Pre-treatment with tocilizumab reduces lipopolysaccharide-induced acute lung injury in biliary cirrhotic rats.

Infection-related lipopolysaccharide (LPS) release causes cytokine storm and acute lung injury. Emerging data show that the interleukin 6 (IL-6) inhibitor tocilizumab can improve lung damage in patients with sepsis. This study aimed to investigate the therapeutic effect of tocilizumab on acute lung injury in cirrhotic rats. Biliary cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL). Sham-operated rats served as surgical controls. Tocilizumab was administered on post-operative day 21, and LPS was injected intraperitoneally on day 29. Three hours after LPS injection, hemodynamic parameters, biochemistry data, and arterial blood gas analysis were evaluated, along with measurements of IL-6 and tumor necrosis factor-α (TNF-α). Liver and lung histology was examined, and protein levels were analyzed. LPS administration reduced portal pressure, portal venous flow and cardiac index in the BDL rats. In addition, LPS administration induced acute lung injury, hypoxia and elevated TNF-α and IL-6 levels. Pre-treatment with tocilizumab did not affect hemodynamic and biochemistry data, but it ameliorated lung injury and decreased TNF-α, IL-6, and CD68-positive macrophage infiltration. Moreover, tocilizumab administration improved hypoxia and gas exchange in the BDL rats, and downregulated hepatic and pulmonary inflammatory protein expression. In conclusion, LPS administration induced acute lung injury in biliary cirrhotic rats. Pre-treatment with tocilizumab reduces lung damage and hypoxia, possibly by downregulating inflammatory proteins and reducing IL-6, TNF-α and CD68-positive macrophage recruitment in the lung.

Depressive symptom as a risk factor for cirrhosis in patients with primary biliary cholangitis: Analysis based on Lasso-logistic regression and decision tree models.

BACKGROUND: Depressive symptoms are frequently observed in patients with primary biliary cholangitis (PBC). The role of depressive symptoms on cirrhosis has not been fully noticed in PBC. We aimed to establish a risk model for cirrhosis that took depressive symptoms into account. METHODS: Depressive symptoms were assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). HAMD-17 score was analyzed in relation to clinical parameters. Least absolute shrinkage and selection operator (Lasso)-logistic regression and decision tree models were used to explore the effect of depressive symptoms on cirrhosis. RESULTS: The rate of depressive symptom in patients with PBC (n = 162) was higher than in healthy controls (n = 180) (52.5% vs. 16.1%; p < .001). HAMD-17 score was negatively associated with C4 levels and positively associated with levels of alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TB), Immunoglobulin (Ig) G, and IgM (r = -0.162, 0.197, 0.355, 0.203, 0.182, 0.314, p < .05). In Lasso-logistic regression analysis, HAMD-17 score, human leukocyte antigen (HLA)-DRB1*03:01 allele, age, ALP levels, and IgM levels (odds ratio [OR] = 1.087, 7.353, 1.075, 1.009, 1.005; p < 0.05) were independent risk factors for cirrhosis. Elevated HAMD-17 score was also a discriminating factor for high risk of cirrhosis in patients with PBC in decision tree model. CONCLUSIONS: Depressive symptoms were associated with disease severity. Elevated HAMD-17 score was a risk factor for cirrhosis in patients with PBC.

[An analysis of related factors in thrombocytopenia combined with cirrhosis: a cross-sectional study of 2 517 cases].

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.

Association between primary biliary cholangitis with diabetes and cardiovascular diseases: A bidirectional multivariable Mendelian randomization study.

BACKGROUND AND AIMS: 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. CONCLUSION: Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.

The potential and pitfalls of using a large language model such as ChatGPT, GPT-4, or LLaMA as a clinical assistant.

OBJECTIVES: This study aims to evaluate the utility of large language models (LLMs) in healthcare, focusing on their applications in enhancing patient care through improved diagnostic, decision-making processes, and as ancillary tools for healthcare professionals. MATERIALS AND METHODS: We evaluated ChatGPT, GPT-4, and LLaMA in identifying patients with specific diseases using gold-labeled Electronic Health Records (EHRs) from the MIMIC-III database, covering three prevalent diseases-Chronic Obstructive Pulmonary Disease (COPD), Chronic Kidney Disease (CKD)-along with the rare condition, Primary Biliary Cirrhosis (PBC), and the hard-to-diagnose condition Cancer Cachexia. RESULTS: In patient identification, GPT-4 had near similar or better performance compared to the corresponding disease-specific Machine Learning models (F1-score ≥ 85%) on COPD, CKD, and PBC. GPT-4 excelled in the PBC use case, achieving a 4.23% higher F1-score compared to disease-specific "Traditional Machine Learning" models. ChatGPT and LLaMA3 demonstrated lower performance than GPT-4 across all diseases and almost all metrics. Few-shot prompts also help ChatGPT, GPT-4, and LLaMA3 achieve higher precision and specificity but lower sensitivity and Negative Predictive Value. DISCUSSION: The study highlights the potential and limitations of LLMs in healthcare. Issues with errors, explanatory limitations and ethical concerns like data privacy and model transparency suggest that these models would be supplementary tools in clinical settings. Future studies should improve training datasets and model designs for LLMs to gain better utility in healthcare. CONCLUSION: The study shows that LLMs have the potential to assist clinicians for tasks such as patient identification but false positives and false negatives must be mitigated before LLMs are adequate for real-world clinical assistance.

