Prevalence of abnormal glucose homeostasis in Chinese patients with non-transfusion-dependent thalassemia.

Purpose: To determine the prevalence and underlying pathology of abnormal glucose homeostasis in Chinese patients with non-transfusion-dependent thalassemia (NTDT). Patients and methods: In this study, we enrolled 211 patients aged 4-63 years with NTDT, including 79 ß thalassemia intermedia patients, 114 Hb H disease patients and 18 Hb E/ß thalassemia patients. All had oral glucose tolerance test, serum ferritin (SF), homeostasis model assessment (HOMA) and liver iron concentration (LIC) measurement. One hundred and twenty healthy age-matched controls were also used for the comparative purpose. Iron load was assessed by using SF and hepatic load by LIC using validated MRI techniques. Results: The 211 patients were divided into three groups according to their fasting and 2 hrs postprandial blood glucose levels: hypoglycemic, normal glucose tolerance (NGT) and hyperglycemic groups. In this study, 149 patients had NGT, 33 had hypoglycemia, 4 had diabetes and 25 had impaired glucose tolerance (IGT). None had impaired fasting glucose. There was a significant correlation between 2 hrs postprandial blood glucose levels and age, PINS120, HOMA-IR, alanine aminotransferase and LIC (P<0.05). Risk factors for IGT in NTDT patients were older age (≥24 years) and SF concentration of ≥2,500 ng/mL. Conclusion: Age ≥24 years and SF ≥2,500 ng/mL of NTDT patients were at a greater risk for impaired glucose tolerance.

A 10-year longitudinal study of evaluation of ovarian reserve in women with transfusion-dependent beta thalassaemia major.

OBJECTIVE: Although spontaneous fertility and successful pregnancies have been reported in well-chelated and transfused women with beta thalassaemia major (BTM), majority of women are subfertile due to hypogonadotropic hypogonadism (HH). Little is known about the effect of iron overload on ovarian follicles and whether ovarian reserve is affected by the disease or treatment status. This study compares the markers of ovarian reserve in women with transfusion-dependent BTM over a period of ten years with healthy women from a control population. STUDY DESIGN: We performed a 10-year mixed (retrospective and prospective) longitudinal study in 17 women with transfusion-dependent BTM from our thalassaemia clinic between July 2007 to June 2017. The results were compared with 52 age-matched healthy women without any medical conditions (control population) attending our fertility clinic. Patient demographics, medical history, menstrual history, hormonal parameters (serum levels of FSH, estradiol, TSH and AMH) and antral follicle count were recorded in all women from both groups. Serum levels of ferritin, cardiac T2*, liver iron concentration, thyroid function (TSH) and liver function test results were also recorded at three different time points. RESULTS: Serum AMH levels, estradiol levels and antral follicle count were significantly lower in women with BTM compared with the control group (p < 0.05 for all). Low AMH levels were noted in both groups of women (with and without HH) with a background of BTM. Serum AMH levels positively correlated with AFC in women with BTM. CONCLUSION: Serum AMH level and AFC were significantly lower in women with transfusion dependent BTM as compared to age-matched healthy controls suggesting a direct impact of the disease activity or iron overload on the ovary.

Hepatic Hemosiderosis Contributes to Abnormal Vitamin D-PTH Axis in Thalassemia Major.

OBJECTIVE: The aim of this study was to evaluate the vitamin D-PTH axis in thalassemia major (TM) in relation to hepatic siderosis liver iron content. DESIGN AND PARTICIPANTS: In this case-controlled observational study, vitamin D-PTH axis was studied in 158 TM and 84 age and ethnicity-matched healthy nonthalassemic controls attending University College Hospital, London. Patients were classified as 25-hydroxy vitamin D (25-OHD) insufficient and sufficient if the value was less than or greater than 50 nmol/L, respectively. 25-OHD data were evaluated in relation to markers of iron load in TM. RESULTS: In TM, 25-OHD insufficiency was 8-fold higher than the control group (odds ratio [OR], 8.1; 95% confidence interval [CI], 4.3-15.0; P<0.001). Similarly, serum PTH (P<0.001), calcium (P<0.001), and phosphate levels (P<0.05) were also significantly lower in TM compared with the controls. In TM, serum ferritin of >2500 µg/L (OR, 5.3; 95% CI, 2.3-12.3; P<0.01), liver iron of >7 mg/g dry weight (OR, 8.8; 95% CI, 3.5-10.3; P<0.001), and serum alanine aminotransferase of >50 IU/L (OR, 9.7; 95% CI, 4.0-23.5; P<0.001) were independent risk factors for low 25-OHD levels. CONCLUSIONS: Our results suggest that TM had a 8-fold higher risk of 25-OHD insufficiency compared with the controls. This was likely to be associated with hepatic hemosiderosis.

