ABSTRACT
Introduction:
There is limited literature comparing the resolution of hypertension after adrenalectomy for pheochromocytoma and Conn’s syndrome endocrine hypertension. We assessed the rate of hypertension remission and factors predicting it among patients undergoing adrenalectomy.
Methods:
As part of an institutional review board-approved study, we retrieved data of patients who underwent adrenalectomy for localized pheochromocytoma or Conn’s syndrome between 2020 and 2024 at our institution. Patients were contacted telephonically to assess the status of their hypertension.
Results:
Out of 61 eligible patients, 31 with pheochromocytoma and 16 with Conn’s syndrome were included in this study. Patients with pheochromocytoma were younger (mean age: 30.8 years vs. 42.8 years), had a lower body mass index (20.7 kg/m2 vs. 28.4 kg/m2), had a lower preoperative duration of hypertension (median– 12 vs. 84 months), and had fewer antihypertensive medicines (median 2 vs. 4) than patients with Conn’s syndrome. At discharge, 82.6% (n = 19/23) of pheochromocytoma patients achieved complete hypertension remission vs. 31.2% (n = 5/16) of Conn’s syndrome patients (P < 0.01). At 1 year after surgery, remission was maintained in 85% (17/20) and 50% (7/14) of patients, respectively (P = 0.05). Older age (odds ratio [OR]: 1.08), worse preoperative disease burden (OR: 2.23), multifocal lesions on histopathology (OR: 12.27), and chronic kidney disease (OR: 15.43) were associated with persistence of hypertension postoperatively.
Conclusions:
Adrenalectomy achieves quicker and more complete resolution of hypertension in patients with pheochromocytoma than in Conn’s syndrome. Persistent hypertension is more likely in older patients with long standing, severe baseline hypertension, and other comorbidities.
INTRODUCTION
Hypertension has a global prevalence of up to 40% and is secondary to an identifiable cause in only 15% of all affected individuals.[1] Endocrine hypertension (EH), arising predominantly due to adrenal pathologies, contributes to a majority of cases diagnosed with secondary hypertension.[2] Though uncommon, identifying EH is very relevant as it offers an opportunity for significant improvement in the hypertensive status with surgical removal of the affected adrenal gland. Within this niche of individuals with EH, Conn’s syndrome and pheochromocytoma form two common entities encountered in a surgical clinic.
Pheochromocytomas arise from the adrenal medulla and occur in 0.4% of all hypertensive individuals.[3] In patients with pheochromocytoma, the complications associated with catecholamine excess, apart from the hypertension itself, mandates a surgical excision of the adrenal lesion in all cases, including those with a normotensive status at presentation.[4] Primary hyperaldosteronism, on the other hand, is the most common cause of secondary hypertension and can arise due to unilateral aldosterone hypersecretion in up to 40% of cases.[5] Although hyperaldosteronism secondary to bilateral adrenal hyperplasia has been shown to respond well to pharmacotherapy, an aldosterone-secreting adenoma (Conn’s syndrome) is best addressed with an adrenalectomy.[6]
There is limited literature describing hypertension remission following adrenalectomy in patients with EH, particularly on the extent and duration to which these individuals may require antihypertensive therapy in the postoperative period. A direct comparison of changes in hypertensive status following adrenalectomy for pheochromocytoma and Conn’s syndrome would help in improving our understanding of the differences in postoperative outcomes in these individuals. Furthermore, identification of factors that can be associated with persistence of hypertension following adrenalectomy would help in addressing the patients’ expectations before offering surgical intervention and in tailoring the follow-up plan for patients according to their chances of hypertension remission.
PATIENTS AND METHODS
Among patients who underwent adrenalectomy in the past 5 years (2020–2024), we identified patients who were diagnosed with either pheochromocytoma or an aldosterone-secreting adenoma (Conn’s syndrome). Patients with localized disease, corroborating histopathological reports, and who could be contacted telephonically for follow-up were included in this study. The primary objective was to compare the resolution of hypertension between patients with pheochromocytoma versus Conn’s syndrome, whereas the secondary objective was to evaluate factors that may predict the persistence of hypertension in these patients after surgery. The study was conducted as part of an institutional ethics committee approved project (IEC No. 461/17.06.2022) and was reported as per STROBE guidelines.[7] All patients provided informed consent for the surgeries. The authors confirmed the availability of, and access to, all original data reported in this study. The author/s did not use artificial intelligence (AI) and AI-assisted technologies, including large language learning models, in the preparation of the manuscript.
