Growth hormone and adrenal response to intramuscular glucagon test and its relationship to IGF-1 production and left ventricular ejection fraction in adult B-thalassemia major patients.

In patients with b-thalassemia major (TM), the anterior pituitary gland is particularly sensitive to free radical stresses. It has been reported that the GH deficiency (GHD) may be secondary to either pituitary or hypothalamic dysfunction. The duration of the disease, the patient's age and the severity of iron overload are the most important factors responsible for the defect of growth hormone (GH) secretion. Recent reports have documented a frequency of severe growth hormone deficiency in 13%-32% of patients with b-thalassemia major. All of these patients underwent GH-releasing hormone (GH-RH) plus arginine (ARG) testing. We undertook the present study to evaluate the GH and adrenal response during glucagon stimulation test (GST) in patients with TM because the GH-RH plus ARG test in patients with hypothalamic GHD may be misleading. Thirty-three adult TM patients were recruited (mean age 36.6 years). Fifty four percent were included in the severe GHD group (GH peak below 3mg/l). The IGF-1 level in TM patients was consistently low (60.3 ± 35.3 mg/l) and 86.6% of patients with a normal GH response to GST had a low IGF-1 level. These findings are also indicative of a relative resistance to GH. In eight out of 18 TM patients (44.4%), the GHD was associated with hypogonadotropic hypogonadism. A positive correlation was found between GH peak after GST and IGF-1 level (r = 0.8, p: 0.003) and a negative correlation between the age of female TM patients and GH peak (r = 0.711, p: 0.007). All patients but one had no evidence of cardiac iron overload (mean T2* 30.4 ± 8.2 ms; range 14-44 ms). The mean LVEF (%) in TM patients was no different when compared to healthy controls. However, three patients with severe GHD and normal T2*were found to have reduced LVEF.One patient (4%) had a peak cortisol response to GST compatible to adrenal insufficiency. Nausea, headache and\or hypoglycemia occurred in 3 patients (12%) during GST. In conclusion, our study demonstrates that the presence of GHD is frequent in adult TM patients. According to the international guidelines for medical practice, we believe that before considering hormone replacement therapy, a second test to confirm the diagnosis of GHD and adrenal insufficiency is required.

Gender differences in the prevalence and severity of bone disease in thalassaemia.

BACKGROUND: The pathogenesis of bone disease in thalassaemia major (TM) is multifactorial and remains unclear, although gonadal dysfunction probably has the most dominant role. OBJECTIVE: The aim of the study is to investigate the impact of several factors on the development of reduced bone mass in patients of both sexes with TM, treated in our Center. SUBJECTS AND METHODS: 76 thalassaemic patients (26 males, 50 females) of Greek Cypriot origin with a mean age of 31.4 (17-53) years were included in the study. All patients were on the standard treatment protocol for thalassemia at our Center. Bone mineral density (BMD) of lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Factors known to be associated with low bone mass (gender, endocrine disorders, iron overload) were included in the analysis to ascertain possible associations. Iron overload calculation was based on the mean ferritin level over a 6-year period and T2* MRI of the liver and the heart. Statistical analysis was performed with the SPSS program. RESULTS: Bone disease was present in the spine of 89.5% of the patients and in 84.2% at the femoral site. Male patients were more frequently affected than females (92.3% vs. 88.0% in the spine and 88.5% vs. 82% at the femoral neck). Hypogonadal patients were found to be more frequently affected compared to eugonadal patients (94.1% in spine and 88.2% cyat the femoral neck compared to 89.5% and 81.6% respectively). Males with normal gonadal function were more severely affected in the lumbar spine than eugonadal women (male mean BMD z-score was -3.0 vs. -2.037 in women, p=0.004). Low BMD values were found to be more common in the presence of endocrinopathies. No correlation was found between ferritin status and severity of bone disease. Patients with severe liver iron overload seemed to be more affected in the spine. Heart T2* MRI measurements showed that patients with severe and moderate iron overload in the heart were more affected with bone disease in both the spine and femoral neck. CONCLUSIONS: This study demonstrates a gender difference not only in the prevalence of osteoporosis/osteopenia in patients with TM, but also in the severity of the disorder, as males are more frequently and severely affected than females. Moreover, hypogonadism may have a greater impact on spine BMD in females than in males. The underlying pathogenic mechanisms contributing to the development of bone disease in thalassaemia are multiple and complicated, indicating the necessity of further investigation in order to understand the pathophysiology of this highly prevalent complication. Further research in this field will allow the design of preventive and therapeutic measures.

Effect of bisphosphonate treatment on bone mineral density in patients with thalassaemia major.

BACKGROUND: Bisphosphonates are potent inhibitors of osteoclastic bone resorption and have been recently used in thalassaemia major (TM) osteoporosis with encouraging results. OBJECTIVE: The aim of the study is to investigate the effect of two Bisphosphonate drugs, Alendronate and Pamidronate on bone mass in patients of both genders with TM, treated in our Center. SUBJECTS AND METHODS: 53 (22 males, 31 females) Thalassaemic patients of Greek Cypriot origin were randomly divided into two groups. 29 patients in group A with a mean age of 33, 32 years were treated with alendronate and 24 patients in group B with a mean age of 34, 36 years received pamidronate for a period of 2 years. The effectiveness of both drugs was estimated based on the change of Bone mineral density (BMD) values of lumbar spine and femoral neck. Bone mineral density (BMD) of lumbar spine and femoral neck was measured by dual-energy X-ray absiorptiometry. All patients were on the standard treatment protocol of Thalassaemia. Statistical analysis was performed with the SPSS program. RESULTS: After completion of treatment with pamidronate the mean lumbar spine BMD has improved from -2.813 to -2.174 (p<0.001) and the mean hip BMD from -2.138 to -2.078 (p=0.018). The change of spine BMD in patients who received alendronate was from -2.720 to -2.602 (p=0.059) and the changes in BMD at the femoral neck from -2.035 to -2.007 (p=0.829). CONCLUSIONS: This study demonstrates the efficacy of two bisphosphonate drugs in improving BMD values in patients with TM and osteoporosis. Since the origin of bone disease in TM is multifactorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed, which will allow the design of optimal therapeutic measures.