In today’s article, Matt Quinn discusses the relation between folic acid supplementation and neural tube defects.

Each year approximately 220,000 babies are born worldwide with spina bifida or anencephaly due to maternal folic acid deficiency during the periconceptual period. [1] These cases account for roughly 70% of the global incidence of spina bifida and anencephaly and have been termed folic acid-preventable spina bifida and anencephaly, respectively. Fortifying food with folic acid could prevent these debilitating illnesses. The current RDA of 400 mg can be found in most over-the-counter multivitamins. This paper will provide a brief overview of the pathogenesis of spina bifida and anencephaly, the evidence supporting the use of folic acid supplementation during the periconceptual period, the disparities between different countries use of folic acid fortified food, and the ethical and safety concerns for why some countries have chosen not to implement mandatory folic acid fortified food programmes.

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Prof Hervé Puy MD, Prof Laurent Gouya MD, Prof Jean-Charles Deybach MD

Summary

Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants.

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Dr Ambady Ramachandran MD, Ronald Ching Wan Ma MRCP, Chamukuttan Snehalatha DSc

Summary

Prevalence of type 2 diabetes has rapidly increased in native and migrant Asian populations. Diabetes develops at a younger age in Asian populations than in white populations, hence the morbidity and mortality associated with the disease and its complications are also common in young Asian people. The young age of these populations and the high rates of cardiovascular risk factors seen in Asian people substantially increase lifetime risk of cardiovascular disease. Several distinctive features are apparent in pathogenetic factors for diabetes and their thresholds in Asian populations. The economic burden due to diabetes at personal, societal, and national levels is huge. National strategies to raise public awareness about the disease and to improve standard of care and implementation of programmes for primary prevention are urgently needed.

Introduction

Diabetes and associated complications pose a major health-care burden worldwide and present major challenges to patients, health-care systems, and national economies (panel 1). WHO estimates that between 2000 and 2030, the world population will increase by 37% and the number of people with diabetes will increase by 114%.1 Asia is the major site of a rapidly emerging diabetes epidemic.1, 2 Conservative estimates based on population growth and ageing and rate of urbanisation in Asia show that India and China will remain the two countries with the highest numbers of people with diabetes (79·4 million and 42·3 million, respectively) by 2030.1 Additionally, among the top ten countries, four more are in Asia—Indonesia, Pakistan, Bangladesh, and the Philippines. Prevalences are probably underestimated because changes due to other diabetes-related risk factors have not been considered.

Panel 1
Burden of type 2 diabetes

*
Prevalence of diabetes is rising worldwide.
*
The incidence is highest in developing countries, especially in Asia.
*
Among Asian countries, India and China have the highest numbers of people with diabetes.
*
The high prevalence and large population size contribute to the huge burden of diabetes on these countries.
*
The poorest economic strata bear the highest cost burden of diabetes treatment.
*
The economic cost increases many times with the development of vascular complications.
*
Developing countries need to increase national capacity for early diagnosis, encourage effective management, and improve primary prevention to combat the rising burden due to this chronic disease.

The world population is expected to reach 7·9 billion by 2025. Six countries account for almost 50% of the population increase every year; among them, three Asian countries, India, China, and Pakistan, contribute 21%, 12%, and 5%, respectively.3 Asian populations are racially heterogeneous and have differing demographic, cultural, and socioeconomic characteristics. Differences in genetic and environmental attributes affecting diabetogenesis could also be heterogeneous. We discuss type 2 diabetes in Asian countries other than Japan.

Epidemiology

In 2003, an estimated 194 million adults worldwide had diabetes (5·1%) and 314 million people had impaired glucose tolerance (8·2%).4 These prevalences increased to 6·0% and 7·5% in 2007 and are predicted to increase to 7·3% and 8·0% by 2025.2 380 million people are expected to have diabetes in 2025.2 85—95% of all diabetes cases are of type 2 in developed countries and this percentage is even higher in developing countries.2 Roughly 80% of people with diabetes are in developing countries, of which India and China share the largest contribution. Prevalence estimates (adjusted to world population) of diabetes and impaired glucose tolerance in all Asian countries are high and are expected to increase further during the next two decades.2

The increase is likely to be most substantial in developing countries that are undergoing the most rapid economic growth. The gross domestic product per head in India and China is lower than in some other Asian countries, despite increases of three and five times, respectively, over the past two decades (figure 1). The increases in diabetes prevalence in India and China are especially alarming compared with more developed regions within Asia, showing a mismatch between affluence and diabetes prevalence—an Asian diabetes paradox. Epidemiological data from Asian countries draw attention to the high prevalence of type 2 diabetes in urban and rural populations (table 1).2,5—38 Prevalence of impaired glucose tolerance is high in many Asian countries, suggesting the presence of a large pool of people with potential to develop diabetes.2 In southeast Asia, the estimated prevalence of impaired glucose tolerance was 6·0% in 2007.2 The rapidly increasing rate of diabetes in Asia is associated with a strong gene—environmental interaction, which is propelled by lifestyle changes caused by modernisation. Migrant Asian groups have a higher susceptibility to adverse environmental influences than do co-inhabitants of different races.39

Economic development and prevalence of diabetes in selected Asian countries, 1981—2008
(A) Real gross domestic product per head. Data from the US Department of Agriculture Economic Research Service (http://www.ers.usda.gov/Data/Macroeconomics/Data/HistoricalRealPerCapitaIncomeValues.xls, accessed April 28, 2009). (B) Prevalence of diabetes. Data derived from table 1. GDP=gross domestic product.

Prevalence of diabetes, number of people with diabetes, and percentage of urbanisation in Asian countries
* As projected by WHO.
† Based on fasting plasma glucose.
‡ Estimated prevalence.
§ Crude prevalence.

Pathophysiology

Asian populations are multiracial and have multifactorial causes of type 2 diabetes. The mechanisms underlying development of the disease are complex and varied, even within these populations. The major aetiological components of type 2 diabetes are impaired insulin secretion and impaired insulin action, which are aggravated by the presence and degree of glucotoxicity. Both components might also be genetically predetermined. Lipotoxicity plays an important part in causing insulin resistance and β-cell damage.40 In the natural history of type 2 diabetes, β-cell function undergoes a series of changes. With the development of obesity and other adverse effects on insulin sensitivity, β cells respond with compensatory hyperinsulinaemia. Such changes are seen even in non-diabetic people with strong familial history of diabetes.41 With increasing duration, β-cell function declines and insulin-to-glucose ratio diminishes, before an ultimate decompensation occurs with expression of clinical diabetes. Asian populations are more insulin resistant than are people of many other races.42—45 Insulin resistance and compensatory hyperinsulinaemia are reported even in children and adolescents of Asian Indian origin.46, 47 These factors probably play a major part in the escalating prevalence of type 2 diabetes in young populations in Asia.

Risk factors for diabetes show substantial racial and geographical variations in expression and intensity. The escalating prevalence of diabetes and cardiovascular diseases in developing countries is mostly related to environmental changes. Asian populations have several important characteristics with respect to biological and environmental risk factors for diabetes (panel 2).

Panel 2
Characteristics of risk factors for type 2 diabetes in Asian countries

*
Most Asian countries are undergoing a socioeconomic transition.
*
Increasing levels of modernisation, industrialisation, and economic advancements adversely affect biological and environmental risk factors for diabetes.
*
Asian populations have low thresholds for conventional risk factors such as age, body-mass index, upper-body adiposity.
*
Adverse effects on health are manifested on pre-existing genetic predisposition, insulin resistance, and other metabolic features, at a younger age in Asian populations than they are in white populations.
*
Diabetes develops at least a decade earlier in Asian than in white people. Prevalence of young-onset diabetes is increasing in Asian populations.
*
Young-onset diabetes and type 2 diabetes in children are common and their rising trend is linked to epigenetic factors, such as maternal imprinting, and to unhealthy lifestyle changes leading to high rates of obesity.
*
Both the thrifty genotype and thrifty phenotype might be operative in Asian groups.
*
These characteristics are heterogeneous in Asian populations.
*
These populations also have high rates of clustering of cardiovascular risk factors—ie, metabolic syndrome even at a young age.

