NORD gratefully acknowledges 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.
Liddle syndrome is a rare genetic disorder caused by abnormal kidney function that results in high blood pressure (hypertension). This disorder is caused by a disease-causing variant (mutation) in one of 3 genes (SCNN1A, SCNN1B, and SCNN1G) that encode the epithelial sodium channel (ENaC).
While ENaC is present throughout the body in organs such as the lungs and kidney, ENaC activity in the kidney characterizes the clinical presentation. Mutation of one of the 3 genes that cause Liddle syndrome results in higher-than-normal ENaC activity. Over-active ENaC in the distal nephrons of the kidney leads to excessive sodium reabsorption and associated electrolyte imbalances. The excess sodium retention effects blood pressure control, resulting in hypertension that is resistant to most anti-hypertensive medications. Potassium secretion in the kidney is affected, and low concentration of serum blood potassium (hypokalemia) is present in most, but not all, patients.
Plasma renin activity and serum aldosterone levels are low. Severity of hypertension, which is the presenting finding, varies from mild to severe, even in patients in the same family. The symptoms and severity can vary by age, sex and life events such as pregnancy. Amiloride, a potassium-sparing diuretic, inhibits ENaC, and is the mainstay of therapy. Additional treatment includes a low-salt diet and additional anti-hypertensive medications, as needed.
Liddle syndrome is a monogenic cause of hypertension, meaning that a mutation in just one gene (either SCNN1A, SCNN1B, or SCNN1G) is sufficient to cause hypertension. Other single gene mutations resulting in hypertension (including familial hyperkalemic hypertension, glucocorticoid remedial aldosteronism, apparent mineralocorticoid excess, and activating mineralocorticoid receptor mutation) also cause hypertension by increasing sodium reabsorption in the kidney. Monogenetic hypertensions are remarkable because most cases of hypertension have no single, identifiable cause and are termed “essential” or “primary” hypertension. While monogenic hypertension disorders are rare, their scientific impact in the understanding of hypertension has been immense. They have led to the identification of the kidney’s role in the pathophysiology of hypertension as well as the importance of dietary salt in hypertension management.
Liddle syndrome is sometimes grouped with other disease processes affecting renal tubules, known as “tubulopathies,” including the subtypes of renal tubular acidosis (proximal, distal, and hyperkalemic) and nephrogenic diabetes insipidus. It is also sometimes discussed with other “channelopathies”, or disorders caused by the dysfunction of an ion channel, or regulation of an ion channel (Kim 2014). Ion channels are proteins which facilitate the movement of inorganic ions such as Ca2+, K+, Mg2+, or Na+ across cell membranes. Liddle syndrome is also sometimes grouped as a form of pseudohyperaldosteronism, or conditions that present with similar symptoms to hyperaldosteronism (such as elevated blood pressure, hypokalemia, metabolic acidosis and low levels of plasma renin activity) in the absence of elevated aldosterone. Other kinds of pseudohyperaldosteronism can be caused by mutations to 11-beta-hydroxysteroid dehyrdrogenase type 2 gene, which is responsible for lowering cortisol levels in aldosterone sensitive principal cells of the nephron, congenital overproduction of 11-deoxycorticosterone, tumors, or natural licorice consumption.
The identification of Liddle syndrome as an autosomal dominant, monogenetic renal tubulopathy of the ENaC was driven by the work of Dr. Grant Liddle, the efforts of “GS”‘ the first reported patient, and the pioneering work of Drs. David Warnock, Richard Lifton, Bernard Rossier, Richard Shimkets and Mauricio Botero-Velez. Dr. Warnock has called GS, the patient ‘sparkplug,’ who enabled the charting of the first Liddle syndrome pedigree.
In 1960, Dr. Liddle examined a 16-year-old female (GS) who had been referred to him with a diagnosis of aldosteronism, producing negligible amounts of aldosterone and high levels of sodium in her bloodstream and saliva. In 1963, Liddle wrote the results of her treatment, as well as his treatment of her younger brother. Liddle concluded that the siblings, “had an unusual tendency to conserve sodium and excrete potassium, even in the virtual absence of mineralocorticoids (Liddle and GW 1963). He administered triamterene, an inhibitor of ENaC and designed a low sodium diet. In his article, Dr. Liddle also presented a survey of 23 family members, noting that their mother and maternal grandmother had both died in their forties of hypertensive vascular disease, but no such issues were identified in the father’s family. Liddle hypothesized that this pseudo-aldosteronism was a familial renal disorder.
In 1989, GS, 43 years old, was admitted to the University of Alabama at Birmingham (UAB) Medical Center to receive a cadaver kidney transplant. Most fascinating was that the transplanted kidney had “normalized” her ability to process sodium, “curing” her symptoms. Interest in Dr. Liddle’s work was reignited when she identified herself to UAB researchers as the patient described in his 1963 article.
GS facilitated the expansion of her lineage to 43, the results confirming the hypothesis of a familial disorder. The specimens were provided for genetic analysis, to the Howard Hughes Medical lnstitute, Lifton Laboratory at Yale University. The analysis, combined with four other subject specimens, identified the linkage of symptoms with a subunit of the kidney ENaC, the three genes that cause Liddle syndrome. GS lived to learn of the genetic identification, the fruition of Dr. Liddle’s familial renal disorder hypothesis.
There is no overt set of symptoms that is distinct in persons with Liddle syndrome to uniquely distinguish it from other disorders. The lack of an easily observable set of traits in the patient’s physical examination, other than an elevated blood pressure reading, presents difficulties for diagnosis (see sections below on Diagnosis and Related Disorders).
The most notable finding in those with a Liddle syndrome mutation is a high risk of developing hypertension (high blood pressure). Hypertension is estimated to affect about 92% of people with a disease-causing mutation for Liddle syndrome (Tetti et al. 2018). Many Liddle syndrome patients have been observed to develop hypertension at an unusually early age, often in the teenage years (Cui et al. 2017). Resistant hypertension in children and teenagers may alert the clinician to consider tests for Liddle syndrome. The degree of hypertension in patients with Liddle syndrome is variable, as are the downstream effects of hypertension such as damage to other organs caused by high blood pressure.
Typical clinical findings include hypokalemia (low potassium in the blood), hypertension, metabolic alkalosis (high pH in the blood) and low plasma aldosterone and renin activity. Each of these findings is variable, for example, hypokalemia is not found universally among Liddle syndrome patients. The reabsorption of sodium from overactive ENaC in the kidney facilitates a loss of potassium and protons in the urine, causing both hypokalemia and metabolic alkalosis. These findings are similar to patients with an excess of aldosterone, since upregulating ENaC is an important action of aldosterone in the kidney. However, in Liddle syndrome ENaC is highly active in the absence of aldosterone. In the salt-expanded state caused by Liddle syndrome, the renin-angiotensin-aldosterone cascade is downregulated or suppressed, resulting in both low plasma renin activity and low serum aldosterone levels.
Liddle syndrome is an autosomal dominant genetic disorder caused by mutations in the genes that code for the epithelial sodium channel (SCNN1A, SCNN1B, and SCNN1G). These mutations result in an increase in ENaC activity, sodium and water retention and hypertension.
The epithelial sodium channel (ENaC) is an ion channel. Each channel is composed of three subunits, alpha, beta, and gamma (each subunit transcribed from a separate gene: SCNN1A, SCNN1B, and SCNN1G, respectively). Each of these subunits spans the cellular membrane at both ends and has a large extracellular loop. ENaC is expressed on the surface of many cells including epithelial cells of the lung, skin, colon, reproductive tracts, brain and kidney. Most relevant to Liddle syndrome is ENaC function in kidney principal cells, where ENaC facilitates movement of sodium from filtrate into the cell. A balance of insertion and removal of ENaCs in the cell membrane is one of many factors that influence ENaC activity. In Liddle syndrome, retrieval of ENaC from the cell membrane is impaired, resulting in an over-abundance of ENaC and therefore an overall increase in activity.
Mutations identified in SCCN1A, SCNN1B and SCNN1G genes alter the retrieval and degradation of these subunits from the cellular membrane by preventing a process known as ubiquitination, which tags subunits for retrieval from the membrane. Most Liddle syndrome cases identified to date have been caused by mutations to SCNN1B or SCNN1G. However, a family with Liddle syndrome caused by an SCNN1A mutation has been identified recently (Salih, 2017).
The recovery of sodium and water from the kidney back to blood are linked and are a regulator of the plasma volume. Most of the sodium and water is recovered with little regulation early in nephrons, the units in the kidney that process plasma and produce urine. The last, and regulated, step in recovery of sodium, involves ENaC. The high activity of ENaC in patients with Liddle syndrome results in more sodium reabsorption and a salt-expanded state. The relative excess of salt in the body causes the blood pressure to increase due to the linked increase in plasma volume.
The principal cells in the kidney, where ENaC reabsorbs sodium, have multiple functions. One of these functions is to secrete potassium. When sodium ions are removed from the filtrate, potassium and hydrogen ions move into the urine, balancing charge. Overtime, the loss of potassium and protons in the urine can lead to hypokalemia (low potassium in the blood) and metabolic alkalosis (elevated pH in the blood), respectively.
Liddle syndrome is inherited in an autosomal dominant manner, so it is likely to occur in multiple members of the same family. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Estimates of how common Liddle syndrome is vary. A survey of symptoms of veteran patients with hypertension found that 6% met the non-genetic diagnostic criteria for Liddle syndrome (Tapolyai et al. 2010), which is a much higher prevalence than confirmed cases by genetic testing. Gene sequencing studies of early onset hypertension have suggested a population prevalence of about 0.9–1.5% among those who develop hypertension before age 30 (Liu et al. 2018). While most confirmed cases of Liddle syndrome are identified in children through evaluation of early-onset hypertension, cases have also been identified later in life (Pepersack et al. 2015).
