Haemochromatosis type 3

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Haemochromatosis type 3
Other namesTFR2-related hemochromatosis [1]
Specialty Hematology

Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern. [2] [3] [4] The first confirmed case was diagnosed in 1865 by French doctor Trousseau. Later in 1889, the German doctor von Recklinghausen indicated that the liver contains iron, and due to bleeding being considered to be the cause, he called the pigment "Haemochromatosis." [5] In 1935, English doctor Sheldon's groundbreaking book titled, Haemochromatosis, reviewed 311 patient case reports and presented the idea that haemochromatosis was a congenital metabolic disorder. [5] Hereditary haemochromatosis is a congenital disorder which affects the regulation of iron metabolism thus causing increased gut absorption of iron and a gradual build-up of pathologic iron deposits in the liver and other internal organs, joint capsules and the skin. [5] The iron overload could potentially cause serious disease from the age of 40–50 years. In the final stages of the disease, the major symptoms include liver cirrhosis, diabetes and bronze-colored skin. There are four types of hereditary hemochromatosis which are classified depending on the age of onset and other factors such as genetic cause and mode of inheritance. [6]

Contents

Signs and Symptoms

The presence of Haemochromatosis type 3 can be realized through its many signs and symptoms throughout bodily systems. Systems affected by Haemochromatosis type 3 include the skeletal, endocrine, cardiovascular, neurological, genitourinary, and integumentary systems. [7] [8] [9] [10] There are also implications associated with a person's hematology, laboratory analysis results, and their liver. [11]

Those that inherit Haemochromatosis type 3 can be asymptomatic in up to 75% of cases. [12] The most common symptoms for those with symptoms can include severe fatigue (75%), impotence (45%), arthralgia (44%), hepatomegaly (13%), skin pigmentation, and arthritis. [12]

The specific diseases and conditions that show a correlation with Haemochromatosis type 3 are the following:

Systems Affected and Associated Symptoms [11]
SystemSymptom/Disease
SkeletalArthritis
HematologyAnemia

Lymphopenia

Neutropenia

Thrombocytopenic Purpura

Genitourinary (Male)Impotence

Decreased Libido

Hypogonadism

Genitourinary (Female)Amenorrhea
EndocrineDiabetes
NeurologicFatigue
Abdomen, LiverCirrhosis

Fibrosis

CardiovascularCardiomyopathy
IntegumentaryHyperpigmentation
Laboratory AbnormalitiesIncreased Serum Ferritin

Increased Serum Iron

Increased Transferrin Saturation

Increased Liver Transaminases

Genetics

Inheritance Pattern

The disease haemochromatosis type 3 is inherited in an autosomal recessive manner. Individuals with this disease exhibit a mutation in either both copies of the TFR2 or as compound heterozygotes (two mutations with one mutation in TFR2 and one in HFE). People with only one copy of TFR2 that is mutated and no mutations in HFE are labeled as carriers. Carriers typically do not exhibit signs or symptoms of the disease. This disease is shown to have reduced penetrance. Thus, some people with pathogenic variants of the TFR2 gene may never present symptoms related to the disease. [13]

Gene Involved

The gene involved with patients diagnosed with type 3 hemochromatosis is TFR2 ( or HFE3).

HFE (not the same as HFE3) is most often the cause of hereditary hemochromatosis. [14] The HFE gene provides instructions for producing a protein that is located on the surface of cells, primarily liver and intestinal cells. The HFE protein is also found on some immune system cells. The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. When the HFE protein is attached to a protein called transferrin receptor 1, the receptor cannot bind to a protein called transferrin. When transferrin receptor 1 is bound to transferrin, iron enters liver cells. So, it is likely that the HFE protein regulates iron levels in liver cells by preventing transferrin from binding to transferrin receptor 1. The HFE protein regulates the production of a protein called hepcidin. Hepcidin is produced by the liver, and it determines how much iron is absorbed from the diet and released from storage sites in the body. When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. The formation of this protein complex triggers the production of hepcidin. So when the HFE protein is bound to transferring receptor 1, hepcidin production is turned off and when the HFE protein is not bound to transferring receptor 1, hepcidin production is turned on. [15]

The transferrin receptor 2 (TFR2) gene is responsible for encoding a single-pass type II membrane protein. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. [16]

