A total of 361 subjects, 176 males (48.8%) and 185 females (51.2%), mean age 23.2 years (range 6.1 to 75.4 years) were enrolled in the study (). Of these, 236 were diagnosed with beta TM, 43 with beta TI, 43 with E- β, 19 with HbH, and 20 with HbH/CS or other non-deletional mutations. There were three patients with Hz α thalassemia, who were not included in this analysis because of the small sample size. Details on the demographics of the participants, and their transfusion and chelation regimens are presented in .
Characteristics of study participants1
Growth abnormalities were common among children and adolescents (age <20 years): height z-score: -1.20 ± 1.16; mean ± SD; range -5.08 to 1.56 (). Twenty-five percent were of short stature (height z-score < -2), compared to <3% of the general population. Their mean weight and BMI were in the normal range (weight z-score: -0.89 ± 1.25, range -4.47 to 2.78; BMI z-score: -0.26 ± 1.1; range -4.5 ± 2.71). The final height z-score (calculated in participants >20 years) was -1.34 ± 1.2; range -4.8 to 1.81. Short stature occurred in 28.5%. As in the case of children, mean adult weight and BMI were in the normal range (weight z-score = -0.72 ± 1.2, range − 4.57 to 2.48; BMI z-score = -0.07 ± 1.05, range -4.51 to 2.44). The difference of final height from midparental height was -0.72 ± 1.23 SDs or -4.3 ± 7.4 cm.
Figure 1 Plots of height, bone age and weight of study participants. A. Stature of male participants vs. calendar age (●) and bone age (■). B: Stature of female participants vs. calendar age (●) and bone age (■). Individuals are (more ...)
The type of thalassemia syndrome had no effect on growth before the age of 20 years, final height or difference of final height from midparental height. Among children and adolescents (age < 20 years), hypogonadism was associated with decreased height (p = 0.04), weight (p < 0.01) and BMI (p = 0.02) in a model that included age, gender, race and type of thalassemia as co-variants. Growth hormone deficiency was also a significant negative predictor of height (p = 0.05) and weight (p = 0.03). Further multivariate analyses that, in addition, included IGF1 concentrations and serum ferritin and transferring receptor concentrations as co-variants showed a 1.3-fold increase in the odds of short stature with advancing age (p = 0.022) and a 4.5-fold increase in Asians compared to Caucasians (p = 0.045). Similar analyses in adults found that the only significant predictor of short stature was GH deficiency (OR = 3.8 [184.108.40.206]); p = 0.025).
Among participants younger than 20 years, bone age (BA) was close to chronological age (CA; ). The difference between CA and BA was greater in patients with hypogonadism (p = 0.01) and among patients with beta thalassemias compared to HbH disease (p = 0.02). Gender, race, and serum IGF1 concentrations were not significantly associated with delayed BA.
Serum IGF1 and IGFBP3 concentrations were plotted against normative values for sex and age (). Seventy-one percent of all patients had IGF1 concentrations below normal (57.7%, 56.8% and 83.3% for the age groups 6 - 11, 12 - 19 and > 20 years, respectively). IGFBP3 concentrations were below normal in 34.4% of the subjects. Increased ferritin concentrations (p ≤ 0.001), male gender (p ≤ 0.02), the presence of hypogonadism (p ≤ 0.01), and TI (p ≤ 0.02) were all associated with lower serum IGF1 and IGFBP3 concentrations. Of interest, IGF1 and IGFBP3 concentrations were not found to be predictors of short stature.
Figure 2 IGF1 and IGFBP3 vs. age stratified by gender and hypogonadal status. +: hypogonadal, o: not hypogonadal. IGF1 concentrations below normal range were found in 57.7% of children 6-11y, 56.8% of those 12-19y and 83.3% of subjects older than 20y. All children (more ...)
Hypogonadism and other endocrinopathies
Hypogonadism was the most frequent endocrinopathy and affected both genders. It was present in 14.3% of females and 25.5% of males younger than 20 years. Its frequency was significantly higher after age 20 at 52.4% in woman and 60.0% in men.
Hypogonadism was more frequent in patients with beta TM compared to those with beta TI (p < 0.001) or those with E-beta (p = 0.006) () among participants greater than 10 yrs old and after adjustment for age, gender, and serum ferritin levels. In addition to diagnosis, both age and serum ferritin concentration at the time of the study were associated with the development of hypogonadism. Specifically, the odds of hypogonadism increased by 13.9% for every 5 years of age (p < 0.001) and by 11.8% for every 1,000 ng/mL increase in ferritin concentration (p = 0.04).
