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Patient-reported outcomes (PROs), such as health-related quality of life (HRQL), are important outcome measures for patients with chronic liver diseases (CLDs). Presence of cirrhosis and advanced liver disease have been associated with worsened HRQL and fatigue. On the other hand, some patients with earlier stages of CLD also experience fatigue, causing PRO impairment. Treatment for some CLDs may improve HRQL and, sometimes, levels of fatigue. We aimed to provide an in-depth expert review of concepts related to fatigue and HRQL in patients with primary biliary cholangitis, hepatitis C virus and MASLD (metabolic dysfunction-associated steatotic liver disease). A panel of experts in fatigue and CLD reviewed and discussed the literature and collaborated to provide this expert review of fatigue in CLD. Herein, we review and report on the complexity of fatigue, highlighting that it is comprised of peripheral (neuromuscular failure, often in conjunction with submaximal cardiorespiratory function) and central (central nervous system dysfunction) causes. Fatigue and HRQL are measured using validated self-report instruments. Additionally, fatigue can be measured through objective tests (e.g. grip strength). Fatigue has deleterious effects on HRQL and one's ability to be physically active and socially engaged but does not always correlate with CLD severity. Treatments for hepatitis C virus and MASLD can improve levels of fatigue and HRQL, but current treatments for primary biliary cholangitis do not seem to affect levels of fatigue. We conclude that obtaining PRO data, including on HRQL and fatigue, is essential for determining the comprehensive burden of CLD and its potential treatments. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC‐AIH overlap syndrome (OS), have rarely been investigated and compared in Asia.At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC‐AIH OS patients (85.7% treated with UDCA and IST) were enrolled.Compared with AIH patients, PBC patients were older at baseline and had greater female‐to‐male sex ratios, alkaline phosphatase (ALP) and γ‐glutamyl transferase (γ‐GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22‐year all‐cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC‐AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases.Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively. [ABSTRACT FROM AUTHOR]

Environmental sampling around a landfill site in the UK previously identified the methylimidazolium ionic liquid, 1-octyl-3-methylimidazolium (M8OI), in the soil. More recently, M8OI was shown to be detectable in sera from 5/20 PBC patients and 1/10 controls and to be oxidised on the alkyl chain in the human liver. The objective of this study was to examine the metabolism of M8OI in humans in more detail. In human hepatocytes, M8OI was mono-oxygenated to 1-(8-Hydroxyoctyl)-3-methyl-imidazolium (HO8IM) then further oxidised to 1-(7-carboxyheptyl)-3-methyl-1H-imidazol-3-ium (COOH7IM). The addition of ketoconazole—in contrast to a range of other cytochrome P450 inhibitors—blocked M8OI metabolism, suggesting primarily CYP3A-dependent mono-oxygenation of M8OI. Hepatocytes from one donor produced negligible and low levels of HO8IM and COOH7IM, respectively, on incubation with M8OI, when compared to hepatocytes from other donors. This donor had undetectable levels of CYP3A4 protein and low CYP3A enzyme activity. Transcript expression levels for other adult CYP3A isoforms—CYP3A5 and CYP3A43—suggest that a lack of CYP3A4 accounted primarily for this donor's low rate of M8OI oxidation. Insect cell (supersome) expression of various human CYPs identified CYP3A4 as the most active CYP mediating M8OI mono-oxygenation, followed by CYP3A5. HO8IM and COOH7IM were not toxic to human hepatocytes, in contrast to M8OI, and using a pooled preparation of human hepatocytes from five donors, ketoconazole potentiated M8OI toxicity. These data demonstrate that CYP3A initiates the mono-oxygenation and detoxification of M8OI in adult human livers and that CYP3A4 likely plays a major role in this process. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is one of the most prevalent types of cancer among women. Contralateral breast carcinoma is the most prevalent second malignancy in breast cancer patients. There are two types of bilateral breast carcinomas: synchronous, in which both tumors arise simultaneously, and metachronous, in which they occur at different periods. When a patient is diagnosed with breast cancer, the contralateral breast should be thoroughly examined for a synchronous tumor. Screening for hidden contralateral breast cancer is crucial for the early detection of malignancy Method: The data will be collected in prospective way. The study subjects will be involved who pre-diagnosis of unilateral breast cancer and attending surgery OPD and admitted in surgery ward. After physical examination and assessment of the patients Data will be collected pre designed proforma. They have to undergo routine blood investigation, X-ray, Mammogram and MRI for diagnosis of contralateral breast carcinoma. Results: In our study of 101 married female cases, the incidence of contralateral breast carcinoma was 3.96%. Most women in both contralateral breast carcinoma (CBC) and primary breast carcinoma groups experienced menarche at ages 13-14. The majority were diagnosed at stage 2, with CBC showing highest incidence among ages 41-50 and primary breast carcinoma among ages 51-60, indicating earlier presentation of CBC. Postmenopausal CBC patients were aged 40-50 at menopause, suggesting varying protection compared to primary breast carcinoma. No patients had a positive family history of breast carcinoma. Symptoms commonly included breast lump and mastalgia in CBC. Parity and breastfeeding duration did not significantly protect against CBC. Tumor characteristics revealed multifocality in CBC with equal distribution across breast quadrants, while primary breast carcinoma predominantly affected the upper outer quadrant. CBC tumors varied in size and showed no chest wall involvement but higher rates of skin and lymph node involvement compared to primary breast carcinoma. IDC was uniformly predominant in both CBC and primary breast carcinoma cases. Conclusions: In conclusion, our study underscores several key insights into contralateral breast carcinoma (CBC) among married females. CBC tends to manifest earlier than primary breast carcinoma, typically between ages 41-50, contrasting with the later onset of primary breast carcinoma in the 51-60 age range. Postmenopausal CBC cases aged 40-50 at menopause suggest varied protective effects compared to primary breast carcinoma, emphasizing the need for tailored screening strategies. The absence of positive family history and common symptoms such as breast lump and mastalgia highlight the sporadic nature of CBC cases. All CBC cases were of invasive ductal carcinoma (IDC) type, reinforcing IDC as the predominant histopathological subtype in both primary and contralateral breast carcinomas. Hormone receptorpositive subtype (ER+ve, PR+ve, Her2nu-ve) was prevalent in both groups. Early detection through comprehensive clinical, radiological, and histopathological assessments remains critical for improving outcomes and underscores the importance of rigorous breast examination and screening protocols. [ABSTRACT FROM AUTHOR]

