Cardiovascular risk improvement after laparoscopic adrenalectomy in patients with cortisol-secreting adrenal adenoma, a retrospective cohort study

Introduction

Cushing syndrome is a serious and rare endocrine disease caused by prolonged exposure to excess glucocorticoids. European population-based studies reported an incidence of two to three cases per one million per year (1). Endogenous Cushing syndrome is categorized as adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome and ACTH-independent Cushing syndrome. The most common subtype of endogenous Cushing is Cushing disease, which accounts for 80% to 85% while adrenal Cushing, characterized by ACTH-independent, accounts for 15% to 20% (2,3).

Clinical presentation characterizes by symptoms and signs of hypercortisolism include moon face, central obesity, acne, buffalo hump, abdominal striae, osteoporosis, and irregular menstruation. Cushing syndrome is associated with various complications, especially cardiovascular morbidity and metabolic syndrome including visceral obesity, impairment of glucose metabolism, and dyslipidemia. Furthermore, long-term cortisol excess leads to cardiovascular diseases such as hypertension (HT), vascular atherosclerosis, cardiac remodeling, and thrombosis which is the main cause of death in Cushing patients (3). Despite treatment, the mortality rate among these patients is 4 times higher than the general population (4).

The diagnosis of adrenal Cushing is primarily made based on the patient’s clinical characteristics and hormonal evaluation. Imaging studies including computed tomography (CT) or magnetic resonance imaging (MRI) abdomen are used to identify the tumor location. As an imaging technology, cortisol-secreting adrenal adenoma can also be identified from gemstone spectral imaging dual-energy CT (5).

Adrenal insufficiency (AI) usually occurs after adrenalectomy in cortisol-secreting adenoma due to long-term suppression from high cortisol levels. This is one of the most common reasons for readmission after surgery. However, recent studies reported a 27–34% incidence of hypocortisolism that occurs after unilateral adrenalectomy in non-cortisol secreting tumors (6,7).

Nowadays the outcome of cardiovascular risk after adrenalectomy is lacking. The objective of this study is to report the cardiovascular risk outcomes at 3, 6, and 12 months after unilateral laparoscopic adrenalectomy in cortisol-secreting adrenal tumors and to identify the preoperative parameters predicting the resolution of cardiovascular risk factors after surgery. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-398/rc).

Methods

We retrospectively reviewed all clinical data of the patient with cortisol-secreting adrenal tumor who underwent laparoscopic adrenalectomy in King Chulalongkorn Memorial Hospital between 2001–2022. All patients had excessive cortisol production from the adrenal gland after completion of the standard hormonal evaluation by an endocrinologist. Exclusion criteria in this study were adrenocortical carcinoma, bilateral adrenal tumor, adrenal hyperplasia, ectopic Cushing syndrome, and Cushing disease.

All demographic clinical data were collected and analyzed. Analyzed parameters included age, gender, tumor size, tumor side, body mass index (BMI), duration of symptoms before surgery, operative time, estimated blood loss (EBL), and duration of corticosteroid replacement after surgery.

Cardiovascular risk factors included BMI which was calculated by weight (kg)/height (m²), normal values range from 18.5–22.9 kg/m², overweight defined as BMI 23–24.9 kg/m², and obesity defined as BMI ≥25 kg/m². HT was defined as systolic blood pressure (SBP) values ≥140 mmHg and/or diastolic blood pressure (DBP) values ≥90 mmHg (8). Diabetes mellitus (DM) was defined as fasting blood sugar (FBS) ≥126 mg/dL, or 2-hour plasma glucose ≥200 mg/dL during oral glucose tolerance test, or hemoglobin A1C (HbA1C) ≥6.5%, or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, random plasma glucose ≥200 mg/dL (9). Dyslipidemia was defined as low-density lipoprotein (LDL) cholesterol ≥140 mg/dL, or high-density lipoprotein (HDL) cholesterol <40 mg/dL, or triglyceride (TG) ≥150 mg/dL (10).

