Guidelines for the management of primary biliary cirrhosis
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Hepatology Research 2014; 44 (Suppl. 1): 71–90 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
1. INTRODUCTION
T
Komori, Clinical Research Center, National Hospital HE JAPANESE VERSION of the clinical practice
Organization Nagasaki Medical Center; Atsushi Tanaka,
Department of Medicine, Teikyo University School of Medicine; guidelines for primary biliary cirrhosis (PBC) was
Hajime Takikawa, Department of Medicine, Teikyo University developed in 2012 by the Intractable Hepatobiliary
School of Medicine; §Hirohito Tsubouchi, Digestive Disease and Disease Study Group, with the support of the Ministry
Life-style Related Disease, Kagoshima University Graduate of Health, Labour and Welfare of Japan, for the use of
School of Medical and Dental Sciences and Kagoshima City
general physicians, gastroenterologists and hepatolo-
Hospital; †Hiromi Ishibashi, International University of Health
and Welfare/Fukuoka Sanno Hospital and Clinical Research gists who treat patients with PBC.
Center, National Hospital Organization Nagasaki Medical In preparation for developing the guidelines, the
Center; Hiroto Egawa, Department of Surgery, Institute of study group reviewed recent studies that provided
Gastroenterology, Tokyo Women’s Medical University; Junko important evidence or that were published in leading
Hirohara, Third Department of Internal Medicine, Kansai
journals with a high impact factor, in addition to con-
Medical University; Ken Shirabe, Department of Surgery and
Science, Kyushu University; Kenichi Harada, Department of sidering the formal consensus of experts on PBC or
Human Pathology, Kanazawa University Graduate School of related subjects. Using the core keywords “primary
Medicine; Makoto Nakamuta, Department of Gastroenterology, biliary cirrhosis,” a PubMed search was conducted for
National Hospital Organization Kyushu Medical Center; Mikio English-language clinical trials, randomized clinical
Zeniya, Department of Gastroenterology, Jikei University
trials (RCTs) and meta-analyses that were published
Graduate School of Medicine; Minoru Nakamura, Clinical
Research Center, National Hospital Organization Nagasaki from January 1998 to December 2009 and that
Medical Center and Department of Hepatology, Nagasaki addressed treatment of PBC and its complications,
University Graduate School of Biomedical Sciences; Nobuyoshi follow-up, indication of and time of consultation for
Fukushima, Department of Gastroenterology, National Hospital liver transplantation, or time of consultation with
Organization Kyushu Medical Center; Shinji Shimoda, Medicine
specialists. Medical systems and other culture-specific
and Biosystemic Science, Graduate School of Medical Sciences,
Kyushu University; Shotaro Sakisaka, Department of factors in Japan were also taken into account. Members
Gastroenterology and Medicine, Fukuoka University Faculty of of the task force exchanged ideas frequently during the
Medicine; Toshio Morizane, Japan Council for Quality Health drafting process to try and establish a consensus. The
Care; Yasuaki Takeyama, Department of Gastroenterology and final draft was made after collecting comments from
Medicine, Fukuoka University Faculty of Medicine; ‡Yasuni
the public and all the committee members. The level of
Nakanuma, Department of Human Pathology, Kanazawa
University Graduate School of Medicine; Yoshiyuki Ueno, evidence (LE; Table 1) and the grade of recommenda-
Department of Gastroenterology, Yamagata University Faculty of tion (GR; Table 2) were based on the Medical Informa-
Medicine (†Chairperson of the Working Group, ‡Chairperson of tion Network Distribution Service in Japan (MINDS).
the PBC Subcommittee, §Chairperson of the Intractable After being modified by recent literatures published
Hepatobiliary Disease Study Group).
since 2010, the present English version of the guidelines
**Correspondence: Hiromi Ishibashi, Fukuoka Sanno Hospital,
International University of Health and Welfare, 3-6-45 was developed in order to spread our ideas and
Momochihama, Sawara-ku, Fukuoka, 814-0001, Japan. exchange opinions with physicians who are involved in
Email: hiishibashi-gi@umin.ac.jp the management of PBC patients overseas.
© 2014 The Japan Society of Hepatology 7172 H. Ishibashi et al. Hepatology Research 2014; 44 (Suppl. 1): 71–90
Table 1 Level of evidence (LE) tion techniques, and have specificity of 98% for the
1a Systematic review/meta-analysis of RCTs
disease (Supporting information Memo 1). Approxi-
1b Based on one or more RCTs mately 20–30% of PBC patients are positive for
2a Based on non-randomized control study (prospective anti-nuclear pore proteins, e.g., anti-gp210, and/or anti-
study) centromere antibodies. Most patients with PBC have an
2b Based on non-randomized control study (historical elevated serum IgM concentration, although high serum
cohort study and retrospective cohort study) IgM is not highly specific or sensitive for diagnosis of
3 Case control study PBC. The total gamma globulin concentration remains
4 Analytical epidemiological study (cross-sectional study) normal until late in the disease when cirrhosis develops.
5 Descriptive study (case report or case series) Histologically, chronic non-suppurative destructive
6 Opinion of expert committee, or an expert, not based on
cholangitis (CNSDC) is seen in the intrahepatic small
patient data
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 cirrho-
These clinical practice guidelines should be revised at sis and, in some cases, hepatocellular carcinoma.