Genetic factors

Type 2 diabetes has a strong genetic component and most Asian patients have a first-degree relative with diabetes.48, 49 Much progress has been made in our understanding of the genetics of this disease. Importantly, most of the loci originally associated with diabetes in European populations have been replicated in Asian populations. Whereas monogenic forms of diabetes result from rare genetic mutations with large effects, such as those seen in maturity-onset diabetes of young people,50 most cases of type 2 diabetes are thought to be due to genetic variations that are more common but exert less effect. In early studies, genetic variants in the peroxisome proliferator-activated receptor-γ gene (PPARG)51 and the ATP-sensitive potassium channel Kir6·2 (KCNJ11) were reproducibly associated with type 2 diabetes.52 In Asian populations, the protective effect of the PPARG*A12Ala allele on insulin resistance and risk of type 2 diabetes was not consistently seen.53 Polymorphisms in the gene encoding transcription-factor-7-like protein 2 (TCF7L2) was reported to be associated with type 2 diabetes in 2006.54 With a combined odds ratio of 1·46 for the rs7903146 variant,55 this gene has the strongest effect on type 2 diabetes. However, the at-risk T allele in rs7903146 is rare, and different genetic variations in TCF7L2 are associated with type 2 diabetes in Asian populations.56, 57

Several other genetic variants have been identified through genome-wide association studies, which is a strategy that uses the genotyping of hundreds of thousands of single-nucleotide polymorphisms on a single array. These variants are associated with type 2 diabetes in different Asian groups, including Chinese, Japanese, Korean, and Indian populations (table 2).53—74 A meta-analysis showed that, although risk alleles of the different variants seem to confer similar risk for type 2 diabetes in European and Asian populations, ethnic differences in their frequencies lead to differences in population-attributable risk, showing the need for population-specific studies.65 Two recent Japanese genome-wide association studies replicated several loci previously identified in Europeans, and reported variants in the KCNQ1 gene that are associated with type 2 diabetes in Japanese and other east Asian populations.73, 74

Replicated type 2 diabetes gene nearest to the identified marker
Genetic variants with suggestive association with type 2 diabetes but without genome-wide statistical significance are not included. OR=Odds ratio.
* Approximate effect size for the variant associated with type 2 diabetes.
† No published data.

Most genetic variants associated with type 2 diabetes seem to be related to insulin secretion rather than insulin resistance, and several of the risk alleles are associated with reduced islet-cell function 58, 59, 68, 73, 75, 76 (table 2 and figure 2). One of the variants, FTO, is associated with changes in fat mass and predisposes to diabetes via the effects of obesity; it is the first common variant to be associated with obesity and diabetes in European as well as Asian populations. However, by contrast with European groups, the association in Asian populations is not entirely mediated through body-mass index.77 Mechanisms linking body size with type 2 diabetes seem to vary between Indian and European populations. Several other variants have been linked to obesity, although none has so far been associated with diabetes. The present catalogue of type 2 diabetes risk variants probably accounts for only a small proportion of the genetic basis of type 2 diabetes. Nevertheless, the identification of these variants has provided insights into pathogenesis of type 2 diabetes.

The role of type 2 diabetes genes in insulin secretion
Pancreatic β-cell genes associated with type 2 diabetes are in italics. G6P=glucose-6-phosphate. Adapted from Florez JC. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 2008; 51: 1100—10, by kind permission of the author and Springer Science + Business Media.

Urbanisation and migration

Rates of urbanisation are variable, but substantial increases in urbanisation will occur in most Asian countries 5 (table 1). By 2010, the proportion of urbanisation will be more than 50% in Singapore, Korea, Malaysia, the Philippines, and Indonesia, and more than 30% in China, Pakistan, India, and Thailand. The remaining countries (Bangladesh and Sri Lanka) have slow rates of urbanisation. Increasing urbanisation is due to natural population growth and expansion of urban areas. It is also affected by rural to urban migration.78 The expected increase in urban population would be a main determinant, besides ageing, of the rise in the global prevalence of diabetes. Data from Asian countries show the effect of urbanisation on diabetes prevalence.5—38 Physical activity decreases and body-mass index and upper-body adiposity increase substantially with urbanisation.79 Internal rural to urban migration results in similar adverse changes. Most Asian countries, in particular India and China, are experiencing rapid socioeconomic progress and are susceptible to such consequences.

The prevalence of diabetes is increasing in urban and rural populations in both India and China, although prevalence is substantially higher in India than in China (table 1 and figure 1). A nationwide study done in China in 2000 revealed that 7·3% of the population are affected by impaired glucose tolerance, with striking rural—urban differences.14 Importantly, only 30% of the 20 million people estimated to have diabetes on the basis of fasting plasma glucose had previously been diagnosed.14 These findings suggest that China is still in the early stages of an evolving diabetes epidemic. The prevalence will probably rise further as China continues to develop economically and becomes increasingly urban.80 This conclusion is supported by higher prevalence rates in Chinese populations in Hong Kong and Taiwan than in their mainland counterparts.80

Urban lifestyles cause enormous changes in diet, physical activity, and health. Urban populations eat more diverse diets and more macronutrients and animal food than do rural residents, but with higher intake of refined carbohydrates, processed foods, and saturated and total fat and lower intake of fibre. Increasing incomes partly account for these differences, but such changes are evident at any income.81 The effect of nutrition transition is large and most of the emerging epidemic of chronic disorders, such as diabetes, cardiovascular diseases, stroke, and hypertension, are diet related.
Migration to more affluent countries results in high prevalence of diabetes in many populations. This effect is seen, for example, in Asian Indian migrants,39, 42 Chinese groups from mainland China,82 and Japanese migrants 82 to several other countries. The rise in prevalence is a result of environmental and behavioural changes and not due to changed gene frequencies, since the increases have occurred within a few decades.

Age

The results of the Diabetes Epidemiology Collaborative Analysis of Diagnosis Criteria in Asia (DECODA) study have shown several variations in age-specific prevalence within Asian populations.83 In Indian populations, the prevalence of diabetes peaks at 60—69 years of age, whereas in Chinese populations it peaks at age 70—89 years. Indian people have higher age-specific prevalence and higher prevalence of impaired glucose regulation at a younger age than do Chinese people.83 Findings from India,6 Pakistan,25 and Sri Lanka 34 are similar. These differences are probably related to environmental and genetic influences.

One of the hallmarks of diabetes in Asian countries is the rapidly increasing prevalence of young-onset diabetes. A high prevalence of maturity-onset diabetes in the young has been reported in India.84 In China, from 1994 to 2000, there was an 88% increase in prevalence in the 35—44 years age group.14 Data from southern India show that the prevalence of diabetes in people younger than 44 years has increased from 25·0% of the total prevalence in 2000 to 35·7% in 2006.6, 8 Factors that have contributed to the epidemic of obesity and young-onset diabetes are the rapid transition in dietary habits, reduced physical activity, changing pattern in leisure activities, longer working hours, and decreasing sleep hours.80, 85, 86 Asian people with young-onset diabetes have substantial phenotypic heterogeneity, many with positive family history, impaired β-cell function, no islet autoantibodies, and coexistence of cardiometabolic risk factors.49, 87 This tendency to impaired β-cell secretory function might be due to genetic factors, although visceral adiposity and lipotoxicity, low birthweight and maternal imprinting,88 β-cell loss and amyloid deposits might also have contributory roles.80, 89

Type 2 diabetes in children is increasing at an alarming rate, especially in Asian children in both native lands and in migrant populations.90 Its prevalence in the UK is 14 times higher in Asian children than in white European children.91 Population-based and community-based studies of type 2 diabetes in children are few,92 but several clinic-based studies have been done.87, 90 The epidemic of type 2 diabetes in children is expected to become worse with the increasing rate of obesity in children in developing countries.90 The 2002 National Nutrition and Health Survey in China showed that 4·1% of children aged 7—12 years and 5·6% of children aged 12—18 years were overweight, and the respective obesity prevalences were 2·5% and 1·6%.93 In Hong Kong, the results of a community-based study showed that 8—10% of children aged 12—13 years were obese.94

Adipose tissue and insulin resistance

The prevalence of insulin resistance and metabolic syndrome is high in Asian people.95 Features of insulin resistance are manifested in children and adolescents of south Asian origin even in the absence of obesity.46, 47 Obesity is a major determinant of type 2 diabetes, and is associated with many metabolic aberrations that impair insulin sensitivity.96, 97 These abnormalities include excess lipolysis causing increased concentrations of non-esterified fatty acids and triglycerides in blood and skeletal muscle. Glucose uptake by muscle is suppressed. Obesity also impairs insulin action by changing secretion of cytokines, specifically of leptin and adiponectin,98 and leads to proinflammatory conditions.99 Features of insulin resistance, including hypertriglyceridaemia 100, 101 and increased abdominal or visceral fat,43—45 are seen even in non-obese Asian populations. Insulin resistance has been studied extensively in Asian Indian groups. Hyperinsulinaemia, a characteristic of insulin resistance, is common in Asian people, especially in southeast Asian populations.43—45

Unusually, Asian Indian groups have high concentrations of non-esterified fatty acids in plasma during fasting despite relative hyperinsulinaemia, and this concentration is not suppressed by oral glucose administration.43 They also concomitantly have high plasma leptin and low plasma adiponectin concentrations. These changes are independent of obesity or intra-abdominal fat distribution. With development of obesity, these abnormalities will be aggravated.42, 43

Asian people generally have a lower body-mass index than do people of many other races, but the association between body-mass index and glucose intolerance is as strong as in any other population. Asian populations seem to differ from European populations in associations between body-mass index and percentage of body fat and health risks. On the basis of the evidence, a WHO expert consultation concluded that a substantially increased risk of type 2 diabetes and cardiovascular diseases occurs at body-mass index lower than 25 kg/m2. However, for Asian populations there is no uniform threshold for body-mass index to identify people who are overweight and obese. Although the WHO body-mass index figure should be retained as an international classification, individual countries could make decisions about the definition of increased risk for their populations.102 WHO recommends that a body-mass index of 18·5—22·0 kg/m2 is healthy for Asian people.102 The International Diabetes Federation criteria for healthy waist circumference for Asian people is less than 90 cm for men and less than 80 cm for women.103 Revised guidelines for diagnosis of obesity, abdominal obesity, and metabolic syndrome in Asian Indian populations were put forward by a consensus group in India.104 According to these guidelines, the criteria are a healthy body-mass index of 18·0—22·9 kg/m2, an overweight body-mass index of 23·0—24·9 kg/m2, and obesity greater than or equal to 25 kg/m2. The healthy waist circumference limits are 90 cm for men and 80 cm for women.

