Pursuing living donor liver transplantation improves outcomes of patients with autoimmune liver diseases: An intention-to-treat analysis.

Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with autoimmune liver disease (AILD), autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. We compared the survival of patients with a potential living donor (pLDLT) on the waitlist versus no potential living donor (pDDLT) on an intention-to-treat basis. Our retrospective cohort study investigated adults with AILD listed for a liver transplant in our program between 2000 and 2021. The pLDLT group comprised recipients with a potential living donor. Otherwise, they were included in the pDDLT group. Intention-to-treat survival was assessed from the time of listing. Of the 533 patients included, 244 (43.8%) had a potential living donor. Waitlist dropout was higher for the pDDLT groups among all AILDs (pDDLT 85 [29.4%] vs. pLDLT 9 [3.7%], p < 0.001). The 1-, 3-, and 5-year intention-to-treat survival rates were higher for pLDLT versus pDDLT among all AILDs (95.7% vs. 78.1%, 89.0% vs. 70.1%, and 87.1% vs. 65.5%, p < 0.001). After adjusting for covariates, pLDLT was associated with a 38% reduction in the risk of death among the AILD cohort (HR: 0.62, 95% CI: 0.42-0.93 [ p <0.05]), and 60% among the primary sclerosing cholangitis cohort (HR: 0.40, 95% CI: 0.22-0.74 [ p <0.05]). There were no differences in the 1-, 3-, and 5-year post-transplant survival between LDLT and DDLT (AILD: 95.6% vs. 92.1%, 89.9% vs. 89.4%, and 89.1% vs. 87.1%, p =0.41). This was consistent after adjusting for covariates (HR: 0.97, 95% CI: 0.56-1.68 [ p >0.9]). Our study suggests that having a potential living donor could decrease the risk of death in patients with primary sclerosing cholangitis on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups.

Imaging-based diagnosis of sarcopenia for transplant-free survival in primary sclerosing cholangitis.

BACKGROUND: Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC. METHODS: A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause. RESULTS: Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141). CONCLUSION: Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation.

Primary Sclerosing Cholangitis: Gender Effects in Valencia's Low-Prevalence Region.

BACKGROUND AND AIMS: Recent studies point out to epidemiological changes in primary sclerosing cholangitis (PSC). Our aims were to determine in PSC patients followed in several centers in a Mediterranean geographic area: (i) changes in baseline features and (ii) effect of gender on clinical course. METHODS: Retrospective multicenter study of PSC patients treated in 8 hospitals in a Mediterranean area between 2000 and 2021. Charts were reviewed compiling demographic, clinical, radiological, and histological variables. RESULTS: Cohort of 112 PSC patients included, 42% women, 70% diagnosed after 2010. Women were increasingly diagnosed in recent cohorts. The median time from diagnosis to the combined endpoint liver transplantation (Lt) and/or death was 6.9 years. Asthenia at diagnosis (p = 0.009) was associated with lower transplant-free survival, while diagnosis before 2005 was associated with greater LT-free survival (p < 0.001). By Cox regression, LT-free survival was not influenced by age, sex, or cirrhosis at the time of diagnosis. Women were found to have less jaundice at diagnosis (2 vs 14%; p = 0.013), higher prevalence of ANA antibodies (43.9 vs 15.7%; p = 0.003), and lower GGT levels at diagnosis (GGT 123 vs 209U/L; p = 0.014) than men. CONCLUSION: In an area traditionally considered to have low prevalence, the prevalence of affected women surpasses expectations based on existing literature. There appear to be gender-related variations in the presentation of the condition, highlighting the need for confirmation through larger-scale studies.

Influence of socioeconomic factors on liver transplant survival outcomes in patients with autoimmune liver disease in the United States.

INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILDs): autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) have different survival outcomes after liver transplant (LT). Outcomes are influenced by factors including disease burden, medical comorbidities, and socioeconomic variables. MATERIALS AND METHODS: Using the United Network for Organ Sharing database (UNOS), we identified 13,702 patients with AILDs listed for LT between 2002 and 2021. Outcomes of interest were waitlist removal, post-LT patient survival, and post- LT graft survival. A stepwise multivariate analysis was performed adjusting for transplant recipient gender, race, diabetes mellitus, model for end-stage liver disease (MELD) score, and additional social determinants including the presence of education, reliance on public insurance, working for income, and U.S. citizenship status. RESULTS: Lack of college education and having public insurance increased the risk of waitlist removal (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.09; 95 % CI, 1.00-1.18; respectively), and negatively influenced post-LT patient survival (HR, 1.16; 95 % CI, 1.06-1.26, and HR, 1.15; 95 % CI, 1.06-1.25; respectively) and graft survival (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.15; 95 % CI, 1.06-1.25; respectively). Not working for income proved to have the greatest detrimental impact on both patient survival (HR, 1.41; 95 % CI, 1.24-1.6) and graft survival (HR, 1.21; 95 % CI, 1.09-1.35). CONCLUSIONS: Our study highlights that lack of college education and public insurance have a detrimental impact on waitlist mortality, patient survival, and graft survival. Not working for income negatively affects post-LT survival outcomes. Not having U.S. citizenship does not affect survival outcomes in AILDs patients.

Ileal pouch-anal anastomosis and end ileostomy result in equivalent graft survival following liver transplantation for inflammatory bowel disease-primary sclerosing cholangitis.

INTRODUCTION: Patients with inflammatory bowel disease and primary sclerosing cholangitis may require both liver transplantation and colectomy. There are concerns about increased rates of hepatic artery thrombosis, biliary strictures, and hepatic graft loss in patients with ileal pouch-anal anastomosis compared to those with end ileostomy. We hypothesized that graft survival was not negatively affected by ileal pouch-anal anastomosis compared to end ileostomy. MATERIALS AND METHODS: A tertiary center's database was searched for patients meeting the criteria of liver transplantation because of primary sclerosing cholangitis and total proctocolectomy with ileal pouch-anal anastomosis or end ileostomy because of ulcerative colitis. Primary endpoints were hepatic graft survival and post-transplant complications. RESULTS: Fifty-five patients met the inclusion criteria between January 1990 and December 2022. Of these, 46 (84%) underwent ileal pouch-anal anastomosis, and 9 (16%) underwent end ileostomy. The average age at total proctocolectomy (41.5 vs. 49.1 years; p = 0.12) and sex distribution (female: 26.1% vs. 22.2%; p = 0.99) were comparable. The rates of re-transplantation (21.7% vs. 22.2%; p = 0.99), hepatic artery thrombosis (10.8% vs. 0; p = 0.58), acute rejection (32.6% vs. 44.4%; p = 0.7), chronic rejection (4.3% vs. 11.1%; p = 0.42), recurrence of primary sclerosing cholangitis (23.9% vs. 22.2%; p = 0.99), and biliary strictures (19.6% vs. 33.3%; p = 0.36) were similar between the ileal pouch-anal anastomosis and end ileostomy groups, respectively. None of the end ileostomy patients developed parastomal varices. The log-rank tests for graft (p = 0.97), recipient (p = 0.3), and combined graft/recipient survival (p = 0.73) were similar. CONCLUSION: Ileal pouch-anal anastomosis did not negatively affect graft, recipient, and combined graft/recipient survival, or the long-term complications, compared to end ileostomy.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Male Sex Is Associated With Higher Rates of Liver-Related Mortality in Primary Biliary Cholangitis and Cirrhosis.

BACKGROUND AND AIMS: The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis. APPROACH AND RESULTS: We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P < 0.0001), liver-related death or transplantation (5.5 vs. 2.7 per 100 PY; P < 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P < 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01-3.19; P = 0.046), and liver-related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15-4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings. CONCLUSIONS: In patients with PBC and well-compensated cirrhosis, male sex is associated with a higher risk of both death and liver-related death or transplantation.

Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.

