Hemochromatosis type 4

Last updated
Haemochromatosis type 4
Other namesFerroportin disease
Specialty Hepatology, Medical genetics
CausesMutation in ferroportin gene
Differential diagnosis Hereditary hemochromatosis
Treatment Phlebotomy, Iron chelation
FrequencyRare

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. [1] 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. [2]

Contents

Signs and symptoms

Symptoms vary greatly between individuals with type 4 hemochromatosis. This difference in symptoms is likely due to the different types of SLC40A1 mutations patients may have. [3] In general, signs and symptoms of type 4 hemochromatosis are caused by excess iron in cells, which leads to tissue damage. The damage is largely due to iron-catalyzed oxidative reactions. Iron can exchange electrons with a variety of substrates, which can lead to generation of reactive oxygen species. This can lead to oxidative stress, lipid peroxidation, and DNA damage, which may result in cell death. [4] Two main forms of hemochromatosis type 4 exist (A and B), and the symptoms of these forms are distinct from one another. [3]

Type 4A hemochromatosis typically has milder symptoms than other types of hemochromatosis. Individuals with type 4A hemochromatosis tend to have hyperferritinemia (elevated ferritin in the blood plasma) and low saturated transferrin levels. These individuals are likely to have liver and spleen iron overload, primarily in Kupffer cells and other macrophages. [5] Because iron export is impaired, iron is unavailable for transport by circulating transferrin. This iron unavailability potentially leads to mild anemia in type 4A hemochromatosis patients because iron is necessary for hemoglobin synthesis, and red blood cells have a relatively high turnover rate. [4] Over time, iron stores increase, and individuals with type 4A hemochromatosis may develop hepatic fibrosis. [3]

The symptoms of type 4B hemochromatosis tend to be more severe. They resemble the symptoms of hemochromatosis types 1, 2, and 3. Plasma iron concentration is elevated, and symptoms include joint pain, diabetes, and arrhythmia. Liver iron deposition tends to be greater in type 4B than in type 4A. [5] Liver damage occurs more frequently in this form of hemochromatosis than in type 4A, and some individuals develop cirrhosis of the liver. [3]

Genetics

Type 4 hemochromatosis is caused by mutations of the SLC40A1 gene, located on the long arm of chromosome 2, specifically at 2q32.2. The SLC40A1 gene encodes ferroportin, a protein responsible for exporting iron from cells in the intestine, liver, spleen, and kidney, as well as from reticuloendothelial macrophages and the placenta. [6] [7] More than 39 mutations to the SLC40A1 gene have been identified in patients with type 4 hemochromatosis. [7] All reported SLC40A1 mutations are deletions or missense mutations, which lead to amino acid substitution. [8]

Mutations to SLC40A1 that change the amino acid sequence can result in loss of function or gain of function for the resulting ferroportin protein. The loss of function mutation results in a phenotype that is different from that of a gain of function mutation, and these phenotypes are associated with two different forms of type 4 hemochromatosis. Loss-of-function mutations are more frequent and are associated with type 4A hemochromatosis. These mutations lead to a defect in the localization of ferroportin. Gain-of-function mutations are associated with type 4B and lead to production of ferroportin that resists negative regulation by hepcidin. [8] [9]

Unlike other forms of hemochromatosis, which have a recessive pattern of inheritance, type 4 is an autosomal dominant dominant disorder. The dominant inheritance pattern occurs in hemochromatosis type 4 because ferroportin is multimeric. Consequently, mutant ferroportin can associate with wild-type ferroportin in multimers and interfere with the function of normal ferroportin proteins. [8]

