Background & Aims The biochemical response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) correlates with the long-term prognosis and thus could allow the identification of the ...patients needing new therapeutic approaches. Due to variation in both endpoints and studied populations, there is still no full agreement on the definition of the biochemical response. The aim of our study was to determine, in a population of patients with only early-stage disease, the best biochemical criteria of response to UDCA allowing to predict the absence of poor outcome, as defined by liver-related death, liver transplantation, complications of cirrhosis, or histological evidence of cirrhosis development. Methods The efficiency of several combinations of serum bilirubin, alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcome was assessed after 1 year of UDCA in 165 patients with early-stage PBC followed up for an average 7 years. The Barcelona, Paris, Rotterdam, and Toronto criteria were also assessed. Results The most accurate discrimination of the patients according to the multiple endpoints was given by the following criteria: ALP and AST ⩽1.5× upper limit of normal, with a normal bilirubin level. Responders and non-responders were equally distributed, while all adverse events were observed in non-responders ( p <0.001). These criteria remained valid when early PBC was defined by both normal bilirubin and albumin concentrations at baseline. Conclusions This study defines the best efficient biochemical response to UDCA that identifies patients with early PBC at very low risk of long-term development of liver failure or cirrhosis.
Chazouilleres expresses compliment on Fickert et al on their study of double blind randomized, placebo-controlled study evaluating the safety and efficacy of 24-norursodeoxycholic acid (norUDCA) in ...patients with primary sclerosing cholangitis (PSC). The study demonstrated the role of norUDCAin reducing alkaline phosphatase (ALP) values in a dose-dependent manner. The effect is associated with significant decrease in other liver enzyme levels but not in serum bilirubin values. He added the safety profile of norUDCA was unremarkable, the pruritus did not change and there was no effect on inflammatory bowel disease (IBD). He explores the aspects of possible application of norUDCA in the future treatment of PSC.
Magnetic resonance imaging (MRI) with magnetic resonance cholangiography (MRC) has become the radiologic standard of reference for diagnosis of primary sclerosing cholangitis (PSC). However, natural ...history of radiologic features of PSC is poorly known. In the current study, we aimed at analyzing the course of PSC using three‐dimensional (3D) MRC and liver MRI to find predictive radiologic features of progression. PSC patients, followed up in our center, with at least two 3D MRCs performed in at least a 1‐year interval, were retrospectively reviewed. We built an interpretation standard model to score precisely bile ducts and liver parenchyma features. The primary endpoint was overall radiologic course, including worsening, improvement, or stabilization. Radiologic features were analyzed by logistic regression. We reviewed 289 MRIs from 64 patients upon a mean radiologic follow‐up of 4 years (range, 1‐9). Radiologic features worsened in 37 patients (58%) and stabilized in 27 (42%); no patient showed improvement. Multivariate analysis resulted in two MRI progression risk scores, based on the combination of predictive radiologic features (score without gadolinium administration = 1 × dilatation of intrahepatic bile ducts + 2 × dysmorphy + 1 × portal hypertension; score with gadolinium administration = 1 × dysmorphy + 1 × parenchymal enhancement heterogeneity). These scores were associated with radiologic progression, with an area under the curve of 80 and 83% ± 4%. Conclusion: A majority of PSC patients develop radiologic aggravation upon MRI over 4 years. Two simple scores can predict radiologic progression.(Hepatology 2014;58:242–250)
Background & Aims Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that leads to extensive liver fibrosis and cirrhosis, which are associated with poor outcome. However, there ...are no validated noninvasive markers of liver fibrosis in patients with PSC. We assessed the diagnostic performance, reproducibility, longitudinal changes, and prognostic value of liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). Methods In a prospective study, we analyzed percutaneous liver biopsy specimens from 73 consecutive patients with PSC from January 2005 to December 2010. Patients underwent VCTE no more than 6 months after the biopsy specimens were collected. The biopsy specimens were analyzed by a pathologist blinded to the results of VCTE for the stage of fibrosis, and LSM was associated with the stage of fibrosis and other variables using the Kruskal–Wallis and Spearman correlation tests. The cutoff values of LSM were selected based on the accuracy with which they identified the stage of fibrosis on receiver-operating characteristic analysis. The rates of LSM progression were assessed using a linear mixed model, and the association between LSM values and clinical outcomes were evaluated using Cox regression analysis in 168 patients with PSC treated with ursodeoxycholic acid and followed up from November 2004 to July 2013 (mean follow-up period, 4 years). Results LSM was independently linked to the stage of fibrosis. Cutoff values for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 7.4 kPa, 8.6 kPa, 9.6 kPa, and 14.4 kPa, respectively. The adjusted diagnostic accuracy values for severe fibrosis and cirrhosis were 0.83 and 0.88, respectively. The diagnostic performance of LSM was comparable to that of hyaluronic acid measurement but superior to the aspartate aminotransferase/platelet ratio index, FIB-4 score, and Mayo risk score in differentiating patients with significant or severe fibrosis from those without. LSM had a high level of reproducibility between operators for the same measurement site and for the same operator between 2 adjacent sites. LSM increased significantly and exponentially over time. Baseline measurements and rate of LSM progression were strongly and independently linked with patients' outcomes. Conclusions VCTE is able to differentiate severe from nonsevere liver fibrosis with high levels of confidence in patients with PSC. Baseline measurements of LSM and longitudinal changes are prognostic factors for PSC.