Abdominal obesity is a characteristic feature in many Asian populations, especially in southeast Asia. Insulin resistance is associated with visceral and subcutaneous fat content.105 Young south Asian men in the USA had insulin resistance even without increased intraperitoneal fat mass, unlike the white population studied.42 The ethnic difference in Asian Indian people could be mostly related to the higher amount of truncal fat and to the large dysfunctional subcutaneous fat cells,106 rather than to presence of excess visceral fat. Glucose disposal rate and plasma adiponectin concentration are inversely related to fat-cell size. South Asian groups generally have a low rate of glucose disposal and low adiponectin concentrations, but high leptin concentrations.42 A high proportion of body fat is seen even in newborn babies. A large, prospective study in India has shown that Indian newborn babies are thinner, shorter, and lighter than UK babies, but are relatively fat because of paucity of non-fat tissues.88

Fatty acid influx to the liver is an important pathogenetic factor for fatty liver and is also a determinant of excess triglyceride-rich lipoproteins. Dyslipidaemia in type 2 diabetes is more severe in the presence of fatty liver. Ectopic fat accumulation in the liver and skeletal muscle are important determinants of insulin resistance and can also predispose to development of type 2 diabetes.107 The twin cycle hypothesis put forth in a review by Taylor 108 explains the cycle of reactions linking muscle insulin resistance, ectopic fat deposition in the liver and islets, hepatic insulin resistance, and β-cell dysfunction eventually resulting in onset of type 2 diabetes (figure 3). Such pathogenetic mechanisms are likely to be operating in Asian people who have features of insulin resistance and have been adversely affected by maladaptation to modernisation and affluence.

The twin vicious cycles in pathogenesis of type 2 diabetes108
Cycle A: Development of fatty liver, which leads to increases in basal plasma glucose and basal insulin secretion leading to hepatic insulin resistance. Cycle B: Sequence of changes in tissues when exposed to higher concentrations of triacylglycerols that leads to decreased insulin response to ingested glucose. Postprandial response to glucose becomes blunted. These vicious cycles have inhibitory effects on islet-cell functions leading to a sudden onset of clinical diabetes.

Low adiponectin concentrations in plasma in Asian people have been linked to low insulin sensitivity and high prevalence of diabetes and cardiovascular diseases.109 In Asian populations, low adiponectin concentrations are predictive of type 2 diabetes.110 However, the investigators did not find a direct association between adiponectin and insulin resistance or other cardiometabolic risk variables.111 A study in migrant south Asian women in the USA 112 had similar findings. The mechanism by which adiponectin is linked with diabetes might also differ in south Asian populations. More detailed studies are needed to explain the mechanisms underlying insulin resistance in these populations.

Asian Indian people produce higher amounts of adenosine triphosphate despite being more insulin resistant, and have higher intramuscular triglyceride concentrations than do white people in the USA.113 Concentrations of intramuscular triglycerides are similarly high in Asian Indian people with and without diabetes, suggesting a possible difference in the association of insulin resistance and diabetes in this population.113 Moreover, in Asian Indian populations, plasma triglycerides and non-muscle triglycerides are strongly associated with insulin sensitivity.114

A pathophysiological link has been shown between obstructive sleep apnoea and excess visceral fat, independent of overall body fat.115 Obstructive sleep apnoea might be directly related to insulin resistance in both obese and non-obese people.116 Physical inactivity and sleep deprivation might also be contributing factors for many of the inflammatory, oxidative, endothelial, and coagulation abnormalities that are associated with obstructive sleep apnoea.115

Intrauterine environment and imprinting

Intrauterine and postnatal environment can affect future risk of diabetes and cardiovascular disease via fetal programming.117 The thrifty genotype and thrifty phenotype hypotheses seem to apply to Asian populations. Maternal undernutrition, infant’s low birthweight, and rapid postnatal child growth are all associated with increased risk of diabetes in offspring, and these factors might be especially relevant to developing countries such as India 88 and China.118 Additionally, offspring of women who are obese or have diabetes are at increased risk of diabetes and other cardiometabolic complications.117—119 In view of the increase in childhood obesity and increasing number of women with young-onset diabetes in Asia, this link will further exacerbate the situation by creating a vicious cycle of diabetes begetting diabetes.

The mechanism underlying such transgenerational inheritance of disease risk is under intense investigation; it is thought to involve epigenetic silencing of target genes via methylation or histone modification during development, resulting in a mismatch between the metabolic phenotype that was programmed during development and the nutritionally rich adult environment.117 Again, this mismatch might be most pronounced in countries that are undergoing the most rapid economic development. Improved understanding of the effect of maternal imprinting is needed to help to address the epidemic of diabetes in Asia.

Diagnosis and complications

The latest WHO report on the definition and diagnosis of diabetes recommended that the oral glucose tolerance test be retained as a diagnostic test.120 The need to identify postprandial hyperglycaemia seems especially relevant in Asian populations. In the DECODA study,83 more than half the patients with diabetes had isolated postprandial hyperglycaemia, which is also a powerful predictor of cardiovascular disease and premature death.121 In Asian populations, fasting plasma glucose 83, 122 and glycosylated haemoglobin (HbA1c) concentrations 123 have much lower sensitivity than does 2 h postglucose concentration for detection of diabetes.

Owing to the early onset of disease, Asian patients with diabetes are at high risk of developing long-term diabetic complications. In urban areas, prevalence of diabetes is lower in poor socioeconomic strata than in high-income groups, but glycaemic control is poor, so the occurrence of vascular complications is higher.101, 124 Few population-based data are available for vascular complications of diabetes from developing countries. In Asian countries, an estimated 30% of people with type 2 diabetes have retinopathy. In North America, the prevalence of diabetic end-stage renal disease is nearly 80% higher in Asian than in white patients with diabetes; however, rates of below-the-knee amputations are 60—69% lower and the incidence of cardiovascular disease is 24—33% lower.125 Although the prevalence of peripheral vascular complications is low in Asian Indian people, because of the large population the number with foot complications is high. Prevalence of neuropathy is high and it is a risk factor for foot infections.126

High rates of cardiovascular complications have been reported in native and migrant south Asian populations.127 Heterogeneity in the occurrence of cardiovascular risk variables is manifested in migrant south Asian groups, based on their socioeconomic strata.127 Possible discrepancies in adjustment for comorbidities might explain the conflicting findings. Within Asia, susceptibility to vascular complications varies. In the WHO Multinational Study of Vascular Disease in Diabetes, Chinese patients with diabetes had much lower rates of coronary artery disease than did patients in other centres, but they had substantially higher rates of retinopathy and nephropathy.128 A high prevalence of nephropathy was also shown in the results of the Microalbuminuria Prevalence (MAP) study, which noted a prevalence of 40% for microalbuminuria and 20% for macroalbuminuria in hypertensive patients with type 2 diabetes in Asia.129 In addition to genetic factors, the tendency towards visceral adiposity is also likely to contribute to development of cardiovascular and renal complications.130

Health-care outcome

The diabetes health-care situation is similar across most developing countries. Economic disparities, scarcity of adequate health-care facilities, and low educational status prevalent in these countries pose major hurdles for achievement of optimum glycaemic control. The cost of diabetes care is high and is increasing worldwide. The economic burden is very high, especially in developing countries, and more so in the lower economic groups, who spend 25—34% of their income on diabetes care.131, 132 The cost of care increases substantially when complications occur or when admission to hospital, surgery, or insulin treatment is needed. The results of a few studies suggest that treatment of patients with diabetes in developing countries is far from optimum.133, 134

