Plasma visfatin concentrations increase in both hyper and hypothyroid subjects after normalization of thyroid function and are not related to insulin resistance, anthropometric or inflammatory parameters

Objective The objective of this study was to evaluate plasma visfatin levels in thyroid dysfunction and its relationship with inflammatory, anthropometric and insulin resistance parameters. Design and patients Twenty‐four hyperthyroid and 27 hypothyroid patients were studied before and after treatment. Forty‐five euthyroid subjects were used as control group. Measurements Fasting plasma visfatin, IL‐6, C reactive protein, adiponectin, thyroid hormones, waist‐to‐hip ratio, BMI, percentage of body fat and homeostasis model insulin resistance index (HOMA‐IR) were measured. Results Hyperthyroid patients showed increased insulin resistance, IL‐6 and visfatin levels compared with controls (3·21 ± 3·0 vs. 1·67 ± 0·75, P = 0·022; 3·35 ± 0·41 vs. 2·10 ± 0·25 pg/ml, P = 0·016; and 37·4 ± 5·81 vs. 23·79 ± 4·2 ng/ml, P = 0·061 respectively). After normalization of thyroid function, IL‐6 levels and HOMA‐IR decreased (2·35 ± 0·37 vs. 2·10 ± 0·25 pg/ml, P = 0·045 and 3·21 ± 0·60 vs. 2·28 ± 0·38, P = 0·032 respectively), while body weight, adiposity and visfatin levels increased (26·1 ± 1·2 vs. 26·7 ± 1·2 kg/m², P = 0·049; 30·9 ± 1·6 vs. 32·2 ± 1·6%, P = 0·007; and 37·4 ± 5·81 vs. 63·13 ± 8·72 ng/ml, P = 0·047 respectively). C reactive protein and adiponectin levels were similar to those of the control group. Hypothyroid patients showed high visfatin levels (40·59 ± 3·07 vs. 29·34 ± 4·9 ng/ml, P = 0·049) that increased after treatment (81·4 ± 9·2 ng/ml, P = 0·001) without changes in anthropometric or insulin resistance parameters. C reactive protein, IL‐6 and adiponectin levels were similar to those of the control group. No correlations between visfatin and any analysed parameter were found in either hyper‐ or hypothyroidism. Conclusion Visfatin exhibits a marked increase after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that visfatin may play a role in the hormone stabilization process independent of anthropometric, inflammatory or insulin resistance variables.     

A high normal TSH is associated with the metabolic syndrome

Objective Obesity and insulin resistance are key features of the metabolic syndrome. In euthyroidism, the relationships between TSH and insulin resistance or the metabolic syndrome are less clear. We investigated the associations between TSH and the features and prevalence of the metabolic syndrome in euthyroid German subjects. Methods In a cross‐sectional study, glucose metabolism was defined by an oral glucose tolerance test (oGTT) (except for those with evident diabetes) in 1333 subjects with TSH values between 0·3 and 4·5 mU/l who did not take any thyroid medication. Lipid parameters were measured, blood pressure and anthromopmetric parameters were taken, and insulin resistance was quantified as HOMA%S. Results TSH was weakly correlated with BMI (R = 0·061, P = 0·025). This association remained significant after adjustment for sex, age, and impaired glucose metabolism (P = 0·002). Subjects with a TSH in the upper normal range (2·5–4·5 mU/l, n = 119) had a significantly higher BMI (30·47 ± 0·57 vs. 28·74 ± 0·18 kg/m², P = 0·001) and higher fasting triglycerides (1·583 ± 0·082 vs. 1·422 ± 0·024 mmol/l, P = 0·023), and their likeliness for fulfilling the ATP III criteria of the metabolic syndrome was 1·7‐fold increased (95% CI: 1·11– 2·60). Conclusion In euthyroidism, subjects with a TSH in the upper normal range (2·5–4·5 mU/l) were more obese, had higher triglycerides, and had an increased likeliness for the metabolic syndrome. Therefore, a TSH below 2·5 mU/l is associated with a favourable metabolic profile. Whether lowering TSH to levels below 2·5 mU/l improves metabolism needs to be investigated in intervention trials.     

The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized,double blind,cross‐over study in thyroidectomized patients

Context The substitution of liothyronine (L‐T3) for levothyroxine (L‐T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L‐T3 for L‐T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L‐T3 and L‐T4. Design Randomized, double‐blind, cross‐over intervention study. Setting NIH clinical center. Patients Ten thyroidectomized patients. Interventions Study participants were treated with L‐T3 or L‐T4 with a target TSH ≥ 0·5 ≤ 1·5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed‐over according to the same scheme. Main outcome measures Area under the serum concentration–time curve of TSH from 0 to 60 min (AUC_0–60) and peak TSH serum concentration (C_max) following thyrotropin‐releasing hormone (TRH) stimulation test, total L‐T4 and L‐T3 dose (mcg/kg), and L‐T4/L‐T3 ratio. Results No difference was observed for time 0 TSH values between L‐T3 and L‐T4 replacement phases (1·48 ± 0·77 vs. 1·21 ± 0·62 mU/l, P = 0·293) at average daily doses of 40·3 ± 11·3 mcg L‐T3 and 115·2 ± 38·5 mcg L‐T4, L‐T3: L‐T4 ratio 0·36 ± 0·06. TRH stimulation test resulted in similar L‐T3 vs. L‐T4 TSH responses with AUC_0–60 of 326·1 (95% CI 232·6–457·1) and 247·1 (95% CI 153·8–397·1) mU* min/l (P = 0·285); and C_max of 6·83 (95% CI 4·88–9·55) and 5·23 (95% CI 3·31–8·3) mU/l (P = 0·383). Conclusions This is the first study addressing the equivalency between L‐T3 and L‐T4 therapy measured by baseline and TRH‐stimulated TSH. The therapeutic substitution of L‐T3 for L‐T4 was achieved at approximately 1:3 ratio.     

Thyroidal effect of metformin treatment in patients with polycystic ovary syndrome

Objective Metformin is widely used for the treatment of type 2 diabetes. Growing evidence supports the beneficial effects of metformin also in patients with polycystic ovary syndrome (PCOS). It was recently reported that metformin has a TSH‐lowering effect in hypothyroid patients with diabetes being treated with metformin. Design Aim of this study was to evaluate the effect of metformin treatment on the thyroid hormone profile in patients with PCOS. Patients and measurements Thirty‐three patients with PCOS were specifically selected for being either treated with levothyroxine for a previous diagnosis of hypothyroidism (n = 7), untreated subclinically hypothyroid (n = 2) or euthyroid without levothyroxine treatment (n = 24) before the starting of metformin. The serum levels of TSH and FT₄ were measured before and after a 4‐month period of metformin therapy. Results Thyroid function parameters did not change after starting metformin therapy in euthyroid patients with PCOS. In the 9 hypothyroid patients with PCOS, the basal median serum levels of TSH (3·2 mIU/l, range = 0·4–7·1 mIU/l) significantly (P < 0·05) decreased after a 4‐month course of metformin treatment (1·7 mIU/l, range = 0·5–5·2 mIU/l). No significant change in the serum levels of FT4 was observed in these patients. The TSH‐lowering effect of metformin was not related to the administered dose of the drug, which was similar in euthyroid as compared with hypothyroid patients with PCOS (1406 ± 589 vs 1322 ± 402 mg/day, respectively; NS). Conclusions These results indicate that metformin treatment has a TSH‐lowering effect in hypothyroid patients with PCOS, both treated with l ‐thyroxine and untreated.     

Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency

objective To investigate the role of IGF‐1 on intima–media thickness (IMT) at common carotid arteries by Doppler ultrasonography. subjects Thirty‐nine patients (17 women, 22 men, aged 25–70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF‐1 levels, and 39 sex‐, age‐ and body mass index (BMI)‐matched healthy controls. results Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0·88 ± 0·26 vs. 0·69 ± 0·14 mm, P < 0·001), and systolic and diastolic peak velocity (P < 0·001) compared to controls. Eight patients (18%) and one control (2·1%, P = 0·04) had well‐defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0·78, P < 0·001). In both controls (r = ?0·82; P < 0·0001) and patients with GHD (r = ?0·84, P < 0·0001), serum IGF‐1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH‐deficient patients were total cholesterol levels (t = 5·2, P < 0·001), followed by disease duration (t = 2·4, P = 0·02), while in controls the variables most significantly related to IMT were IGF‐1 levels (t = ?9·9, P < 0·001), followed by low density lipoprotein (LDL)‐cholesterol levels (t = ?2·3, P = 0·02). Compared to patients with normal IGF‐1 levels, those with low IGF‐1 levels had lower high density lipoprotein (HDL)‐cholesterol levels (1·0 ± 0·2 vs. 1·3 ± 0·2 mmol/l, P = 0·0002), and higher glucose (54·3 ± 6·1 vs. 48·9 ± 5·9 mmol/l, P = 0·008), insulin (25·2 ± 6·8 vs. 18·8 ± 6·0 mUl/l, P = 0·004), total cholesterol (7·1 ± 1·1 vs. 4·9 ± 0·6 mmol/l, P < 0·0001), total/HDL‐cholesterol ratio (7·2 ± 1·8 vs. 3·9 ± 0·7, P < 0·0001), fibrinogen levels (319·8 ± 56·9 vs. 241·8 ± 53·0 mg/dl, P < 0·0001) and mean IMT at common carotid arteries (1·05 ± 0·25 vs. 0·69 ± 0·07 mm, P < 0·0001). Atherosclerotic plaques were found only in GH‐deficient patients with low IGF‐1 levels. conclusions GH‐deficient patients have alterations in lipid profile with an increase in the total/HDL‐cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF‐1 deficiency have increased IMT.     

Recombinant human prolactin for the treatment of lactation insufficiency

Context Lactation insufficiency has many aetiologies including complete or relative prolactin deficiency. Exogenous prolactin may increase breast milk volume in this subset. We hypothesized that recombinant human prolactin (r‐hPRL) would increase milk volume in mothers with prolactin deficiency and mothers of preterm infants with lactation insufficiency. Design Study 1: R‐hPRL was administered in an open‐label trial to mothers with prolactin deficiency. Study 2: R‐hPRL was administered in a randomized, double‐blind, placebo‐controlled trial to mothers with lactation insufficiency that developed while pumping breast milk for their preterm infants. Patients Study 1: Mothers with prolactin deficiency (n = 5). Study 2: Mothers of premature infants exclusively pumping breast milk (n = 11). Design Study 1: R‐hPRL (60 μg/kg) was administered subcutaneously every 12 h for 28 days. Study 2: Mothers of preterm infants were randomized to receive r‐hPRL (60 μg/kg), placebo or r‐hPRL alternating with placebo every 12 h for 7 days. Measurements Change in milk volume. Results Study 1: Peak prolactin (27·9 ± 17·3 to 194·6 ± 19·5 μg/l; P < 0·003) and milk volume (3·4 ± 1·6 to 66·1 ± 8·3 ml/day; P < 0·001) increased with r‐hPRL administration. Study 2: Peak prolactin increased in mothers treated with r‐hPRL every 12 h (n = 3; 79·3 ± 55·4 to 271·3 ± 36·7 μg/l; P < 0·05) and daily (101·4 ± 61·5 vs 178·9 ± 45·9 μg/l; P < 0·04), but milk volume increased only in the group treated with r‐hPRL every 12 h (53·5 ± 48·5 to 235·0 ± 135·7 ml/day; P < 0·02). Conclusion Twice daily r‐hPRL increases milk volume in mothers with prolactin deficiency and in preterm mothers with lactation insufficiency.     

Coronary artery disease is associated with higher epicardial retinol-binding protein 4 (RBP4) and lower glucose transporter (GLUT) 4 levels in epicardial and subcutaneous adipose tissue

Objective Retinol‐binding protein 4 (RBP4), produced by adipocytes and hepatocytes, contributes to an unfavourable lipid profile and insulin resistance, which can contribute to the development of coronary artery disease (CAD). Recently, several studies have shown that epicardial adipose tissue (EAT) differs from subcutaneous adipose tissue (SAT) and plays a role on the physiopathology of CAD because of its proximity to the coronary arteries. We aimed to study the expression and secretion levels of RBP4 in both fat tissues and explore its possible association with CAD. Research Design and Methods Fifty‐eight patients undergoing heart surgery were included in the study. We analysed RBP4 mRNA expression by real‐time PCR, protein expression by Western blot and immunohistochemistry, and secretion of EAT and SAT explants from CAD and non‐CAD patients by Enzyme Immunoassay. Results Retinol‐binding protein 4 is expressed at similar levels in EAT and SAT, mainly from adipocytes. Protein levels were higher in EAT from CAD than non‐CAD patients (0·63 ± 0·09 arbitrary units (a.u).; n = 10) vs (0·41 ± 0·04 a.u.; n = 13, P = 0·039). In contrast, GLUT4 mRNA levels were lower in EAT from CAD than non‐CAD patients (6·55 ± 0·16 a.u.; n = 13) vs (7·21 ± 0·18 a.u.; n = 14, P = 0·012). We also found differential expression in SAT between samples from CAD and non‐CAD patients [(6·63 ± 0·16 a.u.; n = 14) vs (7·21 ± 0·14 a.u.; n = 14, P = 0·009)]. Besides, EAT releases higher RBP4 levels than SAT after 3, 6, 24 and 48 h of culture. These levels were independent of CAD but significantly higher in diabetic than nondiabetic patients. Conclusion Retinol‐binding protein 4 levels behave differently in EAT and SAT with respect to CAD. However, both adipose tissues have lower GLUT4 levels in patients with CAD. These findings suggest a differential regulation of RBP4 production in EAT and SAT that may be influenced by local factors.     

Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease

Aim The aim of this study was to investigate the relationships between bone mineral density (BMD) vs insulin resistance and metabolic risk factors in obese adolescents with nonalcoholic fatty liver disease (NAFLD). Patients and methods Eighty‐two obese adolescents [45 girls and 37 boys, mean age: 12·3 ± 1·7 years, mean body mass index‐standard deviation score (BMI‐SDS): 1·9 ± 0·2] and 30 control subjects (15 girls and 15 boys, mean age: 12·3 ± 1·45 years, mean BMI‐SDS: 0·5 ± 0·7) were enrolled the study. The obese subjects were divided into two groups based on the presence or absence of liver steatosis with high transaminases (NAFLD group and non‐NAFLD group). Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR) from fasting samples. BMD was determined by dual‐energy X‐ray absorptiometry. Results Fasting insulin levels in the NAFLD group were significantly higher than in the non‐NAFLD obese (32·3 ± 24·0 vs 11·02 ± 2·95 mU/l, P < 0·001) and control groups (8·4 ± 2·4 mU/l, P< 0·001). The NAFLD group had higher values of HOMA‐IR than the non‐NAFLD obese (7·3 ± 0·1 vs 2·3 ± 0·7, P < 0·001) and control groups (1·8 ± 0·5, P < 0·001). BMD‐SDS measurements were lower in the NAFLD group than in the non‐NAFLD (0·56 ± 0·3 vs 1·02 ± 0·9, P < 0·001) and control groups (0·56 ± 0·3 vs 1·37 ± 1·04, P < 0·001). BMD‐SDS was positively correlated with BMI‐SDS (r = 0·530, P = 0·004) and negatively correlated with HOMA‐IR (r = ?0·628, P = 0·017) in the NAFLD obese group. Conclusion This study reports the association between BMD‐SDS and insulin resistance in obese adolescents both with and without NAFLD, although the NAFLD group had a lower BMD‐SDS than the non‐NAFLD group. We suggest that NAFLD has a detrimental effect on bone health in adolescents, and it is correlated with increased insulin resistance.     

Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly

Objectives In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex‐ and age‐matched healthy controls. Patients Eighteen patients with active acromegaly and 18 controls were studied. Measurements Glucose levels, hormonal status, lipoprotein profile and C reactive protein (CRP) were evaluated by standardized methods. Cholesteryl ester transfer protein (CETP) and lipoprotein‐associated phospholipase A₂ (Lp‐PLA₂) were measured by radiometric techniques, endothelin‐1 and vascular cell adhesion molecule (VCAM)‐1 by enzyme‐linked immunosorbent assay, and leucocytes CD18, CD49d and CD54 by flow cytometry. Results After adjusting for body mass index (BMI), acromegalic patients presented a more atherogenic lipoprotein profile, consisting of higher levels of triglycerides and apolipoprotein B and alterations in the ratios which estimate insulin resistance and atherogenic risk. CETP activity was significantly increased in acromegalic patients as compared to controls (168 ± 17 vs. 141 ± 30% per ml h, respectively; P < 0·05). Endothelin‐1 levels evidenced an increase in the patients’ group (0·9 ± 0·2 vs. 0·7 ± 0·2 ng/l, respectively; P < 0·01) and showed positive and significant correlations with GH, IGF‐1 and IGFBP‐3 (r = 0·45, 0·42 and 0·44, respectively; P < 0·01 for all of them; with BMI as a fixed variable). Lymphocytes from acromegalic patients showed increased CD49d content (282 ± 59 vs. 246 ± 48 arbitrary units, respectively; P < 0·05). Conclusions Taken together, the alterations described seem to contribute to constituting a state of higher propensity for the development of atherosclerotic cardiovascular disease, which adds to the presence of specific cardiomyopathy.     

Glucose homeostasis in patients with acromegaly treated with surgery or somatostatin analogues

Objective Long‐acting somatostatin analogues (SSA) are widely used for the treatment of acromegaly; however, they also alter β‐cell function by inhibiting insulin secretion. In this study, we assess the effect of SSA on glucose homeostasis in patients with acromegaly treated with SSAs, compared to patients treated with surgery. Design We studied four groups of patients with acromegaly: at the time of diagnosis (group I, n = 53), after successful transsphenoidal surgery (TSS, group II, n = 30) and under successful SSA treatment (group III, n = 20); 22 patients were studied only before treatment, 19 only post‐treatment, while 31 patients (group IV) were studied before and after the treatment. Measurements Patients underwent an oral glucose tolerance test. Insulin sensitivity and β‐cell insulin secretion were estimated using appropriate mathematical models. Results Control of acromegaly with either TSS or SSA improved insulin sensitivity as evident by significantly lower fasting and postglucose insulin levels and HOMA‐IR. In addition, patients of group III compared to patients of group II demonstrated significantly lower HOMA‐β% (52·5 ± 10·9 vs 189·6 ± 86·7, P < 0·05) and lower first and second phase insulin release (443 ± 83·5 vs 1077 ± 140·8, P < 0·05 and 150 ± 18·2 vs 285 ± 33·3, P < 0·05), respectively. Also, lower fasting glucose levels and a lower prevalence of diabetes were noted in group II compared to group III (5·1 ± 0·2 vs 6·2 ± 0·2 mm , P < 0·05, and 13·3%vs 40%, P < 0·0031, respectively). Conclusions Control of acromegaly with SSA seems to exhibit a negative effect on pancreatic β‐cell function. Whether this has long‐term clinical implications remains to be established. Nevertheless, careful monitoring of glucose metabolism in patients under SSA is beneficial for their optimal management.     

Enhanced proatherogenic inflammation after recombinant human TSH administration in patients monitored for thyroid cancer remnant

Objective To evaluate the effect of recombinant human TSH (rhTSH) on biomarkers of vascular endothelial cell and platelet activation in patients monitored for thyroid carcinoma remnant. Methods Circulating levels of soluble(s) intercellular adhesion molecule (sICAM)‐1 and sE‐selectin, as indices of vascular endothelial cell activation, of sP‐selectin and sCD40 ligand (sCD40L), as indices of platelet activation, and of 8‐iso‐prostaglandin F_2α (8‐iso‐PGF_2α), as an index of lipid peroxidation, were evaluated in 20 patients (16 females, 48·0 ± 13·6 years) at baseline and after intramuscular rhTSH injection (0·9 mg/day on two consecutive days). Results At baseline, serum TSH values were below normal whereas free T3 and free T4 were within the normal range. After rhTSH injection, serum TSH increased significantly but free T3 and free T4 remained unchanged. Concomitantly, plasma sICAM‐1 concentrations increased significantly (from 155·9 ± 39·1 to 183·6 ± 38·1 ng/ml, P < 0·03), as did those of sE‐selectin (from 74·8 ± 15·4 to 91·4 ± 12·2 ng/ml, P < 0·0006), sP‐selectin (from 56·4 ± 13·7 to 72·2 ± 14·9 ng/ml, P < 0·002), sCD40L (from 2·1 ± 0·9 to 2·8 ± 1·1 ng/ml, P < 0·03) and total 8‐iso‐PGF_2α(from 238·5 ± 47·0 to 307·8 ± 41·2 pg/l, P < 0·0001). Changes in circulating levels of sCD40L were directly correlated with changes in levels of plasma total 8‐iso‐PGF_2α (r = 0·523, P < 0·02) and sP‐selectin (r = 0·480, P < 0·03). Conclusions Supraphysiological concentrations of rhTSH might exert proatherogenic effects by promoting activation of vascular endothelial cells and platelets probably through enhanced oxidative stress.     

HDL cholesterol as a diagnostic tool for clinical differentiation of GCK-MODY from HNF1A-MODY and type 1 diabetes in children and young adults

Introduction Confirmation of monogenic diabetes caused by glucokinase mutations (GCK‐MODY) allows pharmacogenetic intervention in the form of insulin discontinuation. This is especially important among paediatric and young adult populations where GCK‐MODY is most prevalent. Methods The study evaluated the utility of lipid parameters in screening for patients with GCK‐MODY. Eighty‐nine children with type 1 diabetes and 68 with GCK‐MODY were screened for triglyceride (TG), total and HDL cholesterol levels. Standardization against a control group of 171 healthy children was applied to eliminate the effect of development. Clinical applicability and cut‐off value were evaluated in all available patients with GCK‐MODY (n = 148), hepatocyte nuclear factor 1‐alpha‐MODY (HNF1A MODY) (n = 37) or type 1 diabetes (n = 221). Results Lower lipid parameter values were observed in GCK‐MODY than in patients with type 1 diabetes. Standard deviation scores were ?0·22 ± 2·24 vs 1·31 ± 2·17 for HDL cholesterol (P < 0·001), ?0·16 ± 2·14 vs 0·60 ± 1·77 for total cholesterol (P = 0·03) and ?0·57 ± 0·97 vs?0·22 ± 0·97 for TG (P = 0·05). Validation analysis confirmed that HDL cholesterol was the best parameter for GCK‐MODY selection [sensitivity 87%, specificity 54%, negative predictive value (NPV) 86%, positive PV 56%]. A threshold HDL concentration of 1·56 mm offered significantly better diagnostic efficiency than total cholesterol (cut‐off value 4·51 mm ; NPV 80%; PPV 38%; P < 0·001). TG did not offer a meaningful cut‐off value. Conclusions HDL cholesterol levels measured in individuals with likely monogenic diabetes may be useful in screening for GCK‐MODY and differentiation from T1DM and HNF1A‐MODY, regardless of treatment or metabolic control.     

Viral kinetics and early prediction of nonresponse to peg-IFN-alpha-2b plus ribavirin in HCV genotypes 1/4 according to HIV serostatus

Summary. To evaluate, among 70 hepatitis C virus (HCV)‐monoinfected and 36 human immunodeficiency virus (HIV)‐coinfected naïve patients with genotypes 1/4 receiving weight‐adjusted pegylated interferon‐α‐2b/ribavirin, viral kinetics and the feasibility to predict treatment failure measuring early HCV‐RNA decreases. HCV‐RNA was assessed at baseline, weeks 4, 12 and 24. Receiver operating characteristic (ROC) curves were calculated to determine the most sensitive cut‐off values of viral decrease at week 4 predicting treatment failure. Baseline predictors of failure were evaluated by univariate and multivariate analyses. Despite similar baseline HCV‐RNA (5·75 vs 5·72 log₁₀IU/ml, P = 0·6), HCV monoinfection led to significantly lower HCV‐RNA values at weeks 4 (3·7 vs 4·3 log₁₀IU/ml, P = 0·01), 12 (2·3 vs 3·5 log₁₀IU/ml, P = 0·01) and 24 (1·4 vs 3·3 log₁₀IU/ml, P = 0·001) and a higher rates of viral clearance at weeks 24 (60%vs 36%, P = 0·02), 48 (46%vs 25%, P = 0.03) and 72 (37%vs 17%). The lack of achieving an HCV‐RNA decrease of at least 1 log₁₀ at week 4 was highly predictive of treatment failure for HCV‐monoinfected patients (Se 100%, Sp 50%, positive predictive value (PPV) 57%, negative predictive value (NPV) 100%, ROC curve area, 0·86 [95% confidence interval (CI) 0·77–0·95], but not for HCV/HIV‐coinfected patients (cut‐off, 0 log₁₀, Se 100%, Sp 27%, PPV 21%, NPV 100%, ROC curve area, 0·71 (95% CI 0·49–0·93). HIV coinfection was independently associated with failure (odds ratio 2.95, 95% CI 1·08–8.04, P = 0·01). Thus the magnitude of HCV‐RNA decreases at week 4 correlated with treatment response. Significant differences in viral kinetics and cut‐off values predicting nonresponse suggest a slower HCV clearance rate in HIV coinfection, which was independently associated with treatment failure.     

High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management

Objective The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. Design Observational retrospective study in a single secondary/tertiary centre. Patients One hundred and seventy‐two patients with adrenal incidentalomas (41 with BI). Measurements Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA‐S), midnight F, 24‐h urine collection for cortisol (UFC), low‐dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F‐post‐LDDST>70 nmol/l and one more abnormality; several diverse cut‐offs were also examined. Results No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F‐post‐LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P < 0·001) and lower DHEA‐S (1·6 ± 1·5 vs 2·5 ± 2·3 μmol/l, P = 0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5%vs 12·2%, P < 0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F‐post‐LDDST (P = 0·008) and a decrease in midnight F (P = 0·015) levels. Conclusions Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management.     

Uterus and ovaries in girls and young women with Turner syndrome evaluated by ultrasound and magnetic resonance imaging

Objective To determine uterine and ovarian size in Turner syndrome (TS) and to compare uterine and ovarian size evaluated by transabdominal ultrasound (US) and magnetic resonance imaging (MRI) in girls with TS and two groups of controls. Design A cross‐sectional study. Patients Forty‐one girls with TS (17·0 ± 3·3 years, range 11·2–24·9 years), 50 healthy age‐matched controls (16·9 ± 3·2 years, range 12·5–25·0 years) and 107 Tanner‐stage‐matched controls (15·0 ± 3·2 years, range 10·1–24·2). Measurements Uterine and ovarian volume by US and MRI. Results Ovaries were detected in 37% in TS by US and in 55% in TS by MRI (P = 0·1). Total ovarian volume was lower in TS compared to both groups of controls (TS vs C‐US: median 1·1 ml (range 0·1–29·3) vs 11·52 ml (1·9–77·9), P = 0·001, TS vs C‐MRI: 1·0 ml (0·1–34·2) vs 13·2 ml (2·4–30·1), P < 0·0005). Mean difference in total ovarian volume measured by MRI and US in patients with TS was 2·3 ± 3·8 ml (P = 0·01). Mean uterine volume by MRI was lower in TS compared to controls (29·5 ± 25·1 vs 54·3 ± 23·3 ml, P < 0·0005). Uterine volume by US was lower in TS at Tanner stage B5 compared to controls (TS vs C: 33·6 ± 18·2 vs 50·2 ± 18·0 ml, P = 0·007). Conclusions A larger ovarian volume was detected by MRI in TS compared to US. This finding is important with the advancements of performing ovarian biopsies for cryopreservation and later reimplantation. Mean uterine volumes by MRI and US in fully matured TS were lower compared to controls despite appropriate hormonal replacement therapy in TS.     

