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In this study, 251 Sardinian patients (187 adults and 64 children) with haemoglobin (Hb) H disease were evaluated. Two-hundred and sixteen patients (86%) had the deletional type (- -/-α) and 36 (14%) patients had the non-deletional type (- -/αNDα). A clear genotype–phenotype correlation was found, with the non-deletional type more severe than the deletional type. Diagnosis of Hb H disease was incidental in about 60% of cases. Aplastic crises due to B19 parvovirus infection were found in five patients (2·1%), while 23 patients (9·6%) experienced one or more haemolytic crises. Nineteen patients with Hb H received sporadic red blood cell transfusions and three patients were repeatedly transfused. Forty-seven of 61 married women (77%) had 82 pregnancies. In children, mean serum ferritin was 87 ±92 μg/l and in adults, was 192 ± 180 μg/l in females and 363 ± 303 μg/l in males. For the 98 male patients, a significant correlation was found between ferritin values and age (r2 = 0·33, P < 0·0001). In the Sardinian population, Hb H disease needs regular monitoring for early detection and treatment of possible complications, such as worsening of anaemia that may require red cell transfusion, cholelithiasis and iron overload.
Deletion or inactivation of three of the four α-globin genes located on chromosome 16, gives rise to haemoglobin (Hb) H disease, an intermediate clinical form of α-thalassaemia characterised by microcytic, hypochromic haemolytic anaemia that is frequently associated with hepatosplenomegaly and mild jaundice (Higgs & Bowden, 2001). Hb H disease is relatively common in south-east Asian, Middle Eastern and Mediterranean populations and shows a wide spectrum of clinical phenotypes, ranging from asymptomatic to severe forms, requiring occasional or even regular transfusions and, exceptionally, to Hb H-hydrops foetalis syndrome. This clinical variability depends on a considerable genetic heterogeneity.
In Hb H disease, the severely reduced production of α-globin chains results in a relative excess of β-chains which aggregate into β4 tetramers (Hb H). Patients with significant amounts of Hb H have a defect in the oxygen-carrying capacity that is more severe than expected on the basis of the Hb concentration. Red cells containing Hb H are sensitive to oxidative stress and thus may be more susceptible to haemolysis when oxidant drugs, such as sulphonamides, are administered. Ageing erythrocytes contain more precipitated Hb H than younger erythrocytes and are removed from the circulation prematurely. Thus, Hb H disease is primarily a haemolytic disorder, while ineffective erythropoiesis, which is the main cause of anaemia in β-thalassaemia, plays a secondary role (Wasi et al, 1974; Papassotirious et al, 1998; Pootrakul et al, 2000).
Two main types of Hb H disease, deletional and non-deletional, are characterised. The deletional Hb H disease, caused by a deletion removing both α-globin genes on one chromosome 16 and a deletion of a single α-globin gene on the other chromosome (- -/-α), is the most common type. Less frequently, the deletion of both α-globin genes on one chromosome is associated with a point mutation, or an oligonucleotide insertion/deletion in the α1 or α2-globin gene on the other chromosome (non-deletional Hb H disease, - -/αNDα) (Higgs, 2001). Patients with non-deletional Hb H disease have a more severe phenotype when compared with those with the deletional type (Galanello et al, 1983; Chen et al, 2000; Kanavakis et al, 2000). An Hb H disease-like phenotype of variable severity can be sometimes due to homozygosity or compound heterozygosity for non-deletional α-thalassaemia mutations in α2-globin genes, which normally account for the majority of α-chain production (Liebhaber et al, 1986). Several authors have investigated the correlation between haematological, biochemical and clinical findings and α-globin genotypes in different populations, but systematic studies of the natural history of Hb H disease are lacking (Galanello et al, 1983; Chen et al, 2000; Kanavakis et al, 2000; Chui et al, 2003). This study aimed to define the natural history of Hb H disease in a Mediterranean population, with special attention to children and pregnancies in affected women.
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We studied a large group of patients with Hb H disease from the Mediterranean area, evaluating the prevalence of clinical and haematological findings according to the genotype and age. The deletion of three structural α-genes is the commonest defect producing Hb H disease (86% of cases) in this group of patients and a similar prevalence of deletional and non-deletional genotypes has been reported in patients with Hb H disease from California, Hong Kong and Ontario (Chen et al, 2000; Lorey et al, 2001; Waye et al, 2001), while non-deletional genotypes were more common (43%) in the Greek population (Kanavakis et al, 2000). A clear phenotype–genotype correlation was found in terms of Hb and reticulocyte values, MCV, bilirubin in children, LDH and splenomegaly, while erythropoietin values were normal or only mildly increased also in patients with non-deletional genotypes, due to the secondary role of ineffective erythropoiesis in the genesis of anaemia in Hb H disease. A significant microcytic hypochromic anaemia with a marked increase of Hb Bart's was present at birth in all four patients for whom data at birth were available. Diagnosis of Hb H disease was incidental in most of the patients, independently from the genotype and, although the mean age at diagnosis was about 10 years, many patients were recognised in adulthood or old age. This diagnostic delay could be due to the relatively benign clinical phenotype of Hb H in Sardinia, or most probably, to an inadequate knowledge of this condition among paediatricians and family doctors or parental neglect.
