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, and liver and can in of patients PSC the risk of cholangiocarcinoma (CCA) and cancer is therapy for PSC, and clinical with a of diagnostic for A of new biliary strictures, is in Table for the of Liver guidance a to the diagnosis and management of PSC and CCA. are by of the of the of the and of the if of results the of and In guidance by of an and guidance on and analysis of the on the with by the at all of guidance The to a guidance on a of not available to the of a meaningful In to the of to the 2010 new for the of biliary strictures, an on for diagnosis retrograde cholangiopancreatography (ERCP) and liver of and for clinical and management of OF PSC of PSC have The majority of to have in and of and are and have that the and of PSC may be of the a PSC to the United and the United to be by PSC at to of PSC is the of and with a age at diagnosis to but PSC can occur at any In the to be for of patients with but patients with PSC without the male is with PSC are at of patients with PSC have and the of PSC in patients with IBD and to be overlap in to of and of with liver or cholangiography of patients with IBD have PSC of in and in that may be of of patients in OF PSC to to PSC and (Figure 1). There is a and have Less is known of PSC a to that IBD may PSC an A have an in and an of on the of the in of and/or of or have to of biliary cells and of and a or to be cells and cells for of bacterial have to a in and to of by cells in the of cholestatic fibrosis and inflammation in and to have a in PSC as The fibrosis of bile ducts in PSC is associated with and of a of bile ducts, bile biliary and in bile associated with cholestasis may disease is therapy and not to the disease that are in the of PSC but have on disease of The of the of PSC on a of and risk the is an and an or and/or the to the and or the may to biliary cells and inflammatory and a a leading to biliary OF PSC PSC should be considered in all patients with in the setting of IBD. The diagnosis is on strictures on cholangiography (Figure 2). of secondary sclerosing cholangitis is in the absence of IBD (Table 2). Small‐duct PSC is on histological that are typical or with PSC in the of a normal cholangiogram In of suspected small‐duct PSC without of the known as should be In the of clinical, biochemical, and features of AIH and of PSC, the diagnosis of known as PSC with overlapping features of should be overlap should be considered in patients with AIH and cholestatic findings, or to TABLE - of secondary sclerosing cholangitis cholangiopathy cholangitis or cholangitis cholangiopathy and patients intrahepatic metastasis cholangitis inflammatory cholangitis cholangiopathy fibrosis liver disease biliary stricture cholangiopathy with for with suspected PSC should have a clinical and of serum liver by The of biliary strictures, in the absence of secondary causes of sclerosing is considered MRI should at an with for in a or liver biopsy. the MRI/MRCP is a liver should be performed to small‐duct PSC of patients with PSC with or and symptoms 5 years of of PSC and in to and and can on the of biliary and/or cholangitis. can be by the of the disease, of and elevated cancer of PSC symptoms is in patients with causes symptoms as and There is a in PSC symptoms for patients with the PSC and the however, to clinical and are but not for the diagnosis of A cholestatic with elevated liver as alkaline phosphatase and transferase is in of elevated occur frequently and not overlapping are or 5 the of normal diagnostic for overlap have not of serum and in patients with PSC is likely an In to primary biliary cholangitis and have diagnostic for of serum IgG4 in to of patients with PSC, but the clinical is IgG4 is and a diagnosis of whereas an < can cholangitis the serum IgG4 is MRI with cholangiopancreatography should be the diagnostic in patients with suspected should be performed on a with a of a MRI retrograde cholangiopancreatography with is to and should and with an or is recommended at diagnosis and is in to a in clinical or due to for CCA. There is to of A high‐quality is in is or and biliary and can be the of ERCP as the in ERCP is associated with and should be performed for or tissue have that MRI/MRCP diagnostic to in a with a of PSC, remains a of PSC if the is in the setting of an MRI/MRCP that is or the should be at an is bile duct and/or bile duct may be is in the of strictures of intrahepatic bile A normal or is not to MRI/MRCP features of PSC are to the of the disease (Figure as stricture, and are as or of bile in the of the disease, intrahepatic strictures with normal or are may biliary and of the biliary fibrosis the strictures and the ducts of PSC, of the liver on and cholestasis and may be by and liver defined as of a hepatic of the liver and/or of the MRI of strictures of intrahepatic biliary ducts and stricture of the biliary duct MRI with of the and with of the liver MRI biliary with MRI with of the and liver in with the liver liver stricture defined as a with a diameter of ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct by in clinical the term without on The term stricture should not be in MRI of of MRI/MRCP and with is performed with A term for common bile duct and hepatic duct strictures on MRI is stricture, is defined by a reduction in the by remains a for a term to a stricture that clinical