Introduction
Hypertension is the leading risk factor for cardiovascular morbidity and mortality [1]. Although most patients have primary hypertension, approximately 5%–10% of patients have secondary hypertension [2]. These patients usually have a definite cause, and might experience cardiovascular damage independent of elevated blood pressure, such as electrolyte disturbances, endocrine disorders, or hypoxemia [2, 3]. Secondary hypertension can be effectively treated with surgery or drug therapies after their cause is determined.
Primary aldosteronism (PA), a major cause of secondary hypertension, has a prevalence of approximately 5% in the hypertensive population [4–6]. PA is characterized by excess secretion of aldosterone from the adrenal glands, and patients usually present with symptoms of hypertension, hypokalemia, and hyporeninemia. Unilateral adrenalectomy is a recommended treatment for patients diagnosed with unilateral PA [4]. Most patients achieve biochemical success (defined as correction of hypokalemia and normalization of the aldosterone-renin ratio) and approximately half maintain normal blood pressure without antihypertensive medication [7]. However, almost half of all patients develop recurrent hypertension after adrenalectomy [8].
At our hypertension center, we examined a cohort of patients admitted for diagnosis and treatment of elevated blood pressure after adrenalectomy. In this study, we sought to assess the etiology, clinical characteristics, and diagnosis of these patients with recurrent hypertension after adrenalectomy, to provide evidence supporting the diagnosis of such patients and guide adrenalectomy clinical practice.
Methods
Study Population
Forty-five patients with hypertension and a history of adrenalectomy admitted to the FuWai Hospital between December 2016 and December 2021 were identified. Patients with multiple hospitalization records were considered single patients. Patients were included in this study if they had (1) systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or use of antihypertensive drugs, or (2) a history of unilateral adrenalectomy. Two patients were excluded because of a diagnosis of pheochromocytoma or Cushing’s syndrome before surgery. A total of 43 patients were ultimately included in this study.
The study was approved by the Ethics Committee of FuWai Hospital. Informed consent was not required, because this study was retrospective.
Data Collection
Demographic data, pre- and post-operative clinical manifestations, laboratory examinations, and imaging features were retrospectively collected. Pre-operative laboratory examinations and imaging records were obtained from the medical centers that performed the operation, or the diagnosis was otherwise confirmed. Post-operative data were collected from medical records from FuWai hospital. Blood pressure was measured with an automatic blood-pressure monitor (Omron Healthcare). Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters.
All patients underwent adrenal CT scans for evaluation of alterations in adrenal glands after surgery. Adrenal lesions were classified into adrenal nodules or thickening according to the imaging characteristics. Adrenal thickening was diagnosed when the adrenal limb was ≥1 cm or thicker than the ipsilateral diaphragm.
Criteria for Etiological Diagnosis
Secondary causes of hypertension were diagnosed through routine screening. PA was screened and confirmed in accordance with the Endocrine Society Practice Guidelines [4] at FuWai Hospital. The orthostatic aldosterone to renin ratio (ARR) was used for PA screening. The ARR was calculated as the plasma aldosterone concentration divided by the direct renin concentration. If the ARR was >3.7 ng dL−1/μIU mL−1 in the screening, a subsequent intravenous saline infusion test or captopril challenge test was performed as a confirmatory test. Phenotyping was confirmed through adrenal venous sampling (AVS) and adrenal computed tomography (CT). Cushing’s syndrome was diagnosed with a low-dose dexamethasone suppression test [9]. Pheochromocytoma and paraganglioma were diagnosed according to plasma catecholamine levels, and urine and plasma free metanephrine levels [10]. Renal artery stenosis (RAS) was diagnosed on the basis of Doppler flow imaging, multidetector row CT angiography, and selective renal artery arteriography; diagnosis was confirmed if the diameter of the trunk section and/or primary branch of RAS was ≥50%. Takayasu arteritis was diagnosed in accordance with the American College of Rheumatology’s revised criteria (1990) [11] or the revised criteria of Sharma and coworkers [12]. Obstructive sleep apnea (OSA) was diagnosed through sleep apnea monitoring. Patients were diagnosed with essential hypertension (EHT) if no secondary causes of hypertension were confirmed.