In the International Diabetes Management Practice Study, investigators analysed diabetes care outcome in urban areas in 18 countries, including eight countries from Asia, and showed that about a third of patients who were treated by diabetologists or endocrinologists had reached the goal of HbA1c concentrations of less than 7%.134 However, the proportion was similar in other developing regions, namely eastern Europe, Latin America, and Africa. Up to 40% of patients were not screened for risk factors or complications. In developing countries, factors pertinent to patients, doctors, and health-care systems all affect glycaemic control.134

Prevention and future action

Prevention of obesity and diabetes is more cost effective than is the treatment of complications resulting from diabetes. A 2—3% reduction in energy intake or an extra 10—15 min of walking each day could offset weight gain in roughly 90% of the population in China.85 Lifestyle intervention can have a sustained benefit, with a 43% reduction in incidence of diabetes over a 20-year period.135 The results of a primary prevention study in India have also shown that lifestyle modification is effective with an approximate reduction of 30% in comparison with the control group.136 Lifestyle modification was the most cost-effective intervention for prevention of diabetes in high-risk groups.137

The challenges for diabetes care in India, China, and other Asian countries will include improved education to alert the population to risk factors for diabetes, training of patients to manage their disease more effectively, and development of more structured care delivery and management of cardiometabolic risk factors.138, 139 A mismatch of national health-care budget and health-care burden, especially due to the epidemic of non-communicable diseases, poses a huge challenge in most countries. More data are needed for the economics of diabetes and the quality of life and cost-effectiveness of various interventions. Well targeted basic research is needed to provide insight into feasible strategies for prevention of diabetes and its complications.

A UN resolution has recognised type 2 diabetes as a serious epidemic for which urgent steps to improve management and prevent disease development are needed. It urges member states to develop national policies towards these goals.140 In many Asian countries (eg, India, China, Pakistan, Bangladesh, Malaysia, Vietnam, and Singapore), governments have initiated national programmes for prevention and control of non-communicable diseases. Programmes targeting greater public awareness of these diseases and strategies to build national capacity by training medical and paramedical personnel to manage the disorders are expected to curb the epidemic.

Search strategy and selection criteria

We searched PubMed using the keywords “diabetes in developing countries”, “diabetes in Asia”, “type 2 diabetes in Asia”, “risk of diabetes in Asian populations”, “obesity and diabetes in Asians”, “genetics of type 2 diabetes in Asian populations”, “Chinese”, “polymorphisms”, and “adipokines and diabetes in Asian populations”. Peer-reviewed reports published between 1980, and 2009, in English and Chinese were included. Several International Diabetes Federation and WHO publications were used, in addition to reviews and book chapters. We also searched the reference lists of reports identified by the search strategy and selected those judged relevant.

Contributors

All authors have seen and approved the revised version of the Seminar. AR had final responsibility for the decision to submit for publication.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

We thank S Selvam and C J Thirupurasundari for help with compiling the references, L Vijaya and A Bobby for secretarial assistance, J Chan for her helpful comments, and J C Florez for permission to reproduce figure 2. RM acknowledges research funding support from the research fund of the Department of Medicine and Therapeutics, Chinese University of Hong Kong, the Research Grants Council of Hong Kong (CUHK4724/07M), and the Innovation and Technology Fund of the Government of the Hong Kong Special Administrative Region (ITS/088/08).

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Prof Janet Treasure FRCPsych, Angélica M Claudino PhD, Nancy Zucker PhD

Summary

This Seminar adds to the previous Lancet Seminar about eating disorders, published in 2003, with an emphasis on the biological contributions to illness onset and maintenance. The diagnostic criteria are in the process of review, and the probable four new categories are: anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder not otherwise specified. These categories will also be broader than they were previously, which will affect the population prevalence; the present lifetime prevalence of all eating disorders is about 5%. Eating disorders can be associated with profound and protracted physical and psychosocial morbidity. The causal factors underpinning eating disorders have been clarified by understanding about the central control of appetite. Cultural, social, and interpersonal elements can trigger onset, and changes in neural networks can sustain the illness. Overall, apart from studies reporting pharmacological treatments for binge eating disorder, advances in treatment for adults have been scarce, other than interest in new forms of treatment delivery.

(more…)

Enrico Heffler, MD, is a young italian allergist & immunologist, and his main clinical research field is asthma and its comorbidity. Enrico is the current Junior Member representative for asthma section board of European Academy of Allergology and Clinical Immunology (EAACI), and the current national coordinator of Junior Members of Italian Society of Allergology and Clinical Immunology (SIAIC).

Enrico, which is the current prevalence of asthma and which is the predictable trend of it for the next decades?

Asthma is one of the most common chronic diseases in the world: its global prevalence is estimated about 1-18% of the population, depending on the considered country. Around 300 million people in the world currently have asthma and probably there is still a large proportion of asthmatic patients, particularly in low income countries, who are not included in this estimate because they are not properly diagnosed.

In the last decades, the worldwide prevalence of asthma dramatically increased both in children and adults, similar to what happened to other allergic diseases such as rhinitis or eczema, in parallel with an increase in atopic sensitisation which seems to be somehow related to western lifestyle and to urbanisation. It is estimated that in 2025 about 60% of the whole world’s population will live in urban settings and that will be probably accompanied with a further increase of about 100 million people suffering for asthma in the next 15 years.

Is there any difference in prevalence and impact of asthma in different countries?

There is now evidence that there is a progressive increase of asthma symptoms prevalence in regions where prevalence was previously low, such as Africa, South America and some regions of Asia, while the prevalence decreases in North America and Western Europe. The result of these different trends in prevalence of asthma is that, despite the fact that international differences are lessening, the global burden of asthma is continuing to rise, particularly in countries in which patients may have difficulties to access to basic asthma medication or medical care.

Hence, disadvantaged countries are now experiencing an increase of need of asthma medications and cures, but without enough resources to face this emerging clinical problem; in these countries it is particularly troublesome to correctly treat patients with more severe asthma.

As happens for several other diseases, the economic condition of a country deeply influences the way asthma is diagnosed and treated; increasing the economic wealth and improving the distribution of resources between and within countries should represent important priorities to enable better health care to be provided.

Do people still die from asthma?

Yes they do! It is estimated that asthma accounts for about 1 in every 250 deaths worldwide, with the highest rates of disease-related mortality in China and Russia (36.7 and 28.6 asthma death per 100,000 asthmatics, respectively), Uzbekistan (27.2), Albania (20.8) and South Africa (18.5).

Many of these deaths could be largely preventable improving long-term medical care, giving the opportunity to all patients to access to basic medications, promoting prevention campaigns and reducing the delay in obtaining help during the final attack.

Which is the public health impact/cost for asthma?

The economic cost of asthma is considerable both in terms of direct medical costs (such as costs of medications used to prevent and treat asthma, hospital admissions etc.) and indirect medical costs (such as time lost from work and school, and premature death). As far as costs and disease-related disability, asthma impacts on health-related costs similarly to other chronic diseases such as diabetes, liver cirrhosis or schizophrenia, leading scientific societies, health-care systems and governments to look for the right way to better prevent, diagnose and treat such an impacting disease.

How can we reduce the impact and cost of asthma?

First of all, it is fundamental that governments and health-professionals recognise asthma as an important cause of morbidity and mortality worldwide, so that they can put to use all preventative measures in order to reduce the morbidity and better control symptoms of asthma. Particularly, it is important to reduce environmental factors (such as indoor and outdoor pollution) which may affect respiratory morbidity: promoting anti-tobacco public health policies and reducing occupational exposures may be good starting points!

Since it is acknowledged worldwide that prevalence and economic/health impact of chronic diseases are more elevated where there are poverty, poor education and poor infrastructures, it is fundamental to improve accessibility to essential drugs and medical care for the management of asthma to all social classes and to low- and middle-income countries, also by adapting international asthma guidelines for developing countries to ensure they are practical and realistic in terms of different health care systems.

What is, in your opinion, the major unmet need in asthma management?

The main asthma-related problem that scientific community should find the way to solve is, in my opinion, that about 10% of the patients have a severe form of asthma, characterized by a particular resistance to typical treatment modalities, including administration of high dose of inhaled or systemic corticosteroids and high dose of bronchodilators. This severe end of the disease spectrum accounts for approximately 30% of health care costs of asthma. Thus there is a compelling need to look for new therapeutical tools for patients resistant to typical asthma medications. Different strategies, almost all of them targeting specific different phenotypes of severe asthma, have been proposed, but only few of them are currently used and suggested for severe asthmatics. Omalizumab (an anti-IgE monoclonal antibody) has been recently introduced in clinical practice and it showed to be greatly effective for the treatment of severe allergic asthmatics with high levels of serum IgE. Other therapeutical approaches that have been studied in the last decade include anti-Tumor Necrosis Factor alpha (anti-TNFα) strategies (biological agents against TNFα axis unfortunately gave contrasting results in improving severe asthma outcomes), anti-IL5 drugs (recently Mepolizumab, an anti-IL5 monoclonal antibody has been showed to be effective in reducing severe exacerbations and to improve disease-related quality of life in a particular subset of patients: those with refractory eosinophilic asthma), anti-IL2 biological agents (Daclizumab, a humanized monoclonal antibody against the IL-2R alpha chain, has been recently described to improve pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on inhaled corticosteroids), and even interventions to decrease airway smooth muscle, such as bronchial thermoplasty (a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall). Unfortunately, apart from Omalizumab, none of these novel thereapeutical modalities are currently available and recommended to treat patients with severe asthma.

