Hereditary hemochromatosis (HH)

The condition known as hereditary hemochromatosis (HH) is brought on by homozygosity of the HFE gene mutation C282Y. Leitman, S. F. (2013) claims that HH is a genetic condition that affects white people whose ancestry is linked to northern Europe. However, it is also widespread in the US. Iron is continuously deposited in the joints, endocrine glands, skin, heart, liver, and other organs due to a lack of hepcidin, which also serves as an indicator of the condition that it is connected with. By starting the phlebotomy therapy early enough, patients whose organs have been destroyed can be encouraged to survive. Mainous, A. G et al. (2012), states that the hemochromatosis gene (HFE) was discovered in 1991 and that two HH-associated mutants (C282Y and H63D) were brought to book. Various studies demonstrated that majority of individuals with HH had C282Y homozygotes while those who had H63D homozygotes and compound heterozygotes had a minimum risk to HH exposure (Mohamed & Phillips, 2016).

According to the National Health Service (NHS), the symptoms associated with hemochromatosis normally affect people aged between 30 and 60 years old. However, it is also argued that the symptoms of hemochromatosis may also occur earlier in life. The symptoms of hemochromatosis appear to occur earlier in men. Women minimally experience problems until they reach menopause. Some of the initial symptoms of hemochromatosis include fatigue, abdominal pain, and weakness (Brissot et al, 2017). Later on in life, the major symptoms of hemochromatosis cause complications such as low libido, diabetes, impotence, liver failure, as well as heart failure (Røsvik et al, 2016).



Regarding demographics, various studies conducted in the United States indicate that about 6 million US citizens possess the H63D allele or the homozygous C282Y of HFE. In the meantime, there are also another group of 6 million American citizens who have the heterozygotes compounds. The heterozygotes compounds are subject to possessing either of the above-mentioned mutations (Mainous, A. G et al., 2012).

Normal Biology

According to Bacon, B. R. et al. (2011), they emphasized that the HFE principle gene is a G - to - A mutant that leads Tyrosine to substitute for Cysteine. Hepcidin, a peptide hormone whose production is done by the liver hepatocytes transfers iron across the gut (Leitman, 2013). TRF2 and HFE levels help regulate Hepcidin. Consequently, when HFE and TRF2 genes mutate, they can abruptly lead to iron overload. Therefore, the changing mutations within the HFE gene whose location is within the short arm of the chromosome 6 lead to iron overload which is an inherited disorder (Vujić, 2014).

The mutation transformation of Cysteine to Tyrosine within position 282 normally interferes with Cysteine’s disulphide bridge (Griffiths & Cox, 2015). Such a result leads to the disruption of the protein structure, the HFE as well as its binding with beta-2 macroglobulin which also disintegrates in the process (Kowdley, 2010). The transferrin receptor 1 (the link between HFE and TRF1) then becomes subject to no binding. The mutant HFE protein will therefore not maintain the production of hepcidin. Hepcidin is a protein that assists in the regulation of Iron metabolism (Publishing, 2010). The body responds by absorbing and storing high iron amounts thus resulting to overloading of iron in the body and this alone becomes the chief cause of Hereditary Hemochromatosis (HH). There is the interaction of the HFE protein with the other proteins on the cell wall in order to discover iron contents in the body (Miller & Levy, 2015). The production of the other protein, commonly referred to as hepcidin, is regulated by the HFE protein. Hepcidin is viewed as the master regulatory hormone of iron. In addition, live produces hepcidin. Hepcidin helps in the determination of the amount of iron absorbed in the body from a particular diet and then released from the various storage sites within the body. Absorption of iron is strongly regulated when the proteins used for absorption and sensing of iron functions properly (Souto et al, 2016 & III et al, 2012).

Individuals who have homozygous Cys282Try have higher chances of developing the HH disease as compared to their homozygous H63D counterparts.

Mutation Description

The regulation of the absorption of the dietary iron is very complex. HFE is one of the characterized genes that are responsible for HH. There are two common mutations of the HFE gene such as H63D and C282Y. C282Y mutation is linked to the majority of the cases of HH (Kanwar & Kowdley, 2013). It is a conversion point mutation in the HFE gene from guanine to adenine as illustrated in Table 1. The transition point results into a missense mutation that substitutes the cysteine residues at the 282 point with the tyrosine amino acid. The heterozygotes for C282Y allele do actually not patent the overload of clinical iron, however, might indicate an increase in the uptake of iron (Sood et al, 2013).

The HFE gene mutations contribute to 90% of the various cases of an overload of no-transfusional iron. HFE gene is closely associated with the HLA-A3 locus. One of the common genotypes responsible for the accretion of clinical iron is homozygosity for the mutation of C282Y. On the other hand, the heterozygosity for mutations of C282Y and H63D, usually known as compound heterozygotes, leads to the overload of clinically apparent iron. There are numerous debates about the penetrance. Majority of the males homozygous for the HFE C282Y mutations will demonstrate manifestation of the dysfunction of the liver, for instance, the elevated particular enzymes for the liver. Nevertheless, the female homozygous can normally delay up to the commencement of the accumulation of iron due to the loss of iron through menstruation period (Clark et al, 2010).

