Best Practice & Research Clinical Gastroenterology

Vol. 20, No. 6, pp. 1075e1083, 2006

doi:10.1016/j.bpg.2006.05.009
available online at http://www.sciencedirect.com

Epidemiology, pathogenesis, and classification

of biliary stones (common bile duct
and intrahepatic)

Susumu Tazuma* MD
Professor and Chairman
Department of General Medicine and Clinical Pharmacotherapeutics, Hiroshima University Hospital and
Graduate School of Biomedical Sciences, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan

Gallstones are common in Western countries and Japan. Most gallstones are found in the gall-
bladder, but they sometimes pass through the cystic duct into extrahepatic and/or intrahepatic
bile ducts to become bile-duct stones, causing conditions known as choledocholithiasis and hep-
atolithiasis. Some 10e15% of gallstone patients concomitantly suffer from bile-duct stones. Bile-
duct stones can also be formed in the absence of gallbladder stones, and such primary bile-duct
stones are more common in East Asian countries than in the Western world. Thus pathogenesis
of primary and secondary bile-duct stones is unlikely to be similar. Furthermore, the gallbladder
stones are primarily cholesterol or black-pigment stones, whereas most bile-duct stones are
brown-pigment stones (calcium bilirubin stones). Thus, epidemiology, pathogenesis and classifi-
cation of biliary stones are very likely to differ according to stone location (intrahepatic and/or
extrahepatic bile duct).

Key words: choledocholithiasis; hepatolithiasis; cholesterol gallstone; pigment gallstone; bile

infection; bile stasis.

COMMON-BILE-DUCT STONES

Incidence and distribution

Gallstones are extremely common in Western societies and also in Japan. Approxi-
mately l5% of the American population is found to have gallstones, and over 0.7 million
cholecystectomies are performed every year.1 Of these, 10e15% cases are found to
have concomitant common-bile-duct (CBD) stones, but in the Western world few

* Tel./Fax: þ81 82 257 5461.

E-mail address: stazuma@hiroshima-u.ac.jp
1521-6918/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
1076 S. Tazuma

cases are reported with CBD stones in the absence of gallbladder stones. In contrast,
in Japan the overall incidence of gallstones is approximately 10% of the population.2
Among these, the incidence of bile-duct stones increases with age to become approx-
imately 20% of all gallstones. The gallbladder stones are concomitantly found in 67% of
CBD-stone cases, whereas the prevalence of CBD stones in gallbladder-stone cases is
15% (Table 1). Thus, the gallstone incidence in Japan is epidemiologically similar to that
in the Western world. In addition, the prevalence of asymptomatic CBD stones,
coincidently detected at cholecystectomy, is 6% in Western countries.3 Coexisting
gallbladder and CBD stones are correlated with increasing age, chronic bile-duct
inflammation, Asian descent, and possibly hypothyroidism.
Primary bile-duct stones which are not associated with gallbladder stones occur
frequently in Asia. This is associated with the high incidence of intrahepatic bile-
duct stones seen primarily in Southeast Asian countries, Taiwan, Hong Kong, and
Singapore.4 The relative prevalence of intrahepatic bile-duct stones in all gallstone
cases in Taiwan is extremely high (>50%), and coexisting intra- and extrahepatic
bile-duct stones are found in approximately 70% of these. Primary bile-duct stones
are composed predominantly of bilirubin, regardless of the concomitant presence of
intrahepatic bile-duct stones, whereas those secondary to gallbladder stones are com-
posed mainly of cholesterol. Thus, the pathogenesis of the two types of bile-duct
stones probably differs.
The ratio of women to men with CBD stones is 0.89:1,2 although the prevalence of
gallbladder stones is higher in women than in men (1.22:1). The incidence of gallstones
increases with increasing parity, and biliary sludge is formed in approximately 30% of
pregnant women; 1e3% of these form gallstones.5,6 The mean age of CBD-stone
patients is 67 years, which is older than that of gallbladder-stone patients (56 years).
Similarly, gallbladder diseases are found in 5e8% of young women but in 25e30% of
women over 50 years of age.7 Thus, risk factors for gallstones include biological fac-
tors such as increasing age, female gender, and pregnancy.8

Origin e secondary to gallbladder or primitive from the bile duct?

