Is late-night salivary cortisol a better screening test for possible cortisol excess than standard screening tests in obese patients with Type 2 diabetes?

AIM: To compare the performance, in terms of specificity for cortisol excess, of late-night salivary cortisol with 24-hour urine-free cortisol (24hr UFC) and overnight 1mg dexamethasone suppression test (1mg DST) in a group of obese T2DM patients. METHODS: Forty obese patients with T2DM without clinical features of Cushing's syndrome were recruited. Plasma, urinary and salivary cortisol were measured directly by an enzyme-linked immunosorbent assay using monoclonal antibodies. The specificities of the three tests using various cutoffs were calculated and compared, employing the assumption that none of the patients had hypercortisolism. RESULTS: The patients had a mean age and BMI of 56 years (range 31-75) and 37 kg/m² (31-56) respectively. All 40 provided late-night salivary cortisol samples. Thirty-eight patients completed all three tests. Two patients only completed two screening tests. The specificities of late-night salivary cortisol (cutoff 10 nmol/L), 24hr UFC (400 nmol) and 1mg DST (50 nmol/L) were 70% (95% CI 53-83%), 90% (76-97%) and 72% (55-85%) respectively. The specificity of late-night salivary cortisol was significantly less than 24 hr UFC (P=0.039) but not 1mg DST (P>0.99). CONCLUSION: Late-night salivary cortisol has a poor specificity for cortisol excess in obese patients with T2DM with 24 hr UFC showing significantly better specificity in our population.

C-type natriuretic peptide forms in adult hyperthyroidism: correlation with thyroid hormones and markers of bone turnover.

CONTEXT: Plasma C-type natriuretic peptide (CNP) forms correlate with linear growth velocity in juveniles. In hyperthyroid children, plasma CNP products fall in parallel with height velocity and thyroid hormones (TH) as euthyroidism is restored. The effect of TH on CNP forms after completion of endochondral growth is unknown. OBJECTIVE: To determine the effect of restoring euthyroidism on plasma CNP forms and bone turnover markers (BTMs) in hyperthyroid adults. DESIGN AND SETTING: We performed a prospective observational study in 20 adults (19 women) with acquired hyperthyroidism before and during carbimazole treatment. INTERVENTION AND MAIN OUTCOMES: Blood levels of CNP, amino-terminal propeptide of CNP (NTproCNP), TH and BTMs - bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 amino-terminal propeptide and type 1 collagen C-telopeptide (CTx) - were measured before and during the first 6 months of carbimazole treatment and correlations determined. RESULTS: Both CNP and NTproCNP were significantly correlated with TH at baseline. As in children, decreases in CNP forms were closely associated with fall in TH. Significant associations were found between CNP forms and CTx. CONCLUSIONS: CNP production from tissues other than endochondral cartilage is responsive to TH. Strong temporal links with markers of bone resorption suggest that CNP may also participate in bone remodelling in the adult skeleton.

FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study.

CONTEXT: Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation. OBJECTIVE: Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23. DESIGN, SETTING, AND PARTICIPANTS: Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk. RESULTS: Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05). CONCLUSION: Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone.

UNLABELLED: Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone. OBJECTIVE: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105). MAIN OUTCOME MEASURES: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity. RESULTS: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine. CONCLUSIONS: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.

Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia.

Iron-induced renal phosphate wasting, hypophosphataemia and osteomalacia have previously been reported in a small number of Japanese patients receiving parenteral iron sucrose. We report the case history of a European male who, as a result of regular intravenous iron polymaltose, developed prolonged hypophosphataemia complicated by widespread insufficiency fractures. The pathogenesis of this complication remains unknown however our novel finding of a marked elevation in fibroblast growth factor 23 (FGF23), which normalized after ceasing parenteral iron, suggests an important and previously unreported effect of iron on FGF23 homeostasis.

Comparison of insulin resistance, metabolic syndrome and adiponectin in overweight bipolar patients taking sodium valproate and controls.

OBJECTIVE: Metabolic abnormalities in patients with bipolar disorder may be secondary to obesity, aspects of the disorder or its treatment. To investigate this further, the purpose the present study was to compare insulin resistance, components of the metabolic syndrome and adiponectin levels in a group of overweight bipolar patients taking sodium valproate and a group of non-psychiatric control subjects. METHODS: Data were collected from 60 overweight bipolar patients who had experienced clinically significant weight gain thought to be related to sodium valproate treatment and from 60 control subjects without psychiatric illness matched for age, gender, body mass index and ethnicity. RESULTS: The frequency of the metabolic syndrome was high in both groups (50% and 32%, respectively), although not significantly different between groups (p = 0.06). Similar frequencies of insulin resistance (HOMA-IR), abdominal obesity, hypertriglyceridaemia, hypertension and fasting hyperglycaemia were found in both groups. High-density lipoprotein cholesterol levels were lower in patients (p = 0.006), while adiponectin was unexpectedly higher than in control subjects (9.6+/-5.9 microg mL(-1) vs 7.4+/-4.3 microg mL(-1), p = 0.03). The frequencies of insulin resistance (HOMA-IR), the metabolic syndrome and its individual components were not significantly different in patients taking atypical antipsychotic medication and patients not on these medications. CONCLUSIONS: Frequencies of insulin resistance and the metabolic syndrome were similar in bipolar patients taking sodium valproate and matched control subjects, but dyslipidaemia was more frequent. Adiponectin levels were higher in patients. Further research is required to clarify the reasons for these findings.

Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial.

CONTEXT: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected. OBJECTIVE AND DESIGN: In a double-blind trial, we randomized 106 subjects (44 males, 62 females) with Addison's disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue. RESULTS: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (P < 0.05) but not at other sites; DHEA enhanced total body (P = 0.02) and truncal (P = 0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (Short Form-36, General Health Questionnaire-30), were significantly worse in Addison's patients vs. control populations (P < 0.001), and one subscale of SF-36 improved significantly (P = 0.004) after DHEA treatment. There was no significant benefit of DHEA treatment on fatigue or cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects. CONCLUSION: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison's disease.

Carnitine does not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet.

OBJECTIVES: Carnitine deficiency impairs fatty acid beta-oxidation and may partly explain weight gain in valproate-treated patients. The aim of this study was to determine whether l-carnitine supplementation improves weight loss outcomes in bipolar patients taking sodium valproate. METHODS: Sixty bipolar patients with clinically significant weight gain thought to be related to sodium valproate, who had been taking sodium valproate for >or=6 months, were randomized to l-carnitine (15 mg/kg/day) or placebo for 26 weeks, in conjunction with a moderately energy-restricted, low-fat diet. The primary outcome measure was weight change. RESULTS: l-carnitine had no effect on mean weight loss compared with placebo (-1.9 kg versus - 0.9 kg) (F = 0.778, df = 1,58, p = 0.381). The number of people in each group able to lose any weight was identical ( = 0, p = 1.0); more patients in the carnitine group (nine versus five) achieved a clinically significant weight loss (>or=5%) but this was not statistically significant (p = 1.0, Fisher's exact test). CONCLUSIONS: At the dose prescribed in this study carnitine supplementation did not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet.