- Email: [email protected]
Clinical characteristics of primary aldosteronism: its prevalence and comparative studies on various causes of primary aldosteronism in Yokohama Rosai Hospital
Biomed & Pharmacother 2000 ; 54 Suppl 1 : 83-5 © 2000 l~ditions scientifiques et mtdicales Elsevier SAS. All rights reserved
Short article
Clinical characteristics of primary aldosteronism: its prevalence and comparative studies on various causes of primary aldosteronism in Yokohama Rosai Hospital T. Nishikawa, M. Omura Department of Medicine, Yokohama Rosai Hospital, Yokohama City, Japan Summary - We studied 1,020 patients with hypertension visiting our outpatient clinic during a five-year period, from 1995 until 1999.Those
subjects were screened by determining plasma renin activity (PRA) and plasma aldosterone concentration (PAC) after testing routine laboratory examinations in order to differentiate secondary hypertension from essential hypertension. All patients with low-reninemic hypertension were examined by furosemide plus the upright test. This led to an increase in diagnoses of primary aldosteronism (PA) (confirmed by captopril-loading test). Our studies demonstrated that the incidence of PA is 5.4%, and also that the plasma potassium level is not always beneficial for suspecting the presence of PA, because 28% of the patients with PA show only hypokalemia. We would like to emphasize that adrenal venous sampling plays a critical role in establishing the optimal management for patients with PA, because CT imaging is limited to detection of adrenal masses. © 2000 [~ditions scientifiques et mtdicales Elsevier SAS adrenal venous sampling / prevalence / primary aldosteronism
It was believed that primary aldosteronism (PA), which is one of the main causes of surgically curable hypertension, is very rare among various hypertensive disorders in Japan as well as in other countries. On the other hand, it had recently been reported that its prevalence is almost 10% in Australia [1], and also 20% in the Mayo Clinic [2]. They also emphasized that PA should always be ruled out before treating high blood pressure in hypertensive cases because o f its high incidence among various causes of hypertension. In this study we compared clinical, endocrinologic and histopathological findings in patients with PA who were admitted for clinical examinations to our Department of M e d i c i n e with those o f essential hypertensin (EHT). We describe here recent data concerning the prevalence of PA in our hospital in order to clarify the characteristics and nature of Japanese patients with PA.
Correspondence and reprints: Tetsuo Nishikawa, M.D., PhD, Department of Medicine,YokohamaRosai Hospital, 3211 Kozukuecho, Kohoku-ku,YokohamaCity, Kanagawa, 222-0036, Japan.
INCIDENCE The division o f E n d o c r i n o l o g y and M e t a b o l i s m at Yokohama Rosai Hospital has been providing a diagnostic service for hypertensive patients since 1991, and currently sees new 200 outpatients per year and five inpatients on average per week. We checked basal levels of p l a s m a aldosterone concentration (PAC) and plasma renin activity (PRA) in all hypertensives whose blood was obtained at recumbent position for at least 30 minutes in the morning. The low-reninemic patients were selected according to our criteria, such as less than 1.0 ng/mL/hr of PRA. Then furosemide plus a two-hour upright test was performed for detecting unresponsiveness of PRA to this test. The patients showing unresponsiveness of PRA to furosemide plus the upright test were tentatively diagnosed with PA. All cases tentatively diagnosed at the outpatient clinic were admitted to the Department of Endocrinology and Metabolism, Yokohama Rosai Hospital, in order to clarify exactly the diagnosis and imaging of adrenals. The diagnosis of PA was confirmed by a captopril-loading test. Laterality of hyperaldosteronism was determined by CT and selective adrenal venous sampling. This led to an increase in diagnoses of PA.
