AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma.

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. 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 adults[39, 40] and 15.1% in children,[41] suggesting that there may be tens of thousands of undiagnosed patients in North America alone. 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 lymphocytes[73, 74] and/or translocation of microbial constituents or metabolites[67, 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 PSC[88] 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.[98-101] 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] HIV-related cholangiopathy Recurrent pyogenic cholangitis Cholangitis lenta or subacute nonsuppurative cholangitis Parasitic cholangiopathy Critically ill patients Hereditary hemorrhagic telangiectasis Intra-arterial chemotherapy Hepatic artery thrombosis Cholangiocarcinoma Diffuse intrahepatic metastasis Langerhans cell histiocytosis Lymphoma Eosinophilic cholangitis Hepatic inflammatory pseudotumor IgG4-associated cholangitis Mast cell cholangiopathy Sarcoidosis Choledocholithiasis Intrahepatic lithiasis Cystic fibrosis liver disease Surgical biliary trauma Anastomotic stricture Portal hypertensive biliopathy Recurrent pancreatitis Sickle cell cholangiopathy Choledochal cyst 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 Score[107, 108]; however, they require further validation prior to routine clinical use. 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] 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.[124] 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). 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] 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] 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] 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] 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] 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 ERCP[180] 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] 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 uncertain.[183, 188] Like other causes of cirrhosis, PSC cirrhosis increases the risk for HCC. However, the risk is lower than for CCA, with one large study reporting HCC in 2.4% during nearly 10 years of follow-up.[189] Gallbladder cancer in PSC is 9–78 times greater compared to the general population.[3, 33] Gallbladder polyps may be a premalignant stage and are present in 6%–16% of patients with PSC.[177, 178, 190] The risk for malignant development of a gallbladder polyp increases with size, but evidence for a specific size cutoff for malignancy is lacking. In one study, small polyps < 10 mm were reported to be a transient finding or were stable in size over time, and only 6% increased in size at follow-up.[178] Underlying malignancy in polyps < 5 mm is low.[178, 191] The prevalence of adenocarcinoma in cholecystectomy specimens from patients with PSC and a gallbladder polyp or mass lesion varies between 18% and 56%.[177, 178, 190, 191] The risk of CRC in PSC is 5–12 times greater compared to the general population[3, 19, 181, 192] and 4–5 times greater compared to patients with IBD without PSC,19, 33, 193, 194] with a tendency toward right-sided lesions and younger age at onset.[33, 195] A meta-analysis of 1022 patients from 16 studies estimated the risk of CRC/dysplasia to be 3 times greater in patients with PSC-IBD compared with IBD alone.[196] Early studies found a cumulative incidence of CRC in PSC-IBD of up to 40% after 20 years of disease,[197] but more recently the incidence rates of CRC in PSC-IBD seem to have decreased, with one study reporting 5-year and 10-year CRC incidence rates of 7% and 9%, respectively.[32] Children develop CRC at similar rates as adults, with 5% affected at 10 years.[145] In addition, patients with PSC more frequently have endoscopically invisible dysplasia; and when low-grade dysplasia is present, it progresses to high-grade dysplasia (HGD) or CRC more rapidly compared to IBD alone.[198, 199] Young age at IBD diagnosis is a risk factor for CRC in PSC-IBD.[33, 145, 199] Children with PSC and IBD onset before age 6 had a greater risk of CRC than those diagnosed in their teenage years.[145] Chronic inflammation may contribute to the CRC risk and is often underestimated in PSC, in both adults and children.[144, 199] The risk of CRC in patients with PSC without IBD relative to the average-risk population is unknown, but in one study of 590 patients with PSC, 20 developed CRC and all but one had IBD.