World J. Surg.
22, 1114 –1118, 1998
Pathophysiology of Bile Duct Stones
Johnson L. Thistle, M.D.
Department of Medicine, Division of Gastroenterology, Mayo Clinic Medical Center, 200 First Street, SW, Rochester, Minnesota 55905, USA
Abstract. Secondary duct stones are usually detected and easily removed
at the time of cholecystectomy either during surgery or endoscopically
before or after the operation. Primary duct stone diseases, although much
less common, are often a greater therapeutic challenge. These stones may
be huge, distributed throughout the biliary tree (including areas difficult
to access), and unresponsive to pharmacologic measures. Recurrence of
primary duct stones is the rule rather than the exception, and reliable
methods for prevention remain to be established. Moreover, morbidity
and mortality due to biliary obstruction, sepsis, and choliangiocarcinoma
make primary bile duct stone disease a formidable adversary. A better
understanding of their pathogenesis can facilitate more effective ap-
proaches to treatment and, most important, prevention.
Much has been learned about the pathogenesis of bile duct stones
during the past two decades. For more than a century it has been
recognized that biliary stasis and infection were contributing
factors to stones developing de novo in the bile duct system, but
these primary duct stones were thought to be unusual [1]. In 1978
Madden noted, “the universally accepted teaching is that common
duct stones are predominantly secondary,” having originated in
the gallbladder [2]. He described a personal experience, however,
based on the gross inspection of stones from 126 patients during
a 27-year period and concluded that primary duct stones were
almost twice as common as secondary stones. During the past two
decades it has become apparent that there are seven or eight types
of stones in the bile ducts, most of which probably have different
pathophysiologies. The pathophysiology often has important im-
plications with regard to the detection, treatment, and prevention
of the specific type of duct stone present.
Bile duct stones are usually classified as primary stones, those
formed de novo in the bile ducts, and secondary stones, those
having passed out of the gallbladder but retained in the bile ducts.
A classification of duct stones is shown in Table 1.
Primary Duct Stones
Convincing evidence has evolved that intrahepatic stones differ
significantly from extrahepatic stones. Two distinct intrahepatic
stones can be identified [3, 4].
“Pure” cholesterol stones have been reported from Far Eastern
countries, Europe, and the United States” [3– 8]. In composition
they are similar to the almost pure cholesterol stones that form in
the gallbladder, but the patient may have no stones in the
gallbladder. Infection does not seem to contribute to their forma-
WORLD
Journal of
SURGERY
© 1998 by the Société
Internationale de Chirurgie
tion. An increase in the rate-limiting enzyme for cholesterol
synthesis in the liver, hydroxymethyl coenzyme A reductase
(HMG CoA reductase) and a reduced concentration of the
rate-limiting enzyme for degradation of cholesterol to bile acids,
7a-hydroxylase, have been found in the liver in some of these
patients [9]. Stasis is thought to be important in the pathogenesis
of cholesterol gallbladder stones for (1) retention of cholesterol-
supersaturated bile in the gallbladder long enough to provide time
for nucleation and precipitation of cholesterol crystals and (2)
retention of crystals to allow them to grow into stones [10]. The
pathogenesis of intrahepatic pure cholesterol stones is probably
different [3– 8]. The intrahepatic ducts are usually not dilated or
strictured, and cholesterol stones may not be present elsewhere in
the biliary tract, which argues against just a severe predisposition
to cholesterol gallstones. Although a localized reduction in bile
flow in the involved intrahepatic bile duct might provide time for
nucleation, an alternative or additional factor might be a focal
deficiency in antinucleating factors, which normally counteract the
cholesterol nucleating factors in bile and delay crystal precipita-
tion and growth for days to weeks [10]. Decreased activity of
apolipoprotein A-1, a cholesterol antinucleating factor, in the
liver and bile ducts in patients with intrahepatic cholesterol stones
has been reported [11].
