Letters

Simon J Vanlint Lecturer, Department of General Practice, University of Adelaide, SA 5005. simon.vanlintATadelaide.edu.au To the Editor: The Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia and Osteoporosis Australia are to be commended for their clear and succinct position statement on vitamin D and bone health.1 This statement highlights an important public health issue which is under-recognised in this country. Of particular value is the box of recommendations on high-risk groups, testing and treatment. However, I believe an important high-risk group has been omitted, a group which too often escapes the notice of the broader medical community. People with intellectual disability have been shown to be at particularly high risk of low vitamin D levels, reduced bone density and fractures.2-5 The reasons for this are multifactorial and include poor mobility, insufficient sun exposure, reduced muscle mass and strength, problems with dietary intake, and medications which interfere with vitamin D metabolism.3,4 There is also some evidence that people with intellectual disability are prone to premature ageing, together with the health problems associated with older age in the general population.3 Some conditions which cause or are associated with intellectual disability are also linked with hypogonadism and reduced peak bone mass.4 To add to all of this, several of the above risk factors, vitamin D deficiency itself, and the increased incidence of epilepsy in the population with intellectual disability, also result in an increased incidence of falls and trauma.5 This unfortunate combination of poor bone health and increased risk of falls and trauma results in a markedly increased incidence of fracture when compared with age- and sex-matched controls from the general population.2-5 In conclusion, people with intellectual disability, particularly those with poor mobility or who are also being treated for epilepsy, should be added to the list of high risk groups. It is likely that the relatively simple steps set out in the position statement (screening for vitamin D deficiency and supplementation) will result in substantial health benefits for this small but particularly vulnerable group of people.

Simon J Vanlint

Alvin L K Chia,* Stephen Shumack,† Peter Foley‡ * Research Fellow, † Dermatologist, St George Dermatology and Skin Cancer Centre, Level 3, 22 Belgrave St, Kogarah, NSW 2217; ‡ Dermatologist, St Vincent’s Hospital, Melbourne, VIC. sshumackATbigpond.com To the Editor: We read with alarm the extraordinary statements in the position statement on vitamin D and adult bone health published recently in the Journal.1 The suggestion that “it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight” is not true. The suggested basis for this statement is an extraordinary extrapolation from a single study in which a small number of volunteers had whole body exposure on one occasion for 10–15 minutes to midday summer sun in Boston. It is not possible to extrapolate in such a way from this single demonstration, as the effect of shorter exposure times or repeated daily exposures were not examined. In fact, a study in Australia showed that the adult population (including those aged over 70 years) received sufficient sunlight while using sunscreen to ensure that no-one was found to have vitamin D deficiency during the study period.2 While it is well accepted that ultraviolet B (UVB) radiation is essential for the formation of vitamin D3 in the skin, it is equally well established that continued exposure of vitamin D to UVB radiation results in its degradation. Hence, the importance of knowing the effect of lower sun exposures on vitamin D production. It is intriguing that the authors of the position statement recommended a daily sun exposure dose that they calculate will produce 1000 IU of vitamin D, but, if sun exposure is not possible, a vitamin D supplement of at least 400 IU per day. The high prevalence of vitamin D deficiency among institutionalised older Australians is a tragedy, but this cannot be used as the basis of advice for the general population who do receive daily sun exposure and appear to be the target of the statement. Nor can the mild vitamin D deficiency found in a single study in southern Victoria be used to recommend sun exposure in more northern Australian climes. Finally, while vitamin D supplementation has been shown to reduce the risk of fractures in the elderly, the proposed beneficial effect of deliberate sun exposure has not been demonstrated. Recently, a joint position statement was approved by the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia, the Australasian College of Dermatologists and the Cancer Council Australia. This included the statement that “The majority of Australians generally have sufficient ultraviolet radiation exposure to enable adequate vitamin D production . . . to form and maintain healthy, strong bones”.3 This statement, endorsed only a few weeks ago, is in obvious conflict with the position statement from the same organisations that was published in this Journal. The latter puts the vast majority of Australians at further risk of skin cancers, which are already epidemic in our country.4

Alvin L K Chia · Stephen Shumack · Peter Foley

Terrence H Diamond,* John A Eisman,† Rebecca S Mason,‡ Caryl A Nowson,§ Julie A Pasco,¶ Philip N Sambrook,** John D Wark†† * Associate Professor, Endocrinology, University of NSW, Sydney, NSW; † Professor and Director, Bone and Mineral Research Program, Garvan Institute of Medical Research, Sydney, NSW; ‡ Associate Professor of Physiology, ** Professor of Rheumatology, University of Sydney, NSW; § Associate Professor, School of Health Sciences, Deakin University, Melbourne, VIC; ¶ Senior Research Fellow, Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, PO Box 281, Geelong, VIC 3220; †† Professor of Medicine, The University of Melbourne, VIC. juliepATbarwonhealth.org.au In reply: We agree with Vanlint that any individual who has limited mobility, or is housebound or institutionalised, is at risk of vitamin D deficiency, as highlighted in Box 3 of the position statement.1 Disability in general is likely to be a risk, with motor disability as well as intellectual disability liable to limit sun exposure. The problem may be further exaggerated by any increased risk of falls or convulsions. Chia and colleagues have raised important issues. After a number of meetings, the Cancer Council of Australia, the Australasian College of Dermatologists and the Australian and New Zealand Bone and Mineral Society developed a considered consensus statement on vitamin D deficiency, risk of skin cancers and sunlight exposure, which was published at <http://www.cancer.org.au/documents/Risks_Benefits_Sun_Exposure_MAR05.pdf>. This document refers to the position statement published in this Journal in relation to sun-exposure guidelines for vitamin D. Chia and colleagues’ objection to the abstract of this position statement appears ill-founded. If “a significant number of Australians are deficient in vitamin D”, then it follows logically that “it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight”, as sunlight is the main source of vitamin D in Australia. The significant number of Australians deficient in vitamin D are not the majority, as was clearly shown in the article, so this statement does not conflict with the complementary statement in the risks and benefits statement. We stand by our original claim that a number of groups in the Australian community have a high prevalence of vitamin D deficiency, including elderly men with hip fracture (63%), Muslim women (68%), elderly ambulant men with prostate cancer (34%), “healthy” elderly men living in Southern Sydney (16%), healthy community-dwelling, ambulatory women in Geelong (20% in the age group 20–39 years, increasing to 53% in older age groups), men and women (some with psychiatric disorders) in south-east Queensland (23%), and even pregnant women in south-eastern Australia (7%) (references are available from the authors on request). As noted in the position statement, and by Chia and colleagues, continued exposure to ultraviolet (UV) radiation may lead to degradation of pre-vitamin D, so that short exposures are likely to be more efficient. This degradation is marked only at relatively high UV doses.2 Studies that used lower UV doses2,3 produced indirect UV equivalence data similar to those quoted in the position statement.1 As the relationship between UV exposure and vitamin D dosage varies from person to person, and as sun exposure is also likely to be variable and on most days, rather than every day, the recommendation that vitamin D supplementation be at least 400 IU/day in people likely to be at risk of inadequate skin-derived vitamin D is entirely appropriate. We strongly agree with Chia and colleagues about the need to avoid sun damage while still obtaining the small amount of sun exposure needed to make adequate vitamin D, which is why the position statement advocates short exposures, easily achieved by casual exposure, and reiterates other Sun-Safe messages, such as avoidance of exposure in peak UV periods and the use of sunscreens where appropriate.

