What is Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)?
Gitelman syndrome (GS) is a rare inherited condition that affects the body’s ability to balance salts. This leads to problems like urinary potassium loss, low potassium levels in the blood, changes in the blood’s acid balance, low calcium in the urine, and low magnesium levels. This syndrome is also referred to as familial hypokalemia-hypomagnesemia, meaning that it runs in families and causes abnormally low levels of potassium and magnesium.
GS is perhaps the most common inherited kidney-related disorder, affecting about 1 to 10 out of every 40,000 people globally, with higher rates in Asia. It’s caused by genetic mutations that stop certain functions. Low magnesium levels and low calcium in the urine are strong indicators of the syndrome; however, low magnesium levels could be absent, and calcium levels could vary. In some cases, it becomes hard to tell GS apart from other kidney conditions that cause salt loss. Genetic testing for GS is becoming more common, but it’s still costly.
For a long time, doctors thought Gitelman syndrome was harmless and would likely only show symptoms during adolescence or adulthood. Often, the symptoms may not appear or may be mild or vague. However, some studies have challenged this belief, noting that the syndrome can show up in many forms and can be severe. It has been argued that GS significantly reduces quality of life, similar to heart failure or diabetes. Serious cases of the syndrome can lead to early childhood onset, bone changes, slow growth, muscle spasms, seizures, muscle breakdown, and irregular heart rhythms. Do bear in mind that in many severe cases, GS was identified based on its symptoms rather than on a genetic basis, potentially causing confusion with similar disorders.
There are several treatments available for GS, but we don’t have a lot of evidence on their effectiveness and safety. We still need more information about the syndrome’s potential long-term impacts. These could include chronic kidney disease, bone changes, irregular heartbeats, high blood pressure caused by other conditions, and handling the syndrome during pregnancy. Further efforts are needed to fully understand the syndrome, including criteria and methods for diagnosis, its different forms, clinical tests and follow-ups, its symptoms, the precise nature and severity of the chemical imbalances it causes, as well as treatments and the long-term impacts of the disease.
What Causes Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)?
Gitelman syndrome is a disorder that affects how your kidneys process certain minerals in your body. It’s an inherited condition, meaning it’s passed down from parents to their children. Specifically, it’s caused by changes (mutations) in certain genes that affect how the cells in a part of the kidney called the distal convoluted tubule work. This part of the kidney takes care of about 7% to 10% of the absorption of minerals called electrolytes from our urine. Mutations also affect how magnesium is processed in the cells of the small intestine.
The mutations interfere with two specific genes:
1. The SLC12A3 gene, which makes a protein involved in balancing the levels of sodium and chloride (two important electrolytes) in the body.
2. The TRPM6 gene, which plays a role in how our kidneys manage magnesium levels in the body.
It’s actually quite common to see Gitelman syndrome caused by mutations in the SLC12A3 gene, with over 350 different alterations to this gene identified in patients. Sometimes, a patient might have more than one of these alterations in the same gene. And on occasion, Gitelman syndrome features can be seen when there are mutations in a different gene, the CLCNKB gene, which is more commonly associated with another kidney disease known as Bartter syndrome.
The symptoms of Gitelman syndrome can vary widely even between patients who have the same mutations. This suggests that other factors, such as other genes, sex, how the body compensates for the disease, environmental factors, and eating habits, can influence the disease.
Risk Factors and Frequency for Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
Gitelman syndrome is a rare disease, with an estimated occurrence of 25 cases per million people. Despite its rarity, it’s the most common inherited kidney disorder that results in loss of salt. Roughly 1% of people with a white ethnic background are heterozygous for this condition, meaning they possess one normal and one abnormal gene of a pair.
Signs and Symptoms of Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
Gitelman syndrome, a medical condition, can showcase a diverse range of symptoms, which can depend on several factors like the patient’s age, severity of their symptoms, and their specific biochemical imbalances. Some people may not experience any symptoms and only discover they have the condition when routine medical tests reveal low potassium levels. On the other hand, some may experience fatigue and a general feeling of discomfort, muscle cramps, and even have lower than average blood pressure. Certain severe conditions like muscle spasms and paralysis due to low potassium may occur, particularly in Asian populations. Alongside low potassium levels, imbalances like the high alkaline level in the body and low calcium in urine are common. Some individuals may also have low magnesium levels, a condition seen in many cases, but not always. These symptoms are similar to what one might experience when taking a specific type of water-pill called a thiazide diuretic.