appropriate intervals to incorporate advances in meth- The differential diagnosis includes autoimmune
odology and treatment. hepatitis, primary sclerosing cholangitis, drug-induced
chronic cholestasis, and paucity of intrahepatic bile
ducts, after excluding obstructive jaundice and
2. DIAGNOSIS OF PBC cholestatic diseases of known etiologies.
2.1 Diagnosis of PBC: general principles Recommendations:
P BC IS AN autoimmune-mediated, chronic
cholestatic liver disease that predominantly affects
middle-aged women. The initial symptom is most often
1 Patients with one of the following criteria should be
diagnosed with PBC: (1) histologically confirmed
CNSDC with laboratory findings compatible with
pruritus, though the disease generally progresses insidi- PBC; (2) positivity for AMAs with histological find-
ously without symptoms for many years. Jaundice pro- ings compatible with PBC but in the absence of char-
gresses without improvement once it becomes overt, acteristic histological findings of CNSDC; and (3) no
and portal hypertension occurs at a high rate. histological findings available, but positivity for
Clinically, increased levels of serum biliary enzymes AMAs as well as clinical findings and a course indica-
[alkaline phosphatase (ALP) and γ-glutamyl transferase tive of typical cholestatic PBC. (GR A)
(GGT)] and detection of antimitochondrial antibodies 2 Diagnosis of PBC should be performed using the
(AMAs) are characteristic. AMAs are found in 95% of criteria endorsed by the Intractable Hepatobiliary
patients with PBC when using the most sensitive detec- Disease Study Group with the support of the Japanese
Ministry of Health and Welfare (2010 version,
Table 3). (GR A)
Table 2 Grade of recommendation (GR) 3 Differential diagnosis should be performed for a spec-
A Strong recommendation, with high level of evidence
trum of diseases that manifest chronic cholestatic
B Moderate recommendation, with certain level of liver dysfunction or immunological disorder with
evidence autoantibodies (Table 4). (GR A)
*Supported by an intermediate level of evidence and
considered to be clinically useful
Table 3 Diagnosis of PBC endorsed by the Intractable
*Supported by a high level of evidence but not considered to
Hepatobiliary Disease Study Group in Japan (2010 version)
be clinically very useful
*Evidence level is low, but usefulness has already been With histological findings
established in clinical practice 1) Biochemical evidence of cholestasis accompanied by
C1 Recommendation to be done, without a high level of histological evidence of CNSDC
evidence 2) Presence of AMA accompanied by histologically
C2 Recommendation not to be done, without a high level compatible features of PBC, even without CNSDC
of evidence Without histological findings
D Recommendation not to be done, as evidence indicates 3) Presence of AMA accompanied by clinical features and
ineffectiveness or harm course of classical and cholestatic PBC
© 2014 The Japan Society of HepatologyHepatology Research 2014; 44 (Suppl. 1): 71–90 Guidelines for PBC 73
Table 4 Differential diagnosis of PBC cells in these patients react with mitochondrial antigen,
1) Cholestatic liver diseases
despite being negative for AMA. Special consideration
Intrahepatic cholestasis: chronic drug-induced cholestasis for their treatment is not warranted.
Primary sclerosing cholangitis
IgG4-related sclerosing cholangitis PBC–AIH overlap syndrome
Adult-onset bile duct paucity
Patients with PBC who manifest clinicopathological fea-
Obstructive jaundice
tures of autoimmune hepatitis (AIH) in conjunction
2) Diseases with immunological abnormalities
Autoimmune hepatitis
with elevated levels of aminotransferases could be
Drug-induced liver injury recognized. These cases have also been referred to as
3) Elevation of serum ALP and/or GGT PBC with features of AIH. Prednisolone may effectively
Space occupying lesions of the liver reduce aminotransferase levels in such cases.
Bone lesions
Hyperthyroidism 2.3 Diagnosis of PBC: symptoms, signs,
Fatty liver diseases and complications
Approximately 70–80% of PBC cases are diagnosed in
the early and asymptomatic phase. Although this phase
4 Non-invasive imaging of the liver and biliary trees is likely to persist for years, the clinical and histological
should be considered mandatory to exclude diseases progression precipitates several symptoms (symptom-
manifesting as obstructive jaundice. (GR A) atic PBC). The symptoms and complications of PBC
include cholestasis, liver injury, and comorbid autoim-
2.2 Diagnosis of atypical PBC mune disease(s) (Table 5).
Pruritus accompanied by cholestasis is characteristic
Pathognomonically-related but atypical PBC cases that
of PBC. It may occur initially before overt jaundice.
do not fulfill the diagnostic criteria should be handled
distinctively and appropriately; treatment strategies for
these cases are different from those for typical PBC.
