Alpha Thalassemia

Alpha-thalassemia (α-thalassemia) is a comprehensive group of hereditary anemias, which features two clinical types, the hemoglobin Bart's hydrops fetalis syndrome, abbreviated as Hb Bart, and the hemoglobin H (HbH) disease.

The disease is related to the following processes:  hereditary and has an incidence of about  2 / 100.000.

Presentation

The two types of alpha thalassemia, hydrops fetalis and Hemoglobin H disease, are the ones that lead to observable symptomatology amongst the various types of alpha thalassemia; this is due to the extremely diminished concentration of functional hemoglobin [6].

Embryos with hydrops fetalis experience death in utero or shortly after birth, if their condition is not diagnosed in advance. Typical findings include hepatomegaly, splenomegaly, profound anemia, edema and an extremely decreased cardiac output. Expectant mothers also experience pregnancy complications, when carrying an embryo with hydrops fetalis. Preeclampsia, premature labor, oligo- or polyhydramnios are common issues accompanying such a pregnancy.   

With regard to Hemoglobin H disease, symptomatology is individualized. Patients may be diagnosed at any point between childhood and adulthood and some may even be asymptomatic at the time of diagnosis. Hemolytic anemia is the primary finding (hypochromic microcytic), accompanied by splenomegaly and occasional hepatomegaly, jaundice and some facial skeletal defects, such as hypertrophic maxilla. The administration of drugs that cause oxidative stress exacerbates the hemolytic phenomena in patients with HbH disease, who may also display hypersplenism as a reaction. 

Workup

Thalassemia is diagnosed via laboratory tests and specifically a complete blood count, serum ferritin, hemoglobin electrophoresis and a peripheral smear. Hypochromic microcytic anemia is the primary finding in tests of individuals with thalassemia; the severity depends on the type of thalassemia

Differential diagnosis is extensive when hypochromic microcytic anemia is discovered. Possible causes include alpha thalassemia, iron deficiency, sideroblastic anemia, anemia of chronic disease and lead poisoning. The following observations are useful tools in order to distinguish thalassemia from the other possible causes:

  •  Mean corpuscular volume (MCV): Patients with thalassemia usually exhibit an MCV< 75 fl. Anemia that is a result of iron deficiency usually leads to an MCV> 80 fl.
  • Red cell distribution width (RDW): Over 90% of the cases of iron deficiency anemia exhibit an increased RDW. Contrary to that, only half of the patients with thalassemia have an augmented RDW.
  • Mentzer index: The Mentzer index is the ratio of MCV/red blood cell count. It is >13 in patients affected by iron deficiency anemia and <13 in patients that have inherited thalassemia [4] [5].

Treatment

Treatment of alpha thalassemia is individualized and depends on the type of the condition an individual suffers from. Mild cases of thalassemia that cause no clinical disturbance or profound laboratory findings may be simply monitored, without any treatment. On the other hand, markedly low levels of hemoglobin may be an indicator of treatment initiation: extremely low hemoglobin levels usually require transfusions for the whole of the patient's life, whereas surgical intervention is reserved for some patients [7] [8] [9]. Individuals with low levels of iron and/or folic acid may also require the administration of supplements.

General supportive care

Hemoglobin abnormalities usually need supportive care in patients with HbB disease. Blood transfusions are not conducted in fixed intervals, but rather when the patient displays markedly low levels of hemoglobin caused by acute HbH episodes, infections, etc [10] [11]. Transfusions can be initiated as soon as the first days of a neonate's life.

Patients generally need a few transfusion sessions throughout their lives, as hemoglobin levels fluctuate between the values of 7 to 10 g/dL. However, severer cases with hemoglobin levels constantly below 7 g/dL may need lifelong transfusions, which renders the patient susceptible to the complication of iron overload. To prevent this, chelation therapy is implemented. Iron chelation therapy may be necessary even for patients who do not receive a great number of transfusions. In patients affected by HbH, hemolysis is caused by various infections or the use of drugs.

