Acquired hemophilia A is an uncommon disease often presented with bleeding episodes causing a significant mortality risk. The main responsible for the threatening hemorrhagic disorder is the Factor VIII autoantibody's development. Acquired inhibitors' presence is frequently idiopathic, but it can be associated with malignancy, pregnancy, drugs and autoimmune diseases. In this report, we present the first case of acquired hemophilia A associated with primary biliary cholangitis. A 48-year-old man, presented with diffuse oral bleeding after a tooth extraction. Hemostasis testing revealed a markedly prolonged activated partial thromboplastin time. The search for an anti-factor VIII inhibitor returned positive. The etiological investigation concluded primary biliary cholangitis, and the patient was treated with bypassing agent, immunosuppressive therapy, and ursodeoxycholic acid.

Sarcopenia is a common complication in patients with cirrhosis. However, research on sarcopenia in patients with noncirrhotic primary biliary cholangitis (PBC) is limited. This study aimed to investigate the prevalence of sarcopenia and the associations between concomitant sarcopenia and the biochemical response to ursodeoxycholic acid (UDCA) treatment and clinical outcomes in patients with noncirrhotic PBC.

This retrospective study enrolled consecutive patients whose baseline visits occurred between January 2009 and December 2023. Sarcopenia was assessed via pretreatment CT or MRI at the mid-L3 level through the skeletal muscle index (SMI). Baseline characteristics, response rate after UDCA administration, liver-related events were compared. And baseline liver and plasma C-reactive protein (CRP) and IL-6 levels in a subset of patients were also evaluated.

A total of 164 patients were included and sarcopenia was identified in 66 (40.2 %) patients. The median duration of follow-up was 4.75 (1.71, 6.40) years. The PBC patients with sarcopenia had a lower biochemical response rate (45.9 % vs. 65.9 %; P = 0.014) after 12 months of UDCA treatment and a higher incidence of liver-related events (24.2 % vs. 11.2 %, P = 0.027) during follow-up. Furthermore, higher levels of baseline CRP and IL-6 in the plasma and liver were also observed(P < 0.05).

Sarcopenia was highly prevalent in patients with noncirrhotic PBC. Concomitant sarcopenia may adversely affect the biochemical response to UDCA treatment and the occurrence of liver-related adverse events in PBC patients without cirrhosis.

Elevated liver biochemistries are associated with increased risk of negative outcomes in patients with primary biliary cholangitis (PBC).

To evaluate whether longitudinal monitoring of liver biochemistries and fibrosis scores provides additional prognostic value and to assess the relationship between the degree of elevation of multiple biomarkers within different alkaline phosphatase (ALP) strata.

Adults with PBC were identified from Komodo's Healthcare Map. A Cox proportional hazards model examined time to first occurrence of hospitalisation due to hepatic decompensation, liver transplantation, or death as a function of the proportion of time during follow-up that liver biochemistries and fibrosis scores exceeded thresholds. Within ALP strata (ALP ≤ upper limit of normal [ULN]; ALP>ULN to ≤ 1.67 × ULN; ALP > 1.67 × ULN), separate multivariate Cox hazard models assessed the association between time-varying covariates and the composite endpoint.

Overall, 3974 patients were included; 88.2% were female, with a mean age of 59.4 years. The median follow-up was 2.5 years. Increasing magnitude and duration beyond established thresholds of ALP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), AST/platelet ratio index (APRI) and fibrosis-4 (FIB-4) were associated with increased risk of negative outcomes. Elevated ALT, AST, TB, APRI and FIB-4 were associated with increased risk of negative outcomes across all ALP strata.

Prolonged elevation of multiple hepatic biomarkers and fibrosis scores is associated with a greater risk of negative clinical outcomes, underscoring the importance of ongoing monitoring beyond the guideline-recommended initial treatment response to guide timely treatment decisions and improve PBC management.

While ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC), the autoimmune nature of PBC underscores the need for treatments targeting immunological pathways that may achieve a cure. E6011, a novel humanized anti-fractalkine monoclonal antibody, has emerged as a potential therapeutic option for PBC. We conducted a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of E6011 in patients with PBC with an incomplete response to UDCA.

The study was composed of 12-week Double-Blind Phase (placebo, E6011 10 mg/kg/month, 15 mg/kg/month, or 10 mg/kg/every other week [eow]) followed by a 52-week Open-Label Phase. The primary endpoint was the percent change in alkaline phosphatase (ALP) at Week 12.

A total of 29 patients were enrolled. Histological evaluation at screening revealed that 83 % of the enrolled patients were classified as Stage 4 according to the Nakanuma Classification. The mean percent changes in ALP at Week 12 were +0.45 % in the placebo, +0.65 % in the 10 mg/kg/month, +1.23 % in the 15 mg/kg/month and +1.19 % in the 10 mg/kg/eow, with no observed trends toward ALP reduction in the E6011 treatment. Based on the interim analysis, the study was discontinued due to a lack of the efficacy. E6011 was generally safe and well tolerated.

This study of E6011 failed to meet the primary endpoint in patients with PBC with an incomplete response to UDCA. The advanced histological severity present in more than 80 % of patients at baseline may have contributed to these findings.

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

Prevalence estimates of primary biliary cholangitis (PBC) in the United States have evolved with the introduction of newer real-world data capture approaches. Little is known about the geographic distribution of PBC in the United States and the health care provider (HCP) landscape for patients with PBC. This real-world study aimed to estimate the prevalence of PBC in the United States, assess regional variability in its prevalence, and describe HCPs for patients with PBC.

Patients with PBC were identified using Komodo's Healthcare Map, a large national administrative claims database. PBC prevalence per 100,000 adults was adjusted by age and gender at the 3-digit ZIP Code tabulation area level. Patients' PBC-related medical or pharmacy claims were used to determine HCP specialties and affiliations (academic vs. nonacademic); the latest claim and all claims were examined.

