While there are many things we are still working to understand about PSC, there is one thing we know already: it is a progressive disease. Naturally, this raises the question – what stages are there in PSC?
It is actually quite difficult to stage PSC, as there are so many variations in its clinical course. Furthermore, the disease can be clinically silent for a number of years.
In the early stages of PSC, patients frequently do not have any symptoms as a result of the changes going on at the cellular level in their bile ducts and liver. This means that PSC may only be evident in abnormal liver biochemistry tests. An elevated level of alkaline phosphatase (ALP) in the blood is usually one of the earliest signs of PSC. After diagnosis, there are many different ways PSC patients may be ‘staged’ depending on their clinical circumstances, and this can be very confusing.
Staging PSC Through Liver Biopsies
Scientists and doctors can try to stage PSC by the appearance and changes seen in liver tissue obtained by a biopsy. The study of tissue structure and appearance is known as histology, and the histological stages of PSC defined by Ludwig and colleagues in 1981 are as follows:
Stage 1 (Portal): Microscopic examination reveals infiltration of white blood cells (inflammation) and bile duct cell degeneration in liver tissue from an area called the portal triad. Fibrous tissue accumulation through collagen deposition (fibrosis) follows loss of bile ducts. The portal triad is where the hepatic artery and hepatic vein meet with the common bile duct, into which tributary liver ducts drain.
Stage 2 (Periportal): The portal triad tissue may be enlarged, and there is more widespread inflammation and scarring of the bile ducts. There is also evidence of cell death in liver cells (hepatocytes) close to the ducts.
Stage 3 (Septal): There is severe degeneration of the bile ducts and bile duct disappearance.
Stage 4 (Cirrhosis): There is obvious damage (cirrhosis) of the liver and end stage liver disease.
Monitoring PSC by Non-Invasive Means
The system described above stages PSC by the degree of fibrosis observed in biopsies of the liver. However, most PSC patients do not undergo regular liver biopsies because the procedure for removing a piece of liver tissue is invasive and carries a risk of bleeding. Also, a sample of liver tissue taken by biopsy only provides insight into what is occurring in 0.002 % of the whole liver. Less invasive techniques are under development for assessing liver fibrosis, and some have been shown to predict stage of fibrosis (as measured with a liver biopsy) well, especially advanced fibrosis. Elastography is a technique that can be used to determine the stiffness of tissue using an external device. The technique employs either ultrasound or magnetic resonance imaging (MRI) to determine tissue stiffness, which in the liver generally corresponds with the degree of fibrosis. You may hear about FibroScan™, which uses ultrasound technology, or Magnetic resonance elastography (MRE), which uses MRI technology. Also in the pipeline are other techniques that aim to overcome some of the limitations of elastography, for example quantitative MRI, which has been commercialized as Perspectum Diagnostic’s LiverMultiScan.
Monitoring PSC by ERCP/MRCP
The scarring and hardening of the bile ducts in PSC causes narrowing of the bile ducts that can be seen by a technique called endoscopic retrograde cholangiopancreatography (ERCP), in which an endoscope is passed through a patient’s esophagus and stomach to the duodenum, where the bile ducts empty into the gastrointestinal passage. With use of a camera and/or injection of an X-ray-blocking dye, ERCP is used to diagnose PSC. Doctors may also be able to monitor disease progression with periodic ERCPs. The more narrowing the doctors see in subsequent ERCPs, the more PSC is progressing. ERCP can also be used to scan for signs of cholangiocarcinoma (CCA, cancer in the bile ducts) and to insert a stent (drainage tube) into narrowed bile ducts to encourage bile drainage and slow the development of liver failure. MRCP generates the same type picture of the biliary tree using non-invasive MRI, but does not allow for interventional procedures or biopsy collection like ERCP. There is no universally agreed upon PSC staging using the results of ERCPs or MRCPs. Nevertheless, some centers have studied the value of bile duct imaging for predicting patient survival time, and found it to be useful.
PSC Staging and Clinical Complications
It would be most useful if we could translate physical changes in liver and bile duct tissue to a prognosis that predicts the impact of PSC on each patient’s health over time. However, many PSC patients have co-morbid diseases such as inflammatory bowel disease and autoimmune hepatitis. Some of these diseases may influence the progression of PSC, making patient prognosis complicated. Also, different PSC patients progress at different rates. Perhaps these differences reflect the fact that PSC can be asymptomatic for many years and it is caught earlier in some patients than others, purely by chance. In 2008 it was known that between 15 and 55% of patients are asymptomatic at presentation. Finally, some PSC patients may be more susceptible to developing cancer than others. Cancers (liver, bile duct, and colorectal) then have their own degrees of staging, which can further confuse PSC patients who are trying to understand the staging of their disease.
Scores and Grades
Not only may liver, bile duct or colon cancer have their own disease stages, but the tumors themselves can be graded according to the behavior of the cells in them. Meanwhile, even in the absence of cancer there are various other scores and grades that can be applied to PSC patients. One is the MELD score (Model for End-stage Liver Disease). This score is calculated based on serum bilirubin, serum creatinine, and the international normalized ratio (INR, which assesses blood clotting) to assess the severity of liver disease and determine transplant priority. While this score is good for determining the degree of liver failure in patients with primary liver disease, it doesn’t provide a full picture for PSC patients because they could develop comorbidities that the MELD score doesn’t account for. For example, PSC patients are more susceptible to infections and CCA, which lack reliable predictors. Therefore, having a better MELD score may not necessarily mean a PSC patient is in better shape overall. This has been a concern for PSC patients on the transplant waiting list, although some studies suggest that PSC patients on liver transplant lists do not have an increased chance of death or withdrawal due to clinical complications compared to other end-stage liver disease patients. We all know someone who has not made it up the list fast enough, and for those individuals and their families, the consequences are devastating.
The MELD score has been adjusted for different clinical scenarios, including the development of liver cancer and advanced kidney failure. The Mayo clinic has also devised a score specific to PSC to predict risk of mortality (due to PSC) every year for up to four years. To calculate patient survival probabilities, the Revised Natural History Model for PSC accounts for age, as well as bilirubin levels and additional liver biochemistry values, and any history of esophageal/stomach bleeding (which results from increased blood pressure in the portal vein supplying the liver, or portal hypertension).
It is important for PSC patients to realize that scores and grades are not necessarily the same as disease stages. In general, staging of most chronic liver diseases and cancers relates to the spread/progression and functional effect of the disease at the organ/whole body level, whereas grade refers to what the disease looks like at the underlying cellular level. In the case of PSC, the formal staging we do is based on liver biopsy histology, which makes it more similar to what we would call “grading” in cancer evaluation. Nevertheless we assign a stage to estimate how far the disease has progressed.
For PSC patients, disease progression can vary wildly over time and across different parts of the liver. We need to get better at characterizing PSC progression in order to stop it in its tracks.
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