The age of menarche was 15.7 ± 3.9 years for the overall group. For females who experienced normal puberty, menarche occurred at 13.3 ± 1.0 years (the youngest being11y). Girls with delayed puberty reached spontaneous menarche at 17.2 ± 1.2 years. Among those with a diagnosis of hypogonadism, menses were induced at 17.1 ± 4.0 years. Hypogonadal females were treated with either standard postmenopausal gonadal steroid replacement regimens (i.e. a combination of premarin and provera) or a birth control given not for contraception but as a form of gonadal replacement. Twenty-five percent of hypogonadal females were untreated at the time of the study. Among hypogonadal males, 36.2% were treated with either testosterone, given intramuscularly or transdermally by patch or gel, 7.25% were treated with HCG and 56.5% remained untreated. Of those treated, 27% had serum testosterone concentrations below the normal range indicating inadequate gonadal steroid replacement. The mean testosterone concentration among adequately replaced hypogonadal males was 672 ± 236 ng/dl (range 353 - 1102 ng/dl) vs. 113 ± 102 ng/dl (range 10 - 323 ng/dl) among poorly replaced patients. The type of steroid replacement made no difference on serum testosterone concentrations.
Growth hormone deficiency was the second most frequent endocrinopathy and was reported in 9.6% of the study participants, with a mean age at diagnosis of 14.3 years (range 5 – 28 years). Most (90.3%) of the growth hormone deficient patients (8.5% of all study participants) had been treated with growth hormone. There were no adults currently receiving growth hormone replacement.
Diabetes mellitus (DM) was seen only in TM, with a frequency of 14.1% and a mean age at diagnosis of 22 years, range 10 - 45 years. Of the diabetics, 29.5% were treated with an oral hypoglycemic and 47.1% with insulin. Analysis of fasting blood glucose concentrations in the non-diabetic, otherwise asymptomatic, participants identified 37 patients (13.9%) with impaired glucose tolerance (mean age 26 years, range 8.8 - 47.5 years) and 4 additional patients (1.5%) with diabetes. In the group of patients who were Hep C positive, 35.7% had either a diagnosis of diabetes or an abnormal fasting blood glucose (either in the diabetic or impaired glucose tolerance range), compared to 16.3% of patients without Hep C (p = 0.0001, chi-square test). The overall prevalence of hypothyroidism was 8.7% (mean age at diagnosis 23.8 years, range 10 – 44 years). Hypoparathyroidism occurred only in TM (2.1% prevalence; mean age at diagnosis, 19 years, range 12-30 years).
An increase of 5 years in age was associated with a 13.6% increase in the risk of hypothyroidism and 14% increase in the odds of DM using multivariate analysis. In the same analysis, the serum ferritin concentration at the time of the study was not a predictor of the above-mentioned endocrinopathies. However, the results differed when factors that affected the development of multiple combined endocrinopathies were considered. Patients with increasing serum ferritin concentrations (p = 0.05) and those with beta TM had higher rates of multiple endocrinopathies compared to beta TI, E-β and α hemoglobinopathies (p < 0.0001). Finally, increasing serum ferritin concentrations (p = 0.002), the presence of hypogonadism (p = 0.01) and having beta TM (p = 0.05) were all associated with higher fasting glucose levels in multivariate analysis.
Calcium Metabolism and Vitamin D
Measurements of serum 25 vit D concentrations revealed that 12.0% of the subjects were vitamin D deficient and 69.8% had insufficient levels. There were no differences in the prevalence of abnormal 25 vit D concentrations according to the thalassemia syndrome. 25 Vit D concentrations were lower among adolescents (47 ± 20 nmol/l in the 11- to 19-yr old group vs. 62 ± 21 nmol/l in the 6- to 10-year old group and 58.4 ± 31 nmol/l among the 20 years+ group; p = 0.0014) and among Asians (p = 0.02). As expected, 25 vit D was higher during the summer months (p = 0.0001). Patients with vitamin D deficiency had decreased urinary calcium excretion (p = 0.0004).
Total daily calcium intake (dietary and supplementation) was adequate across all thalassemia syndromes and age groups. Dietary calcium intake was lower among older subjects (p < 0.0001) and Asians (p = 0.018) and did not differ according to the type of thalassemia syndrome. Calcium supplementation was prescribed more frequently in older patients (p = 0.004) and in beta TM (p = 0.03), most likely reflecting efforts to treat patients with low bone mass. The total calcium intake in beta TM was 1,721 ± 924 mg/day.
PTH levels decreased with increasing vit D concentrations (p<0.001), in a pattern similar to what has been described in the general population. Hypoparathyroidism was rare, and was seen in only 5 patients with beta TM. However, patients with beta TM had lower PTH concentrations compared to those with beta TI for the same 25 vit D levels (p = 0.02; ). This finding can not be attributed to differences in calcium intake, since total Calcium intake did not significantly vary according to the thalassemia diagnosis or vitamin D sufficiency (). Hypercalciuria was present in 29% of patients with beta TM compared to none with beta TI (p = 0.002; ). Among patients with beta TM, the incidence of hypercalciuria was increased in vitamin D sufficient subjects compared to those with vitamin D deficiency (OR = 3.2, p = 0.007).
Figure 3 Parathyroid hormone and total Calcium intake by vitamin D sufficiency and diagnosis. Parathyroid hormone is significantly lower in beta TM compared to beta TI (p=0.02), and decreases with vitamin D (p<0.001). Total Calcium intakes does not significantly (more ...)
Calcium metabolism data and prevalence of hypercalciuria according to vit D sufficiency status and diagnosis1