HFE mutation H63D

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The HFE mutation H63D is a mutation of the HFE - gene with replacement of histidine through aspartic acid at the position 63 of the Hereditary hemochromatosis-protein . It occurs to about 15% ( heterozygous ) in the normal population.

distribution

For frequency and distribution, see type 1 hemochromatosis # Distribution .

Advantages of mutation

The mutation H63D appears to be useful against iron deficiency and leads to higher hemoglobin concentrations in males. Homozygous carriers have a higher transferrin saturation .

Disease value

People with a homozygous H63D mutation ( H63D / H63D ) rarely develop the classic type 1 hemochromatosis with clinical manifestations and then only have a low iron accumulation.

H63D / H63D alone is not a sufficient genetic cause of iron overload. If hyperferritinemia is found, other factors are usually present. As listed in Hemochromatosis , symptoms of the disease can include liver damage , diabetes , skin pigmentation, enlarged spleen , joint inflammation , atrial fibrillation , signs of mental illness, and testicular changes.

Associated diseases

Irrespective of a clinical disease, carriers of this mutation are associated with various syndromes and diseases.

Familial Alzheimer's disease , porphyria cutanea tarda type II, porphyria variegata , neurodegenerative diseases such as Alzheimer's disease and - and others - have already been mentioned in hemochromatosis type 1 . a. Increases in blood triglycerides .

In addition, other associations were described:

and other diseases with iron overload, see hemochromatosis # Other congenital diseases with iron overload

heart

Iron deposits in the heart can lead to cardiomegaly and decreased ejection fraction and manifest clinically as congestive heart failure and arrhythmia . A significant connection with the mutation H63D could not be demonstrated.

Brain damage

A relevant potential risk is damage to the brain ( neurodegeneration ) through iron accumulation, which can lead to oxidative stress within the affected cells and subsequently to cell death (scarring of brain tissue) with severely impaired neurotransmitter activity, which can result in excitotoxicity . An increased risk of Parkinson's disease is assessed inconsistently.

Liver disease

As far as the liver is concerned, the literature data are partly contradictory. The frequency of the mutation is not increased in alcohol-related liver disease. The mutation does not lead to a significant increase in hepatopathies (diseases of the liver) such as liver fibrosis or fatty liver

In male homozygous mutation carriers there is a different correlation with cirrhosis of the liver : increased risk of non-alcoholic fatty liver (NAFLD) and hepatocellular carcinoma (HCC) yes, but not for cirrhosis.

There is another significant relationship to liver cell carcinoma and its tumor aggressiveness:

meaning

According to the current state of research, people with a homozygous H63D mutation of HFE should be screened for syndromic symptoms that affect the brain, nervous system, heart, liver and, to a lesser extent, kidney function , skin diseases, blood formation and other vulnerable ones Affect organ systems.

A causal treatment is not available because free iron (NTBI) that is not bound to proteins cannot be removed from cells by bloodletting or similar procedures. In this way, in the event of illness, at most some of the symptoms can be alleviated. In the case of a homozygous H63D mutation, dietary control of iron intake should only be carried out under the supervision of a medical nutritionist , as the body can be overloaded with non-protein-bound iron (NTBI), for example due to hypotransferrinaemia , parallel to a ferritin deficiency.

Individual evidence

  1. ↑ P. Nielsen, R. Fischer, Roland, R. Engelhardt et al .: New-possibilities-in-the-diagnosis-of-hereditary-hemochromatosis. In: Deutsches Ärzteblatt Vol. 95, No. 46, 1998, Ärzteblatt
  2. ↑ A. Allen, A. Premawardhena, S. Allen, R. Rodrigo, A. Manamperi, L. Perera, K. Wray, A. Armitage, C. Fisher, A. Drakesmith, K. Robson, D. Weatherall: The p.H63D allele of the HFE gene protects against low iron stores in Sri Lanka. In: Blood cells, molecules & diseases. Volume 76, 05 2019, pp. 72-77, doi: 10.1016 / j.bcmd.2019.02.004 , PMID 30827762 .
  3. ↑ KH Barbara, L. Marcin, A. Jedrzej, Z. Wieslaw, AD Elzbieta, M. Malgorzata, M. Ewa, KJ Jacek: The impact of H63D HFE gene carriage on hemoglobin and iron status in children. In: Annals of hematology. Volume 95, number 12, December 2016, pp. 2043-2048, doi: 10.1007 / s00277-016-2792-x , PMID 27553379 , PMC 5093215 (free full text).
  4. ↑ a b Guidelines of the European Association for the Study of the Liver: EASL clinical practice guidelines for HFE hemochromatosis. In: Journal of Hepatology . Volume 53, Number 1, July 2010, pp. 3-22, doi: 10.1016 / j.jhep.2010.03.001 , PMID 20471131 .
  5. ↑ H. Gabriel, M. Stuhrmann-Spangenberg: Guideline for the molecular genetic diagnosis of hereditary hemochromatosis, 2006, gfhev
  6. ↑ M. Kelley, N. Joshi, Y. Xie, M. Borgaonkar: Iron overload is rare in patients homozygous for the H63D mutation. In: Canadian Journal of Gastroenterology & Hepatology. Volume 28, Number 4, April 2014, pp. 198–202, doi: 10.1155 / 2014/468521 , PMID 24729993 , PMC 4071918 (free full text).
  7. ↑ A. Finkenstedt, M. Schranz, N. Baumgartner et al .: HFE genotypes, iron status and survival. In: Zeitschrift für Gastroenterologie , Vol. 52 - P65, 2014, doi: 10.1055 / s-0034-1376049 .
  8. ↑ P. Joly, H. Vignaud, J. Di Martino, M. Ruiz, R. Garin, L. Restier, A. Belmalih, C. Marchal, C. Cullin, B. Arveiler, P. Fergelot, AD Gitler, A . Lachaux, J. Couthouis, M. Bouchecareilh: ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency. In: PLOS ONE . Volume 12, number 6, 2017, p. E0179369, doi: 10.1371 / journal.pone.0179369 , PMID 28617828 , PMC 5472284 (free full text).
  9. ↑ S. Selvaraj, S. Seidelmann, OM Silvestre, B. Claggett, CE Ndumele, S. Cheng, B. Yu, MM Fernandes-Silva, ML Grove, E. Boerwinkle, AM Shah, SD Solomon: HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study. In: Hypertension. Volume 73, number 1, 01 2019, pp. 68-74, doi: 10.1161 / HYPERTENSIONAHA.118.11730 , PMID 30571559 .
  10. ^ RM Mitchell, SY Lee, Z. Simmons, JR Connor: HFE polymorphisms affect cellular glutamate regulation. In: Neurobiology of Aging. Volume 32, number 6, June 2011, pp. 1114-1123, doi: 10.1016 / j.neurobiolaging.2009.05.016 , PMID 19560233 .
  11. ↑ H. Fujii, N. Takagaki, T. Yoh, A. Morita, T. Ohkawara, K. Yamaguchi, M. Minami, Y. Sawa, T. Okanoue, Y. Ohkawara, Y. Itoh: Non-prescription supplement- induced hepatitis with hyperferritinemia and mutation (H63D) in the HFE gene. In: Hepatology Research. Volume 38, Number 3, March 2008, pp. 319-323, doi: 10.1111 / j.1872-034X.2007.00266.x , PMID 17944940 .
  12. ↑ M. Zhang, H. Xiong, L. Fang, W. Lu, X. Wu, YQ Wang, ZM Cai, S. Wu: Meta-Analysis of the Association between H63D and C282Y Polymorphisms in HFE and Cancer Risk. In: Asian Pacific Journal of Cancer Prevention: APJCP. Volume 16, number 11, 2015, pp. 4633-4639, doi: 10.7314 / apjcp.2015.16.11.4633 , PMID 26107216 .
