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CASE REPORT
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Primary Aldosteronism Presenting with an Atypical Aldosterone-renin Ratio in the Acute Phase of Cerebral Hemorrhage Naoka Murakami 1,a, Naohiro Yoshida 1, Kunihisa Hamano 1, Hisanori Suzuki 1, Megumi Miyakawa 1, Akira Takeshita 1,2 and Yasuhiro Takeuchi 1,2
Abstract The aldosterone-renin ratio (ARR) is considered to be the most reliable and sensitive screening parameter for primary aldosteronism (PA). However, little is known regarding how stroke influences the ARR. We herein present a case of a 35-year-old man who was ultimately found to have PA after diagnostic challenges. The patient showed an atypical ARR in the acute phase of cerebral hemorrhage. We therefore conclude that the ARR may be inappropriately decreased immediately after stroke in patients with PA, presumably due to sympathetic activation and the effects of medications. When diagnosing PA in patients with stroke, we suggest reevaluating the ARR in the stable phase. Key words: primary aldosteronism, aldosterone-renin ratio, cerebral hemorrhage (Intern Med 54: 415-420, 2015) (DOI: 10.2169/internalmedicine.54.3267)
Introduction Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, accounting for 5-13% of all cases of hypertension (1, 2), although it is generally underdiagnosed. PA is defined as the autonomous secretion of aldosterone resulting in the excessive retention of sodium and water, which subsequently leads to resistant hypertension. PA is usually caused by the presence of an adrenal adenoma or unilateral or bilateral adrenal hyperplasia. In rare cases, the disease may be due to an inherited condition (3), such as glucocorticoid-remediable aldosteronism. PA is associated with higher rates of cardiovascular and cerebrovascular morbidity and mortality compared to those observed in age- and sex-matched patients with essential hypertension (4-7). For example, the incidence of cerebrovascular accidents is 12.9% among patients with PA in comparison with 3.4% among patients with essential hypertension (6). Surgical and medical interventions, such as the administration of mineralocorticoid receptor (MR) antagonists,
can significantly improve long-term outcomes (7). Therefore, it is crucial to diagnose PA in a timely manner. The aldosterone-renin ratio (ARR) is the most reliable and accessible screening parameter for PA (1, 2, 8). The ARR is calculated based on the plasma aldosterone concentration (PAC, ng/dL) and plasma renin activity (PRA, ng/ mL/hr) and has a high sensitivity for PA. However, several different cut-off values for the ARR have been proposed (8, 9). In general, an ARR of >20 ng/dL per ng/mL/hr is suggestive of PA, and the possibility of PA increases with a concomitant PAC of >15 ng/dL (1). However, imaging studies, including abdominal computed tomography (CT), are less sensitive in such cases, as aldosterone-producing adenomas measuring less than 5 mm in diameter are often difficult to detect on CT and adrenal hyperplasia is indistinguishable from normal adrenal glands on CT scans. Therefore, the ARR is currently considered to be the screening test of choice for PA. Nevertheless, as with all biochemical screening tests, the ARR has limitations. Certain medications and other pathophysiological conditions, such as differences in the patient’s posture during blood sampling (i.e. sit-
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Department of Endocrinology and Metabolism, Toranomon Hospital, Japan, ２Okinaka Memorial Institute for Medical Research, Japan and Department of Medicine, Beth Israel Medical Center, USA Received for publication May 12, 2014; Accepted for publication July 3, 2014 Correspondence to Dr. Akira Takeshita, [email protected]
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Figure 1. A: Plain head computed tomography (CT) showed pontine hemorrhage and right cerebellar hemorrhage. B: Abdominal CT revealed an approximate 10-mm right adrenal mass with low attenuation (2 Hounsfield Units). C: Macroscopic image of the resected adrenal mass (diameter 11 × 8 mm). D, E: Hematoxylin and Eosin staining (magnification ×10, ×200) showed no apparent nuclear atypia, necrosis or invasion, indicating the presence of a benign clear-cell adrenal adenoma.
ting or supine), hypo- or hyperkalemia, dietary sodium intake and renal impairment, are known to modify the ARR (1, 2, 9). Therefore, it is recommended that the ARR be reevaluated after correcting these potentially influential factors. We herein present a case of PA with diagnostic challenges in which the patient presented with an atypical reninaldosterone profile in the acute phase of cerebral hemorrhage. We discuss the potential pitfalls of which clinicians should be aware when diagnosing PA.
