Best Practice & Research Clinical Gastroenterology

Vol. 20, No. 6, pp. 1117e1137, 2006

doi:10.1016/j.bpg.2006.05.010
available online at http://www.sciencedirect.com

10

Management of intrahepatic stones

Toshiyuki Mori*
Masanori Sugiyama
Yutaka Atomi
Department of Surgery, Kyorin University, 6-20-2 Shinkawa Mitaka, Tokyo, 181-8611, Japan

Hepatolithiasis (oriental cholangiohepatitis) has reportedly been endemic only in East Asia. The
disease is now occasionally recognized in Western societies, especially in people who have lived
in the Orient. Hepatolithiasis is characterized by its intractable nature and frequent recurrence,
requiring multiple operative interventions, which is in distinct contrast to gallbladder stones.
In addition to frequent cholangitis and chronic sepsis, it is widely known that longstanding intra-
hepatic stones lead to intrahepatic cholangiocarcinoma. Symptoms of hepatolithiasis include
abdominal pain, jaundice and cholangitis. Pyogenic cholangitis due to strictures and hepatolithia-
sis tends to recur, and sometimes patients may present with liver abscesses. Radiological studies
and percutaneous procedures are keys in the diagnosis and treatment of hepatolithiasis. Non-
invasive imaging modalities such as ultrasonography (US), computed tomography (CT), and
magnetic resonance imaging (MRI) accurately depict the normal anatomy and presence of
intrahepatic stones. It should be stressed that each modality has its pros and cons, and imaging
studies should be performed on the basis of understanding the pathophysiology. As the diagnos-
tic role of magnetic resonance cholangiopancreatography (MRCP) evolves, the roles of both
endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic chol-
angiography (PTC), and their most significant advantage, is primarily therapeutic with their ability
to extract stones, biopsy intraductal lesions, and place stents easily. The primary goals of treat-
ment are to eliminate attacks of cholangitis and to stop the progression of the disease (which
leads to biliary cirrhosis). Surgery has a primary role in hepatolithiasis because hepatolithiasis
tends to recur, so that multiple sessions of the endoscopic approach (i.e. two or three times
a year) are often required. PTC is an alternative when surgical resection of the affected lobe
is difficult. Techniques for lithotripsy, including shockwave and laser, can be applied in endoscopic
sessions, offering a better chance of clearing the stones.

Key words: hepatolithiasis; oriental cholangiohepatitis; MRCP; cholangiocarcinoma.

* Corresponding author. Tel.: þ81 422 47 5511; Fax: þ81 422 47 9926.
E-mail address: mori@kyorin-u.ac.jp (T. Mori)
1521-6918/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
1118 T. Mori et al

Intrahepatic gallstone disease (hepatolithiasis) is commonly described as oriental chol-

angiohepatitis, a problem seen frequently in East Asia (hence its name). Hepatolithiasis
is now occasionally recognized in Western societies, especially in people who have
lived in the Orient. The cause of the disease was commonly attributed to parasitic in-
fection of the bile system with concomitant biliary infection. Although bile-duct stric-
ture and infections by bacteria that produce enzymes such as b-glucuronidase seem to
play key roles in stone formation, parasitic infestation of the bile duct is now not usu-
ally evident in the resected liver specimens. Nevertheless, intrahepatic gallstone dis-
ease continues to be a serious health-care problem because of its intractability and
resulting bile-duct cancer. Intrahepatic stones consist of calcium bilirubinate in most
cases, but contain more cholesterol than similar stones found in the common bile
duct. Cases with intrahepatic stones that consist of almost pure cholesterol are spo-
radically reported in the literature. These facts suggest that our understanding of the
pathogenesis of hepatolithiasis should be updated.