84s
T. Nishikawa, M. Omura
PA was suspected in 120 of 1,020 hypertensive patients during the past five years, from 1995 until 1999, and confirmed in all of them by the captopril test. A diagnosis of PA was made in 55 (5.4%) among 1,020 EHT patients. The plasma levels of potassium were less than 3.3 mEq/L only in 28% of all patients with c o n f i r m e d PA. It was r e p o r t e d that o f the 90 patients with EHT, not more than three patients (less than 3.3%) satisfied the diagnostic criteria for PA [3], and also reported that hypokalemia is of great value in suggesting the presence of PA [3]. Komiya had recently reported that there were 31 patients with PA (20 cases of aldosterone-producing adenoma and 11 patients of idiopathic hyperaldosteronism) among 772 Japanese hypertensives, suggesting that the prevalence of PA is 4.0% [4]. From our data at the Yokohama Rosai Hospital, the incidence of PA is 5.4%. The prevalence of PA is gradually increasing, although PA was thought to be a very rare cause of hypertension. It has recently been reported that diagnoses of PA increased from fewer than ten cases per year to 90 per year in the Hypertension Unit at Greenslopes Hospital, Brisbane, Australia, since the PAC/PRA ratio for identifying patients with PA, combined with the fludrocortisone suppression test, has been applied to all hypertensives [1 ]. Most o f their patients with PA c o m e f r o m s c r e e n i n g normokalemic hypertensives [3], suggesting that the incidence o f PA rises after screening previously untested normokalemic hypertensives. On the other hand, Gordon described that the incidence of PA among hypertensives is unknown, and may vary with geography and ethnicity [1]. A recent incidence of PA is reported to be almost 20% among patients with EHT, from the data of the Mayo Clinic [2].They screen PA by a PAC/PRA ratio of more than 15 ng/dl of PAC, and the annual incidence of PA now shows a tenfold increase during these eight years, compared with that before 1990 [2].
HOW TO SCREEN A N D DIAGNOSE We used a criterion for screening PA as less than 1.0 ng/mL/hr of PRA and more than 12.0 ng/dL of PAC in those outpatients. Furosemide plus the upright and captopril-loading tests were then performed in the cases showing less than 1.0 ng/mL/hr of PRA and more than 12.0 ng/dL of PAC in order to detect the presence of hyporeninemic hyperaldosteronism. PA was mostly suspected when the patients showed less than 1.0 ng/mL/hr of PRA and more than 12.0 ng/dL of PAC at two hours after a 40 mg intravenous injec-
Table I. Endocrinologicfindings in patients with aldosterone-producing adenoma, idiopathic hyperaldosteronism, and essential hypertension. Furosemide plus upright test PRA (ng/mL/h) 120 minutes
APA IHA EHT
0.5 -+0.1" 1.0 + 0.1" 3.2 -+0.9
Captopril test PAC/PRA ratio 90 minutes
100.7 - 12.0" 37.1 _+4.5* 5.6 + 1.2
The parameters obtained from APA, IHA and EHT were statistically calculated and the results are expressed as Mean _+ SE. Statistical analysis was performed as unpaired Student's t test. * P < 0.01 compared with EHT; PAC: plasma aldosterone concentration; PRA: plasma renin activity;APA: aldosterone-producing adenoma; IHA: idiopathic hyperaldosteronism; EHT: essential hypertension.
tion of furosemide in the upright position and also when the ratio of PAC to PRA at 90 minutes after administration of 50 mg captopril was more than 20 (table I). The plasma potassium level is not always beneficial for suspecting the presence of PA, because 28% of the patients with PA show only hypokalemia. The data from Greenslopes Hospital are also consistent with our results concerning the serum concentration of potassium in PA [1]. Gordon emphasized that normokalemic and hypokalemic aldosteronism are not separate entities, and all patients with PA start with normokalemia. Serum potassium concentrations may be mainly influenced by food, such as sodium intake, severity and duration of hyperaldosteronemia, and sensitivity of renal tubules to aldosterone in each case of PA. Imaging of adrenal glands is quite important for the diagnosis of PA in order to detect laterality of hyperaldosteronemia. CT is a common method for detection of adrenal masses, while an abnormal shadow in the adrenals is limited to discovery since adrenal masses sizing less than 6 mm in diameter are not always detectable by CT examination. The size of aldosteroneproducing adenomas diagnosed in our hospital ranged between 1 and 30 mm in diameter. Adrenal tumors were not able to be detected in 47% of those cases even by the highest-resolution CT scanning because they were less than 5 mm in diameter of the adrenal adenoma. We always performed selective adrenal venous sampling in probable PA patients who were already screened as described above. All patients with PA undergo adrenal venous sampling (AVS) in order to differentiate bilateral hyperplasia from aldosteroneproducing adenoma (APA) and to lateralise APAs preoperatively. The plasma levels of cortisol and
Clinical characteristics of primary aldosteronism aldosterone in each adrenal venous blood sample obtained by AVS were always estimated, and normal values of aldosterone and cortisol are 129 _+60 ng/dL and 46 _+ 8 ~tg/dL, respectively. An overproduction of aldosterone and laterality of hyperaldosteronemia are definitively clarified by comparing the sample values with those of normal ranges. Then, surgical treatment for resection of the affected adrenal which was clearly recognized by AVS was performed, and pathological examinations of the resected adrenals demonstrated that AVS completely and correctly lateralized thepresence of APA. We would therefore like to emphasize that AVS, in experienced hands, is safe and reliable, and plays a critical role in establishing the optimal management for patients with PA.