Definition of Functions of Adrenal Lesions before Surgery
Patients underwent unilateral adrenalectomy in other hospitals. On the basis of endocrine functional examinations, patients were diagnosed with confirmed PA, suspected PA, or nonfunctioning lesions. Patients were considered to have confirmed PA if they had positive results in one of the four recommended confirmation tests; suspected PA if they had only positive consequences of orthostatic ARR; and nonfunctioning lesions if none of the screening tests were positive. Subtype classification was performed with adrenal CT scans.
Results
Clinical Characteristics
Thirty-four percent of the patients were women. The mean patient age was 50.8 ± 13.0 years at the time of diagnosis of recurrent hypertension at our center and 45.6 ± 11.9 years at the time of adrenalectomy. Most patients (60.5%) were 30–55 years old at the time of adrenalectomy. Neary half the patients (46.5%) had a history of diagnosis with hypertension more than 5 years before surgery (Table 1).
General Characteristics of Patients Diagnosed with Recurrent Hypertension after Adrenalectomy.
| Characteristics | |
|---|---|
| N | 43 |
| Age, years | 50.8 ± 13.0 |
| Female | 15 (34.9) |
| BMI, kg/m2 | 25.7 ± 3.3 |
| <24 | 12 (27.9) |
| ≥24 | 31 (72.1) |
| Family history of hypertension | 25 (58.1) |
| Age at surgery, years | 45.6 ± 11.9 |
| <30 | 7 (16.3) |
| 30–55 | 26 (60.5) |
| ≥55 | 10 (23.3) |
| Hypertension course until surgery | |
| <1 year | 13 (30.2) |
| 1–5 years | 10 (23.3) |
| >5 years | 20 (46.5) |
| Diagnosis of current hypertension | |
| PA | 10 (23.3) |
| OSA | 9 (20.9) |
| RAS | 4 (9.3) |
| EHT | 19 (44.2) |
| TA | 1 (2.3) |
Data are presented as mean (± standard deviation) or number (with percentage).
Abbreviations: BMI, body mass index; PA, primary aldosteronism; OSA, obstructive sleep apnea; RAS, renal artery stenosis; EHT, essential hypertension; TA, Takayasu arteritis.
The cause of recurrent hypertension was diagnosed with a standard routine screening workflow in FuWai Hospital. Among these patients, 19 (44.2%) were diagnosed with essential hypertension, 10 (23.3%) were diagnosed with PA, 9 (20.9%) were diagnosed with OSA, 4 (9.3%) were diagnosed with renal artery stenosis, and 1 (2.3%) was diagnosed with Takayasu arteritis.
Preoperative Functional Tests and Imaging Features
Regarding functional tests before surgery, 17 (39.5%) patients were diagnosed with PA via confirmatory tests (n = 7, 16.3%) or ARR screening (n = 10, 23.3%), and 12 (27.9%) patients were shown to have nonfunctioning adenoma. Four of seven patients diagnosed with PA before adrenalectomy through confirmatory tests were also confirmed to have PA as the cause of elevated blood pressure at our center. Seven of the twelve patients diagnosed with nonfunctioning adenomas before surgery were diagnosed with essential hypertension, and four were diagnosed with OSA at our center.
CT scans were performed on all patients (Figure 1). Lesions were observed on the left side in 29 (67.4%) patients, on the right side in 12 (27.9%) patients, and on both sides in 2 (4.7%) patients. Most (90.7%) lesions were classified as limited, including aldosterone-producing adenomas, aldosterone-producing nodules, and aldosterone-producing micronodules. No patients had AVS tests performed before adrenalectomy (Table 2).
Computed tomography (CT) scans of resected adrenal glands in patients.
A: CT scan of a resected left adrenal gland from a 60 year old man diagnosed with essential hypertension; B: CT scan of a resected right adrenal gland from a 49 year old man diagnosed with obstructive sleep apnea.