Surgical techniques

Laparoscopic adrenalectomy was performed by transperitoneal lateral approach in all patients. Our techniques have been described previously (11). Briefly, we used 3 trocars in the left-side tumor and added one additional trocar for the liver retractor in the right-side tumor. Small vascular supplies of the adrenal gland were controlled by using LigaSure (a vessel sealing device, Covidien-Medtronic, Minneapolis, USA). We did not routinely place the closed-suction drain in uncomplicated cases.

Follow-up

Intravenous corticosteroid supplementation was given to the patient on the day of surgery, then taper and continued supplementation by oral form after discharge. Patients were followed up at 3, 6, and 12 months after surgery. Blood pressure, BMI, serum cortisol, fasting plasma glucose, and lipid profiles were monitored.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University (IRB No. 475/65) and individual consent for this retrospective study was waived. All procedures were performed in accordance with relevant guidelines and regulations.

Statistical analyses

The statistical analyses were performed by STATA version 17 (Stata Corp LP, Texas, USA). Continuous variables data were expressed as mean with standard deviation (SD). Categorical variables data were presented with numbers (N) and percentages (%). Univariable and multivariable logistic regression analyses were used to calculate the predictive factors for the resolution of HT, DM, and dyslipidemia. We included all the important baseline demographic factors in the analysis as independent variables. Results are described as odds ratio (OR) and corresponding 95% confidence interval (CI). Statistical significance was defined as P value <0.05 (two-sides).

Results

Sixty-eight patients with excessive cortisol production from the adrenal gland underwent laparoscopic adrenalectomy during the study period. Twenty-three patients were excluded from the study (12 adrenal hyperplasia, 6 adrenocortical carcinoma, 2 bilateral adrenal adenoma, 2 Cushing disease, 1 ectopic ACTH production). Therefore, forty-five patients were included in the analysis.

All demographic data and peri-operative outcomes are summarized in Table 1. The mean (SD) age was 44.2 (14.7) years. The mean BMI (SD) was 25.9 (5.4) kg/m². Most of the patients were female (97.8%). The mean (SD) tumor size was 3.1 (1.0) cm. There was no difference in tumor laterality. The mean (SD) duration of postoperative oral corticosteroid supplementation was 23.6 (20.4) months.

Cardiovascular risks comparison

Prevalences of cardiovascular risks before and after surgery are presented in Figure 1. Details of all parameters are shown in Table 2. Serum cortisol was significantly decreased after surgery. Before surgery, 73% of patients had HT. The mean (SD) SBP and DBP were 147 (21.8) and 87 (13.9) mmHg respectively. After adrenalectomy, HT was significantly improved at 3, 6, and 12 months (26.7%, 28.9%, and 26.7%, respectively, P<0.001). The mean (SD) SBP at 3, 6, and 12 months were 128.6 (17.4), 127.3 (19.8), and 127.9 (20.3) mmHg, respectively (P<0.001).

Figure 1 Comparison of incidence of cardiovascular risks before and after laparoscopic adrenalectomy in cortisol-secreting adrenal adenoma. HT, hypertension; DM, diabetes mellitus; DLP, dyslipidemia.

DM was evaluated by both FBS and HbA1C. There were 14 diabetic patients (31.1%) preoperatively. The mean (SD) preoperative HbA1c and FBS were 6.1% (1.0%) and 108.8 (40.6) mg/dL. Diabetes was improved at 3 months after surgery and was statistically significant at 12 months after surgery (P=0.001). The mean (SD) postoperative HbA1C and FBS levels at 12 months were 6% (0.8%) and 90.8 (12.5) mL/dL.

For dyslipidemia, 60% of patients were diagnosed with dyslipidemia preoperatively. The mean (SD) serum cholesterol level was 235.5 (58.4) mg/dL. There were 26.7%, 28.9%, and 26.7% of patients still had dyslipidemia at 3, 6, and 12 months after surgery (P=0.01, P=0.06, and P=0.001 respectively). The details of lipid profile improvement are summarized in Table 2.

