Type 1 hemochromatosis

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Classification according to ICD-10
E83.1 Iron metabolism disorders
hemochromatosis
ICD-10 online (WHO version 2019)

The hemochromatosis type 1 is the classic and common with about 80% by far the form of hemochromatosis , too much when a disease iron from the small intestine is absorbed.

Synonyms are: Symptomatic form of classic hemochromatosis; Symptomatic form of HFE gene-associated hereditary hemochromatosis; English HFE-Associated Hemochromatosis; HFE-HH

The term "hemochromatosis" is sometimes used as a synonym for this type 1.

A US research group sequenced the HFE gene in 1996 and demonstrated its link to hemochromatosis.

root cause

The disease are mutations in the HFE - gene on chromosome 6 locus p21.3 basis that the HFE encodes .

Mutations in this gene can be found in other diseases or increase the risk of them:

Mutations in the HFE gene can also cause pathological changes independent of the hemochromatosis. Among other things, increases in blood triglycerides have been described.

The mutation in the HFE gene is caused in over 80% of those affected by a point mutation , which causes a specific amino acid exchange. The most common is C282Y followed by H63D , there are also combinations ( H63D-C282Y mutation). 93% of the affected Swiss have a C282Y mutation and 7% a combined H63D-C282Y mutation.

So far, about 20 different mutations in the HFE gene have been described, including S65C , but it is unlikely to result in increased iron storage .

C282Y

In the most common point mutation C282Y , cysteine ​​is replaced by tyrosine at 282 in the hereditary hemochromatosis protein .

It is assumed that the C282Y mutation occurred about 4000 years ago in a person in Central Europe with presumably Celtic descent and that, starting from there, it spread to the European population with their descendants (so-called founder effect ). It is still most common in Ireland today . One possible hypothesis for the spread of the mutation is the assumption that excessive iron storage in the event of a prolonged deficiency of iron could offer a survival advantage.

This mutation is thought to increase the risk of developing cancer , particularly breast cancer , colorectal cancer, and hepatocellular carcinoma .

H63D

H63D is the replacement of histidine with aspartic acid at position 63 in the hereditary hemochromatosis protein. This second mutation occurs in about 15 percent of the normal population, but apparently not together with the C282Y mutation in one allele .

In Switzerland, symptomatic homozygous carriers of an HFE mutation are on average 4.3 cm, carriers 3.3 cm taller than unaffected Swiss of the same age.

There is an association between homozygous H63D predisposition and neurodegenerative diseases such as amyotrophic lateral sclerosis (differently :) and Alzheimer's disease .

See also HFE mutation H63D .

distribution

Inheritance is autosomal - recessive .

The frequency is very different worldwide, the hemochromatosis is very common in (Northern) - Europeans , especially in Irish and Norwegians with a frequency of up to 1 in 200. The male sex is affected about 24 times more often.

Most people of Northern European descent have a frequency of homozygous C282T mutation between 2 in 1000 and 5 in 1000.

In the German population, C282Y mutations occur in 3.9% and H63D in 14.8%.

In Australians white Appearance 14% were heterozygous , 0.5% homozygous carrier of an HFE mutation, but only 0.25% had a clinically relevant iron storage.

85–90% of those affected with clinically manifest hemosiderosis have a homozygous C282Y mutation ( C282Y / C282Y ).

The penetrance of the mutation is low, around 30% of men with a homozygous mutation and only around 1% of homozygous women develop a clinically relevant clinical picture; the occurrence of a disease is very rare in heterozygous carriers of traits.

Compound heterozygosity ( C282Y / H63D ) is present in another 35% of those affected with clinically manifest hemosiderosis . Only 12% get sick.

A heterozygous ( C282Y / + ) mutation does not lead to an increased risk of the disease.

Individuals with a homozygous H63D mutation ( H63D / H63D ) rarely become clinically manifest and then have only a low iron accumulation.

The BMP2 gene on chromosome 20 locus p12.3, which codes for the bone morphogenetic protein BMP2 (bone morphogenetic protein 2), plays a role as a modifier of HFE hemochromatosis for penetrance.

Clinical manifestations

The spectrum of clinical manifestations includes:

Diagnosis

If hereditary hemochromatosis is suspected, detection or exclusion of the HFE mutations C282Y and H63D is essential.

Details on diagnosis, treatment, and prognosis are described in the article hemochromatosis .

literature

  • European Association guidelines 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 .

