Anatomy and physiology

Lower specificity and lower positive predictive value necessitate a cautious approach. The advent of cardiac troponin (cTn) assays has redefined acute myocardial infarction (AMI) and revolutionised the care of patients with suspected AMI presenting to emergency departments (EDs). So central has cTn measurement become to the diagnosis of AMI that, since 2000, the formal criteria start with detection of rise and/or fall in serum troponin levels ...

Ian A Scott FRACP, MHA, MEd · Louise Cullen MB BS, FACEM · Jillian R Tate MSc, FFSc(RCPA) · William Parsonage BM BS, BMedSci, FRACP

The publication of the Australasian Creatinine Consensus Working Group’s position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. ...

Australasian Creatinine Consensus Working Group

Optimal detection and subsequent risk stratification of people with chronic kidney disease (CKD) requires simultaneous consideration of both kidney function (glomerular filtration rate [GFR]) and kidney damage (as indicated by albuminuria or proteinuria). Measurement of urinary albuminuria and proteinuria is hindered by a lack of standardisation regarding requesting, sample collection, reporting and interpretation of tests. A multidisciplinary working group was convened with the ...

Australasian Proteinuria Consensus Working Group

To the Editor: The position statement by Jones and colleagues regarding the change of HbA1c reporting to the new Système International (SI) units — which has been recommended by the Australasian Association of Clinical Biochemists, the Australian Diabetes Educators Association, the Australian Diabetes Society and the Royal College of Pathologists of Australasia — provides a comprehensive summary of the rationale behind the proposed change and suggests a 2-year period of dual reporting.1 However, Jones et al did not specify targets for children and adolescents, and we believe that it is important to do so. The incidence of type 1 diabetes in Australian children and adolescents is among the highest in the world2 and, in New South Wales, type 2 diabetes represents at least 10% of cases of new-onset diabetes in adolescents.3 National evidence-based clinical care guidelines for type 1 diabetes in children, adolescents and adults4 include age-specific targets for HbA1c, while recognising that such targets are predominantly consensus based. HbA1c targets for young people with type 1 diabetes are higher, with a level of < 7.5% recommended for children and adolescents in the Australian guidelines4 and in those produced by the International Society for Pediatric and Adolescent Diabetes (ISPAD).5 Jones et al note that “Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia, especially among older people”;1 this is also the case for young people. For children and adolescents with type 2 diabetes, the ISPAD guidelines recommend an HbA1c target of < 7%.5 The move to SI units represents a major change in the established, widely recognised outcome measure of glycaemia; during the transition period, the specific needs of young people with diabetes must not be forgotten.

Maria E Craig · Kim C Donaghue · Fergus J Cameron · Martin Silink

In reply: We appreciate Craig and colleagues’ comments regarding the importance of reporting general HbA1c targets for children and adolescents with type 1 and type 2 diabetes. In our position statement, the headings of Box 2 and Box 3 indicated that the targets listed were for adults with type 1 diabetes and adults with type 2 diabetes, respectively.1 While it is not possible to highlight every clinical situation, we agree that providing general HbA1c targets for children and adolescents will add value to our article, and we have updated it accordingly,1 recognising the differences in these targets for type 1 diabetes (≤ 58 mmol/mol, ≤ 7.5%) and type 2 diabetes (≤ 53 mmol/mol, ≤ 7.0%).2-4 In the interests of uniformity and simplicity, the paediatric targets expressed as “<”2-4 have been adjusted to “≤”, which represents differences of less than 1.5% of the target values. Addendum p 524

Graham R D Jones · George Barker · Ian Goodall · Hans-Gerhard Schneider · Mark D S Shephard · Stephen M Twigg

AddendumHbA1c targets for young people not specified: In the position statement “Change of HbA1c reporting to the new SI units” in the 4 July 2011 issue of the Journal (Med J Aust 2011; 195: 45-46), HbA1c targets for young people with diabetes were not specified. The following HbA1c target ranges have been added to Boxes 2 and 3, respectively: for children and adolescents with type 1 diabetes, ≤ 58 mmol/mol (≤ 7.5%); for children and adolescents with type 2 diabetes, ≤ 53 mmol/mol (≤ 7.0%). Further details are published in this issue of the Journal.

Graham R D Jones · George Barker · Ian Goodall · Hans-Gerhard Schneider · Mark D S Shephard · Stephen M Twigg

To the Editor: The article by Ramsey-Stewart and colleagues1 reports a welcome addition to supplemental anatomy education in graduate-entry medical courses in Australia. Increasing medical student numbers are increasing pressure on teaching resources, further propagating the nationally recognised deficiency in anatomy teaching.2,3 In 2010, the University of Queensland Discipline of Surgery developed an extracurricular applied anatomy course to meet the needs of clinical students (Years 3 and 4) with varying foundations in anatomy.4 The course is based on a clinically oriented anatomy education model, using prosected specimens and computer resources, which has been shown to deliver learning outcomes.5 Student representatives were involved in all facets of curriculum development and evaluation. The course was taught by surgeons and provided an overview of whole-body applied anatomy in an interesting and engaging way. As the course had no seed funding, a modest course fee of $90, which was intended to be easily affordable but enough to encourage committed attendance, was charged. Class size was restricted to 44 students, with selections from the 150 applicants (from about 800 students across both years) made on a first-come, first-served basis. Over seven Saturday mornings, the students received 2-hour tutorials from surgeons with expertise in specific fields of regional anatomy. This scheduling minimised disruption for both surgeons and students. Various educational resources, including three-dimensional virtual modelling and potted pathology specimens, were used. Participants completed a short multiple choice test before each week’s tutorial. The course concluded with a wet laboratory session, staffed by surgeons using prosected cadaveric specimens at multiple stations, with a one-to-five surgeon–student ratio. Students completed a post-course exam of collated pre-tutorial multiple choice questions, as well as five-point Likert-scale evaluation forms. The students evaluated the course well (mean Likert score: 4.6 at 4 weeks, 4.8 at 8 weeks). Post-course exam scores demonstrated a small but significant improvement (mean ± SD: pre-course, 43% ± 16.7% v post-course, 50% ± 10.6%; P = 0.004). Scores were correlated with attendance. The course was highly valued by students and surgeons, effectively improved students’ knowledge and satisfied their desire for further anatomy education. The course structure is time-efficient and cost-effective. However, this course, like that of Ramsey-Stewart et al,1 is extracurricular and does not deliver educational benefit to an entire cohort of students. Further development and evaluation are required to extrapolate the benefits of these extracurricular courses into the wider medical curriculum within the constraints of graduate MB BS programs. Our model has expanded to two courses in 2011.

Matthew J Roberts · Bavahuna Manoharan · Marianne Vonau · Russell W Stitz · Owen A Ung

21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia, with an incidence of 1 : 14 000 live births and equal prevalence among males and females. Newborns with the most severe “salt-wasting” form of 21-OHD are susceptible to salt-wasting crises in the first few weeks of life. This is associated with morbidity and mortality. 21-OHD newborn screening (NBS) is currently performed in many countries. Despite several prominent medical societies recommending 21-OHD NBS, no state in Australia currently screens for this condition. We report a case that illustrates the need to reconsider including 21-OHD in NBS. 21-OHD NBS can be reliable, sensitive and effective in reducing morbidity and mortality.

Joyce Y Wu MB BS, MAACB, FRCPA · Sudeep MB BS, FRACP, DCH · David M Cowley MB ChB, FRCPA, FHGSA · Mark Harris MB BS, FRACP, MD · Ivan N McGown BSc, MIT, MHGSA · Andrew M Cotterill MB BS, FRACP, MD

HbA1c may be a practical alternative to blood glucose for the diagnosis of diabetes For more than 15 years, glycated haemoglobin (HbA1c) has been recommended as the key tool for assessing glycaemic control in people with diabetes. Only in 2009 did the first advice to use HbA1c levels for diabetes diagnosis appear, using a cut-point of ≥ 6.5%.1 To date, no clear argument has been articulated to explain why HbA1c levels have been deemed superior to laboratory-determined blood glucose levels for determining the need for insulin therapy, but not for diagnosing diabetes; however, it is likely that implications of the former are greater than those of the latter, for both individuals and society. Blood glucose values are considered the gold standard for diabetes diagnosis, but they have significant limitations. Day-to-day variability in glucose levels is considerable, and the glucose concentration in a plasma sample falls within a short period, even if the blood has been collected in a fluoride tube. In addition, when stable samples are tested in two different laboratories, the results will differ by at least 14% in more than a third of cases.2 Furthermore, even when using a single laboratory, only 70% of people with a blood glucose value that indicates a diagnosis of diabetes have the diagnosis confirmed by repeat testing 2 weeks later, compared with 83% for HbA1c.2 So, is HbA1c the answer to the challenges of diabetes diagnosis? Until recently, the problem with HbA1c has been the concern that results vary considerably between laboratories. In the 1990s, laboratory differences of more than two percentage points were not uncommon, but the United States National Glycohemoglobin Standardization Program (NGSP) has progressively driven improvements in assay standards. The latest results from the largest global survey of quality of HbA1c measurement show that, for reference samples with HbA1c levels of 4.0%–6.0%, 91% of more than 3000 laboratories could obtain an HbA1cvalue that was within 6.0% of the target.3 In a recent Australian study, whole blood samples were sent to more than 200 laboratories and more than 90% obtained HbA1c values that were within 6% of the median.4 Thus, for a sample with a median value of 5.3%, over 90% of laboratories obtained values within the range 5.0%–5.6%, and for a median value of 7.4%, over 90% obtained values within the range 7.0%–7.8%. In addition, combined data from eight studies conducted between 1988 and 2004 (using assays in eight different laboratories, none of which may have performed as well as those available now) showed that HbA1c levels were at least as strongly correlated with diabetic retinopathy as were blood glucose levels.5 HbA1c is not without limitations. First, an HbA1c test is more expensive than a fasting glucose test, but costs about the same as an oral glucose tolerance test. The extra cost of using HbA1c instead of fasting glucose as the initial blood test needs to be weighed up against the potential for the HbA1c test (which does not require the patient to fast) to be used more widely, to identify more undiagnosed cases of diabetes, and to save money by preventing complications of diabetes. To our knowledge, no cost–benefit analyses comparing the HbA1c test with the fasting glucose test have been published — this should be a high priority. Second, HbA1c can be unreliable in the presence of haemoglobin variants or alterations in red blood cell turnover. Most HbA1c assays are now able to adjust for the most common haemoglobin variants, but where there is uncertainty relating to the reliability of HbA1c, blood glucose will remain the preferred test. If the potential exists to use HbA1c for the diagnosis of diabetes, how can a practitioner know whether a particular laboratory can be relied on? A joint working party of the Australian Diabetes Society, the Royal College of Pathologists of Australasia, and the Australasian Association of Clinical Biochemists is developing a formal laboratory and clinical framework within which the diagnosis of diabetes by HbA1c testing can be undertaken. In the meantime, it would be reasonable to think that a laboratory can be relied on, in the context of using HbA1c as a diagnostic tool, if the routine coefficient of variation is ≤ 3.0% (the 2010 accreditation target used by the NGSP) and the external quality assurance results are consistently within the Royal College of Pathologists of Australasia Quality Assurance Programs method-specific performance targets (allowable limits of performance). This information should be available from laboratories on request. Practical aspects of using HbA1c for the diagnosis of diabetes remain to be finalised. One option may be to request a fasting glucose test and HbA1c test at the same time, with the HbA1c to be performed only if the fasting glucose level is ≥ 5.5 mmol/L. This strategy would limit the additional costs of HbA1c testing while decreasing the number of patients who are lost to follow-up for an oral glucose tolerance test. The cost of an HbA1c test that is used for diagnosis is not currently reimbursed by Medicare. However, when used appropriately, the HbA1c test appears to be at least as useful for diagnosing diabetes as a blood glucose test. Australia may soon be ready to join countries such as the United States and Japan in using HbA1c, a measure of chronic glycaemia, for the diagnosis of diabetes, a disease of chronic glycaemia.

On behalf of the Joint HbA1c Working Party of the Australian Diabetes Society, the Royal College of Pathologists of Australasia, and the Australasian Association of Clinical Biochemists