CBD stones are classified according to origin: (1) primary bile-duct stones, forming
initially in the bile ducts; (2) secondary to gallbladder stones, originating in the gallblad-
der and passing into the bile ducts; and (3) secondary to or coexisting with intrahe-
patic bile-duct stones.
Primary bile-duct stones which do not involve the gallbladder are also composed
predominantly of bilirubin, and this is presumably associated with biliary stasis and
infection.9,10 The incidence of primary CBD stones is low in Western societies, where
stones are most commonly found in the gallbladder. Gallstones can pass through the

Table 1. Incidence of common bile-duct stones in Japan.

1989e1995 1996e1997
All gallstone cases 140,884 6814
Gallbladder stone 117,920 (83.7%) 5335 (78.3%)
Common bile-duct stone 20,006 (14.2%) 1384 (20.3%)
With gallbladder stone e 934/1384 (67.5%)
Without gallbladder stone e 450/1384 (32.5%)
Intrahepatic duct stone 2959 (2.1%) 95 (1.4%)
 Epidemiology, pathogenesis, and classification of biliary stones 1077

cystic duct into extrahepatic and/or intrahepatic bile duct to become bile-duct stones
secondary to gallbladder stones. In this regard, bile-duct stones coexisting with gall-
bladder stones are presumably formed secondarily to gallbladder stones. In such cases,
the bile-duct stone composition is biochemically identical or extremely similar to that
of gallbladder stones, which are composed predominantly of cholesterol.
In addition, CBD stones are concomitantly found in approximately 70% of intrahe-
patic bile-duct stones.4 These stones are identical or extremely similar to intrahepatic
bile-duct stones in biochemical composition. Most of intrahepatic bile-duct stones are
brown-pigment stones, relatively rich in cholesterol. Thus, the pathogenesis of primary
bile-duct stones probably differs from that of secondary bile-duct stones.

Congenital and acquired risk factors

Risk factors for gallstones include congenital, biological, and behavioural factors. Bile
stasis and infection are important factors for primary CBD-stone formation. On
this basis, an anatomical abnormality causing bile stasis is one of the major risk factors,
in association with bile infection.9 In contrast, the dilatation of the common bile duct is
frequently associated with bile-duct stones after cholecystectomy, and a cystic duct
dilatation in the aged gallbladder-stone population is directly associated with passage
of gallbladder stones into bile ducts to form secondary bile-duct stones. Thus, such
an acquired risk in anatomy is also important in both primary and secondary bile-
duct stone formation.
Genetic factors are believed to account for the ethnic difference in the risk of gall-
stone formation. The prevalence of cholesterol gallstones is higher in Native Americans,
Chileans, and Hispanics than in age-matched white control subjects, whereas African
Americans have a lower prevalence of gallstones than whites,11 and concomitant CBD
stones are found in 10e15% of these populations. Primary bile-duct stones, composed
mainly of bilirubin, are much more common in Asians than in Europeans. Another
genetic factor, gallstone formation-associated genes Lith1 and Lith2, have been
recognized in mice,12 but no human genes definitely linked to gallstones have been
identified to date. Furthermore, polymorphisms in the apolipoprotein E gene, which
are associated with gallstone formation, have been identified.13 However, these genetic
factors are not specific for primary bile-duct gallstone formation.
Acquired risk factors for gallstone formation include not only biological factors
such as age, gender, and lipid metabolism, but also behavioural factors such as nutri-
tion, obesity, rapid weight gain and loss, and exercise. In addition to these factors, cho-
lecystectomy at young ages leading to CBD dilatation is another acquired risk factor
for CBD stones.14 Furthermore, chronic inflammatory conditions e such as hypofunc-
tion of Oddi, primary sclerosing cholangitis, acquired immunodeficiency syndrome,
and parasites e can lead to bile-duct stone formation. Certain drugs are secreted
into bile and may precipitate with calcium to form stones.15

Classification based on biochemical structure

CBD stones are composed predominantly of bilirubin, whereas cholesterol is a major

component in gallbladder stones (Table 2). Thus, primary bile-duct stones tend to be
higher in bilirubin content and lower in cholesterol content than secondary stones.
The pathogenesis of primary bile-duct stones probably differs from that of secondary
bile-duct stones.
1078 S. Tazuma

Table 2. Classification of gallstones based on biochemical structure.