Data collection
All medical records of the patients (discharge summaries, resident notes, in-hospital progress file, biochemical records, and the histopathological reports) were retrieved from the hospital database and a separate, prospectively maintained database of these cases. The age, body mass index (BMI), clinical history, preoperative hypertensive medication, family history, comorbidity status (including chronic kidney disease [CKD] [defined based on KDIGO guidelines[8]], diabetes mellitus [DM], cerebrovascular accidents [CVA], and coronary artery disease [CAD]), preoperative lesion characteristics, use of adrenal venous sampling (in patients with Conn’s syndrome), and lesion characteristics on the final histopathological report were retrieved.
Perioperative management of patients with functional adrenal tumors is conducted through a multidisciplinary team involving endocrinologists, anesthesiologists, and urologists, details of which have been described previously.[9] For follow-up, patients were contacted telephonically to enquire about details of hypertensive medications taken since discharge. Hypertensive status was assessed according to a patient-reported need for antihypertensive medications with remission defined as normal home blood pressure recordings without the use of any antihypertensive medications, with at least one blood pressure reading done within 3 months preceding the date of follow-up. For each patient using antihypertensive medication, the duration of antihypertensive pharmacotherapy along with the details (drug type, dose, and frequency) was noted. Prescription notes were requested in cases of inadequate reporting during the telephonic follow-up. Data for pheochromocytoma patients were compared with those of Conn’s syndrome.
Statistical analysis
Data were analyzed using Stata 15.0 statistical software (Stata Corp, Texas, USA) and Python. Categorical data were expressed as frequency and percentage. Quantitative variables were expressed as mean ± standard deviation (if parametric) or as median with the interquartile range (if nonparametric). Independent t-test or rank-sum test was used to compare quantitative variables between the two diagnoses. Chi-square and Fisher’s exact test were used to compare categorical variables. A univariate logistic regression analysis was run to identify factors showing a significant association with persistence of hypertension postoperatively. P < 0.05 was considered statistically significant for all comparisons. Need for antihypertensive pharmacotherapy was evaluated using Kaplan–Meier analysis graphs.
RESULTS
Of 61 patients who underwent adrenalectomy for localized pheochromocytoma or Conn’s syndrome during the study, baseline data were incomplete in 7 cases and 54 patients were considered for further evaluation. A further 7 cases were excluded for varying reasons [Figure 1], leaving 47 patients (31 with pheochromocytoma and 16 with Conn’s syndrome) who were included in the final analysis [Table 1].
Figure 1.
STROBE flow diagram of patient selection for the study cohort
Table 1.
Preoperative characteristics, histopathological reporting, and hypertensive outcomes of study cohort
| Variable | Pheochromocytoma | Conn’s syndrome | P |
|---|---|---|---|
| Baseline data (n=47) | |||
| Number of patients | 31 | 16 | - |
| Age (years) | 30.8±10.7 | 42.8±14.7 | <0.01 |
| BMI (kg/m2) | 20.7±4.8 | 28.4±11.2 | <0.01 |
| Duration of follow-up | 33.5±16.1 | 33.6±17.8 | 0.98 |
| Female sex, n (%) | 22 (71.0) | 7 (43.8) | 0.07 |
| Presence of HTN, n (%) | 23 (74.2) | 16 (100) | 0.03 |
| Comorbidity assessment (n=47) | |||
| CAD | 0 | 1 (6.3) | - |
| CVA | 2 (6.5) | 2 (12.5) | 0.42 |
| CKD | 1 (3.2) | 4 (25) | 0.04 |
| DM | 8 (25.8) | 4 (25) | 0.62 |
| Presentation and evaluation | |||
| Duration of HTN (n=39) (months), median (IQR) | 12 (3–24) | 84 (48–156) | <0.01 |
| Number of anti-HTN (n=39), median (range) | 2 (0–4) | 4 (0–6) | <0.01 |
| Duration of symptomsa (n=38) (months), median (IQR) | 10 (3–24) | 96 (60–156) | <0.01 |
| Histopathological evaluation (n=46) | |||
| Largest dimension of lesion | 5.0±3.1 | 1.6±1.1 | <0.01 |
| Presence of bilateral lesions, n (%) | 8 (25.8%) | 0 | - |
| Multifocal lesions, n (%) | 7 (23.3) | 8 (50) | 0.07 |
| Antihypertensive requirement | |||
| Overall datab (n=39) | 4 (17.4) | 7 (43.8) | 0.15 |
| Antihypertensive requirement stratified according to time from surgery | |||
| At discharge (n=39) | 4 (17.4) | 11 (68.8) | <0.01 |
| At 1 month (n=39) | 3 (13.0) | 11 (68.8) | <0.01 |
| At 3 months (n=39) | 3 (13.0) | 9 (56.3) | <0.01 |
| At 6 months (n=39) | 3 (13.0) | 8 (50.0) | 0.03 |
| At 1 year (n=34) | 3 (15.0) | 7 (50.0) | 0.05 |
aSymptoms refer to abdominal pain/lower limb weakness in patients with Conn’s syndrome or adrenergic symptoms in patients with pheochromocytoma, bOverall data analysis evaluated need for antihypertensive drugs at time of study, irrespective of time from surgery. CAD=Coronary artery disease, CVA=Cerebrovascular accident, CKD=Chronic kidney disease, DM=Diabetes mellitus, BMI=Body mass index, IQR=Interquartile range, HTN=Hypertension
Baseline characteristics
Patients with pheochromocytoma were younger (30.8 ± 10.7 years) than those with Conn’s syndrome (42.8 ± 14.7 years, P < 0.01). Their mean BMI was significantly lower (20.7 ± 4.8 kg/m2 vs. 28.4 ± 11.2 kg/m2, P < 0.01), and the median duration of symptoms before seeking medical attention was shorter (10 months [interquartile range (IQR): 3–24] vs. 96 months [IQR: 60–156], P < 0.01).