The effect of recombinant IGF-I on anterior pituitary function in healthy volunteers

OBJECTIVE Insulin-like growth factor-I is the mediator of many of the actions of GH and is a potent metabolic regulator. Recombinant IGF-I (rhIGF-I) is of potential value in the treatment of syndromes associated with either GH or insulin resistance. This study was designed to assess the effects of subcutaneous (s.c.) rhIGF-I on anterior pituitary function. DESIGN Double-blind, placebo controlled, randomized cross-over study. The interval between investigations was 2 weeks. SUBJECTS Twelve normal volunteers received on one occasion a single S.C. dose of 40 μg/kg rhIGF-I and on the other, placebo. MEASUREMENTS Circulating levels were measured, over 24 hours, of GH, LH, FSH, PRL, TSH, cortisol, ACTH, glucose, IGF-I, IGF-II, Insulin, C-peptide; IGF binding proteins by Western ligand blotting; total IGF bioactivity using FRTL-5 thyroid cells; and glucose by the glucose oxidase method. RESULTS Recombinant IGF-I Increased AUC for plasma IGF-I, measured by radioimmunoassay (rhIGF-I mean 7065 ± SEM 33 vs 3895 ± 204 μg/l, P < 0·0001) and IGF bioactivity (22·5 ± 3·4 vs 14·2 ± 1·8 U/ml, P < 0·001) but plasma IGF-II fell (9308 ± 403 vs 11052 ± 451 μg/l, P < 0·0001). There was no biochemical or clinical evidence of hypoglycaemia and no difference in mean glucose levels. No difference existed in AUC for GH, LH, FSH, ACTH and cortisol between rhIGF-I and placebo; additionally, pulse number and amplitude for GH and LH were unaffected. TSH fell following rhIGF-I (33·0 ± 3·36 vs 42·5 ± 5·98 mU h/l, P= 0·01). Both mean plasma C-peptlde (0·73 ± 0 06 vs 0·91 ± 0±05 nmol/l, P= 0·03), and insulin (10·81 ± 1·02 vs 15·36 ± 1·18 mU/l, P= 0·03) were lower following rhIGF-I. There was no change In IGFBPs. CONCLUSION A single injection of 40 μg/kg of subcutaneous rhIGF-I does not cause hypoglycaemia. IGF bioactivity was increased without inhibition of GH secretion. The only change observed in anterior pituitary function was a fall in plasma TSH.     

Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

Context Patients with congenital adrenal hyperplasia (CAH) because of 21‐hydroxylase deficiency have multiple vascular risk factors. Young adults with CAH have increased intima media thickness, but there have been no studies of vascular function and structure in children with CAH. Objective To establish whether children with CAH have reduced vascular function and increased carotid intima media thickness (cIMT) when compared to healthy and obese children. Design and Patients Cross‐sectional study of 14 patients (14·8 years ± 3·2, seven boys) with CAH secondary to 21‐hydroxylase deficiency compared to 28 obese and 53 healthy controls. Measurements All subjects had assessment of endothelial function flow‐mediated dilatation, (FMD), smooth muscle function glyceryl tri‐nitrate dilatation (GTN) and cIMT. Anthropometric data, resting blood pressure and biochemical variables were also measured. Results Congenital adrenal hyperplasia subjects had significantly reduced FMD (4·5 ± 3·0%vs 7·5 ± 5·2%; P = 0·04) and GTN (17·2 ± 1·6%vs 28·4 ± 8·4%; P < 0·001) when compared to controls and the impairment was comparable to the obese cohort. There was no significant difference in cIMT between groups. CAH subjects had increased homoeostasis model of assessment‐insulin resistance [HOMA‐IR 2·5 (0·2–2·9) vs 1·8 (0·5–4·2); P = 0·04], waist‐to‐height ratio (0·47 ± 0·05 vs 0·44 ± 0·04; P = 0·02) and higher systolic blood pressure Z score (0·29 ± 0·9 vs?0·24 ± 0·64, P = 0·01) compared to healthy controls but not when compared to obese controls. Conclusions Subjects with CAH have evidence of vascular dysfunction by adolescence.     

Low Copeptin Levels in Patients With Intradialytic Hypotension

Intradialytic hypotension (IDH) is related to high morbidity and mortality. There is evidence that arginine‐vasopressin (AVP) responses could play a role. Copeptin is a reliable biomarker of AVP. In this study, copeptin, aldosterone, epinephrine, and norepinephrine levels in patients with IDH were evaluated throughout a hemodialysis (HD) session and compared with the control group. The study includes 15 patients who were normotensive during HD and 15 patients with IDH with a minimum HD vintage of 1 year. Blood samples were collected before the initiation of an HD session (T₀), in the mid‐session for control group, 30 min after mean arterial pressure drop for IDH patients (T₁), and at the end of the session (T₂). Groups had similar demographic features and health parameters, interdialytic weight gains, and ultrafiltration amounts. The IDH group had a mean arterial pressure decline of 39.9 (±6.4) mm Hg. Copeptin levels of the control group increased an average of 79.9 (±97.5) pmol/L at T₁ and an additional 24.8 (±33.9) pmol/L at T₂. In the IDH group, copeptin level increases at T₁ and T₂ were 3.2 (±5.5) pmol/L and 34 (±44.6) pmol/L, respectively_. Copeptin levels of the IDH group were significantly lower at T₁ (P < 0.001) and at the T₀–T₂ interval than control group (P = 0.05). In the control group, aldosterone levels distinctly decreased, and in the IDH group, aldosterone levels were elevated (P < 0.001). Small changes were detected in epinephrine and norepinephrine levels for both groups but did not reach significance (P = 0.6 and P = 0.3, respectively). Lower copeptin level alterations suggest inadequate AVP responses in patients with IDH.     

In anorexia nervosa, even a small increase in abdominal fat is responsible for the appearance of insulin resistance

Context The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients’ body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment. Objective We hypothesized that changes in body composition, particularly in abdominal fat, are responsible for the variability in insulin sensitivity (IS) in different stages of AN. Design and Measurements We compared 20 anorectic patients in the acute stage, 19 in the weight‐recovery stage and 21 controls. All subjects underwent an oral glucose tolerance test, hyperinsulinaemic euglycaemic clamp and dual energy X‐ray absorptiometry to measure body composition. Results The percentage of trunk fat was higher in weight recovery than in the acute phase (47·7 ± 8·4%vs 34·6 ± 7·6%; P ≤ 0·01) and in the control group (33·4 ± 7·6; P < 0·01 vs weight recovery). Although the recovery group gained weight, their body mass index (BMI) was not statistically different from that of the acute group (14·4 ± 1·1 vs 13·6 ± 1·8 kg/m²). Insulin sensitivity was lower in the weight‐recovery group than the acute group (4·7 ± 1·5 vs 7·8 ± 1·6 mg/kg/min; P < 0·01) and controls (7·7 ± 1·4 mg/kg/min; P < 0·01). A linear negative correlation was found between IS and the percentage of abdominal fat in the weight‐recovery and acute groups (r = ?0·51; P = 0·04 and r = ?0·53; P = 0·04 respectively), while IS did not correlate with BMI. Conclusion Although weight‐recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight‐recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.     

Discrepant influence of vitamin D status on parathyroid hormone and bone mass after two years of calcium supplementation

Objective To investigate the influence of vitamin D status on parathyroid hormone and bone mass after a 2‐year supplementation of calcium alone. Patients and Methods Randomized, double‐blind, placebo‐controlled clinical trial, in healthy postmenopausal women without osteoporosis: three hundred and thirty‐six subjects aged 60–97 years were studied and randomized to receive elemental calcium 500 mg/day (n = 175) or placebo (n = 161) for 2 years. Measurements Changes in parathyroid hormone (PTH) and bone mineral density (BMD) from baseline and vitamin D status. Values are presented as means ± SD. Results After 2 years, subjects with calcium supplementation had significant decrease in plasma PTH level (4·4 ± 1·7 vs 4·7 ± 1·9 pmol/l, P < 0·01), improved lumbar BMD (1·031 ± 0·12 vs 1·004 ± 0·12 g/cm², P < 0·001) and total hip BMD (0·890 ± 0·10 vs 0·883 ± 0·10 g/cm², P < 0·001) without change in femoral neck BMD. In the placebo group, PTH level significantly increased (4·8 ± 1·6 vs 4·5 ± 1·5 pmol/l, P < 0·001), lumbar BMD slightly increased (1·027 ± 0·14 vs 1·018 ± 0·14 g/cm², P < 0·001), total hip and femoral neck BMD decreased (0·876 ± 0·11 vs 0·887 ± 0·11 g/cm², P < 0·001 and 0·783 ± 0·10 vs 0·798 ± 0·10 g/cm², P < 0·001, respectively). When subjects were classified according to baseline 25‐hydroxyvitamin D [25(OH)D] levels into those with 25(OH)D in the lower tertile (lowVitD) and those in the middle and upper tertiles combined (normVitD). The degree of PTH suppression after calcium supplementation was significantly higher in the normVitD compared to the lowVitD groups (?5·6 ± 26·7%vs 1·3 ± 27·2%, P < 0·05). No effect of vitamin D status on the change in lumbar BMD after calcium supplementation was demonstrated. Despite the higher suppression of PTH, there was a slight decrease in femoral neck BMD after calcium supplementation in the normVitD group while femoral neck BMD was more or less maintained in the lowVitD group (?0·6 ± 3·2%vs 0·5 ± 2·9%, P < 0·05). Conclusion Calcium supplementation appears to affect femoral bone mass less in Thai postmenopausal women with adequate vitamin D status, despite higher suppression of PTH.