Congenital disorders of intestinal electrolyte transport

Introduction Congenital diarrheal disorders (CDD; OMIM 251850) are a group of rare chronic enteropathies characterized by a het- erogeneous etiology with a typical onset early in the life. In the first weeks of life, patients affected by CDD usually pres- ent with severe diarrhea that within a few hours leads to a life-threatening condition secondary to massive dehydration and metabolic acidosis (or alkalosis in the case of congeni- tal chloride diarrhea, CLD) [1]. The number of conditions included within the CDD group has gradually increased, and many new genes have been identified and functionally related to CDD, opening new diagnostic and therapeutic perspectives [1]. We have proposed a CDDs classification in four groups in relation to main defect: 1. Defects of digestion, absorption, and transport of nutri- ents and electrolytes 2. Defects of enterocyte differentiation and polarization 3. Defects of enteroendocrine cells differentiation 4. Defects of intestinal immune response modulation In the context of the first group, congenital disorders of intestinal electrolytes transport are a subset of diseases char- acterized by early clinical presentation due to autosomal recessive defect. These disorders are challenging clinical conditions for pediatric gastroenterologists because of the severity of the clinical picture and the broad range of con- ditions in differential diagnosis. Frequently, abnormal fluid absorption begins in utero, manifesting itself as maternal polyhydramnios. Then soon after birth, patients usually pres- ent with severe diarrhea that within few hours leads to a life- threatening condition secondary to massive dehydration and metabolic acidosis [1]. Consequently, these patients require a prompt diagnosis and assistance. Milder forms with subtle clinical signs may remain undiagnosed until adulthood when patients developed irreversible complications. In particular, patients with cystic fibrosis (CF) may have a subtle clinical presentation, with prevalent non-intestinal symptoms. Different mechanisms are responsible for transepithelial ion transport at intestinal level (Fig. 36.1). In the jejunum, NaHCO − is absorbed via Na+/H+ exchange (the secreted H+ 3 neutralizes an equivalent amount of luminal NaHCO −) and 3 Cl− movement is purely passive [2]. In the ileum (and, as shown later, also in the proximal colon), NaCl is absorbed via equal rates of Na+/H+ and Cl−/ NaHCO − exchanges [2]. At least three Na+/H+ exchangers (NHEs)3have since been localized to intestinal brush border membranes and cloned; NHE2 and NHE3 are found in both small intestine and colon. NHE3 appears to be quantitatively more important, since the NHE2 knockout mouse suffers gastric dysfunction but no in- testinal disability, whereas the NHE3 knockout mouse suffers from chronic diarrhea. A third, Cl−-dependent NHE is found in crypt cells of rat distal colon. The NHE first identified in intestine, NHE1, is present only in the basolateral membrane of enterocytes and is involved in HCO − secretion [3]. Two anion exchangers have also been localized to small- intestinal and colonic brush border membranes and cloned: downregulated in adenoma (DRA) and putative anion trans- porter 1 (PAT1) [1]. DRA was first cloned from colonic mu- cosa; it was found to be downregulated in villus adenomas and carcinomas and subsequently was found to incur muta- tions in the rare diarrheal disorder familial chloride diarrhea (see “Congenital chloride diarrhea” below). Both DRA and PAT1 are abundant in the duodenum and present at higher density there than NHE2 and NHE3, suggesting a role in duodenal alkalinization. In the colon, DRA appears to pre- dominate over PAT1. More than two brush border ion exchangers are required, of course, for the enterocyte to engage in transcellular salt absorption. Increased turnover of the Na+/K+pump and the opening of Cl− and K+channels are also necessary, the latter to counteract associated cell swelling, to permit serosal exit of Cl− taken up from the lumen, and to dissipate the added uptake of K+through the pump.