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Hepatology Research 2014; 44 (Suppl. 1): 7190
doi: 10.1111/hepr.12270
Special Report
Guidelines for the management of primary biliary cirrhosis

The Intractable Hepatobiliary Disease Study Group supported by
the Ministry of Health, Labour and Welfare of Japan
Working Subgroup (English version) for Clinical Practice Guidelines for Primary Biliary
Cirrhosis*,**
*Working Subgroup (English version) for Clinical Practice Guidelines

for Primary Biliary Cirrhosis (in alphabetical order): Atsumasa
Komori, Clinical Research Center, National Hospital
Organization Nagasaki Medical Center; Atsushi Tanaka,
Department of Medicine, Teikyo University School of Medicine;
Hajime Takikawa, Department of Medicine, Teikyo University
School of Medicine; Hirohito Tsubouchi, Digestive Disease and
Life-style Related Disease, Kagoshima University Graduate
School of Medical and Dental Sciences and Kagoshima City
Hospital; Hiromi Ishibashi, International University of Health
and Welfare/Fukuoka Sanno Hospital and Clinical Research
Center, National Hospital Organization Nagasaki Medical
Center; Hiroto Egawa, Department of Surgery, Institute of
Gastroenterology, Tokyo Womens Medical University; Junko
Hirohara, Third Department of Internal Medicine, Kansai
Medical University; Ken Shirabe, Department of Surgery and
Science, Kyushu University; Kenichi Harada, Department of
Human Pathology, Kanazawa University Graduate School of
Medicine; Makoto Nakamuta, Department of Gastroenterology,
National Hospital Organization Kyushu Medical Center; Mikio
Zeniya, Department of Gastroenterology, Jikei University
Graduate School of Medicine; Minoru Nakamura, Clinical
Research Center, National Hospital Organization Nagasaki
Medical Center and Department of Hepatology, Nagasaki
University Graduate School of Biomedical Sciences; Nobuyoshi
Fukushima, Department of Gastroenterology, National Hospital
Organization Kyushu Medical Center; Shinji Shimoda, Medicine
and Biosystemic Science, Graduate School of Medical Sciences,
Kyushu University; Shotaro Sakisaka, Department of
Gastroenterology and Medicine, Fukuoka University Faculty of
Medicine; Toshio Morizane, Japan Council for Quality Health
Care; Yasuaki Takeyama, Department of Gastroenterology and
Medicine, Fukuoka University Faculty of Medicine; Yasuni
Nakanuma, Department of Human Pathology, Kanazawa
University Graduate School of Medicine; Yoshiyuki Ueno,
Department of Gastroenterology, Yamagata University Faculty of
Medicine (Chairperson of the Working Group, Chairperson of
the PBC Subcommittee, Chairperson of the Intractable
Hepatobiliary Disease Study Group).
**Correspondence: Hiromi Ishibashi, Fukuoka Sanno Hospital,
International University of Health and Welfare, 3-6-45
Momochihama, Sawara-ku, Fukuoka, 814-0001, Japan.
Email: hiishibashi-gi@umin.ac.jp
2014 The Japan Society of Hepatology
1. INTRODUCTION
HE JAPANESE VERSION of the clinical practice

guidelines for primary biliary cirrhosis (PBC) was
developed in 2012 by the Intractable Hepatobiliary
Disease Study Group, with the support of the Ministry
of Health, Labour and Welfare of Japan, for the use of
general physicians, gastroenterologists and hepatologists who treat patients with PBC.
In preparation for developing the guidelines, the
study group reviewed recent studies that provided
important evidence or that were published in leading
journals with a high impact factor, in addition to considering the formal consensus of experts on PBC or
related subjects. Using the core keywords primary
biliary cirrhosis, a PubMed search was conducted for
English-language clinical trials, randomized clinical
trials (RCTs) and meta-analyses that were published
from January 1998 to December 2009 and that
addressed treatment of PBC and its complications,
follow-up, indication of and time of consultation for
liver transplantation, or time of consultation with
specialists. Medical systems and other culture-specific
factors in Japan were also taken into account. Members
of the task force exchanged ideas frequently during the
drafting process to try and establish a consensus. The
final draft was made after collecting comments from
the public and all the committee members. The level of
evidence (LE; Table 1) and the grade of recommendation (GR; Table 2) were based on the Medical Information Network Distribution Service in Japan (MINDS).
After being modified by recent literatures published
since 2010, the present English version of the guidelines
was developed in order to spread our ideas and
exchange opinions with physicians who are involved in
the management of PBC patients overseas.
71
72
H. Ishibashi et al.
Table 1 Level of evidence (LE)

1a Systematic review/meta-analysis of RCTs
1b Based on one or more RCTs
2a Based on non-randomized control study (prospective
study)
2b Based on non-randomized control study (historical
cohort study and retrospective cohort study)
3 Case control study
4 Analytical epidemiological study (cross-sectional study)
5 Descriptive study (case report or case series)
6 Opinion of expert committee, or an expert, not based on
patient data
These clinical practice guidelines should be revised at

appropriate intervals to incorporate advances in methodology and treatment.
2. DIAGNOSIS OF PBC
2.1 Diagnosis of PBC: general principles
BC IS AN autoimmune-mediated, chronic
cholestatic liver disease that predominantly affects
middle-aged women. The initial symptom is most often
pruritus, though the disease generally progresses insidiously without symptoms for many years. Jaundice progresses without improvement once it becomes overt,
and portal hypertension occurs at a high rate.
Clinically, increased levels of serum biliary enzymes
[alkaline phosphatase (ALP) and -glutamyl transferase
(GGT)] and detection of antimitochondrial antibodies
(AMAs) are characteristic. AMAs are found in 95% of
patients with PBC when using the most sensitive detec-
Table 2 Grade of recommendation (GR)

A
B
Strong recommendation, with high level of evidence

Moderate recommendation, with certain level of
evidence
*Supported by an intermediate level of evidence and
considered to be clinically useful
*Supported by a high level of evidence but not considered to
be clinically very useful
*Evidence level is low, but usefulness has already been
established in clinical practice
C1 Recommendation to be done, without a high level of
evidence
C2 Recommendation not to be done, without a high level
of evidence
D
Recommendation not to be done, as evidence indicates
ineffectiveness or harm
tion techniques, and have specificity of 98% for the

disease (Supporting information Memo 1). Approximately 2030% of PBC patients are positive for
anti-nuclear pore proteins, e.g., anti-gp210, and/or anticentromere antibodies. Most patients with PBC have an
elevated serum IgM concentration, although high serum
IgM is not highly specific or sensitive for diagnosis of
PBC. The total gamma globulin concentration remains
normal until late in the disease when cirrhosis develops.
Histologically, chronic non-suppurative destructive
cholangitis (CNSDC) is seen in the intrahepatic small
bile ducts at the level of the interlobular and septal bile
ducts. Disease progression in PBC results in bile duct
loss and liver fibrosis, which develop into biliary cirrhosis and, in some cases, hepatocellular carcinoma.
The differential diagnosis includes autoimmune
hepatitis, primary sclerosing cholangitis, drug-induced
chronic cholestasis, and paucity of intrahepatic bile
ducts, after excluding obstructive jaundice and
cholestatic diseases of known etiologies.
Recommendations:
1 Patients with one of the following criteria should be
diagnosed with PBC: (1) histologically confirmed
CNSDC with laboratory findings compatible with
PBC; (2) positivity for AMAs with histological findings compatible with PBC but in the absence of characteristic histological findings of CNSDC; and (3) no
histological findings available, but positivity for
AMAs as well as clinical findings and a course indicative of typical cholestatic PBC. (GR A)
2 Diagnosis of PBC should be performed using the
criteria endorsed by the Intractable Hepatobiliary
Disease Study Group with the support of the Japanese
Ministry of Health and Welfare (2010 version,
Table 3). (GR A)
3 Differential diagnosis should be performed for a spectrum of diseases that manifest chronic cholestatic
liver dysfunction or immunological disorder with
autoantibodies (Table 4). (GR A)
Table 3 Diagnosis of PBC endorsed by the Intractable
Hepatobiliary Disease Study Group in Japan (2010 version)
With histological findings
1) Biochemical evidence of cholestasis accompanied by
histological evidence of CNSDC
2) Presence of AMA accompanied by histologically
compatible features of PBC, even without CNSDC
Without histological findings
3) Presence of AMA accompanied by clinical features and
course of classical and cholestatic PBC
Table 4 Differential diagnosis of PBC

