Liddle Syndrome


Article Author:
Ateeq Mubarik


Article Editor:
Narothama Aeddula


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Vijay Lapsia


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Phillip Hynes


Updated:
3/14/2019 5:27:06 PM

Introduction

Resistant hypertension is a condition in which blood pressure continues to be greater than 140/90 mm Hg despite compliance with a regimen of 3 antihypertensive agents including a diuretic. Liddle syndrome is one of the rare causes of resistant hypertension that presents in early childhood. Grant Liddle et al. first explained Liddle syndrome in 1963. It is also known as pseudo aldosteronism. It is a rare cause of secondary hypertension due to a genetic mutation, affecting the function of the collecting tubule sodium channel.[1]

Etiology

Liddle syndrome is a congenital disorder due to a single gene mutation. Patients inherit the disorder in an autosomal dominant with early penetrance. Diverse populations affected by the syndrome. Genetic studies showed that this syndrome occurs from a gain of function mutations in the epithelial sodium in the distal nephron. In 1995, Hansson et al. discovered the germline mutation in the SCNN1G gene as a cause of the Liddle syndrome.[2] Later, researchers showed that ENaC comprises 3 homologous subunits alpha, beta, and gamma coded by SCNN1A, SCNN1B, and SCNN1G genes.[3] Mutation in beta or gamma subunits of the epithelial sodium channel (ENaC) leads to an amplified activity of this channel, independent of aldosterone activity.

Epidemiology

Researchers have not extensively studied the incidence of Liddle syndrome in the hypertensive population. Lin-Ping Wang et al. and Liu and his team studied the prevalence of Liddle syndrome. According to them, it was 0.92% to 1.52% in the Chinese population.[1][4] In these studies, the study population was a group of hypokalemic patients, but Liddle syndrome can be seen in patients with normal potassium levels. Therefore, if researchers studied the incidence of Lidle syndrome in normal potassium patients with hypertension, it would likely be much higher.[5] There is no gender or race predisposition.

Researchers of one study of US veterans concluded that there was approximately a 6% prevalence of symptomatic Liddle syndrome.[6]

Pathophysiology

Epithelial sodium channel is present in the distal colon, ducts of exocrine glands, lungs, and apical surface of the epithelial surface of distal nephron.[7] Patients with Liddle syndrome have an abnormality in the epithelial sodium channels in distal nephrons due to mutations in 1 of the 3 subunits. Due to this mutation, the degradation of the sodium channels has been impaired; therefore, the quantity of these channels on the apical surface of distal nephron increases inappropriately.[8] The sodium feedback inhibition system is also impaired in patients with Liddle syndrome.[9] Typically, increased intracellular sodium in distal nephron cells inhibit apical epithelial sodium channels, but in patients with Liddle syndrome, they become insensitive to sodium concentration. Increased sodium channels cause increased sodium retention which results in chronic volume retention and a hypertension state and suppressed renin and aldosterone levels.[10] In this population, renal biopsy showed atrophy of juxtaglomerular cells due to chronically suppressed renin and aldosterone levels.

History and Physical

Patients with Liddle syndrome can be symptomatic or asymptomatic. It presents with early onset of hypertension between the age of 11 and 31 and resistant hypertension due to sodium reabsorption at the level of distal nephron. The healthcare provider may take years or decades to diagnose it. Providers often misdiagnose the symptoms. Hypertension due to Liddle syndrome is sensitive to a salt-restricted diet.[5] Hypertension presents with a headache, dizziness, retinopathy, chronic kidney disease, left ventricular hypertrophy, and sudden death. Due to resistant hypertension, hypokalemia, and ventricular hypertrophy, a patient can develop lethal arrhythmias which can lead to sudden death.

Resistant hypertension can cause muscle weakness, polyuria, and polydipsia due to hypokalemia. Hypokalemia and metabolic alkalosis happen due to excessive loss of potassium in the urine at the expense of sodium reabsorption.[11][12]

The incidence of hypertension and hypokalemia in patients with Liddle syndrome is about 92.4% and 71.8% respectively.[13] Healthcare providers can order genetic testing to diagnose patients with Liddle syndrome who do not have hypertension or hypokalemia. In these individuals, genetic testing is usually done because of family history.