[19] The characteristics of PSC present challenges to creating distinct definitions of disease stages, and formal criteria do not yet exist. Unlike other liver diseases, clinical complications in PSC are not isolated to those who have developed cirrhosis, and severe symptomatic biliary strictures in PSC can occur before the onset of advanced fibrosis or cirrhosis. CCA and CRCs can occur at any disease stage. Additionally, PSC progression is variable; some patients at a low fibrosis stage may progress rapidly, and some patients with advanced fibrosis may remain asymptomatic and stable for many years. In clinical practice, risk assessment for clinical events such as hepatic decompensation or transplant-free survival, rather than disease staging, may be useful for guidance on follow-up and management strategies. Advanced fibrosis in PSC is associated with worse prognosis. The Nakanuma, Ishak, and Batts-Ludwig staging systems were each associated with transplant-free survival and time to LT with similar prognostic ability.[200] In the prospective simtuzumab trial, baseline Ishak fibrosis stage was strongly correlated with 2-year outcomes.[164] Liver histology in PSC is hampered by a large sampling variability because high-grade strictures and cholestasis may lead to unequal distribution of fibrosis throughout the liver.[201] A blinded review of paired biopsies obtained from the same liver location showed that Batts-Ludwig stage differed by one stage in 16% and two stages in 11% of patients with PSC.[201] Therefore, liver biopsy is not recommended for staging of fibrosis or prognostication in PSC outside of the clinical trial setting. Liver stiffness (LS) measurements in PSC by transient elastography (TE) or magnetic resonance elastography (MRE) are reasonably accurate for estimation of liver fibrosis and correlate with long-term patient outcomes.[127, 202-207] Cutoff values of 9.6 kPa by TE for extensive fibrosis (F3) and 14.4 kPa for cirrhosis (F4) have a diagnostic accuracy > 0.80.[202] Similarly, LS of 4.6 kPa by MRE has an area under the receiver-operator curve of 0.82 for cirrhosis.[208] Higher LS by TE or MRE has been associated with increasing risk of clinical outcomes.[202, 203, 206, 209] Changes of LS over time increase slowly through early stages of fibrosis and then exponentially as fibrosis progresses to cirrhosis.[202, 205] Importantly, LS is affected not only by fibrosis but also by blood flow, inflammation, and cholestasis. In PSC, the impact of transient episodes of cholestasis due to biliary obstruction may influence these results. The optimal frequency and clinical utility of repeated LS measurements remains unclear and needs further study. In 204 patients who underwent serial MRE a median of 1.1 years apart, mean change in LS was only 0.05 kPa/year overall. Larger changes in LS predicted worse clinical outcomes, with the highest risk of hepatic decompensation seen with LS worsened by > 0.34 kPa/year.[205] Mean LS by TE was unchanged over 2 years for nearly all patients in the simtuzumab trial.[164] The Enhanced Liver Fibrosis (ELF) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino-terminal peptide, and tissue inhibitor of metalloproteinase 1. ELF is strongly associated with transplant-free survival in PSC[210-212] and may be useful as a surrogate marker in clinical trials. Stable versus worsened ELF from baseline to Week 12 in a clinical trial was associated with more favorable outcomes, regardless of treatment.[164] ELF had less variability on serial measurements than ALP.[156] However, the ELF test is not widely available commercially. Serum matrix metalloproteinase 7 was more accurate than GGT or ALP in distinguishing PSC from AIH in children and correlated with histopathologic stage of fibrosis and MRE.[213] Aspartate aminotransferase (AST) to platelet ratio index correlates with fibrosis stage, TE, and clinical outcomes in adults[202, 214, 215] and children.[155] Fibrosis-4 index, a score based on patient age, AST, alanine aminotransferase (ALT), and platelet count designed to assess the need for biopsy in chronic hepatitis C,216] performs reasonably well in PSC, though it is inferior to LS measurement.[202, 214, 215] Despite recent advances in diagnostic imaging, the interpretation of MRI/MRCP examinations of patients with PSC remains challenging, with high interreader disagreement.[131, 217] The MRI/MRCP-based Anali scores summarize intrahepatic ductal dilation, dysmorphy, and portal hypertensive features without contrast and hepatic dysmorphy and parenchymal enhancement with contrast.[124] These scores are associated with long-term outcomes in PSC[123] and may offer complementary prognostic value with LS.[204] Relativ