EPIDEMIOLOGY AND PATHOGENESIS

Hepatolithiasis is defined as gallstones present in the bile ducts peripheral to the con-
fluence of the right and left hepatic ducts, irrespective of the coexistence of gallstones
in the common duct and/or gallbladder.1 Hepatolithiasis has reportedly been endemic
only in East Asia. The disease is now occasionally recognized in Western societies,
especially in people who have lived in the Orient (see also Chapter 1).
According to recent surveys of hepatolithiasis worldwide,2e7 the relative propor-
tion of hepatolithiasis to all cholelithiasis varies with geographical region. In Taiwan,
hepatolithiasis accounts for more than 50% of all cholelithiasis. The relative proportion
of hepatolithiasis to all cholelithiasis was reportedly 3.1% in Hong Kong and 1.7% in
Singapore. Although the ethnic background is identical, a higher relative proportion
of hepatolithiasis (21.1%) was reported in Shenyang in north-eastern China, whereas
it was only 9.2% in Beijing. In the Western world, the prevalence of hepatolithiasis
seems much lower, less than 1%,8 as revealed by only occasional reports. However,
the overall relative proportion of hepatolithiasis seems to be increasing, since the
number of immigrants from endemic areas entering the West is considerably increas-
ing. In fact, most reports on hepatolithiasis from the West concern such immigrant
populations. In Latin America, the relative proportion of hepatolithiasis is reportedly
as high as 2e7%.9 In Japan, the relative proportion was reportedly 1.7% in 1998.7
Intrahepatic gallstone disease is characterized by its intractable nature and frequent
recurrence, requiring multiple operative interventions, which is in distinct contrast to
gallbladder stones. In addition to frequent cholangitis and chronic sepsis, it is widely
known that longstanding intrahepatic stones lead to intrahepatic cholangiocarcinoma.
Intrahepatic gallstone disease continues to be a serious health-care problem in
Japan, and the Hepatolithiasis Research Group was organized in 1970 by the Ministry
of Health, Labour and Welfare of Japan. Epidemiology, pathogenesis, carcinogenicity, and
therapeutic options of hepatolithiasis have been investigated. A nationwide survey was
conducted five times, and a chronological shift in the prevalence of hepatolithiasis was
noted.10e13 In the years 1970e1977 the survey showed that the relative proportion of
hepatolithiasis to all cholelithiasis was 4.1% (1590/38,606). The proportion has been
constantly decreasing since then: 3.0% (4381/148,017) in the years 1975e1984,
2.3% (1813/79,052) in the years 1985e1988, 2.2% (2253/105,062) in the years
1989e1992, and 1.7% in the years 1993e1995. The increase of ordinary cholelithiasis
 Management of intrahepatic stones 1119

in post-war Japan may have partly contributed to the decrease in the relative propor-
tion of hepatolithiasis. The relative proportion is also reportedly decreasing in Taiwan
as well as in Korea.14,15
In most cases intrahepatic stones consist of calcium bilirubinate, but contain more
cholesterol than similar stones found in the common bile duct. Cases with intrahepatic
stones that consist of almost pure cholesterol are sporadically reported in the litera-
ture.16,17 Nevertheless, the proportion of cholesterol stones in hepatolithiasis con-
tinues to be 5.8e13.1%.11e13 This is strongly contrasted by the increased number
of gallbladder cholesterol stones, probably due to the westernization of the diet in
post-war Japan.
Patients with hepatolithiasis are most likely to present the first symptoms in their
sixth and seventh decades. The intrahepatic type, in which the stones exist only above
the confluence, is more likely to be found in the younger age group (e.g. fifth and sixth
decades), while intra- and extrahepatic types—in which the stones exist in intra- and
extrahepatic ducts—may be found in the older groups (e.g. seventh and eighth decades).
The male/female ratio is persistently 1:1.2 in each survey.11e13
Gallstones in hepatolithiasis are in most cases brown, soft, and friable. They con-
sist of two groups: brown pigment stones (calcium bilirubinate stones) and choles-
terol stones, the former predominating.18 It should be stressed that intrahepatic
brown pigment stones contain less bilirubin and bile acid and more cholesterol
than those in either the common bile duct or the gallbladder, and the complex na-
ture of the pathogenesis should be considered: e.g. not only the formation and pre-
cipitation of calcium bilirubinate but also alteration in cholesterol metabolism in
hepatic bile.19 Bile-duct stricture and dilatation of the duct peripheral to the stric-
ture are usually present in cases with brown pigment stones, but are often absent
in cases with cholesterol stones. Bile-duct stricture and infection with bacteria
that produce enzymes such as b-glucuronidase seem to play key roles in bilirubin
precipitation and stone formation;20 other mechanisms that alter cholesterol
metabolism in the hepatocytes should also be considered.19 As mentioned above,
parasitic infestation of the bile duct does not seem to play an important role in
hepatolithiasis.

SYMPTOMS

Symptoms of hepatolithiasis include abdominal pain, jaundice and cholangitis. Pyogenic

cholangitis due to strictures and hepatolithiasis tend to recur, and sometimes the pa-
tient can present with liver abscesses. The Hepatolithiasis Research Group in Japan
has proposed a grade classification in order to scale the severity of hepatolithiasis.21
Grade 1 is defined as having no symptoms, grade 2 as having abdominal pain, grade 3
as having either transient jaundice or cholangitis, and grade 4 as having continuous
jaundice, sepsis, or cholangiocarcinoma. In a recent (1998) survey of 473 hepatolithia-
sis patients, 20% of cases were classified as grade 1, 25% as grade 2, and 55% as grades
3 and 4. It should be noted that more than half of the hepatolithiasis cases were clas-
sified as grade 3 or 4. Chronic cholangitis and resulting sepsis are characteristic symp-
toms of the disease. In a review over a 10-year period of 303 patients with
hepatolithiasis who underwent surgical treatment, 12% of patients were still symptom-
atic with fever or abdominal pain. Surprisingly, 30% had died in this study, and it is
noteworthy that cholangiocarcinoma was the cause of death in 25% of the cases.22
In the surveys conducted by the Hepatolithiasis Research Group in Japan, the
1120 T. Mori et al

association of biliary-tract carcinomas with hepatolithiasis was 5.2%, and among carci-
nomas, intrahepatic cholangiocarcinoma was reportedly the most frequent.23 In cases
with cholangiocarcinoma, association with hepatolithiasis is reportedly 5.7e17.5% in
Japan.24,25

