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Hemochromatosis type 5(HFE5)

MedGen UID:
341982
•Concept ID:
C1851316
•
Disease or Syndrome
Synonym: Iron overload, autosomal dominant
SNOMED CT: FTH1-associated iron overload (1230310007); Ferritin heavy chain 1-related iron overload (1230310007); FTH1-related iron overload (1230310007); FTH1 (ferritin heavy chain 1) related iron overload (1230310007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Gene (location): FTH1 (11q12.3)
 
Monarch Initiative: MONDO:0014225
OMIM®: 615517
Orphanet: ORPHA247790

Definition

A rare disorder of iron metabolism and transport characterised by elevated serum ferritin levels, increased serum iron, increased transferrin saturation and heavy iron deposition in hepatocytes. Iron deposition has also been indicated in heart and bone marrow, while haematological examination of peripheral blood shows no abnormalities. [from SNOMEDCT_US]

Clinical features

From HPO
Elevated hepatic iron concentration
MedGen UID:
868497
•Concept ID:
C4022891
•
Finding
An increased level of iron in liver tissues.
See: Feature record | Search on this feature
Anemia
MedGen UID:
1526
•Concept ID:
C0002871
•
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
See: Feature record | Search on this feature
Increased circulating iron concentration
MedGen UID:
57739
•Concept ID:
C0151900
•
Finding
The concentration of iron in the blood circulation is above the upper limit of normal.
See: Feature record | Search on this feature
Increased circulating ferritin concentration
MedGen UID:
69130
•Concept ID:
C0241013
•
Finding
Increased concentration of ferritin in the blood circulation.
See: Feature record | Search on this feature
Elevated transferrin saturation
MedGen UID:
868498
•Concept ID:
C4022892
•
Finding
An above normal level of saturation of serum transferrin with iron.
See: Feature record | Search on this feature
Abnormal circulating copper concentration
MedGen UID:
892610
•Concept ID:
C4023689
•
Finding
An abnormal concentration of copper.
See: Feature record | Search on this feature
Abnormal circulating transferrin concentration
MedGen UID:
1694121
•Concept ID:
C5139308
•
Finding
Any deviation from the normal concentration of transferrin in the blood circulation.
See: Feature record | Search on this feature
Abnormal circulating ceruloplasmin concentration
MedGen UID:
1726009
•Concept ID:
C5421638
•
Finding
Any deviation of the concentration of ceruloplasmin in the blood from the normal range.
See: Feature record | Search on this feature
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Term Hierarchy

Follow this link to review classifications for Hemochromatosis type 5 in Orphanet.

Professional guidelines

PubMed

Risk of Hepatocellular Carcinoma in Patients with Various HFE Genotypes.
Natarajan Y, Patel P, Chu J, Yu X, Hernaez R, El-Serag H, Kanwal F
Dig Dis Sci 2023 Jan;68(1):312-322. Epub 2022 Jul 5 doi: 10.1007/s10620-022-07602-9. PMID: 35790703
Correlation of genotype and phenotype in 32 patients with hereditary hemochromatosis in China.
Wu L, Zhang W, Li Y, Zhou D, Zhang B, Xu A, Wu Z, Wu L, Li S, Wang X, Zhao X, Wang Q, Li M, Wang Y, You H, Huang J, Ou X, Jia J
Orphanet J Rare Dis 2021 Sep 28;16(1):398. doi: 10.1186/s13023-021-02020-y. PMID: 34583728Free PMC Article
Genetic testing in the European Union: does economic evaluation matter?
Antoñanzas F, Rodríguez-Ibeas R, Hutter MF, Lorente R, Juárez C, Pinillos M
Eur J Health Econ 2012 Oct;13(5):651-61. Epub 2011 May 20 doi: 10.1007/s10198-011-0319-x. PMID: 21598012

