Last updated:
6/12/2025
Years published: 2022, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders; Jonathan Berman, PhD, Assistant Professor, Department of Basic Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University; Eric Judd, MD, Associate Professor, Department of Nephrology, Nephrology Clinic of the Kirklin Clinic, University of Alabama and Deborah Kraut, MILR, Patient Advocate, for the preparation of this report.
Summary
Liddle syndrome is a rare genetic condition characterized by early-onset, salt-sensitive high blood pressure (hypertension), often beginning in childhood or adolescence, low potassium levels (hypokalemia), metabolic alkalosis (elevated blood pH with excess bicarbonate), suppressed plasma renin activity (indicating disrupted blood pressure regulation) and low aldosterone levels, despite high blood pressure.
This condition is caused by abnormalities in the body’s ability to regulate sodium and potassium, leading to fluid retention and persistent hypertension.
Most people with high blood pressure don’t have a clear cause, which is called essential hypertension. But Liddle syndrome is different: it’s a monogenic disorder, meaning one gene change (variant) is enough to trigger the condition. Liddle syndrome is caused by variants in the SCNN1A, SCNN1B, or SCNN1G genes. These are genes that regulate the epithelial sodium channels (ENaC) in the kidney. Inheritance is autosomal dominant.
The severity of hypertension, which is the presenting finding, varies from mild to severe, even in people in the same family. The symptoms and severity can vary by age, sex and life events such as pregnancy.
Treatment is targeted at blocking the overactive sodium channels. The most effective therapies include amiloride or triamterene and a low-sodium diet.
Introduction
Liddle syndrome shares features with other rare kidney-related conditions called tubulopathies which affect how the kidneys handle substances like salt and potassium. It’s also grouped with channelopathies that are diseases that involve faulty ion channels which are special proteins that help move important minerals like sodium and potassium in and out of cells.
Because people with Liddle syndrome often have low aldosterone levels but still show symptoms like having too much of it (hyperaldosteronism) such as high blood pressure and low potassium, it’s sometimes called “pseudohyperaldosteronism”.
The syndrome is named after Dr. Grant Liddle, who first described it in the 1960s. He treated a teenage girl (referred to as “GS”) and her brother who had very high blood pressure and low potassium levels even though they had very low levels of aldosterone. Dr. Liddle prescribed a low-sodium diet, and a medicine called triamterene which blocks the faulty sodium channel in the kidneys.
Later in life, GS received a kidney transplant, and her blood pressure returned to normal, proving the problem was in the kidneys. She helped scientists trace the condition through her family and provided samples that led to the discovery of the genes responsible for Liddle syndrome.
Most people with Liddle syndrome develop resistant hypertension (high blood pressure that doesn’t improve with typical medications). This usually begins between ages 11 and 31, though it can go undiagnosed for years. The high blood pressure is caused by the kidneys reabsorbing too much salt.
Symptoms can vary from mild to severe but may include:
These results are often seen in blood and urine tests:
Liddle syndrome is caused by variants in genes that affect how the kidneys regulate salt (sodium) and fluid balance. The kidneys contain specialized proteins called epithelial sodium channels (ENaC) which help control how much sodium is reabsorbed from urine back into the body. These ENaC channels function like gates that allow sodium to pass through.
ENaC is composed of three subunits, alpha, beta, and gamma, each encoded by different genes:
In Liddle syndrome, the most common variants occur in the SCNN1B or SCNN1G genes.
ENaC channels are present on the surface of many cell types, including those in the lungs, skin, colon, reproductive tract, brain and kidneys. However, in Liddle syndrome the most relevant cells affected are the principal cells of the kidneys, where they control sodium reabsorption from urine.
In healthy kidneys, ENaC channels are dynamically inserted into and removed from the cell surface to maintain proper sodium balance. A process called “ubiquitination” normally tags ENaC channels for removal when they are no longer needed. In Liddle syndrome, this tagging process is disrupted due to the variants in SCNN1A, SCNN1B, or SCNN1G genes. As a result, ENaC channels remain active on the cell surface for too long, leading to excessive sodium reabsorption.
This increased reabsorption of sodium draws more water into the body (since water follows sodium) leading to higher blood volume and elevated blood pressure (hypertension), often beginning at a young age.
In addition to sodium handling, principal cells are responsible for eliminating potassium and hydrogen ions (acid) in the urine to help regulate the body’s acid-base and electrolyte balance. When too much sodium is retained, more potassium and hydrogen ions are lost which can lead to low blood potassium (hypokalemia) and metabolic alkalosis, a condition where the body’s pH is elevated above the normal range (7.35-7.45).
In Liddle syndrome, the renin-angiotensin-aldosterone system (RAAS), a hormone system that helps regulate blood pressure and fluid balance, is also affected.