The mean (SD) preoperative BMI was 25.9 (5.4) kg/m² and 57.8% of patients were defined as obese. After surgery, BMI and obesity were significantly decreased at 3 months (P<0.001, P=0.02 respectively). At 12 months after surgery, only 17.8% of patients were still obese.

Predictive factors for resolution of cardiovascular risks

The predictive factors for the resolution of HT, diabetes, and dyslipidemia after surgery are presented in Tables 3-5 respectively. Age, BMI, tumor size, SBP, and DBP were the significant factors for predicting the resolution of HT in the univariate analysis. However, in the multivariate analysis, only age (OR 0.95, 95% CI: 0.91–0.99, P=0.01), BMI (OR 0.85, 95% CI: 0.77–0.95, P=0.003), and SBP (OR 0.97, 95% CI: 0.94–1, P=0.03) were the predictive factors for the resolution of HT.

For the resolution of DM, preoperative serum cortisol was only the significant predictive factor in multivariate analysis (OR 1.12, 95% CI: 1.01–1.25, P=0.04). For the resolution of dyslipidemia, both cholesterol and LDL levels were significant factors in the univariate analysis. However, in the multivariate analysis, only the preoperative cholesterol level was a predictive factor for the resolution of dyslipidemia (OR 0.97, 95% CI: 0.96–0.99, P=0.003).

Discussion

ACTH-independent Cushing syndrome or cortisol-secreting adrenal adenoma accounts for 10–15% of Cushing syndrome (2). Nowadays, laparoscopic adrenalectomy is favored over open surgery for almost all indications and is the gold standard treatment for small adrenal tumors including cortisol-secreting adrenal adenoma, resulting in excellent clinical and biochemical outcomes with minimal complications (12,13). As known, Cushing syndrome predominantly affects females, with a female-to-male ratio of 3–4:1 (2,14). However, our study showed the number of females was 44 times higher than that of males (only one man in this study).

Untreated Cushing syndrome leads to physical and functional disabilities. Metabolic syndromes such as HT, DM, dyslipidemia, and obesity cause cardiovascular morbidity and mortality which is a major cause of death in Cushing syndrome patients. In this study, we focused on the improvement of these cardiovascular risk factors after adrenalectomy in patients with unilateral cortisol-secreting adrenal adenoma.

The causes of HT in Cushing syndrome are multifactorial. The binding of glucocorticoid receptors to cortisol activates epithelial sodium channels and glomerular hyperfiltration, causing fluid retention. The excess cortisol can act on the mineralocorticoid receptor which results in sodium and fluid retention. Hypercortisolism increases the hepatic production of angiotensinogen and upregulation of angiotensin II receptors which enhances vasoconstriction (12,14,15). Moreover, the vasoregulatory system has been related to HT in hypercortisolism. Several potent vasodilators including nitric oxide, prostaglandin E2 and I2, and urinary kallikrein are decreased due to the inhibitory effect of cortisol. In contrast, vasoconstrictor concentration (endothelin-1) is increased in patients with hypercortisolism (16).

In our study, 73% of patients had HT preoperatively. The mean blood pressure was significantly improved after 3 months. One-third of hypertensive patients had persistent HT at 1 year. This could be due to the prolonged effects of hypercortisolism on cardiac remodeling and dysfunction, especially left ventricular hypertrophy (15,17). We identified the significant predictive factors in HT resolution following surgery that were correlated with younger age, lower BMI, and lower preoperative SBP. Our findings were consistent with the previous study that adrenalectomy can improve HT in Cushing syndrome by up to 30–70% (18-22).

Jha et al. (19) reported the outcomes of HT after adrenalectomy in 75 patients with ACTH-dependent Cushing syndrome. At 1 year, 44% of patients had remission from HT and 48% of patients had partial improvement of HT. Longer estimated duration of Cushing syndrome, younger age, and low BMI were the significant predictive factors for HT remission. Suzuki et al. (21) found that high preoperative blood pressure and long duration of HT before surgery were associated with persistent HT after surgery. Moreover, Iacobone et al. (22) showed the result of postoperative HT was better in the younger patients with lower preoperative SBP levels. Therefore, intensive control of preoperative blood pressure and prompt surgical treatment after diagnosis were very important for improving the prognosis of HT.

