We reported a case of primary aldosteronism. Although the initial screening test (ARR) was negative, we further confirmed the diagnosis with the inhibitory test with saline and concluded that PA could not be excluded when ARR was negative. According to the guidelines [6], PA can be diagnosed by a positive orthostatic ARR and confirmatory tests, but many factors affect the results of PA screening and confirmatory tests. As a clinical disease, the diagnosis of PA should be based on complete clinical manifestations, laboratory examination, AVS, histopathology and treatment response.
Aldosterone is a hormone regulating blood volume in the human body which regulated by renin-angiotensin system (RAS), angiotensin II, adrenocorticotropic hormone(ACTH) and potassium ions. In PA, the relative high blood volume caused by increased aldosterone further inhibits RAS; aldosterone secretion is relatively independent of the inhibited RAS, but can be affected by body position, hormone [9] and various receptor ligands [10], which may lead to great variability of aldosterone levels in PA patients. It has been reported that chronic stress induced by ACTH leads to ACTH dependent hyperaldosterone secretion in hypertensive patients without PA [11]. When hypokalemia and resistant hypertension exist, the possibility of PA is very high. In the case of low renin level, the production of aldosterone at any level suggests that there may be potential PA. Two studies have shown that even normal aldosterone levels(< 10 ng/dl) may be an indicator of PA [12, 13]. Oelkers et al. [14] reported three patients with PA complicated by renal insufficiency whose plasma renin was not inhibited. In these patients, plasma renin activity was in the normal/high normal range, which may have been related to renal vascular injury leading to glomerular ischaemia and renin escaping excess aldosterone inhibition. In the diagnosis of PA with the ARR, the effect of renal damage on plasma renin concentration (PRC) may cause an increase in the PRC, which leads to a false lower ARR value, thus masking PA [15].
This patient had mild renal insufficiency, which may have been a cause of the negative ARR. There are different reports on the ARR cut-off point in the diagnosis of PA in domestic and foreign studies [4]. At present, the ARR cut-off point recommended by previous studies is used in the screening of PA in patients with hypertension, and whether this cut-off point is in line with the local population has not been further discussed; therefore, PA may be missed in some people with an ARR lower than the cut-off point. In 2017, Zorzl et al [16] reported a 27-year-old patient with hypertension who was diagnosed with essential hypertension after a negative ARR was determined. Many years later, the patient repeatedly went to the hospital due to poor blood pressure control (taking four kinds of antihypertensive drugs at the same time) and hypokalaemia. After 14 years, the ARR was positive, and PA was confirmed by the inhibitory test with saline and AVS. After the operation, blood pressure and potassium levels returned to normal. Therefore, when the ARR is negative, PA cannot be easily excluded. Comprehensive analysis and diagnosis should be based on the medication and clinical conditions of patients.
Bilateral adrenal diseases can be divided into three types: idiopathic adrenal hyperplasia (IAH), bilateral aldosterone-producing adenoma (APA) and glucocorticoid-remediable aldosteronism (GRA) [6]. It is difficult to distinguish bilateral APA from IAH even with successful AVS [17]. In 2016, Japanese scholars used segmental AVS (S-AVS) to confirm that the veins in the tumour segment secreted too much aldosterone and inhibited the bilateral secretion of veins in the nontumour segment, leading to the diagnosis of bilateral APA [17]. In theory, bilateral APA can also be cured by surgery, but there are few successful cases reported in the literature. Few patients with bilateral APA underwent surgery and were cured by surgery [17,18,19,20].
Guidelines recommend mineralocorticoid receptor (MR) antagonists for PA patients with bilateral adrenal disease [6]. However, it has been reported that the cardiovascular risk of PA patients is higher than that of patients with essential hypertension, despite good blood pressure control [21]. When MR antagonists are used, the decline in glomerular filtration rate increases the risk of hyperkalaemia, and large doses of MR antagonists, which can block MR sufficiently, are also limited [22]. The use of high-dose spironolactone also has anti-androgen side effects. A Japanese national survey also showed that surgical treatment can improve hypertension and hypokalaemia in unilateral and bilateral adrenal lesions [23]. Scholars have raised the following question: Can adrenalectomy reduce aldosterone exposure in PA patients with bilateral adrenal diseases? [24] There is a lack of effective clinical research to answer this question, and more prospective studies are needed. For PA patients whose blood pressure cannot be controlled sufficiently or whose hypokalaemia is difficult to correct or whose renal function is impaired and the dosage of MR antagonist cannot be increased to the maximum, scholars propose the choice of unilateral adrenalectomy to reduce the severity of the disease, coupled with long-term MR antagonist treatment [24]. We performed a unilateral adenoma resection for this patient, who continued taking spironolactone to control blood pressure. Currently, blood pressure is well controlled, and good clinical effects have been achieved.
Finally, we summarize some experience gained from this case and some hints for future clinical work. Clinically, for patients with atypical suspected PA, we should not rely only on hormone level and ARR screening to exclude PA, but we should make a judgement after comprehensive evaluation of clinical manifestations and laboratory and imaging examinations. For PA patients, long-term clinical follow-up observation, including the monitoring of drug side effects, blood pressure and various cardiovascular complications, is also needed, regardless of the choice of drugs or surgical treatment.