Black mixed cholesterol stones are the most common type of
intrahepatic stone [3– 8]. Their pathogenesis is not as well under-
stood as that of the more common extrahepatic brown stones,
which contain much less cholesterol (Table 2) [4]. The intrahe-
patic mixed stones often have a black, thin outer layer that is
predominantly calcium bilirubinate, but the remainder of the
stone consists of up to 50% cholesterol (Table 3). Bacterial
infection probably contributes importantly to these stones, but few
clues exist to explain why they seem to be convincingly different
from the predominantly extrahepatic brown stones.
Brown stones are generally thought of as brown, earthy, friable
stones secondary to biliary stasis with bacterial overgrowth result-
ing in bacterial degradation of bile. They are the most common
type of bile duct stones encountered, and as a consequence have
been most extensively studied [2, 12–17]. They are various shades
of brown, from tan to almost black, reflecting variable amounts of
fatty acid and cholesterol diluting the calcium bilirubinate. On the
cut surface they may be laminated but do not have the cholesterol
crystals radiating from the center, which is characteristic of
cholesterol stones. These stones are typically associated with
Thistle: Pathophysiology of Bile Duct Stones 1115

Table 1. Bile duct stones.

Primary stones
Intrahepatic
“Pure” cholesterol
Black mixed cholesterol
Brown
Extrahepatic
Brown
Secondary stones
Black bilirubin polymer
“Pure” cholesterol
Mixed cholesterol
Brown and other rare

Table 2. Chemical composition of primary intrahepatic stones by

infrared spectroscopy.

Brown pigment stones

(calcium bilirubinate stones) Mixed stones Fig. 1. Brown extrahepatic duct stone formed around a black silk suture
Intrahepatic stones (n 5 49) (n 5 23) from a previous cholecystectomy. Stone has been bisected and the suture
removed from the center.
Cholesterol (%) 14.1 6 5.8* 46.6 6 6.6
Bilirubin (%) 43.6 6 10.6* 25.9 6 9.8
Calcium palmitate (%) 25.8 6 6.2* 14.9 6 2.9 Table 4. b-Glucuronidase activity in bacteria isolated from bile.
Calcium carbonate (%) 0 0
Calcium phosphate (%) 0 0 b-Glucuronidase-
Results are expressed in weight percent, mean 6 SEM. Bacteria No. of strains Cases positive (%)
*p , 0.0001 versus mixed stones. Aerobes
Escherichia coli 29 29 100.0
Table 3. Chemical composition of intrahepatic mixed stones. Klebsiella 16 1 5.9
Enterobacter 17 0 0
Inner yellow Streptococcus (D) 13 0 0
Intrahepatic mixed Outer shell body Pigmented core Citrobacter 9 0 0
stones (n 5 10) (n 5 10) (n 5 10) Pseudomonas 7 0 0
Others 8 1 0
Cholesterol (%) 10.7 6 2.1* 63.2 6 8.9 15.2 6 3.4
Bilirubin (%) 35.7 6 8.2* 10.1 6 1.9 44.8 6 7.5 Total 99 31 12.5
Calcium palmitate (%) 11.5 6 3.5 18.6 6 7.1 16.2 6 2.3 Anaerobes
Calcium carbonate (%) 0 0 0 Bacteroides 13 12 92.3
Calcium phosphate (%) 0 0 0 Clostridium 10 10 100.0
Peptococcaceae 2 0 0
Results are expressed in weight percent, mean 6 SEM.
Total 25 22
*p , 0.0001 versus inner yellow body.

ectatic bile ducts with strictures, papillary stenosis, or other
features predisposing to stasis and encouraging bacterial over-
growth. A broad spectrum of foreign materials have been found to
participate in the initiation of these stones. A nonabsorbable black
silk suture from previous biliary surgery is a typical example (Fig.