DIAGNOSTIC TOOLS

Radiological studies and percutaneous procedures are keys in the diagnosis and treat-
ment of hepatolithiasis.26e28 Non-invasive imaging modalities such as ultrasonography
(US),29,30 computed tomography (CT),31,32 and magnetic resonance imaging (MRI)33,34
accurately depict the normal anatomy and presence of intrahepatic stones. It should be
stressed that each modality has its pros and cons, and imaging studies should be per-
formed on the basis of understanding pathophysiology.35e37 In the diagnosis of hepa-
tolithiasis, imaging studies should aim not only to diagnose intrahepatic calculi but also
to evaluate in detail the precise location of stones, stricture of bile ducts, and even
concurrent cholangiocarcinoma.38,39 Furthermore, it is widely known that longstand-
ing hepatolithiasis leads to atrophy of the affected lobe. In the diseased lobe, paren-
chyma and blood flow of the portal vein and hepatic artery may not be proved.40
Pneumobilia may exist as a consequence of previous treatment, and it is sometimes
difficult to differentiate pneumobilia from intrahepatic calculi.30,31 These specific
conditions associated with hepatolithiasis pose difficulties in the accurate diagnosis
of hepatolithiasis. Several techniques—including modified protocols in MRIs and a
combination of drip infusion cholangiography (DIC) and multidetector CT (MDCT)
with subsequent processing—are reportedly useful.41,42 It should be stressed that
even with progressions in modern imaging modalities, endoscopic retrograde cholan-
giography (ERC) and percutaneous cholangiograms continue to be invaluable tools in
detailed diagnosis.43e45

Ultrasonography (US)

Ultrasonography29,30,46 is free from ionizing radiation and contrast is not required. US

study of the liver and biliary tree requires minimal patient preparation. It is portable
and therefore may be used at the bedside of critically ill patients. Emergency studies
are performed without specific preparation. Nevertheless, US study is a powerful
tool to show intrahepatic calculi and bile-duct dilatation. It is appropriate to perform
US study first when hepatolithiasis is suspected.
Intrahepatic calculi usually appear as echogenic spots (areas) with an acoustic
shadow behind. A high echo rim on the front surface of stones indicates that the stone
contains much calcium. The lower the calcium content, the better the whole stone can
be visualized. When the entire stone is visualized, calcium bilirubinate stones should be
differentiated from cholesterol stones, because the treatment differs. In calcium bilir-
ubinate stones, marked biliary dilatation peripheral to the stone is usually observed,
whereas dilatation of the ducts in cholesterol stones is usually limited in the stone
location (Figure 1).
It is generally difficult to differentiate air bubbles from stones in the biliary tree, be-
cause sonographic characteristics are similar in both. In such cases, postural migration
of the high echoic spot may be of help. US study is performed in supine and knee-
elbow positions so that air bubbles move upward. When the dilated duct is packed
with stones it poses further difficulty in differentiating intrahepatic calculi from
 Management of intrahepatic stones 1121

Figure 1. Ultrasonography (US). (a) Calcium bilirubinate stones. Intrahepatic calculi usually appear as an
echogenic spot (area) with an acoustic shadow behind. Note the marked dilatation of the duct peripheral
to the stones in calcium bilirubinate stones. (b) Cholesterol stones. In cholesterol stones, dilatation of
the bile duct peripheral to the stones is usually absent.

pneumobilia, since in both cases only the front surface is visualized as a hyperechoic rim. It
is also difficult to precisely show the stricture of the biliary duct because of the presence
of stones. Up-to-date ultrasound technology offers studies with excellent tissue resolu-
tion for depiction of normal anatomical structures and pathological conditions. It
should be stressed that US study of the biliary tree is equipment- and operator-
dependent.
1122 T. Mori et al

Computed tomography (CT)

Trans-sectional CT imaging31,32,47 is the single most cost-effective method when hep-

atolithiasis is suspected. Although even newer-generation CT scanners cannot identify
normal peripheral ducts, dilated segmental bile ducts as well as stricture of the duct
can be demonstrated. Dilated bile ducts appear as low-density, tubular, tortuous
branching structures best appreciated on contrast-enhanced studies. Calcium bilirubi-
nate stones in hepatolithiasis contain less calcium than similar stones in CBD, so the
density (measured in Hounsfield units, HU) of the intrahepatic stones may be similar
to that of bile juice in the affected ducts (Figure 2). In such cases, stones themselves
are not visualized by CT study. Contrast-enhanced studies are of no help in this
situation.
CT cholangiography is a technique in which a slow intravenous infusion of meglu-
mine iotroxate is given.34 Contrast medium is excreted in the bile, and the
contrast-filled biliary system is displayed on CT. It has a higher sensitivity for intraduc-
tal calculi (92%) than plain CT. In the diagnosis of hepatolithiasis, however, contrast
media may not be excreted enough to generate contrast between bile juice and stones
because of impaired hepatic function of the affected segment of the liver. In cases with
hepatic atrophy resulting from longstanding hepatolithiasis, the affected segment of the
liver may be recognized just as defect(s) of the biliary tree. It is reportedly useful to
perform a combination of contrast-enhanced multidetector CT and DIC with subse-
quent processing (Figures 3 and 4).48 Subsequent processing may demonstrate the seg-
mental branch of the hepatic artery and defective biliary ducts in the corresponding
segment. It is widely known that portal blood flow of the affected segment in hepato-
lithiasis is markedly decreased, and the portal branch of the atrophic segment may also
be defective.

