Trine Folseraas

• Molinaro, Antonio; Braadland, Peder Rustøen; Carpino, Guido; Carreras, Alba; Nikolaidis, Marios & Hanzely, Petra [Show all 40 contributors for this article] (2026). Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling. Nature Metabolism. 8(9), p. 1910–1925. doi: 10.1038/s42255-026-01600-1. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut–liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.

• Breder, Sigurd; Wang, Benny; Villard, Christina; Båve, Aiva; Lindström-Älgå, Lina & Eide, Emma [Show all 15 contributors for this article] (2026). Liver transplantation in primary sclerosing cholangitis with hepatobiliary neoplasia: survival outcomes and impact of diagnostic uncertainty. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. p. 1–12. doi: 10.1080/00365521.2026.2709611. Full text in Research Archive
• Braadland, Peder Rustøen; Ali, Ahmad H.; Puchas, Philip; Juran, Brian D.; Atkinson, Elizabeth J. & Schlicht, Erik M. [Show all 19 contributors for this article] (2026). Vitamin B6 predicts poor outcomes in geographically distinct populations with primary sclerosing cholangitis. Journal of Hepatology. ISSN 0168-8278. 85(2), p. 227–237. doi: 10.1016/j.jhep.2026.03.048. Full text in Research Archive Show summary

  Background & Aims: Primary sclerosing cholangitis (PSC) has a variable disease course, complicating patient counseling and the timing of liver transplantation. Vitamin B6 deficiency predicts reduced liver transplantation-free survival in Scandinavian PSC cohorts. Here, we aimed to validate this observation in US and German PSC cohorts and to expand our analyses to include hepatic decompensation as a clinical outcome. Methods: Serum active vitamin B6 (pyridoxal 5’-phosphate [PLP]) was analyzed using liquid chromatography-tandem mass spectrometry in retrospective cohorts of people with PSC from Norway (n = 315), the USA (n = 756), and Germany (n = 149). Cox proportional hazards and Fine and Gray competing risk models were fitted to estimate the ability of PLP to predict liver transplantation-free survival and the cumulative incidence of hepatic decompensation, respectively. Results: The prevalence of vitamin B6 deficiency (PLP <20 nmol/L) in pre-transplant PSC was 50% in the Norway cohort and 25% in the USA cohort. The prevalence was higher among those with previous hepatic decompensation. The cumulative incidence of hepatic decompensation was higher in the USA cohort, while individuals in the Norway cohort were more commonly transplanted for indications other than hepatic decompensation. Despite differences in clinical practice, low PLP was consistently associated with shorter liver transplantation-free survival, and PLP added predictive value for liver transplantation or death from PSC over and above contemporary prediction models. Low PLP was also associated with a higher incidence of hepatic decompensation, which was mainly evident in the USA cohort, where decompensation was more common. The risk of both outcomes increased sharply within the deficient and marginal ranges and plateaued at sufficient PLP levels. Conclusions: Vitamin B6 deficiency is common in PSC outside Scandinavia and is consistently associated with poor outcomes across geographically distinct PSC populations. Impact and implications We previously showed that vitamin B6 deficiency is prevalent and associated with reduced liver transplantation-free survival in Scandinavian PSC cohorts. The current work shows that these observations generalize to a US population and that low vitamin B6 is also associated with the development of hepatic decompensation. Our results indicate that vitamin B6 provides incremental value for predicting outcomes in PSC across geographically distinct populations and that efforts to restore B6 sufficiency should be focused on the many individuals who present with vitamin B6 levels within the marginal-to-definitive deficiency range.

• Banales, Jesus M.; Rodrigues, Pedro M.; Affò, Silvia; Andersen, Jesper B.; Aspichueta, Patricia & Boulter, Luke [Show all 147 contributors for this article] (2025). Cholangiocarcinoma 2026: status quo, unmet needs and priorities. Nature reviews: Gastroenterology & hepatology. ISSN 1759-5045. 23(1), p. 96–96. doi: 10.1038/s41575-025-01153-w. Full text in Research Archive
• ElAbd, Hesham; Pesesky, Mitchell; Innocenti, Gabriel; Chung, Brian K.; Mahdy, Aya K.H. & Kriukova, Valeriia [Show all 40 contributors for this article] (2025). T and B cell responses against Epstein–Barr virus in primary sclerosing cholangitis. Nature Medicine. ISSN 1078-8956. 31(7), p. 2306–2316. doi: 10.1038/s41591-025-03692-w. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC.

• Mol, Bregje; Nieuwamerongen, Moyrha van; Munster, Kim N. van; Färkkilä, Martti; Folseraas, Trine & Tjønnfjord, Sara Kristina Viberg [Show all 19 contributors for this article] (2025). Proctocolectomy with permanent ileostomy is associated with improved transplant-free survival in patients with PSC. JHEP Reports. 8(3). doi: 10.1016/j.jhepr.2025.101700. Full text in Research Archive Show summary

  Background & Aims The gut–liver axis is believed to be crucial in the pathogenesis of primary sclerosing cholangitis (PSC). However, the impact of colectomy on liver disease progression is unclear. Our study estimated the effect of colectomy on PSC progression with correction for time dependency and established risk factors by pooling data from several cohorts across different countries. Methods We analysed data from the International PSC Registry (IPSCR), comprising patients from Finland, The Netherlands, Norway, and Sweden. Primary endpoint was defined as liver transplantation (LT) or PSC-related death. Cox proportional hazards regression onto time-dependent colectomy status, with specification for extent, was performed with adjustment for sex, age at diagnosis, large or small duct PSC, features of autoimmune hepatitis, time-dependent inflammatory bowel disease (IBD) status, centre of inclusion, and country of residence. Results A total of 3,110 participants were included, of whom 470 (15%) had undergone colectomy. During a total follow-up of 32,236 patient-years, 395 deaths and 653 LTs were observed. Compared with patients with PSC with intact colon, the hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy with permanent ileostomy (HR 0.41; 95% CI 0.24–0.71). This effect was less pronounced in case of hemi- or subtotal colectomy (HR 0.81; 95% CI: 0.58–1.12) and not observed for proctocolectomy with pouch (HR 1.00; 95% CI: 0.73–1.38). The reduced risk was mainly associated with a lower rate of LT or death resulting from liver failure (HR 0.24; 0.10–0.53). Conclusions Proctocolectomy with permanent ileostomy was associated with decreased risk for LT and PSC-related death. These findings support the role of the gut–liver axis in the pathophysiology of PSC and call for consideration in counselling patients who face impending colorectal surgery. Impact and implications The impact of the gut-liver axis in the pathophysiology of primary sclerosing cholangitis (PSC) has remained uncertain. In this study, proctocolectomy with ileostomy was associated with improved transplant-free survival, defined as a reduced risk of liver transplantation or PSC-related death, indicating that intestinal factors may influence disease progression. These findings are important for clinicians, researchers, and patients as they suggest that surgical management of colonic disease may have prognostic implications in PSC, and for further studies to clarify mechanisms and guide clinical decision-making.