The adjusted 2021 PBC prevalence was 40.9 per 100,000 adults. The highest absolute number of patients with PBC in the United States was in heavily populated urban areas, but prevalence adjusted for population size was highest in some rural areas. Among all claims, most (83.2%) patients received care from a specialist (gastroenterologist/hepatologist) at one time. However, only approximately half (53.5%) of patients with PBC, irrespective of therapy use, were most recently treated for PBC by a specialist.

This is the most comprehensive and contemporary estimation of PBC prevalence in the United States to date. The pockets of high prevalence of PBC located in some rural areas highlight the need to better evaluate PBC risk factors and potential barriers in access to specialist care once patients are diagnosed. Greater awareness of PBC and its management are needed.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct destruction, leading to cirrhosis and liver failure. Recent advancements in treatment have focused on targeting specific molecular pathways involved in the disease's pathogenesis. Iqirvo, a dual peroxisome proliferator-activated receptor alpha and delta agonist, has shown promise in addressing the unmet medical needs of PBC patients. This review examines the clinical development and efficacy of Iqirvo, which recently received accelerated approval from the U.S. Food and Drug Administration. The approval was based on data demonstrating improvements in biochemical markers associated with liver function and bile acid metabolism. We also discuss the safety profile, potential side effects, and future implications for the management of PBC. The expedited approval of Iqirvo represents a significant advancement in PBC therapy, offering new hope for patients unresponsive to existing treatments.

We aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, on patients with primary biliary cholangitis (PBC) complicated by dyslipidemia.

In total, 61 patients with PBC (Add-on group: 33 patients on ursodeoxycholic acid [UDCA] + pemafibrate combination therapy; Switch group: 28 patients who switched from UDCA + other fibrates to UDCA + pemafibrate combination therapy) were included in the study. Changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and GLOBE scores were retrospectively analyzed from 6 months before to 12 months after treatment. The POISE criteria were also used to evaluate the treatment efficacy after 12 months.

After 12 months of UDCA + pemafibrate combination therapy, AST significantly decreased from 45 ± 3 to 28 ± 3 U/L (p < 0.05), ALT from 49 ± 5 to 32 ± 5 U/L (p < 0.005), GGT from 155 ± 223 to 91 ± 182 U/L (p < 0.005), and ALP from 1.4 ± 0.9 to 0.9 ± 0.8 × upper limit of normal (p < 0.0005) in all patients. ALT, GGT, and ALP levels were significantly lower after 12 months of UDCA + pemafibrate combination therapy in both the Add-on and Switch groups. After 12 months of combination therapy, the mean GLOBE score of all patients significantly decreased from 0.37 to 0.01 (p < 0.05) and the percentage of patients with a GLOBE score of 0.3 or higher decreased.

In patients with PBC who showed an inadequate response to prior therapy, pemafibrate add-on or switch therapy improved liver biochemistry and GLOBE scores. Pemafibrate may be useful as a second-line drug when UDCA alone is inadequate, or as an alternative after combination therapy with other fibrates.

Bile acids are carcinogens causing mutations leading to colorectal cancer (CRC). Higher total bile acid concentrations in the serum of patients with primary biliary cholangitis (PBC), compared to healthy controls, have been reported in previous studies. However, the association between PBC and the risk for CRC remains controversial. We investigated the association between PBC and the development of colonic polyps leading to CRC overall in this study.

The study enrolled 1,936,512 individuals from the Longitudinal Health Insurance Database spanning 2000 to 2017 for cohort analysis. Individuals assigned to ICD-9-CM and ICD-10-CM codes representing PBC were incorporated. A 1:4 control cohort was randomly selected. After adjusting for CRC risk factors using Cox regression analysis, we calculated the hazard ratios for developing colon polyps and CRC in PBC patients compared to the general population.

Within the study cohort, consisting of 2024 individuals meeting the inclusion criteria, 199 patients developed colon polyps or CRC. In contrast, among the 8096 individuals in the comparison cohort, 650 cases of colon polyps or CRC were observed during the 17-year-follow-up period. According to Cox regression analysis, the adjusted hazard ratio indicated that the risk was 1.678 times higher in the PBC group compared to the comparison group.

This population-based retrospective cohort study identified a 1.68-fold increased risk of colon polyps and CRC in patients with PBC, suggesting a potential association with colonic neoplasia. Further research is warranted to evaluate the role of endoscopic surveillance in patients with PBC.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases characterized primarily by muscle inflammation. Anti-mitochondrial antibodies (AMA) are typically associated with primary biliary cholangitis; however, they have also been linked to a rare subgroup of IIMs, namely "AMA-positive myositis," marked by a chronic disease course and muscle weakness, particularly affecting the paravertebral muscles, alongside muscle atrophy and cardiopulmonary complications. We report the case of a 40-year-old woman diagnosed with AMA-positive myositis, predominantly involving axial myopathy complicated by multiple arrhythmias and biopsy-proven focal segmental glomerulosclerosis with mitochondrial abnormalities on electron microscopy. The patient presented with progressive back pain and palpitations over a 3-month period. Although high-dose glucocorticoids and intravenous cyclophosphamide improved the axial myopathy and proteinuria, the cardiac condition remained unstable, necessitating permanent pacemaker implantation for persistent sinus dysfunction and radiofrequency catheter ablation for worsening atrial fibrillation (Af). Our literature review focusing on cardiac involvement in AMA-positive myositis revealed tachyarrhythmia was the most common (87.7%), particularly Af (55.4%), followed by cardiomyopathy (74.2%), myocarditis (43.2%), and bradyarrhythmia (40.0%). Arrhythmias and/or cardiac function deteriorated in 41.7% of patients treated with immunosuppressants and in 66.7% of patients treated without immunosuppressants, respectively. Furthermore, in the treated group, more patients with worsened cardiac lesions required additional electronic devices compared to those without (53.3% vs. 4.8%). Early detection and adequate management of cardiac complications in AMA-positive myositis are critical to prevent irreversible myocardial damage and fatal outcomes. In addition to cardiac complications, concomitant renal involvement associated with AMA-positive myositis may be also considered.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease predominantly affecting middle-aged women. While ursodeoxycholic acid (UDCA) is the first-line treatment, 30-40% of patients do not respond adequately, necessitating alternative therapies like Obeticholic Acid (OCA), an FXR agonist. The long-term safety of OCA remains insufficiently studied.