Every patient who has susceptible genotype normally collects iron at various rates dependent on the intake of iron, accurate type of mutation as well as the existence of the other insults to an individual’s liver such as viral disease and alcohol (Niederau, 2010). Inheritance of either C282Yor H63D mutation contributes to the risk of overload of iron in the body. Nevertheless, inheritance of two copies of C282Y mutation seems to showcase higher risk of iron overload on an individual. Loading of iron from HH might contribute to joint and bone disease, liver and heart disease, and hormone imbalances. In addition, it might also lead to the other types of diseases such as cancers and infections (Cherfane et al, 2010).

Pathology

Protein encoding undertaken by the HFE gene constitutes a small cytoplasmic portion, the transmembrane region as well as peptide-binding extracellular domains. There are four crystein residues within alpha-3 and alpha-2 extracellular domains that normally form disulfide bridges (Santos et al, 2015). This represents one of the features of the MHC class-1 molecules. The interaction between beta2-microglobulin and HFE occurs and the relationship allows for effective transportation of HFE to the surface of the cells where it also associates with TfR1 (Bacon et al, 2011). Disulfide bridges within the extracellular domains are disrupted by the C282Y mutations. This prevents the interaction of HFE with the TfR1 and beta2-microglobulin. Inadequate association of the TfR1 with HFE increases its affinity for iron that is transferring-bound. As a result, it modulates the absorption rate of iron (Cherfane et al, 2013). Contrary to C282Y mutation, the H63D HFE mutant led to the formation of stable complexes that resembles the clinical information that the absorption of iron is affected by the marginal H63D HFE mutations hence rarely contributing to hemochromatosis. The molecular association between TfR1 and HFE protein increased the prospect that it played a major task in the pathogenesis of hemochromatosis. The argument on whether HFE changes the uptake of cellular iron acts as a sensor technique in the duodenal enterocytes (Babitt & Lin, 2011).

Prevention and Therapies

An inherited or primary hemochromatosis cannot be prevented. Nevertheless, not every individual who develops the HFE genes develops complications or symptoms of hemochromatosis. In individuals who develop the complications or symptoms of HH, there are certain treatment measures that can help prevent it from getting worse (Salgia et al, 2012). Some of the treatment techniques for HH include iron chelation therapy, therapeutic phlebotomy, dietary changes as well as other treatment measures for complications. The main aim of treating HH is to reduce the quantity of iron in the human body to a normal level. Besides, the treatment of HH helps to delay or prevent damages of organs of iron overload (Ayres et al, 2013). Therapeutic phlebotomy helps to remove iron and blood from the body. On the other hand, iron chelation therapy employs the use of medicine in order to eliminate the excess amount of iron from the body. It is an excellent treatment option for individuals who cannot be able to undergo routine blood removal (Pan & Wang, 2011). Phlebotomy continues to be a major treatment method for hemochromatosis. It ameliorates some clinical features while there are other features that are not responsive to the removal of iron. Some of the unresponsive features include advanced cirrhosis, hypogonadism, and arthropathy (Pan, 2016). It is vital for patients who have iron overload and HH to continue undertaking weekly therapeutic phlebotomy tests. Individuals who have a family history or suffer from HH would consider going for counseling and genetic counseling in case they are planning to give birth to children. Genetic testing is essential since it will establish whether the parents of the child have defective HFE genes. In addition, a genetic counselor can assist to figure out the prospect of the parents transferring the defective HFE genes to their children (Adams & Barton, 2012).

Summary

Hemochromatosis is a type of disease that occurs as a result of the excessive build-up of iron in the body. An excessive amount of HH is very dangerous to the human body. This is attributed to the fact that it can poison human organs and contribute to the failure of the body organs. Hemochromatosis can become very dangerous if not treated as it can cause death in the patients. H63D and C282Y are the two common mutations of the HFE gene. C282Y mutation is linked to the majority of the cases of HH. It is a conversion point mutation in the HFE gene from guanine to adenine. Survival of the patients whose organs had been damaged can be induced by instituting the phlebotomy therapy earlier enough in order to treat HH. Nevertheless, it is not easy to prevent an inherited or primary hemochromatosis. Accumulation of iron in female homozygous might delay because of the loss of iron during the menstrual period.

