Clinically, J3-thalassaemia can be divided into the following:
• Thalassaemia major with severe anaemia requiring regular transfusions
• Thalassaemia intermedia, with moderate anaemia, rarely requiring transfusions
• Thalassaemia minor (or trait), the symptomless heterozygous carrier state.
This common carrier state is asymptomatic. Anaemia is mild or absent. The red cells are hypochromic and microcytic with a low MCV and MCH and it may be confused with iron deficiency. However, the two are easily distinguished as in thalassaemia trait the serum iron, the serum ferritin and the iron stores are normal. Hb electrophoresis usually shows a raised Hb Az and often a raised Hb F (Fig. 6.19). Iron should not be given to these patients unless they develop coincidental iron deficiency.
Thalassaemia intermedia includes patients who are symptomatic with moderate anaemia (Hb 7-10 g dl-‘) and who do not require regular transfusions, i.e. more severe than in f3-thalassaemia trait but milder than in transfusion dependent thalassaemia major.
Thalassaemia intermedia may be due to a combination of homozygous mild W- and o-thalassaemia, where there is reduced a chain precipitation and less ineffective erythropoiesis and haemolysis. The inheritance of hereditary persistence of Hb F with homozygous f3-thalassaemia also results in a milder clinical picture than unmodified f3-thalassaemia major because the excess a chains are partially removed by the increased production of y chains.
Patients may have splenomegaly and bone deformities. Recurrent leg ulcers, gallstones and infections are also seen.
J3-Thalassaemia major (Cooley’s anaemia) Children affected by severe f3-thalassaemia present during the first year of life with:
• Failure to thrive and recurrent bacterial infections
• Severe anaemia from 3-6 months when the switch from y- to f3-chain production should normally occur
• Extramedullary haemopoiesis that soon leads to hepatosplenomegaly and bone expansion, giving rise to the classical thalassaemic facies.
Skull X-rays in these children show the characteristic ‘hair on end’ appearance of bony trabeculation as a result of expansion of the bone marrow into cortical bone.
BLOOD COUNT shows a moderate to severe anaemia with reduced MCV and MCH. The reticulocyte count is raised and nucleated red cells are present in the peripheral blood. The WCC and the number of platelets are normal unless hypersplenism is present.
BLOOD FILM shows a hypochromic and predominantly microcytic picture. Postsplenectomy features will be present after splenectomy has been carried out.
SATURATED IRON-BINDING CAPACITY AND HIGH SERUM FERRITIN LEVELS are caused by multiple blood transfusions.
HB ELECTROPHORESIS shows an increase in Hb F, markedly reduced or absent Hb A, and Hb A2 is normal or slightly increased.
The aims of treatment are to suppress ineffective erythropoiesis, prevent bony deformities and allow normal activity and development. Regular transfusions should be given to keep the Hb above 10 g dl-‘. Blood transfusions may be required every 4-6 weeks. Febrile transfusion reactions can be prevented by the use of leucocytedepleted blood. If transfusion requirements increase, splenectomy should be considered although this is usually delayed until after the age of 6 years because of the risk of infection. Prophylaxis against infection is required for patients undergoing splenectomy.
Iron overload caused by repeated transfusions (transfusion haemosiderosis) may lead to damage to the endocrine glands, liver, pancreas and the myocardium by the time patients reach adolescence. The iron-chelating agent of choice remains desferrioxamine although it has to be administered parenterally. It is given as an overnight subcutaneous infusion on five to seven nights each week. Ascorbic acid 200 mg daily is given, as it increases the urinary excretion of iron in response to desferrioxamine. With current therapy, normal growth and sexual development occur but compliance may be a problem especially in teenagers. Intensive treatment with desferrioxamine has been reported to reverse damage to the heart in patients with severe iron overload but excessive doses of desferrioxamine may cause cataracts, retinal damage and nerve deafness. Infection with Yersinia enterocolitica occurs in iron-loaded patients treated with desferrioxamine. There are some promising reports of the use of oral iron-chelating agents and clinical trials are in progress. Iron overload should be periodically assessed by measuring the serum ferritin and assessing damage to organs, particularly the heart, liver and endocrine glands. Bone marrow transplantation has been used in young patients with HLA-matched siblings. It has been successful in about 80% of cases but there is a mortality of 5- 10% due to graft-versus-host disease or other transplantrelated complications. Prenatal diagnosis and gene therapy are discussed.
