Volume 116, Issue 6, Pages 1420-1427 (June 1999) Enterohepatic cycling of bilirubin: A putative mechanism for pigment gallstone formation in ileal Crohn's disease  Menno A. Brink*, J.Frederik M. Slors‡, Yolande C.A. Keulemans‡, Kam S. Mok*, D.Rudi De Waart*, Martin C. Carey§, Albert K. Groen*, Guido N.J. Tytgat*  Gastroenterology  Volume 116, Issue 6, Pages 1420-1427 (June 1999) DOI: 10.1016/S0016-5085(99)70507-X Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 1 (A) Total bilirubin, (B) UCB, and (C) total calcium concentrations in gallbladder bile (in mmol/L) obtained intraoperatively in 18 patients with Crohn's disease without prior ileectomy in relation to duration of ileal disease: <4 years duration of ileal disease (n = 10) and >4 years duration of ileal disease (n = 8). *Statistically significant difference between groups: P ≤ 0.05. Data are expressed as means ± SD. Gastroenterology 1999 116, 1420-1427DOI: (10.1016/S0016-5085(99)70507-X) Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 2 In health, bilirubin conjugates (CB) are hydrolyzed by bacterial β-glucuronidases in the large intestine,53 and UCB either precipitates as insoluble calcium salts54 or is further converted by bacterial catabolism into urobilinogens.53 We postulate that in patients with ileal exclusion or disease, bile salt malabsorption increases colonic bile salt levels, which solubilize UCB in dimeric and micellar complexes55,56 and prevent precipitation and calcium complexing. Solubilization facilitates passive colonic UCB absorption,57 and UCB returns to the liver bound to albumin in portal venous blood. After hepatic sinusoidal uptake, UCB is efficiently reconjugated, but now principally as monoglucuronides32 because of the increased flux, and resecreted into bile, establishing a pathological enterohepatic cycling of bilirubin.57 At the level of the gallbladder, conjugated bilirubins are hydrolyzed in part by endogenous biliary β-glucuronidase and nonemzymatically58 and UCB levels exceed normal values, principally because of elevated conjugated bilirubin levels,32 increased BMG/BDG ratios,32,46 and prolonged gallbladder residence time.48-50 The gallbladder hypomotility is promoted by deficient cholecystokinin release from the proximal small intestine because of poor bile salt micellar solubilization of dietary fatty acid secondary to noncompensated bile salt malabsorption.47 If UCB is not complexed with calcium to precipitates as pigment stones, it may be absorbed passively at both gallbladder45 and small intestinal sites,40 thereby amplifying the enterohepatic cycling. Gastroenterology 1999 116, 1420-1427DOI: (10.1016/S0016-5085(99)70507-X) Copyright © 1999 American Gastroenterological Association Terms and Conditions