Hypertension was present in 74.2% (n = 23/31) of pheochromocytoma patients at initial diagnosis compared to all patients (n = 16/16) with Conn’s syndrome (P = 0.03). The median duration of hypertension before surgery was significantly lower in pheochromocytoma (12 months [IQR: 3–24]) than in Conn’s syndrome (84 months [IQR: 48–156], P < 0.01). On average, patients with pheochromocytoma were on two antihypertensive medications before surgery, in comparison to four in patients with Conn’s syndrome (P < 0.01). CKD was significantly more prevalent in Conn’s syndrome (25.0%) compared to pheochromocytoma (3.2%, P = 0.04). The prevalence of CAD (6.3%), CVA (12.5%), and DM (25%) in Conn’s syndrome, however, did not differ significantly from that in pheochromocytoma (0%, 6.5%, and 25.8%, respectively).
On histopathological evaluation, the average tumor size was larger for pheochromocytoma (5.0 ± 3.1 cm) than for Conn’s syndrome (1.6 ± 1.1 cm, P < 0.01). Bilateral lesions were observed in 8 (25.8%) patients with pheochromocytoma, while all Conn’s syndrome cases underwent unilateral adrenalectomy based on either preoperative radiological evaluation or on adrenal venous sampling. Multifocal lesions were noted in 7 (23.3%) cases of pheochromocytoma and in 8 (50%) cases of Conn’s syndrome (P = 0.07). All eight Conn’s syndrome patients with multifocal disease had unilateral micronodular hyperaldosteronism. Only 1 of these 8 patients achieved complete remission of antihypertensive medication requirements during follow-up, compared to 7 of 8 patients with solitary aldosterone-secreting macroadenomas.
Postoperative outcomes
The mean duration of follow-up was comparable between the groups: 33.5 ± 16.1 months for pheochromocytoma and 33.6 ± 17.8 months for Conn’s syndrome (P = 0.98). Remission of hypertension following adrenalectomy was significantly higher in the pheochromocytoma group at all early follow-up time points [Figure 2 and Supplementary Table 1]. The requirement for antihypertensive therapy persisted in 17.4% versus 68.8% of patients at discharge (P < 0.01), 13.0% versus 68.8% at the 1st follow-up visit (P < 0.01), 13.0% versus 56.3% at 3 months (P < 0.01), and 13.0% versus 50% at 6 months (P = 0.03) for patients with pheochromocytoma and those of Conn’s syndrome, respectively. This difference gradually diminished over time, with persistence of hypertension noted in 15.0% versus 50.0% (of patients in the two groups) at 1 year after surgery (P = 0.05). One of the patients who underwent adrenalectomy for pheochromocytoma was found to have elevated blood pressure recordings at 1 year of follow-up and has been on a stable regimen of low-dose antihypertensive since then. Follow-up catecholamine levels in this patient were found to be normal, and no evidence of recurrence of the pheochromocytoma was seen on further evaluation.
Figure 2.
Kaplan–Meier analysis graph showing persistence of antihypertensive pharmacotherapy following adrenalectomy for pheochromocytoma (blue line; 23 patients who had hypertension at baseline) and Conn’s syndrome (red line; all 16 patients)
Supplementary Table 1.