In contrast to ,8-thalassaemia, o-thalassaemia is caused by gene deletions. The gene for a chains is duplicated on both chromosomes 16, i.e. there are four genes. Deletion of one a-chain gene (0’+) or both a-chain genes (0’0) on each chromosome 16 may occur. If all four genes are absent (deletion of both genes on both chromosomes) there is no a-chain synthesis and only Hb Barts (Y4) is present. Hb Barts cannot carry oxygen and is incompatible with life. Infants are either stillborn at 28–40 weeks or die very shortly after birth. They are pale, oedema to us and have enormous livers and spleens-a condition called hydrops fetalis.
If three genes are deleted, there is moderate anaemia (Hb 7-10 g dl’) and splenomegaly (Hb H disease). Thepatients are not usually transfusion dependent. Hb A, Hb Barts and Hb H (,84) are present. If one or two genes are deleted i a -thalassaemia traits) there is microcytosis with or without mild anaemia. Hb H bodies may be seen on staining a blood film with brilliant cresyl blue. Globin chain synthesis studies for the detection of a reduced ratio of 0′- to ,8 chains may be necessary for the definitive diagnosis of o-thalassaemia trait.
Less commonly, o-thalassaemia may result from genetic defects other than deletions, for example mutations in the stop codon producing an a chain with many extra amino acids (Hb Constant Spring).
The most important structural abnormality of the Hb chain is sickle cell haemoglobin (Hb S). Hb S results from a single-base mutation of adenine to thymine which produces a substitution of valine for glutamine at the sixth codon of the ,8-globin chain. In the homozygous state (sickle cell anaemia) both genes are abnormal (Hb SS), whereas in the heterozygous state (sickle cell trait, Hb AS) only one chromosome carries the gene. As the synthesis of Hb F is normal, the disease usually does not manifest itself until the Hb F decreases to adult levels at about 6 months of age.
The disease occurs mainly in Africans (25% carry the gene) but is also found in India, the Middle East, and southern Europe.
Deoxygenated Hb S molecules are insoluble and polymerize. The flexibility of the cells is decreased and they become rigid and take up their characteristic sickle appearance. This process is initially reversible but, with repeated sickling, the cells eventually lose their membrane flexibility and remain in the sickle form. Sickling can produce:
1 A shortened red cell survival
2 Impaired passage of cells through the microcirculation leading to obstruction of small vessels and tissue infarction
Sickling is precipitated by infection, dehydration, cold, acidosis or hypoxia. In many cases the cause is unknown. Hb S releases its oxygen to the tissues more easily than normal Hb (see Fig. 13.5) and patients therefore feel well despite being anaemic except during crises or complications.
SICKLE CELL ANAEMIA
Symptoms vary from a mild asymptomatic disorder to a severe haemolytic anaemia and recurrent severe painful crises. The condition may present in childhood with anaemia and mild jaundice. The hand-and-foot syndrome due to infarcts of small bones is quite common in children and may result in digits of varying lengths. In the older patient, vaso-occlusive problems occur owing to sickling in the small vessels of any organ, mimicking many medical and surgical emergencies.
Typical infarctive sickle crises include:
• Bone pain (commonest)
• Chest-pleuritic pain
• Cerebral- hemiparesis, fits
• Kidney-papillary necrosis causing haematuria, renal tubular defect resulting in lack of concentration of the urine
• Spleen-painful infarcts
• Liver-pain with abnormal biochemistry
Attacks of pain with low-grade fever last from a few hours to a few days. In a given patient the degree of anaemia is usually stable and during a crisis Hb does not fall unless there is one or more of the following:
APLASIA: due to decreased erythropoiesis, associated with viral infections particularly parvovirus.
ACUTE SEQUESTRATION: the liver and spleen become engorged with sickle cells.
HAEMOLYSIS: due to drugs, acute infection or associated G6PD deficiency.
SUSCEPTIBILITY TO INFECTIONS: particularly to Streptococcus pneumoniae, which can cause a fatal meningitis or pneumonia. Osteomyelitis can occur in necrotic bone, often due to Salmonella.