• Zompo, Fabio Del; Crouchet, Emilie; Ostyn, Tessa; Nehme, Zeina; Messé, Mélissa & Jühling, Frank [Show all 36 contributors for this article] (2025). Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis. Journal of Hepatology. ISSN 0168-8278. 83(6), p. 1305–1319. doi: 10.1016/j.jhep.2025.08.005. Full text in Research Archive Show summary

  Background & Aims Primary sclerosing cholangitis (PSC) is a cholangiopathy associated with a high risk of progression to end-stage liver disease and hepatobiliary cancer. Its pathogenesis remains poorly understood, and current clinical management offers limited therapeutic options, primarily liver transplantation. Claudin-1 (CLDN1), a transmembrane protein highly expressed in liver epithelial cells, plays a critical role in cell-cell communication and signaling. We aimed to investigate the functional role of CLDN1 as both a mediator and potential therapeutic target for PSC using patient cohorts alongside murine and patient-derived intervention models. Methods CLDN1 expression patterns and associated cellular phenotypes were analyzed in liver tissues from five PSC patient cohorts using single-cell RNA sequencing, spatial transcriptomics, and multiplex proteomics. Proof-of-concept studies employing CLDN1-specific monoclonal antibodies (mAbs) and genetic loss-of-function approaches were performed in state-of-the-art mouse models of PSC and cholangiopathies. Perturbation studies in human cell-based models were conducted to explore underlying mechanisms. Results In liver tissues from patients with PSC, CLDN1 expression was markedly upregulated and correlated with disease progression. Spatial transcriptomics and proteomics revealed elevated CLDN1 expression in diseased cholangiocytes and cholestatic periportal hepatocytes, accompanied by activation of pro-inflammatory and pro-fibrotic signaling pathways. Therapeutic administration of CLDN1-specific mAbs or genetic knockout improved liver function in PSC mouse models by reducing hepatobiliary fibrosis and cholestasis. Mechanistic studies indicated that mAb treatment inhibited pro-inflammatory and pro-fibrotic signaling in cholangiocytes and hepatocytes perturbed in PSC liver tissues. Conclusions These findings demonstrate a functional role for CLDN1 in the pathogenesis of PSC and biliary fibrosis. In vivo proof-of-concept studies, combined with expression analyses in patients with PSC, support the clinical development of CLDN1-specific mAbs as a therapeutic strategy for PSC. Impact and implications Primary sclerosing cholangitis (PSC) is a chronic fibrosing cholangiopathy with limited therapeutic options. We identified the cell surface protein Claudin-1 as a key mediator and potential therapeutic target for PSC. In patients, Claudin-1 expression correlates with disease stage and clinical outcomes. Conditional liver epithelial-specific Claudin-1 knockout in mice reduced liver injury, fibrosis, and cholestasis. Monoclonal antibodies targeting Claudin-1 inhibited fibrosis, cholestasis, and the ductular reaction across advanced PSC mouse models by suppressing pro-inflammatory and fibrogenic signaling. These preclinical findings support the clinical development of Claudin-1-specific antibodies for PSC treatment and have significant implications for physicians, researchers, and drug developers in the field of biliary disease.

• Holmer, Magnus; Ingre, Michael; Färkkilä, Martti; Ponsioen, Cyriel; Mol, Bregje & Schramm, Christoph [Show all 17 contributors for this article] (2025). Cirrhosis and age are key determinants of HCC risk in individuals with primary sclerosing cholangitis: A multicenter longitudinal cohort study. Hepatology. ISSN 0270-9139. doi: 10.1097/HEP.0000000000001351. Full text in Research Archive
• Singh, Yashbir; Eaton, John E.; Venkatesh, Sudhakar K.; Welle, Christopher L.; Smith, Byron & Faghani, Shahriar [Show all 24 contributors for this article] (2025). Deep learning analysis of MRI accurately detects early-stage perihilar cholangiocarcinoma in patients with primary sclerosing cholangitis. Hepatology. ISSN 0270-9139. 83(1), p. 30–39. doi: 10.1097/HEP.0000000000001314. Full text in Research Archive
• Breder, Sigurd; Villard, Christina; Eide, Emma; Wang, Benny; Engesæter, Lise Katrine & Reims, Henrik Mikael [Show all 15 contributors for this article] (2025). A retrospective evaluation of preemptive liver transplantation for bile duct dysplasia in primary sclerosing cholangitis: Balancing risks and benefits. JHEP Reports. 7(12), p. 1–11. doi: 10.1016/j.jhepr.2025.101598. Full text in Research Archive Show summary

  Background & Aims Liver transplantation (LT) to prevent cholangiocarcinoma (CCA) in individuals with primary sclerosing cholangitis (PSC) and bile duct dysplasia was introduced in Norway and Sweden in the early 2000s. We aimed to evaluate this practice to potentially improve future selection of candidates for LT. Methods We conducted a retrospective study of 512 adults with PSC who underwent first-time LT between 2000–2021 at Oslo and Karolinska University Hospitals. Pre-LT findings in bile duct brush cytology and/or biopsy of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) were compared with histological findings in the explanted livers and survival rates were assessed. Results Bile duct dysplasia, low-grade (LGD) or high-grade (HGD), was the primary LT indication in 17% (88/512). Among individuals transplanted for LGD, only 10% (3/29) had HGD or CCA in the explant, compared to 48% (28/59) in the HGD group. No neoplasia was found in 42% (12/29) of LGD and 24% (14/59) of HGD cases, meaning nearly one-third of patients transplanted for suspected bile duct dysplasia had no histological evidence of neoplasia in the explant. Five-year post-transplant survival according to the explant histology was 95% for no neoplasia, 89% for LGD, 85% for HGD, decreasing to 33% in those with CCA in the explant. Conclusions While favorable survival in confirmed dysplasia supports the role of preemptive LT, the absence of neoplasia in a substantial proportion of explants, particularly in suspected LGD, calls for a cautious, individualized approach. LT appears more clearly justified in accurately diagnosed HGD, given its strong association with early malignancy and the poor prognosis of advanced CCA. Impact and implications Individuals with primary sclerosing cholangitis (PSC) are at increased risk of developing bile duct cancer. In precancerous stages (bile duct dysplasia), liver transplantation (LT) may prevent progression to advanced, incurable cancer. In our evaluation of 512 patients with PSC who underwent LT, we found that the low diagnostic accuracy and unpredictable detection of mild dysplasia support a cautious, individualized approach to LT in precancerous stages of PSC, while more advanced dysplasia remains a valid indication for LT.

• Fossdal, Guri; Braadland, Peder Rustøen; Hov, Johannes Espolin Roksund; Husebye, Eystein Sverre; Folseraas, Trine & Ueland, Per Magne [Show all 10 contributors for this article] (2025). Mitochondrial dysfunction and lipid alterations in primary sclerosing cholangitis. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 60(2), p. 165–173. doi: 10.1080/00365521.2024.2447521. Full text in Research Archive Show summary

  Objectives: Indications of mitochondrial dysfunction are commonly seen in liver diseases, but data are scarce in primary sclerosing cholangitis (PSC). Analyzing circulating and liver-resident molecules indirectly reflecting mitochondrial dysfunction, we aimed to comprehensively characterize this deficit in PSC, and whether this was PSC specific or associated with cholestasis. Materials and methods: We retrospectively included plasma from 191 non-transplant patients with large-duct PSC and 100 healthy controls and explanted liver tissue extracts from 24 PSC patients and 18 non-cholestatic liver disease controls. Using mass spectroscopy, we profiled lipids and fatty acids, carnitine, acylcarnitines, and metabolites in the tryptophan-kynurenine-nicotinamide pathway. Results: Hierarchal clustering of fatty acid levels identified patients with PSC and healthy controls as separate clusters. Compared to healthy controls, PSC patients had increased levels of monounsaturated fatty acids (MUFA) and palmitate (C16:0) in plasma, but reduced levels of long-chain saturated fatty acids (SFAs). These findings were more pronounced in PSC patients with cholestasis. Several n-3 polyunsaturated fatty acids were elevated in PSC but not associated with cholestasis. Acylcarnitine ratios C2/C5 and C2/C3 were elevated while C2/C16 was reduced in PSC, indicating impaired mitochondrial fatty acid oxidation of medium-long chained fatty acids. Levels of intermediates in the tryptophan-kynurenine pathway indicated impaired NAD biosynthesis, suggesting impaired energy supply to mitochondria in PSC. Conclusions: We found that mitochondrial dysfunction was prominent in PSC and associated with increasing cholestasis. Whether this is merely a marker of liver disease and severity, or an underlying driver and potential therapeutic target in PSC remains to be explored.

