Hemochromatosis

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Hemochromatosis is a hereditary disease that occurs when the body absorbs too much iron from foods and vitamins containing iron. If hemochromatosis is left untreated it may result in cirrhosis of the liver. It is estimated that nearly 1 in 300-400 people in the United States are affected by this disease, which primarily includes individuals of Northern European and Anglo-English ancestry. Armand Trousseau was the first to describe the disease in 1865, but Friedrich Daniel von Recklinghausen coined the term hemochromatosis while providing a connection between iron accumulation in body tissue and hemochromatosis in 1890 [8].

HFE gene and iron overload within the body [1]

History

Armand Trousseau [2]

Hemochromatosis was initially described by a French Internist, Armand Trousseau. Trousseau made the discovery in 1865 in an article describing a diabetic patient with cirrhosis of the liver that expressed a bronzed skin color [8, 9, 10]. This dark pigmentation is one of the many symptoms of patients with hemochromatosis [10]. As mentioned above, although Trousseau was the first to describe the symptoms of the hemochromatosis, the term hemochromatosis was first coined by Friedrich Daniel von Recklinghausen in 1890. Recklinghausen was a German pathologist that provided a connection between iron accumulation in body tissue and hemochromatosis [8, 9, 10].

In 1935 J.H. Sheldon, a British physician, was able to explain the inherited nature of the disease through his writings in his text Haemochromatosis [9, 11, 12, 13]. Sheldon also described the pathophysiology mechanism linked to iron metabolism for the first time [14]. Not until 1977 was hemochromatosis characterized as an autosomal recessive disease by Simon and his colleagues [9, 11, 12]. Also in 1977, Stevens showed the existence of an HH gene, which was located on chromosome 6 found near the HLA-A gene. A support group and information center for individuals affected by hemochromatosis called Iron Overload Diseases Association (IOD) was formed in 1978 [10]. In 1996 Felder identified the hemochromatosis gene, HFE gene. Felder found that the HFE gene has two main missense mutations, C282Y and H63D, which were the main cause of HH [9, 14].

Finally in 1997 the CDC and the National Human Genome Research Institute sponsored an examination of hemochromatosis following the discovery of the HFE gene. The panel of experts conducting the examination concluded that a large-scale population screening is not recommended for two reasons. One reason is different genetic mutations can result in various levels of disease severity. For example individuals with hemochromatosis who carry a copy for the mutation of HH may express a severe case of the disease, a mild case, or even exhibit no symptoms. Diagnosing an individual with hemochromatosis that is a carrier, but displays no symptoms could cause that individual to develop negative psychological effects. Another issue associated with large-scale population screening is current genetic-testing methods fail to detect about 10% of mutations, therefore individuals could go undiagnosed leaving them vulnerable to developing hemochromatosis later in life. Until the complex genotype-phenotype relationship accompanying hemochromatosis is better understood the need for a large-scale screening will be argued [9].

Symptoms

Symptoms and signs of hemochromatosis [3]


The most common symptoms with hemochromatosis are fatigue and joint pain [1]. Other symptoms that are present in a person with hemochromatosis are dark pigmentation, abdominal pain, loss of sex drive, heart problems, weakness, change in skin color, and increased urination [17]. Symptoms generally start to appear in men around 40 years of age and in women around 50 years of age [1][17]. Other conditions that could result are arthritis, cirrosis of the liver, and diabetes [1] [17]. Four tests are done to diagnose hemochromatosis; they include a transferrin saturation test, serum ferritin test, a liver biopsy, and genetic testing [1]. A transferrin saturation test measures how much iron is bound to protein (transferrin) that carries iron in ones blood [1]. A serum ferritin test measures how much iron is in your liver [1]. This test is generally done after the transferrin saturation test comes back with high iron results [1]. A liver biopsy is where a piece of one's liver is cut out, then tested for damage and high iron count [1]. The final test is a genetic test to see if a person has mutations in their HFE gene [1]. This also shows a person who has inherited hemochromatosis [1].

Mechanism

Iron regulation is one of the many examples in your body of a homeostatic mechanism. Hemochromatosis occurs when your body is unable to adequately regulate iron. [6] . Iron is absorbed in the gastrointestinal tract, more specifically the duodenum and proximal jejunum, which are areas located at the beginning of the small intestine. When iron homeostasis is working normally, your body is able to decrease absorption of iron when you are undergoing iron overload, and is able to increase absorption of iron when you are in an iron deficient state. How does your body know? Precursor cells to your enterocytes are able to detect the concentration of iron in your body and your need to increase or decrease absorption. Once these cells mature and become enterocytes they can signal for the absorption or decrease in absorption of iron. This specific mechanism is still unknown. To be absorbed, iron must be oxidized from Fe3+ to Fe2+, and this take place in the lumen of the duodenum due to its acidic environment. Uptake across the villi lining the duodenum and jejunum occurs and then the iron travels into the enterocyte and eventually into the portal venous system where it is picked up by its transporter ferritin. If iron is not stored in the villi as ferritin, it is circulated throughout the body to its desired locations [7]. In individuals suffering from hemochromatosis, studies suggest that the hereditary hemochromatosis gene (HFE) has a mutation which impacts iron absorption. One of the most common mutations occurs because the amino acid cystine is replaced with the amino acid tyrosine. The other most common mutation occurs when the amino acid histidine is replaced with the amino acid aspartate. When tyrosine replaces cystine, the HFE protein is inhibited from interacting with ferritin and too much iron is absorbed. The other mechanisms are still unknown [18]. The mechanisms of HFE mutation are not understood completely, but it is also believed that the mutation could influence the precursor cells in the duodenum and jejunum to be coded for iron absorption, even if levels of iron are already sufficient or elevated [6].

