NEW S & V IE W S
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severe hypoglycaemia—a relationship that was seen in participants w ho were ra n domly assigned to the intensive and standard glycaemia treatment arms of the trial.7 Analysis of data from the UK G eneral Practice Research Database, demonstrated a U-shaped association between circulating levels of HbAlc and an increased incidence of all-cause m ortality and cardiac events in p atien ts w ith T2DM w ho w ere aged >50 years.8 This observation suggests that both extreme hyperglycaemia and hypo glycaemia contribute to poor outcomes. Severe hypoglycaemia has also been associ ated with cognitive dysfunction in patients with diabetes mellitus. For example, in the Edinburgh Type 2 Diabetes Study, a history o f severe hypoglycaemia in patients with T2DM was associated with both poor ini tial cognitive ability and accelerated cogni tive decline over 4 years.9 Hypoglycaemia, particularly when severe, seems to be asso ciated with, if not contributing to, poor out comes in older patients with T2DM. If the frequency with which older patients with T2DM experience severe hypoglycaemia can be reduced, it is possible that the cost of health care for these patients, as well as their risk of morbidity and mortality, could be substantially reduced. A major limitation of the study by Geller et al. is that they probably underestim ate the n um ber of episodes o f severe hypo glycaem ia th a t tru ly occur in the USA. Most episodes of severe hypoglycaemia are treated at home by family members or para medics and are never seen in the emergency department. The authors’ ability to identify precipitating risk factors was also limited because they relied only on medical history collected in the em ergency departm ents. Severe hypoglycaem ia related to insulin and insulin secretagogue therapies, such as sulphonylurea, is a major challenge in the treatment of patients with T2DM, especially in the elderly population. Glycaemic targets and diabetic therapy should be individualized according to patient age, duration of diabetes mellitus, life expec tancy and other m edical considerations. Many of the precipitating factors that can
NATURE REVIEWS | ENDOCRINOLOGY
lead to severe hypoglycaemia are prevent able. Increased education for patients and caregivers on how to prevent, recognize and treat hypoglycaemia is critical. Patients should be screened regularly to detect pre vious episodes of severe hypoglycaem ia and im paired hypoglycaemia awareness, such as by using the questionnaires devel oped for this purp o se by the A m erican Diabetes Association and the Endocrine Society working group on hypoglycaemia,10 therapies can then be adjusted accordingly. Additional studies are needed to improve understanding of the relationship between glycaemic targets and the risk of hypergly caemia in older adults with diabetes melli tus. Such studies are particularly important for individuals with multiple comorbidities, so that management strategies can be devel oped to provide maximum benefit to these patients without exposing them to the risk of severe hypoglycaemia. New classes of antidiabetic medications th a t do n o t cause hypoglycaem ia have become available in the past decade; how ever, additional research is needed to exam ine the role of these m edications in the treatment of patients with diabetes mellitus who are >70 years. In the future, we may find that the description selected by Geller and colleagues for their work applies to the use of insulin in elderly patients with diabetes mellitus; less is more. Division o f Endocrinology and Diabetes, Department o f Medicine, University o f Minnesota, 42 0 Delaware Street SE, Minneapolis, MN 55455, USA (A.M., E.R.S.). Correspondence to: E.R.S. [email protected]
Com peting interests E.R.S. receives research grant funding from AMG Medical and Eli Lilly. She also has served as a consultant fo r AMG Medical, BMS-AZ, Merck, Sanofi and SkyePharma. A.M. declares no com peting interests. Geller, A. I. et al. National estim ates o f insulinrelated hypoglycemia and errors leading to emergency departm ent visits and hospitalizations. JAMA Intern. Med. h tt p :// dx.doi.org/ 1 0 .1 0 0 1 /ja m a in te rn m e d .2 0 1 4 .1 3 6 . 2. Jhung, M. A. etal. Evaluation and overview o f th e National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project (NEISS-CADES). Med. Care 45, S 9 6 -S 1 0 2 (2 007). 3. Schiller, J. S „ Lucas, J. W „ Ward, B. W. & Peregoy, J. A. Sum m ary health s ta tis tic s for U. S. adults: National Health Interview Survey, 2 0 1 0 . Vital Health Stat. 1 0 ,1 - 2 0 7 (2012). 4. Centers fo r Disease Control and Prevention. Diabetes Public Health Resource [online]. h ttp ://w w w .cd c.g o v/d ia b e te s (2014). 5. Fu, H. et al. Frequency and causes o f hospitalization in older com pared to younger adults with type 2 diabetes in th e United States: a retrospective, claim s-based analysis. J. Diabetes Complications h ttp ://d x .d o i.o rg / 1 0 .1 0 1 6 /j.jd ia c o m p .2 0 1 4 .0 2 .0 0 9 . 6. The Action to Control Cardiovascular Risk in Diabetes study group. Effects o f intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 35 8, 2 5 4 5 -2 5 5 9 (2 008). 7. Bonds, D. E. etal. The association between sym ptom atic, severe hypoglycaemia and m o rtality in type 2 diabetes: retrospective epidem iological analysis o f th e ACCORD study. BMJ 3 4 0 , b 4 9 0 9 (2010). 8. Currie, C. J .e ta l. Survival as a function o f HbAlc in people w ith type 2 diabetes: a retrospective cohort study. Lancet 3 7 5 ,4 8 1 -4 8 9 (2010). 9. Feinkohl, I. et al. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes Care 3 7 ,5 0 7 - 5 1 5 (2014). 10. Seaquist, E. R. et al. Hypoglycemia and diabetes: a report o f a workgroup o f the American Diabetes Association and the Endocrine Society. Diabetes Care 3 6 ,1 3 8 4 -1 3 9 5 (2013).
