Comment
toxicity, a Hawthorne or observation effect might well have played a part.2,3 The fact that the participants knew that they were under observation is likely to have promoted the required changes in lifestyle so fundamental in the treatment of type 2 diabetes. A short course of insulin therapy could amplify this effect, certainly if accompanied by hospital admission, as was done in three of the four studies reporting on remission. All studies included in the meta-analysis but one were done in China, the last reported from Taiwan. This does of course affect the external validity of the findings. Received wisdom tells us that type 2 diabetes in Asia and China has special features such as good responsiveness to acarbose and sulfonylureas, and low insulin dose requirements. Remission of type 2 diabetes after a short intensive insulin course could well be another of these features. Furthermore, three of the four studies on remission come from one centre, which also took the lead in the fourth multicentre study. Fortunately, the standard of science is improving in China,4 and the fact that the confirmatory multicentre study was done in nine centers lends credibility to the data. Since all studies were uncontrolled, further studies should include a control group with equal attention given to diet and exercise and pharmacological treatment given according to a well established guideline.
So should these findings find their way into daily practice? When a Chinese patient is diagnosed with type 2 diabetes, to offer a short course of intensive insulin therapy with the aim to induce remission seems reasonable. For other ethnic groups, I fully agree with the authors that short-term intensive insulin therapy warrants further investigation as a therapeutic strategy in early type 2 diabetes. Awaiting this, there is no reason to deviate from current treatment guidelines. J Hans DeVries Academic Medical Centre, 1105 AZ Amsterdam, Netherlands [email protected] I declare that I have no conflicts of interest. 1
2
3
4
Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy and its impact on type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2013; published online Jan 30. http://dx.doi. org/10.1016/S0898-5898(13)00002-8. DeVries JH, Snoek FJ, Kostense PJ, Heine RJ. Improved glycaemic control in type 1 diabetes patients following participation per se in a clinical trial—mechanisms and implications. Diabetes Metab Res Rev 2003; 19: 357–62. Gale EA, Beattie SD, Hu J, Koivisto V, Tan MH. Recruitment to a clinical trial improves glycemic control in patients with diabetes. Diabetes Care 2007; 30: 2989–92. Pan Z, Trikalinos TA, Kavvoura FK, Lau J, Ioannidis JP. Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med 2005; 2: e334.
Sidney Moulds/Science Photo Library
Congenital adrenal hyperplasia: one hundred years of data
Published Online February 26, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70009-3 See Articles page 35
4
It is rare to find a data-rich review of the diagnosis of only one disorder that spans over a hundred years. But, in The Lancet Diabetes & Endocrinology, Sebastian Gidlöf and colleagues1 describe the known cases of congenital adrenal hyperplasia in Sweden between 1910 and 2011, a period that encompasses the discovery and implementation of effective treatment in 1950, the gradual development of better diagnostic methods, and the introduction of early diagnosis by neonatal screening in the 1980s. Congenital adrenal hyperplasia is the most common adrenal disorder in children. Indeed, it is a group of disorders, the most common type being 21-hydroxylase deficiency, associated with low cortisol and aldosterone production. Clinical presentation includes potentially fatal salt-wasting
crises, female genital virilisation, and premature pubarche. Gidlöf and colleagues’ Article contributes to our understanding of the disorder in interesting and surprising ways. Most high-income countries have introduced neonatal screening for congenital adrenal hyperplasia, some as much as 30 years ago,2 and indeed it has recently been introduced in Laos, a country with no previous neonatal screening programme.3 However, congenital adrenal hyperplasia screening has not been implemented in either the UK4 or Australia.5 Early detection of the disorder is mainly aimed at the prevention of salt-wasting crises, wrong sex-assignment, and premature pubarche or accelerated growth. Gidlöf and colleagues’ data clearly show the apparent increase in incidence over time, which they attribute www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
Comment
