Abstract
Background/Aim
Hypertension does not always improve after adrenalectomy for primary aldosteronism (PA), and antihypertensive medications cannot always be discontinued. This study aimed to identify the prognostic predictors of hypertension following adrenalectomy for PA.
Patients and Methods
This retrospective cohort study included patients undergoing adrenalectomy for PA between 2008 and 2022 at a tertiary hospital, grouping them based on whether they had normal blood pressure without antihypertensive medications or still required medications postoperatively. Age, sex, body mass index (BMI), biochemical data, hypertension duration, pre- and post-operative defined daily dose (DDD) of antihypertensive drugs, presence of metabolic syndrome (MetS)-related diseases, and visceral fat area and volume (recorded using preoperative abdominal computed tomography) were the outcome measures.
Results
A total of 71 (clinical success, n=21) (nonclinical success, n=50) patients were included. A high BMI (p=0.038), DDD (p=0.008), and visceral fat volume (p=0.048); long hypertension duration (p=0.034); and the presence of MetS-related diseases (p=0.014) were associated with a low clinical success rate on univariate analyses. After adjusting for age and sex, hypertension duration (p=0.047), MetS-related diseases (p=0.021), and DDD (p=0.011) were potential prognostic predictors.
Conclusion
Hypertension duration, MetS-related diseases, and DDD are potential prognostic predictors of hypertension following surgery for PA.
Keywords: Adenoma, adrenalectomy, antihypertensive agents, hyperaldosteronism, visceral fat
Primary hyperaldosteronism (PA) is caused by hypersecretion of aldosterone from adenomas or secondary to hyperplasia of the glomerular layer of the adrenal cortex. It is among the most common causes of secondary hypertension. Excess aldosterone causes hypertension and suppresses renin secretion due to extracellular fluid retention, resulting in hypokalemia owing to increased potassium excretion. Several studies have shown a higher prevalence of cardiovascular and cerebrovascular morbidity and mortality in patients with primary aldosteronism compared to those with essential hypertension (1-4). In addition, aldosterone is involved in inflammatory and fibrotic processes within the kidney, as well as in mesangial cell proliferation and podocyte injury, thereby increasing the risk of kidney damage (5,6).
The goals of PA treatment include blood pressure control, cardiovascular and cerebrovascular disease risk reduction, and kidney damage prevention. PA is classified into unilateral and bilateral PA. Unilateral PA is treated with adrenalectomy on the affected side. Appropriate treatment of PA is essential to minimize the increased risk associated with this disease. Furthermore, reducing or discontinuing antihypertensive medications after surgery can greatly improve patients’ quality of life (7,8).
However, there are certain patients whose hypertension does not improve after surgery or who are unable to discontinue antihypertensive medications. A recent meta-analysis found that clinical success rates after surgery vary widely among centers, ranging from 24% to 86% (9). Various predictors of clinical success after surgery, including age, sex, body mass index (BMI), duration of hypertension, and the amount of antihypertensive medication taken, have been reported (10). Adipocytes stimulate the adrenal cortex and may be involved in aldosterone secretion (11). Although the ratio of visceral fat volume (VFV) to subcutaneous fat volume (SFV) has been reported as a risk factor for renal dysfunction in patients with PA (12), few reports describe the association between visceral fat and persistent hypertension after surgery.
Identifying prognostic factors is important for determining appropriate indications for surgery and explaining the post-operative course to patients in detail when obtaining preoperative informed consent. This study investigated the prognostic predictors of outcomes in patients with persistent hypertension after surgery. We believe that our study will aid clinical decision-making and help patients understand the risks and benefits of surgery, providing them with the information needed to make informed decisions about whether to proceed with the procedure.
Patients and Methods
Patient selection. Patients who underwent adrenalectomy for PA at our hospital between 2008 and 2022 were enrolled in this study. Computed tomography (CT) and adrenal vein sampling were performed in all patients to determine the tumor location, diagnosis, and surgical suitability.
