Reassessment of the new diagnostic thresholds for gestational diabetes mellitus: an opportunity for improvement

In reply: Callaway and McElduff are dismissive of the concerns I raised in my recent article,1 asserting incorrectly that they are old arguments. The potential reduction of the risk of macrosomia (birthweight > 90th centile; large for gestational age babies) when one or more blood glucose levels (BGLs) on an oral glucose tolerance test are normal was only suggested recently, in February 2014.2 In response, new data3 confirmed the statistical flaw in the new diagnostic criteria for gestational diabetes mellitus (GDM). These data showed that (i) nearly 50% of women having only one elevated BGL test result do not reach the diagnostic risk threshold, and (ii) women having two or more BGL results just below the new diagnostic levels may be at greater risk, yet will not be identified.1

The many international organisations mentioned by Callaway and McElduff were early adopters of the new criteria, and the impact of this interaction was not considered. Australia has an opportunity to develop a better, statistically valid, diagnostic approach. The rate of GDM and its management can then be benchmarked against other countries that have adopted the new statistically flawed diagnostic criteria. The benefit of this approach cannot be understated.

Zheng and colleagues question the statement that it is a concern that women with GDM may be charged a higher insurance premium. Their hypothetical applicant had been diagnosed with GDM 10 years previously. The Australian Diabetes in Pregnancy Society states that the risk of developing diabetes is up to 50%.4 Most cases occur within 10 years and the risk appears to plateau after that time.5 Thus, it would appear that the insurance actuaries have read carefully the medical literature about the conversion to type 2 diabetes with minimal additional risk after 10 years. The industry response may be different if the application for insurance was made 3 months after delivery. This may explain why many of my patients and a colleague who had GDM were recently quoted higher premiums when applying for life insurance soon after the delivery of their children. The hypothetical case does not invalidate the real concerns expressed in the article.

My article was factual, not alarmist. It suggests that the available data can be used to establish the diagnosis more accurately. Improving the identification of women who truly have an odds ratio for the threshold level for risk of 1.75 or greater will still result in more women being diagnosed with GDM than currently. However, these women will belong to a higher risk group and their management should result in even greater improvements in obstetric and neonatal outcomes.

The world I want — a world with less diabetes

An open letter to Ban Ki-moon, Secretary General of the United Nations

Your Excellency,

I am an Australian endocrinologist and academic with links to diabetes care in more than 45 countries. I am impressed by and congratulate all who contributed to the progress towards the Millennium Development Goals (MDGs). When committed people come together toward common goals, even ones as challenging as the eradication of poverty and illness on a global scale, much can be achieved.

In the post-2015 MDGs, I strongly recommend that global health, in particular diabetes, be given primacy, as “our health is our greatest wealth” and diabetes is already a global burden. The MDGs included a focus on communicable diseases, particularly HIV/AIDS, and substantial achievements resulted. Non-communicable diseases (NCDs), such as diabetes, already threaten human health and global development. NCDs account for almost two-thirds of deaths globally, with 80% of these deaths, often in young and middle-aged people, being in low- and middle-income countries.1

Someone dies of diabetes every 6 seconds. In 2013, there were 382 million people with diabetes globally, most in low- to middle-income countries, and this figure is predicted to rise to over 592 million within 25 years.2 Most of this is preventable, but will require united global action. As you know, in 2006 the UN formally recognised the burden and importance of diabetes by the unanimous passing of Resolution 61/225.3 This resolution affirms diabetes as a major global health threat and encourages the development of sustainable national policies for diabetes prevention and care. Diabetes-related indicators are already being quantified, so we can monitor progress — an important factor in setting and reaching goals.

The personal and economic costs of diabetes are enormous. Diabetes is a chronic, usually incurable condition characterised by an absolute or relative lack of insulin, high blood glucose levels, abnormal blood lipid levels, and blood vessel damage that can affect every organ system. People of all ages, including babies in their mothers’ wombs, may be affected by diabetes. People of all ethnicities, religions, occupations, geographies and socioeconomic groups can develop it. Diabetes is a common cause of vision loss, kidney failure, heart disease, amputations, stroke, disability and premature death. As well as each person with diabetes, the disease affects their family, friends, colleagues and community, including the health care system, and the national and global economy.

On a daily basis, I see the negative impact that diabetes can have. I also know how much can be done to prevent it and to ease and save the lives of those with the condition. Sadly, I also know that resources are not equitably distributed. In 1939, as a child in a rural Australian community, my mother developed type 1 diabetes. With then recently available insulin injections and increasingly sophisticated medical care, she married, raised children, worked and volunteered, and lived until 91 years of age. In Australia, the European Union and the United States, I have worked with thousands of people with diabetes who live long and full lives.

Yet, from a global perspective, almost a century after Banting and Best’s Nobel Prize-winning discovery of insulin, the commonest cause of death in a child with diabetes is lack of access to insulin.4 In low socioeconomic countries, I know of children who have died of diabetes within weeks of diagnosis because of lack of insulin, and of people who have developed blindness or kidney failure or required amputations due to lack of affordable drugs and health care. In disadvantaged regions, many people with diabetes are outcasts, deemed not marriageable, trainable or employable. Medical colleagues in disadvantaged countries tell me of people blinded by diabetes who have chosen to discontinue life-saving insulin so as to no longer burden their families. I have seen people hours from death from diabetes-related kidney failure, as no treatments were available in their country.

Through my work with two internationally active diabetes aid organisations, Insulin for Life (http://www.insulinforlife.org) and the International Diabetes Federation’s Life for a Child program (http://www.idf.org/lifeforachild), I have seen that many people working together have already substantially improved outcomes for people with diabetes in over 45 countries. We have found ways around many obstacles, including distance, language barriers, cultural challenges, need for health education, insufficient funding, lack of equipment and medication, and supply chain problems. Many important milestones have been met, but much remains to be done. As shown by our diabetes aid endeavours, and by the progress towards the MDGs, “the impossible can always be broken down into possibilities” (author unknown) and can be achieved.

Unfortunately, the global burden of diabetes is likely to increase unless we act now. With affluence, urbanisation and modernisation, sedentary lifestyles and obesity become more prevalent and, with these, diabetes incidence increases. Type 2 diabetes, traditionally regarded as a condition of middle-aged and older people, is now not uncommon in children, particularly in those from high-risk ethnic groups such as Indigenous Australians, Indians, Native Americans, Asians and people from the Middle East.

Prediabetes, a condition in which blood glucose levels are intermediate between normal and diabetes, is a major risk factor for type 2 diabetes, gestational diabetes and cardiovascular disease. It is also common and increasing. Medical research has shown that the risk of prediabetes and type 2 diabetes can be substantially reduced. Lifestyle choices related to a healthy diet, weight and physical activity are effective and low-cost. Such knowledge can be included in primary education and efforts to improve maternal health, as were the MDG goals. For people diagnosed with diabetes, being a healthy weight, not smoking, self-providing foot care and receiving good diabetes care can greatly reduce diabetes complications and costs.

Malnourishment and gestational diabetes can adversely affect the health of the mother and of her offspring, even into adulthood, with increased risk of type 2 diabetes and cardiovascular disease. Diabetes, health, nutrition, agriculture, urban design, the environment, the economy and politics are all interconnected. Empowering women, better education, clean accessible water, food production and nutrition are well known to improve the health and economy of communities. Improving maternal health will reduce the risk of diabetes and cardiovascular disease in future generations. Improving diabetes care will reduce morbidity, health care costs and premature death. Lack of conflict, work opportunities, good urban design and stable governments with enlightened health policy will facilitate better health, including diabetes prevention and care. Diabetes may be regarded as a “canary in the coal mine”, an indicator of many adverse global, local and individual factors, and can be used as a marker of the success of worthy endeavours that are likely to feature in the post-2015 MDGs.

A world with less diabetes and more equitable access to health care is a major part of “the world I want”. There are many national and international organisations, including the International Diabetes Federation, Insulin for Life, national diabetes associations, and many community groups, health care professionals and individuals who are ready to help improve global health by reducing the burden of diabetes. Please do all you can to include health and diabetes as a post-2015 MDG. Much is at stake. Much needs to be done, yet there are many prepared to help.

Sincerely,

Alicia Jenkins

Treatment for gender dysphoria in children: the new legal, ethical and clinical landscape

Gender dysphoria is a serious condition in which a child’s subjectively felt identity and gender are not congruent with her or his biological sex, causing clinically significant distress or impairment in social functioning or other important areas of functioning. Over the past 10 years, the Family Court of Australia has received an increasing number of applications seeking authorisation for the commencement of hormone therapy to treat children diagnosed with gender dysphoria.1–11

Treatment of children with gender dysphoria is given in two stages. Stage 1 treatment involves the provision of puberty blocking medication, and stage 2 comprises cross-sex hormone treatment. Until very recently, courts considered both stages of treatment together and regarded them at law as a form of special medical procedure, which can only be lawfully performed with court approval. In a significant recent development, courts have drawn a distinction between the two stages of treatment, permitting parents to consent to stage 1 treatment. In addition, it has been held that a child who is determined by a court to be Gillick competent can consent to stage 2 treatment. A Gillick-competent child is one who is found to possess sufficient understanding and intelligence to enable her or him to understand fully what is proposed.12 Medical practitioners working in this field require an understanding of these principles, so that they know when and why they must obtain court approval before conducting treatment.

In this article, we outline the nature of gender dysphoria and its treatment, explain the legal principles regarding special medical procedures, and analyse the recent legal developments concerning treatment for gender dysphoria. These developments make substantial changes to the previous legal position about who can consent to both stages of treatment for gender dysphoria, and have important ethical, clinical and practical implications for medical practitioners in this field.

Gender dysphoria in children and treatment for the condition

A number of changes in the definition of the condition of gender dysphoria, previously generally referred to as gender identity disorder, have been made in the most recent version of the Diagnostic and statistical manual of mental disorders.13,14 According to the updated definition, gender dysphoria is a condition which lasts for at least 6 months. A child must feel, and must verbalise, a strong desire to be of the other gender.14 In diagnostic terms, there is a strong, clear and persistent difference between the individual’s expressed and or experienced gender and the gender that others would assign her or him. Due to the mismatch between biological sex and perceived identity, those with gender dysphoria may experience profound psychological and physical tensions, and may have difficulties with socialisation. Consequently, it is common for those with gender dysphoria to have psychological symptoms including anxiety and depression, to self-harm, and to have suicidal ideation.15 The condition is not characterised by genetic, anatomical or hormonal abnormalities.16 When gender dysphoria intensifies with the onset of puberty, it will seldom subside.17

Treatment for gender dysphoria involves two stages of hormonal therapy, accompanied by psychological treatment that commences well in advance.18 Stage 1 of treatment involves administration of hormones such as gonadotropin-releasing hormone analogues, to prevent the onset of puberty in the child’s biological sex, and has been administered to children as young as 10 years old. Stage 1 treatment is reversible, as puberty in the child’s biological sex will continue if the treatment is stopped. The second stage of treatment is administered when the child is slightly older — around the age of 16 years. Stage 2 treatment involves, for example, the administration of oestrogen or testosterone for the purpose of encouraging the development of physical characteristics in the sex with which the child psychologically identifies. The effects of stage 2 treatment are more serious than the first and are considered to be irreversible.