• Yaqub, Sheraz; Busund, Sondre; Smedman, Tor Magnus; Syversveen, Trygve; Khan, Ammar & Solheim, Jon Magnus Aarstrand [Show all 11 contributors for this article] (2025). Liver transplantation for locally advanced non-resectable intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: early results from the TESLA trial. British Journal of Surgery. ISSN 0007-1323. 112(3). doi: 10.1093/bjs/znaf054. Full text in Research Archive
• Poch, Tobias; Bahn, Jonas; Casar, Christian; Krause, Jenny; Evangelakos, Ioannis & Gilladi, Hilla [Show all 25 contributors for this article] (2024). Intergenic risk variant rs56258221 skews the fate of naive CD4⁺ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis. Cell Reports Medicine. 5(7). doi: 10.1016/j.xcrm.2024.101620. Full text in Research Archive
• Keulen, Anne-Marleen van; Buettner, Stefan; Olthof, Pim B.; Klümpen, Heinz-Josef; Erdmann, Joris I. & Izquierdo-Sanchez, Laura [Show all 33 contributors for this article] (2024). Comparing Survival of Perihilar Cholangiocarcinoma After R1 Resection Versus Palliative Chemotherapy for Unresected Localized Disease. Annals of Surgical Oncology. ISSN 1068-9265. doi: 10.1245/s10434-024-15582-5. Full text in Research Archive
• Grimsrud, Marit Mæhle; Forster, Michael; Goeppert, Benjamin; Hemmrich-Stanisak, Georg; Sax, Irmi & Grzyb, Krzysztof [Show all 21 contributors for this article] (2024). Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis. Hepatology communications.. 8(7). doi: 10.1097/HC9.0000000000000461. Full text in Research Archive Show summary

  Background: People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. Methods: We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. Results: We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. Conclusions: In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.

• Braadland, Peder Rustøen; Bergquist, Annika; Kummen, Martin; Bossen, Lars; Engesæter, Lise Katrine & Reims, Henrik Mikael [Show all 21 contributors for this article] (2023). Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation. Journal of Hepatology. ISSN 0168-8278. 79(4), p. 955–966. doi: 10.1016/j.jhep.2023.05.038. Full text in Research Archive Show summary

  Background and aims We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5’-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). Methods We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. Results In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. Conclusions Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. Impact and implications We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.

• Steiert, Tim A.; Parra, Genís; Gut, Marta; Arnold, Norbert; Trotta, Jean-Rémi & Tonda, Raúl [Show all 23 contributors for this article] (2023). A critical spotlight on the paradigms of FFPE-DNA sequencing. Nucleic Acids Research (NAR). ISSN 0305-1048. 51(14), p. 7143–7162. doi: 10.1093/nar/gkad519. Full text in Research Archive Show summary

  Abstract In the late 19th century, formalin fixation with paraffin-embedding (FFPE) of tissues was developed as a fixation and conservation method and is still used to this day in routine clinical and pathological practice. The implementation of state-of-the-art nucleic acid sequencing technologies has sparked much interest for using historical FFPE samples stored in biobanks as they hold promise in extracting new information from these valuable samples. However, formalin fixation chemically modifies DNA, which potentially leads to incorrect sequences or misinterpretations in downstream processing and data analysis. Many publications have concentrated on one type of DNA damage, but few have addressed the complete spectrum of FFPE-DNA damage. Here, we review mitigation strategies in (I) pre-analytical sample quality control, (II) DNA repair treatments, (III) analytical sample preparation and (IV) bioinformatic analysis of FFPE-DNA. We then provide recommendations that are tested and illustrated with DNA from 13-year-old liver specimens, one FFPE preserved and one fresh frozen, applying target-enriched sequencing. Thus, we show how DNA damage can be compensated, even when using low quantities (50 ng) of fragmented FFPE-DNA (DNA integrity number 2.0) that cannot be amplified well (Q129 bp/Q41 bp = 5%). Finally, we provide a checklist called ‘ERROR-FFPE-DNA’ that summarises recommendations for the minimal information in publications required for assessing fitness-for-purpose and inter-study comparison when using FFPE samples.

• Grant, Caroline W; Juran, Brian D; Ali, Ahmad H; Schlicht, Erik M; Bianchi, Jackie K & Hu, Xin [Show all 19 contributors for this article] (2023). Environmental chemicals and endogenous metabolites in bile of USA and Norway patients with primary sclerosing cholangitis. Exposome. 3(1). doi: 10.1093/exposome/osac011. Full text in Research Archive Show summary

  Abstract Primary sclerosing cholangitis (PSC) is a complex bile duct disorder. Its etiology is incompletely understood, but environmental chemicals likely contribute to risk. Patients with PSC have an altered bile metabolome, which may be influenced by environmental chemicals. This novel study utilized state-of-the-art high-resolution mass spectrometry (HRMS) with bile samples to provide the first characterization of environmental chemicals and metabolomics (collectively, the exposome) in PSC patients located in the United States of America (USA) (n = 24) and Norway (n = 30). First, environmental chemical- and metabolome-wide association studies were conducted to assess geographic-based similarities and differences in the bile of PSC patients. Nine environmental chemicals (false discovery rate, FDR &amp;lt; 0.20) and 3143 metabolic features (FDR &amp;lt; 0.05) differed by site. Next, pathway analysis was performed to identify metabolomic pathways that were similarly and differentially enriched by the site. Fifteen pathways were differentially enriched (P &amp;lt; .05) in the categories of amino acid, glycan, carbohydrate, energy, and vitamin/cofactor metabolism. Finally, chemicals and pathways were integrated to derive exposure–effect correlation networks by site. These networks demonstrate the shared and differential chemical–metabolome associations by site and highlight important pathways that are likely relevant to PSC. The USA patients demonstrated higher environmental chemical bile content and increased associations between chemicals and metabolic pathways than those in Norway. Polychlorinated biphenyl (PCB)-118 and PCB-101 were identified as chemicals of interest for additional investigation in PSC given broad associations with metabolomic pathways in both the USA and Norway patients. Associated pathways include glycan degradation pathways, which play a key role in microbiome regulation and thus may be implicated in PSC pathophysiology.

• Lapitz, Ainhoa; Azkargorta, Mikel; Milkiewicz, Piotr; Olaizola, Paula; Zhuravleva, Ekaterina & Grimsrud, Marit Mæhle [Show all 35 contributors for this article] (2023). Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma. Journal of Hepatology. ISSN 0168-8278. 79(1), p. 93–108. doi: 10.1016/j.jhep.2023.02.027. Full text in Research Archive Show summary

  Background & Aims Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. Results High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients’ survival, respectively. Conclusions Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine. Impact and implications The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.