1.
THYROID GLAND
Do nuclear power plants increase the risk of thyroid cancer? Kiyohiko Mabuchi and Arthur B. Schneider The major accident at the Chernobyl nuclear power plant has resulted in an increased risk of thyroid cancer in exposed individuals. A new report attempts to quantify the risk of thyroid cancer associated with living near nuclear facilities; however, the findings are inconclusive due to flaws in the study design. Mabuchi, K. & Schneider, A. B. N at Rev. Endocrinol. 1 0 ,3 8 5 - 3 8 7 (2 0 1 4 ); published online 2 9 April 2 0 1 4 ; d o i:1 0 .1 0 3 8 /n re n d o .2 0 1 4 .5 9
The operation of nuclear reactors generates large quantities o f radioactive m aterials, including the radioisotope 131I.' Exposure
to 131I as a result of accidental releases is of particular concern as it is absorbed by the thyroid gland. Infants and children are
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p articularly susceptible to the effects of 131I as they typically drink large am ounts o f m ilk and have fairly sm all th y ro id glands, which can result in especially high doses o f ra d ia tio n from co n tam in ate d sources. In addition to the small num ber o f m ajor ac cid en ts—W indscale, T hree Mile Island, Chernobyl and, most recently, Fukushima—many less serious events that involved release of radioactive m aterials have occurred. Countless other less serious events have potentially gone unreported or undetected, leading to concern about pos sible risks of cancer resulting from these events. Bollaerts and colleagues studied the incidence of thyroid cancer in com mu nities near five Belgian nuclear sites (Doel, Tihange, Fleurus, Mol-Dessel and Chooz).2 A lth o u g h th e s tu d y w as in itia lly p rom pted by an accident in 2008 at the Fleurus nuclear facility, the authors also address the incidence of thyroid cancer before 2008 owing to concern about earlier releases. Bollaerts and co-workers report a significant increase in the risk of thyroid cancer among residents living in proximity to the Fleurus and Mol-Dessel sites (which contain a m ix of a nuclear research and industrial activities). The risk was increased in residents near the Chooz nuclear plant, but not significantly so, possibly due to the small size of the population. No increased risk was o b serv ed for people residing near the nuclear power plants at Doel and Tihange; in fact, the risk was decreased for these residents. The accurate assessment of individual radiation doses is fundamental to studying
3 8 6 | JULY 2014 | VOLUME 10
the effects that a nuclear reactor accident has on health.3 The Belgian investigators provide no data regarding th e possible extent of radioactive releases or the doses received by the residents. In particular, it is im portant to have data on atmospheric releases of radionuclides from the Fleurus and M ol-Dessel sites, around w hich the incidence of thyroid cancer is reportedly increased. The Belgian study falls short in this im portan t aspect. A previous study estim ated that the 2008 Fleurus incident, w hich released 48 GBq o f 131I, resulted in a m axim um thyroid dose of 0.6 mGy for a 2-year-old child.4 This dose is very sm all and is equivalent to ~20-30% of the average dose received each year from natural background radiation.5 The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has also re p o rte d th a t th e an n u a l atm o sp h e ric release of 131I at the Doel and Tihange plants in the 1990s was an average of 0.1 -0.2 GBq, w hich is at least 100-fold less th a n the am ount released by the Fleurus accident.5 The available evidence on radiation-related thyroid cancer suggests that the additional risk of these doses at usual levels or even from the Fleurus accident is extremely small and unlikely to translate into a statistic ally detectable increase in the incidence of thyroid cancer.6 The Belgian study com pared the in ci dence of thyroid cancer in people residing in close proximity to nuclear sites with the incidence in people living fu rth er away. The ecological design of the study means that aggregate data were used. This type of data is easier to obtain than data by the tra ditional epidemiological m ethods that are typically used to study individuals exposed to radiation. W ithout estimates of the doses received by individuals, it is impossible to be certain w hether the individuals who developed thyroid cancer were actually exposed to radiation. The observed asso ciation between cancer and the surrogate measure of radiation exposure (in this case, proxim ity to the site) m ight be caused by factors other than radiation that correlate with where people live. Correcting for such correlations is difficult, and is often impos sible w ith aggregate data. These correc tions become especially challenging when the level of exposure is very small,1 as the effect of other factors is simply too large compared with the relatively weak effect of radiation exposure. O f note, when the level of exposure is quite low, detecting a small additional increase in risk of cancer requires
a huge sample size and clearly defined doses of radiation exposure. However, ecological studies, if im proved, could still provide sufficiently compelling data; for example, by estim ating aggregate doses based on dose reco n stru ctio n m odels th a t in c o r porate data on atm ospheric release, and spatial and tem poral distribution patterns of radioactivity together with data on diet and lifestyle.3 In the unfortunate event of an accidental release of radioactive materials, it is impor tant for public health officials to assess the risk among children and adolescents, as this group are known to have an especially high radiation-related risk of developing thyroid cancer.6 As a result of an increasing inci dence of thyroid cancer in 131I-contaminated regions in Russia after the Chernobyl acci dent,7 a case-control study o f childhood and/or adolescent cancer was undertaken in contam inated areas.8 Individual radia tion doses to the thyroid were estimated by modelling and from data collected during interview s w ith exposed individuals or their parents. A significant dose-response was found and the estimates of radiationrelated risk were consistent with those from other radiation-exposed populations, which provides credence to the theory that there is a relationship between 131I exposure and thyroid cancer.