Gallbladder stones Common bile-duct stones
Cholesterol stone (%) 58.3 31.1
Bilirubin stone
Black-pigment stone (%) 23.7 11.8
Brown-pigment stone (%) 15.9 54.3
Others (%) 2.1 2.8

Pigment gallstones are divided into two categories: black-pigment stones composed
primarily of bilirubin polymers, and brown-pigment stones composed predominantly
of calcium bilirubinate. Brown-pigment stone is frequently found in primary CBD
stones, and this contains more cholesterol than black-pigmented stones. In the pro-
cess of the formation of brown-pigment stone, bacterial infection and biliary stasis
are important factors.9 Thus, bacteria are frequently found in brown-pigment stones,
and bile infection appears to precede stone formation.10 Parasitic infection is also as-
sociated with primary duct stones as well as intrahepatic bile-duct stones, particularly
in Asia. The pathogenesis of these stones is complex, and seemingly involves not only
bile infection and stasis but also malnutrition and/or dietary factors. Hydrolysis of bil-
irubin by bacterial b-glucuronidase leads to formation of unconjugated bilirubin which
can precipitate as calcium bilirubinate. Recent investigations clarify the presence of
bacteria not only in brown-pigment stones but also in cholesterol stones, indicating
that bacterial infection commonly plays a pathogenic role in cholesterol stone forma-
tion.16 Thus, after brown-pigment stone core formation is initiated by bacterial infec-
tion and subsequent bilirubin deconjugation, bile composition may change eventually
to form brown-pigment stone or cholesterol stones. Similarly, such precipitates and/
or microcalculi can act as foreign bodies to induce bacterial colonization, eventually
enhancing precipitation of calcium bilirubinate or modifying original cores.
In contrast, bilirubin polymerization is based upon non-enzymatic deconjugation of
bilirubin, and therefore black-pigmented stone formation in the gallbladder is not
associated with bile infection, but rather from chronic haemolysis caused by genetic
disorders and/or artificial organs, leading to overproduction of bilirubin. Mucin origi-
nating from the biliary tree, bile duct and gallbladder traps precipitates of calcium
bilirubinate and bilirubin polymers to form brown- and black-pigment stones.

Natural history

The natural history of CBD stones varies a great deal according to the life-style of the
subjects, especially dietary habits. CBD stones present with acute cholangitis, pancre-
atitis, and hepatic abscesses caused by the obstruction of the bile-duct or Ampulla of
Vater, while approximately 10% are asymptomatic. Such complications are frequently
accompanied by bacterial sepsis because the bacterial biofilm on stones is activated
under stone obstruction-induced bile stasis. Patients become jaundiced with colic
pain and fever, requiring urgent drainage. In very few cases with malignant bile-duct
obstruction without stones does sepsis result. Also, small CBD stones spontaneously
pass into the duodenum without any serious complication. Secondary CBD stones are
diagnosed incidentally in screening examination of the biliary tree, and thus in most
 Epidemiology, pathogenesis, and classification of biliary stones 1079

cases are asymptomatic or associated with symptoms and complications similar to

those of gallbladder stones. However, chronic bile stasis based upon biliary obstruc-
tion by stones can cause secondary biliary cirrhosis and portal hypertension over
the course of years,17 and acute obstructive suppurative cholangitis and acute pancre-
atitis frequently need urgent and intensive care. Thus once diagnosed, CBD stones
should be removed by endoscopic techniques or surgery.

INTRAHEPATIC STONES

Worldwide epidemiology

Intrahepatic stones are rare in the Western world but frequent in Eastern Asia. The
prevalence of intrahepatic stones in the West is 0.6e1.3%,18,19 but extremely high
in Asian societies: for example, 47.3% in Taiwan, 38.0% in China, 17.0% in Korea,
and 11.7% in Malaysia.20 In Japan it is 2.1%.2 Also, a relatively high incidence is found
in Latin America (around 2%), especially in Brazil.21,22
There are two types of intrahepatic stones: (1) primary stones formed in the intra-
hepatic bile duct, found in East Asian countries, and (2) secondary stones originating
from the gallbladder, commonly found in the Western world. The retrospective study
in East Asia indicates that the concomitant intrahepatic and extrahepatic stones are
found in approximately 70% of all hepatolithiasis cases, and that the left hepatic
duct involvement is similarly predominant in stone location and biliary strictures
(70e90%).23 Half of the intrahepatic stones occur concomitantly with gallbladder
stones, suggesting secondary stones. The mean age at presentation is the 50s and
60s, with a similar gender distribution.24,25
The aetiology of intrahepatic stones is not completely understood, but the higher
incidence in Asian countries and Brazil, compared to that in Western societies, suggests
poor sanitary and nutritional conditions as key factors in the pathogenesis.20,26 Mal-
nutrition and low socio-economic class are associated with a high incidence of intra-
hepatic stones.27 There is a gradual increase in the incidence of gallbladder stones with
Westernization of life-style, and this is associated with a decrease in intrahepatic stones
and CBD stones in Taiwan and Japan.28,29 Intrahepatic stones used to be common in
Japan during the 1950s when the diet was low in fat and protein, but with economic
development and improvement in the quality of life its prevalence is clearly declining.20