85S REFERENCES
1 Gordon R. Incidence and workup of primary aldosteronismGreenslopes Hospital Series. Primary aldosteronism and adrenal incidentaloma - into a new millennium [abstract]. Couran Cove Resort, South Stradbroke Island Queensland, Australia. 13 September 1999. p. 13. 2 YoungJr WE Incidenceand workup of primary aldosteronismMayo Clinic.Primaryaldosteronismand adrenalincidentalomainto a new millennium [abstract]. Couran Cove Resort, South StradbrokeIslandQueensland,Australia.13 September1999.p. 12. 3 Fishman LM, Kuchel O, Liddle GW, Michelakis AM, Gordon RD, ChickWT. Incidenceof primaryaldosteronismuncomplicated essential hypertension.JAMA 1968 ; 205 : 497-502. 4 Komiya I, YamadaT, Takasu N, Asawa T, Akamine H, Yagi N, et al. An abnormalsodiummetabolismin Japanese patientswith essential hypertension,judged by serum sodium distribution, renal function and the renin-aldosterone system. J Hypertens 1997 ; 15 : 65-72.
Short article
Clinical characteristics of primary aldosteronism: its prevalence and comparative studies on various causes of primary aldosteronism in Yokohama Rosai Hospital T. Nishikawa, M. Omura Department of Medicine, Yokohama Rosai Hospital, Yokohama City, Japan Summary - We studied 1,020 patients with hypertension visiting our outpatient clinic during a five-year period, from 1995 until 1999.Those
subjects were screened by determining plasma renin activity (PRA) and plasma aldosterone concentration (PAC) after testing routine laboratory examinations in order to differentiate secondary hypertension from essential hypertension. All patients with low-reninemic hypertension were examined by furosemide plus the upright test. This led to an increase in diagnoses of primary aldosteronism (PA) (confirmed by captopril-loading test). Our studies demonstrated that the incidence of PA is 5.4%, and also that the plasma potassium level is not always beneficial for suspecting the presence of PA, because 28% of the patients with PA show only hypokalemia. We would like to emphasize that adrenal venous sampling plays a critical role in establishing the optimal management for patients with PA, because CT imaging is limited to detection of adrenal masses. © 2000 [~ditions scientifiques et mtdicales Elsevier SAS adrenal venous sampling / prevalence / primary aldosteronism
It was believed that primary aldosteronism (PA), which is one of the main causes of surgically curable hypertension, is very rare among various hypertensive disorders in Japan as well as in other countries. On the other hand, it had recently been reported that its prevalence is almost 10% in Australia [1], and also 20% in the Mayo Clinic [2]. They also emphasized that PA should always be ruled out before treating high blood pressure in hypertensive cases because o f its high incidence among various causes of hypertension. In this study we compared clinical, endocrinologic and histopathological findings in patients with PA who were admitted for clinical examinations to our Department of M e d i c i n e with those o f essential hypertensin (EHT). We describe here recent data concerning the prevalence of PA in our hospital in order to clarify the characteristics and nature of Japanese patients with PA.
