Acknowledgement of Liddle's Syndrome has not been added yet.

Among the world’s population, Liddle’s syndrome occurs with an unknown prevalence rate. This may be due to the difficulty in diagnosing a cause of hypertension across all age groups, as hypertension in individuals under 30 years old is more rare and is often treated with more scrutiny to understand the cause than in the older population. It is estimated that Liddle’s syndrome is the cause of about 0.9-1.5% cases of hypertension in people under 30. 

 

Name	Abbreviation
Pseudohyperaldosteronism
Pseudoprimary hyperaldosteronism

The cause of Liddle’s syndrome is a mutation in the genes encoding the epithelial sodium channel, or ENaC, in the kidney. The “Na” in this acronym is attributed to the chemical formula for sodium, “Na”. This is an autosomal dominant inherited mutation (see Rareshare Guide on Genetic Inheritance). The genetic mutation of ENaC is a gain of function mutation (meaning the mutation increases activity) of the following genes that encode different components of the ENaC channel protein: SCNN1A, SCNN1B, and SCNN1G which encode the α, β, and γ subunits of ENaC respectively. When these genes are mutated, certain components of the protein they encode are not formed properly. This disrupts a process called ubiquitination, where normally ubiquitin (a small protein in the cell) attaches to other proteins such as ENaC channels. Other proteins in the cell normally recognize ubiquitin on the surface of proteins and target them for degradation, which is a normal and healthy way to control cellular pathways. When the ENaC channel proteins are not formed properly, they cannot be “marked” with ubiquitin. Without this check-and-balance process, more ENaC channel proteins are left in the membrane and thus the process of sodium uptake and potassium release is increased.

 

The most common and recognizable symptom of Liddle’s syndrome is early onset hypertension (high blood pressure) in people as young as 2 years old. Some symptoms associated with hypertension that lead to seeking medical treatment are headaches, fatigue, dizziness/fainting, and changes in vision. Long term hypertension can cause organ damage: left ventricular hypertrophy (increasing size of the left ventricular cavity in the heart), hypertensive retinopathy (damage to retina blood vessels in the eyes) and nephrosclerosis (damage to the kidney). 

Another key symptom specific to Liddle’s syndrome is hypokalemia, or low amounts of potassium ions in the blood leading to elevated pH levels of the blood. Hypokalemia symptoms can resemble muscle weakness or pain, fatigue, constipation, or heart palpitations.

Early onset hypertension in young people is rare and requires critical examination by a physician in order to determine the cause. More specifically, people under 30 years old with resistant hypertension are tested for Liddle’s syndrome, which is described 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”. Diagnosis of Liddle’s syndrome causing hypertension involves identification of symptoms, analysis of family history, laboratory testing, and finally genetic testing.

In order for a diagnosis of Liddle’s Syndrome to be determined, the cause of hypertension must be distinguished from other rare disorders or causes of hypertension (high blood pressure). Some key symptoms that are found in only individuals with Liddle’s hypertension are suppressed renin (an enzyme that controls salt levels in the body) and suppressed aldosterone (a hormone that controls salt levels and blood pressure). Two common tests are used to determine Liddle’s syndrome, followed by genetic testing confirmation:

1. Urine tests - analysis of ion content in the urine to determine proper kidney function; low sodium levels and high potassium levels in the urine are indicators for Liddle’s syndrome

2. Improvement of hypertension in response to potassium sparing diuretics (amiloride) - a class of medicine that causes urination without the loss of potassium ions, meaning that they are still in the bloodstream and lowering the alkaline levels which are features of Liddle’s syndrome

Treatment of Liddle’s syndrome focuses on lowering blood pressure by controlling sodium and potassium ion levels in the bloodstream. This involves pharmaceuticals targeting the over-activated ENaC channels in the kidney. These medications, called potassium sparing diuretics, target and block ENaC channels in the kidneys and prevent sodium reabsorption and loss of potassium in the urine. Amiloride is the most common of these diuretics prescribed for Liddle’s syndrome, and while triamterene may also be effective it often requires a larger and more frequent dosage. A different diuretic, spironolactone, once prescribed for this cause of hypertension is actually how Liddle’s syndrome got its name. A physician named Grant Liddle was the first to determine that spironolactone was ineffective against this particular type of hypertension, and thus is no longer used as a therapeutic. Amiloride paired with a low-salt diet is the current treatment prescribed for Liddle’s syndrome.

As the treatment regimen for Liddle’s syndrome has been perfected in recent years, many individuals with early diagnosis and treatment of Liddle’s syndrome have a good prognosis. Often, Liddle’s syndrome is diagnosed before age 30 because symptoms of hypertension are less common in young people, which can increase the potential of a good prognosis. Left untreated, Liddle’s syndrome can lead to cardiovascular complications and damage to the kidneys, which worsens the prognosis with time. 

 

Tips or Suggestions of Liddle's Syndrome has not been added yet.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731958/#:~:text=Liddle's%20syndrome%20is%20a%20genetic,reabsorption%20in%20the%20distal%20nephron.

2. https://medlineplus.gov/genetics/condition/liddle-syndrome/

3. https://rarediseases.org/rare-diseases/liddle-syndrome/

4. https://www.merckmanuals.com/professional/genitourinary-disorders/renal-transport-abnormalities/liddle-syndrome

5. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=526

6. https://my.clevelandclinic.org/health/articles/24158-aldosterone