Our purpose was to evaluate the performance of MR imaging/cholangiography for ductal cholangiocarcinoma (CCA) diagnosis and to search for specific MR features of ductal CCA among primary sclerosing cholangitis (PSC) patients.

We retrospectively analyzed 31 patients from a single center, each with a diagnosis of PSC, and suspicion of ductal CCA. Ductal CCA had been suspected during multidisciplinary team meetings when high-grade biliary stenosis was associated with focal thickening of the biliary wall. Two radiologists blinded to clinical information and imaging history independently reviewed patients' MR examinations using a standardized model created for this study. Fisher's exact test and Student's t-test were used to analyze the population's characteristics. Fisher's exact test and the chi-square test were used to compare associations of categorical variables (each standard model's item) with the final diagnosis. Interobserver agreement was assessed by Cohen's κ coefficient.

Our population had a mean age of 42.7 ± 13.6 years and included 68% males. The final diagnosis was ductal CCA for 14 patients, and inflammatory stenosis for 17 patients. For diagnosing CCA, MR imaging/cholangiography exhibited a sensitivity of 43-50% and specificity of 70-76%, with low positive predictive (58-60%) and negative predictive (62-63%) values. Interobserver agreement ranged from κ = 0.04-0.75. Univariate analysis revealed no significant association between individual MR imaging/cholangiography features and CCA diagnosis.

MR imaging/cholangiography showed suboptimal performance for ductal CCA diagnosis among PSC patients and we did not find any specific feature to distinguish ductal CCA from inflammatory stenosis.

Question Diagnosing ductal cholangiocarcinoma in patients with primary sclerosing cholangitis remains challenging without known predictive MR imaging features. Findings MR imaging/cholangiography exhibited low sensitivity, specificity, and interobserver reliability for ductal cholangiocarcinoma diagnosis in primary sclerosing cholangitis and lacks reliability for distinguishing between benign and malignant strictures. Clinical relevance Diagnosing ductal cholangiocarcinoma in patients with primary sclerosing cholangitis remains challenging and our retrospective study demonstrates that MR imaging lacks reliability in distinguishing between benign and malignant high-grade strictures and did not find any specific MR feature of ductal CCA.

The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.

Primary sclerosing cholangitis (PSC) is a rare pathology seen in patients with inflammatory bowel disease (IBD), especially ulcerative colitis. PSC increases patients' morbidity and requires the attention of a multidisciplinary team as those patients require frequent colonoscopies and biopsies due to the elevated risk of malignancy, biliary screening and management of progressive disease that could leave patients in liver failure requiring liver transplant. Some consider this a separate form of IBD in addition to Crohn's and ulcerative colitis. These patients should be monitored closely and managed carefully due to implications of ongoing management on quality of life and survival.

There are limited data examining racial disparities in PSC-related clinical features and events. We aimed to leverage a new PSC ICD-10 code to characterize racial differences in a nationwide contemporary cohort of patients with PSC.

We used de-identified clinical/administrative data from the Vizient® Clinical Data Base to identify outpatient and inpatient adult patients with PSC using a PSC-specific ICD-10-CM code (K83.01). We compared demographic and clinical characteristics between patients who self-identified as Black versus White race. Primary and secondary outcomes included clinical and healthcare utilization outcomes.

We identified 9850 patients with PSC: 79% White, 13% Black, 2% Asian, and 6% other. Compared with White patients, Black PSC patients were more likely to be female, younger, and have a higher Elixhauser Comorbidity Index (p<0.001). Black patients were less likely to have concurrent inflammatory bowel disease (IBD) but more likely to have overlap syndromes (p<0.001) compared to White patients. The black race was significantly associated with intensive care unit stays (aOR 1.69, 95%CI 1.38-2.06) and longer length of stay (aIRR 1.15, 95%CI 1.04-1.28), but similar total number of hospitalizations (aIRR 1.05, 95%CI 0.98-1.13) compared to the White race.

Black patients had sociodemographic and clinical features suggestive of more severe disease compared to White patients. Although hospitalization rates were similar, Black patients received higher-intensity care. There was no significant difference in liver transplantation between Black and White patients. Additional research on optimal diagnosis and management of PSC in Black populations specifically is necessary to reduce healthcare disparities in this disease.

Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA.

