GH and IGF-I deficiency are associated with reduced loss of fat mass after laparoscopic-adjustable silicone gastric banding

Context GH secretion is reduced in obese subjects and increases after body weight loss. It is still unclear if changes in the GH/IGF‐I axis after laparoscopic‐adjustable silicone gastric banding (LASGB) are associated with changes of body composition. Objective To analyse the relationships between changes in the GH/IGF‐I axis and those of body weight and composition before and after LASGB. Design Observational, prospective. Setting University ‘Federico II’ of Naples (Italy). Patients Seventy‐two severely obese females (BMI: 44·9 ± 4·68; mean age: 33·1 ± 11·34 years) were studied. Main outcome measures GH peak after GHRH plus arginine test, IGF‐I, IGFBP‐3 and ALS levels, fat mass (FM) and free fat mass (FFM) (by Bioelectrical Impedance Analysis) at baseline and 6 months after LASGB. The change in percentage of individual variables was calculated as well as that of excess of body weight loss (EBWL%). The FM%, FFM% and EBWL% were correlated with peak GH and IGF‐I levels changes. Results At baseline, GH deficiency (GHD) (GH peak = 4·1 µg/l) was found in 22 patients (31%), 16 of them also had IGF‐I deficiency (< –2SDS). IGF‐I levels were inversely correlated with waist circumference (r = –0·72, P < 0·001) and FM% (r = –0·75, P < 0·001). Post‐LASGB the patients were classified as follows: group (1) GH and IGF‐I sufficient (n = 44; 61·1%); group (2) GH and IGF‐I deficient (n = 14; 19·4%) and group (3) GH sufficient and IGF‐I deficient (n = 14; 19·4%). The percentage changes of EWBL (P < 0·05, P = 0·051, respectively) and FM (P < 0·001, P < 0·01, respectively) were lower in groups (2) and (3) than in group (1). At the stepwise linear regression analysis, postoperative IGF‐I levels were the strongest determinant of percent changes of FM (P < 0·0001), of FFM (P = 0·009) and of EBWL (P < 0·0001). Conclusions IGF‐I levels is the most sensitive to unfavourable changes in body composition 6 months after LASGB making investigation of the somatotropic axis useful in the evaluation of bariatric surgery outcomes.     

Does partial surgical tumour removal influence the response to octreotide‐LAR in acromegalic patients previously resistant to the somatostatin analogue?

Objective To compare the intrapatient response to the same dose of slow‐release octreotide (OCT‐LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT‐LAR. Design Prospective clinical study. Patients Eleven acromegalic patients (eight men, aged 42·45 ± 11·15 years, 10 macroadenomas) received OCT‐LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT‐LAR) for 11·3 ± 4·2 months, without IGF‐I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT‐LAR for 8·0 ± 6·5 months (2ndOCT‐LAR). Measurements GH and IGF‐I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF‐I was also expressed as a percentage of the upper limit of the normal age‐ and sex‐matched range (%ULNR IGF‐I). Results After 1stOCT‐LAR, there was a decrease in GH levels (P = 0·003) and %ULNR IGF‐I (P = 0·009) compared to baseline (B), but no IGF‐I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63·7%, range 24·5–75·5%). After surgery, mean levels of GH and %ULNR IGF‐I were lower than those at baseline (P = 0·0004 and P = 0·003, respectively), but not when compared to values during 1stOCT‐LAR (P = 1·000 and P = 0·957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4·9–96·6%) in eight of the 10 patients. Comparing the 2ndOCT‐LAR results with postsurgical results, there were no significant decrease in %ULNR IGF‐I (P = 0·061) and GH levels (P = 0·414). Nine patients (82%) achieved IGF‐I normalization. The degree of surgical tumour reduction did not correlate with IGF‐I normalization (P = 0·794). When comparing the results between 1stOCT‐LAR and 2ndOCT‐LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0·059) and a significant decrease in %ULNR IGF‐I (P = 0·011). Conclusions Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT‐LAR treatment in acromegalic patients resistant to primary therapy with SA.     

