Congenital chloride diarrhea is characterized by a chronic electrolyte transport-related diarrhea that starts in utero, commonly resulting in polyhydramnios in pregnancy and severe diarrhea at birth with concomitant hypochloremic hypokalemic metabolic alkalosis. A pathognomonic feature of the diarrhea is a high fecal chloride level (>90 mmol/L) that can be used as an initial diagnostic test.53 Congenital chloride diarrhea is caused by mutations in the Cl–/HCO3– exchanger DRA (SLC26A3), which is required for electroneutral sodium absorption (in conjunction with Na+/H+ exchange) particularly in the ileum and colon. SLC26A3 mutations, therefore, result in a loss of intestinal sodium-driven fluid absorption, with resulting profuse watery diarrhea. More than 50 different mutations have been reported with founder mutations in specific populations (eg, Finnish and Arab).84,85 Management of congenital chloride diarrhea revolves around preventing dehydration and alkalosis through enteral fluid and electrolyte supplementation. Oral administration of butyrate was found to reduce diarrheal output, although subsequent studies have reported more equivocal results.86,87
Congenital sodium diarrhea (CSD) is characterized by a severe electrolyte transport-related diarrhea that starts in utero, and infants are often born with dilated fluid-filled loops of intestine. In rare cases, infants can develop pseudo-obstruction-like features and volvulus due to dilated fluid-filled bowel. The diarrhea in CSD is characterized by a high fecal Na+ content, and induces a metabolic acidosis. The genetic basis of CSD is heterogeneous, currently with 3 major known genes involved that primarily impact Na+ absorption in the intestine. Classical or non-syndromic CSD results from loss-of-function mutations in the Na/H+ exchanger NHE3, which is critical for normal Na+ and fluid absorption from the intestine, as well as normal acid-base homeostasis.37 CSD also results from activating mutations in the guanylin receptor GC-C (GUCY2C), resulting in elevated cellular cyclic guanosine monophosphate levels, inhibition of NHE3 function, and stimulation of chloride secretion via CFTR chloride channels.50 Lastly, a syndromic form of CSD (SPINT2) that overlaps in phenotype with CTE has been decribed.88 Infants with CSD typically require intensive fluid, nutrient, and electrolyte support via PN during the first year of life. Classical CSD caused by NHE3 or GUCY2C mutation appears to improve over time, with eventual weaning of PN. However, both NHE3 or GUCY2C variants appear to be associated with an increased risk of IBD in later life.89
Glucose and galactose are 2 monosaccharides transported across the apical membrane by the Na-dependent glucose/galactose cotransporter (SLC5A1). Bi-allelic loss-of-function mutations of SLC5A1 are associated with a selective form of malabsorption, glucose-galactose malabsorption, which has been described thoroughly.49 While the majority of the missense mutations impaired the trafficking of the co-transporter to the plasma membrane, those that did reach the membrane provided important insight into the structure of the transporter. Nonetheless, these children present with severe dehydration with a metabolic acidosis, and a diarrhea that ceases on a glucose/galactose-free diet. The dietary carbohydrate is limited to fructose lifelong, which is transported across the brush border by GLUT5 (SLC2A5).
Among the rarest causes of CODE is a selective inability to reabsorb bile salts in the intestinal portion of the enter-ohepatic circulation. A bi-allelic loss-of-function mutation of the sodium coupled bile salt re-uptake (SLC10A2) has been associated with watery diarrhea that stimulates colonic chloride secretion and can be managed using a bile acid seques-trant.51 More recently bi-allelic loss-of-function mutations in the basolateral bile acid transporter OST-β (SLC51B) have been associated with diarrhea, severe fat-soluble vitamin deficiency, and features of cholestatic liver disease.52
In contrast to the diarrhea that is associated with excessive luminal bile acids, their deficiency is also associated with diarrhea and malabsorption of fat. Certainly, inherited and non-inherited conditions associated with cholestatic liver disease and surgical resection of the distal bowel may result in steatorrhea, and as many as 6 rare selective autosomal recessive congenital defects of bile acid synthesis have been described.98