^ T h e accurate assessm ent o f in dividual radiation doses is fundam en tal... W Following the im m ediate m easures to determine the extent of radiation exposure, long-term studies of health are necessary.3As a result, the public might request diagnostic testing and clinicians should be aware that thyroid ultrasonography, although seemingly harmless, carries a risk o f ‘over diagnosis’.9 The clinical im portance of very small thy roid cancers detected by ultrasonography is not clear. Widespread screening can also lead to a seemingly dramatic increase in thyroid cancers, as was observed following the acci dent in F ukushim a.10 The nature o f this increase, that is, whether or not it is related to radiation, remains to be determined. A num ber of shortcom ings and lim ita tions of the study by B ollaerts and col leagues calls its findings into question and, as the authors acknowledge, point to the need for fu rth e r investigation. In ad d i tion to m ethodological issues, the safety of living near nuclear facilities is a matter of
www.nature.com /nrendo
NEWS & VIEWS public concern.1Whichever study approach is taken next, it must be credible, not only to the scientific com munity but also to the general public. Division o f Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850, USA (K.M.). Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, 1819 W.Polk Street, MC 640, Chicago, IL 60616, USA (A.B.S.). Correspondence to: K.M. [email protected] A cknow ledgem ents The authors wish to acknowledge J. Loukissas of th e Division o f Cancer Epidemiology and Genetics, National Cancer in stitu te , Rockville, MD, USA, who provided valuable insights during th e w riting o f th is article . Com peting interests A.B.S. has served as an advisor and expert w itness fo r a law firm dealing with radiation releases from the Hanford Nuclear Facility. K.M. declares no com peting interests. 1.
National Research Council. Analysis o f cancer risks in populations near nuclear facilities: phase 1 (The National Academies Press,
2012). 2.
3.
4.
Bollaerts, K. e t at. Thyroid cancer incidence in th e vicinity o f nuclear sites in Belgium, 2 0 0 0 -2 0 0 8 . Thyroid h ttp ://d x .d o i.o rg / 1 0 .1 0 8 9 /th y .2 0 1 3 .0 2 2 7 . Bouville, A., Linet, M. S., Hatch, M., Mabuchi, K. & Sim on, S. L. Guidelines fo r exposure asse ssm ent in health risk stud ies follow ing a nuclear reactor accident. Environ. Health Perspect. 1 2 2 , 1 - 5 (2014). Vandecasteele, C. M., Sonck, M. & Degueldre, D. Rejet accidentel d ’iode-131 par I’ lRE su r le site de Fleurus: retour d ’experience de I'au torite de surete beige [French], Radioprotection 4 6 ,1 5 9 -1 7 3 ( 2011).
5.
United N ations S cientific C om m ittee on the Effects o f Radiation. Sources and effects of
ionizing radiation. UNSCEAR 2000: Report to the general assembly with scientific annexes, Volume I [online], h ttp ://w w w .u n sce a r.o rg / u n s c e a r/e n /p u b lic a tio n s /2 0 0 0 _ l.h tm l (2013). 6. Ron, E. et al. Thyroid cancer a fte r exposure to external radiation: a pooled analysis o f seven studies. Radiat. Res. 1 4 1 ,2 5 9 -2 7 7 (1995). 7. Shakhatarin, V. V. et al. Iodine deficiency, radiation dose, and the risk o f thyroid cancer am ong children and adolescents in th e Bryansk region o f Russia follow ing the Chernobyl power statio n accident. lnt.J. Epidemiol. 3 2 ,5 8 4 -5 9 1 (2003). 8. Davis, S. eta /. Risk o f thyroid cancer in the Bryask O blast o f th e Russian Federation a fter th e Chernobyl power plant statio n accident. Radiat. Res. 16 2, 2 4 1 -2 4 8 (2004). 9. Davies, L. & Welch, H. G. Increasing incidence o f thyroid cancer in th e United States, 1 9 7 3 -2 0 0 2 . JAMA 29 5, 2 1 6 4 -2 1 6 7 (2006). 10. Nose, T. & Oiwa, Thyroid cancer cases increase am ong young people in Fukushima. The Asahi Shimbun [online], h t t p :// a jw .a s a h i.c o m /a rtic le /0 3 1 1 d is a s te r/ fu k u s h im a /A J2 0 1 4 0 2 0 8 0 0 4 7 (2014).
