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Corresponding author. , MD, PhD, Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. ;. Tel: +81-263-37-2634; Fax: +81-263-32-9412
Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, JapanConsultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
In Japan, nationwide surveys on PBC have been conducted every 3 years since 1980.
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The ALBI score was associated with Scheuer’s classification in PBC.
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ALBI grade > 2 had significant associations with mortality in this cohort study.
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Baseline measurements of ALBI grade may be a simple predictor of prognosis in PBC.
Abstract
Background & Aims
The albumin-bilirubin (ALBI) score is calculated using serum levels of total bilirubin and albumin as a simple method to assess liver function. This study investigated the ability of baseline ALBI score/grade measurements to assess histological stage and disease progression in primary biliary cholangitis (PBC) in a large Japanese nationwide cohort.
Methods
A total of 8,768 Japanese patients with PBC were enrolled between 1980 and 2016 from 469 institutions, among which 83% received ursodeoxycholic acid (UDCA) only, 9% received UDCA and bezafibrate, and 8% were given neither drug. Baseline clinical and laboratory parameters were retrospectively retrieved and reviewed from a central database. Associations of ALBI score/grade with histological stage, mortality, and need for liver transplantation (LT) were evaluated using Cox proportional hazards models.
Results
During the median follow-up period of 5.3 years, 1,227 patients (including 789 liver-related) died and 113 underwent LT. ALBI score and ALBI grade were significantly associated with Scheuer’s classification (both p < 0.0001). ALBI grade 2 or 3 had significant associations with all-cause mortality or need for LT as well as liver-related mortality or need for LT according to Cox proportional hazards regression analysis (hazard ratio 3.453, 95% confidence interval 2.942–4.052 and hazard ratio 4.242, 95% confidence interval 3.421–5.260, respectively; both p < 0.0001). Cumulative LT-free survival at 5 years in the ALBI grade 1, 2, and 3 groups was 97.2%, 82.4%, and 38.8%, respectively, while respective non-liver related survival rates were 98.1%, 86.0%, and 42.0% (both p < 0.0001, log-rank test).
Conclusions
This large nationwide study of patients with PBC suggested that baseline measurements of ALBI grade were a simple non-invasive predictor of prognosis in PBC.
Lay Summary
Primary biliary cholangitis (PBC) is an autoimmune liver disease causing progressive destruction of intrahepatic bile ducts. This study examined the ability of ALBI score/grade to estimate histological findings and disease progression in PBC by means of a large-scale nationwide cohort in Japan. ALBI score/grade were significantly associated with Scheuer’s classification stage. Baseline ALBI grade measurements may be a simple non-invasive predictor of prognosis in PBC.
The dataset generated during this study is available from the corresponding author upon reasonable request.
Conflict of interest declaration for all authors
Dr. A. Komori reports receiving consultant fees from Kowa Company and Kaken Pharmaceutical Co. Dr. A. Tanaka reports receiving consultant fees from GlaxoSmithKline and Kowa Company. The remaining authors have nothing to disclose regarding industry funding or other conflicts of interest with respect to this manuscript.
Financial Support
This work was supported by JSPS KAKENHI Grant Number 20K08282 and the MHLW Research Program on Intractable Hepatobiliary Disease, grant number JPMH20FC1023.
Authors’ contributions
Conceptualization: YY, TU. Data curation: JH, TN. Formal analysis: YY. Investigation: YY, TU. Resources: YY, TU, TK, SJ, AK, AT. Supervision: AK, AT. Visualization: YY, TU. Writing – original draft: YY, TU. All coauthors were involved in the process of reviewing the drafts at various stages, giving their expertise-based suggestions and critical comments to produce the final version of the manuscript. The final version of the manuscript has been approved by all co-authors.
Introduction
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the presence of highly specific anti-mitochondrial autoantibody (AMA) in the serum and the progressive destruction of intrahepatic bile ducts.
Ursodeoxycholic acid (UDCA) is a first-line treatment for PBC. The drug ameliorates liver biochemistry, delays histological progression to cirrhosis, and improves liver transplantation (LT)-free survival.
