Endocrinology

Fast facts: thyroid disorders. Gilbert H Daniels, Colin M Dayan. Oxford: Health Press, 2006 (143 pp). ISBN 1 903734 65 7. Thyroid disorders are common, and encountered by all in clinical practice. In the population, evident hyperthyroidism is present in 0.5% and subclinical hyperthyroidism in a further 0.7%. Frank hypothyroidism (treated and untreated) has a prevalence of 0.3% and subclinical hypothyroidism is present in over 4%. Clinically evident thyroid nodules or goitre are found in 5%, with ultrasonographically detectable nodules in over 50% by the age of 60 years. The incidence of new thyroid nodules is one per 1000 per year and about one in 25 is malignant. Mild iodine deficiency has re-emerged in Australia, at least in the south-eastern states. Forty million dollars worth of thyroid function tests are ordered every year in Australia. Despite all this, recognition and treatment of thyroid disease could still be much improved throughout Australia. While Werner and Ingbar’s The thyroid, now in its eighth edition, remains the authoritative text, at over 2.5 kg it is not likely to become the bedside reading of any but the most devoted subspecialists. Various brief books have been produced to serve patient education on thyroid disease but we lack a brief text specifically on the thyroid for the non-endocrinologist. This book sets out to fulfil this need and does so admirably. Gil Daniels and Colin Dayan are eminent endocrinologists, well credentialled in the thyroid field, from the United States (Massachusetts General Hospital) and the United Kingdom (University of Bristol), respectively. They have produced a practical and very readable account of clinical thyroidology. As I agree completely with virtually all of their text, I think they have a remarkably clear understanding of thyroid disease and its treatment options. In addition to a clearly written text, the book is well provided with tables, figures, key point summaries, and key references. Duncan J ToplissDirector, Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, VIC Order this book

Duncan J Topliss

To the Editor: Routine school vision screening has been discontinued in many regions.1 Since 2000, children around Newcastle and Lake Macquarie in New South Wales only have their vision checked at school if their parents request it. I am particularly concerned that this may disadvantage young children with diabetes, who may also have undetected amblyopia. These children are already at risk of diabetes-related vision impairment, and simple screening could prevent further disability related to amblyopia. Amblyopia, commonly known as “lazy eye”, is an asymptomatic, potentially treatable condition of poor vision in a “normal” eye. It is caused by the brain suppressing an unclear image from the affected eye. Amblyopia occurs in 2.5%–3.2% of the population.2 The condition needs to be detected early, and treatment needs to be instituted before the end of practical vision development at about 7–8 years of age, otherwise even intensive treatment is unlikely to restore normal vision.3 This is especially important because people with untreated amblyopia have an increased lifetime risk of loss or impairment of vision in their good eye,4 as well as the poor vision in their amblyopic eye. The current Australian screening guidelines for children with diabetes recommend screening for retinopathy after 5 years of diabetes in those who are prepubertal, and annually in adolescents after 2 years of diabetes.5 The International Society for Pediatric and Adolescent Diabetes recommends retinopathy screening in children with diabetes of prepubertal onset at 5 years after the onset of diabetes, or 11 years of age, or at puberty, whichever is earlier.6 Neither document specifies other visual screening (although the National Health and Medical Research Council guidelines do recommend a clinical examination of the eyes for cataract soon after diagnosis). Thus, a 6-year-old child with diabetes would not have his or her vision screened until 11 years of age. An eye with significant amblyopia detected at this age will not achieve normal vision, and the child would be reliant on only one eye for his or her lifetime. Even a 3-year-old child with diabetes would not have visual screening until 8 years of age, the end of practical vision development. The case has been made recently for biennial retinopathy screening for children with diabetes.7 I propose that diabetic children under 9 years of age have their vision fully assessed soon after the diagnosis of diabetes. Should amblyopia be detected then, treatment could commence before the end of active vision development.

Catherine Dunlop

This European approach to insulin management is now being introduced in Australia Since the publication of the Diabetes Control and Complications Trial (DCCT) in 1993,1 improved glycaemic control in type 1 diabetes has been acknowledged as a desirable goal in theory, but frustratingly difficult to achieve in practice. Although bodies such as the American Diabetes Association recommend a glycated haemoglobin (HbA1c) target of < 7%,2 only around 20% of adults with type 1 diabetes under specialist supervision in Australian centres achieve this goal (data from the Australian National Diabetes Information Audit and Benchmarking Survey; Associate Professor Jeff Flack, Director, Diabetes Centre, Bankstown–Lidcombe Hospital, NSW, personal communication). Intensive insulin treatment in the North American-based DCCT involved an initial inpatient stay of 2–4 days. Patients received formalised dietary and insulin prescriptions, emphasising consistent distribution of carbohydrate across the day and intensive glucose monitoring. The program was medically directed and labour intensive, with patients maintaining weekly telephone contact and attending monthly clinic visits. No Australian diabetes centre has been able to routinely offer this level of support to patients. The reduction in microvascular complications seen with intensive treatment in the DCCT was accompanied by a threefold increase in severe hypoglycaemia and a 33% increase in the risk of becoming overweight.1 Overall quality of life did not improve.1 These adverse effects have been seen by many as inevitable consequences of tight glycaemic control and may have discouraged many clinicians and patients from pursuing a “DCCT-style” approach to intensive insulin treatment. As in other endeavours, the Europeans took a different approach from that used in North America. The Dose Adjustment for Normal Eating (DAFNE) program3 is a UK-based adaptation of the German Diabetes Training and Treatment Programme (DTTP).4 DTTP has been progressively developed in Germany since the late 1970s, under the leadership of the late Michael Berger (former President of the European Association for the Study of Diabetes). It is a 5-day structured inpatient education program facilitated by diabetes educators and dietitians. It aims to encourage and equip people who have type 1 diabetes to manage their insulin regimens actively and independently. DTTP has also been adopted in Romania,5 Austria6 and Russia,7 with positive results reported by all groups. In DTTP, patients follow a normal diet and receive intensive training in precise, but not restrictive, estimation of dietary carbohydrate in terms of 10 g carbohydrate portions. Prandial short-acting insulin doses are calculated as a ratio to intake of carbohydrate portions at each meal and major snack (eg, 1 unit per carbohydrate portion). Basal insulin generally comprises twice daily isophane (NPH) insulin or once or twice daily long-acting insulin analogues. Insulin ratios and basal insulin doses are adjusted to meet defined preprandial and bedtime glycaemic targets, with corrective insulin or carbohydrate given as required. General care of diabetes, adaptations of insulin for exercise and alcohol intake, and management of “sick days” are also addressed in the 35-hour program. The 5-day inpatient DTTP course has become part of standard care for type 1 diabetes in Germany. Active clinical audits involving a network of 96 diabetes clinics across Germany continue to demonstrate clinically meaningful improvements in HbA1c (especially for those with poor baseline control) and reduced hypoglycaemic episodes (especially for those with good baseline control) after DTTP training.8,9 Reduced rates of ketoacidosis and hospital admissions have also been noted.9 In Austria and the UK, DTTP has been adapted to a 5-day outpatient program with eight patients per group. Content remains very similar to the German program. The UK DTTP (DAFNE) approach was evaluated in a formal randomised controlled trial.3 Reported benefits in a cohort of 169 patients with poorly controlled type 1 diabetes included a fall of 1% in HbA1c without increased hypoglycaemia or mean weight gain. Quality of life was also improved.3 However, DAFNE is a complex intervention, and it remains unclear which element of the program is most important in improving diabetes control. Aside from the efficacy of the insulin algorithms per se, the effect may be in part due to increased contact with health care professionals and peer group support. Further, there are some weaknesses in the DTTP–DAFNE approach. Only two randomised controlled trials have been conducted,3,5 and, by current standards, the first3 would not be considered of high quality. Also, DAFNE is more expensive than current “routine” diabetes education. To benefit from DAFNE, patients need to perform regular glucose testing and self-adjustment of insulin doses, so it is unlikely to benefit those who struggle with the day-to-day demands of basic diabetes self-care. DAFNE insulin adjustment requires reasonable English literacy and numeracy, which may exclude some patients. Developed in the 1980s, DAFNE was designed around soluble and isophane insulin, rather than more recent insulin analogues. It does not include glycaemic index concepts. The standard glucose targets used in DAFNE (eg, fasting glucose 5.5–7.7 mmol/L) are higher than those recommended for pregnancy10 and will require revision in patients planning to become pregnant. Participation in a DAFNE course is clearly not the only possible pathway to improved glycaemic control in type 1 diabetes. Some people with this condition have been able to achieve excellent glycaemic control over many years without such a program, generally using either multiple-dose insulin regimens or continuous subcutaneous insulin infusion (or insulin pump) therapy. A recent randomised controlled crossover trial reported HbA1c values 0.25 percentage points lower with subcutaneous insulin infusion than with multiple dose insulin therapy,11 but this must be weighed against the increased cost. DAFNE has been costed in the UK at $A1300 per patient,12 and a published health cost modelling analysis suggested mean savings of $A5500 per patient over 10 years, arising primarily from a reduction in microvascular complications.12 Even the most conservative analyses have suggested that DAFNE is cost-saving rather than simply cost-effective.12 The use of DAFNE as one means of improving care for people with type 1 diabetes has been supported by reviews conducted by the UK National Institute for Clinical Excellence13 and the UK Department of Health.14 In January 2006, provision of structured patient education for people with type 1 diabetes became a requirement of the National Service Framework for diabetes in the UK, with DAFNE recognised as the one program which currently meets all the Framework’s requirements for type 1 diabetes.15 DAFNE courses are now provided in 39 centres across the UK, with 3537 DAFNE “graduate” patients reported in January 2006.16 In November 2004, clinicians from four centres in Australia completed DAFNE course observation and post-course training in the UK. The UK DAFNE course materials were then adapted to the Australian health care context. These four centres have now conducted around 12 DAFNE courses in Australia, with positive patient feedback. All centres have committed to the collection of baseline and follow-up data. An “OzDAFNE” collaborative, with strong links to the UK, has been established to ensure consistent standards of course resources and delivery across Australia, and to facilitate training and accreditation of further DAFNE centres within Australia. The processes of accreditation, peer review and quality assurance are seen as essential by all groups involved in the DTTP–DAFNE collaboratives and represent a great strength of the program. The capacity of current OzDAFNE centres to make DAFNE available to people with type 1 diabetes is limited. We hope that other diabetes services will undertake DAFNE training and join the OzDAFNE collaborative. This requires a doctor, diabetes educator and dietitian to observe a 5-day DAFNE course, attend further training and participate in peer review and quality assurance. Two further centres in Queensland have recently completed training and plan to provide courses, while further training is planned in Victoria in the near future. The study reported by Davis and colleagues in this issue of the Journal clearly demonstrates that poor glycaemic control affects people with type 2 as well as type 1 diabetes in Australia.17 The authors also note distinct therapeutic procrastination in proceeding from diet to oral agents to insulin in patients with type 2 diabetes. Previous studies have described “provider frustration” in dealing with diabetes care,18 and this may represent a further barrier to effective implementation of published guidelines. DAFNE was designed with type 1 diabetes in mind, but type 2 patients with marked insulin deficiency, requiring intensive insulin treatment, might also benefit. However, the DAFNE insulin algorithms have not been formally evaluated in patients with type 2 diabetes. The “dietary freedom” of DAFNE may be less appropriate in type 2 diabetes, in which obesity is a common comorbidity. DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed) is a 1-day structured education program for type 2 diabetes developed in the UK, primarily targeted at the earlier stages of this condition.14 Currently, most people with type 1 and type 2 diabetes in Australia have suboptimal glycaemic control and remain at risk of the devastating long-term complications of diabetes. Active strategies to improve glycaemic control and meet other therapeutic targets, including the expansion of DAFNE programs for patients with type 1 diabetes, should be developed across Australia.