1). Before World War II Ascaris eggs or cuticle and Clonorchis
sinensis were thought to be contributing factors, but these para-
sites have been largely eliminated in many regions of the Far East,
which nevertheless continue to have a high prevalence of brown
duct stones [18]. Once ectatic ducts have developed, the patho-
genic mechanisms of stasis and bacterial overgrowth are difficult
to reverse; but whether the ectasia is primary or secondary and
what the initiating event has been is often unclear. The association
of duodenal diverticuli especially close to the sphincter of Oddi
has been correlated with the prevalence of bactibilia and duct
stones [19 –21]. It has been postulated that adjacent diverticuli
may compromise the competence of the sphincter, allowing
bacterial reflux. Probably more importantly, the diverticuli may
provide an excellent harbor for high concentrations of bacteria
with ready access to the duct system. The incidence of brown
stones increases with age, which may be associated with a less
competent sphincter of Oddi. Noting that primary duct stones are
more common in the left hepatic ducts than the right, possible
contributing factors proposed include the observations that the
left main duct is more horizontal than the right and there is less
bile flow from the left side, both of which can potentially
contribute to enhanced stasis.
Considerable evidence has been accumulated to support the
central role of bacterial b-glucuronidase in the pathogenesis of
brown stones [22, 23]. Several species of bacteria produce this
enzyme, most notably Escherichia coli, Bacteroides, and Clostrid-
ium (Table 4) [23, 24]. Although tissue b-glucuronidase exists, its
optimal pH (4.2) is much lower than that of bile (pH 6 to 8), in
contrast to bacterial b-glucuronidase, which has an optimal pH of
about 6.8. b-Glucuronidase deconjugates bilirubin diglucuronide,
and the free bilirubin complexes with calcium to form an insoluble
precipitate, calcium bilirubinate. Brown stones are more common
in rural Asians of low socioeconomic status compared to their
urban counterparts. Moreover, emigrants who have left Asia for
Western countries have a reduced incidence of brown stones.
These observations have led to the speculation that some nutri-
tional or other environmental factors, rather than primarily
1116
Fig. 2. Combination of primary and secondary stones. Multiple small
stones formed in the gallbladder were dissected out of the brown primary
stone matrix found in the common bile duct.
genetic ones, are important in the pathogenesis. One hypothesis is
that a low-protein diet may be a risk factor, and this has been
supported by the observation that an inhibitor of b-glucuronidase
normally present in bile, glucaro-1,4-lactone, is reduced in pro-
tein-deficient animals [22]. A report from Taiwan also described a
circulating intercellular adhesion molecule that was present at a
significantly higher level in patients with hepatolithiasis than in
controls [25]. Whether this difference is related to pathogenesis or
is a secondary phenomenon remains to be established.
Bacterial phospholipases split phosphatidylcholine (lecithin),
resulting in a high content of fatty acids, predominantly calcium
palmitate in brown stones. The bacterial enzymes deconjugate
and dehydroxylate bile acids, the consequence of which is appar-
ent on stone analysis. With the destruction of the cholesterol-
solubilizing agents in bile, it is not surprising that brown stones
may contain up to 30% cholesterol.
Combinations of primary and secondary duct stones are also
found in the extrahepatic duct system, as illustrated in Figure 2.
Retained secondary stones probably contribute to stasis, provide a
sanctuary for bacteria, and initiate the pathophysiologic prereq-
uisites for brown stone formation, much as a foreign body would.
Secondary Duct Stones
Stones formed in the gallbladder but that escape into the duct
system reflect the pathophysiology of gallbladder stones, a de-
tailed analysis of which is outside the purpose of this discussion [7,
10, 26]. Briefly, however, most gallbladder stones are of three
types: black, “pure” cholesterol, and mixed cholesterol.
Black (“pure pigment”) stones are usually irregular, 5 mm or less,
and multiple. They are pure black or dark brown and rather
homogeneous on cross-sectional gross inspection; they consist
predominantly of bilirubin polymer. These stones are not associ-
ated with infection and are almost always formed in the gallblad-
der rather than the bile ducts. They comprise about 15% of
gallbladder stones.