1) Cholestatic liver diseases
Intrahepatic cholestasis: chronic drug-induced cholestasis
Primary sclerosing cholangitis
IgG4-related sclerosing cholangitis
Adult-onset bile duct paucity
Obstructive jaundice
2) Diseases with immunological abnormalities
Autoimmune hepatitis
Drug-induced liver injury
3) Elevation of serum ALP and/or GGT
Space occupying lesions of the liver
Bone lesions
Hyperthyroidism
Fatty liver diseases
4 Non-invasive imaging of the liver and biliary trees

should be considered mandatory to exclude diseases
manifesting as obstructive jaundice. (GR A)
2.2 Diagnosis of atypical PBC

Pathognomonically-related but atypical PBC cases that
do not fulfill the diagnostic criteria should be handled
distinctively and appropriately; treatment strategies for
these cases are different from those for typical PBC.
Guidelines for PBC 73
cells in these patients react with mitochondrial antigen,

despite being negative for AMA. Special consideration
for their treatment is not warranted.
PBCAIH overlap syndrome
Patients with PBC who manifest clinicopathological features of autoimmune hepatitis (AIH) in conjunction
with elevated levels of aminotransferases could be
recognized. These cases have also been referred to as
PBC with features of AIH. Prednisolone may effectively
reduce aminotransferase levels in such cases.
2.3 Diagnosis of PBC: symptoms, signs,

and complications
Approximately 7080% of PBC cases are diagnosed in
the early and asymptomatic phase. Although this phase
is likely to persist for years, the clinical and histological
progression precipitates several symptoms (symptomatic PBC). The symptoms and complications of PBC
include cholestasis, liver injury, and comorbid autoimmune disease(s) (Table 5).
Pruritus accompanied by cholestasis is characteristic
of PBC. It may occur initially before overt jaundice.
Table 5 Symptoms and complications of PBC
Early PBC
AMA may be detectable in the serum of individuals
without symptoms of PBC and with normal liver tests.
Histopathological changes of PBC with no or mild progression are apparent and this condition is designated
early PBC. Follow-up without medication is appropriate.
Autoimmune cholangitis, autoimmune
cholangiopathy
Patients whose clinical features are compatible with
PBC may be negative for AMA but have a high titer of
antinuclear antibody (ANA) in their serum. In 1987,
Brunner and Klinge first described this condition as
immunocholangitis, while others have used different
terminology, such as autoimmune cholangiopathy,
primary autoimmune cholangitis, or autoimmune cholangitis. The current understanding is that this condition
is atypical PBC.
AMA-negative PBC
Approximately 10% of patients who have biochemical
evidence of cholestasis, accompanied by histological
features of PBC, are negative for AMA. Autoreactive T
Symptoms
1) None of the following
2) General fatigue
3) Cholestasis-associated
Pruritus (scratching)
Jaundice
4) Liver injury and cirrhosis-associated
Hematemesis and melena
Abdominal fullness
Consciousness disturbance
5) Comorbid autoimmune diseases -associated
Sicca syndrome, etc.
Complications
1) Cholestasis-associated
Osteoporosis
Hyperlipidemia
2) Liver injury and cirrhosis-associated
Portal hypertension
Hepatocellular carcinoma
Ascites
Hepatic encephalopathy
3) Comorbid autoimmune diseases -associated
Sjgrens syndrome
Rheumatoid arthritis
Hashimoto thyroiditis, etc.
74
H. Ishibashi et al.
Prolonged cholestasis results in jaundice, xanthoma

coupled with lipid abnormalities, and osteoporosisrelated bone lesions/fractures.
Persistent fatigue is another common symptom,
occurring in 2070% of Caucasian patients, although
less frequently in Japanese patients. No correlation has
been found between fatigue and age, sex, jaundice, liver
function parameters, or histological stage of the disease.
PBC patients can experience profound distress associated with fatigue.
Cirrhosis-associated symptoms include esophagogastric varices. Portal hypertension is more likely to occur
in PBC than in liver diseases with other etiologies, and
can develop even in the non-cirrhotic stage of PBC;
some patients are diagnosed by the presence of
esophagogastric variceal bleeding as an initial symptom.
Prevalent comorbid autoimmune diseases include
Sjgrens syndrome, Hashimoto thyroiditis, and rheumatoid arthritis. aPBC may be masked by the symptoms
of comorbid autoimmune diseases. Appropriate diagnosis of comorbid autoimmune diseases is important
because they may influence the outcome of PBC.
2.4 Diagnosis of PBC: pathological

examinations
PBC is histologically characterized by autoimmunemediated progressive destruction of the intrahepatic
small bile ducts, as well as by chronic intrahepatic
cholestasis, hepatocellular damage, fibrosis, and septal
formation.
Bile duct damage
PBC is histologically characterized by CNSDC and progressive bile duct loss, which preferably affects the intrahepatic small bile ducts, especially the interlobular bile
ducts. Non-caseating epithelioid granuloma formation
is often seen in the portal tracts. Granulomatous cholangitis consisting of CNSDC and periductal granuloma
formation is valuable for pathological diagnosis.
CNSDC is characterized by marked lymphoplasmacytic
accumulation around the damaged bile ducts, and lymphoid cell infiltration is found in the biliary epithelial
layer of CNSDC. Some biliary epithelial cells in CNSDC
show eosinophilic apoptotic changes and swelling.
Moreover, chronic cholangitis, which does not fulfill the
criteria of CNSDC, is also found. Bile duct loss is seen
during the progression of PBC, and the interlobular bile
ducts are mostly lost in the terminal cirrhotic stage. The
presence of arteries in the absence of bile ducts is useful
for identification of bile duct loss or ductopenia.
Table 6 Histological staging of PBC

Stage
Stage
Stage
Stage
1
2
3
4
no progression
mild progression
moderate progression
advanced progression
Parenchymal change
In the early stage of PBC, non-specific necroinflammatory changes are found in the parenchyma.
Interface hepatitis and chronic cholestatic changes are
also found. During the progression of irreversible bile
duct damage and loss, there are several characteristic
findings that reflect cholestasis, including ductular reaction (proliferating bile ductules), copper deposition
(orcein-positive granules), bile plaques, hepatocellular
ballooning (cholate stasis), MalloryDenk bodies, and
feathery degeneration. These features are associated with
the progression of biliary fibrosis and biliary cirrhosis.
Changes similar to small cell dysplasia are also often
found in zone 1 (periportal area), which is useful for
the diagnosis of PBC. In addition to these cholestatic
changes reflecting bile duct loss, chronic hepatitic
changes resembling autoimmune hepatitis, such as
interface and lobular hepatitis, are also found in most
PBC cases, and are involved in the progression of
hepatic fibrosis and cirrhosis.
Histological staging
The characteristic histological findings of PBC are heterogeneously distributed throughout the liver. Thus, in
small specimens such as those taken from needle liver
biopsy, sampling errors are likely to be recognized when
using the classification systems of Scheuer and Ludwig,
because these two systems define each stage by a sole
histological feature (Supporting information Memo 2).
Therefore the novel staging system of Nakanuma (2009)
(Tables 68) is recommended for histological staging of
PBC, as this system could avoid the sampling errors
caused by the heterogeneous distribution of histological
features.
Recommendations:
1 The novel system for histological grading and staging
of PBC proposed by Nakanuma et al. is recommended (LE6, GRC1).
2.4 Diagnosis of PBC: clinical staging and

disease severity
Clinical staging
PBC is classified into two groups depending on the
absence or presence of symptoms caused by liver
Table 7 Histological staging system of PBC (Nakanuma et al.)