Patient categorization. We assessed whether the patients could discontinue all antihypertensive medications at six months after adrenalectomy and divided them into two groups:
1. The clinical success group had normal blood pressure (systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg) without using antihypertensive medications after surgery.
2. The nonclinical success group had high blood pressure (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) or required antihypertensive medications after surgery.
Data collection. Age; sex; BMI; plasma sodium, potassium, aldosterone, renin, and creatinine; estimated glomerular filtration rate; duration of hypertension; dosage of antihypertensive drugs before and after surgery; presence of metabolic syndrome (MetS)-related diseases; abdominal circumference (AC); visceral fat area (VFA); VFV; subcutaneous fat area (SFA); SFV; and total abdominal fat volume (TAV) were investigated. The following parameters were used to evaluate visceral and subcutaneous fat: VFA/SFA, VFV/SFV, SFV/TAV, and VFV/TAV. We considered diabetes and dyslipidemia as MetS-related diseases.
The dosage of antihypertensive drugs was evaluated using the defined daily dose (DDD), as described by the World Health Organization (13), for the main indication of the drugs. The DDD is the average maintenance dose of a medication. Using the DDD enables a standardized comparison of dosages between drug classes.
All body fat measurements were performed using preoperative abdominal CT images and a 3D image analysis system (SYNAPSE VINCENT; Fujifilm, Tokyo, Japan) (Figure 1). The AC, VFA, and SFA were measured using scans of the umbilical section obtained in the end-tidal position on an empty stomach, as described previously. The VFV and SFV were measured using CT image slices from the diaphragm to the pelvic floor.
Figure 1.
CT images used to measure body fat accumulation. The red area represents visceral fat, and the blue area represents subcutaneous fat. A) Abdominal circumference, visceral fat area, and subcutaneous fat area were measured using scans of the umbilical section. B and C) Visceral fat volume and subcutaneous fat volume were measured using CT images from the diaphragm to the pelvic floor.
Statistical analysis. The analyses were performed using standard descriptive statistical methods. Continuous variables are expressed as mean±SD. We used the Mann-Whitney U-test for continuous variables and Fisher’s exact test for categorical variables to compare the clinical and nonclinical success groups. To evaluate prognostic factors, we performed univariate and multivariate logistic regression analyses, and the results are presented as odds ratios (OR), 95% confidence intervals (CI), and statistical significance. All statistical analyses were performed using EZR (version 1.61, Saitama Medical Center, Jichi Medical University, Saitama, Japan) (14), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria).
Results
Table I shows the characteristics of the 71 patients included in the study. Table II compares the characteristics of the patients in the clinical success (n=21, 29.6%) and nonclinical success (n=50, 70.4%) groups. The BMI (p=0.036), DDD (p=0.002), duration of hypertension (p=0.012), rate of MetS-related diseases (p<0.001), and VFV (p=0.027) were significantly higher in the nonclinical success group compared to the clinical success group.
Table I. Characteristics of patients.
SD: Standard deviation; BMI: body mass index; Na: plasma sodium; K: potassium; Cr: creatinine; eGFR: estimated glomerular filtration rate; DDD: defined daily dose; MetS: metabolic syndrome; CT: computed tomography; HU: Hounsfield Unit; AC: abdominal circumference; VFA: visceral fat area; VFV: visceral fat volume; SFA: subcutaneous fat area; SFV: subcutaneous fat volume; TAV: total abdominal fat volume.
Table II. Characteristics of patients.
SD: Standard deviation; BMI: body mass index; Na: plasma sodium; K: potassium; Cr: creatinine; eGFR: estimated glomerular filtration rate; DDD: defined daily dose; MetS: metabolic syndrome; CT: computed tomography; HU: Hounsfield Unit; AC: abdominal circumference; VFA: visceral fat area; VFV: visceral fat volume; SFA: subcutaneous fat area; SFV: subcutaneous fat volume; TAV: total abdominal fat volume.