Limited data exists regarding impact of graft type on outcomes following liver transplantation (LT) in Primary Sclerosing Cholangitis (PSC). Our goal was to evaluate the impact of graft type on outcomes following LT in PSC and determine predictors of outcomes.

Using the Scientific registry of transplant recipients (SRTR), retrospective cohorts were constructed of recipients with PSC over the time period 2010-2020, divided into 2 eras: 2010-2014, 2015-2020, stratified by graft type: living donor (LDLT), donation after circulatory death (DCD) and donation after brain death (DBD). Outcome measures evaluated were graft and patient survival. Survival comparison was performed using Kaplan-Meier method and multivariable analysis using Cox proportional hazard models.

2966 recipients underwent LT for PSC over the study period: LDLT-PSC 153 (5.2%), DCD-PSC 131 (4.4%) and DBD-PSC 2682 (90.4%). While LDLT utilization was higher in PSC (5.2% vs. 1.3%; p < 0.001), DCD use was lower (4.4% vs. 7.2%; p < 0.001) but increased over time (era 1 vs. era 2: 3.3% vs. 5.2%; p = 0.02). Outcomes following DCD-PSC were comparable to DBD and improved over time. Compared to DBD-PSC, there was a trend toward lower short-term graft survival following LDLT-PSC (1 Yr. 85.3 vs. 91.9; p = 0.07) with higher retransplant rate (LDLT-PSC vs. DCD-PSC vs. DBD-PSC: 15% vs 11% vs 7%; p < 0.001). Compared to recipients without PSC, long-term patient survival was superior in LDLT-PSC (5 Yr. 90.1 vs. 83.7%; p = 0.05) and DCD-PSC (93.3 vs. 79.7%, p = 0.01). On multivariable analysis, LDLT but not DCD graft type, was associated with inferior graft survival in PSC (adjusted hazard Ratio = 1.65 (1.16-2.34); p = 0.005).

In PSC, utilization of LDLT is higher, while DCD use is lower but increased over time. Outcomes following DCD LT in PSC are comparable to DBD and superior to recipients without PSC. Reduced graft survival and higher re-transplant rate following LDLT in PSC warrants further study. Consideration of DCD could help expand the donor pool in PSC.

This study aims to explore the clinical significance of antinuclear antibodies (ANA) patterns in liver diseases.

We included 396 patients with a request for ANA testing for suspected autoimmune liver disease (AILD). For each patient, we collected demographical, clinical, and laboratory data.

Among the patients, 33% had AILD, predominantly aiutoimmune hepatitis (AIH). The AC1 pattern was significantly more prevalent in AIH patients, while the AC21 pattern was strongly associated with primary biliary cholangitis (PBC). AC4-AC5 patterns were less frequent in AIH and PBC patients but more common in non-alcoholic hepatitis. Elevated alkaline phosphatase and gamma-glutamyl transferase levels were observed in AILD patients with AC11, AC12, and AC21 patterns.

These findings highlight the different distribution of ANA patterns in liver diseases, with specific patterns showing strong associations with distinct liver conditions.

Tissue fibrosis results from a dysregulated and chronic wound healing response accompanied by chronic inflammation and angiogenesis. Regardless of the affected organ, fibrosis shares the following common hallmarks: the recruitment of immune cells, fibroblast activation/proliferation, and excessive extracellular matrix deposition. Chemokines play a pivotal role in initiating and advancing these fibrotic processes. CCL24 (eotaxin-2) is a chemokine secreted by immune cells and epithelial cells, which promotes the trafficking of immune cells and the activation of profibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the tissue and sera of patients with fibro-inflammatory diseases, including primary sclerosing cholangitis (PSC), systemic sclerosis (SSc), and metabolic dysfunction-associated steatohepatitis (MASH). This review delves into the intricate role of CCL24 in fibrotic diseases, highlighting its impact on fibrotic, immune, and vascular pathways. We focus on the preclinical and clinical evidence supporting the therapeutic potential of blocking CCL24 in diseases that involve excessive inflammation and fibrosis.

Anti-glycoprotein 2 (anti-GP2) IgA and antineutrophil-cytoplasmic antibodies to proteinase 3 (PR3-ANCA) have been reported as predictive markers of cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC), but their prevalence in CCA patients without PSC remains unclear.