Case Report A 35-year-old overweight man [height: 157 cm, body weight: 71 kg, body mass index (BMI): 28.1 kg/m2] with a history of early-onset hypertension starting at 29 years of age who was currently under treatment with valsartan and nifedipine (dosage unknown) presented to the emergency department with a hypertensive emergency associated with dysarthria and right-sided hemiparesis. His blood pressure was 240/140 mmHg at presentation following medication non-compliance for two weeks. According to his medical record, his regular baseline blood pressure was controlled at approximately 140/80 mmHg with medication. A head CT scan revealed acute intracranial hemorrhage in the pontine and right cerebellum (Fig. 1A). Intravenous glycerol was administered to prevent cerebral edema, with the continuous infusion of nicardipine (5 μg/min/kg) to control the patient’s blood pressure. The nicardipine infusion was subsequently switched to oral azelnidipine and doxazosin on the second
day, and the azelnidipine was switched to oral nifedipine on the third day (Fig. 2). The patient was maintained on an nil per os (NPO) status with intravascular hydration (2,400 mL/ day) for three to four days after admission, then started on a sodium-restricted diet with hydration by mouth ad libitum. His neurological symptoms gradually improved from an National Institute of Health (NIH) stroke scale (NIHSS) score of 4 to 0 on day 14, without any residual symptoms. Due to the detection of early-onset hypertension, hypokalemia (2.7 mEq/L) and slight metabolic alkalosis (pH 7.46, HCO3 26 mmol/L, base excess 2.2 mmol/L) on the first day of admission, we considered a diagnosis of secondary hypertension due to PA. An unenhanced CT scan showed a 10mm right adrenal mass (Fig. 1B, arrow) with low attenuation (2 Hounsfield Units), indicating a lipid-rich structure consistent with a cortical adenoma (10). In contrast to our expectations, endocrinology tests performed on hospital day 2 (Table 1) showed a PRA of 15.0 ng/mL/hr, PAC of 11.3 ng/dL and ARR of 0.75, which are not consistent with a diagnosis of PA. However, follow-up ARR tests showed a gradual increase in this parameter, which is consistent with PA. On day 12, the PRA decreased to 1.9 ng/mL/hr, the PAC increased to 19.3 ng/dL and the ARR increased to 10.2. On day 20, the PRA was 0.8 ng/mL/hr, the PAC was 23.2 ng/dL and the ARR was 29.0 (Table 1). In addition to renin-aldosterone profiles, we determined the levels of catecholamines and their metabolites in the plasma and urine. Consequently, the morning plasma noradrenaline and dopamine (day 2) and urinary noradrenaline, dopamine and normetanephrine (day 7) levels were each elevated within
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5 ȝJ/min/kg nicardipine
80 mg/day
40 mg/day
nifedipine
doxazosin 2 mg/day 4 mg/day
8 mg/day
12 mg/day
Systolic blood pressure (mmHg)
azelnidipine 16 mg/day
240 220 200 180 160 140 120 100
ARR
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5
10
0.75
15
20 days
10.2
29.0
Figure 2. Clinical course of the patient after admission. The systolic blood pressure, aldosteronerenin ratio and antihypertensive drugs and their dosages are noted. ARR: aldosterone-renin ratio
Table 1. Sequential Changes in Plasma Renin Activity, Aldosterone, Serum Potassium, and Plasma/Urinary Catecholamines after Cerebral Hemorrhage Day 2
Day 7
Day 12
Day 19
Day 20
Reference range 0.3-2.9 2.99-15.9
PRA (ng/mL/hr) 15.0 n.d. 1.9 n.d. 0.8 PAC (ng/dL) 11.3 n.d. 19.3 n.d. 23.2 ARR (ng/dL per ng/mL/hr) 0.75 n.d. 10.2 n.d. 29.0 n.d. n.d. n.d. n.d. 7.2-63.3 ACTH (pg/mL) 31.4 Cortisol (μg/dL) 17.4 n.d. n.d. n.d. n.d. 4.0-19.3 DHEA-S (ng/mL) 2,590 n.d. n.d. n.d. n.d. 1,060-4,640 n.d. 3.3 3.3 3.6 3.7-4.8 Serum potassium (mmol/L) 2.7 Plasma adrenaline (ng/mL) 0.02 n.d. n.d. n.d. n.d. < 0.17 Plasma noradrenaline (ng/mL) 0.83 n.d. n.d. n.d. n.d. 0.15-0.57 n.d. n.d. n.d. n.d. < 0.03 Plasma dopamine (ng/mL) 0.05 Urinary adrenaline (μg/day) n.d. 10.6 n.d. n.d. n.d. 3.4-26.9 Urinary noradrenaline (μg/day) n.d. 306.4 n.d. n.d. n.d. 48.6-168.4 n.d. 1,393.4 n.d. n.d. n.d. 365.0-961.5 Urinary dopamine (μg/day) Urinary metanephrine (mg/day) n.d. 0.09 n.d. 0.07 0.07 0.04-0.19 Urinary normetanephrine (mg/day) n.d. 0.38 n.d. 0.28 0.28 0.09-0.33 Blood samples were drawn at 8AM after overnight recumbency. PRA: plasma renin activity, PAC: plasma aldosterone concentration, ARR: aldosterone-renin ratio, ACTH: adrenocorticotropic hormone, DHEA-S: dehydroepiandrosterone sulfate, n.d.: no data Abnormal values are underlined.
