The Vitamin D paradox: bone density testing in females aged 45 to 74 did not increase over a ten-year period despite a marked increase in testing for vitamin D.

AIM: To determine whether increased vitamin D testing resulted in improved osteoporosis detection in Australian females aged 45-74 yr. METHODS: Longitudinal analysis of bone densitometry, 25-hydroxyvitamin D (25(OH)D) and full blood count (FBC) testing between 2001 and 2011. The number and rate of tests per 100,000 individuals and benefit in dollars for bone densitometry, 25(OH)D and FBC from 2001-2011 for individuals aged 45-74 yr were obtained from Medicare Australia. RESULTS: There was a disproportionate increase in 25(OH)D testing compared to bone density testing from 2001 to 2011, whereby 25(OH)D testing increased from 26,666 to 1.65 million p.a. and bone density testing increased from 41,453 to 66,100 p.a. Bone densitometry increased approximately 1.2 fold, whereas 25(OH)D testing increased by 55.2, 41.2 and 34.3 fold in females aged 45-54, 55-64 and 65-74 yr, respectively. This represents an increase in annual benefits from approximately $2.5-$4.1 million for bone density testing and $0.7-$40.5 million for 25(OH)D testing over the period. CONCLUSIONS: This study demonstrates that improved detection of vitamin D deficiency is not being translated into better detection in at-risk women of the consequences of vitamin D deficiency on target organs such as bone. This failure to translate rising awareness and better detection of vitamin D deficiency into physiological outcomes is a massive missed opportunity for improved bone health and reduced fracture risk.We propose that clinical practice guidelines be introduced not only for the purpose of diagnosis and testing for vitamin D, but to include recommendations for bone health testing in at-risk individuals.

Relationship of Type 2 diabetes to the prevalence, incidence and progression of age-related hearing loss.

AIMS: Type 2 diabetes and associated microvascular abnormalities are postulated to affect hearing. Our study reports on the relationship between Type 2 diabetes and the prevalence, 5-year incidence and progression of hearing impairment in a representative, older, Australian population. METHODS: The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss conducted in a defined suburban area, west of Sydney. Hearing loss was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz > 25 decibels hearing level (dB HL) in the better ear (bilateral hearing loss). Type 2 diabetes was defined from reported physician-diagnosed diabetes or fasting blood glucose > or = 7.0 mmol/l. RESULTS: Age-related hearing loss was present in 50.0% of diabetic participants (n = 210) compared with 38.2% of non-diabetic participants (n = 1648), odds ratio (OR) 1.55 [95% confidence interval (CI) 1.11-2.17], after adjusting for multiple risk factors. A relationship of diabetes duration with hearing loss was also demonstrated. After 5 years, incident hearing loss occurred in 18.7% of participants with, and 18.0% of those without diabetes, adjusted OR 1.01 (CI 0.54-1.91). Progression of existing hearing loss (> 5 dB HL), however, was significantly greater in participants with newly diagnosed diabetes (69.6%) than in those without diabetes (47.8%) over this period, adjusted OR 2.71 (CI 1.07-6.86). CONCLUSIONS: Type 2 diabetes was associated with prevalent, but not incident hearing loss in this older population. Accelerated hearing loss progression over 5 years was more than doubled in persons newly diagnosed with diabetes. These data explore further reported links between Type 2 diabetes and age-related hearing loss.

Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression.

Severe cytopenias in patients with autoimmune conditions treated with azathioprine are well-recognized. Thiopurine methyltransferase (TPMT) enzymatic activity is subject to individual and ethnic variability. Patients with low TPMT activity (poor metabolizers) are at high risk of developing severe and potentially fatal haematopoietic toxicity. Studies have shown that essentially all TPMT-deficient patients will develop haematopoietic toxicity on administration of conventional thiopurine dosages (6-mercaptopurine, azathioprine). Therefore, screening for TPMT polymorphisms in patients before prescribing thiopurine drugs has been proposed. However, despite normal in vitro enzymatic activity, cytopenia may still occur in vivo. This is the case report of an Asian patient with Crohn disease harbouring a rare TPMT mutation on DNA sequencing, who developed neutropenic sepsis and anaemia after a flare of Crohn disease. The report illustrates the importance of monitoring for cytopenia in the setting of active inflammatory disease despite prior normal phenotyping, the role of predictive pharmacogenetics and the limitations of TPMT phenotype assays that may result in misclassification of at-risk patients.

Patterns of care as a risk factor for the development of vision-threatening diabetic retinopathy: a population-based matched case-control study using insurance claims (Medicare) data.

