The incidence of autoimmune liver diseases (ALDs) and research on their pathogenesis are increasing annually. However, except for autoimmune hepatitis, which responds well to immunosuppression, primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive therapy. Besides the known effects of the environment, genetics, and immunity on ALDs, the heterogeneity of target cells provides new insights into their pathogenesis. This review started by exploring the heterogeneity in the development, structures, and functions of hepatocytes and epithelial cells of the small and large bile ducts. For example, cytokeratin (CK) 8 and CK18 are primarily expressed in hepatocytes, while CK7 and CK19 are primarily expressed in intrahepatic cholangiocytes. Additionally, emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study ALDs. This review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

OBJECTIVE: Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs).
METHODS: Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836).
RESULTS: SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models.
CONCLUSIONS: Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.

Cholestatic liver disease is a group of diseases in which bile acid accumulates in the liver for various reasons, resulting in abnormal liver biochemical indicators and histological damage. Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis, which will contribute to liver damage and progress to liver fibrosis and cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis are the two most typical cholestatic liver diseases. Ursodeoxycholic acid is currently the first-line treatment for PBC, while obeticholic acid, budesonide and fibrates have also shown good potential in the treatment of PBC. There are currently no official drugs approved to treat primary sclerosing cholangitis, and the use of ursodeoxycholic acid may have certain clinical benefits. At present, progress has been made in new treatment directions for cholestatic liver disease, including fibroblast growth factor 19, cholestyramine, S-adenosyl-L-methionine, steroid drugs, farnesoid X receptor agonists, and more. Considerable progress has been made in the management of cholestatic liver disease but there are still many opportunities and challenges. In this review, we summarized the recommended guidelines for the management of cholestatic disease and the progress of new drug research and development, in order to provide an important reference for the clinical practice of cholestatic liver disease.

UNASSIGNED: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria.
UNASSIGNED: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC.
UNASSIGNED: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043).
UNASSIGNED: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy.
UNASSIGNED: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Objective: To explore the related factors of thrombocytopenia (TCP) occurrence in patients with cirrhosis. Methods: A cross-sectional study was conducted. Inpatients with an initial diagnosis of cirrhosis at Peking University First Hospital from January 1, 2010 to December 31, 2020 were included. Clinical data such as demographic characteristics, etiology of cirrhosis, complications of cirrhosis, laboratory indicators, Child-Pugh grade, invasive procedures, and mortality during hospitalization were collected. A logistic regression model was used to explore the related factors of TCP occurrence in patients with cirrhosis. Categorical variables were compared by the χ(2) test. The inter-group comparison was performed using continuous variables, a t-test, one-way analysis of variance (ANOVA), or a nonparametric test. Results: There were a total of 2 592 cases of cirrhosis. 75 cases with incomplete clinical data were excluded. 2 517 cases were included for analysis. The median age was 58 (50, 67) years. Males accounted for 64%. 1 435 cases (57.0%) developed TCP, and 434 cases (17.2%) had grade 3-4 TCP. Gender, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and concomitant esophagogastric varices (EGV) were the major factors associated with TCP. Females were more prone to combine with TCP (OR=1.32, 95%CI: 1.12-1.56, P=0.001). Patients combined with EGV (OR=3.09, 95%CI: 2.63-3.65, P<0.001) were more prone to develop TCP, which was associated with the increased incidence of hypersplenism (P<0.001). Patients with PBC (OR=0.64, 95%CI: 0.50-0.82, P<0.001) and PSC (OR=0.23, 95%CI: 0.06-0.65, P=0.010) were less prone to develop TCP, which was due to the shorter prothrombin time and better coagulation function of PBC patients (P<0.001), and the lower proportion of hypersplenism in combined PSC patients (P=0.004). Patients with TCP and grade 3-4 TCP had a higher rate of hemostatic procedures (P<0.05), but a lower rate of liver biopsy (P<0.05). Patients with grade 3-4 TCP had a higher nosocomial mortality rate compared to those without (P=0.004). Conclusion: TCP is common in patients with cirrhosis. However, TCP occurrence is higher in female patients with EGV and lower in patients combined with PBC and PSC. TCP affects invasive procedures and is associated with adverse outcomes.
目的： 探究肝硬化患者中发生血小板减少症（TCP）的相关因素。 方法： 该研究为横断面研究。纳入北京大学第一医院2010年1月1日至2020年12月31日初次诊断为肝硬化的住院患者，收集人口统计学特征、肝硬化病因、肝硬化并发症、实验室指标、Child-Pugh分级、有创操作、住院期间病死率等临床资料。用logistic回归模型探索肝硬化患者发生TCP的相关因素。分类变量以χ(2)检验进行比较；连续变量的组间比较用t检验、单因素方差分析（ANOVA）或非参数检验。 结果： 共2 592例肝硬化患者，排除临床资料不完整的75例，纳入2 517例进行分析。其年龄为58（50，67）岁，男性占64%，1 435例（57.0%）发生TCP，434例（17.2%）出现3～4级TCP。性别、原发性胆汁性胆管炎（PBC）、原发性硬化性胆管炎（PSC）、合并食管胃静脉曲张（EGV）为TCP的主要相关因素。女性（OR=1.32，95%CI：1.12～1.56，P = 0.001）更易合并TCP。合并EGV（OR=3.09，95%CI：2.63～3.65，P<0.001）者更易发生TCP，这可能与其脾功能亢进并发比例更高有关（P < 0.001）；PBC（OR=0.64，95%CI: 0.50～0.82，P < 0.001）和PSC（OR=0.23，95%CI: 0.06～0.65，P = 0.010）患者更少发生TCP，这可能是由于PBC患者的凝血酶原时间更短、凝血功能更好（P < 0.001），及PSC患者合并脾功能亢进的比例更低（P = 0.004）。TCP及3～4级TCP患者止血操作率更高（P值均<0.05），肝活检率更低（P <0.05）。3～4级TCP患者院内病死率高于未发生3～4级TCP患者（P = 0.004）。 结论： 肝硬化患者常见TCP，其中女性合并EGV患者TCP发生率较高，合并PBC和PSC者TCP发生率较低。TCP影响有创操作，且与不良结局相关。.

