HFE hemochromatosis: an overview about therapeutic recommendations

Rodolfo D Cancado Aline Morgan Alvarenga Paulo Caleb JL Santos About the authors

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

Introduction

Hemochromatosis is currently characterized by the iron overload caused by a hepcidin deficiency. This hormone is a key iron modulator in the control of the ferroportin, an iron exporter protein in the cells. In hemochromatosis, plasmatic concentration of hepcidin is low in most cases. Thus, ferroportin activity is high in the enterocytes and, consequently, leads to high uptake and iron overload. But in rare cases, as in the ferroportin deficiency, there is a resistance to hepcidin. Large advances in the knowledge on the hemochromatosis pathophysiology occurred due to a better understanding of the protein in the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype.11 Santos PC, Krieger JE, Pereira AC. Molecular diagnostic and pathogenesis of hereditary hemochromatosis. Int J Mol Sci. 2012;13(2):1497-511., 22 Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers. 2018;4:18016., 33 Barton JC, Edwards CQ. HFE Hemochromatosis. GeneReviews®. Seattle, Seattle (WA): University of Washington; 1993.

In 2018, a Taskforce of the Hemochromatosis International (HI) published a practical set of recommendations on the therapeutic aspects of HFE hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on published scientific studies and guidelines.44 Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6. In this scenario, physicians have the tools that allow them to make a differential diagnosis and to adequately manage the hemochromatosis patients.

The main aims of this study are to show updates on hemochromatosis and to report some aspects of the published therapeutic recommendations.

Diagnosis: clinical aspects, biochemical, genetic and imaging tests

Clinical aspects

Patients can be asymptomatic for decades and subsequently show the manifestation of symptoms for HFE hemochromatosis at approximately 40 years of age in men and 50 years of age in women. Patients with HFE hemochromatosis usually present non-specific symptoms, such as chronic fatigue, abdominal pain, skin hyperpigmentation, arthropathies, diabetes mellitus, hepatomegaly and cirrhosis (when the serum ferritin is > 1,000µg/L). A current study on the quality of life (QoL) showed that patients with the HFE p.Cys282Tyr homozygous genotype had a worse QoL, measured by the short form health survey (SF-36) scale, compared to patients with other genotypes.66 Fonseca PF, Cançado RD, Naoum FA, Dinardo CL, Fonseca GH, Gualandro SF, et al. Quality of life scores differs between genotypic groups of patients with suspected hereditary hemochromatosis. BMC Med Genet. 2018;19(1):3.

Biochemical tests

Laboratory tests routinely used to investigate biochemical evidence of iron overload are the serum ferritin (SF) and transferrin saturation (TS). Box 1 shows values for SF and TS indicated by therapeutic recommendations from the HI taskforce.

Box 1.
Serum ferritin and transferrin saturation values indicated by therapeutic recommendations from the HI taskforce.

The SF is a highly sensitive test for measuring iron overload. However, ferritin is an acute-phase protein and, consequently, elevated SF values are very frequently associated with other causes, such as general inflammations, metabolic syndrome, alcohol consumption and liver damages.22 Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers. 2018;4:18016.,33 Barton JC, Edwards CQ. HFE Hemochromatosis. GeneReviews®. Seattle, Seattle (WA): University of Washington; 1993.,77 Wood MJ, Crawford DH, Wockner LF, Powell LW, Ramm GA. Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis. Liver Int. 2017;37(9):1382-8. It is pivotal to identify the cause of high SF values. SF values > 300µg/L in males and postmenopausal females and > 200 µg/L in premenopausal females were indicated in the therapeutic recommendations from the HI taskforce, in the diagnosis scenario.44 Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6.

The TS is the ratio between serum iron and total iron-binding capacity (TIBC), expressed as a percentage. This is performed with patient fasting and it can be a helpful biomarker of iron overload when the values are ≥ 45% and it corresponds to the basic and earliest biochemical abnormality in the hemochromatosis. The interpretation of the SF and TS values needs to be performed for each individual, taking into account age, gender and co-morbidities, as well as local reference values.88 Santos PC. Variables related to iron status and genetic background among korean populations: ironing out the differences. Dig Dis Sci. 2015;60(10):2871-2.,99 Bardou-Jacquet E, Lainé F, Guggenbuhl P, Morcet J, Jézéquel C, Guyader D, et al. Worse outcomes of patients with HFE hemochromatosis with persistent increases in transferrin saturation during maintenance therapy. Clin Gastroenterol Hepatol. 2017;15(10):1620-7.

