Striking Alterations in Bilirubin and Bile Salt Solution Chemistry of Gallbladder Bile in a Germ-Free Mouse Model of “Black” Pigment Gallstones

Leonard, Monika R.; Andrade, Jon D.; Whary, Mark T.; Fox, James G.; Carey, Martin C.

doi:10.1016/s0016-5085(11)60278-3

Cited by 1 publication

(3 citation statements)

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“…A hepatic source of ROS is unlikely since Ca(HUCB) 2 in ‘brown’ stones remains unpolymerized [2]. ROS are more likely products of mucosal macrophages or neutrophils from an inflamed gallbladder that accompanies pigment stone disease [2,72,75]. This is consistent with observations of bacterially-derived oxysterols in human bile as well as in black pigment gallstones [77].…”

Section: Putative Role Of Ros In ‘Black’ Stone Polymerization and Oximentioning

confidence: 52%

“…The ROS secreted by an inflamed gallbladder mucosa apparently causes Ca(HUCB) 2 polymerization and oxidation [82]. The germ-free Swiss Webster mouse, a newly described animal model of ‘black‘ pigment gallstone formation [72,75], promises to answer many of the vexing questions regarding the pathophysiology and physical chemistry of this disease.…”

Section: Discussionmentioning

confidence: 99%

“…Absence of UCB reduction in the intestinal lumen is a contributing factor to neonatal jaundice [73], but also for pigment gallstone disease as well as the hyperbilirubinemia associated with oral antibiotic therapy [74]. As alluded to above, germ-free Swiss Webster mice exhibit extremely high prevalences of spontaneous black pigment gallstone formation [72,75], apparently secondary to what appear to be at least four factors: inability to degrade UCB to urobilinoids, decreased intestinal motility, gallbladder hypomotility from a pre-diabetic state, and diminution in intestine mucosal barrier function [72,75]. …”

Section: The Intestinal Microflora Dietary Factors and Pigment Gallsmentioning

confidence: 99%

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New pathophysiological concepts underlying pathogenesis of pigment gallstones

Vı́tek¹,

Carey

2012

Clinics and Research in Hepatology and Gastroenterology

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101

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SUMMARY Pigment gallstones, which are much less frequent than cholesterol stones, are classified descriptively as ‘black’ or ‘brown’. They are composed mostly of calcium hydrogen bilirubinate, Ca(HUCB)2, which is polymerized and oxidized in ‘black‘ stones but remains unpolymerized in ‘brown’ stones. Black stones form in sterile gallbladder bile but brown stones form secondary to stasis and anaerobic bacterial infection in any part of the biliary tree, including the gallbladder. Other calcium salts coprecipitate in both stone types; crystalline calcium phosphate and/or carbonate in the case of ‘black’ stones and amorphous calcium salts of long chain saturated fatty acids (‘soaps’) in the case of ‘brown’ stones. Cholesterol is present in variable proportions in ‘brown’ more than ‘black’ stones and, in the latter, the bile sterol may be totally absent. The ‘scaffolding’ of both stone types is a mixed mucin glycoprotein matrix secreted by epithelial cells lining the biliary tree. The critical pathophysiological prerequisite for ‘black’ stone formation is ‘hyperbilirubinbilia’ (biliary hypersecretion of bilirubin conjugates). It is due principally to hemolysis, ineffective erythropoiesis, or pathologic enterohepatic cycling of unconjugated bilirubin. Endogenous biliary β-glucuronidase hydrolysis of bilirubin conjugates in gallbladder bile provides HUCB− molecules that precipitate as insoluble salts with ionized Ca. Putatively, reactive oxygen species secreted by an inflamed gallbladder mucosa are responsible for transforming the initial soft yellow precipitates into hard black [Ca(HUCB)2]n polymers. Despite ‘brown’ gallstones being soft and amenable to mechanical removal, chronic anaerobic infection of the biliary tree is often markedly resistant to eradication.

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