Y.
NATURE REVIEWS | ENDOCRINOLOGY
DIABETES
M e a s u rin g in te ra rm blood pressure d ifferen ces in d ia b e te s Gianfranco Parati and Alberto Zanchetti Interarm differences in systolic blood pressure are associated with a significant risk of morbidity and mortality. A new study reports that these differences are frequently observed in patients with diabetes mellitus and recommends routine measurement of interarm blood pressure differences to improve diagnostic and prognostic stratification of these patients. Parati, G. & Zanchetti, A. Nat. Rev. Endocrinol. 1 0 ,3 8 7 - 3 8 8 (2 014); published online 3 June 2 0 1 4 ; d o i:1 0 .1 0 3 8 /n re n d o .2 0 1 4 .8 0
Patients with diabetes m ellitus and ele vated blood pressure have a higher risk of cardiovascular disease than normotensive or hypertensive individuals w ithout dia betes mellitus.1 The inaccurate assessment of blood pressure in prim ary care settings is a contributing factor in the increased cardiovascular risk observed in patients with diabetes mellitus. This increased risk is due not only to the intrinsic limitations of prim ary care blood pressure m easure ments (such as, the inaccuracy of readings obtained under constraints of time, poten tial white coat effects, investigator bias and digit preference, and the inability of limited blood pressure measurements to faithfully reflect norm al daily blood pressure),2 but also to the frequent failure of practicing physicians to follow the guideline recom mendations for measuring blood pressure. One such recommendation consists of mea suring blood pressure in both arms at the first visit to detect possible interarm differ ences, and using the arm with the highest blood pressure value as the reference for making decisions about treatm ent.3 This recommendation is supported by the asso ciation betw een interarm differences in systolic blood pressure (> 10 mmHg) and vascular damage, cerebrovascular disease and increased risk of cardiovascular-related and all-cause mortality.4 However, although ~77% of primary care physicians are aware of guideline recom m endations for m ea suring blood pressure in both arms, only a minority of them (~30%) follow this advice, and even fewer (~13%) routinely implement this recommendation, even when receiving a financial incentive.5 These observations indicate that the main barrier to the effec tive implementation of interarm blood pres sure m easurem ents in clinical practice is physicians’ inertia. A call for action against this inertia comes from the results of a new
study by Clark and colleagues,6which high lights the prognostic relevance of interarm systolic blood pressure differences during the initial evaluation of patients with type 1 and type 2 diabetes mellitus. At recruitment, two pairs of blood pres sure m easu rem en ts w ere p erfo rm ed in b oth arm s by sim ultaneous activation of two autom ated sphygmom anometers and then repeated after swapping the cuffs. In a cross-sectional analysis performed in 727 patients w ith type 1 and type 2 diabetes mellitus and 285 individuals w ithout dia betes mellitus, interarm systolic blood pres sure differences >10 mmHg were associated with an increased risk of peripheral arterial disease (OR 3.4, 95% Cl 1.2-9.3) and dif ferences >15 m mHg were associated with an increased risk of diabetic retinopathy (OR 5.7, 95% Cl 1.5-21.6) and chronic kidney disease (OR 7.0, 95% Cl 1.7-29.8).6 These associations rem ained significant even after adjusting for age, sex, w aist/ h ip ratio , sm o k in g statu s an d systolic blood pressure. Over a m edian follow-up of 52 m onths, the risk of cardiovascularrelated m ortality was markedly increased in patients with diabetes mellitus who had systolic interarm blood pressure differences >10 mmHg (HR 3.5, 95% Cl 1.0-13.0) and >15 mmHg (HR 9.0, 95% Cl 2.0-41.0).6 Remarkably, when sensitivity and speci ficity analyses were perform ed, interarm b lood pressure differences d eterm in ed from single pairs of sequentially performed blood pressure measurements were shown to correctly identify interarm systolic blood pressure differences >10 mmHg. This find ing highlights the value of a single pair of sequential blood pressure m easurem ents that are easy to implement in clinical prac tice. This is of relevance if we consider that failure to identify interarm differences in blood pressure can lead to underestimating
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lt &Emerge' u
g