Terrence H Diamond · John A Eisman · Rebecca S Mason · Caryl A Nowson · Julie A Pasco · Philip N Sambrook · John D Wark

Elizabeth A Hender,* Corrine R Balit† * Scientific Officer, Hazardous Substances Section, Environmental Health Service, Department of Health, PO Box 6 Rundle Mall, Adelaide, SA 5000; † Research Pharmacist, New South Wales Poisons Information Centre, The Children’s Hospital, Westmead, NSW. elizabeth.henderAThealth.sa.gov.au To the Editor: Although there are few deaths due to poisoning in Australian children, from 1993 to 1997 there was an average of more than 2500 admissions to hospital per year for assessment of poisoning with medicines in children younger than 5 years.1 Child-resistant packaging has been effective in preventing accidental poisoning with prescription medicines and aspirin in young children in the United States.2,3 In the US, both reclosable and non-reclosable (blister or strip) packaging used for pharmaceuticals required to be in child-resistant packaging is tested to confirm its effectiveness in preventing access by children.4 In Australia, only reclosable packaging is required to be child-tested. Blister or strip packaging, which has not usually been child-tested, is accepted as an alternative to child-resistant reclosable packaging.5 We conducted a study at the New South Wales Poisons Information Centre (NSWPIC) over 9 weeks from 18 July to 17 September 2003. Our aims were to ascertain which medicines children younger than 5 years access directly from blister or strip packaging, and whether assessment at a hospital was recommended. The study was approved by the Ethics Committee of the Children’s Hospital, Westmead. Callers ringing about a suspected accidental ingestion of a solid dose medicine in a child younger than 5 years were asked whether the child accessed the medicine directly from a blister or strip pack. There were 318 accidental exposures to solid dose medicines in these children during the study period. In 186 exposures (58%), the caller said the medicine was normally in a blister or strip pack and the child obtained it directly from the pack. A wide range of medicines (40 different drugs or drug groups) were associated with the exposures; the most common were oral contraceptives (49 exposures) and paracetamol (27 exposures). Some of the exposures involved medicines that can cause severe toxicity when children ingest a small number of dose units, such as clonidine, olanzapine, narcotic analgesics, and tricyclic antidepressants. In 36 exposures where the child obtained the medicine directly from the pack, the caller was advised to take the child to hospital (Box). Many of the medicines associated with these exposures (eg, paracetamol, preparations containing narcotic analgesics, antidepressants, antihistamines, iron and clonidine) are required to be in child-resistant packaging.5 Our study shows that blister or strip packs currently in use did not prevent children accessing drugs. This finding calls into question whether blister or strip packaging that has not been child-tested presents an adequate safety barrier. No outcomes of drug ingestion are known in this study, which is a limitation. However, assessment of these children in hospital represents a financial burden to the health care system regardless of the outcome. Further studies would be required to quantify the harm associated with exposures to medications packaged in blister or strip packaging in young children and to assess the effectiveness of such packaging in the prevention of poisoning. Drugs accessed from blister or strip packs where child required referral to hospital Drug or drug group Number of exposures Paracetamol 8 Paracetamol/narcotic combination analgesics 3 Selective serotonin re-uptake inhibitors 3 Antidepressant: other/unknown 2 Antiemetics 2 Antihistamines 2 Cough/cold preparations, no paracetamol 2 Iron 2 Other (eg, clonidine, olanzapine) 12 Total 36

Elizabeth A Hender · Corrine R Balit

Timothy C Crowe,* David Cameron-Smith† * Lecturer, † Senior Lecturer, School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC 3125. tcroweATdeakin.edu.au To the Editor: Low-carbohydrate diets have re-emerged into the public spotlight and are enjoying widespread popularity. However, current evidence indicates that low-carbohydrate diets have no significant advantage over more traditional energy-restricted diets for long-term weight loss and maintenance.1-3 While these diets have shown short-term efficacy in modifying some lipid parameters and measures of insulin sensitivity, questions remain about the risk of adverse effects with long-term carbohydrate restriction.4 The scientific literature has not addressed the questions of how the general public perceive these diets, and what dieting approaches they adopt. Dieting perceptions and practices within the community may be far removed from the strictly controlled situation of published research. A national telephone survey of 1200 adults aged 18 years and over was conducted by the private market research company Newspoll from 6 to 8 August 2004. The survey asked about knowledge of and attitudes to carbohydrates and dieting. Telephone numbers were randomly selected, with a quota for capital city and non-capital city areas. Selection of an individual in each household was based on the last birthday. Response rate to the survey was 11%. Sex, age, marital status and working status demographics were representative of the Australian adult population. The main findings are summarised in the Box. Most of those surveyed correctly identified foods such as pasta and bread as “carbohydrate foods”. Only a third of people identified soft drinks and lollies as carbohydrate foods, and 20% incorrectly identified cheese and eggs as carbohydrate foods. Almost 17% of people had either tried, or intended to try, a low-carbohydrate diet, with women more likely to have tried this diet. Half of those surveyed believed that carbohydrate foods should make up a quarter or less of the daily diet (current health recommendations are that about half the diet should comprise carbohydrates). Almost 70% of those surveyed believed they needed to cut back on carbohydrates to lose weight. Based on this survey, low-carbohydrate dieting practices are as widespread in Australia as in the United States.5 Interestingly, the US study noted a greater propensity to use carbohydrate-reduced diets among those who were obese, had diabetes, hypertension or high cholesterol. Our data demonstrated widespread misunderstanding of what constitutes a high-carbohydrate food, which may leave many individuals at risk of choosing a diet that selectively excludes wholegrain foods, fruits and some dairy products. Health professionals should be aware that low-carbohydrate diets remain popular, that the people who are following these diets may represent a more “at risk” population, and that the food choices made by those following this dietary pattern may have adverse long-term health effects. Respondents’ knowledge of and attitudes to carbohydrate foods and low-carbohydrate dieting Question Total (n = 1200) Men (n = 600) Women (n = 600) Which of the following foods, if any, do you regard as carbohydrate foods? Bread 89% 85% 93% Pasta 90% 88% 93% Rice 80% 76% 83% Breakfast cereal 79% 77% 80% Lollies 35% 36% 35% Soft drink 34% 31% 36% Cheese 20% 22% 19% Eggs 18% 20% 16% Have you tried or do you intend to try the Atkins diet, or some other low-carbohydrate diet? 17% 11% 22% Based on official recommended guidelines for a healthy diet, about how much of a person’s diet should be made up of foods such as bread, breakfast cereal, pasta and rice? Less than a quarter 7% 7% 7% About a quarter 43% 34% 51% About half 29% 31% 26% About three quarters 6% 8% 4%