I. Histological findings and scoring for the determination of stage of PBC
A. Scoring of fibrosis
Score 0
Score 1
Score 2
Score 3
B. Scoring of bile duct loss
Score 0
Score 1
Score 2
Score 3
C. Scoring of deposition of
orcein-positive granules
Score 0
Score 1
Score 2
Score 3
No portal fibrosis, or fibrosis limited to portal tracts

Portal fibrosis with periportal fibrosis or incomplete septal fibrosis
Bridging fibrosis with variable lobular disarray
Liver cirrhosis with regenerative nodules and extensive fibrosis
No bile duct loss
Bile duct loss in < 1/3 of portal tracts
Bile duct loss in 1/3 to 2/3 of portal tracts
Bile duct loss in > 2/3 of portal tracts
No deposition of granules
Deposition of granules in a few periportal hepatocytes in < 1/3 of portal tracts
Deposition of granules in several periportal hepatocytes in 1/3 to 2/3 of portal tracts
Deposition of granules in many hepatocytes in > 2/3 of portal tracts
II. Staging by sum total of two (A and B) or three (A, B, and C) criteria
Stage
Stage
Stage
Stage
Stage
Sum of scores
1
2
3
4
(no progression)
(mild progression)
(moderate progression)
(advanced progression)
Two criteria
Three criteria
0
12
34
56
0
13
46
79
Two criteria: fibrosis and bile duct loss.

Three criteria: fibrosis, bile duct loss and deposition of orcein-positive granules.
damage: aPBC and sPBC. aPBC is considered the

non-advanced stage (stage I), while sPBC is considered
the advanced stage. sPBC is further classified as
s1PBC, with serum bilirubin level <2.0 mg/dL, and
s2PBC, with serum level 32.0 mg/dL (Table 9). s1PBC

is considered a non-icteric advanced stage (stage II),
and s2PBC is considered an icteric advanced stage
(stage III).
Table 8 Grading of chronic cholangitis and hepatitis activity in PBC

I. Cholangitis activity (CA)
CA0 (no activity)
CA1 (mild activity)
CA2 (moderate activity)
CA3 (marked activity)
II. Hepatitis activity (HA)
HA0 (no activity)
HA1 (mild activity)
HA2 (moderate activity)
HA3 (marked activity)
No cholangitis, but mild duct damage may be present

One bile duct with evident chronic cholangitis
32 bile ducts with evident chronic cholangitis
31 bile duct with CNSDC
(CNSDC: chronic nonsuppurative destructive cholangitis.)
No interface hepatitis, and no or minimum lobular hepatitis
Interface hepatitis affecting > 10 continuous hepatocytes in 1 portal tract or fibrous septa,
and mild to moderate lobular hepatitis
Interface hepatitis affecting > 10 continuous hepatocytes in 32 portal tracts or fibrous septa,
and mild to moderate lobular hepatitis
Interface hepatitis affecting > 20 continuous hepatocytes in 3 1/2 of portal tracts, and
moderate lobular hepatitis or bridging or zonal necrosis
76
H. Ishibashi et al.
Table 9 Clinical staging of PBC

1) Asymptomatic PBC (aPBC): Condition absent from
symptoms caused by liver damage
2) Symptomatic PBC (sPBC): Condition with symptoms
caused by liver damage.
2-1) s1PBC: serum bilirubin level below 2.0 mg/dL
2-1) s2PBC: serum bilirubin level equal or over 2.0 mg/dL
Symptoms caused by liver damage: jaundice, pruritis,
esophageal varices, ascites, encephalopathy, and hepatocellular
carcinoma.
Disease severity
PBC progresses insidiously on a chronic course without
acute exacerbation, and a good hepatic reserve is maintained for a long period. Therefore, severity is evaluated
at the advanced stage (sPBC) and the modified Child
Pugh grading system with a modified total bilirubin
level is applied (Table 10).
2.5 Diagnosis of PBC: clinical type

and prognosis
The progression of PBC varies among individuals, and
more than 70% of those with aPBC do not progress over
10 years. PBC is largely classified into three clinical types
(Fig. 1). Many patients progress gradually and remain
in the asymptomatic stage for longer than a decade
(gradual progressive type). However, some patients
progress to portal hypertension presenting without
jaundice (portal hypertension type), and others progress
Death
T.Bilirubin (mg/dL)
Albumin (g/dL)
PT (%)
INR
Ascites
Encephalopathy
14
3.5<
70%<
<1.7
None
None
410
2.83.5
4070%
1.72.3
Mild
Grade12
>10
<2.8
<40%
>2.3
Moderate
Grade 34
Grade A: 56 points; Grade B: 79 points; Grade C: 1015

points.
rapidly to jaundice and ultimately hepatic failure

(jaundice/hepatic failure type). The jaundice/hepatic
failure type tends to affect relatively younger patients
compared to the other two types. Patients with the
jaundice/hepatic failure-type PBC are often positive
for anti-gp210 antibody, while those with the portal
hypertension-type PBC have anti-centromere antibodies
(Supporting information Memo 3).
Several models for predicting the prognosis of PBC have

been proposed. In the updated Mayo Clinic Natural
History Model for PBC, the key factors are age, serum
total bilirubin, albumin, prothrombin time (PT),
edema/ascites, and use of diuretics. This model is used
worldwide to predict the prognosis of PBC patients. The
updated version is better than the original one for prediction of shorter prognosis (Supporting information
Memo 4).
Portal hypertension type
Hepatic failure
Jaundice
Non-jaundice
Symptomatic
Jaundice/hepatic failure type
Clinical jaundice/
stage non-jaundice
Asymptoatic
Score
Prognosis
Clinical type
Table 10 Modified Child-Pugh score for evaluating the severity of PBC
HCC
Varices
Itching
Anti-gp210
Slow progression type
Anti-centromere
Age
Figure 1 Three types of natural course

of PBC.
In the logistic model developed by the Japanese Liver

Transplantation Study Group (Ref.VII-1) (Supporting
information Memo 5), serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase
(ALT) ratio are necessary. The probability of death after
6 months is calculated by means of a logistic regression
formula, and transplantation is recommended if the
value exceeds 50%.
Finally, for the MELD (Model for End-Stage Liver
Disease) score, the serum creatinine level, total bilirubin, and prothrombin time (PT) are the key factors. The
MELD score is used for the evaluation of end-stage liver
failure. The score is high if hepatorenal syndrome is
present, and the pre-transplantation value correlates
well with the likelihood and magnitude of complication
after liver transplantation. Therefore, it is recommended
that transplantation should be performed before complication by hepatorenal syndrome (Supporting information Memo 6).
The common factor among these different schemes is
serum total bilirubin. A life expectancy of 10 years is
predicted for patients with a serum bilirubin level
<2.0 mg/dL, 5 years for 2.03.0 mg/dL, and 1 year for
>6.0 mg/dL.
Recommendations:
1 Total bilirubin, prothrombin (INR), albumin, and
the serum creatinine level, which are essential to calculate the MELD score, should be measured when
considering liver transplantation. (LE 2b (2a in part),
GR A)
2 Patients with PBC should be referred to transplant
hepatologists when serum total bilirubin level is
>5 mg/dL. To encourage the patients to prepare for
liver transplantation, an earlier and appropriate
explanation of liver transplantation is desirable. (LE
4, GR B)
3. TREATMENT AND MANAGEMENT OF PBC

3.1 Treatment and management of PBC:
general principles
LTHOUGH THERE IS no completely curative treatment for PBC, ursodeoxycholic acid (UDCA) is currently considered the first-line treatment for the disease.
UDCA delays the progression of PBC, although it does
not have a significant benefit for PBC at the advanced
stage.
The clinical usefulness of UDCA is evaluated according to the following factors: (i) improvement of serum
biochemical markers, such as ALP, GGT, AST, ALT and
total bilirubin; (ii) histological improvement of cholan-
gitis, liver inflammation and liver fibrosis; and (iii)