Pathogenesis

Pathogenesis of primary intrahepatic stones, seen primarily in East Asian countries, is

complicated and probably involves a combination of bile stasis, bile infection, malnutri-
tion, and parasitic infestation,9,10 namely oriental cholangiohepatitis.30 Bile stasis asso-
ciated with biliary stenosis leads to bacterial colonization, mostly by Escherichia coli and
Enterobacter species (>95%) that pass into the liver through the portal vein secondarily
to repeated parasite intestinal mucosal lesions. Biliary parasites are relatively common
in East Asian countries, where sanitary conditions are poor in some places. Biliary
infestation by Clonorchis sinensis and Ascaris lumbricoides leads to inflammation of the
biliary epithelium, enhancing mucin secretion and providing a nidus for stone formation
together with fragments of parasites and/or their eggs.31
Bacterial enzymes, such as b-glucuronidase, initiate the hydrolysis of bilirubin
diglucuronides to form unconjugated bilirubin which can precipitate as calcium
1080 S. Tazuma

bilirubinate.32 Also, bacterial phospholipase induces the breakdown of biliary phospho-

lipids to produce free fatty acids and lysophospholipids, both of which are quite water-
insoluble.33 This enhances the precipitation of calcium salts of fatty acids, along with
the enhancement of mucin secretion from biliary epithelium. Thus, primary intrahe-
patic stones are brown-pigment stones composed predominantly of calcium bilirubi-
nate with more cholesterol.
The pathogenesis of primary intrahepatic cholesterol stones remains unclear. Re-
cent investigations indicate that intrahepatic stone formation is based upon the dual
defects of up-regulation of cholesterol synthesis and down-regulation of bile-acid syn-
thesis in the liver, possibly in association with defective secretion of phospholipid by its
canalicular transporter, multidrug resistance protein (MDR3).34

Congenital and acquired risk factors

Intrahepatic stone formation is affected by congenital and acquired risk factors. Con-
genital factors include: (1) anatomical anomalies such as biliary strictures associated
with sclerosing cholangitis, and extrahepatic anomalies caused by choledochal cyst or
Caroli’s disease, and (2) genetic diseases such as haemolytic diseases. The prevalence
of left hepatic lithiasis is relatively high, and this can be explained by the anatomical dif-
ference between the left and right hepatic ducts. The left hepatic duct forms an acute
angle at the junction with the common bile duct, and tends to induce bile stasis when
associated with biliary strictures.35,36 Another anatomical anomaly e branching of the
right segmental bile ducts from the left hepatic duct e is possibly associated with left
intrahepatic stone formation. Congenital choledochal dilatation, including choledochal
cyst, is frequent in the Orient, but its causal relationship to intrahepatic stones has yet
to be established. In contrast, haemolytic diseases lead to bilirubin overproduction; this
is associated with pigment stones regardless of stone location e intrahepatic, extra-
hepatic, common bile duct and/or gallbladder. In contrast, acquired risk factors include
postoperative biliary strictures caused after cholecystectomy, partial hepatectomy, and
liver transplantation, and to a lesser degree iatrogenic bile-duct strictures as well
as benign and malignant bile-duct stenosis. Benign strictures can also occur after
chemo-embolization of hepatic tumours and chronic pancreatitis. In addition, chronic
biliary inflammation is associated with acquired immunodeficiency, leading to secondary
sclerosing cholangitis and liver cirrhosis/bile stenosis.
Furthermore, environmental rather than ethnic factors are implicated in the cause
of intrahepatic stones.23 The prevalence of intrahepatic stones differs significantly in
areas of East Asia, where the majority of the population is of Chinese descent, and
behavioural factors are likely to predispose to intrahepatic stone formation. Among
such environmental factors, dietary behaviour, bacterial infection, and biliary parasites
are to be considered. Socio-economic status is also speculated to be one of the aetio-
logical factors. In Taiwan, the majority of intrahepatic patients have been reported to
belong to low-income brackets.27

