Classification of Beta Thalassaemia: A person normally inherits two genes (β/β) for the production of beta globin chains, the number of the genes affected and the type of mutation determines if the Beta- thalassaemia is major, inter-media or minor.
Β-thalassaemia can be basically classified into three;
- Beta- thalassaemia major
- Beta- thalassaemia intermedia
- Beta- thalassaemia minor
Other type of Beta- thalassaemia includes:-
- Beta- thalassaemia with associated hemoglobin anomalies. Examples include.
- HbC/ Beta- thalassaemia
- HbE/ Beta- thalassaemia
- HbS/ Beta- thalassaemia
- Hereditary persistence of foetal Hb and β-thalassaemia.
- Autosomal dominant forms of Beta- thalassaemia.
- Beta- thalassaemia associated with other manifestation.
- Beta- thalassaemia tricothiodystophy
- X-linked thrombocytopenia with thalassaemia.
Beta- thalassaemia major: This is a form of Beta- thalassaemia that occurs due to absent synthesis (βO/βO) or reduced synthesis (β+)/β+) of the two beta-globin chain. Beta-thalassaemia major is caused by the following genotypes.
- βo/βo, called homozygous βo thalassaemia in which there is no production of any of the two beta chains due to no expression of the beta genes and thus no production of HbA.
- βo/,β+ called heterozygous βo thalassaemia in which there is absent synthesis of one beta globin chain and reduced production of the other chain (Monica, 2004).
Clinical description of Beta-thalassaemia major patients
Clinical manifestation of B-thalassaemia major is severe as in alpha-thalassaemia major that causes hydrops foetalis, however, clinical presentation occurs between 6 and 24 months of age. Affected infants fail to thrive and become progressively pale.
Feeding problems, diarrhea, irritability, and recurrent bouts of fever and progressive enlargement of the abdomen caused by spleenomegally may occur. Establishment of diagnosis at this stage and treatment using regular transfusion program maintains a minimum Hb concentration of 95-105g\l which is normal for growth & development till 10-11 years.
After age of 10-11 years, there is a high possibility that affected individuals will develop severe complications related to iron overload, depending on their compliance with chelation therapy.
Complication of iron overload in children includes; growth retardation, failure of sexual maturation in adult, heart failure (dilated cardiomyopathy), liver fibrosis and cirrhosis and endocrine gland (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary and less commonly adrenal glands).
Other complications includes viral infections eg; Hepatitis B virus, venous thrombosis and osteoporosis. The risk for hepatocellular carcinoma is increased secondary to liver viral infection, iron overload and longer survival (Borgna-Pignatti et al., 2004).
At present, prognosis for individuals who have been transfused and treated with appropriate chelation is attainable open-ended. Myocardial disease caused by transfusional siderosis is the most important life limiting complication of iron overload in B-thalassaemia. Infact, cardiac complication are reported to cause 71% of the deaths in individuals with B-thalassaemia major (Borgna-Pignatti et al., 2004).
In some developing countries where the resources for carrying out long-term blood transfusion programs are not available, the poorly transfused individual usually presents with growth retardation, pallor, jaundice, brow pigmentation of the skin, poor musculature, genu valgum, hepato spleenomegally, leg ulcers, extra medullary haematopoiesis with craniofacial change, (bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to mongoloid slant of the eye and hypertrophy of the maxillae which tends to expose the upper teeth),skeletal changes that results from expansion of the bone marrow and osteoporosis (Renzo and Raffaella, 2010).
Βeta-thalassaemia intermedia: This is caused by the phenotype β+/β+(i.e homozygous β+), in which there is reduction in the synthesis of the two beta chains.
Clinical manifestation of Beta-thalassaemia intermedia
Individuals with thalassaemia intermedia presents later than thalassaemia major, have milder anaemia and by definition do not require or only occasionally require transfusion. Clinical features are pallow, jaundice, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extra medullary masses to hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis and thrombotic complications resulting from iron accumulation and hypercoagulable state secondary to the lipid membrane composition of abnormal red blood cells. (Eldor & Rachmilemitz, 2002. Cappellini et al., 2012).
Iron overload occurs mainly from increased intestinal absorption of iron caused by deficiency of hepcidin, a 25-amino acid peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis (Nemeth & Ganz 2006, Origa et al., 2007).