severe hypoglycaemia—a relationship that was seen in participants w ho were ra n domly assigned to the intensive and standard glycaemia treatment arms of the trial.7 Analysis of data from the UK G eneral Practice Research Database, demonstrated a U-shaped association between circulating levels of HbAlc and an increased incidence of all-cause m ortality and cardiac events in p atien ts w ith T2DM w ho w ere aged >50 years.8 This observation suggests that both extreme hyperglycaemia and hypo glycaemia contribute to poor outcomes. Severe hypoglycaemia has also been associ ated with cognitive dysfunction in patients with diabetes mellitus. For example, in the Edinburgh Type 2 Diabetes Study, a history o f severe hypoglycaemia in patients with T2DM was associated with both poor ini tial cognitive ability and accelerated cogni tive decline over 4 years.9 Hypoglycaemia, particularly when severe, seems to be asso ciated with, if not contributing to, poor out comes in older patients with T2DM. If the frequency with which older patients with T2DM experience severe hypoglycaemia can be reduced, it is possible that the cost of health care for these patients, as well as their risk of morbidity and mortality, could be substantially reduced. A major limitation of the study by Geller et al. is that they probably underestim ate the n um ber of episodes o f severe hypo glycaem ia th a t tru ly occur in the USA. Most episodes of severe hypoglycaemia are treated at home by family members or para medics and are never seen in the emergency department. The authors’ ability to identify precipitating risk factors was also limited because they relied only on medical history collected in the em ergency departm ents. Severe hypoglycaem ia related to insulin and insulin secretagogue therapies, such as sulphonylurea, is a major challenge in the treatment of patients with T2DM, especially in the elderly population. Glycaemic targets and diabetic therapy should be individualized according to patient age, duration of diabetes mellitus, life expec tancy and other m edical considerations. Many of the precipitating factors that can
NATURE REVIEWS | ENDOCRINOLOGY
lead to severe hypoglycaemia are prevent able. Increased education for patients and caregivers on how to prevent, recognize and treat hypoglycaemia is critical. Patients should be screened regularly to detect pre vious episodes of severe hypoglycaem ia and im paired hypoglycaemia awareness, such as by using the questionnaires devel oped for this purp o se by the A m erican Diabetes Association and the Endocrine Society working group on hypoglycaemia,10 therapies can then be adjusted accordingly. Additional studies are needed to improve understanding of the relationship between glycaemic targets and the risk of hypergly caemia in older adults with diabetes melli tus. Such studies are particularly important for individuals with multiple comorbidities, so that management strategies can be devel oped to provide maximum benefit to these patients without exposing them to the risk of severe hypoglycaemia. New classes of antidiabetic medications th a t do n o t cause hypoglycaem ia have become available in the past decade; how ever, additional research is needed to exam ine the role of these m edications in the treatment of patients with diabetes mellitus who are >70 years. In the future, we may find that the description selected by Geller and colleagues for their work applies to the use of insulin in elderly patients with diabetes mellitus; less is more. Division o f Endocrinology and Diabetes, Department o f Medicine, University o f Minnesota, 42 0 Delaware Street SE, Minneapolis, MN 55455, USA (A.M., E.R.S.). Correspondence to: E.R.S. [email protected]
Com peting interests E.R.S. receives research grant funding from AMG Medical and Eli Lilly. She also has served as a consultant fo r AMG Medical, BMS-AZ, Merck, Sanofi and SkyePharma. A.M. declares no com peting interests. Geller, A. I. et al. National estim ates o f insulinrelated hypoglycemia and errors leading to emergency departm ent visits and hospitalizations. JAMA Intern. Med. h tt p :// dx.doi.org/ 1 0 .1 0 0 1 /ja m a in te rn m e d .2 0 1 4 .1 3 6 . 2. Jhung, M. A. etal. Evaluation and overview o f th e National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project (NEISS-CADES). Med. Care 45, S 9 6 -S 1 0 2 (2 007). 3. Schiller, J. S „ Lucas, J. W „ Ward, B. W. & Peregoy, J. A. Sum m ary health s ta tis tic s for U. S. adults: National Health Interview Survey, 2 0 1 0 . Vital Health Stat. 1 0 ,1 - 2 0 7 (2012). 4. Centers fo r Disease Control and Prevention. Diabetes Public Health Resource [online]. h ttp ://w w w .cd c.g o v/d ia b e te s (2014). 5. Fu, H. et al. Frequency and causes o f hospitalization in older com pared to younger adults with type 2 diabetes in th e United States: a retrospective, claim s-based analysis. J. Diabetes Complications h ttp ://d x .d o i.o rg / 1 0 .1 0 1 6 /j.jd ia c o m p .2 0 1 4 .0 2 .0 0 9 . 6. The Action to Control Cardiovascular Risk in Diabetes study group. Effects o f intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 35 8, 2 5 4 5 -2 5 5 9 (2 008). 7. Bonds, D. E. etal. The association between sym ptom atic, severe hypoglycaemia and m o rtality in type 2 diabetes: retrospective epidem iological analysis o f th e ACCORD study. BMJ 3 4 0 , b 4 9 0 9 (2010). 8. Currie, C. J .e ta l. Survival as a function o f HbAlc in people w ith type 2 diabetes: a retrospective cohort study. Lancet 3 7 5 ,4 8 1 -4 8 9 (2010). 9. Feinkohl, I. et al. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes Care 3 7 ,5 0 7 - 5 1 5 (2014). 10. Seaquist, E. R. et al. Hypoglycemia and diabetes: a report o f a workgroup o f the American Diabetes Association and the Endocrine Society. Diabetes Care 3 6 ,1 3 8 4 -1 3 9 5 (2013).
