Summary
Background
In patients with primary sclerosing cholangitis follow‐up magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is performed by many centres, ...particularly for the early detection of biliary malignancies and strictures. Clinically meaningful MRI‐based definitions of primary sclerosing cholangitis related complications are, however, lacking.
Aim
To investigate how primary sclerosing cholangitis experts interpret follow‐up MRI/MRCP with a focus on conclusions that may impact clinical decision‐making in primary sclerosing cholangitis.
Methods
Within the International Primary Sclerosing Cholangitis Study Group, an online survey on 16 real‐life primary sclerosing cholangitis cases including clinical and biochemical information as well as a T2‐weighted liver MRI/3D‐MRCP was conducted. The interpretation of images and subsequent recommendations were assessed using a multiple‐choice questionnaire. An inter‐rater reliability calculation (Fleiss′ kappa) was performed and factors potentially affecting the interpretation of magnetic resonance images were analysed using generalised linear mixed‐effect models.
Results
Forty‐four members/associates of the International Primary Sclerosing Cholangitis Study Group (median experience in the care of primary sclerosing cholangitis patients: 14 years) completed the survey. The MRI interpretation significantly varied among the participants. The lowest agreement was found with respect to the indication to perform subsequent endoscopic retrograde cholangiopancreatography (ERCP; Κ = 0.12, 95%CI 0.11‐0.14). Elevated total bilirubin was the variable with the strongest effect on the rate of suspected dominant strictures, cholangiocarcinoma or ERCP recommendations. Liver cirrhosis did not prevent participants from recommending ERCP. Overall, the survey participants′ recommendations contrasted the real‐life management and outcome.
Conclusions
In primary sclerosing cholangitis, the interpretation of follow‐up MRI/3D‐MRCP significantly varies even among experts and seems to be primarily affected by bilirubin levels. Generally accepted MRI‐based definitions of primary sclerosing cholangitis‐related complications are urgently needed.
Linked ContentThis article is linked to Stratton and Williams paper. To view this article visit https://doi.org/10.1111/apt.14898.
Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of ...intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver.
Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs.
We identified a population of intrahepatic naive-like CD4+ T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (TH17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards TH17 cells.
We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4+ T cells in PSC harbour the propensity to develop into TH17 cells.
The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4+ T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
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•First single-cell atlas of intrahepatic T cell landscape in PSC.•Identification of tissue-resident naive-like CD4+ T cells in human liver which are expanded in livers of patients with PSC.•Trajectory inference suggested a developmental propensity of these cells to acquire a TH17 polarization state.•Functional experiments, using circulating naive CD4+ T cells, support the inferred propensity to acquire a TH17 polarization state.•Chromatin accessibility studies revealed imprinting of naive CD4+ T cells towards effector function in PSC.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Characteristic features are multifocal strictures and dilatations of the bile ducts. In 60-80 % of ...cases the PSC is strongly associated with chronic inflammatory bowel disease, mostly in the form of pancolitis. The diagnosis is established based on detection of typical cholangiographic lesions of the bile ducts and exclusion of secondary causes of sclerosing cholangitis. There is no approved medical treatment, but in Germany ursodeoxycholic acid is frequently used. Clinically relevant stenoses can be successfully treated by interventional endoscopy. Patients with PSC suffer from a greatly increased risk of hepatobiliary malignancies, especially with respect to cholangiocarcinoma and colorectal cancer and therefore require regular surveillance and screening. Liver transplantation is currently the only curative treatment option.
Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this ...short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4
T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4
T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4
T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
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