Chen et al (2000) reported that growth was impaired in 13% of children with Hb H disease from Hong Kong and we found a similar percentage (13·7%). Complications, such as gallstones and heart dilatation, although more frequent in adults, also appeared in childhood. Although the correlation between serum unconjugated bilirubin levels and UGT1A1 genotype was significant, the coexistence of the (TA)7/(TA)7 genotype associated with Gilbert's syndrome does not seem a risk factor for developing gallstones, probably because the number of patients with the (TA)7/(TA)7 genotype was small. Transfusion need, especially for haemolytic crises, was higher in patients with non-deletion genotypes and in adults. A possible explanation of this could be the greater use of therapeutic drugs in adults when compared with children. Aplastic crises, less common than haemolytic crises, were due to B19 parvovirus infection in all cases and had a similar incidence in adults and children.
Serum ferritin was in the normal range in most of the children, while it was increased in more than 50% of adult males, with a significant age correlation. The reason for the high serum ferritin levels could be increased iron absorption secondary to chronic anaemia. The blood loss by menses could be the reason for the less frequent high ferritin values in women. Serum ferritin levels in the normal range have been reported in non-transfused patients with Hb H disease from Greece (Kanavakis et al, 2000), while raised ferritin values were found by Hsu et al (1990); Lin et al (1990) and, more recently, by Chen et al (2000) in Asian patients. However, Chen et al (2000) reported more marked iron overload, with no difference between males and females. Ferritin levels were not associated with the α-globin genotype, Hb level or reticulocyte count. LIC was higher than expected on the basis of ferritin levels in three evaluated patients, suggesting that ferritin levels may underestimate the degree of iron overload, as in other conditions, such as thalassaemia intermedia (Fiorelli et al, 1990).
Chen et al (2000) found three cases of heart failure secondary to iron overload and suggested a correlation between abnormal diastolic function and increasing serum ferritin. However, the systolic function was normal in our patients and the abnormal relaxation pattern found in a small group of patients can be a common pattern in elderly and may represent the earliest manifestation of diastolic dysfunction in younger individuals. This apparent mild cardiac involvement in Sardinian patients with Hb H disease could be due to the relatively young age of this patient cohort and needs to be confirmed by a longer follow-up. Further studies are also necessary to understand if the dilatation of the aortic root is clinically relevant in patients with Hb H disease and to investigate its cause. Haemolytic disease is now known to be an important causative factor in pulmonary hypertension, because the high levels of Hb in the plasma result in the consumption of nitric oxide, a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression and platelet activation and aggregation (Rother et al, 2005). If the absence of pulmonary hypertension is confirmed by a longer follow-up, it could be explained by the low grade of intravascular haemolysis in Hb H disease.
During pregnancy, worsening of anaemia, with occasional need of red cell transfusions, has been associated with the expansion of blood volume (Vaeusorn et al, 1988; Lin et al, 1990). Vaeusorn et al (1998) reported pre-eclampsia in 18% and congestive heart failure in 9% of 34 pregnancies among 29 Thai women, while in our group only 5·5% had pre-eclampsia and none had heart failure. An 11% risk of miscarriage was found in our population. This percentage is similar to that of the general Italian population, even when threatened abortions, preterm newborns, and Caesarean deliveries are taken into account (Sabbadini & Sebastiani, 2002). In Italy, in the general population, the prevalence of neonates born at term with a birth weight <2·5 kg is only 2% while in newborns of mothers with Hb H disease it was 5·5%. Thus it is possible that maternal anaemia may compromise the fetal growth, even if only rarely. On the other hand, pregnancy is confirmed as one of the most significant causes of transfusion need in adulthood, regardless of genotype.
From our findings we conclude that Hb H disease is usually more benign in the Sardinian population than in south-east Asia and the Middle East. It needs regular monitoring for early detection and treatment of possible complications, such as worsening of anaemia that may require red cell transfusion, cholelithiasis and iron overload. For this reason, a better knowledge of Hb H among paediatricians will enable earlier diagnosis, which should be suspected in patients with microcytic hypochromic anaemia with reticulocytosis. Screening the partners of women with Hb H disease, to detect their α-thalassaemia carrier status, is needed to provide these couples with the appropriate genetic counselling before planning a pregnancy. A longer follow-up is required to monitor the clinical manifestations of the disease, to detect unknown complications that may manifest later in life and to better evaluate the quality of life in these patients.