This study utilized the US FDA Adverse Event Reporting System (FAERS) to evaluate OCA safety through large-scale data mining, using disproportionality analyses (ROR, PRR, BCPNN, and MGPS) to identify adverse event signals.

From Q2 2016 to Q1 2024, 5,864 reports linked to OCA usage were identified among 13,245,871 AE reports. Significant signals across 27 System Organ Classes were found, with pruritus (12.54%), fatigue (4.16%), and nausea (1.64%) being the most prevalent adverse events. Severe hepatic events like liver failure were rare (0.6%). Median time to onset of AEs was 178 days. The most common outcomes reported were important medical events (18.6%), hospitalization (17.8%), and death (6.5%).

This study provides key insights into the safety profile of OCA, highlighting the importance of monitoring for pruritus and hepatic complications, particularly within the first six months of treatment.

Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune liver disease. Some patients with PBC do not adequately respond to Ursodeoxycholic acid (UDCA) as a first-line treatment, putting them at an increased risk of disease progression. Peroxisome Proliferator-Activated Receptor (PPAR) agonists are emerging as promising therapeutic options for PBC. We aim to investigate the efficacy and safety of PPAR agonists in treating PBC patients.

PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov were searched for Randomized Controlled Trials (RCTs) investigating the use of PPAR agonists in combination with UDCA in patients with PBC, compared to UDCA alone. Mean differences (MD) for continuous variables and risk ratios (RR) for dichotomous variables were calculated to compare treatment response endpoints.

A total of 17 studies with 1219 PBC cases were included in the current review. Alkaline phosphatase (ALP) levels had a significantly greater decline in PPAR and UDCA arms than in UDCA alone (MD - 131.15, 95% CI - 155.95 to - 106.36). Furthermore, in combination therapy arms, gamma-glutamyl transferase (GGT) (MD - 55.69, 95% CI - 76.26 to - 35.13) and total bilirubin (MD - 0.08, 95% CI - 0.14 to - 0.03) were significantly lower than in the UDCA alone group.

The current study demonstrates that combining UDCA and PPAR agonists effectively reduces ALP, GGT, and Bilirubin levels, crucial markers for effective therapy in PBC patients.

Aim: To evaluate the clinical characteristics and healthcare resource utilization for acute care and its costs for patients with primary biliary cholangitis (PBC) with or without cirrhosis. Materials & methods: This retrospective observational cohort study was conducted using two datasets (Komodo's Healthcare Map™ [Komodo Health] and Optum Clinformatics® Data Mart [CDM] database) between 2015 and 2023. Patients (≥18 years) with PBC were identified based on ≥1 inpatient or ≥2 outpatient claims. Healthcare resource utilization for acute care (hospitalizations and emergency department [ED] visits [not leading to hospitalization]) were assessed in both datasets, and associated medical costs were evaluated in Optum CDM. Results: In Komodo Health, of the 29,758 patients with PBC (mean age: 59.2 years), 21.6% had cirrhosis and 50.4% of patients with cirrhosis had Medicaid or Medicare coverage. Of the total 8143 patients in Optum CDM (mean age: 67.0 years), 20.7% had cirrhosis, and most were enrolled in Medicare (69.7%). There was a larger proportion of men in the cirrhosis group compared with the no-cirrhosis group in Komodo Health (31.7 vs 16.3%) and Optum CDM (29.7 vs 16.5%). Annually, among patients with cirrhosis who had a hospitalization, 69.3% had additional hospitalizations, and among patients who had an ED visit, 52.9% had additional ED visits in Komodo Health; similar results were observed in Optum CDM. Among patients with at least one acute-care event, the mean annual acute-care costs with and without cirrhosis were $113,568 and $47,436, respectively. Conclusion: Data from two large healthcare claims databases showed that the majority of patients who had at least one acute-care event experienced additional acute-care events, particularly among those with cirrhosis. Timely treatment to avoid hospitalization and disease progression may help mitigate the clinical and economic burden for patients with PBC.

The pathological characteristics of lymphocyte infiltration in the hepatic portal tracts of patients with primary biliary cholangitis (PBC) remain unclear. Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues associated with the exacerbation of autoimmune reactions. Here, we evaluate the role of TLSs in PBC and investigate their potential therapeutic value.

We recruited 75 patients with PBC and 53 control patients with liver biopsies who were followed more than 2 years. TLSs and their maturity were identified by the amount and spatial distribution of immune cells. Bulk RNA sequencing of liver was performed in PBC patients with different TLS maturity. The sphingosine-1-phosphate receptor (S1PRs) modulator FTY720 was administered to dnTGFβRII mice to assess the role of TLSs on cholangitis.

TLSs presented in 61.3% (46/75) of liver tissues from patients with PBC, including 26 patients with mature TLS (mTLS) and 20 patients with immature TLS (imTLS). The proportion of mTLS was higher in PBC compared with chronic hepatitis B and autoimmune hepatitis. PBC patients with mTLS exhibited the highest serum levels of biochemical indicators, immune globulin and proportions of liver cirrhosis. Gene sets for lymphocyte migration and chemokine signalling pathways were enriched in patients with PBC presenting with TLS. FTY720 inhibited TLS formation and relieved cholangitis and fibrosis in dnTGFβRII mice.

TLSs are characteristics of lymphocyte accumulation in the portal tracts of PBC, of which the maturity of TLSs correlates with the inflammation and fibrosis of PBC. Targeting TLSs formation is a potential treatment of PBC.

Cholestatic liver disease encompasses a broad group of disorders related to impaired normal bile formation, secretion, or excretion. These diseases present with symptoms of fatigue, jaundice, pruritus, and biochemical changes.

