Congenital Chloride Diarrhoea

Congenital chloride diarrhoea is an autosomal recessive disorder caused by variants in SLC26A3, which encodes the apical chloride bicarbonate exchanger in the ileum and colon. It causes lifelong watery, chloride rich diarrhoea from birth, with hypochloraemic hypokalaemic metabolic alkalosis.

It is rare worldwide but more frequent in Finland, Poland and the Arabian Gulf (including Kuwait and Saudi Arabia), where founder variants and consanguinity increase incidence. Prenatal presentation includes polyhydramnios, preterm birth and dilated bowel loops on ultrasound.

With early diagnosis and lifelong electrolyte replacement, outcome is good. Delayed diagnosis causes dehydration, kidney injury and growth failure.

Pathophysiology.

Failure of chloride absorption in exchange for bicarbonate leaves chloride in the stool, causing osmotic diarrhoea and loss of chloride. Bicarbonate secretion into the gut is reduced, so the stool is acid, and bicarbonate is retained, causing metabolic alkalosis.

Secondary hyperaldosteronism from volume depletion increases potassium loss and worsens alkalosis. Chronic hypovolaemia damages the kidneys.

• Polyhydramnios and preterm delivery, abdominal distension and watery, greenish diarrhoea in the first days (often mistaken for urine in the nappy).
• Dehydration, failure to thrive, hypotonia and lethargy.
• Metabolic alkalosis with hypochloraemia, hyponatraemia and hypokalaemia.
• Later: nephrocalcinosis, kidney impairment, hyperuricaemia and gout, inflammatory bowel disease, hernias and male infertility in some.

Red flags.

• Neonatal dehydration with alkalosis, hypokalaemia and persistent watery diarrhoea.
• Antenatal dilated bowel loops with polyhydramnios.
• Rising creatinine, hypertension or nephrocalcinosis on ultrasound.

• Stool chloride over 90 mmol/L (and higher than the sum of stool sodium and potassium), with low urinary chloride (under 10 mmol/L) in the setting of alkalosis.
• Blood gas and electrolytes showing hypochloraemic hypokalaemic metabolic alkalosis, hyponatraemia and raised renin and aldosterone.
• SLC26A3 genetic testing confirms the diagnosis.
• Abdominal X-ray (dilated bowel loops), renal ultrasound for nephrocalcinosis and renal function.

Differential diagnosis. Congenital sodium diarrhoea (acidosis, high stool sodium), Bartter syndrome, cystic fibrosis (pseudo-Bartter), intestinal obstruction, pyloric stenosis, infectious diarrhoea, laxative misuse and other congenital diarrhoeal disorders.

Acute dehydration. IV 0.9% sodium chloride with potassium chloride (20 mmol/L once urine output is established), adjusted to electrolytes, followed by oral replacement. Avoid chloride poor fluids.

Long term replacement.

• Sodium chloride 3 to 6 mmol/kg/day and potassium chloride 2 to 4 mmol/kg/day orally, in divided doses throughout the day, titrated to normal serum electrolytes, urinary chloride over 20 mmol/L, and normal growth.
• Requirements rise during illness, with increased losses, and may fall with age.
• Proton pump inhibitor (omeprazole 1 mg/kg/day) or butyrate may reduce stool chloride in some patients.
• Adequate nutrition with a normal diet.

Complications. Monitor for nephrocalcinosis, kidney impairment, gout, inflammatory bowel disease and hernia. Maintain hydration and avoid overtreatment, which causes acidosis and hypernatraemia.

Monitoring. Electrolytes, blood gas, creatinine, urine chloride and growth every 3 months in infancy and 6 to 12 months later. Renal ultrasound annually.

Referral and escalation. Refer to paediatric gastroenterology and nephrology, with genetic counselling for the family.