| Thalassemia |
| Classification and external resources |
| ICD-10 |
D56 |
| ICD-9 |
282.4 |
| MedlinePlus |
000587 |
| eMedicine |
ped/2229 radio/686 |
| MeSH |
D013789 |
Thalassemia (British English: thalassaemia) are forms of inherited autosomal recessive blood disorders that originated in the Mediterranean region. In thalassemia, the disorder is caused by the weakening and destruction of red blood cells. Thalassemia is caused by variant or missing genes that affect how the body makes hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen. People with thalassemia make less hemoglobin and fewer circulating red blood cells than normal, which results in mild or severe anemia. Thalassemia will be present as microcytic anemia which may be differentiated from iron deficiency anemia using the mentzer index calculation.
Thalassemia can cause significant complications, including iron overload, bone deformities and cardiovascular illness. However this same inherited disease of red blood cells may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common. This selective survival advantage on carriers (known as heterozygous advantage) may be responsible for perpetuating the mutation in populations. In that respect, the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.[1] [2]
Contents
- 1 Signs and symptoms
- 2 Cause
- 3 Pathophysiology
- 3.1 Alpha (α) thalassemias
- 3.2 Beta (β) thalassemia
- 3.3 Delta (δ) thalassemia
- 3.4 Combination with other hemoglobinopathies
- 4 Management
- 4.1 Medications
- 4.2 Carrier detection
- 4.3 Bone marrow transplant
- 5 Epidemiology
- 6 Etymology
- 7 Society and culture
- 8 References
- 9 External links
Signs and symptoms[edit]
- Iron overload: People with thalassemia can get an overload of iron in their bodies, either from the disease itself or from frequent blood transfusions. Too much iron can result in damage to the heart, liver and endocrine system, which includes glands that produce hormones that regulate processes throughout the body. The damage is characterized by excessive deposits of iron. Without adequate iron chelation therapy, almost all patients with beta-thalassemia will accumulate potentially fatal iron levels.[3]
- Infection: people with thalassemia have an increased risk of infection. This is especially true if the spleen has been removed.
- Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow expansion also makes bones thin and brittle, increasing the risk of broken bones.
- Enlarged spleen: the spleen aids in fighting infection and filters unwanted material, such as old or damaged blood cells. Thalassemia is often accompanied by the destruction of a large number of red blood cells and the task of removing these cells causes the spleen to enlarge. Splenomegaly can make anemia worse, and it can reduce the life of transfused red blood cells. Severe enlargement of the spleen may necessitate its removal.
- Slowed growth rates: anemia can cause a child's growth to slow. Puberty also may be delayed in children with thalassemia.
- Heart problems: such as congestive heart failure and abnormal heart rhythms (arrhythmias), may be associated with severe thalassemia.[4]
Cause[edit]
Thalassemia has an autosomal recessive pattern of inheritance
Both α and β thalassemias are often inherited in an autosomal recessive fashion, although this is not always the case. Cases of dominantly inherited α and β thalassemias have been reported, the first of which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease, both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% risk with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait.
There are an estimated 60-80 million people in the world carrying the beta thalassemia trait.[citation needed] This is a rough estimate; the actual number of those thalassemia major is unknown due to the prevalence of thalassemia in less developed countries.[citation needed] Countries such as Nepal, Bangladesh and Pakistan are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening.[citation needed] There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the world's blood bank supplies and the health system in general.[citation needed] There are an estimated 1,001 people living with thalassemia major in the United States and an unknown number of carriers.[citation needed] Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.[citation needed]
Evolution[edit]
Having a single gene for thalassemia may protection against malaria and thus be an advantage.[5]
People diagnosed with heterozygous (carrier) β thalassemia have some protection against coronary heart disease.[6]
Pathophysiology[edit]
Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β globin chains arranged into a heterotetramer. In thalassemia, patients have defects in either the α or β globin chain causing production of abnormal red blood cells (In sickle-cell disease, the mutation is specific to β globin).
The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.
The β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16.[7] Thus, in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α thalassemias. β Thalassemias are not only common in Africans, but also in Greeks and Italians.