to poor diagnosis before the 1960s and to the fact that the availability of treatment and increased awareness of the disorder increases the likelihood of physicians identifying and diagnosing the disease. Importantly, the investigators postulate that the frequency of this global disease is likely to have remained steady over the period, and thus they are able to calculate the probable number of missed cases over time, assuming that almost all severe cases (the saltwasting phenotype) are now effectively diagnosed. Their postulations of the numbers of missed cases are enlightening. Male neonates with the severe saltwasting phenotype are thought to have a higher risk of death than their female counterparts, because diagnosis of female neonates is easier owing to their virilised genitalia, leading to the possibility that they receive treatment earlier and more often than do boys. Findings from Gidlöf and colleagues’ study, however, showed that in people with the salt-wasting form of the disorder, the risk of death was substantial—some five to ten patients died every year before 19701—and much the same in both female and male patients without early diagnosis. Evidently, both male and female babies die undiagnosed, and not, as previously thought, only male babies. Other important information provided by Gidlöf and colleagues—information usually unavailable in reports of screening—is an estimated false-negative rate of almost 16%. Such estimates are not usually given in reports of screening, but one report that did, from Minnesota, USA,6 showed a false-negative rate of 22% (15 of 67 cases) for people with the classic form of the disorder during 12 years of neonatal screening between January 1999 and 2010. Of 15 missed cases, five had the salt-wasting form, but four of these five were girls who were diagnosed on the basis of their virilised genitalia. In Gidlöf and colleagues’ Swedish study, more than half of patients had late-onset, non-classic forms of the disorder that were missed by screening.1 However, the detection of late-onset cases is, arguably, not the main target of neonatal screening. Publication of more detailed data from existing screening programmes would be welcome. It is surprising that after 30 years of neonatal screening worldwide there is still a need for additional screening data and, importantly, followup, so that the benefits of screening can be accurately www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
assessed, and screening efficiency can be maximised. Uncertainty still exists about outcomes, and how screening can improve outcomes. An adrenal crisis with accompanying hyponatraemia is thought to cause brain damage, but available evidence does not lend support to the suggestion that patients with congenital adrenal hyperplasia have any intellectual deficits compared with otherwise healthy individuals.7,8 A clear need exists for more research in this area to be sure that more subtle learning difficulties are not present. However, there is little doubt that screening for the disorder fulfils the essential criteria for screening—it is, after all, a potentially lethal disorder—and a 2010 study in the UK concluded that a case can be made for screening.4 Certainly paediatric endocrinologists from Australia agree.5 The Swedish study underlines what can be learned from long-term follow-up, good record keeping, and registers. This type of activity should not only be encouraged but also funded if we are to make best use of our accumulated experience. At the same time, we should remember that for any long-term study, data collected at the beginning might not be entirely comparable with those collected towards the end. Medical diagnostic and therapeutic expertise moves on, so we need to draw conclusions with care. Bridget Wilcken Sydney Children’s Hospitals Network and University of Sydney, Sydney, Australia [email protected] I declare that I have no conflicts of interest. 1
2 3
4
5 6
7 8
Gidlöf S, Falhammar H, Thilén A, et al. One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol 2013; published online Feb 26. http:// dx.doi.org/10.1016/S2213-8587(13)70007-X. White PC. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 2009; 5: 490–498. Hoehn T, Lukacs Z, Stehn M, Mayatapek E, Philavan K, Bounnack S. Establishment of the first newborn screening program in the People’s Democratic Republic of Laos. J Trop Pediatr 2012; published online Oct 26. DOI:10.1093/tropej/fms057. Khalid JM, Oerton JM, Dezateux C, Hindmarsh PC, Kelnar CJ, Knowles RL. Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Arch Dis Child. 2012; 97: 101–06 Warne GL, Armstrong KL, Faunce TA, et al. The case for newborn screening for congenital adrenal hyperplasia. Med J Aust 2010; 192: 107. Sarafoglou K, Banks K, Kyllo J, Pittock S, Thomas W. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012; 307: 2371–74. Berenbaum S. Cognitive function in congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30: 173–92 Berenbaum SA, Bryk KK, Duck SC. Normal intelligence in female and male patients with congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010; 2010: 853103.