Background: There are only a few and mostly small population-based epidemiological studies of primary sclerosing cholangitis (PSC).Objective: We aimed to estimate prevalence and incidence rates of PSC, and survival and malignancy risk for PSC patients in a large population-based study.Methods: We retrieved 632 PSC patients from 1990 to 2015 in the Hospital District of Helsinki and Uusimaa (HUS), comprising 29% of the Finnish population. Mortality information of the PSC patients was obtained from the national Population Registry, malignancy information from the Finnish Cancer Registry and the causes of death from the Statistics Finland. Standardized incidence ratio and standardized mortality ratio (SMR) were calculated for predefined malignancy types.Results: The crude incidence of PSC in the HUS area was 1.58/100,000 person-years, and the point prevalence in 2015 was 31.7/100,000 inhabitants. The mean time from diagnosis to death was 21.9 years. The risk for any malignancy was three-fold and the risk for colorectal carcinoma was five-fold when comparing with the general population. During the first year after diagnosis of PSC, the risk for cholangiocarcinoma is 900-fold compared to the general population and after that 150-fold. SMR for all malignant neoplasms was 5.9 (95% CI 4.2-8.1).Conclusion: We found that the incidence of PSC in the HUS area in Finland is similar or higher than previously reported from other countries. The prevalence is markedly higher than reported elsewhere, probably due to the active search of the disease, suggesting that the disease is underdiagnosed.

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.

BACKGROUND: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. METHODS: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. RESULTS: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. CONCLUSIONS: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Validation, clinical utility and limitations of the Amsterdam-Oxford model for primary sclerosing cholangitis.

BACKGROUND & AIMS: Recently the Amsterdam-Oxford model (AOM) was introduced as a prognostic model to assess the risk of death and/or liver transplantation (LT) in primary sclerosing cholangitis (PSC). We aimed to validate and assess the utility of the AOM. METHODS: Clinical and laboratory data were collected from the time of PSC diagnosis until the last visit or time of LT or death. The AOM was calculated at yearly intervals following PSC diagnosis. Discriminatory performance was assessed by calculation of the C-statistic and prediction accuracy by comparing the predicted survival with the observed survival in Kaplan-Meier estimates. A grid search was performed to identify the most discriminatory AOM threshold. RESULTS: A total of 534 patients with PSC and a mean (SD) age of 39.2 (13.1) years were included. The diagnosis was large duct PSC in 466 (87%), PSC with features of autoimmune hepatitis in 52 (10%) and small-duct PSC in 16 (3%). During the median (IQR) follow-up of 7.8 (4.0-12.6) years, 167 patients underwent LT and 65 died. The median LT-free survival was 13.2 (11.8-14.7) years. The C-statistic of the AOM ranged from 0.67 at baseline to 0.75 at 5 years of follow-up. The difference between the predicted and observed survival ranged from -1.6% at 1 year to + 3.9% at 5 years of follow-up. Patients that developed AOM scores >2.0 were at significant risk of LT or death (time-dependent hazard ratio 4.09; 95% CI 2.99-5.61). CONCLUSIONS: In this large cohort of patients with PSC, the AOM showed an adequate discriminative performance and good prediction accuracy at PSC diagnosis and during follow-up. This study further validates the AOM as a valuable risk stratification tool in PSC and extends its utility. LAY SUMMARY: In our study we assessed whether the Amsterdam-Oxford model (AOM) is able to correctly estimate the risk of liver transplantation or death in patients with primary sclerosing cholangitis (PSC). This model uses 7 objective and readily available variables to estimate prognosis for individual patients at the time of PSC diagnosis. The AOM may aid in patient counselling and timing of diagnostic procedures or therapeutic interventions for complications of liver disease. We confirm that the model works well at PSC diagnosis, but also when the AOM is recalculated at different timepoints during follow-up, greatly improving the applicability of the model in clinical practice and for individual patients.

Contributing factors and outcomes of burn-associated cholestasis.

