Haemochromatosis Disease

Running head: HEMOCHROMATOSIS AND ITS GENE 1

HEMOCHROMATOSIS AND ITS GENE 10

Hemochromatosis and Its Gene

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Abstract

Haemochromatosis is an autosomal recessive genetic disorder resulting in increased intestinal absorption of iron and eventually to iron overload (Raju and Venkataramappa, 2018). Hemochromatosis is one of the genetic ailments that an individual can inherit. This hereditary disorder compels the body to uptake high levels of iron from the food that is consumed. Vital organs of the body like the liver, pancreas and heart store this excessive iron which may exacerbate other health complications (Jonathan, 2016). Mutation in the HFE gene has been cited as the primary cause of hemochromatosis. The disorder is subsequently passed to other generations through inheritance. The person must inherit a copy of the defective gene from each parent to take on this condition. A person who inherits only one copy of a mutated gene is considered a carrier of the condition, but they may never experience symptoms(Kahn, 2016). The disorder manifests itself through early symptoms like tiredness, a general loss in the sexual drive, abdominal and joint pains. In the advanced stages, the ailment causes heart and liver failure, impotence and diabetes. There are limited treatment options for this kind disorder. The widely applied medical procedure to alleviate the pain and suffering of the victims entails periodically draining blood from the body to reduce iron levels. The red blood cells contain a high percentage of iron in the body. In spite of the critical role that iron plays in the body, excessive iron is poisonous. The continued accumulation of iron around critical body organs like liver eventually leads to their failure. This paper examines in detail the genes that are responsible for the disease Hemochromatosis through background informtation, research findings, experimentation, and commentary.

Background and Significance

The background to this hereditary disorder emanates from the HFE gene that is inherited from parents during conception. Genetic research indicates that the mutations that this gene undergoes are responsible for hemochromatosis. H63D and C282Y are the common mutations that this gene can undergo (Elizabeth & Elaine, 2015). With the advancement in medical technology, testing can reveal whether these mutations are present in an individual so that remedial action can be taken.

Illustration of a normal and mutated gene

HFE gene plays a significant role in the homeostatic function of regulating irons in the body. In a nutshell, it maintains equilibrium in the secretion of hepcidin protein. Hepcidin is responsible for determining the amount of iron that can be absorbed from the diet and regulating the release of iron from the storage. Mutations in this gene have the adverse effect of altering the normal functioning of hepcidin causing an abnormal intake of iron from diet above the recommended levels. The human body only requires 10 percent of iron from the ingested food to sustain the production of blood and cells (Gatlin, 2017).

The mutations can result in the inheritance of two or one abnormal HFE genes. Presence of two abnormal genes in the body of an infant implies a high probability of developing hemochromatosis. The defective genes can also be passed to the off springs. However, it is important to note that not all people who inherit this condition develop complications related to iron overload in the body. People who inherit one abnormal gene are considered to mutation carriers. They cannot develop hemochromatosis but they can pass the gene to subsequent generations. Numerous studies have linked C282Y mutation with hereditary hemochromatosis. H63D mutation cannot be tied directly to the disorder but it acts synergistically with the other mutation to complicate matters (Elizabeth & Elaine, 2015). The other types of hemochromatosis can be categorized as juvenile, neonatal, and secondary. Juvenile hemochromatosis affects mainly people of a younger age. In this case, iron accumulation begins at a very tender age and the defining symptoms begin to manifest from the ages of 15. Mutations in the hepcidin genes are the main causative agents. Neonatal hemochromatosis is characterized by the rapid accumulation of irons in the liver of the fetus in the early developmental stages. The main explanation for this disorder is autoimmunity in which the body immune system attacks itself. Secondary hemochromatosis is caused by other factors like anemia or liver diseases that cannot be directly linked to defects in the inherited genes.