Overview of classification (pathogenetic, biochemical,

anatomical and others)

Intrahepatic stones are classified pathogenetically into two types: (1) primary stones
formed in the intrahepatic bile duct, which result primarily from bile stasis and infec-
tion, and (2) secondary stones originating from the gallbladder and passing through the
 Epidemiology, pathogenesis, and classification of biliary stones 1081

cystic duct. As a biochemical classification, primary stones are divided into calcium
bilirubinate stones (>90%), cholesterol stones, and mixed stones. Intrahepatic calcium
bilirubinate stones are known as brown-pigment stones, which contain relatively large
amounts of cholesterol (up to 20%).
There is no universal classification of intrahepatic stones, but the anatomical clas-
sification is easy to apply clinically and is useful in determining operative treatment.
Important parameters are shown in Table 3. In East Asia, incidences are as follows:

 concomitant intrahepatic and extrahepatic stones, 69%;

 left lobe involved and predominates, 78% (unilateral, 45%);
 with gallbladder stones, 48%;
 presence of strictures in intrahepatic bile duct, 76%.

To date, a clinical classification of intrahepatic stones is under consideration by

the Hepatolithiasis Research Group organized by the Ministry of Health, Labour, and
Welfare of Japan, and will be released shortly.

Natural history

Intrahepatic stones lead to the syndrome of recurrent pyogenic cholangitis,11 present-

ing with abdominal pain, fever, and jaundice e the typical Charcot’s triad. Jaundice is
due to persistent obstruction of the bile duct, but such an obstruction is usually
incomplete. A typical attack can last for hours to days, with the biliary colic located
in the upper right quadrant. In some cases, the pain is located in the epigastrium.
The severe state of this attack, the Raynold’s pentad e defined as the onset of hypo-
tension and mental confusion in addition to Chardot’s triad e predicts a poor out-
come. The recurrent pyogenic cholangitis causes cholestasis with symptoms of
jaundice and pruritus, and this leads to liver abscess and/or secondary liver cirrhosis.
As a more important complication, cholangiocarcinoma develops in 10% of the intra-
hepatic stone population in Japan.37 This occurs even after the complete removal of
intrahepatic stones, because bile stasis and bacterial infection are likely aetiological
factors. Thus, the careful screening for malignant lesions is important in the follow-up
of this disease, regardless of whether or not the stones are removed.

SUMMARY

In this chapter the epidemiology, pathogenesis, and natural history of CBD stones
(choledocholithiasis) and intrahepatic stones (hepatolithiasis) have been reviewed. Gall-
stones are extremely common in Western countries, where the prevalence of bile-duct

Table 3. Classification of intrahepatic stones.

Intrahepatic and/or extrahepatic ducts
Right and/or left lobe involvement (unilateral or bilateral)
With or without gallbladder stones
Location of strictures in intrahepatic bile duct
Symptomatic or asymptomatic
Complications
1082 S. Tazuma

stones is relatively low. In contrast, primary choledocholithiasis and hepatolithiasis

appear to be more frequent in East Asian countries than in Western societies, where
bile-duct stones are mostly secondary to gallbladder stones passing through the cystic
duct. Primary bile-duct stones are composed predominantly of calcium bilirubinate,
namely brown-pigment stones. The pathogenesis of primary bile-duct stones is based
upon bile stasis and infection, which are associated with bile-duct strictures, extrahe-
patic anomalies and biliary parasites. In contrast, secondary stones are considered to
originate from gallbladder stones, and are commonly composed of cholesterol. Con-
genital and acquired risk factors predisposing to bile-duct stones include anatomical
anomalies, genetic diseases of bilirubin and cholesterol, bacterial infection, and socio-
economic problems. Bile-duct stones typical present with fever, abdominal pain, and
jaundice (Charcot’s triad), and in severe cases also hypotension and mental confusion
(Raynold’s pentad) which predicts a poor clinical outcome. Furthermore, silent cholan-
giocarcinoma develops in 10% of the intrahepatic stone cases even after the removal of
stones, and therefore the follow-up of these cases is of clinical importance.

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