Liddle syndrome has been identified in populations worldwide, although specific genetic lineages might be distributed non-uniformly (Enslow, Stockand, and Berman 2019). The strength of the autosomal dominant mutation has been demonstrated in its persistence in a pedigree through generations. For example, a Liddle syndrome causing mutation may have occurred in a population decades ago, leaving an isolated region with a higher-than-normal prevalence (Pagani et al. 2018).
Diagnosis of Liddle syndrome often includes identification of symptoms, patient and family history and laboratory testing (e.g., plasma renin activity, serum aldosterone levels). Diagnosis begins with identification of resistant hypertension, and then analysis of laboratory values. This is followed by genetic testing. Clinicians consider the diagnosis of Liddle syndrome when evaluating secondary causes of hypertension and/or difficult-to-control hypertension. Resistant hypertension is defined by the American Heart Association as “blood pressure that remains above goal despite optimal doses of 3 antihypertensive agents of different classes, one ideally being a diuretic.”
The gold standard for diagnosing Liddle syndrome is genetic sequencing of the three genes where mutations are known to be associated with Liddle syndrome: SCNN1A, SCNN1B, and SCNN1G. More than 30 different mutations in these genes have been found to cause Liddle syndrome. Most of these mutations are in SCNN1B and SCNN1G genes, and in many patients only these genes will be sequenced.
Genetic counseling is recommended prior to testing. A positive genetic test should include communication with the patient about familial decisions and outreach to potentially affected family members.
The robust response to amiloride, a potassium sparing diuretic, continues to be integral to the diagnosis of Liddle syndrome. Although other diuretics are often prescribed first for hypertension, other classes of diuretics are not appropriate as they either do not alter the activity of ENaC, or in the case of some other potassium sparing diuretics will not be effective due to the mechanism of Liddle syndrome.
A person diagnosed with Liddle syndrome may not develop chronic kidney disease (CKD), but it does preclude them from donating a kidney. Placement on the registry to receive a renal transplant has been effective in some patients, as the replacement of the mutated ENaC with functioning ENaC in the donated kidney may resolve the symptoms of Liddle syndrome.
The goal of treatment is to resolve the patient’s hypertension, lowering blood pressure measurements to achieve guideline targets of control. A controlled blood pressure reduces cardiovascular risk and often has a positive effect on the patient’s overall health, including mental health.
In a patient with Liddle syndrome the response to standard treatments for hypertension such as thiazide diuretics or ACE inhibitors may be reduced compared to other hypertensive patients, especially in the absence of treatment with amiloride. This may lead healthcare providers to falsely believe that patients are failing to comply with prescribed medication regimens. Repeated questioning of patient compliance to medication regimens can have psychological and emotional consequences. For this reason, response to amiloride should be considered in the process of diagnosing Liddle syndrome and developing a treatment plan.
Amiloride is the first-line treatment of Liddle syndrome. It targets and blocks ENaC in the kidney, thereby directly countering the pathologic pathway. Other potassium sparing diuretics, like triamterene, eplerenone, spironolactone and finerenone are less effective or ineffective. Eplerenone, spironolactone and finerenone have mechanisms of action different from amiloride and triamterene which renders them ineffective in the treatment of Liddle syndrome. For example, spironolactone antagonizes binding of aldosterone to its receptor, preventing aldosterone from binding and acting in cells in the kidney. In patients with Liddle syndrome, aldosterone levels are low, and so inhibiting aldosterone’s action with spironolactone has little effect. In fact, the lack of response to spironolactone was a feature identified by Grant Liddle in his initial description of Liddle syndrome. Despite triamterene being described as the first effective treatment for Liddle syndrome, amiloride has superior efficacy to triamterene and is preferred.
When the diagnosis of Liddle syndrome is made later in life, additional anti-hypertensive medications are also needed to achieve blood pressure control. Amiloride is not time-release formulated, and it is recommended to take at similar times each day, some patients with Liddle syndrome may opt for a twice daily regimen. The treatment is life-long. Amiloride is available for custom-compounding by pharmacists. The pharmacist can prepare a dose in capsule form, without other medications or stabilizing compounds. This specialized formulation may be appropriate for ‘fine-tuning’ dose level.
While amiloride does not have sufficient data in pregnant women to be confirmed as safe, it has not been found to cause fetal harm in animal studies. Women with Liddle syndrome have continued amiloride in pregnancy without fetal or maternal complications. Blood pressure during pregnancy may be difficult to treat without amiloride, particularly in the 3rd trimester.
Limiting salt in the diet is an important component to the medical management of hypertension. In Liddle syndrome, a low salt-diet is particularly effective, especially when paired with amiloride. Because sodium retention is directly involved in the mechanism of persistent hypertension in Liddle syndrome, a low sodium diet can be helpful in achieving a goal blood pressure (Pagani et al. 2018).
Genetic counseling is recommended for patients with Liddle syndrome and their family members.
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