Preoperative Imaging Features of Adrenal Glands and Functional Tests, Grouped by Etiology of Hypertension after Adrenalectomy.
| Total (n = 43) | PA (n = 10) | EHT (n = 19) | OSA (n = 9) | Others* (n = 5) | |
|---|---|---|---|---|---|
| Functional tests before surgery | |||||
| Confirmed PA | 7 (16.3) | 4 (40.0) | 1 (5.3) | 1 (11.1) | 1 (20.0) |
| Suspected PA | 10 (23.3) | 3 (30.0) | 3 (15.8) | 2 (22.2) | 2 (40.0) |
| Nonfunctioning adenoma | 12 (27.9) | 0 (0.0) | 7 (36.8) | 4 (44.4) | 1 (20.0) |
| No exam performed | 14 (32.6) | 3 (30.0) | 8 (42.1) | 2 (22.2) | 1 (20.0) |
| Imaging features before surgery | |||||
| Site | |||||
| Left | 29 (67.4) | 6 (60.0) | 15 (78.9) | 5 (55.6) | 3 (60.0) |
| Right | 12 (27.9) | 3 (30.0) | 3 (15.8) | 4 (44.4) | 2 (40.0) |
| Both | 2 (4.7) | 1 (10.0) | 1 (5.3) | 0 (0.0) | 0 (0.0) |
| Morphology | |||||
| Limited lesions† | 39 (90.7) | 10 (100.0) | 17 (89.5) | 8 (88.9) | 4 (80.0) |
| <1 cm | 5 (11.6) | 2 (20.0) | 1 (5.3) | 1 (11.1) | 1 (20.0) |
| 1–3 cm | 18 (41.9) | 4 (40.0) | 8 (42.1) | 4 (44.4) | 2 (40.0) |
| ≥3 cm | 3 (7.0) | 0 (0.0) | 2 (10.5) | 0 (0.0) | 1 (20.0) |
| Unknown | 13 (30.2) | 4 (40.0) | 6 (31.6) | 3 (33.3) | 0 (0.0) |
| Hyperplasia | 4 (9.3) | 0 (0.0) | 2 (10.5) | 1 (11.1) | 1 (20.0) |
Data are presented as number (with percentage).
*Includes renal artery stenosis and Takayasu’s arteritis.
†Limited lesions include adenoma, nodule, and micronodule.
Abbreviations: PA, primary aldosteronism; EHT, essential hypertension; OSA, obstructive sleep apnea.
Surgical Methods and Pathological Diagnosis of Patients with Recurrent Hypertension after Adrenalectomy
In our study cohort of 43 patients who underwent adrenalectomy, various operative methods and pathological changes were observed, stratified by the reason of recurrent hypertension post-adrenalectomy (Table 3). Among all patients, 31 (72.1%) underwent partial adrenalectomy, whereas 12 (27.9%) underwent total adrenalectomy. Among patients with EHT (n = 19), partial adrenalectomy was performed in 57.9% (n = 11). Among patients with OSA (n = 9), 88.9% (n = 8) underwent partial adrenalectomy. Among patients with renal artery stenosis and Takayasu’s arteritis (n = 5), 80% (n = 4) underwent partial adrenalectomy. Out of the patients diagnosed with primary aldosteronism (PA), a majority of them (n = 8, 80%) underwent partial adrenalectomy, possibly resulting in hypertension due to the incomplete removal of aldosterone-producing lesions.
Operative Methods and Pathological Changes, Grouped by Diagnosis of Recurrent Hypertension after Adrenalectomy.
| Total (n = 43) | PA (n = 10) | EHT (n = 19) | OSA (n = 9) | Others* (n = 5) | |
|---|---|---|---|---|---|
| Unilateral adrenalectomy procedure | |||||
| Partial adrenalectomy | 31 (72.1) | 8 (80.0) | 11 (57.9) | 8 (88.9) | 4 (80.0) |
| Total adrenalectomy | 12 (27.9) | 2 (20.0) | 8 (42.1) | 1 (11.1) | 1 (20.0) |
| Surgical method | |||||
| Laparotomy adrenalectomy | 20 (46.5) | 3 (30.0) | 9 (47.4) | 4 (44.4) | 4 (80.0) |
| Open adrenalectomy | 23 (53.5) | 7 (70.0) | 10 (52.6) | 5 (55.6) | 1 (20.0) |
| Pathology | |||||
| Cortical adenoma | 20 (46.5) | 5 (50.0) | 7 (36.8) | 4 (44.4) | 4 (80.0) |
| Cortical hyperplasia | 6 (14.0) | 2 (20.0) | 2 (10.5) | 1 (11.1) | 1 (20.0) |
| Others | 5 (11.6) | 1 (10.0) | 3 (15.8) | 1 (11.1) | 0 (0.0) |
| Unknown | 12 (27.9) | 2 (20.0) | 7 (36.8) | 3 (33.3) | 0 (0.0) |
Data are presented as number (with percentage).
