Dr. Jagdish Chandra MD, FIAP*
Prof. of Pediatrics
Lady Hardinge Medical College, &
Kalawati Saran Childrens' Hospital, New Delhi. *
| Care of patients with thalassemia major (TM) has significantly improved over the last four decades. Hypertransfusion regimen has lead to proper growth and development of the patients and chelation with desferrioxamine (DFO) and deferiprone has helped eliminating or restricting the complicationsarising out of organ damage from iron overload. Bone marrow transplantation (BMT) being used for treatment of TM patients has added another dimension of care of thalassemics that of "intent to cure". Survival of Thalassemics into Adulthood:
Evidence of improved survival of TM has accumulated over the last 10-15 years. Studies have included cases in their fifties (1, 2). Modell et al have reported 50% survival up to 40 years or more (3). It is amply evident that quality of care provided to the patients and their adherence to chelation has a significant impact on survival and quality of life. Olivieri et al reported survival beyond 15 years in 91% in best chelated group compared to only 18% in worst chelated group. Davis et al reported 78% survival at 40 year at a single specialist unit from UK (4). Ehrelers et al estimated median age of 17.4 years in patients on low transfusion and poor chelation compared to 31 years median age among those on hypertransfusion and DFO chelation (5). Piga et al have reported 55% survival at 30 years - 88% among those having strict adherence to chelation compared to only 10% with poor chelation (6). Further improvement from UK has been reported recently - 83% beyond 40 years (7).
Survival of TM patients in India is not precisely known. However it is obvious from available data that there are 10-15% (or even more) of TM patients above the age of 18 years. Although the survival of TM patients has improved, it is not without problems. The complications arising out of anemia, iron overload and transfusion transmitted infections now are getting compounded by those arising out of issues related to higher education and jobs, sexuality, marriage, psychological and quality of life. This article focuses on some of the problems of adult thalassemics their prevalence, pathogenesis, prevention and treatment.
Cardiac disease remains most striking cause of death among patients with TM - accounting for 60%, which greatly exceeds deaths from infections (13%) and liver disease (6%) (8). Prevalence of heart disease increases with increasing age. A recent report from USA shows absence of heart disease at age <15 years, 5% in 16-24 years and 23% among those above 25 years of age (9). An incidence of overt heart disease in 6.9% with additional 5% having left ventricular dysfunction has been reported from Greece among TM patients between 23-37 years (10).
Cardiac disease in TM occurs due to transfusional siderosis. Higher values of serum ferritin and later age at starting of chelation have been correlated with overt / asymptomatic cardiac disease (11). Symptomatic patients present with palpitation, syncope, effort intolerance, breathlessness and dependent edema. Cardiac arrhythmias both atria and ventricular origin have been documented. Cardiac evaluation of the patients can be done using ECG, echocardiography and MUGA scan. Degree of myocardial iron deposition can be assessed by using non-invasive techniques - MRI by using either Signal Intensity Ratio (SIR) or Magnetic Resonance T2* star) gradient technique (8, 11).
Development of cardiac disease can be prevented by early introduction of appropriate iron chelators. Regular cardiac monitoring helps by early detection of cases requiring therapy. One important aspect of thalassemic cardiac disease is its complete reversibility with intensive chelation therapy (12). High dose DFO continuous infusion is recommended for such cases. Addition of deferiprone may be helpful as this drug has been shown to remove iron from heart more efficiently than DFO (2).
Growth and other Endocrine Complications:
Among children with TM, growth retardation is commonly described. Chronic anaemia, malnutrition, iron overload, hypersplenism, DFO toxicity and chronic liver disease are well-recognized factors contributing to poor growth (13). Hypogonadism and hypothyroidism also contribute to growth retardation. A Thalassemia unit from USA has reported following important observations on growth of children, adolescents and adults with TM: (14).
- All patients under 10 years had normal growth
- After 10 years, an increasing number fell below third centile
- After 20 years, there is tendency for normalization of growth
Among patients with growth retardation, hypogonadism was usually present. Significant observation is that reduced growth rates are associated with prolongation of growth period female patients continue to grow beyond 14-15 years up to 20 years and boys beyond 16-17 years up to 22-24 years. Similar observations were made earlier with patients having delayed skeletal maturation which may be reason for prolonged growth period (15).
A more recent survey of 342 TM patients reported the absence of endocrine complications under 15 years. Among patients above 25 years patients on treatment for hypothyroidism, hypoparathyroidism and diabetes mellitus was 17%, 9% and 21% respectively. Sixty-two percent patients were / had been on treatment for hypogonadism (9). An earlier report described spectrum of delayed sexual maturation among female patients with TM (age 12-35 years). More than 40% had hypogonadism. While menarche was delayed in most cases, only 48% had menarche and 12% of them developed secondary amenorrhoea (14). Among male patients, delayed or arrested growth with low testicular volume and decreased sperm motility has been described (16).
Age appropriate assessment of growth and endocrinal evaluation should be an integral part of thalassemia care. Adequate transfusion and nutrition will prevent early growth retardation. During adolescence, development of secondary sex characteristics should be monitored. Glucose tolerance test, serum calcium levels and monitoring for thyroid functions should be periodically undertaken. Sex hormone replacement therapy is recommended for girls with hypogonadism over 13-14 years with bone age over 11 years and boys older than 14-15 years with bone age over 12 years (14).