Timothy C Crowe · David Cameron-Smith

Ian W Boyd Executive Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australian Government Department of Health and Ageing, PO Box 100, Woden, ACT 2606. ian.boydAThealth.gov.au To the Editor: Labate and colleagues note that tramadol is the most frequently suspected cause of provoked seizures at their First Seizure Clinic.1 Early in 2003, the Adverse Drug Reactions Advisory Committee (ADRAC) reported to Australian prescribers the results of the first 4 years of experience with tramadol in Australia.2 At the time, ADRAC noted that 26 cases of convulsions had been reported among a total of 354 reports on tramadol. By January 2005, ADRAC had received a total of 921 reports involving tramadol, of which 66 described convulsions. (Labate et al reported that 83 cases of convulsions associated with tramadol had been reported to ADRAC. This is incorrect, but the mistake probably resulted from an error in interpretation of information supplied by the Adverse Drug Reactions Unit.) In 27 cases, tramadol was the only suspected drug, but in the other 39 cases there were various other suspected drugs. This included 20 reports in which there was a suspected drug interaction. Both oral and injected tramadol have been implicated. The product information for tramadol states that convulsions have been reported in patients using tramadol at the recommended dose levels and that the risk may be greater when doses of tramadol exceed the recommended limits.3 In addition, tramadol may increase the seizure risk in patients taking other medications that lower the seizure threshold. Drugs specifically mentioned in this context include the selective serotonin reuptake inhibitors, tricyclic antidepressants and antipsychotic drugs. In the 39 cases reported to ADRAC in which there were one or more suspected drugs in addition to tramadol, tramadol was being used with selective serotonin reuptake inhibitors (10 cases), tricyclic antidepressants (6 cases) and, in 13 cases, other drugs that may also have the potential to lower the seizure threshold, such as pethidine (2 cases), venlafaxine (2), propofol (2) and bupropion (2). In two of the cases in which tramadol was the only suspected cause and two of the cases with multiple suspected causes, the patients were also taking anticonvulsant drugs for seizure control. ADRAC data indicate that, although tramadol alone can induce seizures, these are more likely to occur in the setting of the concomitant use of other drugs that also have the potential to lower the seizure threshold.

Ian W Boyd

Graham R Wicks Medical Hypnotherapist, Department of Psychological Medicine, Women’s and Children’s Hospital, North Adelaide; 9 Collins Street, Collinswood, SA 5081. grwicksATbigpond.net.au To the Editor: I was interested to read the article about managing nocturnal enuresis in children,1 but was surprised and disappointed that there was no mention of the place of medical hypnotherapy. Hypnotherapy can be particularly valuable in the treatment of monosymptomatic nocturnal enuresis in children aged from 7 or 8 years upwards, and has the advantage of being completely non-invasive with no side effects. It focuses on empowering the children to take control of their own bodily functions.2 Hypnotherapy is also of value in the management of nocturnal enuresis associated with day-time symptoms, such as urgency with or without incontinence, and can also be used to enhance the efficacy of treatments like enuresis alarm systems. While there are few well documented comparative studies3 on the benefits of hypnosis versus other treatments for nocturnal enuresis, there are numerous anecdotal reports and studies involving a series of patients being successfully treated with hypnotherapy. Hypnosis should only be used by properly trained doctors or psychologists who have access to the full range of medical investigations. Hypnosis is of course not a panacea, but is an excellent first-choice treatment for monosymptomatic nocturnal enuresis, the commonest type seen by general practitioners. If, after three or four treatment sessions, hypnosis is not effective, other approaches can be employed. A quick search of the internet using the terms “enuresis and hypnotherapy” will reveal over 700 sites with information on the subject, and there are several highly respected professional journals that publish clinical and research papers and articles on the use of hypnosis in medicine and psychology. All of these are published by reputable professional societies whose membership is limited to registered health professionals. The Australian Society of Hypnosis (http:// www.ozhypnosis.com.au) conducts ongoing training courses in all states of Australia for graduates in medicine, psychology and dentistry. Hypnotherapy is now becoming more and more accepted worldwide as a valuable and legitimate tool that can be used, in conjunction with the more traditional approaches, in a wide variety of medical and psychological problems. It is a great pity that many clinicians are either not aware of its value or are still loathe to accept it because of negative connotations associated with its use for entertainment purposes and in the hands of non-professional therapists.

Graham R Wicks

Patrina H Y Caldwell,* Denise Edgar,† Elisabeth Hodson,‡ Jonathan C Craig§ * Staff Specialist and Lecturer, † Head, Department of Nephrology, § Associate Professor and Head of Clinical Research, NHMRC Centre of Clinical Research Excellence in Renal Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145; ‡ Clinical Nurse Consultant, The Continence Foundation of Australia in NSW, Sydney, NSW. PatrinacATchw.edu.au In reply: Thank you for your interesting comments regarding hypnotherapy in the treatment of nocturnal enuresis in children. There are a number of therapies, such as hypnotherapy, electrotherapy and acupuncture, which show great promise for the management of nocturnal enuresis. We only included in our article1 treatments that were supported by evidence from well documented comparative studies. Using comprehensive search strategies, we have not found comparative studies for these complementary therapies. We would be very interested to be directed to studies that have formally evaluated other interventions. There is a huge need for randomised controlled trials comparing alternative treatment strategies with conventional therapy in this area.

Patrina H Y Caldwell · Denise Edgar · Elisabeth Hodson · Jonathan C Craig

Edwin P Kirk,* Annette Hattam,† Anne Turner‡ * Co-ordinator of Advanced Training, † Chair, Specialist Advisory Committee in Clinical Genetics, Royal Australasian College of Physicians; and Geneticists, Department of Medical Genetics, Sydney Children’s Hospital, High Street, Randwick, NSW 2031; ‡ Chairperson, Board of Censors in Genetic Counselling, Human Genetics Society of Australasia. kirkedATsesahs.nsw.gov.au To the Editor: Genetic risk estimation is a key element of the practice of clinical geneticists and genetic counsellors. Given this, it was with some concern that we read the findings of Bonke and colleagues regarding the performance of (mainly European) geneticists and counsellors in the application of Bayesian analysis to risk estimation.1 Bayesian analysis is taught as part of Australasian training in both clinical genetics and genetic counselling, and has been for as long as there have been formal programs. Thus, most Australian geneticists and counsellors should be familiar with the application of Bayes’ theorem to risk estimation. In actual clinical practice, it is rare to need to perform this type of analysis. This is partly because of the rapid progress in molecular genetic testing, which often obviates the need for such calculations, and partly because situations in which Bayesian analysis is clinically helpful are uncommon. Pedigrees like those in the study by Bonke et al do not come along often; when they do, the modification of prior risk by Bayesian analysis is not often important. For example, modification of a risk from 50% to 33% or from 25% to 17% (as in two of the examples used by Bonke et al) is unlikely to alter decision-making for the families involved. Specifically, as these examples all involve testing for Huntington’s disease, in which molecular analysis is usually quite straightforward, we would expect very few individuals would decide whether to proceed with testing based on being given information about modification of risk expressed this way. Moreover, when you are not performing this type of calculation regularly, it is time-consuming to do. It seems possible that many of those who completed the questionnaire would have taken greater care, and achieved greater accuracy, if faced by a real clinical situation. Nonetheless, for those of us who are involved in training clinical geneticists and genetic counsellors, the article is a useful reminder of the importance of this skill, and we will communicate with supervisors to reinforce the importance of teaching Bayesian analysis to our trainees.