Evaluation

A patient often presents with secondary or resistant hypertension. Laboratory investigation may reveal hypokalemia and metabolic alkalosis.[13] Hyperaldosteronism can also present with same features and biochemical abnormalities. Renin and aldosterone levels should be checked to differentiate between hyperaldosteronism and pseudo-hyperaldosteronism (Liddle syndrome). In patients with Liddle syndrome, renin and aldosterone levels are low in contrast to patients with hyperaldosteronism in whom aldosterone levels are high. Due to normal levels of aldosterone, spironolactone does not work for patients with Liddle syndrome.[14]

Once a patient diagnosed with low-renin and low-aldosterone levels, a patient should take aldosterone for two months under the healthcare providers observation. Some conditions like glucocorticoid resistance syndrome, apparent mineralocorticoid excess syndrome, and congenital adrenal hyperplasia also respond well to this drug. If the patient does not respond to aldosterone, then the clinician should be suspicious for Liddle syndrome. 

Ultimate the diagnosis made by genetic analysis of the gene that regulates ENaC.

Treatment / Management

As discussed above, low levels of aldosterone render spironolactone ineffective for this condition. The drug of choice is amiloride. It works well in this syndrome as it directly inhibits ENaC. Amiloride is prescribed daily with a dose ranges from 5 to 20 mg. Triamterene, another potassium-sparing diuretic, similar to amiloride can also be used to manage this syndrome. A sodium-restricted diet showed a cumulative effect with these drugs.[15] However, excessive sodium accumulation on the receptor makes is unavailable for the medication.[16] If renal function is normal, then the incidence of hyperkalemia is very rare. Avoidance of excessive potassium in the diet is suggested along with the use of potassium-sparing diuretics. Amiloride is safe in pregnancy.[17]

Differential Diagnosis

Low renin hypertension can be classified as follows[14]:

  1. Low renin with low aldosterone 
  2. Low renin with normal aldosterone 
  3. Low renin with elevated aldosterone

Liddle syndrome is classified under low renin with low aldosterone. Others causes of hypertension which are classified under low renin with low aldosterone are as follows:

  • Apparent mineralocorticoid excess
  • An 11-beta-hydroxyl deficiency
  • A 17-alpha-hydroxyl deficiency
  • Gordons syndrome
  • Mineralocorticoid receptor activation mutation
  • Glucocorticoid resistance
  • Ectopic ACTH
  • Liquorice

Mineralocorticoid excess is an autosomal recessive syndrome due to 11beta-hydroxysteroid dehydrogenase type 2 enzyme deficiency. This enzyme converts cortisol (active) into cortisone (inactive) form and this inactive form is unable to bind the mineralocorticoid receptor.[18]

Gordon syndrome is an autosomal dominant condition due to a gene mutation responsible for ion transport in the kidney which results in increased reabsorption of sodium and decreased excretion of potassium.[19]

Toxicity and Side Effect Management

Potassium-sparing diuretics including triamterene and amiloride can cause hyperkalemia if glomerular filtration rate is not within normal range. Other major side effects of amiloride are aplastic anemia and neutropenia.

Triamterene can cause ventricular arrhythmias.

Prognosis

Patients with Liddle syndrome respond well to medical therapy such as potassium-sparing diuretics. No researchers have investigated long-term mortality of Liddle syndrome. Clinicians often under treat and misdiagnose these patients. Further studies are needed to establish mortality in the population suffering from secondary hypertension due to this syndrome.

Complications

Complications include hypokalemia, metabolic alkalosis, and resistant hypertension. The resistant hypertension patients can develop end-organ damage that includes myocardial infarction, transient ischemic attack/cerebrovascular accident, pulmonary edema, ventricular hypertrophy.

Consultations

Consultations should include nephrology, pediatrics, and a clinical hypertension specialist.

Enhancing Healthcare Team Outcomes

Late diagnosis of the Liddle syndrome carries important adverse clinical outcomes; therefore, early diagnosis is essential. Coordination between pediatrician and pediatric nephrologist is very important. It is highly advised to provide genetic counseling among the other family members.

Clinical genetic testing is available through the Genetic Testing Registry (GTR). Geneticists sequence exon 13 of SCNN1B and SCNN1G.


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Liddle Syndrome - Questions

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What channel is involved in the pathogenesis of Liddle syndrome?



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What is the most common electrolyte abnormality associated with Liddle syndrome?



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What are the levels of renin and aldosterone in patients with Liddle syndrome?



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A 17-year-old male with a family history of early onset, uncontrolled hypertension was recently diagnosed with hypertension. It has not been controlled with hydrochlorothiazide, amlodipine, losartan, and spironolactone for the last two months. Laboratory results show hypokalemia, metabolic alkalosis, low renin, and low aldosterone levels. What is the most likely diagnosis?