Haemoglobin A1c (HbA1c — a term that is sometimes used interchangeably with “glycated haemoglobin”) measurements are an indicator of time-averaged blood glucose levels (previous 2–3 months), and are used as the best marker of long-term diabetes control. A recent consensus statement on the worldwide standardisation of HbA1c measurement1 has updated previous international recommendations on the standardisation of HbA1c measurement and reporting.2 Here, we provide the rationale and guidance for implementation of HbA1c reporting in the new Système International (SI) units in Australia. This article represents the views of the Australasian Association of Clinical Biochemists, the Australian Diabetes Educators Association, the Australian Diabetes Society and the Royal College of Pathologists of Australasia, and was prepared by a working party of representatives of these organisations. The International HbA1c Consensus Committee recommends that all HbA1c levels be reported in SI units (mmol/mol, no decimal places) — with results directly traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method — and in the currently used, National Glycohemoglobin Standardization Program (NGSP) units (percentage, one decimal place). We recommend that dual reporting in Australia begins in July 2011, and that reporting of percentages ceases 2 years later. In New Zealand, dual reporting commenced in August 2009. The key reasons for implementing this recommendation in Australia are that: the SI units relate to a scientifically valid measure of HbA1c; the SI units remove potential confusion between HbA1c values as a percentage and blood glucose values in mmol/L; the change is in keeping with the international consensus statement;1 and the change has already been initiated in New Zealand and a number of countries in the European Union. Until now, all HbA1c measurements performed in Australia have been reported as percentages (HbA1c as a percentage of total haemoglobin) that are aligned with those produced in the Diabetes Control and Complications Trial.3 These units and this standardisation have been promoted by the NGSP in the United States, and the activities of this organisation have produced marked improvement in the accuracy of HbA1c results worldwide. More recently, the IFCC has developed a reference method that is more specific for HbA1c and more analytically robust.4 The IFCC method is now used as the reference system by the NGSP and for all routine methods for measurement of HbA1c, although a numerical conversion is required during the calibration process. The changes recommended here will provide results that are directly aligned with the IFCC method. As the IFCC method is more specific for HbA1c, not measuring several other haemoglobin–sugar complexes, the results are 10% to 40% lower than those from the NGSP system, depending on HbA1c concentration. Because reporting these results as percentages may lead to confusion (eg, producing a result of 5.3% rather than 7.0%), the units are changed to mmol/mol (millimoles HbA1c per mole of total haemoglobin [53 mmol/mol in the previous example]), which is consistent with the SI units recommended for use in Australia. There is a linear relationship between results from the two methods, and the “master equation” is used to convert results between the two methods: HbA1c SI unit (mmol/mol) = 10.93 × HbA1c NGSP unit (%) − 23.50.5 To make the conversion easier for clinicians, it is important to translate current treatment advice to the new units. A general conversion table for clinical use is provided in Box 1. The general HbA1c target of ≤ 7.0% for patients with type 1 and type 2 diabetes mellitus equates to ≤ 53 mmol/mol, although these values need to be individualised for patients. The recently updated diabetes treatment guidelines are shown with SI units in Box 2 and Box 3,6 and recommendations for reporting HbA1c levels in Australia are summarised in Box 4. In addition, supporting material for doctors and patients will be presented in SI units in the future. The routine reporting of an estimated average glucose (eAG) value may be useful for consultations with individual patients. However, the working party strongly agrees with the revised consensus statement that routine reporting of eAG with all requests for HbA1c analysis is not appropriate.1 The reasons for this include variability in the methods used to measure eAG, the risk of confusing a measure of long-term glycaemia (eAG) with a measure of short-term blood glucose control (actual blood glucose level), and its lack of applicability in the majority of patients with type 2 diabetes (in whom blood glucose levels are not measured at frequent intervals).7 Nonetheless, eAG values will be used as an educational tool at the discretion of individual clinicians, who can assist patients to understand the significance and limitations of the result. 1 Conversion table for haemoglobin A1c (HbA1c) values HbA1c as percentage (old units) HbA1c in mmol/mol (new units) 5.0 31 6.0 42 6.5 48 7.0 53 8.0 64 9.0 75 10.0 86 11.0 97 12.0 108 2 Recommended haemoglobin A1c (HbA1c) target ranges for patients with type 1 diabetes6 HbA1c target General target ≤ 53 mmol/mol, ≤ 7.0%* Specific clinical situations Pregnancy or planning pregnancy ≤ 53 mmol/mol, ≤ 7.0%*† Children and adolescents ≤ 58 mmol/mol, ≤ 7.5%* Recurrent severe hypoglycaemia or hypoglycaemia unawareness ≤ 64 mmol/mol, ≤ 8.0% Patients with major comorbidities likely to limit life expectancy Symptomatic therapy of hyperglycaemia‡ and avoidance of ketosis * Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia. † An HbA1c level of ≤ 42 mmol/mol (≤ 6.0%) is desirable if it can be achieved safely. ‡ Where practical, suggest blood glucose target level < 15 mmol/L to help minimise risk of infection. 3 Recommended haemoglobin A1c (HbA1c) target ranges for patients with type 2 diabetes6 HbA1c target General target ≤ 53 mmol/mol, ≤ 7.0%* Specific clinical situations Diabetes of short duration† and no clinical cardiovascular disease Requiring lifestyle modification ± metformin ≤ 42 mmol/mol, ≤ 6.0%* Requiring any antidiabetic agents other than metformin or insulin ≤ 48 mmol/mol, ≤ 6.5%* Requiring insulin ≤ 53 mmol/mol, ≤ 7.0%* Pregnancy or planning pregnancy ≤ 42 mmol/mol, ≤ 6.0%* Children and adolescents ≤ 53 mmol/mol, ≤ 7.0%* Diabetes of longer duration† or clinical cardiovascular disease (any therapy) ≤ 53 mmol/mol, ≤ 7.0%* Recurrent severe hypoglycaemia or hypoglycaemia unawareness (any therapy) ≤ 64 mmol/mol, ≤ 8.0% Patients with major comorbidities likely to limit life expectancy‡ (any therapy) Symptomatic therapy of hyperglycaemia§ * Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia, especially among older people. † In an older adult, long duration might be considered to be > 10–20 years, but for a person who develops type 2 diabetes at a young age, it might be considerably longer. ‡ Examples of major comorbidities include chronic medical conditions, such as chronic kidney disease stages 4 or 5; heart failure stages III or IV (New York Heart Association grading); incurable malignancy; and moderate to severe dementia. § Where practical, suggest blood glucose target level < 15 mmol/L to help minimise risk of infection. 4 Recommendations for reporting haemoglobin A1c (HbA1c) levels in Australia From July 2011, HbA1c levels should be reported in both National Glycohemoglobin Standardization Program units (percentage) and the Système International (SI) units (mmol/mol) by all pathology laboratories and, where possible, from point-of-care devices. The period of dual reporting will be 2 years, after which only the SI units will be used. These recommendations are consistent with international recommendations and are already in place in New Zealand.

Graham R D Jones MB BS, DPhil, FRCPA, Chemical Pathologist · George Barker BHSc, CDE-RN, NP · Ian Goodall BSc, FAACB, FFRCPA · Hans-Gerhard Schneider MD, FRACP, FRCPA · Mark D S Shephard MAACB, FFRCPA, PhD · Stephen M Twigg MB BS, PhD, FRACP