two-fold of the upper limit of normal. The levels of urinary metabolites of catecholamines were measured on follow-up examinations, which showed that the urinary normetanephrine value normalized on day 19 (Table 1). Because the ARR exceeded 20 on day 20, a captoprilchallenge test and rapid adrenocorticotropic hormone (ACTH)-stimulation test were performed as confirmatory tests for PA on days 30 and 31, respectively. For the captopril-challenge test, 50 mg of captopril was administered orally and blood samples were obtained prior to (base-
line) and at 60 and 90 minutes after administration. The PRA was 1.3 ng/mL/hr at baseline, which was somewhat higher than that observed on day 20. Meanwhile, the ARR was 16.9 (less than 20, as discussed later). After the captopril challenge, the PRA slightly increased to 1.5 ng/mL/hr, while the PAC decreased from 22.0 ng/dL (baseline) to 13.4 ng/dL (90 minutes, 40% decrease). These data are not consistent with the typical findings of PA (PAC >15.0 ng/dL and ARR >20 ng/dL per ng/mL/hr) (Table 2). A rapid ACTH-stimulation test with 0.25 mg of Cortro-
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Table 2. Confirmatory Tests and Venous Sampling Captopril test (day 30) Time (minutes) 0 60 90 PRA (ng/mL/hr) 1.3 1.3 1.5 PAC (ng/dL) 22.0 14.3 13.4 ARR (ng/dL per ng/mL/hr) 16.9 11.0 8.93 Rapid ACTH test (day 31) Time (minutes) 0 30 60 90 120 PAC (ng/dL) 19.1 25.2 28.1 29.4 28.6 Cortisol (μg/dL) 15.7 22.4 25.0 27.4 29.8 Venous-sampling test (day 40) After ACTH injection (minutes) 0 30 PAC (ng/dL) Peripheral vein 13.9 31.5 Left adrenal vein 66.1 256.0 Right adrenal vein 3,480.0 3,160.0 Cortisol (μg/dL) Peripheral vein 7.1 18.1 Left adrenal vein 47.1 223.3 Right adrenal vein 67.5 1,036.5 PRA: plasma renin activity, PAC: plasma aldosterone concentration, ARR: aldosterone-renin ratio, ACTH: adrenocorticotropic hormone
synⓇ (cosyntropin, Daiichi-Sankyo, Tokyo, Japan) elicited a marked increase in the PAC value to 29.4 ng/dL at 90 minutes, whereas the cortisol level was 27.4 μg/dL; thus, the maximum PAC/cortisol ratio after ACTH-stimulation was 1.07 (Table 2). The results of the rapid ACTH-stimulation test met the criteria for PA proposed by Omura et al. (11), in that the maximum PAC/cortisol ratio was greater than 0.85 in the setting of a PAC of >12 ng/dL and PRA of 20 ng/dL per ng/mL/h, 10-mm lowattenuation mass on abdominal CT and ACTH-stimulation test with a PAC/cortisol ratio above 0.85 suggested a diagnosis of PA. Therefore, we proceeded with an adrenal venous-sampling study (Table 2). Prior to ACTH injection, the PAC values on the right and left sides were 3,480.0 ng/dL and 66.1 ng/dL, respectively. The cortisol-corrected aldosterone ratio from the high side to the low side was more than 2:1, which met the criteria for PA proposed by Rossi et al. (12). The PAC values on the right and left sides 30 minutes after the bolus ACTH injection were 3,160.0 ng/dL and 256.0 ng/dL, respectively. These results met the criteria for PA (PAC >1,400 ng/mL) proposed by Omura et al. (11) (Table 2). Based on these findings, we diagnosed the patient with unilateral PA caused by a right cortical adenoma. Laparoscopic right adrenalectomy was performed three months after the patient’s cerebral hemorrhage. The pathology results confirmed the presence of a clear-cell adrenal adenoma (Fig. 1C-E). The patient’s postoperative course was uneventful, and his PRA and PAC levels returned to normal (PRA: 2.0 ng/mL/hr, PAC: 6.8 ng/dL) on postoperative day 7. In addition, his blood pressure control was significantly improved at the one-year follow-up visit, being within the range of 120 mmHg systolic, under treatment with nifedipine (60 mg daily) and valsartan (80 mg daily).
Discussion In this report, we discuss the diagnostic challenges of PA in the acute phase of cerebral hemorrhage, focusing specifically on the atypical renin-aldosterone profile observed at presentation and the interpretation of confirmatory tests for PA. In the present case, the endocrinology data, including an elevated PRA, PAC within the normal range and low ARR obtained on hospital day 2, were atypical for PA. Although the ARR is currently the most reliable screening tool for PA, it is easily influenced by several factors, such as day-to-day variations, dietary sodium intake, the sampling time, posture, age and medications (1, 2, 9, 13, 14). In this case, we speculate that sympathetic nerve activation and the effects of medications may be two major factors causing the initial “false-negative” low ARR value. Hiraiwa et al. (15) reported a similar case of PA in which the patient presented with an atypical ARR in the acute phase of cerebral hemorrhage. In that case, the plasma norepinephrine and urinary metanephrine levels were elevated to approximately five times above the upper limit of normal at presentation and normalized on day 23. In the acute phase of intracranial hemorrhage, sympathetic nerve activation occurs secondary to an elevated intracranial pressure (16), which stimulates renin secretion (17). Leow et al. (18) reported an excessive amount of catecholamines and metanephrine triggered by sympathetic dysautonomia in the setting of acute intracranial hemorrhage, describing this phenomena as “biochemically pseudopheochromocytoma,” as the plasma catecholamine and urinary metabolite levels mimic the endocrinological laboratory findings of pheochromocytoma. Patients with a large hematoma volume develop significantly elevated urinary catecholamine metabolite levels (16). In most cases of acute cerebral hemorrhage without pheochromocytoma, however, the increase in plasma
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catecholamines and urinary metabolites is slight to moderate and the levels remain within three- to five-fold of the upper limit of normal (15-17). Therefore, it is not generally difficult to make the differential diagnosis of pheochromocytoma. Nevertheless, one should exclude concomitant pheochromocytoma by repeating the tests of the catecholamine levels during the stable phase, as pheochromocytoma is associated with a higher incidence of cerebral bleeding (2%) and cerebral infarction (3%) (19). The timeframe for normalization of catecholamines has been previously discussed. In general, the urinary catecholamine metabolite levels peak between days 3 and 10 after the onset of bleeding (16). The surge in catecholamines then normalized after one month, corresponding with the duration of diaschisis and maximum neurological deficits (15, 18). In the present case, the morning plasma catecholamine and urinary normetanephrine levels were elevated on days 2 and day 7, respectively, and remained within two-fold of the upper limit of normal, although the urinary normetanephrine value normalized on day 12. These findings are significant and may have affected the ARR, although they were relatively mild compared with those of previous reports (15, 16, 18). Along with sympathetic activation, the administration of osmotic diuretics and antihypertensive drugs may have contributed to the atypical ARR at presentation observed in this case. Diuretics stimulate renin production via volume contraction, thereby lowering the ARR (9, 20). The concentrated glycerol administered under emergency conditions may have led to a “falsely” low ARR. In addition, the continuous infusion of nicardipine and oral nifedipine may have affected the ARR. Dihydropyridine calcium-channel blockers (CCBs) are known to suppress calcium-dependent aldosterone secretion in vivo and in vitro (21). However, the effects of dihydropyridine CCBs on the ARR in screening for PA are generally mild and controversial compared with those of other antihypertensive agents, such as diuretics, angiotensinconverting enzyme-inhibitors and angiotensin-receptor blockers. For example, Mulatero et al. (22) studied the effects of various antihypertensive agents, including amlodipine, on hypertensive patients positive for ARR screening tests (ARR>50 and PAC>15) after a washout period of previous antihypertensive therapy and found that only one of the 55 patients taking amlodipine (1.8%), compared to four of the 17 patients taking irbesartan (23.5%), exhibited a false-negative ARR (0.85 after ACTHstimulation with a PRA of 12.0 ng/dL as criteria for probable PA in hypertensive patients. This screening test is based on the observation that aldosterone-producing adenomas produce an exaggerated amount of aldosterone in response to exogenous ACTHstimulation in the setting of sustained inhibition of renin (30). Our patient had a PAC/cortisol ratio of >0.85, PRA value of 0.8 ng/mL/hr (12.0), consistent with the criteria for PA (11). Recently, the disease concept of MR-associated hypertension has emerged (31). Obesity is a known diseasemodifying risk factor for cardiovascular events in patients with MR-associated hypertension. In the present case, the patient’s blood pressure control significantly improved after surgery. However, he continued to require multiple antihypertensive agents. This partial resolution of postoperative blood pressure may be attributed to the patient’s obesity and lengthy disease course. In conclusion, the PRA may be inappropriately elevated
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in the acute phase of cerebral hemorrhage in patients with PA, presumably due to sympathetic activation and the effects of medications. In order to make a definitive diagnosis of PA in patients with acute cerebral hemorrhage, it is necessary to reevaluate the PRA and PAC during the stable phase more than one month after presentation in most cases, although individualization is required.
13.
14.
The authors state that they have no Conflict of Interest (COI). 15.
Acknowledgement We wish to thank all of the health-care professionals who dedicated their expertise to the care of the patient described in the present report.
16.
17.
Financial Support This work was supported by a grant from the Okinaka Memorial Institute for Medical Research.
18.
Naoka Murakami and Naohiro Yoshida contributed equally to this work.
19.
References
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1. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf) 66: 607-618, 2007. 2. Stowasser M. Update in primary aldosteronism. J Clin Endocrinol Metab 94: 3623-3630, 2009. 3. Funder JW. The genetic basis of primary aldosteronism. Curr Hypertens Rep 14: 120-124, 2012. 4. Takeda R, Matsubara T, Miyamori I, Hatakeyama H, Morise T. Vascular complications in patients with aldosterone producing adenoma in Japan: comparative study with essential hypertension. The Research Committee of Disorders of Adrenal Hormones in Japan. J Endocrinol Invest 18: 370-373, 1995. 5. Nishimura M, Uzu T, Fujii T, et al. Cardiovascular complications in patients with primary aldosteronism. Am J Kidney Dis 33: 261266, 1999. 6. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45: 1243-1248, 2005. 7. Catena C, Colussi G, Nadalini E, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med 168: 80-85, 2008. 8. Montori VM, Young WF. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am 31: 619-632, 2002. 9. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93: 3266-3281, 2008. 10. Hamrahian AH, Ioachimescu AG, Remer EM, et al. Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab 90: 871-877, 2005. 11. Omura M, Nishikawa T. Screening tests and diagnostic examinations of hypertensives for primary aldosteronism. Rinsho Byori (The official Journal of Japanese Society of Laboratory Medicine) 54: 1157-1163, 2006 (in Japanese, Abstract in English). 12. Rossi GP, Sacchetto A, Chiesura-Corona M, et al. Identification of
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the etiology of primary aldosteronism with adrenal vein sampling in patients with equivocal computed tomography and magnetic resonance findings: results in 104 consecutive cases. J Clin Endocrinol Metab 86: 1083-1090, 2001. Tanabe A, Naruse M, Takagi S, Tsuchiya K, Imaki T, Takano K. Variability in the renin/aldosterone profile under random and standardized sampling conditions in primary aldosteronism. J Clin Endocrinol Metab 88: 2489-2494, 2003. Tiu SC, Choi CH, Shek CC, et al. The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab 90: 72-78, 2005. Hiraiwa T, Ibata R, Tanimoto K, et al. Acute cerebral hemorrhage normalized plasma renin activity in a patient with primary aldosteronism. Endocrine 36: 383-384, 2009. Hamann GF, Strittmatter M, Hoffmann KH, et al. Pattern of elevation of urine catecholamines in intracerebral haemorrhage. Acta Neurochir (Wien) 132: 42-47, 1995. Gordon RD, Küchel O, Liddle GW, Island DP. Role of the sympathetic nervous system in regulating renin and aldosterone production in man. J Clin Invest 46: 599-605, 1967. Leow MK, Loh KC, Kiat Kwek T, Ng PY. Catecholamine and metanephrine excess in intracerebral haemorrhage: revisiting an obscure yet common “pseudophaeochromocytoma”. J Clin Pathol 60: 583-584, 2007. Thomas JE, Rooke ED, Kvale WF. The neurologist’s experience with pheochromocytoma. A review of 100 cases. JAMA 197: 754758, 1966. Stowasser M, Gordon RD. Primary aldosteronism--careful investigation is essential and rewarding. Mol Cell Endocrinol 217: 3339, 2004. Ikeda K, Isaka T, Fujioka K, Manome Y, Tojo K. Suppression of aldosterone synthesis and secretion by Ca2+ channel antagonists. Int J Endocrinol 2012: 519467, 2012. Mulatero P, Rabbia F, Milan A, et al. Drug effects on aldosterone/ plasma renin activity ratio in primary aldosteronism. Hypertension 40: 897-902, 2002. Seifarth C, Trenkel S, Schobel H, Hahn EG, Hensen J. Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism. Clin Endocrinol (Oxf) 57: 457-465, 2002. Seiler L, Rump LC, Schulte-Mönting J, et al. Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication. Eur J Endocrinol 150: 329-337, 2004. Nadler JL, Hsueh W, Horton R. Therapeutic effect of calcium channel blockade in primary aldosteronism. J Clin Endocrinol Metab 60: 896-899, 1985. Yokoyama T, Shimamoto K, Iimura O. Mechanism of inhibition of aldosterone secretion by a Ca2+ channel blocker in patients with essential hypertension and patients with primary aldosteronism. Nihon Naibunpi Gakkai Zasshi (Folia Endocrinologica Japonica) 71: 1059-1074, 1995 (in Japanese, Abstract in English). Grasko JM, Nguyen HH, Glendenning P. Delayed diagnosis of primary hyperaldosteronism. BMJ 340: 1358-1360, 2010. Hambling C, Jung RT, Gunn A, Browning MC, Bartlett WA. Reevaluation of the captopril test for the diagnosis of primary hyperaldosteronism. Clin Endocrinol (Oxf) 36: 499-503, 1992. Mulatero P, Bertello C, Garrone C, et al. Captopril test can give misleading results in patients with suspect primary aldosteronism. Hypertension 50: e26-e27, 2007. Kem DC, Weinberger MH, Higgins JR, Kramer NJ, Gomez-Sanchez C, Holland OB. Plasma aldosterone response to ACTH in primary aldosteronism and in patients with low renin hypertension. J Clin Endocrinol Metab 46: 552-560, 1978. Shibata H, Itoh H. Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension. Am J Hypertens 25: 514-523, 2012.
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CASE REPORT
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Primary Aldosteronism Presenting with an Atypical Aldosterone-renin Ratio in the Acute Phase of Cerebral Hemorrhage Naoka Murakami 1,a, Naohiro Yoshida 1, Kunihisa Hamano 1, Hisanori Suzuki 1, Megumi Miyakawa 1, Akira Takeshita 1,2 and Yasuhiro Takeuchi 1,2
Abstract The aldosterone-renin ratio (ARR) is considered to be the most reliable and sensitive screening parameter for primary aldosteronism (PA). However, little is known regarding how stroke influences the ARR. We herein present a case of a 35-year-old man who was ultimately found to have PA after diagnostic challenges. The patient showed an atypical ARR in the acute phase of cerebral hemorrhage. We therefore conclude that the ARR may be inappropriately decreased immediately after stroke in patients with PA, presumably due to sympathetic activation and the effects of medications. When diagnosing PA in patients with stroke, we suggest reevaluating the ARR in the stable phase. Key words: primary aldosteronism, aldosterone-renin ratio, cerebral hemorrhage (Intern Med 54: 415-420, 2015) (DOI: 10.2169/internalmedicine.54.3267)
Introduction Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, accounting for 5-13% of all cases of hypertension (1, 2), although it is generally underdiagnosed. PA is defined as the autonomous secretion of aldosterone resulting in the excessive retention of sodium and water, which subsequently leads to resistant hypertension. PA is usually caused by the presence of an adrenal adenoma or unilateral or bilateral adrenal hyperplasia. In rare cases, the disease may be due to an inherited condition (3), such as glucocorticoid-remediable aldosteronism. PA is associated with higher rates of cardiovascular and cerebrovascular morbidity and mortality compared to those observed in age- and sex-matched patients with essential hypertension (4-7). For example, the incidence of cerebrovascular accidents is 12.9% among patients with PA in comparison with 3.4% among patients with essential hypertension (6). Surgical and medical interventions, such as the administration of mineralocorticoid receptor (MR) antagonists,
can significantly improve long-term outcomes (7). Therefore, it is crucial to diagnose PA in a timely manner. The aldosterone-renin ratio (ARR) is the most reliable and accessible screening parameter for PA (1, 2, 8). The ARR is calculated based on the plasma aldosterone concentration (PAC, ng/dL) and plasma renin activity (PRA, ng/ mL/hr) and has a high sensitivity for PA. However, several different cut-off values for the ARR have been proposed (8, 9). In general, an ARR of >20 ng/dL per ng/mL/hr is suggestive of PA, and the possibility of PA increases with a concomitant PAC of >15 ng/dL (1). However, imaging studies, including abdominal computed tomography (CT), are less sensitive in such cases, as aldosterone-producing adenomas measuring less than 5 mm in diameter are often difficult to detect on CT and adrenal hyperplasia is indistinguishable from normal adrenal glands on CT scans. Therefore, the ARR is currently considered to be the screening test of choice for PA. Nevertheless, as with all biochemical screening tests, the ARR has limitations. Certain medications and other pathophysiological conditions, such as differences in the patient’s posture during blood sampling (i.e. sit-
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Department of Endocrinology and Metabolism, Toranomon Hospital, Japan, ２Okinaka Memorial Institute for Medical Research, Japan and Department of Medicine, Beth Israel Medical Center, USA Received for publication May 12, 2014; Accepted for publication July 3, 2014 Correspondence to Dr. Akira Takeshita, [email protected]
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Figure 1. A: Plain head computed tomography (CT) showed pontine hemorrhage and right cerebellar hemorrhage. B: Abdominal CT revealed an approximate 10-mm right adrenal mass with low attenuation (2 Hounsfield Units). C: Macroscopic image of the resected adrenal mass (diameter 11 × 8 mm). D, E: Hematoxylin and Eosin staining (magnification ×10, ×200) showed no apparent nuclear atypia, necrosis or invasion, indicating the presence of a benign clear-cell adrenal adenoma.
