Endocrinology

A 44-year-old woman was brought to hospital by police. Over a period of years she had isolated herself and her daughter from society, arousing the concern of neighbours. A scant history of “schizophrenia”, personality disorder and intellectual disability was obtained from distant relatives. Examination revealed classic clinical features of profound hypothyroidism. In addition, a lump was found on the patient’s ring finger (Box 1, A). Her mental state necessitated admission, after a psychiatric consultation, as an involuntary patient. Investigations confirmed the diagnosis of hypothyroidism and indicated anaemia due to iron deficiency (Box 2). An x-ray of the lump (Box 1, B) revealed a wedding ring totally encased in the soft tissue. The patient was started on thyroxine and antipsychotic medication and transferred to a psychiatric institution, with marginal improvement in her mental state. Her daughter was removed to the care of child welfare authorities. The wedding ring was surgically removed. Histopathological examination of the lump revealed a foreign body granuloma with chronic low-grade Staphylococcus aureus infection. Photographs and x-ray of lump on patient’s ring finger 2: Results of biochemical and haematological tests Test Result Reference range TSH (thyrotropin) 404 mIU/L 0.1–4.0 mIU/L T4 (thyroxine) 3 pmol/L 9–26 pmol/L Antithyroglobulin antibody >2000 IU/mL < 100 IU/mL Antithyroid peroxidase antibody >3000 IU/mL <100 IU/mL Total cholesterol 9.0 mmol/L 2.0–5.5 mmol/L Triglycerides 2.4 mmol/L < 1.7 mmol/L Haemoglobin 67 g/L 115–155 g/L White cell count 4.1 x 109/L 4.0–11.0 x 109/L MCV 72 fL 80–96 fL MCHC 315 g/L 300–350 g/L Platelets 329 x 109/L 150–400 x 109/L Vitamin B12 619 pmol/L 150–600 pmol/L Serum folate 17 nmol/L 7–39 nmol/L Red cell folate 965 nmol/L 390–1600 nmol/L Iron 8 μmol/L 7–35 μmol/L Transferrin 3.5 g/L 1.9–3.2 g/L Transferrin saturation 9% 20%–60% Ferritin 7 μg/L 20–120 μg/L MCV = mean cell volume. MCHC = mean cell haemoglobin concentration. TSH = thyroid-stimulating hormone.

Andrei Catanchin MB BS · Peter R Ebeling MD

Richard X Davey Chemical Pathologist, Melbourne Health Shared Pathology Service, Pathology Department, Western Hospital, Footscray, VIC, 3011. richard.daveyATwh.org.au To the Editor: Stone and colleagues must be complimented for their study of gestational diabetes mellitus (GDM) published recently in the Journal.1 Although the study was comprehensive, in that it linked two pertinent records for 99.3% of the women delivering in Victoria in 1996, their analysis was necessarily limited to the parameters recorded in those two data sets. Stone et al do not refer to relevant recent work from Toronto, Ontario,2 and Sunshine, Victoria,3 which has already determined the maternal risk factors for GDM: increasing age, racial origin, family history of diabetes mellitus, and pre-pregnancy body mass index. Data on the latter two of these four factors were specifically noted as not available to Stone's group, but could have been mentioned as established risk factors to consider in patient management. The findings of Stone et al regarding age are similar to those previously reported. However, the relative risk for GDM in the Sunshine cohort increased from 25 years of age (odds ratio, 1.9; 95% CI, 1.3–2.7).3 Recasting the all-Victorian data1 with "< 25 years" as the reference datum would most likely produce a similarly significant result to that found in the Sunshine study. Again, the Victorian data on racial origin are but the Sunshine data writ large. Stone and colleagues had to choose a reference datum for this parameter, but have not avoided a problem that bedevils all such work in the "New World": there is as yet no definitive Australian reference datum available for racial origin. For example, the designation "Australian" may be used, but parents who are themselves second or third generation Australian-born may have, say, pure Maltese ancestry, giving them a high risk of GDM and thus distorting the reference datum. I have argued this case in more detail elsewhere,4 and took measures to circumvent the problem in the Sunshine study.3 Among their findings, Stone et al confirm that there is a significantly increased incidence of macrosomia in GDM-affected infants. I agree. Their work is unquestionably the definitive statement of Victoria's GDM-related macrosomia status (as at 1996), but it lacks one vital ingredient: it defines macrosomia, but does not cite the source of the data used as the study's benchmark. To enable comparisons with their work in future years, could we please have that benchmark referenced so that others may use it too?

Richard X Davey

Christine A Stone,* Kylie A McLachlan,† Jane L Halliday,‡ Peter Wein,§ Christine Tippett¶ * Epidemiologist, Prevention and National Health Priorities, ‡ Epidemiologist, Birth Defect Registry, Perinatal Data Collection Unit, Public Health Division, Department of Human Services, 17th Floor, 120 Spencer Street, Melbourne, VIC 3001; † Research Fellow in Endocrinology, Department of Endocrinology and Diabetes, St Vincent's Hospital, Fitzroy, VIC; § Senior Lecturer, Department of Obstetrics and Gynaecology, University of Melbourne, East Melbourne, VIC; ¶ Director, Maternal Fetal Medicine, Monash Medical Centre, Clayton, VIC. christine.stoneATdhs.vic.gov.au In reply: We thank Davey for his comments, which provide us with the opportunity to highlight the benefits and limitations of reports using population-based data. The value of population-based data is that the reported incidence, risk factors and outcomes reflect current practice in the whole of Victoria and are not subject to bias introduced by local referral patterns or clinical practice. Our study1 shows that, in addition to established risk factors for gestational diabetes mellitus (GDM), the reported incidence varies according to hospital size and geographic location, demonstrating the type of bias that can occur. In addition, the large number of subjects in our study (over 60 000) enables more accurate analysis of subgroups. A limitation, already highlighted in our discussion, is that we are restricted to the parameters available within the data sources used. Davey and Hamblin's article2 demonstrates the difficulty of obtaining individual patient data on body mass index, racial grouping, and family history of diabetes. Even working at the hospital level, they had to extrapolate from population-level data to derive an estimate of these risk factors among the control subjects.2 Given that their study population is a subgroup of ours,1 it is no surprise that the two studies showed similar results. An important implication for providers of health services is that, with increases in the age at which mothers give birth and in the number of births to Asian-born mothers,3 we predict that the prevalence of GDM in Victoria will rise. Davey correctly points out that our article does not refer to a relevant 1997 study by the Toronto group.4 However, we do actually refer to a later publication by the same group.5 The problem of ethnicity and migration arises in studies of conditions that are not only polygenic but also a result of complex interactions between a person's genes and his or her environment. Lastly, the source of information on macrosomia was 1996 population data. We have since produced a percentile chart of weight (g) for gestational age (weeks) based on 15 years of Victorian data.6

Christine A Stone · Kylie A McLachlan · Jane L Halliday · Peter Wein · Christine Tippett

The main indication for hormone replacement therapy (HRT) is to control menopausal symptoms and improve quality of life. Ideally, withdrawal of HRT should be attempted after 4–5 years of therapy. HRT reduces fracture risk and remains appropriate therapy for osteoporosis, particularly in women with symptoms. HRT is not appropriate for primary or secondary cardioprotection. HRT leads to a small increase in breast cancer incidence, which increases with duration of therapy and age. HRT increases the risk of thromboembolism. Patient management and therapy should be reviewed annually with risk–benefit counselling.

Rodney J Baber B Pharm, FRACOG, MRCOG · Justine L O'Hara BSc(Biomed Sci) · Frances M Boyle PhD, FRACP

To the Editor: Metformin is a commonly prescribed oral hypoglycaemic agent used to treat type 2 diabetes mellitus. Its major effect is on hepatic glucose production and thereby fasting blood glucose level (f-BGL). Metformin does not commonly cause weight gain, and may be associated with significant weight loss.1 Over the past year, we have prescribed metformin as adjunctive therapy for five patients with type 1 diabetes (T1DM). ...

Jenny E Gunton · Stephen M Twigg

To the Editor: An 8-month-old girl, born in Perth, Western Australia, who received only breast milk feeds for her first six months of life, was referred urgently to Princess Margaret Hospital for Children (the tertiary paediatric hospital in Western Australia) for investigations of seizures. Her parents described the seizures as episodic, involving all limbs, lasting less than five minutes and occurring over the 10 days before presentation. At presentation, the infant had carpopedal spasm. She was afebrile, and a septic screen gave negative results. Venous blood gas analysis showed a low ionised serum calcium level of 0.71 mmol/L (reference range [RR], 1.13–1.32 mmol/L). An x-ray film of her wrists showed signs of rickets, with cupping and fraying of the distal metaphyses of both radius and ulna. Other blood tests revealed elevated parathyroid hormone levels of 8.6 pmol/L (RR, 0.80–8.00 pmol/L), an elevated alkaline phosphatase level of 523 U/L (RR, 100–350 U/L), and an extremely low level of serum 25-hydroxyvitamin D3 (25OHD3) of 5 nmol/L (RR, 30–150 nmol/L). The infant responded to treatment with an infusion of 0.5 mg/kg of calcium gluconate and a 4-month oral course of 0.2 μg calcitriol daily. After treatment commenced, she did not have any further seizures. Radiogaphy performed 4 months later showed increasing calcium deposition at the distal metaphyses of the radius and ulna. Seizures are described as a presenting feature of hypocalcaemia in vitamin D deficiency rickets.1,2 Ultraviolet radiation and/or dietary vitamin D are required to prevent rickets in children. Perth, Western Australia, located at latitude 32° South has an average daily sunshine duration of at least five hours per day. However, even with this amount of sunshine, vitamin D deficiency can still occur in people who, for various reasons, receive little or no sun exposure, especially if their skin is darkly pigmented, and who have an inadequate dietary intake of vitamin D. The girl's mother, who wore a veil and clothing which protected her body from exposure for religious reasons, had a serum 25OHD3 level of 7 nmol/L. Breast milk is a poor source of dietary vitamin D, especially when the lactating woman is vitamin D deficient.3 In Australia, vitamin D deficiency rickets in infants of parents who have migrated from Mediterranean, African, Middle Eastern and southern Asian regions has been reported since the 1960s.4,5 Education of healthcare providers and their patients about the requirement for sunlight exposure or dietary supplementation to prevent vitamin D deficiency rickets needs to continue.