Genetic tests

The HFE hemochromatosis is an autosomal recessive disease and the most frequent genotype associated with the phenotype is the p.Cys282Tyr homozygosity (C282Y/C282Y). An important piece of information is that the penetrance of the HFE hemochromatosis is incomplete, i.e., from a low to moderate frequency of individual carrying homozygous genotype (C282Y/C282Y) will have clinical symptoms.

Patients with iron overload carrying the HFE p.Cys282Tyr/p.His63Asp compound heterozygous or p.His63Asp homozygous genotypes are frequently identified in some cohort studies on hemochromatosis, especially in countries with admixed populations. However, a study concerning best practices for the molecular genetic diagnosis of hemochromatosis concluded, according to the level and strength of the evidence, that both genotypes had the following interpretations: at low risk for development of significant iron overload (may be at risk of developing mild to moderate iron overload in association with comorbid factors), or at no increased risk of developing HFE hemochromatosis.1010 Santos PC, Pereira AC, Cançado RD, Schettert IT, Sobreira TJ, Oliveira PS, et al. HFE gene mutations in patients with primary iron overload: is there a significant improvement in molecular diagnosis yield with HFE sequencing? Blood Cells Mol Dis. 2010;45(4):302-7.

Patients with hemochromatosis not linked with HFE (non-HFE hemochromatosis) are usually younger patients aged 20 to 30 years old, presenting symptoms, such as heart failure, diabetes and hypogonadism.33 Barton JC, Edwards CQ. HFE Hemochromatosis. GeneReviews®. Seattle, Seattle (WA): University of Washington; 1993.,55 Sandhu K, Flintoff K, Chatfield MD, Dixon JL, Ramm LE, Ramm GA, et al. Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease. Blood. 2018 Jul 5;132(1):101-10. Non-HFE hemochromatosis includes very rare forms, associated with mutations in the HJV, HAMP, TFR2 and SLC40A1 genes. Genetic investigation for the non-HFE hemochromatosis will be needed when the result for the p.Cys282Tyr homozygosity is negative, mainly in the case of a younger patient with manifestations of the juvenile form and severe iron overload.1111 Santos PC, Dinardo CL, Cançado RD, Schettert IT, Krieger JE, Pereira AC. Non-HFE hemochromatosis. Rev Bras Hematol Hemoter. 2012;34(4):311-6., 1212 Santos PC, Cançado RD, Pereira AC, Schettert IT, Soares RA, Pagliusi RA, et al. Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients. Blood Cells Mol Dis. 2011;46(4):302-7., 1313 Lescano MA, Tavares LC, Santos PCJL. Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox. World J Clin Cases. 2017;5(10):381-3., 1414 Brissot P. Optimizing the diagnosis and the treatment of iron overload diseases. Expert Rev Gastroenterol Hepatol. 2016;10 (3):359-70. Table 1 shows data on the hemochromatosis types and some other genetic diseases that present abnormal values of iron parameters and thus, participate in the context of the differential diagnosis for hemochromatosis.

Table 1.
Data on hemochromatosis types and some genetic diseases that present abnormal values of iron parameters, suggesting hemochromatosis.

Imaging tests

Magnetic resonance imaging (MRI), when available, may be useful to measure parenchymal iron overload, mainly in the liver, but additionally in other organs, such as the heart, pancreas, spleen and pituitary. Iron overload in other organs besides the liver can be a suggestion of the juvenile form. In addition, the MRI can be used for the differential diagnosis of hemochromatosis with other genetic diseases (Table 1). Regarding the hemochromatosis evaluation, the MRI and laboratorial tests have been preferred over the liver biopsy, except in rare cases.22 Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers. 2018;4:18016.,33 Barton JC, Edwards CQ. HFE Hemochromatosis. GeneReviews®. Seattle, Seattle (WA): University of Washington; 1993.,1919 Golfeyz S, Lewis S, Weisberg IS. Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI. Expert Rev Gastroenterol Hepatol. 2018;12(8):767-78.

Treatment

Phlebotomy (venesection therapy) is the standard treatment for patients with hemochromatosis and it is very effective to prevent hemochromatosis damages, safe and has a low cost. Thus, the early diagnosis and initiation of the phlebotomies are important actions to prevent tissue and cell damages due to reactive oxygen species from the iron overload. One phlebotomy of 450mL removes approximately 225mg of iron from the body.