• Wacker, Eike Matthias; Uellendahl-Werth, Florian; Bej, Saptarshi; Wolkenhauer, Olaf; Vesterhus, Mette Nåmdal & Lieb, Wolfgang [Show all 10 contributors for this article] (2023). Whole blood RNA sequencing identifies transcriptional differences between primary sclerosing cholangitis and ulcerative colitis. JHEP Reports. 6(2). doi: 10.1016/j.jhepr.2023.100988. Full text in Research Archive Show summary

  Background & Aims: Genetic and microbiome studies across patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have indicated that UC in PSC is a separate disease entity to primary UC, but expression studies for PSC are lacking. Methods: We conducted whole blood RNA sequencing experiments for 495 patients with UC, 220 patients with PSC (including 177 with UC), and 320 healthy controls from Germany and Norway. Differential expression analyses, gene ontology and coexpression analyses and random forest machine learning were performed to identify genes, ontologies and transcriptional features that discriminate diagnoses. Results: The blood transcriptome in UC and PSC is dominated by neutrophil activation genes (e.g. S100A12). In UC, but not in PSC (neither PSC alone nor patients with an additional diagnosis of UC [PSC/UC]), ribosomal, mitochondrial, and energy metabolism genes are upregulated in conjunction with antibody transcript expression (MZB1, IGJ). In PSC, there is an increase in modules related to apoptosis and expression of genes of interferon-I-related ontologies. Random forest analysis could poorly discriminate PSC alone from PSC/UC (AUROC 0.56), but could discriminate PSC, UC, and controls with high accuracy (AUROC UC vs. controls 0.95, PSC vs. controls 0.88, UC vs. PSC 0.986). The main coexpression modules relevant for distinguishing PSC, UC, and controls are enriched in neutrophil degranulation and antibody production genes. Conclusions: Supported by machine learning results, PSC and UC appear to be separate entities on a molecular level, while PSC/UC and PSC are indistinguishable. Impact and implications: Clinical and genetic studies suggest that the colitis-like symptoms in primary sclerosing cholangitis (PSC) represent a different disease entity from primary ulcerative colitis (UC). The present study supports this assumption with transcriptomic data from whole blood and describes notable differences in gene expression between primary UC and PSC, providing insights into the still unclear pathophysiology of both diseases. These findings are of interest to scientists seeking to decipher the molecular pathophysiology of both diseases and provide evidence that a redefinition of the PSC-UC phenotype should be considered. The study practically supports future molecular research by providing a large transcriptomic whole blood reference cohort.

• Mikalsen, Ina; Breder, Sigurd; Medhus, Asle Wilhelm; Folseraas, Trine; Aabakken, Lars & Ånonsen, Kim Vidar (2023). ERCP for the initial management of malignant biliary obstruction–real world data on 596 procedures. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. doi: 10.1080/00365521.2023.2282375. Full text in Research Archive Show summary

  Aims To evaluate outcomes of ERCP as first-line management in patients with malignant biliary obstruction (MBO) of all causes and stages, reflecting a real-life setting. Methods Retrospective observational study of patients with ERCP as the first-line management of MBO at Oslo University Hospital between 2015 and 2021. Primary outcome measure was a ≥ 50% decrease from the pre-procedural bilirubin within 30 days after ERCP. Secondary outcome measures were technical success of ERCP, complications and overall mortality. Results A total of 596 patients were included, median age 70 years. ASA score was ≥ III in 67% of patients. The most common cancers causing MBO were pancreatic cancer (52%), metastatic lesions (20%) and cholangiocarcinoma (16%). The primary outcome measure was achieved in 62% of patients. With endoscopic access, overall technical success was 80% with 85% for the distal extrahepatic group, 71% for the perihilar, 40% for the intrahepatic and 53% for multiple level MBOs. Reinterventions were performed in 27% of the patients. Complications occurred in 15% of the patients, including post-ERCP pancreatitis in 9%. Most complications were of minor/moderate severity (81%). Overall mortality was 33% within the first 90 days. Patients deceased by the end of the study period (83%) had median survival of 146 days (range 1–2,582 days). Conclusions ERCP has a high rate of clinical effect and technical success in the management of both distal extrahepatic and perihilar MBO. Our data indicate that ERCP is a valid option in the first-line management of MBO.

• Han, Younghun; Byun, Jinyoung; Zhu, Catherine; Sun, Ryan; Roh, Julia Y. & Cordell, Heather J. [Show all 26 contributors for this article] (2023). Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis. Nature Communications. 14(1), p. 1–13. doi: 10.1038/s41467-023-36678-8. Full text in Research Archive Show summary

  Abstract Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5 . Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.

• Muynck, Kevin De; Heyerick, Lander; Ponti, Federico F. De; Vanderborght, Bart; Meese, Tim & Campenhout, Sanne Van [Show all 23 contributors for this article] (2023). Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis. Hepatology. ISSN 0270-9139. 79(2), p. 269–288. doi: 10.1097/HEP.0000000000000557. Full text in Research Archive Show summary

  Background and Aims: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood. Approach and Results: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 (Trem2) and osteopontin (Spp1), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF-Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro, while monoclonal antibody–mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival. Conclusions: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC.

• Nooijen, Lynn E.; Banales, Jesus M.; Boer, Marieke T. de; Braconi, Chiara; Folseraas, Trine & Forner, Alejandro [Show all 19 contributors for this article] (2022). Impact of Positive Lymph Nodes and Resection Margin Status on the Overall Survival of Patients with Resected Perihilar Cholangiocarcinoma: The ENSCCA Registry. Cancers. 14(10). doi: 10.3390/cancers14102389. Full text in Research Archive Show summary

  Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from resection margin status on OS has not been evaluated. Methods: From the European Cholangiocarcinoma (ENSCCA) registry, patients who underwent resection for pCCA between 1994 and 2021 were included in this retrospective cohort study. The primary outcome was OS stratified for resection margin and lymph node status. The secondary outcome was recurrence-free survival. Results: A total of 325 patients from 11 different centers and six European countries were included. Of these, 194 (59.7%) patients had negative resection margins. In 113 (34.8%) patients, positive lymph nodes were found. Lymph node status, histological grade, and ECOG performance status were independent prognostic factors for survival. The median OS for N0R0, N0R1, N+R0, and N+R1 was 38, 30, 18, and 12 months, respectively (p &lt; 0.001). Conclusion: These data indicate that in the presence of positive regional lymph nodes, resection margin status does not determine OS or RFS in patients with pCCA. Achieving negative margins in patients with positive nodes should not come at the expense of more extensive surgery and associated higher mortality.

• Singh, Yashbir; Jons, William A.; Eaton, John E.; Vesterhus, Mette Nåmdal; Karlsen, Tom Hemming & Bjørk, Ida Torunn [Show all 21 contributors for this article] (2022). Algebraic topology-based machine learning using MRI predicts outcomes in primary sclerosing cholangitis. European Radiology Experimental. 6. doi: 10.1186/s41747-022-00312-x. Full text in Research Archive Show summary

  Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can lead to cirrhosis and hepatic decompensation. However, predicting future outcomes in patients with PSC is challenging. Our aim was to extract magnetic resonance imaging (MRI) features that predict the development of hepatic decompensation by applying algebraic topology-based machine learning (ML). Methods: We conducted a retrospective multicenter study among adults with large duct PSC who underwent MRI. A topological data analysis-inspired nonlinear framework was used to predict the risk of hepatic decompensation, which was motivated by algebraic topology theory-based ML. The topological representations (persistence images) were employed as input for classification to predict who developed early hepatic decompensation within one year after their baseline MRI. Results: We reviewed 590 patients; 298 were excluded due to poor image quality or inadequate liver coverage, leaving 292 potentially eligible subjects, of which 169 subjects were included in the study. We trained our model using contrast-enhanced delayed phase T1-weighted images on a single center derivation cohort consisting of 54 patients (hepatic decompensation, n = 21; no hepatic decompensation, n = 33) and a multicenter independent validation cohort of 115 individuals (hepatic decompensation, n = 31; no hepatic decompensation, n = 84). When our model was applied in the independent validation cohort, it remained predictive of early hepatic decompensation (area under the receiver operating characteristic curve = 0.84). Conclusions: Algebraic topology-based ML is a methodological approach that can predict outcomes in patients with PSC and has the potential for application in other chronic liver diseases.

