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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 4  |  Page : 769-772
Liddle's syndrome: A case report

1 Department of Internal Medicine, ETSU Quillen College of Medicine, Johnson City, TN, USA
2 James H. Quillen VA Medical Center, Mountain Home, TN, USA

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Date of Web Publication8-Jul-2015


Liddle's syndrome or pseudoaldosteronism is a rare autosomal dominant disease mimicking primary hyperaldosteronism, characterized by early-onset hypertension, hypokalemia and hypoaldosteronism, caused by excessive salt and water reabsorption in the distal nephron. As of 2008, there are <30 pedigrees or isolated cases that have been reported worldwide. We present an isolated case of a Liddle's syndrome in a 48-year-old female. A 48-year-old female presented to the clinic with palpitation and a three to four-year history of low potassium level and hypertension. She was initially treated with a high potassium diet and potassium supplements. Her cardiac work-up including echocardiography, stress test and Holter monitoring were all negative. After a few months, she was admitted to the hospital with an acute hypertensive episode and hypokalemia. On evaluation, she was found to have low renin and aldosterone levels. Liddle's syndrome was considered with the clinical picture of hypokalemia, hypertension and low renin/ aldosterone level. The patient was successfully treated with a high potassium diet, triamterene and atenolol. Liddle's syndrome should be considered as the differential diagnosis in patients presenting with the clinical picture of hypokalemia, hypertension and low renin/aldosterone level.

How to cite this article:
Patel P, Kuriacose R. Liddle's syndrome: A case report. Saudi J Kidney Dis Transpl 2015;26:769-72

How to cite this URL:
Patel P, Kuriacose R. Liddle's syndrome: A case report. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2022 Nov 28];26:769-72. Available from: https://www.sjkdt.org/text.asp?2015/26/4/769/160211

   Introduction Top

Liddle's syndrome, a rare disease with autosomal dominant inheritance, is characterized frequently by severe early-onset, salt-sensitive hypertension, hypokalemia, metabolic alkalosis, low plasma renin activity and hypoaldosteronism, caused by disproportionate salt and water reabsorption at the distal nephron. [1],[2] It responds to treatment with epithelial Na+ channel blocker drugs (e.g., amiloride or triamterene) and a low sodium diet. [3] As of 2008, there are <30 pedigrees or isolated cases that have been reported worldwide. [4] We present a case of a 48-year-old female who presented with Liddle's syndrome.

   Case Report Top

A 48-year-old woman presented to the office with a three to four year history of hypertension and hypokalemia. The patient was not on any diuretics and also denied licorice ingestion. She had tried potassium supplements and a high-potassium diet in the past without any help. The potassium level ranged from 2.7 to mEq/L. No family member had any electrolyte disorders or early hypertension. She also had on and off palpitation, for which she had been evaluated by a cardiologist in the past and had normal echocardiogram, stress test and Holter monitor.

As the blood pressure and potassium were normal on the first visit, we decided to monitor the potassium level and the patient was recommended to take a high-potassium diet. After six weeks, the patient presented to the emergency room with chest discomfort, elevated heart rate and elevated blood pressure up to 220/120 mm Hg. The potassium level was 2.6 mEq/L and the serum creatinine level was 0.7 mg/dL on admission. The patient again had a negative cardiac work-up. Urine metanephrine and vanilyl mandelic acid levels were normal. The patient was placed on spironolactone and atenolol without any effect on the elevated blood pressure. The 24-h urine sodium level and urine potassium were 254 mmol/d and 83 mmol/d, respectively. Her serum cortisol levels were within normal limits (8 am and 4 pm cortisol values were 14.5 and 8.06 μg/dL, respectively). Her 24-h urine cortisol and cortisone level were also normal (30.2 μg/d and 118 μg/d, respectively). The renin and aldosterone levels were low at 1.2 and 2.1, respectively. Computed tomography of the abdomen was negative for adrenal enlargement or adenoma. Although rare, Liddle's syndrome was considered to be due to a clinical combination of hypokalemia, metabolic alkalosis, hypertension and low renin/aldosterone level. Spironolactone was switched to triamterene. The patient responded exceptionally well to triamterene and her potassium level gradually improved over a six-week period. Her blood pressure also got controlled with the combination of triamterene and atenolol. She has not had any further episode of hypertension or hypokalemia on follow-up for two years.