Juvenile hemochromatosis (JH) is a rare but severe form of the disease. It is very severe when compared to the HFE one. Its genesis can be traced to childhood or during the adolescence stage. Mutations that occur in two sets of genes in the body which include hemojuvelin (HJV) and hepcidin are responsible for this genetic disorder. Hemojuvelin and hepcidin situated in chromosome 1 and 19 respectively (Lescano, Tavares & Santos, 2017). Hemojuvelin gene plays a critical role in body of sending instructions for the formation of a protein known as hemojuvelin that is responsible for maintaining a steady balance of ironic levels in the body. It also regulates another protein in the body known as hepcidin that also maintains a balance of levels of iron in the body system. Mutations in HJV gene lead to significant alterations in the amino acids that make hemojuvelin protein. Amino acids are the building components of the proteins. In most cases, amino acid glycerin is subsequently replaced by the valine form of the amino acid at the protein position. Other mutation forms lead to the issuance of premature signals that led to stoppage of hemojuvelin protein. The result is abnormally small protein that cannot adequately handle its homeostatic functions of regulating iron in the body.

The significance of studying the mutations in HFE genes and hemojuvelin gene that cause hereditary diseases is numerous. First, it helps to highlight that not all the mutations in this gene are bad. The recessive C282Y mutation is responsible for the disease and diabetes. This plays a vital role in the field of genetic engineering in which scientists attempt to make alterations in the genetic constitution of individuals with a view of eliminating undesired mutations that are responsible for hereditary disorders. There is hope that with the continued advancement in technology in the field of medicine, a solution can be found to some of these disorders. Secondly, the background is critical in spreading awareness concerning the disorder. People are encouraged to conduct early genetic screening or tests to ascertain whether they are afflicted by these diseases. Research indicates that individuals who are diagnosed with the disease on early stage live longer lives compared to those who discover it on advanced stages (Gatlin, 2017). Leaving hemochromatosis to metamorphose to advanced stages is a recipe for disaster. On this secondary stage, it is hard to control as causes a failure in major body organs like the liver and heart.

Current research findings

The recent findings concerning hemochromatosis (HH) have focused extensively on HFE gene variants that have cited as the main causative agents of many genetic diseases. The findings have conclusively suggested that C282Y and H63D mutations are responsible for HH (McGee & Thomas, 2018).

Illustration of C282Y and H63D mutations

Such findings have triggered the recent interest in the use of genetic screening as the main tool of providing awareness concerning the susceptibility of individuals to the disease. This triggers remedial actions in the form of treatments to annihilate the severity of the disorder (Neff, 2014). There is no doubt that the current findings are premised on a discovery that was made by scientist in 1976. It was the first direct linkage between hemochromatosis and gene mutations. Elaborate studies on the recessive C282Y HFE gene mutation have generated the following findings that are supportive in the study of the disorder. First, the H63D mutation when inherited alone is harmless as it does not contribute to the disease. It only acts as a contributing factor to HH when inherited together with C282Y mutation. This produces a heterozygous genotype in which the two mutations are transmitted on separate chromosomes. It is very rare for the two mutations to be prevalent on the same chromosomes.

Secondly, the occurrence of C282Y mutation is dependent on population. For instance, the mutation has high allele presence in populations of Caucasian origin(Neff, 2014). The mutation has been directly tied to a specific haplotype that is unique to this type of demography. Haplotypes are composed of a pair of genes that are passed to an individual from the same parent. Further research indicates that the C282Y mutation has low footprint in the non-Caucasian populations of Africa and Asia. It is thus fair to argue that the probability of hemochromatosis to occur in Caucasian population is high compared to the non-Caucasian ones (Bauduer, 2017). Thirdly, the C282Y mutation has a very high iron level penetration ratio compared to the H63D one. Some scientists estimate the penetration ratio of iron to be as high as 70 – 80 % (Martins, Silva & Faustino, 2013). This ratio is substantially high compared to the body requirement of 10 percent from the food that is consumed. However, there are substantial differences on the scale of measuring the iron overload.