• Izquierdo-Sanchez, Laura; Lamarca, Angela; Casta, Adelaida La; Buettner, Stefan; Utpatel, Kirsten & Klümpen, Heinz-Josef [Show all 44 contributors for this article] (2022). Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry. Journal of Hepatology. ISSN 0168-8278. 76(5), p. 1109–1121. doi: 10.1016/j.jhep.2021.12.010. Full text in Research Archive Show summary

  Background & Aims Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. Methods The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. Results Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. Conclusion CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality.

• Yu, Jingru; Refsum, Erle; Helsingen, Lise Mørkved; Folseraas, Trine; Ploner, Alexander & Wieszczy, Paulina [Show all 15 contributors for this article] (2022). Risk of hepato-pancreato-biliary cancer is increased by primary sclerosing cholangitis in patients with inflammatory bowel disease: A population-based cohort study. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 10(2), p. 212–224. doi: 10.1002/ueg2.12204. Full text in Research Archive Show summary

  Background There is continued uncertainty regarding the risks of hepato-pancreato-biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). Objective To give updated estimates on risk of hepato-pancreato-biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra – and extrahepatic cholangiocarcinoma. Methods In a population-based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato-pancreato-biliary cancers by PSC and other clinical characteristics. Results Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow-up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8–5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0–2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2–1.5). The relative risks were considerably higher in PSC-IBD patients, with SIR of 140 (95% CI 123–159) for biliary tract, 38.6 (95% CI 29.2–50.0) for hepatocellular, and 9.0 (95% CI 6.3–12.6) for pancreatic cancer. The SIRs were still slightly increased in non-PSC-IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC-IBD patients, and 0.4% in non-PSC-IBD patients. Conclusions The dramatically increased risks of hepato-pancreato-biliary cancers in PSC-IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non-PSC-IBD patients were not trivial compared to non-IBD related risk factors.

• Laursen, Tea Lund; Bossen, Lars; Pihl, Rasmus; Troldborg, Anne; Sandahl, Thomas Damgaard & Hansen, Annette Gudmann [Show all 10 contributors for this article] (2022). Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases. Journal of Clinical and Translational Hepatology (JCTH). ISSN 2225-0719. 10(5), p. 796–802. doi: 10.14218/JCTH.2021.00515. Full text in Research Archive
• Degenhardt, Frauke; Ellinghaus, David; Juzenas, Simonas; Lerga-Jaso, Jon; Wendorff, Mareike & Maya-Miles, Douglas [Show all 51 contributors for this article] (2022). Detailed stratified GWAS analysis for severe COVID-19 in four European populations. Human Molecular Genetics. ISSN 0964-6906. 31(23), p. 3945–3966. doi: 10.1093/hmg/ddac158. Full text in Research Archive Show summary

  Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ∼0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

• Uellendahl-Werth, Florian; Maj, Carlo; Borisov, Oleg; Juzenas, Simonas; Wacker, Eike Matthias & Jørgensen, Isabella Friis [Show all 21 contributors for this article] (2022). Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease. Communications Biology. 5(1). doi: 10.1038/s42003-022-03031-6. Full text in Research Archive Show summary

  Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies for 23 tissues of the gut-brain-axis using genome-wide association studies data sets (total 180,592 patients) for Crohn’s disease, ulcerative colitis, primary sclerosing cholangitis, schizophrenia, bipolar disorder, major depressive disorder and attention-deficit/hyperactivity disorder. We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory ulcerative colitis) as shared susceptibility genes with transcriptome-wide significance both for Crohn’s disease, ulcerative colitis and schizophrenia, largely explaining fine-mapped association signals at nearby genome-wide association study susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the gut-brain-axis. PPP3CA together with three further suggestive loci can be linked to calcineurin-related signaling pathways such as NFAT activation or Wnt.

• Lei, Lin; Bruneau, Alix; Mourabit, Haquima El; Guégan, Justine; Folseraas, Trine & Lemoinne, Sara [Show all 18 contributors for this article] (2022). Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis. Hepatology. ISSN 0270-9139. doi: 10.1002/hep.32456. Full text in Research Archive
• Eliasson, Johanna; Lo, Bobby; Scramm, Christoph; Chazouilleres, Olivier; Folseraas, Trine & Beuers, Ulrich [Show all 7 contributors for this article] (2022). Survey uncovering variations in the management of primary sclerosing cholangitis across Europe. JHEP Reports. 4(11). doi: 10.1016/j.jhepr.2022.100553. Full text in Research Archive Show summary

  Background & Aims Data on the management of primary sclerosing cholangitis (PSC) in European expert centres are sparse. In this study, a PSC group from the ERN RARE-LIVER surveyed European hepatologists to uncover differences in real-life clinical practices. Methods In April 2020 a survey questionnaire was sent to members of the International PSC Study Group and ERN RARE-LIVER. Participants were asked about the size of their PSC cohort, use of medical treatments including ursodeoxycholic acid (UDCA) and surveillance for cholangiocarcinoma, gallbladder polyps and inflammatory bowel disease (IBD). Data were presented descriptively. Results Eighty-two of 278 members responded. Fifty percent of physicians prescribed UDCA routinely to all their patients with PSC, whereas 12% never prescribed UDCA. UDCA was used for one or more indications including: alkaline phosphatase >1.5x the upper limit of normal, severe PSC changes, pruritus, PSC-IBD or patient demand. Few physicians offered other medical treatments than UDCA. The use of medical treatments was generally comparable in small (<99 patients) and large (≥99 patients) cohorts, as well as for adult and paediatric physicians. Most physicians routinely screened for cholangiocarcinoma and the most frequent modalities used were MRI and ultrasound. At detection of a gallbladder polyp of 6 mm, 46% of physicians recommended repeated ultrasound after 3-6 months, whereas 44% of physicians recommended immediate cholecystectomy. In patients with PSC without IBD at PSC diagnosis, 68% of physicians repeated colonoscopy within 3-5 years whereas 27% referred only patients who developed symptoms of IBD. Conclusion Substantial variations in treatment and monitoring of European patients with PSC were discovered. Harmonisation of strategies is desirable to enable improved interpretation of outcome data and to optimise clinical patient care.

• Hammer, Quirin; Dunst, Josefine; Christ, Wanda; Picarazzi, Francesca; Wendorff, Mareike & Momayyezi, Pouria [Show all 51 contributors for this article] (2022). SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells. Cell reports. 38(10). doi: 10.1016/j.celrep.2022.110503. Full text in Research Archive Show summary

  Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.

• Niemi, Mari E.K.; Karjalainen, Juha; Liao, Rachel G.; Neale, Benjamin M.; Daly, Mark & Ganna, Andrea [Show all 84 contributors for this article] (2021). Mapping the human genetic architecture of COVID-19. Nature. ISSN 0028-0836. 600(7889), p. 472–477. doi: 10.1038/s41586-021-03767-x. Full text in Research Archive Show summary

  The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

• Vedeld, Hege Marie; Grimsrud, Marit Mæhle; Andresen, Kim; Pharo, Heidi Dietrichson; Seth, Erik von & Karlsen, Tom Hemming [Show all 15 contributors for this article] (2021). Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile. Hepatology. ISSN 0270-9139. doi: 10.1002/hep.32125. Full text in Research Archive Show summary

  Background and Aims Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. Approach and Results Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77–0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow-up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSC ≤ 12 patients, all positive for the biomarkers, included both early-stage and late-stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels. Conclusions Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.

