A 21-year-old woman who has recently emigrated from Pakistan is referred to your clinic. She is known to have β-thalassaemia major and has been receiving regular blood transfusions.
How would you approach the initial assessment of this patient?
β-Thalassaemia major is a genetic disorder of haemoglobin synthesis caused by mutations affecting both β-globin genes on chromosome 11. Reduced production of β-globin chains leads to an excess of α-globin, which precipitates in red cell precursors resulting in their premature destruction and ineffective haematopoiesis. α-Chain precipitation also interferes with the red cells’ passage through the microcirculation, shortening their survival time. Raised erythropoietin drives haematopoietic expansion in the spleen and marrow while increased iron absorption from the gut results in damage to the heart, liver and endocrine system. β-Thalassaemia major describes those individuals with a severe phenotype for whom normal growth and development would be impossible without regular transfusion. Symptoms develop around the age of 6 months as the main haemoglobin switches from haemoglobin F (HbF) to HbA. The affected child will be pale and fail to thrive. Marrow expansion causes skull bossing, zygomatic enlargement (‘mongoloid facies’) and dental malocclusion. Growth is stunted and long bone thinning may result in spontaneous fractures. Increased red cell turnover and the resulting hypermetabolic state may cause fever, wasting, gout and folate deficiency. Liver cirrhosis and thrombocytopenia due to hypersplenism lead to a bleeding tendency. Untreated, death occurs from infection or heart failure, often before the age of 2 years.
Regular blood transfusion to maintain haemoglobin at >9.5–10 g/dl, usually every 3–4 weeks, will inhibit marrow and spleen expansion and, initially, allow normal growth and development. However, transfusion also results in progressive iron loading, leading to hypogonadotrophic hypogonadism, short stature, failure of menarche and infertility. Liver disease and endocrine disturbance such as hypothyroidism, diabetes, growth hormone deficiency and hypoparathyroidism may also occur. Cardiac failure or acute arrhythmias usually prove fatal in the second or third decade of life.
These complications are largely preventable through iron chelation. Desferrioxamine 20–50 mg/kg subcutaneously (SC) for 8–12 hours, 5–7 days per week, is usually commenced before serum ferritin is >1000 μg/l or liver iron is >7 mg/g dry weight, which generally occurs after the twelfth transfusion. Oral vitamin C 100–250 mg on days when chelation is given increases urinary iron excretion. Iron stores must be monitored during therapy as excess chelation leads to toxicity. The target serum ferritin is usually around 1000 μg/l, while levels persistently greater than 2500 μg/l predict cardiac complications and death. Over the last few decades, survival has progressively improved and in a recent long-term follow-up study, 65% of patients were alive aged 35 years.1 However, the majority of deaths are still due to cardiac events, and poor compliance with chelation, which is a particular challenge during adolescence, is associated with worse survival.1,2 Since the 1980s, children with ...