Influence of ethnicity on IGF-I and procollagen III peptide (P-III-P) in elite athletes and its effect on the ability to detect GH abuse

Context A method based on the two GH dependent markers, IGF‐I and procollagen III peptide (P‐III‐P) has been proposed to detect exogenously administered GH. As previous studies involved predominantly white European elite athletes, it is necessary to validate the method in other ethnic groups. Objective To examine serum IGF‐I and P‐III‐P in elite athletes of different ethnicities within 2 h of competing at national or international events. Design Cross‐sectional observational study. Setting National and International sporting events. Subjects 1085 elite athletes of different ethnicities. Intervention Serum IGF‐I and P‐III‐P were measured and GH‐2000 discriminant function score was calculated. Effect of ethnicity was assessed. Results In men, IGF‐I was 21·7 ± 2·6% lower in Afro‐Caribbeans than white Europeans (P < 0·0001) but there were no differences between other ethnic groups. In women, IGF‐I was 14·2 ± 5·1% lower in Afro‐Caribbeans (P = 0·005) and 15·6 ± 7·0% higher in Orientals (P = 0·02) compared with white Europeans. P‐III‐P was 15·2 ± 3·5%, 26·6 ± 6·6% and 19·3 ± 5·8% lower in Afro‐Caribbean (P < 0·0001), Indo‐Asian (P < 0·0001) and Oriental men (P = 0·001), respectively, compared with white European men. In women, P‐III‐P was 15·7 ± 4·7% lower in Afro‐Caribbeans compared to white Europeans (P =0·0009) but there were no differences between other ethnicities. Despite these differences, most observations were below the upper 99% prediction limits derived from white European athletes. All GH‐2000 scores lay below the cut‐off limit proposed for doping. Conclusions The GH‐2000 detection method based on IGF‐I and P‐III‐P would be valid in all ethnic groups.     

Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported. Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes. Subjects and methods Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls. Results In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls (P < 0·001) and increased (P < 0·001) after treatment, together with IL‐6 (P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls (P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease (P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment. Conclusion The results point to the possibility of a relationship between GH disturbances and inflammatory processes.     

Growth hormone (GH) replacement in hypopituitary adults with GH deficiency evaluated by a utility-weighted quality of life index: a precursor to cost-utility analysis

Objectives To examine quality of life (QoL) measured by a utility‐weighted index in GH‐deficient adults on GH replacement and analyse the impact of demographic and clinical characteristics on changes in utilities during treatment. Design Utilities for items in the QoL‐Assessment of Growth Hormone Deficiency in Adults (QoL‐AGHDA_utility) were estimated based on data obtained from the general population in England and Wales (E&W). These estimates were used to calculate QoL changes in GH‐treated patients and compare these with normative population values. Patients A total of 894 KIMS patients (53% women) from E&W were followed for 1 to 6 years. Measurements QoL‐AGHDA_utility at baseline and at the last reported visit, total QoL‐AGHDA_utility gain and QoL‐AGHDA_utility gain per year of follow‐up. Results QoL‐AGHDA_utility in patients before GH treatment differed from the expected population values [0·67 (SD 0·174) vs. 0·85 (SD 0·038), P < 0·0001], constituting a mean deficit of –0·19 (SD 0·168). There was a difference in the mean QoL‐AGHDA_utility deficit for men [–0·16 (SD 0·170)] and women [–0·21 (SD 0·162)] (P < 0·001). The main improvement occurred during the first year of treatment [reduction of a deficit to –0·07 (SD 0·163) (P < 0·001) in the total cohort]; however, patients’ utilities remained lower than those recorded for the general population during subsequent follow‐up (P < 0·001). Despite an observed impact of age, primary aetiology, disease onset and comorbidities on QoL‐AGHDA_utility, all patients showed a similar beneficial response to treatment. Conclusions QoL‐AGHDA_utility efficiently monitors treatment effects in patients with GHD. The study confirmed the QoL‐AGHDA_utility deficit before treatment and a similar QoL‐AGHDA_utility gain observed after commencement of GH replacement in all patients.     

Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD)

Objective At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF‐I within the reference range. It is unclear whether in such patients serum IGF‐I levels are regulated by factors other than GH. Design and patients We performed a double‐blind, randomized, placebo‐controlled, cross‐over study to investigate the effect of the GH receptor antagonist – pegvisomant (20 mg daily for 14 days) on GH and IGF‐I levels in three cohorts: patients with GHD and a normal IGF‐I (NORMS); patients with GHD and a low IGF‐I (LOWS) and healthy volunteers (CONS). Results Pegvisomant decreased IGF‐I in CONS and NORMS [158·5 (101–206) vs. 103 (77–125) µg/l, P < 0·01; 124 (81–136) vs. 95 (51–113) µg/l, P < 0·01 respectively], but not in LOWS [31 (< 31–32) vs. 34·5 (< 31–38) µg/l], and this was associated with an increase in mean 24 h GH in CONS [0·49 (0·12–0·89) to 1·38 (0·22–2·45) µg/l (P = 0·03)] and in NORMS [69 (0–320)% from 0·1 (< 0·1–0·13) to 0·17 (0·11–0·42) µg/l (P = 0·03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6·1 (0·8–9) vs. 20·4 (13·1–28·8) µg/l, P = 0·03; 0·4 (0·1–0·5) vs. 0·5 (0·3–0·6) µg/l, respectively], but not in LOWS. Conclusions These data indicate that patients with severe GHD with a normal IGF‐I are able to increase GH secretion in response to a pegvisomant‐induced fall in IGF‐I, whereas those with low IGF‐I levels are unable to increase GH secretion. Therefore circulating IGF‐I appears to be GH‐independent in GHD patients with a low IGF‐I, but remains partially GH‐dependant in GHD patients with a normal IGF‐I.     

Glucocorticoid replacement is associated with hypertriglyceridaemia, elevated glucose and higher non-HDL cholesterol and may diminish the association of HDL cholesterol with the -629C>A CETP promoter polymorphism in GH-receiving hypopituitary patients

Objectives The effect of glucocorticoid substitution on the prevalence of metabolic syndrome components (NCEP ATP III criteria) and serum lipid levels was determined in GH‐replaced hypopituitary patients. As glucocorticoid replacement is associated with a pronounced decrease in plasma cholesteryl ester transfer protein (CETP) activity, we also tested associations of HDL cholesterol with the –629C>A CETP promoter polymorphism in subjects with and without ACTH deficiency. Design and patients In a university setting, we retrieved protocolized clinical and laboratory data from 165 adult hypopituitary patients, who had received GH for 1 year. Results After adjustment for age, sex and smoking, non‐HDL cholesterol (P = 0·05) and triglycerides (P = 0·004) were higher, but HDL cholesterol was not decreased in 117 glucocorticoid (mainly cortisone acetate in two divided doses) receiving subjects compared to 48 ACTH‐sufficient subjects. The prevalence of elevated plasma glucose and/or diabetes (P = 0·04) and hypertriglyceridaemia (P = 0·005), but not of other metabolic syndrome components, was higher in glucocorticoid‐replaced subjects. HDL cholesterol was higher in –629 A allele carriers compared to –629CC homozygotes in ACTH‐sufficient subjects (P = 0·04), but not in glucocorticoid‐treated subjects (P = 0·13). Multiple linear regression analysis demonstrated that only in ACTH‐sufficient subjects, HDL cholesterol was independently related to this CETP gene variation (P = 0·03). Conclusions In GH‐ and glucocorticoid‐replaced hypopituitary patients, serum non‐HDL cholesterol and triglycerides are higher and the prevalence of hyperglycaemia is increased, but HDL cholesterol is not decreased. Conventional glucocorticoid replacement appears to diminish the association of HDL cholesterol with a common CETP gene variation.     