Figure 2. Computed tomography (CT). CT displays dilated bile ducts which appear as low-density, tubular,
tortuous branching structures best appreciated on contrast-enhanced studies. Intrahepatic stones have
a density similar to that of the bile juice in the affected ducts, and the stones themselves may not be
displayed.
 Management of intrahepatic stones 1123

Figure 3. Multidetector computed tomography (MDCT) with subsequent processing (virtual endoscopy).
Although its clinical value has not been fully investigated, MDCT with subsequent processing can effectively
explore the biliary tree. A stone is identified in B5 with virtual endoscopy.

Stricture of the bile duct appears as a thickened segment central to the dilated bile
duct. Bile-duct stricture is usually enhanced with contrast media, reflecting inflamma-
tory change. Typically, cholangiocarcinoma is an infiltrative, slow-growing malignancy. It
is generally difficult to differentiate by CT bile-duct stricture from cholangiocarcinoma

Figure 4. Multidetector computed tomography (MDCT) with subsequent processing (MIP, maximal inten-
sity projection). Stenosis of the common hepatic duct and the dilated bile tree above the stenotic segment is
clearly visualized on MIP.
1124 T. Mori et al

at an early stage. Serum CA19-9 level is reportedly more sensitive in this differentia-
tion. Contrast-enhanced CT can demonstrate cholangiocarcinoma as a hypovascular
lesion when a mass is formed. In such cases, cholangiocarcinoma is usually at an ad-
vanced stage and surgery is not indicated.38,39
In an acute exacerbation of cholangitis in hepatolithiasis, hepatic abscesses may be
formed. An abscess may appear on CT as a cystic mass with debris inside.49,50

Magnetic resonance imaging (MRI) (Figures 4 and 5)

MR scanning has seen a rapid development in technology in recent years, with a

significant improvement in techniques and diagnostic accuracy for both abdominal
scanning and MR cholangiopancreatography (MRCP).33,34,51 A combination of T1-
and T2-weighted gradient echo axial, heavily T2-weighted thin-section scans in coro-
nal and coronal oblique planes, together with thick-slab radial cholangiographic
T2-weighted images to delineate anatomy is obtained for MRCP. This has the added
advantage that these two techniques can be performed in one setting. MR has proved
to be an excellent non-invasive and accurate imaging technique without the use of
ionizing radiation or, in many cases, the need for contrast administration. It is rela-
tively operator-independent with negligible morbidity. The most commonly used

Figure 5. Magnetic resonance cholangiopancreatography (MRCP). MRCP is a non-invasive imaging study

that can investigate upstream of the strictured bile duct. Intrahepatic stones are recognized as low-intensity
areas in the dilated bile duct.
 Management of intrahepatic stones 1125

contrast is a gadolinium chelate, which has good patient safety and tolerability.52 The
limitations of MR scanning are predominantly the difficulty in scanning certain groups
of patients: for example those with claustrophobia or patients with pacemakers. MRI
is not suitable when therapeutic intervention is planned. In obstructive jaundice,
MRCP has an overall accuracy of 96e100% for level of obstruction and 90% accuracy
for the cause of obstruction. Comparisons have mostly been made with direct chol-
angiography, usually endoscopic retrograde cholangiopancreatography (ERCP) in
stone diseases. In a retrospective study by Sugiyama et al, the sensitivity, specificity,
and accuracy of MRCP for detecting and locating intrahepatic stones in hepatolithiasis
were 97%, 99%, and 98%, respectively.53 The sensitivity, specificity, and accuracy of
MRCP for detecting and locating intrahepatic bile-duct strictures were reportedly
93%, 97%, and 97%, respectively. MRCP allows intrahepatic stones and accompanying
biliary strictures to be located accurately (Figure 5). Stones are recognized as defec-
tive low-intensity areas; MRCP may therefore be able to replace diagnostic ERCP in
patients with hepatolithiasis. However, MRCP has a limited ability to reveal concur-
rent intraductal cholangiocarcinoma associated with hepatolithiasis (Figure 6). MRI is
also an invaluable tool in the diagnosis and location of hepatic abscesses. An abscess
may appear on T2-weighted MRI as a cystic mass with variable intensity inside
(Figure 7).