Edwin P Kirk · Annette Hattam · Anne Turner

In reply: Geneticists and counsellors must be able to calculate risks according to professional standards, regardless of whether modified risks lead to decision changes. Does training in genetic risk calculation help? Only 21% of our respondents who had had such training recently (< 3 years ago) estimated all target risks correctly. In response to Kirk et al, calculating conditional risks need not be time-consuming in scenarios similar to our target pedigrees,1 and is often helpful when at-risk (grand)parents do not wish to be tested but their offspring do. Given n children at 25% prior risk tested negative and no other (grand)children tested, the conditional risk for at-risk individuals in generation g (with g = 0 at 50% prior risk, g = 1 at 25% prior risk, etc) is 1/[2g(2n+1)]. Thus, in target #4 (n = 1), the father’s risk (g = 0) equals 1/[20(21+1)] = 0.33. In target #9 (n = 2), the unborn’s risk (g = 2) equals 1/[22(22+1)] = 0.05. Similar formulas for more complicated scenarios are available upon request. In calculating risks, however, care must be taken that the pedigrees and target individuals are comparable to our scenarios. In target #7, for instance, the risk for the untested aunt does not increase simply because of the decreased risk for her brother (gambler’s fallacy).2

Benno Bonke · Aad Tibben · Dick Lindhout · Angus J Clarke · Theo Stijnen

Scott Kinlay Director, Vascular Medicine and Endovascular Therapy, Veterans Affairs Medical Center and Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. skinlayATpartners.org To the Editor: Wang and Hoy1 deserve much credit for highlighting yet again the poor state of health of Indigenous Australians. However, their conclusion that the Framingham equation underestimated risk and that better prediction equations are needed may miss the point. The Framingham equations work well in other populations if the aim is to rank groups of individuals into higher or lower risk categories. Box 4 in the article by Wang and Hoy shows that they do this pretty well across increasing age groups. Framingham equations fall down when they are used to estimate absolute risk in populations whose coronary heart disease (CHD) rates are different from those in the Framingham study. Some years ago, we showed that adjusting the Framingham risk estimates in line with the overall incidence of CHD in the population modestly improved their performance.2 This is all very nice, but is better risk estimation the solution? We don’t estimate risk in other high-risk groups (eg, patients with CHD), because all are at high risk and all need risk factor reduction. A brief look at the risk factor profile in Box 2 of Wang and Hoy’s article reveals an alarming picture of uncontrolled CHD risk factors in a relatively young population (average age, 33–36 years). Cigarette smoking, dyslipidaemia, diabetes and overweight prevail. Perhaps, rather than concentrating on quantifying the exact risk in such a high-risk population, we should look at the reasons for the high rates of risk factors. What motivates some Indigenous people to smoke more, be more overweight and have a higher incidence of dyslipidaemia and diabetes than other Australians?3,4 Do they feel disenfranchised when governments infer they are “dirty” by tying financial aid to face-washing?5 Do they have attractive employment opportunities? Do they have enough sense of control over their lives to reduce their need to indulge in cigarettes and other short-term pleasures? Are there adequate supplies of healthy foods that they like? These factors may differ, as some rural Abori-ginal communities have much lower rates of smoking, overweight and diabetes6 than others. Exploring these issues will aid preventive methods aimed at the whole community. In the meantime, I would suggest that the Framingham equation does rank members of this community — into modest, high, and very high risk (the average 45–54-year-old has a 20% risk of a CHD event over 10 years1). This may help guide the medical treatment of risk factors and the pursuit of the medical model of prevention while social changes dictated by Aboriginal communities take effect.

Scott Kinlay

In reply: We agree with Kinlay that it is important to prevent risk factors at the population level (a population strategy). However, there is also a need to properly identify high-risk individuals who require immediate medical intervention (a high-risk strategy) and to understand the full spectrum of factors that determine such risk. The primary focus of our study was to assess whether the widely used Framingham risk functions were applicable to Aboriginal people in remote communities. Our data show that the Framingham functions significantly underestimated the risk of coronary heart disease (CHD). 1 The high CHD risk in Aboriginal people cannot be fully explained by traditional risk factors. Some major risk factors such as abnormal total cholesterol level and obesity in the study population are actually not as prevalent as those in the general Australian population. 2 Evaluation of traditional risk factors and identification of novel factors in this population are useful for the development of intervention strat-egies. Novel factors such as infection, inflammation, albuminuria and low birthweight have been suggested as predictors of CHD risk in this population. 3,4 Kinlay suggests that Framingham functions should be used to predict CHD risk in Aboriginal people. We disagree. Guidelines for the management of Aboriginal people need to recognise the serious underestimation of risk that the Framingham formulas provide. We agree that some high-risk groups, such as patients with established CHD, do not need additional risk estimates. With our current knowledge, however, we can not say whether the whole Aboriginal community should be treated as a very high-risk population.

Zhiqiang Wang · Wendy E Hoy

Anna Peeters,* Reannan L Cashen,† Paul E O’Brien‡ * Senior Research Fellow, † Honours Student, Epidemiology and Preventive Medicine, ‡ Director, Centre for Obesity Research and Education, Monash University, The Alfred Hospital, Commercial Road, Melbourne VIC 3004. anna.peetersATmed.monash.edu.au To the Editor: We support the warning of Talbot and colleagues regarding the inequities of the current system for provision of bariatric surgery to the morbidly obese in Australia.1 We recently analysed data on the number of separations for bariatric surgery for morbid obesity in Australia. The two most common procedures in Australia are gastric reduction surgery (procedure code 30511, which includes gastric stapling, laparoscopic adjustable gastric banding [LAGB] and gastroplasty) and gastric bypass surgery (procedure code 30512). The number of separations for procedure 30512 has remained quite stable and relatively low (around 200 a year) over the past few years. By contrast, the number of separations for procedure 30511 has been continually increasing. While the exact number of LAGB procedures can not be identified from this single code, it is assumed that the majority of the increase is due to LAGB, as it is a less invasive pro-cedure and therefore generally more acceptable to patients.2 However, the number of separations for gastric reduction surgery in public hospitals is low and has remained so. In the financial year 2000–01 there were 1529 separations for gastric reduction for morbid obesity across Australia, only 194 (13%) of which were performed in public hospitals (see Box). In 2001–02 the total number increased to 2351, but the number performed in public hospitals increased only marginally, to 238 (10% of the overall number). In 2002–03, the last year of available data, there were 2612 separations, of which only 287 (11%) were performed in public hospitals (unpublished data, courtesy of the Australian Institute of Health and Welfare). Clearly, if this issue is not addressed systematically, it will only serve to widen the socioeconomic inequalities in health associated with obesity in Australia. Separations for all gastric reduction surgery for morbid obesity, Australia

