Myosteatosis and sarcopenia are linked to autonomous cortisol secretion in patients with aldosterone-producing adenomas

Primary aldosteronism (PA) is associated with high prevalence of metabolic syndrome and obesity, and excess aldosterone contributes to cardiac remodeling and metabolic sequelae such as visceral obesity, insulin resistance, and impaired glucose homeostasis. Concurrent autonomous cortisol secretion (ACS) is often underdiagnosed in PA due to incomplete screening. ACS increases the prevalence of obesity and diabetes and independently elevates cardiovascular event risk in PA. Prior studies in ACS without PA link higher cortisol secretion to greater visceral adipose tissue (VAT) and reduced muscle mass, but data in PA are limited and conflicting: one study found no differences in fat volumes between ACS and non-ACS in PA, while another in aldosterone-producing adenoma (APA) showed lower skeletal muscle area in ACS. Myosteatosis (excess fat within skeletal muscle) is a negative prognostic factor in multiple diseases and offers a distinct perspective within sarcopenia research. While Cushing’s syndrome is known for visceral obesity and muscle wasting, evidence in ACS—particularly in PA—is scarce, and the relationship between myosteatosis and ACS has not been investigated. This study aimed to clarify the relationship between muscle fat content (especially myosteatosis), muscle quantity and quality, and ACS in patients with APA.

The background literature indicates: (1) PA is linked to metabolic syndrome, visceral obesity, insulin resistance, and glucose dysregulation due to aldosterone excess. (2) ACS, frequently underrecognized in PA, is associated with higher rates of obesity and diabetes and independently increases cardiovascular events in PA cohorts. (3) In non-PA populations, greater cortisol secretion correlates with increased VAT and reduced skeletal muscle. (4) Evidence within PA is limited and inconsistent: one study reported no difference in total, visceral, or subcutaneous fat volumes between ACS and non-ACS groups, while another found lower skeletal muscle area in APA patients with ACS. (5) Myosteatosis is increasingly recognized as a prognostic factor in cancer and is associated with cardiovascular disease and hepatic steatosis, but its relationship with ACS—particularly within PA—had not been previously examined. These gaps motivated the current investigation into muscle fat infiltration and sarcopenia features in APA with ACS.

Design and data source: Retrospective analysis using the multicenter Taiwan Primary Aldosteronism Investigators (TAIPAI) database, which prospectively collects standardized biochemical, imaging, and clinicopathological data. Ethics approval was obtained from the National Taiwan University Hospital Ethics Committee, and informed consent was secured from all participants. Population: Adults (≥18 years) with aldosterone-producing adenoma (APA) who underwent unilateral laparoscopic adrenalectomy between January 2009 and April 2024 (n=228). A subset (n=44) had a follow-up abdominal CT one year post-adrenalectomy. Diagnostic criteria: - Primary aldosteronism (PA): Aldosterone-renin ratio >35 ng/mL/h; and either seated saline infusion test with plasma aldosterone concentration (PAC) >16 ng/dL, or captopril/losartan challenge with PAC/plasma renin activity >35 ng/dL. - APA: Evidence of PA; lateralization confirmed by adrenal vein sampling; histopathological adenoma after adrenalectomy; and correction of PA by surgery. - Autonomous cortisol secretion (ACS): Overnight 1 mg dexamethasone suppression test (DST). ACS defined as post-DST serum cortisol ≥5 µg/dL. For 1.8–4.9 µg/dL, at least one of the following was required: ACTH <10 pg/mL, nocturnal cortisol ≥5 µg/dL, low DHEA-S, or 24-h urinary free cortisol (UFC) >70 µg/24 h. Postoperative outcomes: Classified per Primary Aldosteronism Surgical Outcome (PASO) consensus criteria into complete, partial, or absent clinical and biochemical success based on BP, antihypertensive medication use, potassium, aldosterone, and renin levels. Biochemical measurements: Serum cortisol by chemiluminescent immunoassay (Architect, Abbott). PAC and plasma renin activity by radioimmunoassay (Biochem Immunosystems; Stillwater, MN). Antihypertensives and medications interfering with DST were held per protocol. CT body composition analysis: Abdominal CT on scanners from GE, Philips, Siemens, and Toshiba; parameters: 120 kVp, automated dose modulation, 5 mm slice thickness, scan range from diaphragm upper edge to lower kidney poles. A blinded trained researcher, guided by two radiologists, analyzed images using sliceOmatic v5.0. Single-slice analysis at mid L3 vertebral level quantified areas using predefined Hounsfield Unit (HU) thresholds: skeletal muscle area (SMA, −29 to 150 HU), visceral adipose tissue (VAT, −150 to −50 HU), subcutaneous adipose tissue (SAT, −190 to −30 HU), and intermuscular adipose tissue (IMAT, −190 to −30 HU). Skeletal muscle density (SMD) and IMAT density were defined as the mean HU of SMA and IMAT respectively. Statistical analysis: Data reported as mean ± SD. Group comparisons used two-sample t-tests for continuous variables and chi-square tests for categorical variables. Associations assessed with multivariable linear regression adjusted for age, sex, BMI, systolic BP, diabetes, triglycerides, and cholesterol, with checks for collinearity. Pearson correlation evaluated relationships between continuous variables (e.g., post-DST cortisol with IMAT area, SMA, SMD). Pre-post adrenalectomy comparisons used Wilcoxon signed-rank tests. Two-sided P < 0.05 considered significant. Analyses in SPSS v25; figures in GraphPad Prism 9.