*Includes renal artery stenosis and Takayasu’s arteritis.
Abbreviations: PA, primary aldosteronism; EHT, essential hypertension; OSA, obstructive sleep apnea.
Regarding the surgical method used, 20 (46.5%) patients had a laparotomy adrenalectomy, and 23 (53.5%) had an open adrenalectomy. In the PA group, seven (16.3%) patients underwent open adrenalectomy, and three (7.0%) patients underwent laparotomy adrenalectomy. Among patients with EHT, ten (23.3%) were treated with open adrenalectomy, and eight (18.6%) received laparotomy adrenalectomy. In the OSA group, five (11.6%) patients underwent open adrenalectomy, whereas four (9.3%) patients were treated with laparotomy adrenalectomy. Post-surgery pathological reports indicated that most patients (n = 20, 46.5%) were diagnosed with cortical adenomas or cortical hyperplasia (n = 6, 14.0%).
Time Duration and Severity of Recurrent Hypertension after Adrenalectomy
We investigated the time duration from operation to recurrence of hypertension (Table 4). The blood pressure in 19 (44.2%) patients remained uncontrolled after surgery. Elevated blood pressure developed in eight (18.6%) patients within 1 month, seven (16.3%) patients in 1–6 months, and nine (20.9%) patients >6 months after surgery. Regarding the degree of recurrent hypertension, 5 (11.6%) patients had grade 1 hypertension, 17 (39.5%) had grade 2 hypertension, and 21 (48.8%) patients had grade 3 hypertension. More than half the patients diagnosed with PA or essential hypertension for recurrent hypertension had grade 3 hypertension, and most patients diagnosed with obstructive sleep apnea had grade 2 hypertension.
Time and Severity of Postoperative Recurrent Hypertension, Grouped by Etiology of Hypertension after Adrenalectomy.
| Total (n = 43) | PA (n = 10) | EHT (n = 19) | OSA (n = 9) | Others* (n = 5) | |
|---|---|---|---|---|---|
| Time of BP increase | |||||
| Persistent elevation | 19 (44.2) | 4 (40.0) | 8 (42.1) | 4 (44.4) | 3 (60.0) |
| <1 month | 8 (18.6) | 1 (10.0) | 4 (21.1) | 2 (22.2) | 1 (20.0) |
| 1–6 months | 7 (16.3) | 3 (30.0) | 3 (15.8) | 1 (11.1) | 0 (0.0) |
| ≥6 months | 9 (20.9) | 2 (20.0) | 4 (21.1) | 2 (22.2) | 1 (20.0) |
| Degree | |||||
| Grade 1 | 5 (11.6) | 1 (10.0) | 3 (15.8) | 1 (11.1) | 0 (0.0) |
| Grade 2 | 17 (39.5) | 3 (30.0) | 5 (26.3) | 6 (66.7) | 3 (60.0) |
| Grade 3 | 21 (48.8) | 6 (60.0) | 11 (57.9) | 2 (22.2) | 2 (40.0) |
Data are presented as number (with percentage).
*Includes renal artery stenosis and Takayasu arteritis.
Abbreviations: PA, primary aldosteronism; EHT, essential hypertension; OSA, obstructive sleep apnea.
Discussion
In the current study, we investigated the etiology and clinical features of 43 patients with recurrent hypertension after adrenalectomy, who were diagnosed and treated at our hypertensive center. The causes of recurrent hypertension included essential hypertension, PA, OSA, renal artery stenosis, and Takayasu arteritis, which accounted for 44.2%, 23.3%, 20.9%, 9.3%, and 2.3% of patients, respectively.
Patients with PA have an elevated risk of cardiovascular disease [13, 14], and PA is the most common surgically correctible cause of endocrinal hypertension. Current guidelines recommend adrenalectomy for unilateral PA [4]. Currently, laparoscopic adrenalectomy is considered the most effective treatment approach to normalize blood pressure levels and serum potassium, and improve cardiac function [15, 16]. Most instances of PA are curable after unilateral adrenalectomy. Williams and colleagues [7] have established an international consensus to evaluate clinical and biochemical outcomes of adrenalectomy in the Primary Aldosteronism Surgical Outcome Study. Their results have indicated that 94% of patients achieved complete biochemical success (in terms of normalization of hypokalemia and the aldosterone-renin ratio), and approximately half of patients had lower blood pressure or took less antihypertensive medication as compared with before surgery.