H David McIntyre FRACP

Objective: To assess the effectiveness of the management of type 2 diabetes in an urban Australian setting.Design and setting: The Fremantle Diabetes Study (FDS), a community-based longitudinal observational study.Patients: 531 FDS participants with type 2 diabetes, with mean age, 62.4 years (95% CI, 40.9–79.3 years), 54% male, median diabetes duration 3.0 years (interquartile range [IQR], 0.7–7.0 years), with valid data from the baseline FDS assessment and five subsequent annual reviews between 1993 and 2001.Main outcome measures: Glycated haemoglobin (HbA1c) levels at annual review visits before and after change in blood glucose-lowering therapy.Results: Over 2893 patient-years of follow-up, 97 patients (18%) progressed from dietary management to therapy with oral hypoglycaemic agents (OHA), and 45 (9%) progressed from OHA to insulin therapy, after a median duration of diabetes of 4.0 years (IQR, 2.9–5.5 years) and 8.1 years (IQR, 5.5–13.0 years), respectively. Median HbA1c concentrations (IQR) at the review before OHA or insulin were started were 7.7% (6.9%–8.8%) and 9.4% (8.0%–10.7%), respectively. At the next annual review, HbA1c levels in the two groups had fallen to 7.4% (6.5%–8.1%) and 7.9% (7.2%–9.5%), respectively (P ≤ 0.001). Intensification of therapy was associated with beneficial changes in serum lipid profiles, but not with an increase in frequency of hypoglycaemia.Conclusions: Most Australian patients with type 2 diabetes may be spending most of the duration of their disease with suboptimal glycaemic control (HbA1c > 7.0%), despite the availability of a range of effective therapies, including insulin.

Timothy M E Davis BMedSc, MRCP, DPhil, FRACP · Wendy A Davis BA(Hons), MSc, MPH, PhD · David G Bruce MD, FRACP

Objective: To examine the influence of geographical and seasonal factors on duration of solar ultraviolet (UV) radiation exposure of skin to produce recommended vitamin D levels without producing erythema.Design and setting: An ecological study using daily Ultraviolet Index (UVI) data collected in major population centres across Australia for 1 year (1 January – 31 December 2001) to calculate sun exposure times for recommended vitamin D production and erythema.Main outcome measures: Sun exposure times to produce either serum vitamin D concentrations equivalent to an oral intake of 200–600 IU/day or erythema for people aged 19–50 years with fair skin (Fitzpatrick type II skin) exposing 15% of the body.Results: In January, across Australia, 2–14 minutes of sun three to four times per week at 12:00 is sufficient to ensure recommended vitamin D production in fair-skinned people with 15% of the body exposed. However, erythema can occur in as little as 8 minutes. By contrast, at 10:00 and 15:00, there is a greater difference between exposure time to produce erythema and that to produce recommended vitamin D levels, thereby reducing the risk of sunburn from overexposure. From October to March, around 10–15 minutes of sun exposure at around 10:00 or 15:00 three to four times per week should be enough for fair-skinned people across Australia to produce recommended vitamin D levels. Longer exposure times are needed from April to September, particularly in southern regions of Australia.Conclusion: Our study reinforces the importance of existing sun protection messages for the summer months throughout Australia. However, fair-skinned people should be able to obtain sufficient vitamin D from short periods of unprotected sun exposure of the face, arms and hands outside of the peak UV period (10:00–15:00) throughout Australia for most of the year. The greater variability in sun exposure times during winter, means that optimal sun exposure advice should be tailored to each location.

Amanda J Samanek BPhysEd, GDipHlthProm · Emma J Croager PhD · Peter Gies PhD · Elizabeth Milne MPH, PhD · Richard Prince MD, FRACP · Anthony J McMichael PhD · Robyn M Lucas MB ChB, PhD, FAFPHM · Terry Slevin BA(Hons), MPH

GPs can play an important role in helping women to realise their plans for a family You don’t think of a first-time, breastfeeding mum experiencing hot flushes, but that’s how my story begins. I was 40 years old when I conceived my daughter — and very easily, I might add. When Abby was about a year and a half old, my husband and I began trying to conceive a second child. Deceived by our luck the first time, we assumed we’d have no problem. Misguided by the prevailing advice, we persevered for 12 months before seeking professional help. When we finally did, my general practitioner advised that I discontinue breastfeeding even once a day, and, a month later, sent me to have my serum follicle-stimulating hormone (FSH) level tested. We might have reversed those steps because the results showed, at 98 IU/L, that I wasn’t conceiving, not because I had been breastfeeding, but because I was menopausal. The penny dropped — the sweatiness I’d been experiencing while still breastfeeding had been hot flushes. My doctor was as surprised as we were that menopause would follow so closely upon the heels of immediate conception and birth, but the results were confirmed. A fertility centre informed us that the only real option for conception was with donated eggs. And, fortunate as we were to have a friend to donate hers (Box 1), after three failed in-vitro fertilisation (IVF) cycles we have resigned ourselves to the reality that Abby will be our one and only child. That resignation is not without some resentment, however, that my GP, knowing that I was already 41 and trying to conceive, didn’t intervene with a fertility assessment well before a crucial year was lost. Given my age and very sporadic cycles (which naively I had attributed to my still once-daily breastfeeding), my chances of becoming pregnant were slim to remote1 and conception at that point called for a more aggressive strategy. At the age of 40, or even 35, a basic infertility evaluation has been recommended after 6 (rather than the usual 12) months of trying unsuccessfully to conceive,2 as has early referral to a fertility specialist.3 In fact, given my age, rather than prescribing birth control pills postpartum, as you might with a younger woman, a candid discussion about whether I intended to try for a second child, while perhaps awkward in those early days, could have been key to conserving my chances. Why wait?But isn’t it a woman’s own responsibility, and not her doctor’s, to begin a family while she’s still fertile? Perhaps, but what if she lacks accurate information about how long to expect to remain fertile? The current trend to delay childbearing is the result of many factors.4 Maybe I did take my mother’s admonition not to marry early a bit too far — but not by choice. I was eager to start a family and would have done so well before turning 40 if I had I found a suitable partner. And I was in very good company. A full 50% of women surveyed at Monash IVF reported that they had delayed childbearing because they lacked a partner.5 Another study found that many women delay childbearing in favour of establishing careers, relationships and financial security (often believing fertility treatments will be available as a “backup” if needed).2 And if we take into consideration the tendency of women to overestimate their window of fertility,6 or to be unaware of the relationship between age and fertility,5 we can only expect my experience to be repeated many times over. I am writing this article to give a wake-up call to GPs and family planning professionals and to urge them to proactively address a suite of problems related to the rapidly ageing population of women seeking to become mothers for the first time. I hope that, in this way, my experience may help to prevent similar “missed conceptions”. “Positive” family planningThe feminist movement that helped to shape me and my choices was itself shaped by women escaping the confines of the traditional roles of wife and mother. Largely because of this, an emphasis has been placed on “negative” family planning — helping women to prevent unwanted pregnancy or to control the number and timing of children. Contraception and the availability of affordable, legal abortion have meant that women have been free to develop other important dimensions of their lives, such as robust careers and relationships, before having children. But times have changed — again. Years down the track, major advances in women’s ability to break through professional “glass ceilings” and the perception that we can extend indefinitely our ability to become parents have contributed to a growing number of women reaching “biological ceilings” that are even more difficult to break through. It is therefore now time that “positive” family planning be promoted as well. Health practitioners, particularly GPs, now need to provide guidance about the waxing and waning of fertility, preconception care and protective fertility — conception as well as contraception.7 A partnership between government, GPs and their representative organisations, as well as the family planning community, could help to educate women to have a more realistic understanding of their reproductive lifespan, enabling them to make more informed choices. Because although there may be many women who would not be surprised to find themselves infertile at 42, there are others, some as publicly prominent as ABC Television’s Virginia Haussegger, who have been as surprised as I was.8 The “misconception” seems to prevail, consciously or unconsciously, that we can expect to be able to naturally conceive throughout our forties, or if we can’t, that we can expect IVF treatment to “fix it” for us.6 And the truth is, not only does fertility take a nose-dive at about 30 years of age, but the success of IVF, as astounding as its results can be, dives as well (Box 2).7,10 Knowing betterThe media are teeming with fertility information. Books with names like What, no baby?,11 Inconceivable12 and Hot flashes, warm bottles13 have been published in recent years describing women’s experiences of meeting the challenges of subfertility, of being older first-time mothers, and of dealing with the social problem of infertility. While one news article might bust the “you can have everything” myth and report on the challenges of age-related infertility, another may announce a “miraculous” birth at 60, perpetuating the evergreen fertility myth still further. In the absence of individualised guidance by GPs, patients (as in many areas of medicine) arm themselves with information obtained on the Internet.14 Fertility consumers seek advice from sites such as the “Over 40 high FSH” discussion group (www.network54.com/Forum/53068) and “Mothers via egg donation” (www.surrogacy.com/online_support/mved). Such sites are replete with research, anecdotes and coaching about endocrinology, variations in protocols and success rates, and offer moral support to women wanting to take on the expertise of their reproductive endocrinologists, together with advice on how to discern valid treatments from quackery. Such sites also bring to the surface a widespread fervour relating to the desire to conceive, with some women willing to try almost anything to have a child. As in other areas, less scrupulous operators prey on this desperation and confusion. In another, parallel universe, new fertility innovations and studies are continually being reported in scientific and medical research. And while we medical consumers may be able to sift through to the best information on our own, how much more likely are we to find what we are looking for if we have the help of a GP who knows us? What’s a doctor to do?Because of their ongoing interactions with so many women, their knowledge and the resources available to them, GPs are uniquely well suited to convey from the medical world the current and reliable information a woman will need to realise her plans for a family — whether or not to have one, its timing and its size. GPs can play a central and vital role in educating women patients about our fertility’s natural expected lifespan while there is still time to act on it.5 Perhaps this is more important than ever, given the federal government’s recent attempts to restrict Medicare-funded access to assisted reproductive technology — especially for older women.15 The first step involves a doctor’s willingness to broach the subject. And if most Australian doctors are not inviting patients to discuss their family plans, they would not be alone. In one German study, many of the GPs surveyed viewed infertility as a private matter.16 In a related study of GPs and their infertile patients, most GPs did not ask childless patients about their plans to have children, even though 25% of infertile women and 50% of infertile men said they would prefer their doctor to raise the issue.17 Beyond that, I offer some suggestions for what GPs and others can do (Box 3). ConclusionThe growing tendency of women to delay parenthood either by choice or circumstance has implications as we have discussed for the likelihood of successful conception, for the wellbeing of the mother compressing her fertility, and for the children.21 It has repercussions not only for the individuals involved, but on the overall fertility rate.22 Sadly, there is cause for concern that patients may now be bypassing GPs and going directly to fertility specialists.23 This would be an unfortunate trend likely to lead to more heartbreak, more unnecessary individual and public expense and less holistic and continuous care for the woman or couple involved. All of these factors provide compelling reasons for GPs to engage in “positive” family planning by helping younger women to grasp the biological imperative to start their families earlier and helping older women to salvage their residual fertility. Of course, “positive” family planning will not solve all fertility problems. It will not be a treatment for endometriosis, chlamydia or polycystic ovaries. It will not necessarily help women to choose suitable partners during their more fertile years (although it may sharpen their focus). And it will not, in itself, effect the industrial and societal changes required to relieve mothers of the burden of having to compromise their professional lives so much more than fathers do. What it will do, however, is give women the information and tools they need to plan and create families responsibly. 1 Donor’s superovulation ultrasound image 2 Live births per transfer for ART cycles using fresh embryos from own and donor eggs, by ART patient’s age, 2002* ART = assisted reproductive technology. * Reproduced with permission from the US Centers for Disease Control and Prevention.9 3 “Positive” family planning* What an individual general practitioner could do When a childless woman comes for a health check-up or for contraceptive advice or prescription, take the opportunity to refresh her understanding of her reproductive lifespan, discuss her plans for children and make contraceptive recommendations commensurate with those plans.18 Advise women over 35 of the technological advances available for helping to salvage residual fertility. For example: Ovarian reserve screening by transvaginal sonography to establish when a woman’s fertility window is likely to close19 and whether she is a candidate for in-vitro fertilisation (IVF);20 Ovulation tracking by blood testing; Cryopreservation of embryos (or eggs, when the technology to achieve that becomes readily available). What organisations could do Family Planning Australia and its local affiliates could draw from relevant courses they currently offer to doctors, nurses and others to address “positive” family planning, the growing problem of the postponement of parenthood and age-related infertility. With government support, the divisions of general practice could incorporate fertility into their women’s health priorities and assist with informational posters, brochures and other strategies. The Royal Australian College of General Practitioners’ Women’s Health Committee could incorporate fertility into their agenda and urge fertility updates in continuing education programs. In light of Australia’s declining fertility,4 rather than simply cutting off access to IVF at a given age, the government should launch an educational campaign that would help to prevent the need to spend such large sums on IVF. * Planning for conception rather than contraception.