delay in the disease progression until end-stage liver
disease, death, or liver transplantation. The following
Paris and Barcelona criteria are useful for evaluating the
clinical outcome of UDCA treatment. (i) Paris criteria:
total bilirubin 21.0 mg/dL, ALP 23 the upper normal
limit (UNL), and AST 2 2 UNL at 1 year after introduction of UDCA. (ii) Barcelona criteria: decrease of ALP
340% at 1 year after introduction of UDCA.
Liver transplantation is the only therapeutic approach
for patients in the advanced stage when medical treatment shows little improvement. Prevention and treatment strategies for comorbid autoimmune diseases,
cholestasis, and cirrhosis-related symptoms and complications are required.
Although the term cirrhosis is included in the name
PBC, most patients (7080%) with PBC have little clinical and histological evidence of liver cirrhosis. Patients
should be informed accordingly to prevent misunderstanding of their prognoses. Currently, patients are
likely to be diagnosed at earlier stages and disease progression is likely to be delayed by UDCA. Therefore, the
prognosis of patients with aPBC, as long as they remain
asymptomatic, is equivalent to that in the general population. No restrictions are necessary in daily life for
patients with aPBC. By contrast, some restrictions in
daily life and nutritional education are required for
patients with sPBC, depending on symptoms, expected
future complications, and disease severity.
3.2 Prescription
Ursodeoxycholic acid (UDCA)
Extensive clinical trials including randomized clinical
trials (RCT) and meta-analyses were carried out for
UDCA after the first report by Poupon et al. After lively
debates, it was concluded that UDCA not only improves
the serum biochemical values of PBC patients but also
prolongs the period to death or liver transplantation.
The clinical guidelines for PBC by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASD)
recommend that UDCA be given at a dose of 1315 mg/
kg/day, whereas in Japan, it is usually given at 600 mg/
day. In clinical trials performed with Japanese PBC
patients, 600 mg/day UDCA was given to PBC patients
for 48132 weeks and then the results of liver tests were
analyzed. Improvement was demonstrated in 81.8%
(27/33) of cases. Therefore, 600 mg/day is considered
as a standard dose, irrespective of body weight. The
dose can be increased up to 900 mg/day or decreased
78
H. Ishibashi et al.
depending on weight and adverse events. Coadministration with bezafibrate is then considered if
900 mg/day UDCA has little effect. UDCA results in
biochemical improvement, but is not likely to act
against the core pathogenesis of PBC; administration
is usually maintained throughout life.
Recommendations:
1 Administration of bezafibrate (Bezatol, 400 mg/
day) may be considered in patients who exhibit a
suboptimal response to UDCA. (LE 2a, GR B)
Recommendations:
UDCA should be used to improve liver biochemical
tests and histological findings, and to prolong the
time until death or liver transplantation, though it
does not provide significant benefit for those at the
advanced stage. (LE 1a, GR A)
In general, UDCA should be administered at 600 mg/
day, and increased to 900 mg/day if the response is
suboptimal. (LE 2a, GR B)
UDCA is usually given TID, but the effects have been
shown to be similar even if it is given as a single daily
dose or BID. (LE 2a, GR B)
The following definitions are proposed by the Intractable Hepatobiliary Disease Study Group of Japan for
evaluation of the effects of UDCA after starting
therapy. Good response: serum ALP, ALT and IgM
become normal within 2 years; Fair response: serum
ALP, ALT and IgM become <1.5 UNL at 2 years;
Poor response: serum ALP, ALT and IgM remain
>1.5 UNL at 2 years. (LE 6, GR C1)
UCDA is the only drug shown to have long-term
efficacy. (LE 2a, 2b, C, GR C1)
PSL has been considered to be contraindicated for PBC,

because it brings about little improvement of PBC and
may even cause deterioration of osteoporosis in postmenopausal women. Co-administration of PSL with
UDCA is indicated for patients with PBCAIH overlap
syndrome, especially those whose symptoms of hepatitis are clinically and histologically relevant. The recommended initial corticosteroid dose is <0.5 mg/kg/day. It
is advised to switch to UDCA monotherapy after hepatitis subsides.
Bezafibrate
Bezafibrate, a peroxisome proliferator-activated receptor
(PPAR ) agonist, has been reported to show biochemical improvements and effectiveness in patients
with PBC, mainly by Japanese researchers. However, the
long-term effects of bezafibrate have not yet been evaluated, and the use of the drug for PBC is not recommended in the clinical guidelines by EASL and AASLD.
When possible, bezafibrate should be administered in
combination with UDCA, because the drugs have different pharmacological mechanisms of action and demonstrate additive effects. Bezafibrate is given at 400 mg/day
in patients who exhibit a suboptimal response to
UDCA. However, in Japan, prescription of bezafibrate is
only approved for patients with hypertriglyceridemia;
PBC patients are still subject to off-label use.
Some reports indicate that fenofibrate, the other
PPARagonist, is also effective against PBC. Both
bezafibrate and fenofibrate are known to increase the
risk of rhabdomyolysis, and elevation of ALT is occasionally observed as an adverse effect of fenofibrate.
Prednisolone (PSL)
3.3 Treatment by clinical stage

sPBC
UDCA improves liver tests as well as histological findings, and as a consequence, prolongs the time until
death or liver transplantation. However, the therapeutic
effects of UDCA are negligible in patients with advanced
PBC and marked jaundice. Liver transplantation is indicated for these patients of advanced stage.
aPBC
There is no evidence to assist in the decision as to
whether PBC with mildly elevated ALP should be
treated, and thus no consensus has been reached.
Although it has been proposed that all PBC patients
should be treated as soon as the diagnosis is established,
some physicians have argued that patients with mild
elevation of ALP could be followed up without UDCA
treatment until disease progression is apparent, in consideration of the costs and adverse effects of UDCA.
Recommendations:
1 UDCA should be initiated immediately when the
serum ALP level is increased to up 1.5 UNL. In
patients with ALP <1.5 UNL, liver enzymes should
be measured every 34 months and UDCA treatment
should be started when an increase in serum ALP to
1.5 UNL is detected. (LE 6, GR C1)
2 As elevation of AST and/or ALT suggests hepatitis
features of PBC and likely disease progression, UDCA
should be administered in these cases. (LE 6, GR C1)
Early PBC
Early PBC is defined as PBC without any elevated liver
tests. Patients in this category require no treatment and
Table 11 Diagnostic criteria for corticosteroid use in PBCAIH overlap syndrome (Intractable Hepatobiliary Disease Study Group
in Japan, 2011)
PSL is recommended in addition to UDCA for cases that are considered to be PBCAIH overlap syndrome and meet the two
following criteria simultaneously:
(1) diagnosed with PBC using the criteria of the Intractable Hepatobiliary Disease Study Group in Japan (2010)
(2) diagnosed as probable/definite AIH using International Autoimmune Hepatitis Group (IAIHG) simplified criteria (2008).
(Supporting information Memo 7)
As for liver histology, HA scores in the PBC grading/staging systems in Table 8 should be used as follows: 0 for HA score 0 or 1,
1 point for HA score 2, and 2 points for HA score 3.
are followed up every 12 years. Development of overt

PBC may be preventable in these patients if etiologyoriented medical treatment becomes available in the
future.
Autoimmune cholangitis
When the response to UDCA is not optimal, PSL administration should be considered. It is advisable to switch
to UDCA monotherapy after hepatitis subsides, as in
cases of PBCAIH overlap syndrome.
AMA-negative PBC
The diagnosis of PBC should be confirmed by liver histology. The treatment strategy is identical to that for
AMA-positive PBC.
PBCAIH overlap syndrome
PSL is recommended in addition to UDCA for cases that
are considered to be PBCAIH overlap syndrome,
because superimposed AIH could deteriorate the clinical
course of PBC toward cirrhosis.
Recommendations:
1 When patients with PBC are diagnosed with PBC
AIH overlap syndrome due to clinical and histological features of AIH, and meet the criteria for
corticosteroid use for PBCAIH overlap syndrome
(Table 11), PSL administration is strongly recommended. (LE 2b, GR B)
2 It is advised that treatment should be switched to
UDCA monotherapy when hepatitis features subside.
(LE 3, GR C1)
3.4 Liver transplantation