This study involved Asian discovery (n = 118) and European validation (n = 38) cohorts of CCA patients without PSC, alongside 49 Asian and 82 European pancreatic ductal adenocarcinoma (PDAC) patients, 21 with benign pancreatic neoplasms (BPN) and 45 with hepatocellular carcinoma (HCC), and 157 healthy controls (HC) from Asia and Europe. We analyzed the prevalence of PR3-ANCA, IgA and IgG against GP21 and GP24, and the CA19-9 levels.

Anti-GP21 IgA was the most prevalent in both CCA cohorts (discovery: 55.1 %; validation: 42.1 %) and significantly higher than in other groups except PDAC (all p < 0.05). It demonstrated the best diagnostic performance in distinguishing CCA from disease controls and HC, outperforming tumor markers. No significant correlation was found between anti-GP21 IgA levels and CA19-9 levels.

Our findings show that anti-GP21 IgA revealing the loss of mucosal tolerance is a potential novel diagnostic biomarker for CCA.

The aim of this review is to explore the potential of new regenerative medicine approaches in the treatment of cholestatic liver fibrosis. Cholestatic liver diseases, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and biliary atresia (BA), due to the accumulation of bile, often progress to liver fibrosis, cirrhosis, and liver failure. When the disease becomes severe enough to require liver transplantation. Deeply understanding the disease's progression and fibrosis formation is crucial for better diagnosis and treatment. Current liver fibrosis treatments mainly target the root causes and no direct treatment method in fibrosis itself. Recent advances in regenerative medicine offer a potential approach that may help find the ways to target fibrosis directly, offering hope for improved outcomes. We also summarize, analyze, and discuss the current state and benefits of regenerative medicine therapies such as mesenchymal stem cell (MSC) therapy, induced pluripotent stem cells (iPSCs), and organoid technology, which may help the treatment of cholestatic liver diseases. Focusing on the latest research may reveal new targets and enhance therapeutic efficacy, potentially leading to more effective management and even curative strategies for cholestatic liver diseases.

To analyze the role of qualitative and quantitative 3 T MR imaging assessment as a non-invasive method for the evaluation of disease severity in patients with primary sclerosing cholangitis (PSC).

A series of 26 patients, with histological diagnosis of PSC undergoing 3 T MRI and hepatological evaluation, was retrospectively enrolled. All MR examinations included diffusion-weighted imaging (DWI), T2-weighted (T2w) and T1-weighted (T1w) sequences, before and after administration of Gd-EOB-DTPA with the acquisition of both dynamic and hepato-biliary phase (HBP). Qualitative analysis was performed by assessment of liver parenchyma and biliary tract changes, also including biliary excretion of gadoxetic acid on HBP. Quantitative evaluation was conducted on liver parenchyma by measurement of apparent diffusion coefficient (ADC) and relative enhancement (RE) on 3-minute delayed phase and on HBP. Results of blood tests (ALT, ALP, GGT, total and direct bilirubin, albumin, and platelets) and transient elastography-derived liver stiffness measurements (TE-LSM) were collected and correlated with qualitative and quantitative MRI findings.

Among qualitative and quantitative findings, fibrosis visual assessment and RE had the best performance in estimating disease severity, showing a statistically significant correlation with both biomarkers of cholestasis and TE-LSM. Statistical analysis also revealed a significant correlation of gadoxetic acid biliary excretion with ALT and direct bilirubin, as well as of ADC with total bilirubin.

Qualitative and quantitative 3 T MR evaluation is a promising non-invasive method for the assessment of disease severity in patients with PSC.

