AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma

WHAT'S NEW SINCE THE 2010 GUIDELINES? Inclusion of guidance for the diagnosis and management of cholangiocarcinoma (CCA) in patients with and without primary sclerosing cholangitis (PSC) (Figures 5, 8, and 9). Introduction of the term relevant stricture, defined as any biliary stricture of the common hepatic duct or hepatic ducts associated with signs or symptoms of obstructive cholestasis and/or bacterial cholangitis (Table 1). In patients with equivocal MRI with cholangiopancreatography (MRI/MRCP) findings, a repeated high‐quality MRI/MRCP should be performed for diagnostic purposes. Endoscopic retrograde cholangiopancreatography (ERCP) should be avoided for the diagnosis of PSC (Figure 2). In patients with PSC without known inflammatory bowel disease (IBD), diagnostic colonoscopy with histological sampling should be performed and may be repeated every 5 years if IBD is not initially detected. Colon cancer surveillance should begin at age 15 years in patients with PSC and IBD. New clinical risk tools for PSC are available for risk stratification, but probabilities of events in individual patients should be interpreted with caution (Figure 4 and Table 3). All patients with PSC should be considered for participation in clinical trials; however, ursodeoxycholic acid (13–23 mg/kg/day) can be considered and continued if well tolerated with a meaningful improvement in alkaline phosphatase (γ‐glutamyl transferase in children) and/or symptoms with 12 months of treatment. ERCP with biliary brushings for cytology and fluorescent in situ hybridization analysis should be obtained in all patients with suspected perihilar or distal CCA. There is a new United Network for Organ Sharing policy regarding standardization of Model for End‐Stage Liver Disease exceptions for patients with PSC and recurrent cholangitis. Liver transplantation following neoadjuvant therapy is recommended for patients with perihilar CCA < 3 cm in radial diameter that is unresectable or arising in the setting of PSC and in the absence of intrahepatic or extrahepatic metastasis (Figure 9). TABLE 1 - Definitions in PSC PSC Chronic, cholestatic liver disease likely of autoimmune origin characterized by inflammation and fibrosis of intrahepatic and/or extrahepatic bile ducts, leading to the formation of bile duct strictures, and frequently associated with IBD Small‐duct PSC Less common variant of PSC that is characterized by typical cholestatic and histological features of PSC but with normal bile ducts on cholangiography PSC–AIH overlap Concurrent diagnostic features of PSC and clinical, biochemical, and histological features of AIH Secondary sclerosing cholangitis Biliary strictures due to identifiable causes that can result in secondary biliary cirrhosis IgG4 sclerosing cholangitis Biliary strictures due to elevated IgG4‐positive plasma cells in tissue and serum IgG4 elevation frequently associated with pancreatic involvement Dominant stricture A biliary stricture on ERCP with a diameter of ≤1.5 mm in the common bile duct or of ≤1 mm in the hepatic duct High‐grade stricture A biliary stricture on MRI with cholangiopancreatography with >75% reduction in the common bile duct or hepatic ducts Relevant stricture Any biliary stricture of the common bile duct or hepatic ducts associated with signs or symptoms of obstructive cholestasis and/or bacterial cholangitis INTRODUCTION AND SCOPE OF GUIDANCE Primary sclerosing cholangitis (PSC) is a cholangiopathy characterized by chronic fibroinflammatory damage of the biliary tree and is frequently associated with inflammatory bowel disease (IBD). The majority of patients with PSC have fibrotic biliary strictures on cholangiogram, whereas a minority have small‐duct PSC, characterized by a normal cholangiogram but with histological features of PSC on liver biopsy. A small percentage have overlapping features of autoimmune hepatitis (PSC‐AIH). PSC affects both male and female individuals and can occur at any age. PSC is considered an autoimmune disease, though the pathophysiology remains poorly understood. PSC frequently results in cholestatic liver damage, cirrhosis, and liver failure and can recur in 20%–30% of patients after transplantation. PSC also significantly increases the risk of cholangiocarcinoma (CCA) and colorectal cancer (CRC). Currently, there is no effective medical therapy for PSC, and clinical research has been challenging, with a PSC‐specific International Classification of Diseases (ICD)‐10 diagnostic code (K83.01) only approved for use since 2018. A glossary of key definitions, including new terminology defining biliary strictures, is provided in Table 1. This American Association for the Study of Liver Diseases (AASLD) guidance provides a data‐supported approach to the diagnosis and management of PSC and CCA. It differs from AASLD guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence and strength of the recommendations, and, if appropriate, meta‐analysis of results using the Grading of Recommendations Assessment, Development, and Evaluation system. In contrast, this guidance was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee at all stages of guidance development. The committee chose to perform a guidance on this topic because a sufficient number of randomized controlled trials were not available to support the development of a meaningful guideline. In addition to the inclusion of CCA, updates to the 2010 guideline include new terminology for the description of biliary strictures, an emphasis on imaging for diagnosis rather than endoscopic retrograde cholangiopancreatography (ERCP) and liver biopsy, use of prognostic models and noninvasive staging for clinical practice, and comprehensive management of PSC. EPIDEMIOLOGY OF PSC Population‐based epidemiological studies of PSC have been limited. The majority of studies to date have been based in North America and western Europe, where estimates of incidence and prevalence are approximately 1–1.5 cases per 100,000 person‐years and 6–16 cases per 100,000, respectively.1–10 Some studies have suggested that the prevalence and incidence of PSC may be increasing.4,11 Limited data from other parts of the world suggest a lower PSC prevalence there compared to the United States and northern Europe.12–15 Within the United States, African Americans appear to be affected by PSC at rates similar to Whites.16–18 Peak incidence of PSC is between the ages of 25 and 45 years, with a median age at diagnosis ranging from 36 to 39 years; but PSC can occur at any age.19–21 In children, the incidence rate has been estimated to be 0.2 per 100,000 person‐years.8,22 Overall, men account for approximately two thirds of patients with PSC; but among patients with PSC without IBD, the male predominance is much lower.20 Women with PSC are generally older at diagnosis. At least 70%–80% of patients with PSC have concurrent IBD, and the prevalence of PSC in patients with IBD including non‐Europeans and children has been estimated to be 0.6%–4.3%.18,23–35 PSC‐AIH overlap occurs in up to 35% of children and 5% of adults with PSC.36–38 Studies employing universal liver biopsy or cholangiography screening of patients with IBD have yielded PSC prevalence of 8.1%–9.0% in adults39,40 and 15.1% in children,41 suggesting that there may be tens of thousands of undiagnosed patients in North America alone. ETIOLOGY OF PSC Multiple simultaneous mechanisms appear to lead to PSC and its progression (Figure 1). There is a clear genetic predisposition involving human leukocyte antigen (HLA) variants,42–48 and many additional non‐HLA loci have been implicated.46,49 Less is known about environmental risks of PSC other than a possible link to nonsmoking.25,50,51 Evidence suggests that IBD may drive PSC rather than this being an epiphenomenon.52,53 A few studies have demonstrated an impaired gut barrier in PSC,54–56 and an expanding body of evidence has developed on the dysbiosis of the intestinal gut microbial community in PSC.57–72 Aberrant trafficking of gut lymphocytes73,74 and/or translocation of microbial constituents or metabolites67,75,76 have been proposed to induce activation of biliary epithelial cells and peribiliary inflammation, which consists of macrophages,77,78 eosinophils,79–81 and T cells.82–84 However, a specific antigen or immune response has yet to be delineated.85–87 Unconventional T cells including mucosa‐associated invariant T and γδ T