Hypercortisolism relates to impaired fasting glucose and DM by dysregulation of glucose metabolism. Increased liver gluconeogenesis, increased hepatic and peripheral insulin resistance, and effect on pancreatic insulin secretion are the important mechanisms. The prevalence of DM in adrenal Cushing ranges from 34–41% (16). Mishra et al. (23) assessed the long-term outcome of adrenalectomy in patients with various causes of Cushing syndrome. At the median follow-up of 60 months, 29% of patients had persistent diabetes. Similarly, Sippel et al. (24) found 41% of patients had diabetes in their study and 79% of them achieved remission of diabetes at a median follow-up of 41.4 months after adrenalectomy.

In our study, 31.1% of cases had DM preoperatively. The DM was reduced to 20% and 17.6% at 3 and 6 months after surgery. However, the statistically significant of improvement was found at 12 months (P=0.001). There were only 4 patients (8.9%) exhibited DM at 12 months after surgery. These results were different from the HT outcome, which showed significant improvement starting 3 months after surgery. This may be due to the supraphysiologic cortisol level from oral corticosteroid replacement which leads to an increase in blood glucose level. Additionally, we found that high preoperative serum cortisol level was the significant predictor for the resolution of diabetes in Cushing syndrome.

The prevalence of dyslipidemia in Cushing syndrome varies between 12–72% (16). Hypercortisolism induces lipolysis, free fatty acid production, and accumulation of hepatic fat. The lipid profiles frequently exhibit elevated levels of total cholesterol, LDL, and TGs, with decreased levels of HDL (25,26). In this study, dyslipidemia was found in 60% of cases. After surgery, dyslipidemia was significantly improved after 3 months and 26.7% of patients had persistent dyslipidemia at 1 year of follow-up. Cholesterol levels were significantly improved but no significant reduction in TG levels after surgery.

Giordano et al. (27) evaluated the metabolic profiles of 15 patients with adrenal Cushing syndrome after 1 year of remission. Dyslipidemia exhibited a notable reduction from 53% to 27% among this patient population, with significant decreases in both cholesterol and LDL. Nevertheless, no significant changes were observed in HDL and TG levels. Our data showed comparable outcomes with this previous study. Furthermore, our finding suggested that preoperative lower cholesterol levels may serve as a predictive factor for the resolution of dyslipidemia after surgery.

Excessive weight is a common presentation that occurs in 57–100% of Cushing syndrome patients, with 33–48% classified as overweight and 25–100% classified as obese (28). Before surgery, 57.8% of patients in our study were classified as obese. BMI and prevalence of obese patients were significantly decreased after 3 months. From the previous studies, BMIs were significantly improved from 1–10 years after surgery (22,29,30). However, persistent obesity can be observed in 41–59.6% of patients (4,22,23). Moreover, Giordano et al. (27) found the mean BMI was not significantly different in Cushing patients after 1 year of disease remission.

The study’s limitations included its retrospective nature. The sample was relatively small from a single institution. Lastly, our results represented only the short-term follow-up within 1 year after surgery. Long-term follow-up with a high number of patients will justify the outcomes of adrenalectomy to the cardiovascular events.

Conclusions

Adrenalectomy significantly improves cardiovascular risk factors in patients with cortisol-secreting adrenal adenoma. Predicting factors for the resolution of HT are younger age, lower BMI, and lower SBP. The high serum cortisol level serves as a crucial predictive factor for DM, while low serum cholesterol is a significant predictor for the resolution of dyslipidemia.

Acknowledgments

The authors would like to thank Miss Dollapas Punpanich for assisting with statistical analysis.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-398/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-398/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-398/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-398/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University (IRB No. 475/65) and individual consent for this retrospective study was waived. All procedures were performed in accordance with relevant guidelines and regulations.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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