Clinical Endocrinology (2015) 82, 155–157
LETTERS TO THE EDITOR
ACTH stimulation test in patients with type 1 diabetes and recurrent severe hypoglycaemia Dear Editors, Adrenal insufficiency has been reported as cause of severe hypoglycaemia in patients with type 1 diabetes in several case reports.1 The pathophysiological mechanisms include altered glucose metabolism and impaired hormonal counter-regulatory response to hypoglycaemia. Thus, lack of cortisol results in increased insulin sensitivity due to reduced hepatic glucose production and enhanced glucose uptake and utilization by peripheral tissues. During hypoglycaemia, cortisol is secreted as part of the hormonal counter-regulatory response to increase hepatic glucose production. Particularly in subjects with long-standing type 1 diabetes and failure of glucagon and adrenalin responses, the cortisol response may be of great importance. Hence, adrenal insufficiency may predispose to development of severe hypoglycaemia. The prevalence of adrenal insufficiency is higher among people with type 1 diabetes than in the background population and vice versa (12% of adult patients with Addison’s disease had type 1 diabetes in a recent Norwegian registry-based nationwide sample of 426 patients 2), probably due to the common autoimmune pathogenesis of primary adrenal insufficiency and type 1 diabetes. It is possible that undiagnosed adrenal insufficiency may contribute to the occurrence of recurrent severe hypoglycaemia in type 1 diabetes that affects approximately 20% of patients with type 1 diabetes.3 Data on the prevalence of undiscovered adrenal insufficiency among patients with type 1 diabetes and recurrent severe hypoglycaemia are very limited,4 and it is debated whether screening for Addison’s disease should be carried out in patients with type 1 diabetes. We screened a large cohort of patients with type 1 diabetes and recurrent episodes of severe hypoglycaemia (≥2 episodes in the past year) for adrenal insufficiency using a 30-min ACTH stimulation test. Our aim was to determine whether undiagnosed adrenal insufficiency is common in patients with type 1 diabetes prone to severe hypoglycaemia. The study is part of the HypoAna trial, an investigator-initiated prospective, randomized, open, blinded end-point (PROBE) cross-over trial in which the effect of insulin analogues vs human insulin on the frequency of severe hypoglycaemia is assessed during a 2-year period.5 A total of 159 subjects entered the study, but two patients were treated continuously with corticosteroids due to renal replacement (making interpretation of the ACTH test impossible), and 9 subjects did not complete the ACTH test, leaving 148 patients for analysis. The participants arrived at the outpatient clinics after an overnight fast. Baseline information was gathered as described in,5 and a short ACTH test (Synacthenâ, 025 mg i.v.) was performed in the supine © 2014 John Wiley & Sons Ltd
position. Basal and stimulated (after 30 min) cortisol levels were measured. A normal plasma cortisol response to Synacthenâ was defined as a poststimulation concentration ≥500 nM. Plasma cortisol from all participating clinics was measured centrally at Steno Diabetes Center using an immunoassay (Aia Pack) from Tosoh Bioscience (San Francisco, USA). According to manufacturer’s datasheet, the assay does not interfere with haemoglobin or bilirubin. The coefficient of variation (CV%) of the assay as provided by the manufacturer is maximum 46%. Other biochemical analysis is described elsewhere.5 Clinical characteristics of the participants are presented in Table 1. In short, the prevalence of risk factors for hypoglycaemic events was high. Thus, a majority of the patients reported impaired awareness of hypoglycaemia or hypoglycaemia unawareness and 84% were C-peptide negative. The baseline cortisol levels of 441 119 (mean SD) nM increased to 717 127 nM 30 min after ACTH stimulation. All participants had a 30-min plasma cortisol level above 500 nM. In this study, the prevalence of previously undiagnosed primary adrenal insufficiency in 148 people with type 1 diabetes and recurrent severe hypoglycaemia was zero (95% CI = 0% to 24%). Our data are in accordance with a study by Likhari et al.4 who performed ACTH stimulation tests in 95 patients with type 1 diabetes and recurrent hypoglycaemia and found a low prevalence of Addison’s disease, that is, one patient = 1.05% (95% CI = 003% to 57%, calculated by the author of the present paper). ‘Recurrent hypoglycaemia’ was not defined in this study in terms of frequency and severity of the hypoglycaemic episodes. When combining the data from the study by Likhari et al.4 with our data, the prevalence of undiagnosed primary adrenal insufficiency in patients with type 1 diabetes prone to severe hypoglycaemia can be estimated to 1/(148 + 95) = 04% (95% CI = 001% to 225%). The strength of our study is the relatively large number of patients (n = 148), the precise definition of recurrent severe hypoglycaemia and systematic gathering of clinical data. Inclusion of patients based on questionnaires assessing the frequency of episodes of severe hypoglycaemia could be hampered by recall bias. However, recall of episodes of severe hypoglycaemia is a robust measure compared with prospectively recorded episodes of severe hypoglycaemia, although some patients with hypoglycaemia unawareness may underestimate the frequency of episodes of severe hypoglycaemia. In the HypoAna trial, known adrenal insufficiency was an exclusion criterion.5 This could potentially make it less probable to find patients in our cohort suffering from that disease, thereby underestimating the frequency of adrenal insufficiency. However, symptoms and signs (including laboratory data) of adrenal insufficiency are often vague and not specific. Therefore, identification of patients with adrenal insufficiency may be difficult, and diagnostic delay is 155
156 Letters to the Editor Table 1. Baseline clinical characteristics in 148 patients with type 1 diabetes and recurrent, severe hypoglycaemia N = 148 Gender (men/women), % Age (years) Duration of diabetes (years) Body mass index (kg/m2) HbA1c (mmol/mol) HbA1c (%) Plasma C-peptide
