Clues for early detection of autoimmune Addison's disease - myths and realities.

BACKGROUND: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce. OBJECTIVE: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD. MATERIAL AND METHODS: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values. RESULTS: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L-1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L-1 [2-442]) than in those without (81 nmol L-1 [1-668], P < 0.001). CONCLUSION: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency.

OBJECTIVE: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). DESIGN: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. METHODS: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). RESULTS: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. CONCLUSIONS: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Increased cardiovascular risk in South African patients with Addison's disease.

Patients with Addison's disease (AD) are believed to be at risk for cardiovascular disease (CVD). South Africa, like the rest of the developing world is experiencing an increase in CVD and patients with AD may be at double the risk of their peers. We wished to explore AD patients' CVD risk factors. A cross-sectional nationwide study in South Africa of patients with AD was conducted. A cohort of 147 patients with AD and 147 healthy control subjects were matched by age, gender, ethnicity, and BMI as far as was possible. Lipoproteins and highly-sensitive C-reactive-protein (hs-CRP) were the main outcome measures. AD patients had significantly higher triglycerides; (p=0.001), lower HDLC (p<0.001), higher hs-CRP (p<0.001), and more small dense LDL; (p=0.002) than controls. Nonesterified fatty acids were lower in patients (p<0.001). Approximately 65% [95% confidence interval (CI 55.6-72.4%)] had hypercholesterolaemia, 75% (CI 64.8-81.2%) had low HDLC, and 75% (CI 68.0-84.1%) had a higher LDLC. Thirteen percent of AD patients had diabetes mellitus, but none of the risk factors differed from the nondiabetics. Only HDLC correlated positively with daily hydrocortisone dose (r=0.32; p=0.005). In conclusion dyslipidaemia is common in South African AD patients; CVD risk assessment and intervention are probably warranted in the management of these patients.

Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation.

CONTEXT: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile. OBJECTIVE: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. DESIGN AND SETTING: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers. PATIENTS: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). INTERVENTION: The same daily dose of hydrocortisone was administered as OD dual-release or TID. MAIN OUTCOME MEASURE: We evaluated cortisol pharmacokinetics. RESULTS: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004). CONCLUSION: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.