Autoimmune hepatitis (AIH) is a condition resulting in chronic, inflammatory changes to the liver. Primary biliary cholangitis (PBC) is an autoimmune condition that destroys intrahepatic bile ducts. Overlap syndrome with concomitant AIH and PBC comprises a rare subgroup of patients with immune-mediated liver disease, with incidence rates of male patients being exceedingly uncommon in a predominantly female patient population. Our case report investigates a rare case of a 41-year-old male patient diagnosed with overlapping AIH and PBC. He initially presented with symptoms of fatigue, pruritus, and episodes of Raynaud\'s phenomenon, in addition to findings of persistently elevated liver enzymes despite lifestyle modifications. He had no past medical history, no history of alcohol use disorder, and no family medical history of chronic liver disease. Imaging did not reveal evidence of cirrhosis. Further diagnostic workup was significant for elevated immunologic markers for antinuclear antibodies (ANA) with positive centromere and cytoplasmic patterns, antimitochondrial antibodies (AMA) with F-actin antibodies, anti-smooth muscle antibodies (ASMA), and cytoplasmic antinuclear cytoplasmic antibodies (ANCA C). Liver biopsy showed prominent plasma cells and rare granulomas, consistent with the diagnosis of AIH with a component of PBC, respectively. He was started on ursodeoxycholic acid (UDCA), demonstrating a near-complete clinical response with resolution of symptoms and normalization of liver enzymes. Studies investigating the low incidence of male patients with overlap syndrome are limited, as current research is overwhelmingly based on studies with predominantly female subjects. However, most studies generally recommend treatment with both UDCA and corticosteroids to reduce symptoms and biochemical markers. Our case report highlights a rare case of a male patient documenting excellent biochemical and clinical responses to monotherapy with UDCA. A possible theory is that our patient\'s early treatment (prior to advanced disease progression) is associated with his near-complete biochemical response and symptomatic resolution on UDCA alone. Further research is needed to fully understand the clinical course and long-term prognosis of male patients with overlap syndrome. Our patient remains in life-long follow-up to monitor if or when he requires treatment with corticosteroids in addition to current monotherapy with UDCA.​.

Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the long-term outcomes of the affected patients have not been fully investigated. Herein, the long-term outcomes of PBC-CREST were evaluated. Next, the GLOBE and UK-PBC scores were validated and compared between the PBC alone and PBC-CREST groups. A total of 302 patients who were diagnosed with PBC between December 1990 and August 2021 at Fukushima Medical University Hospital were included. The liver transplantation (LT)-free survival rates were compared between patients with PBC alone (n = 245) and those with PBC-CREST (n = 57). Moreover, 173 patients, excluding those with liver-related death/LT within 1 year after ursodeoxycholic acid administration, were divided into two subgroups (PBC alone (n = 147) and PBC-CREST (n = 26)), and the GLOBE and UK-PBC scores were compared between the subgroups. The survival rates without LT (3/5/10 years) were 92/87/80% for the PBC-alone group and 98/96/96% for the PBC-CREST group, with a significantly better prognosis in the PBC-CREST group (log-rank P = 0.0172). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis. The predicted 5/10/15-year risks of liver-related death or LT based on the UK-PBC score were significantly lower in the PBC-CREST group (2.4/7.6/13.2%) than in the PBC-alone group (4.8/11.8/18.8%) (P < 0.05). The predicted 3/5-year LT-free survival rates based on the GLOBE score were significantly higher in the PBC-CREST group (93/88%) than in the PBC-alone group (88/81%) (P < 0.05). Patients with PBC-CREST may have better long-term outcomes than those with PBC alone.

Erythroderma, also known as exfoliative dermatitis, is a rarely reported atypical cutaneous manifestation of adult-onset Still\'s disease (AOSD). We present the case of erythroderma in association with AOSD that was steroid dependent and responded to tocilizumab therapy. Skin rash, pruritis, and related laboratory findings were significantly improved upon the addition of tocilizumab, while prednisolone was successfully tapered to an ever-lowest maintenance level. To our knowledge, this is the first to report the sole therapeutic effect of tocilizumab in erythroderma related to AOSD.

UNASSIGNED: Inflammation contributes to the development of metabolic bone diseases. The C-reactive protein-to-albumin ratio (CAR) is an inflammation-based marker with a prognostic value for several metabolic diseases. This study investigated the relationship between the CAR and osteoporosis (OP) in patients with primary biliary cholangitis (PBC).
UNASSIGNED: Patients with PBC treated at Beijing Ditan Hospital between January 2018 and June 2023 were enrolled. Logistic regression analysis was performed to investigate the factors influencing OP. The predictive value of CAR for OP was evaluated using receiver operating characteristic (ROC) curves. Moreover, a restricted cubic spline (RCS) fitted with a logistic regression model was used to analyze the relationship between CAR and OP.
UNASSIGNED: The prevalence of OP among the patients with PBC was 26.9% (n = 82). CAR levels were higher in the OP group than in the non-OP group (0.33 (0.09, 0.61) vs. 0.08 (0.04, 0.18), P < 0.001). Logistic regression analysis showed that CAR was an independent predictor of OP in patients with PBC (odds ratio = 2.642, 95% confidence interval = 1.537-4.540, P < 0.001). CAR exhibited a good predictive ability for OP, with an areas under the curve (AUC) of 0.741. We found that individuals with CAR values > 0.1 have higher odds of OP. In addition, high CAR levels were associated with an increased prevalence of fragility fractures and high 10-year fracture risk.
UNASSIGNED: High CAR levels were associated with greater odds of developing OP, and the CAR could serve as an independent predictor of OP in patients with PBC.

BACKGROUND: Extrahepatic manifestations in patients with primary biliary cholangitis (PBC) are frequently observed recently. We aimed in this study to explore the clinicopathological characteristics and prognosis of glomerulonephritis in patients with PBC.
METHODS: Consecutive PBC patients admitted to Peking Union Medical College Hospital from January 2002 to May 2019 were retrospectively enrolled. PBC patients with other autoimmune diseases which may have nephritis were excluded. Structured interview, systemic rheumatologic examination, and laboratory tests were conducted for each patient. Literature about patients with PBC and glomerulonephritis was reviewed and summarized.
RESULTS: Among the 330 PBC patients enrolled, glomerulonephritis were identified in 10 patients (3.0%). Eight (80.0%) were females and 2 (20.0%) were males. The mean age was 58.4 ± 9.5 years old. Membranous nephropathy (MN) was revealed in 4 patients, IgA nephropathy (IgA N) in 2 patients, minimal change disease (MCD) in 2 patients, mesangial proliferative glomerulonephritis in 1 patient, and renal amyloidosis in 1 patient. Compared to the literature reviewed, 10 cases of MN, 1 case of MCD, 1 case of IgA N, and 1 case of acute poststreptococcal glomerulonephritis (APSGN) were observed.
CONCLUSIONS: Glomerulonephritis may not be a well-recognized feature of PBC and is not a rare complication and deserved to be routinely screened in clinical practice. As MN is the most common form of glomerulonephritis in PBC patients and PBC can be asymptomatic at an early stage, patients presented with MN should be screened for PBC, so to avoid cirrhosis. Key Points • Patients with primary biliary cholangitis (PBC) can be complicated with glomerulonephritis, and membranous nephropathy (MN) is the most common form.