E-mail address: paulo.caleb@unifesp.br (P.C.J. Santos).

Section ^* ⁎ See further data in the Section 3.4,14, 15, 16, 22 “How to treat”
Initial or induction phase	Maintenance phase
Frequency	Frequency
A phlebotomy schedule on the order of 400 - 500mL, considering body weight, weekly or every two weeks has been proposed.	One phlebotomy every 1 to 4 months, depending on the patient's iron status.¹⁴14 Brissot P. Optimizing the diagnosis and the treatment of iron overload diseases. Expert Rev Gastroenterol Hepatol. 2016;10 (3):359-70.,²¹21 European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22.
Objective and tolerance	Objective and tolerance
Usually, to reach serum ferritin of 50µg/L. Serum ferritin should be checked once a month until the values reach the upper normal limits and every two weeks thereafter until the final goal of serum ferritin is reached. Hemoglobin levels should not decrease below 11 g/dL.	Usually, to maintain ferritin levels around 50µg/L. Hemoglobin levels should not be < 11 g/dL.