“Pure” cholesterol gallstones are typically at least 98% choles-
terol and are white as a mothball, albeit always with some pigment
in the center. These stones are often large and solitary, although
they may be multiple. Infection does not seem to be an important
World J. Surg. Vol. 22, No. 11, November 1998
contributing factor. Whether their pathogenesis is similar to that
of the “pure” cholesterol stones in the intrahepatic bile ducts is
unclear, although if so it seems likely that such stones would
almost always develop in the gallbladder if they developed in the
ducts, but this does not seem to be the case.
About 80% of stones in the gallbladder are mixed stones but
predominantly cholesterol. They have been the focus of a vast
literature directed toward understanding the pathogenesis of
cholesterol gallstone disease. I refer the reader to some recent
excellent reviews [7, 10]. Large stones can find their way out of the
gallbladder via a dilated (or at least an elastic) cystic duct.
Rare stones may also be found.
Brown stones are often found in the gallbladder in the Orient,
but they are rare in the West. A variety of stones occur in the
gallbladder under unusual circumstances; e.g., inorganic, spicu-
lated, and ceftriaxone-comprised stones.
Implications of Duct Stone Pathogenesis and Composition:
In Vivo Detection and Characterization, Treatment, and
Prevention
Detection and characterization of stones in vivo may provide an
opportunity to interrupt the otherwise progressive, increasingly
severe clinical consequences. Cholesterol stones are isodense or
hypodense compared to bile on an abdominal plain film or a
computed tomography (CT) scan [27, 28]. These stones are
distinctly visible on magnetic resonance imaging (MRI) scans,
however, as illustrated in a patient with multiple cholesterol
stones in the gallbladder in Figure 3. The evolving expertise in
MRI cholangiography may prove useful especially if combined
with a CT scan [29]. Duct stones containing sufficient calcium
bilirubinate have variably increased radiodensity compared to bile
on CT scans, as illustrated in Figure 4. These typical brown stones
contained a combination of calcium bilirubinate and cholesterol,
as further illustrated microscopically in Figure 5. Ultrasonography
can sometimes detect an inner or outer rim of calcium but is
usually of little value for characterizing stone composition. Duo-
denal drainage in the presence of pure cholesterol stones may
reveal diffuse cholesterol crystals without the orange-brown cal-
cium bilirubinate.
Because recurrence is a frequent problem after complete
removal of primary duct stones, the development of effective
prophylactic regimens is of major importance. Analysis of re-
moved stones, or at least microscopic examination of duodenal
bile, may be helpful for developing a potentially effective ap-
proach. Unfortunately, few data exist on controlled or uncon-
trolled long-term studies of prevention of recurrence. Pure cho-
lesterol intrahepatic stones seem to have a high probability of
being prevented by long-term use of ursodiol, but personal and
published experience is only anecdotal [6]. Because these stones
are often asymptomatic initial treatment with ursodiol, even
though it may require 6 to 24 months to dissolve cholesterol
stones, would be a reasonable consideration. In contrast, the
mixed but predominantly cholesterol intrahepatic stones have a
low-cholesterol-content black outer shell and would be predict-
ably unresponsive to primary treatment with ursodiol. Direct-
contact dissolution with methyl tert-butyl ether or even mono-
octanoin can clearly be rapidly effective for pure cholesterol
stones, but for mixed stones they would likely only soften or
Thistle: Pathophysiology of Bile Duct Stones
Fig. 3. On the left is an MRI scan revealing multiple “pure” cholesterol
gallstones in the gallbladder. On the right the stones are isodense with bile
on a CT scan.
Fig. 4. These large brown extrahepatic primary duct stones contain
sufficient calcium to be more radiodense than bile on CT scan.
possibly partially fragment such stones, based on limited in vitro
and in vivo experience [27, 30, 31]. Because intrahepatic mixed
stones do have a high overall cholesterol content, however,
long-term ursodiol would be a logical approach to preventing
recurrence once the stones have been mechanically removed.