The current findings concerning Juvenile hemochromatosis indicate the following: First, alterations Hemojuvelin gene lead to significant alterations in the normal functioning of hemojuvelin protein. Deficiency of this crucial protein leads to a reduction on hepcidin levels in the body. An imbalance in iron regulation in the body subsequently occurs. As a consequence, excessive iron is absorbed from the ingested food in the body. The iron overload continues to be deposited around vital organs of the body like heart and liver which accelerates the pace at which they fail down. Other findings have linked HJV and hepcidin genes to JH. Studies that have been conducted on patients with this recessive autosomal genetic disorder have linked it to chromosome 1 q (Hamdi-Rozé, Ali, Ropert, Detivaud, Aggoune, Simon, & Bardou-Jacquet, 2019). This chromosome is an associate of hemojuvelin protein. Conclusive evidence has also suggested of the existence of a linkage between mutations of these genes and the disease.

Mutation in HFE gene not only affects the uptake of irons in the body but also other ingredients like glucose. Patients with these mutations have increased risk of developing diabetes (Campos, Massaro, Teixeira & Donadi, 2019). Presence of high concentration of irons in the body interferes with the normal functioning of the mitochondria in the body. Mitochondria play a critical role of breaking down glucose in body to produce energy that powers body processes. If the rate of breakdown of glucose is low compared to the influx of glucose in the body, then an imbalance is going to arise leading to too much glucose in the body. Presence of high levels of glucose in body is a contributing factor to diabetes. The findings offer an alternative perspective to approaching the issue of diabetes. Contrary to the popular belief that diabetes is a lifestyle disease, these findings help to shed some light that diabetes can be a hereditary disease due to gene mutations.

Experimentation

The study of hemochromatosis and its causative genes has been characterized by much experimentation that has pushed the field in the right direction. Majority of the experiments that have been conducted have been entirely focused on the HFE gene (McGee & Thomas, 2018). The major objectives of such systematic experimentations is to understand the nature of the gene and how mutations cause a significant alteration in the performance leading to excess irons in the body. The irons in the body must neither be deficient nor excess. Any of the options would cause a dysfunction in the organ (McGee & Thomas, 2018). Experiments have revealed that HFE gene is composed of six domains. A typical HFE is composed of a peptide, extracellular domains that are normally three, a transmembrane and cytoplasmic tail (Martins, Silva & Faustino, 2013). It is difficult to study any biological phenomenon without first understanding its nature.

Further experimentations on juvenile hemochromatosis have suggested the following; HJV gene mutations lead to premature halt in the cordoning of hemojuvelin protein at the 320 position. The result is a truncated protein before its domain membrane. The truncation subsequently causes a loss of functionality of the hemojuvelin protein. As a result, iron overload occurs in majority of the patients before attaining the age of 20 years. Other studies have indicated an overexpression of hepcidin cause it to be unresponsive towards the iron. Considering the important function that this iron plays in the body, absorption of iron that is above the recommended levels would subsequently arise.

Currently, the treatment options of JH begin with an accurate diagnosis of the disease. Blood tests are normally conducted to indicate an abnormality in the iron levels in the blood stream. A surge in saturation of transferrin indicates an increase in ironic levels in the blood. Transferrin is a compound in the body that plays the role of moving iron from the intestines into the blood stream. The treatment options share similarities with the HFE hemochromatosis. Additional tests that can be conducted on patients include the magnetic resonance imaging (MRI). This test can reveal the thickness of the liver that has come about as a result deposition of iron compounds around it. This is an indicator of the presence of the disease in an individual. MRI exploit magnetism and radio waves to provide detailed images of vital organs like the liver. The resulting images are compared with normal images to detect disparities. Phlebotomy is common treatment option for the disease (Lescano, Tavares & Santos, 2017). This is the periodic removal of blood from the body in an attempt to reduce iron content in it. A significant proportion of the iron is contain in the red blood cells and hence the need for the periodical removal of the blood. This medical procedure is administered either once or twice a week. Once the recommended levels are achieved, the treatment approach transitions in a maintenance mode. Early detection of this disease is the only key to the prolonged life of the affected patients. Damage to critical organs can be averted through medical interventions that reduce the severity of the ailment.