There is a great need for risk stratification in patients with chronic cholestatic diseases in order to allow for more personalized care and adapted management as well as for well-designed ...therapeutic trials. Novel tools for monitoring primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) patients have been recently proposed. In addition, major insight has been gained into bile acid (BA) physiology during the last decade including the role of BAs as metabolic modulators and the gut-liver axis. As a consequence, alongside drugs targeting immune response or fibrotic processes, a number of novel anti-cholestatic agents have undergone pre-clinical and clinical evaluation and have shown promising results although none has been approved yet.
Biochemical non-response to ursodeoxycholic acid (UDCA) (mainly defined by bilirubin and alkaline phosphatase levels at 1 year) is a strong prognostic factor in PBC whereas present biochemical surrogates are far from robust in PSC. By contrast, liver stiffness measurement by vibration-controlled transient elastography (VCTE) is a very promising tool in both PBC and PSC. Novel therapeutic approaches include (i) agonists of nuclear receptors, especially farnesoid X receptor (FXR), pregnane X receptor (PXR), glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor α (PPARα) that are transcriptional modifiers of bile formation; (ii) agonists of TGR5, a BA membrane receptor expressed in various tissues; (iii) inhibitors of the ileal apical sodium BA transporter; (iv) derivatives of the FXR-induced fibroblast growth factor 19 from the ileum that suppresses hepatic BA synthesis and (v) norUDCA, a side chain shortened UDCA derivative with specific physicochemical and therapeutic properties. The most advanced clinical evaluation (PBC patients) relates to agonists for PPARα, FXR and GR/PXR most often in combination with UDCA, namely fibrates, obeticholic acid (OCA) and budesonide, respectively. Existing results look promising even though some side effects are worrisome such as pruritus in OCA-treated patients. Results of large well-designed studies are eagerly awaited.
Major advances in the management of cholestatic liver diseases are in progress and promising times for these patients seem likely in the near future.
Some patients present with features of both primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) on the one hand and autoimmune hepatitis (AIH) on the other hand, either ...simultaneously or consecutively. The term 'overlap syndrome (OS)' is used to describe these settings, but lack of universal agreement on what precisely constitutes an OS has generated considerable confusion. The low prevalence of OS (roughly 10% of PBC or PSC) has made it impracticable to perform randomized controlled trials. It remains unclear whether this syndrome forms a distinct entity or is a variant of PBC, PSC or AIH.
Moderate to severe interface hepatitis is a fundamental component and histology is vital in evaluating patients with overlap presentation. Use of the International Autoimmune Hepatitis Group criteria for the diagnosis of OS is not recommended. For PBC-AIH OS, EASL has provided diagnostic criteria and, in most cases, it is possible to define one primary disorder ('dominant' disease), usually PBC. Patients with OS seem to have a more severe disease compared to conventional PBC. PSC-AIH OS is assumed to exist in a considerable part of mainly young patients with autoimmune liver disease and long-term progression towards cirrhosis seems to occur in the majority of cases. In children, the hepatitic feature can be very dominant, and up to 50% of pediatric AIH have cholangiographic abnormalities suggestive of PSC (autoimmune sclerosing cholangitis). Treatment of OS is empiric and includes ursodeoxycholic acid for the cholestatic component (depending on local policy for PSC) and immunosuppressive agents for the hepatitic component, either simultaneously or sequentially. The dominant clinical feature should be treated first and therapy adjusted according to the response.
OS is not uncommon but should not be over-diagnosed in order not to expose unnecessarily PBC or PSC patients to the risk of steroid side effects. Therapy has to be individualized and not be static.
Biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) is variable. It has been recently proposed that an alkaline phosphatase (ALP) decline of more than ...40% in baseline value or a normal level after 1 year of UDCA treatment (Barcelona criteria) could serve as a good marker of long‐term prognosis. Our aim was to define the best efficient set of biochemistries able to identify UDCA‐treated patients at risk of death or liver transplantation (LT). The efficiency of several combinations of serum bilirubin, ALP, and aspartate aminotransferase (AST) threshold values to predict outcome was assessed after 1 year of treatment in 292 patients with PBC. Patients showing ALP <3 upper limit of normal (ULN), AST <2 ULN, and bilirubin ≤1 mg/dL after 1 year of UDCA had a 10‐year transplant‐free survival rate of 90% (95% confidence interval, 81%–95%), compared to 51% (95% confidence interval, 38%–64%) for those who did not (P < 0.001). Patients were less well discriminated by the Barcelona criteria (79% versus 63%). Independent predictive factors of death or LT were baseline serum bilirubin level >1 mg/dL (relative risk RR, 1.7), histologic stage ≥3 (RR, 1.5), interface hepatitis (RR, 1.9), and the absence of biochemical response (ALP >3 ULN or AST >2 ULN, or bilirubin >1 mg/dL) (RR, 2.3). Antinuclear antibodies against gp210 or Sp100 proteins were associated with death or LT in univariate but not in multivariate analysis. Conclusion: This study defines the best efficient biochemical response to UDCA, which, independent of baseline predictive factors, identifies patients with PBC with a good long‐term prognosis. Patients who fail to achieve this response and those with interface hepatitis or advanced histological stage should be targeted for further therapeutic research. (HEPATOLOGY 2008.)
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