We focus on updates in the management of autoimmune cholestatic liver disease. The mainstay therapy in PBC is UDCA (ursodeoxycholic acid), but OCA (obeticholic acid) can be considered if suboptimal response or intolerance. Fibrates have shown some promising effects in PBC patients who have not responded to or are intolerant of UDCA and/or OCA; however, they are not FDA approved. Peroxisome Proliferator-Activated Receptor Agonists (PPARs) have emerged as a promising new class of oral agents in PBC. Also, Ileal Bile Acid Transporter (IBAT) inhibitors are being investigated for the treatment of pruritus related to PBC. There are no available treatments for PSC; however, there have been previous investigations into many agents. There are ongoing clinical trials investigating the role of various antibiotics, PPARs, and immunomodulators for the treatment of PSC.

Ongoing investigations into the treatment of both PBC and PSC are essential. We anticipate that alternative management strategies for PBC and PSC will continue to arise in the next 5-10 years.

The diagnostic value of primary biliary cholangitis (PBC)-specific antibodies in patients with elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels, and other identifiable causes, was unclear. Our study aimed to determine whether etiological treatments in PBC-specific antibody-positive patients could improve liver biochemical tests, thereby distinguishing them from individuals with PBC.

We enrolled patients who were positive for PBC-specific antibodies and elevated ALP and/or GGT levels but with other identifiable etiologies. Changes in liver biochemistry following non-ursodeoxycholic acid etiological treatments were monitored.

A total of 155 patients with positive PBC-specific antibodies and elevated ALP and/or GGT levels due to non-PBC diseases were enrolled. Among them, 100 patients were diagnosed with non-PBC liver diseases, mainly metabolic-associated fatty liver disease, drug-induced liver injury, and autoimmune hepatitis. Additionally, 55 patients had non-liver diseases, predominantly connective tissue diseases. The median follow-up duration was 15.9 (4.7-25.6) months. Among 141 patients who completed follow-up after receiving etiological treatments, 85.1% (120/141) showed improvement in ALP and/or GGT levels, with 51.8% (73/141) achieving normalization of both ALP and GGT. However, 68 patients continued to exhibit elevated ALP and/or GGT, with 55 patients displaying isolated GGT elevation and 11 patients showing liver histological changes not consistent with PBC.

PBC-specific antibodies, along with elevated ALP and GGT levels, may occur in various non-PBC diseases. Etiological treatments may improve or even resolve cholestatic biochemistry. For these patients, initiating etiological treatment rather than immediately starting ursodeoxycholic acid therapy would be justified.

Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis, but their validation is limited because of insufficient data.

To investigate the diagnostic performance of three fibrosis noninvasive tests [FibroTest, vibration-controlled transient elastography (VCTE), and the fibrosis-4 index (FIB-4) and two activity biomarkers (alanine aminotransferase (ALT) and ActiTest].

This study enrolled 103 patients for whom liver biopsy, hepatic elastography results, and laboratory markers were available. Diagnostic performance was assessed with receiver operating characteristic (ROC) curves, the Obuchowski measure (OM), and the Bayesian latent class model.

FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis (≥ F2), with areas under the ROC curve of 0.83 [95% confidence interval (CI): 0.73-0.90], 0.86 (95%CI: 0.77-0.92), and 0.71 (95%CI: 0.60-0.80), respectively. The mean (standard error) OM values were 0.92 (0.01), 0.93 (0.01), and 0.88 (0.02) for FibroTest, VCTE, and FIB-4, respectively; FibroTest and VCTE performed comparably, and both were superior to FIB-4 (P = 0.03 and P = 0.005). The areas under the ROC curve values for activity biomarkers were 0.86 (95%CI: 0.76-0.92) for ActiTest and 0.84 (95%CI: 0.73-0.90) for ALT (P = 0.06). The OM values for ActiTest and ALT were 0.92 (0.02) and 0.90 (0.02), respectively (P = 0.005).

FibroTest and VCTE outperformed FIB-4 according to the OM. FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.

Gallstone disease is a relatively common complicating condition in patients with autoimmune liver disease (AILD) in clinical practice, yet this phenomenon has not been reported previously. Thus, we investigated the prevalence and the clinical characteristics of gallstones in patients with AILD.

We retrospectively analyzed 560 patients with AILD, comprising 207 with primary biliary cholangitis (PBC), 289 with autoimmune hepatitis (AIH), and 64 with PBC-AIH overlap syndrome (PBC-AIH), who attended the General Hospital of Tianjin Medical University from November 2012 to October 2022. In addition, 937 control (CTRL) individuals matched for age and sex were included.

The proportion of patients with AILD, PBC, AIH, and PBC-AIH complicated by gallstones was 32.5, 35.7, 28.4, and 40.6%, significantly higher than in the CTRL (14.3%). Types of gallstones are predominantly multiple stones (43.4%), followed by single stones (32.4%) and sludge stones (6%). Patients with AILD with gallstones exhibited significantly higher age at the first visit (P = 0.007) and serum biochemical markers associated with bile duct injury, such as gamma-glutamyl transpeptidase (P = 0.003) and alkaline phosphatase (P = 0.001). Patients with AILD aged 61.5 and older were significantly more prone to gallstones (P = 0.003).

Gallstones are a common comorbidity in patients with AILD, predominantly multiple stones. Patients with gallstones should be aware of the early diagnosis of AILD to prevent delayed treatment. Older patients with AILD should be alerted and prevented from developing stones. Our findings provide new ideas for clinical diagnosis and etiologic investigation.

Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its treatment. Because the cause of primary biliary cholangitis (PBC), a chronic, slowly progressive cholestatic liver disease, is still unknown, treatment remains symptomatic. Knowledge of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the disease. Advances in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this disease. For 35 years, ursodeoxycholic acid (UDCA) has been the unique drug of choice for the treatment of patients with PBC. In recent years, the list of hydrophilic bile acids used to treat cholestatic liver diseases, including PBC, has expanded. In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC.

Liver histology is the classic method for staging the severity of liver fibrosis, which in turn is an important predictor of clinical outcome. Here, we have hypothesized that the susceptibility to develop fibrosis varies among racial groups.