OBJECTIVES: To evaluate systematically the effectiveness of the primary healthcare system in Australia in preventing the development of advanced diabetes complications. METHODS: Diabetes patients (n = 4632) who had received their first laser photocoagulation treatment in 2000 were compared with a random sample of diabetes patients who had never received this treatment (n = 4632). Patterns of health care utilization were compared over a 7-year period (1993-1999) using the Australian Medicare database. RESULTS: There were significant differences in levels of healthcare utilization: cases were less likely to attend a general practitioner, from odds ratio (OR) = 0.21 (P < 0.0001) in 1993 to 0.53 (P < 0.0001) in 1999; less likely to be tested for HbA(1c), from OR = 0.24 in 1997 (P < 0.0001) to 0.38 in 1999 (P < 0.0001); for HDL-cholesterol, from OR = 0.017 (P < 0.0001) in 1999 to 0.04 (P < 0.0001) in 1993; and to attend specialists and consultant physicians, from OR = 0.25 (P < 0.0001) in 1994 to 0.44 (P < 0.0001) in 1999. The multivariate analysis emphasized the importance of timely diagnosis, HDL-cholesterol testing and optometry attendances in the prevention of advanced diabetes complications. CONCLUSIONS: The study supports the contention that healthcare utilization may be as important a determinant of health outcomes as clinical risk factors such as blood glucose control. This highlights the importance of early diagnosis and the need to address systemic barriers so as to increase primary care utilization for people at risk of advanced diabetes complications.

Glycometabolic status and acute myocardial infarction: has the time come for glucose-insulin-(potassium) therapy?

Glucose-insulin-potassium infusion as a metabolic therapy was first advocated for the management of acute myocardial infarction (AMI) in 1960s. Over the subsequent decades, enthusiasm for its use has been patchy, especially with the availability of other effective treatments such as reperfusion therapy for AMI. Several clinical studies in the mid-1990s revived the interest in the glycometabolic aspects of patients with AMI. The somewhat conflicting results of these recent studies have generated debate over the significance of the glycometabolic state following acute coronary occlusion and the role of insulin-based infusion therapy. Although most of the available evidence is in favour of an insulin-based therapy, there are still many aspects of this therapy that require clarification. More evidence will be required from further clinical trials before it is adopted in routine clinical practice.

Re-emergence of iodine deficiency in Australia.

Iodine is an essential nutrient for human growth and development. The thyroid gland is dependent upon iodine for production of thyroid hormone. It is a common perception that iodine deficiency is not a major public health concern in mainland Australia, with sporadic studies carried out about a decade ago showing average urinary iodine excretion levels of around 200 microg/day. Recent evidence, however, has shown that the consumption of iodine is declining in Australia. A similar situation has occurred in the USA. The present study was designed to evaluate the urinary iodine excretion (UIE), as the indicator of iodine nutrition, in samples obtained from various demographic groups in the Sydney metropolitian area, namely: schoolchildren, healthy adult volunteers. pregnant women and patients with diabetes. Urinary iodine in spot urine sample was measured in a Technicon II autoanalyser using an in-house, semiautomated method. The results in this communication show that all four study groups had the median UIE below 100 microg/L. the criteria set by the World Health Organization for iodine repletion, and confirm what has been described previously, that iodine deficiency has reemerged in Sydney, Australia. One of the major causes of the reduced iodine intake is the reduction of iodine in milk since the dairy industry replaced iodine-rich cleaning solutions with other sanitisers. Secondly, less than 10% of the population are currently using iodised salt. A national survey into the iodine nutrition status in Australia is urgently required as part of the establishment of a systematic surveillance and legislation is required to iodise all edible salt.

Study of biochemical prevalence indicators for the assessment of iodine deficiency disorders in adults at field conditions in Gujarat (India).

The main objective of this study was to assess the severity of iodine deficiency disorders (IDD) in the adult populations of the Baroda and Dang districts from Gujarat, western India using biochemical prevalence indicators of IDD. The other aim of this study was to establish a biochemical baseline for adequate iodine intake as a result of program evolution in the face of multiple confounding factors, like malnutrition and goitrogens responsible for goiter. A total of 959 adults (16-85 years) were studied from two districts (Baroda and Dang) and data was collected on dietary habits, anthropometric and biochemical parameters such as height, weight, urinary iodine (UI) and blood thyroid stimulating hormone (TSH). Drinking water and cooking salt were analyzed for iodine content. All subjects, irrespective of sex and district, showed median UI = 73 microg/L and mean blood TSH +/- SD = 1.59+/-2.4 mU/L. Seven per cent of the studied population had blood TSH values > 5 mU/L. Females in Baroda and males from Dang district were more affected by iodine deficiency as shown by a lower median UI. Mean TSH was significantly higher in women from both districts as compared to men (P = 0.001). The blood spots TSH values > 5 mU/L were seen in 20% of women from Dang. The normative accepted WHO values for UI and TSH for the severity of IDD as a significant health problem are not available for target population of adults. Urinary iodine normative limits and cut-offs are established for school-aged children. Blood spot TSH upper limit and cut-off values are available for neonate populations. The IDD has not been eliminated so far, as more than 20% of both male and female subjects had UI < 50 microg/L. Males were more malnourished than females in both districts (P < 0.05). Pearl millet from Baroda contained flavonoids like apigenin, vitexin and glycosyl-vitexin. Dang district water lacked in iodine content. Iodine deficiency disorder is a public health problem in Gujarat, with the Baroda district a new pocket of IDD. High amounts of dietary flavonoids in Baroda and Dang, malnutrition and an additional lack of iodine in Dang water account for IDD.

