Correspondence
Causes of Chronic Diarrhea
N Engl J Med 2006; 355:1833-1834October 26, 2006
- Article
To the Editor:
In the table about congenital diarrheal disorders in the Perspective by Binder (July 20 issue),1 congenital sodium diarrhea is attributed to mutations in the gene encoding the sodium–hydrogen exchanger (NHE) isoform 3 (SLC9A3, also known as NHE3). Although NHE3-knockout mice (those deficient in Slc9a3) are the only available animal model of congenital diarrhea,2 genetic analyses of patients with congenital sodium diarrhea have excluded all mapped NHE loci except NHE4 (which houses SLC9A4), but even this locus has not been firmly implicated.3,4
4 ReferencesDaniele Focosi, M.D.
Azienda Ospedaliera Universitaria Santa Chiara, 56100 Pisa, Italy
dfocosi@tin.it 1
Binder HJ . Causes of chronic diarrhea. N Engl J Med 2006;355:236-239
Full Text | Web of Science | Medline2
Schultheis PJ ,Clarke LL ,Meneton P , et al. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 1998;19:282-285
CrossRef | Web of Science | Medline3
Muller T ,Wijmenga C ,Phillips AD , et al. Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes. Gastroenterology 2000;119:1506-1513
CrossRef | Web of Science | Medline4
Online Mendelian Inheritance in Man (OMIM) database. Diarrhea 3, secretory sodium, congenital. (Accessed October 5, 2006, at http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=270420.)
Author/Editor Response
Focosi is correct that a molecular explanation for congenital sodium diarrhea has not been identified. Several circumstantial observations suggest that a mutation in SLC9A3 (encoding NHE3) is likely. First, NHE2 and NHE3 are the only sodium–hydrogen exchangers identified in small intestinal apical membranes. Second, mice lacking NHE3, but not those lacking NHE2, have diarrhea. Third, glucocorticoids increase both intestinal sodium absorption secondary to enhanced sodium–hydrogen exchange function and NHE3 (but not NHE2) messenger RNA and protein.1 Thus, NHE3 is generally believed to be responsible for intestinal sodium absorption.2
However, Muller et al.3 did not find any defects in known NHE genes in two Austrian families with congenital sodium diarrhea. These authors did not study sodium–hydrogen exchange in affected family members, who had partial villous atrophy. However, it seems likely that these children had congenital sodium diarrhea with different etiologic factors than those with a functional defect in sodium–hydrogen exchange and histopathologically normal jejunum.4 Furthermore, their results do not exclude other explanations for congenital sodium diarrhea that would involve NHE3, such as a defect in a regulatory protein responsible for NHE3 trafficking to the apical membrane.
4 ReferencesHenry J. Binder, M.D.
Yale University, New Haven, CT 065201
Yun CH ,Gurubhagavatula S ,Levine SA , et al. Glucocorticoid stimulation of ileal Na+ absorptive cell brush border Na+/H+ exchange and association with an increase in message for NHE-3, an epithelial Na+/H+ exchanger isoform. J Biol Chem 1993;268:206-211
Web of Science | Medline2
Zachos NC ,Tse M ,Donowitz M . Molecular physiology of intestinal Na+/H+ exchange. Annu Rev Physiol 2005;67:411-443
CrossRef | Web of Science | Medline3
Muller T ,Wijmenga C ,Phillips AD , et al. Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes. Gastroenterology 2000;119:1506-1513
CrossRef | Web of Science | Medline4
Booth IW ,Stange G ,Murer H ,Fenton TR ,Milla PJ . Defective jejunal brush-border Na+/H+ exchange: a cause of congenital secretory diarrhoea. Lancet 1985;1:1066-1069
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Bai-Sui Feng, Shao-Heng He, Peng-Yuan Zheng, Linda Wu, Ping-Chang Yang. (2007) Mast Cells Play a Crucial Role in Staphylococcus aureus Peptidoglycan-Induced Diarrhea. The American Journal of Pathology 171:2, 537-547
CrossRef