General principles
Liver transplantation is considered in cases with continuous elevation of total bilirubin, intractable pleural
effusion and/or ascites, hepatic encephalopathy,
repeated rupture of esophageal and/or gastric varices,
and markedly reduced quality of life (QOL) due to

severe pruritus. On the other hand, liver transplantation
is generally contraindicated for patients with severe
complications, such as lung and kidney disease, other
organ disease, infection, and malignancy.
It should be borne in mind, however, that not every
patient for whom liver transplantation is indicated succeeds in finding a donated liver. Living donor liver transplantation (LDLT) is more common in Japan because
deceased donor livers are scarcely offered for transplantation. In order to plan for LDLT, a 1-month period is
desirable for the living donor. This period is required for
medical examination, preparation for early rehabilitation and approval by the appropriate ethical committee.
Earlier registration for deceased donor liver transplantation (DDLT) is recommended. Given this situation,
there is no difference in timing between cases in which
LDLT is indicated and those in which DDLT is indicated.
Moreover, there is no difference in the outcome of PBC
patients who undergo LDLT and DDLT.
Recommendations:
1 When PBC progresses to cholestatic cirrhosis, medical
treatment has little effect on further disease progression and liver transplantation is the only therapeutic
approach for survival. (LE 1, GR B) Appropriate
timing of liver transplantation is the most important
consideration. (LE 2b, GR B)
2 The following criteria (Table 12) should be consulted
to determine whether liver transplantation is indicated. (LE 6, GR A)
Indication for liver transplantation
As described in the Prognosis portion of section 2.5,
three scoring systems have been widely implemented for
predicting prognosis in PBC. The most popular system is
the updated Natural History Model for PBC from the
Mayo Clinic. Once the Mayo risk score is >7.8, the
outcome after liver transplantation is poor. Furthermore, this score was a significant predictor for liver-
80
H. Ishibashi et al.
Table 12 Criterion for the indication of liver transplantation
Table 14 Recommendation for consultation to specialists
1) Both of the following items (I) and (II) should be met.

I. Sum of ChildPugh score 38.
II. Serum levels of total bilirubin 35.0 mg/dL, with at
least one complication depicted below (ag).
a) Hepatic coma
b) Gastrointestinal bleeding with portal hypertension
c) Refractory ascites and/or pleural effusion
d) Spontaneous bacterial peritonitis, hepatorenal
syndrome, hepatopulmonary syndrome
e) Hepatocellular carcinoma
f) Itch sensation, causing insomnia
g) Severe general malaise, and deterioration of QOL,
by severe osteomalacia
1) Decision of initial treatment approach, in particular,

diagnosis and evaluation of atypical cases
2) Decision of treatment strategy
3) Suboptimal response of UDCA
4) Apparent progression to symptomatic PBC
5) 35 mg/dL of total bilirubin (consult to liver transplant
surgeons; earlier explanation is necessary for patients)
related death before liver transplantation, but not for

post-transplantation prognosis. Thus, liver transplantation should be performed before the Mayo risk score
reaches 7.8.
Secondly, the indication model of the Japanese Liver
Transplantation Indication Study Group recommends
liver transplantation when the mortality rate after 6
months is >50%, as estimated by a logistic model. In
this model, the severity of disease is estimated as a score
of 1, 3, 6, 8 or 10 points. At present, patients with scores
>6 points, which means the expected mortality rate after
6 months is >70%, are candidates for DDLT. In contrast,
patients in whom the expected mortality rate after 6
months is >50% are candidates for LDLT.
Finally, the cumulative survival rate at 1 year after
liver transplantation is about 50% in patients whose
MELD score is >20. The higher the MELD score, the
poorer is the outcome after liver transplantation. In a
previous report from a single center in Japan, the
outcome became poorer when the MELD score was >25.
The average MELD score is 15 in patients who have
undergone liver transplantation, and thus the timing of

consultation may be adequate when the MELD score
reaches 12.
Recommendations:
1 The use of scores for the evaluation of liver failure is
mandatory.
a Updated Natural History Model for PBC from the
Mayo Clinic: risk score >7.8 (LE 2b, GR B)
b Mortality rate after 6 months: 3 50%, as estimated
by the Japan liver transplantation indication
society model (LE 2b, GR, B)
c MELD score 315 (LE 2b, GR, B)
Management of patients after liver transplantation
Liver-transplanted patients should be administered
immunosuppressive agents and closely monitored.
Postoperative complications, acute/chronic rejection,
recurrence of PBC, and infections should all be carefully
monitored. Postoperative recurrence of PBC is an
important cause of graft dysfunction. The five-year recurrence rate after liver transplantation is reported as
033% in representative facilities in Japan. The ten-year
survival rate of patients with PBC after liver transplantation is equal to the survival in those with other
diseases.
Table 13 Clinical tests for follow-up of patients with PBC

1) Assessment of activity and progression of PBC
1 Liver tests (albumin, total bilirubin, AST, ALT, ALP, GGT, PT) every 36 months
2) Assessment of complications
2 Thyroid function (TSH, free T4)
3 Bone mineral density testing
4 Upper GI endoscopy
5 Abdominal ultrasound and serum AFP
Intervals of tests vary depending on the stage of the patient.
Every 1 year
Every 24 years
Every 12 years
Every 1 year
(every 36 months in liver cirrhosis)
3.5 Management of symptoms

and complications
Dermal pruritus
Pruritus is the most specific symptom in PBC, and may
appear even before development of jaundice. Although
it has been debated whether increased concentrations
of bile salts, histamine, progesterone metabolites or
endogenous opioids are potential pruritogens in
cholestasis, recent experimental evidence has implicated the lysophospholipase, autotaxin (ATX), and its
product, lysophosphatidic acid (LPA), as potential
mediators of cholestatic pruritis. Pruritus is more often
exacerbated at night more than in the daytime, and may
decrease along with progression of liver damage.
Cholestyramine is a non-absorbable basic anionexchange resin, and is a drug of first choice for pruritus
in PBC. It improves pruritus by inducing adsorption of
bile acids in the intestinal tract. In patients treated with
UDCA, an interval of a few hours is necessary in order to
avoid the attenuating effect caused by binding of cholestyramine and UDCA. Cholestimide, which is also a
basic anion-exchange resin, is used empirically in Japan.
Antihistamines are also frequently prescribed in Japan
due to their ease of use. They can be effective for insomnia due to their sedative action.
The efficacy of rifampicin, which is an antituberculosis agent, for pruritus has been validated in
two meta-analyses. As there is a possibility of various
side effects, including liver damage, close and regular
follow-up are necessary. A dose of 150300 mg twice
daily is used for pruritis.
Recommendations:
1 Cholestyramine is effective against dermal pruritus in
PBC patients, and should be considered the first
choice agent. (LE 2a, A)
2 Antihistamines might be effective against severe
dermal pruritus which may cause insomnia. (LE 5,
GR C1)
3 Rifampicin is effective against dermal pruritus in PBC
patients. (LE 1a, GR B)
Osteoporosis
Osteoporosis is frequently observed in patients with PBC
because intestinal absorption of fat-soluble vitamins
is disturbed due to reduced secretion of bile acids, and
PBC is common in middle-aged and postmenopausal
women. For prevention of osteoporosis, abundant oral
intake of calcium (1 to 1.2 g/day) and vitamin D (plentiful in fish and mushrooms) and weight-bearing exer-
cise are recommended, and medical treatment should be

given if necessary. Bisphosphonates, bioactive vitamin
D3 agents, and vitamin K2 are prescribed.
Among bisphosphonates, alendronate improves bone
density more than etidronate. Nevertheless, there is no
evidence that alendronate suppresses bone fracture.
Administration once weekly is preferable to daily
administration. Alendronate is contraindicated for
cases with esophageal stenosis due to sclerotherapy for
esophageal varices.
Vitamin D3 and vitamin K2 formulations have frequently been prescribed for PBC in Japan. Both drugs
have been proven to be effective for osteoporosis itself,
and are regarded as Grade B in guidelines for the prevention and treatment of osteoporosis.
Recommendations:
1 It is desirable to start treatment for the prevention of
fractures in cases with a T score below 1.5. (LE 4, GR
C1)
2 Alendronate improves bone density in PBC patients.
(LE 1b, GR A)
3 Although there is scarce evidence in PBC patients,
vitamin D3 and vitamin K2 formulations can be
effective for osteoporosis. (LE 1b, GR C1)
Dyslipidemia
Hypercholesterolemia is likely to develop in PBC due to
cholestasis. Xanthoma is seen around the eyelids. No
specific treatment for hypercholesterolemia in PBC is
required in most cases, while bezafibrate is expected to
be effective for both PBC and hypercholesterolemia.
Sicca syndrome
Sicca syndrome, a major symptom of Sjgrens syndrome, is frequently complicated with PBC. The
diagnosis of Sjgrens syndrome should be made by
detection of serum anti-SS-A/SS-B antibodies, presence
of corneal erosion, and lip biopsy if necessary. Artificial
lachrymal fluids are indicated for eye symptoms. If the
response is not favorable, pilocarpine hydrochloride
and cevimeline hydrochloride hydrate are used under
the guidance of ophthalmologists. As for oral symptoms, artificial saliva should be used first, and pilocarpine hydrochloride and cevimeline hydrochloride
hydrate can also be prescribed.
Recommendations:
1 Cevimeline hydrochloride and pilocarpine hydrochloride may be effective for xerostomia in PBC,
although there are no studies evaluating their
potential to alleviate the symptoms occurring in PBC
82
H. Ishibashi et al.
patients with concurrent Sjgrens syndrome. (LE 6,