5
toxicity, a Hawthorne or observation effect might well have played a part.2,3 The fact that the participants knew that they were under observation is likely to have promoted the required changes in lifestyle so fundamental in the treatment of type 2 diabetes. A short course of insulin therapy could amplify this effect, certainly if accompanied by hospital admission, as was done in three of the four studies reporting on remission. All studies included in the meta-analysis but one were done in China, the last reported from Taiwan. This does of course affect the external validity of the findings. Received wisdom tells us that type 2 diabetes in Asia and China has special features such as good responsiveness to acarbose and sulfonylureas, and low insulin dose requirements. Remission of type 2 diabetes after a short intensive insulin course could well be another of these features. Furthermore, three of the four studies on remission come from one centre, which also took the lead in the fourth multicentre study. Fortunately, the standard of science is improving in China,4 and the fact that the confirmatory multicentre study was done in nine centers lends credibility to the data. Since all studies were uncontrolled, further studies should include a control group with equal attention given to diet and exercise and pharmacological treatment given according to a well established guideline.
So should these findings find their way into daily practice? When a Chinese patient is diagnosed with type 2 diabetes, to offer a short course of intensive insulin therapy with the aim to induce remission seems reasonable. For other ethnic groups, I fully agree with the authors that short-term intensive insulin therapy warrants further investigation as a therapeutic strategy in early type 2 diabetes. Awaiting this, there is no reason to deviate from current treatment guidelines. J Hans DeVries Academic Medical Centre, 1105 AZ Amsterdam, Netherlands [email protected] I declare that I have no conflicts of interest. 1
2
3
4
Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy and its impact on type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2013; published online Jan 30. http://dx.doi. org/10.1016/S0898-5898(13)00002-8. DeVries JH, Snoek FJ, Kostense PJ, Heine RJ. Improved glycaemic control in type 1 diabetes patients following participation per se in a clinical trial—mechanisms and implications. Diabetes Metab Res Rev 2003; 19: 357–62. Gale EA, Beattie SD, Hu J, Koivisto V, Tan MH. Recruitment to a clinical trial improves glycemic control in patients with diabetes. Diabetes Care 2007; 30: 2989–92. Pan Z, Trikalinos TA, Kavvoura FK, Lau J, Ioannidis JP. Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med 2005; 2: e334.
Sidney Moulds/Science Photo Library
Congenital adrenal hyperplasia: one hundred years of data
Published Online February 26, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70009-3 See Articles page 35
4
It is rare to find a data-rich review of the diagnosis of only one disorder that spans over a hundred years. But, in The Lancet Diabetes & Endocrinology, Sebastian Gidlöf and colleagues1 describe the known cases of congenital adrenal hyperplasia in Sweden between 1910 and 2011, a period that encompasses the discovery and implementation of effective treatment in 1950, the gradual development of better diagnostic methods, and the introduction of early diagnosis by neonatal screening in the 1980s. Congenital adrenal hyperplasia is the most common adrenal disorder in children. Indeed, it is a group of disorders, the most common type being 21-hydroxylase deficiency, associated with low cortisol and aldosterone production. Clinical presentation includes potentially fatal salt-wasting
crises, female genital virilisation, and premature pubarche. Gidlöf and colleagues’ Article contributes to our understanding of the disorder in interesting and surprising ways. Most high-income countries have introduced neonatal screening for congenital adrenal hyperplasia, some as much as 30 years ago,2 and indeed it has recently been introduced in Laos, a country with no previous neonatal screening programme.3 However, congenital adrenal hyperplasia screening has not been implemented in either the UK4 or Australia.5 Early detection of the disorder is mainly aimed at the prevention of salt-wasting crises, wrong sex-assignment, and premature pubarche or accelerated growth. Gidlöf and colleagues’ data clearly show the apparent increase in incidence over time, which they attribute www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
Comment
