Update on PSC from Dr Roger Chapman
Special thanks to Dr Chapman for writing this summary of what we know about PSC for patients.
Dr Roger W Chapman, Dept of Translational Gastroenterology, Oxford University Hospital. Oxford, UK OX3 9DU
Primary Sclerosing Cholangitis (PSC) is a relatively rare liver disease characterised by inflammation, narrowing and scarring of the biliary system, both inside and outside the liver. The narrowing of the small and large bile ducts ultimately leads to blockages in bile flow which can progress to biliary cirrhosis in some but not all patients.
The diagnosis is established by visualising the bile ducts (cholangiography) usually by MRCP, often in patients with inflammatory bowel disease presenting with abnormal, cholestatic liver function tests (see figure 1).
Liver biopsy is only required in a small number of patients in whom the diagnosis is not made by cholangiography. It is important to exclude IgG4-related sclerosing cholangitis which is a separate and distinct disease from PSC.
PSC has become increasingly recognised as one of the major causes of autoimmune liver disease. Major advances in the treatment of other commoner liver diseases such as Hepatitis C, has led to PSC being called “the last black box remaining in hepatology”.
However, there have been a number of advances in all aspects of PSC over the last decade, which will be discussed below.
PSC is a male predominant disease, with a Male:Female ratio of around two to one. Whilst the disease can present at any age, the mean age of presentation is 40 years old. The number of people who have been diagnosed with PSC in Northern Europe is increasing: approximately 16 people per 100,000 of the population will have PSC.
The exact cause (pathogenesis) of PSC is unknown, although it is strongly associated with inflammatory bowel disease (IBD). However, genetic factors appear to play an important role. The strongest genetic association is with HLA genes on Chromosome 6, which are involved with the immune system. Recent studies have shown that a further 15 or so non-HLA risk loci have been identified, including other genes which are commonly found in other autoimmune diseases. An important new finding, is association with the FUT-2 gene which is involved in regulating the type of bacteria which live in the intestine (“the biome”). This indicates the importance of the immune response and its interaction with “the biome”. Recent studies have shown a distinctive and specific gut microbial profile in patients with PSC patients compared with patients with UC patients without PSC and normal controls.
Other factors are felt to play a role in the cause of PSC, such as a toxic effect of bile on damaged biliary lining; the so called “leaky gut” theory, where pre-existing IBD predisposes to increased “leakiness” of the bowel wall, and therefore increased exposure of the bile ducts to bacteria and other pathogens and toxins. Another factor is the diversion of specialised white blood cells (T-cells) from the bowel to the liver where they can damage the bile ducts. Current evidence suggests that PSC is a complex, immune mediated disease, related to a specific microbiome involving many genes (polygenic) (see figure 2).
Figure 2. PSC is a complex disease - how it might develop
Whilst there is a strong genetic predisposition to the disease, environmental factors play a role. PSC is predominantly a disease of non-smokers, irrespective of the presence of underlying IBD. Coffee drinking (three cups a day) appears to be protective, as it reduces fibrosis and scarring in the liver.
PSC and Inflammatory Bowel Disease
Up to 80% of patients with PSC have also have inflammatory bowel disease (IBD). The characteristic phenotype is a pancolitis (involving the whole colon), usually worse in the right colon. Ulcerative colitis makes up around 75-80% of cases of IBD, with 10-15% being Crohn’s (colitis), and 5-10% IBD-unspecified.
Conversely, around 5-10% of patients with IBD will develop PSC. Recently 8 to 12 % of patients with total UC and persistently normal liver blood tests have been shown to have diagnostic changes of PSC on cholangiography. It may be that in the future, all patients with pancolitis will be offered an MRCP to diagnose PSC at an early stage.
The clinical course of colitis in PSC/UC is usually mild, with infrequent attacks of bleeding and diarrhoea compared with patients with UC alone. In PSC/UC the bowel inflammation runs an independent course from the PSC. In contrast, PSC/ Crohn’s have a better prognosis from their liver disease although unlike PSC/UC, the bowel disease runs a similar course to Crohn’s disease without PSC.