GR B)
2 Patients with PBC frequently experience cholestasis,
comorbid autoimmune diseases, and symptoms associated with liver injury and cirrhosis. Prevention and
management of these symptoms are required. (GR A)
3.6 Follow-up
Prognosis of asymptomatic PBC is excellent with little
progression, but 25% of patients with aPBC develop
some symptoms within 10 years. Serum total bilirubin
and cholestatic enzymes (ALP, GGT) are important for
assessing the activity and progression of PBC. Liver
biochemical tests should be done every 36 months.
In addition, thyroid hormone (every year) and bone
mineral density (every 24 years) tests are recommended because PBC is likely to be complicated with
other autoimmune diseases, such as Sjgrens syndrome, chronic thyroiditis, and rheumatoid arthritis.
Regular upper gastrointestinal endoscopy, depending
on stage (1 or 2 times per year), is required because
esophageal/gastric varices may develop even in patients
without jaundice. Abdominal ultrasound (US) and
serum AFP testing every 612 months are necessary in
patients with definite or suspected liver cirrhosis. Liver
cirrhosis, older age, and male sex are high risk factors for
developing hepatocellular carcinoma (HCC). Therefore,
testing for tumor markers and imaging studies [US and
computed tomography (CT)] are required for early
detection of HCC in patients with advanced PBC. Management for other complicating autoimmune diseases
should be done depending on each symptom.
Finally, special attention should be paid to pregnancy
in PBC and patients who have a desire to bear children.
The chance for pregnancy could be the same in the early
stage of aPBC as in the normal population; there is
no evidence to recommend avoidance of pregnancy in
patients with aPBC. In sPBC, however, if worsening of
icterus or varices is reported, then avoidance of pregnancy could be justified.
The impact of pregnancy on PBC is unclear because
both exacerbation and improvement of cholestasis
have been reported. Estrogen could potentially worsen
cholestasis; pruritus may become severe in pregnancy
and could be prolonged even after delivery. Conversely,
it should be noted that cholestasis could be symptomatic after pregnancy. After a patient has become pregnant, monitoring for varices is necessary as in other
cirrhotic patients, especially after the second trimester,
due to increase in circulating blood volume. The use of
blockers is considered to be safe. It is also advisable
to shorten the second trimester of pregnancy, if

possible.
Recommendations:
1 The blood and other clinical tests should be undertaken regularly to investigate complicating comorbidities, prevent complications, and detect portal
hypertension and liver cancer as early as possible.
(Table 13) (LE 3, GR B)
2 It is advisable to consult with hepatologists when the
diagnosis of PBC is made, or when patients with PBC
become symptomatic. In patients with atypical forms
of PBC such as PBCAIH overlapping syndrome,
earlier referral is recommended. (Table 14) (LE 6, GR
A-B)
3 For patients in the symptomatic stage, there is a likelihood of worsening of pruritus or icterus in the pregnancy, as well as an increased possibility of variceal
rupture. It is advisable that these patients undergo
upper gastrointestinal endoscopy by the second trimester of pregnancy. (LE 5, GR C1)
4 Administration of UDCA or bezafibrate should be
withheld, if the patient with PBC is possibly pregnant
or in the early stage of pregnancy. In the third trimester of pregnancy, administration of UDCA is possible
for cholestasis if necessary. (LE 5, GR C1)
ACKNOWLEDGMENTS
HIS STUDY WAS supported by Grants-in-Aid from

the Research Program of lntractable Disease provided by the Ministry of Health, Labor and Welfare of
Japan.
CONFLICTS OF INTEREST
HOTARO SAKISAKA IS given research funds from

MSD K.K., Mikio Zeniya is given research funds from
Daiichi Sankyo Co. Ltd. and Chugai Pharmaceutical
Co., Ltd., Hirohito Tsubouchi is given research funds
from Chugai Pharmaceutical Co., Ltd., MSD K.K. and
KAN Research Institute, Inc. All other authors have no
conflicts of interest to declare.
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4 Anti-mitochondrial antibody, anti-gp210antibody

70 Gershwin ME, Rowley M, Davis PA et al. Molecular
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71 Nishio A, Coppel R, Ishibashi H et al. The pyruvate dehydrogenase complex as a target autoantigen in primary
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72 Worman HJ. Nuclear envelope protein autoantigens in
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IV Clinical course and prediction

of prognosis
1 Clinical course
73 Mitchison HC, Bassendine MF, Hendrick A et al. Positive
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75 Metcalf JV, Mitchison HC, Palmer JM et al. Natural history
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76 Mattalia A, Quaranta S, Leung PS et al. Characterization
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77 Springer J, Cauch-Dudek K, ORourke K et al. Asymptomatic primary biliary cirrhosis: a study of its natural history
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78 Nakano T, Inoue K, Hirohara J et al. Long-term prognosis
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79 Prince M, Chetwynd A, Newman W et al. Survival and
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80 Takeshita E, Kumagi T, Matsui H et al. Esophagogastric
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81 Lee YM, Kaplan MM. The natural history of PBC: has it
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83 Abe M, Onji M. Natural history of primary biliary cirrhosis. Hepatol Res 2008; 38: 63945.
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2 Progression of liver histology and

hepatocarcinogenesis
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86 Drebber U, Mueller JJ, Klein E et al. Liver biopsy in
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89 Shibuya A, Tanaka K, Miyakawa H et al. Hepatocellular
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3 Prediction of prognosis
91 United network for organ sharing. Available at: http://
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92 Dickson ER, Grambsch PM, Fleming TR et al. Prognosis in
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93 Murtaugh PA, Dickson ER, Van Dam GM et al. Primary
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94 Liermann Garcia RF, Evangelista GC, McMaster P et al.
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95 Hasegawa K, Sugawara Y, Imamura H et al. Living donor
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96 Cholongitas E, Marelli L, Shusang V et al. A systematic
review of the performance of the model for end-stage liver
disease (MELD) in the setting of liver transplantation.
Liver Transpl 2006; 12: 104961.
97 Charatcharoenwitthaya P, Pimentel S, Talwalkar JA et al.

Long-term survival and impact of ursodeoxycholic acid
treatment for recurrent primary biliary cirrhosis after liver
transplantation. Liver Transpl 2007; 13: 123645.
98 Japanese Liver Translation Society. Liver Transplantation
in Japan Registry by the Japanese Liver Transplantation
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99 Montano AJ, Wasilenko S, Bintner J et al. Cyclosporine A
protects against primary biliary cirrhosis recurrence after
liver transplantation. Am J Transplant 2010; 10: 8528.
100 Ishibashi H, Komori A, Shimoda S et al. Risk factors and
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4 Autoantibody and prognosis

101 Muratori L, Granito A, Muratori P et al. Antimitochondrial antibodies and other antibodies in primary
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102 Yang WH, Yu JH, Nakajima A et al. Do antinuclear antibodies in primary biliary cirrhosis patients identify
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104 Itoh S, Ichida T, Yoshida T et al. Autoantibodies against a
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105 Invernizzi P, Podda M, Battezzati PM et al. Autoantibodies against nuclear pore complexes are associated with
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106 Muratori P, Muratori L, Ferrari R et al. Characterization
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107 Miyachi K, Hankins RW, Matsushima H et al. Profile and
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108 Wesierska-Gadek J, Penner E, Battezzati PM et al.
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109 Nakamura M, Shimizu-Yoshida Y, Takii Y et al. Antibody
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110 Nakamura M, Takii Y, Ito M et al. Increased expression
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111 Nakamura M, Kondo H, Mori T et al. Anti-gp210 and