Background: Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease that may lead to biliary strictures and destruction. It is associated with p-ANCA positivity and inflammatory bowel disease, typically ulcerative colitis. The aim of this study is to investigate the trends of inpatient healthcare utilization and mortality from 2008 to 2017 in the United States. Methods: The Nationwide Inpatient Sample (NIS) was examined to identify adult patients diagnosed with PSC between 2008 and 2017. Data on patient demographics, resource utilization, mortality, and PSC-related complications were collected. STATA version 16.0 was employed to perform forward stepwise multivariate regression analysis, generating adjusted odds ratios for both primary and secondary outcomes. Primary outcomes included the inpatient mortality rate and healthcare resource utilization (length of stay, total charges, and trends over the study period). Secondary outcomes focused on trends in associated comorbidities and malignancies in patients with PSC. Results: The average total charge increased by 32.2% ± 2.12 from USD 61,873 ± 2567 in 2008 to USD 91,262 ± 2961 in 2017. Concurrently, the average length of stay declined from 8.07 ± 0.18 days in 2008 to 7.27 ± 0.13 days in 2017. The APR-DRG severity of illness and risk of death significantly increased (major or extreme) during the study period (2008 to 2017), with severity rising from 73.6% to 82.7% (coefficient: 0.21, 95% CI: 0.13-0.28) and risk of death from 45.3% to 60.9% (coefficient: 0.15, 95% CI: 0.08-0.23). The proportion of patients with HCC increased from 1.3% to 7.9% (coefficient: 2.13, 95% CI: 1.9-2.8). Conversely, the percentage of patients with cholangiocarcinoma (CCA) decreased from 5.1% to 2.8% (coefficient: -0.36, 95% CI: -0.25 to -0.46). Conclusions: There was rising mortality and healthcare resource utilization among patients with PSC from the years 2008 to 2017. These trends were paralleled by increasing rates of decompensated cirrhosis, HCC, and liver transplants. However, the incidence of CCA decreased during this time period. African American patients with PSC had worse inpatient mortality outcomes and healthcare utilization as compared to white patients. Further studies are warranted to investigate a possible causal link amongst these trends.

Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) frequently undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for medically refractory disease or colonic dysplasia/neoplasia. Subtotal colectomy with ileosigmoid or ileorectal anastomosis may have improved outcomes but is not well studied. Due to increased risk for colorectal cancer in PSC-IBD, there is hesitancy to perform subtotal colectomy. We aim to describe the frequency of colorectal dysplasia/neoplasia following IPAA vs subtotal colectomy in PSC-IBD patients.

We completed a retrospective study from 1972 to 2022 of patients with PSC-IBD who had undergone total proctocolectomy with IPAA or subtotal colectomy. We abstracted demographics, disease characteristics, and endoscopic surveillance data from the EMR.

Of 125 patients (99 IPAA; 26 subtotal), the indication for surgery was rectal sparing medically refractory disease (51% vs 42%), dysplasia (37% vs 30%) and neoplasia (11% vs 26%) in IPAA vs subtotal colectomy patients, respectively. On endoscopic surveillance of IPAA patients, 2 (2%) had low-grade dysplasia (LGD) in the ileal pouch and 2 (2%) had LGD in the rectal cuff after an average of 8.4 years and 12.3 years of follow-up, respectively. One (1%) IPAA patient developed neoplasia of the rectal cuff after 17.8 years of surgical continuity. No subtotal colectomy patients had dysplasia/neoplasia in the residual colon or rectum.

In patients with PSC-IBD, there was no dysplasia or neoplasia in those who underwent subtotal colectomy as opposed to the IPAA group. Subtotal colectomy may be considered a viable surgical option in patients with rectal sparing PSC-IBD if adequate endoscopic surveillance is implemented.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

Patients with ulcerative colitis (UC) receiving liver transplantation (LT) due to primary sclerosing cholangitis (PSC) have higher risk of developing colorectal cancers (CRC). Aim of this systematic review was to define the patients' features, immunosuppressive management, and oncological outcomes of LT recipients with UC-PSC developing CRC.

Searches were conducted in PubMed (MEDLINE), Cochrane Library, Web of Science for all English articles published until September 2023. Inclusion criteria were original articles including patients specifying outcomes of interest. Primary endpoints comprised incidence of CRC, disease free survival (DFS), overall survival (OS) and cancer recurrence. Secondary endpoints were patient's and tumor characteristics, graft function, immunosuppressive management and PSC recurrence. PROSPERO CRD42022369190.

Fifteen studies included, 88 patients were identified. Patients (mean age: 50 years) had a long history of UC (20 years), mainly with active colitis (79%), and developed tumor within the first 3 years from LT, while receiving a double or triple immunosuppressive therapy. Cumulative incidence of tumor was 5.5%. At one, two and three years, DFS was 92%, 82% and 75%, while OS was 87%, 81% and 79% respectively. Disease progression rate was 15%. After CRC surgery, 94% of patients maintained a good graft functionality, with no reported cases of PSC recurrence.

After LT, patients with PSC and UC have an increased risk of CRC, especially in presence of long history of UC and active colitis. Surgical resection guarantees satisfactory mid-term oncological outcomes, but samples are limited, and long-term data are lacking. National and international registry are auspicial to evaluate long-term oncological outcomes and to optimize clinical management.