Amy Bachrach BA

Mu Li,* Kay V Waite,† Gary Ma,‡ Creswell J Eastman§ * Senior Lecturer, School of Public Health, University of Sydney, Sydney, NSW 2006; † Technical Officer, ‡ Principal Scientist, § Director, Australian Centre for Control of Iodine Deficiency Disorders, ICPMR, Westmead Hospital, Sydney. muliAThealth.usyd.edu.au To the Editor: Iodine is essential for production of thyroid hormone. The recommended daily intake is 100 μg for children, 150 μg for adults and 250 μg for pregnant and lactating women.1 Sporadic surveys of population iodine intake in Sydney, New South Wales, between 1985 and 1992 showed median levels of urinary iodine excretion (UIE) > 200 μg/L, indicating iodine sufficiency.2 However, a recent national study demonstrated mild iodine deficiency (median UIE < 100 μg/L) in New South Wales and Victoria, borderline levels in South Australia and adequate intake in Queensland and Western Australia.3 The major sources of dietary iodine are dairy milk and dairy products, seafood and iodised salt. In Australia, few people purchase iodised salt, and, except in Tasmania, the food industry does not use iodised salt in the production and preparation of food.4 For decades, milk contaminated with iodine residues from sanitising solutions (iodophors) used in the dairy industry has probably been the largest source of iodine in the Australian diet. We undertook a survey of the iodine content of milk samples from supermarkets around metropolitan Sydney in 2001 and 2004. In each year, iodine levels were measured in 13 samples, comprising a range of milk types (including whole, full cream, lite and skim) and brands (including Dairy Farmers, Devondale, Farmdale, Farmland, Perfection, Pura and Woolworths). Iodine concentrations were highly variable. Median concentrations were 140 μg/L in 2001 (range, 60–220 μg/L) and 195 μg/L in 2004 (range, 66–412 μg/L). Iodine concentrations varied between samples of the same brand and type by up to 100 μg/L. Many samples contained less than 200 μg/L (10/13 in 2001 and 7/13 in 2004). A 1975 survey of iodine concentration in milk conducted by the Australian Consumers’ Association found mean concentrations of 593.5 μg/L and 583 μg/L in NSW and Victoria, respectively.5 Because of concerns about iodine toxicity, Food Standards Australia and New Zealand specified an iodine limit of 500 μg/L in the Food Standards Code 1982. The replacement of iodophors by other sanitisers in the dairy industry appears to be the reason for the decrease in iodine content of Sydney milk. The perception that milk is a rich source of iodine is no longer true. A cup (250 mL) of milk a day would provide at most 50–60 μg iodine, approximating a third of the daily requirement for an adult. We suggest that the reduced amount of iodine in milk is likely to be one of the explanations for the re-emergence of iodine deficiency in Sydney and perhaps elsewhere in Australia. Despite these changes, dairy milk remains an important source of dietary iodine. The iodine content in milk should be monitored.

Mu Li · Kay V Waite · Gary Ma · Creswell J Eastman

Objective: To determine whether pancreatic islet transplantation can control diabetes and prevent severe life-threatening hypoglycaemia.Design, setting and participants: A single-arm observation study of six patients undergoing islet transplantation. All patients had had type 1 diabetes mellitus for over 5 years and documented episodes of repeated severe hypoglycaemia. Islets were isolated from donor pancreases digested by Liberase. Separated islets were infused into the recipient’s liver via the portal vein. Patients were immunosuppressed with daclizumab, sirolimus and tacrolimus. The transplants were performed at Westmead Hospital, NSW, between October 2002 and February 2005.Main outcome measures: Normal blood glucose control without administration of exogenous insulin; demonstration of islet function and abolition of hypoglycaemia.Results: Five of the patients received two islet infusions, and the sixth was withdrawn after one infusion following a portal vein thrombosis. Three patients became insulin-independent, with excellent glycaemic control. Two had islet function with circulating C-peptide, improved glycaemic control, reduced insulin requirement and abolition of severe hypoglycaemia. However, over a 2-year period, graft function deteriorated. Recipients who were initially insulin free remained C-peptide positive but required supplemental insulin. Complications included one postoperative bleed, two portal vein thromboses (which resolved completely), presumed recurrence of tuberculosis in one patient, and deterioration in renal function in one patient.Conclusions: Islet transplantation is effective at improving glycaemic control and hypoglycaemia unawareness in the short to medium term. However, problems with long-term safety of immunosuppression, islet-induced thrombosis and early detection of loss of islet function remain to be addressed.

Philip J O’Connell MB BS, FRACP, PhD · Wayne J Hawthorne MHSc, MD · Brian J Nankivell MD, PhD, FRACP · Anita T Patel BSc · Stacey N Walters DipAppSci · Henry C C Pleass MD, FRCS, FRACS · Richard D M Allen MB BS, FRACS · Jeremy R Chapman MD, FRACP, FRCP · D Jane Holmes-Walker MB BS, FRACP, PhD · Jenny E Gunton MB BS, FRACP, PhD

Objective: To document the population iodine nutritional status in Australian schoolchildren.Design and setting: Cross-sectional survey of schoolchildren aged 8–10 years, based on a one-stage random cluster sample drawn from all Year 4 school classes in government and non-government schools in the five mainland Australian states of New South Wales, Victoria, South Australia, Western Australia and Queensland. The study was conducted between July 2003 and December 2004.Participants: 1709 students from 88 schools (881 boys and 828 girls), representing 85% of the estimated target number of students. The class participation rate was 65%.Main outcome measures: (i) Urinary iodine excretion (UIE) levels (compared with the criteria for the severity of iodine deficiency of the World Health Organization/International Council for the Control of Iodine Deficiency Disorders: iodine replete, UIE ≥ 100 μg/L; mild iodine deficiency, UIE 50–99 μg/L; moderate iodine deficiency, UIE 20–49 μg/L; severe iodine deficiency, UIE < 20 μg/L); (ii) Thyroid volumes measured by ultrasound (compared with new international reference values).Results: Overall, children in mainland Australia are borderline iodine deficient, with a national median UIE of 104 μg/L. On a state basis, NSW and Victorian children are mildly iodine deficient, with median UIE levels of 89 μg/L and 73.5 μg/L, respectively. South Australian children are borderline iodine deficient, with a median UIE of 101 μg/L. Both Queensland and Western Australian children are iodine sufficient, with median UIE levels of 136.5 μg/L and 142.5 μg/L, respectively. Thyroid volumes in Australian schoolchildren are marginally increased compared with international normative data obtained from children living in iodine sufficient countries. There was no significant association between UIE and thyroid volume.Conclusion: Our results confirm the existence of inadequate iodine intake in the Australian population, and we call for the urgent implementation of mandatory iodisation of all edible salt in Australia.

Mu Li PhD · Creswell J Eastman AM, MD, FRACP · Kay V Waite Biological Technicians Certificate · Gary Ma PhD · Karen Byth PhD · Margaret R Zacharin MB BS, FRACP · Duncan J Topliss MD, FRACP · Philip E Harding MB BS, FRACP · John P Walsh PhD, FRACP · Lynley C Ward BS, SRN · Robin H Mortimer MB BS, FRACP · Emily J Mackenzie MB BS · Zelda Doyle MSc(Epidemiology)

Duncan A Howard,* Sue D Waygood,* Sharon L Desmond† * General Practitioner, † Registered Nurse and Practice Manager, Brunswick Community Medical Centre, St Vincents Health, 11 Glenlyon Road, Brunswick, VIC 3056. duncan.howardATsvhm.org.au To the Editor: It is well known that people with serious mental health problems are more likely to suffer substantial physical health problems, or die younger, than those in the general population.1,2 We would like to report some early results from a program that is aiming to improve primary health care for people with serious mental health problems. The Stewart Lodge program was developed through cooperation between the local Moreland Community Health Service, two general practitioners and one registered nurse from the medical clinic collocated with the Community Health Service, the local area mental health service, and the managers of the Victorian Government Supported Residential Services program. The Stewart Lodge program includes a regular non-appointment doctor’s session, complete health assessments for all residents, and regular case conferences involving all carers and clinicians. Initial establishment was funded through a Victorian Government Department of Human Services GPs in Community Health Services strategy grant, which focused on improving integration and service coordination. There are around 85 people living in this community, most of whom have chronic schizophrenia or another serious mental health problem. We plan to report the findings from our program in more detail when we have completed the assessments of most Stewart Lodge residents. However, we would like to report our interim findings on vitamin D levels, which are likely to be relevant to many others in similar circumstances. Of the 30 residents tested so far, three have had vitamin D levels in the normal range (> 50 nmol/L), 20 in the deficient range, (25–50 nmol/L) and seven in the severely depleted range (< 25 nmol/L). An increased risk of low vitamin D levels has been previously reported in populations of older institutionalised people,3 and a recent position statement in the Journal on accepted levels of 25-hydroxyvitamin D (25-OHD) warned of risks of vitamin D deficiencyfor various groups in the community.4 We suggest that people with serious mental illness are another group that should be included in those at risk. The people we work with are at risk because of decreased exposure to the sun through inactivity, and because of their illness and medication. Of note, the median age of our residents is 49 years. We aim to tackle this issue by giving Vitamin D supplementation (although this is currently problematic because there is no suitable vitamin D supplement supported by the Pharmaceutical Benefits Scheme). We will be encouraging more physical activity, particularly outdoors, as this is most likely to be of overall benefit to our residents’ general health.

Duncan A Howard · Sue D Waygood · Sharon L Desmond

Simon D J Gibbs,* John O'Grady,† John F Seymour,‡ H Miles Prince§ * Haematology Registrar, † Dental Oncologist, ‡ Haematoncologist, § Head, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC 8006. simongibbs02ATyahoo.com.au To the Editor: We read with interest the article by Carter and colleagues reporting five cases of jaw osteonecrosis associated with bisphosphonate use.1 To emphasise the association, we report a further eight cases seen at our institution between February 2004 and June 2005. After Marx’s report of the condition in 2003,2 we instituted a policy of active screening for jaw osteonecrosis in patients taking bisphosphonates. Patients were asked about suggestive symptoms, such as tooth pain or dental infection, and underwent oral examination by the treating haematologist or oncologist. Suspected cases were referred to our dental oncology unit. Bisphosphonate therapy was discontinued in established cases to prevent further bisphosphonate accumulation and possible worsening of the complication. Of the eight patients detected with jaw osteonecrosis, five had multiple myeloma, two breast cancer, and one prostate cancer. All were receiving monthly intravenous bisphosphonate therapy: zoledronic acid (4 mg) in seven patients, and pamidronate (90 mg) in the other. Median duration of bisphosphonate therapy before onset of symptoms was 22 months (range, 6–66 months). Five patients were male, and three female. Seven had undergone tooth extraction before presentation (Box), and the five with multiple myeloma had received high-dose corticosteroids. Management was conservative in all eight. No improvement was seen in any patient by 3 months, but, with continued withholding of bisphosphonates, some signs of healing were seen in all by 6 months. Four of the patients had a change in therapy from pamidronate to zoledronic acid (because of the latter’s shorter infusion time) in the 2–18 months before onset of symptoms. None had experienced osteonecrosis while taking pamidronate. It is postulated that zoledronic acid is more often associated with osteonecrosis than pamidronate.3 Appropriate management for patients who need to resume bisphosphonate therapy after osteonecrosis remains to be determined. Clodronate is an orally administered first-generation bisphosphonate which has been used widely in Europe with no reports of associated osteonecrosis.4 Unlike pamidronate and zoledronic acid, it does not contain a nitrogen ring. On this basis, we recently began clodronate therapy in a patient with complete jaw healing after osteonecrosis. Avoiding tooth extractions while taking bisphosphonates should minimise the incidence of osteonecrosis. Our active screening policy allowed earlier detection of osteonecrosis and prompt intervention, including cessation of bisphosphonates and avoidance of debridement of necrotic bone (which often exacerbates the condition), thereby limiting the extent of osteonecrosis. It is uncommon for physicians to ask about dental problems and for dentists to ask about bisphosphonate use. This new complication highlights the need for this to change. Osteononecrosis of the jaw in a patient with multiple myeloma taking zoledronic acid Necrotic maxillary bone and sequestrum formation which developed after tooth extraction. Computed tomography scan showing failure of the bone to heal at the extraction site.

Simon D J Gibbs · John O'Grady · John F Seymour · H Miles Prince

Jim R Stockigt,* Zita E Ballok,† Victor Kalff† * Endocrinologist, † Nuclear Medicine Physician, Epworth Hospital, Richmond, and Alfred Hospital, Commercial Road, Prahran, VIC 3181. jrsATnetspace.net.au To the Editor: An Australian businessman travelled to the United States by air 1 week after receiving a second therapeutic dose of 8 mCi (300 MBq) iodine-131 for thyrotoxicosis due to Graves’ disease. He carried no medical documentation, but had with him carbimazole tablets, to be recommenced 1 week after the dose. While awaiting passport clearance at Los Angeles, he noticed that an attendant from homeland security was monitoring the line of passengers with a hand-held device no larger than a mobile phone. He was approached and asked if he was a doctor, or if he was under medical treatment. He indicated that he had received radioiodine recently. The official appeared to be aware of the situation and moved him to the front of the line. He was asked whether he had a letter from his doctor or whether he had medication with him. No letter was to hand, but the medication was shown. He was escorted to collect his baggage and was taken aside for detailed questioning. His luggage and person were searched in detail and information entered into a database. The episode caused significant distress. On two occasions during the next week, he re-entered the US from Canada, by which time he had a letter that documented his medical treatment. On each occasion he was detected by the surveillance system, and questioning and search procedures were repeated. Current radiation detection devices in use at airports appear to have very high sensitivity.1 A recent detailed study that compared the sensitivity of various hand-held radiation detectors in recording various radionuclides,2 showed that therapeutic doses of I-131 could be detected for up to 95 days, F-18 FDG was detectable for 1 day, Tc-99m would trigger the alarm for 3 days, and Tl-201 or Ga-67 could be detected for up to 30 days.2 The authors of that study concluded: . . . personal radiation detectors used for Homeland Security are extremely sensitive and may detect low levels of radionuclides for long periods of time. Patients should be appropriately counselled to carry information regarding administration of diagnostic and therapeutic radiopharmaceuticals for these extended periods. Some devices are quoted as being able to detect 0.01 MBq of I-131 at 2 m —3 m,1 a level of activity that might still be present 3–4 months after treatment with 400 MBq (about 11 mCi) I-131, within the standard dose range for thyrotoxicosis. It is now a medical responsibility to make people who have received relevant radionuclides such as I-131, Tl-201 or Ga-67 aware of this travel hazard, to avoid unexpected apprehension in circumstances that cause delay and distress. Such patients should ensure that they carry appropriate medical documentation with them when they travel and should be aware that they may be interrogated and searched, even if they have documentation. To our knowledge, no similar surveillance is currently used at Australian airports.

Jim R Stockigt · Zita E Ballok · Victor Kalff

Strict control of blood glucose levels should be pursued before conception and maintained throughout the pregnancy (glycohaemoglobin [HbA1c] level as close as possible to the reference range). Before conception: high-dose (5 mg daily) folate supplementation should be commenced; oral hypoglycaemic agents should be ceased; and diabetes complications screening should take place. Management should be by a multidisciplinary team experienced in the management of diabetes in pregnancy. Blood glucose monitoring is mandatory during pregnancy, and targets are: fasting 4.0–5.5 mmol/L; postprandial < 8.0 mmol/L at 1 hour; < 7 mmol/L at 2 hours. A first trimester nuchal translucency (possibly with first trimester biochemical screening with pregnancy-associated plasma protein A and β-human chorionic gonadotropin) should be offered. Ultrasound should be performed for fetal morphology at 18–20 weeks, if required, for cardiac views at 24 weeks and for fetal growth at 28–30 and 34–36 weeks. Induction of labour or operative delivery should be based on obstetric and/or fetal indications. Level 3 neonatal nursing facilities may be required and should be anticipated when birth occurs before 36 weeks, or if there has been poor glycaemic control. Insulin requirements fall rapidly during labour and in the puerperium. At this time, close monitoring and adjustment of insulin therapy is necessary.