cells important for recognition of bacterial pathogens have also been suggested to play a role in PSC88 and localize to areas of fibrosis.84 IL‐17 production by γδ T cells has been implicated in the development of cholestatic fibrosis and inflammation in animal models,89,90 and IL‐17 appears to have a significant role in PSC as well.88,91,92 The fibrosis of large bile ducts in PSC is associated with peribiliary gland hyperplasia and activation of peribiliary mesenchymal cells, which acquire a myofibroblast phenotype.93,94 Strictures of large bile ducts, reduced bile flow, increased biliary pressure, and alterations in bile composition associated with cholestasis may further drive disease progression.95–97 Still unresolved is why immunosuppressive therapy and colectomy do not appear to alter the disease course, perhaps indicating that some mechanisms are involved in the initiation of PSC but have little influence on disease progression.98–101FIGURE 1: Pathogenesis of PSC. The current model of the pathogenesis of PSC involves four major themes on a background of underlying genetic and environmental risk factors. (1) Within the intestine, there is an altered microbiome, inflamed mucosa, and an impaired intestinal barrier or "leaky gut." (2) Intestinal lymphocytes, microbial products, and/or metabolites translocate through the portal vein directly to the liver, activating innate and adaptive immune responses. (3) Microbial components or metabolites from the gut may also act directly to activate biliary epithelial cells and further perpetuate inflammatory responses. (4) Peribiliary glands expand, and peribiliary mesenchymal cells, through a Hedgehog pathway, acquire a myofibroblast phenotype leading to large‐duct fibrosis. Abbreviations: BEC, biliary epithelial cell; MHC II, major histocompatibility complex class II; TLR, toll‐like receptor; Treg, regulatory T cell.DIAGNOSIS OF PSC PSC should be considered in all patients with cholestasis, especially in the setting of IBD. The diagnosis is based on characteristic strictures on cholangiography (Figure 2). Careful exclusion of secondary sclerosing cholangitis is required, especially in the absence of IBD (Table 2). Small‐duct PSC is diagnosed based on histological findings that are typical or compatible with PSC in the presence of a normal cholangiogram (see "Histology" section below). In cases of suspected small‐duct PSC without IBD, variants of the ATP binding cassette subfamily B member 4, also known as multidrug resistance protein 3, gene should be excluded.102 In the presence of clinical, biochemical, and histologic features of AIH and cholangiographic findings of PSC, the diagnosis of PSC‐AIH overlap, also known as PSC with overlapping features of AIH, should be considered. Conversely, PSC‐AIH overlap should be considered in patients with AIH and IBD, unexplained cholestatic laboratory findings, or nonresponse to conventional glucocorticoid therapy.36 TABLE 2 - Etiologies of secondary sclerosing cholangitis Infectious HIV‐related cholangiopathy Recurrent pyogenic cholangitis Cholangitis lenta or subacute nonsuppurative cholangitis Parasitic cholangiopathy • Hydatid cyst • Echinococcosis • Clonorchiasis and opisthorchiasis • Ascariasis • Fascioliasis • Schistosomiasis Ischemic Critically ill patients Hereditary hemorrhagic telangiectasis Intra‐arterial chemotherapy Hepatic artery thrombosis Malignant Cholangiocarcinoma Diffuse intrahepatic metastasis Langerhans cell histiocytosis Lymphoma Autoimmune Eosinophilic cholangitis Hepatic inflammatory pseudotumor IgG4‐associated cholangitis Mast cell cholangiopathy Sarcoidosis Anatomic Choledocholithiasis Intrahepatic lithiasis Cystic fibrosis liver disease Surgical biliary trauma Anastomotic stricture Portal hypertensive biliopathy Recurrent pancreatitis Sickle cell cholangiopathy Choledochal cyst Drug‐induced Immunotherapy with checkpoint inhibitors Pembrolizumab Nivolumab Atezolizumab FIGURE 2: Diagnostic algorithm for PSC. Patients with suspected PSC should have a careful clinical evaluation including history, physical examination, and measurement of serum liver tests, followed by MRI/MRCP. The presence of biliary strictures, in the absence of secondary causes of sclerosing