| The
etiology of pigment gallstones.Hepatology.
1984 Sep-Oct;4(5 Suppl):215S-222S.
Pigment
gallstones are of two major types, black and earthy brown, each
consisting of calcium salts of bilirubin and other anions, along
with an unmeasured residue that is largely mucin glycoproteins.
Studies in model systems indicate that the small proportion of
unconjugated bilirubin in bile is solubilized by bile salts and that
the ionized bilirubin is more soluble than the protonated diacid.
Solubility is decreased by added lecithin but is unaffected by
cholesterol. At the pH of bile, unconjugated bilirubin exists mainly
as a monoanion with sufficient solubility in mixed micelles not to
precipitate, were it not for the presence of calcium, which forms
highly insoluble salts with unconjugated bilirubin anions.
Supersaturation of bile with calcium bilirubinates is inhibited by
bile salts, which bind calcium, reducing the activity of free
calcium ions. When supersaturation occurs, usually due to increased
concentrations of bilirubinate anion, nucleation may be initiated by
binding of calcium bilirubinate to mucin glycoproteins in bile. In
earthy brown stones, which form mainly in the bile ducts, the
pigment is mostly calcium bilirubinate, combined with calcium
palmitate. These components form due to hydrolysis, by enzymes in
infecting bacteria, of conjugated bilirubin and lecithin,
respectively. In black stones, which form mainly in the gallbladder,
the pigment is mostly a highly cross-linked network polymer of
bilirubin, which is insoluble in all solvents. Concomitant
polymerization and oxidation of calcium bilirubinate probably occur
in the solid state, after precipitation of the pigment due to
hydrolysis of conjugated bilirubin by endogenous beta-glucuronidase
from the biliary tract and/or liver.
Pigment gallstone disease.Gastroenterol
Clin North Am. 1991 Mar;20(1): 111 -26.
Black and brown pigment gallstones are
morphologically, compositionally, and clinically distinct. Black
stones form primarily in the gallbladder in sterile bile and are
associated with advanced age, chronic hemolysis, alcoholism,
cirrhosis, pancreatitis, and total parenteral nutrition. Brown stones
form not only within the gallbladder but also within the intrahepatic
and extrahepatic ducts; they are uniformly infected with enteric
bacteria and are usually associated with ascending cholangitis. Brown
stones are related to juxtapapillary duodenal diverticula and are the
predominant type of de novo common bile duct stones. Cholecystectomy
is usually curative in black pigment stone disease, whereas stones
often recur after cholecystectomy for brown stone disease. The
pathogenesis of black stones is probably related to nonbacterial,
nonenzymatic hydrolysis of bilirubin conjugates. At the pH of bile,
this results in two monohydrogenated bilirubin anions that precipitate
with calcium ions. Bilirubin monoconjugates that are increased in
several conditions, such as Gilbert's syndrome and chronic hemolysis,
may play a pivotal role in black stone formation as a source of
unconjugated monohydrogenated bilirubin and as a possible
co-precipitant with calcium. The precipitation of calcium carbonate
and phosphate is influenced by local gallbladder factors. Brown
pigment stones are formed in bile infected with enteric bacteria that
elaborate hydrolytic enzymes: beta-glucuronidase, phospholipase A, and
conjugated bile acid hydrolase. The resulting anions of bilirubin and
fatty acids form insoluble calcium salts. We used nb/nb mice with a
chronic hemolytic anemia as a model of hemolysis-induced black stone
disease. The presence of 40% bilirubin monoconjugates in mouse
gallstones indicated the importance of this moiety in the pathogenesis
of black stones. Other data obtained by marrow transplantation
experiments in mice revealed the relative importance of genotype
versus the hemolytic anemia on determinants such as biliary bile acid
composition and mucin secretory glands in the mouse gallbladder neck.
Additional physical chemical studies of the interaction of
unconjugated bilirubin in model bile solutions will be helpful in
further delineating the pathogenesis of both black and brown pigment
gallstones.
Inhibition of
cholesterol crystallization under bilirubin deconjugation: partial
characterization of mechanisms whereby infected bile accelerates
pigment stone formation.Biochim
Biophys Acta. 2003 Jun
10;1632(1-3):48-54.
Pigment
gallstones have been reported to be closely associated with biliary
tract infection. We previously reported that addition of
unconjugated bilirubin (UCB), which is deconjugated by beta-glucuronidase
in infected bile, could enhance cholesterol crystal formation in
supersaturated model bile (MB). The present study evaluated the
effect of beta-glucuronidase on the processes of pigment gallstone
formation and cholesterol crystallization. Supersaturated MB (taurocholate/lecithin/cholesterol
at 71:18:11, a total lipid concentration of 10.0 g/dl and a
cholesterol saturation index (CSI) of 2.0) and native rat bile were
mixed at a ratio of 3:1. Then, mixed bile was incubated with or
without beta-glucuronidase and changes of the following parameters
were investigated over time: (1) the UCB/total bilirubin ratio; (2)
cholesterol crystal formation; (3) the precipitate weight and the
cholesterol concentration in the precipitate and supernatant; and
(4) the lipid distribution of vesicles in the supernatant. Compared
with beta-glucuronidase-free bile, (1) beta-glucuronidase-containing
bile showed a significant increase of the UCB/total bilirubin ratio,
(2) as well as a significantly longer nucleation time (96+/-17.0 vs.
114+/-20.0) and fewer cholesterol crystals. (3) The precipitate
weight and the cholesterol concentration in the precipitate were
significantly increased, while the cholesterol concentration in
supernatant was decreased. (4) When mixed bile was incubated with
beta-glucuronidase, the cholesterol concentration in the vesicles
was lower than in bile without beta-glucuronidase. The precipitate
weight and the cholesterol concentration in the precipitate was
increased by incubation with beta-glucuronidase, while cholesterol
concentration was decreased in the supernatant (especially in the
vesicles). This means that bile vesicles were more stable and it was
more difficult for cholesterol crystals to form. Thus, the presence
of beta-glucuronidase may inhibit the formation of pure cholesterol
stones even in the presence of cholesterol supersaturation.
The role of
bacteria in pigment gallstone disease.
Ann Surg.
1991 Apr;213(4):315-26.
One hundred ten
of nine hundred sixty consecutive patients who underwent surgery for
gallstones (GS) had pigment stones (PS) (11.45%). Fifty brown PSs
contained calcium bilirubinate, small amounts of cholesterol, and
always calcium palmitate, were usually found in the common duct
(96%), and were almost always associated with bile infection (98%)
and diffuse erosion of the biliary mucosa. Fifty-one black PSs
contained bilirubin polymers, calcium carbonate, and/or phosphate,
seldom cholesterol, and never evident amounts of calcium palmitate,
were mostly found in the gallbladder, and were associated with
hemolysis or liver damage and with hyperplastic cholecystosis. Bile
infection was found in 19.6% of cases, but bacteria were never found
in the center of black PSs by scanning electron microscopy. Nine
additional patients (8.2% of PSs, 0.9% of GSs) had concomitant black
and brown PSs that were mostly found in the common duct and were
always associated with bile infection. It is suggested that, even if
PSs with concomitant black and brown material can be found, black
and brown PSs greatly differ not only in pathogenesis but also in
clinical behavior and treatment. In particular bacterial infection
is important only in the pathogenesis of brown PSs while it plays no
role in the initial formation of cholesterol, mixed or black GSs.
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