Subsequently, surgery for gender reassignment can occur, if required, usually once the individual is an adult (surgical intervention that is contemplated before a child reaches 18 years of age would require additional court approval). Once diagnosed, early treatment for gender dysphoria appears to optimise psychological and social development, as well as subsequent modifications to the child’s physical appearance.18

Legal principles relevant to consent for treatment of gender dysphoria in children

Consent and special medical procedures

A child’s parents generally have power to consent to their child’s medical treatment. Under s 61C of the Family Law Act 1975 (Cwlth), each parent of a child aged under 18 years has parental responsibility for the child. Parental responsibility is defined in s 61B to include “all the duties, powers, responsibilities and authority which, by law, parents have in relation to children”, and this includes the right to consent to the child’s medical treatment in most cases (Box 1). This right must be exercised in accordance with a child’s best interests, and s 60CC outlines the factors that a court will consider when determining these.

This general parental power has limits. Notably, in the landmark decision of Marion’s case,19 the High Court of Australia referred to key principles to explain why some medical procedures fall outside the scope of parental consent, and instead require court approval. The High Court held that the parents of an intellectually disabled girl were unable to consent to a non-therapeutic sterilisation procedure. The non-therapeutic nature of the treatment was emphasised as a reason for requiring court authorisation, together with the procedure being considered to be major, invasive and irreversible (Box 1). Court approval was seen as a necessary safeguard.22

In special medical procedures, authorisation can be granted by the Supreme Court in its parens patriae jurisdiction, or by the Family Court under the Family Law Act. Section 67ZC provides the Family Court with the authority to make orders relating to the welfare of children, which includes special medical procedures. The Family Law Rules 2004 complement s 67ZC. In particular, rule 4.09 sets out the process for providing evidence to satisfy the court that the medical procedure is in the child’s best interests. The factors set out in the Family Law Rules closely follow the list of matters articulated by Nicholson CJ in Re Marion (No 2) (1994) FLC 92-448.

Authorisation for medical treatment: who can consent, to what, and why

In 2004, the Family Court in Re Alex determined that treatment for childhood gender identity disorder (as the condition was then described) was non-therapeutic and fell outside the boundaries of parental consent; it was a special medical procedure requiring court authorisation.1

Since 2004, an increasing number of applications have been made to the Family Court concerning treatment for gender dysphoria.2–11 This indicates not only the relevance of the issue to patients, clinicians and the community, but it may also suggest a level of unmet clinical need. In a series of recent decisions, the Family Court has adopted a different approach to Re Alex in classifying treatment for gender dysphoria as special. This has reshaped the ethical, clinical and practical basis for making decisions regarding stage 1 treatment. It has also resulted in a significant change to the basis for stage 2 treatment. The key developments are as follows.

In 2013 in Re Lucy,8 it was held that treatment for gender dysphoria is therapeutic treatment because it is administered primarily to ameliorate a psychiatric disorder. The court also held that parents are lawfully permitted to consent to stage 1 treatment, as it is reversible. The same conclusion was reached several weeks later in the case of Re Sam and Terry,9 which reiterated that stage 1 treatment carried only a low risk of error from misdiagnosis and did not present grave consequences. However, in both decisions it was held that stage 2 treatment requires court authorisation because of its irreversible effects and the significant risk of making a wrong decision about a child’s present or future capacity to consent. The consequences of stage 2 treatment were noted to be particularly grave, as physical changes would result from the hormone therapy in line with the change in gender. The court concluded that the correct approach to determining whether court authorisation is required involves not only classifying the treatment as therapeutic but also assessing its potential consequences in the terms described by the High Court in Marion’s case (Box 1).

After these two decisions by single judges, the Full Court of the Family Court heard an appeal in Re Jamie10 in 2013 concerning parental consent to treatment for gender dysphoria. This decision is important as it has higher precedential value than the single judge decisions, binding future decisions by lower courts. The Full Court affirmed the position adopted in Re Lucy and Re Sam and Terry, holding that parental power to consent to the child’s medical treatment extends to stage 1 treatment for gender dysphoria, while court authorisation is required for stage 2 treatment.10 The court’s decision centred on the reversibility of stage 1 treatment and the irreversibility of stage 2 and was therefore clearly underpinned by the factors outlined by the High Court in Marion’s case (Box 1). The decision of the Full Court in Re Jamie was followed in November 2013 in Re Shane.11

Parents can therefore lawfully consent to a child’s stage 1 treatment for gender dysphoria. This is consistent with existing legal principles concerning parental authority and promotes autonomy and beneficence for the child. It is also logistically superior for clinicians, parents and children, rather than having to seek court authority with attendant cost, delay and inconvenience. However, stage 2 treatment for gender dysphoria must still be approved by a court, despite being regarded as therapeutic.10 On one view, this is an unnecessary incursion into parental power, which normally extends to therapeutic treatments. On another view, there is value in the court retaining its power to authorise stage 2 treatment as a procedural safeguard, because of the complexity of this condition and the relevance of the principles articulated in Marion’s case (Box 2).

Decision making by mature minors in relation to special medical procedures

There is a further important aspect of the decision in Re Jamie. The principle of Gillick competence (approved by the High Court in Marion’s case) was considered by the Full Court of the Family Court in Re Jamie to determine whether a Gillick-competent minor could consent to stage 2 treatment and, if so, by what mechanism (which may also extend to circumstances where legislation provides the minor with a right to make the decision for him or herself, such as in South Australia’s Consent to Medical Treatment and Palliative Care Act 1995). The Full Court determined that a Gillick–competent minor is able to provide consent to stage 2 treatment. However, Bryant CJ imposed the requirement that the parties make an application to the court for determination of whether the child is Gillick competent.

This is a significant change in principle, enabling children deemed competent by the court, to consent to this type of medical treatment. Recognition of the mature minor’s right to consent is a sound development, sitting squarely with the fundamental legal principle in Gillick12 and being ethically consistent with promoting the autonomous wishes of a full moral agent. Additionally, it reposes the decision about the child’s competence in the court, whereas medical practitioners are ordinarily responsible for determining the minor’s competency. This aspect of the decision was also confirmed in the subsequent case of Re Shane.

Conclusion

The recent case law developments concerning treatment for gender dysphoria confirm that parents are lawfully able to consent to the first stage of hormonal treatment on behalf of their children, but that court involvement is required as part of the consent process for stage 2 treatment. In addition, when a minor possesses a sufficient understanding of the nature and consequences of stage 2 treatment, she or he has legal capacity to consent to that aspect of treatment, but the finding of competency must be made by a court.

The growth in applications for approval to treat gender dysphoria suggests a level of unmet need — a phenomenon also apparent in the United States.23 The new legal landscape in Australia for treatment for gender dysphoria is therefore of current, and growing, importance for practitioners and individuals with this condition. Increased awareness of treatment possibilities, the benefits of early intervention, and of the legal framework, would be beneficial.

1 Established principles relevant to determining whether a form of treatment is regarded as a special medical procedure

In Marion’s case,19 it was held that court authorisation must be obtained in circumstances where a procedure performed on a minor is regarded as non-therapeutic, and where:
- there is a significant risk of making the wrong decision without court involvement;
- the procedure in question has particularly grave consequences;
- the procedure is irreversible and invasive; and
- there is potential for conflict in terms of the interests of the parties involved (eg, parents, clinicians and patient).
Case law has established that routine or necessary medical care concerning children falls within the ambit of parental decision making when the treatment is intended to serve a therapeutic purpose.5 This is so even in cases where grave consequences may flow from the provision of such medical care20 or when the medical treatment is regarded as experimental.21

2 Do recent cases concerning treatment for gender dysphoria change established principles relating to special medical treatments?

Previous Family Court decisions have allowed parents to consent to serious, invasive and irreversible medical procedures where there is a potential therapeutic benefit (Box 1). Recent jurisprudence concerning treatment for gender dysphoria has determined that hormonal treatment for the condition is therapeutic; a conclusion that is presumably applicable to both stages of treatment. However, court approval is required for stage 2 treatment because of its irreversible and serious consequences.
The approach adopted in recent cases appears to depart from the principles set out in Marion’s case,19 which regard therapeutic interventions as falling within the realms of parental consent (Box 1). However, based on the reasoning in recent cases,8–11 classification of a specific treatment as special does not appear to rest solely on the therapeutic–non-therapeutic distinction, but on an assessment of all of the factors outlined in Marion’s case. Where there is concern about the nature and effect of a particular treatment, the law may nevertheless impose a requirement to obtain court approval, even where the treatment is regarded as therapeutic. Australian courts may later develop new categories of special medical procedures or interventions, which might include other types of therapeutic treatment. However, at present there are a number of established categories of special medical procedures, and parental consent alone is not sufficient for these different categories of treatment.

Preventing type 2 diabetes: scaling up to create a prevention system

Every day an estimated 280 Australians develop type 2 diabetes.1 By 2023, type 2 diabetes is predicted to become the number one specific cause of burden of disease in Australia.2 Policies and programs to support the prevention of type 2 diabetes need to be scaled up urgently if Australia hopes to limit or reduce the enormous negative impact this serious and complex condition has on individuals, families, employers, businesses and governments. An estimated 1.5 million Australians have type 2 diabetes, and this is predicted to increase to 3.3 million by 2031.3 Prediabetes, which includes impaired glucose tolerance and impaired fasting glucose, is estimated to affect 2 million Australians, putting them at high risk of developing type 2 diabetes.4

Type 2 diabetes is a serious and progressive condition. If not identified and well managed it can lead to many complications, including macrovascular complications (heart attacks, strokes, amputations); microvascular complications (eye, kidney and nerve damage); and mental health problems (depression, anxiety and distress). Importantly, the macrovascular complications may begin early in the prediabetes stage. In Australia, diabetes accounts for one-third of all preventable hospital admissions coupled with longer than average stays. The economic cost is increasing dramatically and is estimated at $14.6 billion per year.5

There can be no doubt that this is a serious epidemic that will have a large negative impact on health and productivity. However, despite strong evidence and many powerful tools to help prevent the future growth of type 2 diabetes, efforts to establish a sustained and effective prevention system in Australia have been patchy, project oriented and subject to frequent funding disruption due to government change and short-term thinking.

