Congenital chloride diarrhoea

Abstract

Congenital chloride diarrhoea is one of the rare causes of diarrhoea during infancy and it is infrequently reported throughout the world. It is an autosomal recessive condition which is more prevalent in Poland, Finland, Saudi Arabia and Kuwait while rarely reported in Pakistan. Our patient was 7.5-month-old baby boy who presented with diarrhoea since neonatal period. He had consanguineous parents. On examination, baby had distended abdomen, hypotonia and hyporeflexia. Investigations revealed hypochloremic hypokalemic metabolic alkalosis. Urinary electrolytes were normal. Stool electrolytes revealed increased stool chloride excretion that confirmed our diagnosis of congenital chloride diarrhoea. Patient was treated with intravenous fluids and electrolyte replacement, followed by oral potassium and sodium replacement. He was also started on butyrate, cholestyramine and proton-pump inhibitors. He started gaining weight during his hospital admission and is being followed up in clinic.

Background

Congenital chloride diarrhoea is a rare inherited cause of diarrhoea that presents during infancy.

It is frequently reported from few middle Eastern and European countries. A few cases have been reported from India and Pakistan.^{1 2} Diagnostically, it becomes a challenge in a resource limited country due to non-availability or cost of tests like stool electrolytes, genetic tests and mutation analysis.³

Case presentation

Our patient was 7.5-month-old baby boy who presented with loose stools from first day of life. The frequency of loose stools was 10 episodes per day since birth. He had consanguineous parents and there was no family history of diarrhoea. He had four healthy siblings. His mother had history of polyhydramnios antenatally. He weighed 2.2 kg at birth and from the records available had no significant examination findings at that time. He remained on mixed breast milk and formula feeds since birth. The child started having loose stools during neonatal period and was admitted multiple times in tertiary care hospitals from second week of life for management of diarrhoea and dehydration. His stool consistency and frequency never became normal despite these interventions. The patient presented to us for the first time at 7.5 months of age. On examination, his weight and height were below fifth centile, that is, 2.7 kg and 55 cm, respectively. He had low volume peripheral pulses with pulse rate of 152/min, and blood pressure of 60/40 mm Hg, Signs of dehydration and malnutrition were present, that is, pallor, emaciation, widely open anterior fontanel, dry mucous membranes and reduced skin turgor. Generalised hypotonia, hyporeflexia was present with abdominal distension and no visceromegaly. Cardiovascular and respiratory system examination was unremarkable.

He was given intravenous fluids initially for correction of dehydration and electrolytes. Omeprazole and oral cholestyramine were given for 2 weeks. Stool frequency reduced to 3 to 4 episodes per day from 15 to 20 episodes per day. Breast feeding was continued and weaning diets were also advised with added table salt. Repeat electrolytes and arterial blood gas values were in normal range at discharge.

Investigations

Initial serum electrolytes showed marked hypochloremia; serum chloride 53.2 mmol/L (98–106 mmol/L), and hyponatremia; serum sodium: 113 mmol/L (136–145 mmol/L). Arterial blood gas showed pH 7.742 (7.35–7.45) and bicarbonate was 26.3 mmol/L (22–28 mmol/L). Stool pH was 5.5 and stool examination for fat globules and reducing sugars was negative.

Stool osmotic gap was calculated that turned out to be 38 mOsm/kg. A normal gap is between 50 and 100 mOsm/kg.⁴ Stool electrolytes showed very high chloride levels, that is, 126 mmol/L (normal value <90 mmol/L) as well as elevated sodium levels; 78 mmol/L (normal value <30 mmol/L). Low stool osmotic gap (<50 mOsm/kg) is typical for secretary diarrhoea and associated elevated stool chloride content strongly favoured the diagnosis of congenital chloride diarrhoea.⁵ Urine electrolytes were also performed to rule out the urinary excretion of chloride and that were normal.

Stool electrolytes were rechecked after correction of serum electrolytes, for confirmation of diagnosis which came back within normal limits. The combination of polyhydramnios, diarrhoea from first day of life, hypochloremic metabolic alkalosis raised strong suspicion of congenital chloride diarrhoea.

Differential diagnosis

We considered Bartter syndrome as our differential diagnosis on the basis of hypochloremic, hypokalemic metabolic alkalosis. Normal urinary electrolytes ruled out Bartter syndrome. We also considered congenital lactase deficiency and that was ruled out on the basis of absence of typical clinical features like excessive flatulence, perianal rash and absent reducing sugars on stool exam.

Cystic fibrosis was ruled out on the basis of history and examination. Sweat test and genetic testing for cystic fibrosis was not available locally.

Outcome and follow-up

Patient was followed up after 1 week of discharge from hospital and then every month. Serum electrolytes were normal and he also showed marked improvement in terms of weight gain and increased muscle mass. He is being treated for last 3 months and on last clinic visit he had gained 2 kg weight since the diagnosis.

Discussion

Congenital chloride diarrhoea, which is also known as Darrow Gamble syndrome, was first described in 1945. It is a very rare cause of congenital diarrhoea. It is more prevalent in Poland, Finland, Saudi Arabia and Kuwait while rarely reported in Pakistan.

Patients presents with watery diarrhoea of prenatal onset, dehydration and failure to gain weight.

The diagnosis is confirmed when stool chloride concentration is >90 mmol/L after water and electrolyte deficits have been corrected. This condition is treated with full oral replacement of the faecal losses of chloride, potassium, sodium and water. Butyrate is proven to have proabsorptive effect on sodium, chloride and potassium, which can be given in the form of pineapple extract.⁶ Proton-pump inhibitors also help in reducing the stool output and chloride loss by reducing the gastric chloride secretion. Oral cholestyramine reduces stool quantity by binding bile acids.⁷

Congenital chloride diarrhoea is caused by mutations in the SLC26A3 gene and inheritance is autosomal recessive.^{6 8 9} The basic defect is in chloride/bicarbonate exchange mechanism of the distal ileum and colon which results in impaired absorption of chloride, impaired excretion of bicarbonate and sodium absorption.

Previously, one case has been documented in India which was vaginally delivered preterm and mother had polyhydramnios. Likewise in a case series that was conducted in Pakistan in 2017 to diagnose the causes of chronic diarrhoea, one case out of that, 5-month-old girl with similar risk factors was identified as having congenital chloride diarrhoea that responded to electrolyte replacement and butyrate therapy.¹ Similarly, another case documented from Pakistan in a 5-month-old child presenting with diarrhoea since first day of life.¹⁰ Both of the cases responded to electrolyte replacement and butyrate therapy.

Learning points.

• Congenital chloride diarrhoea should be considered in any patient presenting with watery diarrhoea in infancy.

• Antenatal risk factors like polyhydramnios, abortions and deaths of siblings must be evaluated in patients with chronic diarrhoea.

• Diarrhoea with metabolic alkalosis should always be investigated further.