Current evidence strongly suggests that PSC/IBD is a separate disease entity from IBD without PSC, with distinct and separate genotypes and phenotypes.
The natural history of PSC is highly variable and unpredictable. The blood test, serum Alkaline Phosphatase (ALP) levels tend to fluctuate over time, but a persistently low ALP (eg less than 1.5 times the Upper Limit of the Normal range, ULN) at one year from diagnosis has been shown to confer a good clinical outcome.
The Enhanced Liver Fibrosis Score (ELF) is a blood test derived from three serum fibrosis markers which has also been shown to predict accurately the prognosis of PSC. It is unclear whether these serum biomarkers will prove to be reliable surrogate endpoints in clinical trials.
Initial studies suggested the median time from diagnosis to liver transplantation of 10-12 years, however a recent study from the Netherlands gave a much more optimistic view of a median time of 21.3 years from diagnosis to PSC-related death or liver transplantation. We have confirmed this in our Oxford population with an even better survival figure of 23 years. This is likely a more accurate estimate, as it represents a PSC population as a whole, as opposed to tertiary centres with potential referral bias. Approximately 15% of PSC patients will require liver transplantation.
PSC and Cancer
PSC is a premalignant disease with a high prevalence of hepatobiliary and colonic malignancy. In contrast, patients with small duct PSC (defined as a raised serum ALP, normal cholangiogram, and features of PSC on liver biopsy) have a good prognosis, with no reports of bile duct malignancy in this group, and progression to advanced liver disease is uncommon.
There is a major, as yet unmet, need to identify subgroups of PSC patients who are at particular high risk of developing cholangiocarcinoma (bile duct cancer), where heightened surveillance may be helpful in identifying cholangiocarcinoma at an earlier, treatable stage. There is increasing evidence that the presence of extrahepatic bile duct involvement in PSC patients, particularly with the development of dominant strictures, have a significantly worse prognosis, associated with a higher risk of cholangiocarcinoma.
Improved surveillance techniques involving serum micro RNA's, cholangioscopy (endoscopic bile duct examination) and improved magnetic resonance imaging are currently being assessed. These advances offer hope that the diagnosis and treatment of cholangiocarcinoma complicating PSC can be greatly improved in the years to come.
There is no proven medical treatment which prolongs survival in PSC. Many immunosuppressive agents have been assessed, including corticosteroids, with little success. Corticosteroids are used with success in a small minority of PSC patients who have a crossover disease with autoimmune disease (AIH). Antibiotics, such as metronidazole and/ or vancomycin are also being assessed in clinical trials, and may have a proven role in the future.
The bile acid, ursodeoxycholic acid (UDCA) has been evaluated in varying doses in multiple double-blinded, placebo-controlled randomised controlled trials, given its beneficial effect shown in PBC. At doses of 13-21mg/kg, it has been shown in PSC to reduce cholestatic liver enzymes, bilirubin, and albumin, but not to reduce death, need for liver transplantation, nor liver histology progression. Higher doses at 28-30mg/kg were associated with an increased mortality, compared with placebo.
Current AASLD and EASL guidelines do not support the administration of UDCA, although a trial of moderate dose UDCA administration has been recently advocated. We have followed this practice in Oxford for several years. From our data, it is possible that about one third of PSC patients will receive benefit from UDCA. This compares with Primary Biliary Cholangitis (PBC), a similar although distinct autoimmune bile duct disease from PSC, where two thirds of patients will respond to UDCA.
Potential Treatments: What's next?
New potential therapies, including new bile acids, antibiotics (such as vancomycin), nuclear agonists, and immunotherapies are currently in development. The only treatment shown to prolong survival in PSC is orthotopic liver transplantation with 5-year survival rates of up to 80%.
However, it is probable that effective medical therapy for PSC will become available in the next decade. It is likely that the treatment will consist of combination therapy, employing different agents targeting different aspects of the disease process together with manipulation of the microbiome. This may involve antibiotics and/or faecal transplantation. A clinical trial of faecal transplantation is about to start in Holland.
Written by Dr Roger Chapman 13 June 2017, based on scientific article 'Update on Primary Sclerosing Cholangitis' published in Clinical Liver Disease 26 May 2017