The International Diabetes Federation consensus statement6 on prevention of type 2 diabetes published in 2007 clearly identified two key target activities for prevention to be undertaken simultaneously — a high-risk population approach combined with an entire population approach. However, few countries have implemented this combined approach on a scale large enough to create a prevention system that can work effectively.

In Australia, the state of Victoria is the most advanced, with the combination of a statewide, high-risk population, diabetes prevention program (Life! program) combined with an entire population and systems approach across 12 local government areas (Healthy Together Victoria), as well as the LiveLighter campaign to encourage Victorians to live healthier lifestyles.

So what works and how do we scale up to create effective prevention?

High-risk population prevention

Up to 58% of type 2 diabetes developing from the prediabetes population can be prevented through intensive, structured lifestyle interventions.7,8 There is strong evidence from randomised controlled trials (RCTs) around the world to support this approach. Furthermore, cost-effectiveness studies and community-based evaluations conclude that these interventions are able to be implemented, and are effective and cost-effective.9,10

The effect of lifestyle intervention has an impact lasting up to 20 years after the active intervention.7 The drug metformin can also prevent type 2 diabetes in individuals at high risk.11 While it is not as effective as a lifestyle modification program, metformin is an appropriate and effective intervention for some people.12 Lifestyle intervention alone is less effective in those with severe obesity, whereas bariatric surgery13 has been shown to be effective.

Translational studies including the Greater Green Triangle Diabetes Prevention Project,14 Sydney Diabetes Prevention Program (SDPP),15 and the large-scale implementation of the Victorian Life! program16,17 have built a strong case that the RCT evidence can be translated into community-based programs. These programs have included face-to-face group interventions and individual telephone interventions, both with 5–6 structured sessions and trained facilitators. Maintaining the fidelity of these lifestyle interventions through accreditation or certification is important.

The questionnaire-based Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK) has made screening to identify and recruit individuals at high risk feasible and effective at a community level. The Workhealth program in Victoria (no longer funded) used the AUSDRISK tool for over 500 000 worker health checks, and around 23% of workers were found to be at high risk.18 Lamentably, most were not systematically referred for any follow-up or prevention intervention. The Life! program has seen over 59 000 people with prediabetes referred to lifestyle-based prevention courses. This has been achieved by establishing multiple recruitment methods that include: integrated social marketing techniques using mass media and online media; effective risk messaging about the seriousness and personal relevance; workplace and community promotions; and a call-to-action response system with a telephone response line similar to Quitline.

A framework for scaling up high-risk population prevention in Australia should be based on international experience (United States Centers for Disease Control National Diabetes Prevention Program) and local implementation models (SDPP and Victorian Life! program). Importantly, a national approach should reflect a national commitment and integrate national and state or territory government funding with private health insurance funding, employer funding (for workplace-based elements) and individual contribution. This partnership of funders has been established in the US program.

A national type 2 diabetes high-risk prevention program should include six key strategies:

Marketing risk messages with a clear call to action as well as a telephone response and support line;
Systematically identifying high-risk individuals in community settings, online and in primary care;
Intervention based on the most appropriate pathway for prevention;
- Intensive lifestyle programs (face-to-face groups, telephone, webinar groups, commercial programs)
- Medication (metformin)
- Surgery (for those with severe obesity)
Building a prevention workforce;
Continuous improvement, evaluation and innovation;
National coordination and collaboration.

Entire population approach

Driving the development and increasing prevalence of type 2 diabetes is the increase in modifiable risk factors, particularly unhealthy diets, physical inactivity, weight gain and overweight and obesity. There is a seven times greater risk of diabetes among obese people compared with those of healthy weight, with a threefold increase in risk among overweight people.19 The modifiable risk factors for type 2 diabetes are common risk factors for cardiovascular disease, kidney disease and many cancers.

Entire population prevention action must be multi-faceted and include legislation or regulation, fiscal incentives, social marketing, health promotion and the provision of public health services.20 It should target policy, structural and environmental factors to reduce the proportion of people shifting from healthy weight to overweight to obese, and low risk to high risk.21

The United Kingdom Foresight report22 provided a clear framework for national action. The experts and evidence pointed to an environments, systems and behaviour approach that reflects the following elements:

Food environment (production and formulation, labelling and consumption, marketing)
Activity environment (built environment, transport)
Societal influences (attitudes, education, cultures)
Individual influences (behaviour, choices, families)
Biological influences (genetics and epigenetics)

National Preventative Health Taskforce report

The evidence has also been reviewed in Australia and an excellent evidence-based framework for national action was proposed in the National Preventative Health Taskforce report.23 However, as described below, implementation by either national or state or territory governments has been scarce.

Driving change in the food supply to increase the availability and demand for healthier food products and decrease the availability and demand for unhealthy food products. There has been some work on improving food labelling to support and empower consumers to make healthier choices. Agreement has been reached around a new interpretive front-of-pack healthy star labelling system that aims to empower people to make healthier choices. Adoption of the system will be supported by a social marketing campaign, and its success will be enhanced if use is widespread. Agreement has also been reached that high-level health claims will not be able to be used on foods that are determined to be unhealthy overall. Next steps could include the development of a nutrition policy to set out strategies for improving diets. Much more needs to be done towards achieving reformulation of processed foods to reduce added sugar, salt and fat.

Reduce the exposure of children and others to the marketing and promotion of unhealthy foods. Australia relies to a large extent on a self-regulatory system; however, there is little evidence that this has significantly reduced the power and volume of marketing to which children are exposed. Increasingly, digital and social media, which are harder for parents to monitor, are being integrated into marketing campaigns. A single agreed definition of unhealthy foods that cannot be marketed to children has not been developed. The excessive marketing and consumption of sugar-sweetened beverages, which especially affects children and young people, and the continuing expansion of this category beyond traditional soft drinks are a particular focus of national and international public health advocacy.

Drive environmental changes throughout the community to increase levels of physical activity and reduce sedentary behaviours. There has been little policy or systematic effort to drive this, and high-level leadership and development of a national framework for active living is still needed.

Embed physical activity and healthy eating in everyday life, including workplaces, school and communities. Some jurisdictions have established a systematic approach; for example, South Australia has established the OPAL (Obesity Prevention and Lifestyle) program and Victoria the Healthy Together Victoria initiative, which target a range of settings.

Encourage people to improve physical activity and healthy eating through social marketing. Some efforts commenced at the national level with the Measure Up and Swap It, Don’t Stop It campaigns, but these are no longer funded. A number of jurisdictions have rolled out the LiveLighter campaign in order to target diets and sedentary behaviour through small, sustainable changes.

Strengthen skill and support primary health care and the public health workforce to support people making healthy choices. Since this recommendation was made, in 2013 the National Health and Medical Research Council developed clinical practice guidelines24 to support the management of overweight and obesity by health professionals.

The entire population approach also requires a focus on low-income communities and cultural and linguistic diversity.

Two population groups requiring special consideration

Indigenous Australians are three times more likely than non-Indigenous Australians to have type 2 diabetes and more likely to develop complications.25 Prevention efforts needed for Indigenous Australians require urgent attention but were beyond the scope of our review.

Women who develop gestational diabetes (about 5%–10% of pregnancies26) have an increased future risk of developing type 2 diabetes, and their children also have an increased health risk. Increasing evidence for the importance of in utero factors to the risk of type 2 diabetes in adult life owing to epigenetic mechanisms27 suggests that further examination of diabetes prevention strategies specific to maternal and child health is also required.

Conclusions

For decades Australia has led the way in large-scale approaches in some key areas of prevention. A prominent example is the international leadership shown in tobacco control through the combination of social marketing, evidence-based interventions, and regulatory and policy initiatives, together with monitoring and evaluation.

It is over 10 years since the first international RCTs reported that we can prevent the development of type 2 diabetes in the high-risk population (with prediabetes). It is over 5 years since the National Preventative Health Taskforce report. Yet there has been little national action.

In 2013, Diabetes Australia called for a new national diabetes strategy with prevention as the focus. It also pointed to the need for sustained national action for prevention of type 2 diabetes through a combined approach of a national diabetes prevention program (targeting the high-risk population) concurrent with serious national, societal change to create healthy food and activity environments and support healthy choices by making them affordable and accessible.

It is encouraging that the Australian Government is proceeding with its commitment to develop a new national diabetes strategy and has formed a national advisory group and established a timeline for completion in early 2015.

Short-term pilot projects will not be enough. Small-scale programs will not be enough. Prevention of type 2 diabetes is proven, possible and powerful — but to achieve this we need to scale up our national effort and create a sustained prevention system for the next decade and beyond.

A new blood glucose management algorithm for type 2 diabetes: a position statement of the Australian Diabetes Society

Large randomised controlled trials (RCTs) have demonstrated that controlling blood glucose level (BGL) in people with type 2 diabetes (T2D) is important for preventing microvascular complications.1,2 Lowering BGL may also reduce myocardial infarction, though not necessarily stroke or all-cause mortality.3

In 2009, the Australian Diabetes Society (ADS) published a position statement recommending individualisation of glycaemic targets.4 The general glycated haemoglobin (HbA1c) target for most people with T2D is ≤ 53 mmol/mol (7%), however:

in people without known cardiovascular disease, a long duration of diabetes, severe hypoglycaemia or another contraindication,4 the target is ≤ 48 mmol/mol (6.5%);
in people with reduced hypoglycaemia awareness or major comorbidities, the target may increase to ≤ 64 mmol/mol (8%);
in people with limited life expectancy, aim for symptom control; and
in women planning a pregnancy, aim for the tightest achievable control without severe hypoglycaemia; preferably ≤ 42 mmol/mol (6.0%).

Despite the increasing range of therapies available, achieving glycaemic targets can be difficult. To assist with selecting glucose-lowering pharmacotherapy for people with T2D, the ADS developed this position statement (Box 1). Its aim is to describe the place of the various drug classes in the glucose-lowering therapeutic algorithm (Box 2), drug options in the setting of renal impairment (Appendix 1) or hepatic impairment, the Pharmaceutical Benefits Scheme (PBS) prescribing restrictions for obtaining subsidised products in Australia (Appendix 2), and the current PBS-subsidised and unsubsidised costs (Appendix 3). A more detailed version of the statement that will be updated annually is available on the ADS website (http://www.diabetessociety.com.au).