Individual evidence

  1. ↑ a b Hemochromatosis type 1, symptomatic form. In: Orphanet (Rare Disease Database).
  2. ↑ a b c J. C. Barton and CQ Edwards: HFE Hemochromatosis. In: RA Pagon, MP Adam, HH Ardinger et al .: (Editor) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. PMID 20301613 , nih.gov
  3. ↑ A. Pietrangelo: haemochromatosis. In: Good. Volume 52 Suppl 2, May 2003, pp. Ii23-ii30, doi : 10.1136 / gut.52.suppl_2.ii23 , PMID 12651879 , PMC 1867747 (free full text) (review).
  4. ↑ hemochromatosis.  In: Online Mendelian Inheritance in Man . (English)
  5. ↑ a b c d H. Gabriel, M. Stuhrmann-Spangenberg: Guideline for the molecular genetic diagnosis of hereditary hemochromatosis , 2006, gfhev
  6. ↑ HFE genes.  In: Online Mendelian Inheritance in Man . (English)
  7. ↑ Porphyria cutanea tarda, familial. In: Orphanet (Rare Disease Database).
  8. ↑ Porphyria variegata. In: Orphanet (Rare Disease Database).
  9. ↑ Transferrin serum Level Quantitative Trait Locus 2.  In: Online Mendelian Inheritance in Man . (English)
  10. ↑ Microvascular complications of diabetes 7.  In: Online Mendelian Inheritance in Man . (English)
  11. ↑ CH Walsh, JM Malins: Proliferative retinopathy in a patient with diabetes mellitus and idiopathic haemochromatosis. In: British medical journal. Volume 2, number 6129, July 1978, pp. 16-17, doi: 10.1136 / bmj.2.6129.16-a , PMID 678784 , PMC 1605750 (free full text).
  12. ↑ M. Solanas-Barca, R. Mateo-Gallego, P. Calmarza, E. Jarauta, AM Bea, A. Cenarro, F. Civeira: Mutations in HFE causing hemochromatosis are associated with primary hypertriglyceridemia. In: The Journal of Clinical Endocrinology and Metabolism . Volume 94, number 11, November 2009, pp. 4391-4397, doi: 10.1210 / jc.2009-0814 , PMID 19820015 .
  13. ↑ LN Alves, EV Santos, E. Stur, AM Silva Conforti, ID Louro: Molecular epidemiology of HFE gene polymorphic variants (C282Y, H63D and S65C) in the population of Espírito Santo, Brazil. In: Genetics and molecular research: GMR. Volume 15, Number 2, April 2016, p., Doi: 10.4238 / gmr.15028189 , PMID 27173269 .
  14. ↑ P. Pedersen, N. Milman: Genetic screening for HFE hemochromatosis in 6,020 Danish men: penetrance of C282Y, H63D, and S65C variants. In: Annals of hematology. Volume 88, Number 8, August 2009, pp. 775-784, doi: 10.1007 / s00277-008-0679-1 , PMID 19159930 .
  15. ↑ CE Wrede, S. Hutzler, LC Bollheimer, R. Buettner, C. Hellerbrand, J. Schöelmerich, KD Palitzsch: Correlation between iron status and genetic hemochromatosis (codon C282Y) in a large German population. In: The Israel Medical Association journal: IMAJ. Volume 6, Number 1, January 2004, pp. 30-33, PMID 14740507 .
  16. ↑ G. Lucotte, G. Mercier: Celtic origin of the C282Y mutation of hemochromatosis. In: Genetic testing. Volume 4, Number 2, 2000, pp. 163-169, doi: 10.1089 / 10906570050114876 , PMID 10953956 .
  17. ^ S. Distante, KJ Robson, J. Graham-Campbell, A. Arnaiz-Villena, P. Brissot, M. Worwood. The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet. 2004 Sep; 115 (4), pp. 269-279. PMID 15290237
  18. ↑ A. Pietrangelo: Hereditary hemochromatosis-a new look at an old disease. In: The New England Journal of Medicine . Volume 350, Number 23, June 2004, pp. 2383-2397, doi: 10.1056 / NEJMra031573 , PMID 15175440 (review).
  19. ↑ 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).