. As one-third of patients treated with UDCA monotherapy show an incomplete treatment response, a combination of UDCA and bezafibrate (BZF) has been used for enhanced biochemical responses and long-term prognosis in early-stage PBC patients.
. In Europe and the U.S., obeticholic acid (OCA) is a second-line therapy for patients with an inadequate response or intolerance to UDCA. Although the therapeutic effects of OCA have been described in several reports,
Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls.
, have therefore been developed to monitor disease progression.
Recently, a novel method was developed in support of the conventional Child–Pugh grade to assess liver function, called the albumin-bilirubin (ALBI) score/grade, which is calculated using only serum albumin and bilirubin values.
, the sample sizes and number of institutions were limited. In Japan, nationwide surveys on PBC have been conducted every 3 years since 1980. The survey database includes information on the background, biochemical laboratory values, histological findings at the time of diagnosis, and prognosis of approximately 8,700 patients registered to date.
The aim of the present study was to validate the ability of ALBI score/grade to estimate histological findings and disease progression in PBC using this large-scale nationwide cohort.
Patients and methods
Patients
Nationwide surveys of PBC patients been performed 16 times at intervals of approximately 3 years by the Intractable Hepato-Biliary Diseases Study Group for Research on Measures for Intractable Disease, which is supported by Health Labor Science Research Grants in Japan. A total of 8,768 subjects were registered between 1980 and 2016 among 469 institutions. This study was conducted following the principles of the 1975 Declaration of Helsinki. The protocol was reviewed and approved by the Institutional Review Board of Shinshu University School of Medicine (approval number: 4906) and the local institutional review board at each participating institution.
The diagnosis of PBC was based on criteria established by the Intractable Hepato-Biliary Diseases Study Group of Japan.
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.
. Patients who met at least 2 of the following criteria were diagnosed as having PBC: 1) biochemical evidence of chronic cholestasis; 2) positive serum AMA; and 3) histological features compatible with PBC. In this registry, center type, date of birth and sex, date of diagnosis, presence of pruritus and biochemical test findings (alkaline phosphatase [ALP], total bilirubin, and albumin) at the time of diagnosis, histological stage (Scheuer’s classification), and treatment protocol (UDCA and/or BZF) were recorded as baseline data. Pruritus status in this study was recorded as with/without, not using such semi-quantitative methods as visual analog scales or PBC-40
. Final follow-up date and outcome at that time (LT, liver-related death, and all-cause death) were noted as well. Longitudinal data on biochemical liver tests, treatment response, and histological stage were unavailable.
. Age was divided into two groups, <65 and ≥ 65 years old. Total bilirubin and albumin were categorized into normal and abnormal values, ALP was divided into low (≤ 1.67 × upper limit of normal [ULN]) and high (> 1.67 × ULN) levels, and histological stage was classified into early (1-2) and late (3-4) stages. PBC symptoms were defined as pruritus, overt jaundice, rupture of esophagogastric varices, ascites, and hepatic encephalopathy.
as follows: (log10 bilirubin × 17.1 × 0.66) + (albumin × 10 × -0.085), with bilirubin in mg/dL and albumin in g/dL. ALBI grade cut-off points were as follows: ≤ −2.60 (grade 1), > −2.60 to ≤ −1.39 (grade 2), and > -1.39 (grade 3).
Statistical analysis
Categorical variables were compared by the chi-squared test. Continuous baseline data were expressed as the median and 95% confidence interval (CI) and statistically evaluated using the Mann–Whitney U test. Receiver operating characteristic (ROC) curves were used to evaluate the prediction accuracy for histological stage. Optimal cut-off values were determined by Youden’s index. Survival without LT and survival without liver-related death or LT were analyzed using a multivariate Cox proportional hazards model. All variables included in the model were obtained at baseline. Multivariate analysis included all significant (p < 0.05) variables in the preceding univariate analysis. The Kaplan–Meier method and log-rank testing were used to estimate disease progression. A p-value of < 0.05 was considered statistically significant after Bonferroni correction for multiple testing. Statistical analyses were performed using StatFlex ver. 7.0.11 (Artech Co., Ltd., Osaka, Japan).