   Discussion Top

Liddle's syndrome is a rare autosomal dominant monogenic type of hypertension that involves abnormalities in the collecting tubule sodium channel function, also called the epithelial sodium channel (ENaC) or the amiloride-sensitive sodium channel. [5],[6] The ENaC has three homologous subunits named αENaC, βENaC and γENaC, which creates a path for sodium reabsorption across the epithelium. ENaC plays a crucial role in controlling the blood pressure by managing extracellular Na+ and volume homeostasis in the renal collecting duct and connecting tubule. EnaC mediates the entry of filtered Na from the tubule lumen at the apical membrane and the Na+-K+-ATPase extrudes the reabsorbed Na at the basolateral membrane. The reabsorption of cationic Na makes the lumen electronegative, creating a favorable gradient for the secretion of K into the lumen via K channels in the apical membrane. Aldosterone binds with cytosolic mineralocorticoid receptors (Aldo-R) and translocates to the nucleus thus helping the expression and subcellular localization of ENaC and the Na+-K+-ATPase pup function [Figure 1]. It also affects other target proteins through aldosterone-induced transcripts and aldosteronerepressed transcripts. This leads to enhanced Na reabsorption and potassium secretion by increasing both the number of open ENaC and the number of Na-K-ATPase pumps. [5]
Figure 1: Schematic representation of sodium and potassium transport in the sodium reabsorbing principal cells in the collecting tubules.

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Liddle's syndrome is caused by mutations in βENaC or γENaC and leads to increased Na+ transport by two different mechanisms. First, this mutation increases ENaC expression at the plasma membrane. The genetic defects either mutate tyrosine or a proline-rich sequence, the PY motif, or delete the intracytoplasmic Cterminus of β or γ ENaC. The PY motif works as a binding site for the Nedd4 family of ubiquitin-protein ligases. Nedd4-2 targets and degrades the channel and decreases ENaC expression to the surface. Thus, Liddle's syndrome mutations increase ENaC surface expression by disrupting its interaction with Nedd4-2. [5],[7] Second, this mutation increases the proteolytically cleaved (active) fraction of ENaC at the plasma membrane leading to more Na+ transport. [7] A combination of hypokalemia, elevated blood pressure and metabolic alkalosis are the usual presentations in patients with Liddle's syndrome. These findings mimic other disorders caused by mineralocorticoid excess. Most patients present at a young age. The consistent findings among such individuals are low plasma renin activity and, in contrast to primary aldosteronism, reductions in both the plasma aldosterone concentration and the urinary excretion of aldosterone. [1] Some patients with Liddle's syndrome have presented without hypokalemia. Liddle's syndrome is usually associated with a positive family history, although our case was a sporadic case. The absence of a family history does not exclude the diagnosis. Genetic testing is the most reliable method for establishing the diagnosis of Liddle's syndrome.

Treatment approach aims toward inhibiting ENaC activity, the rate-limiting step in the nephron for the regulation of Na+ and fluid reabsorption. [8] The ENaC antagonists amiloride and triamterene directly block the ENaC and correct both the hypertension and, if present, the hypokalemia. [9] Spironolactone is ineffective in treating Liddle's syndrome because increased ENaC activity in Liddle's syndrome is not mediated by aldosterone. In conclusion, Liddle's syndrome represents one of the single-gene disorders where mutation results in hypertension. A genetic analysis of the amiloride-sensitive ENaC is recommended in assessment of patients without bilateral adrenal hyperplasia or adrenal adenomas but with suppressed renin level and salt-sensitive hypertension refractory to spironolactone treatment. The molecular diagnosis of Liddle's syndrome helps improve the effectiveness of treatment and prevents morbid outcomes.

Conflict of interest: None

   References Top

Botero-Velez M, Curtis JJ, Warnock DG. Brief report: Liddle's syndrome revisited - A disorder of sodium reabsorption in the distal tubule. N Engl J Med 1994;330:178-81.  Back to cited text no. 1
Oh J, Kwon KH. Liddle's syndrome: A report in a middle-aged woman. Yonsei Med J 2000; 41:276-80.  Back to cited text no. 2
Lifton RP, Somlo S, Giebisch GH. Genetic Disease of the Kidney. Saunders Elsevier; Philadelphia, USA, 2009:313-329  Back to cited text no. 3
Rossier BC, Schild L. Epithelial sodium channel: mendelian versus essential hypertension. Hypertension 2008;52(4):595-600.  Back to cited text no. 4
Shimkets RA, Warnock DG, Bositis CM, et al. Liddle's syndrome: Heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 1994;79:407-14.  Back to cited text no. 5
Kellenberger S, Schild L. Epithelial sodium channel/degenerin family of ion channels: A variety of functions for a shared structure. Physiol Rev 2002;82:735-67.  Back to cited text no. 6
Knight KK, Olson DR, Zhou R, Snyder PM. Liddle's syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage. Proc Natl Acad Sci U S A 2006;103:2805-8.  Back to cited text no. 7
Trimm HH, Hunter W Jr. Recent Advances in Biochemistry CRC Press, 2011,63.  Back to cited text no. 8
Sahay M, Sahay RK. Low renin hypertension. Indian J Endocrinol Metab 2012;16(5):728-739.  Back to cited text no. 9

Correspondence Address:
Pranav Patel
Department of Internal Medicine ETSU Quillen College of Medicine, Johnson City, TN
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.160211

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