ERC and percutaneous cholangiograms54,55

Direct cholangiography remains the gold standard in depicting subtle changes within
the bile ducts and the detection of small calculi. If opacification of the biliary system
is obtained, cholangiography reportedly has a sensitivity of almost 100% in the detec-
tion of obstruction (Figure 8). ERCP is now performed more often than percutaneous
transhepatic cholangiography (PTC). Both are invasive investigations which are signif-
icantly operator-dependent with a relatively high morbidity of 1e7% for ERCP and
3e5% for PTC. ERCP has an unsuccessful cannulation rate of 3e10%. ERCP has a sen-
sitivity of 90e96% and specificity of 98% in detecting CBD stones, although it has re-
cently been suggested that MRCP demonstrates intrahepatic stones better than ERCP.
PTC gives excellent imaging with a success rate of up to 99%, although this is depen-
dent on the presence of biliary dilatation.
As the diagnostic role of MRCP evolves, the roles of both ERCP and PTC—and
their most significant advantage—are primarily therapeutic, with their ability to ex-
tract stones, biopsy intraductal lesions, and place stents easily.

TREATMENT OPTIONS

Stones in the intrahepatic biliary tree offer especially difficult treatment challenges, es-
pecially if the bile ducts are abnormal (stricture or dilatation). The primary goals of
treatment are to eliminate attacks of cholangitis and to stop the progression of the
disease (which leads to biliary cirrhosis).26e28 Surgery has a primary role in hepatoli-
thiasis because hepatolithiasis tends to recur, so that multiple sessions of the endo-
scopic approach (i.e. 2e3 times per year) are often required.56 There is no
definitive treatment, reflecting the complicated nature of the disease and various pa-
tients’ conditions, and a multidisciplinary approach should be considered.57,58
1126 T. Mori et al

Figure 6. Magnetic resonance imaging (MRI). (a) MRI can effectively display both dilatation and stricture of
the bile tree in hepatolithiasis. (b) A high-intensity area around the bile-duct stricture is seen, and cholangio-
carcinoma associated with hepatolithiasis was suspected. No malignant cell was seen in pathological study of
the resected specimen.

Endoscopic approach

Since obstruction and infection hasten the progression of recurrent pyogenic cholan-
gitis, therapeutic goals include the complete clearance of biliary calculi and debris and
adequate drainage of the affected segments of the biliary tree.
Although ERCP is useful in the assessment of anatomy, its role in the treatment of
hepatolithiasis is limited. The treatment of primary intrahepatic stones via the trans-
papillary route is difficult if not impossible in many circumstances because of strictures,
peripheral stone impaction, or ductal angulation (Figure 9).54,55
To study the long-term value of stone extraction in patients with hepatolithia-
sis, Tanaka et al retrospectively followed 57 patients with hepatolithiasis who had
sphincterotomy to remove common bile-duct stones.59 Intrahepatic stones were
 Management of intrahepatic stones 1127

Figure 7. Liver abscess. Magnetic resonance imaging (MRI) is also an invaluable tool in the diagnosis and
location of the hepatic abscess.

Figure 8. Endoscopic retrograde cholangiography (ERC). As the diagnostic role of magnetic resonance chol-
angiopancreatography (MRCP) evolves, the roles of both endoscopic retrograde cholangiopancreatography
(ERCP) and percutaneous transhepatic cholangiography (PTC), and their most significant advantages, are pri-
marily therapeutic, with their ability to extract stones, biopsy intraductal lesions, and place stents easily.
1128 T. Mori et al

Figure 9. Transpapillary treatment of hepatolithiasis. The treatment of primary intrahepatic stones via the
transpapillary route is difficult if not impossible in many circumstances because of strictures, peripheral stone
impaction, or ductal angulation.

removed completely in 18 patients, while some stones remained in 36 patients.

Three patients of the latter group spontaneously passed all the remaining stones
soon after the sphincterotomy. The stones were successfully cleared in four of 11
patients with stones in the right lobe (36%), 11 of 23 with stones in the left lobe
(48%), and seven of 23 with stones in both lobes (30%). The success rate of
clearance did not differ between the right and left lobes, nor did it depend on
the size of the stone; rather, the tortuous or sharply angulated duct, multiple
stones scattered in many ducts, and/or advanced disease prohibited an attempt
at stone removal. Follow-up at 66e183 months (mean 114 months) was available
in 54 patients (94.7%). Late complications occurred in ten patients with remaining
stones, including seven cases of cholangitis (two fatalities) and three of liver ab-
scess (one fatality). In contrast, those with complete clearance developed no com-
plications. Every effort should be made to remove the intrahepatic stones as
 Management of intrahepatic stones 1129

completely as possible shortly after sphincterotomy if adverse effects are to be

avoided.54

Percutaneous approach60

With technical development of percutaneous transhepatic drainage and dilation pro-

