What is Liddle Syndrome (Pseudohyperaldosteronism)?
Liddle syndrome is a rare condition that can cause stubborn high blood pressure. Usually, it is noticed in early childhood, but for some, it isn’t discovered until they’re adults. The syndrome was first explained by Grant Liddle and his team in 1963.
Liddle syndrome involves a specific part of the kidney, called the collecting tubule, absorbing too much sodium and secreting too much potassium. Because of this, it’s also sometimes called pseudohyperaldosteronism. Essentially, Liddle syndrome is a less common reason for high blood pressure that happens because of a genetic mutation. This mutation affects the way the sodium channel in the collecting tubule of the kidney works.
People who are affected by this syndrome often have high blood pressure, low potassium levels in their blood (hypokalemia), and a condition called metabolic alkalosis. These are similar to signs seen in other diseases caused by too much of a hormone called mineralocorticoid, which helps control your body’s balance of salt and water.
What Causes Liddle Syndrome (Pseudohyperaldosteronism)?
Liddle syndrome is a genetic condition that a person is born with due to a change in a particular gene. This condition is passed on from parents to children in a pattern called “autosomal dominant,” meaning the child only needs to inherit the changed gene from one parent to have the condition. Liddle syndrome can affect people from all different backgrounds. Research into genetics has revealed that this syndrome is caused by certain gene mutations that result in overly active sodium channels in a part of the kidney called the distal nephron.
In 1995, a scientist named Hansson and his team discovered a mutation in the SCNN1G gene that causes Liddle syndrome. Later, it was found that these sodium channels in the kidneys are made up of three related parts – alpha, beta, and gamma – which are controlled by the genes SCNN1A, SCNN1B, and SCNN1G.
When there’s a mutation in the beta or gamma parts of the sodium channel, it becomes unusually active. This happens regardless of the activity of a hormone called aldosterone – which usually regulates how much sodium and water your kidneys remove from your bloodstream.
While these genetic mutations are often associated with Liddle syndrome, a study in 2018 by Tetti and colleagues found 31 other different gene changes that were causing Liddle syndrome in over 72 different families. More recent research continues to uncover new mutations that can lead to this condition.
Risk Factors and Frequency for Liddle Syndrome (Pseudohyperaldosteronism)
Liddle syndrome is a condition that isn’t well-studied, especially in people with high blood pressure. Two studies in younger Chinese patients found that about 1.52% and 1.72% of the people with high blood pressure that couldn’t be explained had Liddle syndrome. In the first study, only those with low levels of potassium were tested for the genetic mutation responsible for Liddle syndrome. However, Liddle syndrome can also occur in individuals with normal potassium levels. This suggests that if other researchers were to look into the occurrence of Liddle syndrome in people with high blood pressure and normal potassium levels, the percentage of people found to have the syndrome would probably be higher. This condition does not seem to favor any particular sex or race. A study in US veterans suggested that approximately 6% of them had symptoms of Liddle syndrome.
Signs and Symptoms of Liddle Syndrome (Pseudohyperaldosteronism)
Liddle syndrome is a condition that may or may not show symptoms. It’s most commonly seen as early-onset hypertension, or high blood pressure, appearing between the ages of 11 and 31. This is caused by too much sodium being absorbed in a part of the kidney called the distal nephron. Doctors often take many years, or even decades, to diagnose it. This hypertension is sensitive to a diet low in salt and can lead to headaches, dizziness, eye damage, chronic kidney disease, overgrowth of the left side of the heart, and even sudden death.
Several complications may result from this resistant hypertension, low blood potassium levels, and heart overgrowth. These include harmful irregular heart rhythms that can also lead to sudden death. Hypertension can lead to muscle weakness, excessive urination, and excessive thirst due to low blood potassium levels. Low blood potassium levels and a high blood pH level (metabolic alkalosis) are caused by excessive loss of potassium in the urine.
High rates of hypertension and low blood potassium levels are seen in patients suffering from Liddle syndrome, about 92.4% and 71.8% respectively. Moreover, research has found that around 58.2% of patients with this syndrome may also have low levels of a hormone called aldosterone. For those who do not have hypertension or low blood potassium levels, clinicians may diagnose Liddle syndrome via genetic tests, especially in cases with a significant family history.
Testing for Liddle Syndrome (Pseudohyperaldosteronism)
If you have Liddle syndrome, you usually experience hard-to-control high blood pressure, also known as secondary or resistant hypertension. Your doctor may perform lab tests which might reveal low potassium levels (hypokalemia) and a condition where your blood pH is higher than normal (metabolic alkalosis). These symptoms can be similar to another condition called hyperaldosteronism.
Your doctor will want to confirm whether you have true hyperaldosteronism or a mimic of it, known as pseudo-hyperaldosteronism. This can be done by checking the levels of two substances in your blood, renin and aldosterone. In Liddle syndrome, both renin and aldosterone levels will be low, while in hyperaldosteronism, aldosterone levels will be high. This is important to know because a specific medication called spironolactone, which is normally effective for high aldosterone levels, does not work for Liddle syndrome patients due to their low levels of aldosterone.
