Endocrinol. Japon. 1989, 36(1), 167-173

NOTE

Plasma Level in a Female Case of Pseudohyperaldosteronism (Liddle's Syndrome)

KAZUHISA TAKEUCHI, KEISHI ABE*, MAKITO SATO, MINORU YASUJIMA, KEN OMATA, OSAMU MURAKAMI AND KAORU YOSHINAGA

Second Department of Internal Medicine, and *Department of Clinical Biology and Hormonal Regulation, Tohoku University, School of Medicine, 1-1 Seiryo-cho, Sendai 980, Japan

Abstract

A 22-yr-old female suffering from , hypokalemic alkalosis and suppressed plasma activity was studied. The plasma aldosterone con- centration (PAC) ranged between subnormal and normal levels while the other adrenal mineralocorticoids were normal. Examinations through computed. tomography and ultrasonography showed no abnormal findings. For dif- erential diagnosis, , and triamterene were ad- ministered. Triamterene alone corrected the abnormalities in this case, and the therapeutic effect was further enhanced by restriction. There- fore, the present case is strongly suggested to be one of Liddle's syndrome, which is characterized by a primary defect in renal tubular sodium handling and can be corrected with triamterene. However, the patient in our study is different from the first reported case in which aldosterone secretion was estimated to be low. Analysis of the changes in PAC has shown that PAC is parallel with the level of plasma progesterone in accordance with the rhythm of the menstrual cycle and, in the follicular phase, PAC is rather low. It is concluded that the patient was suffering from Liddle's syndrome, and it is assumed that PAC is not always subnormal and, as same as in normal females, PAC may change in accordance with the rhythm of the menstrual cycle in a female case of Liddle's syndrome.

Pseudohyperaldosteronism is characteriz- either aldosterone or other endogenous ed by hypertension, and hy- mineralocortico id excess (Biglieri, 1981; poreninemia, suggesting a diagnosis of Sebastian et al., 1982). This state is brought . However, pseudo- about by several factors, including the is not associated with administration of synthetic mineralocorti- coids, and the ingestion of substances Received September 22, 1988 causing mineralocorticoid-like activity, as Address correspondence to KAZUHISA TAKE- UCHI, M. D., Second Department of Internal well as Liddle's syndrome. Liddle's syn- Medicine, Tohoku University, School of Medi- drome is markedly different from the other cine, 1-1 Seiryo-cho, Sendai 980, Japan conditions, because its synptoms are not Endocrinol. Japon. 168 TAKEUCHI et al. February 1989

due to the renal action of mineralocorticoid was again confirmed. In spite of the but to a primary defect in renal sodium- administration of a calcium antagonist , handling in renal distal tubules. nifedipine 60mg/day, and a potassium The present case was considered to be a supplement of K+ 24mEq/day, the abnor- case of Liddle's syndrome, although the malities persisted and she was referred to plasma aldosterone concentration (PAC) was our department for a thorough examination. not consistantly subnormal. We evaluated It was determined that she had no history the change in PAC in relation to the men- of excessive licorice ingestion, steroid hor- strual cycle and demonstrated a close rela- mone abuse or use of contraceptives. tionship between them. A physical examination showed the

patient to be a phenotypically normal female, 160cm in height, weighing 50kg , Case Report and having no abnormal skin pigmentation . She had normal secondary sexual character- A 22-yr-old female suffering from hy- istics and a regular menstrual cycle. Her pertension and hypokalemia was admitted menarche had occurred at age 12. Blood

to our department. She had been complain- pressure ranged between 200/120 and 150/ ing of recurrent and general 100mmHg. Her chest X-ray was normal . muscular weakness for several years. An However, electrocardiography revealed left aunt (on her mother's side of the family) ventricular hypertrophy, and fundoscopic had died suddenly of an unkown etiology examination revealed mild ateriolar thicken- at the age of 35, and an uncle , on the ing. Her serum sodium level was found to same side, had died of disease with be 144mEq/L and serum potassium 2.6 edema at age 5. mEq/L (normal value; 3.4-4.2mEq/L). Eight years before admission to our Arterial blood gas analysis showed the department, a school examination had dis- following: PH, 7.47; standard bicarbonate, closed that the patient was suffering from 30.8mmol/L; pCO2, 44.1mmHg; pO2, 88.0 high blood pressure (180/110mmHg) . At mmHg; and base excess, + 7.2mEq/L. that time, she was referred to the depart- Blood urea nitrogen was found to be 12 ment of pediatrics of a general hospital . and creatinine 1.1mg/dl. A complete Tests showed that she had hypertension blood count, urinalysis, and measurements (blood pressure ranged between 190/130 of serum concentrations of calcium, phos- and 170/100mmHg), hypokalemia (serum phorus, magnesium, albumin, globulin, potassium 2.8mEq/L). Plasma renin activity glucose, uric acid, lactic dehydrogenase, (PRA) was low and the plasma aldosterone glutamic-oxaloacetic transaminase and cho- concentration (PAC) was in the high-normal lesterol were done. All were found to be range. A tentative diagnosis of primary within normal limits. Creatinine clearance aldosteronism was made, and 75mg/day of was 73ml/min and para-amino hippuric spironolactone was administered. However, acid clearance 468ml/min. The findings her headaches persisted and the other ab- of travenous pyelography were normal. normal findings remained. After a few Urinary catecholamines, 17-ketosteroids (17- months, she refused to take the medication KS) and 17-hydroxycorticosteroids (17- and terminated her hospital visits. A few OHCS) were normal. PRA was undetec- months before admission to our department, table (<2.5ng/ml/6hr; normal value: 5- she visited a physician due to a common 30ng/ml/6hr), PAC was low within normal cold. At that time, her blood pressure was limits (2.4 ng/dl; normal value: 2-12ng/dl). found to be 180/100mmHg and hypokalemia Adrenal scintigram with 131I-adosterol (6ƒÀ- Vol. 36, No. 1 PLASMA ALDOTERONE LEVELS IN LIDDLE'S SYNDROME 169

iodomethyl-19-nor- cholest-5 (10)-en-3ƒÀ-ol, 80mEq/day. Daiichi Radioisotopes Laboratories Ltd., Blood pressure was measured with a standard sphygmomanometer at 0600h in recumbency Tokyo) showed diffuse accumulation of 131I every day. Plasma ACTH, aldosterone, , on bilateral adrenals and the uptake of 131I progesterone, corticosterone, deoxycorticosterone almost disappeared with the administration (DOC) and 18-hydroxy-deoxycorticosterone (18- of dexamethasone. Examinations through OH-DOC) were measured by radioimmunoassay echosonography and computed tomo- using commercially available kits (Dinabot Co.,

graphy showed normal findings in the Tokyo). PRA was measured by radioimmuno- abdomen. assay of I as previously reported These data were not consistent with the (Abe et al., 1973). 19-hydroxyandrostenedione was measured by Dr. Sekihara of Tokyo Uni- usual findings in primary aldosteronism. versity. Therefore, further diagnostic examinations, including administration of dexamethasone, spironolactone and triamterene were carried Results out.

Baseline Condition (Fig. 1) Methods High blood pressure persisted during this period. Serum potassium was 2.6