The overlap with metabolic dysfunction-associated steatotic liver disease negatively affects outcomes of primary biliary cholangitis.

BACKGROUND AND AIMS: The relationship between primary biliary cholangitis (PBC) and metabolic dysfunction-associated steatotic liver disease, and its impact on treatment response and prognosis, remains underexplored. METHODS: Patient cohort from two centres comprising long-term follow-up data. All patients had histologically confirmed PBC. Biopsies were classified according to Non-Alcoholic Steatohepatitis Clinical Research Network. Diagnosis of metabolic dysfunction-associated steatotic liver disease was established when steatosis exceeded 5%, along with at least one metabolic risk factor. Patients with specific aetiologies of steatosis, other liver diseases, incomplete results and inadequate treatment with ursodeoxycholic acid were excluded. Data from patients initiating second-line treatment were censored. Treatment response was assessed using the Toronto, Paris II and AST-to-platelet at 12-month criteria. The UK PBC and Globe scores, and liver events were utilized as outcome measures. RESULTS: The study included 129 patients, 36 showing histologically confirmed overlap between PBC and steatosis. Patients with overlap showed worse prognosis according to Paris II (61.1% vs. 33.3%, p = 0.004), Toronto (52.5% vs. 24.7%, p = 0.002), AST-to-platelet 12-month >0.54 (36.1% vs. 17.2%, p = 0.021), Globe >0.30 (49.2% vs. 29.2%, p = 0.033) and UK PBC at 5, 10 and 15 years (p ≤ 0.001). Liver-related mortality and liver transplant were more prevalent in the overlap group (p = 0.001). In the multivariate analysis, steatosis, dyslipidaemia and advanced fibrosis were independently associated to worse outcomes. CONCLUSIONS: Our findings suggest that metabolic dysfunction-associated steatotic liver disease worsens the prognosis of PBC.

High C-reactive protein-to-albumin ratio levels are associated with osteoporosis in patients with primary biliary cholangitis.

Objective: 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). Methods: 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. Results: 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. Conclusion: 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.

Coexistence of metabolic-associated fatty liver disease and autoimmune or toxic liver disease.

Fatty liver disease (FLD) affects approximately 25% of global adult population. Metabolic-associated fatty liver disease (MAFLD) is a term used to emphasize components of metabolic syndrome in FLD. MAFLD does not exclude coexistence of other liver disease, but impact of coexisting MAFLD is unclear. We investigated prevalence and characteristics of MAFLD in patients with biopsy-proven autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or toxic liver disease. Liver histopathology and clinical data from Helsinki University Hospital district (1.7 million inhabitants) between 2009 and 2019 were collected from patients with AIH, PBC, PSC, or toxic liver disease at the time of diagnosis. MAFLD was diagnosed as macrovesicular steatosis ≥5% together with obesity, type-2 diabetes, or signs of metabolic dysregulation. Of 648 patients included, steatosis was observed in 15.6% (n = 101), of which 94.1% (n = 95) was due to MAFLD. Prevalence of coexisting MAFLD in the four liver diseases varied between 12.4 and 18.2% (P = 0.483). Fibrosis was more severe in MAFLD among patients with toxic liver disease (P = 0.01). Histopathological characteristics otherwise showed similar distribution among MAFLD and non-FLD controls. Alcohol consumption was higher in MAFLD group among patients with AIH or PBC (P < 0.05 for both). In AIH, smoking was more common in patients with coexisting MAFLD (P = 0.034). Prevalence of coexisting MAFLD in other primary liver diseases is lower than reported in general population. Histopathology of MAFLD patients did not clearly differ from non-FLD ones. Alcohol and smoking were associated with MAFLD in AIH.

Determining the association between systematic lupus erythematosus and the occurrence of primary biliary cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Autoimmune diseases often coexist; however, the concomitant occurrence of systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) is rare. Therefore, this study aims to provide a comprehensive summary of evidence regarding the co-occurrence of SLE and PBC. METHODS: PubMed, Web of Science, ScienceDirect , and Google Scholar databases were systematically and comprehensively searched for records published up to February 2024. Full-text articles that aligned with the study's aim were included, while those published in languages other than English and those designed as case reports, reviews, conference abstracts, or editorials were excluded. Statistical analyses were performed using Comprehensive Meta-Analysis software, and methodological quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Only 14 studies that met the inclusion criteria with 3944 PBC and 9414 SLE patients were included for review and analysis. Pooled data analysis revealed that approximately 1.1% of SLE patients have concomitant PBC (range: 0.02-7.5%), while around 2.7% of PBC patients concurrently have SLE (range: 1.3-7.5%). Furthermore, qualitative data analysis indicated that the prevalence of PBC in SLE patients presenting with hepatic dysfunction or abnormal liver enzymes ranges from 2 to 7.5%. CONCLUSION: Although the concomitant occurrence of SLE and PBC is rare, the small proportion of patients where these diseases coexist warrants close monitoring by clinicians. This underscores the importance of surveillance to prevent their co-occurrence.

Glomerulonephritis in primary biliary cholangitis in China: an important complication.

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.

Long-term outcomes in patients with primary biliary cholangitis complicated with CREST syndrome.

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.

Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial.

BACKGROUND: Cholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients' quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group. METHODS: GLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0-10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40. RESULTS: Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement). CONCLUSIONS: A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

BACKGROUND & AIMS: Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. METHODS: Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. RESULTS: Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). CONCLUSIONS: Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.