cholangitis, is considered diagnostic. Equivocal MRI findings should prompt evaluation at an experienced center with consideration for repeat imaging in a year or liver biopsy. If the initial MRI/MRCP is normal, a liver biopsy should be performed to diagnose small‐duct PSC versus alternative diagnoses.Symptoms Nearly half of adult patients with PSC present with constant or intermittent symptoms, and another 22% develop symptoms within 5 years of diagnosis.103 Symptoms of PSC include fatigue, abdominal pain, fever, and pruritus, in addition to anxiety and depression.21 Pruritus and abdominal pain can fluctuate depending on the presence of biliary obstruction and/or acute cholangitis. Emotional distress can be exacerbated by anxiety about the idiopathic nature of the disease, lack of effective therapy, and elevated cancer risk.104,105 Assessment of PSC symptoms is complex in patients with IBD, which itself causes symptoms such as abdominal pain and fatigue.106 There is a growing interest in measuring PSC symptoms through patient‐reported outcome measures (PROM). Two recent PROMs were developed specifically for patients with PSC: the PSC PRO and the Simple Cholestatic Complaints Score107,108; however, they require further validation prior to routine clinical use. Biochemical and serological tests Biochemical markers are sensitive but not specific for the diagnosis of PSC. A cholestatic biochemical profile with elevated liver enzymes, such as alkaline phosphatase (ALP) and γ‐glutamyl transferase (GGT), is seen in about 75% of patients.40 Notably, elevated aminotransferases occur frequently and do not necessarily suggest overlapping AIH, unless they are predominant or more than 5 times the upper limit of normal (ULN).109 However, precise diagnostic criteria for PSC‐AIH overlap have not been established. Detection of serum autoantibodies, including antinuclear, anti–smooth muscle, and perinuclear antineutrophil antibodies, in patients with PSC is highly variable, likely representing an immune dysregulation state.110,111 In contrast to primary biliary cholangitis (PBC) and AIH, autoantibodies have minimal diagnostic implications for PSC.112 Elevation of serum IgG4 occurs in up to 15% of patients with PSC, but the clinical significance is unclear.113,114 High‐titer IgG4 (> 5.6 g/L) is rare and suggests a diagnosis of IgG4‐sclerosing cholangitis, whereas an IgG4/IgG1 ratio < 0.24 can exclude IgG4‐sclerosing cholangitis when the serum IgG4 is 1.4–2.8 g/L.114,115 Imaging MRI with cholangiopancreatography should be the first diagnostic imaging modality in patients with suspected PSC.116 Imaging should be performed on a scanner with a minimum of a 1.5‐Tesla field strength. T2 weighted (T2w), three‐dimensional (3D) MRI retrograde cholangiopancreatography (MRCP) with 1‐mm slices is preferred to two‐dimensional MRCP, and axial imaging should include T1‐weighted (T1w) and T2w sequences. Enhancement with an extracellular or hepatobiliary contrast agent is recommended at diagnosis and when imaging is done in response to a change in clinical status or due to concerns for CCA. There is insufficient evidence to recommend one type of contrast agent over another. A high‐quality study is one in which there is no artifact or blurring and third‐order biliary branches and beyond can be delineated.117 Before the advent of MRI/MRCP, ERCP was regarded as the gold standard in diagnosing PSC.118 However, ERCP is associated with serious complications and should only be performed for therapeutic intervention or tissue sampling.119 Multiple studies have shown that MRI/MRCP has comparable diagnostic accuracy to ERCP.120 Importantly, in a patient with a high pretest probability of PSC, there remains a 30% probability of PSC even if the MRCP is negative.120 Thus, in the setting of an MRI/MRCP that is suboptimal or equivocal, the study should be repeated, preferably at an experienced imaging center using 3D MRCP reconstruction.116,120 Transabdominal ultrasound (US) is usually nondiagnostic, although bile duct wall thickening and/or focal bile duct dilatations may be demonstrated.121 CT is limited in the assessment of strictures of intrahepatic bile ducts.122 A normal US or CT is not sufficient to rule out