BACKGROUND & AIMS: Cholestasis often occurs after burn injuries. However, the prevalence of cholestasis and its effect on outcomes in patients with severe burn injuries are unknown. The aim of this study was to describe the course and the burden of cholestasis in a cohort of severely burned adult patients. METHODS: We investigated the relationship between burn-associated cholestasis (BAC) and clinical outcomes in a retrospective cohort of patients admitted to our unit for severe burn injuries between 2012 and 2015. BAC was defined as an increased level of serum alkaline phosphatase (ALP) ≥1.5x the upper limit of normal (ULN) with an increased level of gamma-glutamyltransferase (GGT) ≥3x ULN, or as an increased level of total bilirubin ≥2x ULN. RESULTS: A total of 214 patients were included: 111 (52%) patients developed BAC after a median (IQR) stay of 9 (5-16) days. At 90 days, the mortality rate was 20%, including 34 and 9 patients with and without BAC (p <0.001), respectively, which corresponded to a 2.5-fold higher (95% CI 1.2-5.2, p = 0.012) risk of 90-day mortality for patients with BAC. After being adjusted for severity of illness, patients with BAC, hyperbilirubinemia and without elevated ALP and GGT levels had a hazard ratio of 4.51 (95% CI 1.87-10.87) for 90-day mortality. BAC was associated with the severity of the burn injury, shock and bacteraemia. BAC was present in 38 (51%) patients at discharge, and 7 (18%) patients had secondary sclerosing cholangitis. These patients maintained elevated levels of ALP and GGT that were 5.8x (1.7-15) the ULN and 11x the ULN (4.5-22), respectively, 20 months (3.5-35) after discharge. CONCLUSION: BAC is prevalent among patients with severe burn injuries and is associated with worse short-term outcomes, especially when total bilirubin levels were increased without elevated ALP and GGT levels. BAC survivors are at risk of developing sclerosing cholangitis. LAY SUMMARY: Cholestasis is common after burn injuries and is associated with burn severity, sepsis, organ failure and mortality. Patients with hyperbilirubinemia without elevated alkaline phosphatase and gamma-glutamyltransferase levels after the burn injury have a poor prognosis. Patients with burn-associated cholestasis may develop sclerosing cholangitis and secondary biliary cirrhosis.

The Complementary Value of Magnetic Resonance Imaging and Vibration-Controlled Transient Elastography for Risk Stratification in Primary Sclerosing Cholangitis.

OBJECTIVES: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value. METHODS: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models. RESULTS: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively. DISCUSSION: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis.

BACKGROUND & AIMS: One important hypothesis in primary sclerosing cholangitis pathophysiology suggests that bacterial products from an inflamed leaky gut lead to biliary inflammation. We aimed to investigate whether circulating markers of bacterial translocation were associated with survival in a Norwegian primary sclerosing cholangitis cohort. METHODS: Serum levels of zonulin, intestinal fatty acid binding protein, soluble CD14, lipopolysaccharide and lipopolysaccharide-binding protein were measured in 166 primary sclerosing cholangitis patients and 100 healthy controls. RESULTS: Lipopolysaccharide-binding protein and soluble CD14 were elevated in primary sclerosing cholangitis compared with healthy controls (median 13 662 vs 12 339 ng/mL, P = 0.010 and 1657 vs 1196 ng/mL, P < 0.001, respectively). High soluble CD14 and lipopolysaccharide-binding protein (values >optimal cut-off using receiver operating characteristics) were associated with reduced liver transplantation-free survival (P < 0.001 and P = 0.005, respectively). The concentration of soluble CD14 was higher in patients with hepatobiliary cancer compared to other primary sclerosing cholangitis patients and healthy controls. Zonulin was lower in primary sclerosing cholangitis than controls, but when excluding primary sclerosing cholangitis patients with increased prothrombin time zonulin concentrations were similar in primary sclerosing cholangitis and healthy controls. Concomitant inflammatory bowel disease did not influence the results, while inflammatory bowel disease patients without primary sclerosing cholangitis (n = 40) had lower concentration of soluble CD14. In multivariable Cox regression, high soluble CD14 and high lipopolysaccharide-binding protein were associated with transplantation-free survival, independent from Mayo risk score (HR: 2.26 [95% CI: 1.15-4.43], P = 0.018 and HR: 2.00 [95% CI: 1.17-3.43], P = 0.011, respectively). CONCLUSIONS: Primary sclerosing cholangitis patients show increased levels of circulating markers of bacterial translocation. High levels are associated with poor prognosis measured by transplantation-free survival, indicating that ongoing gut leakage could have clinical impact in primary sclerosing cholangitis.

