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.

Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants.

Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. METHODS: We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. RESULTS: At baseline, the median (range) ELF test was 9.3 (7.5-12.9) and median LSM 1.26 m/s (0.66-3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). CONCLUSIONS: ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk.

Diagnosis and treatment of autoimmune hepatitis. / Diagnostikk og behandling av autoimmun hepatitt.

Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

First quality score for referral letters in gastroenterology-a validation study.

OBJECTIVE: To create and validate an objective and reliable score to assess referral quality in gastroenterology. DESIGN: An observational multicentre study. SETTING AND PARTICIPANTS: 25 gastroenterologists participated in selecting variables for a Thirty Point Score (TPS) for quality assessment of referrals to gastroenterology specialist healthcare for 9 common indications. From May to September 2014, 7 hospitals from the South-Eastern Norway Regional Health Authority participated in collecting and scoring 327 referrals to a gastroenterologist. MAIN OUTCOME MEASURE: Correlation between the TPS and a visual analogue scale (VAS) for referral quality. RESULTS: The 327 referrals had an average TPS of 13.2 (range 1-25) and an average VAS of 4.7 (range 0.2-9.5). The reliability of the score was excellent, with an intra-rater intraclass correlation coefficient (ICC) of 0.87 and inter-rater ICC of 0.91. The overall correlation between the TPS and the VAS was moderate (r=0.42), and ranged from fair to substantial for the various indications. Mean agreement was good (ICC=0.47, 95% CI (0.34 to 0.57)), ranging from poor to good. CONCLUSIONS: The TPS is reliable, objective and shows good agreement with the subjective VAS. The score may be a useful tool for assessing referral quality in gastroenterology, particularly important when evaluating the effect of interventions to improve referral quality.

Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis.

OBJECTIVES: Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have concurrent inflammatory bowel disease (IBD). The majority have ulcerative colitis, but there is also an association with Crohn's colitis. The pathogenetic link between PSC and IBD is unknown. We aimed to assess whether genetic risk factors in PSC can be identified on the basis of known IBD susceptibility genes and the shared PSC-IBD phenotype. METHODS: IBD-associated polymorphisms in the CARD15, TLR-4, CARD4, SLC22A4, SLC22A5, DLG5, and MDR1 genes were genotyped in a large cohort of 365 Scandinavian PSC patients and 368 healthy controls using TaqMan technology. RESULTS: No significant association between any of the investigated genetic IBD risk variants and overall susceptibility to PSC was observed. Apart from a tendency toward an increased carrier frequency of the mutant CARD15 alleles in PSC patients with concurrent Crohn's disease as compared with healthy controls (15.6%vs 9.0%, P = 0.22), no association with any of the polymorphisms investigated was evident even when considering only PSC patients with concurrent IBD. CONCLUSION: It seems unlikely that IBD-associated polymorphisms in the CARD15, TLR-4, CARD4, SLC22A4, SLC22A5, DLG5, and MDR1 genes confer susceptibility to PSC. The current knowledge of genetic risk factors in IBD may not contribute to our understanding of molecular mechanisms involved in the pathogenesis of PSC or the IBD phenotype in PSC.

No major effect of the CD28/CTLA4/ICOS gene region on susceptibility to primary sclerosing cholangitis.

OBJECTIVE: Primary sclerosing cholangitis (PSC) is currently thought to be an immune-mediated disease, where both host genes and environmental factors interact. Some of the immunoregulatory genes responsible for individual susceptibility to PSC have been identified. The co-stimulatory receptor gene cluster on chromosome 2q33 encodes both the positive T-cell regulators CD28 and ICOS, and the negative regulator CTLA4. The CTLA4 gene has been implicated in several immune-mediated diseases, but it is not known whether PSC is associated with any of these genes. MATERIAL AND METHODS: Polymerase chain reaction (PCR)-based genotyping was performed on 144 PSC patients and 285 controls. Two single nucleotide polymorphisms (SNPs) in the CTLA4 gene were investigated as well as six microsatellites covering approximately 262 kb of the flanking regions, including the ICOS and CD28 genes. RESULTS: Overall, there were no statistically significant differences between PSC patients and controls in genotype and allele frequencies for the CTLA4 +49AG and CT60 SNPs or for the CD28-A, CD28-B, SARA43, SARA1, SARA31, and SARA47 microsatellite markers. Nor were any associations with clinical subgroups observed. CONCLUSIONS: There are no major effects of the CD28/CTLA4/ICOS gene region on susceptibility to PSC, but minor contributions (OR <1.8) cannot be excluded.

Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients.

Chromosome region 2q33 encodes several regulators of the immune system, among these the CD28, CTLA4, and ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the CD28/CTLA4/ICOS gene region.

Association of matrix metalloproteinase-1 and -3 promoter polymorphisms with clinical subsets of Norwegian primary sclerosing cholangitis patients.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is considered an immune mediated liver disease of multifactorial and multigenetic aetiology. Concomitant ulcerative colitis (UC) is seen in many PSC patients, but the pathogenetic link between these disorders is unknown. Due to association with inflammation, fibrosis, and cancer development, the matrix metalloproteinases MMP-1 and MMP-3 are candidate genes for predisposition to both PSC, UC and cholangiocarcinoma. METHODS: We investigated the association of MMP-1 and MMP-3 promoter polymorphisms in 165 Norwegian PSC patients compared to 118 UC patients and 346 healthy controls. RESULTS: There were no differences in MMP-1 and MMP-3 frequencies between PSC patients and UC patients or healthy controls. PSC patients with UC showed an increased frequency of the MMP-3 allele 5A compared to PSC patients without UC (60% vs. 45%; P(c)=0.01). All patients (100%) with cholangiocarcinoma carried MMP-1 allele 1G, compared to only 72% of PSC patients without cholangiocarcinoma. CONCLUSIONS: We found no general associations of the MMP-1 and MMP-3 genes to PSC or UC among Norwegian patients, but specific alleles were associated to subsets of PSC patients with UC and cholangiocarcinoma. The results support the theory of genetic heterogeneity among PSC patients.