When blood pressure drops, the RAAS acts to increase blood volume and pressure. Normally, the body adjusts renin and aldosterone hormone levels to maintain balance, but in Liddle syndrome renin and aldosterone levels are low, even though blood pressure is high.
Although these biochemical features, hypertension, hypokalemia and metabolic alkalosis, can also occur in hyperaldosteronism, a distinguishing feature of Liddle syndrome is that aldosterone levels are low and not high as in hyperaldosteronism.
Inheritance
Liddle syndrome follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Estimates of how common Liddle syndrome is vary. As of 2023, there were around 108 people reported in the medical literature to be affected with Liddle syndrome caused by SCNN1B gene variants in 47 families. However, due to underdiagnosis and misdiagnosis, the actual number of affected people is likely higher.
A recent survey found that about 6% of veterans with high blood pressure showed signs that match Liddle syndrome, even without genetic testing. This suggests the condition may be more common than previously thought.
Studies of people who develop high blood pressure before age 30 suggest that about 1 in 100 to 1.5 in 100 may actually have Liddle syndrome.
Although most cases are found in children due to early signs of high blood pressure, some people are diagnosed later in life. The condition has been found in people from many different countries. In some locations, a gene variant that causes Liddle syndrome may have been passed down through generations, leading to more cases in certain regions.
Liddle syndrome is often suspected when a person has high blood pressure (hypertension) that is hard to control, especially at a young age or when hypertension does not improve with the usual treatments. This kind of high blood pressure is sometimes called resistant or secondary hypertension.
Blood and urine tests can show low potassium levels, metabolic alkalosis and low levels of the hormones known as renin and aldosterone.
Renin is an enzyme produced by the kidneys that controls the production of aldosterone, a hormone made by the adrenal glands. Aldosterone helps maintain blood pressure by regulating sodium and potassium levels in the blood.
These hormone levels can distinguish between Liddle syndrome and other conditions like hyperaldosteronism which can have similar symptoms. In hyperaldosteronism, aldosterone levels are high, but in Liddle syndrome, these levels are low. That’s why some common blood pressure medications like spironolactone which blocks aldosterone, don’t work in Liddle syndrome.
If blood tests show both renin and aldosterone are low, a short treatment with aldosterone may be considered to see if symptoms improve. If there’s no improvement, a diagnosis of Liddle syndrome can be suspected.
Genetic testing that identifies a variant in one of the three genes (SCNN1A, SCNN1B, or SCNN1G) that control a sodium channel in the kidneys confirms the diagnosis of Liddle syndrome.
The main goal of treatment is to lower blood pressure and reduce the risk of long-term complications like heart or kidney damage.
The most effective medicine for Liddle syndrome is the medication known as amiloride. This medication works by blocking the overactive sodium channels in the kidneys, helping the body get rid of excess sodium and lowering blood pressure. It also helps correct low potassium levels. The usual dose is between 5 to 20 mg per day, and it’s taken once or twice a day.
A similar medication called triamterene may also be used but amiloride is usually preferred because it works better.
When the diagnosis of Liddle syndrome is made later in life, additional anti-hypertensive medications are also needed to control blood pressure. If blood pressure is still not well controlled, other medications like beta blockers or vasodilators can be added to help.
Other common blood pressure medicines like spironolactone, eplerenone and hydrochlorothiazide are not effective for this condition and may cause confusion if the correct diagnosis has not been made.
Because Liddle syndrome involves kidneys retaining too much sodium, a low-sodium (low salt) diet is very helpful. Limiting salt in meals supports the action of amiloride and can make it easier to reach healthy blood pressure levels.
People with Liddle syndrome rarely develop dangerously high potassium levels (hyperkalemia) if kidney function is normal. However, it is recommended to avoid excessive potassium in the diet and to monitor potassium with blood tests.
Amiloride may be used during pregnancy. It is categorized as a pregnancy category B drug by the U.S. Food and Drug Administration (FDA), meaning that while animal studies haven’t shown a risk to the fetus, its use during pregnancy requires careful consideration and should only be used if clearly needed. Blood pressure can be especially difficult to control during pregnancy without it.
Resistant hypertension, if left untreated or poorly managed, can lead to serious damage to major organs. Potential complications include heart attacks (myocardial infarction), strokes or mini strokes (transient ischemic attacks), fluid in the lungs (pulmonary edema) and thickening of the heart muscle (ventricular hypertrophy). Early diagnosis and appropriate treatment are essential to reduce or prevent these risks. Patients should be clearly informed about the health risks associated with resistant hypertension. Treatment is critical to minimizing the risk of heart attack and stroke.
People with Liddle syndrome may need to have coordinated care with medical specialists who should work together as a team. The specialists may include nephrologists (kidney specialists), pediatricians (for children affected), endocrinologists (hormone specialists) and cardiologists with expertise in hypertension.