Among young adults with TM, osteoporosis and osteopenia are commonly observed. Prevalence is higher in male patients than females. Most severe radiological changes are described in lower spine and femoral neck. Patients develop bone pains (lower back), spontaneous fractures, necrosis of femoral head, vertebral fractures and cord compression.
Anemia resulting in bone marrow expansion (sometimes 15-30 times normal) is major causative factor for thalassemic osteopathy. Among well transfused but poorly chelated patients hypogonadism, hypoparathyroidism and diabetes mellitus are also contributory. Chronic illness effect with resultant decreased physical activity may be responsible. DFO toxicity has been incriminated. Certain genetic loci have also been implicated (17).
Thalassemic osteopathy is diagnosed by estimating bone mineral density (BMD) using dual energy X-ray absorptiometry (EEXA). Using WHO criteria, osteoporosis is defined as BMD scores of <2.5 SD of mean and those with BMD score between <1 and <2.5 are described as having osteopenia. Using spine BMD scores, a study from Greece reported 87% overall prevalence of thalassemic osteopathy among 200 young adults between 15-40 years age. Disease was more prevalent among men than women. Diabetes and hypoparathyroidism was observed in 15.5% and 9% patients respectively. Gonadal dysfunction positively correlated with poor spinal BMD scores in both sexes 86.58% women with decreased BMD and 505 with normal BMD scores had severe menstrual irregularities. Among males, 83.7% with decreased spinal BMD and 50% with normal BMD scores had hypogonadism (18).
Management focuses primarily on prevention. Regular transfusions, adequate chelation, increased dietary intake of vitamin D and calcium, regular exercise and detection and treatment of endocrine disturbances help prevent thalassemic osteopathy. Sex hormone therapy of hypogonadal patients is helpful. Once osteoporosis develops, therapy with pamidronate provides an effective therapy (19).
Marriage, Sexuality and Reproduction:
With improved survival and better quality of life, issues related to marriage and fertility are bound to arise. Most patients with TM undergo a phase of hypogonadism and during this phase comparison with peers may lead to certain questions in their mind regarding adequacy as adults. If managed appropriately to prevent hypogonadism and its treatment if it develops, patients with TM may have normal reproductive life. A series from US has reported 11 pregnancies in 8 out of 101 female patients above 18 years. Twelve of 94 male patients above 18 years have also become fathers (9). Figures from Cyprus are even more encouraging. Among 50 adults with TM and 12 with thalassemia intermedia with average age 25 years, 90 pregnancies are recorded, 87 babies were born with four twins and one tripled. Abortions are slightly more common. Overall, 22% TM patients are married and 73% have their children, some of them have three or four (4). There are anecdotal reports of successful pregnancy in patients with TM from India (20). Following issues related to pregnancy, reproduction and its management are no
- TM patients should clearly understand the genetic aspect i.e. If two TM patients marry, all their children will be patients of TM. If TM marries a thalassemia trait, 50% children will have TM and rest will be traits. If they marry a normal person, all children will only be traits.
- Reproductive assistance including assisted ovulation, in-vitro fertilization and artificial insemination are required more commonly than normal individuals.
- Patients will require more transfusions during pregnancy.
- If patient is on DFO chelation, it should be realized that DFO needs to be avoided during pregnancy (except a low dose during later months). Hence, chelation with higher doses is recommended before planning for pregnancy (13).
- Pregnant patients need strict cardiac monitoring particularly if they already have cardiac complications.
- Monitoring for diabetes and other endocrinopathies should be regularly carried out.
Hypercoagulability and Strokes:
Thalassemics have been known to have bleeding manifestations owing to hepatic dysfunction resulting from hepatic siderosis and Hepatitis B and C. Some children and young adults with TM have been described to develop strokes (21, 22). Levels of naturally occurring anticoagulants are described to be low rendering the patients vulnerable for thrombotic events. Pseudoxanthoma elasticum lesions are found in TM patients, which are also risk factors for strokes (23-25).
Chronic nature of disease and pain, physical stress and cost associated with transfusion chelation affects the psyche of TM patients. HIV and other transfusion-transmitted infections add further to the problems. Frustration, disappointment, hostility, helplessness, depression, anxiety and low self-esteem may develop. As the patients enter adolescence and adulthood, they are faced with challenges related to higher education, jobs, marriage and starting their family. Thus the patients need constant support and encouragement. On the positive side, there are some patients who have higher academic and co-curricular achievements and their attitude towards the disease is not entirely negative (26, 27). The patients should be provided with correct information about disease, treatment and hope for better life in future with advances in treatment. When cardiac complications and diabetes mellitus develop, the patients should be encouraged with information about reversibility of the complications with treatment. Doctor-patient, nurse-patient and doctor-parent relationship plays an important role in alleviating the discomfort of treatment, fear, anxiety and depression associated with disease. National Thalassemia Society and Thalassemia international Federation are playing a commendable role in making the life of thalassemic more and more stress-free.
Infections and other Medical Problems:
Transfusion transmitted infection form a major group of complications in patients with TM. Chronic nature of Hepatitis B and C and HIV are frequent occurrence among them. In a recent series from US, Hepatitis C positivity of 35% is reported while 2% were HIV positive (9). Consequent to chronic infection and siderosis, chronic liver disease develops which is third commonest cause of death among adults with TM (7). Patients using venous access devices are prone to develop infective complications. Splenectomized patients are also at increased risk of infection.
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