Enterohepatic cycling of bilirubin as a cause of ‘black’ pigment gallstones in adult life

Abstract

In contrast to bile salts, which undergo a highly efficient enterohepatic circulation with multiple regulatory and physiologic functions, glucuronic acid conjugates of bilirubin are biliary excretory molecules that in health do not have a continuing biologic life.Intestinal absorptive cells are devoid of recapture transporters for bilirubin conjugates, and their large size and polarity prevent absorption by passive diffusion. However, unconjugated bilirubin, the β -glucuronidase hydrolysis product of bilirubin glucuronides can be absorbed passively from any part of the small and large intestines. This can occur only if unconjugated bilirubin is kept in solution and does not undergo rapid bacterial reduction to form urobilinoids. Here we collect, and in some cases reinterpret, experimental and clinical evidence to show that in addition to the well-known occurrence in newborns, enterohepatic cycling of unconjugated bilirubin can reappear in adult life. This happens as a result of several common conditions, particularly associated with bile salt leakage from the small intestine, the most notable ileal dysfunction resulting from any medical or surgical cause. We propose that when present in excess, colonic bile salts solubilize unconjugated bilirubin, delay urobilinoid formation, prevent calcium complexing of unconjugated bilirubin and promote passive absorption of unconjugated bilirubin from the large intestine. Following uptake, reconjugation, and resecretion into bile, this source of 'hyperbilirubinbilia' may be the important pathophysiological risk factor for 'black' pigment gallstone formation in predisposed adult humans.

Coinheritance of Gilbert syndrome–associatedUGT1A1 mutation increases gallstone risk in cystic fibrosis

“…Of note, an augmented enterohepatic cycling of bilirubin due to an increased absorption of unconjugated bilirubin has recently been proposed as the cause of pigment gallstones. 1 It has been suggested that leakage of bile salts from the small intestine to the colon leads to solubilization of unconjugated bilirubin and promotes its absorption from the large intestine, thereby augmenting bilirubin secretion into bile ("hyperbilirubinbilia") with increased lithogenicity. 1 Consequently, any pathological condition with an augmented spillage of bile salts into the colon might represent a risk factor for gallstone formation, as has been demonstrated in patients with Crohn disease who have a lack of functional ileum.…”

“…4 Experimental studies indicate that the formation of pigment gallstones in CF might result, at least in part, from chronic bile salt loss from the small intestine, which induces resorption of unconjugated bilirubin from the large intestine. 1,5 The subsequent enterohepatic cycling of bilirubin from the colon to the liver increases biliary secretion of conjugated bilirubin ("hyperbilirubinbilia"), which precipitates with calcium after deconjugation in the more alkaline bile of CF patients. 5 Gilbert syndrome is characterized by decreased bilirubin conjugation due to a diminished activity of the enzyme UDP glucuronosyltransferase (UGT).…”

Bile acid transporters

“…Indeed, a recent genetic study identifi ed an ASBT haplotype associated with signifi cantly reduced ileal expression of ASBT mRNA and protein ( 191 ). Other disorders associated with intestinal bile acid malabsorption that could potentially involve the ASBT include hypertriglyceridemia ( 192,193 ), idiopathic chronic diarrhea ( 194 ), chronic ileitis ( 195 ), gallstone disease ( 196,197 ), postcholecystectomy diarrhea, Crohn's disease (198)(199)(200)(201)(202), and irritable bowel syndrome ( 203 ).…”

Comparison of Serum Zinc Level Between Neonates With Jaundice and Healthy Neonates

“…Although there may be a benefit to patients with mild hyperbilirubinemia, the subjects with high elevation of serum bilirubin are endangered due to accumulation of bilirubin in the brain tissue (1,2). Enhanced enterohepatic circulation of bilirubin (EHC) that can occur with resection or bypass in adults or ileal inflammation leads to hypersecretion of bilirubin into the bile with increased formation of black pigment gall stones (3,4). Since active transport for non-conjugated bilirubin is not proved in the intestine, bilirubin may cycle only via passive diffusion under certain conditions (3)(4)(5).…”

“…Enhanced enterohepatic circulation of bilirubin (EHC) that can occur with resection or bypass in adults or ileal inflammation leads to hypersecretion of bilirubin into the bile with increased formation of black pigment gall stones (3,4). Since active transport for non-conjugated bilirubin is not proved in the intestine, bilirubin may cycle only via passive diffusion under certain conditions (3)(4)(5). Interestingly, two thirds of bilirubin enter the systemic circulation; the remainder reabsorbed from the intestine is removed from blood by the liver (3-7).…”