The main cholestatic liver diseases comprise primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis. Despite being classified as rare diseases, these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while the viral hepatitis burden is declining. Cholestatic liver diseases now rank among the 3 most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims to provide a comprehensive overview of the current literature on the epidemiology, health-related quality of life, and economic burden of primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis.

Primary biliary cholangitis (PBC) with early cholestasis and extensive bile duct loss but no significant fibrosis or cirrhosis is rare and underrecognized. We aimed to clarify the clinicopathology features and prognosis of these variants of patients with early-stage PBC with ductopenia. From January 2009 to January 2023, we retrospectively collected the laboratory and pathologic data of patients with early-stage PBC and recorded their liver-related events with a median follow-up of 4.5 years. Finally, a total of 141 patients with PBC in the early stage were included and divided into 2 groups: one with ductopenia (n = 36) and the other without ductopenia (n = 105). The median age of the participants was 50 years, with 90.8% being female. The ductopenia group exhibited significantly elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, total bile acid, and total cholesterol (CHOL). Conversely, they showed a reduced biochemical response to ursodeoxycholic acid according to the Paris II, Barcelona, and Rotterdam criteria. A relatively poorer prognosis was observed in patients with early-stage PBC with ductopenia but with no statistical difference (11.8% vs 4.9%, P = 0.352). Baseline total CHOL levels were identified as an independent factor for the presence of ductopenia in early-stage PBC (odds ratio = 1.771, 95% CI: 1.264-2.479, P = 0.001). In conclusion, ductopenia was a significant risk factor for worse biochemical profiles and poor treatment response in patients with early-stage PBC. High levels of total CHOL at baseline are associated with the presence of ductopenia in early-stage PBC.

The study collected liver tissue samples from PBC patients and healthy controls and performed transcriptomic analysis of the cells in the samples using single-cell RNA sequencing. The expression characteristics of SHISA5 in PBC were revealed by comparing the difference of SHISA5 protein in the two groups of samples. The structure of SHISA5 protein was predicted and its possible biological function was analysed by bioinformatics method. The results showed that the expression of SHISA5 protein in liver tissue of PBC patients was significantly higher than that of healthy controls. Single-cell RNA sequencing data showed that SHISA5 was mainly expressed in hepatocytes and bile duct cells, and its expression level was positively correlated with the disease activity of PBC. Through structural prediction, we found that the SHISA5 protein molecule has a unique transmembrane domain and may be involved in cell signaling and intercellular interactions. Further functional analysis revealed that SHISA5 may participate in the pathological process of PBC by regulating the differentiation and function of bile duct cells.

Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis (PBC), but 20-40% of patients do not respond well to UDCA. We aimed to develop and validate a prognostic model for the early prediction of patients who nonresponse to UDCA. This retrospective analysis was conducted among patients with primary biliary cholangitis(N = 257) to develop a predictive model for early-stage nonresponse to ursodeoxycholic acid (UDCA) therapy. The model's reliability was subsequently confirmed through external validation in an independent cohort(N = 71). Multivariate cox regression analysis was used to evaluate variables that were significant in the univariate analysis. Total cholesterol, alkaline phosphatase (ALP), and neutrophil-to-lymphocyte ratio (NLR) were the three independent risk factors associated with early biochemical nonresponse to UDCA treatment. Based on these factors, we established a predictive model that possessed good discriminative ability, as reflected by an AUC of 0.862(95%CI = 0.813-0.911). The ROC curve of the external validation set calculated the AUC of 0.916(95%CI:0.823-1.000). In summary, we developed an early predictive model that could identify potential nonresponse factors to UDCA at baseline, which could facilitate risk evaluation and stratification for PBC patients. The NLR and total cholesterol provided a supplementary means for effectively managing PBC patients.

Primary biliary cholangitis (PBC) is an autoimmune liver disease. During the diagnostic process, the patient's autoimmune antibodies are routinely examined. Approximately 20% of PBC patients have positive anti-centromere antibody (ACA). We evaluated the clinical characteristics of ACA-positive and ACA-negative PBC patients to explain the differences in disease progression between these two groups. Retrospective data from 961 PBC patients at Beijing Youan Hospital from 2010 to 2019 were gathered and separated into two groups based on ACA positivity. We collected and evaluated clinical laboratory indices, gastroscopy findings, and liver function assessments. In addition, 60 liver biopsies were available for comparison between the 2 groups. Pathologists staged the histological findings using the Ludwig staging criteria and Nakanuma staging and grading. Immunohistochemical staining was also performed on liver biopsies to examine the expression of cytokeratin 7 (CK7) in the tissue. A synthesis of clinical indicators in the large cohort showed that alanine transaminase, aspartate aminotransferase, total bilirubin, IgG, white blood cell, and platelet were significantly lower in the ACA-positive group, indicating that the overall status of liver injury was more moderate in the ACA-positive group. Additionally, ACA-positive patients in the non-cirrhotic group were more likely to present with gastroesophageal varices related to portal hypertension. Finally, analysis of pathologic findings showed that parameters were mostly comparable in the two groups, but CK7 differed and was more significantly lower in the ACA-positive group in albumin-bilirubin grade 2 and 3 patients. In summary, we characterized and compared the clinical features of ACA-positive and ACA-negative PBC patients, corroborating previous studies on the relationship between ACA positivity and portal hypertension cross-sectionally. It suggested that gastroesophageal varices might happen in the earlier course of PBC natural progression in the ACA-positive group.

Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC.

A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation.

During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival.

Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC.

One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

CXCR6+CD8+T cells have been implicated in the pathogenesis of various liver and autoimmune diseases. However, their involvement in primary biliary cholangitis (PBC) has not been elucidated.

We used immunohistochemistry and flow cytometry to quantify CXCR6+CD8+T cells in hepatic tissue and peripheral blood samples obtained from CXCR6+CD8+T cells obtained from PBC patients. Then, we performed comprehensive statistical analyses to access the correlation between the abundance of these cells and clinical as well as pathological data across different stages of PBC.

Our research revealed that CXCR6+ cell frequencies in CD3+CD8+T cells from PBC patients significantly exceeded that of healthy controls (HCs) (2.24 vs. 0.61%, p < 0.01). A similar pattern emerged for hepatic CXCR6+CD8+T cell counts, which were notably higher in the PBC cohort compared to HCs. Our cohort consisted of 118 PBC patients, categorized into 62 early-stage (E-PBC) and 56 late-stage (L-PBC) cases. Notably, significant disparities existed between these groups in terms of liver enzyme and lipid profile levels (p < 0.05), with no notable differences observed in gender, age, blood counts, cholesterol levels, or autoantibodies (p > 0.05). Intriguingly, the quantity of hepatic CXCR6+CD8+T cells per high power field (HPF) was significantly elevated in both E-PBC and L-PBC patients as opposed to normal liver samples, indicating a substantial increase in these cells across all stages of PBC (p = 0.000). Spearman's rank correlation analysis showed a positive correlation between CXCR6+CD8+T cell counts and serum levels of Alkaline Phosphatase (AKP) and Gamma-Glutamyl Transferase (GGT), ANA, IgG and IgM, while revealing a negligible correlation with Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST). Subsequent findings indicated significant variances in CXCR6+ cell numbers not only among different PBC stages but also across various degrees of inflammation and fibrosis (p ≤ 0.007). In a follow-up study post-Ursodeoxycholic Acid (UDCA) treatment, stark differences were identified in biochemical and immunohistochemical profiles between responder (31 patients) and non-responder (33 patients) groups (p < 0.05). A Wilcoxon rank-sum test further demonstrated a significant difference in the level of hepatic CXCR6+CD8+T cells between these two response groups (p = 0.002).

CXCR6+CD8+T cells play a vital role in the pathogenesis of PBC, exhibiting correlations with the extent of inflammation, staging of liver fibrosis, and response to pharmacological interventions in PBC patients.

Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.

Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.

To explore the feasibility of pretreatment nonenhanced magnetic resonance imaging (MRI) in predicting insufficient biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cholangitis (PBC).

From January 2009 to April 2022, consecutive PBC patients who were treated with UDCA and underwent nonenhanced MRI within 30 days before treatment were retrospectively enrolled. All MR images were independently evaluated by two blinded radiologists. Uni- and multivariable logistic regression analyses were performed to develop a predictive model for 12-month insufficient biochemical response. Model performances were evaluated by computing the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity.

A total of 74 patients (50.6 ± 11.9 years; 62 females) were included. Three pretreatment MRI features, including hepatomegaly (odds ratio [OR]: 4.580; p = 0.011), periportal hyperintensity on T2-weighted imaging (T2WI) (OR: 4.795, p = 0.008), and narrowing of the bile ducts (OR: 3.491; p = 0.027) were associated with 12-month insufficient biochemical response in the multivariable analysis. A predictive model based on the above indicators had an AUC of 0.781, sensitivity of 85.4%, and specificity of 61.5% for predicting insufficient biochemical response.

A noninvasive model based on three pretreatment MRI features could accurately predict 12-month insufficient biochemical response to UDCA in patients with PBC. Early identification of PBC patients at increased risk for insufficient response can facilitate the timely initiation of additional treatment.

A noninvasive predictive model constructed by incorporating three pretreatment MRI features may help identify patients with primary biliary cholangitis at high risk of insufficient biochemical response to ursodeoxycholic acid and facilitate the timely initiation of additional treatment.

• Noninvasive imaging features based on nonenhanced pretreatment MRI may predict an insufficient biochemical response to UDCA in PBC patients. • A combined model based on three MRI features (hepatomegaly, periportal hyperintensity on T2-weighted imaging, and narrowing of the bile ducts) further improved the predictive efficacy for an insufficient biochemical response to UDCA in PBC patients, with high sensitivity and specificity. • The nomogram of the combined model showed good calibration and predictive efficacy for an insufficient biochemical response to UDCA in PBC patients. In particular, the calibration curve visualised the clinical applicability of the prediction model.

Mildly elevated levels of transaminase and/or immunoglobulin G (IgG) are common in patients with primary biliary cholangitis (PBC). It is still unclear whether adding immunosuppressive therapy to ursodeoxycholic acid (UDCA) benefits those patients who are not fulfilling the diagnostic criteria of PBC with autoimmune hepatitis (AIH) features.

To assess the efficacy of adding immunosuppressive therapy to UDCA for patients with PBC and autoimmune phenomena but not fulfilling the diagnostic criteria of PBC with AIH features.

This is a retrospective-prospective cohort study in a tertiary medical center.

Patients with PBC and autoimmune phenomena were defined by the elevation of IgG and/or transaminase but did not fulfill the diagnostic criteria of PBC with AIH features. We grouped these patients based on with and without add-on immunosuppressive therapy and balanced their baseline characteristics using inverse probability treatment weighting (IPTW).

A total of 652 patients with PBC and autoimmune phenomena were included, with a median follow-up of 4.08 years. After IPTW, the pseudo sample size in the add-on therapy and monotherapy groups was 558 and 655, respectively. After 1 year of observation, patients in the add-on therapy group had a higher biochemical response rate (normalization of transaminase and IgG levels) (49% versus 17%, p < 0.001). Furthermore, add-on therapy improved the transplant-free survival in the subgroup of patients with PBC and transaminase ⩾3 × upper limit of normal (ULN) or IgG ⩾1.3 × ULN (p = 0.033).

Add-on immunosuppressive therapy may improve the normalization rates of transaminase and IgG levels in all patients with PBC and mildly elevated transaminase and IgG levels and the long-term outcomes in the subgroup of the patients with transaminase ⩾3 × ULN or IgG ⩾1.3 × ULN.

In some patients especially those AMA negative, the diagnosis may be a challenge requiring liver biopsy. This study determined whether autotaxin, a secreted lysophospholipase D encoded by the exonucleotide pyrophosphatase phosphodiesterase 2 gene, can be used as a serum biomarker for primary biliary cholangitis.

Plasma samples were collected from 103 patients with PBC and 74 healthy controls. autotaxin levels were determined by Enzyme-linked immunosorbent assay, and its predictive value for diagnosing primary biliary cholangitis was analysed. The relationship between autotaxin and the clinical data was also evaluated.

Autotaxin levels in patients with primary biliary cholangitis were significantly higher than those in healthy control (median: 60.7 ng/ml vs. 32.6 ng/ml, P < 0.001). The cut-off value of autotaxin in patients with primary biliary cholangitis was 38.5 ng/ml, and the positivity rate was 33.9 %, calculated twice. The sensitivity, specificity, positive predictive value, and negative predictive value were 54.3 %, 93.1 %, 84.4 %, and 74.8 %, respectively, and the area under the curve was 0.73. Autotaxin level positively correlated with immunoglobulin M level (r = -0.22, P < 0.05) and Ludwig's classification (r = 0.76, P < 0.01) in patients with primary biliary cholangitis. The positivity rate of autotaxin (50.0 %) was higher than that of anti-sp100 (16.7 %) and anti-gp210 (11.1 %) antibodies in anti-mitochondrial antibody -negative patients with primary biliary cholangitis.

Autotaxin may be an effective noninvasive biomarker used in diagnosis, prognosis of primary biliary cholangitis, particularly in anti-mitochondrial antibody -negative patients.

