Mild subclinical hypothyroidism in thalassaemia major: prevalence, multigated radionuclide test, clinical and laboratory long-term follow-up study.

From 1990 to 1991, the Pediatric and Adolescent Endocrine Outpatient Clinic of Arcispedale S. Anna admitted 97 thalassaemia major (TM) patients for endocrine evaluation. Their mean age was 14.2+/-5.7 years (range 5-28 years). Sixty-eight (70%) had normal thyroid function and twenty-one (21.6%) were discharged with a diagnosis of hypothyroidism of different degrees of severity. Thirteen patients out of 21 (61.9%) were females. Twelve patients (57.1%) fulfilled the criteria for subclinical hypothyroidism (SH). Their mean age was 15.7+/-3.5 years (range 9-22 years). A positive direct correlation was observed between the following variables: TSH and serum ferritin, TG and basal TSH, basal TSH and peak levels after TRH stimulation test. In 6 out of 12 TM patients (50%) with SH type a, the basal ejection fraction assessed by MUGA scan was normal; 1 TM patient (8.3%) showed mild abnormality and 5 TM patients (41.6%) showed severe abnormalities. A normal response during exercise (increase in LVEF greater than 5 percentage units) occurred in 10 patients (83.3%). Global or segmental left ventricular dysfunction at rest and during exercise were found in 8 patients (66.6%) and 10 patients (83.3%), respectively. These cardiac abnormalities were more common in TM patients with severe iron overload and poor compliance to DFX treatment (group A: serum ferritin above 2500 ng/ml) compared to TM patients with mild-moderate iron overload (group B: serum ferritin below 2500 ng/ml). In the control group of TM patients (group C) with normal thyroid function the assessment of MUGA scan was normal in all subjects at rest and after exercise. Global or segmental left ventricular dysfunction was observed only during exercise in 50% of TM patients with normal thyroid function (group C). Our patients with SH exhibited three different thyroid function patterns during follow-up: a. 3 (25%) of 12 studied TM patients showed a normalization of serum TSH levels b. 2 patients (16.6%) showed intermittent elevation of serum TSH with normal serum FT4 concentrations c. 3 patients (25%) had a persistent mild elevation of serum TSH concentration (from 6.3 to 7.6 microU/ml) with serum FT4 concentrations within the normal range. Two TM patients (16.6%) were treated with L-thyroxine. The reason for starting therapy was an abnormality of basal LVEF in the presence of mild iron overload (serum ferritin levels 665 ng/ml and 523 ng/ml). One TM patient with persistent SH type a developed a papillary carcinoma, and another, a multinodular goiter. The serum ferritin levels at diagnosis were 4739 ng/ml and 744 ng/ml,respectively. The thyroid function in TM patients from group C remained normal during the follow-up period. Two patients (Group A: patients no. 1 and 2) with severe iron overload and poor compliance to chelation therapy died during the follow-up, due to heart failure and arrhythmia. The time intervals between the first abnormal LVEF value and the development of symptomatic heart failure were 3.8 and 4.3 years. An improvement of LVEF was observed in three TM patients from group A after 24 months of intensive subcutaneous chelation therapy with DFX, and in two patients from Group B after 12-14 months of L-thyroxine replacement therapy in association with regular iron chelation therapy. In those two TM patients the basal LVEF increased from 37% to 45% and from 45% to 49%. In conclusion, although the findings are limited to a small group of TM patients with SH type a, our results show a high prevalence of primary hypothyroidism with the predominance of its mildest form, its stable course over years in most patients, and the presence of cardiac involvement in patients with severe-moderate iron overload. Regular iron chelation therapy should be advised for these patients to prevent thyroid dysfunction and the development of clinically significant myocardial dysfunction. In addition, therapy with L-thyroxine should be considered in iron overloaded TM patients with SH and a poor response to chelation therapy and in patients with SH and mild iron overload.