Results
Clinical characteristics of patients
The clinical profile of the cohort is shown in Table 1. Median age at the time of diagnosis was 57 years, with a female predominance (86%). Median follow-up period was 5.3 years (95% CI 0.2–20.1). Symptomatic patients were found in 29% of cases. We observed that 83% of patients received UDCA only, 9% received UDCA and BZF, and 8% had no treatment. Median ALBI score was -2.74 and the percentages of ALBI grades 1, 2, and 3 were 63%, 33%, and 4%, respectively. Scheuer’s stage was I for 35%, II for 23%, III for 10%, and IV for 3% of patients. During the observation period, all-cause death, liver-related death, and LT were recorded in 14%, 9%, and 1% of patients, respectively. As the only long-standing cohort of PBC in Japan, the median age of the patients was in the late 50s. Moreover, 87% of the institutions of enrolled patients were tertiary facilities, suggesting a higher presence of individuals with advanced disease than in general clinics and correspondingly higher mortality rates.
Table 1Characteristics of 8,768 PBC patients.
Characteristic
Age at diagnosis (years)
57
(49–65)
Female, n (%)
7,552 (86%)
Follow-up period (years)
5.3
(0.2–20.1)
Clinical stage (asymptomatic / symptomatic), n (%)
Diagnostic ability of ALBI score/grade for histological stage
Figure 1 presents box plots of ALBI score values according to Scheuer’s classification stage. Median ALBI score increased with Scheuer’s stage as -2.85 (stage I), -2.70 (stage II), -2.50 (stage III), and -2.03 (stage IV). We detected a significant correlation between ALBI score and disease progression defined by Scheuer’s classification (corrected p [pc] < 0.0001). Moreover, significant differences were noted for ALBI score among Scheuer’s classifications (p < 0.0001). When stratified as early stage (Scheuer’s stage I and II) or late stage (Scheuer’s stage III and IV), median late-stage ALBI score was significantly higher than early-stage ALBI score (-2.39 vs. -2.81, p < 0.0001) (Fig. S1).
Fig. 1Distribution of ALBI score by Scheuer’s classification in PBC patients. Boxes represent the interquartile range of the data. The lines across the boxes indicate the median value. P values were calculated by the Mann-Whitney U-test with Bonferroni correction. ALBI, albumin-bilirubin; PBC, primary biliary cholangitis.
The proportions of patients with different Scheuer’s classification were stratified by ALBI grade next (Fig. 2). Patients with ALBI grade 1 totaled 76% in stage I, 62% in stage II, 40% in stage III, and 22% in stage IV. The proportion of patients with ALBI grade 1 fell significantly with increasing Scheuer’s stage (p < 0.0001). When stratified as early stage or late stage, the proportions of patients were 70% and 36% for ALBI grade 1, 28% and 55% for ALBI grade 2, and 1% and 10% for ALBI grade 3, respectively (p < 0.0001) (Fig. S2).
Fig. 2Proportion of PBC patients by Scheuer’s classification stratified by ALBI grade. The proportion of patients with ALBI grade 1 was 76% for Scheuer’s stage I, 62% for stage II, 40% for stage III, and 22% for stage IV. The proportion of patients with ALBI grade 1 fell with increasing stage (p < 0.0001). P values were calculated by the chi-squared test. ALBI, albumin-bilirubin; PBC, primary biliary cholangitis.
Since ALBI score is a useful marker to assess histological stage, ROC curve analysis was performed to determine the diagnostic accuracy of ALBI score for each stage of Scheuer’s classification. The calculated area under the ROC curve (AUC), optimal cut-off value, sensitivity, specificity, positive predictive value, and negative predictive value for each stage are listed in Table S1. The AUCs for predicting of stage ≥ III (late stage) and IV (cirrhosis) were 0.726 and 0.808, respectively, for which the respective optimal cut-off values were -2.59, and -2.35.
