Endocrinology

Objectives: To document diagnosis rates of type 2 diabetes mellitus in children and adolescents in Western Australia over the past 12 years, the clinical characteristics of these patients and any comorbidities.Design: Review of a prospectively recorded diabetes database.Setting: Tertiary paediatric referral centre (the only such centre in WA).Patients: All children and adolescents aged < 17 years diagnosed with type 2 diabetes between 1990 and 2002 and managed by Princess Margaret Hospital Diabetes Unit.Main outcome measures: Anthropometric and demographic data; glycohaemoglobin (HbA1c) level; blood pressure; lipid levels; presence of acanthosis nigricans.Results: 43 patients (15 males and 28 females) were diagnosed with type 2 diabetes. Age (SD) at diagnosis was 13.6 (1.8) years. The rate of diagnosis has been progressively increasing (average annual increase in the unadjusted overall rates of type 2 diabetes was 27%). Twenty-three patients (53%) were of Indigenous origin and 18 (42%) resided in rural areas. The mean (SD) HbA1c level at diagnosis was 10.0% (3.2%). Seventy-two per cent of patients had acanthosis nigricans, 59% had hypertension, and 24% had hyperlipidaemia.Conclusions: There has been an increase in the diagnosis rate of type 2 diabetes in children and adolescents in WA. Comorbidities are frequent.

Sarah K McMahon MB BS(Hons) · Aveni Haynes MB BChir · Nirubasini Ratnam BSc(Hons), RN · Maree T Grant RN · Christine L Carne PGRN(Paed) · Timothy W Jones FRACP · Elizabeth A Davis FRACP

No adverse pregnancy outcomes with metformin use have been reported, except in one unmatched study. Otherwise, the studies are small and non-randomised, with the exception of one prospective, randomised controlled trial, currently under way, comparing metformin with insulin in women with gestational diabetes mellitus (the MiG trial). No long-term follow-up data for offspring of mothers receiving metformin have been published. Any woman with diabetes should be as close to euglycaemia as possible before pregnancy. In some circumstances (eg, severe insulin resistance), metformin therapy during pregnancy may be warranted. When metformin treatment is being considered, the individual risks and benefits need to be discussed with the patient so that an appropriate decision can be reached.

David Simmons FRACP, MD · Barry N J Walters FRACP · Janet A Rowan FRACP · H David McIntyre FRACP

QuestionDoes high-impact exercise in the prepubertal period have an osteogenic effect in females? Trial details Design: Randomised, partially blinded clinical trial. Participants: 21 monozygotic twin pairs of prepubertal girls aged 7–10 years; 15 pairs recruited through a twin registry and 6 pairs recruited from local schools. Twin pairs were randomly allocated, one to the intervention group and one to the control group. Intervention: The twin in the intervention group engaged in 10 minutes of impact exercise on three occasions each week for 9 months, supervised by a teacher at school. The twin in the control group received no extra contact with teachers or researchers. Main outcome measures: Adipose tissue measured by skinfold measurements; body weight, lean tissue mass, relative fat mass (%fat) and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry. Main results: At 9 months, girls in the impact exercise group had reduced adipose tissue compared with those in the control group (5.6% reduction v 0.6% increase in skinfold measurements [P < 0.05] and a 3.7% reduction v 1.5% reduction in %fat [P < 0.05]), but no difference in body weight or lean tissue mass. In a post-hoc analysis of 12 pairs of twins who were not undertaking impact activities outside the intervention program, there was a higher proximal femur BMC in the intervention v control group (11.9% v 9.4% increase [P < 0.001]). Conclusion: The authors conclude that a high-impact exercise intervention results in an additive osteogenic bone response in prepubertal girls not undertaking other impact activity, but has no effect on bone status in girls already involved in high-impact sports. CommentaryRationale for the trialTo prevent osteoporosis, it is important to maximise bone mineral accrual in early life and minimise bone loss in later life. It is thought that high-impact exercise in premenarchal years may influence the accrual component of this process, although the most effective exercise regimen remains unknown. Trial methodsMonozygotic twins were selected to assure inherent control of genetic confounders, such as prepubertal status, rate of maturation and body dimension and, to some extent, environmental confounders, such as diet. Twins were not selected on any basis of perceived need, such as low bone mass or low involvement in impact activities. The trial’s methods of randomising twin-pairs to intervention and control groups and group allocation concealment from the radiographer are not described, but would be needed for inclusion of this trial’s findings in a systematic review. Major outcome measurements were based on dual-energy x-ray absorptiometry, a non-invasive, objective test for measuring bone and body composition which was read by a radiographer blinded to group status. The primary outcome was bone mineral content (BMC), a mass measurement that can be estimated with more precision than bone mineral density (BMD). It is unclear whether those measuring physical characteristics or analysing the data were blinded. No measurement of dietary intake was reported, and physical activity was not monitored objectively before or during the study. One girl from each twin-pair was randomly assigned to an impact exercise program, while the other received no intervention. The effect of confounders, which has been problematic in many non-randomised studies of bone health in childhood, was minimised to some extent, but bias may have resulted from parents’, teachers’ and participants’ awareness of group status. Chances for contamination between groups were high, with twins cohabiting and attending the same school. The trial design could have been strengthened by the control group receiving a low-impact exercise program or a placebo intervention such as health education. The success of the intervention would have depended on sustainability of program goals and intensity and motivation provided by teachers, and any differences in teachers’ ability to provide these would influence the nature of the intervention. Effects often overlooked are that more efficient skill execution over time reduces workload and that well trained muscles can attenuate bone load. Load is difficult to measure, but would be an essential component of future trials of physical activity in children. A commentary on compliance from the participants’ perspective would also have been useful to inform future studies. The conclusion that the intervention was more effective in girls not undertaking impact activity outside the intervention is not reflected in the summary statistics. In the 21 girls in the high-impact exercise group, BMC increased by 11.96%, compared with 11.90% in the subgroup of 12 girls inactive outside the intervention. Without further information, it is difficult to understand the large difference in t values between the two analyses (t = 0.78 for the whole group v t = 2.97 for the otherwise inactive subgroup) and why a small effect size was significant in 12 twin-pairs. A mean-versus-differences plot would have shown if the effect was greater in girls with low BMC, and additional statistics, such as 95% confidence intervals and number needed to treat (say, to improve BMC by 5%), would help to clarify the clinical importance of the results. New informationResults of musculoskeletal gains should be interpreted cautiously, as groups improved their bone mass equally, and so the role of exercise in the acquisition and maintenance of peak bone mass remains unclear. Further studies are needed, because many public health recommendations are being made even though there is little evidence supporting them. Implications for clinical practiceIntervention activities were developmentally appropriate and the simplicity of the program, with only 10 minutes of exercise on three occasions each week, could be attractive for public health interventions and inclusion in planning and policy documents. However, it is important to ascertain if certain subgroups, such as inactive children or those with low bone mass, benefit most. Family-based activities to target such groups may be more efficient than wider school-based activities that involve many children who may not benefit. To reliably measure the effects of impact exercise on early bone health, larger studies with a more generalisable population will be needed, with stratified random allocation to groups for greater control of potential confounders, and with more attention paid to issues of quality program delivery. Although large trials are a challenge to conduct, they are essential for increasing confidence in their clinical implications. Risk versus benefit must also be considered. In programs for prepubertal children, it is essential that teachers and parents have the expertise to ensure safe landings from jumps and safe increases in workload.