We report two Australian patients with possible cobalt toxicity related to metal-on-metal total hip replacements. Both patients were treated for osteoarthritis with a DePuy ASR (articular surface replacement) XL Acetabular Hip System prosthesis, which contains cobalt and chromium, and which has recently been recalled from the market. (MJA 2011; 194: 649-651) Clinical recordsPatient 1A 73-year-old woman presented to our orthopaedic clinic in February 2011 for follow-up of a right total hip replacement that had been performed 5 years previously because of osteoarthritis. At review, she had neurological symptoms, including cognitive decline, memory difficulties and depression, which had been present for 7 months since a cerebrovascular episode. She also had a continuous metal taste in her mouth and complained of severe headaches, anorexia and weight loss. She had mild groin pain but otherwise no symptoms related to her hip. X-rays showed a well fixed, well aligned implant, with mild osteopaenia around the acetabular component. Her serum cobalt level was 410 nmol/L (reference range, 0–20 nmol/L) and chromium level was 240 nmol/L (reference range, 0–100 nmol/L). The cerebrovascular episode had occurred in July 2010, when the patient experienced symptoms consistent with a stroke: dizziness, disorientation, nausea, vomiting and being “off balance on the left side”. She had particularly noted difficulty in remembering names and registering information (both written and aural), headaches and cerebellar signs (ataxia and dysdiadochokinesis). She had been admitted to the stroke unit and treated with ongoing clopidogrel. A computed tomography (CT) scan at this time showed a hypodensity in the right anterior commissure, although it could not be confirmed whether this represented a lacunar infarct or a perivascular space. CT angiogram, echocardiogram and thyroid function test results were all normal and she had no previous history of depression or dementia. The patient’s original hip replacement had been done in 2006 with an ASR (articular surface replacement) hip prosthesis (ASR XL Acetabular Hip System [DePuy Orthopaedics, Warsaw, Ind, USA]), comprising a large-diameter metal (cobalt and chromium) cup with a large modular metal head on a titanium Corail stem (Box). A revision total hip replacement was performed in March 2011, principally because of her systemic symptoms and elevated cobalt and chromium levels. The ASR metal cup and head were removed and the stem retained. Her acetabulum was revised with an all-polyethylene cemented cup and the head was changed to a ceramic one. At the time of surgery, 30 mL of turbid fluid was aspirated from the joint and debridement of metal stained tissue was undertaken. The concentration of cobalt in the joint fluid was 4218 nmol/L and chromium was 217 000 nmol/L. Cerebrospinal fluid (CSF) collected at surgery showed a cobalt level of 9 nmol/L and a chromium level of 13 nmol/L (no reference ranges for these in CSF), showing that the ions had crossed the blood–brain barrier. At 8-week follow-up after the revision surgery, the patient felt much improved. She had regained a normal appetite and gained weight, the metallic taste in her mouth had gone, and she had less fatigue and greater energy. The hip pain had completely resolved and she was walking up to 2 km a day. Her serum cobalt level had reduced to 60 nmol/L. Patient 2A 60-year-old male professor of engineering presented in January 2011 with systemic symptoms, for follow-up after a right total hip replacement with a DePuy ASR XL Acetabular Hip System prosthesis 4 years previously. He had no hip symptoms, but an x-ray showed quite marked bone loss around the acetabular component. Before his hip replacement surgery, the patient had been working full time and enjoyed excellent general health, apart from pain and stiffness in his right hip secondary to osteoarthritis. Three years after the surgery, he developed symptoms that steadily increased in severity: painful muscle fatigue in all limbs associated with cramps in the hands and feet, particularly at night; dyspnoea and feeling faint when performing simple tasks; inability to climb a flight of stairs without needing to rest; and a decline in cognitive function (although this was not quantified). He particularly noted problems with remembering names and poor concentration. His previously stable hypertension had become uncontrolled and required additional medication. The patient’s serum cobalt level had been measured in September 2010 and found to be 185 nmol/L, and subsequently remained consistently elevated at between 213 nmol/L and 258 nmol/L. His chromium level was never elevated. In February 2011, the patient had a revision total hip replacement performed because of his systemic symptoms, in spite of having no hip symptoms. At revision surgery, the titanium stem was retained, and the metal head and cup were changed to ceramic and polyethylene versions, respectively. There was no metal debris or localised tissue reaction. Immediately before the revision surgery, the patient’s serum cobalt level was 258 nmol/L, with a normal level of chromium (88 nmol/L). At 8-week follow-up after the revision surgery, the patient reported significant improvement in his energy levels and a decrease in muscle pains. He had significantly improved exercise tolerance and was able to walk without restriction. His serum cobalt level had fallen to 42 nmol/L. DiscussionTotal hip replacement is generally a successful operation, with a long clinical history of good outcomes. Conventional total hip prostheses consist of a metal head that fits into a polyethylene cup. Concerns have been raised, particularly in younger patients, that the plastic cup suffers wear and tear with time and may require revision. In an attempt to decrease wear at the interface of the articulation, metal-on-metal bearings (Box), composed of cobalt and chromium, have gained widespread popularity and have been used extensively, particularly in the United States. However, some of these metal-on-metal prostheses have not lived up to the promise of increased durability. The Australian National Joint Replacement Registry (NJRR) notes large differences in the performance of different types of metal-on-metal hip prostheses. An acceptable upper rate of failure of hip prostheses is considered to be below 1% per year, with the vast majority of implants studied by the NJRR falling well below this failure rate.1 The ASR prosthesis originally implanted in both patients reported here has recently been withdrawn from the market, after about 100 000 were implanted worldwide. Its revision rate reported on the NJRR in 2010 was 6.4% at 3 years when inserted with a Corail stem and 10.9% at 5 years when inserted as a resurfacing.1 Updated guidance from the British Hip Society’s 2011 conference noted a higher than anticipated early failure rate [in large-diameter metal-on-metal hip replacements]. These range from [a] 21% revision rate at 4 years (potentially rising to 35% if all currently known painful implants progress to revision) to 49% at 6 years for the ASR XL device. Other devices have a revision or impending revision rate of 12 – 15% at 5 years.2 An additional problem with metal-on-metal bearings is that they release a variety of metal ions into local tissue and the general circulation, with chromium being the most widely reported of these. Increased cobalt levels have been reported to be associated with neurological3,4 (hand tremor, incoordination, cognitive decline, depression, vertigo, hearing loss and visual changes), cardiac (arrhythmias and cardiomyopathy) and endocrine5,6 symptoms. Symptoms of cobaltism have been previously described when cobalt was used to treat refractory anaemia in patients 40 years ago.7 The term “arthroprosthetic cobaltism” has been coined to describe these manifestations in patients with joint replacements.3 The direct effect of cobalt on cells has recently been explored. Exposure to cobalt ions was found to significantly inhibit osteoblast function by reducing alkaline phosphatase activity and calcium deposition, and to rapidly induce the secretion of proteins IL-8 and MCP-1 in primary human osteoblasts.8 This may have implications for bone ingrowth onto implants and osteolysis around the hip replacement. Other reported effects of elevated cobalt levels on cells include abnormal lymphocyte function,9,10 chemokine secretion11 and ischaemic changes in rat brains.12 A relationship between symptoms and peak cobalt levels, or the length of exposure to cobalt, has not been established. We believe our patients’ symptoms were related to their elevated cobalt levels, resulting from cobalt leaching out of their hip prostheses. Both patients had metal-on-metal hip prostheses, and both patients’ cobalt levels were reduced after removal of the metal-on-metal prosthesis. We are concerned that cobalt toxicity may be under-recognised, particularly if patients consult doctors who may not be aware of the details of the patient’s hip replacement and the potential for release of cobalt into the circulation. The British Hip Society recommends regular follow-up of patients with metal-on-metal hip replacements for at least 5 years and probably for the life of the prosthesis.2 Clinical manifestations of cobalt toxicity may occur many years after implantation of the prosthesis and appear to stay elevated over extended periods of time.13 Long-term exposure to cobalt may also be associated with cancer.14 Patients should therefore be followed up carefully, with specific questioning about alterations in neurological, cardiac, respiratory and endocrine function. In the presence of persistently elevated metal ion levels and symptoms consistent with metal toxicity, once other causes have been excluded, revision hip replacement is the only method available to decrease the ion levels. X-ray of Patient 1’s right metal-on-metal articulation hip replacement, with well fixed cementless femoral and acetabular implant

Xinzhan Mao MD · Andrew A Wong MB BS, PhD, FRACP · Ross W Crawford MB BS, DPhil(Oxon), FRACS(Orth)

To the Editor: We read with interest the article by Ng and colleagues on life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis,1 and wish to present our own experience of four patients presenting to our hospital over a year (Box). The patients all presented with biochemical signs of renal tubular acidosis with severe hypokalaemia and a normal anion gap metabolic acidosis from long-standing misuse of ibuprofen taken in combination with codeine from over-the-counter (OTC) medications. Patients 1 and 2 presented acutely with deliberate misuse that included an ibuprofen–codeine combination product. Both patients subsequently admitted to long-standing misuse of ibuprofen and codeine taken in combination. Patients 3 and 4 presented with constitutional symptoms and generalised weakness with a history of taking large amounts of an ibuprofen–codeine combination product. Both these patients required intensive care unit admission for central venous access and potassium replacement. As in the case series by Ng and colleagues, there was no history to suggest gastrointestinal loss of potassium, and medication histories were negative for drugs known to cause intracellular potassium movement or potassium wasting (eg, diuretics). Ibuprofen cessation, potassium replacement and supportive care resulted in biochemical recovery in all four patients. Opioid addiction appears to be the common thread reported by Ng et al and in our case series. Other case reports support this.2,3 Paracetamol taken in supratherapeutic doses is known to cause hepatotoxicity, and it appears that patients with opioid addiction may now be turning to ibuprofen–codeine combination products. More evidence of the danger of these products comes from a case series reporting 27 patients with ibuprofen–codeine misuse that resulted in significant morbidity, including presentations for opioid dependence, gastrointestinal haemorrhage, hypokalaemia, anaemia and/or renal failure.4 In Australia, ibuprofen–codeine combination products are available OTC, albeit in restricted amounts due to problems related to codeine misuse.1 Further restrictions may need to be considered in light of the significant morbidity related to the ibuprofen component. Baseline laboratory investigations and other characteristics of four patients with ibuprofen-induced renal tubular acidosis* RR Patient 1 Patient 2 Patient 3 Patient 4 Sex, age in years Female, 35 Male, 55 Male, 41 Female, 39 Ibuprofen dose† Unclear, years’ duration 9.0–18.0 g/day 5.0 g/day 8.0 g/day Other medications Amitriptyline 50 mg at night Esomeprazole 40 mg daily Multiple medications Nil Serum pH 7.35–7.45 7.29 7.13 7.26 7.32 Pco2, mmHg 35–45 45 42 30 28 HCO3-, mmol/L 22–32 21 13 13 14 Anion gap, mmol/L 7–17 3 9 12 11 Na+, mmol/L 136–146 137 139 142 135 Cl-, mmol/L 98–106 116 120 120 111 Urea, mmol/L 3.0–8.0 4.7 4.4 3.0 6.9 Creatinine, μmol/L 60–120 70 123 125 99 K+ on presentation, mmol/L 3.5–5.0 2.8 2.9 2.5 1.4 K+ on discharge, mmol/L 3.5–5.0 3.5 3.8 3.7 4.5 RR = reference range. Pco2 = partial pressure of carbon dioxide. HCO3- = bicarbonate ion. Na+ = sodium ion. Cl- = chloride ion. K+ = potassium ion. * Same format as used in Ng et al case series1 to allow direct comparison. † Maximum recommended: 3.2 g/day.

