Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Multiple acyl-Coa dehydrogenase deficiency: an underdiagnosed disorder in adults.

Inherited metabolic diseases, as a first presentation in adults, are an under-recognised condition associated with significant morbidity and mortality. Diagnosis is challenging because of non-specific clinical and biochemical findings, resemblance to common conditions such as neuropsychiatric disorders and the misconception that these disorders predominantly affect paediatric populations. We describe a series of patients with multiple acyl-CoA dehydrogenase deficiency (MADD)/MADD-like disorders to highlight these diagnostic challenges.

Access to a youth-specific service for young adults with type 1 diabetes mellitus is associated with decreased hospital length of stay for diabetic ketoacidosis.

BACKGROUND: Management of type 1 diabetes mellitus in youth with diabetes (YWD) is complex, and glycaemic control often deteriorates during this challenging period. We hypothesise that attendance at a youth-specific diabetes clinic reduces hospital admission rates and length of stay (LOS) for diabetic ketoacidosis (DKA). AIMS: To assess the impact of a youth-specific diabetes service for YWD on DKA admissions in two adjacent local health districts. METHODS: A retrospective cohort analysis of admissions for DKA in YWD aged 15-25 years, presenting to four hospitals in Western Sydney in 2011 was performed. Number of admissions, LOS and DKA severity were assessed. Cost was analysed as a function of LOS. Groups were divided by attendance at a youth-specific diabetes service and no record of attendance. RESULTS: There were 55 DKA admissions from 39 patients (median age 20.0 years); the majority of admissions (82%) was YWD not supported by a youth-specific diabetes service. Median LOS was significantly longer in the unsupported group (3.0 vs 1.5 days, P = 0.028). Median pH at presentation in the unsupported group was significantly lower, 7.11 versus 7.23 (P = 0.05). The admission rate was four times greater for those not supported by youth-specific diabetes services, 5.5% compared with 1.6% (P = 0.001). The estimated cost saved by youth-specific services was over $250,000 pa. CONCLUSIONS: Lack of access to supported care for YWD during transition from paediatric to adult care has an adverse impact on subsequent DKA admission rates and LOS.

Reducing stress and burnout in junior doctors: the impact of debriefing sessions.

BACKGROUND: Internship and residency are difficult times with novice practitioners facing new challenges and stressors. Junior doctors may experience burnout, a syndrome that encompasses three dimensions: emotional exhaustion, depersonalisation and reduced personal accomplishment. While there is some existing literature on the prevalence of burnout in junior doctors, there are few studies on interventional strategies. AIMS: This study aimed to examine the prevalence of burnout in a cohort of junior doctors and whether debriefing sessions reduced levels of burnout. METHODS: A prospective randomised controlled study of a convenience sample of postgraduate year 1 doctors in a single hospital was undertaken during a rotation term in 2011. All participants completed a questionnaire using a validated tool, the Maslach Burnout Inventory, to determine the prevalence of burnout. They were then randomly assigned to a group who were to receive four debriefing sessions over 2 months, or, to the control group, who had no debriefing sessions. Quantitative and qualitative analyses were conducted. RESULTS: Thirty-one postgraduate year 1 doctors participated in the study, with 13 being assigned to the group receiving debriefing sessions and 18 assigned to the control group. At baseline, 21/31 (68%) participants displayed evidence of burnout in at least one domain as measured by the Maslach Burnout Inventory. Burnout was significantly higher in women. There was no significant difference in burnout scores with debriefing. The intervention was well received with 11/18 (61%) suggesting they would recommend the strategy to future junior doctors and 16/18 (89%) found that the sessions were a source of emotional and social support. CONCLUSIONS: Burnout is prevalent among postgraduate year 1 doctors, and they value the emotional and social support from attending debriefing sessions. A larger study is required to determine if debriefing can reduce the incidence of burnout in junior doctors.

Hyperammonaemia: review of the pathophysiology, aetiology and investigation.

Acute hyperammonaemia is a medical emergency as it can progress to cerebral oedema, seizures, coma and death. Hepatic encephalopathy secondary to cirrhotic disease or portosystemic shunting are relatively well-known causes, but non-cirrhotic aetiologies of acute hyperammonaemia are less well-known, especially in the emergency department. However, an elevated ammonia is not required to make the diagnosis of hepatic encephalopathy. Although measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status, as early identification allows early effective management which may prevent irreversible brain damage, there is currently reduced awareness among physicians of the non-cirrhotic aetiologies of acute hyperammonaemia. Furthermore, measurement of ammonia in patients with cirrhosis has been shown to have low sensitivity and specificity, and not to have altered management in the majority of cases; thus, measurement of ammonia is currently not recommended in guidelines for management of hepatic encephalopathy. We sought to describe the pathophysiology of hyperammonaemia and review the non-cirrhotic causes. This was achieved by review of MEDLINE, PubMed and Web of Science databases to include published English literature within the last 20 years. We also present a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases.

Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism that results in impairment of mitochondrial ß-oxidation of fatty acids. It is inherited in an autosomal recessive manner and impairs electron transfer in the electron transport chain. The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations. While late-onset MADD is suggested to have a lower mortality, the severe encephalopathic presentations may well be under-reported as a diagnosis of MADD may not be considered.MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation. The neonatal phenotype differs significantly from late-onset MADD, where diagnosis may be delayed due to heterogeneity in clinical features, atypical presentation and confounding comorbidities, together with lower awareness among physicians.This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation. Subsequent biochemical investigation revealed a diagnosis of MADD. At present, there are no national guidelines in Australia for the management of MADD. This case highlights the investigation and treatment of late-onset MADD.

Low-carbohydrate diets in type 1 diabetes: balancing benefits and risks.

PURPOSE OF REVIEW: Interest in the use of calorie restriction with low-carbohydrate diets for patients with type 1 diabetes appears to be increasing despite physicians' discomfort about its longer term outcomes. A divergence in opinion regarding the balance of benefits and safety may lead to patient disengagement from conventional medical supervision. This review describes the current evidence regarding the benefits and risks of these diets and suggests a way forward to addressing this potential misalignment between the aims of patients and their physicians. RECENT FINDINGS: Benefits on glycaemia are observed in many studies, with improved HbA1c, time within target range and reduced glycaemic variability. A characteristic lipid profile with high LDL cholesterol is observed in many patients, but association with future cardiovascular events is undefined. A negative impact on growth has been identified in the paediatric population, and impact on mental health and disordered eating is of theoretical concern, without measurement in clinical studies. SUMMARY: Patients will continue to trial and, with immediate glycaemic benefits, potentially remain on lower carbohydrate diets irrespective of concern by treating physicians about potential longer term risks. A supportive multidisciplinary approach with greater nutritional supervision and more research is required, to allow these patients to achieve their desired glycaemic outcomes without compromising longer term safety.

Best practice for treating dyslipidaemia in patients with diabetes based on current international guidelines.

PURPOSE OF REVIEW: Dyslipidaemia is a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) in type 2 diabetes. We provide an in-context overview of recent trials of lipid-lowering pharmacotherapies and of recommendations from international guidelines for managing dyslipidaemia in patients with diabetes. RECENT FINDINGS: Clinical trials have demonstrated that patients with diabetes derive greater benefits from ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors owing to the higher absolute ASCVD risk compared with patients without diabetes. Pure eicosapentaenoic acid ethyl ester therapy should be considered in high risk patients with diabetes and hypertriglyceridaemia who have well controlled low-density lipoprotein cholesterol on statin therapy. International guidelines from USA, Canada and Europe have been updated to support a more intensive approach to treating dyslipidaemia in diabetes. SUMMARY: Dyslipidaemia should be identified and treated intensively as part of overall diabetes management to reduce ASCVD risk. Although lifestyle modifications and statin therapy remain the cornerstone of management, add-on therapies should be strongly considered depending on the absolute risk of ASCVD and the degree of dyslipidaemia.

Medium Chain Acyl CoA Dehydrogenase Deficiency and Eating Disorders: An Underreported Coincidence

Abstract Medium chain acyl-coA dehydrogenase deficiency (MCADD), the most common fatty acid oxidation disorder, has been regarded as a relatively benign condition with low risk of mortality in patients with a known diagnosis, if adequate caloric intake is met. However, inadequate energy provision, as occurs in eating disorders, significantly amplifies the risk of metabolic decompensation. This case series describes four patients with MCADD and a concomitant eating disorder and aims to raise awareness of the potentially under-recognised coexistence of these conditions. All patients were female with signs of disordered eating in adolescence and young adulthood though latency in diagnosis was apparent. Three of the patients had low body mass index (BMI) and the other was overweight. Metabolic decompensation and hospitalisation occurred in three of four patients secondary to extreme risk-taking behaviour with caloric restriction. The coexistence of MCADD and eating disorders is of significant concern, placing the patient at substantial risk of decompensation in an otherwise relatively stable metabolic condition. Awareness of disordered eating in this population is paramount, as early recognition of signs and symptoms of eating disorders in the MCADD population may facilitate prompt intervention and avoidance of morbidity and potential mortality.