Jennifer K Peat PhD · Geraldine A Naughton PhD

Clinical record A 43-year-old man presented with myalgia and upper respiratory tract symptoms. He had noted weight gain of 7 kg, lethargy and cold intolerance over the previous 12 months. He had no chest pain, rash or fever. His past history included acute myocardial infarction (AMI) 12 years earlier. Subsequently, he had been taking low-dose aspirin. He commenced simvastatin 2 years after the AMI for hypercholesterolaemia (> 7 mmol/L). His sister and father have hypercholesterolaemia and his father had an AMI before 40 years of age, suggesting heterozygous familial hypercholesterolaemia. Two years before presentation, his hypolipidaemic therapy was switched from simvastatin to atorvastatin, although he denied experiencing any side effects of the former. He reported consuming 40–50 g/day of alcohol, and that he had recently quit smoking. Examination revealed that he was hypertensive (160/90 mmHg) and obese (body mass index, 32 kg/m2). He had marked corneal arcus, but no tendon xanthomas or xanthelasma, and no goitre. There was no muscle tenderness and power was normal. Reflexes were delayed. The results of some of the laboratory tests performed are shown below. In addition, normal findings were recorded for full blood count, erythrocyte sedimentation rate, and C-reactive protein, electrolyte, glucose, and calcium levels. Serological tests for hepatitis, and test results for protein electrophoresis, antinuclear factor, immunoglobulin and prostate-specific antigen levels, were all normal. There was no myoglobinuria, haematuria or proteinuria. Chest x-ray findings were normal, electrocardiography showed old Q waves, and an abdominal ultrasound showed hepatic steatosis. Apart from γ-glutamyltransferase, normal results were obtained for all other liver function tests. Statin-induced myositis was suspected and atorvastatin was stopped. Thyroid function tests instituted after endocrine review 5 days later revealed hypothyroidism (free T4, 1.9 pmol/L [normal range, 11.0–23.0 pmol/L] and thyroid-stimulating hormone, > 100 mU/L [normal range, 0.30–5.00 mU/L]). Tests for thyroid peroxidase and thyroglobulin antibodies both gave positive results, suggesting Hashimoto’s thyroiditis. The patient was prescribed thyroxine 50 μg daily, with subsequent slow-dose titration because of ischaemic heart disease. The Box (page 473) shows the gradual normalisation of the creatine kinase (CK) level over time. Lipid levels remained elevated despite thyroxine therapy. Simvastatin 10 mg/d was recommenced with careful monitoring. The dose was increased progressively up to 80 mg daily for persistent hyperlipidaemia. Despite full-dose statin therapy, there was no change in the findings of liver function tests and only mild asymptomatic elevation of CK levels. Investigation Result (normal range) Creatine kinase (CK) (IU/L) 4890 (< 240) CK-MB index (%) 2.0 (< 5.0) Total cholesterol (mmol/L) 9.0 (< 5.5) Triglycerides (mmol/L) 2.7 (< 2.0) High-density lipoprotein cholesterol (mmol/L) 1.2 (> 1.0) Urea (mmol/L) 6.7 (2.3–7.6) Creatinine (mmol/L) 0.197 (0.05–0.11) γ-Glutamyltransferase (U/L) 196 (10–55) Statin-related muscle complaints include myalgia, myositis and rhabdomyolysis.1 Hypothyroidism itself can cause musculoskeletal symptoms, including myalgia, Hoffmann’s syndrome (muscle stiffness, weakness and increased muscle mass, frequently with elevated creatine kinase [CK] level), Kocher–Debré–Sémélaigne syndrome (diffuse muscular hypertrophy and weakness in congenital hypothyroidism), a polymyositis-like syndrome (with proximal muscle weakness and markedly elevated CK level), and rhabdomyolysis.2 The coexistence of hypothyroidism and statin use may increase the risk of myopathy.3 Statin-induced myopathies tend to resolve within a few days to 1 month after ceasing statin use.4 Persistent elevation of CK level after stopping statin therapy has been reported, prompting further investigation and leading to the discovery of coexisting hypothyroidism.3,5 Thyroxine replacement therapy was reported as normalising CK and total cholesterol levels in these patients. However, to the best of our knowledge, ours is the first report of a patient with treated hypothyroidism in whom statin therapy was safely reintroduced after the resolution of myositis. While the exact aetiology of the myositis in our patient can not be proven, it seems most probable that it was precipitated by a combination of hypothyroidism and statin use. Full-dose statin therapy did not cause a recurrence of myositis once the hypothyoidism had been treated, implicating hypothyroidism as a contributing factor. However, it is uncertain whether the hypothyroidism would have resulted in myositis without coexisting statin therapy. The patient has mild asymptomatic elevation of CK level while taking simvastatin and with adequate thyroxine replacement. Such asymptomatic CK elevation is frequently seen in subjects during statin trials with both placebo and statin therapy, and continued treatment while asymptomatic and with CK levels up to 10 times the upper limit of normal has to date proven to be safe.6 As hypothyroidism can cause hyperlipidaemia, we suggest that thyroid function should be checked before commencing statin therapy, particularly if there are any clinical features to suggest its presence. We also suggest that patients who develop symptoms or signs suggestive of myopathy while taking statin therapy should be tested for hypothyroidism. As in our patient, it may be safe to cautiously reintroduce statin therapy in patients with a history of myopathy, once coexisting hypothyroidism has been treated. Lessons from practice Hypothyroidism should be considered as a secondary cause of hypercholesterolaemia in all patients. Patients developing myopathy when taking statin therapy should be tested for hypothyroidism. It may be safe to cautiously reintroduce statin therapy in patients with myopathy, once coexisting hypothyroidism has been treated. Biochemistry results and drug dosages over time Year 1 Year 2 Year 3 Year 4 Year 5 20 May 25 May 22 Jun 27 Jul 22 Aug 28 Sep 1 Nov 5 Jan 12 Apr 17Aug 18 Mar 17 Jan 23 Jan Thyroid-stimulating hormone (mU/L) (NR, 0.3–5.0) >100 90.9 53.9 23.9 8.13 4.35 1.23 1.02 0.85 0.64 0.58 Total cholesterol (mmol/L) 9 10.2 8.9 8.2 6.2 6.5 5.7 4.4 4.9 4.0 4.4 Creatine kinase (IU/L) (NR, < 240) 4890 1839 336 196 216 209 442 320 Creatinine (mmol/L) (NR, 0.05–0.11) 0.197 0.171 0.14 0.14 0.14 0.12 0.14 0.12 0.12 0.12 0.12 Statin (mg/d) Stopped atorvastatin Started simvastatin 10 10 20 40 80 80 80 80 Thyroxine (μg/d) Started thyroxine 50 75 100 125 150 150 175 175 175 175 175 175 NR = normal range.

Leo P Rando MB BS · Sarah AL Cording · Harvey H Newnham MB BS, FRACP, PhD

Improved understanding of the regulation of body weight and activity is leading to new treatment strategies

Joseph Proietto FRACP, PhD · Louise A Baur FRACP, PhD

This can’t happen to me! Tackling type 2 diabetes. Tim Bowden. Sydney: Allen and Unwin, 2004 (xiii + 207 pp). ISBN 0 86431 473 6. We know that type 2 diabetes is very common in Australia, that its prevalence is increasing, and that a very large minority of the Australian population have several risk factors for diabetes. These facts are now becoming a matter of public, not just professional, knowledge and will lead to increased public demand for information on the disease, and how to avoid it. There are many excellent sources of information for the person with diabetes, but the diversity of those developing the condition means that additional well-written and accurate accounts are welcome. A first-hand account by someone with a condition has the capacity to make a profound impression on others beyond that of medical texts. Tim Bowden has made an important contribution of this sort that can be recommended with confidence to those newly diagnosed as well as those at risk. Bowden is a broadcast journalist well known for his affable and direct style of communication. He brings these skills to an account of his own diagnosis of type 2 diabetes at a routine medical assessment at the age of 65, and his experiences in learning how to cope with it. This is combined with interviews recounting the experiences of others and with key Australian experts. He provides straightforward information on the range of symptoms, causation, principles of management, monitoring and surveillance for complications. His focus is on the person with diabetes and how he or she can and should deal with the problem, including psychological reactions to the diagnosis and the behavioural adaptations subsequently required. Perhaps another round of editing would have reduced some occasionally irritating repetitiveness, but this book appears to have successfully targeted a public health need and is a welcome addition to currently available publications. Duncan J ToplissDirector Department of Endocrinology and Diabetes Alfred Hospital, Melbourne, VIC

Duncan J Topliss

Pituitary adenomas are found in 10%–25% of unselected autopsy series and are evident in about 10% of asymptomatic individuals by magnetic resonance imaging. Diagnosis of pituitary disorders is often delayed by lack of awareness and the subtlety of symptoms and signs. Hypopituitarism is suspected when peripheral hormone concentrations are low without an elevation in the corresponding pituitary tropic hormone(s). Severe adult-onset growth-hormone deficiency results in reduced muscle mass, increased fat mass and diminished quality of life, which are reversed by growth hormone replacement therapy. While trans-sphenoidal surgery remains first-line treatment for acromegaly, drug treatment has an important role in controlling residual growth-hormone excess and, in some circumstances, as first-line treatment. Dopamine-agonist therapy (cabergoline or bromocriptine) is the treatment of choice for micro- and macroprolactinomas. In patients with suggestive clinical features, elevated 24-hour urine free cortisol level is usually sufficient to diagnose endogenous Cushing’s syndrome; careful additional investigation is needed to determine whether the cause is Cushing’s disease (pituitary adenoma secreting adrenocorticotropic hormone [ACTH]), ectopic ACTH secretion or adrenal disease.