Alpha (α) thalassemias[edit]
Main article: Alpha-thalassemia
The α thalassemias involve the genes HBA1[8] and HBA2,[9] inherited in a Mendelian recessive fashion. There are two gene loci and so four alleles. It is also connected to the deletion of the 16p chromosome. α Thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves.
Beta (β) thalassemia[edit]
Main article: Beta-thalassemia
Beta thalassemias are due to mutations in the HBB gene on chromosome 11,[10] also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as either βo or β thalassemia major if they prevent any formation of β chains, the most severe form of β thalassemia. Also, they are characterized as β+ or β thalassemia intermedia if they allow some β chain formation to occur. In either case, there is a relative excess of α chains, but these do not form tetramers: Rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.
Delta (δ) thalassemia[edit]
Main article: Delta-thalassemia
Alpha and beta chains present in hemoglobin, about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations that affect the ability of this gene to produce delta chains can occur.[citation needed]
Combination with other hemoglobinopathies[edit]
Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:
- hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to β thalassemia major or thalassemia intermedia.
- hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly
- hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.
- hemoglobin D/thalassemia, common in north west parts of India and Pakistan (Punjab region)
Management[edit]
Main article: Management of thalassemia
Mild thalassemia: people with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made.[11] People with β-thalassemia trait should be warned that their condition can be misdiagnosed as the more common iron deficiency anemia. They should avoid routine use of iron supplements; yet iron deficiency can develop during pregnancy or from chronic bleeding.[12] Counseling is indicated in all persons with genetic disorders, especially when the family is at risk of a severe form of disease that may be prevented.[13]
Severe thalassemia: People with severe thalassemia require medical treatment. A blood transfusion regimen was the first measure effective in prolonging life.[11]
Medications[edit]
Multiple blood transfusions can result in iron overload. The iron overload related to thalassemia may be treated via chelation therapy with the medications deferoxamine, deferiprone or deferasirox.[14] These treatments have resulted in improved life expectancy in those with thalassemia major.[14]
Deferoxamine is only effective via daily injections which makes its long term use more difficult. It has the benefit of being inexpensive and decent long term safety. Adverse effects are primary skin reactions around the injection site and hearing loss.[14]
Deferasirox has the benefit of being an oral medication. Common side effects include: nausea, vomiting and diarrhea. It however is not effective in everyone and is probably not suitable in those with significant cardiac issues related to iron overload. The cost is also significant.[14]
Deferiprone is given as an oral medication. Nausea, vomiting and diarrhea is relatively common with its use. While available in Europe as of 2010 it is not available in North America. It appears to be the most effective agent when the heart is significantly involved.[14]
Carrier detection[edit]
- A screening policy exists in Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero.[15]
- In Iran as a premarital screening, the man's red cell indices are checked first, if he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.[16]
Bone marrow transplant[edit]
Bone marrow transplantation may offer the possibility of a cure in young people who have an HLA-matched donor.[17] Success rates have been in the 80-90% range.[17] Mortality from the procedure is about 3%.[18]
If the person does not have an HLA-matched compatible donor such as the first curative method requires, there is another curative method called Bone Marrow Transplantation(BMT) from haploidentical mother to child (mismatched donor), in which the donor is the mother. It was invented in 2002 by Dr. Pietro Sodani. The results are these: thalassemia-free survival rate 70%, rejection 23%, and mortality 7%. The best results are with very young patients.[19]
Epidemiology[edit]
The beta form of thalassemia is particularly prevalent among Mediterranean peoples and this geographical association is responsible for its naming[citation needed]. Globally in 2010 it resulted in about 18,000 deaths.[20]
In Europe, the highest concentrations of the disease are found in Greece, coastal regions in Turkey (particularly the Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya, Adana, Mersin), in parts of Italy, particularly Southern Italy and the lower Po valley. The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus, and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including people from West Asia and North Africa. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (16% of the population) being in the Maldives.