cedures, it is now possible to place catheters into the intrahepatic duct without lap-
arotomy and to dilate the route up to 18 Fr in one stage. Moreover, when
hepatolithiasis is not confined to one segment or lobe of the liver, the success rate
of PTCS for complete stone removal and the rate of subsequent stone recurrence
are comparable to those of surgical treatment of hepatolithiasis. However, the efficacy
of PTCS for complete removal of stones is limited in patients with severe biliary stric-
tures. In a retrospective study by Huang et al, 245 patients with hepatolithiasis treated
by PTCS lithotomy were followed for 1e22 years to evaluate the immediate and long-
term results.61 PTCS lithotomy achieved complete clearance of hepatolithiasis in 209
patients (85.3%); the rate of incomplete clearance was higher in patients with intrahe-
patic duct stricture (29/118, 24.6% versus 7/127, 5.5%; P ¼ 0.002). The rate of major
complications was 1.6% (4/245) and included liver laceration (n ¼ 2), intra-abdominal
abscess (n ¼ 1), and disruption of the percutaneous transhepatic biliary drainage fistula
(n ¼ 1). The overall recurrence rate of hepatolithiasis and/or cholangitis was 63.2%.
The absolute rate of stone recurrence was not significantly related to the presence
of intrahepatic duct stricture (51/89, 56.2% versus 53/120, 44.4%; P ¼ 0.08), although
the median time to recurrence was less in those with stricture (11 versus 18 years;
P ¼ 0.007). In the patients without intrahepatic duct stricture, the rate of complete
stone clearance was not related to the presence of dilation (34/38, 89.5% versus
86/89, 96.6%; P ¼ 0.196), but the recurrence rate was higher in those with dilation
(20/34, 58.8% versus 33/86, 38.4%; P ¼ 0.042). Among the 209 patients with a success-
ful initial PTCS lithotomy, the incidence of recurrent cholangitis or cholangiocarcinoma
was significantly higher in those with incompletely removed recurrent hepatolithiasis
than in those without coexisting hepatolithiasis (44.3%, 27/61 versus 16.2%, 24/148;
P < 0.001 and 6.6%, 4/61 versus 0.7%, 1/148; P ¼ 0.026).
A similar result was obtained by Lee et al in the long-term results of 92 patients
who underwent PTCS; 68 patients were followed for 24e60 months (median 42
months).62 Complete clearance of stones was achieved in 74 patients (80%). The
rate of complete clearance was significantly lower in patients with severe intrahepatic
strictures than for those with no strictures (14/24, 58% versus 16/16, 100%, P < 0.01)
and those with mild to moderate strictures (14/24, 58% versus 44/52, 85%, P < 0.05).
Patients with severe intrahepatic strictures had a higher recurrence rate than those
with no or mild strictures (100% versus 28%, P < 0.01). The severity of intrahepatic
disease was graded according to the Tsunoda Classification: I, no marked dilatation
or strictures of intrahepatic ducts; II, diffuse dilatation of the intrahepatic biliary
tree without strictures; III, unilateral solitary or multiple cystic intrahepatic dilatation
of intrahepatic ducts accompanied by stenosis; IV, same as III but with bilateral involve-
ment of hepatic lobes. In patients with hepatolithiasis types I and II, stones recurred in
two patients (12%) at 28 and 32 months after successful stone removal, without fur-
ther recurrence afterwards. The recurrence rate in patients with hepatolithiasis
types III and IV increased gradually up to 50% at 60 months of follow-up. Severe intra-
hepatic stricture was the only factor that affected the immediate success rate of PTCS
in the treatment of hepatolithiasis. Several risk factors—including severe biliary
1130 T. Mori et al

stricture, advanced biliary cirrhosis and Tsunoda types III and IV—affected the long-
term results.63

Techniques of cholangioscopy

Cholangioscopy is an invaluable tool to clear the stones and to dilate the stricture. It
can be used in a transpapillary approach via the jejunal loop or T-tube fistula. As is de-
scribed above, percutaneous transhepatic drainage and dilation procedures allow the
scope to directly approach the affected biliary tree (Figure 10). Cholangioscopy is also
performed in combination with surgery via a choledochotomy. In operative cholangio-
scopy, it is vital to make a meticulous effort to remove the intrahepatic stones as
completely as possible. Although the approaches are different, techniques of cholan-
gioscopy include stone extraction using basket catheters, dilatation of the strictured
segment by placing a guide-wire and balloon, and placement of stents to restore biliary
drainage.
In the transpapillary approach, endoscopic sphincterotomy is generally performed
prior to peroral cholangioscopy. A video cholangioscope can be advanced through
an instrumental channel of a conventional therapeutic duodenoscope (TJF 240; video
cholangioscope system XCHF-B200, Olympus Co., Tokyo).
In PTCS, after performing PTBD, the percutaneous tract is dilated to a diameter of
5.3 mm using a coaxial dilatation catheter (Cook Co. Ltd, Bloomington, IN, USA).
Seven days after the dilation, the cholangioscope (Olympus CHF-P10, CHF-Q10,
CHF-P20Q, ECN-1530 or BF-P200; Pentax Co. Ltd, Tokyo, Japan) can be inserted
into the bile duct through an established sinus tract.
A cholangioscope is inserted through an established sinus tract or choledochot-
omy. Normal saline is infused via the working channel of the scope so that a clear field