1.
THYROID GLAND
Do nuclear power plants increase the risk of thyroid cancer? Kiyohiko Mabuchi and Arthur B. Schneider The major accident at the Chernobyl nuclear power plant has resulted in an increased risk of thyroid cancer in exposed individuals. A new report attempts to quantify the risk of thyroid cancer associated with living near nuclear facilities; however, the findings are inconclusive due to flaws in the study design. Mabuchi, K. & Schneider, A. B. N at Rev. Endocrinol. 1 0 ,3 8 5 - 3 8 7 (2 0 1 4 ); published online 2 9 April 2 0 1 4 ; d o i:1 0 .1 0 3 8 /n re n d o .2 0 1 4 .5 9
The operation of nuclear reactors generates large quantities o f radioactive m aterials, including the radioisotope 131I.' Exposure
to 131I as a result of accidental releases is of particular concern as it is absorbed by the thyroid gland. Infants and children are
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p articularly susceptible to the effects of 131I as they typically drink large am ounts o f m ilk and have fairly sm all th y ro id glands, which can result in especially high doses o f ra d ia tio n from co n tam in ate d sources. In addition to the small num ber o f m ajor ac cid en ts—W indscale, T hree Mile Island, Chernobyl and, most recently, Fukushima—many less serious events that involved release of radioactive m aterials have occurred. Countless other less serious events have potentially gone unreported or undetected, leading to concern about pos sible risks of cancer resulting from these events. Bollaerts and colleagues studied the incidence of thyroid cancer in com mu nities near five Belgian nuclear sites (Doel, Tihange, Fleurus, Mol-Dessel and Chooz).2 A lth o u g h th e s tu d y w as in itia lly p rom pted by an accident in 2008 at the Fleurus nuclear facility, the authors also address the incidence of thyroid cancer before 2008 owing to concern about earlier releases. Bollaerts and co-workers report a significant increase in the risk of thyroid cancer among residents living in proximity to the Fleurus and Mol-Dessel sites (which contain a m ix of a nuclear research and industrial activities). The risk was increased in residents near the Chooz nuclear plant, but not significantly so, possibly due to the small size of the population. No increased risk was o b serv ed for people residing near the nuclear power plants at Doel and Tihange; in fact, the risk was decreased for these residents. The accurate assessment of individual radiation doses is fundamental to studying
3 8 6 | JULY 2014 | VOLUME 10
the effects that a nuclear reactor accident has on health.3 The Belgian investigators provide no data regarding th e possible extent of radioactive releases or the doses received by the residents. In particular, it is im portant to have data on atmospheric releases of radionuclides from the Fleurus and M ol-Dessel sites, around w hich the incidence of thyroid cancer is reportedly increased. The Belgian study falls short in this im portan t aspect. A previous study estim ated that the 2008 Fleurus incident, w hich released 48 GBq o f 131I, resulted in a m axim um thyroid dose of 0.6 mGy for a 2-year-old child.4 This dose is very sm all and is equivalent to ~20-30% of the average dose received each year from natural background radiation.5 The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has also re p o rte d th a t th e an n u a l atm o sp h e ric release of 131I at the Doel and Tihange plants in the 1990s was an average of 0.1 -0.2 GBq, w hich is at least 100-fold less th a n the am ount released by the Fleurus accident.5 The available evidence on radiation-related thyroid cancer suggests that the additional risk of these doses at usual levels or even from the Fleurus accident is extremely small and unlikely to translate into a statistic ally detectable increase in the incidence of thyroid cancer.6 The Belgian study com pared the in ci dence of thyroid cancer in people residing in close proximity to nuclear sites with the incidence in people living fu rth er away. The ecological design of the study means that aggregate data were used. This type of data is easier to obtain than data by the tra ditional epidemiological m ethods that are typically used to study individuals exposed to radiation. W ithout estimates of the doses received by individuals, it is impossible to be certain w hether the individuals who developed thyroid cancer were actually exposed to radiation. The observed asso ciation between cancer and the surrogate measure of radiation exposure (in this case, proxim ity to the site) m ight be caused by factors other than radiation that correlate with where people live. Correcting for such correlations is difficult, and is often impos sible w ith aggregate data. These correc tions become especially challenging when the level of exposure is very small,1 as the effect of other factors is simply too large compared with the relatively weak effect of radiation exposure. O f note, when the level of exposure is quite low, detecting a small additional increase in risk of cancer requires
a huge sample size and clearly defined doses of radiation exposure. However, ecological studies, if im proved, could still provide sufficiently compelling data; for example, by estim ating aggregate doses based on dose reco n stru ctio n m odels th a t in c o r porate data on atm ospheric release, and spatial and tem poral distribution patterns of radioactivity together with data on diet and lifestyle.3 In the unfortunate event of an accidental release of radioactive materials, it is impor tant for public health officials to assess the risk among children and adolescents, as this group are known to have an especially high radiation-related risk of developing thyroid cancer.6 As a result of an increasing inci dence of thyroid cancer in 131I-contaminated regions in Russia after the Chernobyl acci dent,7 a case-control study o f childhood and/or adolescent cancer was undertaken in contam inated areas.8 Individual radia tion doses to the thyroid were estimated by modelling and from data collected during interview s w ith exposed individuals or their parents. A significant dose-response was found and the estimates of radiationrelated risk were consistent with those from other radiation-exposed populations, which provides credence to the theory that there is a relationship between 131I exposure and thyroid cancer.