  13. ↑ A. Castiella, I. Urreta, E. Zapata et al .: H63 / H63D genotype and the H63D allele are associated in patients with hyperferritinemia to the development of metabolic syndrome. In: European Journal of Internal Medicine. 2019, doi: 10.1016 / j.ejim.2019.11.021 .
  14. ↑ M. Luszczyk, B. Kaczorowska-Hac, E. Milosz, E. Adamkiewicz-Drozynska, E. Ziemann, R. Laskowski, D. Flis, M. Rokicka-Hebel, J. Antosiewicz: Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in the Gene. In: BioMed Research International. Volume 2017, 2017, p. 5313914, doi: 10.1155 / 2017/5313914 , PMID 29362711 , PMC 5736923 (free full text).
  15. ↑ C. Ellervik, A. Tybjaerg-Hansen, M. Appleyard, H. Sillesen, G. Boysen, BG Nordestgaard: Hereditary hemochromatosis genotypes and risk of ischemic stroke. In: Neurology. Volume 68, Number 13, March 2007, pp. 1025-1031, doi: 10.1212 / 01.wnl.0000257814.77115.d6 , PMID 17389307 .
  16. ↑ R. Rahmani, P. Naseri, A. Safaroghli-Azar, S. Tarighi, T. Hosseini, MT Hojjati: Investigation of correlation between H63D and C282Y mutation in HFE gene and serum ferritin level in beta-thalassemia major patients. In: Transfusion clinique et biologique: journal de la Societe francaise de transfusion sanguine. Volume 26, number 4, November 2019, pp. 249-252, doi: 10.1016 / j.tracli.2019.05.003 , PMID 31679808 .
  17. ↑ Y. Sharif, S. Irshad, A. Tariq, S. Rasheed, MH Tariq: Association of frequency of hereditary hemochromatosis (HFE) gene mutations (H63D and C282Y) with iron overload in beta-thalassemia major patients in Pakistan. In: Saudi medical journal. Volume 40, number 9, September 2019, pp. 887-892, doi: 10.15537 / smj.2019.9.24482 , PMID 31522215 .
  18. ^ M. Franchini: Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment. In: American Journal of Hematology . 81, 2006, pp. 202-209, doi: 10.1002 / ajh.20493 .
  19. ↑ J. Hannuksela, M. Leppilampi, K. Peuhkurinen, S. Kärkkäinen, E. Saastamoinen, T. Heliö, M. Kaartinen, MS Nieminen, P. Nieminen, S. Parkkila: Hereditary hemochromatosis gene (HFE) mutations C282Y, H63D and S65C in patients with idiopathic dilated cardiomyopathy. In: European Journal of Heart Failure. Volume 7, Number 1, January 2005, pp. 103-108, doi: 10.1016 / j.ejheart.2004.03.007 , PMID 15642540 .
  20. ↑ A. Turedi, Y. Oymak, T. Meşe, Y. Yaman, S. Bayraktaroglu, A. Alpman, F. Ozkinay, Y. Aydınok, C. Vergin: The effect of HFE polymorphisms on cardiac iron overload in patients with beta -thalassemia major. In: Pediatric Hematology and Oncology. Volume 30, Number 8, November 2013, pp. 755-760, doi: 10.3109 / 08880018.2013.825683 , PMID 24087894 .
  21. ↑ W. Nandar, JR Connor: HFE gene variants affect iron in the brain. In: The Journal of Nutrition. Volume 141, Number 4, April 2011, pp. 729S-739S, doi: 10.3945 / jn.110.130351 , PMID 21346098 (review).
  22. ↑ MD Meadowcroft, J. Wang, CJ Purnell, PJ Eslinger, EB Neely, QX Yang, JR Connor: Reduced Cerebral White Matter Integrity Assessed by DTI in Cognitively Normal H63D-HFE Polymorphism Carriers. In: Journal of Neuroimaging. Volume 28, number 1, 01 2018, pp. 126-133, doi: 10.1111 / jon.12461 , PMID 28771940 , PMC 5760459 (free full text).
  23. ↑ GM Bishop, TN Dang, R. Dringen, SR Robinson: Accumulation of Non-Transferrin-Bound Iron by Neurons, Astrocytes, and Microglia. In: Neurotoxicity Research. 19, 2011, pp. 443-451, doi: 10.1007 / s12640-010-9195-x .