Recent clinical studies

Etiology

A Prospective Study on the Prevalence of MASLD in Patients With Type 2 Diabetes and Hyperferritinaemia.
Amangurbanova M, Huang DQ, Noureddin N, Tesfai K, Bettencourt R, Siddiqi H, Lopez SJ, Cervantes V, Madamba E, Loomba R
Aliment Pharmacol Ther 2025 Feb;61(3):456-464. Epub 2024 Nov 5 doi: 10.1111/apt.18377. PMID: 39499168
Hemochromatosis classification: update and recommendations by the BIOIRON Society.
Girelli D, Busti F, Brissot P, Cabantchik I, Muckenthaler MU, Porto G
Blood 2022 May 19;139(20):3018-3029. doi: 10.1182/blood.2021011338. PMID: 34601591Free PMC Article
Diabetes and hemochromatosis.
Creighton Mitchell T, McClain DA
Curr Diab Rep 2014;14(5):488. doi: 10.1007/s11892-014-0488-y. PMID: 24682660
The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease.
Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A, Tagliabue J, Annoni G, Vergani C
Neurobiol Aging 2001 Jul-Aug;22(4):563-8. doi: 10.1016/s0197-4580(01)00219-6. PMID: 11445256
HFE genotypes and haemochromatosis: quantifying the risks of disease.
Lester S, Bardy P, McCluskey J
Tissue Antigens 1999 Sep;54(3):282-4. doi: 10.1034/j.1399-0039.1999.540310.x. PMID: 10519366

Diagnosis

Hemochromatosis classification: update and recommendations by the BIOIRON Society.
Girelli D, Busti F, Brissot P, Cabantchik I, Muckenthaler MU, Porto G
Blood 2022 May 19;139(20):3018-3029. doi: 10.1182/blood.2021011338. PMID: 34601591Free PMC Article
Juvenile haemochromatosis.
Griffiths WJH, Besser M, Bowden DJ, Kelly DA
Lancet Child Adolesc Health 2021 Jul;5(7):524-530. Epub 2021 Apr 15 doi: 10.1016/S2352-4642(20)30392-8. PMID: 33861982
Hyperferritinemia and diagnosis of type 1 Gaucher disease.
Marchi G, Nascimbeni F, Motta I, Busti F, Carubbi F, Cappellini MD, Pietrangelo A, Corradini E, Piperno A, Girelli D
Am J Hematol 2020 May;95(5):570-576. Epub 2020 Feb 22 doi: 10.1002/ajh.25752. PMID: 32031266
HFE-associated hereditary hemochromatosis.
Alexander J, Kowdley KV
Genet Med 2009 May;11(5):307-13. doi: 10.1097/GIM.0b013e31819d30f2. PMID: 19444013
Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells.
Schwake L, Henkel AW, Riedel HD, Schlenker T, Both M, Migala A, Hadaschik B, Henfling N, Stremmel W
Am J Physiol Cell Physiol 2002 May;282(5):C973-9. doi: 10.1152/ajpcell.00415.2001. PMID: 11940510

Therapy

Hyperferritinemia and diagnosis of type 1 Gaucher disease.
Marchi G, Nascimbeni F, Motta I, Busti F, Carubbi F, Cappellini MD, Pietrangelo A, Corradini E, Piperno A, Girelli D
Am J Hematol 2020 May;95(5):570-576. Epub 2020 Feb 22 doi: 10.1002/ajh.25752. PMID: 32031266
Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.
Kallianpur AR, Gerschenson M, Hulgan T, Kaur H, Clifford DB, Haas DW, Murdock DG, McArthur JC, Samuels DC, Simpson DM
AIDS Res Hum Retroviruses 2018 Nov;34(11):942-949. Epub 2018 Aug 22 doi: 10.1089/AID.2018.0025. PMID: 29968489Free PMC Article
Prenatal iron exposure and childhood type 1 diabetes.
Størdal K, McArdle HJ, Hayes H, Tapia G, Viken MK, Lund-Blix NA, Haugen M, Joner G, Skrivarhaug T, Mårild K, Njølstad PR, Eggesbø M, Mandal S, Page CM, London SJ, Lie BA, Stene LC
Sci Rep 2018 Jun 13;8(1):9067. doi: 10.1038/s41598-018-27391-4. PMID: 29899542Free PMC Article
Prevention of hepatocellular carcinoma in nonviral-related liver diseases.
Fan JG, Farrell GC; Asia-Pacific Working Party for Prevention of Hepatocellular Carcinoma
J Gastroenterol Hepatol 2009 May;24(5):712-9. doi: 10.1111/j.1440-1746.2009.05776.x. PMID: 19646014
Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy.
Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH
J Mol Med (Berl) 2006 May;84(5):349-64. Epub 2006 Apr 8 doi: 10.1007/s00109-005-0029-x. PMID: 16604332Free PMC Article