Anna Peeters · Reannan L Cashen · Paul E O’Brien

Colleen T Bruce,* Paul S Thomas,† Deborah H Yates‡ * Research Assistant, † Associate Professor, Department of Respiratory Medicine, Prince of Wales Hospital, Randwick, NSW 2033. ‡ Respiratory Physician, St Vincent’s Hospital, Sydney, NSW. Paul. ThomasATunsw.edu.au To the Editor: The recent article by Willcock and colleagues on the high psychological morbidity and level of burnout that interns experience during their first year in hospital highlights an important topic.1 Willcock et al point out that there is an increase in psychiatric morbidity over the intern period in first-year medical graduates. This corroborates the findings of a larger study we conducted among interns during their first year, in which we showed that psychiatric morbidity rises, particularly during the middle of this first year as a doctor, but then decreases by the end of the year.2 The point made by Willcock et al1 is that psychiatric morbidity is not limited to first year graduates — senior doctors are also susceptible to psychological morbidity and burnout.3 Their article highlights the continuing need for workplace reform and support for the medical profession. In addition to reducing working hours, other interventions need to be considered to prepare medical students for their profession, and to reduce the factors which contribute to morbidity (eg, workload, multiple tasking, incessant paging). It should be feasible to test the efficacy of such interventions with the same instruments (such as the General Health Questionnaire) in future generations of interns, and to compare these results with the above studies. Showing that such interventions are effective will provide a strong platform from which to implement wider change in the workplace.

Colleen T Bruce · Paul S Thomas · Deborah H Yates

Simon M Willcock Director, Academic General Practice Unit, Hornsby Hospital, Palmerston Rd, Hornsby, NSW 2077. simonwATmed.usyd.edu.au In reply: Bruce and colleagues are correct to call for ongoing workplace reform and support for the medical profession in general. Our study, which followed medical students to the end of their intern year, did not show a significant fall in psychiatric morbidity towards the end of the intern year as theirs did. Our review of the recent literature suggests that any “improvement” in psychological morbidity after the mid-year peak during internship is likely to be transient, with the early postgraduate period representing a period of transition from normative population values of burnout and morbidity to levels which remain high throughout a medical career, when compared with the general population. The traditional interpretation of the internship as a “baptism by fire”, which tests and ultimately strengthens the new medical graduate, does not hold up to scrutiny. A realistic assessment of this period suggests that it is one where stress and distress often reach unhealthy levels, and where dysfunctional coping strategies may be developed which persist throughout a medical career. The development of mature personal coping strategies along with systemic changes to promote engagement with work have been identified as the most likely means of limiting burnout and its sequelae among medical practitioners.1

Simon M Willcock

Linsey S Hart,* Jane Vernon-Roberts† * AMC Liaison and Resource Officer, Postgraduate Medical Council South Australia, 71 Edward Street, Norwood, SA 5069. † Head of Clinical Studies, Royal Adelaide Hospital, Adelaide, SA. linseyATpmcsa.org.au To the Editor: McGrath’s article on integrating overseas-trained doctors (OTDs) into the Australian medical workforce noted that the areas of difficulty in this area have been well defined.1 McGrath challenged us to “get on with it”. We interpret this challenge to mean that there has been enough regurgitating and redefining of the problem, and it is time for some action. In South Australia, the difficulties of integrating overseas doctors into the workforce mirror those experienced by other states. The Department of Health Overseas Trained Doctor 2004 database listed 93 OTDs as eligible to work in SA. Seventy were employed. All of these doctors had only completed the Australian Medical Council (AMC) Multiple Choice Question (MCQ) examination. Since its inception in April 2003, the Postgraduate Medical Council of South Australia (PMCSA) AMC doctors subcommittee has worked to put in place a number of educational initiatives to support and assist OTDs to complete the Australian Medical Council Exams, and to advocate for their ongoing needs for better orientation to the workplace and protected education time at work. The programs initiated by the PMCSA are both Government-funded and self-funded. They are: culture and medical communication for doctors, MCQ tutorial program, ready for work program, hospital tutorials, objective structured clinical examination practice exam, clinical bridging program, and study groups. Examination results in 2004 for candidates undertaking the PMCSA programs bettered the national average. Of the 16 enrolled participants in the MCQ tutorial program, which ran from January to April 2004, nine sat the May AMC MCQ exam and seven deferred. Eight of the nine passed, giving a pass rate of 89% (AMC pass rate 56%; Australian Medical Council, personal communication). In the AMC clinical examinations, our candidates achieved an overall pass rate of 67%; 30 sat the exam, 20 passed and 10 were given a re-sit or a fail result. (AMC pass rate 59%; Examinations Officer Clinical, Australian Medical Council, personal communication). Twenty chose to defer after using the various programs and tutorials on offer to gauge their level of preparedness. These doctors are planning to undertake the exam in 2005. These programs constitute the South Australian Action Plan for OTD inclusion in the workforce. 2 All of these programs are available and appropriate for any OTD (permanent resident or temporary resident). To the best of our knowledge, no temporary resident wishing to work in “areas of need” has enrolled in our programs yet.

Linsey S Hart · Jane Vernon-Roberts

Barry P McGrath Professor of Medicine, Monash University; and Chair, Confederation of Postgraduate Medical Education Councils of Australia, Dandenong Hospital, Dandenong, VIC 3175. Barry.mcgrathATmed.monash.edu.au In reply: Hart and Vernon-Roberts outline the South Australian Action Plan by the Postgraduate Medical Council of South Australia Australian Medical Council (AMC) doctors subcommittee to support and assist overseas trained doctors (OTDs). Their worthy efforts are directed predominantly towards the many OTDs preparing for their AMC examinations, with associated bridging and “ready-for-work” programs to facilitate entry into the hospital medical workforce. However, the question that needs to be addressed, and which was the main thrust of my article,1 is why we don’t have a national coordinated approach to all elements of the pathway to integrating OTDs into the Australian health care system. This cannot be a largely political approach, as is the Australian Government’s Strengthening Medicare initiative, which is particularly weak in the areas of assessment for safe practice and support in training. A recent article has highlighted the need for a national approach to coordinated governance for postgraduate medical education in Australia and the unsatisfactory complexity of medical education and training systems in this country.2 This excellent article includes only very brief reference to OTDs, using the term “international medical graduates”, 2 which is becoming the more acceptable term and the one recognised by other countries. It does not address the many gaps and problems in the pathways for this group. The number of international medical graduates seeking employment and/or being actively recruited into the medical workforce in Australia each year is far greater than the number graduating from our own medical schools. Thus, there is a degree of urgency about the debate on postgraduate medical education in Australia. We need a national authoritative body, like the new United Kingdom Postgraduate Medical Education and Training Board.

