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Previous Volume 330:178-181 January 20, 1994 Number 3 Next

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In 1963 Liddle et al.¹ described a disorder that simulated primary aldosteronism, characterized by severe hypertension and hypokalemia but with negligible secretion of aldosterone. They theorized that this was "a disorder in which the renal tubules transport ions with such abnormal facility that the end result simulates that of a mineralocorticoid excess." We describe a woman with this syndrome (the index case¹) in whom renal failure eventually developed and who received a cadaveric renal transplant at our institution in 1989. Her disorder resolved after transplantation, with normalization of the aldosterone and renin responses to salt restriction. The woman's extended pedigree demonstrates autosomal dominant inheritance of severe hypertension and suppressed aldosterone secretion, but hypokalemia is not a constant finding in the affected members of the family.

Case Report

In 1960, the proband, then 16 years of age, had hypertension and hypokalemic metabolic alkalosis. A brother and sister, 14 and 19 years old, respectively, had the same abnormalities. The fact that their urinary aldosterone excretion was low even while they were eating a low-sodium diet (9 mmol per day) excluded a diagnosis of primary aldosteronism. Ingestion or hypersecretion of other mineralocorticoids was excluded by the findings of high sodium:potassium ratios in saliva and sweat, a lack of effect of spironolactone on electrolyte excretion and hypertension, and normal urinary excretion of glucocorticoid metabolites¹.

The proband's hypertension was poorly controlled, and her renal function deteriorated. In 1981 her creatinine clearance was 41 ml per minute (0.68 ml per second); dialysis was begun in May 1989. She underwent transplantation with a cadaveric kidney in November 1989 and now has excellent renal function with mild hypertension and normokalemia. She is the only family member to have had renal failure, and its cause is unknown. A biopsy performed in 1962¹ revealed only a slight increase in the cellularity of several glomeruli with occasional adhesions.

Methods

For the studies described here, which were performed while she was hospitalized in the General Clinical Research Center in July 1991, the woman was given a diet containing 150 mmol of sodium per day for four days and then a sodium-restricted diet (9 mmol per day) for four days. Her potassium intake was 60 mmol per day. Plasma renin activity and aldosterone concentrations were measured after she had spent 30 minutes in a supine position on day 4 of each diet. Electrolytes in serum and urine were measured daily. At the time of the study, her serum creatinine level was 1.0 mg per deciliter (88.4 µmol per liter); sodium, 135 mmol per liter; potassium, 4.3 mmol per liter; bicarbonate, 24 mmol per liter; and chloride, 108 mmol per liter. Her creatinine clearance was 77 ml per minute (1.28 ml per second). She was taking 200 mg of cyclosporine per day, 10 mg of prednisone per day, and 100 mg of azathioprine per day at the time of study. The same tests were carried out in 20 unrelated, stable renal-transplant recipients who were receiving prednisone and either cyclosporine (10 patients) or azathioprine (10 patients).

Blood pressure was measured in seated subjects, and overnight urinary potassium, sodium, and aldosterone excretion² and serum electrolyte levels were determined in the proband and 43 other family members (who were seen as outpatients). No attempt was made to control dietary sodium intake before these measurements. Serum and urine electrolytes were measured by flame photometry, and plasma and urinary aldosterone levels and plasma renin activity were measured by radioimmunoassay.

The studies were approved by the institutional review board at the University of Alabama at Birmingham, and written informed consent was obtained from each subject.

Results

In 1962, the proband's urinary sodium excretion could not be reduced maximally by sodium restriction, and she continued to have hypertension and hypokalemia (Table 1). Liddle et al.¹ concluded that in this syndrome persistent volume expansion blunted any short-term stimulation of aldosterone secretion by sodium restriction. The administration of triamterene during salt restriction decreased urinary potassium excretion, increased urinary sodium excretion, and corrected the hypertension and hypokalemia. There was no response to spironolactone¹.

View this table: [in this window] [in a new window]   Table 1. Serial Measurements of Blood Pressure and Electrolyte Excretion in the Proband.

 
We studied the proband 20 months after renal transplantation. At that time, she had mild hypertension and a normal serum potassium concentration. Urinary sodium excretion averaged 145 mmol per day when her dietary intake was 150 mmol per day, and urinary potassium excretion was not excessive (Table 1). Plasma renin activity and the plasma aldosterone concentration increased normally in response to sodium restriction, and the magnitude of the increases was similar to that in the control transplant recipients (Table 2). In the original report, the proband had negligible urinary aldosterone excretion, which did not increase with sodium restriction¹.

View this table: [in this window] [in a new window]   Table 2. Plasma Renin Activity and Plasma Aldosterone Concentrations, Measured in the Supine Position, in the Proband after Renal Transplantation and in Unrelated Renal-Transplant Recipients.