David M Hurley PhD, FRACP · Ken K Y Ho MD, FRACP

Rickets in children and osteomalacia in adults are caused by undermineralisation of bone, which increases its susceptibility to bending and fracture; treatment is with calcium, vitamin D or phosphate, depending on the specific mineral or vitamin deficiency. In Paget’s disease, osteoclasts are overactive and produce woven or “repair” bone, which is mechanically weaker than lamellar bone; treatment is with antiresorptive bisphosphonate drugs. Cancers can produce bone lysis through direct spread within the skeleton or production of endocrine parathyroid hormone-like factors; treatment is with a bisphosphonate, plus appropriate therapy for the cancer. Cancer can also produce hypercalcaemia if the capacity of the kidneys to excrete the calcium dissolved from bone is exceeded; treatment is with saline infusion to increase excretion and a bisphosphonate. Primary hyperparathyroidism is the other common cause of hypercalcaemia and is usually associated with a single parathyroid adenoma; it is best treated with parathyroidectomy. Hypocalcaemia may result from severe decrease in calcium absorbed or lack of parathyroid action; both are treated with calcium and vitamin D (ergocalciferol or calcitriol).

Richard L Prince FRACP, MD · Paul Glendenning PhD, FRACP

Objectives: (i) To evaluate the benefits and adverse effects of a Diabetes Day Care Program (DDCP); and (ii) to compare outcomes in two cohorts diagnosed before and after implementing the DDCP (“pre-DDCP” and “post-DDCP”).Design: Outcomes from the pre-DDCP cohort were compared with those of the post-DDCP cohort.Setting: The study was conducted from March 2001 to October 2002 at the Children’s Hospital at Westmead.Participants: The pre-DDCP cohort comprised all children newly diagnosed with type 1 diabetes from March 2000 to November 2000 (n = 49). The post-DDCP cohort were those diagnosed from November 2000 to August 2001 (n = 61).Main outcome measures: Length of stay, adverse events, insulin requirement and glycohaemoglobin (HbA1c) level over the first year after diagnosis were ascertained from medical records. Questionnaires to measure parents’ knowledge of diabetes, emotional adjustment to diabetes, and responsibility for and conflict over specific diabetes management tasks were completed by parents at 6-monthly intervals.Results: Median length of hospital stay decreased from 5.14 days (range, 2–10) to 1.70 days (range, 0–10) (P < 0.001). There were no differences between the two cohorts in insulin requirement at 12 months (pre-DDCP: 0.9 U/kg [95% CI, 0.8–1.0]; post-DDCP: 0.8 U/kg [95% CI, 0.7–0.9]; P = 0.22), HbA1c level at 12 months (pre-DDCP: 8.4% [95% CI, 8.0%–8.9%]; post-DDCP: 8.2% [95% CI, 7.9%–8.5%]; P = 0.37) and adverse events over the first year after diagnosis. Both groups reported similar scores for the parental questionnaires.Conclusions: Ambulatory stabilisation of children with type 1 diabetes provides similar metabolic outcomes for the child, and comparable levels of diabetes knowledge and similar psychosocial outcomes for the family, to inpatient stabilisation programs.

Shubha Srinivasan MB BS, FRACP · Maria E Craig FRACP, PhD · Linda Beeney PhD · Rachel Hayes MND · Nuala Harkin RSCN, APN · Geoffrey R Ambler FRACP, MD · Kim C Donaghue FRACP, PhD · Christopher T Cowell MB, FRACP

John B Dixon Senior Research Fellow, Monash University Department of Surgery, Alfred Hospital, Commercial Road, Melbourne, VIC 3181. john.dixonATmed.monash.edu.au To the Editor: I am concerned about a possible misrepresentation in the Journal. A recent Practice Essentials article included a case report describing the management of type 2 diabetes.1 The case involved a 51-year-old man with a 6-year history of type 2 diabetes and body mass index (BMI) of 32 kg/m2. The case report included a photograph, but this was not of a man with a BMI of 32 kg/m2. Ten consecutive professional staff working at a large Melbourne centre for bariatric (obesity) surgery were asked to estimate the man’s BMI. Estimates varied from 50 to 65 kg/m2. None accepted that his BMI was 32 kg/m2. All estimates placed this gentleman in the obesity class III category (BMI > 40 kg/m2). A man with a true BMI of 32 kg/m2 is shown in the Box. If indeed the man depicted previously has class III obesity, he is likely to suffer significant obstructive sleep apnoea,2 physical disability and poor quality of life, in addition to the metabolic syndrome and type 2 diabetes. The case report focused on the management of an unacceptable level of glycosylated haemoglobin (HbA1c) of 8.9%. The management may, arguably, be appropriate if his BMI were 32 kg/m2, although treatment options may promote weight gain. Unfortunately, the options and discussion were inadequate for the man depicted. This ill, disabled man deserves better assessment and care. His obesity-related conditions should be fully explored. The only management likely to have a significant effect on conditions related to class III obesity (diabetes, metabolic syndrome, sleep apnoea, physical disability and poor quality of life) is significant weight loss. The only treatment that reliably provides significant sustained weight loss for those with class III obesity is surgery. Obesity surgery therefore should be an essential inclusion in his treatment options. The beneficial effects of modern obesity surgery on type 2 diabetes, the metabolic syndrome, sleep and quality of life are well documented.3,4 I believe the inclusion of this illustration is a serious misrepresentation. Editor's note: We agree with Dr Nixon's remarks, and have replaced the inappropriate illustration in the article with the image he has kindly supplied. Patient with a body mass index of 32 kg/m2 (height, 172 cm; weight, 96 kg)

John B Dixon

Thyroid nodules are common clinically (prevalence, about 5%) and even more common on ultrasound examination (about 25%). About 5% of thyroid nodules are malignant. Most thyroid cancers are well-differentiated papillary or follicular tumours with an excellent prognosis (10-year survival, 80%–95%). The incidence of papillary thyroid cancer appears to be increasing on the east coast of Australia. Fine-needle aspiration biopsy of the thyroid is the most cost-effective diagnostic tool. Recommended initial management of all follicular carcinomas and of papillary carcinomas > 1.0 cm is total thyroidectomy followed by radioiodine ablation. Most patients should be managed postoperatively with doses of thyroid hormone sufficient to suppress plasma levels of thyroid-stimulating hormone. Recurrences can occur many years after initial therapy, and follow-up should be lifelong.

Emily J Mackenzie MB BS · Robin H Mortimer FRACP, FACP

Shanthi Kannan,* Christine H Rowland,† Gregory I Hockings,† Peta M Tauchmann,‡ Edwin A Blackwell§ * Endocrine Advanced Trainee, † Endocrinologist, ‡ Nurse Educator, § Haematologist, Greenslopes Private Hospital, Brisbane, QLD. Correspondence: Dr Christine Rowland, Greenslopes Private Hospital, Newdegate Street, Greenslopes, Brisbane, QLD 4120. c.rowlandATmailbox.uq.edu.au To the Editor: Intravenous immunoglobulin preparations containing maltose (eg, Intragam P [CSL Limited]) can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase, such as Advantage (Roche).1 Glucose dehydrogenase is an enzyme of the Pyrroloquinolinequinone class which reacts with the disaccharide isomer maltose present in Intragam P at concentrations of 10 g/100 mL,2 resulting in falsely elevated blood glucose level results. Blood glucose monitors, such as Precision (Medisense products), Medisense (Medisense products)3 or Accutrend (Roche), that use the glucose oxidase system, do not react with maltose and can be safely used for patients receiving Intragam P. We have had two patients in whom capillary blood glucose levels were over-estimated. One was a 64-year-old woman with type 2 diabetes who was being treated with haemodialysis, and who received Intragam P for immune-mediated thrombocytopenic purpura. Before being admitted, her diabetes was reasonably controlled by 10 units of protophane twice daily. She received prednisone (100 mg/day) from Day 1 to Day 13 and Intragam P intravenously each day from Day 2 to Day 6 and from Day 14 to Day 18. While the patient was receiving Intragam P, the Advantage monitor gave persistently higher readings than both the Precision monitor and plasma glucose level measurements. The following paired readings were obtained: Advantage capillary glucose reading of 9.3 mmol/L while the plasma glucose level was 2.3 mmol/L; and Advantage capillary glucose reading of 24.4 mmol/L while the plasma glucose level was 10.4 mmol/L. During the second course of Intragam P we noted that readings with the Precision monitor were equivalent to the measured plasma glucose level. This patient developed hypoglycaemia because her insulin doses were increased on the basis of falsely elevated capillary glucose readings as measured on Advantage blood glucose strips. A Precision monitor was used for this patient until after the haemodialysis treatment which followed the final dose of Intragam P. After this time Advantage blood glucose readings approached those obtained with the Precision monitor. A second patient — a 35-year-old woman who was not known to have diabetes, but was having her glucose levels monitored while undergoing total parenteral nutrition — was given Intragam P for idiopathic thrombocytopenic purpura. While receiving Intragam P, capillary glucose levels by the Advantage monitor were elevated by 13–20 mmol/L compared with concurrent (and normal) plasma glucose level measurements. It has previously been reported that icodextrin, used in some peritoneal dialysis fluids, can have similar effects, as it is hydrolysed to oligosaccharides, including maltose, maltotriose and maltotetraose.4,5 The reaction with maltose has important clinical implications. Although it is stated in the product information for Advantage test strips that glucose readings may be affected by maltose levels over 16 mg/dL (0.89 mmol/L), clinicians may not be aware that Intragam P is in a maltose solution. For patients receiving Intragam P, the Advantage monitor is not suitable, and the Precision, Medisense or Accutrend blood glucose monitors, which use glucose oxidase which does not react with maltose, should be used instead. We have reported our experience to the Australian Red Cross Blood Service as an adverse event.

