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 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 MRI findings of PSC. MRCP strictures of intrahepatic biliary ducts and stricture of the biliary duct T2w MRI with of the lobe and atrophy with high signal of the liver Contrast‐enhanced MRI biliary wall thickening with mural contrast enhancement Contrast‐enhanced MRI contrast enhancement with high signal of the and liver in with the Abbreviations: liver liver stricture has been defined as a with a diameter of ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct by However, in clinical practice, the term has been without clear consensus on this The term stricture should not be in MRI because of suboptimal of MRI/MRCP and with which is performed with A similar term for common bile duct and hepatic duct strictures on MRI is stricture, which is defined by a reduction in the by However, there remains a for a term to a stricture that has clinical but may not the criteria of a or the term relevant stricture is to 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). imaging have the for a liver biopsy to diagnose Liver biopsy should be considered if there is for small‐duct PSC or overlap with fibrosis is an histological that can be seen in PSC and other obstructive histologic features of PSC include fibrosis and duct whereas compatible features include bile duct to as a biliary of and chronic cholestatic in The presence of features should be the for the diagnosis of small‐duct PSC when the MRCP is features of AIH, including hepatitis in the setting of PSC, may an overlap with IBD of patients with PSC have IBD, with two thirds diagnosed as and the other as disease or IBD in PSC is more frequently in the and for It is significant endoscopic and histologic In children, 5% of patients with PSC without a prior diagnosis of IBD and no symptoms were to have In histological evidence of IBD without endoscopic of IBD is patients with PSC, including children, do not have known IBD should with at the of PSC diagnosis to for If no is with should be considered at or if symptoms of IBD occur because IBD may develop after PSC diagnosis. The clinical course of IBD in patients with is with for Patients with PSC are to after colectomy with and patients with portal have an increased risk of and statements 1. In patients with suspected PSC, a 3D MRI/MRCP with T1w and T2w axial images and contrast enhancement should be obtained to for cholangiographic features of PSC, including intrahepatic and/or extrahepatic strictures alternating with normal or slightly dilated 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 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 ERCP should be avoided for the diagnosis of PSC. In all patients with possible PSC, serum IgG4 should be to exclude IgG4‐sclerosing cholangitis. A liver biopsy should not be performed in patients with typical cholangiographic findings on MRI/MRCP, when there is for AIH with should be performed in patients with a new diagnosis of PSC and no diagnosis of IBD. In patients without IBD, should be considered at or symptoms of IBD OF PSC PSC is a disease with a course that can be not only by cirrhosis but also by bacterial cholangitis, CCA, and patients have liver disease with hepatobiliary biliary strictures, intermittent bacterial cholangitis, and cirrhosis and liver to or liver transplantation was to be as as years in studies from but more recent studies to be years or As an of patients are from liver disease have but from CCA appear to be PSC is diagnosed in the which is likely due to increased of PSC, use of MRI/MRCP, and screening of liver tests in the and in patients with IBD. However, many with PSC likely and PSC phenotype influence disease age at diagnosis and female are associated with Patients diagnosed age have a times median and a times lower rate of CCA compared to patients diagnosed over age Patients with PSC‐AIH overlap are to have a reduced risk for or compared to with PSC Small‐duct PSC also has a more with liver cirrhosis and lower risk for hepatobiliary of patients with small‐duct disease are to develop large‐duct disease over small‐duct PSC a or an of PSC remains patients with small‐duct PSC should be by MRI/MRCP every years for the development of large‐duct of symptoms and high are associated with a At the of diagnosis and in patients are and can disease the disease < are associated with is in children due to in normal with age and and should be in high rates of of in the disease course are seen in children, and < are associated with of hepatobiliary fibrosis in PSC appears to be the course of a clinical of and measures of fibrosis were in and fibrosis stage on liver in in and in among children with PSC liver months fibrosis stage in in and in the results of studies no significant change in fibrosis stage over a consensus on the criteria to diagnose bacterial cholangitis in patients with PSC is that approximately of patients with PSC have bacterial cholangitis at diagnosis and that this the disease a clinical bacterial cholangitis was the common in of patients over 2 The of bacterial cholangitis for disease progression remains A bacterial of bile in the presence of a stricture was not associated with a and bacterial cholangitis was not associated with among patients with PSC In contrast, in bile is a prognostic chronic and/or occur in half of patients with Intrahepatic bile duct are present in of and some of patients require repeated with ERCP when and to bile duct Biliary strictures of biliary strictures may occur at all in the biliary but strictures of the common bile duct and common hepatic duct have more significant on the of PSC. Dominant strictures are present in up to half of patients at the of diagnosis and may present without symptoms or with increased cholestasis, pruritus, and/or to of patients with PSC develop Patients with the disease limited to intrahepatic ducts to have a High‐grade strictures with dilatation at MRI/MRCP are associated with In stricture on or a progression of a stricture at MRI/MRCP increases the risk of the presence of a stricture, even in the absence of bile duct significantly CCA CCA can occur any the disease course, with the risk within the first year after PSC diagnosis and per In one large the risk of CCA after and years of PSC was and to the the risk of CCA is times In the study the risk of CCA was times in patients with compared to patients with IBD without worsening of symptoms, cholestasis, or should the of CCA, although some patients with CCA can be In the presence of cirrhosis, the signs and symptoms of CCA may not from of liver The risk for CCA is older age. CCA is diagnosed in the or in with small‐duct PSC. risk include male stricture, and with IBD, with elevated The of environmental such as and is