Iodine deficiency in women of childbearing age: not bread alone?

BACKGROUND AND OBJECTIVES: Iodine deficiency remains a public health concern, particularly in pregnant women and those planning pregnancy because of the risk of impaired fetal neurological development. Following implementation of strategies to improve iodine intake in Australia, there has been minimal investigation into current iodine status. We aimed to characterise iodine status in a population of women of childbearing-age in Australia. METHODS AND STUDY DESIGN: A cross-sectional study was performed in 97 women of childbearing-age attending outpatient clinics at a tertiary hospital in Sydney. Pregnant and postmenopausal women were excluded. Iodine intake was surveyed via questionnaire. Spot urinary iodine (UI) was concurrently measured. The relationships between UI, dietary intake and use of iodine-containing multivitamins/medications were examined. RESULTS: Median UI was 117 ug/L. Forty women (41%) were iodine deficient (UI <100 ug/L). The most commonly consumed source of dietary iodine was bread (29/97, 30% daily). Forty-three women took iodine-containing multivitamins but 18/43 (41.2%) remained deficient. There were no significant associations between UI and diet. There was a smaller proportion of deficient people than in our previous study (125/180 non-pregnant subjects, 69%, vs 41% in this study, p<0.001). CONCLUSION: The overall population median is now sufficient, however, a significant proportion of this multicultural group are iodine deficient. There are similar proportions of deficiency in those using iodine supplements versus not. Contributors may include ethnicity-related dietary practices, limited awareness or poor adherence to iodine supplements. Despite public health strategies, a significant proportion of women of child-bearing age remained iodine deficient. Further research involving a larger population and contributors to iodine deficiency is warranted.

Differing clinical phenotype for higher alanine-aminotransferase (ALT) compared with high-risk NAFLD fibrosis score in type 2 diabetes mellitus.

AIMS: The impact of non-alcoholic fatty liver disease (NAFLD) presence and severity on the diabetes phenotype remains unclear. Our study aimed to explore and contrast the phenotypes associated with higher ALT and high-risk NAFLD fibrosis score (NFS) in type 2 diabetes. METHODS: 324 patients with type 2 diabetes mellitus who were seen at a diabetes centre for a complications assessment with data for NFS were available for study. Data regarding co-morbidities and pathology were obtained at assessment and by file audit. Logistic regression was used to determine if there were significant relationships between pre-determined diabetes complications and co-morbidities and ALT or high-risk NFS (>0.675). RESULTS: Significant univariate associations with lower ALT included those of osteoporosis/osteopenia and inability to sense the monofilament. High-risk NFS was associated with arrhythmia, VPT ≥ 25 V and albuminuria. The associations of high-risk NFS with albuminuria and VPT ≥ 25 V remained after adjustment. CONCLUSIONS: In type 2 diabetes, the clinical phenotype of those with higher ALT is dissimilar, sometimes inverse, to those with high-risk NFS. More emphasis should be placed on liver fibrosis risk rather than on liver enzymes alone.

Fluconazole in the treatment of Cushing's disease.

UNLABELLED: Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease. LEARNING POINTS: Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-ß-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.

A case of rhino-orbital mucormycosis in diabetes with haematogenous cerebral spread.

We document the first case of haematogenous cerebral spread in Rhizopus arrhizus rhino-orbital mucormycosis, and of posaconazole related adrenal insufficiency. A patient presenting with diabetic ketoacidosis and sinusitis was treated with right medial maxillectomy, ethmoidectomy and IV liposomal amphotericin. Orbital exenteration was performed after intraorbital spread of infection. IV caspofungin and posaconazole was added but complicated by adrenal insufficiency. MRI revealed a new left lentiform nucleus and thalamus rim-enhancing lesion indicating haematogenous cerebral spread.

Assessment of cardiovascular risk in diabetes: Risk scores and provocative testing.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus, who have a risk of cardiovascular mortality two to four times that of people without diabetes. An individualised approach to cardiovascular risk estimation and management is needed. Over the past decades, many risk scores have been developed to predict CVD. However, few have been externally validated in a diabetic population and limited studies have examined the impact of applying a prediction model in clinical practice. Currently, guidelines are focused on testing for CVD in symptomatic patients. Atypical symptoms or silent ischemia are more common in the diabetic population, and with additional markers of vascular disease such as erectile dysfunction and autonomic neuropathy, these guidelines can be difficult to interpret. We propose an algorithm incorporating cardiovascular risk scores in combination with typical and atypical signs and symptoms to alert clinicians to consider further investigation with provocative testing. The modalities for investigation of CVD are discussed.

