Correspondence
Subclinical Cushing’s syndrome and cardiovascular disease Guido Di Dalmazi and colleagues1 reported that in patients with adrenal incidentalomas and either stable mild hypercortisolism or worsening of cortisol hypersecretion, all-cause and cardiovascular disease-specific mortality was higher compared with in those with adrenal incidentalomas that did not secrete cortisol, after a mean follow-up of 7·5 years. Moreover, cortisol concentrations measured after dexamethasone-suppression test were associated with all-cause mortality independent of the presence of traditional cardiovascular disease risk factors. Subclinical Cushing’s syndrome is the most common hormonal abnormality in patients with adrenal incidentalomas (prevalence 1–29%).2 The proportion of adrenal incidentalomas that progress to subclinical Cushing’s syndrome is low (1·7%) and most are lesions of 3 cm or larger.2 Progression to overt Cushing’s syndrome is controversial (because both spontaneous normalisation of hypersecretion and stable disease have been reported during followup) and spontaneous normalisation of hypersecretion has been reported in 50% of cases.2 Results of the study by Di Dalmazi and co-workers1 are important because they show, for the first time, that patients with subclinical Cushing’s syndrome are at increased risk of cardiovascular disease and all-cause mortality (mainly attributable to cardiovascular disease). The association of cortisol with all-cause mortality might also be attributable to its potential role in the pathogenesis of metabolic syndrome.3 Findings of previous studies have shown an increased prevalence of cardiovascular disease risk factors in patients with subclinical Cushing’s syndrome, but data for optimum management are conflicting. Some
criteria—such as large (>4–6 cm) adrenal incidentalomas, features suggestive of malignancy (eg, heterogeneity, irregular shape, calcification or necrosis, invasion to adjacent tissues), or potentially lethal hormonal hypersecretion (ie, pheochromocytomas)—support the need for adrenalectomy. However, universal surgical management of patients with subclinical Cushing’s syndrome has not been accepted.2,4 Uncertainty about the most effective management strategy for subclinical Cushing’s syndrome is attributable to the variable definitions used, and the small sample size and retrospective nature of most studies.4 Only one prospective study has been published so far showing that laparoscopic adrenalectomy is more beneficial than is conservative management for the normalisation or improvement of cardiovascular disease risk factors, such as diabetes, dyslipidaemia, hypertension, and obesity.5 Prospective studies and registries are needed to document the effect of different approaches on the incidence of cardiovascular disease events and mortality in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Until then, individualised treatment seems prudent. Surgical management of subclinical Cushing’s syndrome can be suggested in young patients (age 4·4 mmol/L fasting). Individuals with higher baseline C-peptide release and higher insulin secretion at 30 min on oral glucose tolerance testing showed greater increases in these variables after vitamin D supplementation than did those with initially lower responses.3 Thus, correction of vitamin D deficiency early in the development of β-cell dysfunction might be important for this intervention to restore normal insulin secretion. If additional research confirms this possibility, maintenance of vitamin D repletion during the life span would gain importance. If this assumption is correct, it would explain the failure of many randomised clinical trials of vitamin D supplementation to correct or prevent type 2 diabetes, given that most trials have been initiated late in disease development. Confirmation of this assumption in human beings would require trials of supplementation from early in life or assessment of outcomes prospectively. Because long-term randomised clinical trials from early life would be difficult and possibly unethical, the best way forward might be to prospectively assess the effects of vitamin D repletion from early life 362
on risk of type 2 diabetes. Such studies would also allow study of the risks of other disorders in which early-life vitamin D status has a potential role, such as autoimmune diseases including multiple sclerosis and type 1 diabetes.2 I declare that I have no competing interests.
Barbara Boucher [email protected] Barts and The London School of Medicine and Dentistry, The Blizard Institute, London E1 2AD, UK 1
2
3
4
5
Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Vitamin D concentration, obesity, and risk of diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2014; 2: 298–306. Pilz S, Gaksh M, Tomaschitz A. Vitamin D and prevention of diabetes: is lifelong endogenous vitamin D needed? Lancet Diabetes Endocrinol 2014; 2: 267–68. Boucher BJ. Vitamin D insufficiency and diabetes risks. Curr Drug Targets 2011; 12: 61–87. Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, Wareham NJ. Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia 2012: 55: 2173–82. Boucher BJ, Mannan N, Noonan K, Hales CN, Evans SJW. Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in East London Asians. Diabetologia 1995: 38: 1239–45.
The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes We read with interest the recent metaanalysis by Bolland and colleagues.1 The investigators reported that vitamin D supplementation (with or without calcium) did not significantly reduce the relative risk of cardiovascular disease, including myocardial infarction, ischaemic heart disease, stroke or cerebrovascular disease, nor that of cancer, hip or total fractures (except fractures in patients in an institution). On the basis of results from a trial sequential analysis, the investigators conclude that future trials with similar design seem unlikely to change these conclusions.