The aim of this study was to evaluate the diagnostic usefulness of two non-invasive, validated, and patented markers of liver fibrosis, the Hepascore and FibroTest, in patients with primary sclerosing cholangitis (PSC). The study group consisted of 74 PSC patients and 38 healthy subjects. All patients had a liver biopsy. The Hepascore and FibroTest were calculated using specific algorithms. The ANOVA rank Kruskal-Wallis test revealed differences in the Hepascore and FibroTest between patients divided according to histological stage (p < 0.001 for both comparisons). The Hepascore and FibroTest had significantly higher results in patients with significant fibrosis (F ≥ 2) in comparison to those with no significant fibrosis (F1) (p < 0.001 for both tests) and higher values in patients with cirrhosis (F4) when compared to those without cirrhosis (F1-F3) (p < 0.001 for both comparisons). The Hepascore test showed a diagnostic sensitivity of 96.8%, a specificity of 100% for fibrosis (at cut-off 0.52) and a diagnostic sensitivity of 95.2%, and a specificity also of 100% for cirrhosis (at 0.80). The FibroTest in point 0.51 for the diagnosis of fibrosis obtained the following values: 58.6%, 90%, 89.5%, and 60%, respectively, and in point 0.73 for the diagnosis of cirrhosis: 42.9%, 100%, 100%, and 45.5, respectively. The Hepascore test reached an excellent diagnostic power in identifying both fibrosis and cirrhosis (AUC = 1.0). The FibroTest and Hepascore are highly valuable for the evaluation of the severity of liver fibrosis and cirrhosis in PSC patients and can be used as a primary screening method, allowing for a significant reduction in the need for liver biopsy. Both markers have the required sensitivity and specificity to detect liver fibrosis and cirrhosis and can be equally used in clinical practice, although the Hepascore seems to be a better test because it is more specific.

Autoimmune liver diseases (AILDs) are complex diseases with unknown causes and immune-mediated pathophysiology. In primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) disease modifying drugs are available which improve patient quality and quantity of life. In primary sclerosing cholangitis (PSC) no medical therapy is available and the only accepted treatment is liver transplantation (LT). PBC, PSC and AIH possess features that describe the archetype of patients within each disorder. On the other hand, the classical disorders are not homogeneous, and patients within each diagnosis may present with a range of clinical, biochemical, serological, and histological findings. Singularly, they are considered rare diseases, but together, they account for approximately 20% of LTs in Europe and USA. Management of these patients is complex, as AILDs are relatively uncommon in clinical practice with challenges in developing expertise, disease presentation can be sneaky, clinical phenotypes and disease course are heterogeneous. Prognostic models are key tools for clinicians to assess patients' risk and to provide personalized care to patients. Aim of this review is to discuss challenges of the management of AILDs and how the available prognostic models can help. We will discuss the prognostic models developed in AILDs, with a special focus on the prognostic models that can support the clinical management of patients with AILDs: in PBC models based on ursodeoxycholic acid (UDCA) response and markers of liver fibrosis; in PSC several markers including biochemistry, disease stage and radiological semiquantitative markers; and finally in AIH, markers of disease stage and disease activity.

Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively.

to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC.

Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan-Meier plots with inverse probability of treatment weighting (IPTW).

A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.75, P=0.015; and HR: 11.66, 95% CI: 5.02-27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort.

Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population.

The purpose of this article is to review fibrosis staging systems, reversibility of fibrosis, histologic pattern of fibrosis regression, and recently proposed fibrosis staging systems that address the more nuanced fibrosis information needed clinically for management purposes. In most chronic liver diseases, the extent of liver fibrosis often drives patient outcomes. The evolving knowledge of the reversibility of fibrosis and the observed patterns of fibrosis seen in the setting of remodeling/regression can create staging difficulties, and problems in applying the existing "conventional" staging systems. The heterogeneity of liver fibrosis in congestive liver disease is an emerging problem in biopsies from patients with congestive heart failure. The fibrosis staging in these biopsies is of significant import as it is used to determine suitability of some congestive heart disease patients for heart transplantation alone, dual heart and liver transplantation, or be denied transplantation. Pathologist should be aware of these newly recognized concepts, the recently proposed staging systems that attempt to incorporate these new fibrosis patterns and be able to apply the knowledge in daily practice.

The clinicopathological features and long-term outcomes of patients with vanishing bile duct syndrome (VBDS) have yet to be elucidated. The study aims to investigate these features and identify factors associated with poor prognosis.

This multicenter retrospective study recruited patients with liver biopsy-proven VBDS who were followed up at five hospitals in northern China from January 2003 to April 2022. Clinical and pathological data at time of biopsy were reviewed. Clinical outcomes including cirrhosis, decompensation events, liver transplantation (LT), and liver-related death were recorded. Cox regression analysis was used to identify the risk factors associated with poor outcomes.

A total of 183 patients were included. The median age was 47 years, with 77.6% being women. During a median follow-up of 4.8 years, 88 patients developed compensated or decompensated cirrhosis, 27 died, and 15 received LT. Multivariate Cox regression analysis showed that hepatocellular cholestasis (HR 2.953, 95% CI: 1.437-6.069), foam cells (HR 2.349, 95% CI: 1.092-5.053), and advanced fibrosis (HR 2.524, 95% CI: 1.313-4.851) were independent predictors of LT or liver-related deaths. A nomogram formulated with the above factors showed good consistency with a concordance index of 0.746 (95% CI: 0.706-0.785).