Disease progression in paediatric- and adult-onset sclerosing cholangitis: Results from two independent Dutch registries.

BACKGROUND & AIMS: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. METHODS: Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. RESULTS: Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. CONCLUSION: Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.

Association between serum IgG level and clinical course in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a chronic cholestatic liver disease. The pathomechanism is still not fully understood, but there is evidence that immune-mediated processes may contribute to disease progression. METHODS: We studied the prognostic relevance of serum immunoglobulin G (IgG) elevated above the upper limit of normal as a marker for immune activation at initial diagnosis and its influence on transplantation-free survival in a well-defined cohort of PSC patients. RESULTS: The final study cohort comprises of 148 PSC patients. Elevated IgG levels were found in 66 patients (44.6%). Apart from their younger age at first diagnosis, there was no significant difference between patients with or without elevated IgG levels. The presence of a concomitant inflammatory bowel disease, an autoimmune hepatitis or immunosuppressive medication was equally distributed between both groups. Patients with elevated IgG levels reached the combined endpoint (34 (59.6%) vs. 23 (40.4%); p = 0.004) significantly more often and had reduced transplantation-free survival (Log-rank: 24.0 (10.2-37.9) vs. 14.0 (8.5-19.5); p < 0.05). Cox regression analysis including age, gender, presence of IBD, presence of dominant stricture (DS), Mayo Risk Score (MRS), immunosuppression, biochemical response to UDCA and elevated IgG-levels confirmed MRS (p = 0.03), DS (p = 0.04), biochemical response (p = 0.04) and elevated IgG level (p = 0.04) as independent risk factors for reduced transplantation-free survival. CONCLUSION: We identified elevated serum IgG levels at first diagnosis as an independent risk factor for reduced transplant free-survival in patients with PSC.

Quantitative spleen and liver volume changes predict survival of patients with primary sclerosing cholangitis.

AIM: To assess the value of quantitative spleen and liver volume changes in predicting the survival of patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: This institutional review board-approved single-centre study included 89 PSC patients with baseline and follow-up liver imaging studies and laboratory data between 2000 and 2018. Change in spleen, total and lobar liver volumes, and lobar-to-total liver volume ratio was compared between patients with and without adverse outcome (liver transplantation, transplant waiting list, and death). Receiver operating characteristic (ROC) and Kaplan-Meier analysis were performed to identify the volumetric threshold for prediction of outcome and show how these thresholds predict survival, respectively. A p-value of <0.05 was considered statistically significant. RESULTS: The present cohort included 53 men (60%), with mean age of 42 years at baseline. The only volumetric parameters with significant differences in change between patients with and without adverse outcome were spleen volume (p<0.001) and left-to-total liver volume ratio (L/T; p=0.025). The probability of transplant-free survival at 36 months was 59.1% versus 11.9% for patients with spleen volume change <50 ml versus ≥50 ml, respectively (AUC=0.731); and 61.3% versus 13.8% for patients with L/T change <0.04 versus ≥0.04, respectively (AUC=0.638). The patients with changes below the cut-off in both spleen volume and L/T, had a higher probability of transplant-free survival at 36 months (76.8%), compared to those with change at or below the cut-offs in one or both of these two parameters (36.7%, 15%, respectively; p=0.001). CONCLUSION: Spleen volume change and L/T change might be useful biomarkers for prediction of transplant-free survival in patients with PSC.

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

A novel prognostic model for transplant-free survival in primary sclerosing cholangitis.

OBJECTIVE: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. DESIGN: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. RESULTS: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. CONCLUSION: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.