Graeme H Johnson · Francis Willis

Comment: Nutritional rickets is highly prevalent in countries such as Mongolia, Tibet and China1 where winter sunlight is reduced and there is no universal vitamin D supplementation. Paradoxically, rickets is also prevalent in developing countries in the tropics and subtropics where sunlight is unlikely to be a limiting factor. Low calcium intakes (including vegetarian diets), prolonged breast feeding, and covering of the skin may all contribute.2,3 Published reports and clinical experience in Sydney suggest an increase in prevalence of rickets, especially in infants and mothers in immigrant populations2,4-7 Other Western countries have reported similar findings. The vitamin D deficiency described by Johnson and Willis in an infant in Perth highlights a high-risk group — infants of mothers who are veiled. Treatment of associated nutritional deficiencies, especially iron deficiency,4,5 and giving a minimum of 300 000 IU of vitamin D over 6–8 weeks, should resolve the rickets. Data on the epidemiology of vitamin D deficiency in these high-risk groups in Australia and other Western societies are lacking and should be the subject of future research. The major source of vitamin D and its circulating form, 25-hydroxyvitamin D3 (25OHD3), in children and adults is the skin. It is estimated that exposure to sunlight for 15 minutes three times per week normalises 25OHD3 levels.8 Dark skin, increasing age, sun protection agents, and the angle of the sun in winter will attenuate this increase in 25OHD3.8 Neonates acquire their vitamin D3 stores from their mothers via the placenta, with only a small amount transferred in breast milk.9 By screening high-risk pregnant women, specifically veiled women and those with dark skin,10,11 prevention of most cases of infant rickets is possible. Levels of 25OHD3 should be measured and, if low, the mother should receive 4000 IU of vitamin D daily until 25OHD3 levels are normal. There is currently no recommendation for routine supplementation of vitamin D in infants, and most cereals and foods are not fortified with vitamin D. However, infant formulas are supplemented with 200 IU of vitamin D per litre. It is estimated that sufficient vitamin D levels to prevent rickets could be achieved if 400 IU of vitamin D were provided daily as part of a multivitamin supplement to high-risk infants.

Christopher T Cowell

Trial: Pan XR, Li GW, Hu YH, et al. Effect of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997; 20: 537-544. QuestionCan changes in diet and/or physical activity levels reduce the progression to type 2 diabetes in people with impaired glucose tolerance (IGT)? Trial details Design: A cluster-randomised controlled trial with four arms. Setting: 33 health clinics in Da Qing, China. Patients: 557 people (mean age, 46.5 years; mean body mass index [BMI], 25.8 kg/m2; 46.6% female) of more than 110 000 screened for diabetes who were found to have impaired glucose tolerance (IGT) on the basis of a two-hour glucose tolerance test (GTT) and who agreed to participate. Interventions: The arms were control, diet only, physical activity only, and diet plus physical activity. For people who were not overweight (BMI < 25 kg/m2), the diet was much the same as the Australian dietary guidelines (10%–15% energy from protein, 25%–30% energy from fat, 55%–60% energy from carbohydrate, reduce simple sugar intake, eat more vegetables, control alcohol intake). People in the diet groups (BMI > 25 kg/m2) who were overweight were encouraged to lose weight gradually but details of the diet were not specified. Patients received individual counselling and also attended group sessions. The exercise intervention was to increase physical activity by one unit, and preferably two units, per day (eg, one unit was 30 minutes of slow walking or five minutes of swimming). The control group was given general information about diabetes and IGT and a pamphlet about diet and exercise. Main outcome measure: Diabetes (glucose level > 11.1 mmol/L), determined by biennial two-hour GTT and confirmed by a repeat GTT. Patients also had three-monthly urine tests; if results were positive, plasma glucose was tested after a standard breakfast (100 g steamed bread). If plasma glucose was > 11.1 mmol/dL, or if the doctor suspected diabetes, a 75 g GTT was performed. Subjects also received a GTT if they had signs of diabetes at any time. Main results: Compared with the control group (six-year incidence, 15.7/100 person-years [py]) the incidence of diabetes was significantly reduced in all three intervention groups: 10.0/100 py in the diet group, 8.3/100 py in the exercise group and 9.6/100 py in the combined group. The interventions also reduced the incidence of diabetes within subgroups of those who were overweight and not overweight at baseline. Among those who were not overweight, all groups gained a small amount of weight, whereas among those overweight at baseline all groups lost weight, with the control and exercise groups both losing an average of 0.9 kg/m2. There was no significant difference in the proportion of dietary energy derived from fat between the groups at follow-up. The two exercise groups significantly increased their exercise by 0.6 units/day (exercise only) and 0.8 units/day (exercise and diet), compared with 0.1 units/day in the control group. Conclusion: The authors concluded that increasing physical activity or altering the diet reduced the incidence of conversion from impaired glucose tolerance to diabetes. Combining physical activity with dietary modification was not more efficacious than altering one component alone. CommentaryRationale for the trialBefore this trial, there had been only a small number of non-randomised studies investigating the value of lifestyle change in reducing the conversion of IGT to diabetes. Trial methodsThe losses to follow-up were small, with only seven people declining follow-up, 11 dying and 29 moving to another location. Techniques to allow for clustering in the design appear to have been used. There are two main methodological questions in this trial. The first relates to assessing endpoints and the second to the lifestyle modifications actually achieved. The decision about who reached an endpoint at the three-monthly visits was made by the chairman of the committee using the single GTT; whether the chairman was blinded to the randomisation code is not stated. Diagnoses made at the biennial visits were based on two consecutive GTTs. However, people diagnosed with diabetes between biennial visits were retested at the next biennial exam. Why this was done if they had already reached an endpoint is unclear. The article does not state whether the 21% diagnosed between scheduled visits were evenly distributed across the four groups, or whether the date of the interim or biennial exam was used when calculating person-time. Hence, it is unclear whether all endpoints were assessed using the same criteria and whether there was differential bias in outcome assessment between the groups. The diet-related information presented does not show that any dietary differences were achieved between the four groups, and overweight people in the control group lost nearly as much weight as those in the diet group. Hence, it is not clear what the dietary intervention actually was. Dietary quality may have improved in the diet groups (eg, a higher intake of micronutrients), but this is not described. The change in incidence of conversion to diabetes in the combined group was no better than that in either of the single intervention groups, although it should have been greater under a no-interaction assumption. This suggests a negative interaction between the two interventions which would be unexpected. New informationThis was the first study to have a control group that was randomly allocated concurrently with the intervention groups to test the theory that lifestyle modification could alter the conversion to diabetes. It is still the only trial to examine the effects of diet and physical activity separately. Implications for clinical practiceIf this were the only trial available, it would be hard to recommend the interventions to delay the onset of diabetes in patients with IGT (although the intervention could be recommended for general health) owing to the methodological uncertainties. However, two subsequent, much larger and well-conducted studies have examined the combined effect of dietary and physical activity change.1,2 Both have documented the intervention that was achieved, and this provides a basis for identifying the level of change in diet and physical activity needed for effect. However, neither of these trials had separate arms examining the effect of diet alone or physical activity alone. As the relative effects of the two interventions are still unknown, patients should be advised to change both dietary and physical activity.

Dorothy EM Mackerras MPH, PhD

Objective: To assess iodine status and goitre prevalence in a sample of schoolchildren in Melbourne.Design: Cross-sectional study of urinary iodine excretion and presence of goitre in a sample of schoolchildren from Years 5–12 attending two urban schools.Participants: 607 children aged 11–18 years consented to thyroid gland palpation and 577 provided a urine sample on the day of examination in August 2001.Outcome measure: Iodine status of the study population, based on median urinary iodine values categorised as normal (≥ 100 μg/L), mild (50–99 μg/L) or moderate–severe (< 50 μg/L), and classified according to sex, school year and presence of goitre.Results: 76% (439/577) of students had abnormal urinary iodine values, with 27% (156/577) having values consistent with moderate–severe deficiency. The median urinary iodine excretion for the total group was 70μg/L, with values for school years 5–12 ranging from 62 μg/L (Year 12) to 76 μg/L (Year 9). The median urinary iodine value in girls was lower than that in boys (64μg/L v 82 μg/L), and girls had significantly lower urinary iodine values overall (P < 0.002). There was no association between goitre grade and moderate–severe (< 50 μg/L; P = 0.39) or mild (50–99 μg/L; P = 0.07) urinary iodine deficiency.Conclusions: We found mild iodine deficiency in a cohort of schoolchildren in Melbourne. Our results support other data showing mild iodine deficiency in Sydney and Tasmania and the argument for a national study of iodine nutrition.

Ciara M McDonnell MB, MRCPI · Mark Harris MD BS, FRACP · Margaret R Zacharin MB BS, FRACP

