Although ursodeoxycholic acid remains the only approved pharmacotherapy for patients with primary biliary cirrhosis, the better characterization of factors responsible for the poor response to this ...drug and the emergence of several new putative therapeutic targets now offer significant opportunities to improve the management of patients and our capacity to treat them more efficiently. The availability of novel treatment options, such as fibrates, budesonide, and obeticholic acid, all capable of improving prognostic markers, invites us to reconsider our management and treatment strategies. Early identification of high-risk patients should remain a priority to deliver adjunctive therapies to appropriately selected populations and increase their chances of success. Given the absence of comparative trials, the choice between second-line treatments should be dictated by the biochemical, histological, and expected tolerance profiles. Here the author presents a brief overview of what should be known in this field and proposes a practical approach to facilitate decision making.
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.
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)
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.)
Methods of liver fibrosis assessment have changed considerably in the last 20 years, and noninvasive markers now have been recognized as major first-line tools in the management of patients with ...chronic viral hepatitis infection. But what about the efficiency and utility of these surrogate indices for the more uncommon chronic cholestatic liver diseases, namely primary biliary cirrhosis and primary sclerosing cholangitis? This article provides clinicians with a global overview of what is currently known in the field. Both diagnostic and prognostic aspects of noninvasive markers of fibrosis in cholestatic liver diseases are presented and discussed.
Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk ...factors for HCC development in patients with PBC.
Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates.
Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001).
This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.
Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential ...contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC‐derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1‐immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1‐expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF‐conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A‐containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. Conclusion: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA‐laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. (Hepatology 2015;61:1041–1055)
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