Endoscopic retrograde cholangiopancreatography (ERCP) may help detect cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC), but it may be associated with complications. This study was aimed at determining the prognostic impact of ERCP on patients with PSC without cholangitis.

Patients with PSC without cholangitis were divided into two groups: those who underwent ERCP within three years after diagnosis (ERCP-performed group) and those who did not (non-ERCP group). These groups were compared in terms of clinical outcomes (liver-related death or liver transplantation, endoscopic treatment requirement and repeated cholangitis) and the composite outcome.

Of 99 patients with PSC with detailed medical history, 49 were included in the ERCP-performed group and 21 in the non-ERCP group. In Kaplan-Meier analysis, the non-ERCP group was less likely to achieve the three outcomes and the composite outcome, showing statistical significance (endoscopic treatment requirement; p = 0.017 and composite outcome; p = 0.014). A Cox proportional hazards model indicated that ERCP in the asymptomatic state was a significant predictor of endoscopic treatment requirement (hazard ratio [HR]: 4.37, 95% confidence interval [CI]: 1.03-18.59) and the composite outcome (HR: 4.54, 95% CI: 1.07-19.28).

ERCP in patients with PSC without cholangitis is likely to require further endoscopic treatment and may be associated with poor prognosis.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disorder without effective medical treatment which is characterized by inflammation and fibrotic structures around the bile ducts. Biliary epithelial cells (cholangiocytes) are the target and potential disease drivers in PSC, yet little is known if cholangiocytes from PSC patients differ from non-PSC controls. To characterize cholangiocytes at early rather than end-stage disease, cholangiocyte organoids (COs) were derived from diseased bile ducts of PSC patients and compared to organoids generated from disease controls.

Cholangiocytes were obtained during endoscopic retrograde cholangiopancreatography (ERCP) brushing of diseased bile duct areas and expanded as organoids using previously established culture methods. Stable CO lines were analyzed for cell type identity, basic cholangiocyte function, and transcriptomic signature.

We demonstrate that cholangiocytes, derived from the damaged area within the bile ducts of PSC patients, can be expanded in culture without displaying functional or genetic disease-related features. We further show that COs from patients who later were diagnosed with dysplasia exhibit higher expression of the cancer-associated genes PGC, FXYD2, MIR4435-2HG, and HES1.

Our results demonstrate that PSC organoids are largely similar to control organoids after culture and highlight the significance of COs as a tool for regenerative medicine approaches as well as their potential for discovering new potential biomarkers for diagnosing cholangiocarcinoma.

The influence of metabolic dysfunction-associated steatotic liver disease (MASLD) on gallbladder polyp development in both sexes remains elusive. Therefore, to clarify the role of MASLD in gallbladder polyp development, we investigated the longitudinal association between MASLD and gallbladder polyps. In this observational study, we included 5,527 gallbladder polyp-free patients who underwent > 2 health check-ups over > 2 years. Generalized estimation equations were used to analyze associations between MASLD and gallbladder polyp development according to repeated measures at baseline and the most recent stage. Gallbladder polyp development rates in men and women were 7.5% and 5.6% (p < 0.01), respectively. MASLD was not significantly correlated with gallbladder polyp development. Regarding the association between gallbladder polyp development (men: ≥6 mm and women: ≥5 mm) and the number of MASLD components following lifestyle habits, men and women with ≥ 4 MASLD components had odds ratios of 3.397 (95% confidence interval: 1.096-10.53) and 5.338 (1.054-27.04), respectively. Higher nonalcoholic fatty liver disease fibrosis scores were associated with significant risk of gallbladder polyp development in women (1.991, 1.047-3.785). Although MASLD influence on gallbladder polyp development differs by sex, close monitoring of patients with an increasing number of MASLD components is essential to prevent gallbladder polyp development. Specifically, men with ≥ 4 MASLD components should be monitored for gallbladder polyps measuring ≥ 6 mm.

Primary sclerosing cholangitis (PSC) increases the risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients; however, there is a paucity of literature to suggest PSC alone as an independent risk factor for CRC. We aimed to determine if PSC is an independent risk factor for CRC in a large tertiary care medical center. Optimizing screening intervals is of great importance, given the burden and risks associated with a lifetime of colonoscopy screening.