ting or supine), hypo- or hyperkalemia, dietary sodium intake and renal impairment, are known to modify the ARR (1, 2, 9). Therefore, it is recommended that the ARR be reevaluated after correcting these potentially influential factors. We herein present a case of PA with diagnostic challenges in which the patient presented with an atypical reninaldosterone profile in the acute phase of cerebral hemorrhage. We discuss the potential pitfalls of which clinicians should be aware when diagnosing PA.
Case Report A 35-year-old overweight man [height: 157 cm, body weight: 71 kg, body mass index (BMI): 28.1 kg/m2] with a history of early-onset hypertension starting at 29 years of age who was currently under treatment with valsartan and nifedipine (dosage unknown) presented to the emergency department with a hypertensive emergency associated with dysarthria and right-sided hemiparesis. His blood pressure was 240/140 mmHg at presentation following medication non-compliance for two weeks. According to his medical record, his regular baseline blood pressure was controlled at approximately 140/80 mmHg with medication. A head CT scan revealed acute intracranial hemorrhage in the pontine and right cerebellum (Fig. 1A). Intravenous glycerol was administered to prevent cerebral edema, with the continuous infusion of nicardipine (5 μg/min/kg) to control the patient’s blood pressure. The nicardipine infusion was subsequently switched to oral azelnidipine and doxazosin on the second
day, and the azelnidipine was switched to oral nifedipine on the third day (Fig. 2). The patient was maintained on an nil per os (NPO) status with intravascular hydration (2,400 mL/ day) for three to four days after admission, then started on a sodium-restricted diet with hydration by mouth ad libitum. His neurological symptoms gradually improved from an National Institute of Health (NIH) stroke scale (NIHSS) score of 4 to 0 on day 14, without any residual symptoms. Due to the detection of early-onset hypertension, hypokalemia (2.7 mEq/L) and slight metabolic alkalosis (pH 7.46, HCO3 26 mmol/L, base excess 2.2 mmol/L) on the first day of admission, we considered a diagnosis of secondary hypertension due to PA. An unenhanced CT scan showed a 10mm right adrenal mass (Fig. 1B, arrow) with low attenuation (2 Hounsfield Units), indicating a lipid-rich structure consistent with a cortical adenoma (10). In contrast to our expectations, endocrinology tests performed on hospital day 2 (Table 1) showed a PRA of 15.0 ng/mL/hr, PAC of 11.3 ng/dL and ARR of 0.75, which are not consistent with a diagnosis of PA. However, follow-up ARR tests showed a gradual increase in this parameter, which is consistent with PA. On day 12, the PRA decreased to 1.9 ng/mL/hr, the PAC increased to 19.3 ng/dL and the ARR increased to 10.2. On day 20, the PRA was 0.8 ng/mL/hr, the PAC was 23.2 ng/dL and the ARR was 29.0 (Table 1). In addition to renin-aldosterone profiles, we determined the levels of catecholamines and their metabolites in the plasma and urine. Consequently, the morning plasma noradrenaline and dopamine (day 2) and urinary noradrenaline, dopamine and normetanephrine (day 7) levels were each elevated within
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DOI: 10.2169/internalmedicine.54.3267
5 ȝJ/min/kg nicardipine
80 mg/day
40 mg/day
nifedipine
doxazosin 2 mg/day 4 mg/day
8 mg/day
12 mg/day
Systolic blood pressure (mmHg)
azelnidipine 16 mg/day
240 220 200 180 160 140 120 100
ARR
1
5
10
0.75
15
20 days
10.2
29.0
Figure 2. Clinical course of the patient after admission. The systolic blood pressure, aldosteronerenin ratio and antihypertensive drugs and their dosages are noted. ARR: aldosterone-renin ratio
Table 1. Sequential Changes in Plasma Renin Activity, Aldosterone, Serum Potassium, and Plasma/Urinary Catecholamines after Cerebral Hemorrhage Day 2
Day 7
Day 12
Day 19
Day 20
Reference range 0.3-2.9 2.99-15.9
PRA (ng/mL/hr) 15.0 n.d. 1.9 n.d. 0.8 PAC (ng/dL) 11.3 n.d. 19.3 n.d. 23.2 ARR (ng/dL per ng/mL/hr) 0.75 n.d. 10.2 n.d. 29.0 n.d. n.d. n.d. n.d. 7.2-63.3 ACTH (pg/mL) 31.4 Cortisol (μg/dL) 17.4 n.d. n.d. n.d. n.d. 4.0-19.3 DHEA-S (ng/mL) 2,590 n.d. n.d. n.d. n.d. 1,060-4,640 n.d. 3.3 3.3 3.6 3.7-4.8 Serum potassium (mmol/L) 2.7 Plasma adrenaline (ng/mL) 0.02 n.d. n.d. n.d. n.d. < 0.17 Plasma noradrenaline (ng/mL) 0.83 n.d. n.d. n.d. n.d. 0.15-0.57 n.d. n.d. n.d. n.d. < 0.03 Plasma dopamine (ng/mL) 0.05 Urinary adrenaline (μg/day) n.d. 10.6 n.d. n.d. n.d. 3.4-26.9 Urinary noradrenaline (μg/day) n.d. 306.4 n.d. n.d. n.d. 48.6-168.4 n.d. 1,393.4 n.d. n.d. n.d. 365.0-961.5 Urinary dopamine (μg/day) Urinary metanephrine (mg/day) n.d. 0.09 n.d. 0.07 0.07 0.04-0.19 Urinary normetanephrine (mg/day) n.d. 0.38 n.d. 0.28 0.28 0.09-0.33 Blood samples were drawn at 8AM after overnight recumbency. PRA: plasma renin activity, PAC: plasma aldosterone concentration, ARR: aldosterone-renin ratio, ACTH: adrenocorticotropic hormone, DHEA-S: dehydroepiandrosterone sulfate, n.d.: no data Abnormal values are underlined.