All examinations were carried out during 4 mEq/L. Urinary excretion of potassium months' hospitalization. The patient recieved a was above 50mEq/day, suggesting the salt restricted diet containing less than 5g NaCl kidney's inability to conserve potassium. (Na+ 85mEq)/day for a full month; for the PRA was undetectable during the furosemide remainder of her stay, she recieved a regular test. PAC was normal (5.8ng/dl) and diet containing 12g NaCl (Na+ 200mEq)/day constant during the furosemide test. Corti- and K+ 80 mEq/day. During hospitalization, 60 mg nifidipine and 50mg/day atenolol had to be costerone, DOC and 18-OH-DOC were all administered to prevent a hypertensive crisis, within normal limits. Urinary 17-OHCS because high blood pressure and complaints of and 17-KS excretions were normal. The persisted following admission. In a basal plasma cortisol level (8.0ƒÊg/dl) was furosemide test, blood samples were collected normal (normal value: 5-16 ƒÊg/dl) and to measure PRA and PAC after the patient had showed a normal response to the rapid stood upright for one and two hours, respec- ACTH test, because the basal plasma tively, following the intravenous injection of furosemide 60mg. A rapid ACTH test was cortisol level was increased to 17.3, 17.4 performed by intravenous injection of 250ƒÊg of and 24.5ƒÊg/dl at 30, 60 or 90min after α1-24ACTH(Cortrosyn: Daiichi Co., Tokyo), the injection of ACTH, respectively. In the as well as a dexamethasone, supression test by dexamethasone (Dx.) suppression test, the means of the oral administration of either 1 or basal plasma cortisol (5.4ƒÊg/dl) was de- 8mg of dexamethasone. Four studies on meta- creased to an undetectable level either by bolic balance were carried out to examine changes in blood pressure and renal electrolyte Dx. 1mg or Dx. 8mg, indicating a normal excretion in response to: 1) inhibition of adrenal response, whereas PAC showed a very weak biosynthesis by dexamethasone 2mg/day for 2 response to both a stimulatory and an in- weeks; 2) administration of triamterene 100 and hibotory procedure. In the rapid ACTH 200mg/day for 3 weeks; 3) administration of test, the basal PAC (8.0ng/dl) was not triamterene 200mg/day and salt restriction (Nat changed significantly at 30 min (8.5ng/dl), 85mEq/day) and, 4) blockade of mineralocorti- coid receptors using 150 and 300mg/ 60min (9.3ng/dl) or 90min (10.1ng/dl) day spironolactone for 2 weeks. During these after the injection of ACTH, and in the Dx. periods dietary potassium was kept at around suppression test, the basal PAC (9.6ng/dl) Endocrinol. Japon. 170 TAKEUCHI et al. February 1989 was not suppressed significantly by either cortisol were under the lower limit for the Dx. 1mg (4.7ng/dl) or Dx. 8mg (4.3ng/dl). assay. PRA was undetectable except at The plasma 19 hydroxyandrostenedione level one point during hospitalization. PAC was was normal (36ƒÊg/mi). not suppressed during this period.

Effect of Dexamethasone (Fig. 1) Effect of Triamterene (Fig. 1) As showni n Fig. 1, the dexamethasone Triamterene was administered at 100 administration (Dx. 2mg/day) for 2 weeks mg/day for 2 weeks, followed by 200mg/ had no effect on blood pressure or serum day for another 2 weeks on a diet contain- potassium. There was no change in urinary ing 12g NaCl (Nat 200mEq)/day. In electrolytes or the urinary sodium/potassium response to triamterene, blood pressure excretion ratio. Plasma ACTH and plasma decreased significantly. Urinary potassium

Fig. 1. Changes in blood pressure, serum potassium, volu- me (UV), urinary so- dium excretion (UNa V), urinary potassium excretion (UKV), uri- nary sodium/potas- sium ratio (Na/K), plasma aldosterone concentration (PAC) and plasma renin ac- tivity (PRA) during hospitalization. PAC, normal value: 2-12 ng/dl. PRA, normal value: 5-30ng/ml/6hr. n. d.: not detectable. Vol. 36, No. 1 PLASMA ALDOTERONE LEVELS IN LIDDLE'S SYNDROME 171 excretion decreased with a concomitant crease. Blood pressure increased significantly increase in the urinary sodium/potassium compared to the level during triamterene ratio, and serum potassium progressively administration. PRA was undetectable and increased within the normal level. PRA PAC was normal. was not detectable. PAC was within normal limits. Subsequently, in addition to tria- Relationship between PAC and Men- mterene 200mg/day, salt intake was res- strual Cycle (Fig. 2) tricted to 5g/day (Nat 85mEq/day). Blood After the patient was discharged, we pressure further decreased and the serum analyzed the change in PAC and found potassium level increased to 4.4mEq/L with that there had been a peak every month a concomitant decrease in the urinary in accordance with the menstrual cycle. As sodium/potassium ratio. PRA was undetec- illustrated in Fig. 2, menses occurred re- table and PAC ranged between the normal gularly every 4 weeks, accompanied by the and subnormal levels. normal biphasic pattern of basal body After discontinuing the treatment with temperature, and the plasma progesterone triamterene and salt restriction, serum level showed a peak in the mid-luteal phase, potassium progressively decreased to the thus indicating that the patient's gonadal subnormal level with increases in blood function was normal. The change in PAC pressure and the urinary sodium/potassium was parallel with that in the plasma pro- ratio. gesterone level. In the follicular phase, PAC was shown to be subnormal. Effect of Spironolactone (Fig. 1) Spironolactone was administered at 150 mg/day for 7 days, followed by 300mg/day Discussion for 3 weeks. The urinary sodium/potassium ratio and serum plasma level did not in- The findings of hypertension, hypoka-