Prediction and risk factors associated with all-cause death, liver-related death, and need for LT
As shown in Table S2, 1,340 patients experienced all-cause death or need for LT and 902 patients experienced liver-related mortality or need for LT during follow-up. Patients with liver-related mortality or need for LT were significantly younger than those with survival (p < 0.0001). The frequencies of asymptomatic and ALBI grade 1 were significantly lower for the all-cause mortality or need for LT and the liver-related mortality or need for LT groups, respectively (all p < 0.0001). The levels of ALP and total bilirubin were significantly higher in the death groups (all p < 0.0001). ALBI score was significantly worse in the mortality groups compared with the survival group (both p < 0.0001). The frequency of female was significantly lower in patients with all-cause mortality (p = 0.002), but not among those with liver-related mortality.
According to Cox proportional hazards regression analysis, all-cause mortality or need for LT and liver-related mortality or need for LT had significant associations with ≥ 65 years (hazard ratio [HR] 2.074; 95% CI 1.777–2.421; p < 0.0001 and HR 1.268; 95% CI 1.026–1.566; p = 0.028, respectively), symptomatic status (HR 2.721; 95% CI 2.347–3.154; p < 0.0001 and HR 3.735; 95% CI 3.084–4.524; p < 0.0001, respectively), ALP ≥ 1.67 × ULN (HR 1.577; 95% CI 1.357–1.834; p <0.0001 and HR 1.927; 95% CI 1.577–2.355; p < 0.0001, respectively), and ALBI grade ≥ 2 (HR 3.453; 95% CI 2.942–4.052; p < 0.0001 and HR 4.242; 95% CI 3.421–5.260; p < 0.0001, respectively) (Tables 2 and 3). Female gender was a protective factor against all-cause mortality or need for LT (HR 1.460; 95% CI 1.211–1.761; p < 0.0001), but not against liver-related mortality or need for LT.
Table 2Factors associated with all-cause mortality or LT in PBC.
Factor
Univariate
Multivariate
HR
95% CI
p-value
HR
95% CI
p-value
Age ≥ 65 years
1.780
1.577–2.013
< 0.0001
2.074
1.777–2.421
< 0.0001
Male
1.524
1.319–1.761
< 0.0001
1.460
1.211–1.761
< 0.0001
Symptomatic
4.937
4.413–5.524
< 0.0001
2.721
2.347–3.154
< 0.0001
ALP ≥ 1.67 × ULN
2.281
1.976–2.634
< 0.0001
1.577
1.357–1.834
< 0.0001
Total bilirubin ≥ 1.0 mg/dL
4.358
3.907–4.862
< 0.0001
Albumin < 3.9 g/dL
3.619
3.247–4.034
< 0.0001
ALBI score ≥ -2.518
5.127
4.587–5.731
< 0.0001
ALBI grade ≥ 2
4.633
4.131–5.195
< 0.0001
3.453
2.942–4.052
< 0.0001
The Cox proportional hazard model included age, sex, symptomatic status, ALP, and ALBI grade for calculations considering the multicollinearity of albumin, total bilirubin, and ALBI grade, whose condition number was 1.443. ALBI, albumin-bilirubin; ALP, alkaline phosphatase; CI, confidence interval; HR, hazard ratio; LT, liver transplantation; PBC, primary biliary cholangitis; ULN, upper limit of normal.
Table 3Factors associated with liver-related mortality or LT in PBC.
Factor
Univariate
Multivariate
HR
95% CI
p-value
HR
95% CI
p-value
Age ≥ 65 years
1.181
1.003–1.390
0.046
1.268
1.026–1.566
0.028
Male
1.268
1.050–1.532
< 0.0001
Symptomatic
7.485
6.470–8.660
< 0.0001
3.735
3.084–4.524
< 0.0001
ALP ≥ 1.67 × ULN
3.107
2.570–3.757
< 0.0001
1.927
1.577–2.355
< 0.0001
Total bilirubin ≥ 1.0 mg/dL
6.702
5.820–7.719
< 0.0001
Albumin < 3.9 g/dL
4.192
3.668–4.790
< 0.0001
ALBI score ≥ -2.518
7.040
6.107–8.115
< 0.0001
ALBI grade ≥ 2
5.928
5.123–6.860
< 0.0001
4.242
3.421–5.260
< 0.0001
The Cox proportional hazard model included age, sex, symptomatic status, ALP, and ALBI grade for calculations considering the multicollinearity of albumin, total bilirubin, and ALBI grade, whose condition number was 1.440.