Table 5 Symptoms and complications of PBC
Early PBC
Symptoms
AMA may be detectable in the serum of individuals 1) None of the following
without symptoms of PBC and with normal liver tests. 2) General fatigue
Histopathological changes of PBC with no or mild pro- 3) Cholestasis-associated
gression are apparent and this condition is designated • Pruritus (scratching)
early PBC. Follow-up without medication is appropriate. • Jaundice
4) Liver injury and cirrhosis-associated
• Hematemesis and melena
Autoimmune cholangitis, autoimmune
• Abdominal fullness
cholangiopathy • Consciousness disturbance
Patients whose clinical features are compatible with 5) Comorbid autoimmune diseases -associated
PBC may be negative for AMA but have a high titer of • Sicca syndrome, etc.
antinuclear antibody (ANA) in their serum. In 1987, Complications
Brunner and Klinge first described this condition as 1) Cholestasis-associated
immunocholangitis, while others have used different • Osteoporosis
• Hyperlipidemia
terminology, such as autoimmune cholangiopathy,
2) Liver injury and cirrhosis-associated
primary autoimmune cholangitis, or autoimmune chol-
• Portal hypertension
angitis. The current understanding is that this condition • Hepatocellular carcinoma
is atypical PBC. • Ascites
• Hepatic encephalopathy
AMA-negative PBC 3) Comorbid autoimmune diseases -associated
Approximately 10% of patients who have biochemical • Sjögren’s syndrome
• Rheumatoid arthritis
evidence of cholestasis, accompanied by histological
• Hashimoto thyroiditis, etc.
features of PBC, are negative for AMA. Autoreactive T
© 2014 The Japan Society of Hepatology74 H. Ishibashi et al. Hepatology Research 2014; 44 (Suppl. 1): 71–90
Prolonged cholestasis results in jaundice, xanthoma Table 6 Histological staging of PBC
coupled with lipid abnormalities, and osteoporosis- Stage 1 no progression
related bone lesions/fractures. Stage 2 mild progression
Persistent fatigue is another common symptom, Stage 3 moderate progression
occurring in 20–70% of Caucasian patients, although Stage 4 advanced progression
less frequently in Japanese patients. No correlation has
been found between fatigue and age, sex, jaundice, liver
Parenchymal change
function parameters, or histological stage of the disease.
PBC patients can experience profound distress associ- In the early stage of PBC, non-specific necroin-
ated with fatigue. flammatory changes are found in the parenchyma.
Cirrhosis-associated symptoms include esophagoga- Interface hepatitis and chronic cholestatic changes are
stric varices. Portal hypertension is more likely to occur also found. During the progression of irreversible bile
in PBC than in liver diseases with other etiologies, and duct damage and loss, there are several characteristic
can develop even in the non-cirrhotic stage of PBC; findings that reflect cholestasis, including ductular reac-
some patients are diagnosed by the presence of tion (proliferating bile ductules), copper deposition
esophagogastric variceal bleeding as an initial symptom. (orcein-positive granules), bile plaques, hepatocellular
Prevalent comorbid autoimmune diseases include ballooning (cholate stasis), Mallory–Denk bodies, and
Sjögren’s syndrome, Hashimoto thyroiditis, and rheu- feathery degeneration. These features are associated with
matoid arthritis. aPBC may be masked by the symptoms the progression of biliary fibrosis and biliary cirrhosis.
of comorbid autoimmune diseases. Appropriate diagno- Changes similar to small cell dysplasia are also often
sis of comorbid autoimmune diseases is important found in zone 1 (periportal area), which is useful for
because they may influence the outcome of PBC. the diagnosis of PBC. In addition to these cholestatic
changes reflecting bile duct loss, chronic hepatitic
changes resembling autoimmune hepatitis, such as
2.4 Diagnosis of PBC: pathological
interface and lobular hepatitis, are also found in most
examinations
PBC cases, and are involved in the progression of
PBC is histologically characterized by autoimmune- hepatic fibrosis and cirrhosis.
mediated progressive destruction of the intrahepatic
small bile ducts, as well as by chronic intrahepatic Histological staging
cholestasis, hepatocellular damage, fibrosis, and septal The characteristic histological findings of PBC are het-
formation. erogeneously distributed throughout the liver. Thus, in
small specimens such as those taken from needle liver
Bile duct damage biopsy, sampling errors are likely to be recognized when
using the classification systems of Scheuer and Ludwig,
PBC is histologically characterized by CNSDC and pro-
because these two systems define each stage by a sole
gressive bile duct loss, which preferably affects the intra-
histological feature (Supporting information Memo 2).
hepatic small bile ducts, especially the interlobular bile
Therefore the novel staging system of Nakanuma (2009)
ducts. Non-caseating epithelioid granuloma formation
(Tables 6–8) is recommended for histological staging of
is often seen in the portal tracts. Granulomatous chol-
PBC, as this system could avoid the sampling errors
angitis consisting of CNSDC and periductal granuloma
caused by the heterogeneous distribution of histological
formation is valuable for pathological diagnosis.
features.