Basal Body Temperature (•Ž)

Fig. 2. Relationship among plasma al- dosterone concen- tration, basal body temperature and plasma progesterone concentration. Endocrinol. Japon. 172 TAKEUCHI et al. February 1989 lemic alkalosis, renal potassium wasting and et al., 1967; Milora et al., 1967; Bravo a low suppressed level of PRA, strongly et al., 1970; Helbock and Reynolds, 1970; suggest a state of hyperaldosteronism in the Ohno et al., 1975; Hyman et al., 1979; patient. However, such a diagnosis was Wang et al., 1981; Sakamoto et al., 1981; excluded for the following reasons: first, Rodriquez et al., 1981). Although no in- the level of PAC was not high, nor were heritability of the syndrome has been con- the levels of the other steroid firmed in this case, several cases of sporadic causing mineralocorticoid activity such as occurrence of Liddle's syndrome have been DOC, 18-OH-DOC and corticosterone; reported (Aaskog et al., 1967; Helbock and second, there was no evidence of adrenal Reynolds, 1970; Hyman et al., 1979; Wang or hyperplasia; third, the patient et al., 1981; Sakamoto et al., 1981; had never used any drugs causing minera- Rodriguez et el., 1981). However, all but locorticoid activity and fourth, the minera- one of the cases showed subnormal plasma locorticoid antagonist spironoractone had aldosterone levels (Ohno et al., 1975). In failed to correct the abnormalities. Finally, the present female patient, PAC was not since dexamethasone administration did not always low, and ranged between normal correct the abnormalities, dexamethasone limits. Analysis of changes in PAC show- suppressive hyperaldosteronism and ACTH- ed that PAC was parallel with plasma pro- dependent mineralcorticoidism were exclud- gesterone levels in close accordance with ed (Biglieri, 1981). Nevertheless, a stat the menstrual cycle. In normal female of salt retention was confirmed by the subjects, PAC has been reported to reach a failure of PRA to respond to a furosemide peak in the mid- or late-luteal phase (Katz test. and Romfh, 1972), and there are some In the present study, triamterene in- studies proposing that the changes in PAC creased serum potassium with a concomitant may be due to stimulation of the renin- decrease in urinary potassium excretion and angiotensin system, possibly caused by an increase in the urinary sodium/potassium progesterone-induced natriuresis (Katz and ratio. Since triamterene is a diuretic Romfh, 1972; Sasaki et al., 1972; Laidlaw directly affecting sodium resorption in the et al., 1962). However, in the present case, renal distal tubules (Baba et al., 1964), since PRA was suppressed throughout the the abnormalites described in the present patient's period of hospitalization, changes case would be attributed to a defect in renal in PAC could not have been caused by resorption of sodium as described by Liddle changes in renin activity. It is possible (1966) and this case is considered to be a that changes in PAC were due to plasma case of .Liddle's syndrome. Liddle et al. progesterone, which may reach the adrenal (1963) reported two siblings with this and serve as a precursor to aldosterone, as renal disorder characterized by hypertension, hypothesized by Laidlaw et al.(1962) in hypokalemic alkalosis, suppressed plasma pregnant subjects. Stein (1985) has sug- renin levels and negligible aldosterone gested the possiblity that the severity, of secretion. In the original cases, the renin- the syndrome may lessen during pre- angiotensin-aldosterone system was thought gnancy because sodium retention would be to be secondarily suppressed by the sodium lessened by an increase in natriuretic pro- retention which is caused by primary renal gesterone; actually a patient with Liddle's abnormality in sodium resorption in renal syndrome, who gave birth to a girl, was distal tubules. reported by Wang et al.(1981). In spite Since the time of Liddle's original report, of these suggestions, the relationship be- similar cases have been described (Aaskog twteen PAC and plasma progesterone has Vol. 36 , No. 1 PLASMA ALDOTERONE LEVELS IN LIDDLE'S SYNDROME 173