The choice of partial and total adrenalectomy remains a controversial topic [17]. In our cohort of patients who developed recurrent elevated blood pressure after adrenalectomy, most (72.1%) underwent partial adrenalectomy; however none of these patients had AVS tests performed before surgery. Four of seven patients diagnosed with PA before adrenalectomy through confirmatory tests were also confirmed to have PA as the cause of elevated blood pressure at our center. Meyer et al. [18] have reported persistent aldosteronism in some patients after adrenalectomy, possibly because of the presence of aldosterone-producing micronodules in unresected adrenal tissue. The concomitant presence of macro-nodules and adenoma may serve as a prognostic indicator of the persistence of hypertension after adrenalectomy. In accordance with this possibility, next-generation sequencing studies have suggested a disease continuum wherein somatic mutations in micronodules develop into adenoma formation [19]. Given that all patients in this study had adrenal CT scans without AVS tests, remaining adrenal tissue not surgically resected might have contained aldosterone-producing lesions that led to recurrent hypertension.
AVS is the gold standard for assessment of lateralization of aldosterone hypersecretion [20], and AVS-guided adrenalectomy has been found to lead to better surgical outcomes [21]. Subtype classification through adrenal imaging alone misdiagnoses the cause of PA in 37.8% of patients [22]. In addition, AVS may ensure appropriate management in the case of rare but probably under-reported cases of coexisting diseases such as concomitant pheochromocytoma [23].
Picado et al. [24] have reported complete, partial, and absent clinical success achieved in 41%, 38%, and 21% of patients with PA at 6 months post-operation, respectively. High pre-operative [8] and post-operative blood pressure, longstanding hypertension, high BMI, and post-operative plasma aldosterone levels are predictive of post-operative long-term hypertension. Accordingly, in our study, most patients had BMI >24 kg/m2 and a hypertension history longer than 5 years.
Some patients’ blood pressure did not return to normal after adrenalectomy, presumably because of poor surgical removal or therapy. Other individuals developed hypertension <6 months after adrenalectomy, and the common cause was essential hypertension (four of nine patients), thus suggesting that those patients had acceptable surgical adrenalectomy but developed recurrent hypertension for other reasons, such as old age. Therefore, clinicians must note the interval between adrenalectomy and recurrent hypertension to identify diagnosis and causation.
Among all patients with recurrent hypertension after adrenalectomy, 44.2% and 20.9% were diagnosed with essential hypertension and OSA, respectively. Most of these patients had no positive endocrine functional test results before adrenalectomy, and adrenal lesions were found only through CT imaging. We inferred that the excised adrenal lesions might have been nonfunctional and consequently might not have caused the previous hypertension. Furthermore, the prevalence of hypertension increases with age, and older patients are more likely to develop hypertension regardless of a history of past adrenal disease [25].
In clinical settings, the choice of surgical procedure and technique, whether through a transperitoneal or retroperitoneal approach, or a single-port or multi-port laparoscopic approach, varies substantially depending on the patient, lesion dimensions and features, hospital, and surgeon. Concurrently, emerging interventions including radiofrequency ablation, transarterial embolization [26], or radiofrequency ablation [27] for adrenalectomy may provide novel options for high-risk patients unable to undergo surgery. However, their long-term efficacy and treatment outcomes remain to be determined.
To our knowledge, this study is the first to investigate the causes and clinical features of recurrent hypertension after adrenalectomy. Our findings emphasize the need for routine standardized diagnosis of PA, and the importance of AVS in subtype classification and surgical guidance. We also suggest performing related clinical examinations to evaluate OSA and renal artery stenosis before adrenalectomy in patients with PA. The present study has several limitations. First, the sample size was small. Second, because this study was retrospective, some selection bias might have been present.
Conclusions
The causes of recurrent hypertension after adrenalectomy in this study included essential hypertension, primary aldosteronism, OSA, renal artery stenosis, and Takayasu arteritis, which accounted for 44.2%, 23.3%, 20.9%, 9.3%, and 2.3% of patients, respectively. Standard endocrine functional evaluations of adrenal lesions and AVS tests should be performed before adrenalectomy to confirm the diagnosis and ensure that patients achieve the expected post-operative clinical benefits. Additionally, individuals often develop essential hypertension because of risk factors such as old age, regardless of past adrenal disease.