Experiments concerning HFE gene mutations have yielded mixed results concerning the treatment for hemochromatosis. In spite of the advancement in genetic engineering technology, scientists have not found conclusive and reliable methods of eradicating the gene mutations that are responsible for the disease which is the overall goal of the entire experimentation process. The current treatment approach of periodically removing blood from patients suffering from the disease in order to regulate the iron levels seems to be unreliable among patients with rare blood samples. Finding donors for them is a great challenge. The real breakthrough would arise when scientists devise methods that would eradicate the real mutants from the gene. Continued experimentations concerning the subject have continuously yielded new information that has added a new dimension into understanding these gene mutations. It is only a matter of time before an eradication methodology for the mutants in the gene is found.

Future Directions

Based on the literature materials that I have reviewed, the study of hereditary disorders is progressing towards modification of genes and gene mapping (Campos, Massaro, Teixeira, & Donadi, 2019). The only treatment option that is seriously being considered for future application entails gene modification. This methodology offers potential to dealing with perennial hereditary disorders like hemochromatosis. However, extensive research needs to be done before the method is fully embraced by patients. Gene modification can be implemented through either addition or deletion. Gene deletion is mainly done by removing or erasing the mutant from the gene that is responsible for the disorder. In this case, if the recessive gene variant C282Y can be removed from the structure of HFE gene then patients suffering from the disorder can find great relief. Despite the numerous benefits that the method presents, gene deletion is prone to serious setbacks that must be surmounted before it is fully embraced. Deletion may result in the loss of crucial genetic code from gene which is irreplaceable. Body processes that rely on such genetic code may be adversely affected.

In addition, genes are modified by adding crucial nucleotides to the gene structure to compensate for the obvious inadequacies that are present in the gene leading to disorders (Jonathan, 2016). This is a difficult medical procedure to execute. It is impossible to gauge the compatibility of the inserted nucleotides with the body system. In some cases, the body immune system may react against the added nucleotides. Such adversarial reaction would do more harm than the anticipated benefits. The uniqueness of the human DNA makes it difficult to replicate. For now, the issue of gene modification continues to be a work in progress. Scientists hope that with the continued advancement in technology, they could find an innovative way of navigating through the complex procedure of modifying the human genome to eradicate undesired traits responsible for hereditary disorders.

The future for the treatment of JH would remain relatively simple and inexpensive despite the sophistication of technology and additional insights on the disease. There are no easy solutions to these ailments and past techniques have proved to be effective. Moving into the future, the treatment options would be centered on depletion and maintenance. The goal of the depletion is to eradicate excess iron from the blood. Periodic removal of the blood can attain that objective. Maintenance guarantees that the ironic quantities do not shoot above the normal. With the advancement in technology, there is hope that some of the irreversible damages that are done by JH through organ failures can be mitigated through organ transplants. Even though the technology may be available to facilitate the application, finding the organ donors of these scarce organs that are not in pairs is a great challenge.

The human genome project that is currently underway represents the future direction in unearthing linkages between genes like HFE and disorders. Knowledge gained from gene mapping is what gave scientists firm evidence to authoritatively link HFE gene with hemochromatosis. A lot of work still needs to be done to map all the genes in the human body and to determine their close association in the functioning of the human body. The relationship is critical in the actualization of the gene modification which is the ultimate cure. Genes do not work in isolation.

