Metabolic alkalosis caused by genetic defect - an unusual case history

Metabolic alkalosis is a disturbance of acid-base balance, with many possible causes, characterized by primary increase in blood bicarbonate (HCO₃) and pH. Hypoventilation is the normal compensatory respiratory response to metabolic alkalosis. This results in increased pCO₂ and, if the metabolic alkalosis is particularly severe, reduced pO₂ (hypoxemia). 

A recent report describes a case history of severe metabolic alkalosis with a very unusual cause. The patient was a 46-year-old lady with a history of chronic alcohol abuse, mild hypothyroidism, and sensorineural hearing loss since childhood that had prompted cochlear implantation 1 year previously. She was found on the floor at home in a confused state with rigid limbs; pulse oximetry revealed reduced oxygen saturation (91 %). 

On admission to hospital arterial blood gas results (pH 7.59, HCO₃ 45 mmol/L, pCO₂ 6.39 kPa, base excess +20.4 mmol/L and pO₂ 7.08 kPa) allowed a diagnosis of severe metabolic alkalosis and hypoxemia. Other abnormal blood results on admission included severe hypokalemia (plasma potassium 1.4 mmol/L) and hypocalcemia (plasma calcium 2.07 mmol/L). 

These electrolyte disturbances, in combination with metabolic alkalosis, likely account for increased muscle tone, bilateral carpal spasm and rightward tonic deviation of the neck evident on clinical examination. 

Curiously, the patient had been hospitalized before with an almost identical biochemical derangement (hypokalemic metabolic alkalosis) following vomiting for 3 days; she was apparently predisposed to development of metabolic alkalosis during intercurrent illness. It eventually emerged following gene sequencing that the patient was suffering Pendred syndrome. 

This is an inherited defect in the gene that encodes a protein called pendrin. Pendrin is expressed in the membrane of cells in the inner ear, thyroid and collecting ducts of the kidney where it mediates the transport of particular ions across cell membranes, (iodide ions in the case of thyroid cells, and bicarbonate ions in the case of inner-ear and renal cells). 

The most significant clinical effect of the abnormal pendrin protein that results from the gene defect is progressive hearing loss from the childhood years. Some affected individuals, as was the case for this lady, eventually develop hypothyroidism. This is only the second documented case of Pendred syndrome being associated with severe metabolic alkalosis. 

The action of normally functioning pendrin in the collecting ducts of the kidneys is to increase, when necessary, the elimination of bicarbonate in urine; thus by minimizing the accumulation of bicarbonate in blood, pendrin protects against metabolic alkalosis. That protection is lost in those with Pendred syndrome. 

In this case severe metabolic alkalosis led to a unifying diagnosis that explained hearing loss, hypothyroidism and apparent propensity to severe metabolic alkalosis. The wider significance of the case history is that it highlights a recently discovered role for renally located pendrin in normal acid-base homeostasis.