| Popis: |
G A A b st ra ct s fecal BA loss, which occurs in the absence of any absorptive defect within the terminal ileum, is due to increased BA synthesis, resulting from impaired FGF19 ileal production or hepatic actions. We aimed to investigate whether BA-induced expression of FGF19 in the ileum is reduced in patients with low SeHCAT retention.Methods: Patients being investigated for unexplained diarrhea (n=16) were prospectively recruited and gave informed consent at colonoscopy to give additional ileal biopsies. All had SeHCAT tests. Groups of 2-3 biopsies (explants) were incubated separately for 6h with either BA-free culture media (unstimulated controls), chenodeoxycholate (CDCA) or glyco-CDCA (GCDCA), both at 50uM. After RNA extraction and cDNA synthesis, FGF19 expression was quantified relative to GAPDH by RT-PCR. Results: SeHCAT 7d retention values were 15% in 9 who were normal diarrhea controls. Previous studies had shown no significant difference in baseline unstimulated FGF19 expression between these groups and this was confirmed with the unstimulated control samples (p=0.76). Median stimulation overall was 184-fold with CDCA and 373-fold with GCDCA. A positive correlation was found between SeHCAT retention and the magnitude of the fold change in FGF19 expression stimulated by either CDCA (r=0.50, n=16, p=0.02) or by GCDCA (r=0.76, n=7, p=0.02). These relationships were still present when the fold changes were normalized to the baseline FGF19 expression found in the unstimulated explants. Conclusion: Ileal explants from patients with lower SeHCAT 7d retention have a lower response to both CDCA and GCDCA. As uptake of GCDCA is dependent on carrier-mediated apical BA uptake but CDCA is not, this implies there is no defect in apical BA uptake, but abnormalities elsewhere in the FGF19 response. A reduced capacity to induce ileal FGF19 expression in response to absorbed BA is proposed to lead to the excess BA production and fecal BA losses found in primary BAD. |