Kaplan–Meier estimates for the persistence of antihypertensive medication following adrenalectomy for pheochromocytoma and Conn’s syndrome
| Time point | Pheochromocytoma | Conn’s Syndrome | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| At riska | Eventb | Risk estimate (95% CI)c | At riska | Eventb | Risk estimate (95% CI)c | |
| Discharge | 23 | 19 | 17.4 (1.9–32.9) | 16 | 5 | 68.8 (46.0–91.5) |
| 1 month | 4 | 1 | 13.0 (0.0–26.8) | 11 | 1 | 62.5 (38.8–86.2) |
| 3 months | 3 | 0 | 13.0 (0.0–26.8) | 10 | 2 | 50.0 (25.5–74.5) |
| 6 months | 3 | 0 | 13.0 (0.0–26.8) | 8 | 1 | 43.8 (19.4–68.1) |
| 1 year | 1 | 0 | 13.0 (0.0–26.8) | 7 | 0 | 43.8 (19.4–68.1) |
| 2 years | 1 | 0 | 13.0 (0.0–26.8) | 6 | 0 | 43.8 (19.4–68.1) |
| 3 years | 1 | 0 | 13.0 (0.0–26.8) | 2 | 1 | 21.9 (0.0–54.5) |
| 4 years | 0 | 0 | - | 0 | 0 | - |
| 5 years | 0 | 0 | - | 0 | 0 | - |
aRisk denotes patients with requirement of antihypertensive drugs prior to the specific time point, bEvent denotes patients entering into remission at the specified time point (among those at risk before the specific time point), cRisk estimate: Probability of persistence of antihypertensive drug requirement. CI=Confidence interval
Univariate regression analysis on this cohort [Table 2] revealed that older age (odds ratio [OR]: 1.08, P = 0.01), longer duration of preoperative hypertension (OR: 1.01, P = 0.02), higher preoperative antihypertensive requirement (OR: 2.23, P = 0.01), presence of multifocal lesions (OR: 12.27, P < 0.01), and presence of CKD (OR: 15.43, P = 0.02) were significantly associated with persistence of postoperative hypertension. A multivariate analysis was not performed in view of the limited sample size.
Table 2.
Univariate analysis of perioperative factors against persistence of hypertension postoperatively
| Variable | OR | 95% CI | P |
|---|---|---|---|
| Age (years) | 1.08 | 1.02–1.15 | 0.01 |
| BMI (kg/m2) | 1.07 | 0.97–1.17 | 0.16 |
| Duration of follow-up | 0.96 | 0.91–1.00 | 0.08 |
| Female sex | 0.40 | 0.09–1.65 | 0.20 |
| Duration of HTN preoperatively | 1.01 | 1.00–1.03 | 0.02 |
| Number of antihypertensive drugs preoperatively | 2.23 | 1.20–4.16 | 0.01 |
| Largest lesion size on histology | 0.57 | 0.35–0.93 | 0.02 |
| Multifocal lesions | 12.27 | 2.37–63.36 | <0.01 |
| CKD | 15.43 | 1.48–160.76 | 0.02 |
| DM | 1.38 | 0.28–6.84 | 0.70 |
BMI=Body mass index, CI=Confidence interval, OR=Odds ratio, DM=Diabetes mellitus, CKD=Chronic kidney disease, HTN=Hypertension
DISCUSSION
Our findings suggest that pheochromocytomas show a more prominent and rapid resolution of hypertension following adrenalectomy than what is seen in Conn’s syndrome with 82.6% of patients with pheochromocytoma being discharged without any antihypertensive therapy, in comparison to 31.2% of patients with Conn’s syndrome. This difference between hypertensive outcomes shows blunting beyond 6 months of postoperative follow-up, with hypertension remission rates in Conn’s syndrome gradually rising to 50% at the end of 1 year (in contrast to 85% in pheochromocytoma).