CNSDC is characterized by marked lymphoplasmacytic
accumulation around the damaged bile ducts, and lym- Recommendations:
phoid cell infiltration is found in the biliary epithelial 1 The novel system for histological grading and staging
layer of CNSDC. Some biliary epithelial cells in CNSDC of PBC proposed by Nakanuma et al. is recom-
show eosinophilic apoptotic changes and swelling. mended (LE6, GRC1).
Moreover, chronic cholangitis, which does not fulfill the 2.4 Diagnosis of PBC: clinical staging and
criteria of CNSDC, is also found. Bile duct loss is seen disease severity
during the progression of PBC, and the interlobular bile
ducts are mostly lost in the terminal cirrhotic stage. The Clinical staging
presence of arteries in the absence of bile ducts is useful PBC is classified into two groups depending on the
for identification of bile duct loss or ductopenia. absence or presence of symptoms caused by liver
© 2014 The Japan Society of HepatologyHepatology Research 2014; 44 (Suppl. 1): 71–90 Guidelines for PBC 75
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 No portal fibrosis, or fibrosis limited to portal tracts
Score 1 Portal fibrosis with periportal fibrosis or incomplete septal fibrosis
Score 2 Bridging fibrosis with variable lobular disarray
Score 3 Liver cirrhosis with regenerative nodules and extensive fibrosis
B. Scoring of bile duct loss
Score 0 No bile duct loss
Score 1 Bile duct loss in < 1/3 of portal tracts
Score 2 Bile duct loss in 1/3 to 2/3 of portal tracts
Score 3 Bile duct loss in > 2/3 of portal tracts
C. Scoring of deposition of
orcein-positive granules
Score 0 No deposition of granules
Score 1 Deposition of granules in a few periportal hepatocytes in < 1/3 of portal tracts
Score 2 Deposition of granules in several periportal hepatocytes in 1/3 to 2/3 of portal tracts
Score 3 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 Sum of scores
Two criteria† Three criteria‡
Stage 1 (no progression) 0 0
Stage 2 (mild progression) 1–2 1–3
Stage 3 (moderate progression) 3–4 4–6
Stage 4 (advanced progression) 5–6 7–9
†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 s2PBC, with serum level 32.0 mg/dL (Table 9). s1PBC
non-advanced stage (stage I), while sPBC is considered is considered a non-icteric advanced stage (stage II),
the advanced stage. sPBC is further classified as and s2PBC is considered an icteric advanced stage
s1PBC, with serum bilirubin level 10 continuous hepatocytes in 1 portal tract or fibrous septa,
and mild to moderate lobular hepatitis
HA2 (moderate activity) Interface hepatitis affecting > 10 continuous hepatocytes in 32 portal tracts or fibrous septa,
and mild to moderate lobular hepatitis
HA3 (marked activity) Interface hepatitis affecting > 20 continuous hepatocytes in 3 1/2 of portal tracts, and
moderate lobular hepatitis or bridging or zonal necrosis
© 2014 The Japan Society of Hepatology76 H. Ishibashi et al. Hepatology Research 2014; 44 (Suppl. 1): 71–90
Table 9 Clinical staging of PBC Table 10 Modified Child-Pugh score for evaluating the sever-
ity of PBC
1) Asymptomatic PBC (aPBC): Condition absent from
symptoms caused by liver damage† Score 1 2 3
2) Symptomatic PBC (sPBC): Condition with symptoms
T.Bilirubin (mg/dL) 1–4 4–10 >10
caused by liver damage†.
Albumin (g/dL) 3.5< 2.8–3.5Hepatology Research 2014; 44 (Suppl. 1): 71–90 Guidelines for PBC 77
In the logistic model developed by the Japanese Liver gitis, liver inflammation and liver fibrosis; and (iii)
Transplantation Study Group (Ref.VII-1) (Supporting delay in the disease progression until end-stage liver
information Memo 5), serum total bilirubin and aspar- disease, death, or liver transplantation. The following
tate aminotransferase (AST)/alanine aminotransferase Paris and Barcelona criteria are useful for evaluating the
(ALT) ratio are necessary. The probability of death after clinical outcome of UDCA treatment. (i) Paris criteria:
6 months is calculated by means of a logistic regression total bilirubin 21.0 mg/dL, ALP 23 × the upper normal
formula, and transplantation is recommended if the limit (UNL), and AST 2 2 × UNL at 1 year after introduc-
value exceeds 50%. tion of UDCA. (ii) Barcelona criteria: decrease of ALP
Finally, for the MELD (Model for End-Stage Liver 340% at 1 year after introduction of UDCA.
Disease) score, the serum creatinine level, total biliru- Liver transplantation is the only therapeutic approach
bin, and prothrombin time (PT) are the key factors. The for patients in the advanced stage when medical treat-
MELD score is used for the evaluation of end-stage liver ment shows little improvement. Prevention and treat-
failure. The score is high if hepatorenal syndrome is ment strategies for comorbid autoimmune diseases,
present, and the pre-transplantation value correlates cholestasis, and cirrhosis-related symptoms and compli-
well with the likelihood and magnitude of complication cations are required.
after liver transplantation. Therefore, it is recommended Although the term cirrhosis is included in the name
that transplantation should be performed before com- PBC, most patients (70–80%) with PBC have little clini-
plication by hepatorenal syndrome (Supporting infor- cal and histological evidence of liver cirrhosis. Patients
mation Memo 6). should be informed accordingly to prevent misunder-
The common factor among these different schemes is standing of their prognoses. Currently, patients are
serum total bilirubin. A life expectancy of 10 years is likely to be diagnosed at earlier stages and disease pro-
predicted for patients with a serum bilirubin level gression is likely to be delayed by UDCA. Therefore, the
6.0 mg/dL. asymptomatic, is equivalent to that in the general popu-
Recommendations: lation. No restrictions are necessary in daily life for
1 Total bilirubin, prothrombin (INR), albumin, and patients with aPBC. By contrast, some restrictions in
the serum creatinine level, which are essential to cal- daily life and nutritional education are required for
culate the MELD score, should be measured when patients with sPBC, depending on symptoms, expected
considering liver transplantation. (LE 2b (2a in part), future complications, and disease severity.
GR A)
2 Patients with PBC should be referred to transplant 3.2 Prescription
hepatologists when serum total bilirubin level is
Ursodeoxycholic acid (UDCA)
>5 mg/dL. To encourage the patients to prepare for
liver transplantation, an earlier and appropriate Extensive clinical trials including randomized clinical
explanation of liver transplantation is desirable. (LE trials (RCT) and meta-analyses were carried out for
4, GR B) UDCA after the first report by Poupon et al. After lively
debates, it was concluded that UDCA not only improves
3. TREATMENT AND MANAGEMENT OF PBC the serum biochemical values of PBC patients but also
prolongs the period to death or liver transplantation.
3.1 Treatment and management of PBC: The clinical guidelines for PBC by the European Asso-
general principles ciation for the Study of the Liver (EASL) and the Ameri-
A LTHOUGH THERE IS no completely curative treat-
ment for PBC, ursodeoxycholic acid (UDCA) is cur-
rently considered the first-line treatment for the disease.
can Association for the Study of Liver Diseases (AASD)
recommend that UDCA be given at a dose of 13–15 mg/
kg/day, whereas in Japan, it is usually given at 600 mg/
UDCA delays the progression of PBC, although it does day. In clinical trials performed with Japanese PBC
not have a significant benefit for PBC at the advanced patients, 600 mg/day UDCA was given to PBC patients
stage. for 48–132 weeks and then the results of liver tests were
The clinical usefulness of UDCA is evaluated accord- analyzed. Improvement was demonstrated in 81.8%
ing to the following factors: (i) improvement of serum (27/33) of cases. Therefore, 600 mg/day is considered
biochemical markers, such as ALP, GGT, AST, ALT and as a standard dose, irrespective of body weight. The
total bilirubin; (ii) histological improvement of cholan- dose can be increased up to 900 mg/day or decreased
© 2014 The Japan Society of Hepatology78 H. Ishibashi et al. Hepatology Research 2014; 44 (Suppl. 1): 71–90
depending on weight and adverse events. Co- Recommendations:
administration with bezafibrate is then considered if 1 Administration of bezafibrate (Bezatol®, 400 mg/
900 mg/day UDCA has little effect. UDCA results in day) may be considered in patients who exhibit a
biochemical improvement, but is not likely to act suboptimal response to UDCA. (LE 2a, GR B)
against the “core” pathogenesis of PBC; administration
is usually maintained throughout life. Prednisolone (PSL)
Recommendations: PSL has been considered to be contraindicated for PBC,
1 UDCA should be used to improve liver biochemical because it brings about little improvement of PBC and
tests and histological findings, and to prolong the may even cause deterioration of osteoporosis in post-
time until death or liver transplantation, though it menopausal women. Co-administration of PSL with
does not provide significant benefit for those at the UDCA is indicated for patients with PBC–AIH overlap
advanced stage. (LE 1a, GR A) syndrome, especially those whose symptoms of hepati-
2 In general, UDCA should be administered at 600 mg/ tis are clinically and histologically relevant. The recom-
day, and increased to 900 mg/day if the response is mended initial corticosteroid dose isHepatology Research 2014; 44 (Suppl. 1): 71–90 Guidelines for PBC 79
Table 11 Diagnostic criteria for corticosteroid use in PBC–AIH overlap syndrome (Intractable Hepatobiliary Disease Study Group
in Japan, 2011)
PSL is recommended in addition to UDCA for cases that are considered to be PBC–AIH 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 1–2 years. Development of overt and markedly reduced quality of life (QOL) due to
PBC may be preventable in these patients if etiology- severe pruritus. On the other hand, liver transplantation
oriented medical treatment becomes available in the is generally contraindicated for patients with severe
future. complications, such as lung and kidney disease, other
organ disease, infection, and malignancy.
