22nd June 2023

Abnormalities of potassium balance

Liddle’s Syndrome

Liddle’s syndrome is a rare autosomal dominant disorder causing higher than normal activity of the epithelial sodium channel (ENaC). It is commonly asymptomatic and picked up on investigation of hypertension in a young person, but patients can also present with symptoms of hypokalaemia such as weakness, fatigue or palpitations.

Biochemically, these patients tend to have a metabolic alkalosis with high sodium and low potassium, similar to hyperaldosteronism. However, patients with Liddle’s syndrome tend to have low to normal aldosterone levels. The diagnosis is then made with genetic testing looking for a mutation in the associated gene (SCNN1A, SCNN1B or SCNN1G).

The first line of treatment for Liddle’s syndrome is amiloride, which blocks ENaC in the kidney. The use of other potassium sparing medications, such as spironolactone, tend to be ineffective in these patients as they act on aldosterone, which is already low in these patients. Patients are also advised to follow a low sodium diet.

Bartter Syndrome

Another rare cause of metabolic alkalosis with hypokalaemia is Bartter syndrome, an autosomal recessive disorder. Unlike the other causes discussed in this section, Bartter syndrome is generally diagnosed in neonates or those in the early years of life.

There are five subtypes of Bartter syndrome; three of the five subtypes (types 1, 2 and 4) are found neonatally, with some signs presenting in the antenatal period (such as polyhydramnios and prematurity of birth). After birth, these infants may present with polyuria and polydipsia, as well as lethargy and a failure to gain weight. If not recognised early and hydrated appropriately, these symptoms can be life threatening. Types 1 and 2 can cause hypercalciuria, and as a result, these patients may have nephrocalcinosis. Type 4 is associated with irreversible sensorineural deafness. The remaining subtypes (Type 3 and 5) generally present later, sometimes within the first two years of life but usually when school aged. Patients tend to present with symptoms of hypokalaemia, as well polydipsia, polyuria and salt craving.

Whilst simple biochemical findings such as potassium and bicarbonate are similar to Gitelman syndrome (see below), Bartter syndrome differentiates itself by high levels of renin and aldosterone, compared to Gitelman syndrome, in which these levels tend to be low.

Management of all subtypes involves adequate hydration, replacement of potassium and sodium through diet and supplementation, a potassium-sparing diuretic such as spironolactone, and NSAIDs such as indomethacin.

Gitelman Syndrome

In 1966, a physician by the name of Hillel Gitelman described in his paper “A new familial disorder characterised by hypokalaemia and hypomagnesemia” a pair of sisters with characteristics in keeping with Bartter’s syndrome but differing through also having hypomagnesaemia. This was later to be known as Gitelman syndrome.

Gitelman syndrome is an autosomal recessive disease affecting approximately 1 in 40000 of the Caucasian population. The clinical markers that would suggest this diagnosis are a metabolic acidosis with low levels of serum potassium, magnesium, chloride and sodium, and high levels of renin and aldosterone. Urinary biochemistry shows low levels of calcium as well as inappropriately high levels of potassium (considering serum hypokalaemia). Urinary chloride levels can also be useful as low urinary chloride would suggest gastrointestinal losses and point towards an alternative diagnosis such as bulimia or chronic diarrhoea.

Symptoms and severity can vary from person to person and tend to stem from the electrolyte abnormalities. These include muscle weakness, spasms, cramping, fatigue and paraesthesia. Some affected adults may also experience salt craving, polydipsia with polyuria, as well as chondrocalcinosis (accumulation of calcium in joints). QTc prolongation may also be seen on ECG and, in some cases, may lead to a fatal arrythmia. Blood pressure tends to be low.
The mainstay of treatment is supplementation of potassium and magnesium. Potassium-sparing diuretics may also be used.