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112 Nakamura M, Komori A, Ito M et al. Predictive role of
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113 Nakamura M, Yasunami M, Kondo H et al. Analysis
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V Drug therapy for PBC

1 UDCA
114 Wada T, Kumashiro R, Taniakawa K et al. Effects of
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115 Wada T, Kumashiro R, Taniakawa K et al. Effects of longterm administration of ursodeoxycholic acid for primary
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116 Poupon R, Chrtien Y, Poupon RE et al. Is ursodeoxycholic acid an effective treatment for primary biliary
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117 Tsochatzis EA, Gurusamy KS, Gluud C et al. Ursodeoxycholic acid and primary biliary cirrhosis: EASL and
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118 Ishibashi H, Komori A, Shimoda S et al. Guidelines for
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UDCA Randomized control study

119 Poupon RE, Balkau B, Eschwge E et al. A multicenter,
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120 Poupon RE, Poupon R, Balkau B. Ursodiol for the
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121 Heathcote EJ, Cauch-Dudek K, Walker V et al. The Canadian Multicenter Double-blind Randomized Controlled
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122 Lindor KD, Dickson ER, Baldus WP et al. Ursodeoxycholic
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123 Combes B, Carithers RL Jr, Maddrey WC et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology
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124 Lindor KD, Therneau TM, Jorgensen RA et al. Effects of

ursodeoxycholic acid on survival in patients with primary
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125 Kilmurry MR, Heathcote EJ, Cauch-Dudek K et al. Is the
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126 Eriksson LS, Olsson R, Glauman H et al. Ursodeoxycholic acid treatment in patients with primary biliary
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127 Pars A, Caballera L, Rods J et al. Long-term effects of
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129 Combes B, Luketic VA, Peters MG et al. Prolonged
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130 Jorgensen R, Angulo P, Dickson ER et al. Results of longterm ursodiol treatment for patients with primary biliary
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131 Chan CW, Gunsar F, Feudjo M et al. Long-term
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132 Corpechot C, Carrat F, Bahr A et al. The effect of ursodeoxycholic acid therapy on the natural course of primary
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133 Pars A, Caballera L, Rods J. Excellent long-term survival
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UDCA Cohort study

134 van de Meeberg PC, Wolfhagen FH, Van BergeHenegouwen GP et al. Single or multiple dose
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enrichment and biochemical response. J Hepatol 1996;
25: 88794.
135 van Hoogstraten HJ, Hansen BE, van Buuren HR
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136 Poupon RE, Bonnand AM, Chrtien Y et al. Ten-year
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Hepatology 1999; 29: 166871.
88
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137 Corpechot C, Carrat F, Bahr A et al. The effect of

ursodeoxycholic acid therapy on the natural course of
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138 Pars A, Caballera L, Rods J. Excellent long-term survival
in patients with primary biliary cirrhosis and biochemical
response to ursodeoxycholic acid. Gastroenterology 2006;
130: 71520.
139 ter Borg PC, Schalm SW, Hansen BE et al. Prognosis
of ursodeoxycholic acid-treated patients with primary
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UDCA Meta-analysis
140 Poupon RE, Lindor KD, Cauch-Dudek K et al. Combined
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141 Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary
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142 Gluud C, Christensen E. Ursodeoxycholic acid for
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143 Shi J, Wu C, Lin Y et al. Long-term effects of mid-dose
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144 Gong Y, Huang Z, Christensen E et al. Ursodeoxycholic
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Setting of administrative dose of UDCA

145 van de Meeberg PC, Wolfhagen FH, Van BergeHenegouwen GP et al. Single or multiple dose
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25: 88794.
146 Toda G, Tanaka N, Ikeda Y et al. Evaluation of clinical
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147 Angulo P, Dickson ER, Therneau TM et al. Comparison of
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148 Verma A, Jazrawi RP, Ahmed HA et al. Optimum dose of
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149 Angulo P, Jorgensen RA, Lindor KD. Incomplete response
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31527.
2 Bezafibrate, Fenofibrate
150 Nakai S, Masaki T, Kurokohchi K et al. Combination
therapy of bezafibrate and ursodeoxycholic acid in
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151 Kurihara T, Niimi A, Maeda A et al. Bezafibrate in the
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152 Miyaguchi S, Ebinuma H, Imaeda H et al. A novel
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155 Iwasaki S, Ohira H, Nishiguchi S et al. Study Group of
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156 Ohira H, Sato Y, Ueno T et al. Fenofibrate treatment in
patients with primary biliary cirrhosis. Am J Gastroenterol
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157 Dohmen K, Mizuta T, Nakamuta M et al. Fenofibrate for
patients with asymptomatic primary biliary cirrhosis.
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158 Honda A, Ikegami T, Nakamuta M et al. Anticholestatic
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2013; 57: 193141.
3 Miscellaneous
159 Neuberger J, Christensen E, Portmann B et al. Double
blind controlled trial of d-penicillamine in patients with
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160 Dickson ER, Fleming TR, Wiesner RH et al. Trial of penicillamine in advanced primary biliary cirrhosis. N Engl J
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161 Christensen E, Neuberger J, Crowe J et al. Beneficial effect
of azathioprine and prediction of prognosis in primary
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Gastroenterology 1985; 89: 108491.
162 Hoofnagle JH, Davis GL, Schafer DF et al. Randomized
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163 Kaplan MM, Alling DW, Zimmerman HJ et al. A prospective trial of colchicine for primary biliary cirrhosis. N Engl
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164 Wiesner RH, Ludwig J, Lindor KD et al. A controlled trial
of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990; 322: 141924.
165 Mitchison HC, Palmer JM, Bassendine MF et al. A
controlled trial of prednisolone treatment in primary
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166 Lombard M, Portmann B, Neuberger J et al. Cyclosporin A
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167 Wolfhagen FH, van Hoogstraten HJ, van Buuren HR et al.
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168 Hendrickse MT, Rigney E, Giaffer MH et al. Low-dose
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169 Battezzati PM, Zuin M, Crosignani A et al. Ten-year combination treatment with colchicine and ursodeoxycholic
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170 Gong Y, Gluud C. Colchicine for primary biliary cirrhosis.
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171 Rautiainen H, Krkkinen P, Karvonen AL et al.
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4 Treatment of Overlap syndrome

174 Chazouillres O, Wendum D, Serfaty L et al. Long term
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VI Drug therapy of associated diseases

1 Pruritis
175 Van Itallie TB, Hashim SA, Crampton RS et al. The treatment of pruritus and hypercholesteremia of primary
176
177
178
179
180
181
182
183
biliary cirrhosis with cholestyramine. N Engl J Med 1961;

265: 46974.
Datta DV, Sherlock S. Cholestyramine for long term relief
of the pruritus complicating intrahepatic cholestasis.
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Khurana S, Singh P. Rifampin is safe for the treatment of
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prospective randomized-controlled trial. Liver Int 2006;
26: 9438.
Tandon P, Rowe BH, Vandermeer B et al. The efficacy and
safety of bile acid binding agent, opioid antagonists or
rifampicin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol 2007; 102: 152836.
Rishe E, Azarm A, Bergasa NV. Itch in primary biliary
cirrhosis: a patients perspective. Acta Derm Venereol 2008;
88: 347.
Kremer AE, Maryens JJ, Kulik W et al. Lysophosphatidic
acid is a potent mediator of cholestatic pruritus. Gastroenterology 2010; 139: 100818.
Kremer AE, Oude Elferink RP, Beuers U. Pathophysiology
and current management of pururitus in liver disease.
Clin Res Hepatol Gastroenterol 2011; 35: 8997.
Oude Elferink RP, Kremer AE, Martens JJ et al. The
molecular mechanism of cholestatic pururitus. Dig Dis
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Kremer AE, van Dijk R, Leckie P et al. Serum autotaxin
is increased in pururitus of cholestasis, but not of
other origin, and responds to therapeutic interventions.
Hepatology 2012; 56: 1391400.
2 Osteoporosis
184 Comittee of Prevention of Osteoporosis and Clinical
Practice Guideline. Prevention of Osteoporosis and Clinical
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Co, 2006.
185 Collier JD, Ninkovic M, Compston JE. Guidelines on the
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186 Guaabens N, Pers A, Ros I et al. Alendronate is more
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187 Zein CO, Jorgensen RA, Clarke B et al. Alendronate
improves bone mineral density in patients with primary
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Gastroenterology 2004; 126: A671.
188 Guaabens N, Cerd D, Monegal A et al. Low bone mass
and severity of cholestasis affect fracture risk in patients
with primary biliary cirrhosis. Gastroenterology 2010; 138:
234856.
3 Sicca syndrome
189 Mavragani CP, Moutsopoulos HM. Conventional therapy
of Sjgren Syndrome. Clin Rev Allergy Immunol 2007; 32:
28491.
90 H. Ishibashi et al.
VII Liver transplantation