Thus, it is to be hoped that the scientific community focuses the attention on novel and possibly affordable treatments for those asthmatic patients who still are at-risk of severe exacerbations, hospital admissions and death

Savino Sciascia is a TLS RA and an intern at the University of Turin
sciascia.savino@gmail.com

Vishal Madan MRCP, Dr John T Lear FRCP, Rolf-Markus Szeimies MD

Summary

The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their pathogenesis and in the search for new non-invasive treatments. Whereas the role of cumulative sun exposure in pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous-cell carcinomas can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective and tissue-salvaging therapies continues.

(more…)

Breast Cancer in India

A 35 year old female presented with bilateral advanced breast carcinoma (Stage 3) with an ulcer in the right breast, bilateral axillary lymphadenopathy and a left supraclavicular lymph node. The description adequately conveys the guarded prognosis.I worked on this case for my Surgery Practical Exam and it reinforced a thought that had been troubling me for a very long time. My patient was seeking medical help for the first time, though the lump had been present over the past two years. She had even continued to breastfeed her baby and stopped only five months ago when she developed excruciating pain. My patient is not one of those surprising exceptions who did not seek medical care on time. I have come across at least 10 such patients of breast cancer during my brief six week surgical rotation. I have tried to interview extensively all these victims, to discover the reason behind not seeking medical advice on time and ignoring a largely noticeable breast lump.

The reasons are so simple and naïve that they are distressing – the present patient did not know that hard lumps in the breasts were of any significance until she developed an ulcer a month ago. She even attributed her pain to excessive breastfeeding. Ignorance comes across as the main factor though other reasons also exist, including abusive and suppressive husbands and in-laws, and lack of knowledge among fellow female well-wishers who also are equally unaware. It is so sad to come across patients like this, especially when women in more developed countries are undergoing regular screening mammographic investigations and are well aware of breast self examination techniques.

In India, cancer of the breast is the most common cancer among women in many regions and has overtaken cervical cancer, which was the most frequent cancer a decade ago (1). It has been estimated that during the year 2001 alone, nearly 80,000 women developed breast cancer in India (2). Studies indicate that as India becomes Westernized, the incidence rate for breast cancer is increasing. A 2005 study conducted by the International Association of Cancer Research, based in Lyon, France, projected that there would be 250,000 cases of breast cancer in India by 2015, a 3% increase per year. Currently, India reports roughly 100,000 new cases annually (3).

Screening and Mortality

Screening by clinical breast examination (CBE) alone has not been demonstrated by randomized controlled trials to reduce mortality although a large trial is currently underway in Bombay by the Tata Memorial Centre(4). An IARC Working Group concluded in 2002 that there is inadequate evidence that breast screening by CBE, either alone or together with mammography, can reduce mortality from breast cancer (5). However, cancers detected by CBE tend to be diagnosed at an earlier stage than those not detected by screening, suggesting a greater potential for effectiveness in a setting where stage at diagnosis is generally poor (6). Although CBE undertaken by health workers seems to offer a cost-effective approach to reducing mortality, the sensitivity of the screening program in the real context was low with a sensitivity of only 25.6% and positive predictive value 1% (7). The UK Preventive Task Force report found that trials for breast self-examination showed no reductions in mortality but increase in benign biopsies. They concluded that no benefit has been shown for clinical breast examination or breast self-examination. On the other hand mammography screening reduces breast cancer mortality by 15% for women aged 39 to 49 years with low radiation exposure and an estimated over diagnosis of 1 to 10% (8).

While studies show that the efficacy of breast self examination is limited, it is imperative to recognize our shortcomings. India’s healthcare system is still in its developing phase, making it virtually impossible for all females to undergo regular screening mammography and general health checkups. Even so, there are still precautions that can be maintained. It is definitely possible to create awareness about the common signs and presentation of breast carcinoma, the common risk factors that may be contributory and the need for breast self examination.

Self-Examination

It is suggested that for very low resource settings in certain parts of India where population based screening, even with clinical breast examination by primary health workers is not feasible, health education combined with access to screening and treatment services, may be a simple and feasible strategy for reduction in cervix and breast cancer mortality (4). A praiseworthy practice about our hospital with a strong focus on women’s health issues, is that they not only perform a “clinical breast examination” on all women but also counsel them regarding the need for regular breast self-examination.

Reeler A et al (9) have defined a public health approach to cancers in developing countries where resources for effective cancer control are very limited and offer a framework for putting women’s cancers in developing countries on the global public health agenda. The key areas as proposed by them are: 1. Proposals for a new, integrated public health approach to women’s cancers (breast and cervical) in resource poor settings; 2. Reviews of the evidence for cost-effective screening and early detection of breast and cervical cancer; 3. Outlines of ways to make a priority of breast and cervical cancers in developing countries on the political agenda of international agencies. Implementation of such an integrated program may be the solution that we are looking for. A multilevel approach can be initiated only with active government policies and we hope that it would take shape in the near future. A number of Breast Cancer support groups and NGOs like Aastha Breast Cancer Support Group, Aarogya etc. are already doing very good work in providing medical and emotional support to affected women. Meanwhile given the current burden of breast cancer in India, it is the duty of everyone associated with medicine and anyone with a good outreach to be aware of the need of breast self-examination and to promote it whichever way they can. It is so unfortunate that even literate, educated, and well-read females are unaware of the need and method of self-examination.

We as a nation have a very long way to go. It is our duty as members of the healthcare delivery team – medical students and physicians alike – to do our part by educating and creating awareness about breast cancer and its early detection.

Gurmeen Kaur is a TLS RA and a final year medical student at Lady Hardinge Medical College, India
kaur.gurmeen(at)gmail.com

The author would like to acknowledge the assistance of Dr. Anurag Srivastava, a Breast Oncosurgeon at the All India Institute of Medical Sciences, New Delhi, India for his contributions to the paper.

References

1. Murthy NS, Agarwal UK, Chaudhry K, Saxena S. A study on time trends in incidence of breast cancer – Indian scenario. Eur J Cancer Care (Engl). 2007 Mar;16(2):185-6.

2. Murthy N.S., Juneja A., Sehgal A. & Luthra U.K. (1990) Cancer projection by the turn of century. Indian Journal of Cancer 27, 74–82.

3. Bagchi S.Breast Cancer rises in India. CMAJ. 2008 July 1; 179(1): 27.

4. Mittra I, Mishra GA, Singh S et al. A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening. International Journal of Cancer. 2010; 126(4): 976-984.

5. IARC Working Group on the Evaluation of Cancer-Preventive Strategies. IARC Handbooks of Cancer Prevention: Breast Cancer Screening (2002) Lyon, France: IARC Scientific Publications.

6. Duffy SW, Tabar L, Vitak B, Warwick J. Tumor size and breast cancer detection: what might be the effect of a less sensitive screening tool than mammography? Breast J (2006) 12(suppl_1):S91–S95.

7. Pisani P, Parkin DM, Ngelangel C et al. Outcome of screening by clinical examination of the breast in a trial in the Philippines. 2005; 118(1): 149-154.

8. Nelson HD, Tyne K, Naik A et al. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009 Nov 17;151(10):727-37, W237-42.

9. Reeler A, Qiao Y, Dare L, Li J, Zhang AL, Saba J. Women’s cancers in developing countries: from research to an integrated health systems approach. Asian Pac J Cancer Prev. 2009 Jul-Sep;10(3):519-26

Chronic mountain sickness (CMS) is the least studied cerebrovascular impairment of the high-altitude illnesses. Unlike acute mountain sickness (AMS) which may affect people within hours of exposure to high-altitude, CMS only affects certain populations who are native or long-time residents of high-altitude. AMS is characterized by nausea, fatigue and insomnia as well as other symptoms in individuals who have recently ascended to high altitude. More serious progression of AMS can lead to life-threatening problems such as high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE). CMS, in contrast, although sharing many symptoms with AMS, only affects permanent high-altitude dwellers.