Prevalence of diabetes mellitus in Chinese children with thalassaemia major.

OBJECTIVE: Diabetes mellitus is a common endocrinopathy in patients with ß-thalassaemia major (ß-TM), which is high prevalent in southern China. This study aimed to determine the cause and prevalence of glycaemic disorders in Chinese children with ß-TM. METHODS: In this prospective study, fasting glucose and insulin (FINS) levels were assessed in 267 ß-TM and 80 non-TM control children. Homeostatic model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI) were evaluated. Iron overload was assessed by serum ferritin (SF), total units of blood transfused and cardiac T2*. RESULTS: ß-TM had higher FPG (P < 0.001), FINS (P < 0.001) and HOMA-IR (P < 0.05), but lower QUICKI (P < 0.01) than those of controls. The impaired fasting glucose (IFG) was present in 30% of children, whereas 2% had diabetes. The prevalence of IFG in ß-TM group was higher in children aged >10 years (OR 6.5; 95% CI 3.7-11.4; P < 0.001), SF of >2500 µg/l (OR 4.8; 95% CI 2.1-11.1; P < 0.01), serum ALT levels of >50 IU/l (OR 2.1; 95% CI 1.2-3.7; P < 0.05) and cardiac T2* of <20 ms (OR 3.3; 95% CI 1.7-6.6; P < 0. 01). The children on deferiprone (DFP) had a reduced incidence of glycaemic aberrations than those on other chelating agents (OR 0.4; 95% CI 0.23-0.8; P < 0.05). CONCLUSIONS: Our data suggest that IFG occurred in 30% of ß TM children, perhaps due to insulin resistance secondary to iron overload. Deferiprone-containing chelating agent may have a protective effect.

Impaired steroidogenesis and apoptosis of granulosa-luteal cells in primary culture induced by cis-platinum.

OBJECTIVE: The purpose of this study was to test the hypothesis that the cytotoxic drug cis-platinum (CP) induces premature ovarian failure by reducing the viability of human granulosa cells. STUDY DESIGN: We incubated cultured human granulosa-luteal cells (GLCs) with varying concentrations of CP for 48 hours. Steroidogenesis and apoptosis were assessed by progesterone and estradiol, annexin V/propidium iodide, phase contrast, and transmission electron microscopy. RESULTS: CP caused impaired production of progesterone and estradiol in a dose- and a time-dependent fashion. The estradiol production was more pronounced than progesterone for each concentration of CP that was studied. The phase contrast microscopy of CP-treated GLCs showed loss of cell number with condensed nuclei. CP-induced apoptosis was maximum at 20 µg/mL compared with a 10-µg/mL concentration (79.9% ± 4.6% vs 58.3% ± 3.9%; P < .01). The hallmark of apoptosis (ie, nuclear condensation, cell size shrinkage) was seen in CP-treated cells by transmission electron microscopy. CONCLUSION: CP induces apoptosis of human GLCs in culture with impaired steroidogenesis, which may be one mechanism by which a CP-containing regime induces premature ovarian failure.

Prospective study of histomorphometry, biochemical bone markers and bone densitometric response to pamidronate in ß-thalassaemia presenting with osteopenia-osteoporosis syndrome.

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic-therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1-collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre-therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre-therapy with high turnover bone disease (HTO) in TM and low-turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low-turnover disease.

Use of hormone replacement therapy for correction of high turnover bone disease in hypogonadal ß-Thalassemia major patients presenting with osteoporosis: comparison with idiopathic premature ovarian failure.

Osteopenia-osteoporosis syndrome (OOS) causes considerable morbidity in 60-80% ß-thalassemia major (ß-TM) patients. We evaluated the effect of sex hormone replacement therapy (HRT) in ß-TM patients with hypogonadism presenting with OOS using premature ovarian failure (POF) for comparative purposes. We undertook a 10-year prospective study of in 50 ß-TM and 375 patients with POF and OOS. All were treated with HRT for 2-5 years. We used dual X-ray absorptiometry (DEXA), and plasma type 1-collagen markers of bone turnover for monitoring of response to therapy. Our results suggest that prior to HRT, both groups had comparable degrees of OOS. Both groups had significant improvement but the POF group had normalization of spinal T scores following HRT in contrast to the ß-TM patients. Femoral T scores did not normalize in both groups. These data indicate for the first time from comparative POF control studies that hypogonadism is not the only cause of OOS in ß-TM.

Sex steroid priming for induction of puberty in thalassemia patients with pulsatile reversible hypogonadotrophic hypogonadism.

