African iron overload

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African iron overload
Protein TF PDB 1a8e.png
Transferrin
Specialty Hematology

African iron overload is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. [1] It is now recognized to actually be two disorders with different causes, possibly compounding each other: [2]

Contents

This disorder can be treated with phlebotomy therapy or iron chelation therapy.[ citation needed ]

Signs and symptoms

Symptoms can vary from one person to another. It depends on the extent of accumulation and on the body location of the accumulation. African iron overload can be considered in patient with some of these conditions. [1] [7]

Mechanism

Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get an iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., African Americans). [2]

This led investigators to the discovery of a gene polymorphism in the gene for ferroportin, which predisposes some people of African descent to iron overload. [8]

Diet

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. [3]

Genetics

The SLC40A1 gene encodes for ferroportin. Ferroportin/SLC40A1 Q248H mutation in exon 6 occurs as a polymorphism in individuals of sub-Saharan African descent, [8] [9] [10] but it was not identified in western Caucasians. [8]

Q248H has not yet been conclusively found to be responsible for iron overload. It is found in a minority of African American and Native African with primary iron overload [8] [9] but was not found more regularly in Native southern Africans with dietary iron overload. [11] It is also not associated with a statistically significant increase of risk in African Americans and Native Americans. [4] In fact, studies have shown that SLC40A1 Q248H aggregate allele frequency is higher in Native Africans than the aggregate allele frequency in African Americans. [4]

On the other hand, evidence suggests that Q248H may have an effect on iron supply. Ferroportin Q248H mutation in African families with dietary iron overload showed lower mean cell volume and higher ferritin concentration. [11] Mice homozygous for the Q248H mutation show similar symptoms. They display only slight iron loading on a normal diet, but accumulates iron when fed a high-iron diet. [12]

The probable cause of African iron overload is the combination of excess iron intake and functional changes in ferroportin. [4] [5] Penetrance of Q248H as a cause of iron overload is most likely low. [4] [11]

Hepatocellular carcinoma

Excess hepatic iron in dietary iron overload is typically associated with serum ferritin saturation of greater than 700pg/L and transferrin saturation of greater than 55%. [13]

Increased hepatic iron generates chronic oxidative stress by disrupting the redox balance of the cell, which damages DNA, protein, hepatocytes and lipids. [14] [15] [16] Increased lipid peroxidation is thought to be a vital contributor to hepatocellular carcinoma in iron overload. [17] Oxidative stress leads to lipid peroxidation of unsaturated fatty acids in organelles and cell membrane. [3]

Diagnosis

Elevation in ferritin concentration without elevation in transferrin saturation does not rule out an iron overload disorder. This combination can be observed in loss-of-function ferroportin mutation and in aceruloplasminemia. [5] Elevated level of ferritin concentration can be observed in acute or chronic inflammatory process without pathologic iron overload. [18]

Measurement of iron status
CharacteristicNormal rangeUnit
Ferritin-male12–300 [19] ng/mL
Ferritin-female12–150 [19] ng/mL
Transferrin saturation-male10–50 [20]  %
Transferrin saturation-female15–50 [20]  %

Ferritin level above 200 ng/mL (449 pmol/L) in women or 300 ng/mL (674 pmol/L) in men who have no signs of inflammatory disease need additional testing. Transferrin saturation above normal range in male and female also need additional testing. [21]

Chemical evidence of tissue vitamin C deficiency and mild to moderate liver dysfunction are likely to be seen in individuals with African iron overload. [1] Elevation in gamma-glutamyl transpeptidase can be used as a marker for abnormalities in liver function.[ citation needed ]

Measurement of iron-related features
CharacteristicNormal rangeUnit
Vitamin C 0.2–2 [22]
11–114 [22] 		mg/dL
μmol/L
Gamma-glutamyl transpeptidase in male< 55.2 [23]
0.92 [23] 		U/L
μkat/L
Gamma-glutamyl transpeptidase in female< 37.8 [23]
0.63 [23] 		U/L
μkat/L

The severity of iron overload can be determined and monitored using a combination of tests. Measurement of serum ferritin indicates for total body iron overload. [18] Liver biopsy measures the iron concentration of liver. It provides the microscopic examination of the liver. [5] Measurement of serum hepcidin levels may be useful in diagnostic for iron overload. [5] MRI can detect the degree of magnetic disruption due to iron accumulation. MRI can measure iron accumulation within the heart, liver, and pituitary. [18] Accumulation of iron in a single organ does not provide proper representation of the total body iron overload. [18]

It is important to use both the imaging techniques and serum ferritin level as indicators to start the therapy of iron overload. Serum level and the imaging techniques can be used as markers for treatment progress.[ citation needed ]

Treatment

A person's hemoglobin is important in the physician's consideration of iron reduction therapy. A physician can provide therapeutic phlebotomy if the patient's hemoglobin level is sufficient to sustain blood removal. The physician can also recommend the patient to routinely donate blood. When a patient's hemoglobin is not sufficient for phlebotomy. Iron reduction will likely require the removal of iron using specific drugs (iron-chelation). The physician may use a combination of these therapies in some situations. [24]

Prognosis

Individuals of sub-Saharan African descent with ferroportin Q248H are more likely to be diagnosed with African iron overload than individual without ferroportin mutation because individuals with ferroportin Q248H have elevated level of serum ferritin concentration. [11] Individuals of African descent should also avoid drinking traditional beer.[ citation needed ]

Recent research

Distinctive phenotypes of individuals with SLC40A1 Q248H are minor, if any. Serum ferritin concentration is likely to be high in persons with Q248H (mostly heterozygotes) than in wild-type SLC40A1. [10] In xenopus oocytes and HEK 293 cells, the expression of wild type ferroportin was similar to the expression of ferroportin Q248H at the plasma membrane. [25] In HEK 293 cells, Q248H was as predisposed to the activities of hepcidin-25 as wild type ferroportin. [26] Ferroportin Q248H also unregulated the expression of transferrin receptor-1 in the same way as wild type. This indicates the ferroportin Q248H is associated with mild clinical phenotype or causes iron disorder in the presence of other factors. [26] [27]

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 mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating

<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">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. 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">Aceruloplasminemia</span> Medical condition

Aceruloplasminemia is a rare autosomal recessive disorder in which the liver can not synthesize the protein ceruloplasmin properly, which is needed to transport copper around the blood. Copper deficiency in the brain results in neurological problems that generally appear in adulthood and worsen over time. .

<span class="mw-page-title-main">HFE (gene)</span> Mammalian protein found in Homo sapiens

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">Beta thalassemia</span> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<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.

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.

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.