Barry P McGrath

Deborah J Verran Senior Transplant Surgeon, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050. deborahATemail.cs.nsw.gov.au To the Editor: A recent editorial by Mathew et al1 and an article by Kennedy et al2 tackle the issue of commercial kidney transplantation. In their editorial, Mathew and colleagues conclude that if the nationwide Australian deceased donor organ donation rate approached South Australian levels, dialysis patients would not travel overseas to purchase renal allografts.1 I believe that this statement oversimplifies the situation with respect to organ trafficking and the motives behind patients’ acceptance of this option. Organ trafficking is illegal under all state and territory laws within Australia and hence cannot occur. In a number of other countries around the world this is not the case. Although laws have been introduced in India, this has not necessarily led to cessation of trafficking in kidneys.3 Compounding this, the option of purchasing an organ is becoming more readily accessible by means of an increasing number of Internet sites.4,5 What motivates patients to go through with purchasing an organ overseas is not explored either in the editorial by Mathew et al1 or the article by Kennedy et al.2 Kennedy et al do not state whether any of the patients who travelled overseas for a kidney had been deemed not fit to be on the renal transplant waiting list in New South Wales. They also do not give the waiting time on dialysis for each patient before he or she decided to travel overseas. What is clear is that only patients who can afford to pay the US$70 000 or more currently quoted for a renal allograft will be the ones who end up travelling overseas. It would be nice to think that, with an increased organ donor rate in Australia, patients will no longer travel overseas to purchase organs. However, the ready availability of the commodity in not-too-distant countries and the increasing ease of access to this organ trade, combined with sufficient cash, will mean that there is no major barrier to some individuals.

Deborah J Verran

Sean E Kennedy,* Yvonne Shen,* John A Charlesworth,† James D Mackie,‡ John D Mahony,§ John J P Kelly,¶ Bruce A Pussell** * Renal Registrar, † Professor of Renal Medicine, Prince of Wales Hospital, Sydney, NSW. ‡ Renal Physician, Prince of Wales Hospital, Sydney, and Illawarra Regional Hospital, Wollongong, NSW. § Renal Physician, Royal North Shore Hospital, Sydney, NSW. ¶ Renal Physician, St George Hospital, Sydney, NSW. ** Professor of Medicine, Department of Nephrology, Prince of Wales Hospital, Sydney NSW 2031. b.pussellATunsw.edu.au In reply: We agree that the motives for organ trafficking are complex. The reasons that people choose to travel overseas to obtain an organ was not addressed in our article on this occasion, but some possible reasons may be self evident given the long waiting time, especially in New South Wales. Our aim was to alert our colleagues to the increased risks associated with overseas commercial transplant procedures so that they could ensure that their patients were fully informed when making a decision. Most of our patients were on the waiting list, and the time on dialysis was detailed in Box 2 in our article.1 However, two were not on the waiting list — one had a pre-emptive transplant and another was not on the list because of age-related medical problems.

Sean E Kennedy · Yvonne Shen · John A Charlesworth · James D Mackie · John D Mahony · John J P Kelly · Bruce A Pussell

To the Editor: We read with interest the recent cross-sectional survey of Helicobacter pylori infection in remote and urban Aboriginal populations in Western Australia.1 The prevalence of H. pylori was shown to be consistent with that in developing countries. This is not surprising, given the high prevalence of diseases such as chronic suppurative otitis media, rheumatic fever, scabies, and tuberculosis affecting Aboriginal peoples — all of which relate to poverty and overcrowding.2 Aboriginal and Torres Strait Islander people have a massively disproportionate share of the overcrowded households in Australia. In the 2001 Census, Aboriginal people in WA accounted for 53% and 93% of the two-bedroom and three-bedroom households that accommodated seven to nine and ten or more people, respectively (from 3% of the population).3 Windsor et al speculate that high H. pylori infection rates may be the result of children not wearing nappies and of poor personal hygiene — even though these matters (and housing standards, the presence of functional washing facilities and the degree of overcrowding) were not investigated. We are concerned that such conclusions reflect negatively on the Aboriginal population who took part in the survey in good faith with good will. Moreover, it is misleading to suggest that H. pylori is a cause of poor growth among Aboriginal children. There is insufficient evidence to support screening for H. pylori infection in children, as no studies have demonstrated that treating H. pylori infections improves their growth. It is expected that “some of the participants who tested positive for H. pylori have asked to be treated with antibiotics”. We assign considerable importance to research protocols that adhere to the criterion “no research proceeds without service”.4 Did those who were H. pylori positive with dyspepsia, a history of peptic ulcer complications, or a family history of gastric cancer5 receive treatment? Windsor et al do not describe what follow-up their survey participants received. Without clarity on this point (especially appropriate advice to those who were asymptomatic), we wonder what negative impacts a positive H. pylori finding had on participants’ social and emotional well-being. We are concerned by the authors’ anthropological musings: “Indigenous people may have their own H. pylori strains”. Given Australia’s heterogeneous Indigenous population, this potential research question is of no strategic relevance.4 The promotion of expanded testing for H. pylori is not supported by the evidence. Talley’s accompanying editorial prioritises a “randomised controlled trial to test the health benefits (and risks) of population-based screening and antibiotic treatment [for H. pylori] in Indigenous Australians”.5 In the absence of a clinical endpoint for an as-yet undefined health problem, there is no convincing argument for such a trial. Narrow medical answers to health problems that ignore economic and environmental solutions are not evidence-based. Both articles should have argued strongly for political commitment to these solutions to address a wide range of existing poverty-related diseases which currently affect Abori-ginal and Torres Strait Islander people on a massive scale.

Naomi R Mayers · Sophie Couzos · Richard Murray · John Daniels

In reply: We agree with Mayers and colleagues that the vexing issue of Indigenous health is a political one. We undertook this study because we thought it very strange that the prevalence of Helicobacter pylori was known in most populations on the globe, but not in Australian Indigenous people. Results from each participant in the study were forwarded to the clinicians at the test sites. These results were discussed with the participants and those who needed, or asked for, treatment received antibiotic therapy. In a previous editorial in the Journal, Mayers and Couzos state that “preventive health assessments are obviously needed earlier, given the occurrence of preventable chronic disease at younger ages and higher rates than in other Australians”.1 We agree with this, and it is to be hoped that our data will encourage further assessment and awareness of H. pylori infection in people of all ages in the Australian Indigenous community.