Nowadays, it is found in populations living in Africa, the Americas and also, in Tharu people in the Terai region of Nepal and India.[21] It is believed to account for much lower malaria sicknesses and deaths,[22] accounting for the historic ability of Tharus to survive in areas with heavy malaria infestation, where others could not. Thalassemias are particularly associated with people of Mediterranean origin, Arabs (especially Palestinians and people of Palestinian descent), and Asians.[23] The Maldives has the highest incidence of Thalassemia in the world with a carrier rate of 18% of the population. The estimated prevalence is 16% in people from Cyprus, 1%[24] in Thailand, and 3-8% in populations from Bangladesh, China, India, Malaysia and Pakistan. Thalassemias also occur in descendants of people from Latin America and Mediterranean countries (e.g. Greece, Italy, Portugal, Spain, and others).
Etymology[edit]
The name of this condition derives from the Greek Thalassa (θάλασσα), sea, and haema (αἷμα), blood. The term was first used in 1932.
Society and culture[edit]
In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's thalassemia. The child was born from an embryo screened to be free of the disease before implantation with in vitro fertilization. The baby's supply of immunologically compatible cord blood was saved for transplantation to his brother. The transplantation was considered successful.[25] In 2009, a group of doctors and specialists in Chennai and Coimbatore registered the successful treatment of thalassemia in a child using an unaffected sibling's umbilical cord blood.[26]
References[edit]
- ^ Weatherall David J, "Chapter 47. The Thalassemias: Disorders of Globin Synthesis" (Chapter). Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT: Williams Hematology, 8e: http://www.accessmedicine.com/content.aspx?aID=6123722.
- ^ "Complications". Thalassemia. Mayo Clinic. Feb 4, 2011. Retrieved 20 September 2011.
- ^ Cianciulli P (October 2008). "Treatment of iron overload in thalassemia". Pediatr Endocrinol Rev. 6 Suppl 1: 208–13. PMID 19337180.
- ^ "Thalassemia Complications". Thalassemia. Open Publishing. Retrieved 27 September 2011.
- ^ Wambua S (May 2006). "The Effect of α +-Thalassaemia on the Incidence of Malaria and Other Diseases in Children Living on the Coast of Kenya". PLoS Medicine 3 (5): e158. doi:10.1371/journal.pmed.0030158. PMC 1435778. PMID 16605300.
- ^ Tassiopoulos S (2005). "Does heterozygous beta-thalassemia confer a protection against coronary artery disease?". Annals of the New York Academy of Sciences 1054: 467–70. doi:10.1196/annals.1345.068. PMID 16339699.
- ^ Robbins Basic Pathology, Page No:428
- ^ Online 'Mendelian Inheritance in Man' (OMIM) 141800
- ^ Online 'Mendelian Inheritance in Man' (OMIM) 141850
- ^ Online 'Mendelian Inheritance in Man' (OMIM) 141900
- ^ a b "Pediatric Thalassemia Treatment & Management". Medical Care. Open Publishing. 30 April 2010. Retrieved 27 September 2011.
- ^ Claude Owen Burdick. "Separating Thalassemia Trait and Iron Deficiency by Simple Inspection". American Society for Clinical Pathology. Retrieved 27 September 2011.
- ^ Harrison's Principles of Internal Medicine 17th Edition. McGraw-Hill medical. September 2008. p. 776. ISBN 0-07-164114-9.
- ^ a b c d e Neufeld, EJ (2010). "Update on iron chelators in thalassemia.". Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2010: 451–5. doi:10.1182/asheducation-2010.1.451. PMID 21239834.
- ^ Leung TN, Lau TK, Chung TKh (April 2005). "Thalassaemia screening in pregnancy". Current Opinion in Obstetrics and Gynecology 17 (2): 129–34. doi:10.1097/01.gco.0000162180.22984.a3. PMID 15758603.
- ^ Samavat A, Modell B (November 2004). "Iranian national thalassaemia screening programme". BMJ (Clinical Research Ed.) 329 (7475): 1134–7. doi:10.1136/bmj.329.7475.1134. PMC 527686. PMID 15539666.
- ^ a b Gaziev, J; Lucarelli, G (June 2011). "Hematopoietic stem cell transplantation for thalassemia.". Current stem cell research & therapy 6 (2): 162–9. PMID 21190532.
- ^ Sabloff, M; Chandy, M; Wang, Z; Logan, BR; Ghavamzadeh, A; Li, CK; Irfan, SM; Bredeson, CN et al. (2011). "HLA-matched sibling bone marrow transplantation for β-thalassemia major". Blood 117 (5): 1745–50. doi:10.1182/blood-2010-09-306829. PMC 3056598. PMID 21119108.