Trial: Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403. QuestionCan treatment with lifestyle modification (changes in diet and physical activity) or metformin reduce the conversion from impaired glucose tolerance (IGT) to type 2 diabetes? Do these treatments differ in effectiveness? Trial details Design: A three-arm multicentre, stratified, randomised controlled trial. Setting: 27 centres in the United States. Patients: 3234 (mean age, 50.6 years; 45.3% non-white; 67.7% female). Inclusion criteria were age 25 years or older; body mass index 25 kg/m2 or more if white, 24 kg/m2 or more if Native American, or 22 kg/m2 or more if Asian; fasting plasma glucose level of 5.3–6.9 mmol/L or < 6.9 mmol/L if Native American; a 2-hour plasma glucose level of 7.8–11 mmol/L after a 75 g glucose tolerance test (GTT); and no previous history of diabetes except gestational diabetes. Patients taking medication affecting glucose tolerance or with a disease which would affect life expectancy or participation in the activity recommendations were excluded. Intervention: The three groups were standard lifestyle recommendations plus twice-daily placebo (control group); intensive lifestyle program plus twice-daily placebo (lifestyle group); and standard lifestyle recommendations plus metformin (metformin group). The intensive program aimed to reduce patients' weight by at least 7% by dietary means and to have them engage in physical activity of moderate intensity for at least 150 minutes a week.1,2 The program was taught in 16 one-to-one lessons followed by individual and group sessions. The standard lifestyle intervention included similar information to the intensive program, but this was given as a written brochure and advice at the annual visit. Patients taking metformin were given one 850 g tablet plus one placebo per day for the first month and two metformin tablets daily thereafter. Main outcome measures: Progression from impaired glucose tolerance (IGT) to diabetes on the basis of six-monthly fasting plasma glucose measurements and an annual 75 g oral GTT. If a result met the 1997 American Diabetes Association (ADA) definition of diabetes,3 the test was repeated within six weeks. If the repeat result also met the ADA definition, the primary endpoint was reached. Otherwise, the patient continued in the assigned group. Main results: The trial was stopped one year early after an average follow-up of 2.8 years. Compared with the control group, the rate of type 2 diabetes was reduced by 58% (95% CI, 48%–66%) in the lifestyle group and by 31% (95% CI, 17%–43%) in the metformin group. The three-year cumulative incidence was 14.4% in the lifestyle group, 21.7% in the metformin group and 28.9% in the control group. The general pattern of the results did not vary by age, sex or race. At the final visit, 38% of the lifestyle group had reduced weight by 7% or more, average fat intake had declined by 6.6% from a baseline of 34.1% of total energy, and 58% were achieving the activity goal. More than 70% of patients took at least 80% of their medication. Hospitalisation and death rates were not different among the three groups. Conclusion: Both lifestyle modification and metformin reduce progression rates from impaired glucose tolerance to diabetes but lifestyle changes were more effective than metformin. The number needed to treat to prevent one case of diabetes in three years is 6.9 for lifestyle and 13.9 for metformin. CommentaryRationale for the trialThe prevalence of type 2 diabetes and its precursor stages is increasing. In 1999, the prevalence of diabetes was 7.4% and of impaired glucose tolerance (IGT) and abnormal fasting blood glucose (FBG) level was 16.4% in Australians aged 25 years and older.4 People with IGT have an increased risk of macrovascular disease, but not of microvascular disease. IGT is associated with obesity, sedentary lifestyle and increasing age, and is more common in some racial and ethnic groups. The only well conducted previous study of lifestyle modification was smaller and included only white people.5 Previous studies of pharmacological agents to reduce the conversion rate had been underpowered.1 Trial methodsThis was a well-conducted study with great attention to detail. For example, the requirement that an endpoint was diagnosed based on the results of two GTTs or two FBG tests was a potential source of bias and unblinding for participants and trial staff. This was addressed by retesting a sample of patients with normal results on these tests and not disclosing the result until progression to diabetes was confirmed.1 Patients were randomly assigned to groups only after completing an extensive run-in phase. An intention-to-treat analysis was done. Sample size for the trial was based on having a 90% power to detect a 33% reduction in the expected incidence of diabetes (6.5% per year). Greater methodological detail is available elsewhere.1,2 Although the focus was on progression to diabetes, reversion to normoglycaemia was also reported. At one year, more than 20% of the control group and 40% of the lifestyle group had normal values for both fasting and post-load glucose levels, and this declined to about 20% and 30%, respectively, at three years' follow-up. This highlights the need for a control group when evaluating interventions. Without this, most of the reversion in the intervention group might have been attributed to the intervention. Instead, it is clear that much of the reversion is related to "regression to the mean".6 That is, when a group defined using a cut-off point in a measure with substantial intra-individual variability is retested, the average value on the second test will be closer to the total population mean.6 New informationThis study is the first to test lifestyle against pharmacological prevention for type 2 diabetes and also the first to include groups that are often under-represented — the elderly, women and non-white people. The results confirm the findings of the previous lifestyle trial5 and extend their generalisability. Whether the interventions actually prevent diabetes, or simply delay its onset, or what happens if the interventions stop, cannot be answered by either study. The variability of glucose levels has been previously described. However, the size of this trial means that the magnitude of the reversion to normal is probably a good estimate of what would happen in the clinical setting in patients who were retested. The size of the variability also has implications for interpreting the results of national surveys such as AusDiab,4 as it means that the proportion of people with abnormal glycaemia found on a single test overestimates the proportion who would have had the abnormality confirmed on a later test. Implications for clinical practiceThis study shows that 5–6 kg weight loss combined with dietary modification to reduce fat intake to less than 30% of energy and increasing activity for 150 minutes per week will halve the conversion rate to diabetes in people with IGT. Because the mean baseline body mass index (BMI) was 34.0 kg/m2, losing 5–6 kg reduced this to about 31.5 kg/m2, which is still in the obese range. Patients should not be given the false impression that they must achieve a body weight in the healthy range (BMI of 18.5–24.99 kg/m2) before any benefits occur. As Native Americans and Pacific Islanders were included, it is reasonable to conclude that the results of this study would apply to Indigenous Australians, who have high levels of diabetes and cardiovascular mortality.7 At present, it is not possible to separate the effects of dietary and activity change on the outcomes, so both need to be recommended together. The intervention for the control group was similar to what a general practitioner might do during a consultation. A lot of support was given to help the lifestyle group patients achieve their lifestyle changes,2 which means that this is not a cheap intervention. The challenge for clinical practice is to provide this support either directly or by referral to community groups and to advocate for environmental changes that support beneficial lifestyle changes.

Dorothy EM Mackerras BSc, MPH, PhD GradDipNutrition

Background: In 1889, Brown-Séquard, aged 72, reported dramatic rejuvenating effects after self-administering testicular extracts of dogs and guinea-pigs. His report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. More recently, the male ageing process has been attributed to partial androgen deficiency, or "andropause", and testosterone treatment is claimed to improve well-being in middle-aged and elderly men.Design: We prepared extracts from five dog testes using Brown-Séquard's methods and assayed testosterone concentrations.Results: Testosterone concentrations were four orders of magnitude less than that required for a biological effect.Conclusions: Our study illustrates the marked placebo response that can be evoked by androgen treatment. It cautions against the empirical use of testosterone treatment for older men, unless a diagnosis of hypogonadism has been substantiated.

Andrea J Cussons MB BS · John P Walsh FRACP, PhD · Chotoo I Bhagat MD, FRCPA · Stephen J Fletcher MSc, Dip CB

Objectives: To describe the epidemiology of gestational diabetes mellitus (GDM) in Victoria.Study design: Population study of all women having singleton births in Victoria in 1996.Methods: Probabilistic record linkage of routinely collected data and capture–recapture techniques to provide an estimate of the incidence of GDM.Main outcome measures: Risk factors for and the adverse outcomes associated with GDM compared with the non-diabetic population by univariate and multivariate analysis.Results: The estimated incidence of GDM was 3.6% (95% confidence interval [CI], 3.60%–3.64%). GDM is associated with women who are older, Aboriginal, non-Australian born, or who give birth in a larger hospital. The adverse outcomes associated with GDM pregnancies were hypertension/pre-eclampsia (adjusted odds ratio [OR], 1.6; 95% CI, 1.4–1.9), hyaline membrane disease (1.6; 1.2–2.2), neonatal jaundice (1.4; 1.2–1.7) and macrosomia (2.0; 1.8–2.3). Interventions during childbirth were also associated with GDM — for example, induction of labour (3.0; 2.7–3.4) and caesarean section (1.7; 1.6–1.9).Conclusion: Women with GDM had increased rates of hypertension, pre-eclampsia, induced labour, and interventional delivery. Their offspring had a higher risk of macrosomia, neonatal jaundice and hyaline membrane disease.

Christine A Stone GradDipEpidBiostat, MPH, MHSc(PHP) · Kylie A McLachlan MB BS, FRACP · Jane L Halliday PhD · Peter Wein MB BS, FRANZCOG, GradDipEpidBiostat · Christine Tippett MB BS, FRANZCOG, MRCOG

To the Editor: Diabetes is a leading cause of morbidity and mortality in Australia, with 50% of cases remaining undiagnosed.1 Consequently, the Australian National Diabetes Strategy has early detection of diabetes as a key priority.2 We undertook a study to determine the prevalence of abnormal glucose metabolism (impaired fasting glycaemia [IFG] and diabetes) in patients presenting in the fasted state for endoscopy or colonoscopy at a metropolitan teaching hospital. We used the definitions of abnormal glucose metabolism outlined by the World Health Organization in 19993 and published in a position statement in the Journal in April 1999.4 Two hundred and twenty-four patients gave informed consent and participated in the study, comprising 126 men and 98 women. Mean age (SD) was 75.1 years (6.9) for men and 60.9 years (17.6) for women. Twenty-four participants (11%) had known diabetes. The remaining 200 patients had fasting venous plasma glucose levels determined (Box). Patients with abnormal glucose metabolism (fasting plasma glucose level > 6.1 mmol/L) were offered further testing with a 2-hour oral glucose tolerance test (OGTT) after a 75 g glucose load. Nine patients initially classified with IFG had diabetes based on OGTT results. No patient classified with diabetes on initial testing was subsequently classified as not having diabetes by the OGTT. The overall prevalence of undiagnosed diabetes was 7% (15 patients). We demonstrated a high prevalence of abnormal glucose metabolism in a group of predominantly elderly patients presenting for gastroenterological procedures. Furthermore, subsequent investigation of these patients revealed that a substantial proportion who were classified with IFG on initial screening were classified with diabetes based on 2-hour OGTT results, highlighting the importance of this test in diagnosing diabetes. It is likely that we underestimated the prevalence of abnormal glucose metabolism, as OGTT was not performed in all patients. This is supported by results of the AusDiab study that revealed a high prevalence of abnormal glucose metabolism in older patients — 37% of those aged 55–64 years, 47% of those 65–74 years, and 53% of those 75 years and over.1 National Health and Medical Research Council guidelines suggest that all patients with a fasting plasma glucose level of 5.5–6.9 mmol/L be referred for OGTT.5 Based on this suggestion, an additional 28 patients in our study group would have had an OGTT. Measurement of fasting venous plasma glucose level is safe, relatively simple and inexpensive. Patient presentations in the fasted state for investigations and procedures provide an ideal opportunity for screening with this test. Patients with abnormal results should be referred for further testing with repeat fasting glucose determination or OGTT. This process may be facilitated by involving patients' general practitioners. Results of fasting plasma glucose tests in 224 patients presenting for gastroenterological procedures Fasting plasma glucose level Normal (< 6.1 mmol/L) 172 (77%) Impaired fasting glycaemia (≥ 6.1 mmol/L, < 7.0 mmol/L) 22 (10%)* Diabetes (≥ 7.0 mmol/L) 6 (3%)† Not tested (known diabetes) 24 (11%) * Diabetes was confirmed on subsequent oral glucose tolerance test (OGTT) in nine of these patients (four refused further testing). † Diabetes was confirmed on subsequent OGTT in all six patients.

Anthony T Zimmermann · Stephen N Stranks · Sally L Gall · Geoffrey S Hebbard

Re "Thiazolidinediones and type 2 diabetes: new drugs for an old disease", the New Drugs, Old Drugs article by Trisha M O'Moore-Sullivan and Johannes B Prins in the 15 April issue of the Journal (Med J Aust 2002; 176: 381-386), in which an editing error resulted in the word "tryglyceride" replacing "total cholesterol". Thus, on page 383, the first sentence in the second dot point under the subheading "Both drugs increase HDL and LDL and decrease FFA levels; pioglitazone lowers triglyceride levels", the sentence should read "Rosiglitazone also tends to increase total cholesterol level and studies have reported variable effects on ratios of total cholesterol to high-density lipoprotein (HDL) and of LDL to HDL." The html and pdf versions of this article were corrected on Monday 30 September 2002.