Figure 10. A PTCD route is dilated up to 18 Fr to accommodate a biliary endoscope. When hepatolithiasis
is not confined to one segment or lobe of the liver, the success rate of percutaneous transhepatic cholangio-
scopy (PTCS) for complete stone removal and the rate of subsequent stone recurrence are comparable to
those of surgical treatment of hepatolithiasis.
 Management of intrahepatic stones 1131

of view is maintained. A basket catheter is inserted via the working channel. Under
direct vision, the basket is deployed in an open position near the stone in such
a way that the stone rolls in the basket. The basket is then closed and the stone is
extracted by pulling out the scope (Figure 11). In the same way a guide wire is in-
serted through the strictured segment of the biliary tree. A balloon catheter is
then inserted over the guide wire. The balloon is then inflated to the maximum
size (i.e. 5 mm) for 10 min. The balloon is then deflated and the stricture is dilated.
Although there are no guide wires or balloon catheters specifically designed for biliary
use, those designed for the ureter are appropriate in length and diameter (Boston
Scientific, USA).

Figure 11. Percutaneous transhepatic cholangioscopy (PTCS). (a) A cholangioscope is inserted through an
established sinus tract or choledochotomy. (b) Cholesterol stones are identified in the dilated duct. Erosive
change of the biliary mucosa is observed. (c) A basket catheter is inserted through the working channel of
the scope. The basket is opened near the stone to make stones roll in. The basket is then closed and the
catheter is withdrawn with the scope, retrieving the stone.
1132 T. Mori et al

Techniques of lithotripsy64

Extracorporeal shock-wave lithotripsy used in conjunction with percutaneous radio-

logical techniques was applied to the difficult stone problem associated with hepato-
lothiasis, with a success rate >90%.
Kim et al reported a series of 18 patients with hepatolithiasis who underwent ex-
tracorporeal shock-wave lithotripsy (ESWL);65 a Dornier MPL 9000 with ultrasound
guidance was used in this study. The patients had a T-tube (n ¼ 9) or a percutaneous
transhepatic biliary drainage tube (n ¼ 9). The average treatment session was four, and
the number of shock waves was in the range 3064e12,000 (average 6288 shocks). In-
trahepatic stones were removed completely by ESWL in 16 patients over a 3-month
period. Kim et al concluded that ESWL, followed by percutaneous stone extraction,
will provide an improvement in the success rate and duration of treatment required
for complete removal of primary hepatolithiasis.
Electrohydraulic shock-wave lithotripsy and NdYAG laser lithotripsy are also avail-
able to disintegrate stones that are were too large to be removed using ordinary per-
cutaneous transhepatic cholangioscopy. Chen et al reported a series of 18 patients
with common bile-duct and intrahepatic stones treated by cholangioscopic litho-
tripsy.66 Stones were completely fragmented in seven cases (six with intrahepatic
stones and one with common bile-duct stone) and partially disrupted in five cases
with intrahepatic stones. Intrahepatic duct angulation and stricture was the factor
most often responsible for failure. All the disintegrated stones were removed by sub-
sequent transhepatic cholangioscopy. Amongst the seven patients with complete
stone fragmentation, six stones were found with electrohydraulic shock-wave litho-
tripsy and one with NdYAG laser lithotripsy. Complications of percutaneous transhe-
patic cholangioscopic lithotripsy using electrohydraulic shock waves were found in
three cases, two had transient haemobilia, and one had fever and chills after the pro-
cedures. They all recovered with conservative treatment. NdYAG laser treatment
was expensive, time-consuming and inconvenient to use. They thus concluded that
percutaneous transhepatic cholangioscopic lithotripsy by using electrohydraulic shock
wave is an effective and safe method to fragment biliary stones and to facilitate their
removal.

Indications for surgical resection

When the disease is confined to one lobe, a preferred method of treatment for hep-
atolithiasis is surgical removal of the stones and resection of the stenotic bile duct and
the destroyed hepatic parenchyma. Jan et al retrospectively reviewed a series of 614
patients.67 In this report, 427 patients were followed up for 4e10 years after surgical
treatment (380 cases) or PTCS (47 cases) Results of this study included recurrent
stone rate 29.6% (105/355), repeated operation 18.7% (80/427), secondary biliary cir-
rhosis 6.8% (29/427), late development of cholangiocarcinoma 2.8% (12/427), and
mortality rate 10.3% (44/427). The patients with hepatectomy had a better quality
of life (symptom-free) with a lower recurrent stone rate (9.5%), lower mortality
rate (2.1%), and lower incidence of secondary biliary cirrhosis (2.1%) and cholangio-
carcinoma (0%) than did the non-hepatectomy group (P < 0.01). The patients without
residual stones after choledochoscopy had a better quality of life than did the residual
stone group (P < 0.01). When only the left lobe of the liver is affected, surgical resec-
tion is generally the treatment of choice.68,69 Hepatic resection is not an option in
 Management of intrahepatic stones 1133