Drugs

Metformin

Metformin decreases hepatic glucose output, lowers fasting glucose levels and is generally weight-neutral. It decreases HbA1c level by up to 15–22 mmol/mol.5 Gastrointestinal side effects are common. Metformin should be started at low doses and titrated. People with gastrointestinal side effects should be offered one of the slow-release formulations, which cost about 40% more per dose (Appendix 3). Metformin is contraindicated for patients who have severe renal, hepatic or cardiac failure (Appendix 1).

Sulfonylureas

Sulfonylureas have favourable long-term safety and outcome data and are cheap and effective, with decreases in HbA1c level of up to 7–16 mmol/mol when combined with metformin.6–8 They trigger insulin release in a glucose-independent manner. Their main side effects are hypoglycaemia and weight gain. The risk of hypoglycaemia is highest with sulfonylureas with long half-lives and renally excreted active metabolites, such as glibenclamide.7

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors decrease inactivation of glucagon-like peptide-1 (GLP-1), thereby increasing its availability. GLP-1 improves β-cell function and insulin secretion and slows gastric emptying. A meta-analysis reported decreases in HbA1c level of 7–8 mmol/mol, except for vildagliptin (11 mmol/mol).9 Common side effects include gastrointestinal disturbance and nasopharyngitis, which often subside over 10–14 days. Rash is a rare but potentially serious side effect. Postmarketing surveillance has reported an association between DPP-4 inhibitors and pancreatitis. People with diabetes have an increased background risk of pancreatitis and it remains unclear whether DPP-4 inhibitors augment this risk.10

At the time of writing, there were five DPP-4 inhibitors available in Australia that were approved for PBS-subsidised use with either metformin or a sulfonylurea but not both. Triple therapy and monotherapy are not PBS-subsidised; nor is dual therapy with insulin or sodium–glucose cotransporter 2 (SGLT2) inhibitors (Appendix 2).

Thiazolidinediones

Thiazolidinediones (TZDs) are transcription factor peroxisome proliferator-activated receptor PPARγ agonists, which lower BGL through insulin sensitisation. Side effects include weight gain, fluid retention, heart failure and an increased risk of non-axial fractures in women.11 Pioglitazone is associated with an increased risk of bladder cancer. In a limited number of people, TZDs combine well with metformin and sulfonylureas.

Acarbose

Acarbose is an α-glucosidase inhibitor that slows intestinal carbohydrate absorption and reduces postprandial BGL. Its main side effects are bloating and flatulence, which lead to discontinuation in up to 25% of people. If tolerated, it can be effective, particularly when combined with metformin.

Sodium–glucose cotransporter 2 inhibitors

Two SGLT2 inhibitors (canagliflozin and dapagliflozin) were listed on the PBS in 2013. These drugs inhibit a renal sodium–glucose cotransporter to produce urinary glucose loss and decrease BGL. Urinary glucose loss is the mechanism for the weight loss associated with these drugs. Side effects include dehydration, dizziness and increased risk of genitourinary infections. The first two can be prevented with adequate fluid intake, and the latter diminished with meticulous hygiene. Use with loop diuretics should be avoided. SGLT2 inhibitors have diminished efficacy in people with renal impairment. PBS reimbursement requires use with metformin or a sulfonylurea but not both.

Glucagon-like peptide-1 receptor agonists

GLP-1 receptor agonists (GLP-1RAs) are administered by subcutaneous injection. They stimulate β-cell insulin release and slow gastric emptying, which contributes to weight loss but may cause nausea and vomiting. Effects on BGL are slightly superior to those of oral agents. An increased risk of pancreatitis (about 50% above a baseline of one to two episodes per 1000 patient-years in T2D) has been reported.10 These agents should be avoided in patients with a history of pancreatitis or pancreatic malignancy.

Insulin

Insulin has extensive effects on metabolism and is generally necessary for cellular glucose uptake. Short-, intermediate- and long-acting insulins are available, as well as premixed preparations. The major side effects are hypoglycaemia and weight gain. In many people, insulin is initiated only after an unnecessarily prolonged period of hyperglycaemia. Insulin is the most potent glucose-lowering agent. With adequate dosage and dietary adherence, it can almost always achieve target BGL. Insulin should be considered early if BGL is very high.

Treatment algorithm

The algorithm in Box 2 summarises the available clinical evidence for pharmacotherapeutic strategies to achieve target HbA1c levels in people with T2D. At each step, there are proven and effective approaches. Indications that may be PBS-subsidised are highlighted in the algorithm by a red border. It should be noted that use of a medication outside PBS-approved indications requires that it be purchased through private prescription. The current cost of these medications is given in Appendix 3. The algorithm is structured with a usual approach to treatment initiation, and intensification and alternative approaches at each stage.

First-line treatment

First-line treatment is appropriate diet and exercise. This should be reinforced at every stage. Both weight loss and prevention of weight gain are important.

When lifestyle measures alone no longer achieve desired targets, metformin should be added if there is no contraindication. If metformin is not tolerated or is contraindicated, a sulfonylurea should be used. Other medications are also available but, apart from acarbose and insulin, are not PBS-subsidised as initial treatment.

Second-line treatment

If glucose control is not achieved with a single agent, there are many second-line treatment options. Sulfonylureas are good second-line agents, achieving similar decreases in HbA1c level as other second-line oral agents, for about 25% of the daily cost (Appendix 3). For patients who experience problematic hypoglycaemia, weight gain or other side effects, an alternative agent should be considered. The most common alternative second-line agent is a DPP-4 inhibitor. These are available in combination tablets with metformin, which may improve compliance.

SGLT2 inhibitors are another option and are PBS-subsidised with either metformin or a sulfonylurea. Addition of acarbose is another second-line alternative. GLP-1RAs can also be used with metformin or a sulfonylurea as second-line therapy. As always, insulin is an option that should be considered, especially if the HbA1c level is > 75 mmol/mol (9%) after use of an oral agent, as the likelihood of achieving good glycaemic control with oral agents alone becomes lower.

Third-line treatment

After failure of dual oral therapy, treatment options become more complex. Metformin should be continued for its insulin-sensitising effects unless contraindications develop. Ineffective therapies should be ceased and substituted with a different medication. Comparative evidence from RCTs to inform prescribing is scarce. The options are triple oral therapy or the addition of a GLP-1RA or insulin.

Triple oral therapy

Metformin, sulfonylurea and DPP-4 inhibitor: Limited RCTs examining the addition of sitagliptin12 and linagliptin13 to metformin–sulfonylurea have demonstrated reductions in HbA1c level of 7–10 mmol/mol versus baseline and placebo, respectively,12,13 but with small increases in weight that are significant in some studies. With triple therapy, the advantage of lower risk of hypoglycaemia with DPP-4 inhibitors appears to be lost.12,13 It is reasonable to escalate from metformin and a sulfonylurea or metformin and a DPP-4 inhibitor to triple therapy with all three. However, this combination is not currently PBS-subsidised.

Metformin, sulfonylurea and thiazolidinedione: Trials of triple therapy with metformin, a sulfonylurea and a TZD show HbA1c lowering of about 11 mmol/mol, but with an increase in weight of 3–5 kg and increased hypoglycaemia.14 Pre-emptive decreases in the sulfonylurea dose should be considered. Pioglitazone is PBS-subsidised for triple oral therapy with metformin and a sulfonylurea.

Metformin, sulfonylurea and SGLT2 inhibitor: Limited trials indicate that triple therapy with metformin, a sulfonylurea and an SGLT2 inhibitor may be an effective combination, but this is not PBS-subsidised. A 52-week RCT comparing the addition of canagliflozin or a DPP-4 inhibitor to metformin–sulfonylurea found that HbA1c level decreased by 11 mmol/mol with the SGLT2 inhibitor versus 7 mmol/mol with the DPP-4 inhibitor. There were greater reductions in weight and blood pressure with the SGLT2 inhibitor, and no difference between groups in hypoglycaemia.12

Metformin, sulfonylurea and acarbose: Acarbose is PBS-approved for triple therapy with metformin and a sulfonylurea. One double-blinded crossover trial of this combination reported a 1.9% decrease in weight and a 15 mmol/mol decrease in HbA1c level with the addition of acarbose.15 Acarbose in other dual-therapy combination studies more commonly decreases HbA1c level by about 6–9 mmol/mol.16

Injected agents

Metformin, sulfonylurea and GLP–1RA: Triple-therapy studies of metformin, a sulfonylurea and a GLP-1RA are few but show reductions in HbA1c level of about 11 mmol/mol, with a little weight loss.17–19 Hypoglycaemia is common but may be attenuated by reducing sulfonylurea dosage. The available GLP-1RAs have approval from the Therapeutic Goods Administration for use with metformin and sulfonylurea, but only exenatide is PBS-subsidised.

Insulin: Insulin can be used at any stage in the treatment cascade. It is commonly initiated as once-daily basal insulin added to oral drugs, particularly metformin. Alternatively, it can be initiated as once- or twice-daily premixed insulin, again usually in combination with metformin. Insulin therapy can be intensified by combining long-acting insulin with multiple injections of short-acting insulin.

Recent studies have explored combining insulin with newer therapies, including DPP-4 inhibitors, SGLT2 inhibitors and GLP-1RAs, with good effect. These combinations are not PBS-subsidised.

Glucose-lowering therapy in people with renal or hepatic impairment

In the setting of renal dysfunction, pharmacokinetic changes develop that may increase the risk of hypoglycaemia and side effects. Changes are most evident with chronic kidney disease stages 4 and 5, and must be considered when deciding on therapy (Appendix 1). Drug doses may need reduction or cessation. Among the oral agents, glipizide and gliclazide can be used at a reduced dose up to stage 4, as can sitagliptin. Linagliptin is acceptable without dose adjustment, even with dialysis.

Liver disease may also affect pharmacokinetics. Most drugs do not need discontinuation in the setting of mild–moderate hepatic impairment. Drug half-lives, doses, interactions and risks of drug-specific adverse effects should be considered. There is little experience with use of the newer drug classes in people with advanced hepatic impairment.

Glucose-lowering therapy in older people

In older people, glycaemic targets need to be moderated in light of life expectancy, cognitive impairment or frailty.4 This may mean that the glycaemic target should be symptom control only, or ≤ 64 mmol/mol (8%). Assessment of estimated glomerular filtration rate is important, as serum creatinine level is not as reliable a marker of renal function. Cardiac dysfunction is more common in older people, and severe congestive cardiac failure is a contraindication to metformin. Use of multiple drugs should prompt regular review, to minimise polypharmacy. Drugs should be used at the minimum doses needed to achieve practical and safe glycaemic targets.