Autoimmune cholangitis It should be borne in mind, however, that not every
When the response to UDCA is not optimal, PSL admin- patient for whom liver transplantation is indicated suc-
istration should be considered. It is advisable to switch ceeds in finding a donated liver. Living donor liver trans-
to UDCA monotherapy after hepatitis subsides, as in plantation (LDLT) is more common in Japan because
cases of PBC–AIH overlap syndrome. deceased donor livers are scarcely offered for transplan-
tation. In order to plan for LDLT, a 1-month period is
AMA-negative PBC desirable for the living donor. This period is required for
medical examination, preparation for early rehabilita-
The diagnosis of PBC should be confirmed by liver his-
tion and approval by the appropriate ethical committee.
tology. The treatment strategy is identical to that for
Earlier registration for deceased donor liver transplanta-
AMA-positive PBC.
tion (DDLT) is recommended. Given this situation,
there is no difference in timing between cases in which
PBC–AIH overlap syndrome
LDLT is indicated and those in which DDLT is indicated.
PSL is recommended in addition to UDCA for cases that Moreover, there is no difference in the outcome of PBC
are considered to be PBC–AIH overlap syndrome, patients who undergo LDLT and DDLT.
because superimposed AIH could deteriorate the clinical
Recommendations:
course of PBC toward cirrhosis.
1 When PBC progresses to cholestatic cirrhosis, medical
Recommendations: treatment has little effect on further disease progres-
1 When patients with PBC are diagnosed with PBC– sion and liver transplantation is the only therapeutic
AIH overlap syndrome due to clinical and histologi- approach for survival. (LE 1, GR B) Appropriate
cal features of AIH, and meet the criteria for timing of liver transplantation is the most important
corticosteroid use for PBC–AIH overlap syndrome consideration. (LE 2b, GR B)
(Table 11), PSL administration is strongly recom- 2 The following criteria (Table 12) should be consulted
mended. (LE 2b, GR B) to determine whether liver transplantation is indi-
2 It is advised that treatment should be switched to cated. (LE 6, GR A)
UDCA monotherapy when hepatitis features subside.
(LE 3, GR C1) Indication for liver transplantation
3.4 Liver transplantation As described in the Prognosis portion of section 2.5,
three scoring systems have been widely implemented for
General principles predicting prognosis in PBC. The most popular system is
Liver transplantation is considered in cases with con- the updated Natural History Model for PBC from the
tinuous elevation of total bilirubin, intractable pleural Mayo Clinic. Once the Mayo risk score is >7.8, the
effusion and/or ascites, hepatic encephalopathy, outcome after liver transplantation is poor. Further-
repeated rupture of esophageal and/or gastric varices, more, this score was a significant predictor for liver-
© 2014 The Japan Society of Hepatology80 H. Ishibashi et al. Hepatology Research 2014; 44 (Suppl. 1): 71–90
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. 1) Decision of initial treatment approach, in particular,
I. Sum of Child–Pugh score 38. diagnosis and evaluation of atypical cases
II. Serum levels of total bilirubin 35.0 mg/dL, with at 2) Decision of treatment strategy
least one complication depicted below (a–g). 3) Suboptimal response of UDCA
a) Hepatic coma 4) Apparent progression to symptomatic PBC
b) Gastrointestinal bleeding with portal hypertension 5) 35 mg/dL of total bilirubin (consult to liver transplant
c) Refractory ascites and/or pleural effusion surgeons; earlier explanation is necessary for patients)
d) Spontaneous bacterial peritonitis, hepatorenal
syndrome, hepatopulmonary syndrome
e) Hepatocellular carcinoma
f) Itch sensation, causing insomnia
g) Severe general malaise, and deterioration of QOL, undergone liver transplantation, and thus the timing of
by severe osteomalacia
consultation may be adequate when the MELD score
reaches 12.