but may not the 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). have the for a liver to Liver should be considered if is for small‐duct PSC or overlap with fibrosis is an histological that can be in PSC and obstructive features of PSC fibrosis and duct whereas features bile duct to as a biliary of and chronic cholestatic in The of features should be the for the diagnosis of small‐duct PSC the is features of hepatitis in the setting of PSC, may an overlap with IBD of patients with PSC have with as and the as disease or IBD in PSC is frequently in the and for is and In of patients with PSC without a diagnosis of IBD and symptoms to have In histological of IBD without of IBD is patients with PSC, not have known IBD should with at the of PSC diagnosis to for is with should be considered at or if symptoms of IBD occur IBD may PSC The clinical of IBD in patients with is with for with PSC are to with and patients with have an risk of and In patients with suspected PSC, a MRI/MRCP with and and should be obtained to for features of PSC, intrahepatic and/or extrahepatic strictures with normal or In patients with suspected PSC and a high‐quality liver should be considered to small‐duct with an equivocal MRI/MRCP should be to an for of a high‐quality MRI/MRCP or liver biopsy. A MRI/MRCP may be considered in 1 if the diagnosis remains ERCP should be avoided for the diagnosis of In all patients with PSC, serum IgG4 should be to cholangitis. A liver should not be performed in patients with typical on is for AIH with should be performed in patients with a new diagnosis of PSC and diagnosis of IBD. In patients without should be considered at or symptoms of IBD OF PSC PSC is a disease with a that can be not by cirrhosis but by bacterial and patients have liver disease with biliary strictures, bacterial and cirrhosis and liver to or liver transplantation to be as as years in but to be years or an of patients are liver disease have but CCA to be PSC is in the is likely due to of PSC, of and of liver in the and in patients with IBD. with PSC likely and PSC disease age at diagnosis and female are associated with age have a and a of CCA to patients age with overlap are to have a risk for or to with PSC Small‐duct PSC a with liver cirrhosis and risk for of patients with small‐duct disease are to disease small‐duct PSC a or an of PSC remains patients with small‐duct PSC should be by MRI/MRCP every years for the of of symptoms and are associated with a the of diagnosis and in patients are and can disease the disease < are associated with is in due to in normal with age and and should be in of of in the disease are in and < are associated with of fibrosis in PSC to be the of a clinical of and of fibrosis in and fibrosis on liver in in and in with PSC liver months fibrosis in in and in the results of in fibrosis a on the to bacterial cholangitis in patients with PSC is that of patients with PSC have bacterial cholangitis at diagnosis and that the disease a clinical bacterial cholangitis the common in of patients The of bacterial cholangitis for disease remains A bacterial of bile in the of a stricture not associated with a and bacterial cholangitis not associated with patients with PSC In in bile is a chronic and/or occur in of patients with bile duct are in of and of patients repeated with ERCP 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 on the of Dominant strictures are in to of patients at the of diagnosis and may without symptoms or with and/or to of patients with PSC with the disease to intrahepatic ducts to have a High‐grade strictures with at MRI/MRCP are associated with In stricture on or a of a stricture at MRI/MRCP the risk of the of a stricture, in the absence of bile duct CCA CCA can occur any the disease with the risk the PSC diagnosis and In the risk of CCA and years of PSC and to the the risk of CCA is In the the risk of CCA in patients with to patients with IBD without of or should the of patients with CCA can be In the of the signs and symptoms of CCA may not of liver The risk for CCA is age. CCA is in the or in with small‐duct risk male stricture, and with with elevated The of as and is causes of PSC cirrhosis the risk for the risk is for with in years of cancer cancer in PSC is to the may be a and are in of patients with The risk for of a with but for a for is In small < mm to be a or in and in at in < 5 mm is The of in patients with PSC and a or and The risk of in PSC is to the and to patients with IBD without with a and age at A of patients the risk of to be 3 in patients with with IBD a of in of to years of but the of in to have with and of and at as with at In patients with PSC frequently have and is to or to IBD age at IBD diagnosis is a risk for in with PSC and IBD age a risk of in inflammation may to the risk and is in PSC, in both and The risk of in patients with PSC without IBD to the is but in of patients with PSC, and all but of PSC and tools The of PSC to of disease and not liver clinical in PSC are not to have and biliary strictures in PSC can occur the of fibrosis or CCA and can occur at any disease PSC is patients at a fibrosis may and patients with fibrosis may and for In clinical risk for clinical events as hepatic or disease may be for guidance on and management Liver fibrosis in PSC is associated with The and associated with and to with In the fibrosis with Liver in PSC is by a sampling strictures and cholestasis may to of fibrosis the A of obtained the liver that by in and in of patients with liver is not recommended for of fibrosis or in PSC of the clinical Liver Liver in PSC by or are for of liver fibrosis and with of by for fibrosis and for cirrhosis have a diagnostic of by an the of for by or associated with risk of clinical of of fibrosis and as fibrosis to is not by fibrosis but by and In PSC, the of of cholestasis due to biliary may The and clinical of repeated remains and In patients a of years in in clinical with the risk of hepatic with by by years for all patients in the fibrosis The Liver is a of serum of and tissue of is associated with in and may be as a in clinical to 12 in a clinical associated with of on the is not available or in PSC AIH in and with of fibrosis and to with fibrosis and clinical in and a on and to the for in chronic hepatitis well in PSC, though is to in diagnostic the of MRI/MRCP of patients with PSC remains with The intrahepatic and features without and hepatic and with are associated with in and may with of hepatic is associated with as well as risk and clinical and fibrosis on of of intrahepatic and extrahepatic on ERCP with and In the ERCP to on the intrahepatic and extrahepatic of and ERCP may poorly with of may but are not or available tools or risk obtained and is with clinical and risk that have for with a risk of have a fibrosis are to clinical events in the 5 patients with a risk of as with are likely to and can to of the and of and the of clinical probabilities of events should be interpreted with caution in the individual on or obtained liver have by The and the in of the disease, of in small‐duct and to to and in clinical and of serum and have the risk (Table The patients as risk of clinical as hepatic or though of the in can the risk for or can occur at any disease probabilities of events by the should be interpreted with and may not be for all patients due to and of the individual (Figure In the are for at PSC The in PSC and years but are on the and clinical of repeated patients have liver disease, the Model for End‐Stage Liver Disease or End‐Stage Liver Disease is TABLE 3 - clinical of PSC SCOPE PSC or of extrahepatic biliary disease of PSC diagnosis or small‐duct or by 15 years or by years or by years by 5 years biliary for or liver disease by 5 years < < < to patients with or risk of or 5 not for the however, as patients as in a risk of a of a risk of or in for patients with PSC should the age of the and the of small‐duct PSC and/or overlap with End‐Stage Liver Disease with small‐duct PSC should be by MRI/MRCP every years for the of and fibrosis should be at diagnosis of PSC and risk tools can be considered for but probabilities of events should be interpreted with caution in the individual by or is the for of fibrosis in Liver is not recommended for fibrosis in clinical OF PSC is for the of PSC, and to disease and the of PSC is recommended for patients with cholangitis and/or management and have to but to or any clinical and have to of clinical in PSC are to due to the regarding the of the disease, and a of clinical to the disease of patients for in clinical is to acid acid is the in is a bile in PSC bile and of of the bile acid and of In and for in PSC not mg/kg/day) have improvement in by 12 months but improvement in liver or for the of mg/kg/day) In the to at a of not for reduction in the for or however, with of patients A of patients with mg/kg/day) or due to associated with an risk of in patients with PSC and associated with an risk of is not recommended and should not be The 2010 on PSC recommended the of as in have that meaningful in have associated with reduction of to < reduction or of and of In a reduction in or a < associated with the In associated with in liver and PSC the of reduction or for patients are or in clinical is to with and can patients should be for months to to that the are of or should be are to mg/kg/day) or mg/kg/day) the patients with a elevated can be considered for at and can be continued if is tolerated and is a meaningful reduction or of in children) or improvement of symptoms with 12 months of treatment. the of in biliary of the with as a of PSC have and with The is but have small in with In patients with and patients with with an improvement to 12 in the A of with a reduction in PSC risk in and have in liver but a not any In the to patients the PSC with associated with in or clinical to the for and of clinical at is to the of for the of A clinical is The of and for the management of associated IBD is the of in are is a in a of patients with PSC with an elevated and without a reduction in 12 of with the In a of a of a by 12 acid an for the of in a in PSC the of or and of a that in but is not available in the United and have results in however, clinical are a in that associated with a risk of and or leading to an of overlap and IgG4 disease should be considered for the management of patients with of AIH and patients with IgG4 sclerosing cholangitis cholangitis is common in patients with PSC and can be the of the disease in to In bacterial cholangitis may occur cholangitis should be with in patients to be on to recurrent an of bacterial should be considered to for the of a relevant with bacterial cholangitis have an to management should be for PSC is a disease, patients liver The management