Conclusions

Diabetes is a progressive condition and, as such, glycaemic targets should be reviewed at regular intervals. The importance of diet and exercise should be reinforced at each step of the therapeutic pathway.

With the range of therapies now available in Australia, there is considerable scope for individualising therapy. If the patient experiences adverse effects with one glucose-lowering agent, another should be substituted. This will often take the form of combination therapy. With diabetes education and an engaged patient, it is now possible to achieve good glycaemic control in more people with T2D.

Abbreviations

ADS	Australian Diabetes Society
BGL	Blood glucose level
DPP-4	Dipeptidyl peptidase-4
GLP-1	Glucagon-like peptide-1
GLP-1RA	GLP-1 receptor agonist
HbA1c	Glycated haemoglobin
PBS	Pharmaceutical Benefits Scheme
RCT	Randomised controlled trial
SGLT2	Sodium–glucose cotransporter 2
TZD	Thiazolidinedione

1 Position statement development process

The Australian Diabetes Society (ADS) council appointed the authors to draft the position statement, with a focus on results of recent trials of triple therapy and newer agents.

The draft statement was reviewed by the current ADS council and revised, then sent to all ADS members for comment and revision.

2 Australian management algorithm for lowering blood glucose level in people with type 2 diabetes*

HbA1c = glycated haemoglobin. UKPDS = United Kingdom Prospective Diabetes Study. DPP-4 = dipeptidyl peptidase-4. SGLT2 = sodium–glucose cotransporter 2. TZD = thiazolidinedione. GLP1-RA = glucagon-like peptide-1 receptor agonist.

* Blue boxes indicate usual therapeutic strategy; white boxes indicate alternative approaches; and red borders indicate therapies that are potentially subsidised by the Pharmaceutical Benefits Scheme. Compliance should be assessed before changing or adding new therapies, and therapies that do not improve glycaemic control should be ceased.

† Unless metformin is contraindicated or not tolerated, it is often therapeutically useful to continue it in combination with insulin in people with type 2 diabetes.

‡ Switching to another oral agent is likely to have the smallest impact on glycaemia.

§ Basal plus refers to continuing oral agents.

Diabetes prevention and care: we know what to do, so why aren’t we doing it?

Reducing the national diabetes burden

The diabetes epidemic continues unabated. Globally, 382 million people have diabetes and this is projected to increase to 592 million by 2035.1 In Australia, there are an estimated 1 million people with diabetes and another 2 million at high risk of developing diabetes.2 While the contribution of many chronic diseases to the national burden of disability is decreasing, the diabetes burden continues to increase and is predicted to become the largest contributor by 2017.3 Diabetes affects individual patients, their families and society in general, and is estimated to cost in excess of $15 billion annually.4 This burden is not shared equally, and no group is more severely affected than Australia’s Indigenous population, who have higher rates of diabetes, significant premature mortality and high rates of complications, especially cardiovascular and renal disease.

There is strong evidence that the diabetes burden can be reduced, but there is an appreciable evidence–practice gap in implementing proven clinical care programs and translating prevention studies into community-based programs. Multifactorial intervention including control of blood glucose, blood pressure and lipids can reduce the broad range of diabetes-related microvascular and macrovascular complications and premature mortality.5 Some of these effects can be achieved in the short term, whereas others take several years. The United Kingdom Prospective Diabetes Study in type 2 diabetes and the Diabetes Control and Complications Trial in type 1 diabetes showed that it took many years for the effects of improved glycaemic control to accrue in relation to reducing macrovascular complications.6,7 In addition, a number of randomised controlled studies have demonstrated that the development of type 2 diabetes can be prevented by up to 60% through lifestyle modification in high-risk individuals.8,9 These prevention benefits persist for many years; and even in people who develop diabetes, the delay in progressing to diabetes also provides benefit.10 In some individuals, medications or bariatric surgery are appropriate interventions to prevent the development of diabetes.

Australia has the fundamental infrastructure to narrow the evidence–practice gap with its national health system, the National Diabetes Services Scheme, National Health and Medical Research Council-endorsed guidelines, and an established diabetes workforce. But there are significant barriers. Australia has not had a national diabetes strategy since 2005. The general community does not appreciate the impact of diabetes and consequently fails to take it seriously. Clinical inertia in treating diabetes among health professionals and consumers is common. Reimbursed access to the full armamentarium of proven therapies is restricted and the associated prescribing rules are confusing for clinicians and consumers. At-risk individuals prepared to engage in health-promoting activity face an unfriendly and challenging environment, and the lessons of other successful public health interventions are not being applied to diabetes.

In an upcoming issue, the Journal will begin a series of articles providing an update on the diabetes scene in Australia and tackling important issues related to diabetes prevention and care. With the advent of new classes of blood glucose-lowering medications, the Australian Diabetes Society has developed an updated treatment algorithm for people with type 2 diabetes that incorporates these new therapies, provides prescribing precautions in the presence of coexisting renal and liver disease, and highlights the difference between approved and reimbursed therapies. The epidemiology and management of diabetes-related complications will also be addressed. The Australian experience with community-based diabetes prevention programs will be reviewed, as will the potential critical role of legislation and regulation. Although much of the series will highlight type 2 diabetes, one article will focus on recent advances in type 1 diabetes. As the important topic of gestational diabetes has recently received attention in the Journal,11,12 it will not be covered in the series.

Despite the many challenges, there is cause for cautious optimism. There is now a strong international commitment to act on non-communicable diseases, including diabetes. In Australia, the federal government has commissioned a new national diabetes strategy, scheduled for completion and release in mid 2015, which will provide fresh impetus to reducing the diabetes burden. Success will require a coordinated effort underpinned by an integrated model of care and regular data collection to monitor quality of care and outcomes.

The global response to diabetes: action or apathy?

Hands up everyone who thinks the United Nations is weak and ineffectual and the World Health Organization is risk-averse and unresponsive?

While both organisations were slow to arrive at their current position on diabetes and its partners in crime — cardiovascular disease, cancer and chronic respiratory diseases — recent developments indicate that those with raised hands may need to rethink. Certainly, many programs following the 1989 World Health Assembly resolution on the prevention and control of diabetes1 had little political buy-in. Nonetheless, the resolution left a legacy of WHO and International Diabetes Federation (IDF) cooperation on regional declarations that encouraged political commitment and national action on diabetes and seeded a new approach to the prevention and control of non-communicable diseases (NCDs). This and subsequent civil society action, including the 2006 UN resolution designating 14 November as World Diabetes Day,2 were instrumental in shaking political apathy and alerting the world to the threat of NCDs.

The current UN response

The global policy response to diabetes is inextricably linked with cancer, cardiovascular disease and chronic respiratory diseases and, in 2011, the UN General Assembly held a high-level meeting on NCDs. This resulted in all 193 member states signing a Political Declaration that set out policy directions and actions to mitigate the impact of NCDs and reduce their upward trend.3 At first glance, the Political Declaration appeared to be too vague and “high level” to effect tangible change. On closer examination, it is surprisingly detailed and action-oriented, requiring member states to report progress on national NCD action plans to the 2014 General Assembly. It also recognised the development challenges posed by NCDs and cited the detrimental role of unhealthy food and physical inactivity.

The cynics claimed the NCD high-level meeting and Political Declaration were just another empty gesture, but within 6 months the World Health Assembly adopted a global target of 25% reduction in premature mortality from NCDs by 2025. This was followed in 2013 by a comprehensive global monitoring framework for NCDs of nine targets and 25 indicators — including a target of 0% increase in obesity and diabetes.4 Proclaiming “what gets measured gets done”, WHO Director-General Dr Margaret Chan demonstrated the WHO’s determination to prevent and control NCDs by launching a new global action plan5 and a global coordination mechanism to oversee its implementation.

Subsequently, in July 2014, UN members returned to New York for a high-level review of progress on the 2011 Political Declaration, to maintain the momentum on NCDs at the highest political level. The review signalled a shift from global dialogue to national implementation and adopted a new outcome document detailing bold, specific, time-bound and measurable national commitments (eg, setting NCD targets and multisectoral plans and mechanisms).6 The outcome document reaffirms that NCDs are a major health and development challenge and calls for their inclusion in the post-2015 development agenda. It includes specific commitments to implement cost-effective interventions for prevention and control, improve monitoring and surveillance, strengthen international cooperation, scale up resources and convene a UN review of NCDs in 2018.

Why diabetes? Why now?

The UN, WHO and global public health community were slow to recognise the true magnitude of NCDs. Focused on eradicating infectious diseases and reducing perinatal mortality, they failed to appreciate both the size of the NCD problem and its implications.

Taking diabetes alone, globally in 2013, it:

accounted for 5.1 million deaths, or one person dying of diabetes every 6 seconds;
cost US$548 billion in health care expenditure for 20–79-year-olds;
was among the top 10 causes of disability due to complications such as lower limb amputations and renal and visual impairment;
affected more than 21 million live births through diabetes during pregnancy;
was set to almost double in numbers from 382 million people to 592 million by 2035; and
disproportionately affected poor societies, with around 80% of the mortality and the increase in diabetes occurring in low- and middle-income countries.7

Mortality from diabetes outstrips the combined mortality from malaria (around 600 000 annual deaths), tuberculosis (1.5 million) and AIDS-related causes (1.6 million).8–10 In contrast, combining cardiovascular disease, cancer and chronic respiratory diseases with diabetes brings the total annual global NCD death toll to 35 million — over 60% of the world’s mortality. However, it was not this, but the macroeconomic impact, that prompted global action on NCDs. It was estimated that for every 10% rise in NCDs, a country could lose 0.5% of its gross domestic product,11 and NCDs were ranked among the top global risks to business due to the trillions of dollars incurred annually through lost productivity.12

Others voiced alarm at the societal implications of NCDs, citing intergenerational poverty, changing patterns of dependency and lost educational opportunity — thus framing NCDs as an impediment to human development and achievement of the Millennium Development Goals (MDGs). A vital influence in this was the game-changing advocacy of civil society. The IDF-led 2006 UN resolution on diabetes2 paved the way, as did the joined-up, whole-of-society approach encapsulated in the Oxford Health Alliance’s Sydney Resolution.13 By 2010, when the IDF launched its global A call to action on diabetes14 in China (then home to 92 million people with diabetes and another 148 million with prediabetes15), it had its advocacy word perfect. The IDF’s graphic illustration of the interaction of diabetes with other NCDs, infectious diseases, poverty, lost productivity, gender inequality and even climate change (Box) undoubtedly exerted strong influence on the UN high-level meeting process and outcomes. So, too, did the formation of the NCD Alliance (http://www.ncdalliance.org) in 2009. This coalition of the four major global NCD federations — the IDF, the World Heart Federation, the Union for International Cancer Control and the International Union Against Tuberculosis and Lung Disease — was timely, well organised and powerful. Running advocacy side events at UN, World Health Assembly and European Union meetings and backed by its membership of 2000 civil society associations in 170 countries, the NCD Alliance sent strong signals to the UN, WHO and national governments that it was time to stem the rising tide of NCDs.