Nearly half of VBDS patients studied progressed to end-stage liver disease and 23% of them had LT or liver-related death within two years of diagnosis. Hepatocellular cholestasis, foam cells and advanced fibrosis rather than the degree of bile duct loss or underlying etiologies were independently associated with poor prognosis in VBDS patients.

Primary biliary cholangitis (PBC) is a rare chronic autoimmune-mediated cholestatic liver disease involving medium and small bile ducts that can lead to liver fibrosis and cirrhosis. To date, the pathogenesis of PBC remains elusive, and there is currently no curative medical treatment. Computed tomography (CT) and magnetic resonance (MR) imaging, as common technical tools that allow non-invasive monitoring of liver tissue in vivo, play crucial roles in the diagnosis, staging, and prognosis prediction in PBC by enabling assessment of abnormalities in liver morphology and parenchyma, irregular configuration of bile ducts, lymphadenopathy, portal hypertension, and complications of cirrhosis. Moreover, CT and MRI can be used to monitor the disease progression after treatment of PBC (e.g. the onset of cirrhotic decompensation or HCC) to guide the clinical decisions for liver transplantation. With the optimization of imaging technology, magnetic resonance elastography (MRE) offers additional information on liver stiffness, allows for the identification of early cirrhosis in PBC and provides a basis for predicting prognosis. Gadoxetic acid-enhanced MRI enables the assessment of liver function in patients with PBC. The purpose of this review is to detail and illustrate the definition, pathological basis, and clinical importance of CT and MRI features of PBC to help radiologists and clinicians enhance their understanding of PBC.Critical Relevance StatementCharacteristic CT and MR imaging manifestations of primary biliary cholangitis may reflect the course of the disease and provide information associated with histological grading and altered cellular function.Key points• Imaging has become highly useful for differentiating PBC from other diseases.• Key pathological alterations of PBC can be captured by CT and MRI.• Characteristic manifestations provide information associated with histological grade and cellular function.• Despite this, the CT or MRI features of PBC are not specific.

Primary biliary cholangitis (PBC) has been long associated with impairment of various aspects of health-related quality of life (HRQoL) with substantial differences among populations. This study evaluated for the first-time the HRQoL in Greek PBC patients in conjunction with clinical and laboratory parameters of patients.

We analyzed prospectively collected data regarding the HRQoL by using the PBC-40 and SF-36 questionnaires in 374 Greek PBC patients and 131 age- and sex-matched non-PBC controls.

The PBC-40 questionnaire is a reliable tool for HRQoL assessment in Greek PBC patients (Cronbach's α > 0.7 for all domains). Implementation of PBC-40 and SF-36 demonstrated significant impairment of HRQoL in Greek PBC patients compared to controls (P < 0.001 for all comparisons). Emotional dysfunction, social impairment, and fatigue (100%, 80.5% and 78%, respectively) were amongst those with the highest, while cognitive dysfunction (32%) with the least impact on quality of life. Fatigue was associated with female sex (P = 0.02), longer disease duration (P = 0.01), presence of cirrhosis (P = 0.02) and positivity for PBC-specific ANA (P < 0.05), while social dysfunction with increased age (P < 0.001), longer disease duration (P < 0.001) and presence of cirrhosis (P = 0.004). Living in urban areas was linked to impaired social function (P = 0.04), cognition (P = 0.02), fatigue (P = 0.04) and increased total PBC-40 score (P = 0.01).

Implementation of PBC-40 and SF-36 revealed impaired HRQoL in Greek PBC patients with fatigue, social and emotional dysfunction exerting the highest impact. However, total, and individual PBC-40 scores were lower than that reported in studies from Northern/Central Europe and Canada. Deranged HRQoL was associated with severity of liver disease and presence of PBC-specific ANA.

Liver fibrosis staging has many challenges, including the large number of proposed staging systems, the heterogeneity of the histopathologic changes of many primary liver diseases, and the potential for slight differences in histologic interpretation to significantly affect clinical management. This review focuses first on fibrosis regression. Following this, each of the major categories of liver disease is discussed in regard to (1) appropriate fibrosis staging systems, (2) emerging concepts, (3) current clinical indications for liver biopsy, (4) clinical decisions determined by fibrosis stage, and (5) histologic challenges and pitfalls related to staging.