Legend





Official Gene Symbol

HFE

Gene Name

Hemochromatosis

Chromosomal position

Location 6p21

Number of Exons

6

Table 1

















References

Adams, P. C., & Barton, J. C. (2010, July 22). How I treat hemochromatosis. Retrieved October 28, 2017, from http://www.bloodjournal.org/content/116/3/317?sso-checked=true

Ayres, L. R., Jayasekeran, V., & Olynyk, J. K. (2013). Genotype-Phenotype Relationship in Hereditary Hemochromatosis. ELS. doi:10.1002/9780470015902.a0024259

Babitt, J., & Lin, H. (2011). The Molecular Pathogenesis of Hereditary Hemochromatosis. Seminars in Liver Disease, 31(03), 280-292. doi:10.1055/s-0031-1286059

Bacon, B. R., Adams, P. C., Kowdley, K. V., Powell, L. W., & Tavill, A. S. (2011). Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology, 54(1), 328-343. doi:10.1002/hep.24330

Brissot, P., Loréal, O., & Jouanolle, A. (2017). Molecular Testing in Hemochromatosis. Diagnostic Molecular Pathology, 245-253. doi:10.1016/b978-0-12-800886-7.00020-0

Cherfane, C. E., Hollenbeck, R. D., Go, J., & Brown, K. E. (2013). Hereditary Hemochromatosis: Missed Diagnosis or Misdiagnosis? The American Journal of Medicine, 126(11), 1010-1015. doi:10.1016/j.amjmed.2013.07.013

Clark, P., Britton, L. J., & Powell, L. W. (2010, February). The Diagnosis and Management of Hereditary Haemochromatosis. Retrieved October 28, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826266/

Griffiths, W. J., & Cox, T. M. (2015). Hereditary haemochromatosis. Oxford Medicine Online. doi:10.1093/med/9780199204854.003.120701_update_003

III, P. A., Knoll, M. M., Everett, P. C., Hulihan, M. M., Grant, P. A., Garrison, B. C., . . . And, C. S. (2012). Arch G. Mainous III. Retrieved October 28, 2017, from http://www.jabfm.org/content/25/4/432.full

Kanwar , P., & Kowdley, K. (2013). Diagnosis and treatment of hereditary hemochromatosis: an update. Retrieved October 28, 2017, from http://www.tandfonline.com/doi/abs/10.1586/17474124.2013.816114

Kowdley, K. V. (2010). Hereditary Hemochromatosis. Netters Gastroenterology, 645-647. doi:10.1016/b978-1-4377-0121-0.50252-x

Leitman, S. F. (2013). Hemochromatosis: the new blood donor. Hematology, 2013(1), 645-650. doi:10.1182/asheducation-2013.1.645

Miller, M. R., & Levy, M. L. (2015). Chronic obstructive pulmonary disease: missed diagnosis versus misdiagnosis:. Bmj. doi:10.1136/bmj.h3021

Niederau, C. (2010). Hereditary Hemochromatosis and Iron Overload. Clinical Hepatology, 1045-1070. doi:10.1007/978-3-642-04519-6_28

Mohamed, M., & Phillips, J. (2016). Hereditary haemochromatosis. Bmj, I3128. doi:10.1136/bmj.i3128

Pan, H. Y., & Wang, L. J. (2011). Case report of HFE gene testing for the diagnosis of hereditary hemochromatosis. Journal of Digestive Diseases, 12(5), 409-411. doi:10.1111/j.1751-2980.2011.00515.x

Patricia, Q. (2016). Hereditary hemochromatosis: Dealing with iron overload : Nursing2017. Retrieved October 28, 2017, from http://journals.lww.com/nursing/Fulltext/2016/05000/Hereditary_hemochromatosis__Dealing_with_iron.11.aspx

Publishing, S. R. (2016, August 26). Compound Heterozygous C282Y/H63D Mutation in Hemochromatosis: A Case Report. Retrieved October 28, 2017, from http://www.scirp.org/journal/PaperInformation.aspx?paperID=70736

Røsvik, A. S., Ulvik, R. J., Wentzel-Larsen, T., & Hervig, T. (2010). Blood donors with hereditary hemochromatosis. Transfusion, 50(8), 1787-1793. doi:10.1111/j.1537-2995.2010.02627.x

Røsvik, A. S., Ulvik, R. J., Wentzel-Larsen, T., & Hervig, T. (2010). Blood donors with hereditary hemochromatosis. Transfusion, 50(8), 1787-1793. doi:10.1111/j.1537-2995.2010.02627.x

Salgia, R. J., & Brown, K. (2015). Diagnosis and Management of Hereditary Hemochromatosis. Clinics in Liver Disease, 19(1), 187-198. doi:10.1016/j.cld.2014.09.011

Santos, P. C., Krieger, J. E., & Pereira, A. C. (2012). Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis. Retrieved October 28, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291973/

Sood, R., Bakashi, R., Hegade, V. S., & Kelly, S. M. (2013, June). Diagnosis and management of hereditary haemochromatosis. Retrieved October 28, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662451/

Souto, N. L., Pugliesi, P. R., & Lopes, I. C. (2016). Hereditary hemochromatosis: literature review. Revista Médica de Minas Gerais, 26. doi:10.5935/2238-3182.20160091

Vujić, M. (2014). Molecular basis of HFE-hemochromatosis. Retrieved October 28, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949417/