Iron and folic acid

Patients with alpha thalassemia must be closely monitored to detect a possible iron deficiency, for which they may be treated with iron supplements if necessary, although this treatment does not lead to improved blood test results. Special attention should also be drawn to the fact that, many individuals who display low levels of iron, actually suffer from hemochromatosis, which implies that excessive amounts of iron have accumulated within organs and tissue. If a patient is found to have raised levels of ferritin, its consumption should be restricted in the diet. Lastly, a patient may also receive folic acid supplements, particularly if they display increased levels of reticulocytes.

Surgical intervention

Splenectomy may be a measure taken to address cases of patients with HbH, complicated with hypersplenism. Erythroid hyperplasia, when present, can also induce skeletal irregularities, which can be corrected with surgery, dental or orthopedic. 

Additional treatment options

After a splenectomy has been performed, patients are susceptible to various infections and should therefore be cautious and vaccinate themselves against pathogens , such as pneumococcus. As a last resort, allogeneic hematopoietic stem cell transplantation can be an option, but is reserved for extremely severe cases with no response to other treatment plans, due to the increased mortality and morbidity accompanying the procedure.

Prognosis

The prognosis depends on the type of thalassemia a patient suffers from. Individuals with the alpha thalassemia trait and silent carriers are clinically unaffected by the condition and require no treatment. Patients with HbH disease face a comprehensively good prognosis too, although each case is individualized, with complications varying. 

Embryos that are diagnosed with hydrops fetalis, which implies the complete absence of functional alpha genes, are in need of transfusions in utero, so that they can survive past birth. Blood transfusions have to be continued for the whole of the individual's life, as they are unable to produce functional hemoglobin of any type. This type of treatment renders it possible for patients with hydrops fetalis to live longer than before, but complications pose a significant danger: frequent transfusions lead to the accumulation of excessive iron in the organs of the body and heart dysfunction. Diabetes mellitus and various abnormalities of the endocrine glands are also observed in patients with alpha thalassemia major [4] [5].

Etiology

Alpha thalassemia is a group of genetic conditions. The primary abnormality that leads to the particular genotype includes deletions of the alpha globin genes, or deletions of the non-coding DNA that regulates their transcription (regulatory elements) and may be found either on the same chromosome or on a different one. Deletion, however, is not the only type of mutation that can lead to alpha thalassemic syndromes: nonsensical mutations, frame shifts, point mutations and chain termination mutations have been detected, which can also be located in the regions adjacent to the alpha globin gene. The editing of the nascent pre-messenger RNA transcript (splicing) may be subsequently impaired, the initiation of mRNA translation may be prevented and various other disruptions can result in alpha thalassemic anemia [1].

Epidemiology

Countries located in the tropical zones and adjacent regions display a high prevalence of alpha thalassemia, with the population carrying the gene at a rate of nearly 90% in some occasions. Specifically, the subcategory of HbH disease is most commonly observed in Southeast Asia, the Mediterranean and the Middle East, whereas hydrops fetalis is most prevalent in Southeast Asia. It is believed that the simultaneous high frequency of alpha thalassemia in tropical regions is a result of the natural selection process: the mutation offers some protection against malaria, also prevalent in those locations, and it has been selected during the evolution process, because it enhances the individuals' prospects of survival. Migration and the subsequent redistribution of the world's population have led to the presence of alpha thalassemia in regions of America or North Europe [5].

Sex distribution
Age distribution

Pathophysiology

Alpha thalassemia is a direct result of diminished alpha-chain production. The excessive amounts of beta chains lead to a lack of molecular stability and to an insoluble hemoglobin compound that forms Heinz bodies within the cell (insoluble inclusions). Heinz bodies exert further pressure and damage the membrane of the red blood cells. Due to the red blood cells' inability to produce adequate amounts of fully functional hemoglobin, the cells are hypochromic and relatively smaller in size, when compared with healthy red cells [5]. Depending on the result of the genetic mutation, the following alpha thalassemic syndromes have been described:

Alpha(0) thalassemia

Alpha (0) thalassemia is a subcategory of alpha thalassemia, involving the complete dysfunction of both genes encoding for the alpha globin (--/--). A patient with this genetic abnormality does not have the ability to synthesize any of the hemoglobin types and usually dies before birth or shortly after. It is the most severe type of alpha thalassemia and is otherwise referred to as hydrops fetalis or hemoglobin Bart's. Currently, over twenty different mutations have been discovered, that account for alpha (0) thalassemia

Alpha(+) thalassemia

Alpha (+) thalassemia is a wider category of disease type and encompasses the silent carrier, alpha thalassemia trait and hemoglobin H types. Patients display diminished production of alpha globin, but possess at least one functional alpha gene.

The silent carrier type is the mildest form of alpha (+) thalassemia. The patients possess three functional alpha genes (-α/αα) and in the majority of the cases exhibit no abnormal findings in a standard blood test. The mean corpuscular volume (MVC) and mean corpuscular hemoglobin (MCH) might be slightly affected sometimes.

On the other hand, patients with the trait of alpha thalassemia possess two functional alpha genes, either in the pattern of (-α/-α) or (--/αα). Patients suffer from mild anemia, with a red blood count greater than 5.5 x 1012/L. Their MCH and MCV are also affected.

Finally, the most severe type of alpha (+) thalassemia is the HbH disease (Hemoglobin H disease. Patients have one functional alpha gene (-α/--); as a result, the beta globin chains greatly predominate is the structure of the red blood cells and these beta chains are conjoined in masses. This type of abnormal hemoglobin constitutes up to 1/3 of the total hemoglobin of the patient. Hemolytic phenomena are common when oxidative agents (e.g sulfonamide) are administered to these patients, due to the erythrocytes' increased sensitivity. Furthermore, the conjunction of HbH increases as the erythrocytes age: this results in their early destruction, as they are recognized as dysfunctional, and the subsequent hemolysis is the predominant finding.

Prevention

Alpha thalassemia can be diagnosed prenatally. The test is carried out if the pregnancy occurs in a family with a prior history of alpha thalassemia or if the parents belong to an ethnic group with a high disease prevalence. The diagnosis of HbH disease cannot be accurately made before birth; however, neonatal screening allows for the detection of elevated levels of hemoglobin Bart's after birth [12] [13]. 

Summary

In the human organism, blood is responsible for carrying oxygenized molecules to the tissues so that they can remain functional and viable. Oxygen is transported to every region of the body via the red blood cells, which contain hemoglobin, a metalloprotein capable of binding with oxygen molecules.

Hemoglobin consists of a heme molecule and four globin chains. There are four types of globin chains, the alpha (α), beta (β), gamma (γ) and delta (δ) chains. Depending on the type of chains a particular hemoglobin is made of, the molecule presents with 3 forms:

  • Hemoglobin A. It is the primary counterpart in adult individuals and consists of two alpha and two beta chains.
  • Hemoglobin F. It is primarily found in fetal blood and consists of two alpha and two gamma chains. Its concentration is extremely reduced in the adult population.
  • Hemoglobin A2, containing two alpha and two delta chains.

Patients affected by alpha thalassemia display a distorted production of alpha chains, which are contained in all three types of hemoglobin molecules. Alpha chains are reduced and beta chains dominate, leading to decreased molecular stability and anemic symptoms.

Alpha thalassemia syndromes exhibit a higher prevalence in individuals born in the Mediterranean region, Asia and the Middle East. A single gene accounts for the disruption of the production of the alpha chains; various mutations or deletions are responsible for the condition. An interesting fact is that the thalassemic, impaired structure of the red blood cells offers some protection against malaria; as a result, populations with a high prevalence of malaria appear to exhibit higher rates of alpha thalassemia. This is viewed as a result of the natural selection process [1] [2] [3] [4]. 