Barry J Marshall · Helen M Windsor

Laurelle J Burrell,* Elizabeth A Grabsch,† Alexander A Padiglione,‡ M Lindsay Grayson§ * Infectious Diseases Research Nurse, † Infection Control Scientist, § Director of Infectious Diseases, Austin Hospital, Studley Road, Heidelberg, VIC 3084; ‡ Infectious Diseases Physician, Department of Epidemiology and Preventive Medicine, Monash University (Alfred Hospital), Melbourne, VIC. Lindsay. GraysonATaustin.org.au To the Editor: Patients with end-stage renal failure are a key risk group for colonisation and infection with vancomycin-resistant enterococcus (VRE). Consequently, many renal units in Australia screen these patients regularly for VRE colonisation, to assist with infection control and treatment.1-3 Screening protocols are usually applied equally to inpatients and outpatients, even though the risk of VRE colonisation among outpatients (and therefore the cost–benefit of such screening) has not been clearly defined. To assess the prevalence of faecal VRE colonisation among haemodialysis outpatients, we conducted a cross-sectional survey of outpatients attending 12 Victorian in-centre haemodialysis units — Austin Health (four units), Southern Health (three units) and five regional haemodialysis units (Bendigo, West Gippsland, La Trobe Valley, Central Gippsland and Bairnsdale). Patients attending these units represent about a third of the state’s in-centre haemodialysis population. The study was approved by the ethics committee at each hospital, and written informed consent was obtained from all participants. All patients who attended the units between 1 October 2001 and 3 April 2002 were invited to participate. VRE faecal carriage was assessed by three rectal swabs and one faecal specimen taken on at least three separate occasions. Specimens were inoculated onto Enterococcosel agar (BBL, Sparks, USA) containing 6 μg/mL vancomycin. All cultures were processed by standard methods for VRE identification, as described previously.2,3 Of 345 available haemodialysis patients, 269 (78%) consented to participate in the study (205 [76%] metropolitan, and 64 [86%] regional; participation rate per centre, 70%–91%). The 269 patients represented approximately 30% of Victorian in-centre haemodialysis patients. Overall, 74% of participants had assessment of all three rectal swabs and a faecal specimen. VRE faecal colonisation was found in three of the 269 participants (1.1%) — two were from separate metropolitan hospitals, and one from a regional centre. All isolates were Enterococcus faecium vanB (the most common type of VRE in Australia).3 None of these three patients were known to be previously colonised. This 1.1% prevalence was substantially lower than the 3.0%–4.6% prevalence previously described in renal inpatients in Melbourne,2,3 and the 10% rate reported in the United States (where 33% of dialysis centres have one or more VRE-positive patients).1,4 Statistical comparisons of this study with our previous two Australian studies2,3 should be undertaken cautiously, as screening methods differed in specimen frequency, type and number. Bearing in mind this caveat, the rate of faecal VRE carriage was significantly lower among the haemodialysis outpatients in our current study compared with renal inpatients in a 1997 study by Grayson et al2 (3/269 v 9/194; P = 0.02 by χ2 test), but less definitely so when compared with renal inpatients in the 1998–1999 study of Padiglione et al3 (3/269 v 22/739; P = 0.09, by χ2 test). Since the outpatient study, screening surveys at our hospital have shown intermittent high rates of colonisation in renal inpatients and environmental contamination (unpublished data). Given our findings in outpatients, we believe future VRE screening protocols in Australian hospitals should focus primarily on inpatients, rather than faecally continent outpatients, who have both a low rate of colonisation and low potential risk for VRE transmission or acquisition. Good compliance with practical infection control guidelines remains important to avoid widespread dissemination of VRE in our haemodialysis centres.5

Laurelle J Burrell · Elizabeth A Grabsch · Alexander A Padiglione · M Lindsay Grayson

Adam P Morton,* H David McIntyre† * Endocrinologist, † Director, Endocrinology and Obstetric Medicine, Mater Hospital, Raymond Terrace, Sth Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: We read with interest the article by Hussein and colleagues on their experience with thiazolidinediones (TZDs).1 These agents are only approved by the Pharmaceutical Benefits Scheme as part of dual therapy. We wish to present our experience of adding TZDs to metformin and sulfonylureas — hence, triple therapy — in patients with suboptimally controlled type 2 diabetes mellitus. The records of 28 patients (15 men, 13 women) with type 2 diabetes, for whom pioglitazone was added to maximal doses of metformin and sulfonylurea because of suboptimal control, were reviewed. Baseline patient characteristics are shown in . Mean follow-up was 9.6 months (range, 3–24 months); the average pioglitazone dose was 31.3 mg. The mean fall in the level of glycohaemoglobin (HbA1c) was 1.26% — 10 patients achieving an HbA1c level of less than 7% at last review. Four patients did not respond to therapy; none withdrew because of side effects. Eight patients whose HbA1c fell less than 0.5% after 3 months continued taking pioglitazone, achieving an average fall in HbA1c of 1.25% after a mean of 12 months follow-up. Mean weight gain was 3.35 kg (– 3.2 kg to 11.6 kg). Mean changes in HbA1c level and weight compared with baseline over 24 months are shown in . There was no correlation between these outcomes, and no baseline characteristic predicted glycaemic response. Six studies have reported the efficacy of TZDs in triple therapy (), and show a consistent fall in HbA1c level at the expense of weight gain, with a low rate of withdrawals because of adverse effects. Our findings were similar to those of these previous reports in terms of glycaemic response and low rate of side effects. The much higher rate of side effects reported by Hussein et al1 is likely to be the result of the coprescription of TZDs with insulin in 64% of patients in their study. While fluid retention has been reported in up to 5% of patients taking TZDs as monotherapy or in combination with oral hypoglycaemics, 15% of patients using TZDs with insulin may develop significant oedema. Most reports describing precipitation of cardiac failure with TZDs have been in patients using combination therapy with insulin. It would be interesting to know what proportion of the patients who developed peripheral and pulmonary oedema in the study by Hussein et al1 were also receiving insulin. One prospective randomised trial comparing the addition of pioglitazone and bedtime insulin to maximal metformin and sulfonylurea found similar efficacy in improving glucose control, but less hypoglycaemia and improved high density lipoprotein cholesterol levels with pioglitazone.3 A study of the long-term efficacy of triple therapy found 26 of 35 patients (74%) had good control after a mean follow-up of 37 months, their HbA1c level having fallen from 8.7% to 6.9%.8 In conclusion, the experience of our unit and the published literature is that TZDs are efficacious in improving suboptimal diabetic control in patients on maximal doses of metformin and sulfonylurea. Eight individuals in our group had a significant improvement in control subsequent to minimal response after the initial 3 months of treatment, suggesting a longer trial of TZDs should be employed before classifying patients as non-responders. It is to be hoped that the regulatory authorities will allow the use of TZDs in triple therapy. 1 Characteristics of our 28 patients at baseline Variable Mean (range) Age (years) 57.4 (31–74) Weight (kg) 96.3 (56–137) Body mass index (kg/m2) 34.6 (24–50.3) Duration of diabetes (years) 11 years (1–48) Glycohaemoglobin (HbA1c) level (%) 9.0 (7.1–10.4) 2 Changes in glycohaemoglobin (HbA1c) level and weight compared with baseline values 3 Studies of thiazolidinediones added to maximal dose metformin and sulfonylurea Variable Roy et al2 Aljabri et al3 Dailey et al4 Kiayias et al5 Kiayias et al5 Byrne et al6 Yale et al7 Thiazolidinedione Rosiglitazone Pioglitazone Rosiglitazone Rosiglitazone* Rosiglitazone† Rosiglitazone Troglitazone Duration (weeks) 16 16 24 20 20 nr 24 No. of patients 48 30 181 19 19 24 101 Baseline body mass index (kg/m2) nr 26 32 31 31 nr 30.1 Baseline HbA1c level (%) 9.3 9.7 8.1 8.9 9 9.6 9.6 Fall in HbA1c level (%) 1.8 1.9 0.9 1.1 1.4 1.2 1.3 Weight gain (kg) nr 2.6 3 4.2 4.6 0.7 0.9 % Patients withdrawn 4.2 0 5.5 0 0 0 2 % Patients with satisfactory control (HbA1c level) 65 (< 7.5) 23 (< 7) 42 (< 7) nr nr nr 43 (< 8) HbA1c = glycohaemoglobin. nr = not reported. * 4 mg/day; † 8 mg/day.