The absence of NCDs in the MDGs had long been an obstacle to mobilising political leadership and resources. The official UN process to scope the post-2015 development agenda will determine the contours of global health and development architecture, which national policies and programs are implemented, and the extent to which current gains are sustained and extended. Since its inception, the NCD Alliance has coordinated a global campaign to integrate NCDs into the successor goals to the MDGs. Consequently, health and NCDs have become a consistent priority in the post-2015 framework thus far. For example, the outcomes document from the 2012 Rio+20 UN Conference on Sustainable Development acknowledges NCDs as one of the greatest development challenges of the 21st century and an area for urgent investment and action.16 Further, the UN Secretary-General’s MDG progress report called for reducing the burden of NCDs as part of the vision and transformative actions of the future development agenda.17 Consistent with the WHO’s global monitoring framework for NCDs, the current draft of the post-2015 agenda includes a standalone target:

By 2030, reduce by one-third premature mortality from [NCDs] through prevention and treatment, and promote mental health and wellbeing.18

Where does Australia sit in all of this?

Australia enjoys an excellent reputation in global and international health policy — receiving special thanks from the WHO for its assistance in negotiating the NCD global monitoring framework with fellow member states and acclaim for its tobacco plain packaging. Growing over time since its ratification of the 1989 World Health Assembly resolution urging countries to develop national diabetes action plans,1 Australia’s standing was evidenced in 2013 by the election of Jane Halton, then Secretary of the Australian Department of Health and Ageing, as Chair of the World Health Assembly Executive Board.

Australia’s history of political will for diabetes has long been underpinned by its bipartisan Parliamentary Diabetes Support Group, which has provided an exemplary model for the establishment of similar groups in other countries. Australian diabetes professionals have also been active, having contributed a recent IDF president, an ongoing supply of IDF vice-presidents, and leadership of global and regional diabetes action plans and declarations.

Diabetes was added to Australia’s national health priority areas in 1997. A comprehensive National Diabetes Strategy and Implementation Plan was launched in 199819 and widely implemented, with considerable success in improving processes of diabetes care. However, population health outcomes data were not forthcoming and, in recent years, some of the original commitment and momentum has been lost. More recently, responding to calls by Diabetes Australia, in December 2013 the incoming Coalition government announced a new National Diabetes Strategy Advisory Group to:

provide expert policy advice to Government that prioritises the national response to diabetes within the broader context of prevention and primary health care, supporting patients with complex health conditions and the growing burden of chronic disease on our health system.20

The advisory group is due to report to the Minister for Health in April 2015 and will almost certainly adopt the targets and indicators detailed in the WHO global monitoring framework.4

Also in December 2013, a pragmatic political response to the relentless march of diabetes began to unfold in Melbourne when the IDF World Diabetes Congress hosted the inaugural global Parliamentary Champions for Diabetes Forum. This was attended by senior parliamentarians from countries across four continents and the Pacific and Caribbean Islands, who signed the Melbourne Declaration on Diabetes, thereby establishing a new global advocacy program and network. Diabetes events have since been held in parliaments around the world, and the network has more than doubled to represent some 40 countries — an auspicious omen for sustaining an action-oriented, political response to diabetes, and its fellow NCDs, at the highest level worldwide. However, the most arduous part of the task — widespread implementation of the new global policies — still lies ahead, and success can only be claimed when measurable population-based improvements in diabetes and related NCD outcomes are achieved.

Diabetes and its critical connections*

NCD = non-communicable disease. * Reproduced from A call to action on diabetes,14 with permission of the International Diabetes Federation.

Lithium-induced thyrotoxicosis in a patient with treatment-resistant bipolar type I affective disorder

Clinical record

In June 2012, a 19-year-old woman presented to an emergency department with a 2-week history of headaches, lethargy, 2 kg weight loss and tremor. Her medical history included treatment-resistant bipolar type I affective disorder, subclinical hypothyroidism and polycystic ovarian syndrome. Her medications included lithium carbonate 1250 mg daily, quetiapine 1000 mg daily, chlorpromazine 200 mg daily, cyproterone acetate/ethinyloestradiol 2 mg/35 µg daily, cholecalciferol 1000 IU daily, and lorazepam 1 mg at night for insomnia as needed. She had not been given an iodine-containing contrast medium, and she reported that she had not been taking thyroxine and that she had not ingested excessive amounts of iodine or kelp. She had no history of ocular symptoms. Her paternal grandmother had had a thyroidectomy.

In April 2010 (several months after commencing lithium therapy), she had developed subclinical hypothyroidism. Results of serum tests showed an elevated thyroid-stimulating hormone (TSH) level of 5.94 mIU/L (reference interval [RI], 0.4–3.5 mIU/L) and a normal free thyroxine (FT4) level of 12.8 pmol/L (RI, 9.0–19.0 pmol/L). This had resolved spontaneously within months.

On presentation at the emergency department, the patient was afebrile and tachycardic with a heart rate of 120 beats/min. She had a small, diffuse, non-tender goitre without bruit. Lid lag and tremor were evident. Results of a general examination were otherwise unremarkable.

Results of initial serum tests showed hyperthyroidism — an elevated FT4 level of 63.6 pmol/L (RI, 12.0–22.0 pmol/L) and a suppressed TSH level of 0.01 mIU/L (RI, 0.4–4.0 mIU/L). Results of thyroid antibody tests were negative (and remained so on repeat testing until February 2013). Results of serial thyroid function tests and thyroid antibody tests are summarised in the Table. The patient’s renal function and results of a full blood examination were normal. A technetium thyroid scan showed no significant tracer uptake, a result that is consistent with thyroiditis.

The patient was prescribed propranolol therapy (10 mg three times a day). She continued taking lithium therapy and was discharged 2 days later. Within 2 days of discharge, her thyroid function had improved markedly and her serum lithium level was 0.75 mmol/L, which is within the therapeutic range (0.50–1.20 mmol/L). In August 2012, repeat thyroid function tests showed hypothyroidism, so she was prescribed thyroxine 50 µg daily. The treating psychiatrist later prescribed clozapine therapy. In December 2012, she was taking clozapine 150 mg in the morning and 200 mg at night, and weaning from lithium was initiated.

Long-term lithium therapy is frequently used to treat psychiatric conditions and has been associated with a variety of thyroid abnormalities. The effects of lithium on the thyroid gland are largely inhibitory. Lithium hinders the action of thyroid-stimulating hormone (TSH) and interferes with thyroid hormone synthesis through the inhibition of adenylate cyclase. Lithium decreases thyroid iodine release, reduces iodide organification and increases thyroid iodide content.1

Lithium prolongs the retention of radioiodine in the thyroid gland. In patients treated with lithium, elevated and diffuse uptake on a radioiodine scan can be misinterpreted as a sign of Graves disease. However, this was not the case in our patient, who had a technetium scan. Other explanations for low tracer uptake on the technetium scan include recent iodine ingestion or surreptitious or inadvertent thyroxine ingestion. Our patient had not been ingesting iodine and her thyroglobulin levels were high, not low, which excluded the possibility of thyroxine ingestion. The decline in free thyroxine was more rapid than expected, given the usual half-life of thyroxine. This may be partly due to the shortened half-life of free thyroxine in the context of hyperthyroidism, but laboratory error is also possible.

In patients treated with lithium, goitre is the most common thyroid abnormality.2 Reported prevalence ranges from 4%3 to 51%.4 Goitre is thought to be due to the inhibitory effects of lithium causing increased TSH concentrations. Hypothyroidism and subclinical hypothyroidism are also common. In a study of 274 patients who were taking long-term lithium therapy, the prevalence of hypothyroidism was 10.3%.5 In the same study, only one case of thyrotoxicosis was observed. In another study, no cases of thyrotoxicosis were observed over 768 patient-years,6 suggesting that lithium-induced hyperthyroidism is extremely rare.

Results from a retrospective review of medical records suggest that a significant proportion of patients with lithium-associated thyrotoxicosis have — as seen in our patient — transient, painless thyroiditis.7 Of 19 patients with lithium-associated thyrotoxicosis, 13 were diagnosed with silent thyroiditis, five with Graves disease and one with toxic nodular goitre. In patients receiving lithium, there was an increased relative prevalence of silent thyroiditis versus Graves disease and a greater than expected incidence of silent thyroiditis. A possible explanation for our patient’s presentation may have been a coincidental episode of painless silent thyroiditis unrelated to lithium therapy.

Most cases of lithium-associated thyroiditis occur while patients are taking lithium7,8 and while the serum lithium level is in the therapeutic range.7 In a review of 11 cases of lithium-associated silent thyroiditis, the duration of therapy before the development of thyrotoxicosis ranged from 6 days to 15 years.8 However, in some cases, thyrotoxicosis occurred 4 days to 5 months after withdrawal of lithium therapy.7,8 A review of cases of lithium-induced thyroiditis from 1978 to 1995 showed that most patients subsequently developed hypothyroidism, as seen in our patient; in the remainder, thyroiditis remitted spontaneously.7 This was independent of the decision to continue or withdraw lithium therapy. Thus, the decision to discontinue lithium therapy in the context of thyroid dysfunction should be made with attention to the severity of the underlying psychiatric disorder.

The mechanism of lithium-induced thyrotoxicosis is not well understood. Some authors have suggested that lithium, by expanding the intrathyroidal iodide pool, may precipitate thyrotoxicosis in patients with a genetic predisposition to Graves disease or thyroid nodules.9 Autoimmunity may play a significant role in lithium-induced thyroiditis. In a case–control study of patients with primary affective disorders, eight of 40 who were receiving lithium tested positive for thyroid antibodies, compared with three of 40 who were receiving drugs other than lithium. Patients receiving lithium had significantly reduced numbers of suppressor and/or cytotoxic T cells, and increased B cell activity was seen in patients receiving lithium and those receiving drugs other than lithium.10 Painless thyroiditis may also be the result of a direct toxic effect of lithium on the thyroid, as occurs in amiodarone-induced toxic thyroiditis.7 This seems the likely mechanism in our patient, in whom results of tests for thyroid antibodies remained negative.