Shanthi Kannan · Christine H Rowland · Gregory I Hockings · Peta M Tauchmann · Edwin A Blackwell

The most common cause of hyperthyroidism in Australia is Graves disease, caused by a defect in immunoregulation in genetically predisposed individuals, leading to production of thyroid-stimulating antibodies. Each of the three modalities of therapy for Graves disease — thionamide drugs, subtotal or total thyroidectomy, and radioactive iodine ablation — can render the patient euthyroid, but all have potential adverse effects and may not eliminate recurrences. Hypothyroidism occurs in about 5% of the adult population; most present with “subclinical” hypothyroidism (mild thyroid failure), characterised by raised levels of serum thyroid stimulating hormone (TSH) but normal free thyroxine (T4). The most common cause of hypothyroidism in Australia is autoimmune chronic lymphocytic thyroiditis, characterised by raised circulating levels of thyroid peroxidase antibody. Symptoms and signs of hypothyroidism are often mild or subtle and, when there is clinical suspicion, thyroid function tests are needed; if serum TSH level is raised, free T4 and thyroid peroxidase antibody should be measured. Replacement therapy with thyroxine is the cornerstone of therapy (1.6 μg/kg lean body weight daily, taken on an empty stomach); combination therapy with thyroxine and liothyronine (T3) is promoted, but there is little evidence of its clinical benefit. Despite the development of highly sensitive laboratory tests, clinical assessment and judgement remain paramount

Duncan J Topliss MD, FRACP, FACE · Creswell J Eastman AM, MD, FRACP, FRCPA

Five years after the completion of the study, some of its benefits have been maintained The United Kingdom Prospective Diabetes Study (UKPDS) provided definitive evidence for the benefit of intensive management of blood glucose level and blood pressure in people with type 2 diabetes.1,2 When the main findings of the UKPDS were published in 1998, a year after the study had closed, several questions arose. How much would the UKPDS findings influence usual care? Would the vascular benefits of intensive therapy be sustained? Would the status of borderline or unexpected results change with longer observation? 1: Key findings of 5-year post-study monitoring after the United Kingdom Prospective Diabetes Study1,2 Diabetes control (assessed by haemoglobin A1c levels) in patients treated either conventionally or with intensive pharmacotherapy converged The effect of intensive blood glucose control on diabetes end-points was maintained The reduced risk of a fatal or non-fatal myocardial infarction became statistically significant The benefit of metformin treatment in overweight people was maintained The increased risk of all-cause and diabetes-related mortality with combination sulfonylurea and metformin therapy was no longer evident Blood pressure levels converged in the conventionally and intensively treated groups, but the beneficial effects of aggressive antihypertensive therapy were only maintained for microvascular complications To answer these questions, post-study monitoring was initiated after completion of the UKPDS. All patients stopped protocol-driven management but were asked to participate in further regular assessment. The 5-year post-study monitoring period ran from September 1997 to September 2002. Some early results were presented at the International Diabetes Federation Scientific Meeting in Paris in August 2003. The Chief Investigator, Professor Rury Holman, stressed the preliminary nature of the data, and foreshadowed full peer-reviewed publication in 2004. Nevertheless, given the impact of the UKPDS since 1998, the data were of great interest to many delegates present. In the UKPDS, 3867 patients newly diagnosed with type 2 diabetes were randomly allocated to receive either conventional diet-based blood glucose control therapy or intensive pharmacotherapy, primarily with sulfonylurea or insulin (with a target fasting plasma glucose level of < 6.0 mmol/L). Of the original cohort, 489 died during the study period and 76 were lost to follow-up. Thus, 3302 patients (85.4%) entered post-study monitoring. Endpoint data were collected for all of these patients. More detailed results were available for the 1696 (51.4%) patients who were followed up in UKPDS clinics. Regardless of whether or not the patients elected to continue attending UKPDS clinics after the study had finished, management was left to the discretion of the treating physician. The median haemoglobin A1c (HbA1c) values in the two therapy groups were close to 7% at the start of the UKPDS; they diverged during the first year of the study, then rose in parallel, with a separation approaching 1%.1 After the end of the UKPDS, the median HbA1c levels in the conventional therapy group plateaued at about 8.5%, while those in the intensive therapy group continued to rise. By the end of 3 years of post-study monitoring, the curves had converged. Over the next 2 years, the median HbA1c level fell progressively in both groups by about 1%. Only a quarter of patients had achieved the target HbA1c level of < 7.0% by the end of post-study monitoring, even though most were receiving insulin treatment at the time. The post-UKPDS changes in median HbA1c level mirror those found after the end of the equivalent type 1 diabetes study, the Diabetes Control and Complications Trial.3 The convergence during the first 3 years of post-study monitoring probably reflects a combination of patient reluctance to maintain intensive therapy (in view of the risks of hypoglycaemia and weight gain), set against increasing acceptance of lower glycaemic targets by patients and their doctors in the conventionally managed group. The subsequent downward trend suggests that incorporation of UKPDS-based recommendations into usual care was increasing, but the availability of new therapies, including thiazolidinediones, may have contributed. When analysed on an intention-to-treat basis, post-study monitoring data confirmed that participation in the intensive blood glucose lowering policy group was associated with a significantly lower rate of any diabetes-related endpoint (eg, myocardial infarction, stroke, renal failure, retinopathy, death from hyper- or hypoglycaemia) and of microvascular complications 5 years after the UKPDS had finished. This sustained effect has been termed “metabolic imprinting”.3 Although there were no group-specific differences in all-cause mortality and diabetes-related deaths during the UKPDS, intensive therapy during the study period was associated with a lower risk of diabetes-related death during post-study monitoring. The benefit of intensive therapy on fatal or non-fatal myocardial infarction — borderline in the UKPDS — was still weak by the end of post-study monitoring, but had become statistically significant. During the UKPDS, metformin therapy in overweight patients substantially reduced the risk of any diabetes-related endpoint, all-cause mortality, diabetes-related deaths and myocardial infarction compared with conventional therapy.4 During post-study monitoring, these risk reductions were attenuated but remained significant. There were unexpected increases in all-cause mortality (relative risk, 1.60; 95% CI, 1.02–2.52) and diabetes-related deaths (relative risk, 1.96; 95% CI, 1.02–3.75) in patients taking combination sulfonylurea plus metformin compared with sulfonylurea monotherapy in the UKPDS.4 This was considered a chance finding resulting from the low number of deaths in the latter group. These differences were no longer evident at the end of post-study monitoring. In the UKPDS, a subset of 1148 hypertensive patients were randomly allocated to tight blood pressure control (target, < 150/85 mmHg) or less tight control (target, < 180/105 mmHg).2 Of these, 884 were available for post-study monitoring, of whom 522 continued to attend UKPDS clinics. The pattern of change in systolic and diastolic blood pressure was similar to the pattern of change in HbA1c levels during post-study monitoring, with convergence between groups during the first 3 years and progressive reduction over the next 2 years. Despite a doubling of the percentage of patients taking three or more antihypertensive medications during the post-study period, only one in six patients had achieved a systolic blood pressure of < 130 mmHg and a diastolic blood pressure of < 80 mmHg at the end of this time. Compared with event rates in the less tightly controlled patients at the end of the UKPDS, there were impressive reductions in any diabetes-related endpoint, diabetes-related deaths, stroke and microvascular disease among patients subject to tight blood pressure control.2 By the end of post-study monitoring, the relative risk reductions in the first three of these categories were no longer statistically significant. For microvascular disease, a significant but attenuated risk reduction remained in the tight-control group. The UKPDS design was complex, and analysis of post-study monitoring data will be further complicated by the fact that clinical management was non-uniform after completion of the UKPDS. Nevertheless, it appears that the microvascular benefit of tight glycaemic control is maintained after resumption of usual care. This was also seen in the Diabetes Control and Complications Trial,3 and argues for early and aggressive blood glucose management strategies. Concerns about the safety of combination metformin–sulfonylurea therapy appear to have been allayed, and the macrovascular benefits of metformin in overweight patients are supported by the data presented in Paris. Disappointingly, it appears that the effects of aggressive antihypertensive therapy may wane relatively quickly. Formal analysis of post-study monitoring data is eagerly awaited, but, until then, there is reason to believe that the legacy of the UKPDS continues.