Adam P Morton · H David McIntyre

Nirusha Arnold,* Mark McLean,† David R Chipps,† N Wah Cheung† * Advanced Endocrinology Trainee, † Endocrinologist, Centre for Diabetes and Endocrinology Research, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145. nirusha_arnoldATozemail.com.au To the Editor: It was with interest that we read the recent article on real-life experience with thiazolidinediones by Hussein et al.1 The authors noted the absence of severe liver toxicity with the newer agents, rosiglitazone and pioglitazone, in contrast to troglitazone, which was withdrawn because of cases of hepatic failure.2 However, the sample was too small to conclude that these thiazolidinediones (TZDs) carry no hepatic risk, and they endorsed the current Pharmaceutical Benefits Scheme recommendations that liver function tests (LFTs) be monitored every 2 months. We have collected similar clinic data showing that the development of significant abnormalities in results of LFTs with TZD therapy is uncommon, and in fact, there are often improvements in LFT findings. We reviewed the files of 166 patients with type 2 diabetes treated with TZDs between 1 August 2000 and 30 November 2002, with the aim of assessing their long-term effect on LFT results. Therapy was discontinued within 3 months in 26 patients. The reasons were non-compliance (7), therapy ineffective (8), weight gain (5), dyspnoea (1), peripheral oedema (1), malaise (1), dizziness (1), angio-oedema (1), and pre-existing LFT abnormality (1). We analysed data on the remaining 140 patients (see Box) treated for a mean of 188 ± 4 days with either pioglitazone (109 patients) or rosiglitazone (31 patients). All LFT results improved significantly (Box). At baseline, 90 patients had abnormal findings on LFTs. These findings normalised in 43 of these patients (including one with steatohepatitis proven on biopsy); improved in 29 patients; and were unchanged in nine patients. LFT findings deteriorated in nine patients, leading to cessation of therapy in two. Most patients with normal LFT results at baseline experienced improvements of these parameters within the normal range. Three patients developed new abnormalities in their LFT findings, and therapy was stopped in one patient, leading to resolution of LFT abnormalitites. Changes in glycohaemoglobin (HbA1c) levels correlated positively with changes in activity of alkaline phosphatase (correlation coefficient [r], 0.33; P < 0.01), aspartate aminotransferase (r, 0.27; P < 0.01) and alanine aminotransferase (r, 0.29; P < 0.01). Our findings support those of Hussein et al, that TZD therapy is usually stopped for reasons other than hepatic dysfunction. In contradistinction to early concerns about their hepatic safety, the improvements in LFT findings seen in our patients suggest that TZDs may even benefit hepatic function. In patients with diabetes, abnormal findings on LFTs are often attributed to fatty liver, which predisposes to steatohepatitis. TZDs may well alleviate or prevent steatohepatitis,3 thereby providing benefits beyond that of improved glycaemic control, and mild abnormalities in LFTs should not discourage their use in patients with diabetes. Changes in liver function and glycohaemoglobin (HbA1c) level Variable Baseline 6-month follow-up Change P* Weight (kg) 93 ± 2 96 ± 2 3 ± 0.4 < 0.001 HbA1c (%) 8.9 ± 0.1 7.9 ± 0.1 – 1.0 ± 0.1 < 0.001 Albumin (g/L) 41 ± 0.2 41 ± 0.2 – 0.5 ± 0.2 < 0.02 Bilirubin (μmol/L) 9.4 ± 0.4 8.5 ± 0.3 – 0.9 ± 0.3 < 0.003 ALP (U/L) 92 ± 2 79 ± 2 – 13 ± 2 < 0.001 GGT (U/L) 44 ± 3 31 ± 2 – 13 ± 2 < 0.001 AST (U/L) 26 ± 1 22 ± 1 – 3 ± 1 < 0.001 ALT (U/L) 33 ± 2 25 ± 1 – 8 ± 2 < 0.001 ALP = alkaline phosphatase. GGT = γ-glutamyl transferase. AST = aspartate aminotransferase. ALT = alanine aminotransferase. * Paired t test.

Nirusha Arnold · Mark McLean · David R Chipps · N Wah Cheung

Huong V Nguyen,* Katherine B Ingram,† Jonathan Beilin‡ * Endocrinology Registrar, ‡ Endocrinologist, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6847; † Geriatrician, Swan District Hospital, Middle Swan, WA Huong. NguyenAThealth.wa.gov.au To the Editor: Zoledronic acid is a new bisphosphonate treatment for hypercalcaemia of malignancy, multiple myeloma and documented bone metastases from solid tumours, in conjunction with standard chemotherapy.1 Transient hypocalcaemia, a side effect of bisphosphonate therapy, can occur with zoledronic acid.2 We describe a patient with transient severe hypocalcaemia after zoledronic acid treatment. An 88-year-old white woman with multiple myeloma presented with left hip pain. Imaging revealed multiple lytic lesions in the spine, pelvis and upper femurs. She was commenced on zoledronic acid 4 mg and a 5-day course of melphalan 10 mg/day and prednisolone 100 mg/day. At this stage, her serum calcium concentration was 2.38 mmol/L (normal, 2.15–2.55 mmol/L) and serum phosphate concentration was 0.8 mmol/L (normal, 0.8–1.5 mmol/L). She had renal impairment with reduced creatinine clearance of 35 mL/min. Nine days later, she underwent surgical repair of a duodenal ulcer. Post-operatively, she was found to be hypocalcaemic, with serum calcium concentration of 1.34 mmol/L and ionised calcium concentration of 0.78 mmol/L (normal, 1.14–1.29 mmol/L). Serum phosphate concentration was 0.4 mmol/L and magnesium concentration was 0.87 mmol/L (normal, 0.70–0.90 mmol/L). Her serum 25-hydroxyvitamin D concentration was 14 nmol/L (normal > 50 nmol/L) and her parathyroid hormone level was 44 pmol/L (normal, 1.5–8.0 pmol/L). The patient displayed no symptoms of hypocalcaemia and had negative Chvostek and Trousseau signs. Her QTc interval was normal. Her hypocalcaemia was managed with oral calcium carbonate 4.5 g/day and calcitriol 0.5 g/day. Ten days later, her total serum calcium concentration rose to 2.31 mmol/L and her phosphate concentration was 0.9 mmol/L. Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby reducing serum calcium concentration. Compensatory secondary hyperparathyroidism prevents significant hypocalcaemia by enhancing renal calcium conservation, 1,25-hydroxyvitamin D production, and osteoclastic bone resorption.1,2 In our patient, the 1,25-hydroxyvitamin D concentration was not measured. However, in view of the low 25-hydroxyvitamin D and impaired renal function, this level may have been low, further exacerbating the hypocalcaemia. Transiently low phosphate concentration in this patient may be due to fasting and co-administration of 5% dextrose, as our patient was fasted for 3 days peri-operatively and given a combination of intravenous 5% dextrose and normal saline. Vitamin D insufficiency afflicts a large proportion of the elderly population,3 and its existence needs to be recognised before commencement of bisphosphonate therapy, so that adequate calcium and vitamin D supplementation can be given to reduce the occurrence of hypocalcaemia.

Huong V Nguyen · Katherine B Ingram · Jonathan Beilin