Three distinct high-altitude populations have been studied to determine the incidence of CMS and to determine whether certain populations are better able to live in hypoxic conditions. Studies on Andeans, Ethiopians and Tibetans have shown that the incidence of CMS is not equal between all populations (1). Perhaps owing to time since migration, the incidence of CMS seems to be highest in Andeans (~50% incidence recorded in Peruvian high-altitude dwellers) followed by Tibetans (~35%) and finally Ethiopians (0%) where no report of CMS has been recorded. Given that it is thought Homo sapiens originated around the area that would today be Ethiopia-Kenya, Ethiopian high-altitude dwellers would have been living at these altitudes longer than the other groups (2). The longer time of residence may have increased their adaptation to the environment more so than the Andeans who would have migrated later.

CMS is characterized by extreme polycythemia (haematocrits upwards of 65% have been reported (3)) and shares many symptoms with AMS, such as headache, dizziness, sleep disturbances, fatigue, cyanosis and palpitations (4). Due to the polycythemia CMS can be fatal. Over time the haematocrits of these individuals at altitude increases to cope with the ambient hypoxia and to maintain adequate oxygen delivery to the tissues. However, this increase in haematocrit increases the viscosity of the blood and places a larger afterload on the heart. Ultimately this increased stress on the heart places the individual at higher risk of cardiac failure and possible death (5). Unfortunately, the etiology of CMS remains unclear and has yet to be fully determined. There have been some suggestions that decreased respiratory sensitivity to hypoxia and carbon dioxide with resulting hypoventilation, hypoxia and marked polycythemia may be a potential cause, however, research is currently ongoing (6).

There is currently no well-established medication for the treatment of CMS which poses a considerable problem to the populations affected by it. Presently, treatment for CMS involves descent to sea-level whereupon the symptoms begin to disappear. As soon as these individuals return to altitude, however, the symptoms reappear (3). For most populations affected by CMS, leaving their homes and livelihoods on the mountains to work elsewhere at sea-level is not an option which presents a widespread problem that needs to be addressed. In Andeans, for example, where studies have shown these populations to have the highest incidence of CMS, many people moved to altitude to work in the mines. Generations of people have now lived at altitude and are either unwilling or unable to move back to sea-level where they face the prospect of being unemployed and away from their close social networks at home. As such, people become more desperate for working procedures and many controversial treatments have been reported in the past to help “cure” their CMS. Treatments such as leeches, marrow radiotherapy and phlebotomies (blood-letting) are not uncommon and many people may opt to undergo them to escape the suffering from CMS and to prevent the need to move to sea-level. More serious reports of the use of phenylhydrazine, a toxic haemolytic agent, have also been made. Phenylhydrazine destroys red blood cells which help decrease the haematocrit; however, phenylhydrazine can also cause liver and kidney damage and severely limits the work capacity of an individual due to its disruption of oxygen transport. An overdose of phenylhydrazine can be fatal (7).

Given the desperation of many of these people it is understandable why they may opt for such drastic treatments, however, efforts should be made to find safer treatments for CMS and to stop the practise of these potentially dangerous procedures. Unfortunately, because CMS does not receive much publicity research into potential treatments is slow. Also, as CMS only affects native populations of East Africa, the Andes Mountains and the Himalayas, many researchers opt to work with AMS, which more often affects North Americans and Europeans and does not require them to conduct research at these different locations across the world. Our research team is one of only a handful of teams that travels to these locations to study the native populations and help elucidate the pathology of this disease as well as, importantly, determine safe ways to allow these populations to live at their high-altitude homes. It was due in part to our research that we now know the differences in CMS distributions across the world. By studying the cardiovascular and cerebrovascular physiology of these different groups, especially the well-adapted Ethiopians, we hope to be able to find ways to confer the adaptation measures seen in well-adapted groups to help treat those populations with higher incidences of CMS. Already a research team in Bolivia has managed to test the efficacy of a new drug, acetazolamide, for the treatment of CMS due to past studies by our group, as well as others, in Andean highlanders. Acetazolamide is a carbonic anhydrase inhibitor and is known to promote diuresis, cerebral blood flow and stimulate ventilation via metabolic acidosis. Their study on Andeans showed a ~7% decrease in mean haematocrit and a 5% increase in nocturnal arterial oxygen saturation in the experimental group with no serious side-effects. (8). Although this is a step in the right direction further studies are required to decrease the haematocrits further in a similarly safe manner.

CMS is a debilitating disease that can be fatal if untreated. Just as importantly, however, are the social implications of the illness. The only established way to treat CMS has been to relocate people from their native homes at altitude to sea-level; a transition that can be very difficult to make. Few groups conduct research on CMS and its potential treatments due to the difficulty inherent in conducting field-research at altitude and the fact that it does not affect populations in North America or Europe where most altitude research occurs. Intensifying the publicity of CMS and its associated problems for the populations affected by it could help counter this trend and allow for the creation of better and faster treatments.

Inderjeet Sahota is studying for an MSc in cardiovascular physiology at Simon Fraser University in Canada
isahota(at)sfu.ca

References

1. Claydon, Victoria E., et al. Cerebrovascular Responses to Hypoxia and Hypocapnia in Ethiopian High Altitude Dwellers. Stroke. 2008; 39: 336-342.

2. Brugniaux, Julien V., et al. Cerebrovascular responses to altitude. Respiratory Physiology & Neurobiology. 2007; 158: 212-223.

3. Norcliffe, L. J., et al. Cerebrovascular responses to hypoxia and hypocapnia in high-altitude dwellers. Journal of Physiology. 2005; 566: 287-294.

4. Monge, Carlos C., Leon-Velarde, Fabiola and Arregui, Alberto. Chronic Mountain Sickness in Andeans. In: Thomas F. Hornbein and Robert B. Schoene. High Altitude: An Exploration of Human Adaptation. New York: Marcel Dekker; 2001. p. 815-838.

5. Nadel, Ethan. Environmental Physiology. In: Walter F. Boron and Emile L. Boulpaep. Medical Physiology. Philadelphia : Elsevier; 2005, p. 1256-1267.

6. Hultgren, Herb. High Altitude Medicine. Stanford, USA: Hultgren Publications, 1997.

7. Zubieta-Calleja, G R, Zubieta-Castillo, G and Zubieta-Calleja, L. Inadequate Treatment of Excessive Erythrocytosis. Acta Andina. 1995; 4: 123-126.

8. Richalet, Jean-Paul, et al. Acetazolamide: A Treatment for Chronic Mountain Sickness. American Journal of Respiratory and Critical Care Medicine. 2005; 172: 1427-1433.

Introduction

Forensic psychiatry represents the specific area of identification, discussion and guidance regarding issues that encompass the interconnection between both the legal and medical worlds. (1) It is a subspecialty of general psychiatry which obtained full recognition as a specialty in its own right in the 1970s. (2, 3, 4) It aimed at addressing the pragmatic problems that involved dealing with individuals who committed offences. (5)

This paper aims at reviewing the historical landmarks about the evolution of forensic psychiatry, its practice in various countries and finally its impact on the future of mental health.

History: The Sefeloge Case

The history of forensic psychiatry appears to have been significantly influenced by the framework of two professions, medicine and law. With the increasing power of the legal and medical professions, people gradually developed a quest for greater public esteem in society. (6) One of the major landmarks in the development of forensic psychiatry is the assassination attempt of a mentally ill Sergeant named Maximillian Joseph Sefeloge on the Prussian King Friedrich Wilhelm IV in the 1850s. (7) The case of Sefeloge was one of the first whereby medico-historical examination was sought because the motive of the act was unclear to the authorities. A forensic scientist and three well-known psychiatrists were summoned to carry out this forensic examination. These forensic experts proved to be particularly competent because of their common experience in dealing with psychiatric patients. This radically unique case from nineteenth century Germany showed that the statement of a psychiatrist could be accepted in courts as an expert witness in order to evaluate crimes pertaining to unclear mental conditions and from there the evolution of this specialty could proceed without hindrance. (6,7)

Forensic Psychiatry in Different Countries

During the past few years, forensic psychiatry as a subspecialty has been recognized and accepted in many countries namely US, UK, Canada, Israel, Australia, Sweden, Netherlands and New Zealand. (9, 10) However, forensic psychiatry is yet to be recognized in many countries of Africa and Asia, where there is an acute shortage of human resource. (11) Moreover, most professionals who are involved in the field of forensic psychiatry has not received the proper training before practicing in this area. Besides, it is to be noted that only a limited amount of information is available on the status of forensic psychiatry in African nations which makes it considerably difficult to establish a uniform judgment. (12) Most states in Africa have roughly one psychiatrist per one million inhabitants and in South Africa the number of psychiatrists has remained virtually stagnant for the last 30 years. (13)

Forensic Psychiatry appears to be different from one country to another due to different historical, developmental, legal and mental health systems. (14) However, there are some commonalities shared across countries; the need to ensure the treatment of seriously mentally ill patients who become delinquent and the opportunity use forensic psychiatry as evidence in court. Forensic psychiatrists in different countries work to prevent relapse of mentally disordered offenders. It has developed special knowledge and skills that pertain especially to violence and sexual deviance. (9)

