"Nonfunctional" Adrenal Tumors and the Risk for Incident Diabetes and Cardiovascular Outcomes: A Cohort Study

Abstract

Background: Benign adrenal tumors are commonly discovered on abdominal imaging. Most are classified as nonfunctional and are considered to pose no health risk, but some are considered functional because they secrete hormones that increase risk for metabolic and cardiovascular diseases.

Objective: To evaluate the hypothesis that nonfunctional adrenal tumors (NFATs) increase risk for cardiometabolic outcomes compared with absence of adrenal tumors.

Design: Cohort study.

Setting: Integrated hospital system.

Participants: Participants with benign NFATs ("exposed"; n = 166) and those with no adrenal tumor ("unexposed"; n = 740), with at least 3 years of follow-up.

Measurements: Medical records were reviewed from the time of abdominal imaging for development of incident outcomes (hypertension, composite diabetes [prediabetes or type 2 diabetes], hyperlipidemia, cardiovascular events, and chronic kidney disease) (mean, 7.7 years). Primary analyses evaluated independent associations between exposure status and incident outcomes by using adjusted generalized linear models. Secondary analyses evaluated relationships between NFATs and cortisol physiology.

Results: Participants with NFATs had significantly higher risk for incident composite diabetes than those without adrenal tumors (30 of 110 [27.3%] vs. 72 of 615 [11.7%] participants; absolute risk, 15.6% [95% CI, 6.9% to 24.3%]; adjusted risk ratio, 1.87 [CI, 1.17 to 2.98]). No significant associations between NFATs and other outcomes were observed. Higher "normal" postdexamethasone cortisol levels (≤50 nmol/L) were associated with larger NFAT size and higher prevalence of type 2 diabetes.

Limitation: Potential bias in the selection of participants and ascertainment of outcomes.

Conclusion: Participants with NFATs had a significantly higher risk for diabetes than those without adrenal tumors. These results should prompt a reassessment of whether the classification of benign adrenal tumors as "nonfunctional" adequately reflects the continuum of hormone secretion and metabolic risk they may harbor.

Primary funding source: National Institutes of Health and Doris Duke Charitable Foundation.

Figure 1. Selection of the study participants and identification of exposure status

(NFAT vs. no adrenal tumors). GRA=glucocorticoid-remediable aldosteronism; DST=dexamethasone suppression test; UFC=urinary free cortisol; NFAT= “non-functional” adrenal tumor.

Figure 2. Cases of incident composite diabetes during longitudinal follow-up

Shown are the proportion of participants who developed incident composite diabetes during follow-up. Eligible participants did not have any type of diabetes at baseline (the time of imaging), and had ≥3 years of follow-up. Panel (A) shows all 725 eligible participants (110 with NFAT and 625 without adrenal tumors), where participants with NFAT had subclinical hypercortisolism excluded using either a 1mg DST or a 24h UFC. Panel (B) shows only those participants with NFAT who had subclinical hypercortisolism excluded using a 1mg DST≤1.8 mcg/dL (73 eligible), and panel (C) shows only those participants with NFAT who had subclinical hypercortisolism excluded using a 24h UFC<50 mcg (50 eligible). Panel (D) depicts an exploratory analysis, whereby participants who were initially excluded from the main analysis due to potential subclinical hypercortisolism were included, and compared with all the eligible participants without adrenal tumors and with NFAT to assess incident composite diabetes. Blue squares and lines indicate participants with no adrenal tumors. Red diamonds and lines indicate participants with NFAT. Black circles and lines indicate participants with adrenal tumors and subclinical hypercortisolism. NFAT= “non-functional” adrenal tumor

Figure 3

The relationship between the size of NFAT and (A) the degree of serum cortisol suppression following a 1 mg DST where all values are ≤1.8 mcg/dL, and (B) the 24 hour urinary free cortisol where all values are <50 mcg/24h. Shown are the mean regression line (bold solid green), the 95% C.I. for the mean regression (dashed bold green), and the 95% C.I. for the observed values (dashed green). (C) The prevalence of type 2 diabetes in participants with NFAT by quartile of “normal” serum cortisol levels following 1 mg DST, where all cortisol levels are ≤ 1.8 mcg/dL. Shown are the prevalence (%) and the 95% C.I.. NFAT= “non-functional” adrenal tumor DST=dexamethasone suppression test