  20. ↑ H. Xiao-Bing, Z. Lu, G. Hong, L. Ping, L. Guanghui, L. Hongming, H. Keqiang, L. Jing: Meta analysis on relationship between distributions of C282Y and H63D alleles and genotypes and hepatocellular carcinoma. In: Minerva medica. [Electronic publication before going to press] January 2016, PMID 26765307 .
  21. ↑ F. Jin, LS Qu, XZ Shen: Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. In: Journal of experimental & clinical cancer research: CR. Volume 29, March 2010, p. 18, doi: 10.1186 / 1756-9966-29-18 , PMID 20196837 , PMC 2845109 (free full text).
  22. ↑ 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
  23. ↑ Pietro E. Cippà, Pierre-Alexandre Krayenbühl: Increased height in HFE hemochromatosis. In: The New England Journal of Medicine . 2013, Volume 369, Edition 8 of August 22, 2013, pp. 785–786, doi: 10.1056 / NEJMc1303066 .
  24. ↑ A. Chiò, G. Mora, M. Sabatelli, C. Caponnetto, C. Lunetta, BJ Traynor, JO Johnson, MA Nalls, A. Calvo, C. Moglia, G. Borghero, MR Monsurrò, V. La Bella, P. Volanti, I. Simone, F. Salvi, FO Logullo, R. Nilo, F. Giannini, J. Mandrioli, R. Tanel, MR Murru, P. Mandich, M. Zollino, FL Conforti, S. Penco ,. ,. , M. Brunetti, M. Barberis, G. Rest: HFE p.H63D polymorphism does not influence ALS phenotype and survival. In: Neurobiology of aging. Volume 36, number 10, October 2015, pp. 2906.e7-2906.11, doi: 10.1016 / j.neurobiolaging.2015.06.016 , PMID 26174855 , PMC 5183653 (free full text).
  25. Jump up ↑ Y. Liu, SY Lee, E. Neely, W. Nandar, M. Moyo, Z. Simmons, JR Connor: Mutant HFE H63D protein is associated with prolonged endoplasmic reticulum stress and increased neuronal vulnerability. In: Journal of Biological Chemistry . Volume 286, Number 15, April 2011, pp. 13161-13170, doi: 10.1074 / jbc.M110.170944 , PMID 21349849 , PMC 3075663 (free full text).
  26. ↑ EC Hall, SY Lee, Z. Simmons, EB Neely, W. Nandar, JR Connor: Prolyl-peptidyl isomerase, Pin1, phosphorylation is compromised in association with the expression of the HFE polymorphic allele, H63D. In: Biochimica et Biophysica Acta . Volume 1802, Number 4, April 2010, pp. 389-395, doi: 10.1016 / j.bbadis.2010.01.004 , PMID 20060900 .
  27. ↑ a b B. K. Crownover, CJ Covey: Hereditary hemochromatosis. In: American family physician. Volume 87, Number 3, February 2013, pp. 183-190, PMID 23418762 (review).
  28. ↑ JK Olynyk, DJ Cullen, S. Aquilia, E. Rossi, L. Summerville, LW Powell: A population-based study of the clinical expression of the hemochromatosis gene. In: The New England Journal of Medicine . Volume 341, Number 10, September 1999, pp. 718-724, doi: 10.1056 / NEJM199909023411002 , PMID 10471457 .
  29. ↑ KJ Allen, LC Gurrin, CC Constantine, NJ Osborne, MB Delatycki, AJ Nicoll, CE McLaren, M. Bahlo, AE Nisselle, CD Vulpe, GJ Anderson, MC Southey, GG Giles, DR English, JL Hopper, JK Olynyk, LW Powell, DM Gertig: Iron-overload-related disease in HFE hereditary hemochromatosis. In: The New England Journal of Medicine . Volume 358, Number 3, January 2008, pp. 221-230, doi: 10.1056 / NEJMoa073286 , PMID 18199861 .
  30. ↑ 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).
  31. ↑ HFE hemochromatosis, modifier of.  In: Online Mendelian Inheritance in Man . (English)
  32. ^ Genetics Home Reference
  33. ↑ J. Milet, V. Dehais, C. Bourgain, AM Jouanolle, A. Mosser, M. Perrin, J. Morcet, P. Brissot, V. David, Y. Deugnier, J. Mosser: Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. In: American Journal of Human Genetics . Volume 81, Number 4, October 2007, pp. 799-807, doi: 10.1086 / 520001 , PMID 17847004 , PMC 2227929 (free full text).