Colin B Page · Paul A Wilson · Aidan Foy · Michael A Downes · Ian M Whyte · Geoffrey K Isbister

Computed tomography coronary angiography is the most reliable diagnostic test for coronary atherosclerosis. Stress testing should be reserved for diagnosis of myocardial ischaemia. Revascularisation, either by stenting or bypass grafts, is commonly performed in patients with stable coronary artery disease but is a double-edged sword. In the presence of ischaemia, revascularisation improves outcomes; in its absence, outcomes are worsened. In current practice, the decision of whether to revascularise is mainly made on the basis of the angiographic appearance of the coronary lesion in question. Physiological assessment of coronary lesions by the use of a pressure wire and measurement of fractional flow reserve (FFR) often shows that lesions thought to be sufficiently severe to warrant stenting or bypass do not cause ischaemia. A recent randomised study has shown that using FFR measurements to guide coronary stenting resulted in a lower use of stents, decreased costs and superior outcomes at 2 years, compared with traditional angiographic assessment alone. We believe that changes to the methods of health reimbursement are needed in both the public and private health systems, to facilitate greater use of FFR measurement.

Richard W Harper MB BS, FRACP, FACC · Brian S Ko MB BS, FRACP

To the Editor: About 5% of Australians of Asian, African, Middle Eastern or Mediterranean descent have glucose-6-phosphate dehydrogenase (G6PD) deficiency.1 Affected babies can develop massive haemolysis within hours of exposure to clothes stored with mothballs containing naphthalene. It has long been known that this results in severe jaundice, which may lead to kernicterus2 and profound brain damage, for which the cost is either a lifetime of dependency and very expensive care, or death. We are aware of three cases of kernicterus in babies with G6PD deficiency in Australia in the past 3 years, one of which was associated with exposure to naphthalene in mothballs. One baby died. The exact incidence of severe neonatal jaundice and kernicterus in Australia is unknown, but it is the subject of an ongoing study funded by the Cerebral Palsy Foundation and coordinated through the Australian Paediatric Surveillance Unit. In Australia, packages of naphthalene mothballs must carry a warning that the product is harmful to children. However, clinical directors of neonatal units that comprise the Australian and New Zealand Neonatal Network have unanimously agreed that warning labels give insufficient protection. They have called on the Australian Pesticides and Veterinary Medicines Authority (APVMA) to act in harmony with the European Union, which banned the sale of mothballs containing naphthalene in 2008,3 following a report by the European Chemicals Bureau.4 The adverse risk–benefit ratio for naphthalene provides strong justification for its withdrawal. A submission to this effect has been lodged with the APVMA. Some mothballs contain paradichlorobenzene, a chemical related to naphthalene and associated with haemolysis. Less toxic products that protect clothes against moths exist. Department stores in the United Kingdom have replaced moth repellents containing naphthalene with products containing natural substances, such as sandalwood and lavender. Between 2004 and 2010, the New South Wales Poisons Information Centre reported that it received about one call per week concerning children exposed to naphthalene in moth repellents (Box). The Victorian Poisons Information Centre reported 53 calls in 2008.5 While acknowledging the importance of raising awareness of the dangers of naphthalene, we believe that the safest course is prevention — that is, an Australia-wide ban of mothballs containing naphthalene. Readers who wish to report cases of naphthalene toxicity are encouraged to contact APVMA at aerp@apvma.gov.au. Number of calls to the New South Wales Poisons Information Centre reporting children exposed to napthalene in moth repellents, 2004–2010 Year Number of calls 2004 55 2005 59 2006 65 2007 67 2008 73 2009 45 2010 71 Total (average) 435 (62) Source of data: Judith Kirby, Department Head, NSW Poisons Information Centre, personal communication.

on behalf of the Advisory Committee of the Australian and New Zealand Neonatal Network

Objective: To determine the impact that mandatory fortification with folic acid of wheat flour used in breadmaking has had on the blood folate levels of an Australian population since it was introduced in September 2009.Design, setting and patients: A retrospective analysis of serum and red blood cell (RBC) folate levels of 20 592 blood samples collected between April 2007 and April 2010 from a wide variety of inpatients and outpatients and analysed in a large public hospital diagnostic pathology laboratory.Main outcome measures: Prevalences of low levels of serum and RBC folate and monthly mean levels before and after introduction of mandatory fortification.Results: Between April 2009 and April 2010, there was a 77% reduction in the prevalence of low serum folate levels (from 9.3% to 2.1%) in all samples tested and an 85% reduction in the prevalence of low RBC folate levels (from 3.4% to 0.5%). In April 2010, the prevalence of low RBC folate levels for females of childbearing age was 0.16% for all samples. There was a 31% increase in mean serum folate level (from 17.7 nmol/L to 23.1 nmol/L; t = 9.3, P < 0.01), and a 22% increase in mean RBC folate level (from 881 nmol/L to 1071 nmol/L). The greatest increment in mean serum folate levels occurred in September 2009, the month that mandatory fortification was introduced, although there was evidence of a gradual change during the preceding months.Conclusion: The introduction of mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency in Australia, including in women of childbearing age.

Ross D Brown PhD, MBA, FAIMS · Mark R Langshaw BAppSci, GradDipIT · Elaine J Uhr MSc(BiolSc) · John N Gibson PhD, FRACP, FRCPA · Douglas E Joshua DPhil, FRACP, FRCPA

Objective: To evaluate the 2010 “Anatomy by whole body dissection” course, a 7-week elective course offered to senior medical students at the University of Sydney at the end of their third year.Design, setting and participants: In the 2010 course, 29 students divided into eight groups carried out whole-body dissections on eight cadavers over a 34-day period. Surgical trainees acted as demonstrators, and surgeons and anatomists as supervisors. The students were assessed by practical tests involving the identification of 20 tagged structures in four wet specimens before, during, at the end of, and 1 month after the course. In addition, students were asked to complete an anonymous feedback questionnaire about the course.Main outcome measure: Acquisition of topographical anatomical knowledge, and student feedback on the usefulness of the course.Results: A significant increase in topographical clinical anatomical knowledge was demonstrated among the participants and was maintained in the short term. The median pre-course assessment score was 8/20 (interquartile range [IQR], 4) and the median post-course assessment score was 19/20 (IQR, 1). This difference was statistically significant (P < 0.001). All students rated the course as “very good”, and unanimously recommended that the course be available to all students as part of the medical curriculum.Conclusion: Students’ knowledge of anatomy improved significantly between the pre-course and post-course assessments, and all students rated the course very favourably. This supports our view that dissection anatomy should be an integral component of medical education.