GH replacement reduces increased lipid peroxidation in GH-deficient adults

Background GH replacement improves numerous metabolic abnormalities in GH‐deficient patients; increased lipid peroxidation (LPO) has been observed in GH‐deficient patients; however, it is unknown if LPO is influenced by GH replacement. Aim and methods To evaluate the extent to which GH replacement might reverse the increased LPO in GH‐deficient adults and to analyse if this phenomenon might be involved in the improvement of metabolic disturbances due to GH treatment. Serum concentrations of malondialdehyde + 4‐hydroxyalkenals (MDA + 4‐HDA), as an index of LPO, were measured at baseline, and after 12 and 24 months of GH replacement in 40 adult patients with severe GH deficiency (both in adult‐ and childhood‐onset) and in 40 healthy volunteers, matched for sex, age and body mass index (BMI). Correlations were evaluated between LPO and lipids, IGF‐I, metalloproteinase‐2 and ‐9 (MMP‐2, ‐9), vascular endothelial growth factor (VEGF), BMI and GH dose. Results LPO values in GH‐deficient patients were several‐fold higher than in controls [55·36 ± 2·27 vs. 4·19 ± 0·42 nmol/mg protein (mean ± SEM), P < 0·0001] and decreased significantly over time with GH replacement to 38·61 ± 2·15 nmol/mg protein (i.e. by approximately 30%), though still remaining markedly elevated compared with controls (P < 0·0001). The proatherogenic lipid profile parameters correlated positively with LPO in the childhood‐onset subgroup before GH replacement. GH replacement restored the positive correlation between LPO and age in male patients (r = 0·57, P = 0·013; r = 0·8, P < 0·001, at 12 and 24 months of GH replacement, respectively). Conclusions GH replacement partially reverses the grossly abnormal LPO in GH‐deficient adults. It is highly probable, therefore, that oxidative mechanisms are involved in the overall improvement of metabolic changes due to GH replacement.     

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin

Background Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH‐releasing action, mainly at the hypothalamic level. Objective To evaluate secretory response of GH to ghrelin in PHP patients. Patients Fifteen patients [11 women/4 men, mean age 54 years, range 32–70 years, body mass index (BMI) 25·0 ± 0·7 kg/m²] affected with PHP due to single parathyroid adenoma and 35 normal age‐matched subjects (23 women/12 men, mean age 58 years, range 35–68 years, BMI 24·1 ± 1·1 kg/m²). Methods A measure of 1 µg/kg body weight i.v. acylated ghrelin or 1 µg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0·5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. Results Mean serum GH peak after GHRH + ARG was 32·6 ± 7·8 and 17·4 ± 4·0 µg/l, in controls and PHP patients, respectively (P < 0·05). Mean serum GH peak after ghrelin was 70·4 ± 31·5 and 16·8 ± 1·9 µg/l, in controls and PHP patients, respectively, (P < 0·001). Using ROC curves, a serum GH peak > 22 µg/l after ghrelin stimulation might be considered as a cut‐off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF‐1, PTH or ionized calcium concentrations. Conclusions The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.     

The effect of growth hormone treatment on bone mineral density in prepubertal girls with Turner syndrome: a multicentre prospective clinical trial

Background Patients with Turner syndrome (TS) are treated with GH to increase adult height. Although it is well established that GH promotes longitudinal bone growth, the effects of GH treatment on bone density are less clear. Objective To determine how GH treatment affects trabecular bone mineral density (BMD) in girls with TS at prepubertal ages in a prospective multicentre study. Patients and method Twenty‐two patients with TS in the prepubertal period with a mean age of 9·8 ± 2·5 (range 3·6–12·8) years were included in the study. All girls with TS underwent measurement of areal BMD using dual‐energy X‐ray absorptiometry (DXA) to obtain pretreatment anteroposterior (AP) lumbar spine values at L1–L4. Patients received GH (Genotropin) subcutaneously for 1 year at a dose of 0·05 mg/kg/day. Height and weight were measured at 3‐monthly intervals. The AP lumbar spine areal BMD was remeasured using the same technique after 1 year of treatment. Lumbar spine BMD Z‐scores and volumetric BMD (vBMD) Z‐scores were calculated using national standards. Results The height SDS of our cases showed a significant increase with GH therapy. The pretreatment lumbar spine (L1–L4) BMD Z‐score was –1·2 ± 1·2 SD and the vBMD Z‐score was –0·8 ± 1·6 SD. There were no significant changes in these values after 1 year of GH treatment. Prepubertal TS girls more than 11 years of age had lower vBMD Z‐scores (–1·7 ± 1·7 SD) than the girls aged less than 11 (–0·1 ± 1·0 SD) (P < 0·05) at the onset of therapy. No significant changes were observed in these values after 1 year of GH therapy. Conclusions Osteopaenia becomes apparent in prepubertal TS patients as they reach pubertal age. BMD evaluation may be necessary in these prepubertal TS girls at diagnosis. Short‐term GH therapy in these TS patients does not have a significant effect on bone density when measured at a site with a predominance of trabecular bone.     

Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS)

Objective The beneficial effects of metformin in patients with type 2 diabetes mellitus (T2DM) and polycystic ovarian syndrome (PCOS) are thought to be in part due to weight reduction. However, the mechanisms by which metformin causes weight loss are unclear. We sought to determine whether circulating levels of the anorectic gut hormone peptide tyrosine tyrosine (PYY) show any correlation with metformin‐induced weight loss. Design and patients We examined the acute effects of orally administrated metformin on fasting PYY levels in eight healthy normal‐weight female subjects. Subsequently, we evaluated the effects of 6 months metformin treatment on fasting PYY levels and anthropometric measurements in 20 women with PCOS. Results In normal‐weight females 10 days’ metformin treatment increased fasting PYY levels (P < 0·01). Similarly, in PCOS subjects metformin treatment increased fasting PYY concentrations (P < 0·05). In both groups a marked variation in PYY increase in response to metformin was observed. Long‐term metformin treatment was associated with improvements in weight (P < 0·05), BMI (P < 0·05), fasting glucose (P < 0·05) and menstrual frequency (P < 0·01). Interestingly, change in PYY levels were correlated with change in waist circumference (r = 0·55, P < 0·05). Conclusions Acute and chronic oral metformin administration increase fasting PYY levels and may contribute to metformin's weight loss effect. Further studies are now required to clarify whether changes in circulating PYY levels in response to metformin treatment can be used to predict which patients will subsequently lose weight long‐term and gain cycle restoration.     

Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re‐evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow‐up, investigator‐assessed complete response (CR) rate (21·0% vs 10·8%), median progression‐free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non‐responders. However, patients with objective response or a CR experienced a significantly longer OS than non‐responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first‐line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.     

Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study

Objective To assess vitamin D status and the influences of race, sun exposure and dietary vitamin D intake on vitamin D levels, and to evaluate two vitamin D repletion regimens in extremely obese patients awaiting bariatric surgery. Methods A cross‐sectional analysis of dietary vitamin D, sun exposure, PTH [intact (iPTH) and PTH(1‐84)] and 25‐hydroxyvitamin D (25OHD; differentiated 25OHD2 and 25OHD3) in 56 obese [body mass index (BMI) > 35 kg/m²] men and women (age 20–64 years). In a pilot clinical trial, 27 subjects with 25OHD levels < 62 nmol/l were randomized to receive ergocalciferol or cholecalciferol for 8 weeks. Results Serum 25OHD was low (mean 45 ± 22 nmol/l) and was inversely associated with BMI (r = ?0·36, P < 0·01). Each BMI increase of 1 kg/m² was associated with a 1·3 nmol/l decrease in 25OHD (P < 0·01). BMI, sun exposure, African American race and PTH predicted 40% of the variance in 25OHD (P < 0·0001). Serum 25OHD significantly increased at 4 and 8 weeks in both treatment groups (P < 0·001), whereas PTH(1‐84) declined significantly in subjects treated with cholecalciferol (P < 0·007) and tended to decrease following ergocalciferol (P < 0·09). Conclusions In severely obese individuals, those who are African American, have higher BMI and limited sunlight exposure are at greatest risk for vitamin D insufficiency. These demographic factors can help to identify at‐risk patients who require vitamin D repletion prior to bariatric surgery. Commonly prescribed doses of ergocalciferol and cholecalciferol are effective in raising 25OHD. Further investigation is needed to evaluate whether these regimens have differential effects on PTH, and to determine the optimal regimen for vitamin D repletion in the extremely obese patient.     