Recommendations:
1 The use of scores for the evaluation of liver failure is
related death before liver transplantation, but not for mandatory.
post-transplantation prognosis. Thus, liver transplanta- a Updated Natural History Model for PBC from the
tion should be performed before the Mayo risk score Mayo Clinic: risk score >7.8 (LE 2b, GR B)
reaches 7.8. b Mortality rate after 6 months: 3 50%, as estimated
Secondly, the indication model of the Japanese Liver by the Japan liver transplantation indication
Transplantation Indication Study Group recommends society model (LE 2b, GR, B)
liver transplantation when the mortality rate after 6 c MELD score 315 (LE 2b, GR, B)
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 Management of patients after liver transplantation
>6 points, which means the expected mortality rate after Liver-transplanted patients should be administered
6 months is >70%, are candidates for DDLT. In contrast, immunosuppressive agents and closely monitored.
patients in whom the expected mortality rate after 6 Postoperative complications, acute/chronic rejection,
months is >50% are candidates for LDLT. recurrence of PBC, and infections should all be carefully
Finally, the cumulative survival rate at 1 year after monitored. Postoperative recurrence of PBC is an
liver transplantation is about 50% in patients whose important cause of graft dysfunction. The five-year recur-
MELD score is >20. The higher the MELD score, the rence rate after liver transplantation is reported as
poorer is the outcome after liver transplantation. In a 0–33% in representative facilities in Japan. The ten-year
previous report from a single center in Japan, the survival rate of patients with PBC after liver transplan-
outcome became poorer when the MELD score was >25. tation is equal to the survival in those with other
The average MELD score is −15 in patients who have 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 3–6 months†
2) Assessment of complications
2 Thyroid function (TSH, free T4) Every 1 year†
3 Bone mineral density testing Every 2–4 years†
4 Upper GI endoscopy Every 1–2 years†
5 Abdominal ultrasound and serum AFP Every 1 year†
(every 3–6 months in liver cirrhosis)†
†Intervals of tests vary depending on the stage of the patient.
© 2014 The Japan Society of HepatologyHepatology Research 2014; 44 (Suppl. 1): 71–90 Guidelines for PBC 81
3.5 Management of symptoms cise are recommended, and medical treatment should be
and complications given if necessary. Bisphosphonates, bioactive vitamin
D3 agents, and vitamin K2 are prescribed.
Dermal pruritus
Among bisphosphonates, alendronate improves bone
Pruritus is the most specific symptom in PBC, and may density more than etidronate. Nevertheless, there is no
appear even before development of jaundice. Although evidence that alendronate suppresses bone fracture.
it has been debated whether increased concentrations Administration once weekly is preferable to daily
of bile salts, histamine, progesterone metabolites or administration. Alendronate is contraindicated for
endogenous opioids are potential pruritogens in cases with esophageal stenosis due to sclerotherapy for
cholestasis, recent experimental evidence has impli- esophageal varices.
cated the lysophospholipase, autotaxin (ATX), and its Vitamin D3 and vitamin K2 formulations have fre-
product, lysophosphatidic acid (LPA), as potential quently been prescribed for PBC in Japan. Both drugs
mediators of cholestatic pruritis. Pruritus is more often have been proven to be effective for osteoporosis itself,
exacerbated at night more than in the daytime, and may and are regarded as Grade B in guidelines for the pre-
decrease along with progression of liver damage. vention and treatment of osteoporosis.
Cholestyramine is a non-absorbable basic anion- Recommendations:
exchange resin, and is a drug of first choice for pruritus 1 It is desirable to start treatment for the prevention of
in PBC. It improves pruritus by inducing adsorption of fractures in cases with a T score below −1.5. (LE 4, GR
bile acids in the intestinal tract. In patients treated with C1)
UDCA, an interval of a few hours is necessary in order to 2 Alendronate improves bone density in PBC patients.
avoid the attenuating effect caused by binding of cho- (LE 1b, GR A)
lestyramine and UDCA. Cholestimide, which is also a 3 Although there is scarce evidence in PBC patients,
basic anion-exchange resin, is used empirically in Japan. vitamin D3 and vitamin K2 formulations can be
Antihistamines are also frequently prescribed in Japan effective for osteoporosis. (LE 1b, GR C1)
due to their ease of use. They can be effective for insom-
nia due to their sedative action. Dyslipidemia
The efficacy of rifampicin, which is an anti- Hypercholesterolemia is likely to develop in PBC due to
tuberculosis agent, for pruritus has been validated in cholestasis. Xanthoma is seen around the eyelids. No
two meta-analyses. As there is a possibility of various specific treatment for hypercholesterolemia in PBC is
side effects, including liver damage, close and regular required in most cases, while bezafibrate is expected to
follow-up are necessary. A dose of 150–300 mg twice be effective for both PBC and hypercholesterolemia.
daily is used for pruritis.
Recommendations: Sicca syndrome
1 Cholestyramine is effective against dermal pruritus in Sicca syndrome, a major symptom of Sjögren’s syn-
PBC patients, and should be considered the first drome, is frequently complicated with PBC. The
choice agent. (LE 2a, A) diagnosis of Sjögren’s syndrome should be made by
2 Antihistamines might be effective against severe detection of serum anti-SS-A/SS-B antibodies, presence
dermal pruritus which may cause insomnia. (LE 5, of corneal erosion, and lip biopsy if necessary. Artificial
GR C1) lachrymal fluids are indicated for eye symptoms. If the
3 Rifampicin is effective against dermal pruritus in PBC response is not favorable, pilocarpine hydrochloride
patients. (LE 1a, GR B) and cevimeline hydrochloride hydrate are used under
the guidance of ophthalmologists. As for oral symp-
Osteoporosis toms, artificial saliva should be used first, and pilocar-
Osteoporosis is frequently observed in patients with PBC pine hydrochloride and cevimeline hydrochloride
because intestinal absorption of fat-soluble vitamins hydrate can also be prescribed.
is disturbed due to reduced secretion of bile acids, and Recommendations:
PBC is common in middle-aged and postmenopausal 1 Cevimeline hydrochloride and pilocarpine hydro-
women. For prevention of osteoporosis, abundant oral chloride may be effective for xerostomia in PBC,
intake of calcium (1 to 1.2 g/day) and vitamin D (plen- although there are no studies evaluating their
tiful in fish and mushrooms) and weight-bearing exer- potential to alleviate the symptoms occurring in PBC
© 2014 The Japan Society of Hepatology82 H. Ishibashi et al. Hepatology Research 2014; 44 (Suppl. 1): 71–90
patients with concurrent Sjögren’s syndrome. (LE 6, to shorten the second trimester of pregnancy, if
GR B) possible.
2 Patients with PBC frequently experience cholestasis, Recommendations:
comorbid autoimmune diseases, and symptoms asso- 1 The blood and other clinical tests should be under-
ciated with liver injury and cirrhosis. Prevention and taken regularly to investigate complicating comorbi-
management of these symptoms are required. (GR A) dities, prevent complications, and detect portal
hypertension and liver cancer as early as possible.
3.6 Follow-up
(Table 13) (LE 3, GR B)
Prognosis of asymptomatic PBC is excellent with little 2 It is advisable to consult with hepatologists when the
progression, but 25% of patients with aPBC develop diagnosis of PBC is made, or when patients with PBC
some symptoms within 10 years. Serum total bilirubin become symptomatic. In patients with atypical forms
and cholestatic enzymes (ALP, GGT) are important for of PBC such as PBC–AIH overlapping syndrome,
assessing the activity and progression of PBC. Liver earlier referral is recommended. (Table 14) (LE 6, GR
biochemical tests should be done every 3–6 months. A-B)
In addition, thyroid hormone (every year) and bone 3 For patients in the symptomatic stage, there is a like-
mineral density (every 2–4 years) tests are recom- lihood of worsening of pruritus or icterus in the preg-
mended because PBC is likely to be complicated with nancy, as well as an increased possibility of variceal
other autoimmune diseases, such as Sjögren’s syn- rupture. It is advisable that these patients undergo
drome, chronic thyroiditis, and rheumatoid arthritis. upper gastrointestinal endoscopy by the second tri-
Regular upper gastrointestinal endoscopy, depending mester of pregnancy. (LE 5, GR C1)
on stage (1 or 2 times per year), is required because 4 Administration of UDCA or bezafibrate should be
esophageal/gastric varices may develop even in patients withheld, if the patient with PBC is possibly pregnant
without jaundice. Abdominal ultrasound (US) and or in the early stage of pregnancy. In the third trimes-
serum AFP testing every 6–12 months are necessary in ter of pregnancy, administration of UDCA is possible
patients with definite or suspected liver cirrhosis. Liver for cholestasis if necessary. (LE 5, GR C1)
cirrhosis, older age, and male sex are high risk factors for
developing hepatocellular carcinoma (HCC). Therefore,
ACKNOWLEDGMENTS
testing for tumor markers and imaging studies [US and
computed tomography (CT)] are required for early
detection of HCC in patients with advanced PBC. Man-
agement for other complicating autoimmune diseases
T HIS STUDY WAS supported by Grants-in-Aid from
the Research Program of lntractable Disease pro-
vided by the Ministry of Health, Labor and Welfare of
should be done depending on each symptom. Japan.
Finally, special attention should be paid to pregnancy
in PBC and patients who have a desire to bear children. CONFLICTS OF INTEREST
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 S HOTARO SAKISAKA IS given research funds from
MSD K.K., Mikio Zeniya is given research funds from
Daiichi Sankyo Co. Ltd. and Chugai Pharmaceutical
patients with aPBC. In sPBC, however, if worsening of
icterus or varices is reported, then avoidance of preg- Co., Ltd., Hirohito Tsubouchi is given research funds
nancy could be justified. from Chugai Pharmaceutical Co., Ltd., MSD K.K. and
The impact of pregnancy on PBC is unclear because KAN Research Institute, Inc. All other authors have no
both exacerbation and improvement of cholestasis conflicts of interest to declare.
have been reported. Estrogen could potentially worsen
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