Commentary

Based on the literary materials that I have reviewed, the study of HFE gene mutations have not attracted major controversies that characterize other genetic studies like cloning. The reason for such widespread acceptance emanates from the medical application of the subject. However, there are few areas that require significant modification for the study to serve its rightful purpose of serving humanity. The current scientific publications concerning the subject only exist within academic circles. There has been little effort to educate the general public concerning these genetic disorders. There is no doubt that comprehending mutations in the HFE gene mutations like C282Y and H63D would require some level of intellectual prowess. That should not be an inhibiting factor in spreading such information to the public. This issue should be demystified to enable the public to undertake genetic screening tests to understand their whereabouts.

Secondly, different researchers offer different estimates on the level in which C282Y spikes the rate of iron intake in the body. There was no exactness in the figures that were issued. Most researchers were just offering estimates of between 70 to 80 percent (Gatlin, 2017). Such wide disparities should not exist in this era in which scientific experiments of this nature are computer aided. It is important for researchers to harmonize their figures with other researchers to enhance the reliability and relevance of the information that is publicly available. Ambiguity in scientific figures should not be tolerated. It is ironical that despite the enormous amount of time that has been spent on the research of hemochromatosis, there has not been a revolution in the manner in which treatment is administered. The inconvenient treatment option of periodically removing blood from the patient to lower iron concentration should be re-examined.

It is time to leverage on the benefits of modern technology and invest on treatment approaches that offer great potential. Gene modification should be the focal point of such research. The advancement in genome mapping technology offers hopes that the shortcomings in its applications can be overcome. In the meantime, the extensive knowledge that has been accumulated over the years is sufficient to enable people approach hereditary diseases from a point of information. I concur with most of the information that has been presented in the literature materials. Such baseline of facts has been complemented by scientific evidence leaving little room to critique such information without a credible alternative. Defects in the genes of human beings that cause hereditary diseases typically illustrate the imperfections of the human nature. Achieving perfection would entail a reengineering of the entire genetic constitution of the affected individuals to eradicate the undesirable traits that are responsible. This is something that is difficult to achieve even with the aid of the sophisticated technology that is currently available. Even with such diminishing prospects, research should always continue.

The existing clinical information of the existence of a close relationship between diabetes and hemochromatosis should be taken with caution. Some researchers have termed such conclusions as premature and not sufficiently backed up by the existing information on the HFE gene mutation which is the causative agent of iron overload. It is common knowledge that if screening is conducted to all patients who have been newly diagnosed with diabetes, the early interventions that might be undertaken to lessen the adverse impacts of the situation might be given unfair credit for reducing morbidities related to the iron overload in the body system. The condition of diabetes only sets in when hemochromatosis is at the advanced phases where it is impossible to treat. At this phase, the iron overload would have irreversibly inflicted catastrophic damage to the liver making treatment impossible. Diabetes set in due to the inability of these critical organs to perform their sugar regulatory functions like secretion of insulin to manage sugar level. Absence of insulin in the body would definitely cause a surge in the sugar levels in the body. Conditions of this nature allow diabetes to develop without restriction. Diabetes should not be regarded as a precursor to iron overload. The two conditions are unrelated.

The arguments for not linking the cases of hemochromatosis to diabetes are rooted in the following scientific arguments. First, there have been inconsistent findings to substantiate the fact that hemochromatosis patients are prone to suffer from hemochromatosis than the rest of the population. The results that exist are inconclusive and hence cannot be relied upon to advance studies into the field. Secondly, there is absence of studies to prove that early treatment of and diagnosis of hemochromatosis would positively affect the trajectory of treatment of diabetic patients. In spite of the above assertions, it is important to recognize that the benefits for screening and treating the above ailments simultaneously seem to outweigh any effects on the adverse. Generalized assertions without supportive evidence must be avoided. Very few cases exist of patients who have been diagnosed with diabetes and found to have iron overload within their blood. Such cases leave researchers of the disease in a big dilemma. They are left contemplating on whether diabetes is linked to iron overload or the occurrence is purely coincidental. Regardless of the overlapping opinions, there is still absence of enough data to warrant clinical trials on the issue.