Aidan McElduff MB BS, PhD, FRACP · N Wah Cheung MB BS, FRACP, PhD · H David McIntyre MB BS, FRACP · Janet A Lagström BSc, RM, GradCertDiabetesEd · Barry N J Walters FRACP, FRANZCOG · Jeremy J N Oats MB BS, DM, FRANZCOG · Peter Wein MB BS, FRANZCOG · Glynis P Ross MB BS(Hons), FRACP · David Simmons MD, FRACP

Objectives: To determine the incidence of childhood type 1 diabetes mellitus (T1DM) in New South Wales from 1997 to 2002; to compare with previously published rates (1990–1996); and to analyse trends in incidence from 1990 to 2002.Design, setting and participants: Prospective population-based incidence study. Primary ascertainment of incident cases aged < 15 years was from the Australasian Paediatric Endocrine Group NSW children’s diabetes register. Secondary ascertainment was from the National Diabetes Supply Scheme until 1999 and from the Australian Institute of Health and Welfare thereafter. Childhood population data were obtained from the Australian Bureau of Statistics.Main outcome measures: Age-standardised incidence; trends in incidence by calendar year, and sex and age at diagnosis.Results: There were 3260 incident cases (1629 boys, 1631 girls) in the 13 years. Case ascertainment was 99.7% complete using the capture–recapture method. Mean age-standardised incidence per 100 000 person-years was 20.9 (95% CI, 19.9 to 21.9) from 1997 to 2002 compared with 17.8 (95% CI, 17.0 to 18.7) from 1990 to 1996; there was a plateau in incidence between 1997 and 2002. Overall, the incidence increased on average by 2.8% per year (95% CI, 1.9% to 3.8%, P < 0.001) and increased with age, being 12.2 (95% CI, 11.3 to 13.1) in 0–4 year olds; 18.9 (95% CI, 17.8 to 20.0) in 5–9 year olds and 26.7 (95% CI, 25.4 to 28.1) in 10–14 year olds. The increase per year in 0–4 year olds (3.9%) was not significantly higher than in older children. The mean incidence of T1DM was 19.8 (95% CI, 18.8 to 20.7) in girls and 18.8 (95% CI, 17.9 to 19.7) in boys (P = 0.02).Conclusions: The incidence of childhood-onset T1DM has increased significantly in all age groups in NSW since 1990. Resource planning in the management of childhood diabetes in NSW should take these findings into account.

Craig E Taplin MB BS · Maria E Craig PhD, FRACP, MMed(ClinEpid) · Margaret Lloyd RN · Martin Silink AM, MD, FRACP · Neville J Howard FRACP, FRCP · Claire Taylor MB ChB · Patricia Crock FRACP

Adam P Morton Physician, Department of Medicine, Mater Adult Hospital, Raymond Terrace, South Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: The excellent report by Harding et al in the Diagnostic Dilemmas article in the Journal highlighted medications and conditions that may cause false positive results of biochemical tests for phaeochromocytoma.1 Another group of patients, those with obstructive sleep apnoea (OSA), may have raised urine noradrenaline levels in the absence of a phaeochromocytoma. Of about 170 patients seen at a hypertension screening service at the Mater Adult Hospital between 1998 and 2000, six had elevated levels of urine noradrenaline and normetadrenaline up to twice the upper limit of the normal range on repeated testing. Five were obese and were proven to have significant OSA. All required at least three antihypertensive drugs for reasonable control of their blood pressure, and had normal suppression of catecholamines with clonidine. A recent report described a series of five patients with OSA presenting as pseudophaeochromocytoma who had consistently elevated levels of noradrenaline on measurement of 24-hour urinary catecholamine levels; normetadrenaline levels were not measured.2 Noradrenaline levels became normal in all five patients after treatment with continuous positive airway pressure, and blood pressure levels improved significantly. Excess urinary noradrenaline, rather than being adrenal in origin, was thought most likely to be due to increased neuronal release of noradrenaline from small arteries and arterioles as a result of sympathetic nerve activity and synaptic overflow. In conclusion, OSA is an important reversible cause of elevated urine noradrenaline and normetadrenaline levels in patients with resistant hypertension.

Adam P Morton

Stan B Sidhu In reply: We thank Morton for his letter which highlights another group of patients in whom raised urinary noradrenaline levels exist in the absence of a phaeochromocytoma. His experience and our group of patients1 should serve as a note of caution when making the diagnosis of phaeochromocytoma. A combination of positive results of biochemical tests, along with results of anatomical and functional imaging, should serve to minimise false positive diagnoses.

Stan B Sidhu

This new definition should assist both researchers and clinicians The metabolic syndrome — the clustering of abdominal obesity, dyslipidaemia, hyperglycaemia and hypertension — is a major public health challenge worldwide.1,2 The metabolic syndrome is not benign; it is associated with a substantially elevated risk of type 2 diabetes (5-fold) and of cardiovascular disease (CVD) (2–3-fold),1 and its increasing prevalence could possibly reverse the gains made through recent declining CVD mortality. The metabolic syndrome is not a new condition. It was first described in the 1920s by Kylin, a Swedish physician, as the association of hypertension, hyperglycaemia and gout.3 In the 1940s, attention was drawn to upper body adiposity (android or male-type obesity) as the obesity phenotype commonly associated with type 2 diabetes and CVD.4 This constellation of CVD risk factors has been given a number of names, including “deadly quartet”, “syndrome X”, and “insulin resistance syndrome”,1 but “metabolic syndrome” is likely to hold sway for the foreseeable future. Just as the metabolic syndrome has borne a variety of different names, numerous definitions have also surfaced. The World Health Organization definition,5 and two others, developed by the European Group for the Study of Insulin Resistance6 and the National Cholesterol Education Program — Third Adult Treatment Panel (ATP III),7 have been the main ones in use. Each of these agreed on the core components of obesity, hyperglycaemia, dyslipidaemia and hypertension. However, the definitions differ in the cut-points used for each component, and the way in which the components are combined, leading to considerable confusion.1 The confusion has been particularly apparent in attempts to compare the burden in different populations, where the use of different definitions has seriously hampered the ability to make comparisons between and within communities.1,2 The parameters for assessing obesity have been most problematic, with the current definitions failing to account for ethnic differences for cut-points in waist circumference and body mass index. It was also uncertain which of the definitions best predicted those at risk of CVD and diabetes, although from a clinical perspective, the ATP III definition was probably the most practical for alerting health care professionals to subjects at risk.1,7 Because of the confusion, the International Diabetes Federation (IDF) embarked on the process of developing consensus on a new global definition (Box). The definition recognises the mounting evidence that visceral adiposity is common to each of the components of the metabolic syndrome. Thus, an excessive waist circumference (a good proxy measurement for visceral adiposity) is now a necessary requirement for the metabolic syndrome. Furthermore, as it is clear that the level of obesity at which the risk of other morbidities begins to rise varies between population groups,1,10 ethnic-specific waist circumference cut-points have been incorporated into the definition, so that for South and South-East Asians, 90 cm and 80 cm are the cut-points for men and women, respectively. The cut-points for lipids and blood pressure are unchanged from those used by ATP III, and the glucose cut-point is the value most recently recommended as the upper limit of normal by the American Diabetes Association. As with many previous attempts to define diagnostic criteria for obesity, diabetes, hypertension, and dyslipidaemia, there is always the possibility that new research will force changes, including the possible incorporation of new components such as C-reactive protein and adiponectin. The IDF consensus also includes recommendations for future research into components not currently included in the core definition of the metabolic syndrome. It further highlights strategies for treatment of the metabolic syndrome and its components.8 It addresses both clinical and research needs and: provides a simple entry point for primary care physicians to diagnose the metabolic syndrome; provides an accessible diagnostic tool suitable for worldwide use, taking into account ethnic differences in waist circumference and associated type 2 diabetes and CVD risk; and establishes a comprehensive “platinum standard” list of additional criteria that should be included in epidemiological studies and other research into the metabolic syndrome. Using this new definition, analysis of AusDiab indicates that 29.1% of Australian adults (aged 25 and over) have the metabolic syndrome, compared with 19.3% according to ATP III (P Z Z, J E S, unpublished data). Much recent discussion about the metabolic syndrome has appropriately raised questions about its definition, its clinical role, and even its existence.1,11 At its heart, the syndrome represents the association between a range of factors that appear to be united both in terms of aetiology and consequences. The new IDF definition should provide researchers with a common platform for investigating the metabolic syndrome and its consequences. It should provide a useful practical tool that reminds health care professionals of the metabolic consequences of obesity, and identifies individuals at risk of CVD and type 2 diabetes who are likely to benefit from (lifestyle) interventions. The 2005 International Diabetes Federation definition of the metabolic syndrome8,9 According to the International Diabetes Federation definition, for a person to be defined as having the metabolic syndrome, they must have: Central obesity (defined as waist circumference ≥ 94 cm for Europid men and ≥ 80 cm for Europid women, with ethnicity specific values for other groups*) plus any two of the following four factors: raised serum triglyceride level (≥ 1.7 mmol/L) reduced serum HDL-cholesterol level (< 1.03 mmol/L in males and < 1.29 mmol/L in females), (or specific treatment for these lipid abnormalities) raised blood pressure (systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg), or treatment of previously diagnosed hypertension impaired fasting glycaemia (fasting plasma glucose [FPG] ≥ 5.6 mmol/L), or previously diagnosed type 2 diabetes * South Asian and South-East Asian men ≥ 90 cm, women ≥ 80 cm; Japanese men ≥ 85 cm, women ≥ 90 cm.

Paul Z Zimmet MD, PhD, FRACP · Jonathan E Shaw MD, MRCP(UK), FRACP · K George M M Alberti FRCP, PhD