Univariable logistic regression analyses revealed that a high BMI [odds ratio (OR)=1.19, 95% confidence interval (CI)=1.01-1.40, p=0.038], long duration of hypertension (OR=1.09, 95%CI=1.01-1.18, p=0.034), presence of MetS-related diseases (OR=13.8, 95%CI=1.70-113.0, p=0.014), high DDD [OR=1.72, 95%CI=1.15-2.59, p=0.008], and high VFV (OR=1.00, 95%CI=1.00-1.00, p=0.048) were associated with a low clinical success rate (Table III).
Table III. Univariate logistic regression analyses.
OR: Odds ratio; CI: confidence interval; BMI: body mass index; Na: plasma sodium; K: potassium; Cr: creatinine; eGFR: estimated glomerular filtration rate; DDD: defined daily dose; MetS: metabolic syndrome; CT: computed tomography; HU: Hounsfield Unit; AC: abdominal circumference; VFA: visceral fat area; VFV: visceral fat volume; SFA: subcutaneous fat area; SFV: subcutaneous fat volume; TAV: total abdominal fat volume.
Multivariable logistic regression analyses adjusted for age and sex revealed that the duration of hypertension (OR=1.09, 95%CI=1.01-1.19, p=0.047), MetS-related diseases (OR=12.5, 95%CI=1.47-106.0, p=0.021), and DDD (OR=1.71, 95%CI= 1.13-2.59, p=0.011) were potential prognostic predictors (Table IV).
Table IV. Multivariate logistic regression analyses adjusted for age and sex.
OR: Odds ratio; CI: confidence interval; BMI: body mass index; DDD: defined daily dose; MetS: metabolic syndrome; VFV: visceral fat volume.
Discussion
The main goal of adrenalectomy for PA is to relieve symptoms and improve the patient’s quality of life by enabling them to discontinue antihypertensive medications. Although 29.6% of the patients in this study could discontinue antihypertensive medications, a wide variation in post-operative clinical success rates, which range from 24% to 86%, has been reported from different centers (9).
We found that the duration of hypertension, MetS-related diseases, and DDD are potential prognostic predictors of post-operative hypertension in patients with PA. A high DDD indicates refractory hypertension, which can indicate advanced vascular endothelial damage (15). The duration of hypertension has been reported as a predictor in many studies, with a long duration of hypertension being associated with irreversible vascular endothelial damage due to prolonged hyperaldosteronemia (10,16,17). MetS-related diseases include diabetes, dyslipidemia, hypertension, and obesity, and these factors have been reported to increase cardiovascular risk (18). The presence of MetS-related diseases is thought to be strongly related to the progression and increased morbidity of essential hypertension, as these diseases cause peripheral vascular damage and arteriosclerosis; therefore, it may be a predictive factor (17,18).
Other previously reported predictors include age, sex, and BMI (19-21). In this study, the mean age of the nonclinical success group was higher than that of the clinical success group, but the difference was not significant. Older adults have a high morbidity of essential hypertension due to the age-related progression of arteriosclerosis, and the hypertension risk increases with age (19,22). Furthermore, there were more men than women in the nonclinical success group, although this difference was not statistically significant. Estrogen has been reported to be vasoprotective (20); because estrogen is more abundant in women than in men, women have a higher clinical success rate than men. Moreover, the nonclinical success group had a significantly higher BMI than did the clinical success group, and univariate logistic regression analyses indicated that BMI was a significant prognostic predictor; however, it was not a significant prognostic predictor in the multivariate logistic regression analyses. BMI has also been widely reported as a predictor of hypertension after surgery, and the progression of arteriosclerosis due to obesity is considered a cause of post-operative hypertension (19).
Reports have shown a relationship between visceral fat and essential hypertension and demonstrated that patients with high visceral fat accumulation have a high hypertension morbidity (21,23). However, few reports have shown the relationship between visceral fat, subcutaneous fat, and PA-induced hypertension. The parameters we used to evaluate the visceral and subcutaneous fat (VFA/SFA, VFV/SFV, SFV/TAV, and VFV/TAV) have been used in previous studies to evaluate the ratio of visceral to subcutaneous fat (12,13). In this study, these ratios did not show significant differences between the clinical success and nonclinical success groups. The VFV was significantly higher in the nonclinical success group than in the clinical success group, and univariate logistic regression analyses indicated that it was a significant prognostic predictor; however, the odds ratio was 1.00, making it clinically insignificant. Our results suggest that the absolute VFV may be a more powerful predictor than the visceral-to-subcutaneous fat ratio. We believe that visceral fat, not subcutaneous fat, is associated with arteriosclerosis and peripheral vascular disease; however, no clear cut-off value has been established for VFV. The challenge for future studies is to develop explicit criteria and perspectives.