• Dhillon, Amandeep Kaur; Rupp, Christian; Bergquist, Annika; Voitl, Robert; Folseraas, Trine & Trøseid, Marius [Show all 12 contributors for this article] (2021). Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 56(4), p. 443–452. doi: 10.1080/00365521.2021.1880627. Full text in Research Archive Show summary

  Background and aims Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine–tryptophanratio (KT-ratio) in PSC. Methods Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. Results Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50–0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23–0.42) in all cohorts. Conclusions Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.

• Aune, Dagfinn; Sen, Abhijit; Norat, Teresa; Riboli, Elio & Folseraas, Trine (2021). Primary sclerosing cholangitis and the risk of cancer, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of cohort studies. Scientific Reports. 11. doi: 10.1038/s41598-021-90175-w. Full text in Research Archive Show summary

  Abstract A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42–1267.51, I 2  = 89%, n = 4) for cholangiocarcinoma (CCA), 155.54 (125.34–193.02, I 2  = 0%, n = 3) for hepatobiliary cancer, 30.22 (11.99–76.17, I 2  = 0%, n = 2) for liver cancer, 16.92 (8.73–32.78, I 2  = 88%, n = 4) for gastrointestinal cancer, 7.56 (2.42–23.62, I 2  = 0%, n = 3) for pancreatic cancer, 6.10 (4.19–8.87, I 2  = 14%, n = 7) for colorectal cancer (CRC), 4.13 (2.99–5.71, I 2  = 80%, n = 5) for total cancer, 3.55 (2.94–4.28, I 2  = 46%, n = 5) for all-cause mortality, and 1.57 (0.25–9.69, I 2  = 79%, n = 2) for cardiovascular disease. Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.

• Vesterhus, Mette Nåmdal; Wiencke, Kristine; Haukeland, John Willy; Frigstad, Svein Oskar; Karlsen, Lars Normann & Jørgensen, Kristin Kaasen [Show all 7 contributors for this article] (2021). Klinisk oversiktsartikkel: Diagnostikk og behandling av autoimmun hepatitt. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141. doi: 10.4045/tidsskr.20.1045. Full text in Research Archive
• Fossdal, Guri; Mjelle, Anders Batman; Wiencke, Kristine; Bjørk, Ida Torunn; Gilja, Odd Helge & Folseraas, Trine [Show all 10 contributors for this article] (2021). Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF. JHEP Reports. 3(5), p. 1–10. doi: 10.1016/j.jhepr.2021.100328. Full text in Research Archive Show summary

  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.

• Vedeld, Hege Marie; Folseraas, Trine & Lind, Guro Elisabeth (2020). Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis – The promise of DNA methylation and molecular biomarkers. JHEP Reports. 2(5). doi: 10.1016/j.jhepr.2020.100143. Full text in Research Archive
• Mousa, Omar Y; Juran, Brian D; McCauley, Bryan M.; Vesterhus, Mette; Folseraas, Trine & Turgeon, Coleman T. [Show all 19 contributors for this article] (2020). Bile Acid Profiles in Primary Sclerosing Cholangitis and their Ability to Predict Hepatic Decompensation. Hepatology. ISSN 0270-9139. 74(1). doi: 10.1002/hep.31652. Full text in Research Archive Show summary

  Background and Aims: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). Conclusions: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

• Lamarca, Angela; Santos-Laso, Alvaro; Utpatel, Kirsten; Casta, Adelaida La; Stock, Simone & Forner, Alejandro [Show all 18 contributors for this article] (2020). Liver metastases of intrahepatic cholangiocarcinoma: implications for a potential new staging system. Hepatology. ISSN 0270-9139. doi: 10.1002/hep.31598. Full text in Research Archive
• Goeppert, Benjamin; Folseraas, Trine; Roessler, Stephanie; Kloor, Matthias; Volckmar, Anna-Lena & Endris, Volker [Show all 36 contributors for this article] (2020). Genomic characterization of cholangiocarcinoma in primary sclerosing cholangitis reveals therapeutic opportunities. Hepatology. ISSN 0270-9139. 72(4), p. 1253–1266. doi: 10.1002/hep.31110. Full text in Research Archive Show summary

  Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC‐associated BTC (PSC‐BTC). Approach and Results We analyzed formalin‐fixed, paraffin‐embedded tumor tissue from 186 patients with PSC‐BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC‐BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC‐BTC include a significant number of putative actionable therapeutic targets. Notably, PSC‐BTC shows a distinct extrahepatic morpho‐molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC‐associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome‐based personalized treatment strategies in PSC‐BTC.

• Ellinghaus, David; Degenhardt, Frauke; Bujanda, Luis; Buti, Maria; Abillios, Agustin & Invernizzi, Pietro [Show all 30 contributors for this article] (2020). Genomewide Association Study of Severe Covid-19 with Respiratory Failure. New England Journal of Medicine. ISSN 0028-4793. doi: 10.1056/NEJMoa2020283. Full text in Research Archive
• Grimsrud, Marit Mæhle & Folseraas, Trine (2019). Pathogenesis, diagnosis and treatment of premalignant and malignant stages of cholangiocarcinoma in primary sclerosing cholangitis. Liver international (Print). ISSN 1478-3223. p. 1–8. doi: 10.1111/liv.14180. Full text in Research Archive Show summary

  Patients with primary sclerosing cholangitis (PSC) confer a high risk of cholangiocarcinoma (CCA). The molecular mechanisms of CCA development in PSC are incompletely understood, but pro‐oncogenic processes resulting from chronic biliary inflammation are presumably of central importance. Distinguishing benign from malignant biliary strictures in PSC patients is challenging and accurately diagnosing CCA in PSC often requires a multifaceted approach involving imaging, serological testing, biliary brush cytology and fluorescence in situ hybridization (FISH). Lack of early detection tools leads to a late diagnosis in the majority of cases. Surgical resection or liver transplantation represent the only curative intent treatments in PSC‐CCA, but is only an option for the small subset of patients where CCA is detected at an early stage. Current palliative treatment modalities result in only a modest increase in survival. Overall, PSC‐CCA carries a dismal prognosis with a 5‐year survival less than 20%. Advances aiming at improving strategies for early detection, treatment and surveillance of CCA will be essential to provide better future patient care for PSC patients. Herein, we review the pathogenetic mechanisms for PSC‐CCA as well as strategies for diagnosing and managing premalignant and malignant stages of CCA in PSC.

• Thorgersen, Ebbe Billmann; Melum, Espen; Folseraas, Trine; Larsen, Stein Gunnar & Line, Pål Dag (2018). Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei in a liver-transplanted patient: A case report. World Journal of Surgical Oncology (WJSO). 16:180, p. 1–5. doi: 10.1186/s12957-018-1482-7. Full text in Research Archive Show summary

  Background Diagnostic work-ups in transplanted immunosuppressed patients are a challenge as non-specific findings may be interpreted as transplant-related complications. If the disease in question is rare and slowly developing like pseudomyxoma peritonei (PMP), it is even more difficult. Cytoreductive surgery (CRS) and subsequent hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment for PMP even with extensive peritoneal spread. CRS-HIPEC for PMP after liver transplantation (LTX) has not been described before. Case presentation A 48-year-old female patient with end-stage primary sclerosing cholangitis (PSC) underwent orthotopic LTX and subsequent pancreaticoduodenectomy after the finding of cholangiocarcinoma in situ in the native common bile duct. Ten years after the transplantation, she developed symptoms and signs suspected to represent graft-related complications. An extensive work-up revealed PMP. Upon reassessment, a cystic mass near the coecum could be seen on computed tomography scan 1 year after transplantation. The multidisiplinary team was hesitant to accept the patient for CRS-HIPEC because of extensive PMP and possible risk to the graft. However, she was eventually accepted and underwent the procedure. The Peritoneal Cancer Index (PCI) was 28 of 39, and surgical debulking was performed followed by HIPEC. The transplant control 2 months after surgery showed no harm to the graft. Conclusions Previous LTX should not exclude the possibility for CRS-HIPEC in PMP, even with extensive burden of disease.

