Haemoglobin H Disease in Chinese

Sir David TODD
Emeritus & Honoary Professor, Department of Medicine, The University of Hong Kong, HKSAR

The α-thalassaemias (α-thal) are a group of hereditary anaemias characterised by defective α-globin chain synthesis. Four varieties of α-thal can be defined: (a) α+ thal (b) α° thal (c) Haemoglobin (Hb) H disease and (d) Hb Bart's Hydrops Fetalis. These are the result of deletion of respectively 1, 2, 3 or 4 of the a -globin structural genes with progressive impairment of a-globin chain production. Less commonly the defect may be due to an α-globin gene mutation e.g. Hb Constant Spring. In the more severe forms of α-thal, Hb Bart's (γ4) is found in the fetal and neonatal period and Hb H (β4) in later life. Homozygous α+thal phenotypically resembles α° thal.

Since α+ and α° thal do not give rise to clinical disease, and Hb Bart's Hydrops Fetalis is, with rare exceptions, lethal at birth or shortly after, Hb H disease is the only clinically significant α-thal in children and in adults. In Hong Kong, Hb H disease occurs in about 6 in 10,000 live births.

Hb H disease is associated with a mild to moderate haemolytic anaemia. Development and life expectancy are usually normal. Symptoms vary and may be absent until pregnancy or intercurrent infection occurs and certain oxidant drugs e.g. sulphonamides may aggravate the anaemia. Some patients present with jaundice, symptoms of anaemia or gallstones. In many, the disease is discovered incidentally. Physical examination may reveal mild pallor with or without jaundice, hepatomegaly (mean 1 cm), splenomegaly (mean 1.5 cm) in about 3/4 of patients and rarely dysmorphic facial features and leg ulcers. In the steady state in adults, the following mean haematological changes have been found: Hb 9.5 g/dl; Haematocrit ratio 0.36; MCV 63.6 fl; MCH 18.7 pg; MCHC 29.3 g/dl; Reticulocytes 4.2%; Hb H 7.3% and Hb A2 1.2%. Red blood cells show marked thalassaemic changes with many fragmented forms. Red blood cell survival is shortened with 51Cr T1/2 values from 6 to 23 days, being shortest in those with the larger spleens. The bone marrow shows erythroid hyperplasia with defective haemoglobinization of late normoblasts and increased sideroblasts. Radioactive iron studies reveal mild ineffective erythropoiesis. As Hb H is relatively unstable, intravascular haemolysis and haemosiderinuria may occur. In patients with larger spleens, hypersplenism is sometimes present. In older patients, iron overload of clinical significance has been found.

The diagnosis is established by the demonstration of Hb H inclusions in red blood cells after incubation with 1% brilliant cresyl blue for 30 minutes at 37°C, Hb H on electrophoresis and a low Hb A2. There may be traces of Hb Bart's. If iron deficiency is present, the amount of Hb is decreased. Family studies usually reveal that one parent has α+ thal while the other has α° thal.

The majority of patients require no therapy. However, intercurrent infection should be promptly treated, oxidant drugs avoided and folic acid given during pregnancy. Red blood cell transfusion may be necessary when haemolysis is severe. In some with larger spleens, hypersplenism may occur and splenic infarction and leg ulcers may develop. Splenectomy should not be undertaken lightly as there is a high risk of post-splenectomy thrombo-embolism, probably due to the rise in circulating platelets and continuing intravascular haemolysis. Adults with Hb H disease should be monitored for tissue damage due to iron overload and chelation therapy commenced when it is detected.

It has been mentioned that α-globin gene mutations may be associated with Hb H disease and these are referred to as the non-deletion types. In such cases, a mutated α-globin gene replaces the deletion defect. Of these mutations, the commonest is Hb Constant Spring (TAA to CAA at codon 142). Others are rare and those reported in Chinese include Hb Q, Hb Quong Sze, and defects in the α2-globin gene; deletion of codon 30, DGAG; AGG to AAG at codon 31 and GGC to GAC at codon 59. In the non-deletion types, the abnormal haemoglobin is even less stable and red cell membrane damage severe. These patients have more haemolysis and anaemia, more circulating Hb H and Hb Bart's, larger spleens and are often transfused. Growth retardation may be present. Hb H Hydrops Fetalis has been reported and prenatal diagnosis is indicated in such at risk families.

References

Todd D. Thalassaemia. Pathology 1984;16:5-15.

Chen FE, Ooi C, Ha SY, Cheung BMY, Todd D, Liang R, Chan TK and Chan V. Genetic and Clinical Features of Hemoglobin H Disease in Chinese Patients. N Engl J Med 2000;343:544-50.

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