Timothy M E Davis FRACP · Stephen Colagiuri FRACP

Polycystic ovary syndrome (PCOS) is a common condition characterised by menstrual abnormalities and clinical or biochemical features of hyperandrogenism. Features of PCOS may manifest at any age, ranging from childhood (premature puberty), teenage years (hirsutism, menstrual abnormalities), early adulthood and middle life (infertility, glucose intolerance) to later life (diabetes mellitus and cardiovascular disease). While pelvic ultrasound examination is useful, many women without PCOS have polycystic ovaries; ultrasound evidence is not necessary for the diagnosis. Testing for glucose intolerance and hyperlipidaemia is wise, especially in obese women, as diabetes mellitus is common in PCOS. Lifestyle changes as recommended in diabetes are fundamental for treatment; addition of insulin-sensitising agents (eg, metformin) may be valuable in circumstances such as anovulatory infertility. Infertility can be treated successfully in most women by diet and exercise, clomiphene citrate with or without metformin, ovarian drilling, or ovulation induction with gonadotrophins; in-vitro fertilisation should be avoided unless there are other indications.

Robert J Norman MD, FRANZCOG, FRCPA · Ruijin Wu MD, PhD · Marcin T Stankiewicz MRANZCOG

Attention to known contraindications and intercurrent illness can avoid life-threatening acidosis Metformin, a biguanide derivative, has been used in the treatment of type 2 diabetes for nearly 50 years. It acts as an insulin-sensitising agent, lowering fasting plasma insulin concentrations by inducing greater peripheral uptake of glucose, as well as decreasing hepatic glucose output. In 1998, the United Kingdom Prospective Diabetes Study reported that, in overweight patients with type 2 diabetes, treatment with metformin compared with diet alone resulted in statistically significant absolute risk reductions (ARRs) in all-cause mortality (ARR, 7%), diabetes-related deaths (ARR, 5%), any diabetes-related endpoint (ARR, 10%), and macrovascular disease (myocardial infarction, sudden death, angina, stroke, peripheral vascular disease).1 This was achieved without hypoglycaemia or weight gain. As a result, metformin is now regarded as the oral hypoglycaemic agent of choice in the treatment of overweight people with type 2 diabetes. More recently, the use of metformin has broadened, with evidence for its benefit in other insulin-resistant states. In polycystic ovary syndrome, metformin decreases insulin resistance, restores ovulatory menses, facilitates conception, and reduces the rate of first-trimester spontaneous abortion.2 Metformin also delays progression to type 2 diabetes in people with impaired glucose tolerance.3 It is currently being evaluated in the treatment of gestational diabetes mellitus, and has shown promising results in selected individuals with type 1 diabetes.4 But this increase in the use of metformin is not without risk. The manufacturer’s product information on metformin reminds prescribers that life-threatening lactic acidosis can occur, caused by accumulation of metformin, and that risk factors for this include renal impairment, old age and doses over 2 g per day. The estimated prevalence of life-threatening lactic acidosis is one to five cases per 100 000,5 with mortality in reported cases up to 50%.6 Traditionally, this complication has been thought of as secondary to an accumulation of the drug. Metformin is excreted unchanged in the urine, with the half-life prolonged and renal clearance decreased in proportion to any decrease in creatinine clearance.6 This may occur chronically in chronic renal impairment, or acutely with dehydration, shock, and intravascular administration of iodinated contrast agents, all of which have the potential to alter renal function. Tissue hypoxia also has a significant role, and acute or chronic conditions that may predispose to this condition, such as sepsis, acute myocardial infarction, pulmonary embolism, cardiac failure and chronic liver disease, may act as triggers. Between 1985 and 2001, 48 cases of lactic acidosis with metformin were reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). In 15 of these cases, the complication was fatal. In 35 of the 48 cases, known risk factors were identified. Over the past 4 years, the average number of cases reported to ADRAC has been six per annum. In Australia in 2002–2003, about 200 000 patients were prescribed metformin, giving a reported frequency of lactic acidosis of one in 30 000. However the actual rate of occurrence is likely to be higher, given that under-reporting is an inherent problem with voluntary pharmacovigilance programs. At the Princess Alexandra Hospital in Brisbane, since January 2000, we have identified 13 patients with lactic acidosis thought to be related to use of metformin. Of these 13 patients, two died, while three require ongoing dialysis for renal failure; another was left with severe neurological disability requiring nursing-home care. The average age of the affected patients was 67 years (range, 47–79 years), and the baseline serum creatinine concentration (known in 10 patients) ranged from 0.12 mmol/L to 0.48 mmol/L, with a mean of 0.21 mmol/L (reference range, 0.05–0.11 mmol/L in women, and 0.06–0.12 mmol/L in men). Seven of the 13 patients were taking a metformin dose of 3 g per day, three were taking 2 g, while the remaining patients were taking between 500 mg and 1.7 g. How well do we currently comply with recommendations on prescribing metformin? A study at the University of Pittsburgh Medical Center in the United States reported on 263 hospital admissions involving 204 patients who were taking metformin. Patients had at least one absolute contraindication to metformin in 27% (71) of admissions. In 41% (29) of these, treatment with metformin continued despite the contraindication.7 A Scottish study of 1847 patients taking metformin found that 24.5% (452) had a contraindication.8 It follows that metformin must be prescribed appropriately to avoid potential adverse effects, while offering patients the best treatment possible. In well, ambulatory patients, renal function should be monitored regularly. A cut-off serum creatinine concentration above which metformin should be discontinued has been arbitrarily set at 0.15 mmol/L.9 Obviously, this needs to be individualised, and age, muscle mass, and protein turnover need to be considered. This can be achieved using the Cockcroft–Gault equation, which estimates creatinine clearance from age, weight and serum creatinine concentration. For example, with this equation, a 75-year-old woman, weighing 65 kg, with a serum creatinine concentration of 0.11 mmol/L, has an estimated creatinine clearance of 40 mL/min, which is significantly reduced. We propose: setting an absolute cut-off point (a creatinine clearance of 30 mL/min), below which metformin should be discontinued; and using metformin with extreme caution in patients with a creatinine clearance in the range 30–50 mL/min. No clear guidelines exist on reducing the dose of metformin as renal function declines, but reports of lactic acidosis have occurred with doses as low as 500 mg per day. Alternative strategies for managing diabetes in this situation include the use of insulin, thiazolidinediones and sulfonylureas. The second adverse situation to be considered is the previously well patient with a significant intercurrent illness. This includes illnesses with the potential to alter renal function, such as dehydration, shock, and sepsis. Metformin should be ceased completely while the patient is unwell, and recommenced when the illness has resolved, and renal function is shown to be normal. In addition, illnesses that increase the risk of tissue hypoxia and acidosis, such as acute myocardial infarction, pulmonary embolism, and cardiac failure, can trigger lactic acidosis, and the dose of metformin should be significantly reduced (or the drug discontinued altogether) under these circumstances. Patients need to be educated about these risks. Finally, a special situation is the use of iodinated contrast agents. The current recommendation is that metformin be withheld for 24–48 hours before the procedure and be recommenced 48 hours afterwards and only when renal function is shown to be normal.10 Without doubt, metformin remains the drug of choice for most patients with type 2 diabetes. Careful and thoughtful use of this drug has the potential to avoid life-threatening adverse events.