Insulin secretion and insulin sensitivity are normal in non-diabetic subjects from maternal inheritance diabetes and deafness families.

BACKGROUND: The pathophysiological mechanism of diabetes mellitus in the presence of the 3243 A-G tRNALEU(UR) mitochondrial DNA mutation is thought to result from deficient insulin secretion. However, few subjects with normal glucose tolerance have been studied to determine the sequence of events resulting in the development of diabetes mellitus. AIM: To determine whether abnormalities of insulin sensitivity, insulin secretion or glucose effectiveness are present in non-diabetic subjects with the 3243 A-G tRNALEU(UUR) mitochondrial DNA mutation. METHODS: Twelve non-diabetic subjects with the mutation were compared with 12 controls, matched for age and anthropometric parameters, using both oral and intravenous glucose tolerance tests, the latter with Minimal Model analysis. RESULTS: Following an oral glucose load we found significantly higher blood glucose levels at 90 min and 120 min and significantly higher insulin levels at 120 min and 180 min in non-diabetic subjects with the mutation but no difference in the insulinogenic indices at 30 min and 180 min. From the intravenous glucose tolerance test there was no difference in overall glucose tolerance, insulin sensitivity, first- or second-phase insulin secretion, proinsulin secretion or glucose effectiveness. Insulin-independent glucose disposal was increased in subjects with lower insulin sensitivity and declined with increasing age in subjects with the mutation but not in controls. CONCLUSIONS: While there appear to be subtle defects of glucose handling in non-diabetic subjects with the 3243 mutation, these could not be explained by differences in insulin sensitivity or secretion.

Impact of protein energy malnutrition on thyroid size in an iodine deficient population of Gujarat (India): Is it an aetiological factor for goiter?

OBJECTIVE: To assess the severity of protein energy malnutrition (PEM) in iodine deficient subjects and to assess the impact of PEM on thyroid size. METHODS: 1002 subjects (530 school-aged children and 472 adults) were assessed for PEM by direct anthropometric measurements of height, weight, triceps skinfold (TSF) thickness, mid upper arm circumference (MUAC) and thigh circumference (TC), and derived indices of body surface area (BSA), body mass index (BMI), and Z-scores for weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ). Severity of PEM was based on the World Health Organization (WHO) criteria and the threshold on the Waterlow classification. Thyroid size was measured by ultrasonography to determine the thyroid volume (TV). Linear regression analysis was performed between TV and anthropometric parameters. RESULTS: Children had severe PEM as evident from the WHO percentage prevalence of stunting (HAZ<-2SD)=64% (where <-2SD is the Z-score deficit), wasting (WHZ<-2SD)=43%, underweight (WAZ<-2SD)=82% and BMI<16 kg/m=90%. Waterlow classification showed that children were either stunted or wasted, or stunted and wasted, or stunted and obese. Nearly 100% (529/530) of the children had goiter as evidenced from enlarged TV-for-BSA when compared with the WHO reference. There was a weak but statistically significant (P<0.05) positive correlation between TV and BSA, weight, height, MUAC, TC and HAZ but a negative correlation between TV and WHZ, BMI and TSF (r=-0.1-0.2). Adults had PEM as evident from BMI<18.5 kg/m in 54% subjects. Median MUAC=22.7 cm reveals prolonged severe PEM. Eighty-two percent had enlarged TV (>20 ml). There was a significant (P=0.01) negative correlation between TV and MUAC. CONCLUSIONS: (i) The severity of acute (wasting) and chronic (stunting) PEM is very high in Gujarati children. They are stunted or wasted, or stunted and wasted, or stunted and obese. Gujarati adults are thin with low protein and fat reserves. (ii) Anthropometric parameters showed a significant (P<0.001) correlation (r=0.1-0.2) with thyroid size. (iii) Higher prevalence of goiter may be due to macro-nutrient malnutrition (PEM) in the face of micro-nutrient malnutrition (iodine deficiency disorders, IDD).

Biochemical assessment of iodine deficiency disorders in Baroda and Dang districts of Gujarat State.