^ T h e accurate assessm ent o f in dividual radiation doses is fundam en tal... W Following the im m ediate m easures to determine the extent of radiation exposure, long-term studies of health are necessary.3As a result, the public might request diagnostic testing and clinicians should be aware that thyroid ultrasonography, although seemingly harmless, carries a risk o f ‘over diagnosis’.9 The clinical im portance of very small thy roid cancers detected by ultrasonography is not clear. Widespread screening can also lead to a seemingly dramatic increase in thyroid cancers, as was observed following the acci dent in F ukushim a.10 The nature o f this increase, that is, whether or not it is related to radiation, remains to be determined. A num ber of shortcom ings and lim ita tions of the study by B ollaerts and col leagues calls its findings into question and, as the authors acknowledge, point to the need for fu rth e r investigation. In ad d i tion to m ethodological issues, the safety of living near nuclear facilities is a matter of
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NEWS & VIEWS public concern.1Whichever study approach is taken next, it must be credible, not only to the scientific com munity but also to the general public. Division o f Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850, USA (K.M.). Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, 1819 W.Polk Street, MC 640, Chicago, IL 60616, USA (A.B.S.). Correspondence to: K.M. [email protected] A cknow ledgem ents The authors wish to acknowledge J. Loukissas of th e Division o f Cancer Epidemiology and Genetics, National Cancer in stitu te , Rockville, MD, USA, who provided valuable insights during th e w riting o f th is article . Com peting interests A.B.S. has served as an advisor and expert w itness fo r a law firm dealing with radiation releases from the Hanford Nuclear Facility. K.M. declares no com peting interests. 1.
National Research Council. Analysis o f cancer risks in populations near nuclear facilities: phase 1 (The National Academies Press,
2012). 2.
3.
4.
Bollaerts, K. e t at. Thyroid cancer incidence in th e vicinity o f nuclear sites in Belgium, 2 0 0 0 -2 0 0 8 . Thyroid h ttp ://d x .d o i.o rg / 1 0 .1 0 8 9 /th y .2 0 1 3 .0 2 2 7 . Bouville, A., Linet, M. S., Hatch, M., Mabuchi, K. & Sim on, S. L. Guidelines fo r exposure asse ssm ent in health risk stud ies follow ing a nuclear reactor accident. Environ. Health Perspect. 1 2 2 , 1 - 5 (2014). Vandecasteele, C. M., Sonck, M. & Degueldre, D. Rejet accidentel d ’iode-131 par I’ lRE su r le site de Fleurus: retour d ’experience de I'au torite de surete beige [French], Radioprotection 4 6 ,1 5 9 -1 7 3 ( 2011).
5.
United N ations S cientific C om m ittee on the Effects o f Radiation. Sources and effects of
ionizing radiation. UNSCEAR 2000: Report to the general assembly with scientific annexes, Volume I [online], h ttp ://w w w .u n sce a r.o rg / u n s c e a r/e n /p u b lic a tio n s /2 0 0 0 _ l.h tm l (2013). 6. Ron, E. et al. Thyroid cancer a fte r exposure to external radiation: a pooled analysis o f seven studies. Radiat. Res. 1 4 1 ,2 5 9 -2 7 7 (1995). 7. Shakhatarin, V. V. et al. Iodine deficiency, radiation dose, and the risk o f thyroid cancer am ong children and adolescents in th e Bryansk region o f Russia follow ing the Chernobyl power statio n accident. lnt.J. Epidemiol. 3 2 ,5 8 4 -5 9 1 (2003). 8. Davis, S. eta /. Risk o f thyroid cancer in the Bryask O blast o f th e Russian Federation a fter th e Chernobyl power plant statio n accident. Radiat. Res. 16 2, 2 4 1 -2 4 8 (2004). 9. Davies, L. & Welch, H. G. Increasing incidence o f thyroid cancer in th e United States, 1 9 7 3 -2 0 0 2 . JAMA 29 5, 2 1 6 4 -2 1 6 7 (2006). 10. Nose, T. & Oiwa, Thyroid cancer cases increase am ong young people in Fukushima. The Asahi Shimbun [online], h t t p :// a jw .a s a h i.c o m /a rtic le /0 3 1 1 d is a s te r/ fu k u s h im a /A J2 0 1 4 0 2 0 8 0 0 4 7 (2014).