We examined the histology of all patients over 18 years of age who underwent liver biopsy at the Medical University of South Carolina from 1/1/2013 to 7/1/2021. Patients with malignancy, liver metastases, or missing data were excluded. Fibrosis was quantified using the Batts-Ludwig system (F0 = no fibrosis to F4 = histological cirrhosis). Racial groups were propensity matched based on age, gender, diabetes, alcohol consumption, and CDC/ATSDR Social Vulnerability Index Themes to mitigate the risk of selection bias.

We identified 1101 patients with liver biopsy histological fibrosis scores. The cohort included 23% Black patients. After propensity matching, Black patients were significantly more likely to have Hepatitis C (73/228 (32%) vs 45/228 (20%), p < 0.001) and autoimmune hepatitis (34/228 (15%) vs 6/228 (3%), p < 0.001) than White patients, while White patients were significantly more likely to have metabolic dysfunction associated steatotic liver disease (71/228 (31%) vs 18/228 (8%), p < 0.001). White patients were significantly more likely to have cirrhosis than Black patients (White - 89/228 (39%) vs Black - 68/228 (30%), p < 0.05).

White patients had a greater overall burden of advanced fibrosis (F4/cirrhosis) than Black patients, independent of etiology. The data suggest that fibrosis risk and/or progression may be worse in White than Black patients.

This review explores the emerging concept of "deep response" in primary biliary cholangitis (PBC), defined by the normalization of biochemical markers, particularly alkaline phosphatase and bilirubin. It examines its potential as a new standard for disease management and its implications for long-term patient outcomes, health policies, and clinical decision-making.

Recent studies suggest that achieving a deep response significantly improves long-term outcomes in some patients with PBC. In particular, a significant complication-free survival gain was observed among patients who at baseline were at high risk for disease progression. However, limitations in data and the variability in patient populations pose challenges for universal adoption of this standard.

Deep biochemical response represents a promising new standard for optimizing PBC management, offering measurable goals for clinicians and potentially improved long-term outcomes for patients. However, further research is necessary to better define the appropriate biochemical thresholds, understand the risks of overprescribing, and identify patient subgroups that are most likely to benefit from this strategy. A balanced, patient-centered approach incorporating deep response into comprehensive management could improve care for high-risk PBC patients.

Pruritus affects up to 80% of patients with primary biliary cholangitis (PBC) and reduces health-related quality of life (HRQoL). GLIMMER (NCT02966834) was a randomized, placebo-controlled phase IIb study of linerixibat in patients with PBC and pruritus. Using patient-reported outcome data from GLIMMER, we characterize the impact of pruritus in PBC.

To objectively assess HRQoL impact, EQ-5D-5L data from GLIMMER (0-1 scale; 0 = death, 1 = perfect health) were analyzed post-hoc across pruritus severities. Inter-relationships between pruritus severity (0-10 numerical rating scale [NRS]), depression (Beck Depression Inventory-II, post-hoc), and sleep interference (0-10 NRS) and their impact on HRQoL were explored.

In patients with PBC (n = 147), severe pruritus was associated with worse HRQoL. EQ-5D-5L scores were lower in those with severe pruritus (≥7-10 NRS) versus mild/moderate pruritus (mean [SD]: 0.49 [0.28] and 0.75 [0.17]/0.76 [0.17], respectively). Among patients with severe pruritus, 31% had severe depression, versus 9/3% with mild/moderate pruritus. Patients with both severe pruritus and depression had a mean EQ-5D-5L score of 0.30. In those with severe pruritus, 54% reported severe sleep interference. Improvements in pruritus were accompanied by stepwise improvements in EQ-5D-5L scores.

This analysis of patients in the largest investigational trial of cholestatic pruritus to date shows a clear association between pruritus and impaired HRQoL. Patients with severe pruritus had HRQoL comparable to patients with severe Parkinson's disease. Severe pruritus alongside depression was associated with extremely poor HRQoL, indicating the importance of evaluating itch and managing depression. Sleep interference appears to be a major cofactor for reduced HRQoL. For each 1-point improvement in NRS HRQoL improved, clinicians should offer appropriate and timely intervention.

Serum alkaline phosphatase (ALP) is a commonly obtained laboratory test, but its diagnostic specificity is limited because it is found in multiple tissues. We investigated patients with isolated, elevated, ALP levels without an obvious etiology at presentation to determine the frequency of different causes of an isolated elevated ALP.

This was a retrospective, cohort study of adults (age >18 years old) from January 1st, 2013, to June 30th, 2020 in both the in- and outpatient setting at the Medical University of South Carolina. 260 patients with an isolated, elevated ALP of unknown etiology (patients with known biliary obstruction, underlying parenchymal liver disease, or pregnancy were excluded) were included. A secondary outcome was mean survival time from the ALP result.

The most common cause of ALP elevation was due to underlying malignancy (147, 57 %), with 61 patients having infiltrative intrahepatic malignancy, 52 patients having bony metastasis, and 34 patients having both hepatic and bone metastasis. Bone disease (75, 29 %), unsuspected parenchymal liver disease (18, 7 %), non-malignant infiltrative liver disease (7, 2 %), and other disorders (13, 5 %) accounted for the remainder of the cohort. Notably, 123 of 260 (47 %) patients died within an average of 58 months after identification of isolated, elevated ALP.

An isolated, elevated ALP of unclear etiology is associated with several very specific and important disorders, in particular metastatic intrahepatic malignancy - and is uncommonly associated with primary parenchymal liver disease. Providers should be aware of the potential clinical significance of an elevated ALP.

The identification of autoantibodies associated with autoimmune liver disease (ALD) is crucial for diagnosis and management. Various laboratory methods have been introduced to detect autoantibody profiles. However, the variable performance of these assays may create challenges for clinicians and patients.

To investigate the concordance rates and diagnostic performance of 2 commercially available assays, line immunoassay (LIA) and digital liquid chip method (DLCM), in patients with ALD.

