PSC patients present inconsistent disease manifestations across several organs. There are also differences in age of onset, time to liver failure, and overall clinical outcome, including reoccurrence of PSC after transplant. These differences may define distinct PSC subtypes. We therefore need to better characterize the diverse phenotypes in the heterogeneous PSC population, This requires collection of new clinical data and interrogation of existing clinical data from a large patient cohort. We compare this data (e.g. disease severity, lab values, imaging results, comorbidities, therapeutic history) with patient family history, demographics and environmental/geographic factors (see below) to determine any contextual associations with PSC phenotypes.
Correlating genetic data from as many PSC patients as we can study with their particular phenotype may highlight pathway(s) critical for development of PSC phenotypes. We use exome (protein-coding portion of the genome) sequencing to fully understand the contribution of genetics to disease phenotype, including the role of rare variants. Deep sequencing of regions of interest (e.g. HLA loci) is another useful tool at our disposal to better understand the contribution of immune genetics to PSC pathogenesis. We employ family or pedigree-based analysis where possible to further inform broader population-based analyses.
PSC has been regarded as an autoimmune disorder, which is supported by its comorbidity with autoimmune diseases (IBD, AIH, SLE, other sclerotic conditions, etc). To determine if PSC is a classic T and/or B cell mediated “autoimmune” disease and understand the role of immune cells in PSC, we are performing immune repertoire sequencing in the lymphocyte compartments. We are also scanning for defects at the level of immune surveillance (sensors, e.g. TLRs), activation (e.g. cytokine signaling, costimulatory signaling, coinhibitory signaling, etc), antigen presentation, and response amplification. However, it is possible that PSC results from an understandable immune response to an external aggravator (injury, infection, cancer, etc). We therefore perform specimen screens to rule out rare parasitic infections and imbalances in the microbiome (discussed below).
A growing body of evidence suggests that disruption of the microbiome or of body spaces containing sub-microbiomes (e.g. dysregulated gut permeability) plays a role in PSC pathogenesis. A greater understanding of microbiome(s) in the context of PSC will potentially enable targeted therapies in this domain. We achieve this through profiling microbiome signatures in stool, bile and liver samples (and other body spaces as indicated, e.g. oral microbiome) in PSC patients, family and cohabitor controls, and overlapping and related disease groups through deep sequencing methods. We also correlate the results with phenotype information (discussed above)
PSC is characterized by sclerotic strictures within the biliary tree. It is possible that the wound healing process is corrupted in PSC or that enhanced fibrosis occurs as a result of defects in posttranslational cellular behaviors. We therefore compare the fibrotic behavior of cells from PSC patients with non-cirrhotic and non-PSC cirrhotic liver controls within in vitro systems. Fibrotic behavior is assessed through the matrix remodeling behavior of hepatocytes, biliary epithelial cells and liver-resident immune cells maintained in co-culture systems and/or exposed to appropriate microbial, cytokine or bile acid stimuli.
There are differences in the characteristics of PSC populations from different geographical locations. Furthermore, some autoimmune disorders have been linked to environmental exposures (e.g. fire retardants, crystalline silica). Therefore, we assess demographic/geographic, lifestyle and occupational history information from PSC patients to screen for patterns of environmental exposure that warrant further investigation by epidemiology consultants.
Generation of new biomarkers for diagnosis and disease activity monitoring that can be measured relatively non-invasively will be critical for capturing PSC patients earlier in the evolution of their disease and for detecting response to therapies. The latter is critical for accelerating drug discovery in PSC; We are identifying new PSC biomarkers and improving lab-based assays for these, as well as working to integrate their use with imaging biomarkers.
Imaging is crucial for PSC diagnosis and monitoring. MR- and ultrasound-based elastography techniques are of considerable predictive value in patients with advanced fibrosis. The challenge in PSC is distinguishing fibrosis from severe inflammation, particularly in cases with comorbid AIH. Quantitative MR imaging and spectroscopy are beginning to resolve disease picture across the entire liver. We are working to bring such a tool to market for imaging biliary structures to detect PSC activity, response to therapy and potential cancers.