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Publication History View all

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    ABSTRACT: Context:Acromegaly is associated with reduced life expectancy, which has been reported to be normalized if treatment is successful in controlling GH/IGF-I levels.Objective:Most previous studies have invariably used the last available GH/IGF-I, which may be biased as it only assesses exposure at a single point in time. We compared the last available GH/IGF-I analysis to a 'time dependent' and cumulative method, during follow up to assess risk of mortality in the West Midlands Acromegaly study (n=501).Results:Using the last available GH there was a statistically significant increase in mortality comparing groups as low as GH≤1μg/litre vs. >1μg/litre (RR 1.8,p=0.03). This was not the case when using the 'time-dependent method', where only comparisons of GH values of GH ≤5μg/litre vs. >5μg/litre were suggestive of being associated with an increased risk of mortality (RR=1.5,p=0.08). When the time dependent GH method of analysis was used the RR of mortality at each level was lower and the associated p value less significant.Irrespective of using last available or time dependent method, when IGF-I was divided into levels according to quartile or arbitrary cutoffs, there was no significant increase in mortality with higher levels.Conclusions:This study emphasizes the potential bias of using the latest available GH/IGF-I levels to predict mortality. Our study again highlights the limitations of IGF-I in predicting mortality.
    The Journal of clinical endocrinology and metabolism 11/2013;
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis through to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation world-wide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, growth hormone deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. Whilst in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition amongst common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarize the clinical data endorsing these observations.
    European Journal of Endocrinology 05/2013;
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    ABSTRACT: CONTEXT: Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH- encoded by H6PD) causes Apparent Cortisone Reductase Deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with HPA axis activation and adrenal hyperandrogenism. OBJECTIVE: To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD, and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases. DESIGN: Clinical, biochemical, and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/ CRD patients were compared to identify distinguishing characteristics. RESULTS: Case 1 was compound heterozygous for R109AfsX3, and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/ mass spectrometry (GC/MS) suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualized management. CONCLUSIONS: Steroid profile analysis of a 24h-urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche, and adult females with PCOS.
    European Journal of Endocrinology 11/2012;
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    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2012; 27(11):2238-41.
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    ABSTRACT: ABSTRACTCONTEXT: Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, the conversion of cholesterol to pregnenolone. CYP11A1 deficiency is commonly associated with adrenal insufficiency, and in 46,XY individuals, with variable degrees of disorder of sex development (DSD). PATIENT AND METHODS: The patient was born with hyperpigmentation, micropenis, penoscrotal hypospadias and mild cryptorchidism. Biochemical and hormonal findings were normal except for low testosterone and low-borderline cortisol. However, no short synacthen test was undertaken. Development was unremarkable apart from an episode labeled as sepsis with documented hyperkalemia and elevated C-reactive protein at age 15 days. Diagnosis of 46,XY DSD was made at age 2.5 months. Progression of hyperpigmentation prompted further investigations and diagnosis of adrenal insufficiency was established at 2 yrs with raised ACTH, normal renin activity, and failure of cortisol to respond to short synacthen. Genetic analyses were performed. The novel CYP11A1 mutations were characterized in vitro and/or in silico. RESULTS: The patient was compound heterozygous for two novel CYP11A1 mutations, p.R360W and p.R405X. p.R360W retained 30-40% of wild-type activity. In silico analyses confirmed these findings and indicated that p.R405X is severe. CONCLUSIONS: This study demonstrates the pathogenicity of two novel CYP11A1 mutations found in a patient with delayed diagnosis of CYP11A1 deficiency. Patients with partial deficiencies of steroidogenic enzymes are at risk to be misdiagnosed if adrenal function is not assessed. The adrenocortical function should be routinely assessed in all patients with DSD including severe hypospadias of unknown origin to prevent life-threatening adrenal crises.
    European Journal of Endocrinology 09/2012;
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    ABSTRACT: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0-93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44-5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.
    American Journal of Respiratory and Critical Care Medicine 06/2012; 186(5):434-41.
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    ABSTRACT: Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11β-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11β-HSD1 is implicated in the development of obesity, and selective 11β-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11β-HSD1. We assessed biomarkers for allele combinations of 11β-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11β-HSD1 KO and double KO (DKO) adrenals were ~30% larger than WT - indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2.2-fold higher in H6PDH KO animals and ~1.5-fold higher in 11β-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11β-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11β-HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11β-HSD1/H6PDH deficiency.
    Journal of Endocrinology 06/2012; 214(3):367-72.
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    ABSTRACT: Evidence-based clinical guidelines in Endocrinology attempt to improve and standardise patient care. There has been an expansion in guideline production although some of the heterogeneous methods used to assess the quality of the underlying evidence base might limit interpretation and implementation. Current and archived guidelines from major endocrine organizations were accessed. The organisations used six different methods to rate underlying evidence including, Grading of Recommendations Assessment, Development and Evaluation (GRADE). To allow direct comparison between guidelines produced by different organizations, the levels of evidence used to generate them were graded according to standardized system: "high" based on randomised-controlled trials and meta-analyses, "moderate" based on non-randomised studies and "low" based on expert opinion. There was an increase in guideline production over time (1995-2000=9, 2001-2005=12, 2006-2011=36). Three guidelines were updated with an average delay of 4.3 years and an increase in recommendations per guideline (21.1%). Encouragingly, whilst updates had similar levels of "high" quality evidence, there was increased reliance "moderate" category evidence and less on "low" quality evidence ("high" 6.3% vs. 6.5%, "moderate" 46.1% vs. 59.1% and "low" 47.7% vs. 34.4%). A high proportion of "low" category evidence was seen throughout all organisations. Rarer conditions and recommendations concerning treatment efficacy were particularly reliant on "low" category evidence. The level of evidence underpinning current guidelines highlights areas in need of well-designed, collaborative clinical research. Furthermore, criteria to define when guideline updates are necessary are currently lacking. A standardised method of assessment, such as GRADE, would promote understanding and compliance by guideline users with the ultimate aim of enhancing patient care. © 2012 Blackwell Publishing Ltd.
    Clinical Endocrinology 05/2012;
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    ABSTRACT: Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation. Gene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression. Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression. The mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.
    Arthritis & Rheumatology 01/2012; 64(7):2404-13.
  • Best Practice & Research: Clinical Endocrinology & Metabolism 10/2011; 25(5):703-4.
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