Therapeutic recommendations from the HI Taskforce divided the treatment into two phases: initial phase (or induction) and maintenance phase (Box 2). The authors considered that a high percentage of the recommendations is not shared among the different available guidelines for hemochromatosis and therefore, has proposed objective recommendations which may be used for managing hemochromatosis patients throughout the world.44 Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6.,2020 Vanclooster A, Cassiman D, Van Steenbergen W, Swinkels DW, Janssen MC, Drenth JP, et al. The quality of hereditary haemochromatosis guidelines: a comparative analysis. Clin Res Hepatol Gastroenterol. 2015;39(2):205-14.

Box 2
Treatment indicated by therapeutic recommendations from the HI taskforce.

There are several peculiarities of each hemochromatosis patient and considerations about treatment which must be pondered. Frequencies of the phlebotomies indicated in Box 2 for both phases (initial and maintenance) are significantly different among phases and within the phases. Thus, the phlebotomy frequency should be individualized to the clinical data for each moment of the management of the individualized hemochromatosis patient. Some elderly patients with comorbidities and/or poor vein conditions do not tolerate the “standard phlebotomy regimen”; in these patients, a modified phlebotomy regimen may be required in the induction phase, in which less than 400 to 500 mL blood is drawn and/or the intervals between phlebotomies may be extended and a higher ferritin level of 200 to 400 µg/L may be accepted to avoid anemia and the discomfort due to the phlebotomies.44 Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6.

Patients who have had iron overload should never stop checking his or her iron parameters and should be followed lifelong on an out-patient basis.44 Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6.

Iron chelation therapy is not indicated for classical hemochromatosis. However, in rare cases, iron chelators are an adjuvant treatment (or alternative), such as in severe iron overload without efficacy with phlebotomies, poor vein conditions and severe non-HFE hemochromatosis (mainly juvenile form).2424 Santos PC, Cançado RD, Pereira AC, Chiattone CS, Krieger JE, Guerra-Shinohara EM. HJV hemochromatosis, iron overload, and hypogonadism in a Brazilian man: treatment with phlebotomy and deferasirox. Acta Haematol. 2010;124(4):204-5.,2525 Cançado R, Melo MR, deMoraes Bastos R, Santos PC, Guerra-Shinohara EM, Chiattone C, et al. Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yrPhase2study.Eur JHaematol.2015;95(6):545-50. Erythrocytapheresis have been used to treat hemochromatosis patients, but is more expensive and less available than phlebotomy. Regarding diet, the hemochromatosis patient can have a normal healthy varied diet. Vitamin C, high alcohol consumption and foods with iron fortification should be avoided.22 Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers. 2018;4:18016.,44 Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6.

Two current studies showed the importance of the adequate hemochromatosis treatment and of the early intervention to prevent morbidity caused by the hemochromatosis related to the HFE p.Cys282Tyr homozygosity. Ong and colleagues, enrolling patients with the p.Cys282Tyr homozygous genotype and with a moderate serum ferritin level (300 - 1,000µg/L), performed a randomized controlled trial by dividing the cohort into two groups: iron reduction by erythrocytapheresis (treatment) or sham treatment by plasmapheresis (control). They identified an improvement in the modified fatigue impact scale (MFIS) score in the treatment group, compared to the control. Pilling and colleagues, in a large cohort study at the UK biobank including 2,890 patients with the p.Cys282Tyr homozygous genotype, concluded that hemochromatosis was associated with significant prevalent and incident clinically diagnosed morbidity (liver disease, rheumatoid arthritis, osteoarthritis and diabetes) in both males and females.2222 Ong SY, Gurrin LC, Dolling L, Dixon J, Nicoll AJ, Wolthuizen M, et al. Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial. Lancet Haematol. 2017;4(12):e607-14.,2323 Pilling LC, Tamosauskaite J, Jones G, Wood AR, Jones L, Kuo CL,et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019 Jan 16;364:k5222.. https://doi.org/10.1136/bmj.k5222 Erratum in: BMJ. 2019;367:l6157.
https://doi.org/10.1136/bmj.k5222...

Accessible data for patients and health professionals

The HI, in collaboration with national associations worldwide, has made available the data, with open access to patients and health professionals, including translations in several languages, of the cited “Therapeutic Recommendations” (for details, see at http://hemochromatosis-international.org/translations-therapeutic-recommendations).

References

  • 1
    Santos PC, Krieger JE, Pereira AC. Molecular diagnostic and pathogenesis of hereditary hemochromatosis. Int J Mol Sci. 2012;13(2):1497-511.
  • 2
    Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers. 2018;4:18016.
  • 3
    Barton JC, Edwards CQ. HFE Hemochromatosis. GeneReviews®. Seattle, Seattle (WA): University of Washington; 1993.
  • 4
    Adams P, Altes A, Brissot P, Butzeck B, Cabantchik I, Cançado R, et al. Therapeutic recommendations in HFE hemochromatosis for p. Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83-6.
  • 5
    Sandhu K, Flintoff K, Chatfield MD, Dixon JL, Ramm LE, Ramm GA, et al. Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease. Blood. 2018 Jul 5;132(1):101-10.
  • 6
    Fonseca PF, Cançado RD, Naoum FA, Dinardo CL, Fonseca GH, Gualandro SF, et al. Quality of life scores differs between genotypic groups of patients with suspected hereditary hemochromatosis. BMC Med Genet. 2018;19(1):3.
  • 7
    Wood MJ, Crawford DH, Wockner LF, Powell LW, Ramm GA. Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis. Liver Int. 2017;37(9):1382-8.
  • 8
    Santos PC. Variables related to iron status and genetic background among korean populations: ironing out the differences. Dig Dis Sci. 2015;60(10):2871-2.
  • 9
    Bardou-Jacquet E, Lainé F, Guggenbuhl P, Morcet J, Jézéquel C, Guyader D, et al. Worse outcomes of patients with HFE hemochromatosis with persistent increases in transferrin saturation during maintenance therapy. Clin Gastroenterol Hepatol. 2017;15(10):1620-7.
  • 10
    Santos PC, Pereira AC, Cançado RD, Schettert IT, Sobreira TJ, Oliveira PS, et al. HFE gene mutations in patients with primary iron overload: is there a significant improvement in molecular diagnosis yield with HFE sequencing? Blood Cells Mol Dis. 2010;45(4):302-7.
  • 11
    Santos PC, Dinardo CL, Cançado RD, Schettert IT, Krieger JE, Pereira AC. Non-HFE hemochromatosis. Rev Bras Hematol Hemoter. 2012;34(4):311-6.
  • 12
    Santos PC, Cançado RD, Pereira AC, Schettert IT, Soares RA, Pagliusi RA, et al. Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients. Blood Cells Mol Dis. 2011;46(4):302-7.
  • 13
    Lescano MA, Tavares LC, Santos PCJL. Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox. World J Clin Cases. 2017;5(10):381-3.
  • 14
    Brissot P. Optimizing the diagnosis and the treatment of iron overload diseases. Expert Rev Gastroenterol Hepatol. 2016;10 (3):359-70.
  • 15
    Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328-43.
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    European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53(3):397-417.
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    Pantopoulos K. Inherited disorders of iron overload. Front Nutr. 2018;5:103.
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    Brissot P, Troadec MB, Loréal O, Brissot E. Pathophysiology an d classification of iron overload diseases; update 2018. Transfus Clin Biol. 2019;26(1):80-8.
  • 19
    Golfeyz S, Lewis S, Weisberg IS. Hemochromatosis: pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI. Expert Rev Gastroenterol Hepatol. 2018;12(8):767-78.
  • 20
    Vanclooster A, Cassiman D, Van Steenbergen W, Swinkels DW, Janssen MC, Drenth JP, et al. The quality of hereditary haemochromatosis guidelines: a comparative analysis. Clin Res Hepatol Gastroenterol. 2015;39(2):205-14.
  • 21
    European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22.
  • 22
    Ong SY, Gurrin LC, Dolling L, Dixon J, Nicoll AJ, Wolthuizen M, et al. Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial. Lancet Haematol. 2017;4(12):e607-14.
  • 23
    Pilling LC, Tamosauskaite J, Jones G, Wood AR, Jones L, Kuo CL,et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ. 2019 Jan 16;364:k5222.. https://doi.org/10.1136/bmj.k5222 Erratum in: BMJ. 2019;367:l6157.
    » https://doi.org/10.1136/bmj.k5222
  • 24
    Santos PC, Cançado RD, Pereira AC, Chiattone CS, Krieger JE, Guerra-Shinohara EM. HJV hemochromatosis, iron overload, and hypogonadism in a Brazilian man: treatment with phlebotomy and deferasirox. Acta Haematol. 2010;124(4):204-5.
  • 25
    Cançado R, Melo MR, deMoraes Bastos R, Santos PC, Guerra-Shinohara EM, Chiattone C, et al. Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yrPhase2study.Eur JHaematol.2015;95(6):545-50.

Publication Dates

  • Publication in this collection
    21 Mar 2022
  • Date of issue
    Jan-Mar 2022

History

  • Received
    06 July 2020
  • Accepted
    24 June 2021
  • Published
    17 Nov 2021
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