The VFA was higher in the nonclinical success group than in the clinical success group, but not significantly, and univariate logistic regression analyses showed that it was not a significant prognostic predictor. The AC was significantly higher in the nonclinical success group than in the clinical success group, but univariate logistic regression analysis showed that it was not a significant predictor. A meta-analysis (23) of studies of Japanese individuals showed that regardless of sex, Japanese participants were more likely to accumulate visceral fat than Western participants, even in people with the same BMI. Another study found that Japanese participants had high visceral fat accumulation, even after adjusting for age, sex, and SFV (23). Methods for estimating visceral fat levels include AC measurement, impedance analysis, CT, and magnetic resonance imaging (24). In Japan, the cut-off values for visceral fat accumulation, as denoted by AC, are set at ≥85 cm and ≥90 cm for men and women, respectively. This cut-off value was considered to correspond to a VFA of 100 cm2 at the umbilical level on CT. It was determined based on the finding of an increased risk of occurrence of complications, including hypertension, hyperglycemia, and dyslipidemia, which are components of MetS when the VFA was ≥100 cm2 (24). According to the standards set by the International Diabetes Federation, the cut-off values for AC in Europe and the United States are ≥94 cm for men and ≥80 cm for women, equivalent to a BMI of 25 kg/m2 for Europeans and Americans (25). In our study, the average VFA in the nonclinical success group was ≥100 cm2, which is above the abovementioned VFA cut-off value, although the between-group difference was insignificant. The Japanese are more likely to experience an accumulation of visceral fat than their Western counterparts (12). Because the positions of the internal organs and intestinal contents may vary among individuals, VFV estimation is likely more helpful than SFA estimation for assessing the precise levels of fat tissue accumulation (12).
In the present study, visceral fat was not a predictor of post-operative hypertension. However, visceral fat accumulation may contribute to nonclinical success after surgery, as patients with a large amount of visceral fat have a high morbidity of essential hypertension. We believe that visceral fat measurement is worthwhile in patients with PA because CT is often performed as a preoperative imaging evaluation. BMI only provides information about the patient’s condition at the time of measurement, and it does not indicate how long the person has been obese. Therefore, evaluating the contribution of BMI to arteriosclerosis is generally difficult. However, the DDD and duration of hypertension can be assessed over time, and these factors can indicate that the vascular endothelium has been exposed to hypertension for a long time and suffered from irreversible damage. Therefore, we believe that they better reflect the severity of hypertension and are more promising predictors than BMI.
Study limitations. First, the sample size was relatively small; hence, we believe that further research on more patients is needed. Second, all the participants were Japanese. The tendency to accumulate visceral fat has been reported to differ between Japanese individuals and Westerners (24), which may affect the results of this study and their validity in patients of other races. Future research should, therefore, focus on multiracial populations.
Conclusion
The duration of hypertension, MetS-related diseases, and DDD are potential prognostic predictors of post-operative hypertension in patients with PA. We believe it is crucial to explain the post-operative course to patients in detail when obtaining preoperative informed consent and to consider individual patient background factors to predict treatment outcomes.
Funding
The Authors have nothing to disclose.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Authors’ Contributions
HF and KM designed this study. Data collection and literature searches were performed by HF, KM, JH, YN, TM, KO, and YM. HF, KM, and RI performed the data analysis and interpretation. All researchers interpreted the data and contributed to the draft of the manuscript and figures. Finally, the article was revised and approved by all Authors.
Acknowledgements
The Authors are grateful to all the investigators for their contributions to this study.
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