Mortality Data From the European Adrenal Insufficiency Registry

Patient Characterization and Associations

Marcus Quinkler; Bertil Ekman; Pinggao Zhang; Andrea M. Isidori; Robert D. Murray


Clin Endocrinol. 2018;89(1):30-35. 

In This Article

Abstract and Introduction


Objective: Mortality from primary and secondary adrenal insufficiency (AI; PAI and SAI, respectively) is 2–3–fold higher than in the general population. Mortality relates to cardiovascular disease, acute adrenal crisis (AC), cancer and infections; however, there has been little further characterization of patients who have died.

Design/Methods: We analysed real–world data from 2034 patients (801 PAI, 1233 SAI) in the European Adrenal Insufficiency Registry (EU–AIR; NCT01661387). Baseline clinical and biochemical data of patients who subsequently died were compared with those who remained alive.

Results: From August 2012 to June 2017, 26 deaths occurred (8 PAI, 18 SAI) from cardiovascular disease (n = 9), infection (n = 4), suicide (n = 2), drug–induced hepatitis (n = 2), and renal failure, brain tumour, cachexia and AC (each n = 1); cause of death was unclear in 5 patients. Patients who died were significantly older at baseline than alive patients. Causes of AI were representative of patients with SAI; however, 3–quarters of deceased patients with PAI had undergone bilateral adrenalectomy (3 with uncontrolled Cushing's disease, 3 with metastatic renal cell cancer). There were no significant differences in body mass index, blood pressure, low–density lipoprotein cholesterol, total cholesterol or electrolytes between deceased and alive patients. Deceased patients with SAI were more frequently male individuals, were receiving higher daily doses of hydrocortisone (24.0 ± 7.6 vs 19.3 ± 5.7 mg, P = .0016) and experienced more frequent ACs (11.1 vs 2.49/100 patient–years, P = .0389) than alive patients.

Conclusions: This is the first study to provide detailed characteristics of deceased patients with AI. Older, male patients with SAI and frequent AC had a high mortality risk.


If left untreated, adrenal insufficiency (AI) leads to premature death.[1] Introduction of glucocorticoid replacement therapy in patients with AI has led to greatly improved outcomes;[2] however, it is increasingly recognized that patients with AI continue to experience high levels of morbidity and premature mortality. These adverse outcomes are thought to be due to inappropriate glucocorticoid dosage and the nonphysiological nature of conventional replacement therapy.[3–5]

Hospital record data suggest that mortality associated with primary AI (PAI) is 2–3–fold higher than in the general population.[6] In the Swedish Hospital Registry, the cardiovascular mortality associated with PAI was approximately 2–fold higher, and the mortality owing to infectious disease was approximately 6–fold higher, than that of the normal population.[6] Data from the Norwegian Hospital Registry showed that, between 1943 and 2005, the mortality for PAI related mainly to cardiovascular disease, followed by Addisonian crisis, cancer, infection and sudden death.[7] More recently, the Swedish National Inpatient Register showed a dramatically reduced survival probability for patients with PAI and comorbid diabetes mellitus, compared with patients with diabetes mellitus alone. Cardiovascular disease and complications of diabetes mellitus were the most common causes of death.[8]

Patients with secondary AI (SAI) also showed an increased cardiovascular mortality.[9,10] A large, prospective study of patients with SAI in the UK demonstrated an overall standard mortality ratio (SMR) of 1.87, but could not attribute the increased mortality to any particular endocrine condition other than untreated growth hormone deficiency.[11] Analysis of a large cohort of Swedish patients with pituitary disease showed that the SMR due to infection was 6.32; all 15 individuals who died from infection (from a total of 120 deaths and 1286 patients) had SAI, and 8 of these individuals had adrenal crisis (AC). The authors concluded that AC in response to acute stress and intercurrent illness is an important cause of mortality in patients with hypopituitarism.[12] Similarly, a large cohort study in the USA demonstrated that the relative risk of death was 7.1 in patients with SAI, emphasizing the importance of early intervention when infection occurs in association with AI.[13]

There has been, however, little further characterization of the patients who died.[12] Therefore, we analysed real–world data from the European Adrenal Insufficiency Registry (EU–AIR), with centres across Germany, the Netherlands, Sweden and the UK, to further characterize the patients with AI who have died.