Clinical record A 55-year-old woman with chronic epilepsy and psychiatric problems was admitted to hospital in 2004 with a fractured neck of femur after a trivial fall. She had been diagnosed with epilepsy in childhood and treated with phenytoin and phenobarbitone. Management was complicated by multiple, prolonged psychiatric admissions. Anticonvulsant compliance had been verified with measurement of serum phenytoin levels on a number of occasions. As a result of psychiatric problems, the patient became less able to care for herself and, at the age of 46 years, was admitted to long-term psychiatric hostel accommodation. Four years later, she had a non-displaced fracture of the olecranon after a fall; serum 25-hydroxyvitamin D level and bone mineral density were not assessed at that time. During the current admission, the fractured neck of femur was treated surgically. Biochemical testing indicated vitamin D deficiency (Box), which was treated with daily calcium carbonate (1200 mg) and ergocalciferol (vitamin D2) (2000 IU), and substitution of phenytoin with sodium valproate. This patient had recurrent fractures at a young age caused by a preventable complication from long-term use of anti-epileptic medication. Osteoporotic fractures, particularly hip fractures, result in significant individual morbidity and mortality and major financial cost to the community. It is well documented that enzyme-inducing anticonvulsants increase fracture risk by an average of two- to threefold, and that phenytoin causes osteomalacia. A 7-year longitudinal study of 87 people with epilepsy treated with phenytoin showed that they had a fracture rate six times higher than that of the healthy population.1 Fractures were not related to seizures. This high rate of fracture has been confirmed in many subsequent studies.2,3 Phenytoin induces hepatic microsomal enzymes and increases the catabolic clearance of a number of vitamin D metabolites. Hypermetabolism results in vitamin D deficiency, which induces a compensatory increase in serum parathyroid hormone (PTH) and bone turnover. Patients may develop a severe mineralisation defect and consequent osteomalacia. Other enzyme-inducing anti-epileptic drugs, such as primidone and perhaps carbamazepine, have similar effects on vitamin D metabolism. Anti-epileptic drugs have also been shown to cause bone loss in the absence of vitamin D deficiency.4 This effect was greater in patients taking multiple drugs, those with longer duration of epilepsy, and those taking enzyme-inducing drugs.5 This suggests that anti-epileptic drugs have a direct effect on bone turnover and could cause bone loss without inducing vitamin D deficiency. Vitamin D replacement has been studied in patients taking phenytoin. In at least one study, cholecalciferol and ergocalciferol were not bioequivalent.6 Another found that patients taking phenytoin required larger doses of calciferol to reach positive calcium balance than a control group.7 Other factors predisposing to vitamin D deficiency should also be considered. Institutionalisation leads to low sunlight exposure and reduced skin synthesis of vitamin D. This can produce vitamin D deficiency, even in Australia and without the addition of anti-epileptic drugs.8 People living in institutions may require higher replacement doses of vitamin D than those in the community. For example, a dose of 2400 IU calciferol (well above the accepted dose required for nutritional health) was required to reach adequate serum 25-hydroxyvitamin D levels in three-quarters of institutionalised patients treated with anti-epileptic drugs.9 Many medical practitioners fail to consider the diagnosis of osteoporosis or to provide adequate prevention and treatment. In a recent American study of neurologists, only one in four screened for bone disease, and fewer than one in 10 routinely prescribed prophylactic calcium and calciferol for patients taking anticonvulsants.10 There are no published consensus guidelines, but a recent editorial recommended osteoporosis screening in all adults taking anti-epileptic drugs long term.11 We believe appropriate investigations should include annual screening of serum 25-hydroxyvitamin D level. This is particularly important for those who are institutionalised. Patients taking anti-epileptic drugs long term should be advised about optimal dietary calcium intake, smoking cessation and avoidance of excess alcohol consumption, adequate sun exposure and weight-bearing exercise to prevent osteoporosis. Calcium and calciferol could be offered to those who achieve less than three to four serves of calcium daily or those who have a serum 25-hydroxyvitamin D level < 50 nmol/L. A recent position statement in the Journal provided useful advice about vitamin D replacement in people with vitamin D deficiency.12 Vitamin D replacement is particularly important for those taking phenytoin or phenobarbitone. If an osteoporotic fracture has occurred, bone mineral density should be assessed (this is currently not reimbursed by Medicare unless a fracture has occurred), and specific treatment with bisphosphonate drugs could be considered. However, bisphosphonates should be prescribed only after calcium and vitamin D deficiency has been corrected. These measures may help avoid the occurrence of hip fractures in relatively young patients taking anti-epileptic medication long term. Lessons from practice Patients taking anticonvulsant medication have a two- to threefold increased risk of fracture. Lifestyle measures, with exercise, adequate sunlight exposure, smoking cessation and sufficient calcium intake, should be encouraged for all patients with epilepsy taking anticonvulsant medication. Serum 25-hydroxyvitamin D levels should be assessed annually in all those taking anticonvulsant medication long-term. Calcium and calciferol could be offered to those who achieve less than three to four serves of calcium daily and to those with a serum 25-hydroxyvitamin D level < 50 nmol/L. Larger calciferol doses than typically required may be needed to treat vitamin D deficiency induced by anticonvulsant medication. Bone mineral density should be measured in all patients taking anticonvulsant medication long-term who sustain a fracture. Blood test results for a 55-year-old woman with an osteoporotic fracture* On admission Follow-up RR 3 months 9 months Ionised Ca (mmol/L) 1.1 – 1.22 1.14–1.29 Phosphate (mmol/L) 0.7 1.6 1.3 0.8–1.5 Parathyroid hormone (pmol/L) 58.2 14.5 10.9 1.5–8 25-hydroxyvitamin D (nmol/L) 9 34 70 > 50 Creatinine (μmol/L) 51 – – 30–95 Alkaline phosphatase (U/L) 229 112 103 35–105 Haemoglobin (g/L) 143 – – 115–155 Mean cell volume (fL) 97 – – 81–98 RR = reference range. * Results outside the RR are highlighted in bold.

Hannah M Seymour MRCP · Paul Glendenning PhD, FRCPA, FRACP

Diane A Longstreet,* Deanne L Heath,† Robert Vink‡ * Dietitian, † Research Scientist, Townsville Aboriginal and Islander Health Services, 57–59 Gorden Street, Garbutt, QLD 4814; ‡ Head, Department of Pathology, University of Adelaide, SA. dlongstreetATtaihs.net.au To the Editor: Diabetes in Indigenous Australians occurs at a younger age and at almost four times the rate in non-Indigenous Australians. The age-adjusted prevalence of diabetes among Indigenous people is 16% in remote areas and 9% in non-remote areas, with the actual prevalence estimated to be between 20% and 25%, and possibly higher than 30% in some remote areas.1 The cause for this disparity in diabetes incidence is multifactorial, and recent evidence suggests that nutrition — particularly magnesium intake — may play a role. Although central obesity remains a major risk factor, magnesium deficit has been posited to be an underlying common mechanism for the insulin resistance found in type 2 diabetes, as well as in metabolic syndrome, hypertension, and impaired glucose tolerance.2 The clinical correlations between low magnesium and diabetes have been well documented,3 with serum magnesium deficits being reported in 25%–39% of diabetic outpatients in the United States and Switzerland, and up to 73% of diabetic outpatients in Mexico. With magnesium deficits being observed in diabetes, studies examining the effects of magnesium-rich foods on diabetes risk become relevant. The Nurses’ Health Study and the Health Professionals’ Follow-up Study, which included 85 060 women (18 years follow-up) and 42 872 men (12 years follow-up), demonstrated that, after adjusting for confounding variables, a magnesium-rich diet reduced the relative risk of developing diabetes by 34% in women and 33% in men.4 A similar inverse correlation between magnesium intake and diabetes risk was shown in the Iowa Women’s Health Study with a cohort of 35 988 older women,5 and in the Honolulu Heart Program and the Women’s Health Study with cohorts of 8006 men and 39 345 women, respectively.6,7 Despite this growing body of evidence supporting the involvement of magnesium in diabetes, consideration of magnesium status has not been integrated into Australian medical care for diabetes, and more specifically, for Indigenous Australians. It is known that the traditional diet of hunter-gathers such as Indigenous Australians was much more nutrient- and magnesium-rich than the current estimated Australian intake.8 Nonetheless, there remains a lack of information about current magnesium status, including dietary intake, in Indigenous Australians. It is possible that dietary magnesium intake may be too low to maintain normal serum magnesium homoeostasis, and that this might contribute to the development of type 2 diabetes. Further research into this issue may provide this information.

Diane A Longstreet · Deanne L Heath · Robert Vink

Treating the paradox of an important emerging public health problem The international perception of bronzed Australians inhabiting a “sunburnt country” is under threat. Most Australians, including children, now sensibly avoid excessive sun exposure to reduce the risk of skin cancer. However, other Australians, particularly those who are older, disabled or institutionalised often do not receive even modest levels of sunlight exposure. This has led to the paradox of vitamin D deficiency emerging as a public health issue in sunny Australia. . . . despite Australia being a “sunburnt country”, vitamin D deficiency is common. But why is it important? Besides older and institutionalised Australians, others particularly at risk of vitamin D deficiency are people with pigmented skin from Africa, India and Pakistan; women who practise veiling; those on certain medications (eg, anti-epileptic drugs); and those with malabsorption or a low vitamin D intake. Even young Australians, pregnant women and their infants are at risk of this emerging health problem.1 The prevalence of vitamin D deficiency among Indigenous Australians has not been determined, but is likely to be high. The problem was highlighted recently in the Journal in a position statement on vitamin D and bone health in adults.2 Vitamin D deficiency is usually classified as mild (25-hydroxyvitamin D [25OHD] level, 25–49 nmol/L), moderate (12.5–24 nmol/L) or severe (< 12.5 nmol/L). The Geelong Osteoporosis Study detected mild or moderate deficiency in more than one in three women surveyed in summer, which rose to one in two in winter.3 Even in south-east Queensland, Western Australia, New South Wales and Victoria, nearly a third of men and women have mild to moderate vitamin D deficiency.4 Almost half of nursing home patients, and almost all patients in aged care facilities surveyed have at least mild vitamin D deficiency. Thus, despite Australia being a “sunburnt country”, vitamin D deficiency is common. But why is it important? Severe vitamin D deficiency results in osteomalacia in adults and rickets in children. Milder vitamin D deficiency results in secondary hyperparathyroidism and increased bone turnover, predisposing to osteoporosis. Proximal myopathy and muscle pains may occur in moderate or severe vitamin D deficiency, and the incidence of falls is increased.5 Less well known is the impact of vitamin D deficiency on depression, immunity and autoimmunity, obesity, and the progression of type 2 diabetes mellitus. It is also important to correct vitamin D deficiency to optimise the effects of other anti-osteoporotic drugs. In a recent United States study of 1536 women receiving anti-osteoporotic therapy, 52% had vitamin D deficiency.6 Treatment with intravenous or (more rarely) oral bisphosphonates may also cause severe hypocalcaemia in people with severe vitamin D deficiency,7,8 so it is prudent to screen for vitamin D deficiencies before initiating bisphosphonate therapy. In the broad context of vitamin D deficiency as an emerging public health issue, the article by Diamond et al in this issue of the Journal (page 10)9 is timely. Their prospective open label study of 50 elderly women and men with vitamin D deficiency showed that a single intramuscular injection of 600 000 IU (or 15 mg) of cholecalciferol (vitamin D3) increased serum 25OHD concentrations to above 50 nmol/L in all patients. Over 12 months, serum 25OHD concentration rose, on average, by 128% to 73 nmol/L — a level most would consider to be optimal. Secondary hyperparathyroidism, present in about 50% of participants, was abolished in most. The complications of therapy were mild hypercalcaemia in two participants (4%) and fasting hypercalciuria in 10 participants (20%) tested at 12 months. The study by Diamond and colleagues represents a step forward in currently available treatment options for vitamin D deficiency. Currently, this is limited to doses of 200–1000 IU of either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). The commonest form is 1000 IU of ergocalciferol (Ostelin; Boots Healthcare Australia). Loading doses of 3000–5000 IU per day are required to treat severe vitamin D deficiency and, as commercially available radioimmunoassays do not always measure vitamin D2 as well as vitamin D3, measuring treatment response is difficult. Daily dosing is also difficult or unrealistic for many community-dwelling older people in whom compliance would be expected to be poor. A single intramuscular “megadose” of cholecalciferol would overcome this compliance issue in a simple and cost-effective manner. The mild hypercalcaemia and fasting hypercalciuria are of concern, but further controlled trials are planned, which will include 24-hour urine calcium excretion measurements, to evaluate the safety of “megadose” cholecalciferol therapy. The effect of this treatment on fracture risk is not established. A recent British study of 9440 community-dwelling participants aged 75–100 years, randomly allocated to receive either an annual injection of 300 000 IU cholecalciferol or placebo, showed no reduction in fracture rate.10 Nevertheless, the greatest clinical utility of an annual megadose injection is likely to be in older institutionalised people, most of whom are vitamin D deficient. The most important outcome in osteoporosis prevention or treatment is a reduction in fracture risk. Some data suggest treating vitamin D deficiency may prevent low-trauma fractures. A large French study in institutionalised, ambulatory older women found that daily doses of 800 IU of cholecalciferol and 1.2 g of calcium significantly decreased the incidence of hip and non-vertebral fractures compared with placebo after 18 months.11 Daily vitamin D and calcium treatment also reduced non-vertebral fractures in community-dwelling older American men and women.12 A recent large trial in community-dwelling British men and women aged over 65 years showed that a large oral dose of cholecalciferol (100 000 IU) every 4 months reduced osteoporotic fractures by 33%.13 The RECORD trial attempted to determine the relative contribution of calcium versus vitamin D on fractures. Ambulatory patients (5292) who had sustained a low-trauma fracture were randomly allocated to receive calcium (1000 mg/day), vitamin D3 (800 IU/day), a combination of the two, or placebo. After at least 24 months, fracture rates did not differ between the four groups. However, compliance at 2 years was poor.14 Further large studies of vitamin D and its effects on fractures and falls are still needed, particularly in populations at risk of vitamin D deficiency; these studies need to use varying oral doses of vitamin D and to include men. The treatment described by Diamond et al is a good start to introducing new alternatives for treatment of vitamin D deficiency in targeted people. However, much more work is needed to identify successful public health approaches that can be more broadly applied to this emerging public health problem.