An association of large-fibre peripheral nerve dysfunction with non-invasive measures of liver fibrosis secondary to non-alcoholic fatty liver disease in diabetes.

AIM: To examine for an association of elevated lower-limb vibration perception threshold (VPT) with NAFLD fibrosis. METHODS: Two cohorts from a tertiary diabetes centre were studied - Cohort 1, n=456 with type 1 or 2 diabetes, and Cohort 2, n=106 with type 2 diabetes mellitus. All underwent a detailed assessment, including VPT measurement. Cohort 2 also had liver ultrasound and transient elastography (TE). NAFLD Fibrosis Score (NFS) was calculated for all with available data. Follow-up VPT measurements on participants in Cohort 1 to 2014 were also collected if available. RESULTS: Adjusted risk of higher VPT category (≥25V but <50V, or ≥50V, c.f. < 25V) was greater for high-risk NFS in both cohorts (Cohort 1, OR 2.22 [95% CI 1.24-3.98, p=0.007] and Cohort 2, OR 4.51 [95% CI 1.08-18.87], p=0.039) and higher liver stiffness measurement (LSM) by TE in Cohort 2 (OR for each unit natural log increase in LSM of 2.42 (95% CI 1.13-5.19), p=0.023). In Cohort 1, in those with VPT<50V and complete data, those with higher NFS had greater odds of increasing VPT category after 2.2 (IQR 1.5-2.9) years. CONCLUSIONS: Higher VPT associates with markers of liver fibrosis due to NAFLD in diabetes mellitus.

Opinions of community pharmacists on the value of a cardiovascular polypill as a means of improving medication compliance.

OBJECTIVE: Cardiovascular disease is a major public health problem despite established treatment guidelines and significant healthcare expenditure worldwide. Poor medication compliance accounts in part for some of the observed evidence/practice gaps. Trials of fixed-dose combination pills are currently underway, but the attitudes of relevant health professionals to the routine use of a cardiovascular polypill are generally unknown. Pharmacists are a group of providers who play an important role in patient compliance with long-term medications. The objective was to identify the main perceived barriers to compliance and to investigate pharmacists' opinions regarding the routine use of a cardiovascular polypill. METHODS: The setting was community pharmacies in the metropolitan and greater areas of New South Wales, Australia. Structured questionnaires were administered to a random sample of community pharmacists and peer-to-peer, semi-structured interviews were conducted with a sub-sample. Quantitative data were analysed using SPSS V16.0 and interviews were analysed thematically. KEY FINDINGS: Questionnaires were completed by 72 of the 250 pharmacists invited to participate. The major barrier to cardiovascular medication compliance identified by respondents was polypharmacy. Other barriers included patient disinterest, time constraints and costs. Most pharmacists agreed that a cardiovascular polypill could be one potential solution to poor compliance by simplifying the treatment regimen (73.6% agreed) and reducing patient costs (79.2% agreed). Inability to tailor treatment and to ascribe side effects was among some of the identified concerns. CONCLUSION: The use of a cardiovascular polypill as a means of increasing patient compliance with long-term cardiovascular preventive therapies is seen as potentially valuable by community pharmacists.

Charcot arthropathy presenting with primary bone resorption.

BACKGROUND: The clinical presentation of acute Charcot arthropathy in the diabetic population usually follows the Eichenholtz classification. We present three usual cases of Charcot arthropathy presenting with rapid primary bone resorption in the absence of subluxation, dislocation and/or fracture. METHODS: A review of the literature was performed. To our knowledge Charcot arthropathy has not been previously described as primary bone resorption. CASE REPORTS: Three cases encountered at our specialist multidisciplinary High Risk Foot Clinic (HRFC) presented with primary bony resorption without features of subluxation, dislocation and/or fracture. DISCUSSION: Aggressive primary bone resorption was initially thought due to infection; a diagnostic dilemma that delayed optimal treatment. Late bone resorption in typical Charcot is linked to unregulated proinflammatory cytokines (IL-1ß, IL-6 and TNFα) that lead to increased osteoclastic activity. The pathophysiology of osteolysis in aggressive primary bony resorption may relate to a disturbance in the balance between RANK-L and OPG. CONCLUSION: Primary resorption of bone without subluxation, dislocation and/or fracture can represent an active Charcot process. Prudent use of serial radiography and early MRI to look for the widespread bone and soft tissue oedema is recommended.