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

  1. 1 2 3 MacPhail, AP; Mandishona, EM; Bloom, PD; Paterson, AC; Rouault, TA; Gordeuk, VR (Sep 1999). "Measurements of iron status and survival in African iron overload". Suid-Afrikaanse Tydskrif vir Geneeskunde. 89 (9): 966–72. PMID   10554633.
  2. 1 2 3 Gordeuk V, Mukiibi J, Hasstedt SJ, et al. (January 1992). "Iron overload in Africa. Interaction between a gene and dietary iron content". N. Engl. J. Med. 326 (2): 95–100. doi: 10.1056/NEJM199201093260204 . PMID   1727237.
  3. 1 2 3 Kew, MC; Asare, GA (Aug 2007). "Dietary iron overload in the African and hepatocellular carcinoma". Liver International. 27 (6): 735–41. doi:10.1111/j.1478-3231.2007.01515.x. PMID   17617115. S2CID   37237869.
  4. 1 2 3 4 5 Barton JC, Acton RT, Lee PL, West C (2007). "SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent". Blood Cells Mol. Dis. 39 (2): 206–11. doi:10.1016/j.bcmd.2007.03.008. PMC   1986732 . PMID   17490902.
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  6. ↑ Gordeuk, Victor R; Caleffi, Angela; Corradini, Elena; Ferrara, Francesca; Jones, Russell A; Castro, Oswaldo; Onyekwere, Onyinye; Kittles, Rick; Pignatti, Elisa; Montosi, Giuliana; Garuti, Cinzia; Gangaidzo, Innocent T; Gomo, Z.A.R; Moyo, Victor M; Rouault, Tracey A; MacPhail, Patrick; Pietrangelo, Antonello (November 2003). "Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene☆". Blood Cells, Molecules, and Diseases. 31 (3): 299–304. doi:10.1016/S1079-9796(03)00164-5. PMID   14636642.
  7. ↑ "African Iron Overload". National Organization of Rare Disorder. Retrieved 9 April 2014.
  8. 1 2 3 4 Gordeuk VR, Caleffi A, Corradini E, et al. (2003). "Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene". Blood Cells Mol. Dis. 31 (3): 299–304. doi:10.1016/S1079-9796(03)00164-5. hdl: 11380/611688 . PMID   14636642.
  9. 1 2 Beutler, E; Barton, JC; Felitti, VJ; Gelbart, T; West, C; Lee, PL; Waalen, J; Vulpe, C (Nov–Dec 2003). "Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans". Blood Cells, Molecules & Diseases. 31 (3): 305–9. doi:10.1016/s1079-9796(03)00165-7. PMID   14636643.
  10. 1 2 Barton, JC; Acton, RT; Rivers, CA; Bertoli, LF; Gelbart, T; West, C; Beutler, E (Nov–Dec 2003). "Genotypic and phenotypic heterogeneity of African Americans with primary iron overload". Blood Cells, Molecules & Diseases. 31 (3): 310–9. doi:10.1016/s1079-9796(03)00166-9. PMID   14636644.
  11. 1 2 3 4 McNamara, L; Gordeuk, VR; MacPhail, AP (Dec 2005). "Ferroportin (Q248H) mutations in African families with dietary iron overload". Journal of Gastroenterology and Hepatology. 20 (12): 1855–8. doi:10.1111/j.1440-1746.2005.03930.x. PMID   16336444. S2CID   41825542.
  12. ↑ Alhakami, Fatemah; Ahmad, Asrar; Jerebtsova, Marina; Nekhai, Sergei (15 November 2022). "Ferroportin Q248H Mutation Leads to a Moderate Iron Load in Mutant Slc 40a1Q248H/Q248H Mice". Blood. 140 (Supplement 1): 5343–5344. doi: 10.1182/blood-2022-170019 . S2CID   254217566.
  13. ↑ Moyo, VM; Gangaidzo, IT; Gomo, ZA; Khumalo, H; Saungweme, T; Kiire, CF; Rouault, T; Gordeuk, VR (Mar 15, 1997). "Traditional beer consumption and the iron status of spouse pairs from a rural community in Zimbabwe". Blood. 89 (6): 2159–66. doi: 10.1182/blood.V89.6.2159 . PMID   9058740.
  14. ↑ Hagen, TM; Huang, S; Curnutte, J; Fowler, P; Martinez, V; Wehr, CM; Ames, BN; Chisari, FV (Dec 20, 1994). "Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 91 (26): 12808–12. Bibcode:1994PNAS...9112808H. doi: 10.1073/pnas.91.26.12808 . PMC   45529 . PMID   7809125.
  15. ↑ Jüngst, C; Cheng, B; Gehrke, R; Schmitz, V; Nischalke, HD; Ramakers, J; Schramel, P; Schirmacher, P; Sauerbruch, T; Caselmann, WH (Jun 2004). "Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma". Hepatology. 39 (6): 1663–72. doi: 10.1002/hep.20241 . PMID   15185308.
  16. ↑ Asare, GA; Mossanda, KS; Kew, MC; Paterson, AC; Kahler-Venter, CP; Siziba, K (Feb 15, 2006). "Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity". Toxicology. 219 (1–3): 41–52. doi:10.1016/j.tox.2005.11.006. PMID   16337327.
  17. ↑ Thirunavukkarasu, C; Sakthisekaran, D (Mar 2001). "Effect of selenium on N-nitrosodiethylamine-induced multistage hepatocarcinogenesis with reference to lipid peroxidation and enzymic antioxidants". Cell Biochemistry and Function. 19 (1): 27–35. doi:10.1002/cbf.895. PMID   11223868. S2CID   46673802.
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  21. ↑ McLaren, CE; Barton, JC; Adams, PC; Harris, EL; Acton, RT; Press, N; Reboussin, DM; McLaren, GD; Sholinsky, P; Walker, AP; Gordeuk, VR; Leiendecker-Foster, C; Dawkins, FW; Eckfeldt, JH; Mellen, BG; Speechley, M; Thomson, E; Hemochromatosis (Feb 2003). Iron Overload Study Research, Investigators. "Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults". The American Journal of the Medical Sciences. 325 (2): 53–62. doi:10.1097/00000441-200302000-00001. PMID   12589228. S2CID   20665357.
  22. 1 2 "Vitamin-C". GlobalRPH. Retrieved 9 April 2014.
  23. 1 2 3 4 "Gamma-glutamyl transpeptidase". Medizinsch-Diagnostische Institute. Archived from the original on 25 April 2012. Retrieved 9 April 2014.
  24. ↑ "African Hemochromatosis". Iron Disorders Institute. Retrieved 17 April 2014.
  25. ↑ McGregor, JA; Shayeghi, M; Vulpe, CD; Anderson, GJ; Pietrangelo, A; Simpson, RJ; McKie, AT (Jul 2005). "Impaired iron transport activity of ferroportin 1 in hereditary iron overload". The Journal of Membrane Biology. 206 (1): 3–7. doi:10.1007/s00232-005-0768-1. PMID   16440176. S2CID   28927952.
  26. 1 2 Drakesmith, H; Schimanski, LM; Ormerod, E; Merryweather-Clarke, AT; Viprakasit, V; Edwards, JP; Sweetland, E; Bastin, JM; Cowley, D; Chinthammitr, Y; Robson, KJ; Townsend, AR (Aug 1, 2005). "Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin". Blood. 106 (3): 1092–7. doi: 10.1182/blood-2005-02-0561 . PMID   15831700.
  27. ↑ Schimanski, LM; Drakesmith, H; Merryweather-Clarke, AT; Viprakasit, V; Edwards, JP; Sweetland, E; Bastin, JM; Cowley, D; Chinthammitr, Y; Robson, KJ; Townsend, AR (May 15, 2005). "In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations". Blood. 105 (10): 4096–102. doi: 10.1182/blood-2004-11-4502 . PMID   15692071.
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