LETTERS TO THE EDITOR
ACTH stimulation test in patients with type 1 diabetes and recurrent severe hypoglycaemia Dear Editors, Adrenal insufficiency has been reported as cause of severe hypoglycaemia in patients with type 1 diabetes in several case reports.1 The pathophysiological mechanisms include altered glucose metabolism and impaired hormonal counter-regulatory response to hypoglycaemia. Thus, lack of cortisol results in increased insulin sensitivity due to reduced hepatic glucose production and enhanced glucose uptake and utilization by peripheral tissues. During hypoglycaemia, cortisol is secreted as part of the hormonal counter-regulatory response to increase hepatic glucose production. Particularly in subjects with long-standing type 1 diabetes and failure of glucagon and adrenalin responses, the cortisol response may be of great importance. Hence, adrenal insufficiency may predispose to development of severe hypoglycaemia. The prevalence of adrenal insufficiency is higher among people with type 1 diabetes than in the background population and vice versa (12% of adult patients with Addison’s disease had type 1 diabetes in a recent Norwegian registry-based nationwide sample of 426 patients 2), probably due to the common autoimmune pathogenesis of primary adrenal insufficiency and type 1 diabetes. It is possible that undiagnosed adrenal insufficiency may contribute to the occurrence of recurrent severe hypoglycaemia in type 1 diabetes that affects approximately 20% of patients with type 1 diabetes.3 Data on the prevalence of undiscovered adrenal insufficiency among patients with type 1 diabetes and recurrent severe hypoglycaemia are very limited,4 and it is debated whether screening for Addison’s disease should be carried out in patients with type 1 diabetes. We screened a large cohort of patients with type 1 diabetes and recurrent episodes of severe hypoglycaemia (≥2 episodes in the past year) for adrenal insufficiency using a 30-min ACTH stimulation test. Our aim was to determine whether undiagnosed adrenal insufficiency is common in patients with type 1 diabetes prone to severe hypoglycaemia. The study is part of the HypoAna trial, an investigator-initiated prospective, randomized, open, blinded end-point (PROBE) cross-over trial in which the effect of insulin analogues vs human insulin on the frequency of severe hypoglycaemia is assessed during a 2-year period.5 A total of 159 subjects entered the study, but two patients were treated continuously with corticosteroids due to renal replacement (making interpretation of the ACTH test impossible), and 9 subjects did not complete the ACTH test, leaving 148 patients for analysis. The participants arrived at the outpatient clinics after an overnight fast. Baseline information was gathered as described in,5 and a short ACTH test (Synacthenâ, 025 mg i.v.) was performed in the supine © 2014 John Wiley & Sons Ltd
position. Basal and stimulated (after 30 min) cortisol levels were measured. A normal plasma cortisol response to Synacthenâ was defined as a poststimulation concentration ≥500 nM. Plasma cortisol from all participating clinics was measured centrally at Steno Diabetes Center using an immunoassay (Aia Pack) from Tosoh Bioscience (San Francisco, USA). According to manufacturer’s datasheet, the assay does not interfere with haemoglobin or bilirubin. The coefficient of variation (CV%) of the assay as provided by the manufacturer is maximum 46%. Other biochemical analysis is described elsewhere.5 Clinical characteristics of the participants are presented in Table 1. In short, the prevalence of risk factors for hypoglycaemic events was high. Thus, a majority of the patients reported impaired awareness of hypoglycaemia or hypoglycaemia unawareness and 84% were C-peptide negative. The baseline cortisol levels of 441 119 (mean SD) nM increased to 717 127 nM 30 min after ACTH stimulation. All participants had a 30-min plasma cortisol level above 500 nM. In this study, the prevalence of previously undiagnosed primary adrenal insufficiency in 148 people with type 1 diabetes and recurrent severe hypoglycaemia was zero (95% CI = 0% to 24%). Our data are in accordance with a study by Likhari et al.4 who performed ACTH stimulation tests in 95 patients with type 1 diabetes and recurrent hypoglycaemia and found a low prevalence of Addison’s disease, that is, one patient = 1.05% (95% CI = 003% to 57%, calculated by the author of the present paper). ‘Recurrent hypoglycaemia’ was not defined in this study in terms of frequency and severity of the hypoglycaemic episodes. When combining the data from the study by Likhari et al.4 with our data, the prevalence of undiagnosed primary adrenal insufficiency in patients with type 1 diabetes prone to severe hypoglycaemia can be estimated to 1/(148 + 95) = 04% (95% CI = 001% to 225%). The strength of our study is the relatively large number of patients (n = 148), the precise definition of recurrent severe hypoglycaemia and systematic gathering of clinical data. Inclusion of patients based on questionnaires assessing the frequency of episodes of severe hypoglycaemia could be hampered by recall bias. However, recall of episodes of severe hypoglycaemia is a robust measure compared with prospectively recorded episodes of severe hypoglycaemia, although some patients with hypoglycaemia unawareness may underestimate the frequency of episodes of severe hypoglycaemia. In the HypoAna trial, known adrenal insufficiency was an exclusion criterion.5 This could potentially make it less probable to find patients in our cohort suffering from that disease, thereby underestimating the frequency of adrenal insufficiency. However, symptoms and signs (including laboratory data) of adrenal insufficiency are often vague and not specific. Therefore, identification of patients with adrenal insufficiency may be difficult, and diagnostic delay is 155
156 Letters to the Editor Table 1. Baseline clinical characteristics in 148 patients with type 1 diabetes and recurrent, severe hypoglycaemia N = 148 Gender (men/women), % Age (years) Duration of diabetes (years) Body mass index (kg/m2) HbA1c (mmol/mol) HbA1c (%) Plasma C-peptide