 
The proband's expanded pedigree is shown in Figure 1. The proband and two siblings were extensively studied in 1962¹. The proband had two daughters, one of whom (Subject IV-5) was severely affected with Liddle's syndrome. The proband's sister, Subject III-3, had two affected children (Subjects IV-2 and IV-3), whereas both children of Subject III-5, the proband's brother, were unaffected. Family members whose conditions were not appropriately diagnosed or treated died prematurely or had cerebrovascular accidents or cardiovascular disease (Subjects II-2, II-3, III-1, and III-13).

View larger version (24K): [in this window] [in a new window]   Figure 1. Pedigree of the Original Kindred with Liddle's Syndrome. Subject III-4 (arrow) is the proband. The classification of family members as affected was based on the presence of hypertension, defined as a historically documented diastolic blood pressure of more than 90 mm Hg in the original report1 or the medical records, or measured by us. All the normal subjects had a ratio of urinary aldosterone (in nanograms) to potassium (in millimoles) that was more than 60, as did the proband after renal transplantation. As described in the original report,1 the proband had greatly reduced aldosterone excretion at the age of 16 years.

 
Hypokalemia was originally described in Subjects III-3, III-4, and III-5,¹ but it was not present in all members of this family who had hypertension. Subject III-1 had hypertension (160/100 mm Hg) with normokalemia at 24 years of age and subsequently had a cerebrovascular accident. Subject II-3 had borderline hypertension (160/88 mm Hg) and a serum potassium concentration of 3.8 mmol per liter at 35 years of age; he had two affected children (Subjects III-13 and III-14).

To define this syndrome better, we studied the proband again and also studied 43 other family members as outpatients. The subjects were classified as affected if they had hypertension (diastolic blood pressure >90 mm Hg) or had hypertension as compared with age-matched normal subjects. Unaffected members were normotensive but had an affected parent and were therefore at risk. The control subjects, defined as those who were not at risk, included the spouses and children of unaffected family members.

Eighteen family members had hypertension, and as a group their serum potassium concentrations were lower than those of the 15 unaffected family members and the 10 subjects who were not at risk (Table 3). There were no significant differences between the affected family members and the other two groups in the overnight creatinine clearance (Table 3) or in height; weight; sex; serum creatinine, sodium, or chloride concentrations; or urinary excretion of creatinine, sodium, potassium, or chloride (data not shown). Overnight rates of urinary aldosterone excretion and aldosterone-excretion rates normalized for potassium content were lower in the affected family members than in the other two groups (Table 3).

View this table: [in this window] [in a new window]   Table 3. Clinical Findings in a Family with Liddle's Syndrome.

 
Discussion

Liddle et al. proposed that high urinary potassium excretion and low urinary sodium excretion maintained hypokalemia and volume expansion, causing hypertension and suppressing aldosterone excretion¹. Triamterene and salt restriction corrected the hypokalemia and hypertension, but spironolactone was ineffective, a fact that argued against an unidentified mineralocorticoid hormone as the cause of the syndrome. Renal failure ultimately developed in the proband, and she became normokalemic. She has remained normokalemic since receiving her renal transplant in 1989. Although cyclosporine can raise the serum potassium concentration and hyperkalemia can stimulate aldosterone secretion, we do not attribute the normal plasma renin and aldosterone values in the proband after transplantation to cyclosporine, since she had normokalemia. Furthermore, cyclosporine does not interfere with the renin and aldosterone responses to salt restriction³ and to the administration of captopril⁴. Once she had a well-functioning graft, the response of the proband's renin-aldosterone axis to salt restriction was normal (Table 2), despite the administration of cyclosporine.

Other studies have confirmed the original description by Liddle et al. and have found that amiloride and triamterene, but not spironolactone, were effective treatments for hypertension and hypokalemia in patients with this syndrome as long as dietary sodium intake was restricted^1,5,6,7. Chronic suppression of aldosterone secretion is a constant finding, and renal biopsy shows atrophy of the juxtaglomerular apparatus and loss of renin-secreting granules⁶. Suppression of the renin-angiotensin system is not, however, an integral feature of this disorder⁷; rather, it simply reflects the chronic state of expansion of the extracellular-fluid volume^1,5.

Patients with Liddle's syndrome have an enhanced influx of sodium into the red cells,^6,8 but there is no generalized increase in the permeability of the cell membrane to sodium, because the ratio of sodium to potassium in saliva and sweat is normal,^1,5 and fecal potassium wasting is not a problem¹. The amelioration of the syndrome by renal transplantation suggests that the disorder is not caused by an unidentified mineralocorticoid and provides evidence of a specific transport defect in the segments of the distal nephron that regulate sodium and potassium excretion and respond to aldosterone, amiloride, and triamterene⁹.

The epithelial sodium channel is a multimer that includes an identified membrane-spanning protein,¹⁰ regulatory subunits, and a G protein sensitive to pertussis toxin^11,12. Constitutive activation of any component of this complex could cause Liddle's syndrome. Constitutive activation of the mineralocorticoid receptor, specifically in the collecting tubule, could also explain the syndrome.

