88/12/8

To summarize data on congenital chloride diarrhoea:

INTRODUCTION

Congenital chronic diarrhoeas:

•        being rare and often difficult to diagnose and manage

 Types:

 congenital sodium diarrhoea

 congenital sucraseisomaltase deficiency

 congenital glucose-galactose malabsorption

 congenital lactase deficiency

 congenital chloride diarrhoea (CLD)

Incidence

—  more than 250 cases with CLD have been reported worldwide

—  CLD geographical distribution is uneven

—   Onefifth of all reported patients from Finland with incidence around 1:30 000 to 1:40 000

—  In the countries around the Persian Gulf, and especially in Kuwait, as high as 1:3200 to 1:5000 because of consanguineous marriages

PATHOPHYSIOLOGY

—  Autosomal recessive disorder

—  The gene for CLD, solute carrier family 26 member 3 (SLC26A3 alias DRA), on chromosome 7q3113

—  The SLC26A3 protein is the colon’s most essential apical anion transporter

—  SLC26A3 is expressed in the duodenum and in sweat gland, male reproductive tract and kidney

—  Domain interaction between CFTR and SLC26A3 essential for epithelial HCO3 secretion in small intestine, pancreatic duct and tracheal epithelium

—  As at least two CLD-causing mutations of SLC26A3 prevent the activation of CFTR as well

—  CFTR may also play a role in the pathogenesis of CLD.

CLINICAL PICTURE

—  Polyhydramnios and dilated intestinal loops

—  slightly preterm birth, lack of meconium, abdominal distention and unnecessary surgery neonatally, watery content  stool resembling that of urine

—  Weight loss, dehydration and jaundice

—  Na+ <130 mmol⁄ L, Cl <100 mmol ⁄ L, metabolic alkalosis, activation of RAS and hypokalaemia

DIAGNOSIS

—  Typical clinical picture and a high concentration of faecal Cl, >90 mmol⁄ L after correction of the fluid and electrolyte depletion

—  Excessive volume and salt depletion reduces the amount of diarrhoea and may result in a low faecal Cl of even 40 mmol ⁄ L. Repeated faecal samples are needed for diagnosis.

—  Genetic testing is possible, but simple measurement of faecal Cl is still sufficient

SALT SUBSTITUTION THERAPY

—  In early neonatal period, gradually changed from intravenous to peroral therapy with 3–4 daily doses

—   In infancy, the substitution is dilution of 0.7% NaCl and 0.3% KCl

—  After the three first years of life, more concentrated solution of 1.8% NaCl and 1.9% KCl

—  The optimal dosage of Cl ranges from 6 to 8 mmol ⁄ kg ⁄ day in infants and from 3 to 4 mmol⁄ kg ⁄ day in older patients

—  Salt substitution increases intestinal absorption by unspecified mechanisms

—  The defective SLC26A3-mediated anion transport remains in the intestine and the diarrhoea is persistent

—  Adequate excretion of Cl into the urine, in addition to normal electrolyte and acid-base status, confirms the sufficiency of salt substitution

Diarrhoea, intestinal inflammation and inguinal hernias

—  Soiling in children, in adulthood only during night-time or  physical exertion

In children, short courses of cholestyramine (dose 2 g ・ 2 ⁄ day) may be beneficial

—  Increased risk for unspecified colitis or Crohn’s disease

—  A slightly increased risk for gastrointestinal malignancies

—  During childhood, abdominal distention and inguinal hernias, both are rare after childhood

—  Nephrocalcinosis:  intratubular accumulation of calcium phosphate

—  Post-transplant recurrence of renal changes

—  Male subfertility: Low concentration of poorly motile spermatozoa with abnormal morphology, and a high seminal plasma Cl with a low pH

—  Hyperuricaemia

—  Increased concentrations of sweat Cl similar to that seen in patients with cystic fibrosis 

—  Adding salt substitution during excessive sweating may thus be necessary

FOLLOW-UP

—  In patients aged between 3 and 7 years, concentration of urine Cl should be 10–30 mmol⁄ L,

—  In older children, at least 30–50 mmol⁄ L

—  In adulthood, when the dosage of salt substitution is more constant and electrolyte and acid-base balance acceptable, measurement of urine Cl is unnecessary.

CONCLUSIONS

—  Early diagnosis and sufficient treatment provide favourable long-term outcome in CLD. In non-optimally treated disease, however, risk for renal involvement arises.

—  The major signs of inadequate therapy are metabolic alkalosis and low concentrations of serum electrolytes, especially hypochloraemia and hypokalaemia

—  During gastroenteritis or other infections, adequate treatment of metabolic imbalance and dehydration is crucial.

—  Of the extraintestinal manifestations, major issues are male subfertility and spermatoceles, resulting from the defective Cl ⁄HCO3 exchange in the male reproductive tract

—  Fortunately, normal spermatogenesis makes artificial reproduction technology and even unassisted reproduction possible

—  The rarity of CLD makes any large clinical trials impossible and thus, most of the treatment recommendations are based on our clinical experience in treatment and follow-up of the largest known series of CLD.

—  Normal growth and development, normal renal function and favourable long-term outcome in the patients treated according to these recommendations suggest that the guidelines for the treatment are valid.

—  As any genotype-phenotype correlation in this rare disorder seems to remain non-existent, the treatment recommendations written here are likely to be relevant and universal for all patients with CLD.