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.

BACKGROUND: Ursodeoxycholic acid (UDCA) slows disease progression among patients with primary biliary cholangitis (PBC), yet not all patients receive this standard-of-care medication. Our study aims to identify reasons why PBC patients did not receive the recommended UDCA treatment.
METHODS: Using medical record data collected by the Fibrotic Liver Disease (FOLD) Consortium for 2006-2016, we identified PBC patients from a single site with no UDCA therapy record. Two independent reviewers used a structured data collection instrument to systematically confirm and record the reasons for the lack of treatment.
RESULTS: Among 494 PBC patients (11% men and 13.2% Black patients) with a median follow-up of 5.2 years, 35 (7%) had never received UDCA (16% men and 24% Black patients). Of these, 18 (51%) had laboratory indications of PBC but were not formally diagnosed. Among the remaining 17 patients with recognized PBC, six were never offered UDCA, seven declined treatment, and four remained untreated despite being offered treatment. We did not find a statistically significant association between the lack of PBC diagnosis and treatment and patients\' age (p = 0.139), gender (p = 0.222), race (p = 0.081), or insurance coverage (p = 0.456), perhaps due to our small sample size.
CONCLUSIONS: Multiple factors influencing the lack of evaluation and treatment in PBC patients were identified at the provider and patient levels. The most common reasons included financial barriers, loss to follow-up, severe decompensated disease at diagnosis, and lack of referral to specialists for further evaluation. Future interventions targeting modifiable provider and patient barriers may improve rates and timeliness of PBC diagnosis and treatment.

UNASSIGNED: The association between systemic lupus erythematosus (SLE) and primary biliary cholangitis (PBC) has been increasingly recognized. However, the existence of causal connections between SLE and PBC has yet to be established. In this study, we aimed to investigate the bidirectional causation between SLE and PBC utilizing Mendelian randomization (MR) analysis.
UNASSIGNED: We acquired summary data from Genome-wide association studies (GWAS) for SLE and PBC from the IEU Open GWAS and FinnGen database. The inverse variance weighted (IVW) was employed as the key method to ascertain the causality between SLE and PBC. Subsequently, a range of sensitivity analyses were applied. We also performed a fixed-effects model meta-analysis to combine the MR results from different databases. Moreover, multivariable MR were conducted to clarify the roles of potential confounding factors.
UNASSIGNED: Our univariable MR investigation provided compelling evidence supporting a causal relationship between SLE and PBC in both directions. Specifically, the IVW method demonstrated a strong casual effect of SLE on PBC (odds ratio (OR) = 1.17, 95 % confidence interval (CI) = 1.09-1.25, p < 0.001). In addition, the results of reverse MR analysis revealed that genetically predicted PBC was associated with an increased risk of SLE (OR = 1.39, 95 % CI = 1.32-1.45, p < 0.001). The sensitivity analyses indicated the absence of horizontal pleiotropy and heterogeneity. Furthermore, the causality between SLE and PBC remained significant even after adjusting for common risk factors in the multivariable MR analysis.
UNASSIGNED: Our study provides statistical evidence of a potential causal relationship between SLE and PBC, but further research is needed to the explore of the underlying mechanisms of these disorders.

Undifferentiated carcinoma of the liver is a rare and difficult-to-detect form of primary liver cancer. We herein report the first case of undifferentiated carcinoma of the liver in a 70-year-old Japanese woman with primary biliary cholangitis. The patient was diagnosed with cStage IVA liver cancer (85 mm in diameter) and treated with hepatic arterial infusion chemotherapy, 30 Gy radiotherapy, and 11 courses of on-demand transarterial chemoembolization. Although the hepatic tumor had markedly shrunk (from 85 to 20 mm), the patient ultimately died 16 months after the diagnosis due to rapid growth of lymph node metastases.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5\'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

UNASSIGNED: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS).
UNASSIGNED: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time.
UNASSIGNED: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted incidence rate ratio 4.21, 95% CI 3.76-4.71, p <0.001) and males ≥65 years (adjusted incidence rate ratio 14.41, 95% CI 9.62-21.60, p <0.001) were at the highest risk of being diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100,000 persons in 2018. Average annual percent change in this time period was 5.94% (95% CI 5.77-6.15, p <0.05), and was the highest among the population aged ≥65 years (5.69%, 95% CI 5.32-6.36, p <0.001).
UNASSIGNED: In this nationwide cohort study, we observed an increase in both the incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences.
UNASSIGNED: This nationwide Dutch primary biliary cholangitis (PBC) Cohort Study, including all hospitals in the Netherlands, showed that the incidence and prevalence of PBC have increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population aged ≥65 years, which may have implications for the use of second-line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population.