George Ramsey-Stewart MD, FRCS, FRACS · Annette W Burgess MBT, MEd, MMedEd · David A Hill MB MS, FRCS, FRACS

To the Editor: When I looked at the cover of the 5 April issue of the MJA, I feared finding another article focused on discrediting the prostate-specific antigen (PSA) test. Instead, I congratulate the authors, and the Journal, for presenting one of the rare balanced articles on this topic.1 Denham and colleagues called for an end to taking sides in the debate over PSA testing, and focused instead on helpful guidance. The problem is not whether PSA helps us find prostate cancer, but that we lack clinical tools for deciding which patients would benefit from aggressive treatment. However, the authors point out that there are two important tools that can help with this decision: low free to total PSA ratios, and rapid PSA doubling time (< 3 years).1 The PSA test is now one of the most sensitive, precise and highly standardised immunoassays in the clinical laboratory. The difficulty does not lie with the measurement but with its application. The Royal College of Pathologists of Australasia, together with the Urological Society of Australia and New Zealand, recently produced a monograph that discussed the appropriate use of the PSA test.2 It emphasised using age-related cut-offs for PSA levels, the free to total PSA ratio, and the calculation of PSA doubling time as modern tools to achieve optimal benefit from the test. The Australian Medicare Benefits Schedule (MBS) was changed in May 2009 (following a suggestion from the Urological Society of Australia and New Zealand) to improve utilisation of free to total PSA ratios. The Box indicates the per capita request rates of PSA testing (MBS item number 66655) and free to total PSA ratios (MBS item number 66659) from May 2009 to February 2010. Consistent with Denham et al’s observation that there are regional differences in the attitudes to prostate cancer,1 there is a twofold variation in PSA requesting and a sevenfold difference in free to total PSA ratio requesting across the Australian states. Furthermore, the relationship between the two tests is, if anything, inverse, suggesting that increased use of PSA testing is less commonly followed up by modern tools such as free to total PSA ratio. As a chemical pathologist, the appropriate clinical use of the PSA test has been a career-long concern of mine.3 Even though the discoverer of PSA has labelled the test a public health disaster,4 recent “case–controlled” studies using PSA in an outdated approach (without free to total PSA ratios or doubling times) have shown a marginal benefit for screening.5,6 The indiscriminate use of PSA testing can be helpful to some but disastrous for others. Modern PSA tools may significantly improve management beyond these marginal effects. As always, the value of medical investigations lies in how intelligently we use them. Average per capita request rates of PSA testing* and free to total PSA ratio,† May 2009 – February 2010 PSA = prostate-specific antigen. ACT = Australian Capital Territory. NSW = New South Wales. NT = Northern Territory. Qld = Queensland. SA = South Australia. Tas = Tasmania. Vic = Victoria. WA = Western Australia. * Medicare Benefits Schedule (MBS) item number 66655. † MBS item number 66659.

Kenneth A Sikaris

How far has our understanding of chronobiology come in the past 40 years? An MJA editorial on circadian rhythms published nearly 40 years ago lamented the “neglect ... in part engendered by the air of mysticism which surrounded much of the earlier work in this field” that had obscured recognition of their importance to health.1 Since that time, basic research has explored various aspects, including the intracellular generation of circadian oscillations, their intercellular synchronisation, the entrainment of the circadian “system” by environmental time cues or “zeitgebers” such as light, and circadian variation in biological functioning. Further, clinical research has focused on the consequences of circadian disruption, circadian rhythm sleep disorders (CRSDs), circadian abnormalities in affective disorders, and chronotherapy. Here, we summarise some of these key advances. In 1970, it was known that circadian rhythms are generated endogenously,1 but little was known about the mechanisms involved. The discovery of the first circadian clock gene, in the fruit fly Drosophila melanogaster, was reported the following year.2 A number of mammalian clock genes have now been identified, and there is considerable understanding of the transcription–translation feedback loops that generate circadian oscillations at the cellular level.3 In 1972, the importance to circadian pacing of the suprachiasmatic nuclei (SCN) in the anterior hypothalamus was established. The SCN comprise the “master” circadian clock, which plays a key role in synchronising peripheral (“slave”) oscillators and in the entrainment of the circadian system by light.3 Light information from melanopsin-containing retinal ganglion cells is transferred directly to the SCN via the retino-hypothalamic tract and indirectly via the retino-geniculo-hypothalamic tract. The SCN interpret and transfer this information to the pineal gland, which secretes melatonin accordingly. In the future, further understanding of normal circadian regulation will help to clarify abnormalities that occur in circadian disruption and disorders and hopefully indicate effective strategies for circadian “resetting”. In industrialised societies, 15%–20% of workers are involved in shift work or unusual work hours, and it has been reported that prolonged circadian disruption, especially from rotating night-shift work, increases the risk of cardiovascular disease,4 metabolic syndrome,5 and prostate, breast and colorectal cancer.6 Although important, questions remain about the evidence and explanation for these findings. For example, a recent systematic review concluded that there is limited evidence for the suggested link with breast cancer and insufficient evidence for a causal link with cancer overall.7 There is experimental evidence that circadian disruption can independently produce adverse metabolic and cardiovascular effects,8 but uncertainty remains about the extent to which other factors associated with shift work, particularly sleep disturbance,9 have contributed to reported findings from clinical studies. It is recognised that shift workers are more liable to injuries at work and road accidents when driving home from work, but circadian disruption is probably not solely responsible for this. Despite the need for further clarification, there appears to be sufficient evidence of the ill effects associated with rotating shift work to justify simple precautionary measures: identifying, educating and monitoring shift workers; improving rosters by including shorter shifts; avoiding rotation; scheduling rest or nap periods; and perhaps even favouring chronotype “owls” for night-shift work.10 The relationship between sleep and circadian regulation is complex and not well understood. It is known that the “sleep homeostat”, which monitors the need for sleep based on a person’s prior sleep history, can operate independently of the circadian clock. There is nevertheless an interaction between sleep and circadian regulation, as evidenced by CRSDs and the effects of orexins, which are functionally linked to the SCN and involved in mediating circadian suppression of rapid eye movement (REM) sleep. The clinical relevance of these complexities is that sleep disorders may arise from different combinations of sleep and circadian abnormalities. CRSDs are mainly abnormalities in the timing of sleep and are classified broadly as “extrinsic” or “intrinsic”. Extrinsic disorders include jet lag and shift work sleep disorder. Intrinsic disorders include advanced and delayed sleep phase syndromes, free running disorder, and irregular sleep–wake disorder. Intrinsic CRSDs are of interest, not least because a better understanding of the relationship between circadian and sleep regulation may lead to more effective treatment of insomnia — a frequent complaint in primary health care. Most serious mental illnesses are associated with sleep disturbance, and some, especially affective disorders, are also associated with circadian abnormalities. It remains to be seen whether circadian abnormalities are a primary or secondary manifestation in affective disorders, but there is evidently a relationship between mood and circadian regulation. Mood disorders are associated with a disturbance of circadian rhythms, and disruption of circadian rhythms is associated with a disturbance of mood.11 Under these circumstances, effective circadian resetting to a normal sleep–wake cycle, using methods such as artificial light, chronobiotic medication (antidepressants, melatonin agonists) and sleep deprivation, may be useful in the treatment of mood disorders. Chronotherapy considers the impact of circadian variation on diseases and treatment side effects. Applied to pharmacotherapy, it recognises that optimal treatment depends not only on the dose but also on the time of day that medication is given. Medications for asthma, allergies, cardiovascular disease, pain and cancer can produce better results with fewer side effects when given at particular times.12 The kinetics of antihypertensive medication vary with circadian rhythms in gastrointestinal pH, emptying and motility, and blood flow (“chronokinetics”). So-called “chronodynamic” effects can be seen with the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat arthritis. NSAIDs are more effective for osteoarthritis (symptoms worse at night) when taken around noon, but are more effective for rheumatoid arthritis (symptoms worse in the morning) when taken after the evening meal. Although recognised since antiquity, the scientific study of circadian and other biological rhythms, now referred to as “chronobiology”, did not become firmly established until the second half of the 20th century. There is now a burgeoning literature in the field and, specifically with regard to circadian rhythms, an expectation of useful clinical applications from further progress in understanding. Research conducted in the past 40 years has not only dispelled any remaining mysticism but has also provided a clear justification for teaching on chronobiology and chronotherapy to be included in medical curricula.