Lithium-induced thyroiditis can usually be managed conservatively, with regular monitoring of thyroid function. The role of steroids is unclear and the potential for exacerbation of psychiatric disease must be considered. While cholestyramine sometimes has a role in treating thyroiditis, its role in lithium-induced thyroiditis is unclear. Patients with lithium-induced Graves disease should be treated with carbimazole, and radioiodine therapy and thyroidectomy should be considered. In patients with toxic nodular goitre, thyroidectomy may be indicated.2

Lessons from practice

Lithium has profound effects on thyroid physiology — goitre, hypothyroidism and subclinical hypothyroidism are common.
Although the mechanisms are unclear, there is increasing recognition that lithium is associated with thyrotoxicosis and induction of autoimmunity.
In cases of lithium-induced thyroiditis, conservative management with regular follow-up is indicated because most patients subsequently develop hypothyroidism.
Thyroid function tests and tests for thyroid antibodies should be performed before lithium therapy is started and performed regularly during lithium therapy.

Table

Serum level (RI)

Date

TSH (mIU/L)

FT4 (pmol/L)

FT3 (pmol/L)

Tg (µg/L)

TPO Ab (kIU/L)

Tg Ab (kIU/L)

TSH R Ab (IU/L)

Lithium (mmol/L)

15 Oct 2008

1.43 (0.4–3.7)

14.2 (7.3–22.1)

4.6 (2.5–7.3)

—

< 35 (< 35)

< 40 (< 40)

—

30 Apr 2010

5.94 (0.4–3.5)

12.8 (9.0–19.0)

—

< 35 (< 35)

< 40 (< 40)

—

06 Aug 2010

2.75 (0.4–3.5)

14.3 (9.0–19.0)

3.5 (2.6–6.0)

—

< 35 (< 35)

< 40 (< 40)

—

1.26 (0.5–1.2)

22 Mar 2012

3.24 (0.4–3.5)

10.9 (9.0–19.0)

—

0.64 (0.5–1.2)

13 Jun 2012

—

0.72 (0.5–1.2)

14 Jun 2012*

0.01 (0.4–4.0)

63.6 (12.0–22.0)

—

1180 (< 55)

< 35 (< 35)

< 40 (< 40)

< 1.0 (< 2.0)

—

18 Jun 2012

0.01 (0.4–3.5)

27.8 (9.0–19.0)

13.0 (2.6–6.0)

1570 (< 30)

< 35 (< 35)

< 40 (< 40)

< 1.0 (< 1.0)

0.75 (0.5–1.2)

21 Aug 2012

6.05 (0.3–4.2)

7.0 (12.0–25.0)

—

01 Dec 2012

3.64 (0.4–4.0)

14.2 (12.0–22.0)

—

15 Feb 2013

—

< 10 (< 35)

< 20 (< 40)

—

* Day of presentation at emergency department. FT3 = free triiodothyronine. FT4 = free thyroxine. Tg = thyroglobulin. Tg Ab = thyroglobulin antibodies. TPO Ab = thyroid peroxidase antibodies. RI = reference interval. TSH = thyroid-stimulating hormone. TSH R Ab = thyroid-stimulating hormone receptor antibodies.

Consent, capacity and the right to say no

Case study

A 74-year-old Sicilian woman was admitted to hospital with stridor and dysphonia in the setting of concurrent upper respiratory tract infection. This was on a background of toxic multinodular goitre that had been treated for 8 years with propylthiouracil, as she had reacted adversely to carbimazole. She had been recommended surgery in the past, but had declined.

Clinical examination revealed an obvious stridor and a diffuse, symmetrically large goitre. Pemberton sign was positive. Thyroid function tests had demonstrated a suppressed thyroid-stimulating hormone level (0.03 mU/L; reference interval [RI], 0.5–4.0 mU/L), with a free thyroxine level within the RI (16.3 pmol/L; RI, 10.0–19.0 pmol/L). Ultrasound and computed tomography imaging identified a large, retrosternal, multinodular goitre. Her trachea was significantly compressed, with a diameter of 5.5 mm (Box). We further recommended total thyroidectomy, which she again politely declined.

The night after admission, her condition deteriorated acutely and she was transferred to the intensive care unit with respiratory distress. The need for intubation was avoided and she was sufficiently managed with nebulised adrenaline and intravenous dexamethasone. Again, she refused surgery.

She remained in intensive care for the following week, with extensive discussion involving her family (two sons) and the help of Italian interpreters. She was seen by multiple doctors, including senior endocrine surgeons, ear, nose and throat surgeons, intensivists and anaesthetists, all of whom attempted to convey to her the need for surgery. It was made clear that without surgery, she would almost certainly die from tracheal obstruction.

The reasons for her refusal were several, but simple. In her native Sicily, a scar on one’s neck — the Sicilian bowtie — references the Mafia practice of throat-slitting and depicts the scar-carrier as dishonourable. She also expressed her fears of the risks of surgery, particularly voice changes from recurrent laryngeal nerve injury and the need for lifelong medication with thyroxine following thyroidectomy. Further, she was convinced that the reason for her stridor was her upper respiratory tract infection rather than tracheal compression, and believed that it would improve with time.

During this time, every practitioner regarded her to be competent to make this decision. She had an unconventional attitude towards life and death and the implications of surgery, and did not appear to have any cognitive impairment affecting her capacity to consent to or refuse intervention.

Because of the gravity and implication of her decision, we sought a neuropsychological assessment to formally document her capacity before discharge. Much to the surprise of all practitioners involved, the assessment deemed the patient incompetent to make her own decisions regarding treatment. She was assessed as having underlying cognitive impairment and impaired aspects of executive function. With regard to decision making, the assessment found that although “she could state the risks and consequences, she was not adequately and rationally weighing these up against the benefits”. We discussed the assessment with a senior neuropsychologist, who agreed with the initial assessment without any need for reassessment.

We sought advice from the hospital’s legal counsel, who recommended that, because the patient was deemed incompetent, the treatment decision should rest with her sons. In addition, the legal counsel considered neuropsychology to be the most expert opinion in competence assessment and, as such, no further assessment was warranted. Although keen for surgery, her sons were also aware of the implications of forcing their mother into an operation that she did not want. They would have to live with her anger or disappointment long after the acute surgical issues had passed.

After about a week of consideration, her sons consented to surgery. The patient was not informed for fear of an angry outburst leading to sudden airway compromise. Given the patient’s potentially difficult airway and her non-compliance, extensive anaesthetic planning ensued. An anaesthetic team of two senior anaesthetists and an anaesthetic nurse took a difficult airway trolley to the ward, where a heavily sedating premedication was administered and the patient was transferred to theatre. Total thyroidectomy was completed without complication, and the patient made a good postoperative recovery. She was grateful for our care and satisfied with the outcome. She was discharged 2 days later with no stridor, normal voice and normal parathyroid function.

Discussion

This case presented challenging and interesting medicolegal and social dilemmas. We were confronted by a patient with a serious, life-threatening but very treatable medical problem, who was refusing treatment. Moreover, all clinicians involved felt that she had capacity to make this decision, yet the neuropsychological assessment showed otherwise.

Legally, “capacity” and “competence” are interchangeable. At common law, adults are always presumed to be competent, unless it can be proved that they lack competence.1 The test at common law for competence is functional; that is, whether they have the ability to make the decision rather than basing it on criteria or “reasonableness”.2 Generally, the law requires that the patient be able to understand and retain treatment information, believe the information, weigh the information and reach a decision, and communicate his or her decision.1

Based on this common law approach, four jurisdictions in Australia (New South Wales, Queensland, Tasmania and Victoria) have enacted legislation which adopts a functional test of competence.1 In Victoria (the location of this case), s 36(2) of the Guardianship and Administration Act 1986 states:

a person is incapable of giving consent to the carrying out of a special procedure or medical or dental treatment if the person —

(a) is incapable of understanding the general nature and effect of the proposed procedure or treatment; or

(b) is incapable of indicating whether or not he or she consents or does not consent to the carrying out of the proposed procedure or treatment.

Despite the apparent clarity of the legislation, the Victorian Office of the Public Advocate recognises that an assessment of competence is not always straightforward and may require input from specialists such as neuropsychologists, psychiatrists and geriatricians.3 Assessment of competence can often be fraught with complexity. Of patients with underlying mild–moderate cognitive impairment, about 60% of patients remain undiagnosed, even by family members.4 Further, a cognitive test such as the Mini-Mental State Examination has flaws — it is culture-specific and does not address individual cognitive domains well. Complicating this further, acute illness and medication impairs patients’ abilities to synthesise information. The law, as a result of these inherent difficulties in establishing competence, does not require any specific test to be passed, but instead leaves the decision to the discretion of the clinician.1

In cases of incompetent patients, treatment decisions are made by a substitute decisionmaker — a guardian, a medical power of attorney or a person responsible (in our case, the patient’s elder son). In arriving at the treatment decision, the substitute decisionmaker has a responsibility to satisfy either one of two legal standards. The best interest standard involves making a decision in what is considered to be the patient’s best interest (often used for children). The substituted judgment standard relates to patients like ours, who have previously voiced their preference for treatment. Under this test, decisionmakers should attempt to reach the same decision that the patient would have reached had they remained competent.4

Our patient had refused surgery for her thyroid for 8 years before her presentation. She was considered to have capacity then and was never thought to warrant neuropsychological assessment earlier. The substituted judgment standard would suggest that her son should have had this in mind when considering the appropriate treatment approach now.

There has been debate in law about whether some decisions require more competence than others. The prevailing view is that “the more serious the risk, the greater the level of evidence of capacity that should be sought”.4 Some patients may be competent to consent to minor procedures like vaccinations but not competent to consent to major surgery. Unfortunately, there is no guide for doctors to evaluate the level of evidence of competence required for any one particular procedure.

What about our situation, where a patient is judged by doctors as having capacity but by a neuropsychologist as not? When should doctors be satisfied with their own evaluation and under what circumstances should a specialist be engaged on the basis that a higher level of evidence of competence needs to be demonstrated? The law would suggest that specialists in competence assessment (eg, neuropsychologists) should be employed when there is doubt and the consequences are severe. In our case, the patient was considered competent by multiple clinicians. It was only because of the risk of death without surgery that our patient underwent a neuropsychological assessment; many saw this as being an unnecessary step, given her apparent competence. Nevertheless, the severe consequences of inaction justified a comprehensive assessment of competence.

This case also highlights the blurred boundary between capacity and rationality. Our neuropsychologist identified a lack of rationality as one of the reasons for our patient’s incompetence. However, our legislated definition of capacity (stated above) only requires that patients understand; it does not require an assessment of what is rational. Regarding rationality, the Stanford encyclopedia of philosophy states that a “theory of decisional capacity must allow for the fact that health care subjects can make unpopular decisions, even ones that are considered highly irrational by others”.5 Patients must be afforded the right to make seemingly irrational decisions, provided they can understand and appreciate the consequences. An analogy could be made to a Jehovah’s Witness refusing a life-saving blood transfusion; highly irrational to many, this choice is honoured by doctors.

