| Přispěvatelé: |
Ponsioen, C.Y., de Jonge, W.J., Wildenberg, Manon E., Verheij, J., Faculteit der Geneeskunde, Ponsioen, Cyriel I. J., de Jonge, Wouter J., Verheij, Joanne, Amsterdam Gastroenterology Endocrinology Metabolism, Tytgat Institute for Liver and Intestinal Research, Graduate School |
| Popis: |
Primary sclerosing cholangitis (PSC) is a rare, chronic inflammatory liver disease, with an unknown aetiology. The co-occurrence of PSC with inflammatory bowel disease (IBD) has raised the question whether these two disease entities share a common pathophysiological ground, promoting gut-liver interactions. Previous studies have shown that gut-specific T-cells expressing integrin α4β7 are also present in the peribiliary infiltrates in the livers of patients with PSC. In the first part of this thesis, we showed that hepatic expression of molecules contributing to this gut-homing pathway, differs between disease stages of PSC. Additionally, we showed the presence of integrin α4β7 expressing T-cells in the mucosa of patients with an ileal-anal pouch anastomosis. We also analyzed the methylation profile and immune cell composition in blood samples of patients with PSC and ulcerative colitis (PSC-UC). As therapies interfering with these gut-homing mechanisms are evolving, this research contributes to the search for treatment options in both disease entities. Quantification of fibrosis in liver biopsies of patients with PSC is strongly correlated with long-term clinical outcome in PSC. We validated these findings in a large multi-center cohort. We demonstrated that three staging systems were independent predictors of time to liver transplantation and liver cirrhosis-related events. Additionally, quantification of liver fibrosis using the collagen proportionate area (CPA) measurement correlated strongly-to-moderate with the histologic scoring systems. Possibly, these methods could aid in risk stratification, or serve as surrogate markers for disease progression in clinical trials. The risk of developing colorectal cancer (CRC) is 3-4-fold higher in patients with both PSC and IBD compared to IBD alone, but the underlying molecular basis for this aggravated risk is unknown. In the last part of this thesis, we performed an extensive screen on PSC-associated colorectal cancers and compared this with sporadic and IBD associated CRC. As we found only small differences, we argued that the excess risk of CRC in PSC-IBD was not explained by the investigated molecular changes, setting the stage for further investigation. |