If your tests show low levels of both renin and aldosterone, your doctor may give you a medication containing aldosterone for two months, during which you’ll be closely monitored. Some similar conditions like glucocorticoid resistance syndrome, apparent mineralocorticoid excess syndrome, and a condition where your adrenal glands produce too much hormone (congenital adrenal hyperplasia) usually improve with this treatment. If there is no improvement with the aldosterone medication, it might indicate Liddle syndrome.
The final diagnosis of Liddle syndrome is confirmed through genetic testing, specifically analyzing the gene responsible for a protein that helps regulate how your body maintains its salt balance (ENaC).
Treatment Options for Liddle Syndrome (Pseudohyperaldosteronism)
As previously mentioned, the hormone aldosterone is usually low in patients with Liddle syndrome, which makes the drug spironolactone ineffective for its treatment. Instead, the medication of choice for this condition is amiloride. This is because amiloride directly blocks the ENaC channel, which is overly active in people with Liddle syndrome. Another drug, called triamterene, which is similar to amiloride, can also be used for this syndrome. Consuming a low-salt diet may increase the effectiveness of these medications.
However, it’s important to note that too much sodium can stop the medication from working properly. If a patient’s kidney function is normal, high levels of potassium in the blood are very rare. So, while on these medications, patients are typically advised to avoid consuming too much potassium in their diet. It’s worth noting that amiloride is considered safe for use during pregnancy.
If a patient’s blood pressure is still not controlled with these medications, other drugs may have to be used to help lower it and prevent cardiovascular complications. One has to be careful when using a drug called hydrochlorothiazide due to its common use, but other types of drugs, like beta-blockers and vasodilators, could be effective in controlling blood pressure.
What else can Liddle Syndrome (Pseudohyperaldosteronism) be?
There’s a type of high blood pressure called “low renin hypertension.” This refers to situations where the hormone called renin, which has a role in managing blood pressure, is in low levels. There are three variants of this condition:
- Low renin with low levels of aldosterone. Aldosterone is another hormone that helps to regulate blood pressure.
- Low renin with normal levels of aldosterone.
- Low renin with high levels of aldosterone.
An example of a condition that falls under the category of ‘low renin with low aldosterone’ is Liddle syndrome. Other causes of high blood pressure that also fall under this category include:
- Apparent mineralocorticoid excess
- An 11-β-hydroxyl deficiency
- A 17-α-hydroxyl deficiency
- Gordon syndrome
- Mineralocorticoid receptor activation mutation
- Resistance to glucocorticoids
- Production of ACTH hormones from a location outside the pituitary gland
- Use of licorice
Let’s talk about a couple of these. First, apparent mineralocorticoid excess. This is an inherited condition caused by a deficiency in an enzyme known as 11-β-hydroxysteroid dehydrogenase type 2. This enzyme has the job of converting the active hormone cortisol into its inactive form, cortisone, which can’t bind to the mineralocorticoid receptor. The chronic use of licorice, which contains something called glycyrrhizic acid, can also inhibit this enzyme, leading to similar effects.
Another condition, Gordon syndrome, is due to a gene mutation that impacts how ions are transported in the kidneys. This causes more sodium to be reabsorbed in the body and decreases the excretion of potassium.
What to expect with Liddle Syndrome (Pseudohyperaldosteronism)
People with a condition called Liddle syndrome often respond positively to a type of medicine called potassium-sparing diuretics. At this moment, we don’t have enough information on how this syndrome affects a person’s life expectancy in the long run. Sometimes, healthcare providers may not fully treat or correctly identify this syndrome in patients. More research is needed to figure out the rates of illness and death in individuals who develop high blood pressure as a result of this syndrome.
Possible Complications When Diagnosed with Liddle Syndrome (Pseudohyperaldosteronism)
When hypertension, or high blood pressure, remains uncontrolled, it can cause severe damage to various organs in the body. This can lead to heart attacks, mini-strokes or strokes, fluid build-up in the lungs, and thickening of the heart muscle. By diagnosing and treating hypertension early, we can delay or even prevent this type of severe damage.
Potential complications of uncontrolled high blood pressure:
- Heart attacks
- Mini-strokes
- Strokes
- Fluid in the lungs
- Thickening of the heart muscle
Preventing Liddle Syndrome (Pseudohyperaldosteronism)
Doctors should explain to patients the risks of not properly managing high blood pressure that doesn’t respond to initial treatments, known as resistant hypertension. It’s crucial for patients to understand the importance of sticking to their treatment plan to lower the chances of experiencing heart attacks and strokes. This means they should regularly check-in with their doctors.
Additionally, a diet low in salt and high in potassium can aid in managing this condition. Consistent medication and monitoring of blood pressure can also help maintain healthy levels. It’s important for patients to understand these points and integrate them into their daily routines for their long-term wellbeing.