Thyroid autoantibody profiles in ophthalmic dominant and thyroid dominant Graves' disease differ and suggest ophthalmopathy is a multiantigenic disease

background Thyroid‐associated ophthalmopathy (TAO) occurs in 25–50% of patients with Graves’ disease (GD) and is occasionally seen in hypothyroid Hashimoto's disease or euthyroid individuals. The link between TAO and hyperthyroidism remains unclear. We hypothesized that qualitative or quantitative differences in thyroid antibodies might determine individual predisposition to these features. methods In a prospective study over 3 years, thyroid antibody levels were measured in all patients diagnosed at the Singapore National Eye Centre to have GD. These patients had no known history of thyroid disease, presented with eye complaints and diagnosis was made by an ophthalmologist. A total of 31 patients were identified. Antibody levels were compared against 71 consecutive patients referred to a thyroid clinic (TC) for thyrotoxic symptoms in whom the diagnosis of GD was confirmed by a thyroidologist. findings Thyroid autoantibody profiles of patients diagnosed at the ophthalmology centre (OC) and TC differed markedly. OC patients had significantly higher TSI (P = 0·003) but lower TPOAb (P = 0·008) and TgAb levels (P < 0·001). In contrast, TC patients had higher free T4 (P = 0·048) and higher TBII levels (P < 0·001). Antibody levels were correlated with four parameters of ophthalmopathy – chronic lid retraction, lid swelling, proptosis and extraocular myopathy (EOM). On univariate logistic regression analysis, TSI was a positive predictor and TPOAb and TgAb negative predictors of all four features. In the absence of TgAb, the odds ratios for individual TAO features ranged from 2·8 to 7·9, with corresponding values of 3·9–10·2 when TPOAb was absent. In stepwise logistic regression analysis, TSI was the strongest independent predictor of all aspects studied: lid fullness P = 0·001, proptosis P = 0·001, lid retraction P = 0·008, EOM P = 0·009. Among smokers, TPOAb were significantly lower (P = 0·044) but no association between smoking and the other antibodies was observed. interpretation The study demonstrates markedly different thyroid autoantibody profiles in newly diagnosed GD patients with ophthalmic dominant as opposed to thyroid dominant features. It suggests differing antibody patterns are associated with predisposition to hyperthyroidism and orbitopathy. In addition, an association between smoking and low TPOAb levels was noted.     

Tag SNP screening of the PDCD1 gene for association with Graves' disease

Objective The Programmed Cell Death 1 gene (PDCD1) on chromosome 2q37.3 encodes PD‐1 which is involved in providing a negative signal to activated T cells. Large case‐control studies have shown association of PDCD1 with several autoimmune diseases although, to date, no such studies have been performed for Graves’ disease (GD). The objective of our study was to investigate eight tag SNPs representing the majority of common variation in PDCD1 within a well‐characterized large UK Caucasian GD dataset. Design A case control association study of eight polymorphisms. Patients 2671 Graves’ disease patients and 864 controls. Measurements Tests for association with disease. Results No association with disease was seen for any of the +4163, +5049, +5318, +5640, +5678 and +7078 SNPs genotyped in this study. Association was detected between the +2375 SNP (P = 0·021, OR = 1·14 [95% CI = 1·01–1·29]) and GD and a small protective effect was seen with the +6799 SNP genotypes (P = 0·028, OR = 0·77 [95% CI = 0·58–1·03]). Conclusions This study has, for the first time, shown that small effects within PDCD1 may contribute towards the development of GD, supporting the hypothesis that much of the currently unknown genetic contribution to GD could be due to several small genetic effects with ORs  1·2. Replication of this result is now needed to confirm our findings and justify more detailed fine mapping of a primary aetiological variant in this gene region.     