Conclusion

In conclusions, genetic disorders like hemochromatosis are among the most difficult ailments to control because they are deeply rooted within the genetic makeup of individuals which allows them to be easily transmitted. Hemochromatosis that has been extensively discussed in this essay is caused by mutations in the HFE gene that is responsible for homeostatic functions in the body of regulating iron in the body. H63D and C282Y are the main mutations of the gene. C282Y mutation is what causes this genetic disorder. The adversarial effects of H63D are mainly exposed when it occurs in close association with the other recessive one. In its independent state, it is harmless. According to research, C282Y mutation exists mainly in the Caucasian demography. Mutations that occurred among segments of this population approximately 2000 years have been cited as the major reason for this unfortunate occurrence. The non-Caucasian populations that occupy parts of Africa and Asia are devoid of this mutation making them less susceptible to the disease. Hereditary diseases like the one elaborated in the essay are generally difficult to treat. However, with the sophistication in technology in the field of genetic engineering and gene mapping a solution to these perennial problems could be found. There are significant setbacks that have delayed the roll out of the technology. In the meantime, the treatment approach that has been utilized since the disorder was discovered continues to be the only reliable option. Hemochromatosis is a deadly disease in its advanced stages as it causes diabetes, impotency and failure of major organs like the liver. There is need for continued research on the disorder. It is difficult to ignore a disease of such consequences.

References

Bauduer, F. (2017). C282Y/H63D hemochromatosis mutations and microevolution: Speculations concerning the Basque population. Homo, 68(1), 38-41. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/28034447.

Campos, W. N., Massaro, J. D., Teixeira, A. C.,& Donadi, E. A. (2019). Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload. World journal of hepatology. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/30820268.

Elizabeth, L & Elaine, F. (2015). Hereditary Hemochromatosis since Discovery of the HFE Gene. International Journal on Genetic Studies. Retrieved from: https://www.researchgate.net/publication/11914116_Hereditary_Hemochromatosis_Since_Discovery_of_the_HFE_Gene.

Gatlin, C. K. (2017). A comparative study on hemochromatosis statistics globally. International Journal on Medical Research. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1050911/.

Hamdi-Rozé, H., Ali, Z. B., Ropert, M., Detivaud, L., Aggoune, S., Simon, D., & Bardou-Jacquet, E. (2019). Variable expressivity of HJV related hemochromatosis: Juvenile” hemochromatosis?. Blood Cells, Molecules, and Diseases, 74, 30-33. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/30389309.

Jonathan, S. N. (2016). An overview of Hemochromatosis. Oxford University Press.

Medically reviewed by Steve Kim, MD on January 29, 2016 — Written by April Kahn

https://www.healthline.com/health/hemochromatosis#treatments

Lescano, M. A., Tavares, L. C., & Santos, P. C. (2017). Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox. World journal of clinical cases, 5(10), 381. Retrieved from: https://www.researchgate.net/publication/320427994_Juvenile_hemochromatosis_HAMP_mutation_and_severe_iron_overload_treated_with_phlebotomies_and_deferasirox.

Martins, R., Silva, B., & Faustino, P. (2013). Differential HFE gene expression is regulated by alternative splicing in human tissues. Journal on Medical Research. Retrieved from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017542.

McGee, D. & Thomas, F. (2018). An analysis of the genetic trends of hereditary hemochromatosis. National Institute of Health Journal.

Neff, L. M. (2014). Current directions in hemochromatosis research: towards an understanding of the role of iron overload and the HFE gene mutations in the development of clinical disease. Nutrition Reviews Journal. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/12638463.

Raju, K., & Venkataramappa, S. M. (2018). Primary Hemochromatosis Presenting as Type 2 Diabetes Mellitus: A Case Report with Review of Literature. International Journal of Applied & Basic Medical Research, 8(1), 57–60.