This retrospective cohort study consists of patients diagnosed with PSC preceding IBD (PSC-IBD) and PSC-only before January 6, 2023 from a large, tertiary, academic medical center. Patients diagnosed with IBD concurrently or before PSC were excluded to reduce IBD's impact on CRC risk. Demographic data and colonoscopy findings were collected and assessed.

Overall, 140 patients from all NYU Langone Health clinical settings were included. Patients with PSC-IBD were more likely to be diagnosed with CRC (23.3% vs. 1.8%, p < 0.01) and either low-grade or uncharacterized dysplasia (16.7% vs. 0.0%, p < 0.01) compared with those with PSC-only. Among PSC-only patients, the estimated CRC risk was significantly elevated compared with that expected of the standard NYU Langone population (SIR 9.2, 95% CI 1.1, 33.2).

Our study revealed a significantly heightened CRC risk in PSC-IBD patients compared with those with PSC-only. Importantly, individuals with PSC-only also face a greater CRC risk compared with the general population. Individuals with PSC-alone may require extended screening and surveillance colonoscopy intervals compared with those with PSC-IBD, yet still require more frequent monitoring than screening guidelines recommend for the general population.

Biliary reconstruction technique during liver transplant (LT) for primary sclerosing cholangitis (PSC) remains controversial. This study aimed to evaluate the incidence of biliary complications in patients with PSC having a duct-to-duct (DD) anastomosis or Roux-en-Y hepaticojejunostomy (HJ).

A retrospective medical record review of patients with PSC undergoing LT at a single center between June 1st, 2000 and December 31st, 2022 was performed. Primary and secondary endpoints were the incidence of biliary strictures (anastomotic [BAS] and non-anastomotic strictures [NAS]) and non-stricture complications, respectively. Univariable and multivariable regression analyses were performed to identify associations with BAS formation. Patient survival was assessed using a Kaplan-Meier curve.

From 105 transplants performed for 101 patients, 54 (51.4%) and 51 (48.5%) received DD and HJ anastomoses. Mean recipient age and follow-up was 47 ± 13 years and 98 ± 69 months. BAS was more common (48.1% vs. 27.5%, OR 2.45, 95% CI 1.09-5.54, p = 0.03) and occurred earlier (4.8 months, IQR 2.3-13.1 vs. 41.8 months, IQR 7.2-88.7, p = 0.001) in the DD than the HJ group. NAS (seen in 36.2% of transplants) had a comparable incidence (p = 0.53) in HJ (38.9%) and DD (33.3%) groups. No difference was seen between cohorts regarding time to NAS, requirement for extended biliary dilatation programs (clinically significant biliary stricture), bile leak, and graft failure. On multivariable analysis, only the anastomotic technique was associated with BAS (DD adjusted OR 3.00, 95% CI 1.19-7.56, p = 0.02).

In carefully selected patients with PSC, DD anastomosis yielded similar outcomes to HJ anastomosis after liver transplantation.

Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems.

Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group.

ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.

The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH.

pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers (n = 285).

IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31-73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6-20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21-34% higher accuracy than conventional autoantibodies, was positive in 43-75% of children with AIH and normal IgG and independent from treatment response.

Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity.

The epigenome, the set of modifications to DNA and associated molecules that control gene expression, cellular identity, and function, plays a major role in mediating cellular responses to outside factors. Thus, evaluation of the epigenetic state can provide insights into cellular adaptions occurring over the course of disease.

We performed epigenome-wide association studies of primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) using the Illumina MethylationEPIC Bead Chip.

We found evidence of increased epigenetic age acceleration and differences in predicted immune cell composition in patients with PSC and PBC. Epigenetic profiles demonstrated differences in predicted protein levels including increased levels of tumor necrosis factor receptor superfamily member 1B in patients with cirrhotic compared to noncirrhotic PSC and PBC. Epigenome-wide association studies of PSC discovered strongly associated 5'-C-phosphate-G-3' sites in genes including vacuole membrane protein 1 and SOCS3, and epigenome-wide association studies of PBC found strong 5'-C-phosphate-G-3' associations in genes including NOD-like receptor family CARD domain containing 5, human leukocyte antigen-E, and PSMB8. Analyses identified disease-associated canonical pathways and upstream regulators involved with immune signaling and activation of macrophages and T-cells. A comparison of PSC and PBC data found relatively little overlap at the 5'-C-phosphate-G-3' and gene levels with slightly more overlap at the level of pathways and upstream regulators.

