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Changes over time in the presenting features and clinical course of patients with primary biliary cholangitis are poorly described. We sought to describe temporal trends in patient and disease characteristics over a 44-year period across a large international primary biliary cholangitis cohort of 4,805 patients diagnosed between 1970 and 2014, from 17 centers across Europe and North America. Patients were divided into five cohorts according to their year of diagnosis: 1970-1979 (n = 143), 1980-1989 (n = 858), 1990-1999 (n = 1,754), 2000-2009 (n = 1,815), and ≥2010 (n = 235). Age at diagnosis, disease stage, response to ursodeoxycholic acid, and clinical outcomes were compared. Mean age at diagnosis increased incrementally by 2-3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P < 0.001). The female to male ratio (9:1) and antimitochondrial antibody positivity (90%) were not significantly variable. The proportion of patients presenting with mild biochemical disease (according to Rotterdam staging) increased from 41.3% in the 1970s to 72.2% in the 1990s (P < 0.001) and remained relatively stable thereafter. Patients with a mild histological stage at diagnosis increased from 60.4% (1970-1989) to 76.5% (1990-2014) (P < 0.001). Correspondingly, response to ursodeoxycholic acid according to Paris-I criteria increased; 51.7% in the 1970s and 70.5% in the 1990s (P < 0.001). Recent decades were also characterized by lower decompensation rates (18.5% in the 1970s to 5.8% in the 2000s, P < 0.001) and higher 10-year transplant-free survival (48.4%, 68.7%, 79.7%, and 80.1% for each respective cohort; P < 0.001). Conclusion: In recent decades, a pattern of primary biliary cholangitis presentation consistent with an older age at diagnosis alongside reduced disease severity has been noted; the observed trends may be explained by an increase in routine testing of liver function and/or a changing environmental trigger. (Hepatology 2018;67:1920-1930).

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)

The development of liver fibrosis markers in primary biliary cirrhosis (PBC) is needed to facilitate the assessment of its progression and the effectiveness of new therapies. Here, we investigated the potential usefulness of transient elastography (TE) in the noninvasive evaluation of liver fibrosis stage and disease progression in PBC. We performed, first, a prospective performance analysis of TE for the diagnosis of METAVIR fibrosis stages in a diagnostic cohort of 103 patients and, second, a retrospective longitudinal analysis of repeated examinations in a monitoring cohort of 150 patients followed-up for up to 5 years. All patients were treated with ursodeoxycholic acid. Diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥F1, ≥F2, ≥F3, and =F4 were 7.1, 8.8, 10.7, and 16.9 kPa, respectively. TE showed high performance and was significantly superior to biochemical markers (e.g., aspartate aminotransferase [AST]/platelet ratio, FIB-4, hyaluronic acid, AST/alanine aminotransferase ratio, and Mayo score) in diagnosing significant fibrosis, severe fibrosis, or cirrhosis. Analysis of the monitoring cohort data set using generalized linear models showed the following: (1) an overall progression rate of 0.48 ± 0.21 kPa/year (P = 0.02) and (2) no significant progression in patients with F0-F1, F2, or F3 stages, but a significant increase (4.06 ± 0.72 kPa/year; P < 0.0001) in cirrhotic patients. A cut-off value of 2.1 kPa/year was associated with an 8.4-fold increased risk of liver decompensations, liver transplantations, or deaths (P < 0.0001, Cox regression analysis). Conclusion: TE is one of the best current surrogate markers of liver fibrosis in PBC. Over a 5-year period, on-treatment liver stiffness appears stable in most noncirrhotic PBC patients, whereas it significantly increases in patients with cirrhosis. Progression of liver stiffness in PBC is predictive of poor outcome. (HEPATOLOGY 2012;56:198–208)

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 ALP3 upper limit of normal (ULN), AST2 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 (P0.001). Patients were less well discriminated by the Barcelona criteria (79% versus 63%). Independent predictive factors of death or LT were baseline serum bilirubin level1 mg/dL (relative risk [RR], 1.7), histologic stage/=3 (RR, 1.5), interface hepatitis (RR, 1.9), and the absence of biochemical response (ALP3 ULN or AST2 ULN, or bilirubin1 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.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.

Cirrhosis consists of hepatocyte nodules surrounded by a highly vascularized fibrous tissue. We previously showed that the development of biliary cirrhosis in the rat is associated with the occurrence of hepatocellular hypoxia and the induction of hepatic angiogenesis. We herein examined the occurrence of hypoxia in an experimental model of diethylnitrosamine (DEN)-induced cirrhosis. We also determined whether hypoxia directly affects the expression of vascular endothelial growth factor (VEGF), of VEGF receptors (Flt-1, Flk-1), and of type I and type IV collagens in activated hepatic stellate cells (HSCs) and the expression of VEGF in hepatocytes. Our results show that in DEN-treated rats, although the progression of liver fibrosis is associated with hepatocellular hypoxia and angiogenesis, VEGF and Flt-1 expressions in the liver are increased and correlated with the density of microvessels. In vitro, hypoxia induces the expression of VEGF, Flt-1, and type I collagen in activated HSCs and that of VEGF in hepatocytes. In addition, we show that hypoxia-induced type I collagen expression in HSCs may occur independently of transforming growth factor beta1 (TGF-beta1) overexpression. In conclusion, the present study provides further evidence that hepatocellular hypoxia and angiogenesis progress together with fibrogenesis after liver injury and that hypoxia directly contributes to the progression of liver fibrosis.