Cumulative incidences of survival without LT and survival free of liver-related death or LT
The cumulative survival rates without LT and free of liver-related death or LT at 5 years in the ALBI grade 1, 2, and 3 groups were 97.2%, 82.4%, and 38.8%, and 98.1%, 86.0%, and 42.0%, respectively (Fig. 3). Kaplan-Meier testing by ALBI grade yielded 3 distinct curves (pc < 0.0001, log-rank test). Moreover, significant differences were found in group comparisons (ALBI grade 1 vs. grade 2, ALBI grade 1 vs. grade 3, and ALBI grade 2 vs. grade 3, all pc < 0.0001, log-rank test).
Fig. 3Cumulative survival rates of PBC patients free of all-cause death or free of liver-related death or LT according to ALBI grade. The cumulative incidences of (A) all-cause mortality or LT and (B) liver-related mortality or LT (pc < 0.0001 and pc < 0.0001, respectively, log-rank test). ALBI, albumin-bilirubin; LT, liver transplantation; PBC, primary biliary cholangitis.
Recent studies have shown not only the use of UDCA only, but also UDCA and BZF combination therapy, to improve PBC prognosis. Therefore, 2 groups consisting of patients with UDCA monotherapy and BZF addition to UDCA were created to examine whether ALBI grade could predict survival. Patients who received BZF only were excluded due to insufficient numbers. Patients with UDCA and BZF combination therapy exhibited a more favorable prognosis than those with UDCA alone (p = 0.003) ()Fig. S, which confirmed the results of Tanaka et al..
. Among the patients with UDCA monotherapy, ALBI grade 1 had significantly better survival without LT and survival free of liver-related death or LT compared with ALBI grade 2 and ALBI grade 3, respectively (both p < 0.001) (Fig. 4). We observed a not significant difference between ALBI grade 2 and 3 for all-cause mortality or LT (p = 0.1009), neither for liver-related mortality or LT (p = 0.5432). In addition, patients with ALBI grade 1 had significantly increased rates of survival without LT than those with ALBI grade 2 and ALBI grade 3 in patients with BZF addition to UDCA (both p < 0.005). A significant difference in liver-related mortality or LT was also seen between ALBI grade 1 and 3 (p < 0.0001). Lastly, the cumulative survival rates without LT and free of liver-related death or LT were assessed by log-rank testing to reveal significant differences between ALBI grade and variables including age, sex, clinical stage, and ALP level (all p < 0.05) (Fig. S4-7).
Fig. 4Cumulative survival rates of PBC patients free of all-cause death or free of liver-related death or LT according to ALBI grade and treatment. The cumulative incidences of (A) all-cause mortality or LT and (B) liver-related mortality or LT in patients treated with UDCA only. Cumulative incidences of (C) all-cause mortality or LT and (D) liver-related mortality or LT in patients treated with UDCA and BZF. p values were calculated by the log-rank test. ALBI, albumin-bilirubin; BZF, bezafibrate; LT, liver transplantation; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid.
. To our knowledge, this is the largest multicenter cohort study to date evaluating the efficacy of ALBI score/grade in Japanese patients with PBC. We identified 2 important clinical characteristics: 1) ALBI score/grade may be useful in estimating pathological stage according to Scheuer’s classification, and 2) ALBI grade may be useful in predicting the prognosis of patients with PBC.
The ALBI score has been studied in 181 biopsy-proven PBC patients to date, including only 3 patients with Scheuer’s stage IV.
Since histological findings were available for over 7,000 patients in this cohort as well as 1,184 late-stage patients, there was a sufficient number of cases to clarify the relationship between ALBI score and histopathology. Our results showed that ALBI score/grade correlated significantly with histological stage and between early and late disease stages. It is clinically important to identify histologically late stage or cirrhosis at diagnosis using non-invasive tests since fibrosis level is a key parameter for risk stratification in PBC. In this study, the diagnostic accuracy of ALBI for cirrhosis was 80.1% (Table S1). Elsewhere, the accuracy of liver stiffness measurement (LSM) by vibration-controlled transient elastography was 93.6%
, which indicated that diagnostic ability was highest for LSM. As the ALBI score had a high negative predictive value of 98.2% (Table S1), an ALBI value of -2.38 or less may enable the prognostication of patients without cirrhosis. Murillo et al. reported advanced histological fibrosis as an independent predictor of treatment failure and survival despite a biochemical response to treatment in PBC patients.