to poor diagnosis before the 1960s and to the fact that the availability of treatment and increased awareness of the disorder increases the likelihood of physicians identifying and diagnosing the disease. Importantly, the investigators postulate that the frequency of this global disease is likely to have remained steady over the period, and thus they are able to calculate the probable number of missed cases over time, assuming that almost all severe cases (the saltwasting phenotype) are now effectively diagnosed. Their postulations of the numbers of missed cases are enlightening. Male neonates with the severe saltwasting phenotype are thought to have a higher risk of death than their female counterparts, because diagnosis of female neonates is easier owing to their virilised genitalia, leading to the possibility that they receive treatment earlier and more often than do boys. Findings from Gidlöf and colleagues’ study, however, showed that in people with the salt-wasting form of the disorder, the risk of death was substantial—some five to ten patients died every year before 19701—and much the same in both female and male patients without early diagnosis. Evidently, both male and female babies die undiagnosed, and not, as previously thought, only male babies. Other important information provided by Gidlöf and colleagues—information usually unavailable in reports of screening—is an estimated false-negative rate of almost 16%. Such estimates are not usually given in reports of screening, but one report that did, from Minnesota, USA,6 showed a false-negative rate of 22% (15 of 67 cases) for people with the classic form of the disorder during 12 years of neonatal screening between January 1999 and 2010. Of 15 missed cases, five had the salt-wasting form, but four of these five were girls who were diagnosed on the basis of their virilised genitalia. In Gidlöf and colleagues’ Swedish study, more than half of patients had late-onset, non-classic forms of the disorder that were missed by screening.1 However, the detection of late-onset cases is, arguably, not the main target of neonatal screening. Publication of more detailed data from existing screening programmes would be welcome. It is surprising that after 30 years of neonatal screening worldwide there is still a need for additional screening data and, importantly, followup, so that the benefits of screening can be accurately www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
assessed, and screening efficiency can be maximised. Uncertainty still exists about outcomes, and how screening can improve outcomes. An adrenal crisis with accompanying hyponatraemia is thought to cause brain damage, but available evidence does not lend support to the suggestion that patients with congenital adrenal hyperplasia have any intellectual deficits compared with otherwise healthy individuals.7,8 A clear need exists for more research in this area to be sure that more subtle learning difficulties are not present. However, there is little doubt that screening for the disorder fulfils the essential criteria for screening—it is, after all, a potentially lethal disorder—and a 2010 study in the UK concluded that a case can be made for screening.4 Certainly paediatric endocrinologists from Australia agree.5 The Swedish study underlines what can be learned from long-term follow-up, good record keeping, and registers. This type of activity should not only be encouraged but also funded if we are to make best use of our accumulated experience. At the same time, we should remember that for any long-term study, data collected at the beginning might not be entirely comparable with those collected towards the end. Medical diagnostic and therapeutic expertise moves on, so we need to draw conclusions with care. Bridget Wilcken Sydney Children’s Hospitals Network and University of Sydney, Sydney, Australia [email protected] I declare that I have no conflicts of interest. 1
2 3
4
5 6
7 8
Gidlöf S, Falhammar H, Thilén A, et al. One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol 2013; published online Feb 26. http:// dx.doi.org/10.1016/S2213-8587(13)70007-X. White PC. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 2009; 5: 490–498. Hoehn T, Lukacs Z, Stehn M, Mayatapek E, Philavan K, Bounnack S. Establishment of the first newborn screening program in the People’s Democratic Republic of Laos. J Trop Pediatr 2012; published online Oct 26. DOI:10.1093/tropej/fms057. Khalid JM, Oerton JM, Dezateux C, Hindmarsh PC, Kelnar CJ, Knowles RL. Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Arch Dis Child. 2012; 97: 101–06 Warne GL, Armstrong KL, Faunce TA, et al. The case for newborn screening for congenital adrenal hyperplasia. Med J Aust 2010; 192: 107. Sarafoglou K, Banks K, Kyllo J, Pittock S, Thomas W. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012; 307: 2371–74. Berenbaum S. Cognitive function in congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30: 173–92 Berenbaum SA, Bryk KK, Duck SC. Normal intelligence in female and male patients with congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010; 2010: 853103.
5