Janelle C Nisbet MB BS · Joanna M Sturtevant BPharm, BSc · Johannes B Prins PhD, FRACP

We report a man with longstanding undiagnosed adrenal insufficiency. At 37, our patient is the oldest reported case. Although most cases of Allgrove syndrome are diagnosed during childhood, awareness of this condition when undiagnosed in adults is crucial, as it is life threatening, and can severely affect neurological, sexual and psychological function. Allgrove syndrome was first described in 1978.1 It is an autosomal recessive condition associated with adrenal insufficiency due to adrenocorticotrophic hormone (ACTH) resistance, alacrima, and achalasia of the oesophageal cardia.1,2 Affected patients usually present as children, with achalasia and alacrima,3 but clinical features may be heterogeneous, sometimes including neurological involvement, and they present over a variable time course.4 The disease gene, ALADIN, localises to 12q13,5 with mainly nonsense mutations, resulting in expression of a truncated protein.3 Case reportA 37-year-old man with known achalasia was admitted for investigation of an 18-month history of extreme tiredness, recurrent cough, and weight loss of 10 kg. Previous historyOne year before admission, he had a 2-day history of lethargy, dizziness, and collapse with hypotension. On admission to an intensive care unit, he required crystalloid resuscitation, with inotropes for blood pressure maintenance for 2 days, after which he recovered slowly. Serotonin syndrome was proposed as a diagnosis, because he had recently started taking paroxetine for management of presumed psychogenic impotence. At age 31 he had begun to experience progressive generalised weakness, with soreness of lower limbs. A neurological report described mixed motor neurone abnormalities, with symmetrical four-limb weakness, predominantly distal muscle wasting, bilateral pes cavus, symmetrical hyperreflexia and positive Babinski reflexes. Bulbar involvement and optic atrophy were observed. Computed tomography (CT) scanning and magnetic resonance imaging of his brain showed no abnormality. No clear diagnosis was reached. Over several years he had sought professional help for erectile dysfunction and ejaculatory failure, from urologists, sexual counsellors, psychiatrists and neurologists, without success. Marital separation followed this difficult period. Twenty years before these events the patient had developed swallowing difficulties. Achalasia was diagnosed on radiological and endoscopic findings, with symptomatic improvement following pneumatic dilatation. His family history was unremarkable and did not include consanguinity. Muscle weakness and clumsiness was recognised from age 4 years, but he had always participated in sports activities. Growth and puberty occurred normally. Current admissionAn endocrinological consultation was sought because of increasing lethargy, weakness and reported testicular atrophy. Examination showed minimal pigmentation of skin and palmar creases, severe generalised weakness, proximal and distal myopathy and hypotension (95/50 mmHg) with a postural drop to 60 mmHg systolic on standing. Testicular volume was 25 mL (adult normal range, 12–25 mL) with normal virilisation and no gynaecomastia. Extremely indistinct “bulbar” speech was noted, with nasal escape rendering speech almost incomprehensible. Direct questioning confirmed alacrima, the patient stating that he never produced tears at any age. He also reported extreme difficulties with swallowing, taking an hour to eat a meal, constant cough, poor saliva control and accompanying inhalation of food. A diagnosis of Allgrove syndrome was made clinically, and adrenal insufficiency was confirmed with the discovery of elevated ACTH and low basal cortisol levels (see Box 1). An intramuscular injection of hydrocortisone (100 mg) resulted in rapid improvement of blood pressure and muscle strength, so that he could stand and walk without dizziness. There was significant improvement in his speech, cessation of cough and reported normalisation of eating habits. Replacement therapy with hydrocortisone (20 mg/m2 daily) was initiated. Plasma renin activity was normal. Fludrocortisone was not required as the patient’s blood pressure had returned to normal with no postural drop after glucocorticoid replacement, confirming intact mineralocorticoid function. After discharge from hospital 3 days after the diagnosis was made, he reported ongoing marked improvement in strength and coordination and returned to full-time manual trade work. DiscussionThis patient with Allgrove syndrome, who developed symptoms of severe life-threatening adrenal insufficiency at age 36, but retained normal mineralocorticoid function, is the oldest reported case surviving with undiagnosed adrenal insufficiency. In cases reported previously, adrenal insufficiency was usually diagnosed in the first decade6 (with a few exceptions2,7,8), accompanied by hypoglycaemia and increased skin pigmentation.5 Most patients had normal mineralocorticoid function, but deficiency has been reported.5,9 Achalasia is usually diagnosed at the same time or after the diagnosis of adrenal insufficiency.5 In our patient, achalasia preceded the diagnosis of adrenal insufficiency by 20 years. Such a late diagnosis emphasises the need for assessment of adrenal function in any young person with achalasia or alacrima. The gene is defined for this rare autosomal recessive disorder (ALADIN at 12q13); fewer than 100 cases have been reported, usually in family clusters. Our patient had no family history of the disorder, indicating that he was likely to be the first (index) case with the mutated gene. Diagnosing adrenal insufficiency: Diagnosis of hypocortisolism is frequently delayed for patients with adrenal insufficiency, because of the subtle nature of clinical complaints (weakness, tiredness, dizziness and slow weight loss). When mineralocorticoid function is intact, postural hypotension and electrolyte disturbance, with an acute medical emergency presentation, is less likely. ACTH insensitivity due to adrenocortical atrophy is the resultant clinical picture. Skin pigmentation varies, and is often missed unless a careful search for buccal, crease and scar pigmentary change is sought. A diagnosis of primary adrenal insufficiency usually includes consideration of an autoimmune basis where adrenal antibody status should be tested (with or without other pointers to polyautoimmune endocrinopathy), infective causes (tuberculosis, viruses and mycoses) and, in older patients, malignant infiltration. These problems usually result in extensive adrenal destruction and associated mineralocorticoid deficiency, often with a more dramatic presentation of ill health and electrolyte imbalance. Neurological features: Peripheral motor and sensory neuropathy are common,10 and may be subtle in childhood.5 Impotence is infrequently reported with Allgrove syndrome5,7,8 perhaps because of underreporting, or a diagnosis of psychogenic impotence. Erectile dysfunction in our patient was neurological in origin, and so it is not surprising that it failed to respond to usual therapies. The differential diagnosis includes adrenoleukodystrophy (ALD) in childhood or adolescence, with either neurological abnormality or adrenal insufficiency as the first presentation. Adrenomyelodystrophy occurs when patients with this progressive demyelinating disorder first present in adulthood. As our patient’s first neurological complaint occurred when he was 4 years of age, ALD could be excluded. Similarly, the gene for Duchenne muscular dystrophy is located adjacent to the DAX-1 gene, producing neurological deterioration and adrenal insufficiency, but is generally diagnosed earlier. Although neurological disorder constitutes part of the condition, the severe and progressive muscle weakness of long-term undiagnosed adrenal insufficiency makes a major contribution to reduced motor function and quality of life, as seen in our patient. Unlike other neurological disorders associated with adrenal insufficiency, neurological change with Allgrove syndrome is extremely slow. With adequate cortisol replacement, monitoring of ACTH levels and education to ensure appropriate increases in corticosteroid treatment during intercurrent illness or anaesthesia, the prognosis for health and quality of life is improved. 1: Patient’s blood test results before diagnosis Investigation Results Reference values Sodium 139 mmol/L 135–145 mmol/L Potassium 3.8 mmol/L 3.5–5.0 mmol/L Chloride 102 mmol/L 95–107 mmol/L Bicarbonate 25 mmol/L 23–32 mmol/L Urea 3.4 mmol/L 3.2–7.3 mmol/L Creatinine 57 μmol/L 40–130 μmol/L Cortisol (08:00 h) 43 nmol/L 200–750 nmol/L Adrenocorticotrophic hormone 864 pmol/L < 20 pmol/L Plasma renin activity 1.0 ng/mL/h 0.3–1.4 ng/mL/h 2: Clues to recognising the syndrome Clinical suspicion of adrenal insufficiency in the presence of achalasia in any patient, children or adults. Alacrima — ascertaining this usually depends on direct questioning about tear production. Neurological dysfunction — not universal, but the combination of achalasia and neurological dysfunction should prompt specific questions about symptoms of adrenal insufficiency. Elevated adrenocorticotrophic hormone and low basal cortisol levels confirm the diagnosis.