OBJECTIVE: (i) To assess the severity of Iodine Deficiency Disorders (DD) in Baroda and Dang Districts of Gujarat, using biochemical prevalence indicators of IDD; and (ii) To establish a biochemical baseline, in a sub-sample of the large population of Gujarat, that could be used to monitor the effectiveness of iodine replacement program. METHODS: 1,363 children (<1-15 years) were studied and data was collected on dietary habits, anthropometric and biochemical parameters such as height, weight and urinary iodine (UI) and blood TSH respectively. BSA and BMI were calculated. Drinking water and salt were analyzed for iodine content. RESULTS: Median true urinary iodine was 65 microg/I (interquartile-range 38-108). Mean TSH was 2.08 mU/1 (SD +/- 2.06) and 6% of the studied population had whole blood TSH values > 5 mU/1. Females from both districts were affected more by iodine deficiency as evidenced by lower true urinary iodine and higher mean TSH levels. The interfering substances were significantly higher in Baroda boys and Dang girls as compared to their counterparts (< 0.001). Boys were more malnourished than girls as evidenced by lower BMI. Dang district was more severely affected by IDD as compared to Baroda. Drinking water in Dang district was lacking in iodine content. Iodine in salt varied at around 7 to 2000 PPM. CONCLUSIONS: IDD is a public health problem in Gujarat. Baroda district is a new pocket of IDD. Dang district is the worse affected. The expression of IDD in these two districts of Gujarat revealed interplay of multiple factors.

Thyroid ultrasonography consistently identifies goiter in adults over the age of 30 years despite a diminished response with aging of the thyroid gland to the effects of goitrogenesis.

Iodine deficiency is a national health problem in India and we have recently reported on the severity of IDD in adults and children in Gujarat province. The aim of this study was to determine the utility of thyroid ultrasonography to detect goiter in adults from an iodine-deficient population of Gujarat. We studied 472 adults selected by random household surveys. Data were collected on height, body weight, mid-upper arm circumference, thigh circumference, triceps skinfold thickness, thyroid size (palpation and ultrasonography), and diet. Casual urine samples for iodine (UI) and blood spots for TSH estimation were obtained. Endemic goiter is a major public health problem in Gujarat State, India and is probably caused by multiple factors including iodine deficiency, malnutrition, and other dietary goitrogens. These results indicate that thyroid US consistently detects goiter in adults despite a diminished thyroidal response to variable goitrogenic stimuli.

Thyroid ultrasound is the best prevalence indicator for assessment of iodine deficiency disorders: a study in rural/tribal schoolchildren from Gujarat (Western India).

OBJECTIVES: (i) To assess the severity of iodine deficiency disorders (IDD), (ii) to determine the aetiology of IDD in Gujarat, (iii) to identify the best prevalence indicator of IDD, and (iv) to compare thyroid volume (TV) results with the WHO International reference. METHODS: Five hundred and thirty schoolchildren (6-15 years) were studied from two districts (Baroda and Dang) and data were collected on dietary habits and parameters such as height, weight, thyroid size by palpation and ultrasonography, urinary iodine (UI), and blood thyroid stimulating hormone (TSH). Drinking water was analyzed for iodine content and food articles for goitrogens. RESULTS: In Gujarat children median UI (interquartile range)=56 (30-96)microg/l, mean TSH=1.71 +/- 2.10mU/l, goiter by palpatio n = 30%, and median TV = 27.8 (23-35)ml. Females had lower median UI (48 (27-82) microg/l) and higher mean TSH levels (2.0 +/- 2.5mU/l) than males. Applying the WHO ultrasonography reference to Gujarat children resulted in an enlarged TV-for-body surface area in almost 100% of subjects. Ninety-nine percent of females and 95% of males had enlarged TV-for-age. Three to eight times larger TV were seen in all subjects as compared with European children. Dang children were severely malnourished. Flavonoids like vitexin, glucosyl vitexin and apigenin were detected in pearl millet. Apigenin was never identified in pearl millet. Dang district water was lacking in iodine content. CONCLUSIONS: IDD is a severe public health problem in Gujarat. Baroda district is a new pocket of IDD. High amounts of dietary flavonoids in Baroda and Dang districts, and lack of iodine in Dang water, account for IDD. TV measurement by ultrasound is the best prevalence indicator of IDD.

Beyond evidence-based guidelines to implementation: a model for integrating care for people with diabetes.

There is a growing realization in the health system that integration of effort may be the best way of ensuring optimal outcomes of management both for clinicians and for people using the health system. It is also hypothesized that the impact of diabetes (chronic disease) and its sequelae could be reduced by the provision of well-organized care, based on agreed evidence-based guidelines for best practice, incorporating patient education and early detection of complication. This paper defines the characteristics of an integrated model of providing care to people with diabetes.

Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.

OBJECTIVE: To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. RESULTS: In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). CONCLUSIONS: Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.

Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism.

Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared the effects of AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations of iodide than those seen in the NaI-treated cells. The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects.