PSC is complex liver disease and we don’t fully understand what causes it.
Current evidence suggests PSC is caused by a combination of multiple genetic changes in our DNA and so far unknown environmental triggers making an individual prone to immune attack 13. This means that people with a particular genetic makeup may be sensitive to some sort of environmental trigger that causes their immune system to ‘attack’ their bile ducts. We’re not sure what that trigger is. It could be diet, exposure to toxins, infection, microbiota (the bugs that live inside us) or even a combination of all these factors 14.
There is currently more research investigating our condition than ever before, so we’re hopeful that one day we will understand the exact cause of the disease. Understanding the cause of PSC and how it develops may help scientists to define strategies to interrupt that process and treat PSC. It is possible that drugs already available for other diseases could one day be used to treat PSC 2. This is called ‘drug repurposing’.
Genetics and PSC
The genetics of PSC have been studied closely using an approach called genome-wide association studies (GWAS). This involves scanning complete sets of DNA to find genetic variations that are associated with a particular disease. Once new genetic associations are found, it is hoped that researchers will be able to use the information to develop better strategies to detect, treat or even prevent the disease.
GWAS have shown that PSC is not caused by a problem with a single gene but that there are 23 regions in our DNA associated with PSC 2,15 and has confirmed that PSC may be described as an autoimmune disease 2. Despite these findings, this genetic element explains less than 10% of the risk of developing PSC 16, suggesting that environmental factors play a key role.
The interaction between genes and the environment in PSC is complex. The genes linked with PSC (the genetic risk) may affect how your immune system responds to environmental trigger(s) or influence further changes in the body over time. The interaction of these factors can be visualised as a pathway that results in PSC. See Figure 1. 17.
Microbiome and PSC
The gut microbiome refers to a collection of different microbes in the digestive system (intestinal microbiota), such as bacteria, yeasts, fungi, viruses and protozoans. In PSC there are abnormal changes in the types and numbers of intestinal microbiota. This is called dysbiosis 18. A number of small studies suggest that 1) there is a distinct gut microbiota profile in PSC 19 and that 2) there is not as much variety in gut microbiota present in people with PSC compared to people who do not have PSC and compared to people with IBD only 20.
As discussed above, we do not yet know whether this has something to do with the cause of PSC or whether it is a consequence of having PSC (akin to the chicken and the egg scenario). Larger-scale research in this area is needed 20,21. It is possible that in the future, the distinct gut microbiota pattern seen in PSC could help distinguish PSC-IBD from IBD alone, or help identify early-stage PSC 20. It is possible that manipulation of the gut microbiome could provide a treatment for PSC 21 but caution is urged by Professor Tom Karlsen who warns that manipulation could also affect the protective elements of intestinal microbiota 20.
Dr Kate Lynch (née Williamson) explains microbiome research and emerging results and challenges in this video (watch from 4m15s):