Clarissa C Pedreira MD · Margaret R Zacharin MB BS, FRACP

Clinical records Case 1: An 89-year-old woman was admitted to hospital from a nursing home with a 12-hour history of drowsiness, progressing to an unrousable state and inability to eat or drink. A low dose of long-acting morphine had been commenced 2 days earlier for painful arthritis. A capillary blood glucose (glucometer) reading taken in the nursing home on the morning of hospitalisation was 4.1 mmol/L. Past history included well controlled type 2 diabetes mellitus associated with corticosteroid use, for which she had been prescribed glimepiride 0.5 mg daily 2 months previously. The last dose was given on the morning of hospital admission. She was taking multiple other medications for comorbid conditions. The ambulance officers transporting her to hospital had recorded a “Lo” glucometer reading and administered 25 mL of 50% glucose. Within 5 minutes, a repeat glucometer reading was 14.7 mmol/L. On arrival at hospital the woman was opening her eyes and responding appropriately to pain, but not verbalising. Her Glasgow Coma Score was 9/15. In emergency triage, a glucometer reading showed 4.8 mmol/L, but shortly afterwards her venous serum glucose concentration was 1.3 mmol/L and serum creatinine level was 0.19 mmol/L (normal range, 0.05–0.09 mmol/L). Results of a cerebral computed tomography scan were unremarkable. Over the next 15 hours, there were six more glucometer readings with levels < 3.5 mmol/L, including readings of 0.6 mmol/L and 1.8 mmol/L (18 and 27 hours after the last dose of glimepiride, respectively). Despite a total of 250 mL of 50% glucose in eight bolus doses and a 5% glucose infusion commenced at admission and continued throughout hospitalisation, her level of consciousness deteriorated. She died 18 hours after presentation. Case 2: A 79-year-old woman living in a nursing home had been discharged from hospital several days earlier after internal fixation of a fracture of the femoral neck. She was readmitted after a sudden deterioration, characterised by drowsiness, decreased response to questions and dyspnoea. Her past history included type 2 diabetes mellitus for 4 years, for which she was taking glibenclamide 2.5 mg twice daily, a dose which had not been changed for 3 years. Glucometer readings had ranged between 7 mmol/L and 9 mmol/L during her recent hospitalisation. Other major comorbidities included a dominant middle cerebral artery stroke resulting in persisting hemiplegia and dysphasia, atrial fibrillation, hypertension and congestive cardiac failure. Because of her multiple comorbidities she was taking numerous medications. A glucometer reading was not performed before transfer to hospital. In the emergency department, the woman was initially treated for pulmonary oedema and pneumonia, which were evident clinically and radiologically. Her venous serum glucose concentration was 0.6 mmol/L and her serum creatinine level was 0.04 mmol/L (normal range, 0.05–0.09 mmol/L). Over the ensuing 27 hours, five more glucometer readings were < 3.5 mmol/L, including one of 0.7 mmol/L, and another of 2.3 mmol/L (24 and 36 hours after the last dose of glibenclamide, respectively). In total, she required 300 mL of 50% glucose in six bolus doses and a 5% glucose infusion for 48 hours. Over the ensuing days, her condition improved and she was able to take a purée and thickened fluid diet. One week after presentation, she appeared to vomit and aspirate while eating, and suffered an asystolic cardiac arrest from which she could not be resuscitated. Sulfonylureas act by stimulating insulin secretion from the pancreas and augmenting glucose-stimulated insulin secretion. Some, such as glibenclamide and glimepiride, are long acting and have metabolites that are excreted renally. Others, such as gliclazide and glipizide, are shorter acting and do not have active metabolites.1 Hypoglycaemia is the major risk associated with the use of sulfonylureas, particularly in elderly people. Serious hypoglycaemia is usually defined as that causing death, or requiring hospitalisation or emergency department admission. The rate is probably between 1% and 2% per year.2 Previous reports suggest, and the cases described here demonstrate, that this may occur even with very low doses of a sulfonylurea. The resultant hypoglycaemia can be prolonged and recur for a period of more than 24 hours despite treatment. Case fatality rates of 4%–10% are reported and 5% of survivors may have permanent neurological impairment.3 In elderly people, the classical autonomic adrenergic symptoms and signs of hypoglycaemia may not be present (or evident), and neuroglycopenic features, such as drowsiness or confusion, may dominate the picture (as in the cases described), so the diagnosis can be easily missed.4 Elderly patients with these symptoms who are taking medication for hypoglycaemia need immediate (and repeat) measurement of blood sugar level (BSL). If the BSL is low and the patient is alert and able to swallow, oral carbohydrate loading is the preferred management regimen — otherwise an ambulance should be called and the patient transported to hospital as a matter of urgency. While 10–25 g of carbohydrate delivered in 50% glucose is essential to restore the patient to euglycaemia in the short term, in the presence of sulfonylurea it stimulates more insulin secretion by the pancreas, and therefore can contribute to recurrent hypoglycaemia. The 50% glucose bolus should be followed immediately by an infusion of 5% or 10% glucose, usually at a rate of 100–200 g of carbohydrate daily, and BSL should be monitored for at least 24 hours. Subcutaneous synthetic somatostatin analogues may be used to reduce the likelihood of rebound hypoglycaemia and reduce glucose requirements, but there is no role for glucagon in the management of sulfonylurea-induced hypoglycaemia.5 Numerous studies show that longer-acting sulfonylureas are associated with a higher risk of hypoglycaemia, including serious hypoglycaemia. Gliclazide and glipizide have been shown to cause less hypoglycaemia than glibenclamide, and one study also suggested that glimepiride was safer than glibenclamide.6-9 There are no published reports comparing glimepiride directly with gliclazide or glipizide for hypoglycaemia. Other risk factors for hypoglycaemia, evident in the cases described here, include advanced age, recent hospitalisation, multiple medications, and drug accumulation caused by renal or hepatic impairment (keeping in mind that renal function usually declines linearly with age). Medication changes, including an increase in hypoglycaemics while a patient is unwell in hospital, may not be adequately communicated to the patient’s general practitioner, and recent hospitalisation is perhaps the major risk factor for sulfonylurea-induced hypoglycaemia. The presence of any of these risk factors should affect the choice and dose of medication and increase vigilance in monitoring BSL and renal function. In conclusion, the above cases serve to remind us of the dangers of long-acting sulfonylureas, which should perhaps be avoided in elderly people. Shorter-acting sulfonylureas such as gliclazide and glipizide are safer options. Elderly patients with altered mentation taking sulfonylureas require an urgent BSL measurement and, if they are unable to take food or fluids orally, they should be referred to hospital promptly. Lessons from practice Long-acting sulfonylureas, such as glibenclamide (and perhaps glimepiride) should be used with extreme caution in frail elderly people. Recent hospitalisation is a major risk factor for sulfonylurea-induced hypoglycaemia and necessitates increased vigilance in monitoring the patient’s condition and blood sugar levels. The classical adrenergic features of hypoglycaemia may be absent (or not evident) in frail elderly people. Drowsy or confused elderly patients taking sulfonylureas should have their blood sugar level measured urgently. Once sulfonylurea-induced hypoglycaemia is confirmed, oral carbohydrate loading is the preferred management regimen in alert patients, but those unable to take oral food or fluids should be transferred to hospital as a matter of urgency. Even with low-dose sulfonylurea therapy, hypoglycaemia can be severe, prolonged and recurrent over at least 24 hours.

Peter C Veitch MB BS, FRACP · Rory J Clifton-Bligh MB BS, PhD

To the Editor: Shaw and Chisholm described the increasing prevalence of type 2 diabetes in Australia.1 A similar alarming trend exists in China — there will be nearly 1 million new cases of diabetes per year in the 21st century,2 and a total of 290 million people with diabetes by 2010.3 The main risk factor for the development of diabetes in China is obesity. The Chinese are getting fatter.4 As China becomes modernised, people are eating more and exercising less. That eating a healthy diet and becoming physically more active can prevent diabetes is convincingly proven by China’s Daqing IGT (impaired glucose tolerance) and Diabetes Study.5 A total of 577 subjects with IGT were randomised by clinic to either a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. This is the first randomised controlled clinical trial to demonstrate that weight reduction by diet and exercise can significantly reduce the incidence of diabetes in subjects with impaired glucose tolerance.

Tsung O Cheng MD

Re: "1: Epidemiology and prevention of type 2 diabetes and the metabolic syndrome", by Shaw JE and Chisholm DJ in the 6 October 2003 issue of the Journal (Med J Aust 2003; 179: 379-383). In the section "Who should be screened?" the reference number should be 14 rather than 13 and the year of publication of reference 14 is 2002 not 1992. The second paragraph of this section, should read "Screening should also be offered to people aged 45-54 years with one or more of the following: obesity (body mass index ≥30 kg/m2); a first-degree relative with type 2 diabetes; or hypertension" The authors also wish to add an Acknowledgement: readers are referred to the NHMRC Evidence Based Guidelines for Type 2 Diabetes on case detection and diagnosis (from which the information in reference 14 is derived) and primary prevention, at www.diabetesaustralia.com.au or www.health.gov.au/nhmrc/publications/synopses/cp86syn.htm The html and pdf versions of this article published on the eMJA website were corrected on 30 October 2003.

Jonathan E Shaw · Donald J Chisholm

Diabetes complications are common and almost triple the annual cost of managing diabetes. Microvascular complications are the major risk in type 1 diabetes, while macrovascular complications are the major cause of morbidity and mortality in type 2 diabetes. Control of hyperglycaemia (target HbA1c level ≤ 7%) and hypertension (target blood pressure ≤ 130/80 mmHg) prevents microvascular complications in both types of diabetes; a multifactorial approach, comprising behaviour modification and pharmacological therapy for all risk factors, reduces the development of micro- and macrovascular complications in type 2 diabetes. The benefit of treating dyslipidaemia is at least as great in the diabetic population as in the non-diabetic population. Angiotensin-converting enzyme inhibitors and low-dose aspirin are indicated in people with diabetes and other cardiovascular risk factors. Regular annual screening for diabetes complications allows treatable disease to be identified.

Katherine L Bate FRACP · George Jerums MD, FRACP

As suboptimal blood glucose control has a lasting harmful effect even if control improves later, intensive insulin therapy to minimise hyperglycaemia is now recommended for all patients with type 1 diabetes. The new rapid- and long-acting insulin analogues offer more physiological insulin profiles than traditional insulin preparations. Continuous insulin infusion (“pump therapy”) may provide a solution for some patients with frequent hypoglycaemia or hypoglycaemic unawareness. Continuous blood glucose monitoring reveals postprandial hyperglycaemia and asymptomatic nocturnal hypoglycaemia and may be especially useful for programming overnight basal insulin rates for pump therapy. In type 2 diabetes, management should change with disease progression; introduction of insulin should not be delayed if metabolic control becomes suboptimal. More individualised and physiological therapy is now possible

Jennifer J Couper MD, FRACP · Johannes B Prins PhD, FRACP

Objective: To determine the prevalence of iodine deficiency in primary school children in an Australian urban population.Design and setting: A cross-sectional survey of school children aged 5–13 years attending a public school on the Central Coast of New South Wales in November 2000.Participants: 324 (70%) of the 465 children enrolled in the school (180 boys; 144 girls).Main outcome measures: Thyroid volumes compared with World Health Organization/International Council for the Control of Iodine Deficiency Disorders (WHO/ICCIDD) thyroid volume reference values. Iodine status based on WHO/ICCIDD urinary iodine concentration (UIC) categories (normal, ≥ 100 μg per litre of urine [μg/L]; mild iodine deficiency, 50–99 μg/L; moderate deficiency, 20–49 μg/L; severe deficiency, < 20 μg/L); not more than 20% of the population should have a UIC below 50 μg/L.Results: Median UIC for school children was 82 μg/L, and 14% of children had UICs below 50 μg/L. Thyroid volume reference values indicated a prevalence of goitre of zero. In girls, only four (3%) and one (1%) had thyroid volumes above the WHO/ICCIDD medians by age and body surface area (BSA), respectively (P < 0.001). In boys, three (2%) and one (1%) had thyroid volumes above WHO/ICCIDD medians by age and BSA, respectively (P < 0.001).Conclusion: Despite the median UIC being less than ideal, most children were not goitrous. This underscores the importance of using physiological outcome measures in areas where iodine deficiency is marginal before concluding the need for iodine supplementation based purely on median UIC. We call for a systematic national survey to determine iodine status using a combination of iodine deficiency indicators.

Kamala Guttikonda MB BS, FRACP · Steven Boyages FRACP, PhD · Cheryl A Travers BSc · Peter R Lewis MB BS, FAFPHM

Policymakers need to catch up with the explosion of new tests and therapies The field of endocrinology has expanded dramatically in the past 40 years, both because of increased knowledge about the aetiology, diagnosis and therapy of endocrine disease and because of the increasing number of patients with very common endocrine conditions, particularly type 2 diabetes, osteoporosis and menopausal problems. The development of the radioimmunoassay for hormone measurement in the 1960s was a landmark in endocrinology, as it allowed measurement of hormone concentrations in small blood samples. Since the 1980s, hormone assays have become routine, automated and widespread, with most now readily available to general practice through commercial pathology laboratories. As random measurement of many hormones can give misleading results, it is important that those ordering assays understand their interpretation. In Australia, ageing of the population and lifestyle change have caused an explosion of obesity, type 2 diabetes and osteoporosis. The AusDiab study in 2000 showed that 20% of the Australian population aged over 25 years was obese (body mass index > 30 kg/m2) and, possibly of even greater concern, more than 30% of the population had central obesity, while 7.4% had diabetes, mostly type 2.1 The problem of osteoporosis is also large, caused particularly by population ageing, but possibly also by reduced levels of physical activity, and has a massive impact on the healthcare system and budget. For example, the estimated cost of hip fracture in Australia is $7 billion per annum — $2 billion in direct and $5 billion in indirect costs.2 Endocrinology is at the forefront of evidence-based developments in therapy and primary and secondary prevention. It has been particularly affected by the rapid expansion and improvement of pharmacotherapy and the explosion of information from clinical trials and epidemiological studies on appropriate indications for drug use. In diabetes, new treatments include human insulin analogues with more rapid or more prolonged action. There are newer and better long-acting sulfonylureas, as well as short-acting insulin secretagogues (the glitinides). Alpha-glucosidase inhibitors have been developed to inhibit carbohydrate absorption, and recently the thiazolidinediones (“glitazones” — which combat insulin resistance) have become widely used in most developed countries. Therapy for obesity remains difficult, but better understanding of nutritional approaches, availability of new pharmacological agents (eg, orlistat and sibutramine), and more sophisticated surgical approaches are all important. Our understanding of the molecular mechanisms underlying weight control is improving through cloning of signalling molecules and their receptors. For osteoporosis prevention and treatment, an increasing number of agents have proven efficacy. The selective oestrogen-receptor modulators (eg, raloxifene) have an oestrogen-like effect on bone but not uterus and breast. The newer bisphosphonates are highly effective in preventing decline in, or actually enhancing, bone mineral content by inhibiting bone resorption. Parathyroid hormone is the first drug to increase bone formation and can reduce fracture rates in some patient groups by up to 70%.3 These changes in disease prevalence and in therapy and prevention have raised important issues of health policy. The availability of diagnostic tests for common conditions can be an issue; for example, only four tests of glycosylated haemoglobin (HbA1c) are reimbursable through Medicare per annum for people with diabetes. Of greater concern to physicians, government and the public is the availability and cost of new drugs. For example, thiazolidinediones are not yet available on the Pharmaceutical Benefits Scheme (PBS) over 2 years after the initial application. Nor is growth hormone replacement therapy for adult growth hormone deficiency accepted for PBS subsidy, while patients using corticosteroid therapy are not eligible for reimbursement for effective therapy to prevent bone loss (eg, bisphosphonates), unless they have reached an established diagnosis of osteoporosis with fracture. The availability of such new drugs for the accepted indications will probably pose an increasingly difficult problem as our healthcare system tries to balance restraint on expenditure with improved therapy for the individual. This Practice Essentials series aims to review the most common areas of endocrinological practice, with special emphasis on clinical issues important in general practice. The articles are designed to enable general practitioners, general physicians and physicians in other specialties to remain up to date with the rapidly changing therapies in endocrinology, new diagnostic tests and their interpretations, as well as current issues in health policy and disease prevention.

Jeffrey D Zajac PhD, FRACP · Donald J Chisholm FRACP · Bronwyn Gaut MB BS, DCH, DA

The prevalence of type 2 diabetes in Australia has doubled over the past 20 years; more than 7% of Australian adults now have diabetes. An additional 16% of Australian adults have lesser abnormalities of glucose tolerance. Insulin resistance and increased cardiovascular risk occur in both these groups (the metabolic syndrome). 50% of cases of type 2 diabetes are undiagnosed; screening is indicated in everyone aged over 55 and in younger people with risk factors such as obesity, hypertension, family history or certain ethnic backgrounds. Dietary modification and increased physical activity have been shown to dramatically reduce the incidence of type 2 diabetes in those at high risk. General practitioners should target individuals at high risk, but this needs to be reinforced by community-wide preventive action.

Jonathan E Shaw MD, MRCP · Donald J Chisholm FRACP, AO