Constipation in children is a common, vexing problem for the patient, his or her parents, and the pediatric gastroenterologist. Most cases have no discernible organic cause. Evidence indicates that endogenous C24 dihydroxy- bile acids (chenodeoxycholic and/or deoxycholic acid) act as natural cathartics by inducing colonic secretion and colonic propulsion. Our hypothesis is that some cases of childhood constipation are caused by defects in bile acid biosynthesis resulting in a decreased colonic concentration of C24 dihydroxy bile acids. Possible defects include defective hydroxylation of the steroid nucleus (defective sterol 12 hydroxylase (cyp8B1) or defective side chain oxidation (defects in peroxisomal enzymes). To test this hypothesis, fecal samples will be obtained from children with chronic constipation as well as from children without constipation. Samples will be analyzed by electrospray mass spectrometry (ESI-MS) and by gas chromatography mass spectrometry (GC-MS). ESI-MS provides information on side chain biotransformations involved in oxidation of the C8 cholesterol side chain to the C5 side chain present in C24 bile acids. GC-MS provides information on the efficiency of C-12 hydroxylation. Patients with defects in side chain oxidation or C-12-hydroxylation will receive genetic analysis by collaborators. If successful, this project will show that some cases of constipation are caused by defective bile acid biosynthesis.Preliminary results have identified children with increased C27 bile acids suggesting defects in peroxisomal enzymes. Results of this study should lead to clinical trials that test the efficacy of oral primary bile acids for constipation caused by defective bile acid biosynthesis.
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