PSC. MRI/MRCP features of PSC are highly variable, probably related to the stage of the disease process (Figure 3).123,124 Specific terms such as stenosis, stricture, and dilatation are preferred rather than imprecise descriptions such as beaded, pruned‐tree appearance, or irregularity of bile ducts.124 Early in the course of the disease, diffusely distributed, short, intrahepatic strictures alternating with normal or slightly dilated segments are demonstrated.125,126 Contrast‐enhanced T1w images may demonstrate biliary wall thickening and mural contrast enhancement of the biliary ducts.127 As fibrosis progresses, the strictures worsen and the ducts become obliterated. With worsening of PSC, focal signal abnormalities of the liver parenchyma on T2w and diffusion‐weighted images suggest cholestasis and inflammation. Fibrosis may be demonstrated by focal parenchymal atrophy and liver dysmorphy, defined as atrophy of a hepatic lobe, lobulations of the liver surface, and/or increase of the caudate:right lobe ratio.124FIGURE 3: MRI findings of PSC. MRCP (top left) demonstrates multiple severe strictures of intrahepatic biliary ducts (arrows) and high‐grade stricture of the main biliary duct (arrowhead). T2w MRI (bottom left) demonstrates dysmorphy with marked enlargement of the caudate lobe and atrophy with high signal intensity of the right liver lobe. Contrast‐enhanced MRI (top right) demonstrates biliary wall thickening with marked mural contrast enhancement (arrows). Contrast‐enhanced MRI (bottom right) demonstrates marked contrast enhancement heterogeneity with high signal intensity of the right and left liver lobes in comparison with the caudate lobe. Abbreviations: C, caudate lobe; L, left liver lobe; R, right liver lobe.A dominant stricture has been defined as a stenosis with a diameter of ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct by ERCP.128,129 However, in clinical practice, the term has been used without clear consensus on this definition.130,131 The term dominant stricture should not be used in MRI reports because of suboptimal spatial resolution of MRI/MRCP and basic differences with ERCP, which is performed with high‐pressure injection. A similar term for common bile duct and hepatic duct strictures observed on MRI is high‐grade stricture, which is defined by a reduction in the lumen by >75%.117,124 However, there remains a need for a term to describe a stricture that has clinical relevance but may not meet the strict criteria of a dominant or high‐grade stricture. Therefore, the term relevant stricture is introduced to refer to any biliary stricture of the common bile duct or hepatic ducts associated with signs or symptoms of obstructive cholestasis and/or bacterial cholangitis (Table 1). Histology Modern imaging modalities have decreased the need for a liver biopsy to diagnose PSC.132 Liver biopsy should be considered if there is concern for small‐duct PSC or overlap with AIH. Concentric "onion skin" periductal fibrosis is an infrequent histological feature that can be seen in PSC and other obstructive cholangiopathies. Typical histologic features of PSC include periductal fibrosis and fibro‐obliterative duct lesions, whereas compatible features include bile duct loss, ductular reaction (also referred to as ductular proliferation), a biliary pattern of interface activity, and chronic cholestatic changes in periportal hepatocytes.133,134 The presence of these features should be the basis for the diagnosis of small‐duct PSC when the MRCP is normal.8,135 Histologic features of AIH, including lymphoplasmacytic interface hepatitis in the setting of PSC, may signify an overlap with AIH.22,136–138 IBD Over 70% of patients with PSC have IBD, with two thirds diagnosed as ulcerative colitis and the other third as Crohn's disease or indeterminate colitis.1,20,33,139,140 IBD in PSC (PSC‐IBD) is more frequently localized in the right colon and notable for backwash ileitis.141,142 It is often asymptomatic despite significant endoscopic and histologic activity.143,144 In children, 5% of patients with PSC without a prior diagnosis of IBD and no symptoms were found to have quiescent colitis.145 In addition, histological evidence of IBD without endoscopic changes of IBD is frequent.146 Therefore, patients with PSC, including children, who do not have known IBD should undergo ileocolonoscopy with biopsies at the time of PSC diagnosis to screen for asymptomatic colitis. If no colitis is detected, ileocolonoscopy with biopsies should be considered at 5‐year intervals or if symptoms suggestive of IBD occur because IBD may develop after PSC diagnosis. The clinical course of IBD in patients with PSC‐IBD is often less aggressive with less frequent need for immunosuppression.52,147 Patients with PSC are prone to developing pouchitis after colectomy with ileoanal anastomosis,148 and patients with portal hypertension have an increased risk of peristomal and stomal varices.149 Guidance statements 1. In patients with suspected PSC, a 3D MRI/MRCP with T1w and T2w axial images and contrast enhancement should be obtained to evaluate for cholangiographic features of PSC, including intrahepatic and/or extrahepatic strictures alternating with normal or slightly dilated segments. 2. In patients with suspected PSC and a normal, high‐quality MRI/MRCP, liver biopsy should be considered to rule out small‐duct PSC. Patients with an equivocal MRI/MRCP should be referred to an experienced center for consideration of a repeat high‐quality MRI/MRCP or liver biopsy. A repeat MRI/MRCP may be considered in 1 year if the diagnosis remains unclear. 3. ERCP should be avoided for the diagnosis of PSC. 4. In all patients with possible PSC, serum IgG4 levels should be measured to exclude IgG4‐sclerosing cholangitis. 5. A liver biopsy should not be performed in patients with typical cholangiographic findings on MRI/MRCP, except when there is concern for AIH overlap. 6. Ileocolonoscopy with biopsies should be performed in patients with a new diagnosis of PSC and no previous diagnosis of IBD. In patients without IBD, subsequent ileocolonoscopy should be considered at 5‐year intervals or whenever symptoms suggestive of IBD occur. NATURAL HISTORY OF PSC PSC is a heterogenous disease with a variable course that can be complicated not only by cirrhosis but also by bacterial cholangitis, CCA, and CRC. Most patients have slowly progressive liver disease with increasing hepatobiliary fibrosis, biliary strictures, intermittent bacterial cholangitis, and eventually cirrhosis and end‐stage liver disease. Median time to death or liver transplantation (LT) was reported to be as low as 9 years in studies from referral centers, but more recent population‐based studies estimate it to be 21 years or longer.19 As an increasing proportion of patients are transplanted, deaths from end‐stage liver disease have decreased, but deaths from CCA appear to be unchanged.150 PSC is increasingly diagnosed in the early stage,150,151 which is likely due to increased awareness of PSC, use of MRI/MRCP, and screening of liver function tests in the general population and in patients with IBD. However, many people with PSC likely remain undiagnosed.40,41,152–154 Patient demographics and PSC phenotype influence disease progression. Younger age at diagnosis and female sex are associated with better outcomes.20 Patients diagnosed under age 20 have a 2.5 times longer median transplant‐free survival and a 17 times lower rate of CCA compared to patients diagnosed over age 60.155 Patients with PSC‐AIH overlap are reported to have a reduced risk for LT or death compared to those with PSC alone.20 Small‐duct PSC also has a more favorable prognosis with longer time until liver cirrhosis and lower risk for hepatobiliary malignancy.20,135 Twenty‐three percent of patients with small‐duct disease are reported to develop large‐duct disease over 5–14 years.135 Whether small‐duct PSC represents a separate entity or an early/mild form of PSC remains controversial. Nonetheless, patients with small‐duct PSC should be monitored by MRI/MRCP every 3–5 years for the development of large‐duct disease. Presence of symptoms and high ALP levels are associated with a worse prognosis. At the time of diagnosis and in earlier stages, patients are often asymptomatic and can remain so despite disease progression.103,154 Although ALP often fluctuates during the disease course,151,156 persistently normal/low levels (ALP < 1.5 × ULN) are associated with better prognosis.157–161 ALP is invalid in children due to wide fluctuations in normal values with age and bone growth, and instead GGT should be used. Like in adults, high rates of spontaneous normalization of GGT early in the disease course are seen in children, and persistently normal/low levels (GGT < 50 U/L) are associated with better prognosis.162,163 Progressive fibrosis/cirrhosis Accumulation of hepatobiliary fibrosis in PSC appears to be slow. Over the course of a 2‐year clinical trial of simtuzumab, direct and indirect measures of fibrosis were stable in most patients; and Ishak fibrosis stage on serial liver biopsies improved in 29%, remained unchanged in 34%, and worsened in 37%.164 Similarly, among 141 children with PSC who had serial liver biopsies 12–18 months apart, Batts‐Ludwig fibrosis stage improved in 17%, remained unchanged in 64%, and worsened in 19%,165 confirming the results of smaller studies demonstrating no significant change in fibrosis stage over 1–5 years.166–174 Cholangitis/gallstones Although a consensus on the criteria required to diagnose bacterial cholangitis in patients with PSC is lacking, case series report that approximately 6% of patients with PSC have bacterial cholangitis at diagnosis and that nearly 40% experience this complication during the disease course. During a clinical trial, bacterial cholangitis was the most common disease‐related complication, occurring in 12% of patients over 2 years.164 The importance of bacterial cholangitis for disease progression remains unclear. A positive bacterial culture of bile in the presence of a dominant stricture was not associated with a worse prognosis,175 and bacterial cholangitis was not associated with survival among patients with PSC awaiting LT.176 In contrast, Candida in bile is a poor prognostic sign.175 Gallstones, sludge, chronic cholecystitis, and/or gallbladder polyps occur in near half of patients with PSC.177,178 Intrahepatic bile duct calculi are present in 8% of patients, and some of these patients require repeated interventions with ERCP when stones and sludge contribute to bile duct obstruction.179 Biliary strictures Development of biliary strictures may occur at all levels in the biliary tree, but strictures of the common bile duct and common hepatic duct have more significant effects on the natural history of PSC. Dominant strictures are present in up to half of patients at the time of diagnosis and may present without symptoms or with increased cholestasis, jaundice, pruritus, and/or fevers. Up to 45% of patients with PSC will develop dominant strictures.128,129 Patients with the disease limited to intrahepatic ducts seem to have a better outcome. High‐grade strictures with prestenotic dilatation at MRI/MRCP are associated with poorer outcomes.123 In addition, dominant stricture on ERCP180 or a rapid progression of a stricture at MRI/MRCP increases the risk of CCA.118 Further, the presence of a dominant stricture, even in the absence of bile duct malignancy, significantly reduces survival.175 Malignancy CCA CCA can occur any time during the disease course, with the highest risk (2.5%) reported within the first year after PSC diagnosis and thereafter 1%–1.5% per year.19,181 In one large population‐based study, the cumulative risk of CCA after 10, 20, and 30 years of PSC was 6%, 14%, and 20%, respectively.19 Compared to the general population, the risk of CCA is 160–400 times greater.3,19,182 In the largest population‐based study (N = 2588), the risk of CCA was 28 times greater in patients with PSC‐IBD compared to patients with IBD without PSC.33 Rapid worsening of symptoms, cholestasis, or weight loss should raise the suspicion of CCA, although some patients with CCA can be completely asymptomatic. In the presence of cirrhosis, the signs and symptoms of CCA may not differ from those of end‐stage liver disease.183 The most consistent risk factor for CCA is older age. CCA is rarely diagnosed in the pediatric population or in those with small‐duct PSC. Other risk factors include male sex, dominant stricture, and comorbidity with IBD, along with elevated bilirubin levels.19,20,33,103,183–187 The impact of environmental factors such as smoking and alcohol is uncer