patients with complicated disease, including stones in both lobes and factors that in-
crease the risk of surgery.
Tsunoda et al have proposed a tailored surgical approach by their classification of
the disease.63 In this report, 119 patients with intrahepatic stones treated surgically in
Nagasaki University Hospital from 1969 to 1984 were reviewed. The patients were
divided into four types according to location of the stones and the presence or ab-
sence of stenotic lesions and/or localized dilatation of the intrahepatic bile ducts. Types
I and II patients were treated with choledocholithotomy or choledochojejunostomy,
while type III patients underwent hepatic resection and type IV patients were treated
by partial hepatic resection with bilioenteric anastomosis, including extended
hepatico-choledochojejunostomy. The majority of operative or early deaths belonged
to type IV, and residual stones were present in almost all patients. The long-term
results for the 88 patients revealed that the rate of improvement was 100% for
type I, 87% per cent for type II, 83% for type III and 84% for type IV. In type IV, the
most excellent results (92%) were obtained by extended hepaticocholedochojejunos-
tomy, especially with hepatectomy.
Historically, enterobiliary anastomosis or sphincteroplasty alone were performed in
an expectation of stone passage. It is widely accepted that the presence of intrahepatic
strictures also contraindicates standard bypass operations such as choledochoduode-
nostomy, Roux-en-Y choledochojejunostomy, or sphincteroplasty alone, because of
the increased risk of ascending infection in static regions of the biliary tree. In
these cases, only arrangements for subsequent postoperative choledochoscopy have
merit.
Choledochoscopy can be carried out percutaneously through a T-tube tract or
through a hepaticocutaneous jejunostomy site. Multiple repeated attempts to remove
stones and infected bile and to dilate intrahepatic strictures can be accomplished
through this approach. Gott et al retrospectively reviewed the treatment of hepatoli-
thiasis using a combined approach of surgical access to the biliary tree with a cutaneous
choledochoenteric conduit and interventional radiology to remove intrahepatic stones
and dilate biliary strictures.70 Ten patients underwent cholecystectomy and formation
of a Roux-en-Y choledochojejunostomy with a lateral limb that was brought out as
a cutaneous stoma. After 4 weeks of healing, the intestinal conduit was used by the
interventional radiologist to extract retained stones and dilate strictures using a variety
of techniques. This was easily performed under light sedation. After completion of
therapy, the stoma was closed and buried subcutaneously. This retains the option
for accessing the conduit percutaneously or reopening the stoma if necessary for re-
currence. Eight patients underwent the biliary access procedure and had clearance of
stones and strictures after 1e10 interventional sessions. There was no major morbid-
ity associated with treatment. No patient required liver resection, and there was res-
olution of the hepatic abscesses in all cases.
Percutaneous transjejunal biliary intervention has become an integral part of the
multidisciplinary management of complex intrahepatic strictures.71 Several technical
points in the jejunal loop construction are useful to make it easy to identify and enter.
The access limb should be short and straight between the hepaticojejunal anastomosis
and site of subparietal fixation. The terminal 4 cm of the bowel is sutured to the peri-
toneum of the anterior abdominal wall and marked with a parallel row of metal clips to
provide ‘runway lights’ for radiological identification and puncture. The subparietal at-
tachment and clear marking of the loop simplify identification and allow consistently
successful percutaneous entry. In difficult cases the use of high-frequency ultrasound
facilitates identification of the surgical clips and the needle tip during entry into the
1134 T. Mori et al

access loop. Two additional clips on either side of the hepaticojejunostomy are useful
to identify the site of the anastomosis.

Practice points

 when pyogenic cholangitis often recurs, hepatolithiasis should be in the differ-

ential diagnosis, especially in those who have lived in the Orient
 non-invasive imaging modalities such as ultrasonography (US), computed to-
mography (CT), and magnetic resonance (MR) imaging accurately depict the
normal anatomy and presence of intrahepatic stones
 in addition to frequent cholangitis and chronic sepsis, it is widely known that
longstanding intrahepatic stones lead to intrahepatic cholangiocarcinoma; it is
usually difficult to discriminate cancers from inflammation even with modern
imaging studies
 the primary goals of treatment are to eliminate attacks of cholangitis and to
stop the progression of the disease, which leads to biliary cirrhosis. Reflecting
the complicated nature of the disease and various patients’ conditions, there is
no definitive treatment, and a multidisciplinary approach should be considered.
Surgery has a primary role in hepatolithiasis because hepatolithiasis tends to
recur, so that multiple sessions (i.e. 2e3 times per year) of the endoscopic
approach are necessary

Research agenda

 epidemiology of the hepatolithiasis in Western countries

 pathogenesis of the hepatolithiasis especially in relation to lipid metabolism in
the liver
 mechanism of malignant transformation of the biliary epithelium in hepatolithiasis
 modern imaging modalities for the diagnosis and treatment of hepatolithiasis
 early detection of cholangiocarcinoma
 non-invasive treatment options, including drug therapy (there are already some
candidates)
 improvement in surgical and endoscopic treatments

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