Treatments

Since hemochromatosis occurs when too much iron is maintained in the body, the most common and most efficient treatment deals with removing the excess iron from the body. The treatment, called phlebotomy, involves removing about a pint of blood from the patient every two to four weeks, until the blood ferritin levels are lowered [1] [3]. Ferritin is a protein that stores iron in body tissues [2]. After iron levels start to lower and approaches the normal level, the patient continues phlebotomy every two to four months for the rest of their life to maintain a normal iron concentration in their body [3]. It is also important to maintain a diet that is low in iron. Avoiding red meat, alcohol, and limiting vitamin C intake will help lower iron levels and stop further liver damage [4]. There is medicine, called chelating agents, that is used to remove excess iron from the body. The chelating agents bind to the iron and are removed via urination or defecation. This treatment takes twice as long to normalize iron levels as phlebotomy and is a more uncommon treatment [5]. There is no cure for hemochromatosis, but if treatment begins before body organs are damaged from the excess iron, a normal life span is expected. Treatment started after major damage has occurred is also beneficial and will expand the patients’ life expectancy [1].

Current Research

It is known that Heredity Hemochromatosis is usually caused by HFE C282Y homozygosity. Because it is easy to diagnose and with treatment, patients can live long healthy lives, studies have been done to determine the best way to offer community screenings for young teenagers. In one such study, Delatycki et. al., tested the possibility of offering screenings in high schools. Students were shown a video to learn more about hemochromatosis, and as long as they had parental consent, then had their cheeks swabbed and tested. A total of 88 schools were approached with the opportunity for screening. Of the 88, only 32 participated. A total of 9,187 students were offered screening and of those students 3,743 were given the screening which is 38% [15].

Heredity Hemochromatosis is due to low levels of hepcidin or ferroportin which are two very important proteins that regulate iron levels. Currently the number one used treatment for Heredity Hemochromatosis is venesection therapy when it is caused by low levels of hepcidin. However, studies and are being done to use hepcidin supplementation instead [16].

References

[1] Mayo Clinic. Treatment of Hereditary Hemochromatosis (HHC). http://www.mayoclinic.org/genetic-liver-diseases/hemochromatosis.html

[2] WebMD. Ferritin. 2008. http://www.webmd.com/a-to-z-guides/ferritin

[3] The Hemochromatosis Information Center. Hemochromatosis and Treatment. http://www.hemochromatosis.org/Internal.asp?Page=Treatment

[4] The Hemochromatosis Information Center. Hemochromatosis and Diet. http://www.hemochromatosis.org/Internal.asp?Page=Diet

[5] WebMD. Hemochromatosis Treatment Overview. 2009.http://www.webmd.com/a-to-z-guides/hemochromatosis-treatment-overview

[6] Fleming, R., & Sly, W. (2002). Mechanisms of iron accumulation in hereditary hemochromatosis. Annual Review Of Physiology, 64663-680. Retrieved from MEDLINE with Full Text database. http://web.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=10&hid=9&sid=3ad2ff19-b097-4520-abbe-c10273af93b0%40sessionmgr12

[7] Fletcher, L., & Halliday, J. (2002). Haemochromatosis: understanding the mechanism of disease and implications for diagnosis and patient management following the recent cloning of novel genes involved in iron metabolism. Journal Of Internal Medicine, 251(3), 181-192. Retrieved from MEDLINE with Full Text database. http://web.ebscohost.com/ehost/detail?vid=5&hid=9&sid=3ad2ff19-b097-4520-abbe-c10273af93b0%40sessionmgr12&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=mnh&AN=11886477

[8] WikiDoc. Hemochromatosis. 2010. http://www.wikidoc.org/index.php/Haemochromatosis

[9]Gene Gateway-Exploring Genes and Genetic Disorders. Hemochromatosis. 2002. http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hh.shtml

[10] Wikipedia. Hemochromatosis. 2008. http://en.wikipedia.org.sharedcopy.com/wiki/12134dbe7fac2e8f512aed54d4c30684.html#History

[11] Smith, L.H. (1990).Overview of hemochromatosis. Western Journal of Medicine, 153(3), 296–308. Retrieved November 1, 2010, from PubMed Central.

[12] Cramptom, J.R., & Limdi J.K. (2004). Hereditary haemochromatosis. An International Journal of Medicine, 97(60), 315-324. Retrieved November 2, 2010, from Oxford Journals.

[13] Wolverhampton's Blue Plaques. New Cross Hospital. http://www.localhistory.scit.wlv.ac.uk/plaques/Wednesfield.htm

[14] Girones, C., Loureiro, R., Namora, J., & Vizinho, R. (2008). Hereditary hemochromatosis and alcohol: pathogenic synergism – a clinical case. Medicina Interna, 16(3), 144-148. Retrieved from http://www.spmi.pt/revista/vol16/eng_vol16_n3_2009_144_148.pdf

[15] Wolthuizen, M., Collins, V., Varley, E., Craven, J., & Allen, K. (2010). Implementation of ironXS: a study of the acceptability and feasibility of genetic screening for hereditary hemochromatosis in high schools. CLINICAL GENETICS, 77(3), 241-248. doi:10.1111/j.1399-0004.2009.01308.x

[16] Brissot, P. (2009). Haemochromatoses. New understanding, new treatments. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE, 33(8-9), 859-867. doi:10.1016/j.gcb.2009.04.004

[17] WebMD. Hemochromatosis Symptoms. 2009. http://www.webmd.com/a-to-z-guides/hemochromatosis-symptoms

[18] Genetics Home Reference HFE (Nov. 2010). Retrieved from http://ghr.nlm.nih.gov/gene/HFE