A total of 291 serum samples were collected, consisting of 180 sera from patients with ALD and 111 sera from controls. The samples were detected through LIA and DLCM. The agreement and diagnostic performance of each assay were analyzed.

There was substantial to almost perfect agreement among prevalent autoantibodies (anti-mitochondrial antibody M2; antibodies against gp210, Sp100, and Ro52). Nevertheless, the Cohen κ coefficient of some uncommon autoantibodies (anti-LKM-1, anti-LC-1, and anti-SLA/LP) between the 2 methods was not ideal. LIA showed slightly better sensitivity, accuracy, and negative predictive value, while DLCM exhibited slightly higher specificity and positive predictive value.

LIA and DLCM demonstrated comparable performance for the detection of common ALD-related autoantibodies. LIA seemed to be more sensitive, while DLCM displayed more specificity. However, standardization of ALD autoantibody detection still faces challenges between these diverse detection systems. Comprehensive interlaboratory validation is essential to mitigate potential misunderstanding and confusion among patients and clinicians.

Primary biliary cholangitis and sarcoidosis are the two most common causes of granulomatous liver disease in the US; however, their expected clinical course and management are starkly different. This case involves a patient with granulomas noted on liver biopsy, presumed secondary to known sarcoidosis, later found to have concurrent primary biliary cholangitis. Prompt diagnosis of primary biliary cholangitis is crucial as its natural course of progressive liver fibrosis can be significantly improved with treatment.

We present the case of a 49-year-old woman with autoimmune hepatitis and persistent jaundice. On admission, pathology and laboratory results supported the diagnosis of autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome with vanishing bile duct syndrome (VBDS). Standard treatment, including methylprednisolone pulse therapy, prednisolone, azathioprine, bezafibrate, and ursodeoxycholic acid, failed to resolve jaundice. In addition to jaundice, the patient also had constipation and regularly used magnesium oxide and sennoside. Notably, the addition of elobixibat, initially prescribed for constipation, resulted in a marked improvement in jaundice. This case highlights the diagnostic and therapeutic challenges of AIH-PBC overlap syndrome with VBDS, particularly in cases of refractory jaundice. The observed efficacy of elobixibat suggests that it may be a valuable adjunctive therapy for severe cholestasis. Further research is warranted to clarify its therapeutic potential and underlying mechanisms in similar cases.

The study collected liver tissue samples from PBC patients and healthy controls and performed transcriptomic analysis of the cells in the samples using single-cell RNA sequencing. The expression characteristics of SHISA5 in PBC were revealed by comparing the difference of SHISA5 protein in the two groups of samples. The structure of SHISA5 protein was predicted and its possible biological function was analysed by bioinformatics method. The results showed that the expression of SHISA5 protein in liver tissue of PBC patients was significantly higher than that of healthy controls. Single-cell RNA sequencing data showed that SHISA5 was mainly expressed in hepatocytes and bile duct cells, and its expression level was positively correlated with the disease activity of PBC. Through structural prediction, we found that the SHISA5 protein molecule has a unique transmembrane domain and may be involved in cell signaling and intercellular interactions. Further functional analysis revealed that SHISA5 may participate in the pathological process of PBC by regulating the differentiation and function of bile duct cells.

Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7-alpha-hydroxy-4-cholesten-3-one (C4) measurement is a validated method to identify BA diarrhea. To inform dose selection, we characterized the relationship between linerixibat dose, C4 levels, and patient-reported bother on the gastrointestinal symptom rating scale (GSRS) diarrhea question. A kinetic-pharmacodynamic model was developed using data from five Phase 1/2 trials, to describe the effect of linerixibat dose (1-180 mg) and regimen (once/twice daily) on C4 concentrations over time. GSRS data from patients with PBC and pruritus in the Phase 2b GLIMMER study (NCT02966834) were used to develop a proportional odds model to predict the probability of a score of 1-7 (no-very severe discomfort) to the question "Have you been bothered by diarrhea during the past week?" in relation to linerixibat dose. The two models were linked to describe the linerixibat dose-C4-diarrhea bother relationship. Models were validated using graphical and numerical assessment and visual predictive checks. Linerixibat caused dose-dependent increases in C4 until saturation (~180 mg total daily dose). Increased C4 concentrations trended with increased GSRS diarrhea scores. Simulations demonstrated increases in moderate-to-very severe (≥ 4) diarrhea scores with increasing linerixibat dose. Increases in patient-reported diarrhea scores were linerixibat dose-dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient-reported diarrhea bother is important to support treatment adherence.

Prognosis in autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) has historically been poor. This multicenter retrospective cohort study investigated the natural history and assessed the predictors of outcomes in patients with AIH, PBC, and PSC.

AIH, PBC, and PSC patients were identified from the state-wide Hepascore and Clinical Outcome cohort. Overall death or transplant, liver-related mortality (liver-related death or transplant), and liver-related decompensation were determined using a population-based data linkage system. Baseline Liver Outcome Score (LOS), Hepascore, and MELD were examined for predicting outcomes.

Two-hundred thirty-seven AIH patients (24% male, median age 56.6 years [range, 14.3-94.0]), 157 PBC patients (8.3% male, median age 60.5 years [range, 25.6-87.1]), and 167 PSC patients (52.7% male, median age 55.6 years [range, 18.4-88.6]) were enrolled. Five-year transplant-free survival was 88% (95%CI: 81-92%) in AIH, 92% (95%CI: 85-96%) in PBC, and 61% (95%CI: 51-69%) in PSC. PSC had a significantly worse overall death or transplant, liver-related mortality, and liver-related decompensation when compared to AIH and PBC (p < 0.0001). LOS was a significant independent predictor of overall death or transplant, liver-related mortality, and liver-related decompensation among patients with AIH and PBC. LOS was a significant independent predictor of overall death or transplant in patients with PSC, and Hepascore was a significant independent predictor of liver-related mortality and liver-related decompensation.

Outcomes for AIH and PBC are excellent but remain poor in PSC. LOS is a predictor of outcomes in autoimmune liver disease.