This study provides insights into methylation profiles of patients that support current concepts of disease mechanisms and provide novel data to inspire future research. Studies to corroborate our findings and expand into other -omics layers will be invaluable to further our understanding of these rare diseases with the goal to improve and individualize prognosis and treatment.

The prevalence of liver disease is rising and more patients with liver disease are considered for surgery each year. Liver disease poses many potential complications to surgery; therefore, assessing perioperative risk and optimizing a patient's liver health is necessary to decrease perioperative risk. Multiple scoring tools exist to help quantify perioperative risk and can be used in combination to best educate patients prior to surgery. In this review, we go over the various scoring tools and provide a guide for clinicians to best assess and optimize perioperative risk based on the etiology of liver disease.

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

The relationship between primary sclerosing cholangitis (PSC) and biliary bile acids (BAs) remains unclear. Although a few studies have compared PSC biliary BAs with other diseases, they did not exclude the influence of cholestasis, which affects the composition of BAs. We compared biliary BAs and microbiota among patients with PSC, controls without cholestasis, and controls with cholestasis, based on the hypothesis that alterations in BAs underlie the pathophysiology of PSC.

Bile samples were obtained using endoscopic retrograde cholangiopancreatography from patients with PSC (n = 14), non-hepato-pancreato-biliary patients without cholestasis (n = 15), and patients with cholestasis (n = 13).

The BA profiles showed that patients with PSC and cholestasis controls had significantly lower secondary BAs than non-cholestasis controls, as expected, whereas the ratio of cholic acid/chenodeoxycholic acid in patients with PSC was significantly lower despite cholestasis, and the ratio of (cholic acid + deoxycholic acid)/(chenodeoxycholic acid + lithocholic acid) in patients with PSC was significantly lower than that in the controls with or without cholestasis. The BA ratio in the bile of patients with PSC showed a similar trend in the serum. Moreover, there were correlations between the alteration of BAs and clinical data that differed from those of the cholestasis controls. Biliary microbiota did not differ among the groups.

Patients with PSC showed characteristic biliary and serum BA compositions that were different from those in other groups. These findings suggest that the BA synthesis system in patients with PSC differs from that in controls and patients with other cholestatic diseases. Our approach to assessing BAs provides insights into the pathophysiology of PSC.

Primary sclerosing cholangitis (PSC) is an (auto)immune-mediated cholestatic liver disease with a yet unclear etiology. Increasing evidence points to an involvement of neutrophils in chronic liver inflammation and cirrhosis but also liver repair. Here, we investigate the role of the neutrophil extracellular trap (NET) component myeloperoxidase (MPO) and the therapeutic potential of DNase I and of neutrophil elastase (NE) inhibitor GW311616A on disease outcome in the multidrug resistance 2 knockout (Mdr2-/-) mouse, a PSC animal model. Initially, we observed the recruitment of MPO expressing cells and the formation of NETs in liver biopsies of PSC patients and in Mdr2-/- livers. Furthermore, sera of Mdr2-/- mice contained perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)-like reactivity similar to PSC patient sera. Also, hepatic NE activity was significantly higher in Mdr2-/- mice than in wild type littermates. Flow cytometry analyses revealed that during disease development a highly active neutrophil subpopulation established specifically in the liver of Mdr2-/- mice. However, absence of their MPO activity, as in MPO-deficient Mdr2-/- mice, showed no effect on hepatobiliary disease severity. In contrast, clearance of extracellular DNA by DNase I reduced the frequency of liver-resident neutrophils, plasmacytoid dendritic cells (pDCs) and CD103+ conventional DCs and decreased cholangiocyte injury. Combination of DNase I with a pDC-depleting antibody was additionally hepatocyte-protective. Most importantly, GW311616A, an orally bioavailable inhibitor of human NE, attenuated hepatobiliary injury in a TNFα-dependent manner and damped hyperproliferation of biliary epithelial cells. Further, hepatic immigration and activity of CD11b+ DCs as well as the secretion of IFNγ by hepatic CD4 and CD8 T cells were reduced. Our findings delineate neutrophils as important participants in the immune cell crosstalk that drives cholestatic liver disease and identify NET components as potential therapeutic targets.

Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings.

There are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic).

This study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC.

Patients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement.