Correspondence and reprints: Tetsuo Nishikawa, M.D., PhD, Department of Medicine,YokohamaRosai Hospital, 3211 Kozukuecho, Kohoku-ku,YokohamaCity, Kanagawa, 222-0036, Japan.
INCIDENCE The division o f E n d o c r i n o l o g y and M e t a b o l i s m at Yokohama Rosai Hospital has been providing a diagnostic service for hypertensive patients since 1991, and currently sees new 200 outpatients per year and five inpatients on average per week. We checked basal levels of p l a s m a aldosterone concentration (PAC) and plasma renin activity (PRA) in all hypertensives whose blood was obtained at recumbent position for at least 30 minutes in the morning. The low-reninemic patients were selected according to our criteria, such as less than 1.0 ng/mL/hr of PRA. Then furosemide plus a two-hour upright test was performed for detecting unresponsiveness of PRA to this test. The patients showing unresponsiveness of PRA to furosemide plus the upright test were tentatively diagnosed with PA. All cases tentatively diagnosed at the outpatient clinic were admitted to the Department of Endocrinology and Metabolism, Yokohama Rosai Hospital, in order to clarify exactly the diagnosis and imaging of adrenals. The diagnosis of PA was confirmed by a captopril-loading test. Laterality of hyperaldosteronism was determined by CT and selective adrenal venous sampling. This led to an increase in diagnoses of PA.
84s
T. Nishikawa, M. Omura
PA was suspected in 120 of 1,020 hypertensive patients during the past five years, from 1995 until 1999, and confirmed in all of them by the captopril test. A diagnosis of PA was made in 55 (5.4%) among 1,020 EHT patients. The plasma levels of potassium were less than 3.3 mEq/L only in 28% of all patients with c o n f i r m e d PA. It was r e p o r t e d that o f the 90 patients with EHT, not more than three patients (less than 3.3%) satisfied the diagnostic criteria for PA [3], and also reported that hypokalemia is of great value in suggesting the presence of PA [3]. Komiya had recently reported that there were 31 patients with PA (20 cases of aldosterone-producing adenoma and 11 patients of idiopathic hyperaldosteronism) among 772 Japanese hypertensives, suggesting that the prevalence of PA is 4.0% [4]. From our data at the Yokohama Rosai Hospital, the incidence of PA is 5.4%. The prevalence of PA is gradually increasing, although PA was thought to be a very rare cause of hypertension. It has recently been reported that diagnoses of PA increased from fewer than ten cases per year to 90 per year in the Hypertension Unit at Greenslopes Hospital, Brisbane, Australia, since the PAC/PRA ratio for identifying patients with PA, combined with the fludrocortisone suppression test, has been applied to all hypertensives [1 ]. Most o f their patients with PA c o m e f r o m s c r e e n i n g normokalemic hypertensives [3], suggesting that the incidence o f PA rises after screening previously untested normokalemic hypertensives. On the other hand, Gordon described that the incidence of PA among hypertensives is unknown, and may vary with geography and ethnicity [1]. A recent incidence of PA is reported to be almost 20% among patients with EHT, from the data of the Mayo Clinic [2].They screen PA by a PAC/PRA ratio of more than 15 ng/dl of PAC, and the annual incidence of PA now shows a tenfold increase during these eight years, compared with that before 1990 [2].