CHRONIC LEG ULCERS: due to ischaemia
GALLSTONES: pigment stones from persistent haemolysis
ASEPTIC NECROSIS OF BONE: particularly of the femoral heads
BLINDNESS: due to retinal detachment and proliferative retinopathy
CHRONIC RENAL DISEASE
BLOOD COUNT: the level of Hb may be 6-8 g dl-1 with a high reticulocyte count (10-20%).
BLOOD FILMS can show features of hyposplenism.
SICKLING of red cells on a blood film can be induced in the presence of sodium metabisulphite.
SICKLE SOLUBILITY TEST: a mixture of Hb S in a reducing solution such as sodium dithionite gives a turbid appearance due to precipitation of Hb S whereas normal Hb gives a clear solution.
HB ELECTROPHORESIS confirms the diagnosis. There is no Hb A, 80-95% Hb SS and 2- 20% Hb F.
THE PARENTS of the affected child will show features of sickle cell trait.
The ‘steady state’ anaemia requires no treatment. Precipitating factors (see above) should be avoided or treated quickly. Acute attacks require supportive therapy with intravenous fluids, oxygen, antibiotics and adequate analgesia. Prophylaxis is given to prevent pneumococcal infection. Folic acid is given to pregnant women and those with severe haemolysis. Regular transfusions are given only if there is severe anaemia or if patients are having frequent crises in order to suppress the production of Hb S. Before elective operations and during pregnancy repeated transfusions may be used to reduce the proportion of circulating Hb S to less than 20% to prevent sickling. Exchange transfusions may be necessary in patients with severe or recurrent crises, or before emergency surgery. Transfusion and splenectomy may be life-saving for young children with splenic sequestration.
Research is being carried out to find a way to increase production of Hb F to reduce the number of sickle cells and sickle cell crises; hydroxyurea in combination with recombinant human erythropoietin and butyrate are currently being investigated.
Some patients with Hb SS die in the first few years of life from either infection or episodes of sequestration. However, there is marked individual variation in the severity of the disease and some patients have a relatively normal life-span with few complications.
SICKLE CELL TRAIT
These individuals have no symptoms unless extreme circumstances cause anoxia, such as flying in non-pressurized aircraft or problems with anaesthesia. Anaesthesia should always be carried out with care to avoid hypoxia.
Sickle cell trait protects against Plasmodium falciparum malaria (see p. 71). Typically there is 60% Hb A and 40% Hb S. The blood count and film are normal. The diagnosis is made by a positive sickle test or by Hb electrophoresis.
Other structural globin chain defects
There are many Hb variants (e.g. Hb C, D), many of which are not associated with clinical manifestations. Hb C disease may be associated with Hb S (Hb SC disease). The clinical course is similar to Hb SS but there is an increased likelihood of thrombosis, and in particular this may lead to life-threatening episodes of thrombosis in pregnancy and retinopathy.
Combined defects of globin chain production and structure
Abnormalities of Hb structure, e.g. Hb S, C can occur in combination with thalassaemia. The combination of 13- thalassaemia trait and sickle cell trait (sickle cell 13- thalassaemia) resembles sickle cell anaemia (Hb SS) clinically. Hb E is the commonest Hb variant in South East Asia. Homozygous Hb E causes a mild microcytic anaemia but the combination of Hb E and f3-thalassaemia produces the clinical and haematological features of 13- thalassaemia major.
Prenatal diagnosis of severe haemoglobin abnormalities Of the offspring of parents who both have either f3-thalassaemia or sickle cell trait, 25% will have f3-thalassaemia major or sickle cell anaemia, respectively. Recognition of these heterozygous states in parents and family counselling provides a basis for antenatal diagnosis.
If a pregnant woman is found to have a Hb defect, her partner should be tested. Antenatal diagnosis is offered if both are affected and there is a risk of a severe fetal Hb defect, particularly f3-thalassaemia major. Fetal blood samples can be taken from the umbilical cord in the second trimester and tested for the rate of f3-globin chain synthesis. Abortion is offered if the fetus is found to be affected. Alternatively, fetal DNA analysis of amniotic fluid or chorionic villus samples can be used. Chorionic villus biopsy can be carried out in the first trimester and thus second trimester abortions can be avoided.