Forensic Psychiatry in Sweden

In Sweden, the number of mentally disordered patients is increasing steadily. According to recent studies, a disproportionally large number of former psychiatric inpatients appear in the judicial system because of criminal charges (15,16,17). Further evidence showing that there is a nexus between violence, crime and mental illness has been presented during the last decade. Out of the 15,000 individuals who are convicted of a crime each year in Sweden, 3.5% undergo a forensic psychiatric examination. (18) Individuals in this particular group may require treatment and support services to a significantly larger extent compared to the general population. (10)

Forensic Psychiatry in Netherlands

Forensic Psychiatry is considered very important in Netherlands, with many patients treated in special forensic mental health institutes. Treatment is provided to offenders who at the time of the crime had a psychiatric disturbance such as psychosis and addiction before they are released. (19) These offenders are treated in psychiatric hospitals that are removed from the community. Patients are put into jails, but within the institution there is a psychiatric, not a prison’s culture. (19)

Art therapies are often an integrated part of multidisciplinary treatment in most psychiatric institutions. (20, 21) About 10% of art therapists work in forensic institutions. In forensic psychiatry, art therapists from a range of different professions including drama, music, art and dance-movement collaborate in teams to participate in the overall treatment plan. (22, 23, 24) Treatment in a forensic institution consists of an integrated program involve several professionals namely psychiatrists, psychologists and art therapists.

In the last decade, the art therapies tried to affect the personality of these patients by modifying the way the patient feels, thinks, acts in concrete situations. The therapies become more “re-educative”, which means that the patient is trained to change specific cognitions, feelings and behaviors related to one problem area. This makes art therapies valuable components in the treatment of forensic patients. An important core reason for the use of art therapies in forensic psychiatry is their orientation to action. The experiential and active nature of the art therapies enable regulation of tension, impulse control, regulation of aggression planning and structuring of behavior and the development of interactive competencies. (19)

A reduction of 29% in disciplinary measures in a prison as a result of 13 months of art therapies noted in 1998 and the amount of transgressions requiring disciplinary measures as a result of art therapy decreased by 75–81%. (25,26) Two years after patients were dismissed, 69% of the persons who took part in art therapy did not re-offend compared to the control group without art therapy, in which 42% did not re-offend. (27)

Forensic Psychiatry in Singapore

Singapore is a multiethnic, modern country equipped with state of the art mental health care facilities. It has a large number of mental health professionals for the population as compared to most Asian countries and its crime rate is significantly low in comparison to most Western countries. In Singapore, studies reveal that the number of foreigners who committed homicide was significantly higher compared to the proportion of permanent residents. (29) These foreigners who committed homicide seem to suffer from serious mental illness like mood and psychotic disorders. Hence, psychiatrists recommend strongly that newly appointed employees be offered courses on psychiatric services and work stress reduction programs. (28)

Forensic Psychiatry in New Zealand

New Zealand consists of only 3 million inhabitants and the native New Zealanders are the Maori. Research shows that in New Zealand mentally ill offenders of serious crimes are securely detained for long periods, 6 years for those charged with murder. (30) Even if most patients were re-admitted to the hospital, only 6% had violently re-offended within 2 years of release from prisons. The authors found that re-offending seemed to take place soon after discharge and the Maori ethnicity was associated with violent re-conviction. The New Zealand forensic psychiatric service offers a full package of assertive community treatment programs, reinforced by cultural engagement, integration into the community and familial engagement. (31) Furthermore, in New Zealand innovative, culturally sensitive rehabilitation schemes are helping the Maori patients and these can be used as models for other countries. (28)

Forensic Psychiatry in Australia

A study carried out by Brett and Blumberg described the use of video-conferencing in facilitating the provision of specialized forensic services to courts in remote areas of Australia. (32) The effective use of video-conferencing in forensic psychiatric work allows large sums of money to be saved. Teleconferencing facility costs (Aus) $ 50 per hour compared to the extensive cost of flying patients or transporting them by road using custodial services. Besides, access to care in Australia has been appropriately handled with telemedicine and telepsychiatry. (33)

Forensic Psychiatry in Japan

An article published by Weisstub and Carvey revealed that the new forensic mental health laws adopted in 2003 and put into practice in 2005 addressed a lot of issues concerning reforms in the mental health sector. (34) These included issues concerning the refusal of medical treatment, supervision of mentally ill people who are prone to cause harm and the need to cement the relationships between forensic reforms and other related systems. The new law has been grafted to the existing laws on involuntary commitment, long term care for the aged, substituted decision making and a better system of care for serious offenders. Furthermore, the authors of the study urged a form of diversionary system so that mentally disordered persons who commit minor crimes can be appropriately referred thus avoiding ongoing stigmatization and prolonged institutionalization. (28)

Future

As the availability of beds in mental hospitals is dwindling, the number of people in prisons has increased. (35) Recent studies revealed that there is a high prevalence of people suffering from mental disorders in USA, UK and New Zealand. For instance, in UK, rates of psychosis are reported as 4-10% for remanded prisoners and 2-7 % for sentenced prisoners. (36) These studies highlight the pattern that prisons are gradually becoming the preferred place for the disposal of mentally ill. (40)

A simple examination of the figures for England and Wales shows that the numbers of mental hospital beds and the numbers of prisoners have been inversely related in recent years. Figure 1 shows the rise in the number of prisoners between 1982 and 1997 and the fall in the number of mental hospital beds available over the same period. (The data for this figure were gleaned from various Health & Personal Social Services Statistics published by the Department of Health (England) and Home Office Statistical Bulletins, all available from HM Government Statistical Service.)

Fig. 1 Graph illustrating the increase in number of prisoners and decrease in number of mental hospital beds in England and Wales, 1982-1997 (40)

Nearly 33% of the prison population could be regarded as a psychiatric case. (37) In the UK, the availability of secure hospitals permits other alternative forms of management to choose from and forensic psychiatry represents a discipline that permits the link with community services. However, the policy of the government in the UK is that psychiatric services for offenders should be as far possible provided within the NHS. There are bountiful reasons for the imprisonment of mentally ill individuals, with public concern being most important. This is due to the stigma attached to ‘criminal lunatics’ and compounded by the ubiquitous portrayal of the mentally ill in the media. Other reasons include finance; imprisonment represents a cheaper option than other forms of management of mentally disordered offenders. (38)

American authors believe that their jails are replacing mental hospitals. Torrey (1995) conducted a survey in USA and concluded that:”quietly but steadily, jails and prisons are replacing public mental hospitals as the primary purveyors of public psychiatric services for individuals with serious mental illnesses in the US.” (39)14% of male and 25% female prisoners in San Diego County Jail were on psychiatric medication. 3 years back a report from jail officials revealed that the most common reasons for jailing seriously mentally disordered individuals were said to be because of assault, theft, alcohol and drug related crimes and trespassing.

With the emergence of the internet, obsessional harassers and sexual predators have found in cyberspace a major vehicle capable of helping them to satisfy their needs and potential victims tend to be more within their ambit. These include obtaining information, monitoring, contacting victims, developing fantasy, blackmailing and avoiding apprehension. Hence, there is a need for forensic psychiatrists to bridge the digital divide and become more familiar with computers and the internet so that relevant psychiatric evaluation of such subjects can be performed. (8)

Conclusion

Mentally ill patients are usually encompassed by taboos and the etiquettes stuck on any mentally disordered individuals make it even harder to seek help. If mentally disordered individuals are involved in criminal acts or any sorts of violent conduct or opprobrious behavior, they are likely to bear the contempt of the public. However, it is known to most that anxiety, sickness, accumulated stress caused by personal and professional issues can all potentially trigger mental problems to varied levels and consequences. Forensic psychiatry is a difficult specialty whereby healthcare professionals deal with mentally ill individuals who are offenders. The task of forensic psychiatrists sounds more herculean as compared to the general psychiatrist or even a doctor who helps a patient struggling in the penumbra between life and death. A lot of care is required when dealing with such patients because caring represents a psychologically supportive tool in the treatment of such patients and is tantamount to the evaporation of one’s prejudices to accept the patient as he is, listening to the mentally disordered individuals and to seek his reform from his starting point. Besides, a lot of resources must be targeted at encouraging research and the training of experts in this particular field of mental health.

Forensic psychiatry represents a challenging subspecialty of psychiatry that intersects with the legal and medical professions. It is one of the rare fields of medicine that is concerned with the assessment and management of mentally disordered offenders. The development of forensic psychiatry has been largely influenced by the Sefeloge case in the 1850s. Forensic psychiatrists need to possess a profound knowledge of criminology, law and psychiatry. Furthermore, forensic psychiatry is practiced in many countries such as US, UK, Canada, Israel, Australia and the Netherlands, but its practice varies slightly from one country to another due to different historical, developmental, legal and mental health systems. Likewise, cultural and religious issues also affect the practice of this subspecialty. The future status of treating mentally ill patients do not appear very bright because there is growing proclivity whereby jails are replacing mental hospitals in numerous countries and this is being done at a considerable pace. Still, the future is not so gloomy for mental health in general because a lot of research is underway, for instance improving the outcomes of drugs used in treatment of mentally ill individuals.