. Thus, the prompt identification of clinically relevant fibrosis at diagnosis will enable earlier consideration of treatment escalation. Since Scheuer’s classification was not designed to directly assess liver fibrosis, it was difficult to pinpoint the ability of ALBI score/grade determination of liver fibrosis. Another pathological classification by Nakanuma et al.
might be more suitable to estimate liver fibrosis, but we were unable to adopt it as most patients were enrolled before its development. Fujita et al. assessed ALBI score in 382 Japanese patients with chronic hepatitis C.
. Median ALBI scores in patients with F4 were -1.823 in their study and -2.03 in our own. Although similar, these findings may not be directly comparable due to possible differences in ALBI values for hepatitis C infection and PBC, the latter of which is a cholestatic disease.
Gennaro et al. identified that serum albumin and bilirubin levels were the top significant prognostic variables for survival in cirrhosis in a review of 118 studies.
. Accordingly, ALBI grade is calculated using those parameters. There have been several reports on the efficacy of ALBI grade to predict the clinical outcome of chronic liver disease. Hiraoka et al. witnessed a usefulness of ALBI grade for prognosis evaluation in 2,584 Japanese patients with hepatocellular carcinoma.
. In particular, ALBI score showed the highest AUC values for predicting overall survival and incidence of LT within 2 years after the start of observation in a Japanese 409-patient PBC cohort.
. The present study validated the efficacy of ALBI grade to predict survival in PBC patients using a large-scale nationwide database with a median follow-up period of over 5 years. Another strength of this investigation was a relatively high number of progressed stage cases, including 868 patients at Scheuer’s stage III and 282 patients at stage IV, along with the outcomes of all-cause death in 1,227 patients (14%), liver-related death in 789 patients (9%), and LT in 113 patients (1%). Supported by a larger cohort power, our results showed that all-cause mortality or need for LT and liver-related mortality or need for LT had significant associations with ALBI grade. While patients with ALBI grade 3 tended to exhibit a more rapid progression to death, those with ALBI grade 1 showed a lower mortality risk. Moreover, ALBI grade remained a good prediction marker when patients were stratified by age, symptomatic status, or ALP level, as well as in patients with UDCA monotherapy or the addition of BZF to UDCA.
This study had several limitations mainly due to its retrospective nature. First, there was a lack of several biochemical data to calculate the FIB-4 index and APRI. Second, LSM is reportedly very high in its ability to diagnose cirrhosis,
but had not yet been developed at the start of the present study. We have already begun an investigation of LSM and PBC pathogenesis in another Japanese cohort. Third, although risk scores that take into account treatment responsiveness, such as the UK-PBC risk score,
The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis.
, are often used to predict the prognosis of patients with PBC, our national survey database did not contain laboratory data after the start of treatment, and so we were unable to estimate prognosis based on treatment responsiveness. Therefore, it is difficult to make definitive conclusions on the clinical usefulness of the ALBI score on treatment effect. On the other hand, if prognosis predicted by ALBI score before treatment is judged to be poor, a second line can be added from treatment onset to provide combined therapy. This is a future issue to consider as it is possible to improve long-term prognosis by modifying the initial therapeutic regimen based on pre-treatment ALBI results. Lastly, many reported symptoms in this study were extracted as subjective descriptions from the medical records of each facility, without specific judgement criteria.
In conclusion, this large nationwide study of patients with PBC showed that baseline measurements of ALBI score/grade might serve as a simple non-invasive predictor of histology and prognosis in PBC.
Acknowledgments
The authors thank Trevor Ralph for his editorial assistance.
Appendix A. Supplementary data
The following is/are the supplementary data to this article:
Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls.
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.
The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis.
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