Primary sclerosing cholangitis (PSC)
Autoimmune Liver Diseases (AILD)
PSC is a chronic cholestatic hepatobiliary disease that has an incidence of approximately 1 case per 100,000 persons/year. Two-third of patients are male, and of middle-age. The pathogenesis is not well understood, although immunological mechanisms and the gut-liver axis seems to play a role in the development of the disorder. Consistently, inflammatory bowel disease (IBD) is a frequent found in association with PSC. PSC has a highly variable natural history: it can stay asymptomatic for long periods but may also present with an aggressive course, leading to recurrent biliary tract obstruction, recurrent episodes of cholangitis, and may progress to end-stage liver disease or cholangiocarcinoma.
First-degree relatives of patients with PSC have increased risk of both IBD and PSC.
Evidence suggest an immunopathogenic cause, as elevated IgM or IgG and autoantibodies are frequently found in these patients. More than 20 susceptibility genes have been identified in the pathogenesis of PSC. The most prominent ones are of human leukocyte antigen (HLA), particularly B8 and DRB1 indicating strong involvement of adaptive immune functions. Some other susceptibility genes are T-cell related, while CFTR mutations (contributing to the loss of protective mechanisms against bile acid toxicity) may be detected in one third of patients.
Environmental risk factors are mainly unknown, however an overall reduction in bacterial diversity of the gut and altered abundance of certain bacteria is observed in PSC.
Patients with early disease are rarely symptomatic. End-stage liver disease or cholangiocarcinoma might silently develop before the underlying PSC being diagnosed. In absence of symptoms, an abnormal liver biochemistry with or without associated IBD might draw attention to PSC. However, in some cases, PSC might have a more aggressive disease course. The most common complication of PSC is bacterial cholangitis requiring urgent intervention. Patients with late disease might present with signs of liver failure and portal hypertension.
Abnormal liver tests show a cholestatic profile. ALP and gamma-glutamyl transferase levels are markedly, while aminotransferases are often only modestly elevated. Bilirubin and albumin levels are often normal at diagnosis but may progressively deteriorate. IgM levels are increased in about half of the patients. IgG4 have been found in approximately 10% of patients with PSC and may represent a more rapidly progressive disease curse. Autoantibodies may be present, however anti-GP2 IgA is the first (and so far only) one that was confirmedly associated with worse outcomes in multiple studies.
It may be asymptomatic. When symptoms are present, fatigue is the most common but unspecific sign. Weight loss might be associated with PSC. Sudden onset of pruritus should signal the possibility of obstruction of the biliary tract. Fever and pain can be present during acute cholangitis episodes. Other symptoms are those of advanced liver disease such as jaundice, portal hypertension, gastrointestinal bleeding. Chronic right upper quadrant discomfort is not a prominent feature of PSC.
In patients with persistent cholestatic liver test results, the diagnosis is generally established based on cholangiography showing multiple strictures and dilatations, after ruling out secondary causes of sclerosing cholangitis. Noninvasive magnetic resonance cholangiography is preferred over invasive endoscopy for the diagnosis of PSC. Liver biopsy is necessary for rare cases with suspected small duct disease.
In the majority of cases secondary causes of sclerosing cholangitis can be excluded based on the history of the patient and advanced imaging, like MRCP. Secondary sclerosing cholangitis is caused by a number of heterogenous diseases, that include, but are not limited to obstruction by biliary stones, viral or parasitic infection in patients with organ transplant or AIDS, biliary ischemia in allograft rejection, vasculitis, chemotherapy or critical illness. Other secondary etiologies are histiocytosis and sarcoidosis. Negative antimitochondrial autoantibody test can help exclude primary biliary cirrhosis. IgG4 associated cholangiopathy and autoimmune hepatitis should be considered as alternative diagnoses.
ManagementUrsodeoxycholic acid (UDCA), a hydrophilic bile salt, has a potential to improve liver test abnormalities, but not histology. The British and the American liver societies recommend against its use in PSC. In fact, there is no medical therapy that has been proven to prolong survival in PSC in a phase III clinical trial. Patients with PSC and IBD should have annual colonoscopic surveillance to detect and remove dysplastic lesions and prevent colorectal cancer. In patients without IBD colonoscopy is recommended in 5-year intervals. In case of bacterial cholangitis antibiotics are first line therapy. Treatment of dominant strictures by endoscopic dilatation or stent placement may improve symptoms and clinical findings. Screening and follow-up of end stage liver disease and its complications, cholangiocarcinoma, osteoporosis is required regularly. In advanced liver disease liver transplantation should be considered. Most recent guidelines:
- https://journals.lww.com/ajg/Fulltext/2015/05000/ACG_Clinical_Guideline__Primary_Sclerosing.10.aspx (2015)
- https://www.bsg.org.uk/clinical-resource/bsg-and-uk-psc-guidelines-for-the-diagnosis-and-management-of-primary-sclerosing-cholangitis/ (2019)
- https://www.esge.com/role-of-endoscopy-in-primary-sclerosing-cholangitis/ (2017)
PSC causes accumulation of fibrotic tissue and may lead to cirrhosis with portal hypertension and finally liver failure needing liver transplantation. Bacterial cholangitis are often complications of biliary strictures. Gallbladder abnormalities are frequently observed such as dilatation, cholecystitis, gallstones and benign or malignant lesions. PSC also associates with an increased risk of biliary and colorectal cancer.
Osteoporosis can associate to all cholestatic liver diseases, thus PSC as well.
If you wish to discuss a primary sclerosing cholangitis case with experts from the ERN, you can upload cases to the CPMS: https://cpms.ern-net.eu/login/.
The CPMS is essential for interaction between healthcare professionals and experts on clinical decision-making, and is provided by the European Union to all ERNs. CPMS supports online multidisciplinary meetings (tele-boards) to discuss patients with diagnostic or therapeutic dilemmas in need of expert consultation. CPMS offers the opportunity to upload and share clinical data of patients and pictures such as histological slides or MRI images. Importantly, this is fully in line with European data protection law. It is obligatory to inform patients about CPMS and obtain their informed consent before their data are entered into the system (see CPMS Privacy Statement published by the European Commission on 14 December 2017). The consent form is available in all EU languages in CPMS.
Clinical practice guidelines: Links
Below you will find specific information on the diseases covered by our three pillars. In addition, we provide links to the clinical practice guideline pages of the professional societies:
European Association of the Liver (EASL)
European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN)