Dominant stricture in paediatric-onset primary sclerosing cholangitis is associated with impaired prognosis in a long-term follow-up.

BACKGROUND AND OBJECTIVES: The impact of dominant stricture (DS) on the outcomes of paediatric-onset primary sclerosing cholangitis (PSC) is unknown. This study was aimed at investigating the impact of DS on the clinical course and prognosis of patients with paediatric-onset PSC. METHODS: Patients with paediatric-onset PSC diagnosed between January 1993 and May 2017 were identified from hospital records or our PSC registry. Data including clinical, laboratory, cholangiography, and cytology at diagnosis and during follow-up (until July 2023) were reviewed. We graphed the Kaplan-Meier failure function and fitted crude and multivariable Cox model to calculate hazard ratios (HR) and 95% confidence intervals (CI) for selected variables. In these analyses, DS was treated as a time-varying variable. RESULTS: We identified 68 patients (42 males) with paediatric-onset PSC (median age at diagnosis 15 years). The median follow-up was 13 years and the median age at the last follow-up was 27 years. In total, 35 (51%) had concomitant autoimmune hepatitis. DS was diagnosed in 33 patients (48%): in eight at the time of PSC diagnosis (12%) and in 25 (37%) by the end of follow-up. In patients with DS, two developed cirrhosis, seven were transplanted and one patient was operated for a biliary mass with low-grade dysplasia. In patients without a DS, two developed cirrhosis, and four were transplanted; one female was excluded from survival analysis because she already had cirrhosis at the time of PSC diagnosis. Cirrhosis or biliary dysplasia or needing liver transplantation for these indications were more frequent after the development of DS (10/33, adjusted HR 4.26, 95%CI: 1.26-14.4). No cholangiocarcinomas or deaths occurred during the follow-up. CONCLUSIONS: DS was present at diagnosis or developed during follow-up in about half of the patients with paediatric-onset PSC and was associated with impaired outcome.

NGS of brush cytology samples improves the detection of high-grade dysplasia and cholangiocarcinoma in patients with primary sclerosing cholangitis: A retrospective and prospective study.

BACKGROUND: Biliary dysplasia, a precursor of cholangiocarcinoma (CCA), is a common complication of primary sclerosing cholangitis. Patients with high-grade dysplasia (HGD) or early CCA who have received oncological treatment are candidates for liver transplantation. The preoperative diagnosis of CCA or HGD is challenging, and the sensitivity of biliary brush cytology (BC) is limited. METHODS: By using next-generation sequencing (NGS), we retrospectively analyzed archived tissue samples (n=62) obtained from explanted liver tissue and CCA samples to identify oncogenic mutations that occur during primary sclerosing cholangitis carcinogenesis. BC samples were prospectively collected from patients with primary sclerosing cholangitis (n=97) referred for endoscopic retrograde cholangiography to measure the diagnostic utility of NGS combined with BC compared with traditional cytology alone. RESULTS: Mutations in KRAS, GNAS, FLT3, RNF43, TP53, ATRX, and SMAD4 were detected in archived CCA or HGD samples. KRAS, GNAS, TP53, CDKN2A, FBXW7, BRAF, and ATM mutations were detected in prospectively collected brush samples from patients with histologically verified CCA or HGD. One patient with low-grade dysplasia in the explanted liver had KRAS and GNAS mutations in brush sample. No mutations were observed in brush samples or archived tissues in liver transplantation cases without biliary neoplasia. While KRAS mutations are common in biliary neoplasms, they were also observed in patients without biliary neoplasia during surveillance. CONCLUSIONS: In summary, NGS of BC samples increased the sensitivity of detecting biliary neoplasia compared with traditional cytology. Performing NGS on BC samples may help diagnose HGD or early CCA, benefiting the timing of liver transplantation.

Protocol liver biopsy predicts graft survival after liver transplantation.

BACKGROUND: The use of protocol liver biopsy to monitor liver allograft status remains controversial. There is limited data from modern transplantation populations that includes protocol biopsies to evaluate its value in predicting clinical outcomes. METHODS: All protocol liver biopsies were identified from 875 patients who underwent liver transplantation at Helsinki University Hospital between 2000 and 2019. Each histologic component was analyzed for its ability to predict long-term outcomes, especially graft survival. We determined the frequency of significant biopsy findings based on the Banff working group definition. Liver function tests (LFTs) and clinical markers were evaluated for their ability to predict significant biopsy findings. RESULTS: In total, 867 protocol liver biopsies were analyzed. Significant findings were identified in 20.1% of the biopsies. In the first protocol biopsy, steatohepatitis (hazard ratio [HR] 3.504, p = .03) and moderate or severe congestion (HR 3.338, p = .04) predicted graft loss. The presence of cholangitis (HR 2.563, p = .04), necrosis (HR 7.635, p < .001), mild congestion (HR 4.291, p = .009), and significant biopsy finding (HR 2.540, p = .02) predicted inferior death-censored graft survival. While the degree of elevation of LFTs was positively associated with significant biopsy findings, the discrimination was poor (AUC .572-.622). Combined LFTs and clinical risk factors remained suboptimal for discriminating significant biopsy findings (AUC .696). CONCLUSIONS: Our findings support the use of protocol liver biopsies after liver transplantation since they frequently revealed changes associated with long-term outcomes, even when LFTs were normal.

Genome-wide polygenic risk scores for colorectal cancer have implications for risk-based screening.

BACKGROUND: Hereditary factors, including single genetic variants and family history, can be used for targeting colorectal cancer (CRC) screening, but limited data exist on the impact of polygenic risk scores (PRS) on risk-based CRC screening. METHODS: Using longitudinal health and genomics data on 453,733 Finnish individuals including 8801 CRC cases, we estimated the impact of a genome-wide CRC PRS on CRC screening initiation age through population-calibrated incidence estimation over the life course in men and women. RESULTS: Compared to the cumulative incidence of CRC at age 60 in Finland (the current age for starting screening in Finland), a comparable cumulative incidence was reached 5 and 11 years earlier in persons with high PRS (80-99% and >99%, respectively), while those with a low PRS (< 20%) reached comparable incidence 7 years later. The PRS was associated with increased risk of post-colonoscopy CRC after negative colonoscopy (hazard ratio 1.76 per PRS SD, 95% CI 1.54-2.01). Moreover, the PRS predicted colorectal adenoma incidence and improved incident CRC risk prediction over non-genetic risk factors. CONCLUSIONS: Our findings demonstrate that a CRC PRS can be used for risk stratification of CRC, with further research needed to optimally integrate the PRS into risk-based screening.

Non-erosive gastro-oesophageal reflux disease and incidence of oesophageal adenocarcinoma in three Nordic countries: population based cohort study.

OBJECTIVE: To assess the incidence rate of oesophageal adenocarcinoma among patients with non-erosive gastro-oesophageal reflux disease compared with the general population. DESIGN: Population based cohort study. SETTING: All patients in hospital and specialised outpatient healthcare in Denmark, Finland, and Sweden from 1 January 1987 to 31 December 2019. PARTICIPANTS: 486 556 adults (>18 years) who underwent endoscopy were eligible for inclusion: 285 811 patients were included in the non-erosive gastro-oesophageal reflux disease cohort and 200 745 patients in the validation cohort with erosive gastro-oesophageal reflux disease. EXPOSURES: Non-erosive gastro-oesophageal reflux disease was defined by an absence of oesophagitis and any other oesophageal diagnosis at endoscopy. Erosive gastro-oesophageal reflux disease was examined for comparison reasons and was defined by the presence of oesophagitis at endoscopy. MAIN OUTCOME MEASURES: The incidence rate of oesophageal adenocarcinoma was assessed for up to 31 years of follow-up. Standardised incidence ratios with 95% confidence intervals were calculated by dividing the observed number of oesophageal adenocarcinomas in each of the gastro-oesophageal reflux disease cohorts by the expected number, derived from the general populations in Denmark, Finland, and Sweden of the corresponding age, sex, and calendar period. RESULTS: Among 285 811 patients with non-erosive gastro-oesophageal reflux disease, 228 developed oesophageal adenocarcinomas during 2 081 051 person-years of follow-up. The incidence rate of oesophageal adenocarcinoma in patients with non-erosive gastro-oesophageal reflux disease was 11.0/100 000 person-years. The incidence was similar to that of the general population (standardised incidence ratio 1.04 (95% confidence interval 0.91 to 1.18)), and did not increase with longer follow-up (1.07 (0.65 to 1.65) for 15-31 years of follow-up). For validity reasons, we also analysed people with erosive oesophagitis at endoscopy (200 745 patients, 1 750 249 person-years, and 542 oesophageal adenocarcinomas, corresponding to an incidence rate of 31.0/100 000 person-years) showing an increased overall standardised incidence ratio of oesophageal adenocarcinoma (2.36 (2.17 to 2.57)), which became more pronounced with longer follow-up. CONCLUSIONS: Patients with non-erosive gastro-oesophageal reflux disease seem to have a similar incidence of oesophageal adenocarcinoma as the general population. This finding suggests that endoscopically confirmed non-erosive gastro-oesophageal reflux disease does not require additional endoscopic monitoring for oesophageal adenocarcinoma.

Waist-hip ratio is superior to BMI in predicting liver-related outcomes and synergizes with harmful alcohol use.

BACKGROUND: Obesity is associated with liver disease, but the best obesity-related predictor remains undefined. Controversy exists regarding possible synergism between obesity and alcohol use for liver-related outcomes (LRO). We assessed the predictive performance for LROs, and synergism with alcohol use, of abdominal obesity (waist-hip ratio, WHR), and compared it to overall obesity (body mass index, BMI). METHODS: Forty-thousand nine-hundred twenty-two adults attending the Finnish health-examination surveys, FINRISK 1992-2012 and Health 2000 studies, were followed through linkage with electronic healthcare registries for LROs (hospitalizations, cancers, and deaths). Predictive performance of obesity measures (WHR, waist circumference [WC], and BMI) were assessed by Fine-Gray models and time-dependent area-under-the-curve (AUC). RESULTS: There are 355 LROs during a median follow-up of 12.9 years (509047.8 person-years). WHR and WC emerge as more powerful predictors of LROs than BMI. WHR shows significantly better 10-year AUC values for LROs (0.714, 95% CI 0.685-0.743) than WC (0.648, 95% CI 0.617-0.679) or BMI (0.550, 95% CI 0.514-0.585) both overall and separately among men and women. WHR is predictive also in BMI strata. Absolute 10-year risks of LROs are more dependent on WHR than BMI. Moreover, WHR shows a significant supra-additive interaction effect with harmful alcohol use for liver-related outcomes (excess 10-year cumulative incidence of 2.8% from the interaction), which is not seen between BMI and harmful alcohol use. CONCLUSIONS: WHR is a better predictor than BMI or WC for LROs, and WHR better reflects the synergism with harmful alcohol use. WHR should be included in clinical assessment when evaluating obesity-related risks for liver outcomes.

Obesity has been linked to liver disease, but the most accurate measure for predicting obesity-related liver disease outcomes remains uncertain. In this study, we analyzed data from over 40,000 adults to compare the extent to which different measures of obesity can predict liver-related outcomes, such as severe liver disease, liver failure, or death from liver disease. The measures of obesity were the ratio of waist circumference to hip circumference (waist-hip ratio, WHR), waist circumference (WC), and body mass index (BMI). Our findings reveal that WHR and WC are stronger predictors of these outcomes than BMI. In particular, WHR demonstrated superior predictive ability and this predictive ability was influenced by harmful alcohol use. This study suggests that WHR may be a relatively simple but useful measure for clinicians to use when predicting obesity-related risks for liver health.

Combined use of the ELF test and CLivD score improves prediction of liver-related outcomes in the general population.

BACKGROUND AND AIMS: Effective and feasible population screening strategies are needed for the early detection of individuals at high risk of future severe liver-related outcomes. We evaluated the predictive performance of the combination of liver fibrosis assessment, phenotype profile, and genetic risk. METHODS: Data from 5795 adults attending the Finnish Health 2000 Survey were linked with healthcare registers for liver-related outcomes (hospitalization, hepatocellular cancer, and death). Fibrosis was assessed using the enhanced liver fibrosis (ELF) test, phenotype profile by the chronic liver disease (CLivD) risk score, and genetic risk by a validated Polygenic Risk Score (PRS-5). Predictive performance was assessed by competing-risk analyses. RESULTS: During a median 13-year follow-up, 64 liver-related outcome events were recorded. ELF, CLivD score, and PRS-5 were independently associated with liver-related outcomes. The absolute 10-year risk of liver-related outcomes at an ELF value of 11.3 ranged from 0.3% to 33% depending on the CLivD score. The CLivD score added 51% of new predictive information to the ELF test and improved areas under the curve (AUCs) from 0.91, 0.81, and 0.71 for ELF alone to 0.95, 0.85, and 0.80, respectively, for ELF combined with the CLivD score at 1, 5, and 10 years. The greatest improvement was for 10-year predictions (delta-AUC 0.097, p < .0001). Adding PRS-5 did not significantly increase predictive performance. Findings were consistent in individuals with obesity, diabetes, or alcohol risk use, and regardless of whether gamma-glutamyltransferase was used in the CLivD score. CONCLUSION: A combination of ELF and CLivD score predicts liver-related outcomes significantly better than the ELF test alone.

The role of serology, liver function tests and imaging in screening of primary sclerosing cholangitis: the HelPSCreen score.

OBJECIVES: At present, no sensitive or specific screening test exists for primary sclerosing cholangitis (PSC). PSC screening is mainly based on elevated alkaline phosphatase (ALP) in patients with inflammatory bowel disease (IBD). We aimed to produce a screening score based on laboratory tests to predict the likelihood of PSC. Moreover, we evaluated the additional roles of liver histology and magnetic resonance cholangiopancreatography (MRCP) in the diagnosis of PSC. MATERIALS AND METHODS: The data of 385 patients who came for their first endoscopic retrograde cholangiography (ERC) to confirm PSC diagnosis were retrieved from the PSC registry of the Helsinki University Hospital. Overall, 69 patients referred for ERC with suspected PSC, in whom PSC was excluded by ERC or liver biopsy and MRCP, served as controls. We included patients' demographics and 13 laboratory test results in the analysis. Variables with significant odds ratios were selected for multivariate logistic regression, which was used to create a novel scoring system for PSC. The presence of IBD, serum perinuclear anti-neutrophil cytoplasmic antibodies, and ALP levels demonstrated the highest predictive value for PSC. A score was assigned for each statistically significant predictor. RESULTS: The optimal cut-off point for the score was ≥3, with an AUC of 0.83 (95%CI: 0.78-0.88). The addition of liver histology or MRCP findings to the score did not add a predictive value. CONCUSIONS: In conclusion, we created a novel, simple scoring system to screen the probability of PSC. The HelPSCreen-score may help to assess the disease prevalence and to target further investigations in patients suspected of PSC.

Enhanced liver Fibrosis® test predicts liver-related outcomes in the general population.

Background & Aims: The Enhanced Liver Fibrosis® (ELF) test exhibits good discriminative performance in detecting advanced liver fibrosis and in predicting liver-related outcomes in patients with specific liver diseases, but large population-based studies are missing. We analysed the predictive performance of the ELF test in a general population cohort. Methods: Data were sourced from the Health 2000 study, a Finnish population-based health examination survey conducted in 2000-2001. Subjects with baseline liver disease were excluded. The ELF test was performed on blood samples collected at baseline. Data were linked with national healthcare registers for liver-related outcomes (hospitalisation, cancer, and death). Results: The cohort comprised 6,040 individuals (mean age 52.7. 45.6% men) with 67 liver-related outcomes during a median 13.1-year follow-up. ELF predicted liver outcomes (unadjusted hazards ratio 2.70, 95% CI 2.16-3.38). with 5- and 10-year AUCs of 0.81 (95% CI 0.71-0.91) and 0.71 (95% CI 0.63-0.79) by competing-risk methodology. The 10-year risks for liver outcomes increased from 0.5% at ELF <9.8 to 7.1% at ELF ≥11.3, being higher among men than women at any given ELF level. Among individuals with body mass index ≥30 kg/m2, diabetes, or alanine aminotransferase >40 U/L. Five-year AUCs for ELF were 0.85, 0.87, and 0.88, respectively. The predictive ability of the ELF test decreased with time: the 10-year AUCs were 0.78, 0.69, and 0.82, respectively. Conclusions: The ELF test shows good discriminative performance in predicting liver-related outcomes in a large general population cohort and appears particularly useful for predicting 5-year outcomes in persons with risk factors. Impact and implications: The Enhanced Liver Fibrosis test exhibits good performance for predicting liver-related outcomes (hospitalisation, liver cancer, or liver-related death) in the general population, especially in those with risk factors.

Magnitude and Time-Trends of Post-Endoscopy Esophageal Adenocarcinoma and Post-Endoscopy Esophageal Neoplasia in a Population-Based Cohort Study: The Nordic Barrett's Esophagus Study.

BACKGROUND & AIMS: Post-endoscopy esophageal adenocarcinoma (PEEC) and post-endoscopy esophageal neoplasia (PEEN) undermine early cancer detection in Barrett's esophagus (BE). We aimed to assess the magnitude and conduct time-trend analysis of PEEC and PEEN among patients with newly diagnosed BE. METHODS: This population-based cohort study was conducted in Denmark, Finland, and Sweden between 2006 and 2020 and included 20,588 patients with newly diagnosed BE. PEEC and PEEN were defined as esophageal adenocarcinoma (EAC) or high-grade dysplasia (HGD)/EAC, respectively, diagnosed 30-365 days from BE diagnosis (index endoscopy). HGD/EAC diagnosed from 0-29 days and HGD/EAC diagnosed >365 days from BE diagnosis (incident HGD/EAC) were assessed. Patients were followed up until HGD/EAC, death, or end of study period. Incidence rates (IR) per 100,000 person-years with 95% confidence interval (95% CI) were calculated using Poisson regression. RESULTS: Among 293 patients diagnosed with EAC, 69 (23.5%) were categorized as PEEC, 43 (14.7%) as index EAC, and 181 (61.8%) as incident EAC. The IRs/100,000 person-years for PEEC and incident EAC were 392 (95% CI, 309-496), and 208 (95% CI, 180-241), respectively. Among 279 patients diagnosed with HGD/EAC (Sweden only), 17.2% were categorized as PEEN, 14.6% as index HGD/EAC, and 68.1% as incident HGD/EAC. IRs/100,000 person-years for PEEN, and incident HGD/EAC were 421 (95% CI, 317-558), and 285 (95% CI, 247-328), respectively. Sensitivity analyses that varied time interval for occurrence of PEEC/PEEN demonstrated similar results. A time-trend analysis for IRs demonstrated rising incidence rates of PEEC/PEEN. CONCLUSIONS: Almost a quarter of all EACs are detected within a year after an ostensibly negative upper endoscopy in patients with newly diagnosed BE. Interventions to improve detection may reduce PEEC/PEEN rates.

PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease leading to biliary fibrosis and cirrhosis. Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC. METHODS: Adults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100 mg once daily or placebo for up to 96 weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100 mg daily for up to 96 weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint-chosen in conjunction with guidance from the U.S. Food and Drug Administration-is the proportion of patients with ≥ 1-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor. CONCLUSION: The phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03890120; registered 26/03/2019.

Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population.

BACKGROUND & AIMS: Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. METHODS: Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. RESULTS: Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. CONCLUSIONS: The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

Automated image analysis of keratin 7 staining can predict disease outcome in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that obstructs the bile ducts and causes liver cirrhosis and cholangiocarcinoma. Efficient surrogate markers are required to measure disease progression. The cytokeratin 7 (K7) load in a liver specimen is an independent prognostic indicator that can be measured from digitalized slides using artificial intelligence (AI)-based models. METHODS: A K7-AI model 2.0 was built to measure the hepatocellular K7 load area of the parenchyma, portal tracts, and biliary epithelium. K7-stained PSC liver biopsy specimens (n = 295) were analyzed. A compound endpoint (liver transplantation, liver-related death, and cholangiocarcinoma) was applied in Kaplan-Meier survival analysis to measure AUC values and positive likelihood ratios for each histological variable detected by the model. RESULTS: The K7-AI model 2.0 was a better prognostic tool than plasma alkaline phosphatase, the fibrosis stage evaluated by Nakanuma classification, or K7 score evaluated by a pathologist based on the AUC values of measured variables. A combination of parameters, such as portal tract volume and area of K7-positive hepatocytes analyzed by the model, produced an AUC of 0.81 for predicting the compound endpoint. Portal tract volume measured by the model correlated with the histological fibrosis stage. CONCLUSIONS: The K7 staining of histological liver specimens in PSC provides significant information on disease outcomes through objective and reproducible data, including variables that cannot be measured by a human pathologist. The K7-AI model 2.0 could serve as a prognostic tool for clinical endpoints and as a surrogate marker in drug trials.

Impact on follow-up strategies in patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. METHODS: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. RESULTS: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. CONCLUSIONS: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures.

PNPLA3 allele frequency has no impact on biliary bile acid composition or disease course in patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that leads to bile duct strictures, cholestasis, and biliary cirrhosis. PNPLA3 (patatin-like phospholipase domain containing 3), regulates cellular lipid synthesis by converting lysophosphatidic acid into phosphatidic acid. Isoleucine mutation to methionine at position 148 (I148M) causes a loss of this function. Only two studies, with contradictory results, have evaluated the role of PNPLA3 in PSC. The rs738409(G) variant of PNPLA3 has been associated with an increased risk for transplantation in male patients with dominant strictures (DS). The study aimed to evaluate the PNPLA3 allele frequency effect on the clinical outcomes, progression, and prognosis of PSC. Furthermore, we analyzed the impact of PNPLA3 on phospholipid and bile acid composition to evaluate the effect of the PNPLA3 status on UDCA response. PATIENTS AND METHODS: We recruited 560 patients prospectively and collected clinical and laboratory data as well as liver histology and imaging findings. PNPLA3 (CC, CG, GG) alleles were analyzed with TaqManTM. We also analyzed bile acids (BA), cholesterol and phospholipids and individual BA from a sample aspirated during endoscopic retrograde cholangiography (ERC). RESULTS: Among the recruited patients, 58.4%, 35.7% and 5.9% had the wild (CC), heterozygous (CG) and homozygous (GG) alleles, respectively. The PNPLA3 haplotype did not impact bile composition or individual BA. In addition, we found no differences in age at diagnosis, disease progression, liver fibrosis or survival between the cohorts. CONCLUSIONS: The PNPLA3 I148M variant had no significant impact on on bile composition, including UDCA content, clinical outcomes, progression of liver fibrosis, hepatobiliary cancer risk, liver transplantation, or overall survival.

Quantitative bile and serum proteomics for the screening and differential diagnosis of primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by biliary strictures, cholestasis, and a markedly increased risk of cholangiocarcinoma. New markers for the screening and differential diagnosis of PSC are needed. In this pilot study, we have analyzed both the bile and serum proteomic profiles of 80 PSC patients and non-PSC controls (n = 6 for bile and n = 18 for serum). AIM: The aim of this study was to discover candidates for new biomarkers for the differential diagnosis of PSC. METHODS: Bile and serum samples were processed and subsequently analyzed using ultra performance liquid chromatography-ultra definition mass spectrometry (UPLC-UDMSE). Further analysis included statistical analyses such as receiver operating characteristic curve analysis as well as pathway analysis using Ingenuity Pathway Analysis. RESULTS AND CONCLUSIONS: In bile, we discovered 64 proteins with significantly different levels between the groups, with fold changes of up to 129. In serum, we discovered 112 proteins with significantly different levels. Receiver operating characteristic curve analysis found multiple proteins with high area under the curve values, up to 0.942, indicating that these serum proteins are of value as new non-invasive classifiers of PSC. Pathway analysis revealed multiple canonical pathways that were enriched in the dataset, which have roles in bile homeostasis and metabolism. We present several serum proteins that could serve as new blood-based markers for the diagnosis of PSC after further validation. The measurement of serum levels of these proteins could be of use in the screening of patients with suspected PSC.

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

Can dysplasia surveillance be better targeted in ulcerative colitis by using faecal calprotectin?

Background: In the inflammatory bowel diseases, chronic inflammation predisposes to dysplasia and colorectal carcinoma, leading to the need of surveillance colonoscopies. The most-used marker of colonic inflammation is faecal calprotectin. Its correlation with endoscopic and histological findings is well-documented. In this study, we evaluated the role of sequential faecal calprotectin measurements in predicting colorectal dysplasia, to identify patients with increased risk of dysplasia or colonic malignancy in ulcerative colitis.Methods: We collected the faecal calprotectin measurements and colorectal histology reports of patients with ulcerative colitis treated in Helsinki University Hospital (Helsinki, Finland) between 2007 and 2017, with a focus on IBD-associated neoplasia, inflammatory activity, and sporadic adenomas. Using the time-weighted AUC of faecal calprotectin as a marker of inflammatory burden, we tested the performance of faecal calprotectin to predict the risk for colorectal neoplasia.Results: In total, 982 patients with ulcerative colitis were included. Of them, 845 had pancolitis and 127 concomitant primary sclerosing cholangitis. Forty-one patients (4%) had IBD-associated colorectal dysplasia and seven (0.7%) developed adenocarcinoma. In patients with constantly elevated faecal calprotectin level (>500 µg/g), colorectal neoplasia was more frequent compared to those with low (<200 µg/g) calprotectin (13% and 4%, p < 0.05). Histological inflammatory activity was also related to more frequent dysplastic changes.Conclusions: Colon dysplasia and adenocarcinoma are more common among ulcerative colitis patients with constantly elevated faecal calprotectin than in patients in remission. The role of inflammatory activity in inducing neoplastic changes in colon is further supported by histology, as histological inflammatory activity correlates with dysplasia.

Novel histological scoring for predicting disease outcome in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that may lead to liver cirrhosis or cholangiocarcinoma. Liver histology and fibrosis stage are predictive markers of disease progression, and histological cirrhosis is defined as a significant endpoint. PSC-specific histological scoring methods are lacking at present. We aimed to develop a tailored classification system for PSC, the PSC histoscore, based on histological features associated with disease progression. METHODS: In total, 300 PSC patients diagnosed between 1988 and 2018 were enrolled; their data were collected from the PSC registry (Helsinki University Hospital), and liver specimens were obtained from the Biobank of Helsinki. Five histological features included in the adapted Nakanuma scoring system and three additional parameters typical for PSC histology were evaluated and compared with the clinical and laboratory data. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement. RESULTS: Stage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were found to be independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2-6) and stage (2-4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores. CONCLUSION: The PSC histoscore is a novel histological classification system for PSC. Our findings support the applicability of liver histology as a marker for disease progression.

Development and validation of a model to predict incident chronic liver disease in the general population: The CLivD score.

BACKGROUND & AIMS: Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk prediction model for incident chronic liver disease in the general population based on widely available factors. METHODS: Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts. RESULTS: The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C-statistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (<2%) of the population with >10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort. CONCLUSIONS: Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population. LAY SUMMARY: Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up.