In medicine, we regularly see patients who refuse our recommended treatment. Should we be requesting neuropsychological assessment of all patients refusing our recommendations on the basis that they might be “incapable of understanding the general nature and effect of the proposed procedure or treatment”, as set out in the Victorian Guardianship and Administration Act? To what extent can differences in cultural values cloud the question of whether a patient truly understands the treatment?

These sorts of questions create doubt in the process of assessing capacity and put enormous pressure on doctors making assessments. There is conflict between the doctor’s duty to do what he or she considers to be in the patient’s best interests, while also allowing the patient to make decisions that the doctor considers to be “irrational”. Regarding this conflict, however, the law seems to be clear. In a United Kingdom case, the presiding judge stated: “The doctors must not allow their emotional reaction to or strong disagreement with the decision of the patient to cloud their judgment in answering the primary question whether the patient has the mental capacity to make the decision”.6

Despite her initial reluctance, our patient was happy with her postoperative outcome. We feel that our process was robust and that the appropriate decision was made. But there was still significant unease among the team members that we were operating on a patient against her will. And her satisfaction postoperatively should not be misconstrued as proof that we did the right thing. The right thing is to ensure that a patient’s autonomy is maintained and that we do not confuse our own prejudices with patient competency.

We must remember the social implications of our decisions and interventions. It is not acceptable to consider only the medical issues. Our patients all have unique social circumstances, and our treatments can impact heavily upon these. If our patient refused to speak again to her sons as a result of them consenting to surgery that she had refused, could we consider this a successful outcome?

This case has displayed the many complexities inherent in the assessment of a patient’s capacity to consent to or refuse treatments and interventions. Many social, cultural and legal factors may need to be considered. As clinicians, our understanding of some of these subtleties is limited. Legal principles are complicated and often cases need to be considered carefully on individual merits. Resources such as hospital legal counsel, the Office of the Public Advocate or Guardian (depending on the jurisdiction) and medicolegal handbooks are invaluable in ensuring the protection of both the patient and doctor. In the process of writing this article, our research answered several of the legal questions we had encountered — the answers are available to clinicians if we know where to look. Our experience has taught us to employ the services of multiple teams — medical, psychological and legal — and to engage family in the decision-making process.

Computed tomography scan, showing retrosternal goitre with tracheal compression

First Australian report of vitamin D-dependent rickets type I

A 20-month-old girl presented to hospital with features of rickets. Results of investigations were consistent with vitamin D-dependent rickets type I (VDDR-I), and DNA sequence analysis showed a homozygous mutation in the CYP27B1 gene of c.1325-1326insCCCACCC. This is the first reported Australian case of VDDR-I.

Clinical record

A 20-month-old white Australian girl presented to the Women’s and Children’s Hospital in Adelaide, South Australia, with a 6-month history of developmental regression of gross motor skills, failure to thrive and irritability, in particular distress when “she was wearing her shoes”. At 14 months of age, she had been crawling, pulling to stand and cruising, but at presentation her gross motor skills had regressed to only being able to sit unsupported. Other developmental milestones continued to progress normally for her age. Her weight at presentation was 7.7 kg, having dropped from the 50th centile to below the third centile (weight loss of 3.7 kg over 6 months). Length and head circumference had dropped from the 25th centile to less than the first centile and to the third centile, respectively, over this time.

The patient was the second child born to non-consanguineous white Australian parents. She was born at term with no perinatal complications. There was no history of familial hereditary disease. Maternal vitamin D deficiency had been treated during the pregnancy. The patient had received a multivitamin supplement (0.45 mL/day of Penta-vite [Bayer Australia], containing 10.1 µg of cholecalciferol) from birth until 2 months of age, with no further follow-up until her presentation at 20 months (Box 1).

On examination, the patient was mildly dehydrated, listless, miserable and mildly tachypnoeic, with intercostal recession. Her anterior fontanelle was large. Rachitic rosary, tibial bowing and widened metaphyses of the wrists and knees were evident. No bruising of the skin was noted.

The patient had low serum total calcium and inorganic phosphate levels and a markedly elevated alkaline phosphatase level (Box 1). A skeletal survey showed significantly osteopenic bones, with flaring of the metaphyses in the long bones, soft tissue swelling around the elbow and wrist joints, and steep acetabular angles (Box 2). She had acute and healed fractures in multiple places: the right proximal ulnar shaft; both distal radial shafts; mid shafts of the second, third and fourth metacarpals of the right hand; mid shaft of the second metacarpal of the left hand; and mid shafts of the third metatarsals of both feet.

The clinical, radiological and biochemical findings were consistent with a diagnosis of rickets. She was treated with two doses of intravenous calcium infusion (12.5 mL/day of 10% calcium gluconate), oral phosphate (100 mg/kg/day) for 4 days, oral calcium (75 mg/kg/day) for 5 months, and ongoing calcitriol (0.07 µg/kg/day). She had feeding problems (food refusal and difficulty swallowing), which required nasogastric feedings for a month and a high-calorie diet.

The differential diagnosis included nutritional vitamin D-deficient rickets, vitamin D-dependent rickets (VDDR) type I and II, and hypophosphataemic rickets such as X-linked hypophosphataemia (Appendix 1). In the presence of normal renal function, electrolyte levels and acid–base balance, in addition to a low 1,25-dihydroxyvitamin D (1,25(OH)2D) level, normal 25-hydroxyvitamin D (25(OH)D) level, high alkaline phosphatase and parathyroid hormone (PTH) levels, and hypocalcaemia, the most likely diagnosis was VDDR type I (VDDR-I).

As VDDR-I is caused by a mutation in the CYP27B1 gene that impairs the conversion of 25(OH)D to 1,25(OH)2D, gene sequence analysis of the CYP27B1 gene was undertaken using genomic DNA from the index patient and her parents. All nine exons and intron–exon boundaries of CYP27B1 were amplified by polymerase chain reaction (PCR) from 100 ng of genomic DNA, using the PCR primer sets published previously.1 PCR conditions were 94°C for 5 min, followed by 35 cycles of amplification (94°C for 30 s, 54°C for 30 s, and 72°C for 30 s). The resulting PCR products were directly sequenced using Applied Biosystems 3730 and 3730xl DNA analysers. A biallelic c.1325-1326insCCCACCC sequence variation was found in exon 8 of the CYP27B1 gene (Appendix 2), which in turn led to a frameshift mutation and premature stop codon after 23 altered amino acids (F443PfsX466 or F443fs). As expected, a monoallelic c.1325-1326insCCCACCC sequence variation was found in both parents (Appendix 2). The parents have been counselled regarding their genetic status and the risk of having another child affected in an autosomal recessive manner.

Sixteen months after discharge, at 3 years of age, the patient demonstrated good catch-up in weight (12.6 kg; 10–25th centile), with a growth velocity of 7.8 cm/year (25–50th centile). She was walking unaided and walking up and down stairs. Metaphyseal widening and tibial bowing had decreased but were still present on clinical examination. She continued to receive calcitriol at a dose of 0.07 µg/kg/day, and her PTH, calcium and phosphate levels were within reference intervals (Box 1). A renal ultrasound produced normal results, with no evidence of nephrocalcinosis.

Discussion

We believe this is the first reported Australian case of VDDR-I with an identified mutation, demonstrated by a clinical presentation of severe rickets, severe hypophosphataemia, high PTH level, low 1,25(OH)2D level, failure to thrive and unresponsiveness to 25(OH)D therapy. The patient showed mild hypocalcaemia on admission due to the compensatory high PTH level. These findings are compatible with the current notion that the bone phenotype of rickets and osteomalacia mainly results from hypophosphataemia, not hypocalcaemia. Independent hypocalcaemia will not cause rickets or osteomalacia in hypoparathyroid patients, while hypophosphataemia alone causes rickets and osteomalacia in fibroblast growth factor 23 (FGF23)-related hypophosphataemia.2 The mutation of CYP27B1 in this case, c.1325-1326insCCCACCC, has been reported previously in diverse ethnic groups (Appendix 3).3–9 The final aberrant CYP27B1 protein lacks 44 amino acids in the C-terminus, resulting in reduced or no enzymatic activity to convert 25(OH)D into 1,25(OH)2D. This is the most common mutation among patients with VDDR-I; of 67 families with VDDR-I reported in the literature, including this one, 20 harbour this mutation. The index case is the first reported VDDR-I mutation in the Australian population, but ethnicity is irrelevant to the frequency or phenotype of the disease.

Previously described patients with VDDR-I have presented around the same age, with similar features (failure to thrive and regression in gross motor development) and similar results of biochemical investigations. Clinical data on the frequency of fractures in VDDR-I patients are limited due to the rarity of the disease.3–9 As there were no other causes found for the multiple fractures seen in our patient, these might have been related to the delay in diagnosis and treatment in a child who was increasing in mobility due to developmental progression. Almost all reported patients with VDDR-I have required regular calcitriol treatment. Although the required dose of calcitriol may depend on each patient, generally a dose of 0.01–0.1 µg/kg/day normalises serum calcium and inorganic phosphate levels in patients with VDDR-I.10

1 Results of laboratory investigations and calcitriol dose at each available time point

		Patient’s age
Variable	RI	1 day	3 days	2 months	20 months (admission)	21 months (discharge)	25 months	29 months	32 months	34 months	37 months

Total calcium (mmol/L)	2.10–2.65	—	—	2.36	2.00	2.32	2.20	2.33	2.31	2.32	2.21
Inorganic phosphate (mmol/L)	1.15–2.50	—	—	1.04	0.75	0.70	1.09	0.86	0.75	1.94	1.71
Alkaline phosphatase (U/L)	100–360	—	—	1078	3848	1494	969	1322	953	467	276
Parathyroid hormone (pmol/L)	0.5–5.5	—	—	32.9	37.0	33.1	15.2	29	14.8	3.7	2.3
25(OH)D (nmol/L)	> 60	63	48	89	62	—	—	—	—	—	—
1,25(OH)2D (pmol/L)	50–160	—	—	—	17	—	—	—	—	—	—
Calcitriol dose (µg/kg/day)	na	—	—	—	0.01–0.04	0.07	0.07	0.07	0.07	0.07	0.07

RI = reference interval. na = not applicable. — = data not available. 25(OH)D = 25-hydroxyvitamin D. 1,25(OH)2D = 1,25-dihydroxyvitamin D.

2 X-ray at presentation demonstrating rachitic changes