Pathophysiology

In normal iron regulation, iron is absorbed in the intestine, and ferroportin transports iron from the cells of the intestinal lining into the bloodstream. Iron in the bloodstream is then bound by transferrin, which carries the iron to target cells. Iron is stored in cells and blood serum in a protein called ferritin. Reticuloendothelial macrophages, which can phagocytose red blood cells, are important in the iron recycling process. Ferroportin is upregulated in the reticuloendothelial macrophages after phagocytosis occurs so that iron from the degraded red blood cells can be released into the bloodstream and transported to other types of cells as needed. Hepcidin, a protein synthesized in the liver in response to iron or inflammation, is a regulator of ferroportin expression. When hepcidin binds ferroportin, ferroportin is phosphorylated, endocytosed, tagged with ubiquitin, and degraded. [6] [7] More than 39 mutations to the SLC40A1 gene have been identified in patients with type 4 hemochromatosis. [7] The misregulation of ferroportin in type 4 hemochromatosis can involve a failure of ferroportin to be properly expressed at the cell membrane, or it can involve a failure of ferroportin to respond to negative regulation by hepcidin. [8]

Hemochromatosis type 4A is characterized by impaired iron export in cells. Reticuloendothelial macrophages are most affected. Iron accumulates preferentially in Kupffer cells, which are located in the liver, and serum ferritin increases; less iron is available for circulating transferrin, a protein that binds iron and transports it through the bloodstream to cell receptors. [10] [11] This means that, while iron is trapped in certain types of tissues, it cannot be transported to tissues where it is needed. The accumulation of iron in tissues due to impaired iron export can lead to increasing transferrin iron saturation and liver parenchymal iron overload in advanced stages of the disease. [3] More ferritin is produced to suppress oxidative cell damage, although the amount of ferritin that cells can accumulate is limited. [12]

Hemochromatosis type 4B is characterized by abnormal iron release from macrophages and enterocytes because the mutant ferroportin is resistant to the hepcidin protein, which serves a regulatory function in wild-type ferroportin. [9] Intestinal iron absorption and release of iron from macrophages is increased. [3] Thus, this form of the disease leads to elevated transferrin saturation levels. [9] Systemic iron overload results, and liver iron deposition is primarily in the hepatocytes. [13]

Diagnosis

Diagnosis is based upon identification of symptoms, medical history, family history, and laboratory tests. Blood tests may show high levels of ferritin and low, normal, or high levels of transferrin saturation, depending on the form of hemochromatosis. The diagnosis must be confirmed by genetic testing for SLC40A1 mutations. [14]

Treatment

Treatment is based on the symptoms and severity of the disease. Iron chelators may be used to bind excess iron in tissues and allow for excretion of the excess metal. [15] Individuals with hemochromatosis type 4B may be treated with therapeutic phlebotomy. However, individuals with hemochromatosis type 4A may not require treatment. Additionally, therapeutic phlebotomy may not be tolerated in individuals with type 4A because anemia may develop despite the elevated serum ferritin levels typically found in these individuals. [11]

Epidemiology

Ferroportin disease is rare. [16]

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.

<span class="mw-page-title-main">Ferritin</span> Iron-carrying protein

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload.

<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">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">Hemosiderin</span> Iron-storage complex

Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives rise to biliverdin and iron. The body then traps the released iron and stores it as hemosiderin in tissues. Hemosiderin is also generated from the abnormal metabolic pathway of ferritin.

<span class="mw-page-title-main">Total iron-binding capacity</span> Medical blood test to measure transferrin

Total iron-binding capacity (TIBC) or sometimes transferrin iron-binding capacity is a medical laboratory test that measures the blood's capacity to bind iron with transferrin. Transferrin can bind two atoms of ferric iron (Fe3+) with high affinity. It means that transferrin has the capacity to transport approximately from 1.40 to 1.49 mg of iron per gram of transferrin present in the blood.

Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value tells a clinician how much serum iron is bound. For instance, a value of 15% means that 15% of iron-binding sites of transferrin are being occupied by iron. The three results are usually reported together. A low transferrin saturation is a common indicator of iron deficiency anemia whereas a high transferrin saturation may indicate iron overload or hemochromatosis. Transferrin saturation is also called transferrin saturation index (TSI) or transferrin saturation percentage (TS%)

<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 that in humans is encoded by the HFE gene. The HFE gene is located on short arm of chromosome 6 at location 6p22.2

<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.

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.

<span class="mw-page-title-main">Hemosiderosis</span> Iron metabolism disease

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern. 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." 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. 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. 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.

<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.

Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection.

References

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