HOW TO SCREEN A N D DIAGNOSE We used a criterion for screening PA as less than 1.0 ng/mL/hr of PRA and more than 12.0 ng/dL of PAC in those outpatients. Furosemide plus the upright and captopril-loading tests were then performed in the cases showing less than 1.0 ng/mL/hr of PRA and more than 12.0 ng/dL of PAC in order to detect the presence of hyporeninemic hyperaldosteronism. PA was mostly suspected when the patients showed less than 1.0 ng/mL/hr of PRA and more than 12.0 ng/dL of PAC at two hours after a 40 mg intravenous injec-
Table I. Endocrinologicfindings in patients with aldosterone-producing adenoma, idiopathic hyperaldosteronism, and essential hypertension. Furosemide plus upright test PRA (ng/mL/h) 120 minutes
APA IHA EHT
0.5 -+0.1" 1.0 + 0.1" 3.2 -+0.9
Captopril test PAC/PRA ratio 90 minutes
100.7 - 12.0" 37.1 _+4.5* 5.6 + 1.2
The parameters obtained from APA, IHA and EHT were statistically calculated and the results are expressed as Mean _+ SE. Statistical analysis was performed as unpaired Student's t test. * P < 0.01 compared with EHT; PAC: plasma aldosterone concentration; PRA: plasma renin activity;APA: aldosterone-producing adenoma; IHA: idiopathic hyperaldosteronism; EHT: essential hypertension.
tion of furosemide in the upright position and also when the ratio of PAC to PRA at 90 minutes after administration of 50 mg captopril was more than 20 (table I). The plasma potassium level is not always beneficial for suspecting the presence of PA, because 28% of the patients with PA show only hypokalemia. The data from Greenslopes Hospital are also consistent with our results concerning the serum concentration of potassium in PA [1]. Gordon emphasized that normokalemic and hypokalemic aldosteronism are not separate entities, and all patients with PA start with normokalemia. Serum potassium concentrations may be mainly influenced by food, such as sodium intake, severity and duration of hyperaldosteronemia, and sensitivity of renal tubules to aldosterone in each case of PA. Imaging of adrenal glands is quite important for the diagnosis of PA in order to detect laterality of hyperaldosteronemia. CT is a common method for detection of adrenal masses, while an abnormal shadow in the adrenals is limited to discovery since adrenal masses sizing less than 6 mm in diameter are not always detectable by CT examination. The size of aldosteroneproducing adenomas diagnosed in our hospital ranged between 1 and 30 mm in diameter. Adrenal tumors were not able to be detected in 47% of those cases even by the highest-resolution CT scanning because they were less than 5 mm in diameter of the adrenal adenoma. We always performed selective adrenal venous sampling in probable PA patients who were already screened as described above. All patients with PA undergo adrenal venous sampling (AVS) in order to differentiate bilateral hyperplasia from aldosteroneproducing adenoma (APA) and to lateralise APAs preoperatively. The plasma levels of cortisol and
Clinical characteristics of primary aldosteronism aldosterone in each adrenal venous blood sample obtained by AVS were always estimated, and normal values of aldosterone and cortisol are 129 _+60 ng/dL and 46 _+ 8 ~tg/dL, respectively. An overproduction of aldosterone and laterality of hyperaldosteronemia are definitively clarified by comparing the sample values with those of normal ranges. Then, surgical treatment for resection of the affected adrenal which was clearly recognized by AVS was performed, and pathological examinations of the resected adrenals demonstrated that AVS completely and correctly lateralized thepresence of APA. We would therefore like to emphasize that AVS, in experienced hands, is safe and reliable, and plays a critical role in establishing the optimal management for patients with PA.
85S REFERENCES
1 Gordon R. Incidence and workup of primary aldosteronismGreenslopes Hospital Series. Primary aldosteronism and adrenal incidentaloma - into a new millennium [abstract]. Couran Cove Resort, South Stradbroke Island Queensland, Australia. 13 September 1999. p. 13. 2 YoungJr WE Incidenceand workup of primary aldosteronismMayo Clinic.Primaryaldosteronismand adrenalincidentalomainto a new millennium [abstract]. Couran Cove Resort, South StradbrokeIslandQueensland,Australia.13 September1999.p. 12. 3 Fishman LM, Kuchel O, Liddle GW, Michelakis AM, Gordon RD, ChickWT. Incidenceof primaryaldosteronismuncomplicated essential hypertension.JAMA 1968 ; 205 : 497-502. 4 Komiya I, YamadaT, Takasu N, Asawa T, Akamine H, Yagi N, et al. An abnormalsodiummetabolismin Japanese patientswith essential hypertension,judged by serum sodium distribution, renal function and the renin-aldosterone system. J Hypertens 1997 ; 15 : 65-72.