- ^ Sodani, P; Isgrò, A; Gaziev, J; Paciaroni, K; Marziali, M; Simone, MD; Roveda, A; De Angelis, G et al. (2011). "T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients". Pediatric reports. 3 Suppl 2 (Suppl 2): e13. doi:10.4081/pr.2011.s2.e13. PMC 3206538. PMID 22053275.
- ^ Lozano, R (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- ^ Modiano, G. et al. (1991). "Protection against malaria morbidity: Near-fixation of the α-thalassemia gene in a Nepalese population". American Journal of Human Genetics 48 (2): 390–397. PMC 1683029. PMID 1990845.
- ^ Terrenato, L; Shrestha, S; Dixit, KA; Luzzatto, L; Modiano, G; Morpurgo, G; Arese, P (1988 Feb). "Decreased malaria morbidity in the Tharu people compared to sympatric populations in Nepal.". Annals of tropical medicine and parasitology 82 (1): 1–11. PMID 3041928.
- ^ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review Series.[page needed]
- ^ http://www.dmsc.moph.go.th/webrOOt/ri/Npublic/p04.htm[full citation needed]
- ^ Spanish Baby Engineered To Cure Brother
- ^ His sister's keeper: Brother's blood is boon of life, Times of India, 17 September 2009
External links[edit]
- Thalassemia on the Open Directory Project
- GeneReviews/NCBI/NIH/UW entry on Alpha-Thalassemia
- OMIM etries on Alpha-Thalassemia
- Information on Thalassemia
- Learning About Thalassemia published by the National Human Genome Research Institute.
- Cardiff Sickle Cell & Thalassaemia Centre
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Pathology: hematology, hematologic diseases of RBCs and megakaryocytes / MEP (D50-69,74, 280-287)
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Red
blood cells |
| ↑ |
|
|
| ↓ |
| Anemia |
| Nutritional |
- Micro-: Iron deficiency anemia
- Macro-: Megaloblastic anemia
|
|
Hemolytic
(mostly Normo-) |
| Hereditary |
- enzymopathy: G6PD
- glycolysis
- hemoglobinopathy: Thalassemia
- Sickle-cell disease/trait
- HPFH
- membrane: Hereditary spherocytosis
- Minkowski-Chauffard syndrome
- Hereditary elliptocytosis
- Southeast Asian ovalocytosis
- Hereditary stomatocytosis
|
|
| Acquired |
- Drug-induced autoimmune
- Drug-induced nonautoimmune
- Hemolytic disease of the newborn
|
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Aplastic
(mostly Normo-) |
- Hereditary: Fanconi anemia
- Diamond–Blackfan anemia
- Acquired: PRCA
- Sideroblastic anemia
- Myelophthisic
|
|
| Blood tests |
- MCV
- Normocytic
- Microcytic
- Macrocytic
- MCHC
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|
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| Other |
- Methemoglobinemia
- Sulfhemoglobinemia
- Reticulocytopenia
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Coagulation/
coagulopathy |
| ↑ |
Hyper-
coagulability |
- primary: Antithrombin III deficiency
- Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden
- Prothrombin G20210A
- Sticky platelet syndrome
- acquired:Thrombocytosis
- DIC
- Congenital afibrinogenemia
- Purpura fulminans
- autoimmune
|
|
|
| ↓ |
Hypo-
coagulability |
| Thrombocytopenia |
- Thrombocytopenic purpura: ITP
- TM
- Heparin-induced thrombocytopenia
- May-Hegglin anomaly
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|
| Platelet function |
- adhesion
- aggregation
- Glanzmann's thrombasthenia
- platelet storage pool deficiency
- Hermansky–Pudlak syndrome
- Gray platelet syndrome
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| Clotting factor |
- Hemophilia
- von Willebrand disease
- Hypoprothrombinemia/II
- XIII
- Dysfibrinogenemia
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cell/phys (coag, heme, immu, gran), csfs
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rbmg/mogr/tumr/hist, sysi/epon, btst
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drug (B1/2/3+5+6), btst, trns
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