Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Bile acids (BAs) have gained mainstream attention since the discovery of their key role as signalling molecules in health and disease. The apical sodium-dependent transporter (ASBT) protein located in the terminal ileum plays an important physiological role in the enterohepatic circulation of BAs and therefore essential for the BA homeostasis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the 2 most common cholestatic liver diseases are characterised by altered BA flow and BA composition, which contribute to disease progression and symptom (pruritus) development. Therefore, changing the circulating BA pool in patients with PBC and PSC may have therapeutic implications. To this end, pharmacological inhibition of ASBT is fast emerging as an interesting target. In this review, we discuss the recent evidence for potential therapeutic use of ASBT inhibitors to treat PBC and PSC patients.</jats:p

Seladelpar treatment reduces interleukin-31 and pruritus in patients with primary biliary cholangitis

BACKGROUND AND AIMS: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective PPAR-delta agonist, PBC patients experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's anti-pruritic effects, IL-31 and bile acid levels in PBC patients. APPROACH AND RESULTS: IL-31 levels were quantified in serum samples from the ENHANCE study of PBC patients receiving daily oral doses of placebo (n=55), seladelpar 5 mg (n=53) or 10 mg (n=53) for 3 months and for healthy volunteers (n=55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS (r=0.54, p<0.0001), and total (r=0.54, p<0.0001) and conjugated bile acids (up to 0.64, p<0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p=0.0003) and 10 mg (-52%, p<0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS≥2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS<2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids (r=0.63, p<0.0001) in the seladelpar 10 mg group. CONCLUSIONS: Seladelpar decreased serum IL-31 and bile acids in PBC patients. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement suggesting a mechanism to explain seladelpar's anti-pruritic effects

Transport Properties Calculation in the Superconducting State for a Quasi-Twodimensional System

We performed a self-consistent calculation of the transport properties of a d-wave superconductor. We used for calculations the T-matrix approximation. The coresponding equations were evaluated numerically directly on the real frequecy axis. We studied the ab-plane charge dynamics in the coherent limit. For the c-axis charge dynamics, we considered both, the coherent and the incoherent limit. We also have calculated the penetration depth in this model.Comment: 7 pages, 6 figures, to appear in Physica

Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

BACKGROUND AIMS: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. CONCLUSIONS: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response

Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus

Background and Aims Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor. Methods We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2 weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLC‐MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing. Results \ud In PBC patients with pruritus, serum levels of total and glyco‐conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro‐ and glyco‐conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro‐ and glyco‐ conjugated BAs and increased faecal levels of CA (P = 0.048) and CDCA (P = 0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P = 0.033) and Clostridia (P = 0.04) and decreased Bacteroidetes (P = 0.033) and Bacteroidia (P = 0.04). Conclusions Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition

Toronto HCC Risk Index::A validated scoring system to predict 10-year risk of HCC in patients with cirrhosis

Background: Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. Aim: To assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk. Methods: A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system evaluated in an external cohort for validation. Results: Of 2,079 patients with cirrhosis and ≥6 months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p&lt;0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low (&lt;120 points) medium (120-240) and high (&gt;240) risk groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with PBC, HBV and HCV cirrhosis (n= 1,144) with similar predictive ability (Harrell’s c-statistic 0.77) in the validation and derivation cohorts. Conclusion: HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis

A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease

BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2-2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7-0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls

Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

Copyright \ua9 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.Background &amp; Aims: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. Methods: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response (“responders”), 16 PBC patients with inadequate UDCA response (“nonresponders”), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes (“modules”) associated with response status and the most highly connected genes (“hub genes”) within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation (“latent factors”) across all peripheral blood mononuclear cell subsets. Results: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q &lt; 0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. Conclusions: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

Background & aims: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). Methods: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (4:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changea in mean worst daily itch (MWDI) score. Results: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Conclusions: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. Clinicaltrials: gov ID: NCT02966834. Keywords: Bile Acids; Cholestatic Pruritus; Clinical Trial; IBAT Inhibitor; Patient-Reported Outcomes

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base