The serum levels of the EGF-like homeotic protein dlk1 correlate with different metabolic parameters in two hormonally different children populations in Spain

Background The Dlk1 gene encodes for dlk1, a transmembrane protein belonging to the EGF‐like repeat‐containing family. Dlk1 has been shown to act as a regulator of adipogenesis. Fc‐dlk1 transgenic mice show a decrease in adipose tissue and glucose tolerance, hypertriglyceridaemia and lower insulin sensitivity. Dlk1‐deficient mice show growth retardation, increased serum lipid metabolites and develop obesity. These data advocate for a role of dlk1 in the maintenance of lipid homeostasis, and suggest that dlk1 levels may influence the development of cardiovascular disease. Aim and methods In this study, we analysed whether dlk1 serum levels could be indicative of the different hormonal or metabolic status shown by two Spanish children populations (6–8 years‐old), Orense and Murcia. We determined dlk1 serum levels by ELISA assay, using an antibody raised against the recombinant protein, and performed a correlation analysis against measurements of several hormonal and biochemical parameters in samples from 494 subjects. Results We found a statistically significant positive correlation between serum levels of dlk1 and those of glucose (P < 0·05), total cholesterol (P < 0·01) and high‐density lipoprotein‐cholesterol (HDL‐C) (P < 0·01) in children from Murcia, but not from Orense's population, where dehydroepiandrosterone‐sulphate (DHEA‐S) levels were significantly higher (P < 0·01) and dlk1 correlated positively with insulin (P < 0·01), homeostasis model assessment (HOMA) (P < 0·01) and free fatty acids (FFA) (P < 0·05). Conclusions dlk1 serum levels appear related to the anabolic status of the children in association with changes in the levels of DHEA‐S, which have been associated with hyperinsulinaemia and diabetes. Monitoring dlk1 levels may be important to evaluate the metabolic and hormonal stage of child development.     

The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance

Objective Impaired glucose tolerance (IGT) is considered a transitional phase in the development of type 2 diabetes, and is also independently associated with the occurrence of cardiovascular disease. Endothelial dysfunction (ED) represents a very early step in the development of atherosclerosis. The aim of the present study was to examine ED in the fasting state and after a glucose challenge as well as after administration of an antioxidant agent. Patients and methods The study subjects included 42 IGT patients and 26 healthy individuals (control group). The IGT patients were randomly divided into two groups, 21 in each group (the alpha‐lipoic acid group and the placebo group). In the alpha‐lipoic acid group, 300 mg of alpha‐lipoic acid was administrated before an oral glucose tolerance test (OGTT); in the placebo group, 250 ml of 0·9% sodium chloride was administrated before the OGTT. In addition, 250 ml of 0·9% sodium chloride was also administrated to the control subjects before the OGTT (control group), and then vascular function was examined in the fasting state and repeated 1 and 2 h after the glucose load. High‐resolution ultrasound was used to measure flow‐mediated endothelium‐dependent arterial dilation (FMD) and glyceryltrinitrate (GTN)‐induced endothelium‐independent arterial dilation. Results In the fasting state, and at 60 and 120 min, FMD in both the placebo and alpha‐lipoic acid groups was significantly lower than in the controls (P < 0·01). In the control group, FMD tended to decrease at 60 min after glucose loading and returned to the baseline levels at 120 min (P > 0·05). In the placebo group, FMD decreased significantly at 60 min after glucose loading (P < 0·01) and increased markedly from 60 to 120 min (P < 0·01). The alpha‐lipoic acid‐treated patients showed FMD values intermediate between the control subjects and the IGT patients treated with placebo, at both 60 and 120 min, and the differences were significant (P < 0·01). In multiple regression analysis, FMD was significantly correlated to fasting blood glucose (FBG), low density lipoprotein cholesterol (LDL‐C), lipoprotein (a) [Lp(a)], C‐reactive protein (CRP), thiobarbituric acid reactive substances (TBARS) and age in IGT patients at baseline (P < 0·01). Spearman's analysis showed a significant negative correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients (placebo group) (P < 0·01). There was also a significant correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients treated with alpha‐lipoic acid (P < 0·05), although the power of association decreased. Conclusion In subjects with IGT, FMD was impaired both in the fasting state and after a glucose challenge, probably through increased production of oxygen‐derived free radicals. The ED observed after a glucose challenge is related to the extent of hyperglycaemia and TBARS, and an antioxidant agent can improve the impairment of endothelial function induced by acute hyperglycaemia.