Does Insulin Like Growth Factor-1 (IGF-1) Deficiency Have a "Protective" Role in the Development of Diabetic Retinopathy in Thalassamia Major Patients?

RATIONALE: Both insulin and IGF-1 have been implicated in the control of retinal endothelial cell growth, neovascularization and diabetic retinopathy. Recent findings have established an essential role for IGF-1 in angiogenesis and demonstrated a new target for control of retinopathy that explains why diabetic retinopathy initially increases with the onset of insulin treatment. OBJECTIVE: This cross-sectional study was designed to give insights into relationship between Insulin-Growth-Factor 1 (IGF-1) levels and diabetic retinopathy (DR) in a sample of thalassemia major (TM) patients with insulin dependent diabetes mellitus (IDDM). This relation was not previously evaluated, despite the fact that both diseases co-exist in the same patient. The study also describes the clinical and biochemical profile of the associated complications in TM patients with and without IDDM. DESIGN: A population-based cross-sectional study. PARTICIPANTS: The study includes 19 consecutive TM patients with IDDM and 31 age- and sex-matched TM patients without IDDM who visited our out-patient clinics for an endocrine assessment. METHODS: An extensive medical history, with data on associated complications and current medications, was obtained. Blood samples were drawn in the morning after an overnight fast to measure the serum concentrations of IGF-1, glucose, fructosamine, free thyroxine (FT4), thyrotropin (TSH) and biochemical analysis. Serologic screening assays for hepatitis C virus seropositivity (HCVab and HCV-RNA) were also evaluated; applying routine laboratory methods. Plasma total IGF-1 was measured by a chemiluminescent immunometric assay (CLIA) method. Ophthalmology evaluation was done by the same researcher using stereoscopic fundus biomicroscopy through dilated pupils. DR was graded using the scale developed by the Global Diabetic Retinopathy Group. Iron stores were assessed by direct and indirect methods. RESULTS: Eighteen TM patients with IDDM (94.7 %) and ten non-diabetic patients (32.2 %) had IGF-1 levels below the 2.5(th) percentile of the normal values for the Italian population. The mean serum IGF-1 concentrations were significantly lower in the diabetic versus the non-diabetic TM groups (p < 0.001). DR was present in 4 (21 %) of 19 TM patients with IDDM and was associated with the main classical risk factors, namely inefficient glycemic control and duration of the disease but not hypertension. Using the scale developed by the Global Diabetic Retinopathy Group, the DR in our patients was classified as non proliferative diabetic retinopathy (NPDR). Only a few numbers of microaneurysms [1-3] were detected. Our data also confirm the strong association of IDDM in TM patients with other endocrine and non-endocrine complications.

Insulin-like Growth Factor-1 (IGF-1): Demographic, Clinical and Laboratory Data in 120 Consecutive Adult Patients with Thalassaemia Major.

INTRODUCTION: IGF-1 deficiency in TM patients in children and adolescents has been attributed to chronic anemia and hypoxia, chronic liver disease, iron overload and other associated endocrinopathies, e.g. growth hormone deficiency (GHD). Few data are available in the literature regarding adult TM patients and growth disorders. The aim of this study was to measure IGF-1 values and other clinical data in a large number of adult patients with TM to evaluate the possible relationships between them. PATIENTS AND METHODS: A cohort of 120 adult patients with TM was studied for plasma levels of IGF-1. Plasma total IGF-1 was determined by chemiluminescent immunometric assay (CLIA) method. In eleven patients (3 females) the GH response during glucagon stimulation test (GST) was also evaluated. RESULTS: Fifty percent of patients (33 males and 27 females) had IGF-1 levels <- 2 SDs below normative values for healthy subjects matched for age and sex. In these patients endocrine complications and elevations of aminotransferases (ALT) were more common compared to TM patients with IGF1 > -2SDs. In multivariate regression analyses, height, weight, BMI, serum ferritin, ALT, HCV serology and left ventricular ejection fraction (LVEF) were not significantly related to IGF-1, but a significant correlation was found in females between HCV-RNA positivity and IGF-1, ALT and serum ferritin. AGHD was diagnosed in 6 (4 males) out of 11 patients (54.5%) who had glucagon stimulation tests and in 5 out of 8 (62.5%) with IGF-1 <-2SD. The mean age of patients with GHD was 39.3 years (range: 25-49 years, median: 39 years) versus 35.8 years (range: 27-45 years, median: 37.5 years) in non-GHD patients. A positive correlation between GH peak after GST and IGF-1 level was found (r: 0.6409; p: < 0.05). CONCLUSIONS: In 50% of TM patients the IGF-1 levels were 2SDs below average values for healthy individuals. IGF-1 deficiency was more common in TM patients with associated endocrine complications, and a significant correlation was found in HCV-RNA positive females among IGF-1, ALT, and serum ferritin. Further data in a larger group of patients are needed to confirm whether IGF-1 level <-2 SDs may be a potential criterion for additional studies in TM patients. This datum could avoid performing GH stimulation tests in the majority of them.

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.

Abnormal seminal parameters in patients with thalassemia intermedia and low serum folate levels.

Seminal parameters were evaluated in 16 fully mature patients with thalassemia intermedia. Their ages ranged from 19 to 54 years (mean age 27 yrs) and serum ferritin levels varied from 205 to 3400 ng/ml. Eleven patients (68.7 %) had normal seminal parameters, 1 (1.6 %) had oligospermia, 3 (18.7 %) had asthenospermia and 1 (1.6 %) had oligoasthenospermia. A significant positive correlation was observed between the serum ferritin and ALT and serum ferritin and ?-GT (r: 0.636, p: 0.007; r: 0.497, p: 0.048, respectively), ALT and ?-GT (r: 0.749, p: 0.001) and total sperm concentration and serum folate (r: 0.572, p: 0.02). Despite some limitations, our study has useful clinical implications for the treatment of patients with thalassemia intermedia.

Assessment of cardiac and hepatic iron overload in thalassaemic patients by magnetic resonance: a four year observational study.

In this study, we present results of the determination of cardiac and hepatic iron overload in patients with thalassaemia by means of a non-invasive method based on magnetic resonance. The procedure was applied for a period of four years to a group of patients followed in the Thalassemia Centre of our hospital. The gathered data were stratified to indicate groups of patients with mild, moderate and severe hepatic iron overload. We also studied cardiac iron overload and related it to the ejection fraction. In addition, we addressed the issue of replacement of the resonance equipment with a change in the intensity of the magnetic field from 1 to 1.5 T. The calibration on the new equipment was carried out using a set of MnCl2 standard solutions. The results demonstrated the possibility of using the algorithms reported in the literature and thus the "portability" of the procedure on equipment of the same type. The study has confirmed the usefulness of this non-invasive procedure for the monitoring of the iron load in patients with thalassaemia and the possibility of its use on resonance installations in clinical use.

A statistical method for the quantification of the learning index by means of multiple answer tests-Graduated Response Test.

In the fields of didactics and continuous professional development (CPD) plans, the increasing use of multiple answer tests for the evaluation of the level of knowledge in various kinds of subjects makes it increasingly important to have reliable and effective tools for data processing and for the evaluation of the results. The aim of the present work is to explore a new methodological approach based on a widely tested statistical analysis able to yield more information content when compared with the traditional methods. With this purpose we suggest a Graduated Response Test and the relative operating characteristic curve (ROC) for the evaluation of the results. A short description of a computerized procedure, written in Visual Basic Pro (v.6.0), which automatically performs the statistical analysis, the ROC curves plot and the calculation of a learning index is given as well.