Growth and pubertal disturbances are the most common causes of morbidity, affecting 60-80% ß-thalassemia major (ß-TM) patients worldwide, due mainly to hypogonadotrophic hypogonadism (HH). We undertook a 6-year prospective study of 55 Indian ß-TM children with stunted growth and absent or arrested puberty, aged 15-18 years with pulsatile HH, to evaluate the role of low dose sex steroid priming (6-12 months) for physiological induction of puberty. Eighty percent responded favorably with increase in height, growth spurt and completed pubertal maturation [Tanner stage 4-5 (T4-T5)] and 20% moved from T2 to T3. There was biochemical improvement in maturation of hypothalamic-pituitary (H-P) axis. Those younger than 15 years with minimal iron load had the best outcome. Our data suggest that sex steroid priming is a feasible method of induction of physiological puberty in ß-TM patients with sexual infantilism and reversible apulsatile HH, especially in younger patients with minimal iron loads.

Hypogonadotrophic hypogonadism and diminished gonadal reserve accounts for dysfunctional gametogenesis in thalassaemia patients with iron overload presenting with infertility.

Improved care of ß-thalassemia major (ß-TM) patients has brought with it new challenges for the patient to have a family. We report our 15-year experience with 30 couples with 28 pregnancies following artificial reproductive techniques (ART). Sixty percent of females had hypogonadotrophic hypogonadism (HH) with diminished ovarian reserve and responded favorably to gonadotrophins with 80% success rate within three cycles. Pulsatile gonadotrophin-releasing hormone (GnRH) infusion was used in one and clomiphene in another patient which resulted in successful pregnancies. Males responded less favorably than females. Gonadotrophins were used in 14 pulsatile HH patients for 6-24 months with variable outcomes. Although successful paternity did not occur, successful spermatogenesis with oligoasthenospermia occurred in six men. Two had in vitro fertilization (IVF) and intracytoplasmic injections (ICSI), which resulted in healthy offspring. In conclusion, successful pregnancy and fertility are feasible in ß-TM patients with diminished gonadal reserves. Better outcome is expected in females than males. We report the first two cases of paternity following IVF and ICSI in ß-TM patients with HH.

Virtual learning using interactive multimedia-based tools for knowledge transfer and development of global patient care pathway in haemoglobinopathies.

Hemoglobinopathies are the most common global monogenic disorders with significant mortality and morbidity of the survivors. This is due to poor understanding of the disease(s) by health care professionals and also lack of resources. We have designed a Master's degree in hemoglobinopathies course, the first of its kind, using cutting-edge lively state-of the-art media-based technology, to attain excellence in teaching and learning. The modular program is delivered by 100% virtual learning (VLE) tools. The lectures, given by international experts, are blended with interactive quizzes and assessment tools to make the program engaging. Other activities include video-based tutorials, walk-in surgeries, journal clubs and other web-based activities. We have currently received 40 intakes and the program is running successfully with excellent student feedback using quality control framework of the University College London (UCL), London, UK. In conclusion, we have shown the feasibility of VLE for knowledge and skill transfer to global healthcare professionals for a monogenic disorder.

Critical appraisal of growth retardation and pubertal disturbances in thalassemia.

Growth and pubertal disturbances are the commonest endocrinopathies in homozygous thalassemia, accounting for significant morbidity in 70-80% children and adolescents globally. This review focuses on the pathophysiology of the endocrinopathy from a historical perspective and altered natural history induced by better care due to transfusion and chelation therapy. We have also discussed clinical features, diagnosis, and management strategies of growth retardation, sexual infantilism, pubertal aberrations, and scope of growth hormone, sex steroids, and other endocrine therapies. The article also emphasizes current and future strategies for screening, monitoring of growth and pubertal disturbances, and early intervention for the restoration of fertility potential and bone mass in the affected individuals.

New concept in natural history and management of diabetes mellitus in thalassemia major.

Diabetes Mellitus is a major endocrinopathy, which occurs due transfusional haemosiderosis and is found in 20-30% of adult patients with beta-thalassaemia worldwide, accounting for significant morbidity. It is multifactorial with iron loading being the dominant cause and its management poses a clinical challenge. Diabetes in thalassaemia patients is distinct from type 2 diabetes. It is peculiar in many aspects including its pathophysiology and occurs due to insulin resistance as well as islet cell insufficiency. This article reviews the natural history of diabetes in this presentation with emphasis on prevention monitoring and management. Use of MRI techniques may be useful for future monitoring as well as biochemical monitoring to prevent complications of diabetes. Early intervention with intensified chelation may reverse pancreatic function and structural changes as evident from MRI.