two-fold of the upper limit of normal. The levels of urinary metabolites of catecholamines were measured on follow-up examinations, which showed that the urinary normetanephrine value normalized on day 19 (Table 1). Because the ARR exceeded 20 on day 20, a captoprilchallenge test and rapid adrenocorticotropic hormone (ACTH)-stimulation test were performed as confirmatory tests for PA on days 30 and 31, respectively. For the captopril-challenge test, 50 mg of captopril was administered orally and blood samples were obtained prior to (base-
line) and at 60 and 90 minutes after administration. The PRA was 1.3 ng/mL/hr at baseline, which was somewhat higher than that observed on day 20. Meanwhile, the ARR was 16.9 (less than 20, as discussed later). After the captopril challenge, the PRA slightly increased to 1.5 ng/mL/hr, while the PAC decreased from 22.0 ng/dL (baseline) to 13.4 ng/dL (90 minutes, 40% decrease). These data are not consistent with the typical findings of PA (PAC >15.0 ng/dL and ARR >20 ng/dL per ng/mL/hr) (Table 2). A rapid ACTH-stimulation test with 0.25 mg of Cortro-
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Table 2. Confirmatory Tests and Venous Sampling Captopril test (day 30) Time (minutes) 0 60 90 PRA (ng/mL/hr) 1.3 1.3 1.5 PAC (ng/dL) 22.0 14.3 13.4 ARR (ng/dL per ng/mL/hr) 16.9 11.0 8.93 Rapid ACTH test (day 31) Time (minutes) 0 30 60 90 120 PAC (ng/dL) 19.1 25.2 28.1 29.4 28.6 Cortisol (μg/dL) 15.7 22.4 25.0 27.4 29.8 Venous-sampling test (day 40) After ACTH injection (minutes) 0 30 PAC (ng/dL) Peripheral vein 13.9 31.5 Left adrenal vein 66.1 256.0 Right adrenal vein 3,480.0 3,160.0 Cortisol (μg/dL) Peripheral vein 7.1 18.1 Left adrenal vein 47.1 223.3 Right adrenal vein 67.5 1,036.5 PRA: plasma renin activity, PAC: plasma aldosterone concentration, ARR: aldosterone-renin ratio, ACTH: adrenocorticotropic hormone
synⓇ (cosyntropin, Daiichi-Sankyo, Tokyo, Japan) elicited a marked increase in the PAC value to 29.4 ng/dL at 90 minutes, whereas the cortisol level was 27.4 μg/dL; thus, the maximum PAC/cortisol ratio after ACTH-stimulation was 1.07 (Table 2). The results of the rapid ACTH-stimulation test met the criteria for PA proposed by Omura et al. (11), in that the maximum PAC/cortisol ratio was greater than 0.85 in the setting of a PAC of >12 ng/dL and PRA of 20 ng/dL per ng/mL/h, 10-mm lowattenuation mass on abdominal CT and ACTH-stimulation test with a PAC/cortisol ratio above 0.85 suggested a diagnosis of PA. Therefore, we proceeded with an adrenal venous-sampling study (Table 2). Prior to ACTH injection, the PAC values on the right and left sides were 3,480.0 ng/dL and 66.1 ng/dL, respectively. The cortisol-corrected aldosterone ratio from the high side to the low side was more than 2:1, which met the criteria for PA proposed by Rossi et al. (12). The PAC values on the right and left sides 30 minutes after the bolus ACTH injection were 3,160.0 ng/dL and 256.0 ng/dL, respectively. These results met the criteria for PA (PAC >1,400 ng/mL) proposed by Omura et al. (11) (Table 2). Based on these findings, we diagnosed the patient with unilateral PA caused by a right cortical adenoma. Laparoscopic right adrenalectomy was performed three months after the patient’s cerebral hemorrhage. The pathology results confirmed the presence of a clear-cell adrenal adenoma (Fig. 1C-E). The patient’s postoperative course was uneventful, and his PRA and PAC levels returned to normal (PRA: 2.0 ng/mL/hr, PAC: 6.8 ng/dL) on postoperative day 7. In addition, his blood pressure control was significantly improved at the one-year follow-up visit, being within the range of 120 mmHg systolic, under treatment with nifedipine (60 mg daily) and valsartan (80 mg daily).