• Carpino, Guido; Cardinale, Vincenzo; Folseraas, Trine; Overi, Diletta; Grzyb, Krzysztof & Constantini, David [Show all 11 contributors for this article] (2018). Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis. Hepatology. ISSN 0270-9139. 69(2), p. 622–638. doi: 10.1002/hep.30210. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy frequently complicated by cholangiocarcinoma (CCA). Massive proliferation of biliary tree stem/progenitor cells (BTSCs), expansion of peribiliary glands (PBGs), and dysplasia were observed in PSC. The aims of the present study were to evaluate the involvement of PBGs and BTSCs in CCA which emerged in PSC patients. Specimens from normal liver (n = 5), PSC (n = 20), and PSC‐associated CCA (n = 20) were included. Samples were processed for histology, immunohistochemistry, and immunofluorescence. In vitro experiments were performed on human BTSCs, human mucinous primary CCA cell cultures, and human cholangiocyte cell lines (H69). Our results indicated that all CCAs emerging in PSC patients were mucin‐producing tumors characterized by PBG involvement and a high expression of stem/progenitor cell markers. Ducts with neoplastic lesions showed higher inflammation, wall thickness, and PBG activation compared to nonneoplastic PSC‐affected ducts. CCA showed higher microvascular density and higher expression of nuclear factor kappa B, interleukin‐6, interleukin‐8, transforming growth factor β, and vascular endothelial growth factor‐1 compared to nonneoplastic ducts. CCA cells were characterized by a higher expression of epithelial‐to‐mesenchymal transition (EMT) traits and by the absence of primary cilia compared to bile ducts and PBG cells in controls and patients with PSC. Our in vitro study demonstrated that lipopolysaccharide and oxysterols (PSC‐related stressors) induced the expression of EMT traits, the nuclear factor kappa B pathway, autophagy, and the loss of primary cilia in human BTSCs. Conclusion: CCA arising in patients with PSC is characterized by extensive PBG involvement and by activation of the BTSC niche in these patients, the presence of duct lesions at different stages suggests a progressive tumorigenesis.

• Alberts, R; Vries, EMG de; Goode, EC; Jiang, Xiaojun; Sampaziotis, Fotios & Rombouts, K [Show all 50 contributors for this article] (2017). Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut. ISSN 0017-5749. 67(8), p. 1517–1524. doi: 10.1136/gutjnl-2016-313598. Full text in Research Archive
• Karlsen, Tom Hemming; Folseraas, Trine; Thorburn, Douglas & Vesterhus, Mette (2017). Primary sclerosing cholangitis - a comprehensive review. Journal of Hepatology. ISSN 0168-8278. 67(6), p. 1298–1323. doi: 10.1016/j.jhep.2017.07.022. Full text in Research Archive
• Chung, Brian K.; Karlsen, Tom Hemming & Folseraas, Trine (2017). Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma. Biochimica et Biophysica Acta - Molecular Basis of Disease. ISSN 0925-4439. 1864(4), p. 1390–1400. doi: 10.1016/j.bbadis.2017.08.020. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is an idiopathic cholangiopathy strongly associated with inflammatory bowel disease (IBD) and characterized by cholestasis, chronic immune infiltration and progressive fibrosis of the intrahepatic and extrahepatic bile ducts. PSC confers a high risk of cholangiocarcinoma (CCA) with PSC-CCA representing the leading cause of PSC-associated mortality. PSC-CCA is derived from cholangiocytes and associated progenitor cells - a heterogeneous group of dynamic epithelial cells lining the biliary tree that modulate the composition and volume of bile production by the liver. Infection, inflammation and cholestasis can trigger cholangiocyte activation leading to an increased expression of adhesion and antigen-presenting molecules as well as the release of various inflammatory and fibrogenic mediators. As a result, activated cholangiocytes engage in a myriad of cellular processes, including hepatocellular proliferation, apoptosis, angiogenesis and fibrosis. Cholangiocytes can also regulate the recruitment of immune cells, mesenchymal cells, and endothelial cells that participate in tissue repair and destruction in settings of persistent inflammation. In PSC, the role of cholangiocytes and the mechanisms governing their transformation to PSC-CCA are unclear however localization of disease suggests that cholangiocytes are a key target and potential regulator of hepatobiliary immunity, fibrogenesis and tumorigenesis. Herein, we summarize mechanisms of cholangiocyte activation in PSC and highlight new insights into disease pathways that may contribute to the development of PSC-CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen

• Henriksen, Eva Kristine Klemsdal; Viken, Marte K; Wittig, Michael; Holm, Kristian; Folseraas, Trine & Mucha, Sören [Show all 29 contributors for this article] (2017). HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry. HLA. ISSN 2059-2302. 90(4), p. 228–233. doi: 10.1111/tan.13076. Full text in Research Archive
• Carpino, Guido; Cardinale, Vincenzo; Folseraas, Trine; Overi, D; Floreani, A & Franchitto, Antonio [Show all 12 contributors for this article] (2017). Hepatic stem/progenitor cell activation differs between primary sclerosing and primary biliary cholangitis. American Journal of Pathology. ISSN 0002-9440. 188(3), p. 627–639. doi: 10.1016/j.ajpath.2017.11.010. Full text in Research Archive
• Ellinghaus, David; Jostins, Luke; Spain, Sarah L.; Cortes, Adrian; Bethune, Jörn & Han, Buhm [Show all 45 contributors for this article] (2016). Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nature Genetics. ISSN 1061-4036. 48(5), p. 510–518. doi: 10.1038/ng.3528. Full text in Research Archive
• Folseraas, Trine & Boberg, Kirsten Muri (2016). Cancer Risk and Surveillance in Primary Sclerosing Cholangitis. Clinics in Liver Disease. ISSN 1089-3261. 20(1), p. 79–98. doi: 10.1016/j.cld.2015.08.014. Full text in Research Archive
• Wannhoff, A; Folseraas, Trine; Brune, Maik; Rupp, C; Friedrich, Kilian & Knierim, Johannes [Show all 13 contributors for this article] (2016). A common genetic variant of fucosyltransferase 2 correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary sclerosing cholangitis. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 4(1), p. 84–91. doi: 10.1177/2050640615581577. Full text in Research Archive
• Banales, Jesus M.; Cardinale, Vincenzo; Carpino, Guido; Marzioni, Marco; Andersen, Jesper B. & Invernizzi, Pietro [Show all 24 contributors for this article] (2016). Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nature reviews: Gastroenterology & hepatology. ISSN 1759-5045. 13(5), p. 261–280. doi: 10.1038/nrgastro.2016.51. Full text in Research Archive
• Ji, Sun-Gou; Juran, Brian D.; Mucha, Sören; Folseraas, Trine; Jostins, Luke & Melum, Espen [Show all 39 contributors for this article] (2016). Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nature Genetics. ISSN 1061-4036. 49(20), p. 269–273. doi: 10.1038/ng.3745. Full text in Research Archive
• Li, Jin; Jørgensen, Silje Fjellgård; Maggadóttir, Sólrún Melkorka; Bakay, Marina; Warnatz, Klaus & Glessner, Joseph [Show all 39 contributors for this article] (2015). Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. Nature Communications. 6. doi: 10.1038/ncomms7804. Full text in Research Archive
• Rupp, C.; Friedrich, K.; Folseraas, Trine; Wannhoff, A.; Bode, K.A. & Weiss, K.-H. [Show all 10 contributors for this article] (2014). Fut2 genotype is a risk factor for dominant stenosis and biliary candida infections in primary sclerosing cholangitis. Alimentary Pharmacology and Therapeutics. ISSN 0269-2813. 39(8), p. 873–882. doi: 10.1111/apt.12663. Full text in Research Archive
• Folseraas, Trine; Liaskou, Evaggelia; Anderson, Carl A. & Karlsen, Tom Hemming (2014). Genetics in PSC: What do the “Risk Genes” teach us? Clinical reviews in allergy and immunology. ISSN 1080-0549. 48(2-3), p. 154–164. doi: 10.1007/s12016-014-8417-z. Full text in Research Archive
• Wannhoff, A; Hov, Johannes Espolin Roksund; Folseraas, Trine; Rupp, C; Friedrich, K & Anmarkrud, Jarl Andreas [Show all 13 contributors for this article] (2013). FUT2 and FUT3 genotype determines CA19-9 cut-off values for detection of cholangiocarcinoma in patients with primary sclerosing cholangitis. Journal of Hepatology. ISSN 0168-8278. 59(6), p. 1278–1284. doi: 10.1016/j.jhep.2013.08.005. Full text in Research Archive
• Liu, Jimmy Z.; Hov, Johannes Espolin Roksund; Folseraas, Trine; Ellinghaus, E; Rushbrook, SM & Doncheva, NT [Show all 84 contributors for this article] (2013). Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nature Genetics. ISSN 1061-4036. 45(6), p. 670–675. doi: 10.1038/ng.2616. Full text in Research Archive
• Ellinghaus, David; Folseraas, Trine; Holm, Kristian; Ellinghaus, Eva; Melum, Espen & Balschun, Tobias [Show all 37 contributors for this article] (2013). Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology. ISSN 0270-9139. 58(3), p. 1074–1083. doi: 10.1002/hep.25977. Full text in Research Archive
• Folseraas, Trine; Melum, Espen; Rausch, Philipp; Juran, Brian D.; Ellinghaus, Eva & Shiryaev, Alexey [Show all 40 contributors for this article] (2012). Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. Journal of Hepatology. ISSN 0168-8278. 57(2), p. 366–375. doi: 10.1016/j.jhep.2012.03.031. Full text in Research Archive
• Folseraas, Trine; Melum, Espen; Franke, Andre & Karlsen, Tom Hemming (2011). Genetics in primary sclerosing cholangitis. Baillière's Best Practice & Research Clinical Gastroenterology. ISSN 1521-6918. 25(6), p. 713–726. doi: 10.1016/j.bpg.2011.09.010. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models. (C) 2011 Elsevier Ltd. All rights reserved.