Current perspectives of fertility and pregnancy in thalassemia.

Expectation to have a family is an important aspiration for a better quality of life for the adults with thalassaemia syndrome. Spontaneous fertility can occur in well chelated and transfused patients but majority are infertile due to hypogonadotrophic hypogonadism (HH) and need assisted reproductive techniques (ART). We report our experience of pregnancy following ART in 11 women with ss-thalassaemia major, who had HH with functionally intact ovaries. Pregnancy was achieved successfully by ART only after pre-pregnancy assessment in a multidisciplinary setting. Fourteen healthy newborn infants were delivered. Elective caesarean section was performed in 73%. There were 2 sets of twins and one set of triplet pregnancy. No significant cardiac complications were encountered. The incidence of preterm labour and growth restriction were 3 fold higher than the background population. Breast feeding was encouraged in all cases. In conclusion, pregnancy is feasible and safe in women with ss-thalassemia with normal resting cardiac performance and optimised iron overload in specialist centres under a multi disciplinary team.

Osteopenia-osteoporosis syndrome in patients with thalassemia: understanding of type of bone disease and response to treatment.

With increased life expectancy, thalassaemic bone disease including osteopenia osteoporosis syndrome (OOS) is a major cause of bone pain and fragility fractures especially of the lumbar spine, which may be found in 70-80% adult patients with beta-thalassaemia worldwide, accounting for significant bone morbidity. The causes of OOS in thalassaemia syndromes are multifactorial, and the exact treatment is far from ideal. We undertook a prospective study of 34 thalassaemic patients to evaluate the effect of pamidronate and hormone replacement therapy (if hypogonadal) on bone quantity by DXA scan quality by histomorphometry of bone biopsy and bone dynamics by biochemical markers of bone turnover.Our results show that all patients had osteopenia with abnormal bones on histomorphometry before commencement of treatment. Thalassaemia major patients had high turnover bone disease and all responded favourably to treatment whereas intermedia patients had low turnover bone disease and responded poorly to treatment. Our data also showed that ICTP and PICP is a discriminatory test but histomorphometry is the only test for characterisation of bone morphology.

Type 1 collagen marker of bone turnover, insulin-like growth factor, and leptin in dichorionic twins with discordant birth weight.

OBJECTIVE: We investigated the relationship between IGF-I-IGF binding protein (IGFBP)-1 and leptin levels with type 1 collagen markers of bone turnover in dichorionic twins with or without discordant birth weight of 20% or greater. METHODS: Maternal and cord bloods were collected from gestational age-matched dichorionic twins with (n = 16) or without (n = 16) discordant birth weight. The samples were assayed for cross-linked carboxyl terminal telopeptide (ICTP, a marker of bone resorption) and propeptide (PICP, a marker of bone formation) of type I collagen, leptin, IGF-I, and IGFBP-1 by RIA. RESULTS: The intrauterine growth-restricted (IUGR) twins of the discordant group had higher fetal ICTP (P < 0.001) and IGFBP-1 (P < 0.001) levels, whereas PICP (P < 0.001), IGF-I (P < 0.001), and leptin (P < 0.001) were lower than the cotwins with normal weight (AGA). In contrast, concentrations of IGF-I, IGFBP-1, ICTP, PICP, and leptin were comparable between concordant twin pairs. Leptin levels were positively correlated with PICP (r = 0.61; P < 0.001) and negatively with ICTP (r = -0.57; P < 0.001) in concordant and AGA twins but not in IUGR twins. In IUGR twins, IGF-I had positive association with PICP (r = 0.76; P < 0.001) and negative association with ICTP (r= -0.76; P < 0.001), whereas IGFBP-1 was negatively correlated with PICP levels (r = -0.65; P < 0.01). No such association was found in concordant and AGA twins. CONCLUSION: These data suggest that IUGR twins had high bone turnover, which is independent of maternal factors and perhaps may be due to altered IGF axis.

Comparative study of perinatal outcome of dichorionic and trichorionic iatrogenic triplets.