Peter R Ebeling MD, FRACP

Aim: To evaluate the efficacy and safety of an annual intramuscular injection of cholecalciferol for vitamin D deficiency.Design: Prospective open-label study.Participants: Five men and 45 women (mean age 66.3 years) with vitamin D deficiency who were given a single therapeutic intramuscular injection of 600 000 IU (15 mg) cholecalciferol (vitamin D3).Outcome measures: Serum levels of calcium, creatinine, 25-hydroxyvitamin D3 (25OHD3) and parathyroid hormone, as well as early morning 2-hour urine calcium/creatinine excretion index. Specimens were collected at baseline and after 4 and 12 months of therapy. Data are reported as mean ± 1 SD.Results: Vitamin D deficiency was severe (< 12.5 nmol/L) in one participant, moderate (12.5–24 nmol/L) in 14, and mild (25–49 nmol/L) in 35. Twenty-four participants (48%) had secondary hyperparathyroidism. Following intramuscular cholecalciferol injection, serum 25OHD3 levels normalised in all participants and remained above 50 nmol/L throughout the study. Serum 25OHD3 levels were significantly higher at 4 months (114 ± 35 nmol/L), and 12 months (73 ± 13 nmol/L) compared with baseline (32 ± 8 nmol/L) (P < 0.001), increasing by an average of 128% over the 12 months. There was a corresponding decrease in serum parathyroid hormone levels at 4 months (6 ± 3 pmol/L) and at 12 months (5.2 ± 3 pmol/L), with a 30% decrease at 12 months from baseline (7.4 ± 4 pmol/L) (P < 0.01). Primary hyperparathyroidism was unmasked in one participant at 4 months and mild hypercalcaemia (serum calcium, < 2.70 mmol/L) was noted in two participants (4%) at 12 months. Serum creatinine levels remained normal in all participants throughout the study, while increases in 2-hour urine calcium/creatinine excretion index were seen in 10 participants (20%) at 12 months, three of whom had had elevated values at baseline.Conclusions: Once-yearly intramuscular cholecalciferol injection (600 000 IU) is effective therapy for vitamin D deficiency. While this therapy appears to be safe, the potential for developing hypercalciuria needs to be examined in a large randomised controlled trial.

Terrence H Diamond MB ChB, MRCP, FRACP · Kenneth W Ho MB BS · Peter G Rohl MB BS, FRACP · Matthew Meerkin FRCPA, FAACB, FACB

Six patients being evaluated for phaeochromocytoma had misleading investigative findings: all initially had raised urinary catecholamine levels, and five had adrenal masses on imaging studies. Adrenalectomy in these five patients revealed only one pathologically confirmed phaeochromocytoma. Tricyclic antidepressant use produced misleading elevations in urinary catecholamine levels in three patients. 24-hour urine studies should be performed at least twice, after eliminating confounding factors (stressors, medications). Clinical recordThe details of six patients treated in the period April 1999 – October 2003 by members of the Section of Endocrine Surgery of the Royal Australasian College of Surgeons are outlined in Box 1. In all patients, clinical suspicion of phaeochromocytoma was raised by the presence of hypertension, paroxysmal symptoms, or both. Twenty-four-hour urinary catecholamine levels were found to be elevated, although in Patients 1–5 these abnormalities were confined to one or two analytes only. In all except Patient 2, adrenal lesions were discovered on imaging, with large haemorrhagic masses detected in patients with an acute presentation (Patients 5 and 6). Patients with abnormalities on computed tomography (CT) underwent surgery. In Patients 1, 3, and 4, the excised tissues were found to be pathologically normal or to show mild enlargement (benign). In Patients 5 and 6, blood clot and necrotic tissue comprised the bulk of the specimens (Box 2), with a phaeochromocytoma discovered in the latter patient. Of note, Patients 1–3 were receiving tricyclic antidepressants for non-standard uses that did not include the treatment of major depression. DiscussionFalse positive biochemical test results for phaeochromocytoma are common and present particular problems because of the low prevalence of the disease. The reported incidence of phaeochromocytoma is 2–8 per million people annually, accounting for less than 0.2% of all patients with hypertension.1 Despite the fact that phaeochromocytoma is a rare cause of hypertension, the diagnosis merits consideration in a potentially large group of patients for two reasons. Firstly, although the disease is frequently fatal if unrecognised, surgical removal is highly effective, achieving cure in greater than 90% of cases.2 Secondly, because no array of clinical indicators has proven to reliably include or exclude phaeochromocytoma,3 physicians must maintain a high level of suspicion and consider biochemical testing in patients at risk. The pretest probability for phaeochromocytoma is close to 0.5% (1 in 200 patients tested) in the presence of hypertension and suggestive symptoms.4 Assuming a specificity of 85% for biochemical testing, 30 false positive results are generated for every one patient with phaeochromocytoma identified.5 Fortunately, most false positive tests can be unmasked with careful additional investigation and/or the elimination of factors known to confound biochemical tests for levels of catecholamines and their metabolites. The misleading elevations in urinary noradrenaline levels in Patients 1–3 can be ascribed to their taking tricyclic antidepressants. Medications and conditions that may result in raised levels of plasma and/or urine catecholamines and their metabolites, and result in false positive test results for phaeochromocytoma, are listed in Box 3. Among these drugs, tricyclic antidepressants and phenoxybenzamine have been the most frequently implicated, together accounting for more than 40% of medication-associated false positive results in a recent large study.6 In Patients 3 and 4, false positive biochemical findings led to the identification of small (1.5 cm) adrenal masses on CT scanning, both of which were found, on histopathological examination, to be benign. Clinically unapparent adrenal masses (“incidentalomas”) are found in 2.1% of subjects at autopsy and in 1%–4% of abdominal imaging studies. Most of these masses are benign, hormonally inactive tumours that do not require surgical management.7 Phaeochromocytomas presenting with acute haemorrhage at presentation have been reported previously,8,9 with haemorrhagic tumours often losing characteristic imaging appearances and functional markers. Tumour necrosis may initially result in massive catecholamine release, followed by failure to demonstrate excess catecholamine levels, as was seen in Patient 6. Mildly elevated urinary catecholamine levels may also be seen as a consequence of hyperadrenergia from an acute stress response at the time of haemorrhage into a non-phaeochromocytoma lesion, as occurred in Patient 5. Role of biochemical testingAlthough measurement of plasma free metanephrine levels has been recently advocated by some groups, 24-hour urinary catecholamine levels and total metanephrine level have consistently proven to be the most specific tests available for the diagnosis of phaeochromocytoma.5,10 Elevations in the level of one or more of these analytes (above the 95% reference range designated as the upper limit of normal by laboratories) are common in patients with paroxysmal symptoms or poorly controlled hypertension not due to phaeochromocytoma. Thus, we recommend that higher cut-off values, roughly two times the upper limit of normal for most laboratories, be used to identify patients suitable for further workup. Repeat biochemical testing 6 weeks after stopping drugs likely to confound the results is ideal, and tests performed during major physical or psychological stress should be interpreted with extreme caution (if performed at all). It is important to note that alterations in plasma catecholamine levels may be caused not only by medications, but also by the underlying diseases being treated (eg, major depression in the case of tricyclic antidepressants or severe heart disease in the case of β-blockers).11-13 All patients should undergo at least two 24-hour urine collections for measuring levels of catecholamines and their metabolites. Clonidine suppression testing — the measurement of plasma free normetanephrine before and after the oral administration of 0.3 mg clonidine — is highly sensitive and specific, and may be a useful adjunct in patients with more than one prior set of equivocal tests.6 Role of imagingWhether imaging studies (both anatomical and functional) play a role in diagnosing phaeochromocytoma, as opposed to only localising tumours already diagnosed biochemically, remains controversial. In the patients described above, 131I‑metaiodobenzylguanidine scanning yielded true negative results in Patients 1–3, consistent with its known high specificity.4 However, current evidence suggests that, when appropriate biochemical tests are used, little discriminatory value is to be gained from imaging,14 and our experience illustrates how incidental radiographic findings may lead to unnecessary surgery. 1 Summary of the clinical records of six patients investigated for phaeochromocytoma Patient age/sex Presentation Blood pressure (mmHg) Medications 24-h Urinary catecholamine levels (nmol/d or μmol/d)* Radiological investigation† Surgical findings/ Clinical course Pathology Patient 1 49/M Weight loss (5 kg in 3 months), paroxysmal anxiety attacks, drenching sweats, chronic right flank pain 124/80 Clomipramine, 50 mg/day (anxiety) Adrenaline, 91/84 Noradrenaline, 860/1224 CT: 3 x 6-cm mass abutting upper pole of right kidney MIBG: negative Lobulated upper pole of kidney due to right renal artery branch running within posterior cleft Normal adrenal tissue Patient 2 41/M Migraines, chronic back pain, worsening hypertension, palpitations 145/85 Amitriptyline, 150 mg/day (migraine prophylaxis); amlodipine, 5 mg/day; ramipril, 5 mg/day; indapamide, 2.5 mg/day Adrenaline, 7/12 Noradrenaline, 485/1295 CT: No abnormalities MIBG: No abnormalities Normal findings on repeat urine studies after stopping amitriptyline — Patient 3 64/M Metastatic prostate cancer, poorly controlled hypertension 180/95 Imipramine, 100 mg/day (neuropathic pain); nifedipine, 180 mg/day; ramipril, 5 mg/day; chlorothiazide, 1000 mg/day Adrenaline, 115/99 Noradrenaline, 1070/1130 VMA, 33/38 CT: 1.5-cm left adrenal mass MIBG: negative Small left adrenal mass, macroscopically consistent with an adenoma Benign adrenal adenoma Patient 4 76/F Chronic hypertension, 15-month history of paroxysmal nausea and vomiting 144/80 Captopril, 25 mg/day Adrenaline, 65/129 Noradrenaline, 371/451 Dopamine, 1.55/2.02 CT: 1.5-cm left adrenal mass Smooth lesion palpable within left adrenal gland Enlarged adrenal gland (10.2 g; reference, 4 g) with thickened cortex but normal medulla Patient 5 75/M Sudden onset of intense back and left loin pain, chronic hypertension, weight loss (22 kg in 6 months), atrial fibrillation, diabetes, polymyalgia rheumatica 150/90 Warfarin, 5 mg/day; captopril, 25 mg/day; digoxin, 0.25 mg/day; isosorbide mononitrate, 60 mg/day; verapamil, 240 mg/day; prednisone, 5 mg/day; metformin, 2 g/day; rosiglitazone, 4 mg/day; thyroxine, 0.125 mg/day Adrenaline, 250 Noradrenaline, 720 Metanephrine, 1.68 Normetanephrine, 2.49 CT: 12-cm heterogeneous left adrenal mass (Box 2) Large blood clot with associated desmoplastic reaction occupying most of left adrenal gland Myelolipoma with haemorrhagic fat necrosis Patient 6 58/M Acute abdominal pain and hypertension, otherwise healthy 210/95 — Adrenaline, 2426/51 Noradrenaline, 18 370/464 Metanephrine, 13.3/0.8 Normetanephrine, 35.5/3.6 CT: 5-cm haemorrhagic left adrenal mass MRI (2 weeks after presentation): subacute haemorrhage into area without any distinct adrenal mass 12-cm dumbbell-shaped mass 3-cm phaeochromo-cytoma, large organising blood clot and necrotic tissue * Values separated by a forward slash represent separate collections, with abnormal values in bold. Reference ranges: adrenaline, < 100 nmol/d; noradrenaline, < 680 nmol/d; metanephrine, < 2.1 μmol/d; normetanephrine, < 5.6 μmol/d; VMA (vanillylmandelic acid), < 40 nmol/d; dopamine, < 3.0 μmol/d. †CT = computed tomography; MIBG = 131I-metaiodobenzylguanidine scanning; MRI = magnetic resonance imaging. 2 Computed tomography image of the haemorrhagic left adrenal mass in Patient 5 3 Medications and conditions that may cause false positive results of biochemical tests for phaeochromocytoma Medication or condition Test(s) confounded Tricyclic antidepressants Urinary catecholamines and metanephrines, plasma free metanephrines Clozapine Urinary catecholamines and metanephrines Phenoxybenzamine Plasma free metanephrines Calcium channel blockers Plasma noradrenaline, urinary noradrenaline, urinary adrenaline β-adrenergic blockers Urinary catecholamines and metanephrines, plasma free metanephrines (minor effect) α1-adrenergic blockers Urinary noradrenaline Sympathomimetics Urinary catecholamines and metanephrines, plasma free metanephrines Buspirone Urinary metanephrines Major physical or psychological stress* Urinary catecholamines and metanephrines, plasma free metanephrines * Hypoglycaemia, hypoxia, hypovolaemia, stroke, surgery, myocardial infarction, heart failure, severe pain, depression, panic disorder, sleep apnoea.

