Diabetes, Active Disease, and Afternoon Serum Cortisol Levels Predict Cushing’s Disease Mortality: A Cohort Study

Abstract

Context Cushing disease (CD) is a life-threating disease, with increased mortality in comparison with the general population. Objective This study aimed to evaluate standardized mortality ratios (SMRs) in CD patients. We also analyzed independent risk factors related to increased mortality. Design We conducted a longitudinal cohort study in a third level specialty center, from 1979 to 2018 in patients with CD. Results From 1375 cases with pathology diagnosis of pituitary adenoma, 191 cases have the confirmed diagnosis of CD (14%). 172 patients completed follow-up, with a mean age at diagnosis of 33±11 years, female predominance (n=154, 89.5%), majority of them microadenoma (n=136, 79%), and a median follow-up of 7.5 years (2.4-15). Eighteen patients (10.5%) died; 8 of them (44%) with active CD, 8 (44%) under remission, and 2 (11%) under disease control. Estimated all-cause SMR=3.1, 95%CI 1.9-4.8, p <0.001. Cardiovascular disease was the main cause of death (SMR=4.2, 1.5-9.3, p=0.01). Multivariate Cox regression models adjusted for potential cofounders showed that diabetes (HR=5.2, IC95% 1.8-15.4, p=0.002), high cortisol levels after 1600 h at diagnosis (3.4, 2.3-7.0, p=0.02), and active CD (7.5, 3.8-17.3, p=0.003), significantly increased the risk of mortality. Conclusions Main cause of CD mortality was cardiovascular disease. Main risk factors for mortality were uncontrolled diabetes, persistently high cortisol levels after 1600 h at diagnosis, and active disease at last follow-up.

Increased Mortality Persists after Treatment of Cushing’s Disease: A Matched Nationwide Cohort Study

“…The study also supports findings that mortality continues to be increased despite biochemically successful treatment of hypercortisolism [HR 1.5 (95% CI 1.02-2.2)]. Cardiovascular diseases have been determined to be a main reason for a shorter life span in both active and “cured” CD [ 3 , 5 , 10 , 15 , 16 , 20-22 ], which was confirmed in our study. Out of 66 deaths, 32 (48%) were due to cardiovascular diseases, including 2 fatal pulmonary embolisms.…”

“…Although several smaller studies have reported that the standardized mortality rate (SMR) is not significantly increased [ 10-13 ], a recent meta-analysis concluded that patients “cured” from CD had an increased mortality, with a pooled SMR of 2.5 (95% CI 1.4-4.2) [ 14 ]. Subsequently, 1 large study reported increased mortality for patients in remission [ 3 ], a second smaller study did not [ 15 ], and a third study demonstrated normalized life expectancy in patients who had been in remission for 10 years after only 1 TSS [ 16 ]. Except for 1 study, which included patients with Cushing’s syndrome of both adrenal and pituitary origin [ 17 ], previous studies on mortality in CD have used the expected number of deaths in the total background population as a reference and reported SMRs.…”

Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up

“…Although data are not uniform, previous studies have associated increased mortality with co-existing hypertension (58,101), depression at diagnosis (176) and glucocorticoid replacement therapy (106). Diabetes mellitus that possibly increases the risk of both cardiovascular and infectious diseases was a risk factor in some previous studies (101,102,107) but not in others (106,176). In our study, age at diagnosis was associated with mortality in patients with CD, which is in line with most previous studies (3,11,19,21,28,29).…”

“…CD has the highest mortality rates of pituitary adenomas with standardised mortality rates (SMRs) ranging from 1.9 to 9.3 in the most recent publications (101)(102)(103)(104)(105)(106)(107), Table 4. Compared to non-functioning tumours treated with TSS, patients with CD had an age-adjusted hazard ratio of 2.35 (95% CI 1.13-4.09) (108).SMR in CD have remained high during the last decades (106) while the mortality in acromegaly decreased (109,110).…”

“…The most recent meta-analysis concluded that "cured" patients still had an elevated SMR (pooled SMR from eight studies 2.5 [95% CI 1.4-4.2]) (114). Following that meta-analysis, one study on 502 patients with CD (in remission n=419) demonstrated a significantly higher SMR (1.9, 95% CI 1.5-2.3) for patients in remission (106) while another smaller study did not (107). In a publication from 2016, Clayton et al presented survival data in patients with CD that had already been in remission for 10 years.…”