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease with a heterogeneous presentation, symptomatology, disease progression, and response to therapy. The current risk stratification assessment, aimed at identifying patients with a higher risk of disease progression, encompasses an in-depth analysis of demographic data, clinical and laboratory findings, antibody profiles, and the evaluation of liver fibrosis using both invasive and noninvasive techniques. Treatment response scores after one year of therapy remain to date a major factor influencing the prognosis of PBC patients. While the initial therapeutic approach with ursodeoxycholic acid (UDCA) is universally applied, new second-line treatment options have recently emerged, with many others under investigation. Consequently, the prevailing one-size-fits-all approach is poised to be supplanted by tailored strategies, ensuring high-risk patients receive the most appropriate treatment regimen from diagnosis. This will require the development of a risk prediction model to assess, at the time of diagnosis, the course, outcome, and response to first and additional treatments of PBC patients. This manuscript provides a comprehensive overview of the current and emerging tools used for risk stratification in PBC and speculates on how these developments might shape the disease landscape in the near future.

Primary sclerosing cholangitis (PSC) is a chronic and progressive immune-mediated cholangiopathy causing biliary tree inflammation and scarring, leading to liver cirrhosis and end-stage liver disease. Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases. Despite the rising incidence of PSC, there is no proven medical therapy that can alter the natural history of the disease. While liver transplantation (LT) is the most effective approach for managing advanced liver disease caused by PSC, post-transplantation recurrence of PSC remains a challenge. Therefore, ongoing research aims to develop better therapies for PSC, and continued efforts are necessary to improve outcomes for patients with PSC. This article provides an overview of PSC's pathogenesis, clinical presentation, and management options, including LT trends and future aspects. It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC. Additionally, the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed. Ongoing research into PSC's pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.

Osteoporosis is an extrahepatic complication of primary biliary cholangitis (PBC) that increases the risk of fractures and mortality. However, Epidemiological studies of osteoporosis in patients with PBC in China and the Asia-Pacific region is lack.

To assess the prevalence and clinical characteristics of osteoporosis in Chinese patients with PBC.

This retrospective analysis included consecutive patients with PBC from a tertiary care center in China who underwent bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry between January 2013 and December 2021. We defined subjects with T-scores ≤ -2.5 in any sites (L1 to L4, femoral neck, or total hip) as having osteoporosis. Demographic, serological, clinical, and histological data were collected. Independent risk factors for osteoporosis were identified by multivariate logistic regression analysis.

A total of 268 patients with PBC [236 women (88.1%); mean age, 56.7 ± 10.6 years; 163 liver biopsies (60.8%)] were included. The overall prevalence of osteoporosis in patients with PBC was 45.5% (122/268), with the prevalence of osteoporosis in women and men being 47.0% and 34.4%, respectively. The prevalence of osteoporosis in postmenopausal women was significantly higher than that in premenopausal women (56.3% vs 21.0%, P < 0.001). Osteoporosis in patients with PBC is associated with age, fatigue, menopausal status, previous steroid therapy, body mass index (BMI), splenomegaly, gastroesophageal varices, ascites, Mayo risk score, histological stage, alanine aminotransferase, albumin, bilirubin, platelet and prothrombin activity. Multivariate regression analysis identified that older age, lower BMI, previous steroid therapy, higher Mayo risk score, and advanced histological stage as the main independent risk factors for osteoporosis in PBC.

Osteoporosis is very common in Chinese patients with PBC, allowing for prior screening of BMD in those PBC patients with older age, lower BMI, previous steroid therapy and advanced liver disease.

The expression of the receptor tyrosine kinase Axl and its cleavage product soluble Axl (sAxl) is increased in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this multicenter study, we evaluated the diagnostic value of Gas6, the high-affinity ligand of Axl, in patients with chronic liver disease. Levels of sAxl and Gas6, and their albumin (alb) ratios were analyzed in serum samples of patients with biopsy-proven liver fibrosis, end-stage liver disease, HCC, and healthy controls, and were compared to Fibrosis-4 (FIB-4), enhanced liver fibrosis (ELF™) test, Child-Pugh score (CPS), model of end-stage liver disease (MELD) score, hepatic venous pressure gradient, and α-fetoprotein, respectively. A total of 1111 patients (median age 57.8 y, 67.3% male) was analyzed. Gas6/alb showed high diagnostic accuracy for the detection of significant (≥F2: AUC 0.805) to advanced fibrosis (≥F3: AUC 0.818), and was superior to Fib-4 for the detection of cirrhosis (F4: AUC 0.897 vs. 0.878). In addition, Gas6/alb was highly predictive of liver disease severity (Odds ratios for CPS B/C, MELD ≥ 15, and clinically significant portal hypertension (CSPH) were 16.534, 10.258, and 12.115), and was associated with transplant-free survival (Hazard ratio 1.031). Although Gas6 and Gas6/alb showed high diagnostic accuracy for the detection of HCC in comparison to chronic liver disease patients without cirrhosis (AUC 0.852, 0.868), they failed to discriminate between HCC in cirrhosis versus cirrhosis only. In conclusion, Gas6/alb shows a high accuracy to detect significant to advanced fibrosis and cirrhosis, and predicts severity of liver disease including CSPH.

Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC.

The Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer.

Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p≤0.001), smoking (55% vs. 12.3%, p≤0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p= <0.001), AMA positivity (96.6% vs 80.1%, p≤0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk.

The prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC.

In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology published a consensus on primary biliary cholangitis (PBC). In the past years, numerous clinical studies have been published in the field of PBC. To guide the clinical diagnosis and management of PBC patients, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulate the current guidelines.

The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels.

We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation.

We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51-70)] and 47 patients with incident PBC [77% women, median age 60 y (49-67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages.

In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.

Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease leading to biliary fibrosis and cirrhosis. Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC.

Adults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100 mg once daily or placebo for up to 96 weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100 mg daily for up to 96 weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint-chosen in conjunction with guidance from the U.S. Food and Drug Administration-is the proportion of patients with ≥ 1-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor.

The phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC.

ClinicalTrials.gov NCT03890120; registered 26/03/2019.

This review focuses on recent developments of histopathology in the most common biliary disorders affecting adults. The reader is referred to other sources for the specialized topics on paediatric populations and post liver transplantation.

Fibrosis stage at diagnosis is an independent predictor of liver transplant-free survival in patients with primary biliary cholangitis. Immunohistochemistry might have an important role in predicting response to treatment. New histological scoring systems with excellent correlation with long-term clinical outcomes are being developed in primary sclerosing cholangitis (PSC). Quantification of fibrosis with collagen proportionate area can improve risk stratification and could be particularly useful to assess treatment response in PSC.Gene sequencing on cytology and intrabiliary biopsy may improve risk stratification for cholangiocarcinoma. Genetic variants of ATP8B1, ABCB11 and ABCB4 are relatively common in adults with cholestatic liver disease. New causes of cholestatic liver injury have recently been described.

Histology is often not necessary for the diagnosis of biliary disease, but can provide important information that may assist the clinician in patients' management. Histopathology remains crucial to confirm a diagnosis of cholangiocarcinoma, and to identify the pattern of biliary injury in immune-mediated cholangiopathies and rarer pathological entities.

Non-necrotizing granulomatous inflammation is a rare but easily recognized histopathological finding in skeletal muscle biopsy. A limited number of diseases are known to be associated with non-necrotizing granulomatous myopathy. Once identified, a careful evaluation for evidence of extramuscular granulomatosis and other signs suggestive of sarcoidosis is warranted as about half of the patients have sarcoid myopathy. In addition, the presence of granulomatous myopathy should trigger a search for clinical and pathological clues of inclusion body myositis (IBM), which accounts for most of the remaining patients and can coexist with sarcoidosis. Recognizing the features of IBM in patients with granulomatous myopathy can potentially spare the patients from unnecessary exposure to immunosuppressive therapies. In patients whose granulomatous myopathy remain unexplained, further investigations should aim at identifying myasthenia gravis and other autoimmune disorders, especially those known to cause granulomatous inflammation in other organs. Laboratory investigations should include acetylcholine receptor, antimitochondrial, antineutrophil cytoplasmic, thyroglobulin, and thyroid peroxidase autoantibodies. In the appropriate clinical context, exposure to immune checkpoint inhibitors and chronic graft-vs-host disease can be causes of granulomatous myopathy. In cases of unexplained granulomatous myopathy, natural killer/T-cell lymphoma should be considered and careful histopathological examination for atypical cells and appropriate immunostaining is crucial. Identifying the etiology of granulomatous myopathy in each patient can guide appropriate treatment.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that eventually progresses to cirrhosis and hepatocellular carcinoma (HCC) in the absence of proper treatment. However, Gene expression and molecular mechanisms involved in the pathogenesis of PBC have not been completely elucidated. Methods: Microarray expression profiling dataset GSE61260 was downloaded from the Gene Expression Omnibus (GEO) database. Data were normalized to screen differentially expressed genes (DEGs) using the limma package in R. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed. A protein-protein interaction (PPI) network was constructed to identify hub genes and an integrative regulatory network of transcriptional factor-DEG-microRNA was established. Gene Set Enrichment Analysis (GSEA) was used to analyze differences in biological states for groups with different expressions of aldo-keto reductase family 1 member B10 (AKR1B10). Immunohistochemistry (IHC) analysis was performed to validate the expression of hepatic AKR1B10 in patients with PBC. The association of hepatic AKR1B10 levels with clinical parameters was evaluated using one-way analysis of variance (ANOVA) and Pearson's correlation analysis. Results: This study identified 22 upregulated and 12 downregulated DEGs between patients with PBC and healthy controls. GO and KEGG analysis revealed that DEGs were mainly enriched in immune reactions. AKR1B10 was identified as a key gene and was further analyzed by screening out hub genes from the PPI network. GSEA analysis indicated that high expression of AKR1B10 might promote PBC to develop into HCC. Immunohistochemistry results verified the increased expression of hepatic AKR1B10 in patients with PBC and demonstrated its positive correlation with the severity of PBC. Conclusion: AKR1B10 was identified as a hub gene in PBC by integrated bioinformatics analysis and clinical validation. The increase of AKR1B10 expression in patients with PBC was associated with disease severity and might promote the progression of PBC to HCC.

Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune liver disease that can progress to end-stage liver disease and its complications. A previous expert review panel collaborated on a consensus document for gastroenterologists and other healthcare professionals regarding the care of patients with PBC. Subsequently, there have been several recent important developments in the diagnosis, treatment, and monitoring of patients with PBC. These include updates to prognostic models on risk stratification, new noninvasive tools for staging of disease, updates to the appropriate use of and long-term treatment results with obeticholic acid as a second-line treatment, the emerging therapeutic role of fibrates, and the advancement of investigational agents for managing PBC. In this updated expert consensus document, we provide updates on staging, the use of noninvasive prognostic tools, and a treatment algorithm to provide evidence-based and practical tools for clinicians who manage PBC, with the ultimate goal to improve the long-term outcomes for patients with this chronic liver disease.

Response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has been traditionally assessed 1 to 2 years after treatment initiation. With the development of new drugs, some patients may benefit from an earlier introduction of second-line therapies.

This study aims to identify whether well-validated response criteria could correctly identify individuals likely to benefit from add-on second-line therapy at 6 months.

Analysis of a multicenter retrospective cohort which included only patients with clear-cut PBC.

206 patients with PBC (96.6% women; mean age 54 ± 12 years) were included. Kappa concordance was substantial for Toronto (0.67), Rotterdam (0.65), Paris 1 (0.63) and 2 (0.63) criteria at 6 and 12 months, whereas Barcelona (0.47) and POISE trial (0.59) criteria exhibited moderate agreement. Non-response rates to UDCA was not statistically different when assessed either at 6 or 12 months using Toronto, Rotterdam or Paris 2 criteria. Those differences were even smaller or absent in those subjects with advanced PBC. Mean baseline alkaline phosphatase was 2.73 ± 1.95 times the upper limit of normal (× ULN) among responders versus 5.05 ± 3.08 × ULN in non-responders (p < 0.001).

After 6 months of treatment with UDCA, the absence of response by different criteria could properly identify patients who could benefit from early addition of second-line therapies, especially in patients with advanced disease or high baseline liver enzymes levels.

A variety of autoantibodies have been detected in primary biliary cholangitis (PBC), while the presence of autoantibody clusters and their clinical significance have not been fully understood. We aimed at defining autoantibody clusters and to better understand the clinical features and prognosis of PBC patients based on autoantibody clusters under real-world conditions.

We retrospectively analyzed 788 inpatients with PBC evaluated between October 2008 and July 2019, and included 537 patients. Nineteen autoantibodies which were measured routinely were investigated for cluster analysis. Two-step clustering, Kaplan-Meier survival, and Cox regression analyses were used.

Five clusters were defined. A cluster of antinuclear antibodies (ANA) and anti-gp210 positive patients were identified with a high rate of cirrhosis at baseline and low survival rate; a cluster of ANA, anti-centromere antibodies (ACA) and/or anti-CENP-B female dominant patients with older disease onset, low level of platelet count at baseline, high rate of hepatic decompensation, and low survival rate was also characterized; and another cluster of anti-mitochondrial antibodies (AMA) and/or AMA-M2, anti-Ro52 and a high rate of anti-gp210 positive patients were identified with a high proportion of male patients and low survival rate. A subgroup of patients with anti-SSA and/or anti-SSB coexists with SjS was also identified; patients with only AMA and/or AMA-M2-positive with a benign clinical outcome and relatively high complication of non-alcoholic fatty liver disease (NAFLD) were also identified. Only anti-gp210 was considered as a significant predictor for poor outcomes especially in patients with cirrhosis.

Clustering methods allow the identification of distinct autoantibody profiles of PBC that form clinical subsets and can be useful for personalized approaches to diagnosis, clinical management, and the prediction of clinical outcomes. Anti-gp210 was the strongest predictive factor for poor outcomes especially in PBC patients with cirrhosis under real-world conditions.