not yet been determined. In future, more aldosterone and renin activity during menstrual attention should be paid to the relationship cycle. J. Clin. Endocrinol. 34, 819-821. in order to clarify the pathophysiology of Laidlaw, J. C., J. L. Ruse and A. G. Gornall the syndrome. (1962). The influence of estrogen and pro- gesteone on aldosterone excretion. J. Clin. Endocrinol. 22, 161-171. Liddle, G. W., T. Bledsoe and W. S. Coppage Acknowledgement (1963). A familial renal disorder simulating primary aldosteronism but with negligible The authors wish to thank Miss K. Shiraishi, aldosterone secretion. Trans. Assoc. Am. Miss M. Okamoto and Mrs. N. Hatanaka for Physicians. 76, 199-213. their excellent technical assistance. This work Liddle, G. W.(1966). Aldosterone antagonists was supported in part by Grants-in-Aid from and triamterene. Ann. New York Acad. Sci. the Ministry of Education, Science and Culture, 139, 466-470. Japan (Nos. 62304041 and 63480221) and from Milora, R., A. Vannucci and A. D. Goodman the Ministry of Health and Welfare, Japan (61- (1967). A syndrome resembling primary al- A-1). dosterone but without mineralcorticoid excess. Clin. Res. 15, 482 (abstract). Ohno, F., H. Harada, K. Komatsu, K. Saijo and K. Miyoshi (1975). Two cases of psue- References doaldosteronism (Liddle's syndrome) in siblings. Endocrinol. Japon. 22, 163-167. Aarskog, D., K. E. Stoa, T. Thorsen and K. Rodriguez, J. A., E. G. Biglieri and M. Scham- W. Wefring (1967). Hypertension and hypo- belan (1981). Pseudohyperaldosteronism with kalemic alkalosis with under production of renal tubular resistence to mineralcorticoid aldosterone. Pediatrics. 39, 884-890. hormones. Trans. Assoc. Am. Physicians. 94, Abe, K., Y. Otsuka, T. Saito, B. S. Chin, H. 172-182. Aoyagi, S. Miyazaki, N. Irokawa, M. Seino Sakamoto, N., M. Uda, S. Kojima, M. Tsu- and K. Yoshinaga (1973). Measurement of chiya, K. Ito, K. Ogino, M. Ikeda and R. plasma renin activity by angiotensin I radio- Watabe (1981). Hypertension, hypokalemia immunoassay: A modification of Haber's and with suppressed renin: method. Jpn. Circ. J. 36, 741-749. a clinical study of a patient with Liddle's Baba, W. I., G. R. Tudhope and G. M. Wilson syndrome. Endocrinol. Japon. 28, 357-362. (1964). Site and mechanism of action of the Sasaki, C., W. Nowaczynski, O. Kuchel, C. diuretic, triamterene. Clin. Sci. 27, 181-193. Chavez, F. Ledoux, S. Gauthier and J. Genest Biglieri, E. G.(1981). Enzymatic disorders and (1972). Plasma progesterone in normal subjects hypertension. Clinics in and and patients with benign essential hypertension Metabolism 10, 453-463. on normal, low and high sodium intake. J. Bravo, E. L., H. C. Smith, W. C. Retan and Clin. Endocrinol. 34, 650-660. F. C. Bartter (1970). Hypertension, decreased Sebastian, A., H. N. Hulter, I. Kurtz, T. aldosterone secretion rate (ASR), supressed Maher and M. Schambelan (1982). Disorder renin activity (PRA). Program of the 52 nd of distal function. Am. J. Med. 72, Meeting of the Endocrine Society. St. Louis. 289-307. Mo, 66 (abstract). Stein, J. H.(1985). The pathogenic spectrum Helbock, H. J. and J. W. Reynolds (1970). of Bartter's syndrome. Kidney Int. 28, 85-93. Pseudoaldosteronism (Liddle's Syndrome): evi- Wong, C., T. K. Chan, R. T. T. Yeung, J. P. dence for increased cell membrane permeability Coghlan, B. A. Scoggins and J. R. Stockight to Na. Pediatr. Res. 4, 445 (abstract). (1981). The effect of triameterene and sodium Hyman, P. E., R. I. Sha'afi, S. Y. Tan and R. intake on renin, aldosterone and erythrocyte Hintz (1979). Liddle syndrome. J. Pediatr. sodium transport in Liddle's syndrome. J. 95, 77-78. Clin. Endocrinol. Metab. 52, 1027-1032. Katz, F. K. and P. Romfh (1972). Plasma