190 Hashimotol E, Obata H, Tanikawa K et al. Selection and
timing of liver transplantation in primary biliary cirrhosis. Hepatol Res 2001; 20: 27178.
191 Japanese Liver Transplantation Society. Report of registered cases in 2009. Ishoku (Transplantation) 2009; 44:
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192 UNOS. Annual report. Available at: http://optn.
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193 Murray KF, Carithers RL Jr, AASLD. AASLD practice guidelines: evaluation of the patient for liver transplantation.
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194 Markus BH, Dcikson E, Grambsch P et al. Efficacy of liver
transplantation in patients with primary biliary cirrhosis.
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195 Eastell R, Dickson ER, Hodgson SF et al. Rates of vertebral
bone loss before and after liver transplantation in women
with primary biliary cirrhosis. Hepatology 1991; 14: 296
300.
196 Murtaugh PA, Dickson ER, Van Dam GM et al. Primary
biliary cirrhosis: prediction of short-term survival
based on repeated patients visits. Hepatology 1994; 20:
12634.
197 Kim WR, Wiesner RH, Therneau TM et al. Optimal timing
of liver transplantation for primary biliary cirrhosis.
198 Wiesner RH. Liver transplantation for primary biliary cirrhosis and primary sclerosing cholangitis: predicting outcomes with natural history models. Mayo Clin Proc 1998;
73: 57588.
199 Rust C, Rau H, Gerbes AL et al. Liver transplantation in
primary biliary cirrhosis: risk assessment and 11-year
follow-up. Digestion 2000; 62: 3843.
200 Lazaridis KN, Lindor KD. Management of primary biliary
cirrhosis: from diagnosis to end-stage disease. Curr
Gastroenterol Rep 2000; 2: 948.
201 Angulo P, Dickson ER. The timing of liver transplantation
in primary biliary cirrhosis. Baillieres Best Pract Res Clin
202 Liermann Garcia RF, Evangelista Garcia C, McMaster P
et al. Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center.
203 Hasegawa K, Sugawara Y, Imamura H et al. Living donor
liver transplantation for primary biliary cirrhosis: retrospective analysis of 50 patients in a single center. Transpl
Int 2005; 18: 7949.
204 Cholongitas E, Marelli L, Shusang V et al. A systematic
review of the performance of the model for end-stage liver
205
206
207
208
209
210
disease (MELD) in the setting of liver transplantation.

Liver Transpl 2006; 12: 104961.
Morioka D, Egawa H, Kasahara M et al. Impact of human
leukocyte antigen mismatching on outcomes of living
donor liver transplantation for primary biliary cirrhosis.
Liver Transpl 2007; 13: 8090.
Charatcharoenwitthaya P, Pimentel S, Talwalkar JA et al.
Long-term survival and impact of ursodeoxycholic acid
treatment for recurrent primary biliary cirrhosis after liver
transplantation. Liver Transpl 2007; 13: 123645.
Jacob DA, Bahra M, Schmidt SC et al. Mayo risk score for
primary biliary cirrhosis: a useful tool for the prediction
of course after liver transplantation? Ann Transplant 2008;
13: 3542.
Schreuder TC, Hubscher SG, Neuberger J. Autoimmune
liver diseases and recurrence after orthotopic liver transplantation: what have we learned so far? Transpl Int 2009;
22: 14452.
Montano-Loza AJ, Wasilenko S, Bintner J et al.
Cyclosporine A protects against primary biliary cirrhosis
recurrence after liver transplantation. Am J Transplant
2010; 10: 8528.
Ikegami T, Shirabe K, Yoshiya S et al. A high MELD score,
combined with the presence of hepatitis C, is associated
with a poor prognosis in living donor liver transplantation. Surg Today 2013. [Epub ahead of print].
SUPPORTING INFORMATION
DDITIONAL SUPPORTING INFORMATION may

be found in the online version of this article at the
publishers web-site:
Tips for clinical treatment of primary biliary cirrhosis
(PBC).
Memo 1 AMA (IIF and ELISA)
Memo 2 Histological staging of PBC
Memo 3 Anti-centromere and anti-gp210 antibodies
and prognosis of PBC
Memo 4 Updated Mayo Natural History Model for PBC
Memo 5 Prognosis prediction formula of the Japanese
Liver Transplantation Indication Study Group
Memo 6 MELD (Model for end-stage liver disease) score
Memo 7 Simplified criteria for the diagnosis of AIH by
IAIHG (2008)
Memo 8 Schema for diagnosis and treatment decisions
Memo 9 Summary sheet for diagnosis of PBC and treatment decisions

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Hepatology Research 2014; 44 (Suppl. 1): 7190

Guidelines for the management of primary biliary cirrhosis

*Working Subgroup (English version) for Clinical Practice Guidelines

2014 The Japan Society of Hepatology

HE JAPANESE VERSION of the clinical practice

Table 1 Level of evidence (LE)

These clinical practice guidelines should be revised at

Table 2 Grade of recommendation (GR)

Strong recommendation, with high level of evidence

2014 The Japan Society of Hepatology

Hepatology Research 2014; 44 (Suppl. 1): 7190

tion techniques, and have specificity of 98% for the

Hepatology Research 2014; 44 (Suppl. 1): 7190

Table 4 Differential diagnosis of PBC

4 Non-invasive imaging of the liver and biliary trees

2.2 Diagnosis of atypical PBC

Guidelines for PBC 73

cells in these patients react with mitochondrial antigen,

2.3 Diagnosis of PBC: symptoms, signs,

Table 5 Symptoms and complications of PBC

2014 The Japan Society of Hepatology

Hepatology Research 2014; 44 (Suppl. 1): 7190

Prolonged cholestasis results in jaundice, xanthoma

2.4 Diagnosis of PBC: pathological

2014 The Japan Society of Hepatology

Table 6 Histological staging of PBC

2.4 Diagnosis of PBC: clinical staging and

Hepatology Research 2014; 44 (Suppl. 1): 7190

Guidelines for PBC 75

Table 7 Histological staging system of PBC (Nakanuma et al.)

No portal fibrosis, or fibrosis limited to portal tracts

Two criteria: fibrosis and bile duct loss.

damage: aPBC and sPBC. aPBC is considered the

s2PBC, with serum level 32.0 mg/dL (Table 9). s1PBC

Table 8 Grading of chronic cholangitis and hepatitis activity in PBC

No cholangitis, but mild duct damage may be present

2014 The Japan Society of Hepatology

Hepatology Research 2014; 44 (Suppl. 1): 7190

Table 9 Clinical staging of PBC

2.5 Diagnosis of PBC: clinical type

Grade A: 56 points; Grade B: 79 points; Grade C: 1015

rapidly to jaundice and ultimately hepatic failure

Several models for predicting the prognosis of PBC have

Portal hypertension type

Jaundice/hepatic failure type

Table 10 Modified Child-Pugh score for evaluating the severity of PBC

Slow progression type

2014 The Japan Society of Hepatology

Figure 1 Three types of natural course

Hepatology Research 2014; 44 (Suppl. 1): 7190

In the logistic model developed by the Japanese Liver

3. TREATMENT AND MANAGEMENT OF PBC

Guidelines for PBC 77

gitis, liver inflammation and liver fibrosis; and (iii)

2014 The Japan Society of Hepatology

Hepatology Research 2014; 44 (Suppl. 1): 7190

PSL has been considered to be contraindicated for PBC,

2014 The Japan Society of Hepatology

3.3 Treatment by clinical stage

Hepatology Research 2014; 44 (Suppl. 1): 7190

Guidelines for PBC 79

are followed up every 12 years. Development of overt

3.4 Liver transplantation