Hans G Stampfer MB BS, FRANZCP · Sean D Hood MB BS, MSc, FRANZCP

Although glycated haemoglobin (HbA1c) has become the key biochemical marker of long-term glycaemic control, analytical method-dependent differences in results can occur when haemoglobin variants are present or HbA1c is reduced by decreased red cell survival. When the measured HbA1c level is discordant with the patient’s blood glucose measurements and clinical status, fructosamine is an alternative biochemical marker that can provide a more accurate estimate of the glycaemic control and enable clinicians to appropriately manage patients. Clinical recordA 65-year-old, centrally obese man (body mass index, 32.7 kg/m2) with a 23-year history of type 2 diabetes mellitus was referred to a diabetes clinic in January 2008 for stabilisation of his blood sugar levels. His diabetes was complicated by ischaemic heart disease, peripheral vascular disease, hypertension, dyslipidaemia, and stage 3 chronic kidney disease. His glycated haemoglobin (HbA1c) level on referral was 11.0%, measured using an ion-exchange chromatography (IEC) method on a Bio-Rad Variant II analyser (Bio-Rad Laboratories, Sydney, NSW), and the laboratory fasting glucose measurement was 19.3 mmol/L (Box 1). Both these results were consistent with the patient’s home blood glucose measurements (> 10 mmol/L). On presentation, the patient’s medication included human mixed insulin (Mixtard 30/70; Novo Nordisk, Sydney, NSW) (80 units before breakfast and 75 units before dinner), as well as simvastatin, aspirin, clopidogrel, diltiazem, ramipril, frusemide, omeprazole, bisoprolol, irbesartan and glyceryl trinitrate. The insulin regimen was changed to a basal-bolus regimen of insulin aspart and insulin glargine, which was titrated weekly on the basis of home blood glucose measurements. After 6 weeks, the patient’s HbA1c level had decreased to 5.8%, which appeared to be inconsistent with the home blood glucose measurements and the laboratory fasting glucose measurement (15.1 mmol/L). This change in HbA1c level coincided with the implementation of a modified method (“NU”) on the Bio-Rad Variant II analyser. Haemoglobin (Hb) studies (electrophoresis and chromatography) demonstrated an abnormal Hb variant interfering with the HbA1c measurement. The patient’s fructosamine level was tested and the result indicated improved glycaemic control, but not to the extent suggested by the HbA1c level. A week after the fructosamine measurement, the HbA1c measurement was repeated with a Siemens DCA 2000 analyser (Siemens, Melbourne, Vic) using an immunoassay (IA) method, which is less likely to be influenced by Hb variants. The result was congruent with the fructosamine estimation of the glycaemic control (Box 1). On subsequent visits, the patient’s HbA1c level was measured with a different IEC method on a Bio-Rad D-10 analyser (Bio-Rad Laboratories, Sydney, NSW), from which a substantially higher result was obtained (Box 1). A further fructosamine measurement (280 μmol/L) suggested the glycaemic control was better than the HbA1c results now indicated. To investigate the effect of the Hb variant on the different HbA1c assays, the patient’s 9 December 2008 sample was analysed using the different analytical systems available locally (Box 1). The highest (9.0%) and lowest (4.4%) HbA1c results were obtained from IEC methods on different analysers from the same supplier. Before the modification of the Bio-Rad Variant II method, there was incomplete separation of the Hb variant and HbA1c peaks (Box 2, A). After implementation of the modified method, the separation of the Hb variant and HbA1c peaks was much more distinct (Box 2, B and C). The instrument software integrates only the one HbA1c fraction or peak and therefore underestimates the HbA1c level by about 50%. The Bio-Rad D-10 chromatogram (Box 2, D) is similar in appearance to the chromatogram from the original Bio-Rad Variant II method (Box 2, A). The range of HbA1c values obtained with the affinity chromatography (AC) and IA methods spanned a range from 6.8% to 7.9% (Box 1); this variation is within the anticipated interlaboratory performance. To avoid such variation, one analytical method should consistently be used for monitoring longitudinal changes. The patient’s Hb variant was characterised as a heterozygote for the Hb Athens-Georgia mutation by a reference laboratory (Southern Cross Pathology Australia, Melbourne, Vic). This is a very rare and clinically silent variant detected in Caucasians where only one β-chain is affected,1,2 and, depending on the separation method, it can produce two peaks on the chromatogram, as was the case with the modified Bio-Rad Variant II NU method (Box 2, B). DiscussionThis case illustrates some of the caveats associated with measuring glycaemic control. A multifactorial approach is required to achieve optimal glycaemic control, as failure to recognise the true state of control might result in inappropriate clinical management decisions and less than optimal patient care. The rate of HbA1c formation is proportional to the average blood glucose concentration over the life span of red blood cells (about 120 days). Methods used to measure HbA1c are divided into the three categories of IEC, AC and IA. In the 2008 Royal College of Pathologists of Australasia Quality Assurance Program (http://www.rcpaqap.com.au), 59% of participants used IA, 30% used IEC and 11% used AC methods, performed on 29 different commercial platforms. About 40% of all HbA1c measurements were performed with point-of-care instruments that use either IA or AC methods. Interference from abnormal Hb variants can lead to falsely elevated or lowered HbA1c results with IEC methods. AC methods are the least affected by Hb variants, as the method separates all glucose-modified Hb molecules from non-modified molecules, and calculates the HbA1c value from the total glycated Hb result.3-5 More than 1300 Hb variants have been identified,2 and about half of these are clinically silent.4 An HbA1c level < 6% or > 15% in patients with diabetes can often be due to Hb variant interference.3,6 The prevalence of Hb variants is highest in Mediterranean regions, Africa and Asia, particularly India and Pakistan. IA methods are only affected by Hb variants where the first 4–10 amino acids of the Hb β-chain are altered, and the IA antibody is unable to bind.7 Elevated levels (> 10%) of HbF falsely lower HbA1c results in IA methods.7 HbF levels are normally < 1%, but increased levels occur in hereditary conditions (β-thalassaemias, sickle cell anaemia and congenital aplastic anaemia), late pregnancy, in some patients with abnormal Hb variants, and in neonates.5 As well as recent blood transfusions and abnormal Hb variants, reduced red cell survival (as occurs in haemolytic anaemia, haemorrhage, iron deficiency anaemia, end-stage renal disease, patients on haemodialysis,3 thalassaemias or sickle cell syndromes6) is another cause of falsely low HbA1c results with all analytical methods, as a consequence of less available time for non-enzymatic glycation to occur. Fructosamine measurement is an alternative method for monitoring glycaemic control in patients with reduced red cell survival, and provides an index of glycaemia over the preceding 2–3 weeks.6 Recent studies, including a position statement from the American Diabetes Association, have suggested that simultaneous measurement of HbA1c and fructosamine might complement one another and may provide more useful clinical information than HbA1c alone.8,9 However, unlike with HbA1c, to date there are no published accepted treatment targets for fructosamine, nor are the different fructosamine measurement methods standardised. The most recent consensus statement on the standardisation of HbA1c measurement recommends that laboratories should report an HbA1c-derived average glucose or estimated average glucose (eAG) value alongside the HbA1c level.10 As the eAG is calculated from the HbA1c level, it will not assist in those patients whose HbA1c measurement is not accurate because of Hb variants or reduced red cell survival. The HbA1c result and the eAG should correlate with the patient’s glucose measurements and clinical status. If they are discordant, the HbA1c result should be rechecked using an alternative analytical method that is less susceptible to interference from Hb variants. Alternatively, fructosamine measurement might be a useful adjunct in these cases. It may be prudent to rely more on glucose tests when there is uncertainty about long-term markers of glycaemic control, although the long-term markers may still be valuable for trend analysis. Considering current migration patterns, with more than half of the nearly 150 000 settlers arriving in Australia in the 2007–08 financial year coming from Africa, the Middle East and Asia,11 patients with Hb variants and decreased red cell survival will become more prevalent in the Australian population. This case emphasises the limitations of HbA1c assays in such patients and the importance of communication between clinicians and the laboratory when unexpected results occur. 1 Results from the various glycated haemoglobin (HbA1c) analytical systems and other laboratory measurements Date Analytical system Analytical method HbA1c* eAG (mmol/L) Glucose (mmol/L) Fructosamine (μmol/L)† 29 January 2008 Bio-Rad Variant II‡ (old method) IEC 11.0% 14.9 19.3 — 11 March 2008 Bio-Rad Variant II (new method) IEC 5.8% 6.6 15.1 — 1 April 2008 Bio-Rad Variant II (new method) IEC 4.9% 4.9 — — 3 May 2008 — — — — — 271 10 May 2008 Siemens DCA 2000§ IA 7.4% — — — 28 November 2008 Bio-Rad D-10‡ IEC 9.2% 12.0 7.8 280 9 December 2008 Bio-Rad Variant II (new method) IEC 4.4% 4.4 — 234 Bio-Rad D-10 IEC 9.0% 11.7 — Siemens DCA Vantage§ IA 7.5% 9.3 — Roche Integra¶ IA 7.7% 9.7 — Primus PDQ** AC 7.9% 10.0 — Bio-Rad in2it‡ AC 6.8% 8.2 — 20 January 2009 Bio-Rad in2it AC 7.3% — — 307 eAG = estimated average glucose. IEC = ion-exchange chromatography. IA = immunoassay. AC = affinity chromatography. * All HbA1c results are aligned to the National Glycohemoglobin Standardization Program (http://www.ngsp.org). † Reference range, 190–285 μmol/L. ‡ Bio-Rad Laboratories, Sydney, NSW. § Siemens, Melbourne, Vic. DCA Vantage is an upgraded model of the DCA 2000. ¶ Roche Diagnostics, Sydney, NSW. ** Primus Diagnostics, Kansas City, Mo, USA. 2 Chromatograms from Bio-Rad ion-exchange chromatography analysers* HbA1c values: A: 11.0% B: 4.9% C: 4.4% D: 9.0%. * Bio-Rad Laboratories, Sydney, NSW.