OBJECTIVE: The purpose of this study was to compare the perinatal outcome of dichorionic and trichorionic triplets who were conceived by assisted reproductive techniques. STUDY DESIGN: In this retrospective study, the maternal, neonatal, and chorionicity data were collected from 106 sets of trichorionic triamniotic and 34 sets of dichorionic triamniotic triplet pregnancies who were conceived by assisted reproductive techniques between January 1986 and December 2000. Perinatal and neonatal data were evaluated in relation to chorionicity and intertriplet birth weight discordance. RESULTS: The dichorionic triamniotic triplets have an 8-fold higher risk of perinatal death than trichorionic triamniotic gestations (odds ratio, 7.9; 95% CI, 4.4-14.0; P < .001). This is attributed to a higher risk of very low birth weight (P < .01), delivery at < 30 weeks of gestation (P < .001), and premature rupture of membrane (P < .001) in dichorionic triamniotic triplets compared with trichorionic triamniotic pregnancies. Twin-twin transfusion syndrome (odds ratio, 11.5; 95% CI, 4.8-27.7; P < .001), delivery at < 30 weeks of gestation (odds ratio, 40.5; 95% CI, 16.9-97; P < .01), premature rupture of membrane (odds ratio, 6.7; 95% CI, 3.8-11.9; P < .01), and nulliparity (odds ratio, 3.1; 95% CI, 1.6-6.1; P < .05) had independent effects on perinatal loss rate. CONCLUSION: The dichorionic triplets have an 8 times higher perinatal mortality rate than trichorionic triamniotic pregnancies.

Elevated IGFBP-1 cause high bone turnover in growth-restricted monochorionic twins with discordant birth weight.

OBJECTIVE: To test the hypothesis that low birth weight twins have a higher risk of osteoportotic fracture in later life, we investigated the association between fetal IGF axis and type-1 collagen markers of bone turnover in monochorionic (MC) twins with or without discordant birth weight of >or=20%. METHODS: Maternal and cord bloods were collected from gestational age matched MC twins of discordant (n = 16) and concordant birth weights (n = 16). The samples were assayed for cross linked carboxyl terminal telopeptide (ICTP, a marker of bone resorption) and pro-peptide (PICP, a marker of bone formation) of type I collagen, IGF-1, and IGFBP-1 by radio-immunoassay. RESULTS: The growth-restricted twins (IUGR) of discordant group had higher fetal IGFBP-1 and ICTP (P < 0.001) levels, while PICP (P < 0.001) was lower than the co-twins with normal weight (AGA). In contrast, cord blood levels of IGF-1, IGFBP-1, ICTP, and PICP in concordant twin pairs were comparable to AGA twins. The concordant and AGA twins had a positive correlation between ICTP and PICP levels (y = 23x - 711; r = 0.84; P < 0.001; n = 48) but no such association was found in IUGR twins. Instead, IGFBP-1 levels in IUGR twins had a negative association with PICP (r = 0.81; P < 0.001; n = 16) and a positive correlation with ICTP (r- = 0.51; P < 0.05; n = 16). No such association was found in concordant and AGA twins. CONCLUSION: These data suggest that growth-restricted twins had high bone turnover, due to elevated IGFBP-1. This association seems to be independent of maternal and genetic factors.

Perinatal outcome of spontaneously conceived triplet pregnancies in relation to chorionicity.

OBJECTIVE: The purpose of this study was to determine the perinatal outcome of spontaneously conceived triplet pregnancies in relation to chorionicity. STUDY DESIGN: In this retrospective study, maternal, neonatal, and chorionicity data were collected from 88 sets of triplet pregnancies that were delivered at >20 weeks of gestation from 3 tertiary referral centers in the United Kingdom. The data were collected between January 1986 and December 2000. There were 49 sets of trichorionic triamniotic triplet pregnancies and 39 sets of triplet pregnancies with a monochorionic pair (ie, dichorionic triamniotic triplets). The outcome of each pregnancy was assessed in relation to chorionicity. RESULTS: The overall perinatal mortality rate was 151.5 per 1000 total births, with dichorionic triamniotic triplets having a 5.5-fold higher risk than trichorionic triamniotic gestations (odds ratio, 5.5; 95% CI, 2.5-12.2). The dichorionic triamniotic triplets have a higher risk of delivery at < 30 weeks of gestation (odds ratio, 4.6; 95% CI, 1.6-11.8; P < .05) and birth weight of < 1000 g (odds ratio, 53.6; 95% CI, 17.5-164; P < .05) than those of trichorionic triamniotic pregnancies. The neonatal morbidity in terms of respiratory distress syndrome (P < .001), anemia (P < .01), and intraventricular hemorrhage (P < .001) were higher in dichorionic triamniotic compared with trichorionic triamniotic triplets. The premature rupture of membrane (odds ratio, 7.5; 95% CI, 3.5-15.7) and twin-twin transfusion syndrome (odds ratio, 14.9; 95% CI, 6.6-4) were independent risk factors for perinatal death. CONCLUSION: In spontaneously conceived triplets, the incidence of dichorionicity was 44%. The dichorionic triamniotic triplets have a 5.5-fold higher risk of adverse perinatal outcome predominantly because of twin-twin transfusion syndrome and premature rupture of membranes.