Compared to the general population, PSC patients have a 400-fold increased risk of developing bile duct cancer. This cancer, also known as cholangiocarcinoma (CCA), is the most dreaded complication of PSC because it is so aggressive. CCA progresses quickly, is difficult to treat, and can eliminate a patient’s eligibility for a liver transplant. The rapid deterioration that can follow a CCA diagnosis has been tragically exemplified in the past with famous PSC patients such as Walter Payton and Chris LeDoux, who both lost their lives to CCA just months after diagnosis. What can we do now to prevent this happening to more PSC patients?
Physicians at the Mayo clinic have a conservative surveillance protocol for detecting CCA in PSC patients as early as possible. In PSC patients over the age of 20 with large duct PSC, Mayo physicians obtain liver tests every 3-6 months and annually image the biliary tree and test patient sera for potential indicators of CCA. Unfortunately, there is not yet a well-established biomarker for early CCA, and there are no proven reliable predictors for PSC patients that are at higher risk of developing CCA. However, it is recognized that pediatric PSC patients and patients that only have PSC in the small bile ducts rarely develop CCA. Meanwhile, a history of colorectal cancer or dysplasia, longer duration of IBD, variceal hemorrhage, smoking, and alcohol consumption have been associated with CCA.
Given our lack of understanding of the development of CCA in PSC, surveillance of at-risk patients is key. Imaging the biliary tree can help physicians identify new, large, thickened bile ducts or ‘dominant strictures’, of which 25% may be malignant. Therefore, looking for these and testing them can help to detect CCA earlier. Coupled with testing for other ‘flags’ such as biochemical changes in blood tests, regular imaging is the first line of defense against CCA.
According to Mayo clinic physicians the most widely used serum marker of CCA is ‘Carbohydrate Antigen 19-9’ (CA 19-9), although 7% of people naturally cannot produce this antigen, and it may only help detect advanced CCA. Though more invasive, ERCP to examine the cells lining the bile ducts can help to better identify individuals at risk of CCA. Cells with a suspicious appearance may predict the development of CCA, but the excessive inflammation associated with PSC means that bile duct cells commonly have an atypical appearance, making this a difficult call. Special screens can detect chromosomal abnormalities in bile duct cells, such as fluorescence in-situ hybridization (FISH), and individuals with PSC whose bile duct cells consistently show evidence of chromosomal abnormalities are likely to develop CCA. Evidence of chromosomal abnormalities in multiple bile duct locations is an even stronger predictor of CCA.
The Good News
While we don’t fully understand how CCA develops in PSC, scientists have leads to follow. Causes of cancer in PSC bile ducts could be the inflammation associated with PSC and/or the accumulation of bile. Inflammation can cause DNA damage, leading to mutations that may cause cancer, while bile acids can stimulate growth signals in cells, which may lead to excessive growth and tumor development. Oxygenated cholesterol in the bile of PSC patients could also activate similar pathways in cells. Drugs targeting some of these pathways are already in development for other diseases. Therefore, we may soon have potential preventative CCA therapies we can trial for PSC patients. SJI is working with scientific and pharmaceutical partners to ensure this important work moves forward as soon as possible. If you are a PSC patient or physician, keep up with trials involving SJI by joining one of our clinical trials networks – PSC America (for patients over 18 and their physicians and relatives) or PSC America Peds (for PSC patients under 18 and their physicians and relatives)
This blog post is based on information provided in a larger critically-reviewed journal article published by Rizvi and colleagues in the journal Clinical Gastroenterology and Hepatology.
Image: Begin hepatocytes (left) next to cholangiocarcinoma cells (right) in a section of stained liver tissue. Modified from orginal image by Nephron (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons
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