Type of Mutations

Majority of the cases of hemochromatosis are caused by mutations in the HFE (Homeostatic Iron Regulator) gene. [17] Type 3 HH is characterized by compound heterozygote mutations in both transferrin receptor 2 (TFR2) and HFE, i.e. a single mutation in each gene. HFE is located on chromosome 6 and TFR2 is located on chromosome 7. [18] [19] Multiple types of mutations have been found in TFR2 and associated with HH Type 3, including premature termination mutations, missense mutations, and nucleotide change mutations. [20]

Location of the Genes

Heterozygous mutations in the transferrin receptor-2 gene (TFR2 on chromosome 7) and the mutation in the hemochromatosis type 3 gene (HFE3 on chromosome 6) are the causes of hemochromatosis type 3. [21] [22]

Spectrum of Disease Severity

The disease can manifest itself without showing any symptoms, but these symptoms can emerge over time and the disease can therefore become more severe. Symptoms that emerge early on in the disease are generally less severe, and may include conditions such as fatigue, weakness, skin discoloration, loss of sex drive and joint pain. Late in the disease, people may experience liver disease as well as disease to other major organs as excess iron is deposited over time. People can also develop diabetes, heart problems, and abdominal pain.[ citation needed ]

Diagnosis

Like many genetic or rare diseases, diagnosis of haemochromatosis type 3 is challenging. In order to formulate a diagnosis healthcare professionals view medical history, symptoms, physical exam, and laboratory test results. [23]

Testing Resources

The Genetic Testing Registry provides information about genetic tests for haemochromatosis type 3. There are 62 different clinical tests available including two biochemical Genetics tests and 60 molecular genetics tests. There is also one research test available.[ citation needed ]

Management

Treatment for hemochromatosis type 3 may include reducing iron levels by removing blood (phlebotomy), iron chelation therapy, diet changes, and treatment for complications of the disease. The purpose of the treatment is to reduce the amount of iron in the body to normal levels, prevent or delay organ damage from excess iron, and maintain normal amounts of iron throughout the lifetime. [25] Phlebotomy helps to remove excess iron from the body. Most treatment begins with weekly therapeutic phlebotomy, occasionally treatment is initially twice a week if iron levels are elevated. Maintenance phlebotomy usually involved treatment every 2–4 months. Iron chelation therapy may be recommended for people that have other health issues as well. [25] Dietary recommendations may include avoiding alcohol and red meat. People with hemochromatosis are not recommended to take iron or vitamin C supplements. [25]

Epidemiology

The prevalence in the ethnic Norwegian population of homozygous and heterozygous inheritance is 0.8% and 12-15% respectively, which makes haemochromatosis one of the most common hereditary diseases in Norway. [5] Type 1 hemochromatosis is one of the most common genetic disorders in the United States, affecting about 1 million people. It most often affects people of Northern European descent. The other types of hemochromatosis are considered rare and have been studied in only a small number of families worldwide. [6]

Related Research Articles

<span class="mw-page-title-main">Hereditary haemochromatosis</span> Medical condition

Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron, with the exception of menstruation which, for the average woman, results in a loss of 3.2 mg of iron.

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also expresses an associated trait. In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not.

<span class="mw-page-title-main">Transferrin</span> Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

<span class="mw-page-title-main">Porphyria cutanea tarda</span> Medical condition

Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload or haemochromatosis indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosis, a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Hepcidin</span> Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

<span class="mw-page-title-main">Ferroportin</span> Protein

Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene, and is part of the Ferroportin (Fpn)Family (TC# 2.A.100). Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter.

<span class="mw-page-title-main">African iron overload</span> Iron overload disorder caused by consumption of home-brewed beer

African iron overload, also known as Bantu siderosis or dietary iron overload, is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. Dietary iron overload is the consumption of large amount of home-brewed beer with high amount of iron content in it. Preparing beer in iron pots or drums results in high iron content. The iron content in home-brewed beer is around 46–82 mg/L, compared to 0.5 mg/L in commercial beer. Dietary overload was prevalent in both the rural and urban Black African population, with the introduction of commercial beer in urban areas, the condition has decreased. However, the condition is still common in rural areas. Until recently, studies have shown that genetics might play a role in this disorder. Combination of excess iron and functional changes in ferroportin seems to be the probable cause. This disorder can be treated with phlebotomy therapy or iron chelation therapy.