Goce Dimeski BSc · Carel J Pretorius MB ChB, FCPathChem(SA) · Anthony W Russell MB BS, FRACP, PhD · Stephen P Miller BSc · Robert J Bird MB BS, FRCP(Lon), FRCPA · Jacobus P J Ungerer MB BS, MMed(ChemPath), FRCPA

To the Editor: A recent review of medical textbooks found that the topic of intravenous fluid therapy is poorly covered.1 Hence, the recent article by Hilton and colleagues provides interesting hypothetical examples of the risk of hypovolaemia and hypervolaemia, as well as imbalances in fluid tonicity, in patients receiving intravenous fluid therapy.2 In particular, the authors recommend the use of intravenous 0.9% saline, as it is reportedly isotonic and hence avoids potential imbalances in serum sodium concentration. However, Hilton and colleagues discuss only tonicity as the determining factor when selecting the type of fluid to give patients. They do not mention that 0.9% saline, also known as “normal” saline, distorts fluid, electrolyte and acid–base balance, despite being isotonic. In healthy subjects, 25% more volume is retained 6 hours after infusion of 2 L of 0.9% saline compared with 2 L of Hartmann’s solution.3 Infusion of 0.9% saline also results in hyperchloraemia, which decreases glomerular filtration rate, and is not seen with infusion of Hartmann’s solution.3 Certainly, the most important side effect of 0.9% saline infusion is metabolic acidosis, caused (according to the Stewart approach) by a reduction in the strong ion difference.4 Using the Stewart approach once again, Hartmann’s solution is “balanced”, ensuring the eradication of infusion-related metabolic acidosis.4 Although tonicity is important in considering the appropriate intravenous fluid therapy, it should not take precedence in the choice of therapy. Such an approach ignores the volume, electrolyte and acid–base disturbances induced by 0.9% saline infusions.

Alexander D Franke

In reply: Franke presents some well known problems associated with intravenous administration of large volumes of 0.9% NaCl, particularly its relatively slow elimination (as compared with Hartmann’s solution), and hyperchloraemic acidosis.1 In isolation, we do not dispute these facts. However, 0.9% NaCl is not unique in having problems — no intravenous fluid therapy is without risk, especially when given in excessive volume, or when the composition is inappropriate for the patient’s needs. It is also important to distinguish maintenance therapy from resuscitation. For postoperative maintenance therapy, we advocate a conservative approach with initial use of minimal volumes of isotonic fluids, to decrease the risk of common complications such as postoperative fluid retention, impaired respiratory function, and prolonged bowel dysmotility. We encourage close monitoring of volume and electrolyte status, and do not exclude the later use of hypotonic fluids.2 Disorders of volume and tonicity (hypo- or hypernatraemia) are the most common serious problems associated with intravenous fluid therapy. The approach we recommend follows the priorities of the kidney: restoration of volume, restoration of tonicity, and restoration of acid–base balance, in that order. If the patient’s requirements for fluid volume and tonicity are met, and tissue perfusion and gas exchange restored, then significant morbidity or death is unlikely to be a direct consequence of isolated 0.9% NaCl-induced hyperchloraemic acidosis.

Carlos D Scheinkestel · Andrew K Hilton · Vincent A Pellegrino

The absolute benefit of a treatment varies between individuals depending on their prognosis before treatment and whether their response to the treatment varies from the overall relative risk reduction measured in clinical trials. Based on these principles, biomarkers that can provide information about an individual’s prognosis or predict his or her treatment response can be used to tailor treatment decisions to individual patients. Many novel molecular biomarkers are currently available. Although there is evidence to show that some of these can improve patient outcomes through improved biomarker-guided treatment strategies, others are yet to be adequately evaluated. Randomised controlled trials (RCTs) can distinguish whether a biomarker provides prognostic or predictive information and assess whether using a biomarker to guide treatment improves patient outcomes. Targeted RCTs can be used to demonstrate the efficacy of treatment in a restricted biomarker-defined population, and non-targeted RCTs can compare biomarker-guided versus conventional test-guided treatment strategies in broader populations.

Chee K Lee MB BS, MMedSci, FRACP · Sarah J Lord MB BS, MS(Epi) · Alan S Coates AM, MD, FRACP · R John Simes MB BS, FRACP, SM