UNASSIGNED: Peroxisome proliferator-activated receptor (PPAR) agonists are recognised as a promising treatment for primary biliary cholangitis (PBC). However, the effects and safety of these agonists on PBC remain unexplored. Our study aimed to investigate the efficacy and safety of PPAR agonists in treating PBC.
UNASSIGNED: We searched Cochrane Library, and Web of Science, PubMed, and Embase databases from inception to 15 March 2024 for randomised controlled studies (RCTs) that enrolled individuals with PBC treated with PPAR agonists compared with placebo. The primary outcomes were biochemical response and normalization of the alkaline phosphatase (ALP) level.
UNASSIGNED: Eight RCTs involving 869 participants in total were included. The meta-analysis revealed that compared to placebo, PPAR agonists increased the rate of biochemical response (RR: 5.53; 95% CI: 3.79, 8.06) and normalization of the ALP level (RR: 17.18; 95% CI: 5.61, 52.61). In addition, PPAR agonists can also reduce alanine aminotransferase (ALT) (MD: -12.69 U/L; 95% CI: -18.03, -7.35), aspartate aminotransferase (AST) (MD: -4.18 U/L; 95% CI: -7.28, -1.08), ALP (MD: -142.95 U/L; 95% CI: -167.29, -118.60), γ-glutamyltransferase (GGT) (MD: -63.03 U/L; 95% CI: -92.08, -33.98), and total cholesterol (TC) levels (SMD: -0.71; 95% CI: -1.38, -0.04), and there was no significant difference in overall adverse reactions (RR: 0.99; 95% CI: 0.92, 1.05), serious adverse reactions (RR: 1.10; 95% CI: 0.70, 1.72) between the two groups.
UNASSIGNED: PPAR agonists are safe and well-tolerated in patients with PBC and are effective in improving the rate of biochemical response and related biomarkers.

The role of the gut microbiota in the occurrence and progression of primary biliary cholangitis (PBC) is not fully understood. First, the fecal microbiota of patients with PBC (n = 4) (PBC-FMT) or healthy individuals (n = 3) (HC-FMT) was transplanted into pseudo germ-free mice or 2OA-BSA-induced PBC models. The functions, histology and transcriptome of the liver, and microbiota and metabolome of the feces were analyzed. Second, the liver transcriptomes of PBC patients (n = 7) and normal individuals (n = 7) were analyzed. Third, the liver transcriptomes of patients with other liver diseases were collected from online databases and compared with our human and mouse data. Our results showed that PBC-FMT increased the serum ALP concentration, total bile acid content, liver injury and number of disease-related pathways enriched with upregulated liver genes in pseudo germ-free mice and increased the serum glycylproline dipeptidyl aminopeptidase level and liver damage in a 2OA-BSA-induced PBC model. The gut microbiota and metabolome differed between PBC-FMT and HC-FMT mice and reflected those of their donors. PBC-FMT tended to upregulate hepatic immune and signal transduction pathways but downregulate metabolic pathways, as in some PBC patients. The hematopoietic cell lineage, Toll-like receptor, and PPAR signaling pathway were not affected in patients with alcoholic hepatitis, HBV, HCV, HCV cirrhosis, or NASH, indicating their potential roles in the gut microbiota affecting PBC. In conclusion, the altered gut microbiota of PBC patients plays an important role in the occurrence and progression of PBC. The improvement of the gut microbiota is worthy of in-depth research and promotion as a critical aspect of PBC prevention and treatment.

OBJECTIVE: There is increased interest in utilizing dietary interventions to alter the progression of autoimmune diseases. These efforts are driven by associations of gut microbiota/metabolites with levels of short-chain fatty acids (SCFAs). Propionate is a key SCFA that is commonly used as a food preservative and is endogenously generated by bacterial fermentation of non-digestible carbohydrates in the gut. A thesis has suggested that a diet rich in propionate and other SCFAs can successfully modulate autoimmunity. Herein, we investigated the effect of long-term administration of propionylated high-amylose resistant starches (HAMSP) on the course of murine primary biliary cholangitis.
METHODS: Groups of female ARE-Del mice were fed an HAMSP diet either before or after disease onset. A detailed immunobiological analysis was performed involving autoantibodies and rigorous T-cell phenotyping, including enumeration of T-cell subsets in the spleen, liver, intestinal intraepithelial lymphocytes and lamina propria by flow cytometry. Histopathological scores were used to assess the frequency and severity of liver inflammation and damage to hepatocytes and bile ducts.
RESULTS: Our results demonstrate that a long-term propionate-yielding diet re-populated the T-cell pool with decreased naïve and central memory T-cell subsets and an increase in the effector memory T cells in mice. Similarly, long-term HAMSP intake reduced CD4+CD8+ double-positive T cells in intraepithelial lymphocytes and the intestinal lamina propria. Critically, HAMSP consumption led to moderate-to-severe hepatocellular steatosis in ARE-Del mice, independent of the stage of autoimmune cholangitis.
CONCLUSIONS: Our data suggest that administration of HAMSP induces both regulatory and effector T cells. Furthermore, HAMSP administration resulted in hepatocellular steatosis. Given the interest in dietary modulation of autoimmunity and because propionate is widely used as a food preservative, these data have significant implications. This study also provides new insights into the immunological and pathological effects of chronic propionate exposure.

Multiple sclerosis (MS) is a chronic inflammatory disease that causes demyelination in the brain and spinal cord, leading to significant neurological disability in young adults. Patients with MS are predisposed to other autoimmune disorders, though the co-occurrence of MS and primary biliary cholangitis (PBC) is rare. PBC is an autoimmune liver disease that affects bile ducts, leading to cholestasis and liver cirrhosis, predominantly in women aged over 40 years. We report the case of an 81-year-old woman with a history of MS and hypertension, bedridden for 10 years, who was admitted with a severe sacral ulcer and bacteremia. During hospitalization, she developed persistent itching, and elevated liver enzymes were detected. Imaging ruled out cholecystitis but revealed a large gallstone and hepatomegaly. Elevated M2 antimitochondrial antibodies confirmed PBC. The patient was treated with ursodeoxycholic acid, leading to symptom improvement. This case highlights the necessity for a thorough evaluation of autoimmune comorbidities in patients with MS and suggests a potential genetic and environmental link between MS and PBC. Further research is needed to explore this association and improve treatment strategies.