Abstract Highway maintenance performance measurement is the key to implementing performance-based contracting (PBC). However, contractors have struggled with accurately understanding client intent and translating performance goals into measurable indicators. To make PBC successfully applied, this study proposes a dynamic performance measurement framework of highway routine maintenance based on grey theory. A performance indicator system is established based on the organizational structure of highway assets and the bill of quantities in the real world. In addition, a statistical analysis using the data about maintenance cost and highway condition score has been conducted to ascertain the weights and thresholds assigned to various indicators. As a result, the performance indicators, their corresponding weights, and thresholds can be flexibly adjusted to accommodate diverse periods and areas. Then, the grey theory has been employed to evaluate the comprehensive performance level of service within a region. This framework is experimented with using the data of three maintenance areas in Shaanxi Province, China: Qiaogouwan, Huaziping, and Ansai. At the end of the process, comparison and sensitivity analysis are conducted. The results demonstrate the model’s reasonability and robustness, providing valuable tools for contractors to assess the performance of highway maintenance in meeting client specifications.

Environmental sampling around a landfill site in the UK previously identified the methylimidazolium ionic liquid, 1-octyl-3-methylimidazolium (M8OI), in the soil. More recently, M8OI was shown to be detectable in sera from 5/20 PBC patients and 1/10 controls and to be oxidised on the alkyl chain in the human liver. The objective of this study was to examine the metabolism of M8OI in humans in more detail. In human hepatocytes, M8OI was mono-oxygenated to 1-(8-Hydroxyoctyl)-3-methyl-imidazolium (HO8IM) then further oxidised to 1-(7-carboxyheptyl)-3-methyl-1H-imidazol-3-ium (COOH7IM). The addition of ketoconazole—in contrast to a range of other cytochrome P450 inhibitors—blocked M8OI metabolism, suggesting primarily CYP3A-dependent mono-oxygenation of M8OI. Hepatocytes from one donor produced negligible and low levels of HO8IM and COOH7IM, respectively, on incubation with M8OI, when compared to hepatocytes from other donors. This donor had undetectable levels of CYP3A4 protein and low CYP3A enzyme activity. Transcript expression levels for other adult CYP3A isoforms—CYP3A5 and CYP3A43—suggest that a lack of CYP3A4 accounted primarily for this donor’s low rate of M8OI oxidation. Insect cell (supersome) expression of various human CYPs identified CYP3A4 as the most active CYP mediating M8OI mono-oxygenation, followed by CYP3A5. HO8IM and COOH7IM were not toxic to human hepatocytes, in contrast to M8OI, and using a pooled preparation of human hepatocytes from five donors, ketoconazole potentiated M8OI toxicity. These data demonstrate that CYP3A initiates the mono-oxygenation and detoxification of M8OI in adult human livers and that CYP3A4 likely plays a major role in this process.

Abstract 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 (

Legal education plays a vital role in the country’s justice system. The graduates with good quality of law education have a great impact on the quality of the judiciary, Bar, and Bench. There is a general perception amongst the stakeholders comprising of that the present legal education in Pakistan does not satisfactorily match the needs of the country. Thus, it needs to be reviewed and reformed. In line with this, the objective of the current qualitative study is to analyze the opinions of stakeholders. The article ends with recommendations for improvement in legal education as advocated by the stakeholders.

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. [ABSTRACT FROM AUTHOR]

Background and Aims: Primary biliary cholangitis (PBC) is a chronic, immune‐mediated liver disease that can lead to fibrosis and cirrhosis. In this cohort study, we aimed to investigate morbidity and mortality in conjunction with metabolomic changes of PBC in a UK population‐based cohort. Methods: 454 participants with PBC and 908 propensity score (age, sex, BMI, ethnicity) matched controls without liver disease were included in the study. A subset of participants with PBC and controls were analysed for their metabolomic profile. Further, PBC‐associated comorbidities were investigated by PheWAS analysis. Lastly, we assessed causes of death in individuals with PBC using a Fine and Grey competing‐risks regression model. Results: Compared to the control group, various pathways associated with the metabolism of amino acids, lipids, and liver biochemistry were significantly enriched in individuals with PBC. We found reduced levels of S‐HDL‐cholesterol and Glycoprotein Acetyls in individuals with PBC as well as an association with diseases of the circulatory system. Notably, PBC individuals had a higher prevalence of digestive diseases, autoimmune diseases, cardiovascular diseases, anaemias, mental disorders, and urinary tract infections compared to the control group. Strikingly, the overall mortality was almost three times higher in the PBC group compared to the control group, with diseases of the digestive system accounting for a significant elevation of the death rate. A subsequent analysis, enhanced by propensity score matching that included the APRI score, demonstrated that the observed morbidity could not be exclusively attributed to advanced hepatic disease. Conclusions: Our study provides a detailed perspective on the morbidity of individuals with PBC. The exploration of potential effects of disease state on morbidity suggest that early detection and early treatment of PBC could enhance patient prognosis and prevent the onset of comorbid diseases. Finally, the metabolomic alterations could represent a link between the pathophysiological processes underlying PBC development, progression, and associated morbidity. [ABSTRACT FROM AUTHOR]

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. Plain English summary: Patients with primary biliary cholangitis (PBC) often experience debilitating itching, which can be worse at night. In the GLIMMER study of linerixibat, patients with PBC and itch also had sleep interference. When the severity of itching was reduced, there was a corresponding improvement in sleep. Reduction in itch is likely to have a beneficial impact on quality of life in patients with PBC. [ABSTRACT FROM AUTHOR]

Background & Aims: Chronic liver diseases belong to the most common diseases worldwide and are associated with increased morbidity and mortality. Although more than one in three adults are estimated to have metabolic dysfunction-associated steatotic liver disease (MASLD), awareness of this condition is low amongst the general public, health care professionals and policy makers. However, meaningful knowledge transfer is essential for raising awareness and improving prevention and treatment. This study set out to investigate the use of the major internet search engine to understand how knowledge transfer has evolved by analyzing liver-related searches trends. Methods: We investigated Google search trends by measuring the number of hits relating to liver diseases between 2004 and 2021 in seven languages and European countries but also worldwide. All analyses were performed in R using the R Google trends package gtrendsR. Results: We found that interest in MASLD [formerly non-alcoholic fatty liver disease (NAFLD)] has generally increased over time, but that interest in metabolic associated steatohepatitis (MASH) - the most severe form of MASLD - has decreased. Interest in viral hepatitis C has decreased, whereas the number of queries regarding viral hepatitis B have been stable but dominated by interest in vaccination for it. Recent medical developments (in viral hepatitis) did not lead to a noticeable change in overall search behavior. Users preferred searching using their native language and less complex medical terms and acronyms (e.g., fatty liver instead of NAFLD). Conclusions: In the last two decades, Google search trends have followed the general development in the field of hepatology. Searches were dominated by non-experts and are not being rapidly influenced by novel scientific developments. Also, users preferred search terms in their native languages rather than English and tended to avoid complex medical search terms. Awareness and communication strategies around MASLD should consider these preferences when addressing the general public. [ABSTRACT FROM AUTHOR]

Aims: Aimed to identify a new susceptibility gene associated with primary biliary cholangitis (PBC) in Chinese Han and investigate the possible mechanism of that gene in PBC. Methods: A total of 466 PBC and 694 healthy controls (HC) were included in our study, and genotyping GTF2I gene variants by Sequenom. CD19 + B cells were isolated for Chromatin immunoprecipitation sequencing (ChIP-seq). Additionally, MEME-ChIP was utilized to perform searches for known motifs and de novo motif discovery. The GTF2I ChIP-seq of hematopoietic cell line (K562) results were obtained from ENCODE (GSE176987, GSE177691). The Genomic HyperBrowser was used to determine overlap and hierarchal clustering between ours and ENCODE datasets. Results: The frequency of the rs117026326 variant T allele was significantly higher in PBC patients than that in HC (20.26% compared with 13.89%, Pc = 1.09E-04). Furthermore, we observed an elevated proportion of GTF2I binding site located in the upstream and 5ʹ UTR of genes in PBC in comparison with HC. Additionally, an in-depth analysis of IL21R region revealed that GTF2I might bind to the IL21R promoter to regulate the expression of the IL21R, with four peaks of GTF2I binding sites, including three increased binding sites in upstream, one increased binding site in 5' UTR. Motif analysis by MEME-ChIP uncovered five significant motifs. A significant overlap between our ChIP and GSE176987, GSE17769 were found by the Genomic HyperBroswer. Conclusions: Our study confirmed that GTF2I was associated with PBC in Chinese Han. Furthermore, our gene function analysis indicated that IL21R may be the target gene regulated by GTF2I. [ABSTRACT FROM AUTHOR]

Background: How antimitochondrial antibody (AMA)-positive patients evolve to have primary biliary cholangitis (PBC) in viral hepatitis–endemic areas is unknown. Objectives: We aimed to investigate this evolution in Taiwan. Design/methods: A 16-year medical center-based cohort study of 2,095,628 subjects was conducted in Taiwan, an Asian country endemic to viral hepatitis. AMA-positive subjects were those with positive AMA with alkaline phosphatase (ALP) ⩽1.5 times the upper limit of normal (ULN), and PBC was defined as positive AMA with ALP >1.5 × ULN. Results: AMA-positive subjects had a lower average age- and sex-adjusted prevalence than PBC patients (4.68/105 versus 11.61/105, p = 0.0002), but their incidence was comparable (0.99/105 versus 1.12/105, p = 0.36). The former group had a borderline significantly lower mean age (56.59 years versus 58.10 years, p = 0.06) and a lower female-to-male ratio (2.85:1 versus 5.44:1, p < 0.0001). Both AMA-positive subjects (prevalence change: 20.0%, p < 0.01; incidence change: −9.2%, p < 0.01) and PBC patients (prevalence change: 14.6%, p < 0.01; incidence change: −4.7%, p < 0.01) prevalence rate increased but the incidence rate decreased. Among the 423 AMA-positive subjects, 77 (18.2%) developed PBC, for a mean duration of 1.757 years. Compared with AMA-positive subjects, PBC patients had similar concurrent chronic hepatitis B (CHB) rates (2.7% versus 4.3%, p = 0.197) but lower chronic hepatitis C (CHC) rates (3.69% versus 15.60%, p < 0.01). Conclusion: PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects. Plain language summary: Evolutionary relationship between AMA positivity and PBC in Taiwan PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects. [ABSTRACT FROM AUTHOR]

Abstract Background Autoimmune liver diseases (AILD) are increasing and common forms of chronic liver disease (CLD) with different clinical responses and characteristics which can result in cirrhosis. This study aimed to investigate the natural history and characteristics of AILD in an Iranian population. Methods Patients with AILD [Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC) and Overlap Syndrome (OS)] referred to Middle East Liver Diseases (MELD) center, Tehran, Iran, between January 2002 and December 2022 were included in this retrospective cohort study. The main features of natural history (the trends of liver functional tests (LFT), Auto-Antibodies, response to treatment and cirrhotic status) along with demographic data were studied. Results Two hundred sixty-five patients (160 (60.4%) AIH, 37 (14.0%) PBC, 20 (7.5%) PSC, 48 (18.1%) overlap syndrome) with a median follow-up time of 5 years (IQR 4 to 8 years) were included. Baseline laboratory tests revealed that patients with AIH exhibit elevated transaminase levels. However, patients suffering from PBC and PSC displayed increased alkaline phosphatase levels. Conversely, in overlap syndrome patients, both transaminases and alkaline phosphatase were observed at high levels. Autoantibodies represented themselves as important diagnostic markers for the AIH and PBC but not for PSC. The complete response occurred in 112 (70%) of and 28 (58.4%) patients with AIH and overlap syndrome respectively and 21 patients 11 (6.9%) of AIH and 10 (20.8%) of overlap syndrome) were non-responders. Other patients in these two categories were considered as insufficient responders. On the other side, 32 (91.9%) and 8 (40%) of patients with PBC and PSC biochemically responded to Ursodeoxycholic Acid (UDCA). Unpredictably, cirrhosis regression was observed in some AIH and PBC patients. Conclusion Appropriate medication management for AILD patients may leads to regression from cirrhosis and improvement of manifestations; while discontinuation of medication may cause relapses. However, patient suffering from PSC showed limited response to treatment.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms. [ABSTRACT FROM AUTHOR]

Background: Autoimmune liver diseases (AILD) are increasing and common forms of chronic liver disease (CLD) with different clinical responses and characteristics which can result in cirrhosis. This study aimed to investigate the natural history and characteristics of AILD in an Iranian population. Methods: Patients with AILD [Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC) and Overlap Syndrome (OS)] referred to Middle East Liver Diseases (MELD) center, Tehran, Iran, between January 2002 and December 2022 were included in this retrospective cohort study. The main features of natural history (the trends of liver functional tests (LFT), Auto-Antibodies, response to treatment and cirrhotic status) along with demographic data were studied. Results: Two hundred sixty-five patients (160 (60.4%) AIH, 37 (14.0%) PBC, 20 (7.5%) PSC, 48 (18.1%) overlap syndrome) with a median follow-up time of 5 years (IQR 4 to 8 years) were included. Baseline laboratory tests revealed that patients with AIH exhibit elevated transaminase levels. However, patients suffering from PBC and PSC displayed increased alkaline phosphatase levels. Conversely, in overlap syndrome patients, both transaminases and alkaline phosphatase were observed at high levels. Autoantibodies represented themselves as important diagnostic markers for the AIH and PBC but not for PSC. The complete response occurred in 112 (70%) of and 28 (58.4%) patients with AIH and overlap syndrome respectively and 21 patients 11 (6.9%) of AIH and 10 (20.8%) of overlap syndrome) were non-responders. Other patients in these two categories were considered as insufficient responders. On the other side, 32 (91.9%) and 8 (40%) of patients with PBC and PSC biochemically responded to Ursodeoxycholic Acid (UDCA). Unpredictably, cirrhosis regression was observed in some AIH and PBC patients. Conclusion: Appropriate medication management for AILD patients may leads to regression from cirrhosis and improvement of manifestations; while discontinuation of medication may cause relapses. However, patient suffering from PSC showed limited response to treatment. [ABSTRACT FROM AUTHOR]

Recent data suggest that ursodeoxycholic acid (UDCA) therapy may reduce susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and even improve clinical outcomes when coronavirus disease‐2019 (COVID‐19) was diagnosed. However, clinical evidence of UDCA's ability to prevent severe forms of COVID‐19 remains limited and contradictory. We evaluated the association between UDCA exposure and the risk of hospitalization for COVID‐19 in a large multicenter population of patients with chronic liver disease (CLD) followed during the pandemic period before vaccination. An exposed/unexposed cohort study and a nested case–control study were performed. The primary endpoint was severe COVID‐19, defined as SARS‐CoV2 infection requiring hospitalization. The secondary endpoint was COVID‐19‐associated intensive care unit (ICU) admission or death. Adjusted odds ratios (aOR) and their confidence intervals (CI) were determined after controlling for age, gender, comorbidities at risk for COVID‐19, severity of CLD, and prior hospitalizations. A total of 10 147 patients, including 1322 exposed and 8825 not exposed to UDCA, totaling 21 867 person‐years of follow‐up, were included in the cohort analysis, while 88 patients hospitalized for COVID‐19 and 840 matched controls were eligible for the nested case–control analysis. In both analyses, exposure to UDCA was not associated with a significant reduction in the risk of hospitalization for COVID‐19, with aOR (95% confidence interval) values of 0.48 (0.20–1.19) and 0.93 (0.26–3.29), respectively. Furthermore, there was no significant reduction in the risk of ICU admission or death. In this large population of patients with CLD, UDCA exposure was not associated with a reduced risk of severe COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Primary biliary cholangitis (PBC) is a chronic intrahepatic cholestatic autoimmune liver disease characterized by inflammatory injury of small and medium-sized bile ducts in the liver. The pathogenesis of PBC has yet to be entirely understood. CD47/signal-regulatory protein alpha (SIRPa) is closely related to developing autoimmune diseases by promoting inflammatory response. However, the effect of CD47/SIRPa on inflammatory response in PBC patients is still unclear. Objective: We investigated the expression of CD47/SIRPa and the effect of inflammatory cytokines on the CD47 expression, analyzed potential autoantibodies against CD47 and the effect of anti-CD47 antibody on the inflammatory response in PBC, provided laboratory basis for the study of the pathogenesis and targets for non-invasive diagnosis and treatment on PBC. Methods: The expression levels of CD47 and SIRPa on peripheral blood mononuclear cells (PBMC) were measured in 14 patients with PBC (the PBC group) and 13 healthy subjects (the Control group) by flow cytometry (FCM). The PBMC derived from healthy subjects were stimulated with healthy subjects' serum, PBC patients' serum, IFN-a or TNF-a, and the CD47 expression level on CD14+ monocytes was detected by FCM. The level of serum anti-CD47 antibody or IFN-a in PBC patients and healthy subjects was analyzed by ELISA. FCM was used to examine the TNF-a expression level in CD14+ monocytes of healthy subjects stimulated with isotype control antibody, anti-CD47 antibody, LPS or LPS combined with CD47 antibody. Results: The CD47 expression level on the CD14+ monocytes in PBC patients was statistically higher than that in the Control group (P<0.01). Compared with the Control group (PBMC+healthy serum), the CD47 expression on CD14+ monocyte stimulated with the PBC patients' serum (PBMC+PBC patients' serum) was increased (P<0.001); the CD47 expression on CD14+ monocyte stimulated with IFN-a (PBMC + IFN-a) increased gradually with the increased concentration of IFN-a (P<0.05). However, there was no similar trend on CD14+ monocyte stimulated with the TNF-a (PBMC+TNF-a) (P>0.05). The levels of serum anti-CD47 antibody and IFN-a in the PBC patients were higher than those in healthy subjects (P<0.05). The TNF-a expression level in CD14+ monocyte stimulated with the LPS (PBMC+LPS) or anti-CD47 antibody+LPS group (PBMC +LPS+anti-CD47 antibody) was significantly increased than that in the Control group (PBMC+isotype control antibody) (P<0.01 and P<0.001, respectively). The TNF-a expression level in CD14+ monocyte stimulated with the anti-CD47 antibody + LPS was higher than that with the LPS (P< 0.05). Conclusion: The CD47 may be related to the pathogenesis of PBC by inflammatory response. The CD47/SIRPa signal were imbalanced in PBC patients. The presence of serum anti-CD47 antibodies in PBC patients provides a laboratory basis for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Aalam Sohal,1 Kris V Kowdley1,2 1Department of Hepatology, Liver Institute Northwest, Seattle, WA, USA; 2Department of Gastroenterology and Hepatology, Elson Floyd College of Medicine, Spokane, WA, USACorrespondence: Kris V Kowdley, Liver Institute Northwest, 3216 NE 45th Pl Suite 212, Seattle, WA, 98105, USA, Email kkowdley@liverinstitutenw.orgAbstract: Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.Keywords: PBC, GLOBE scores, treatments, therapeutic options

BackgroundPrimary biliary cholangitis (PBC) is a chronic intrahepatic cholestatic autoimmune liver disease characterized by inflammatory injury of small and medium-sized bile ducts in the liver. The pathogenesis of PBC has yet to be entirely understood. CD47/signal-regulatory protein alpha (SIRPα) is closely related to developing autoimmune diseases by promoting inflammatory response. However, the effect of CD47/SIRPα on inflammatory response in PBC patients is still unclear.ObjectiveWe investigated the expression of CD47/SIRPα and the effect of inflammatory cytokines on the CD47 expression, analyzed potential autoantibodies against CD47 and the effect of anti-CD47 antibody on the inflammatory response in PBC, provided laboratory basis for the study of the pathogenesis and targets for non-invasive diagnosis and treatment on PBC.MethodsThe expression levels of CD47 and SIRPα on peripheral blood mononuclear cells (PBMC) were measured in 14 patients with PBC (the PBC group) and 13 healthy subjects (the Control group) by flow cytometry (FCM). The PBMC derived from healthy subjects were stimulated with healthy subjects’ serum, PBC patients’ serum, IFN-α or TNF-α, and the CD47 expression level on CD14+ monocytes was detected by FCM. The level of serum anti-CD47 antibody or IFN-α in PBC patients and healthy subjects was analyzed by ELISA. FCM was used to examine the TNF-α expression level in CD14+ monocytes of healthy subjects stimulated with isotype control antibody, anti-CD47 antibody, LPS or LPS combined with CD47 antibody.ResultsThe CD47 expression level on the CD14+ monocytes in PBC patients was statistically higher than that in the Control group (P0.05). The levels of serum anti-CD47 antibody and IFN-α in the PBC patients were higher than those in healthy subjects (P

ABSTRACTPrimary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.

This article examines the factors that influence tourists' intention to visit spiritual tourism destinations in Bali, with a focus on those who have seen virtual tours. The study finds that authentic experiences have a significant impact on tourists' cognitive and affective responses, attitude, and attachment to virtual tours, which in turn influence their intention to visit. However, perceived behavioral control does not have an effect on visit intention. The article suggests that service providers in the tourism sector can use virtual tours to increase tourist interest in visiting destinations. It also discusses the concept of spiritual tourism in Bali and proposes the integration of virtual tourism as a solution during the COVID-19 pandemic. The research methods include testing the validity and reliability of the research instrument and conducting a direct effect test. The results show that authentic experience, cognitive response, affective response, attitude, attachment to virtual tour, and perceived behavioral control all have significant effects on tourists' visit intentions. The study highlights the importance of positive experiences and influencing tourists' attitudes, cognitive and affective responses, and attachment to virtual tours through virtual tours. It suggests that future research should involve government authorities and consider mediating variables between perceived behavioral control and visit intention. [Extracted from the article]

Background and Aims: For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long‐term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF. Methods: We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all‐cause death or LT and liver‐related death or LT) were assessed using multivariable‐adjusted Cox proportional hazards models. Results: In total, 772 patients were included. The median follow‐up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73–27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32–22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16–20.5, p = 0.031) were found associated with LT‐free survival. For survival free from liver disease‐related death or LT, albumin (HR 7.72, 95% CI 1.48–40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37–88.5, p = 0.004) were found significantly associated. Conclusion: In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages. [ABSTRACT FROM AUTHOR]

Aim: Data on the geoepidemiology and outcomes of primary biliary cholangitis (PBC) in Asia are limited; thus, we aimed to collect and assess this information for Taiwan. Methods: A nationwide population‐based cohort study was undertaken using data from the Taiwan National Health Insurance Research Database. Primary biliary cholangitis was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification code 571.6 based on alkaline phosphatase and antimitochondrial antibody measurements and ursodeoxycholic acid treatment. Results: During 2002–2015, 2737 patients (2137 female patients; mean age, 57.78 years) had PBC. The average annual age‐ and sex‐adjusted prevalence and incidence rates of PBC were 8.092/105 and 1.148/105, respectively. Prevalent cases peaked in patients aged 50–59 years; the female‐to‐male ratio was 4.21. Annual prevalence rates increased with time (average percentage change, 12.03%; p < 0.0001). The annual incidence rates decreased with time (−7.39%; p = 0.000011) in female patients (−8.94%; p = 0.000003) but remained steady in male patients. Female‐to‐male and northern‐to‐southern relative risks of PBC incidence rates ranged from 2.2675 to 4.3318 and from 1.5707 to 3.1725, respectively. The 14‐year hepatocellular carcinoma (HCC) cumulative incidence was 9.11%, and the mortality rate was 32.44%; the cumulative incidences of dyslipidemia, thyroid disease, and extrahepatic cancers were 65.13%, 24.40%, and 12.79%, respectively. Higher cumulative incidences of HCC (p = 0.0064) and mortality (p < 0.0001) were noted in male than female PBC patients; southern Taiwan PBC patients had higher cumulative incidences of mortality (p < 0.0001) than their northern counterparts. Conclusion: In Taiwan, decreasing trends in incidence rates and the female‐to‐male ratio of PBC patients and specific sex and geographic impacts on the incidence rates and outcomes of PBC demand further investigation. [ABSTRACT FROM AUTHOR]

In this study, we evaluate the effects of donor gender on post-liver transplant (LT) prognosis. We specifically consider patients with primary biliary cholangitis (PBC). The 2005 to 2019 UNOS transplant registry was used to select patients with PBC. The study cohort was stratified by donor gender. All-cause mortality and graft failure hazards were compared using iterative Cox regression analysis. Subanalyses were performed to evaluate gender mismatch on post-LT prognosis. There were 1885 patients with PBC. Of these cases, 965 entries had male donors and 920 had female donors. Median follow-up was 4.82 (25–75% IQR 1.83–8.93) years. Having a male donor was associated with higher all-cause mortality (aHR 1.28 95%CI 1.03–1.58) and graft failure (aHR 1.70 95%CI 1.02–2.82). Corresponding incidence rates were also relatively increased. In the sub-analysis of female recipients (n = 1581), those with gender-mismatch (male donors, n = 769) were associated with higher all-cause mortality (aHR 1.41 95%CI 1.11–1.78) but not graft failure. In the male recipient subanalysis (n = 304), no associations were found between gender-mismatch (female donors, n = 108) and all-cause mortality or graft failure. This study shows that recipients who have male donors experienced higher rates of all-cause mortality following LT. This finding was consistent in the female recipient-male donor mismatch cohort. [ABSTRACT FROM AUTHOR]

Abstract Background Overlap syndrome between primary biliary cholangitis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only few published cases so far in the literature. We highlight here the rarity of this condition and indicate the importance of its recognition. Case presentation We report two cases showing the manifestations of both primary biliary cholangitis and primary sclerosing cholangitis in two Tunisian female patients aged 74 and 42 years, respectively. The first case is a woman who was initially diagnosed with decompensated cirrhosis. Magnetic resonance cholangiopancreatography showed multiple strictures of the common bile duct, and histological findings led to the diagnosis of primary biliary cholangitis/primary sclerosing cholangitis. She was successfully treated with ursodeoxycholic acid. The second case is a middle-aged woman, suffering from primary biliary cholangitis and who was treated with ursodeoxycholic acid. At her 12 month follow-up appointment, she presented with a partial clinical and biochemical response. Tests showed normal thyroid function, liver autoimmune tests for autoimmune hepatitis were negative, and celiac disease markers were also negative. The diagnosis of overlap syndrome of primary biliary cholangitis/primary sclerosing cholangitis was finally made on the results of magnetic resonance cholangiopancreatography that showed multiple strictures of the common as well as intrahepatic bile ducts. The patient was put on ursodeoxycholic acid at a higher dose. Conclusions Our cases raise awareness for this rare condition and indicate the importance of recognizing a possible overlap syndrome, especially in patients with primary biliary cholangitis, to optimize treatment. We suggest considering the overlap syndrome of primary biliary cholangitis/primary sclerosing cholangitis when a patient presents with the diagnostic criteria of both diseases.

Primary biliary cirrhosis (PBC) is a chronic cholestatic immune liver disease characterized by persistent cholestasis, interlobular bile duct damage, portal inflammation, liver fibrosis, eventual cirrhosis, and death. Existing clinical and animal studies have made a good progress in bile acid metabolism, intestinal flora disorder inflammatory response, bile duct cell damage, and autoimmune response mechanisms. However, the pathogenesis of PBC has not been clearly elucidated. We focus on the pathological mechanism and new drug research and development of PBC in clinical and laboratory in the recent 20 years, to discuss the latest understanding of the pathological mechanism, treatment options, and drug discovery of PBC. Current clinical treatment mode and symptomatic drug support obviously cannot meet the urgent demand of patients with PBC, especially for the patients who do not respond to the current treatment drugs. New treatment methods are urgently needed. Drug candidates targeting reported targets or signals of PBC are emerging, albeit with some success and some failure. Single-target drugs cannot achieve ideal clinical efficacy. Multitarget drugs are the trend of future research and development of PBC drugs. [ABSTRACT FROM AUTHOR]

Autoimmune regulator (Aire) and TGF‐β signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)‐like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFβRII Aire−/− mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA‐seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire−/− mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti‐CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA‐seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T‐cell‐mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH‐PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Overlap syndrome between primary biliary cholangitis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only few published cases so far in the literature. We highlight here the rarity of this condition and indicate the importance of its recognition. Case presentation: We report two cases showing the manifestations of both primary biliary cholangitis and primary sclerosing cholangitis in two Tunisian female patients aged 74 and 42 years, respectively. The first case is a woman who was initially diagnosed with decompensated cirrhosis. Magnetic resonance cholangiopancreatography showed multiple strictures of the common bile duct, and histological findings led to the diagnosis of primary biliary cholangitis/primary sclerosing cholangitis. She was successfully treated with ursodeoxycholic acid. The second case is a middle-aged woman, suffering from primary biliary cholangitis and who was treated with ursodeoxycholic acid. At her 12 month follow-up appointment, she presented with a partial clinical and biochemical response. Tests showed normal thyroid function, liver autoimmune tests for autoimmune hepatitis were negative, and celiac disease markers were also negative. The diagnosis of overlap syndrome of primary biliary cholangitis/primary sclerosing cholangitis was finally made on the results of magnetic resonance cholangiopancreatography that showed multiple strictures of the common as well as intrahepatic bile ducts. The patient was put on ursodeoxycholic acid at a higher dose. Conclusions: Our cases raise awareness for this rare condition and indicate the importance of recognizing a possible overlap syndrome, especially in patients with primary biliary cholangitis, to optimize treatment. We suggest considering the overlap syndrome of primary biliary cholangitis/primary sclerosing cholangitis when a patient presents with the diagnostic criteria of both diseases. [ABSTRACT FROM AUTHOR]

Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic liver disease that begins with immune-mediated bile duct damage, and is followed by liver fibrosis, and finally, cirrhosis. PBC primarily affects postmenopausal women, with an average age of diagnosis of 65 years, but younger women are also affected. Here, we analyzed the levels of DHEA, estradiol (E2), and estriol (E3) in the PBC sera of females at an age of diagnosis under 40 (n = 37) and above 65 (n = 29). Our results indicate that in PBC patients at an age of diagnosis under 40, E2 was significantly lower compared to that in healthy women. In contrast, the levels of DHEA and E3 were in a normal range. Furthermore, ELISA assays revealed that in PBC patients at an age of diagnosis above 65, the levels of DHEA, E2, and E3 significantly declined in comparison to those in younger patients. In addition, flow cytometry analysis showed that the level of IL-8 significantly decreased while the level of TNF-α increased in older PBC patients compared to younger ones. Moreover, we showed for the first time that the sulfonated form of DHEA, DHEA-S, reduces the levels of both pro-inflammatory interleukins, IL-8 and TNF-α, in PBC-like cholangiocytes (H69-miR506), while it diminishes the level of the pro-fibrotic interleukin, IL-13, in hepatocytes (Hep-G2). Finally, we demonstrated that the expression of the pro-fibrotic agent TGF-β significantly increased in both the early (F0–F3) and cirrhotic (F4) stages of PBC, and this elevation was accompanied by higher α-SMA expression. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.

The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases. Particular progress has been made in the development of second-line therapies for PBC. These new drugs can be separated into compounds primarily targeting cholestasis, molecules targeting fibrogenesis and molecules with immune-mediated action. Finally, drugs aimed at symptom relief (pruritus and fatigue) are also under investigation. Obeticholic acid is currently the only approved second-line therapy for PBC. Drugs in the late phase of clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid and NADPH oxidase 1/4 inhibitors. [ABSTRACT FROM AUTHOR]

Background and Aims: Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut–liver axis and systemic inflammation. Methods: Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal‐sized groups of women with non‐alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow‐mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota. Results: PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p =.01). Factors associated with LEAD at univariate analysis were VCAM‐1 (p =.002), ICAM‐1 (p =.003), and TNF‐alpha (p =.04) serum levels, but only VCAM‐1 (OR 1.1, 95% CI 1.0–1.1; p =.04) and TNF‐alpha (OR 1.12, 95% CI 0.99–1.26; p =.04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF‐alpha serum levels. Down‐regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched‐chain amino acids degradation was found in the functional gut metagenome of PBC women. Conclusions: LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut–liver axis. [ABSTRACT FROM AUTHOR]

Primary brain calcification (PBC), also known as idiopathic basal ganglia calcification (IBGC), primary familial brain calcification (PFBC) and so on, is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. The causative gene of familial PBC is SLC20A2 , which encodes the phosphate transporter PiT-2. Despite this knowledge, the molecular mechanism underlying SLC20A2 -associated PBC remains unclear. In the present study, we investigated whether haploinsufficiency or a dominant-negative mechanism reduced Pi uptake in two PiT-2 variants (T115 M and R467X). We demonstrated that the presence of T115 M or R467X had no dominant-negative effect on Pi transport activity of wild-type (WT). In addition, the subcellular localization of R467X completely differed from that of WT, indicating that there is no interaction between R467X and WT. Conversely, T115 M and WT showed almost the same localization. Therefore, we examined the interaction between T115 M and WT using the bioluminescence resonance energy transfer (BRET) method. Although WT and T115 M interact with each other, T115 M does not inhibit WT's Pi transport activity. These results suggest that the role of SLC20A2 in the pathogenesis of PBC may involve decreased intracellular Pi uptake by a haploinsufficiency mechanism rather than a dominant-negative mechanism; agents promoting PiT-2 dimerization may be promising potential therapeutic agents for PBC. • The SLC20A2 gene was first identified as a causative gene of PBC. • The role of SLC20A2 in PBC may involve decreased Pi uptake by a haploinsufficiency mechanism. • Agents promoting PiT-2 may be promising potential therapeutic agents for PBC. [ABSTRACT FROM AUTHOR]

The occurrence of other autoimmune conditions in primary biliary cholangitis (PBC) patients is documented in literature and thyroid disease is such an example. Such cases are however rarely seen in the African setting and particularly in Zambia. Here we report a case of a 36-year-old black Zambian female patient who was diagnosed with PBC in 2014 at the University Teaching Hospital(UTH), Lusaka, Zambia. She was lost to follow-up until November 2020 when she presented with a flare of PBC. During the flare the patient reported a 2-weeks history of pruritus, fatigue, passing dark urine and pale stools, coupled with progressive weight loss. Examination revealedmoist skin, scleral jaundice, generalised scratch marks, wasting with a body mass index (BMI) of 15kg/m2, asmall goitre with a bruit heard over it and fine tremors. She did not have proptosis, finger clubbing or cervical lymphadenopathy or pretibial myxoedema. File review showed no prior goitre. Ultrasound of the neck confirmed the homogenous thyroid gland with increased vascularity. Blood tests revealed a suppressed thyroid stimulating hormone (TSH) (<0.005Uiu/ml)elevated free triiodothyronine (FT3) (10.9pmol/l)and elevated free thyroxine (FT4) (53.4pmol/l). TSH receptor antibodies were also elevated. The clinical features and blood tests led to the confirmation of Graves' disease in a patient with PBC. Our patient was subsequently started on carbima zole, propr anolol and cont inued ursodeoxycholic acid with great clinical response to treatment of both the PBC and Graves' disease. Our patient managed to gain weight within six months of commencement of Graves' hyperthyroidism treatment, with her BMI improving to normal, at 22.6 Kg/m2. One year into her treatment she developed agranulocytosis likely from the carbimazole which was subsequently stopped resulting in her thyroid hormones going up again. The patient could not take propylthiouracil (PTU) in view of the liver disease as such radio-active iodine (which is not readily available) was the only feasible option. Our case report contributes to the body of knowledge that PBC tends to coexist with autoimmune thyroid disease and should be looked out for with a high index of suspicion especially in patients with PBC who report weight loss despite doing well on PBC therapy. We also seek to highlight the challenges in management and follow up of such patients in low resource setting. Although PBC is not so common in Black Africans, it should be suspected in patients who present with cholestatic jaundice especially in young female patients. [ABSTRACT FROM AUTHOR]

Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026–1.054) and 1.042 (1.029–1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79–0.87) and 0.92 (0.89–0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials. [Display omitted] • LSM improved prediction of survival beyond established biochemical response criteria and prognostic scores in >3,000 patients with PBC. • The thresholds of 8 kPa and 15 kPa optimally discriminated patients into low, medium, and high-risk groups. • Forty percent of patients were at medium to high risk of poor clinical outcomes according to these thresholds. • LSM by VCTE is a major, validated prognostic marker of PBC whose potential as a surrogate endpoint should be considered. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is an autoimmune liver disease resulting from the destruction and inflammation of intrahepatic bile ducts. This end-stage disease was once the most common cause of liver transplantation. The use of ursodeoxycholic and obeticholic acids as a first-line and second-line treatment, respectively, slows down the disease. However, treatment is not effective in about 40% of PBC patients, and the disease may progress to cirrhosis and end-stage liver disease. These patients undergo liver transplantation to save their lives. After surgery, recurrent PBC can develop in a milder form and rarely requires liver retransplantation.

Abstract Background Primary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. Results We constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P

Introduction: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-β/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. Methods and results: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. Conclusion: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC.

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The research proposes a model based on the theory of planned behavior to examine the relationships on self-confidence with green foods, green consumer attitude, perceived behavioral control, social norms, label knowledge, and eco-labeling. Attitudes, social norms, and PBC were found to be significant Ecolabels mediate the relationship between attitudes and consumer self-confidence, while attitudes were found to mediate between label knowledge and intention to use ecolabels. The study contributes to a wider explanation of the impact of these contextual variables for eco-labels and provides support for both theory and practice that facilitate insights for business practitioners, policymakers, and consumer behavior theorists. [ABSTRACT FROM AUTHOR]

An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC. To assess the perception of illness in a cohort of Italian patients with PBC. Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care. Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist. The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients. [ABSTRACT FROM AUTHOR]