Jane L Harding MB BS · Michael W Yeh MD · Leigh W Delbridge MD, FRACS · Stan B Sidhu MB BS, FRACS · Bruce G Robinson MD, FRACP

Jim Stockigt Senior Endocrinologist, Alfred Hospital, Melbourne; and Professor of Medicine, Monash University, VIC 3004. jrsATnetspace.net.au To the Editor: In May 2004, Sigma, the sole Australian supplier of l-thyroxine sodium, instructed pharmacists that thyroxine tablets should be stored refrigerated, both in pharmacies and after dispensing. Thyroxine bottles now carry explicit labels: “keep refrigerated” or “refrigerate at all times”. This instruction seems to have been accepted by health professionals, but patient-support groups immediately questioned the refrigeration directive. In response, Sigma conceded that thyroxine tablets can be stored at room temperature (< 25°C) for up to 4 weeks, with refrigeration still the preferred option. There are major unresolved issues about the potency, stability and bioavailability of various thyroxine preparations that are marketed competitively in the United States.1 With a single supplier in Australia, we can avoid between-preparation variations, provided that stability and consistency are maintained. The instruction to refrigerate thyroxine tablets seems to be uniquely Australian. None of my co-authors of the website <www.thyroidmanager.org>2 is aware of a refrigeration directive in any other country. The local instruction seems to have followed interaction between the Therapeutic Goods Administration and the manufacturer, so that unopened bottles could be marketed with a longer shelf life. Is the rest of the world missing out on something important? Is there something peculiar about the Australian formulation that makes it unstable at room temperature? Could this directive be without firm basis, or even dangerous? There is currently no evidence on whether thyroxine in already-opened, unsealed bottles is more or less stable at 4°C than at room temperature, but the need to keep the tablets dry has been widely emphasised.3 Consider the condensation that will occur during 200 daily openings of a refrigerated glass bottle, whatever it contains. If damp tablets lose potency, this would lead to apparent under-treatment. In the months since refrigerated storage was recommended in Australia, preliminary observations suggest that apparent under-dosage (ie, unexpected rises in serum TSH) may indeed occur in previously compliant patients (personal observation). If dosage were increased, the adjustment could result in over-treatment after a change to a fresh preparation. Thyroxine has a narrow therapeutic window, and excessive dosage can have serious effects, especially if there is associated cardiac ischaemia. While refrigeration of sealed bottles of thyroxine might extend the shelf life, the instruction to refrigerate unsealed bottles seems ill-advised. When an existing formulation is modified, it is generally the obligation of a manufacturer to demonstrate safety. The stability of tablets in sealed bottles and those in current use are quite separate issues. To establish how tablets in current use are influenced by refrigeration, it is necessary to measure the thyroxine content of remaining tablets from bottles of 200, opened and used daily for up to 6 months. Without such data, it is preferable to instruct patients not to store currently used bottles of thyroxine at refrigerator temperature.

Jim Stockigt

Ovais Siddiqui Regulatory and Medical Manager, Sigma Pharmaceuticals, Locked Bag 268, South Croydon, VIC 3136. ovais.siddiquiATsignet.com.au In reply: Sigma Australia acquired Oroxine (thyroxine sodium) from the original manufacturer in 1999, and launched Eutroxsig, an identical product, in 2002. During 2002–03, as a result of advances in analytical technology for some pharmaceutical products, product specifications, including shelf life and storage conditions, were updated, so that the product’s quality, safety and efficacy could be maximised or maintained throughout the claimed shelf life. For Oroxine and Eutroxsig, the new stability data showed a loss of up to 10% of thyroxine sodium in the first 6 months when stored below 25°C, with some plateauing thereafter. As an interim measure, Sigma, in agreement with the Therapeutic Goods Administration (TGA), decided to immediately reduce the shelf life from 24 to 12 months (“store below 25°C”) and set the lower release to 98.0% (up from 92.5%), while investigating reasons behind the loss in potency. The manufacturing process was confirmed to consistently yield tablets with very reproducible chemical and physical attributes in accordance with the release criteria. During manufacturing, however, about 2% of the thyroxine sodium is lost, with a corresponding similar increase in degradants. To limit the degradants responsible for the reduction in potency of thyroxine at room temperature, it was agreed with the TGA that thyroxine should be stored at 2°– 8°C (“Refrigerate. Do not freeze”), based on good stability data generated at this temperature. Consumer Medicine Information (CMI) and Product Information (PI) were updated in May/June 2004 to reflect this change. The new stability studies support the storage of Oroxine and Eutroxsig in the refrigerator; however, repeated in-use handling may result in an increase in condensation and microbial contamination. This may lead to changes in the physical characteristics of these products, including the growth of mould. There may be a further increase in condensation if the lid is not tightly closed. One possible solution is for patients to place up to 4 weeks’ supply of tablets in a spare, previously used, Oroxine or Eutroxsig amber-coloured bottle and store out of the fridge (below 25°C) for current use, while keeping the remaining stock in the fridge. Sigma is looking at options to improve the packaging so that the above problems are minimised or eliminated. Oroxine and Eutroxsig, manufactured by Sigma, are sold in Australia only. Sigma does not have access to formulation details, stability results and justification for the storage conditions used in other countries; therefore, we are unable to comment on such issues. As an Australian company, we are obliged to follow the regulatory guidelines of the Therapeutic Goods Act 1989 (Cwlth). Sigma recommends that the label instructions regarding storage conditions after opening be strictly followed to maximise the quality, safety and efficacy of the product.

Ovais Siddiqui

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