We found that patients with pheochromocytoma were younger at the time of surgical intervention and had a much shorter duration of symptoms than patients with Conn’s syndrome. Patients with pheochromocytoma seek medical attention early in the course of their disease due to the troublesome nature of hypertensive crises experienced by these individuals. In contrast, patients with Conn’s syndrome typically present with a long-standing hypertension that is often uncovered only during evaluation of hypokalemia, lower limb weakness, abdominal pain or a worsening renal function.[10] This long duration of hypertension in patients with Conn’s syndrome promotes chronic salt and water retention, changes in the extracellular matrix, and upregulation of serum endostatin production, all of which in turn promote a silent, gradually progressive cardiovascular remodeling.[11]
In addition, the histopathological heterogeneity may influence postoperative hypertensive outcomes in patients with Conn’s syndrome. Unilateral primary hyperaldosteronism may result from a classical aldosterone-producing adenoma (APA) or from nonclassical histologies such as aldosterone-producing micronodules (APM).[12] In the current study, 8 out of 16 patients with Conn’s syndrome were found to have APM on the final histopathological report. Among these, 7 out of 8 patients continued to require antihypertensive pharmacotherapy at time of the current study, in comparison to 1 out of the 8 patients who only had an APA in the histopathological reports. This is also in agreement with the existing literature that has shown poorer long-term (>12 months) hypertensive outcomes following adrenalectomy for APM than for solitary APAs.[13]
To the best of our knowledge, there is scarcity of literature reporting a direct comparison of hypertension remission following adrenalectomy in patients with EH.[14] Clemente-Gutiérrez et al[14] evaluated 35 patients with pheochromocytoma and 28 patients with Conn’s syndrome for a mean follow up duration of 46.8 months and 61.1 months, respectively, and reported remission rates of 85.7% in pheochromocytoma and 57.1% in Conn’s syndrome similar to 82.6% for pheochromocytoma and 56.2% for Conn’s syndrome in the current study. There have been various attempts to evaluate hypertensive outcomes in patients with Conn’s syndrome, with both the primary aldosteronism surgery outcome consensus criteria[15] and the aldosteronoma resolution score,[16] describing female sex, younger age, and a lower disease burden preoperatively as factors favorable for hypertension remission. Although Zarnegar et al.[16] also described a BMI of <25 kg/m2 to be favorable for hypertension remission, this was not seen in our cohort, possibly due to the low sample size of our study. Age, on the other hand, has consistently been reported to be predictive of hypertension remission following adrenalectomy,[17] as was also seen in the current study. Lu et al.[18] evaluated 259 patients with pheochromocytoma for persistence of hypertension following adrenalectomy and noted that longer duration of hypertension, older age, and concomitant cardiovascular events were risk factors for persistence of hypertension. They hypothesized that this may be due both age-related changes and a chronic catecholamine excess, resulting in progressive impairment in the nitric oxide pathway and significant endothelial dysfunction. Finally, patients with Conn’s syndrome also had a higher rate of CKD than patients with pheochromocytoma. We found a strong association (OR: 15.43, P = 0.02) between CKD and persistence of hypertension following adrenalectomy. Notably, patients with Conn’s syndrome had a much larger pill burden than what was seen in patients with pheochromocytoma, either due to an intense antihypertensive pharmacotherapy or due to their various comorbidities (including CKD). This can become a significant barrier to retrospective data collection in these patients and may be addressed by requesting copies of past prescriptions.
The Kaplan–Meier analysis showed that patients with Conn’s syndrome may require antihypertensive pharmacotherapy following discharge for a much longer time that patients with pheochromocytoma. This reinforces the need for appropriate preoperative patient counseling and a need for long-term monitoring of blood pressure after adrenalectomy. Interpreting hypertension resolution as a dichotomous variable to describe impact of adrenalectomy on a patient with Conn’s syndrome oversimplifies and undermines the true magnitude of the benefit rendered by surgical intervention. Most patients following adrenalectomy report normalization of serum potassium levels and a decrease in their pill-burden.[19]
The current study was limited by its retrospective nature of data collection and the use of telephonic follow-up for enquiring about need of antihypertensive medications. Although the possibility of recall bias could not be excluded, prescriptions were sought during the telephonic follow-up to minimize this risk. The univariate regression analysis revealed multiple factors that may have an association with persistence of hypertension postoperatively. The lack of a multivariate analysis, however, implies that the factors identified may be unadjusted for possible confounders and may suggest trends but not association and warrants future studies with larger sample sizes.
CONCLUSION
Patients with pheochromocytoma who undergo adrenalectomy have a higher likelihood of hypertension remission than among patients with Conn’s syndrome and this is achieved in the immediate postoperative period for most patients. Older age, worse preoperative hypertensive burden, presence of multifocal lesions, and presence of CKD are factors associated with persistence of antihypertensive therapy in the postoperative period. Larger studies allowing adjustment for these potential confounders may be warranted to identify the extent to which they may influence hypertensive outcomes following adrenalectomy for pheochromocytoma or Conn’s syndrome.
Statement of ethics
The study was conducted as part of an institutional ethics committee approved project (IEC No. 461/17.06.2022). Written informed consent was taken from each participant before the surgical intervention offered to them.
Declaration about use of generative artificial intelligence
The authors did not use generative AI or AI-assisted technologies in the development of this manuscript.
Data availability statement
Request for access to raw data can be made to the corresponding author, following which anonymized data may be shared solely for academic purposes.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Request for access to raw data can be made to the corresponding author, following which anonymized data may be shared solely for academic purposes.