We conclude that late commencement of desferrioxamine and noncompliance are associated with greater iron loading and an increased risk of heart disease.

Previous studies have shown that serum levels of the somatomedin, nonsuppressible insulin-like activity (NSILA-S), are extremely low in patients with thalassemia major. Since these patients are not GH deficient, several other possible mechanisms for the reduced levels of NSIL-S have been explored. No evidence for the presence of NSILA inhibitors was obtained either in mixing experiments of normal serum and thalassemic sera or after acid gel chromatography of thalassemic sera. The high iron and ferritin levels of thalassemia had no effects on the NSILA-S bioassay itself or on the binding of GH to its hepatic receptors. GH molecules secreted as a result of exercise-induced GH stimulation tests were shown to be both immunologically and biologically reactive. No circulating GH-binding proteins were present in thalassemic sera. Since the liver function in the group of patients included in this study was only slightly abnormal, it is considered unlikely that generalized hepatic damage due to the severe iron overload of thalassemia is a major cause. These results suggest that neither NSILA-S inhibitors, abnormal GH molecules, nor hepatic damage contribute to the failure of these patients to produce NSILA-S and that a specific defect may exist at the hepatic GH receptor or postreceptor level.

We have recently demonstrated that nonsuppressible insulin-like activity (NSILA-S) is very low or undetectable in beta-thalassemia major. The mechanism for this deficiency has been proposed to result from a defect at the GH receptor level or at a site distal to the receptor in the pathway leading to NSILA-S generation. To study this proposal further, the NSILA-S response to exogenous human GH (hGH) was assessed in six affected subjects (aged 12-20 yr), four of whom were on or below the third percentile for height and three of whom were prepubertal. On the basis of immunoreactive and receptor-active hGH responses to exercise, GH deficiency as a primary cause of low NSILA-S levels was essentially ruled out in five of the six patients. hGH (5 mg) was administered im daily for 3 days. Bioassayable NSILA-S failed to rise normally in response to the exogenous hGH in four of the six subjects. In the other two, a limited response was seen only on day 4, reaching 54% and 29%, respectively, of the mean peak response in normal adults. The impaired production of NSILA-S in thalassemia major thus appears to be due to hGH insensitivity and not to a biologically inactive endogenous hGH molecule. These results confirm that the site of the defect may therefore be at the membrane receptor for hGH or at a subsequent step in the NSILA-S synthetic pathway, perhaps related to excessive hepatic iron deposition. These results also suggest that in subjects where the defect is partial, treatment of their short stature with hGH may be beneficial.

No abstract