Trisha M O'Moore-Sullivan MB BS, FRACP · Johannes B Prins MB BS, PhD, FRACP

Clinical record A 55-year-old woman with type 2 diabetes of 8 years' duration experienced, over 2–3 days, the onset of pain, tenderness and swelling of the medial aspect of her right thigh. She had recently commenced insulin therapy and was displaying good glycaemic control (HbA1c level of 6.4%). She had diabetic complications of autonomic and peripheral neuropathy, but no retinopathy. Other medical problems included chronic renal impairment, hypertension, polyarticular gout and hydralazine-induced lupus. A renal biopsy had not been performed, but her renal insufficiency was believed to be a result of diabetic nephropathy and hypertension. She was taking twice-daily mixed insulin (16 units in the morning and 10 units at night), felodipine (10 mg/day), paroxetine (10 mg/day), allopurinol (75 mg/day) and prednisolone (7.5 mg/day). Her serum creatinine level had peaked at 0.31 mmol/L, but stabilised at 0.21 mmol/L after cessation of an angiotensin-converting enzyme inhibitor. A 24-hour urine collection showed a creatinine clearance rate of 0.12 mL/s (normal range [NR], 1.5–2.5 mL/s) and a protein excretion rate of 4.6 g/day. Renal duplex ultrasound showed that her kidney size was well preserved, but there was a suggestion of renal artery stenosis on the right side. There was no history of recent injury or injection to her thigh. She had not experienced any rigors and was afebrile. The area of the localised, tender swelling on the medial aspect of her right thigh was not erythematous and no local lymphadenopathy was noted. Apart from the thigh swelling, there was generalised wasting and weakness of the lower limbs, loss of ankle reflexes, and loss of sensation in a stocking distribution, consistent with a diagnosis of peripheral neuropathy. Examination of her left foot revealed two small gangrenous areas. Foot pulses were present and the gangrenous areas were thought to be caused by inappropriate footwear. Figure 1: Computed tomography image of the thigh, showing marked oedema and thickening of the adductor muscle group (A), extensive subcutaneous oedema (B), and sparing of the hamstring muscle (C). Investigations showed an elevated white cell count of 16 x 109/L (NR, 4.0–11.0 x 109/L), a platelet count of 432 x 109/L (NR, 150–400 x 109/L), an erythrocyte sedimentation rate of 110 mm/h (NR, 7–18 mm/h) and a C-reactive protein level of 119.3 mg/L (NR, 1.6–8.7 mg/L). Creatine kinase (174 U/L; NR, < 215 U/L) and lactate (0.6 mmol/L; NR, 0.5–2.0 mmol/L) levels were normal. Separate to the swelling on the medial aspect of the thigh, a presumed thrombus was palpable in the lateral accessory long saphenous vein. A subsequent ultrasound detected this thrombus extending from the mid thigh to the lateral aspect of the knee, but no deep venous thrombosis was found. She was treated with cephalexin and aspirin. Over the next two weeks, the thigh swelling evolved into a tender, palpable mass measuring 6 x 20 cm. A computed tomography (CT) scan revealed marked swelling of the entire adductor muscle group, but no discrete mass (Figure 1). In the absence of a clear diagnosis, an exploratory operation of her right thigh was performed. This showed no haemorrhage or abscess, but evidence of extensive oedema and necrosis of the adductor muscles. Samples taken for microbiological analysis were sterile. Histological examination of a biopsy specimen showed necrotic muscle, an inflammatory cell infiltrate, fibrosis and evidence of muscle fibre regeneration. The occasional small blood vessel containing fibrin thrombus was also seen, but no features of vasculitis were identified (Figures 2 and 3). A diagnosis of diabetic muscle infarction was made. Photomicrographs (original magnification x 250) of a biopsy specimen of the adductor group of muscles. Figure 2: Longitudinal section, showing necrotic muscle fibres (A) and granulomatous tissue (B). Figure 3: Cross-section showing necrotic muscle (A), an inflammatory cell infiltrate (B) and a blood vessel containing a thrombus (C). No evidence of vasculitis was seen. The diagnosis of diabetic muscle infarction was made retrospectively on clinical grounds and after reviewing the subsequent investigations. The differential diagnoses — muscle strain, rupture, haematoma, myositis, infection, deep venous thrombosis, thrombophlebitis, femoral artery aneurysm, fracture or a connective tissue tumour — were excluded by the clinical presentation, together with the ultrasound, computed tomography (CT) scan and biopsy findings. The CT scan did not reveal a discrete mass, but extensive oedema of one muscle group and sparing of an adjacent muscle group. Histologically, there was evidence of skeletal muscle fibre necrosis, with a variable amount of muscle regeneration and fibrosis. These are the typical features of diabetic muscle infarction.1 Reports of spontaneous muscle infarction appear to be virtually confined to patients with diabetes. Spontaneous muscle infarction is a rare diabetic complication. There have been fewer than 100 patients reported since 1965.1-12 However, it is becoming more frequently recognised; almost half of the cases have been reported since 1999.3-12 It has a predilection for the quadriceps (62%), hip adductors (13%), hamstrings (8%) and hip flexor (2%) muscles. Rarely, the calf and anterior tibial muscles are involved. The pathogenesis of diabetic muscle infarction is still unclear, but a diffuse microangiopathic process, possibly associated with hypoxia–reperfusion injury, has been implicated as a cause.1,10,12 Magnetic resonance imaging (MRI) is the preferred diagnostic test, revealing swollen and oedematous muscles (ie, increased signal intensity of T2-weighted images).4,7 Abnormal MRI findings have been reported in all patients with diabetic muscle infarction. Although, in retrospect, our patient's CT findings were consistent with muscle infarction, a CT scan is considered a less sensitive test, as only 83% of patients with muscle infarction have abnormal CT findings.1 An MRI scan was not performed in our patient, as diabetic muscle infarction was not initially considered in the differential diagnosis. Consensus opinion suggests that muscle biopsy is not necessary in a patient presenting with the typical clinical features of diabetic muscle infarction — without fever, erythema, or elevated white cell count — if the MRI findings are appropriate.1 Management consists of the avoidance of weightbearing, and simple analgesia. After resolution of the acute phase, physical therapy and rehabilitation are useful. As with our patient, total recovery over 4–6 weeks can be expected. In about 50% of patients recurrences occur, but not necessarily in the same muscle group.

Richard J MacIsaac BSc, PhD, FRACP · George Jerums MD, FRACP · Lisa Scurrah MB BS, FRACP

Improving glycaemic control in children and adolescents presents unique problems Type 1 diabetes affects one in 500 children and adolescents, and vascular complications remain a major cause of mortality and morbidity in adult life. Blood glucose targets have fallen since confirmation of the unequivocal relationship between glycaemic control and microvascular complications.1,2 In this issue of the Journal (page 235), Craig et al present a population-based, cross-sectional study of 1190 children and adolescents with type 1 diabetes in New South Wales and the Australian Capital Territory.3 Their median HbA1c level of 8.2% probably reflects some selection bias, because 571 (33%) of the population did not participate. However, this level of glycaemic control still represents a considerable improvement over the past 10 years4 and is comparable to levels found in international studies of children with type 1 diabetes.5 This trend accompanies the increasing use of intensive management in children and adolescents, but also the worrying rise in the incidence of severe hypoglycaemia. There are compelling reasons to recommend intensive therapy in adolescents with type 1 diabetes — either multiple daily injections or continuous subcutaneous insulin infusion. The effectiveness of intensive therapy in improving and maintaining good glycaemic control is well established in adolescents under research trial conditions.6 More recent data also indicate that the benefits of intensive therapy and improved glycaemic control persist even when HbA1c levels later rise.7 After completion of the Diabetes Control and Complications Trial (DCCT), adolescents from the former intensive therapy and conventional therapy groups returned to routine care and were advised to use intensive therapy. Despite no difference in their glycaemic control for four years after the end of the DCCT, the benefits of previous better control in the intensive therapy group persisted. Their prevalence of progression to proliferative or severe non-proliferative retinopathy was reduced by 78% during the four years. Suboptimal control during adolescence appears to have a lasting harmful effect, even when better glycaemic control is achieved later. Those caring for children and adolescents with type 1 diabetes may worry about the demands on the family and child of achieving good glycaemic control with intensive therapy. However, good glycaemic control is associated with better quality-of-life scores (QOL) in adolescents and less perceived burden by their parents.8 The intensity of the insulin regimen does not adversely affect QOL. Clearly, the demands of achieving good control are less than the consequences of poor control.8 The limiting factor of achieving ideal glycaemic control remains hypoglycaemia, excluding other problems of adherence or family functioning. Adolescents in the DCCT had higher rates of hypoglycaemia than their adult counterparts, despite having higher HbA1c levels.6 Glucagon secretion, which stimulates hepatic glycogenolysis, is blunted early in the course of type 1 diabetes, increasing the patient's vulnerability to hypoglycaemia. Further, the blood glucose threshold level for catecholamine release in response to hypoglycaemia is lowered in patients with better glycaemic control and this counter-regulatory response is most blunted during sleep.9 Recently available continuous blood glucose monitoring devices have shown that nocturnal hypoglycaemia is frequent in children. However, both new insulin analogues and continuous subcutaneous insulin therapy hold promise of improving control without the attendant increased risk of hypoglycaemia. In Western Australia, children with type 1 diabetes had more hypoglycaemia in association with falling HbA1c levels until 1995;4 since then their control has improved further, but without increased hypoglycaemia. Can the DCCT recommendations that adolescents receive intensive therapy be reproduced in routine care? The Hvidore Study Group has followed more than 2500 children and adolescents over three years in Europe, Canada and Japan.5 Despite more use of intensive therapy, glycaemic control did not necessarily improve with wide differences between paediatric centres. Intensive therapy demands intensive follow-up, education and support, as well as resources that many Australian paediatric diabetes units do not have if most patients are to be supported in this way. Most success in implementing the DCCT recommendations is reported from well-resourced units using diabetes clinical nurse consultants. While it is recommended that adolescents with type 1 diabetes receive intensive therapy, schedules need to be individualised. For example, some schoolchildren need insulin at afternoon tea, most adolescents need longer-acting insulin before bed for night control, and many preschoolers are managed on intermediate-acting insulin in the morning with small doses of insulin analogues to cover hyperglycaemia later in the day. Insulin pumps may provide the best solution for some patients, especially those with frequent hypoglycaemia or hypoglycaemic unawareness, but without government subsidy they are not affordable for most families. None of these options are easy for children and their families and, for some, intensive therapy is not possible. Insulin omission and chronic poor glycaemic control remain problems in adolescence and require ongoing intervention.10 The NSW and ACT study has demonstrated a relatively fast decline in HbA1c levels3 since the DCCT findings. However, glycaemic control (and risk of long term vascular complications) is unlikely to improve further in population studies unless multidisciplinary resources increase. It is especially relevant for more educators to be trained in the unique problems of improving control in this age group, and for their expertise to be available to all children.

Jennifer J Couper MB ChB, MD, FRACP

Objectives: To audit glycaemic control and incidence of severe hypoglycaemia in children and adolescents with type 1 diabetes in New South Wales (NSW) and the Australian Capital Territory (ACT).Design: A multicentre, population-based, cross-sectional study from 1 September to 31 December, 1999.Participants: 1190 children and adolescents aged 1.2–15.8 years with type 1 diabetes, identified from three hospital-based paediatric diabetes units, four private city-based paediatric practices and 18 regional outreach clinics in NSW and the ACT.Main outcome measures: HbA1c level and incidence of severe hypoglycaemia (defined by unconsciousness or seizures).Results: The response rate was 67% (1190 of a target group of 1765). The median HbA1c level was 8.2% (interquartile range, 7.6%–9.1%). Significant predictors of HbA1c level in a multiple regression model were duration (b = 0.05; 95% CI, 0.02–0.07) and insulin dose/kg (b = 0.46; 95% CI, 0.27–0.66). At least one episode of severe hypoglycaemia in the previous three months was reported in 6.7%, and the rate of severe hypoglycaemia was 36/100 patient-years. Significant predictors of hypoglycaemia in a Poisson regression model were younger age (P = 0.03), male sex (P = 0.04), longer diabetes duration (P = 0.02), and > 3 daily insulin injections (P = 0.02), but not HbA1c level. Children with diabetes had higher BMI standard deviation scores compared with population standards, and those in the highest quartile of BMI standard deviation score were younger, had shorter diabetes duration and had higher HbA1c level.Conclusions: Many children and adolescents with type 1 diabetes have suboptimal glycaemic control, placing them at high risk of developing microvascular complications. Those with longer diabetes duration are at increased risk of suboptimal glycaemic control and severe hypoglycaemia and should be targeted for interventional strategies.

for the NSW/ACT HbA1c Study Group

Objective: To examine changes in presentation of primary hyperparathyroidism and rates of parathyroidectomy in Northern Sydney (the Northern Sydney Area Heath Service) and New South Wales (NSW).Design: Retrospective case series January 1962 – December 2001 and audit of the NSW Department of Health inpatient database (1993–1999).Setting: University of Sydney Endocrine Surgical Unit, Royal North Shore Hospital.Participants: 1613 patients undergoing parathyroidectomy during the study period.Main outcome measures: Age-standardised parathyroidectomy rates and indications for surgical intervention.Results: The age-standardised rates of parathyroidectomy for primary hyperparathyroidism in women have increased significantly in Northern Sydney from 0.14 cases per 100 000 in 1976 to 7.7 cases per 100 000 in 1996 (P < 0.001). In NSW there has been an increase in parathyroidectomy rates in women from 5.1 cases per 100 000 in 1993 to 12.3 cases per 100 000 in 1998 (P < 0.001). Osteoporosis was the most common overall indication for surgery in Northern Sydney, accounting for 27% of all cases. The proportion of cases presenting with osteoporosis increased significantly from 4% in 1962–1980 to 34% over the past decade (P < 0.001).Conclusions: The rate of parathyroidectomy procedures has increased markedly in Northern Sydney and in NSW. The investigation of osteoporosis has led to the diagnosis of primary hyperparathyroidism in an increasing proportion of cases and has contributed to the growing surgical referral rates.

Tom S Reeve MD, FRACS · Bruce H Barraclough MB BS, FRACS · Leigh W Delbridge MD, FRACS · Bruce G Robinson MD, FRACP · Phillip Clifton-Bligh MB BS, FRACP · Mark S Sywak MB BS, FRACS · Gordon H Fick PhD

Re the letter "Guidelines for the management of gestational diabetes mellitus revisited", by David S Simmons, Barry N J Walters, Peter Wein and N Wah Cheung, on behalf of the Australasian Diabetes in Pregnancy Society, published in the 1 April issue (Med J Aust 2002; 176: 352), in which the American College of Obstetricians and Gynecologists criterion for diagnosing gestational diabetes mellitus of a 1-hour fasting plasma glucose level of ≥ 10.0 mmol/L was mistakenly placed in the adjacent Australasian Diabetes in Pregnancy Society column. The entire corrected table is reprinted below. Differences between management guidelines for gestational diabetes mellitus (GDM) from the Australasian Diabetes in Pregnancy Society (ADIPS, 1998) and the American College of Obstetricians and Gynecologists (ACOG, 2001) ADIPS ACOG Universal versus selective screening by blood test Universal unless low GDM incidence or resources limited No recommendation. States that "many physicians elect to screen all pregnant patients as a practical matter" Differences in definition of low risk for GDM Age < 30 years, obesity, family history of diabetes Age < 25 years, body mass index < 25 kg/m2. No known diabetes in first-degree relative Oral glucose tolerance test used 75 g, 2-hour, 2-point blood sampling 100 g, 3-hour, 4-point blood sampling Criteria for diagnosis of GDM Plasma glucose level: Fasting, ≥ 5.5 mmol/L and/or 2-hour, ≥ 8.0 mmol/L Plasma glucose level: Fasting, ≥ 5.3 mmol/L; 1-hour, ≥ 10.0 mmol/L; 2-hour, ≥ 8.6 mmol/L; 3-hour, ≥ 7.8 mmol/L (2 or more time points need to elevated) Insulin therapy commenced after medical–nutrition therapy Plasma glucose level: Fasting, ≥ 5.5 mmol/L and/or 1-hour postprandial, ≥ 8.0 mmol/L and/or 2-hour postprandial, ≥7.0 mmol/L Plasma glucose level: Fasting, ≥ 5.3 mmol/L and/or 1-hour postprandial, ≥ 7.2–7.8 mmol/L and/or 2-hour postprandial, ≥ 6.7 mmol/L

David S Simmons · Barry N J Walters · Peter Wein · N Wah Cheung

Objective: To measure bone turnover in Muslim women with vitamin D deficiency.Design: A cross-sectional study of a random sample of Muslim women aged 20–65 years, evaluated over a 6-month period from November 1999 to April 2000.Setting and participants: 146 women living in an urban community in south-western Sydney with adequate opportunities for sun exposure.Main outcome measures: Bone turnover as measured by urinary deoxypyridinoline (DPYD) excretion rates; and vitamin D status as determined by 25-hydroxyvitamin D (25OHD) levels, serum calcium levels and parathyroid hormone (PTH) concentrations.Results: We analysed data on 119 Muslim women (mean [SEM] age, 46.6 [1.1] years) who met the inclusion criteria. There were 81 (68.1%) women with serum 25OHD levels < 30 nmol/L (defined as "severe" vitamin D deficiency). Fifty-five (46.2%) women had evidence of high bone turnover (urinary DPYD excretion > 6.5 nmol/mmol creatinine). The women with "severe" vitamin D deficiency had significantly higher serum PTH levels (7.3 [0.3] v 5.4 [0.5] pmol/L; P = 0.001) and higher urinary DPYD excretion (7.2 [0.3] v 5.4 [0.2] nmol/mmol creatinine; P = 0.003) than women with serum 25OHD levels ≥ 30 nmol/L. No significant differences were seen in their ages, menopausal status or serum calcium and phosphate measurements. The risk of developing high bone turnover was significantly greater in the women with "severe" vitamin D deficiency (relative risk = 5.52; 95% CI, 2–14.8; χ2 = 12.95; P = 0.0003).Conclusion: High bone turnover occurs in Muslim women with vitamin D deficiency.

Terrence H Diamond MB BCh, MRCP, FRACP · Sherel Levy MB BCh · Angelina Smith BSc · Peter Day PhD

An 88-year-old man was admitted to hospital with "collapse", manifested as hypotension and fever. It was noted that he had gaze palsies. He had been admitted for a three-day period, 12 days earlier, with a urinary tract infection, which was treated with intravenous, then oral, antibiotics. On this occasion he was again started on intravenous antibiotic therapy. He was seen by an ophthalmologist, and a cranial computed tomography (CT) scan was arranged. Later that evening, the ward nurses sought further medical review, as the patient remained hypotensive, with a systolic blood pressure of 80 mmHg. On examination he was observed to have a partial left third cranial nerve palsy and complete right third cranial nerve palsy (see Box, A). A presumptive diagnosis of pituitary apoplexy was made, and the patient was commenced immediately on intravenous fluids and hydrocortisone 100 mg, 12-hourly. The CT scan (Box, B) confirmed the diagnosis, showing a pituitary tumour measuring 12 mm in diameter. The salient feature is the variegated appearance, suggesting haemorrhage within the tumour. In patients presenting with the constellation of collapse and gaze palsies, a diagnosis of pituitary apoplexy should be considered. The mechanism of third-nerve palsy is illustrated in the Box (C). The condition is life-threatening, but responds well to appropriate treatment. After the patient had undergone hypophysectomy, the gaze palsies took about three months to resolve completely. The patient remains active on pituitary replacement therapy only. Cranial nerve palsy caused by pituitary tumour This picture of the patient's eyes 12 hours after commencing hydrocortisone (A) shows partial left third cranial nerve palsy and complete right third cranial nerve palsy. A computed tomographic image (B) shows a 12 mm diameter pituitary tumour with haemorrhage (arrow). The mechanism of third cranial nerve palsy is illustrated in C: as the tumour expands, it involves the optic chiasm anteriorly and displaces the carotid siphon laterally. The third cranial nerve is vulnerable to lateral displacement. (Adapted from Patten J. Neurological differential diagnosis. New York: Springer Verlag, 1982.) A: Patient's eyes B: Computed tomography scan C: Mechanism of third cranial nerve palsy

Dan Harmelin BSc DipEd MB BS FRACP

To the Editor: Although treatment with vitamin D has been shown to reduce hip fracture risk in elderly institutionalised people,1 there has been a perception that vitamin D deficiency is generally uncommon in countries with high sunlight exposure such as Australia. We studied the prevalence of vitamin D deficiency in older people in residential aged-care facilities (hostels and nursing homes) in the northern Sydney area as part of the FREE study (Fracture Risk Epidemiology in the Elderly), a prospective study of fracture incidence in more than 2000 participants. Here, we report baseline serum 25(OH) vitamin D concentrations in the first 386 participants, determined in partially purified lipid extracts using a competitive protein binding assay.2 The sample comprised 252 women and 134 men (mean ± SE age, 86.7 ± 0.6 v 81.2 ± 0.7 years, respectively; P < 0.001). The mean serum 25(OH)D level was 17 nmol/L (SD, 12) and median serum 25(OH)D level was 15 nmol/L (interquartile range, 9 to 22). Vitamin D deficiency (defined as a serum 25(OH)D concentration < 28 nmol/L) was present in 86% of women and 68% of men. There was no significant difference in serum vitamin D levels between women in nursing homes versus women in hostels, nor between men in nursing homes versus those in hostels. Although serum vitamin D levels were low throughout the year, a small rise was observed in summer (P < 0.01). Length of stay in the residential facility was not a predictor of serum vitamin D level. Mean parathyroid hormone levels were 93 pg/mL (normal range, 12–72 pg/mL) and rose when vitamin D levels dropped below 21 nmol/L, indicating secondary hyperparathyroidism. A number of previous studies have suggested a high prevalence of vitamin D deficiency in older institutionalised Australians in southern States,2-4 but we are unaware of any published studies in Sydney (latitude 33°S). However, as the prevalence of vitamin D deficiency in older people living in the community in Geelong is low,5 our study suggests that factors like confinement indoors is more important than latitude. Given the relationship between vitamin D status and fracture, with more than 72 500 nursing home residents and 60 200 hostel residents in Australia in 1997, our findings indicate that vitamin D deficiency represents a significant public health problem in elderly institutionalised Australians regardless of geographical location. Importantly, this problem could be solved relatively simply by measures such as a short period of daily sunlight exposure or giving moderate doses of vitamin D annually to nursing home and hostel residents.

Philip N Sambrook · Ian D Cameron · Robert G Cumming · Stephen R Lord · Jennifer M Schwarz · Angelika Trube · Lynnette M March

The recent AusDiab data show that 7.2% of Australians over 25 years of age have type 2 diabetes mellitus and a further 16.1% have impaired glucose tolerance. In fact, 20% of Australians over 65 years have type 2 diabetes and it is well known that morbidity and mortality are significantly increased in affected patients.1,2 However, there is evidence from the United Kingdom Prospective Diabetes Study (UKPDS) that good glycaemic control can improve morbidity by improving microvascular complications of type 2 diabetes, such as retinopathy, nephropathy and neuropathy3 (E2). (See Box 1 for an explanation of level-of-evidence codes.) There is a well-recognised and strong association of type 2 diabetes with obesity and the insulin resistance syndrome. "Syndrome X"5 refers to a collection of pathophysiological sequelae resulting from insulin resistance and includes type 2 diabetes, as well as hypertension, dyslipidaemia, hyperuricaemia and elevated plasminogen-activator-inhibitor-1 levels.6 Pathophysiologically, type 2 diabetes is characterised by defects in insulin action (ie, insulin resistance) and secretion (ie, β-cell dysfunction), and increased hepatic glucose output.2 It is also well established that type 2 diabetes is a progressive condition, and that β-cell failure ensues in many patients. The UKPDS showed that, although monotherapy with sulfonylureas, metformin or insulin can achieve good glycaemic control initially, sustained control with these agents fails in 50% of patients after three years. Most patients will require multiple therapies to obtain adequate long term glycaemic control (E2).7 Currently available therapiesCurrently available therapies for type 2 diabetes include various oral agents such as sulfonylureas, metformin, α-glucosidase inhibitors (such as acarbose) and insulin. These agents can be used as monotherapy or in combination therapy. They have been used extensively, are efficacious and have a low incidence of serious adverse events. Recently, a new class of oral agents, the thiazolidinediones (TZDs), which act to improve the insulin sensitivity of peripheral tissues, has become available for use in clinical practice. Troglitazone was the first agent in this class and was effective, but was withdrawn because of severe and unpredictable hepatic failure. Newer TZDs such as rosiglitazone and pioglitazone are now available and have been approved by the Therapeutic Goods Administration (TGA) for use as monotherapy in patients with type 2 diabetes inadequately controlled by lifestyle measures, and also for use in combination with sulfonylureas or metformin in patients with inadequate glycaemic control.8,9 Pioglitazone is also licensed for use in combination with insulin.9 To date, hepatotoxicity does not appear to be a significant problem with these newer agents. Neither drug is listed on the Pharmaceutical Benefits Scheme yet. A profile of these two drugs is shown in Box 2. Thiazolidinediones and peroxisome proliferator-activated receptor γTZDs reduce hyperglycaemia by improving insulin sensitivity in a manner distinct from that of metformin. These drugs increase peripheral glucose utilisation in skeletal muscle and adipose tissue, reduce hepatic glucose output, increase fatty acid uptake and reduce lipolysis in adipose cells. This ultimately leads to a reduction in fasting and post-prandial plasma glucose, insulin and circulating free fatty acid (FFA) levels.10 TZDs are believed to exert most of their effects through binding to and activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ). PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta. On activation of this nuclear receptor by a ligand such as a TZD, PPARγ–ligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism.10 An endogenous ligand for this receptor has not been identified. Activation of PPARγ also leads to stimulation of adipogenesis,11 and this occurs more so in the subcutaneous rather than the omental fat depot.12 There are other isoforms of PPAR, and one of these, PPAR-α, is predominantly expressed in liver and is activated by hypolipidaemic agents such as fibrates. It mediates the triglyceride-lowering and high density lipoprotein (HDL)-raising effects of fibrates. Recent research has identified agents which are capable of activating PPARγ and PPARα simultaneously, and which could potentially have even greater beneficial effects than current TZDs. The development of TZDs has also led to the identification of non-TZD compounds which are capable of acting as full or partial agonists or as antagonists of PPARγ, depending on the tissue type and the specific target gene, in a manner analogous to the selective oestrogen receptor modulators (SERMs). It is therefore possible that future agents will be more selective and specific in their effects and potentially safer and more efficacious.13 Clinical trialsAlthough the evidence for therapy with these two agents is Level II, some of the data have either been published in abstract form only, or are only available from pharmaceutical company sources or websites or other organisations like the United States Food and Drug Administration (FDA). There are few studies which directly compare these agents as monotherapy or combination therapy with current standard treatment regimens. There are also no long term data on safety or effects on morbidity or mortality related to diabetes and cardiovascular disease. There are no studies directly comparing rosiglitazone and pioglitazone. The clinical trial data are summarised below. ◆ Both drugs lower HbA1c and fasting plasma glucose (FPG) levels when used as monotherapy8,9,14-22 (E2)For rosiglitazone, there was a dose-dependent reduction in HbA1c. The greatest effect was seen with a divided dose of 4 mg twice daily. In the various studies, this resulted in a reduction in HbA1c level of between −0.6 and −0.8 percentage points compared with baseline, and −1.5 to −1.8 compared with placebo. The FPG level was reduced by 2.3–3.6 mmol/L compared with baseline and 3.4–4.6 mmol/L compared with placebo. For pioglitazone, there was also a dose-dependent reduction in HbA1c level of −0.9 percentage points compared with baseline, and −1.6 compared with placebo, for patients taking 45 mg per day. The FPG level was reduced by 3.1 mmol/L compared with baseline, and 3.6 mmol/L compared with placebo. For both drugs, patients who were already receiving treatment with other agents at recruitment into the studies responded less well when swapped to monotherapy with the TZD than drug-naïve patients. ◆ Rosiglitazone and pioglitazone lower HbA1c and FPG levels when used in combination with a sulfonylurea or metformin8,9,23-26 (E2)Rosiglitazone (2 mg twice daily) added to various sulfonylureas over 26 weeks resulted in a reduction in HbA1c level of −0.8 percentage points compared with baseline, and −1.0 compared with placebo plus sulfonylurea. The FPG level was reduced by 2.09 mmol/L. When added to metformin (2.5 g), rosiglitazone (8 mg per day) reduced the HbA1c level by −0.78 percentage points and the FPG level by 2.7 mmol/L compared with baseline, and reduced the HbA1c level by −1.2 percentage points and the FPG level by 2.9 mmol/L compared with placebo plus metformin. Pioglitazone (30 mg) added to sulfonylurea reduced the HbA1c level by −1.3 percentage points compared with baseline and the FPG level was reduced by 2.9 mmol/L. When pioglitazone was added to metformin, the HbA1c level was reduced by about −0.7 percentage points, and the FPG level fell by 2.4 mmol/L compared with baseline. Compared to placebo plus metformin, pioglitazone (30 mg) plus metformin reduced the HbA1c level by −0.83 percentage points and the FPG level by 2.1 mmol/L. ◆ Rosiglitazone and pioglitazone lower HbA1c and FPG levels when used in combination with insulin8,9,27,28 (E2)Rosiglitazone (4 mg or 8 mg per day) added to insulin reduced HbA1c levels by −0.6 and −1.2 percentage points (respectively) compared with baseline and −0.7 and −1.3 compared with placebo plus insulin. Congestive heart failure was reported in two patients in each rosiglitazone group (comprising 106 and 103 patients) and one in the placebo group (103 patients). Rosiglitazone is not registered for use in combination with insulin.27 Pioglitazone (15 mg or 30 mg) per day added to insulin reduced HbA1c levels by −0.99 and −1.26 percentage points (respectively) compared with baseline and −0.73 and −1.00 compared with placebo plus insulin. Sixteen per cent of patients in the 30 mg pioglitazone plus insulin group had a reduction in their insulin dose of more than 25%.28 In these two studies, the incidence of oedema was significantly increased in the groups treated with TZD plus insulin.27,28 ◆ Both drugs lower fasting insulin and C-peptide levels when used as monotherapy or in combination therapy8,9,14-26 (E2)The significant reduction in insulin and C-peptide levels is consistent with the mechanism of action of these drugs as insulin sensitisers. ◆ Both drugs increase HDL and LDL and decrease FFA levels; pioglitazone lowers triglyceride levels8,9,14-32 (E2)Rosiglitazone significantly increased low-density lipoprotein (LDL) levels (mean increase, 15%–20%29) compared with baseline and controls, whereas, although pioglitazone increased LDL levels compared with baseline, there was no difference compared with controls. Rosiglitazone also tends to increase total cholesterol level and studies have reported variable effects on ratios of total cholesterol to high-density lipoprotein (HDL) and of LDL to HDL. In patients taking rosiglitazone, the ratios are either unchanged or increased. In studies over six months, the ratios tended to be unchanged because LDL reached a plateau and HDL continued to increase. There is a trend for these ratios to decrease in patients treated with pioglitazone. A recent, small, non-randomised and unblinded study suggested that pioglitazone increased levels of HDL to a greater, and LDL to a lesser, extent than rosiglitazone30 (E4). No randomised comparative study has been undertaken. It is known that modest increases in LDL levels correlate with increased cardiovascular risk. However, as has been reported for troglitazone,6 the increase in LDL level associated with rosiglitazone and pioglitazone is mainly in the larger, more buoyant and less atherogenic particles of LDL.31,32 Pioglitazone significantly reduced triglyceride levels. The long term effects of these alterations in lipid profile are unknown. Comparison with current antidiabetic drugsIn a published abstract and in the product information, rosiglitazone (2 mg twice daily and 4 mg twice daily) was directly compared with glibenclamide (or glyburide) at "optimally titrated dose". Patients in all three groups showed a statistically significant improvement in glycaemic control. The HbA1c level fell 0.27% and 0.53%, respectively, for the two rosiglitazone groups and 0.72% for the glibenclamide group at one year.8,33 Rosiglitazone was said to be "statistically equivalent" to glibenclamide at lowering HbA1c at one year, although the mean dose of glibenclamide is not stated (but, according to the FDA website, is 7.5 mg/day),29 and the graph in the product information shows that there was a deterioration in glycaemic control in the first six months in the two rosiglitazone groups. There was no statistical analysis provided for any time points other than one year. Rosiglitazone at 4 mg twice daily resulted in a significantly greater reduction in FPG level at one year than glibenclamide (−2.3 mmol/L v −2.0 mmol/L, respectively; P < 0.033).33 A study comparing rosiglitazone with metformin has not been published, but some information can be accessed through the FDA website.29 Patients were placed on metformin therapy at recruitment and the dose was increased to 2.5 g per day. They were then randomly allocated to continue to take metformin, to stop taking metformin and start taking rosiglitazone (4 mg twice daily) or to add rosiglitazone (4 mg twice daily) to their metformin therapy. The combination of the two agents was better than either used as monotherapy, but there was also a subset of patients in the group converted from metformin to rosiglitazone monotherapy who showed an abrupt deterioration of glycaemic control over the 24 weeks.29,34 However, no statistical analysis is provided. There are no similar studies published for pioglitazone. DeFronzo has reviewed studies of monotherapy with conventional agents and compared the efficacy of sulfonylureas, metformin, acarbose and troglitazone. From a similar starting HbA1c level, sulfonylureas and metformin reduced the HbA1c level by 1.5%–2.0% and the acarbose level by 0.7%–1.0%. Troglitazone reduced the HbA1c level by 1%–1.2%.2 The monotherapy studies described above indicate that the reduction in HbA1c level with rosiglitazone and pioglitazone is probably less than that with sulfonylureas or metformin. Concerns about hepatotoxicityTroglitazone was the first agent in this class to be marketed in the United States and was withdrawn by the FDA in March 2000 because of severe and unpredictable hepatotoxicity and 61 related deaths.35 The incidence of troglitazone-induced acute liver failure is estimated to be 1 in 8000 to 1 in 20 000 patients treated.36 The side chain of troglitazone, an α-tocopherol (vitamin E) moiety, or its quinone metabolites, may be the reason for its hepatotoxicity, and therefore this may not represent a class effect.17 To date, there have been three case reports of hepatotoxicty potentially caused by rosiglitazone and one potentially caused by pioglitazone. The agent was not proved to be the cause in any of these cases, all of which resolved with supportive care and withdrawal of the agent.37-40 In clinical trials, asymptomatic, reversible elevations of hepatic enzymes during treatment with both drugs have been noted, but rates were similar to those with placebo and resolved without withdrawal of the drug.41 The product information for both drugs states that these agents are contraindicated in patients with alanine aminotransferase (ALT) levels more than 2.5 times the normal level at baseline. Caution should be exercised when using these drugs in patients with hepatic enzyme level elevations of 1–2.5 times normal at initiation. It is also recommended that liver function tests (LFTs) be performed at baseline and every second month for the first year of therapy, and then periodically thereafter. If symptoms of liver dysfunction occur, LFTs should be checked. If the ALT remains elevated to more than three times the normal level, with or without symptoms, the drug should be discontinued.8,9 Adverse reactions and side-effectsIn all clinical trials for both rosiglitazone and pioglitazone, the incidence of adverse events, with the exception of weight gain and peripheral oedema, was similar to placebo. As monotherapy, neither drug caused hypoglycaemia, but in combination therapy mild hypoglycaemia has been reported and, in some cases, the dose of sulfonylurea, insulin or metformin was reduced8,9,23-28 (E2). Dose-dependent weight gain of 0.5–3.7 kg has been noted in the clinical trials and seems to be a class effect. The least weight gain was seen when used in combination with metformin.8,9,14-17,20-28 Weight gain is likely to be multifactorial in nature and could be the result of increased adipogenesis, increased appetite and oedema.11-15 Despite the weight gain, there are clearly improvements in insulin sensitivity and glycaemic control. Some studies report that the weight gain is associated with a reduction in waist : hip ratio, supporting the theory that there is a "shift" in fat distribution from visceral to subcutaneous fat depots, which confers less cardiovascular risk.15 In all studies, oedema occurred more frequently in the TZD treatment groups, although it was generally mild and did not lead to withdrawal from treatment. The incidence of oedema is about 3%–5%, although, when rosiglitazone or pioglitazone was combined with insulin therapy, the incidence rose to 13%–16%, compared with 5%–7% in the group receiving insulin plus placebo.8,9,14-17,20-28 There is also an increase in plasma volume of 6%–7%, and patients with New York Heart Association Class III and IV cardiac status were excluded from the studies (both drugs are contraindicated in these patients). This increase in plasma volume is also likely to be responsible for the mild reduction in haemoglobin level seen with all TZDs.6 PrecautionsThere are no data on the use of these drugs in pregnancy or lactation. In animal studies both drugs cross the placenta, and fetal loss, retarded fetal development and suppression of postnatal growth have been seen in rats.8,9 There were no significant effects on levels of the oral contraceptive pill in healthy women taking rosiglitazone, and the drug's manufacturer reports that no impairment of efficacy would be expected.8,42 There is no similar study for pioglitazone, but the product information recommends that alternative modes of contraception be used.9 Women with polycystic ovarian syndrome and insulin resistance should be advised that treatment with TZDs may result in resumption of ovulation and advice regarding suitable contraception should be given.8,9 Both drugs are contraindicated in moderate to severe liver dysfunction. Dose reduction is not required in elderly patients or those with renal impairment.8,9 Although animal studies have shown tumour-inducing effects for familial adenomatous polyposis and sporadic colon cancer in mice, there are no clinical data yet.43 However, mutagenicity and carcinogenicity studies have not raised any other significant concerns.8,9 These agents should be avoided in patients with significant cardiac dysfunction. There are no data in humans under 18 years of age. Conclusions and recommendationsThe thiazolidinediones are a unique class of drugs for the management of type 2 diabetes and they act to improve insulin resistance. Current evidence suggests that they are effective in the treatment of type 2 diabetes, but there is no evidence to suggest that they are better than currently available drugs and no data on long term safety or effects on morbidity and mortality related to diabetes and cardiovascular disease. Since the mechanism of action of TZDs is different from other currently available antidiabetic agents, it seems logical that they would be useful in combination therapy. So far, there are no studies assessing the effect of the TZDs when added to the combination of sulfonylurea and metformin, or to insulin combined with sulfonylurea or metformin. There is little difference between the two agents, although pioglitazone may have a more favourable effect on lipid profile than rosiglitazone. There are some data that show that these drugs may preserve beta-cell function, and it has been suggested that they should therefore be used early in the disease process, but there are no studies to support this hypothesis. Until there are more data available, these agents should probably be reserved for use in combination therapy in patients who are unable to be managed with current standard treatment combinations (ie, metformin, sulfonylurea, acarbose and insulin),44,45 and who fulfil the current prescribing guidelines. The development of thiazolidinediones has opened the door to some exciting research and to the development of other new agents for the treatment of type 2 diabetes mellitus. Important messages for patients are shown in Box 3. 1: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system4 for assessing the level of evidence. E1 Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1: Evidence obtained from well-designed, pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case–control studies, or interrupted time series without a parallel control group. E33 Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV: Evidence obtained from case-series, either post-test, or pre-test and post-test. 2: Drug profile of rosiglitazone and pioglitazone Action: TZDs activate peroxisome proliferator-activated receptor γ (PPARγ) and thereby regulate a number of genes involved in glucose and lipid metabolism. They act to improve insulin sensitivity. Onset: Both rosiglitazone and pioglitazone are rapidly absorbed and have high bioavailability. The timing of dose in relation to food does not significantly affect absorption or serum levels. Changes in fasting plasma glucose may start to be seen within two weeks, but maximal effects on glycaemic control may not be evident until 6–14 weeks after commencement of therapy. Dosing: Both rosiglitazone and pioglitazone are available as oral formulation. Rosiglitazone comes in 2 mg, 4 mg and 8 mg tablets and pioglitazone in 15 mg, 30 mg, and 45 mg tablets. No dosage adjustment is required for renal impairment. Recommended dose for rosiglitazone (Avandia; GlaxoSmithKline) — Commence at 4 mg per day, and, if necessary, increase to 8 mg per day after 6–8 weeks as a single or divided dose given with or without food. There is no additional benefit from doses higher than 8 mg per day. The largest dose given in combination with sulfonylurea in clinical studies was 2 mg twice daily. Recommended dose for pioglitazone (Actos; Eli Lilly) — Commence at 15 mg per day, and, if necessary, increase to 30 mg per day up to a maximum of 45 mg per day after 4–6 weeks. Give as a single dose with or without food. The largest daily dose used in clinical studies of pioglitazone in combination with insulin or sulfonylurea was 30 mg. Metabolism: Both drugs are extensively metabolised by hepatic cytochrome P450. Rosiglitazone metabolites are essentially inactive and mainly excreted in the urine. Some of the pioglitazone metabolites are active and are excreted in faeces and urine. Neither drug inhibits cytochrome P450. Although no significant drug interactions have so far been identified, prescribers should be vigilant for possible interactions, especially with drugs metabolised by or affecting the cytochrome P450 system. Adverse effects: Both drugs are well tolerated. There have been some case reports of hepatic dysfunction in patients taking the two drugs but causation was not definite. The incidence of elevations in enzyme levels on liver function tests was the same in treatment and placebo groups. The most common adverse effects include weight gain, oedema and dilutional anaemia. Because of fluid retention, these drugs may exacerbate heart failure and should not be prescribed to patients with New York Heart Association III-IV cardiac status. The drugs are also contraindicated in pregnancy and lactation and have not been tested in children. In women with polycystic ovarian syndrome with insulin resistance, treatment with these drugs may restore ovulation and appropriate advice regarding contraception should be given. When used in combination with other antidiabetic drugs, rosiglitazone and pioglitazone have been associated with mild hypoglycaemia requiring dose reduction of sulfonylurea, metformin or insulin. 3: Important messages for patients Thiazolidinediones (TZDs): Are a new type of drug for the treatment of type 2 diabetes. Improve diabetic control by increasing the body's sensitivity to insulin. Can cause mildly low blood sugar levels if they are used in combination with other medications for diabetes. Can cause some weight gain and mild fluid retention. Should not be taken if you are pregnant or breastfeeding or if you have significant heart or liver problems. Your doctor may need to advise you about methods of contraception, as you should not become pregnant while taking these medications. You will need to have regular liver function tests.

Trisha M O'Moore-Sullivan MB BS, FRACP · Johannes B Prins MB BS, PhD, FRACP

The widespread application of public iodine supplementation programs, which cover about 3–4 billion people worldwide,1,2 is a response to the paucity of iodine in the natural diet in many regions of the world and the severe public health consequences of iodine deficiency.3 However, in some countries, the tendency to low iodine intake has mostly been corrected by haphazard increases in the iodine content of certain parts of the diet.4 In the United Kingdom, dairy products may contain extra iodine as a result of adding iodine to cow feed to increase the animals' reproductive performance or of using iodine-containing cleansing agents in the dairy industry. As reviewed by Phillips,5 this unplanned increase in iodine intake has eliminated endemic goitre in Britain during the last 30–40 years. In the United States, London and colleagues encountered cases of unexplained very high iodine intakes (1100–1300 µg per day) in 1964. Subsequently, they discovered that bakers used iodine-containing conditioners in bread and that this caused high levels of iodine intake.6 Obviously, such unplanned variation in dietary iodine is a hazardous way of providing a population with an adequate intake of iodine, as mechanisms unrelated to disease prevention can profoundly alter iodine intake. To some extent, Australia may be a country where factors other than disease prevention have modulated the intake of iodine, and iodine intake may now be in an unplanned phase of decrease.7 A report by McElduff et al8 (page 317) in this issue of the Journal seems to support this proposition. McElduff and colleagues looked at the frequency distribution of whole-blood thyroid-stimulating hormone (TSH) concentrations in newborns in the northern Sydney area. TSH is measured as part of screening for congenital hypothyroidism. In 5%–10% of infants around 72 hours after birth, TSH values were above 5 mIU/L. The World Health Organization (WHO) recommends assessment of TSH concentrations in newborns to detect population iodine deficiency, and specifies that less than 3% of newborns should have a whole-blood TSH concentration over 5 mIU/L. In a subsample of neonates, McElduff et al found that, during pregnancy, their mothers had a median urinary iodine concentration of 109 µg/L, indicating borderline mild iodine deficiency. WHO specifies that the median urinary iodine concentration in adults should be over 100 µg/L, and an extra iodine intake of 50 µg/day in pregnant and lactating women.1 Thus, the corresponding median urinary iodine concentration of pregnant women would be around 130 µg/L. McElduff et al warn that Sydney may be an area of iodine deficiency, and suggest that iodine intake and risk of disease should be investigated in more detail. Their concern is well founded. Even if there is no documentation that these borderline iodine values are harmful to a mother and child, the margin of safety is small. Furthermore, in Australia, there is apparently no regular surveillance of population iodine status, or of the variable iodine content of dairy products and other foods. The iodine intake may well be even lower in other sections of the Australian population. Severe iodine deficiency may cause brain damage and other developmental disorders,3 and goitre and its complications may affect a significant proportion of the population at all levels of iodine deficiency.9 Any public healthcare system should evaluate iodine intake and prevent disorders caused by iodine deficiency. Several factors need to be taken into account in such an evaluation and prevention program: The relationship between iodine intake and the risk of thyroid disease is not a simple one. Even if iodine supplementation may decrease the risk of some thyroid disorders, the risk of other disturbances at a younger age, such as hypothyroidism and Graves' disease, may increase.4 Severe iodine deficiency, with a median urinary iodine excretion of less than 25 µg/24 h, is an instance where giving any type of iodine supplementation is better than doing nothing. However, at higher levels of intake, careful planning and surveillance are needed. The methods often used for evaluating iodine intake and the risk of disease are not perfect. Neonatal screening showing more than 3% of TSH values over 5 mIU/L is not, by itself, enough to indicate insufficient maternal iodine intake. Detection of neonatal hypothyroidism requires identification of relatively high TSH levels (20–25 mIU/L), and many TSH assays and screening programs are not designed to identify TSH values around 5 mIU/L with reasonable confidence. Technical aberrations can easily give an increased frequency of elevated blood TSH concentrations. One such aberration occurs with sampling of blood before TSH has fully returned to baseline levels after the early postnatal surge. As discussed by McElduff et al,8 early sampling may have contributed to their findings. Iodine deficiency is not the only pathogenetic mechanism leading to an increase in blood TSH levels in neonates. Iodine has an autoregulatory inhibitory effect on the thyroid gland, with a fall in both thyroid hormone synthesis and secretion. Possibly, this mechanism has been developed to protect against hyperthyroidism induced by a sudden iodine load. In a variety of abnormal states the thyroid gland overreacts, producing hypothyroidism. The thyroid of the fetus and infant is considerably more sensitive to iodine inhibition than the maternal thyroid. Excess iodine intake, rather than iodine deficiency, in mother or infant has been a more common cause of transient neonatal hypothyroidism in countries with a relatively low iodine intake, such as Germany, Italy and Belgium.4 In severe iodine deficiency, iodine supplementation to the mother decreases the abnormally high serum TSH in both the mother and the newborn.10 On the other hand, in pregnant women with urinary iodine concentrations around 50 µg/L, iodine supplementation decreases TSH levels in mothers, but not in cord blood. TSH levels in the newborn may even be higher after iodine supplementation.11 The finding of McElduff et al of a positive correlation between maternal urinary iodine concentrations during pregnancy and whole-blood TSH levels in neonates needs further elaboration,8 but it may be an example of iodine autoregulation of the fetal thyroid. Should pregnant women living in mild and moderately iodine-deficient areas receive iodine supplements, and does supplementation involve any risk? An increase in iodine intake will improve thyroid function in pregnant women, which is important for early brain development in their infants.12 There are still things to be learned about the influence of small amounts of iodine on neonatal thyroid function in mild iodine deficiency, and about pituitary/thyroid feedback regulation in the fetus and small infant. A tendency to a slight increase in neonatal TSH level after iodine supplementation may be of little importance, as, in these infants, the serum concentration of T4 (which may be the major thyroid hormone influencing brain development12) does not show a concomitant reduction.11 Finally, iodine supplementation imposes no risk of worsening of postpartum thyroid dysfunction in the mother.13 In conclusion, pregnant women should not be iodine deficient. To strictly follow WHO guidelines on iodine intake, pregnant women with similar urinary iodine levels to those found by McElduff et al could alter their diet towards more iodine-rich foods, or they could take a small iodine supplement as part of the vitamin and mineral supplements recommended for pregnant women in most countries. However, there is at present no evidence that a supplement will have beneficial effects. Ideally, iodine intake should be evaluated and kept optimal in the entire population, taking into account that unnecessary high iodine intakes may be associated with more hypothyroidism.4 The studies by McElduff et al8 and other researchers7 demonstrate the need for national monitoring and adjustment of iodine intake as part of a program of prevention of thyroid disorders and their complications. Such initiatives normally involve government nutrition or public health agencies in collaboration with experts in thyroid diseases, nutrition and epidemiology and prevention.1,2 It would be an added bonus if the program elucidated some of the unresolved issues in the field of population iodine supplementation in developed countries. This would continue the considerable contribution of Australian scientists to the understanding and correction of iodine-deficiency disorders.3,14

Peter Laurberg MD, DMedSci · Susanne B Nøhr

Objective: To determine whether thyroid-stimulating hormone (TSH) concentrations in a large sample of neonates meet World Health Organization criteria for an iodine-replete population (< 3% of neonates with whole-blood TSH concentrations > 5 mIU/L), and, in a small subset of neonates, to examine the correlation between maternal urinary iodine and neonatal TSH concentrations.Design: Cross-sectional study of neonatal whole-blood TSH values obtained as part of a routine newborn screening program.Setting: Royal North Shore Hospital (RNSH) in northern Sydney.Participants: Two anonymous samples of neonates born at RNSH (1316 infants born between August 1998 and April 1999 and 1457 infants born between 1 March and 31 December 2000); and 84 infants whose mothers had attended RNSH between September 1998 and August 1999 and supplied a urine sample for iodine measurement.Main outcome measures: Iodine status of neonates (proportion with whole-blood TSH values > 5 mIU/L), and urine iodine concentrations of pregnant women.Results: In the two large population samples of neonates, 8.1% (95% CI, 6.6%–9.5%) and 5.4% (95% CI, 4.3%–6.6%), respectively, had whole-blood TSH values > 5 mIU/L (prevalence range for mild thyroid deficiency, 3%–19%). Comparing the TSH values of the 1316 anonymous infants and the 84 identified infants showed no difference between the proportions with TSH values > 5 mIU/L (8.1% v 10.7%, respectively; P = 0.39). Urine iodine concentrations in the 84 pregnant women indicated borderline mild iodine deficiency. TSH values in their 84 infants were positively correlated with maternal urine iodine concentrations.Conclusions: Our results suggest that the population of northern Sydney may have mild iodine deficiency. However, the expected relationship between maternal urine iodine levels and neonatal TSH concentrations was not found.

Aidan McElduff PhD, FRACP · Patrick McElduff BMath, PhD · Jenny E Gunton MB BS, FRACP · Graham Hams MAppSc · Veronica Wiley PhD · Bridget M Wilcken MB ChB, FRACP