Primary Sclerosing Cholangitis: A Clinical Update Authors: *Sridhar Sundaram,1 Vaneet Jearth2 1. Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India 2. Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Centre, Mumbai, India *Correspondence to [email protected] Disclosure: The authors have declared no conflicts of interest. Received: 21.01.19 Accepted: 26.02.19 Keywords: Biliary cirrhosis, cholestasis, sclerosing cholangitis. Citation: EMJ. 2019;4[3]:101-110. Abstract Primary sclerosing cholangitis (PSC) is a rare cholestatic disorder of the liver, with strictures in the bile ducts leading to cirrhosis of the liver in a proportion of patients. PSC is commonly associated with inflammatory bowel disease and increased risk of cholangiocarcinoma, gall bladder cancer, colorectal cancer, and hepatocellular carcinoma. Medical therapies are primarily aimed at symptom management and disease-modifying therapies are limited. Endoscopic therapies are used in patients with dominant strictures and liver transplantation is a last resort. In this article, the authors aim to comprehensively review the epidemiology, diagnosis, and management of PSC with emphasis on risk of malignancies and management of PSC. The authors also survey the advances in pathogenesis understanding and novel medical therapies for PSC. INTRODUCTION Diagnosis is largely based on imaging with magnetic resonance cholangiopancreatography (MRCP); however, liver biopsy may be needed in Primary sclerosing cholangitis (PSC) is a rare a small number of cases. Medical therapies are cholestatic disorder of the liver associated limited to management of cholestasis in patients with inflammation and injury with fibrosis in with PSC, while endoscopic therapy remains the intrahepatic and extrahepatic bile ducts. A the mainstay when dominant strictures are large proportion of patients have associated present.5 Liver transplantation remains the last inflammatory bowel disease (IBD) with resort in decompensated liver disease, although PSC.1-3 PSC presents with features of cholestatic recurrence post transplantation is frequent.6 liver disease; however, patients can present Despite the advances in imaging and diagnostics, with decompensated liver disease over the long therapy options for PSC are still limited, with term. PSC is associated with a predisposition most patients diagnosed with end-stage disease. to malignancies, including cholangiocarcinoma (CCA), gall bladder cancer, hepatocellular carcinoma (HCC), and colorectal cancer (CRC).4 Creative Commons Attribution-Non Commercial 4.0 September 2019 • EUROPEAN MEDICAL JOURNAL 101 EPIDEMIOLOGY, GENETICS, and subsequent wound healing by periductal fibrosis. However, a Scandinavian study on this AND PATHOGENESIS hypothesis showed no significant difference in small intestinal bacterial overgrowth or PSC is a rare disease with an incidence rate intestinal permeability between PSC patients and in northern Europe and the USA of 0.4–2.0 controls.15 The gut lymphocyte homing per 100,000 people per year.5 An increasing hypothesis was proposed because PSC usually incidence of PSC has been reported, mainly runs a course independent of IBD. Memory attributed to the use of MRCP leading to an T lymphocytes primed in the inflamed gut increase in early diagnosis.7 The median age of may trigger and continue inflammation in the presentation is 30–40 years, with a male to female periportal region.16 Both these hypotheses are ratio of 2:1.8 In patients of northern European proposed for patients with IBD and PSC. These descent with PSC, 62–83% have associated IBD hypotheses, however, failed to describe PSC while 20–50% patients from southern Europe patients without IBD and those who develop 9 and Asia have associated IBD. The ratio of PSC prior to the development of IBD. The ulcerative colitis (UC) to Crohn's disease (CD) autoimmune hypothesis was proposed due to is 6:1 in patients with PSC. A distinct phenotype the presence of autoantibodies like perinuclear termed as PSC–IBD has recently been described antineutrophil antibodies (pANCA) in in association with PSC with features of both UC association with 80% of PSC patients and 10 and CD. known overlap syndrome between autoimmune PSC is a complex multifactorial disease with hepatitis and PSC. This hypothesis is based known genetic associations, both HLA (HLA B8 on molecular mimicry of biliary antigens on and HLA DR3) and non-HLA associated. There cholangiocytes and immune response to the 17 is known familial association, with the risk being same. In 2010, the biliary umbrella hypothesis 0.7% amongst first-degree relatives andwas proposed. There is a loss of the biliary approximately 1.5% amongst siblings, both bicarbonate umbrella in patients with PSC, which 100-times higher than that in the general may increase permeation of protonated bile 18 population.11 Non-HLA associations are found acids, leading to the injury of cholangiocytes. It with killer immunoglobulin-like receptor (KIR), is also referred to as the toxic bile hypothesis. major histocompatibility complex (MICA The pathogenesis for PSC remains complex, and MICB), intracellular adhesion molecule-1 with need for further studies. In addition, (ICAM-1), chemokine receptor 5 (CCR5), G various ongoing animal studies may help further protein coupled bile acid receptor 1 (GPBAR1) elucidate the pathogenic mechanisms and TGR5, multidrug resistance gene-1 (MDR- potential therapeutic targets for both early and 1), steroid and xenobiotic receptor (SXR), advanced PSC.12 and its analogue pregnane X receptor (PXR) polymorphisms.12 Despite the common CLINICAL FEATURES, DIAGNOSIS, association of PSC with IBD, the HLA association of the two disorders is not characteristic, as AND DIFFERENTIALS demonstrated in a Scandinavian cohort.13 Although PSC is rare, the HLA subtypes Fifteen to forty percent of patients are associated with risk are rather common and asymptomatic at diagnosis. Fatigue and hence the probability of false genetic association pruritus are the most common symptoms of remains a problem in study design. This problem disease. Ascending cholangitis due to transient is not related to statistical power alone but biliary obstruction may be a presenting to the possibility of allelic complexity at a manifestation in patients with fever, chills, susceptibility locus.14 and right upper quadrant pain. Patients may present with recurrent episodes of jaundice. In The leaky gut hypothesis was initially used to patients with cirrhosis and portal hypertension, describe the pathogenesis of PSC. Due to mucosal decompensation is evident in the form of ascites, injury, increased bacterial translocation into the hepatic encephalopathy, or bleeding.19 Laboratory portal venous system leads to an inflammatory anomalies include increased bilirubin and alkaline response in the bile ducts, leading to cholangitis phosphatase. Transaminases <300 U/L are 102 EUROPEAN MEDICAL JOURNAL • September 2019 EMJ EUROPEAN MEDICAL JOURNAL seen in patients with PSC. Albumin is normal in 4) biliary cirrhosis.26 Liver biopsy is performed to early stages and decreases with progression of rule out other diseases, to look for AIH overlap, or liver disease. Hypergammaglobulinaemia and in cases of suspected small duct PSC. elevated IgG levels are seen in patients with PSC. Antimitochondrial antibody (AMA) is rarely VARIANTS OF PRIMARY SCLEROSING positive in patients with PSC.20 Autoantibody CHOLANGITIS testing is not a contributing factor in the diagnosis of PSC. Although pANCA is commonly seen in patients with PSC, it is not specific. Overlap Syndrome Antinuclear and smooth muscle antibodies are Suspicion of overlap with AIH should be high in seen in patients with PSC in low titres. In patients situations with raised transaminases (>5-times with autoimmune hepatitis–primary sclerosing the upper limit of normal) with raised serum Ig cholangitis (AIH–PSC) overlap, the antibodies levels (IgG >2-times the upper limit of normal) are seen in higher titres.21 Although AMA is rarely with features of PSC on imaging and evidence positive in patients with PSC, overlap between of cholestasis (raised alkaline phosphatase and primary biliary cholangitis (PBC) and PSC is gamma-glutamyl transferase) on biochemistry. rarely reported.22 Biopsy is required for confirming the diagnosis. Overlap of PSC with AIH is known to occur Cholangiography is the gold standard for in 7–14% of patients with AIH. Treatment with diagnosis of PSC. MRCP is the investigation of immunosuppressants is useful, although their choice for diagnosis. MRCP avoids radiation impact on fibrogenesis and cirrhosis is not as and contrast media associated with endoscopic pronounced as with AIH without PSC.27 PSC is retrograde cholangiography (ERCP). However, also known to have overlap with PBC in few case MRCP provides suboptimal visualisation of the reports.22 A genetic risk locus has been described intrahepatic bile ducts. Multifocal short segmental for coexistence of PSC with PBC (chromosome strictures are seen on MRCP suggesting a ‘beads 1p36).28 on string appearance'. Both intrahepatic and extrahepatic ducts are Small Duct Primary Sclerosing involved in most of the patients (Figure 1). Cholangitis Isolated intrahepatic ductal involvement is Involvement of small ducts only can be seen in seen in approximately 25% of patients. Isolated 5–15% of patients. Liver biopsy is required for extrahepatic involvement is rare (<5%). Also gall diagnosis of small duct PSC. Small duct