Background and Aims: Primary biliary cholangitis (PBC) leads to the slow, progressive destruction of the small bile ducts with consecutive cholestasis and intrahepatic cholangitis. If this disease remains untreated, liver parenchyma will be damaged resulting in fibrosis and end-stage liver disease with the need for transplantation. The approval of the Farnesoid X receptor agonist obeticholic acid (Ocaliva; OCA) in early 2017 expanded the drug therapy options of PBC, which previously consisted primarily of the administration of ursodeoxycholic acid (UDCA). Patients and Methods: Included in our prospective pilot study were 16 patients with a confirmed diagnosis of PBC who were treated with an add-on therapy with OCA (5 mg/d). None of the patients had an overlap to autoimmune hepatitis. Patients were investigated between 09/2022 and 09/2023. Results: The majority of patients was female (15/16, 93.75%), and the mean age was 57.63 ± 9.59 (43-77) years. OCA treatment led to a statistically significant decrease in aspartate aminotransferase (AST; AST baseline: 38.50 [26.25; 50.00] IU/L vs. AST 6-month follow-up: 23.50 [21.50; 44.25] IU/L, p = 0.0012), alanine aminotransferase (ALT; ALT baseline: 55.50 [28.75; 97.00] IU/L vs. ALT 6-month follow-up: 36.50 [28.00; 57.25] IU/L, p = 0.0035), and gamma-glutamyl transferase (GGT; GGT baseline: 168.00 [100.30; 328.50] IU/L vs. GGT 6-month follow-up: 88.00 [44.50; 259.80] IU/L, p = 0.0063), while the decrease in alkaline phosphatase (AP) was not statistically significant (AP baseline: 197.00 [170.00; 253.30] IU/L vs. AP 6-month follow-up: 196.00 [134.00; 227.00] IU/L, p = 0.0915). In addition, liver stiffness measurement (LSM) showed a statistically significant decrease after six months of treatment with OCA (LSM baseline: 7.85 [5.55; 10.13] kPa vs. LSM 6-month follow-up: 5.95 [4.55; 8.225] kPa, p = 0.0001). However, the increase in enzymatic liver function measured by LiMAx failed to reach statistical significance, but showed a positive trend (LiMAx baseline: 402.50 [341.50; 469.80] μg/kg/h vs. LiMAx 6-month follow-up: 452.50 [412.50; 562.00] μg/kg/h, p = 0.0625). In none of our patients did therapy with obeticholic acid have to be stopped due to pruritus or poor tolerability. Conclusions: In patients with PBC without adequate response to UDCA, OCA is a promising alternative, which in our group of 16 patients led to a significant improvement of liver enzymes, the amelioration of liver fibrosis, and an increase in liver function capacity in a short-term clinical course.

Autoimmune liver diseases involve a heterogeneous group of chronic inflammatory disorders, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Sometimes presented consistently as an overlapping syndrome, their pathogenesis is rather complex and has yet to be fully elucidated, despite extensive research efforts. This review article corroborates the molecular mechanisms of autoimmune liver diseases, as well as existing and potential therapeutic modalities.

To analyze the application value of novel inflammation indicators such as the lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) in patients with primary biliary cholangitis (PBC) undergoing ursodeoxycholic acid (UDCA) treatment. We plan to further seek simple and convenient methods to assess the response of patients to UDCA treatment.

We recorded routine blood tests, liver function, and vitamin D (VD) levels of PBC patients and healthy controls visiting the hospital between October 2022 and October 2023. LMR, NLR, and PLR were calculated, and differences between the two groups were analyzed. PBC patients were divided into good response and poor response groups according to the Paris I criteria, and differences in laboratory tests between the two groups were analyzed. The predictive value of novel inflammation indicators in UDCA treatment response was further analyzed using ROC analysis.

LMR and VD levels were significantly lower in the PBC group compared to the control group (P=0.000, P=0.000). In PBC patients, the good response group had higher LMR than the poor response group (P=0.001) and lower NLR than the poor response group (P=0.015). The areas under the ROC curve for LMR and NLR were 0.682±0.049 and 0.630±0.052, respectively. There was a significant negative correlation between PLR and VD in PBC patients (r=-0.252, P=0.005).

Low LMR and high NLR may indicate poor treatment response. And PLR also have certain predictive values for treatment response.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are immune-mediated liver diseases (IMLDs) that are diagnosed by a combination of clinical, serologic, and histologic features. Diagnosis may be challenging, particularly when patients have mixed features of both AIH and PBC, a disease often called overlap syndrome (OS). In addition, many patients have refractory disease. We hypothesized that adding molecular testing to the current diagnostic criteria would provide an additional tool that could assist in correctly classifying patients. RNA was isolated from liver biopsies from patients with AIH (n = 16), PBC (n = 13), OS (n = 8), drug-induced/serology-negative AIH (AIH DI/Ser-neg, n = 6), or controls (n = 10). Gene expression was determined using an nCounter Sprint Profiler, and principal component analysis delineated distinct clusters for patients with an inflammatory profile due to AIH, PBC, and AIH DI/Ser-neg. Two patients with minimal histologic features of PBC clustered with the control group, and 2 patients with predominantly AIH and minimal PBC features clustered with the PBC group. A patient with OS who received treatment for both conditions showed no disease progression, whereas a patient with OS treated solely for AIH failed to respond. Conversely, one of the gene signatures from a patient diagnosed with PBC fell within the AIH group. This patient did not respond to treatment with ursodiol and ultimately required liver replacement. These findings suggest that the IMLD initially diagnosed in these patients may have been incorrectly classified. As expected, molecular analysis could not identify a distinct cluster for patients diagnosed with OS, and these had variable gene signatures that fell throughout the identified AIH or PBC groups. Cluster analysis was also able to distinguish patients with disease progression from non-progressors with mild disease who responded to treatment. In summary, gene expression analysis may assist in confirming the type of IMLD, especially when the diagnosis is unclear. Combining molecular testing with existing criteria could provide an additional diagnostic tool, improving patient care and response to treatment.

Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by biliary destruction leading to intrahepatic biliary cholestasis. It predominantly affects women during the fifth and sixth decades. Treatment options have progressed from ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) to liver and stem cell transplant. The objectives include summarizing established and new diagnostic approaches for PBC along with reviewing efficacy treatments, their side effects, and future directions. The treatment of PBC is based on risk stratification, including assessment of the patient's age, sex, clinical pattern, biochemical and antibody profile, histology, and markers of fibrosis. UDCA and OCA are Food and Drug Administration (FDA) approved first-line and second-line agents. Elafibranor, a recently FDA-approved agent based on its efficacy, was shown in the ELATIVE trial. Seladelpar, currently under FDA review in the ENHANCE III trial, is also used in PBC. Fibrates, a third-line treatment, are found efficacious in different trials. Other treatment options are in phase II/III clinical trials. The question of whether we use immunotherapy has been answered in the NCT02376335 and NCT00746486 trials, stating that rituximab and budesonide cannot be used as no clinical significance is observed. The emergence of new therapies and the potential of combination treatments offer hope for improving outcomes for all patients with PBC. Personalized treatment strategies, continuous monitoring, and a comprehensive approach to symptom management are key to optimizing care and enhancing the quality of life for individuals affected by this chronic liver disease.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) stand as distinct diseases, yet occasionally intertwine with overlapping features, posing diagnostic and management challenges. This recognition traces back to the 1970s, with initial case reports highlighting this complexity. Diagnostic scoring systems like IAIHG and simplified criteria for AIH were introduced but are inherently limited in diagnosing variant syndromes. The so-called Paris criteria offer a diagnostic framework with high sensitivity and specificity for variant syndromes, although disagreements among international guidelines persist. Histological findings in AIH and PBC may exhibit overlapping features, rendering histology alone inadequate for a definitive diagnosis. Autoantibody profiles could be helpful, but similarly cannot be considered alone to reach a solid and consistent evaluation. Treatment strategies vary based on the predominant features observed. Individuals with overlapping characteristics favoring AIH ideally benefit from corticosteroids, while patients primarily manifesting PBC features should initially receive treatment with choleretic drugs like ursodeoxycholic acid (UDCA).

Large-scale studies on the association between primary biliary cholangitis (PBC) and hepatocellular carcinoma (HCC) in Asians are scarce. This study aimed to evaluate the incidence of HCC and its risk factors in a nationwide cohort.

The data of 4,882 patients with PBC and 38,603 matched controls were extracted from the Korean National Health Insurance Service (2007-2020) and analyzed. The incidence of HCC and its risk factors in patients with PBC were assessed and compared with those in the matched controls. The results were validated in a multicenter hospital cohort of 862 patients with PBC, recruited from Asan Medical Center (n = 815) and Yeouido St. Mary's Hospital (n = 47) in Korea.

In total, 105 patients with PBC developed HCC over the median follow-up period of 5.42 years, yielding an incidence rate of 3.7/1,000 person-years (PYs), which was significantly higher than that in the controls (0.5/1,000 PYs; adjusted hazard ratio: 9.07; 95% CI: 6.71-12.27). PBC, older age, male sex, diabetes, and smoking were identified as significant risk factors for HCC. Twenty-three of the 862 patients with PBC developed HCC in the multicenter hospital cohort, yielding an incidence of 4.0/1,000 PYs (95% CI: 2.4-5.7). Older age (subdistribution hazard ratio [SHR]: 1.05, 95% CI: 1.00-1.10), male sex (SHR: 3.00, 95% CI: 1.11-8.13), current alcohol consumption (SHR: 3.70, 95% CI: 1.08-12.59), and cirrhosis (SHR: 5.17, 95% CI: 2.07-12.93) were identified as risk factors in the hospital cohort.

Patients with PBC were at a significantly higher risk of developing HCC. Older age and male sex were consistent risk factors in both cohorts.

Notable heterogeneity has been observed among different studies in terms of the incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cholangitis (PBC). Large-scale studies on the association between PBC and HCC in Asians are scarce. In our nationwide cohort study, patients with PBC exhibited a significantly heightened risk of developing HCC and mortality than the age- and sex-matched controls. Individuals with PBC had a 9.1-fold higher risk of developing HCC than their matched counterparts, with an incidence rate of 3.7/1,000 person-years. Older age, male sex, smoking, and diabetes were identified as prominent risk factors for HCC in patients with PBC in the nationwide cohort. Older age, male sex, and alcohol consumption were identified as the factors significantly contributing to the elevated risk of HCC in patients with PBC in validation multicenter hospital cohort.

Autoimmune liver disease (AILD) encompasses autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC) and primary sclerosing cholangitis (PSC). A unified disease process evolving over time through these entities has been recently suggested. From this perspective, this study aimed to compare the characteristics of childhood-onset AILD at baseline and after a medium-to-long term follow-up period.

Paediatric-onset cases of AILD diagnosed between 1992 and 2023 at a tertiary-care centre were reviewed. Patients transitioned to adult-care by the time of data collection were asked for clinical updates.

Fifty-five patients were included (AIH = 20, ASC =22, PSC =13). AIH, ASC and PSC exhibited increasing age at the onset (AIH to PSC, p < 0.01). The area under the receiver operating characteristic curve for gamma-glutamyltranspeptidase (GGT) combined with alkaline phosphatase/aspartate aminotransferase (ALP/AST) ratio in predicting sclerosing cholangitis was 0.94, with a sensitivity of 86 % and a specificity of 94 %. At the last follow-up (median duration 5,8 years, interquartile range [IQR] 2,9-10,2, n = 45), 15 patients (33 %) developed portal hypertension, 2 patients (4 %) underwent liver transplantation, no patient died.

A cohort of childhood-onset AILD managed at a single centre reveals a temporal trend in the onset of AIH, ASC and PSC, with progressively older ages. Elevated GGT levels combined with a high ALP/AST ratio predict the diagnosis of sclerosing cholangitis. The occurrence of liver-related adverse events in one-third of patients highlights the progressive nature of paediatric-onset AILD.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.