• Folseraas, Trine; Melum, Espen; Franke, Andre & Karlsen, Tom Hemming (2011). Best Practice & Research Clinical Gastroenterology. Baillière's Best Practice & Research Clinical Gastroenterology. ISSN 1521-6918. 25(6), p. 713–726. doi: 10.1016/j.bpg.2011.09.010. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models. (C) 2011 Elsevier Ltd. All rights reserved.

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• Holmer, Magnus; Ingre, Michael; Färkkilä, Martti; Ponsioen, Cyriel; Mol, Bregje & Schramm, Christoph [Show all 17 contributors for this article] (2025). Reply: Competing risk and surveillance thresholds for HCC in patients with PSC. Hepatology. ISSN 0270-9139. Publish Ahead of Print. doi: 10.1097/HEP.0000000000001651. Full text in Research Archive
• Helgadottir, Holmfridur; Folseraas, Trine; Kemmerich, Gunter; Aabakken, Lars; Jørgensen, Kristin Kaasen & Vesterhus, Mette Nåmdal (2023). Primær skleroserende kolangitt. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(17). doi: 10.4045/tidsskr.23.0156. Full text in Research Archive
• Yakub, Sheraz; Bjørk, Ida; Sugulle, Meryam & Folseraas, Trine (2023). Biopsy helpful in diagnosing a liver mass in pregnancy: focal nodular hyperplasia. The Lancet. ISSN 0140-6736. doi: 10.1016/S0140-6736(23)01606-9. Full text in Research Archive
• Lamarca, Angela; Santos-Laso, Alvaro; Utpatel, Kirsten; Casta, Adelaida La; Stock, Simone & Forner, Alejandro [Show all 18 contributors for this article] (2021). REPLY:. Hepatology. ISSN 0270-9139. 74(4), p. 2319–2321. doi: 10.1002/hep.31904. Full text in Research Archive
• Lamarca, Angela; Santos-Laso, Alvaro; Utpatel, Kirsten; Casta, Adelaida La; Stock, Simone & Forner, Alejandro [Show all 18 contributors for this article] (2021). REPLY:. Hepatology. ISSN 0270-9139. 74(2), p. 1129–1131. doi: 10.1002/hep.31740. Full text in Research Archive
• Wannhoff, Andreas; Folseraas, Trine; Hov, Johannes Espolin Roksund; Weiss, Karl Heinz; Rupp, Christian & Stremmel, Wolfgang [Show all 8 contributors for this article] (2012). FUT2-and FUT3-genotype depending CA19-9 cut-off values in PSC patients. Hepatology. ISSN 0270-9139. 56, p. 1128A–1128A. Full text in Research Archive
• Liu, Jimmy Z.; Folseraas, Trine; Ellinghaus, Eva; Franke, Andre; Anderson, Carl A. & Karlsen, Tom Hemming (2012). Identification of multiple novel susceptibility regions for primary sclerosing cholangitis through dense genotyping of autoimmunity risk loci. Hepatology. ISSN 0270-9139. 56, p. 303A–303A. Full text in Research Archive
• Folseraas, Trine & Karlsen, Tom Hemming (2011). To MMP or not to MMP: a role for matrix metalloproteinase 3 in primary sclerosing cholangitis? Liver international (Print). ISSN 1478-3223. 31(6), p. 751–754. doi: 10.1111/j.1478-3231.2011.02471.x. Full text in Research Archive
• Grimsrud, Marit Mæhle & Folseraas, Trine (2025). Biliary tract cancer in primary sclerosing cholangitis - Genetic landscape and biomarkers. Universitetet i Oslo. ISSN 9788234807220. Full text in Research Archive Show summary

  Primary sclerosing cholangitis (PSC) is a chronic liver disease that greatly increases the risk of developing biliary tract cancer. These cancers are often diagnosed late, partly because symptoms overlap with those of PSC and partly because current biochemical and imaging-based surveillance has limited sensitivity. Most patients are therefore diagnosed at a stage where curative treatment is no longer available. There is a strong need for better tools that can detect cancer earlier and guide more personalised treatment. This thesis combines genetic analyses of tumour tissue with molecular profiling of bile to improve early detection and identify features that may open the door to targeted therapies. Whole exome sequencing of PSC-related tumours showed that this cancer subtype has a distinct molecular profile, including alterations not previously linked to biliary tract cancer. The work further identified alterations in genes that are already targets for existing cancer drugs, suggesting future therapeutic potential for selected patients. The thesis also explored bile as a diagnostic fluid. DNA from bile showed specific methylation patterns that distinguished cancer from non-cancer in PSC with very high accuracy, and these markers may detect cancer months before current methods. In addition, protein analyses of extracellular vesicles in bile identified protein combinations that could both signal early-stage cancer and indicate which patients are at increased short-term risk of developing it. Together, these findings highlight new molecular characteristics of PSC-related biliary tract cancer and demonstrate that bile-based biomarkers may offer more sensitive and earlier detection than today’s tools.

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