This pedigree (Figure 1) clearly demonstrates autosomal dominant inheritance. The male-to-male transmission between Subjects II-3 and III-13, II-5 and III-17, III-17 and IV-18, and II-6 and III-20 is evidence against X-linked inheritance. Liddle et al. reported that the proband's mother (Subject II-1) and maternal grandmother (Subject I-1) had hypertension and died prematurely¹. We learned that the maternal grandfather (Subject I-2) remarried and had six additional, unaffected children; this is consistent with the assumption that Subject I-1 was the source of the genetic abnormality in this family.

The phenotype consists of hypertension, a low rate of urinary aldosterone excretion, and a low ratio of aldosterone to potassium in the urine. Variation in the severity and onset of hypertension implies variable penetrance of the gene or genes involved. Although the onset of hypertension usually occurs during the teenage years, some affected family members (Subjects IV-14 and IV-18) were younger. The value of these measurements will be established once the causal mutation is identified. There are normotensive, normokalemic family members who have low aldosterone-excretion rates and ratios of aldosterone (in nanograms) to potassium (in millimoles) below 60 (0.166 nmol of aldosterone per millimole of potassium) (Subjects III-16, IV-4, IV-11, and IV-15), suggesting that the primary effect of the gene may antedate overt hypertension. This finding makes it unlikely that reduced aldosterone excretion results from hypokalemia or hypertension^13,14.

Hypokalemia is not a universal finding among affected members of this family. Three living family members (Subjects II-6, III-11, and III-13) and one described by Liddle et al.¹. (Subject III-1) had hypertension with serum potassium concentrations greater than 4.0 mmol per liter. Only one of them, Subject III-11, was taking triamterene at the time of the study. Subjects III-2 and II-3 had hypertension but had serum potassium concentrations of 3.6 and 3.8 mmol per liter, respectively¹. Primary aldosteronism is usually associated with hypokalemia,¹⁵ but it is less frequent among patients with other mineralocorticoid-excess syndromes. For example, in a large kindred with glucocorticoid-remediable aldosteronism, the mean serum potassium concentration was 4.3 mmol per liter in 12 affected and 18 unaffected family members¹⁶. It is unknown whether familial syndromes^1,16,17 account for a substantial number of patients with low-renin hypertension. The usefulness of spontaneous hypokalemia as a sign of mineralocorticoid excess is questionable, and direct measurements of the excretion of electrolytes and steroidal metabolites are necessary, at least in the familial hypertensive syndromes.

Supported by a General Clinical Research Center core grant (5 M01 RR00032) from the National Center for Research Resources, by a George M. O'Brien Kidney and Urologic Disease Research Grant (P50-DK39258) from the National Institute of Diabetes and Digestive and Kidney Diseases, and by the Department of Veterans Affairs Research Service.

We are indebted to Drs. Arnold G. Diethelm and Guru Prakash for their ongoing care of the proband; to James K. Bubien, Ph.D., and Richard P. Lifton, M.D., Ph.D., for their interest and suggestions; to the physicians who helped us with the collection of data from family members: Judy Cheng, M.D., Carlton Clark, M.D., Kirit K. Joshi, M.D., Frederick Koehler, M.D., Bradley Merritt, M.D., William Nolin, M.D., John Shilling, M.D., Daniel Sicca, M.D., and Ted Williams, M.D.; and to Patsy Jones, R.N., Mrs. Lee McGuire, Mrs. Juanita Baggett, and Connie Gibson, M.T. (A.S.C.P.), S.H., for their assistance.

Source Information

From the Departments of Medicine (M.B.-V., J.J.C., D.G.W.) and Physiology (D.G.W.), the General Clinical Research Center (J.J.C.), and the Nephrology Research and Training Center (M.B.-V., J.J.C., D.G.W.), University of Alabama at Birmingham, and the Veterans Affairs Medical Center (D.G.W.), both in Birmingham, Ala. Presented in preliminary form at the 25th Annual Meeting of the American Society of Nephrology, Baltimore, November 15-18, 1992 (J Am Soc Nephrol 1992;3:517a. abstract).

Address reprint requests to Dr. Warnock at the Division of Nephrology, University of Alabama at Birmingham, UAB Station, Birmingham, AL 35294-0007.

References

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12. Ausiello DA, Stow JL, Cantiello HF, de Almeida JB, Benos DJ. Purified epithelial Na+ channel complex contains the pertussis toxin-sensitive Galpha_i-3 protein. J Biol Chem 1992;267:4759-4765. [Free Full Text]
13. Kotchen TA, Guthrie GP Jr, Cottrill CM, McKean HE, Kotchen JM. Low renin-aldosterone in "prehypertensive" young adults. J Clin Endocrinol Metab 1982;54:808-814. [Abstract]
14. Guthrie GP Jr, Kotchen TA, Kotchen JM. Suppression of adrenal mineralocorticoid production in prehypertensive young adult men. J Clin Endocrinol Metab 1983;56:87-92. [Abstract]
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