  24. ↑ J. Xia, H. Xu, H. Jiang, J. Xie: The association between the C282Y and H63D polymorphisms of HFE gene and the risk of Parkinson's disease: A meta-analysis. In: Neuroscience Letters . Volume 595, May 2015, pp. 99-103, doi: 10.1016 / j.neulet.2015.04.010 , PMID 25863172 .
  25. ↑ N. Akbas, H. Hochstrasser, J. Deplazes, J. Tomiuk, P. Bauer, U. Walter, S. Behnke, O. Riess, D. Berg: Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra. In: Neuroscience Letters. Volume 407, number 1, October 2006, pp. 16-19, doi: 10.1016 / j.neulet.2006.07.070 , PMID 16935420 .
  26. ↑ RJ Guerreiro, JM Bras, I. Santana, C. Januario, B. Santiago, AS Morgadinho, MH Ribeiro, J. Hardy, A. Singleton, C. Oliveira: Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort. In: BMC Neurology. Volume 6, July 2006, p. 24, doi: 10.1186 / 1471-2377-6-24 , PMID 16824219 , PMC 1534050 (free full text).
  27. ↑ J. Raszeja-Wyszomirska, G. Kurzawski, I. Zawada, J. Suchy, J. Lubinski, P. Milkiewicz: HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland. In: Polskie Archiwum Medycyny Vewnetrznej. Volume 120, Number 4, April 2010, pp. 127-131, PMID 20424537 .
  28. ↑ L. Valenti, AL Fracanzani, E. Bugianesi, P. Dongiovanni, E. Galmozzi, E. Vanni, E. Canavesi, E. Lattuada, G. Roviaro, G. Marchesini, S. Fargion: HFE genotype, parenchymal iron accumulation , and liver fibrosis in patients with nonalcoholic fatty liver disease. In: Gastroenterology. Volume 138, number 3, March 2010, pp. 905-912, doi: 10.1053 / j.gastro.2009.11.013 , PMID 19931264 .
  29. ↑ S. Juzėnas, J. Kupčinskas, I. Valantienė, J. Šumskienė, V. Petrenkienė, J. Kondrackienė, L. Kučinskas, G. Kiudelis, J. Skiecevičienė, L. Kupčinskas: Association of HFE gene C282Y and H63D mutations with liver cirrhosis in the Lithuanian population. In: Medicina. Volume 52, number 5, 2016, pp. 269-275, doi: 10.1016 / j.medici.2016.09.004 , PMID 27816425 .
  30. ↑ Q. Ye, BX Qian, WL Yin, FM Wang, T. Han: Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta- Analysis of 5,758 Cases and 14,741 Controls. In: PLOS ONE . Volume 11, number 9, 2016, p. E0163423, doi: 10.1371 / journal.pone.0163423 , PMID 27657935 , PMC 5033482 (free full text).
  31. ↑ LL Shen, DY Gu, TT Zhao, CJ Tang, Y. Xu, JF Chen: Implicating the H63D polymorphism in the HFE gene in increased incidence of solid cancers: a meta-analysis. In: Genetics and Molecular Research: GMR. Volume 14, number 4, October 2015, pp. 13735-13745, doi: 10.4238 / 2015.October.28.36 , PMID 26535689 .
  32. ↑ YF Lv, X. Chang, RX Hua, GN Yan, G. Meng, XY Liao, X. Zhang, QN Guo: The risk of new-onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants. In: Journal of Cellular and Molecular Medicine. Volume 20, number 7, 07 2016, pp. 1219–1233, doi: 10.1111 / jcmm.12764 , PMID 26893171 , PMC 4929296 (free full text).
  33. ↑ Steven M. LeVine, James R. Connor, Hyman M. Schipper: Redoxactive Metals in Neurological Disorders. New York Academy of Sciences, 2004. ISBN 978-1-57331-503-6 .
  34. ↑ James F. Collins: Molecular, Genetic, Nutritional Aspects of Major and Trace Minerals. Academic Press, London 2017.
  35. ↑ Sareen S. Gropper, Jack L. Smith, Timothy P. Carr: Advanced Nutrition and Human Metabolism. Cengage Learning, 7th edition, Boston 2016, ISBN 978-1-30562-785-7 .
  36. ↑ LC Pilling, J. Tamosauskaite, G. Jones et al .: Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. In: BMJ . 2019, 364, p. K5222, doi: 10.1136 / bmj.k5222 .