Prognosis

A Prospective Study on the Prevalence of MASLD in Patients With Type 2 Diabetes and Hyperferritinaemia.
Amangurbanova M, Huang DQ, Noureddin N, Tesfai K, Bettencourt R, Siddiqi H, Lopez SJ, Cervantes V, Madamba E, Loomba R
Aliment Pharmacol Ther 2025 Feb;61(3):456-464. Epub 2024 Nov 5 doi: 10.1111/apt.18377. PMID: 39499168
HLA-A*03, the hemochromatosis ancestral haplotype, and phenotypes of referred hemochromatosis probands with HFE p.C282Y homozygosity.
Barton JC, Barton JC, Acton RT
Hereditas 2022 Jun 6;159(1):25. doi: 10.1186/s41065-022-00237-w. PMID: 35659379Free PMC Article
Splicing analysis of SLC40A1 missense variations and contribution to hemochromatosis type 4 phenotypes.
Le Tertre M, Ka C, Raud L, Berlivet I, Gourlaouen I, Richard G, Uguen K, Chen JM, Férec C, Fichou Y, Le Gac G
Blood Cells Mol Dis 2021 Mar;87:102527. Epub 2020 Dec 8 doi: 10.1016/j.bcmd.2020.102527. PMID: 33341511
The biochemical and clinical penetrance of individuals diagnosed with genetic haemochromatosis by predictive genetic testing.
Watkins S, Thorburn D, Joshi N, Neilson M, Joyce T, Spooner R, Cooke A, Mills PR, Morris AJ, Stanley AJ
Eur J Gastroenterol Hepatol 2008 May;20(5):379-83. doi: 10.1097/MEG.0b013e3282f3e708. PMID: 18403938
Survival advantage of the hemochromatosis C282Y mutation.
Weinberg ED
Perspect Biol Med 2008 Winter;51(1):98-102. doi: 10.1353/pbm.2008.0001. PMID: 18192769

Clinical prediction guides

A Prospective Study on the Prevalence of MASLD in Patients With Type 2 Diabetes and Hyperferritinaemia.
Amangurbanova M, Huang DQ, Noureddin N, Tesfai K, Bettencourt R, Siddiqi H, Lopez SJ, Cervantes V, Madamba E, Loomba R
Aliment Pharmacol Ther 2025 Feb;61(3):456-464. Epub 2024 Nov 5 doi: 10.1111/apt.18377. PMID: 39499168
Splicing analysis of SLC40A1 missense variations and contribution to hemochromatosis type 4 phenotypes.
Le Tertre M, Ka C, Raud L, Berlivet I, Gourlaouen I, Richard G, Uguen K, Chen JM, Férec C, Fichou Y, Le Gac G
Blood Cells Mol Dis 2021 Mar;87:102527. Epub 2020 Dec 8 doi: 10.1016/j.bcmd.2020.102527. PMID: 33341511
Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases.
Pretorius E, Kell DB
Integr Biol (Camb) 2014 May;6(5):486-510. doi: 10.1039/c4ib00025k. PMID: 24714688
Survival advantage of the hemochromatosis C282Y mutation.
Weinberg ED
Perspect Biol Med 2008 Winter;51(1):98-102. doi: 10.1353/pbm.2008.0001. PMID: 18192769
Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells.
Schwake L, Henkel AW, Riedel HD, Schlenker T, Both M, Migala A, Hadaschik B, Henfling N, Stremmel W
Am J Physiol Cell Physiol 2002 May;282(5):C973-9. doi: 10.1152/ajpcell.00415.2001. PMID: 11940510

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