Discussion In this report, we discuss the diagnostic challenges of PA in the acute phase of cerebral hemorrhage, focusing specifically on the atypical renin-aldosterone profile observed at presentation and the interpretation of confirmatory tests for PA. In the present case, the endocrinology data, including an elevated PRA, PAC within the normal range and low ARR obtained on hospital day 2, were atypical for PA. Although the ARR is currently the most reliable screening tool for PA, it is easily influenced by several factors, such as day-to-day variations, dietary sodium intake, the sampling time, posture, age and medications (1, 2, 9, 13, 14). In this case, we speculate that sympathetic nerve activation and the effects of medications may be two major factors causing the initial “false-negative” low ARR value. Hiraiwa et al. (15) reported a similar case of PA in which the patient presented with an atypical ARR in the acute phase of cerebral hemorrhage. In that case, the plasma norepinephrine and urinary metanephrine levels were elevated to approximately five times above the upper limit of normal at presentation and normalized on day 23. In the acute phase of intracranial hemorrhage, sympathetic nerve activation occurs secondary to an elevated intracranial pressure (16), which stimulates renin secretion (17). Leow et al. (18) reported an excessive amount of catecholamines and metanephrine triggered by sympathetic dysautonomia in the setting of acute intracranial hemorrhage, describing this phenomena as “biochemically pseudopheochromocytoma,” as the plasma catecholamine and urinary metabolite levels mimic the endocrinological laboratory findings of pheochromocytoma. Patients with a large hematoma volume develop significantly elevated urinary catecholamine metabolite levels (16). In most cases of acute cerebral hemorrhage without pheochromocytoma, however, the increase in plasma
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catecholamines and urinary metabolites is slight to moderate and the levels remain within three- to five-fold of the upper limit of normal (15-17). Therefore, it is not generally difficult to make the differential diagnosis of pheochromocytoma. Nevertheless, one should exclude concomitant pheochromocytoma by repeating the tests of the catecholamine levels during the stable phase, as pheochromocytoma is associated with a higher incidence of cerebral bleeding (2%) and cerebral infarction (3%) (19). The timeframe for normalization of catecholamines has been previously discussed. In general, the urinary catecholamine metabolite levels peak between days 3 and 10 after the onset of bleeding (16). The surge in catecholamines then normalized after one month, corresponding with the duration of diaschisis and maximum neurological deficits (15, 18). In the present case, the morning plasma catecholamine and urinary normetanephrine levels were elevated on days 2 and day 7, respectively, and remained within two-fold of the upper limit of normal, although the urinary normetanephrine value normalized on day 12. These findings are significant and may have affected the ARR, although they were relatively mild compared with those of previous reports (15, 16, 18). Along with sympathetic activation, the administration of osmotic diuretics and antihypertensive drugs may have contributed to the atypical ARR at presentation observed in this case. Diuretics stimulate renin production via volume contraction, thereby lowering the ARR (9, 20). The concentrated glycerol administered under emergency conditions may have led to a “falsely” low ARR. In addition, the continuous infusion of nicardipine and oral nifedipine may have affected the ARR. Dihydropyridine calcium-channel blockers (CCBs) are known to suppress calcium-dependent aldosterone secretion in vivo and in vitro (21). However, the effects of dihydropyridine CCBs on the ARR in screening for PA are generally mild and controversial compared with those of other antihypertensive agents, such as diuretics, angiotensinconverting enzyme-inhibitors and angiotensin-receptor blockers. For example, Mulatero et al. (22) studied the effects of various antihypertensive agents, including amlodipine, on hypertensive patients positive for ARR screening tests (ARR>50 and PAC>15) after a washout period of previous antihypertensive therapy and found that only one of the 55 patients taking amlodipine (1.8%), compared to four of the 17 patients taking irbesartan (23.5%), exhibited a false-negative ARR (0.85 after ACTHstimulation with a PRA of 12.0 ng/dL as criteria for probable PA in hypertensive patients. This screening test is based on the observation that aldosterone-producing adenomas produce an exaggerated amount of aldosterone in response to exogenous ACTHstimulation in the setting of sustained inhibition of renin (30). Our patient had a PAC/cortisol ratio of >0.85, PRA value of 0.8 ng/mL/hr (12.0), consistent with the criteria for PA (11). Recently, the disease concept of MR-associated hypertension has emerged (31). Obesity is a known diseasemodifying risk factor for cardiovascular events in patients with MR-associated hypertension. In the present case, the patient’s blood pressure control significantly improved after surgery. However, he continued to require multiple antihypertensive agents. This partial resolution of postoperative blood pressure may be attributed to the patient’s obesity and lengthy disease course. In conclusion, the PRA may be inappropriately elevated
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in the acute phase of cerebral hemorrhage in patients with PA, presumably due to sympathetic activation and the effects of medications. In order to make a definitive diagnosis of PA in patients with acute cerebral hemorrhage, it is necessary to reevaluate the PRA and PAC during the stable phase more than one month after presentation in most cases, although individualization is required.
13.
14.
The authors state that they have no Conflict of Interest (COI). 15.
Acknowledgement We wish to thank all of the health-care professionals who dedicated their expertise to the care of the patient described in the present report.
16.
17.
Financial Support This work was supported by a grant from the Okinaka Memorial Institute for Medical Research.
18.
Naoka Murakami and Naohiro Yoshida contributed equally to this work.
19.
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