Beta-thalassaemia minor: This is also reffered to as B-thalassaemia trait resulting from the heterozygous inheritance of βo or β+ thalassaemia genes (βo/β or β+/β), individual is usually asymptomatic but it is often detected by low mean cell volume, mean corpuscles haemoglobin concentration, increased synthesis of Hb F and Hb A2 in compensation to Hb A.
Beta-thalassaemia associated with other haemoglobin anomalies.
- HbE/Beta-thalassaemia: The interaction of HbE and beta-thalassaemia results in thalassaemia phenotypes.
HbE occurs from a mutation at position 26 of the B-globin chain (glu> lys).i.e lysine is substituted for glutamic acid.The abmormal gene also results in reduced amounts of BE-mRNA and synthesis of BE globin chains (Traegar et al., 1982).This can manifest as mild, moderately severe and severe cases depending on the haemoglobin level.
With HbE/βo thalassaemia, HbE and HbF are present but if it is HbE/β+thalassaemia, HbE, HbF, and HbA are present(Monica 2004).
- Hbc/Beta-thalassaemia- HbC results due to substitution of lysine for glutamic acid in the B-globin chain at the position six. (Hoffbrand and Moss, 2011)
Patients with Hbc/beta-thalassaemia may live free of symptoms and can be diagnosed during routine tests
When present, clinical manifestations are anemia and enlargement of the spleen. Blood transfusions are seldom required.
Individual with Hbs (beta-thalassaemia have a clinical course similar to that of Hb SS
Autosomal dominant form of beta-thalassaemia.
In contrast with the classical recessive forms of beta-thalassaemia, which lead to a reduced production of normal beta globin chains, some rare mutations results in the synthesis of extremely unstable beta globin variants which precipitate in erythroid precursors causing ineffective erythropoiesis.
These mutations are associated with a clinically detectable thalassaemia phenotype in the heterozygote and are therefore referred to as dominant beta-thalassaemia (Thein, 1992)
The presence of hyper unstable haemoglobin should be suspected in any individual with thalassaemia intermedia when both parents are haematologically normal,or in families with a pattern of autosomal dominant transmission of thalassaemia intermedia phenotype. Beta-globin gene sequencing establishes the diagnosis.
Hereditary persistence of foetal haemoglobin (HpFH) and beta-thalassaemia. The fetal haemoglobin is the predominant Hb of a fetus at birth, 3-6 month after birth, the main switch to adult haemoglobin occurs in which the Y-chain is largely replaced by the beta chain with BCL11A acting as transcriptional regulator of the switch and of the silencing of delta-chain synthesis in adult(Hoffbrand 2011).
However, there are condition in which there will be a persistence of foetal haemoglobin in adult usually referred to as HPFH (eg African HPFH).with a HbF level of about 5-15%.
The association of HPFH with beta thalassaemia mitigates the clinical manifestation which varies from normal to thalassaemia intermedia
Beta-thalassaemia associated with other features.
In rare instances, the B-thalassaemia defect does not lie in HBB or in the Beta-globin gene cluster.In some instances in which the beta-thalassaemia trait is associated with other features, the molecular lesion has been found either in the gene encoding the transcription factor TFIIH (B-thalassaemia trait associated with xeroderma pigmentosum and tricothiodystrophy) or in the X-linked transcription factor GATA-1 (X-linked thrombocytopenia with thalassaemia)(viprakasit et al.,2001,Fresan et al.,2002)
Some conditions that share similarities with homozygous B-thalssaemia includes;
- Inherited sideroblastic anaemia- however, it can be differentiated from thalassaemia major because of ring sideroblasts in the bone marrow and variably elvated serum concertration of erythrocyte protoporphyrin. Most sideroblastic anaemia is associated with defects in the heme biosynthetic pathway especially S-aminolevulinic acid synthase.
- Congenital dyserythropoietic anaemia; however this does not cause increase in Hbf but have other distinctive features, such as multinuclearity of the red blood cell precursors.
- Acquired conditions associated with high Hbf-examples includes (juvenile chronic myeloid leukaemia, aplastic anaemia) which may be mistaken for B-thalassaemia even though they have very characteristic hematological features.