For primary brown stones the most logical approach is directed
toward the main pathogenic factors: stasis and bacterial over-
growth. Maximizing drainage by treating papillary stenosis, dilat-
ing strictures, and removing all stone material are probably most
important. Antibiotics are effective for treating other bacterial
overgrowth syndromes and are a logical approach to reducing the
frequency of recurrence of brown stones. A logical regimen would
be antibiotics effective against bacteria recognized to produce
b-glucuronidase, such as third-generation cephalosporins, which
are also excreted in effective concentration in bile [23, 24, 32]. An
alternating and possibly intermittent regimen might be consid-
ered. Unfortunately, because of the wide diversity of the anatomic
and pathophysiologic features of the stone disease in these
patients, controlled randomized studies have not been done in
Western countries, although they should be feasible in the Orient.
A highly effective choleretic agent that might sweep bacteria
downstream as well as any initial stone debris would be potentially
useful. Unfortunately, ursodiol probably has little effect on bile
flow; for example, Friman et al. demonstrated no increase in the
volume outflow of bile in patients given ursodiol 500 mg daily for
2 to 6 weeks (Table 5) [33].
1117
Fig. 5. Typical rhomboid cholesterol crystals mixed with orange-brown
amorphous bilirubin in bile from the patient with brown stones illustrated
in Figure 4.
Table 5. Bile flow, bile acid concentration, and bile salt secretion rate.
Bile acid BSSR
Bile flow concentration (mmol/
Subjects (ml/min) (mmol/L) min)
UDCA (n 5 6) 0.49 6 0.08 39.2 6 2.9 19.1 6 3.6
Control (n 5 8) 0.46 6 0.05 39.6 6 4.6 17.7 6 2.1
NS NS NS
UDCA: patients treated with urso-deoxycholic acid, 500 mg/day for 2
to 6 weeks; Control: patients not on bile acid treatment; BSSR: bile salt
secretion rate.
Résumé
Les calculs de la voie biliaire principale sont généralement
détectés et enlevés au moment de la cholécystectomie soit par
chirurgie, soit par endoscopie avant ou après l’intervention chir-
urgicale. La lithiase de la voie biliaire principale autochtone, bien
que moins fréquente, est un problème thérapeutique majeur. Ces
calculs peuvent être volumineux, se trouver n’importe où dans
l’arbre biliaire, parfois d’un accès peu facile, et sans solution
pharmacologique. La récidive de ces calculs primitifs est la règle
plus que l’exception et les moyens fiables de prévention restent
toujours à trouver. La morbidité et la mortalité en rapport avec
l’obstruction biliaire, le sepsis et le cholangiocarcinome jouent un
rôle redoutable dans le pronostic. Une meilleure compréhension
de la pathogenèse pourrait faciliter une approche efficiente au
traitement et plus important encore, à la prévention.
Resumen
Los cálculos secundarios del colédoco generalmente son detecta-
dos y fácilmente extraı́dos con ocasión de la colecistectomı́a,
durante la cirugı́a o por endoscopia antes o después de la
operación. La enfermedad calculosa primaria de la vı́a biliar
representa un desafı́o terapéutico mayor, puesto que los cálculos
pueden llegar a ser enormes, se distribuyen por todo el árbol
biliar, incluso en áreas de difı́cil acceso, y no responden a agentes
farmacológicos. En el caso de los cálculos primarios la recurrencia
aparece como la regla, más que como la excepción, y todavı́a no
existen métodos de prevención. Por lo demás, la morbilidad y
1118
mortalidad resultantes de la obstrucción biliar, la sepsis y el
colangiocarcinoma, convierten a la enfermedad calculosa prima-
ria de la vı́a biliar en un formidable adversario. Una mayor
comprensión de la patogénesis habrá de facilitar el desarrollo de
mejores métodos terapéuticos y, lo más importante, lograr su
prevención.
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