Genetic counseling should be offered to family members.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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For information about clinical trials sponsored by private sources, contact:
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JOURNAL ARTICLES
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Lu Y, Liu X, Sun L & cols. A frameshift mutation in the SCNN1B gene in a family with Liddle syndrome: A case report and systematic review. Mol Med Rep. 2024 Feb;29(2):19. doi: 10.3892/mmr.2023.13142. Epub 2023 Dec 15. PMID: 38099339; PMCID: PMC10784729.
Enslow BT, Stockand JD and Berman JM. Liddle’s syndrome mechanisms, diagnosis and management. Integr Blood Press Control. 2019 Sep 3;12:13-22. doi: 10.2147/IBPC.S188869. eCollection 2019.
Van Beusecum JP, Barbaro NR, McDowell Z, et al. High salt activates CD11c + antigen-presenting cells via SGK (serum glucocorticoid kinase) 1 to promote renal inflammation and salt-sensitive hypertension. Hypertension. 2019 Sep;74(3):555-563. doi: 10.1161/HYPERTENSIONAHA.119.12761. Epub 2019 Jul 8.
Liu K, Qin F, Sun X, et al. Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. J Hypertens. 2018 Mar;36(3):502-509. doi: 10.1097/HJH.0000000000001556.
Pagani L, Diekmann Y, Sazzini M, et al. Three reportedly unrelated families with Liddle syndrome inherited from a common ancestor. Hypertension. 2018 Feb;71(2):273-279. doi: 10.1161/HYPERTENSIONAHA.117.10491. Epub 2017 Dec 11.
Tetti M, Monticone S, Burrello J, et al. Liddle Syndrome: Review of the literature and description of a new case. Int J Mol Sci. 2018 Mar 11;19(3):812. doi: 10.3390/ijms19030812.
Cui Y, Tong A, Jiang J, Wang F and Li C. Liddle syndrome: clinical and genetic profiles. J Clin Hypertens (Greenwich). 2017 May;19(5):524-529. doi: 10.1111/jch.12949. Epub 2016 Nov 29.
Salih M, Gautschi I, van Bemmelen MX, et al. A missense mutation in the extracellular domain of α ENaC causes Liddle syndrome. J Am Soc Nephrol 2017 Nov;28(11):3291-3299. doi: 10.1681/ASN.2016111163. Epub 2017 Jul 14.
Judd E and Calhoun DA. Management of hypertension in CKD: beyond the guidelines. Adv Chronic Kidney Dis. 2015 Mar;22(2):116-22. doi: 10.1053/j.ackd.2014.12.001.
Pepersack T, Allegre S, Jeunemaitre X, Leeman M and Praet J-P. Liddle syndrome phenotype in an octogenarian. J Clin Hypertens (Greenwich). 2015 Jan;17(1):59-60. doi: 10.1111/jch.12450. Epub 2014 Nov 27.
Judd E and Calhoun DA. Management of resistant hypertension: do not give up on medication. Nephrol Self Assess Program. 2014 Mar; 13(2): 57–63.
Kim J-B. Channelopathies. Korean J Pediatr. 2014 Jan;57(1):1-18. doi: 10.3345/kjp.2014.57.1.1. Epub 2014 Jan 31.
Tapolyai M, Uysal A, Dossabhoy NR, et al. High prevalence of Liddle syndrome phenotype among hypertensive US Veterans in Northwest Louisiana. J Clin Hypertens (Greenwich). 2010 Nov;12(11):856-60. doi: 10.1111/j.1751-7176.2010.00359.x. Epub 2010 Aug 20.
Abriel H, Loffing JF, Rebhun JH, et al. Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle’s syndrome. J Clin Invest. 1999;103(5):667-673. https://doi.org/10.1172/JCI5713.
Botero-Velez M, Curtis JJ and Warnock DG. Brief report: Liddle’s syndrome revisited–a disorder of sodium reabsorption in the distal tubule. N Engl J Med. 1994 Jan 20;330(3):178-81. doi: 10.1056/NEJM199401203300305.
Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP and Rossier BC. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J. 1996 May 15; 15(10): 2381–2387.
Schild L, Canessa CM, Shimkets RA, Gautsch I, Lifton RP and Rossier BC. A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci USA. 1995 Jun 6;92(12):5699-703. doi: 10.1073/pnas.92.12.5699.
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 Nov 4;79(3):407-14. doi: 10.1016/0092-8674(94)90250-x.
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INTERNET
Mubarik A, Anastasopoulou C, Aeddula NR. Liddle Syndrome (Pseudohyperaldosteronism) [Updated 2024 Mar 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536911/ Accessed May 22, 2025.
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