Patient Information

Alpha thalassemia is a disease that affects a compound found in the red blood cells, called haemoglobin. Haemoglobin is the element responsible for carrying oxygen to the organs and tissue in order to keep them functional and living. Patients with alpha thalassemia inherit the disease from their parents and exhibit an abnormal haemoglobin structure, that is unable to carry enough oxygen with the blood. Not every patient with alpha thalassemia is equally affected by the disease, however. The degree of haemoglobin abnormality dictates the severity of the symptoms caused: if a patient has only a small amount of abnormal haemoglobin, they may exhibit no symptoms whatsoever; embryos with no normal haemoglobin, on the other hand, may be stillborn or not even survive until birth. 

Alpha thalassemia is a disease that specifically causes the diminished production of the alpha globin chains, which are a part of the total of the haemoglobin chains. Beta thalassemia is another similar condition, that affects the other chain types, the beta chains. The disease is mostly found in the Mediterranean region, Asia and Africa.   

There are various types of alpha thalassemia, depending on the percentage of the missing alpha chains. Silent carriers only carry a thalassemia gene, but compose adequate functional haemoglobin and, as a result, have no anemic symptoms. Individuals with HbH disease or hydrops fetalis, both alpha-thalassemia subcategories, experience severe medical problems. Fetuses with hydrops fetalis produce no normal haemoglobin and may not survive to birth and patients with HbH require transfusions in order to survive.

Thalassemia can be diagnosed with blood laboratory testing. Prenatal tests are available for parents with a family history of thalassemia or inhabitants of regions where the disease is frequently diagnosed. Neonates may also be screened for alpha thalassemia shortly after birth.

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References

  1. Piel FB., Weatherall, D.J.  The α-thalassemias. N Engl J Med, 2104;371(20):1908-16
  2. Kohne E. Hemoglobinopathies: clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int, 2011;108(31-32):532-40.
  3. Kotila TR. Thalassaemia is a tropical disease. Ann Ib Postgrad Med, 2012;10(2):11-5.
  4. Martin A, Thompson AA. Thalassemias. Pediatr Clin North Am, 2013;60(6):1383-91.
  5. Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet J Rare Dis. 2010;5:13. 
  6. Joly P, Garnier N, Kebaili K, et al. G6PD deficiency and absence of α-thalassemia increase the risk for cerebral vasculopathy in children with sickle cell anemia. Eur J Haematol, 2015 Jun 13
  7. Vichinsky EP. Clinical manifestations of α-thalassemia. Cold Spring Harb Perspect Med, 2013;3(5):a011742.
  8. Elborai Y, Uwumugambi A, Lehmann L. Hematopoietic stem cell transplantation for thalassemia. Immunotherapy, 2012;4(9):947-56
  9. Raja JV, Rachchh MA, Gokani RH. Recent advances in gene therapy for thalassemia. J Pharm Bioallied Sci, 2012;4(3):194-201
  10. Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev, 2012;26 Suppl 1:S31-4.
  11. Vichinsky EP. Alpha thalassemia major--new mutations, intrauterine management, and outcomes. Hematology Am Soc Hematol Educ Program. 2009:35-41.
  12. Chui DH. Alpha-thalassemia: Hb H disease and Hb Barts hydrops fetalis. Ann N Y Acad Sci. 2005;1054:25-32.
  13. Cao A, Kan YW. The prevention of thalassemia. Cold Spring Harb Perspect Med, 2013;3(2):a011775.

  • Alpha thalassemia and stroke risk in sickle cell anemia - RJ Adams, A Kutlar, V McKie, E Carl - American journal of , 2006 - Wiley Online Library
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  • A family with segregating triplicated alpha globin loci and beta thalassemia - R Galanello, R Ruggeri, E Paglietti - , 1983 - bloodjournal.hematologylibrary.org
  • His is deleted, but not that adjacent to the gene for HbG-alpha 30 Glu replaced by Gln; three-fourths of the alpha-globin genes are deleted in HbQ-alpha-thalassemia - LE Lie-Injo, AM Dozy, YW Kan, M Lopes - , 1979 - bloodjournal.hematologylibrary.org


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