of and cirrhosis is the in PSC to chronic liver though PSC is associated with and of a intrahepatic may occur in patients with bile of and are at the absence of in patients with PSC in to In a of patients with cirrhosis and PSC, a for and of have with PSC should be hepatitis A and hepatitis if not and with cirrhosis should be to All patients with PSC should be considered for participation in clinical In patients not or in clinical with elevated or can be considered for and continued if is a meaningful reduction or in in children) and/or symptoms with 12 months of treatment. is to the of for the of with PSC with a diagnosis of AIH should be to the AIH should be for bacterial cholangitis with for to relevant ERCP should be performed for bacterial cholangitis if is an to to for should be performed if the is by or the is for CCA guidance surveillance of for the of risk and in due to a of regarding the of surveillance on clinical the of PSC the of surveillance to all with risk of CCA as with PSC and patients with small‐duct and as to to patients and surveillance of can to have performed to the of CCA surveillance in PSC, in a surveillance associated with a to patients not surveillance < a for CCA in patients with PSC, a to MRI/MRCP In a that MRI/MRCP is to for CCA surveillance in patients with There however, to the of repeated with MRI/MRCP and as and risk of findings, should be a by cancer is the common serum associated with but the in and the A of of and of whereas a of of and of to of patients with PSC with an elevated may not have and to of the not In of individuals by and 3 that of on or may the an elevated may be the of The of MRI/MRCP with a of a of but ERCP at a for CCA but with a of CCA is diagnosis of CCA can be for patients with PSC by cytology (Figure in situ hybridization analysis to for of an of in a is a of cancer and may the diagnostic of CCA in the of or cells with in or of or of all is considered a A and for a and for of to and for CCA is to results in the of for patients with that should be considered or of and elevated at ERCP as well as in of the biliary tree are of CCA in patients with in the setting of a stricture the of in a of patients with PSC, of patients with stricture in the setting of a a of CCA in patients with PSC without a for relevant strictures in The of a relevant stricture in a with PSC should a diagnostic and management that with an ERCP with sampling of the stricture with a biliary brushings for and The of and results should a MRI/MRCP in The of cytology with should a ERCP in 3 a cytology with should a MRI/MRCP and ERCP in a cytology with be with a a cytology result is diagnostic for CCA. The of or with should a ERCP in 3 a cytology result is diagnostic for a cytology with should a MRI/MRCP and ERCP in a cytology with be with a CCA. The of a and/or cytology is diagnostic for and cytology should be with a ERCP with brushings at a (Figure In a with PSC with a or stricture, with or without cytology CCA. biliary or or as to the of biliary is not well of patients with PSC with are with CCA to of patients with cancer cancer the is a and for the of of and with a of on though all < 5 There are on the of MRI to and in the of The management of mm in patients with PSC remains due to the of and a risk of following in patients with PSC with A of in the that a of mm by a of and of for of mm by every months is a the to with every months should the liver and the risk of hepatic and with liver disease should be to an with to be in PSC cirrhosis is surveillance should be performed in patients with PSC and cirrhosis to patients with cirrhosis to CCA and surveillance should be performed and by MRI/MRCP with or without serum is not recommended for patients with PSC years of age or with small‐duct tissue sampling for cytology and should be performed ERCP for relevant should be considered for patients with PSC with at an in patients with mm may be with every with PSC with cirrhosis should surveillance with Colon cancer are on the of surveillance in to surveillance for in patients with with PSC, associated with and have to the of in IBD to but is a of on the of any surveillance for patients with should colonoscopy with at to at the of In patients with PSC age 15 is surveillance should begin at age 15 should be colonoscopy is of should colonoscopy with In patients with PSC in IBD is surveillance colonoscopy with should at age 15 years and be repeated at to to for Endoscopic and therapy In to bacterial cholangitis that an to for ERCP in patients with PSC may or serum liver serum or for a relevant stricture or CCA. the for ERCP be the and MRI/MRCP should be considered to ERCP to the for biliary as well as the patients in ERCP is but a a if or should be cholangitis following ERCP in of patients with PSC should be to patients with PSC ERCP are on therapy biliary The of not defined but is on clinical tissue sampling with and/or should be performed in patients with relevant for cytology and analysis should be considered for patients with PSC ERCP for on the clinical the of biliary on is in the on CCA. or not to biliary in patients with PSC is In and in the absence of should be performed for patients with biliary or an for The of biliary should be with the in patients with and/or The to and of a stricture should be by a the on individual the and of to and to for an of a biliary stricture should not