Y.
NATURE REVIEWS | ENDOCRINOLOGY
DIABETES
M e a s u rin g in te ra rm blood pressure d ifferen ces in d ia b e te s Gianfranco Parati and Alberto Zanchetti Interarm differences in systolic blood pressure are associated with a significant risk of morbidity and mortality. A new study reports that these differences are frequently observed in patients with diabetes mellitus and recommends routine measurement of interarm blood pressure differences to improve diagnostic and prognostic stratification of these patients. Parati, G. & Zanchetti, A. Nat. Rev. Endocrinol. 1 0 ,3 8 7 - 3 8 8 (2 014); published online 3 June 2 0 1 4 ; d o i:1 0 .1 0 3 8 /n re n d o .2 0 1 4 .8 0
Patients with diabetes m ellitus and ele vated blood pressure have a higher risk of cardiovascular disease than normotensive or hypertensive individuals w ithout dia betes mellitus.1 The inaccurate assessment of blood pressure in prim ary care settings is a contributing factor in the increased cardiovascular risk observed in patients with diabetes mellitus. This increased risk is due not only to the intrinsic limitations of prim ary care blood pressure m easure ments (such as, the inaccuracy of readings obtained under constraints of time, poten tial white coat effects, investigator bias and digit preference, and the inability of limited blood pressure measurements to faithfully reflect norm al daily blood pressure),2 but also to the frequent failure of practicing physicians to follow the guideline recom mendations for measuring blood pressure. One such recommendation consists of mea suring blood pressure in both arms at the first visit to detect possible interarm differ ences, and using the arm with the highest blood pressure value as the reference for making decisions about treatm ent.3 This recommendation is supported by the asso ciation betw een interarm differences in systolic blood pressure (> 10 mmHg) and vascular damage, cerebrovascular disease and increased risk of cardiovascular-related and all-cause mortality.4 However, although ~77% of primary care physicians are aware of guideline recom m endations for m ea suring blood pressure in both arms, only a minority of them (~30%) follow this advice, and even fewer (~13%) routinely implement this recommendation, even when receiving a financial incentive.5 These observations indicate that the main barrier to the effec tive implementation of interarm blood pres sure m easurem ents in clinical practice is physicians’ inertia. A call for action against this inertia comes from the results of a new
study by Clark and colleagues,6which high lights the prognostic relevance of interarm systolic blood pressure differences during the initial evaluation of patients with type 1 and type 2 diabetes mellitus. At recruitment, two pairs of blood pres sure m easu rem en ts w ere p erfo rm ed in b oth arm s by sim ultaneous activation of two autom ated sphygmom anometers and then repeated after swapping the cuffs. In a cross-sectional analysis performed in 727 patients w ith type 1 and type 2 diabetes mellitus and 285 individuals w ithout dia betes mellitus, interarm systolic blood pres sure differences >10 mmHg were associated with an increased risk of peripheral arterial disease (OR 3.4, 95% Cl 1.2-9.3) and dif ferences >15 m mHg were associated with an increased risk of diabetic retinopathy (OR 5.7, 95% Cl 1.5-21.6) and chronic kidney disease (OR 7.0, 95% Cl 1.7-29.8).6 These associations rem ained significant even after adjusting for age, sex, w aist/ h ip ratio , sm o k in g statu s an d systolic blood pressure. Over a m edian follow-up of 52 m onths, the risk of cardiovascularrelated m ortality was markedly increased in patients with diabetes mellitus who had systolic interarm blood pressure differences >10 mmHg (HR 3.5, 95% Cl 1.0-13.0) and >15 mmHg (HR 9.0, 95% Cl 2.0-41.0).6 Remarkably, when sensitivity and speci ficity analyses were perform ed, interarm b lood pressure differences d eterm in ed from single pairs of sequentially performed blood pressure measurements were shown to correctly identify interarm systolic blood pressure differences >10 mmHg. This find ing highlights the value of a single pair of sequential blood pressure m easurem ents that are easy to implement in clinical prac tice. This is of relevance if we consider that failure to identify interarm differences in blood pressure can lead to underestimating
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