Our cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age (mean 37.9 vs. 43.0 years, P = 0.045), the IIPSC group was not different from the extra/intrahepatic. The IIPSC group had longer transplant-free survival (log-rank P = 0.001) with a significantly lower risk for liver transplantation (12% vs. 34%, P < 0.001). The IIPSC group had a lower risk of death or transplantation than the extra/intrahepatic PSC group [HR: 0.34, 95% CI: 0.17-0.67, P < 0.001]. No bile duct or gallbladder cancers developed in patients with IIPSC, compared to 24 in the extra/intrahepatic group. The clinical characteristics and outcomes of IIPSC were similar to 23 individuals with small-duct PSC.

Patients with IIPSC have a favorable prognosis similar to small-duct PSC. These data are important for counseling patients and designing therapeutic trials for PSC.

Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation.

The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression.

Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study.

Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, β and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC.

The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.

Hilar cholangiocarcinoma is considered a biologically aggressive disease for which surgical resection remains the only curative treatment. Preoperative evaluation for resectability is challenging given tumor proximity to the porta hepatis, but minimal benefit and increased morbidity precludes recommendation for margin positive resection. This article reviews the determination of unresectability in hilar cholangiocarcinoma through discussion of the preoperative assessment, the intraoperative assessment, and key steps of surgical resection, as well as treatment options for unresectable tumors. Overall, evaluating patients preoperatively for resectability requires a multidisciplinary, holistic, and individualized approach to accurately determine resectability and optimize clinical outcomes for patients with hilar cholangiocarcinoma.

Primary sclerosing cholangitis (PSC) is considered an immunologically mediated disease. However, some of its features are not consistent with the typical profile of autoimmune conditions. PSC is characterized by progressive biliary fibrosis that may ultimately result in the eventual development of cirrhosis. In recent years, multiple studies have reported that the incidence and prevalence of this disease are on the rise. Consequently, patients are often diagnosed without symptoms or signs of advanced liver disease, although many still present with signs of decompensated liver disease. This article discusses the epidemiology, clinical presentation, and diagnostic workup in patients with PSC.

Cholangiocarcinoma (CCA) is a deadly complication observed in the setting of primary sclerosing cholangitis (PSC). When symptoms develop and CCA is diagnosed, it is usually at an advanced stage. Median survival is less than 12 months. Early identification of CCA leads to improved outcomes. Although diagnostic tests have excellent specificity, they are plagued by low sensitivity. No surveillance strategies have been widely agreed upon, but most societies recommend measurement of serum carbohydrate antigen 19-9 and MRCP every 6 to 12 months in patients with PSC. Advances in understanding of the genetic factors that lead to CCA are awaited.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the biliary tree leading to biliary strictures, cholangitis, and cirrhosis. Early in presentation, patients may have normal liver tests, though over time develop a cholestatic pattern of liver injury. Diagnosis is made radiographically with magnetic resonance or endoscopic cholangiography. While several autoantibodies are associated with PSC, none have proven to have adequate diagnostic utility. Liver biopsy is rarely recommended unless to evaluate for small-duct PSC or overlap syndrome. Elastography, in various forms, is an effective, non-invasive modality to evaluate liver fibrosis in PSC.

Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory liver disease characterized by biliary strictures and cholestasis. Due to the lack of effective serological indicators for diagnosis and prognosis, in the present study, we examined the potentiality of the saliva proteome to comprehensively screen for novel biomarkers.

Saliva samples of PSC patients and healthy controls were processed and subsequently analyzed using a liquid chromatography-tandem mass spectrometry technique. A bioinformatic approach was applied to detect the differentially expressed proteins, their related biological functions and pathways, and the correlation with the clinical evidence in order to identify a possible marker for the PSC group.

We identified 25 differentially expressed proteins in PSC patients when compared to the healthy control group. Among them, eight proteins exhibited area under the curve values up to 0.800, suggesting these saliva proteins as good discriminators between the two groups. Multiple positive correlations were also identified between the dysregulated salivary proteins and increased serum alkaline phosphatase levels and the presence of ulcerative colitis. Pathway analysis revealed significant enrichments in the immune system, neutrophil degranulation, and in the interleukine-17 signaling pathway.

We demonstrated the potentiality of saliva as a useful biofluid to obtain a fingerprint of the pathology, suggesting disulfide-isomerase A3 and peroxiredoxin-5 as the better discriminating proteins in PSC patients. Hence, analysis of saliva proteins could become, in future, a useful tool in the screening of patients with suspected PSC.