The syndrome typically appears in teenagers and adults but can sometimes be diagnosed in children, even newborns. Key symptoms and features that suggest a person may have Gitelman syndrome include:
- Craving for salty foods.
- Muscle weakness, fatigue, reduced athletic performance, and endurance.
- Experienced fainting spells, cramps, tingling sensations, spasms in the hands and feet.
- Delay in maturity during puberty, short stature, growth retardation.
- Increased thirst or abnormal drinking behavior.
- Experiences of abdominal pain.
- Dizziness, frequent urination at night, joint pain, heart palpitations, vision problems in adults.
About three-quarters of patients have increased thirst and crave foods with a high salt content, like pickled brine or salted cucumbers, oranges, and lemons. Some patients may experience joint pain. The condition may also lead to calcium deposits in the cartilage and kidneys. Heart arrhythmias, or irregular heartbeats, are common and can cause sensations of palpitations in about 60% of patients. In about 50% of patients, the time taken by the heart to recharge after each beat might get longer than usual causing a condition known as a prolonged QTc interval. However, sudden death as a result of this is rare. It’s also unusual for patients to manifest classical signs of low potassium and low magnesium levels on electrocardiograms.
Testing for Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
Most patients with Gitelman syndrome, a rare kidney disorder, have unremarkable physical signs or only mild symptoms. Typically, they have normal or low blood pressure. Their blood may show a variety of abnormalities. One common one is low serum potassium (hypokalemia). Serum magnesium may be low (hypomagnesemia) or normal. The serum bicarbonate, which helps control the body’s pH level, is usually high which is indicative of metabolic alkalosis, a condition characterized by excessive base (alkali) in the body. The levels of plasma renin and aldosterone, which regulate blood pressure and balance electrolytes, are also high (hyper-reninemic hyperaldosteronism). Urinary calcium excretion is low, which is known as hypocalciuria.
These lab findings are similar to the effects of using certain types of water pills (thiazide diuretics). A urinary diuretic test can be helpful in difficult cases where there’s no known family history of the condition. This especially comes in handy in distinguishing Gitelman syndrome patients who react differently to the thiazide diuretics.
Abuse of laxatives can produce similar symptoms, but typically with metabolic acidosis (a condition where the body is producing too much acid) and a ratio of urine potassium to creatinine of less than 1.5.
Medical professionals suspect Gitelman syndrome in a patient when they see the following symptoms:
– Long-term low potassium in the body, and the patient is not using potassium-lowering drugs
– Metabolic alkalosis
– Low levels of magnesium in the body
– Low levels of calcium in the urine
– Normal or low blood pressure
– Normal kidney ultrasound results with no kidney calcification or kidney disorders
If the patient is taking magnesium or potassium supplements and the levels of these elements in their blood are normal or nearly normal, they should stop taking these at least 48 hours before testing to uncover the abnormalities. Also, doctors suggest taking blood and urine samples for testing. There’s generally not a need to collect 24-hour urine samples; spot urine samples are usually enough to diagnose the condition.
Certain factors suggest that Gitelman syndrome might not be the correct diagnosis:
– If there’s a family history of kidney malformations or any dominant kidney disease
– History of polyhydramnios (excess amniotic fluid) or hyperechogenic (appears bright in ultrasound) fetal kidneys
– Presence of kidney malformations, like only having one kidney or many cysts in the kidneys (polycystic kidneys)
– A long history of hypertension (high blood pressure)
– Chronic use of diuretics (water pills) or laxatives
– Lack of low potassium levels, or inconsistent low potassium levels, in the absence of replacement therapy
– Onset of symptoms before the age of three
– Signs of increased fluids in the body’s tissues
Just note, even if the patient has arterial hypertension (high blood pressure), it does not rule out Gitelman syndrome, particularly in adults.
The sure-fire way to diagnose Gitelman syndrome is genetic testing that identifies mutations in a specific gene (SLC12A3). As genetic testing has rapidly advanced, using water pills for testing is no longer considered a diagnostic tool due to associated risks. For instance, in an attempt to distinguish Gitelman syndrome from Bartter syndrome (a similar but different kidney disorder), water pills can cause sudden fluid loss in patients with a defect in their kidney filtering system. The same goes for children or patients on medications that affect how their kidneys filter. In addition, water pills may cause acute interstitial nephritis (a kidney disorder that results in kidney inflammation) and hypersensitivity reactions (violent immune responses that can lead to allergic reactions). So, a kidney biopsy is usually not required unless there are complications, such as heavy protein loss in the urine.