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A 22-year-old female in her first trimester of pregnancy has a family history of early onset, uncontrolled hypertension. She was recently diagnosed with hypertension, which has not been controlled with hydrochlorothiazide, amlodipine, and spironolactone for the last two months. Laboratory results show hypokalemia, metabolic alkalosis, low renin, and low aldosterone levels. What medication should be prescribed for this patient?



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Liddle Syndrome - References

References

Wang LP,Yang KQ,Jiang XJ,Wu HY,Zhang HM,Zou YB,Song L,Bian J,Hui RT,Liu YX,Zhou XL, Prevalence of Liddle Syndrome Among Young Hypertension Patients of Undetermined Cause in a Chinese Population. Journal of clinical hypertension (Greenwich, Conn.). 2015 Nov     [PubMed]
Hansson JH,Nelson-Williams C,Suzuki H,Schild L,Shimkets R,Lu Y,Canessa C,Iwasaki T,Rossier B,Lifton RP, Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nature genetics. 1995 Sep     [PubMed]
Hanukoglu I,Hanukoglu A, Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene. 2016 Apr 1     [PubMed]
Liu K,Qin F,Sun X,Zhang Y,Wang J,Wu Y,Ma W,Wang W,Wu X,Qin Y,Zhang H,Zhou X,Wu H,Hui R,Zou Y,Jiang X,Song L, Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. Journal of hypertension. 2018 Mar     [PubMed]
Pagani L,Diekmann Y,Sazzini M,De Fanti S,Rondinelli M,Farnetti E,Casali B,Caretto A,Novara F,Zuffardi O,Garagnani P,Mantero F,Thomas MG,Luiselli D,Rossi E, Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor. Hypertension (Dallas, Tex. : 1979). 2018 Feb     [PubMed]
Canessa CM,Schild L,Buell G,Thorens B,Gautschi I,Horisberger JD,Rossier BC, Amiloride-sensitive epithelial Na channel is made of three homologous subunits. Nature. 1994 Feb 3     [PubMed]
Lu C,Pribanic S,Debonneville A,Jiang C,Rotin D, The PY motif of ENaC, mutated in Liddle syndrome, regulates channel internalization, sorting and mobilization from subapical pool. Traffic (Copenhagen, Denmark). 2007 Sep     [PubMed]
Kellenberger S,Gautschi I,Rossier BC,Schild L, Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system. The Journal of clinical investigation. 1998 Jun 15     [PubMed]
Tapolyai M,Uysal A,Dossabhoy NR,Zsom L,Szarvas T,Lengvárszky Z,Fülöp T, High prevalence of liddle syndrome phenotype among hypertensive US Veterans in Northwest Louisiana. Journal of clinical hypertension (Greenwich, Conn.). 2010 Nov     [PubMed]
Unwin RJ,Luft FC,Shirley DG, Pathophysiology and management of hypokalemia: a clinical perspective. Nature reviews. Nephrology. 2011 Feb     [PubMed]
Amlal H,Krane CM,Chen Q,Soleimani M, Early polyuria and urinary concentrating defect in potassium deprivation. American journal of physiology. Renal physiology. 2000 Oct     [PubMed]
Monticone S,Buffolo F,Tetti M,Veglio F,Pasini B,Mulatero P, GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism. European journal of endocrinology. 2018 Mar     [PubMed]
Mulatero P,Verhovez A,Morello F,Veglio F, Diagnosis and treatment of low-renin hypertension. Clinical endocrinology. 2007 Sep     [PubMed]
Yang KQ,Lu CX,Fan P,Zhang Y,Meng X,Dong XQ,Luo F,Liu YX,Zhang HM,Wu HY,Cai J,Zhang X,Zhou XL, Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome. Clinical and experimental hypertension (New York, N.Y. : 1993). 2018     [PubMed]
Warnock DG, Liddle syndrome: an autosomal dominant form of human hypertension. Kidney international. 1998 Jan     [PubMed]
Awadalla M,Patwardhan M,Alsamsam A,Imran N, Management of Liddle Syndrome in Pregnancy: A Case Report and Literature Review. Case reports in obstetrics and gynecology. 2017     [PubMed]
Wilson RC,Nimkarn S,New MI, Apparent mineralocorticoid excess. Trends in endocrinology and metabolism: TEM. 2001 Apr     [PubMed]
Kahle KT,Wilson FH,Lifton RP, Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch. Trends in endocrinology and metabolism: TEM. 2005 Apr     [PubMed]
Nakada T,Koike H,Akiya T,Katayama T,Kawamata S,Takaya K,Shigematsu H, Liddle's syndrome, an uncommon form of hyporeninemic hypoaldosteronism: functional and histopathological studies. The Journal of urology. 1987 Apr     [PubMed]

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