- Cohort: 228 APA patients; mean age 52.6 ± 10.6 years; 49.6% male. ACS prevalence 33.3% (76/228). - Baseline differences (ACS vs non-ACS): Older age (55.7 ± 10.4 vs 51.0 ± 10.3 years, P=0.002); higher serum potassium (3.8 ± 0.6 vs 3.6 ± 0.5 mmol/L, P=0.012); higher post-DST cortisol (5.2 ± 3.8 vs 0.9 ± 0.5 µg/dL, P<0.001); lower ACTH (8.4 ± 7.2 vs 21.1 ± 12.2 pg/mL, P<0.001); lower DHEA-S (2.7 ± 2.2 vs 4.2 ± 2.7 µmol/L, P<0.001). Other clinical, lipid, and comorbidity measures were similar. - Muscle composition (ACS vs non-ACS): Higher IMAT area (9.6 ± 4.9 vs 8.3 ± 4.4 cm², P=0.042); lower IMAT density (−29.3 ± 15.8 vs −23.8 ± 13.5 HU, P=0.006); lower SMD (32.2 ± 10.6 vs 37.3 ± 8.4 HU, P<0.001); lower SMA (119.4 ± 39.1 vs 135.3 ± 33.7 cm², P=0.002). VAT and SAT areas and densities did not differ. - Correlations with cortisol: Post-DST cortisol positively correlated with IMAT area (R²=0.027, P=0.012) and negatively with SMA (R²=0.060, P<0.001) and SMD (R²=0.123, P<0.001). - Multivariable analyses: After adjustment for age, sex, BMI, systolic BP, diabetes, triglycerides, and cholesterol, ACS remained independently associated with greater IMAT area and lower IMAT density, SMA, and SMD (all P<0.05). - One-year postoperative changes: Among ACS patients with follow-up CT (n=15), IMAT area decreased from 9.7 ± 5.7 to 7.3 ± 4.7 cm² (P=0.001) and SMA increased from 111.4 ± 36.1 to 117.0 ± 37.1 cm² (P=0.031); no change in IMAT density, SMD, VAT, or SAT. In non-ACS patients (n=29), VAT area increased (132.9 ± 67.8 to 169.4 ± 82.6 cm², P<0.001) and SAT area increased (165.6 ± 67.4 to 191.5 ± 99.3 cm², P=0.008); no significant changes in IMAT area, densities, SMA, or SMD. - Surgical outcomes: Rates of complete or partial clinical success were 73.3% in ACS and 93.1% in non-ACS; biochemical success 80.0% in ACS and 86.2% in non-ACS; differences not statistically significant.

The study demonstrates that in patients with aldosterone-producing adenomas, concomitant autonomous cortisol secretion is associated with both qualitative and quantitative muscle deterioration: higher intermuscular fat infiltration (IMAT area), lower skeletal muscle density (SMD), and reduced skeletal muscle area (SMA). These relationships persist after adjustment for key metabolic and cardiovascular confounders, suggesting an independent effect of cortisol autonomy on skeletal muscle composition beyond aldosterone-related metabolic sequelae. Correlations between post-DST cortisol and IMAT, SMA, and SMD reinforce a dose-response link between cortisol excess and myosteatosis/sarcopenia phenotypes. Importantly, in the subset with longitudinal imaging, adrenalectomy led to reductions in IMAT and increases in SMA among ACS patients, indicating partial reversibility of cortisol-associated muscle changes. In contrast, non-ACS patients showed increases in visceral and subcutaneous fat without improvement in muscle metrics, underscoring the specific role of ACS in driving myosteatosis and sarcopenia. These findings fill a knowledge gap by connecting ACS to myosteatosis within PA/APA, complementing prior evidence of visceral adiposity and muscle loss in overt hypercortisolism, and have implications for risk stratification and management in APA.

In APA patients, autonomous cortisol secretion is independently associated with myosteatosis (elevated IMAT and reduced SMD) and sarcopenia (reduced SMA). Higher post-DST cortisol correlates with worse muscle composition, and adrenalectomy improves IMAT and SMA in ACS patients over one year, suggesting reversibility of muscle abnormalities with correction of cortisol excess. These results highlight the importance of screening for ACS in APA and considering muscle health assessment via CT-based body composition metrics in clinical evaluation. Future research should validate these findings in larger, prospective cohorts; explore mechanistic pathways linking cortisol to muscle fat infiltration; assess functional outcomes (strength and physical performance) alongside imaging; and determine whether targeted interventions (e.g., resistance training, pharmacologic modulation of cortisol) can further mitigate myosteatosis and sarcopenia in this population.