A few aspects of the methods of previous trials are worth mentioning. First, the short duration (ie,
Subclinical Cushing’s syndrome and cardiovascular disease Guido Di Dalmazi and colleagues1 reported that in patients with adrenal incidentalomas and either stable mild hypercortisolism or worsening of cortisol hypersecretion, all-cause and cardiovascular disease-specific mortality was higher compared with in those with adrenal incidentalomas that did not secrete cortisol, after a mean follow-up of 7·5 years. Moreover, cortisol concentrations measured after dexamethasone-suppression test were associated with all-cause mortality independent of the presence of traditional cardiovascular disease risk factors. Subclinical Cushing’s syndrome is the most common hormonal abnormality in patients with adrenal incidentalomas (prevalence 1–29%).2 The proportion of adrenal incidentalomas that progress to subclinical Cushing’s syndrome is low (1·7%) and most are lesions of 3 cm or larger.2 Progression to overt Cushing’s syndrome is controversial (because both spontaneous normalisation of hypersecretion and stable disease have been reported during followup) and spontaneous normalisation of hypersecretion has been reported in 50% of cases.2 Results of the study by Di Dalmazi and co-workers1 are important because they show, for the first time, that patients with subclinical Cushing’s syndrome are at increased risk of cardiovascular disease and all-cause mortality (mainly attributable to cardiovascular disease). The association of cortisol with all-cause mortality might also be attributable to its potential role in the pathogenesis of metabolic syndrome.3 Findings of previous studies have shown an increased prevalence of cardiovascular disease risk factors in patients with subclinical Cushing’s syndrome, but data for optimum management are conflicting. Some
criteria—such as large (>4–6 cm) adrenal incidentalomas, features suggestive of malignancy (eg, heterogeneity, irregular shape, calcification or necrosis, invasion to adjacent tissues), or potentially lethal hormonal hypersecretion (ie, pheochromocytomas)—support the need for adrenalectomy. However, universal surgical management of patients with subclinical Cushing’s syndrome has not been accepted.2,4 Uncertainty about the most effective management strategy for subclinical Cushing’s syndrome is attributable to the variable definitions used, and the small sample size and retrospective nature of most studies.4 Only one prospective study has been published so far showing that laparoscopic adrenalectomy is more beneficial than is conservative management for the normalisation or improvement of cardiovascular disease risk factors, such as diabetes, dyslipidaemia, hypertension, and obesity.5 Prospective studies and registries are needed to document the effect of different approaches on the incidence of cardiovascular disease events and mortality in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Until then, individualised treatment seems prudent. Surgical management of subclinical Cushing’s syndrome can be suggested in young patients (age 4·4 mmol/L fasting). Individuals with higher baseline C-peptide release and higher insulin secretion at 30 min on oral glucose tolerance testing showed greater increases in these variables after vitamin D supplementation than did those with initially lower responses.3 Thus, correction of vitamin D deficiency early in the development of β-cell dysfunction might be important for this intervention to restore normal insulin secretion. If additional research confirms this possibility, maintenance of vitamin D repletion during the life span would gain importance. If this assumption is correct, it would explain the failure of many randomised clinical trials of vitamin D supplementation to correct or prevent type 2 diabetes, given that most trials have been initiated late in disease development. Confirmation of this assumption in human beings would require trials of supplementation from early in life or assessment of outcomes prospectively. Because long-term randomised clinical trials from early life would be difficult and possibly unethical, the best way forward might be to prospectively assess the effects of vitamin D repletion from early life 362
on risk of type 2 diabetes. Such studies would also allow study of the risks of other disorders in which early-life vitamin D status has a potential role, such as autoimmune diseases including multiple sclerosis and type 1 diabetes.2 I declare that I have no competing interests.
Barbara Boucher [email protected] Barts and The London School of Medicine and Dentistry, The Blizard Institute, London E1 2AD, UK 1
2
3
4
5
Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Vitamin D concentration, obesity, and risk of diabetes: a Mendelian randomisation study. Lancet Diabetes Endocrinol 2014; 2: 298–306. Pilz S, Gaksh M, Tomaschitz A. Vitamin D and prevention of diabetes: is lifelong endogenous vitamin D needed? Lancet Diabetes Endocrinol 2014; 2: 267–68. Boucher BJ. Vitamin D insufficiency and diabetes risks. Curr Drug Targets 2011; 12: 61–87. Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, Wareham NJ. Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia 2012: 55: 2173–82. Boucher BJ, Mannan N, Noonan K, Hales CN, Evans SJW. Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in East London Asians. Diabetologia 1995: 38: 1239–45.
The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes We read with interest the recent metaanalysis by Bolland and colleagues.1 The investigators reported that vitamin D supplementation (with or without calcium) did not significantly reduce the relative risk of cardiovascular disease, including myocardial infarction, ischaemic heart disease, stroke or cerebrovascular disease, nor that of cancer, hip or total fractures (except fractures in patients in an institution). On the basis of results from a trial sequential analysis, the investigators conclude that future trials with similar design seem unlikely to change these conclusions.
A few aspects of the methods of previous trials are worth mentioning. First, the short duration (ie,