<span class="mw-page-title-main">HFE (gene)</span>

Human homeostatic iron regulator protein, also known as the HFE protein, is a transmembrane protein which in humans is encoded by the HFE gene. The HFE gene is located on short arm of chromosome 6 at location 6p22.2

In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other. Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.

<span class="mw-page-title-main">Atransferrinemia</span> Medical condition

Atransferrinemia is an autosomal recessive metabolic disorder in which there is an absence of transferrin, a plasma protein that transports iron through the blood. Atransferrinemia is characterized by anemia and hemosiderosis in the heart and liver. The iron damage to the heart can lead to heart failure. The anemia is typically microcytic and hypochromic. Atransferrinemia was first described in 1961 and is extremely rare, with only ten documented cases worldwide.

<span class="mw-page-title-main">Iron in biology</span> Use of Iron by organisms

Iron is an important biological element. It is used in both the ubiquitous Iron-sulfur proteins and in Vertebrates it is used in Hemoglobin which is essential for Blood and oxygen transport.

<span class="mw-page-title-main">Transferrin receptor 2</span> Mammalian protein found in Homo sapiens

Transferrin receptor 2 (TfR2) is a protein that in humans is encoded by the TFR2 gene. This protein is involved in the uptake of transferrin-bound iron into cells by endocytosis, although its role is minor compared to transferrin receptor 1.

<span class="mw-page-title-main">Transferrin receptor 1</span> Protein-coding gene in the species Homo sapiens

Transferrin receptor protein 1 (TfR1), also known as Cluster of Differentiation 71 (CD71), is a protein that in humans is encoded by the TFRC gene. TfR1 is required for iron import from transferrin into cells by endocytosis.

<span class="mw-page-title-main">Iron metabolism disorder</span> Medical condition

Iron metabolism disorders may involve a number of genes including HFE and TFR2.

Juvenile hemochromatosis, also known as hemochromatosis type 2, is a rare form of hereditary hemochromatosis, which emerges in young individuals, typically between 15 and 30 years of age, but occasionally later. It is characterized by an inability to control how much iron is absorbed by the body, in turn leading to iron overload, where excess iron accumulates in many areas of the body and causes damage to the places it accumulates.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

<span class="mw-page-title-main">HFE H63D gene mutation</span>

The HFE H63D is a single-nucleotide polymorphism in the HFE gene, which results in the substitution of a histidine for an aspartic acid at amino acid position 63 of the HFE protein (p.His63Asp). HFE participates in the regulation of iron absorption.

H63D syndrome is a very rare clinical phenotype based on a homozygous HFE H63D gene mutation of the HFE gene. This mutation is associated with diverse diseases, but H63D syndrome is the only known specific expression of a homozygous HFE-H63D mutation to date.