Treatment Options for Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
Treatment for symptoms involves taking additional potassium and magnesium. This can be a little complicated. For example, increasing your body’s potassium might mean taking large amounts of a substance called potassium chloride. It’s important not to replace this with something similar like gluconate or aspartate because these could actually make the problem worse. Potassium chloride can also be hard on the stomach, so it’s better if it’s not taken on an empty stomach. It can come as a syrup or in water, in a slow-release form, and which one is best will depend on the patient. The amount taken will depend on the person and their specific needs. Sometimes, if the patient can’t take medication orally or if their potassium levels are dangerously low (which can lead to serious health problems like heart arrhythmias, respiratory failure, paralysis of the limbs, or muscle breakdown), it might have to be given intravenously (through a vein).
If a patient’s potassium levels stay low despite these measures, or if side effects are too much to handle, other treatments might be suggested. These can include renin-angiotensin system blockers, diuretics that help the body hold onto potassium, or nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin, or some combination of these.
Replacing magnesium might be necessary too, but this can sometimes cause diarrhea. Magnesium chloride doesn’t usually cause this problem and can be given in daily doses of 4-5 mg/kg. It’s best to split these doses up into 4 or 6 individual doses throughout the day to cut down on the risk of diarrhea. If a patient’s magnesium is also low, the first step is to get those levels back to normal, as this can make it easier to increase potassium levels and reduce the risk of complications. The target level for magnesium is 0.6 mmol/l (1.46 mg/dl). Ideally, it’s better if magnesium comes from oral supplements. Different salts of magnesium are available, but they vary in what the body can actually use and they can cause diarrhea at higher doses. Some types, like aspartate, citrate, and lactate, are easier for the body to use than others.
Intravenous administration of magnesium (given through a vein) is usually only for serious cases, like if the person is experiencing muscle spasms or cardiac arrhythmias (heart rhythm problems) or can’t tolerate oral supplements. In really serious cases, like with acute muscle spasms, an infusion of 20% magnesium chloride is recommended every 6 hours.
There are also other drugs, like amiloride and spironolactone, which can help the body hold onto potassium. However, these might not be suitable for people with low blood pressure and should be used with caution.
Finally, because this condition is actually caused by a problem with a protein that moves sodium chloride around in the body, consuming more of this (basically extra salt) is usually a good idea. Sometimes, the body will crave salt, and it’s a good idea to give in to this. Whether a salt supplement, in addition to increasing salt in the typical diet, is beneficial hasn’t been tested yet.
What else can Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia) be?
Gitelman syndrome can share symptoms with other disorders, particularly those that cause a loss of salt through the kidneys. Conditions that should be considered are:
- Bartter syndrome
- False Bartter-Gitelman syndrome
- Hidden or secretive vomiting
- Excessive use of laxatives
- Consumption of licorice
- Birth-related chloride diarrhea
Medical tests, particularly those examining both blood and urine for levels of certain chemicals, are very important to correctly identify which of these conditions, if any, a person may have.
What to expect with Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
People with Gitelman syndrome generally have a very good outlook. However, a few might be at risk for irregular heartbeats. Additionally, for some patients, severe tiredness can greatly impact their everyday lives. It’s highly uncommon for this condition to get worse or lead to kidney problems.
Possible Complications When Diagnosed with Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
While Gitelman syndrome is generally a benign condition, patients might experience a few rare but serious complications. Here are some noteworthy potential complications:
- Seizures
- Tetany – a symptom characterized by muscle cramps and twitching
- Ventricular tachycardia – abnormal heart rhythm
- Rhabdomyolysis – condition where damaged muscle breaks down fast
- Blurred vision
- Pseudotumor cerebri – a condition that mimics a brain tumor
- Sclerochoroidal calcifications – hardening in eye tissues
Preventing Gitelman Syndrome (Familial Hypokalemia-Hypomagnesemia)
For individuals with Gitelman syndrome and parents of a child with this condition, it’s often suggested they consider genetic counseling. This kind of counseling can also include testing of parents, partners, and brothers and sisters of the patient. Gitelman syndrome is caused by two malfunctioning genes (SLC12A3 mutations), and prenatal tests can detect this condition in unborn babies when these two genes are identified.
However, it’s important to understand that these tests are usually not performed because most people with Gitelman syndrome live healthy lives without significant complications. Nonetheless, in serious cases, the idea of using these advanced predictive tests may come up for possible discussion in order to better manage the condition.