Kevin Mohee is a third year medical student at the University of Leeds
um06krm(at)leeds.ac.uk

References

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10. Holmberg G, Kristiansson M. Contacts with public services, with special reference to mental health care, preceding a serious crime: A retrospective study of 268 subjects of forensic psychiatric investigations. International Journal of Law and Psychiatry, Volume 29, Issue 4, July-August 2006, Pages 281-288
11. Laks J,Werner J, Salvador de Miranda-Sá Jr L. Forensic psychiatry and human rights throughout life: children, adolescents and the elderly. Rev. Bras. Psiquiatr. vol.28 suppl.2 São Paulo Oct. 2006
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Historically, the study of occupational cancers was started in 1775 by Sir Percivall Pott. He recognised that exposure to a chemical agent in the workplace could cause a specific malignancy. In particular, Pott observed an increased incidence of squamous cell carcinoma of the scrotum in “climbing boys”, which he attributed to soot (1). Now it is known that polycyclic aromatic hydrocarbons and particularly 3,4-benzpyrene were the chemicals causing scrotal cancer in the small boys, who assisted chimney sweeps (2). A century after Pott’s report, in 1895, Rehn noted an association between exposure to aromatic amines and bladder cancer among workers in the aniline dye industry (2).

Nowadays, the study of occupational cancers is an important field of research with unique potentials for prevention, which has expanded to an international level. But work-related malignancies still place a heavy psychological and financial burden on our society in terms of compensation, treatment costs and most importantly human suffering. It has been estimated that approximately 4% of all cancer deaths, in people above the age of 15, may have an occupational origin (3,4). This is probably an underestimation of the true health problem posed by work-related cancers. The main contributing factor to this underreporting is the lack of data on the tumourigenic potential of most industrial compounds (2,4). Thus, millions of workers, especially in small private businesses and in the informal sector, might be exposed to occupational carcinogens that have not yet been identified (2). Remember that these people can be our friends, colleagues, relatives or even ourselves!

What is an occupational carcinogen?

Any biological, chemical or physical agent or exposure circumstance in the workplace, which has the potential to cause malignancies in humans can be defined as an occupational carcinogen (3). Siemiatycki et al. identified that 168 out of all the agents classified as carcinogens are related to occupational exposures (5).

Why is it difficult to identify carcinogens?

Most of the evidence for the carcinogenic potential of a substance has been derived either from animal or epidemiological studies. Animal studies have the advantage of controlled environmental conditions, but the findings do not necessarily apply to humans. On the other hand, experiments on humans are not possible due to obvious ethical reasons. Thus, reliance is placed on epidemiological studies, in which unknown factors may exist and confound the analysis of the results (6). Another major difficulty in such studies is that work-related cancers are characterised by a long latency period between initial exposure and disease presentation (3).

Which are the most common occupational carcinogens and their cancer sites?

Several occupational carcinogens have been identified and a well-known example is asbestos. This includes a group of naturally occurring fibrous minerals, which are mainly used in thermal and acoustic insulation (6). It is commonly classified, dependent on its colour, as: blue (crocidolite); brown (amosite); and white (chrysotile). The main sources of exposure have occurred in: ship-building; railway engineering; the construction industry; and asbestos mining and milling (7).

Asbestos exposure is a recognised cause for lung cancer, mesothelioma of the pleura and rarely mesothelioma of the peritoneum (3,6). Mesothelioma of the pleura is a fatal malignancy and it has a median survival of approximately 12 months after the initial diagnosis (3). In the case of lung cancer, there is a synergistic effect between tobacco use and asbestos. Thus, smoking can make the causal relationship between this natural fibre and the malignancy less specific and therefore difficult to assess (7). Asbestos has also been linked to laryngeal and gastrointestinal cancers (7). However, these associations have not yet been firmly established and further research is required into this field of medicine.

Silica (silicon dioxide) is an inorganic particle occurring in two forms, amorphous and crystalline. IARC classified the latter as a definite carcinogen (Group 1) in 1997. The most abundant polymorph of crystalline is quartz, which is used in a wide range of industrial processes. The main sources of exposure include the ceramic industry; foundries; and sandblasting operations. Clapp et al. suggests that there is strong evidence associating crystalline silica with an increased risk of lung cancer (6).

Aromatic amines are organic compounds with a characteristic odour, several of which are potent urinary tract carcinogens. The metabolite formed in the liver, rather than the actual amine, is probably responsible for causing malignancies. The target organ is usually the bladder, but any part of the urothelial tract, which is compromised of transitional epithelium, can be affected (3).

Polycyclic aromatic hydrocarbons are formed by the incomplete combustion of organic material including coal, oil and petrol. Thus, the heaviest exposures occur in coke ovens; coal gas manufacture; aluminium production; and petroleum refineries. Inhalation of polycyclic aromatic hydrocarbons causes lung cancer and probably bladder cancer, whereas dermal exposure can lead to the development of squamous cell carcinoma (6,7).

Regarding metals and metal compounds arsenic, beryllium, cadmium, hexavalent chromium (VI) and selected nickel compounds have been classified as definite human carcinogens (Group 1) by the IARC (5). The main target organ is the lung, but other sites can be affected as well (Table 1).(3,5,7).

Metal & metal compounds Cancer site Arsenic Lung Skin Liver (angiosarcoma) Beryllium Lung Cadmium Lung Hexavalent chromium (VI) Nasal sinuses Lung Nickel Nasal sinuses Lung

Table 1: Common cancer sites of recognised carcinogenic metals and metal compounds

Ultraviolet radiation from excessive occupational exposure to sunlight has been linked to melanoma and the two types of nonmelanomatous skin cancer, basal cell and squamous cell carcinoma (3,7). Another work-related carcinogen is ionising radiation. This, however, has been tightly monitored and exposure now is occurring mainly in the nuclear industry (7).

Occupational carcinogen	Type of cancer
Asbestos	Common cancer types Lung cancer Mesothelioma of the pleura Rare cancer types Mesothelioma of the peritoneum Not firmly established cancer types Laryngeal cancer Gastrointestinal cancers
Silica (silicon dioxide)	Lung cancer
Aromatic amines	Bladder cancer
Polycyclic aromatic hydrocarbons	Lung cancer Bladder cancer Squamous cell carcinoma
Metals and metal compounds (i.e. arsenic & beryllium)	Lung cancer
Ultraviolet radiation	Melanoma Basal cell carcinoma Squamous cell carcinoma
Ionising radiation	Leukaemia

Table 2: The most common occupational carcinogens and their associated cancer types

Final Comments

My personal view is that the workplace should be a safe setting. For this reason, it is crucial to identify carcinogens early and decrease exposures to a minimum, in order to protect workers’ health. Thus, further research should be devoted to this field of medicine. Future studies should aim to: identify yet unknown work-related exposures that can lead to malignancies; further assess the human carcinogenicity of recognised occupational carcinogens; and provide reliable evidence on women and minorities as research has primary focused on men. Finally, as future doctors we should be able to recognise the main occupational carcinogens and their effects (i.e. asbestos and mesothelioma). If in doubt, the health and safety executive website can provide you with up-to-date information on any aspect of work-related illnesses.

Ourania Varsou is a 4th year medical student, University of Aberdeen
o.varsou@googlemail.com

The author wishes to acknowledge the assistance of Dr Paschalis Kapsomenakis (FTSTA in cardiothoracic surgery, University of Aberdeen)

References

1. Hunter D. The diseases of occupations. 1st ed. London, U.K.: English Universities Press Ltd; 1955.

2. Landrigan PJ. The prevention of occupational cancers [guest editorial]. CA Cancer J Clin 1996;46(2):67-69.

3. Veys CA. ABC of work related disorders: occupational cancers. BMJ 1996;313(7057):615-619.

4. Brugère J, Naud C. Recognition of occupational cancers in Europe. TUTB Newsletter 2003 June;21:38-39.

5. Siemiatycki J, Richardson L, Straif K, Latreille B et al. Listing occupational carcinogens. Environ Health Perspect 2004;112(15):1447-1459.

6. Clapp RW, Howe GK, Jacobs MM. Environmental and occupational causes of cancer: a review of recent scientific literature [online publication]. Lowell Center for Sustainable Production 2005 [cited 2009 May 15]. Available from: http://www.sustainableproduction.org/pres.shtml

7. Coggon D. Occupational cancer in the United Kingdom. Environ Health Perspect 1999;107(Suppl 2):239-244.