References

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  2. ↑ Roetto A, Totaro A, Piperno A, et al. (May 2001). "New mutations inactivating transferrin receptor 2 in hemochromatosis type 3". Blood. 97 (9): 2555–60. doi: 10.1182/blood.V97.9.2555 . PMID   11313241. S2CID   36015072.
  3. ↑ Roetto A, Daraio F, Alberti F, et al. (2002). "Hemochromatosis due to mutations in transferrin receptor 2". Blood Cells Mol. Dis. 29 (3): 465–70. doi:10.1006/bcmd.2002.0585. PMID   12547237.
  4. ↑ Roetto A, Camaschella C (June 2005). "New insights into iron homeostasis through the study of non-HFE hereditary haemochromatosis". Best Pract Res Clin Haematol. 18 (2): 235–50. doi:10.1016/j.beha.2004.09.004. PMID   15737887.
  5. 1 2 3 4 Johan Ulvik, Rune (20 December 2016). "Hereditary haemochromatosis through 150 years". Tidsskrift for den Norske Legeforening. 136 (23–24): 2017–2021. doi: 10.4045/tidsskr.15.1003 . PMID   28004554 . Retrieved 26 April 2021.{{cite journal}}: CS1 maint: url-status (link)
  6. 1 2 "Hereditary hemochromatosis". MedlinePlus. 1 February 2019.{{cite web}}: CS1 maint: url-status (link)
  7. ↑ Camaschella, C.; Fargion, S.; Sampietro, M.; Roetto, A.; Bosio, S.; Garozzo, G.; Arosio, C.; Piperno, A. (May 1999). "Inherited HFE-unrelated hemochromatosis in Italian families". Hepatology. 29 (5): 1563–1564. doi: 10.1002/hep.510290509 . ISSN   0270-9139. PMID   10216143. S2CID   25671765.
  8. ↑ Camaschella, C.; Roetto, A.; Calì, A.; De Gobbi, M.; Garozzo, G.; Carella, M.; Majorano, N.; Totaro, A.; Gasparini, P. (May 2000). "The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22". Nature Genetics. 25 (1): 14–15. doi:10.1038/75534. ISSN   1061-4036. PMID   10802645. S2CID   9227077.
  9. ↑ Griffiths, W.; Cox, T. (October 2000). "Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism". Human Molecular Genetics. 9 (16): 2377–2382. doi: 10.1093/hmg/9.16.2377 . ISSN   0964-6906. PMID   11005792.
  10. ↑ Mattman, Andre; Huntsman, David; Lockitch, Gillian; Langlois, Sylvie; Buskard, Noel; Ralston, Diana; Butterfield, Yaron; Rodrigues, Pedro; Jones, Steven; Porto, Graça; Marra, Marco (2002-08-01). "Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation". Blood. 100 (3): 1075–1077. doi:10.1182/blood-2002-01-0133. hdl: 10400.16/826 . ISSN   0006-4971. PMID   12130528. S2CID   32238636.
  11. 1 2 Camaschella, Clara; Roetto, Antonella; Calì, Angelita; De Gobbi, Marco; Garozzo, Giovanni; Carella, Massimo; Majorano, Nunzia; Totaro, Angela; Gasparini, Paolo (May 2000). "The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22". Nature Genetics. 25 (1): 14–15. doi:10.1038/75534. ISSN   1546-1718. PMID   10802645. S2CID   9227077.
  12. 1 2 "Hemochromatosis: Practice Essentials, Background, Pathophysiology". 2019-11-21. Retrieved 2021-04-29.{{cite web}}: CS1 maint: url-status (link)
  13. ↑ "Hemochromatosis type 3 | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-26.
  14. ↑ "Hemochromatosis". Mayo Clinic. Retrieved 26 April 2021.{{cite web}}: CS1 maint: url-status (link)
  15. ↑ "HFE gene homeostatic iron regulator". MedlinePlus. Retrieved 26 April 2021.{{cite web}}: CS1 maint: url-status (link)
  16. ↑ "TRF2 transferring receptor 2 [ Homo sapiens (human) ]". NCBI. 10 April 2021. Retrieved 26 April 2021.{{cite web}}: CS1 maint: url-status (link)
  17. ↑ Crawford, Darrell H. G. (2014). "Hereditary hemochromatosis types 1, 2, and 3". Clinical Liver Disease. 3 (5): 96–97. doi:10.1002/cld.339. ISSN   2046-2484. PMC   6448708 . PMID   30992896.
  18. ↑ Online Mendelian Inheritance in Man, OMIM, entry for gene HFE, May 2022
  19. ↑ Crawford, Darrell (2014). "Hereditary Hemochromatosis Types 1, 2, and 3". Clinical Liver Disease. 3 (5): 96–97. doi:10.1002/cld.339. PMC   6448708 . PMID   30992896.
  20. ↑ Online Mendelian Inheritance in Man, OMIM, entry for gene TFR2, Oct 2018
  21. ↑ Online Mendelian Inheritance in Man, OMIM, entries for genes HFE &TFR2 May 2022, Oct 2018
  22. ↑ Roychoudhury, A. K. (1977-12-29). "Gene diversity in Indian populations". Human Genetics. 40 (1): 99–106. doi:10.1007/BF00280836. ISSN   0340-6717. PMID   604250. S2CID   10350768.
  23. ↑ "Hemochromatosis type 3 | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-26.
  24. ↑ "Hemochromatosis type 3 - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-04-26.
  25. 1 2 3 "Hemochromatosis type 3". Genetics and Rare Diseases Information Center. 15 February 2018.{{cite web}}: CS1 maint: url-status (link)
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