Primary biliary cholangitis management: controversies, perspectives and daily practice implications from an expert panel

Primary biliary cholangitis (PBC) is a rare progressive immune-mediated liver disease that, if not adequately treated, may culminate in end-stage disease and need for transplantation. According to current guidelines, PBC is diagnosed in the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies, and of a cholestatic biochemical profile, while biopsy is recommended only in selected cases. All patients receive ursodeoxycholic acid (UDCA) in first line; the only registered second-line therapy is obeticholic acid (OCA) for UDCA-inadequate responders. Despite the recent advances in understanding PBC pathogenesis and developing new treatments, many grey areas remain. Six Italian experts selected the following topics as the most urgent to address in PBC management:diagnosis and natural history of PBC: as a portion of the subjects with isolated AMA, normal alkaline phosphatase (ALP) levels and no symptoms of liver disease could have PBC by histology, defining how to manage and follow this population is crucial;role of liver biopsy: recent evidence suggests that biopsy may provide relevant information for risk stratification and prediction of UDCA response, possibly facilitating personalized approaches;risk stratification: the tools for risk stratification are well established, but some issues (eg bile acid dosage in routine practice) remain controversial; andtherapy: those in more advanced stages of development are nuclear receptor modulators and fibrates, but more data are needed to plan personalized strategies. In this manuscript, for each topic, current evidence, controversies and future perspectives are summarized with the possible implications for clinical practice

Low Serum Hepcidin in Patients with Autoimmune Liver Diseases

Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum gamma-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients' sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases

The GLOBE score identifies PBC patients at increased risk of liver transplantation or death in different age-categories over time

Background and Aims: The GLOBE score differentiates PBC patients into high- and low risk groups for death or liver transplantation after 1 year of UDCA therapy using age-specific thresholds. We sought to determine whether the GLOBE score is predictive for death and liver transplantation when used over time in patients of different age- categories. Methods: Data from the Global PBC Study Group was used. Every 6 months starting at 1 yearof UDCA therapy we identified patients who passed their age-specific GLOBE score thresholds (aGLOBE-t) (ages <45, 45\u201352, 52\u201358, 58\u201366, and 6566 years, with thresholds 12 0.52, 0.01, 0.60, 1.01 and 1.69, respectively). For those passing their aGLOBE-t and those patients who did not, time to a combined endpoint of liver transplantation (LT) and death were compared with POSTER PRESENTATIONS JOURNAL OF HEPATOLOGY Journal of Hepatology 2017 vol. 66 | S543 \u2013 S750 \ua9 2017 All rights reserved. Cox-proportional hazards analysis with aGLOBE-t as a time-depend- ent covariate. Results: A total of 4340 UDCA-treated PBC patients were included, 924 (21.3%), 885 (20.4%), 875 (20.2%), 876 (20.2%), 780 (18%) in age categories <45 (A), 45 \u2013 52 (B), 52 \u2013 58 (C), 58 \u2013 66 (D), and 65 66 (E), respectively. At 12 months of UDCA therapy a total of 1244 (28.7%) patients passed their aGLOBE-t, 375 (40.6%), 279 (31.5%), 207 (23.7%), 208 (23.7%), and 175 (22.4%) in age categories A-E, respectively. Within the following 10 years there were an additional 841 (46.7%) patients that passed their aGLOBE-t, 183 (41.6%), 163 (45.7%), 172 (46.5%), 156 (41.1%), and 167 (40.6%) within age categories A-E, respectively (Fig 1.) The effect (time-dependent hazard ratio (HR)) on the clinical endpoint (death or LT) of passing the aGLOBE-t during follow-up, in patients that were characterized as low risk patients at 12 months of UDCA therapy, but passed theiraGLOBE-t during further follow-up, was HR 4.9 (95% confidence interval [CI]: 1.4 \u2013 17.2), HR 3.7 (1.1 \u2013 9.7), 4.3 (2.3 \u2013 8.1), 3.7 (2.2 \u2013 6.0) and 3.0 (2.1 \u2013 4.3) in age categories A-E, respectively. Conclusions: Patients of different age-categories with a beneficial GLOBE score at 12 months of UDCA therapy are at significant risk of death or LT when they pass their age-specific GLOBE score threshold during further follow-u

Ursodeoxycholic Acid Treatment-Induced GLOBE Score Changes Are Associated With Liver Transplantation-Free Survival in Patients With Primary Biliary Cholangitis

INTRODUCTION: Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)-free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA). METHODS: Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE 0-1 : during the first year of UDCA, ΔGLOBE 1-2 : during the second year) and the risk of LT or death was assessed through Cox regression analyses. RESULTS: Overall, 3,775 UDCA-treated patients were included; 3,424 (90.7%) were female, the median age was 54.0 (interquartile range [IQR] 45.9-62.4) years, and the median baseline GLOBE score was 0.25 (IQR -0.47 to 0.96). During a median follow-up of 7.2 (IQR 3.7-11.5) years, 730 patients reached the combined end point of LT or death. The median ΔGLOBE 0-1 was -0.27 (IQR -0.56 to 0.02). Cox regression analyses, adjusted for pretreatment GLOBE score and ΔGLOBE 0-12 , showed that ΔGLOBE was associated with LT or death (adjusted hazard ratio 2.28, 95% confidence interval 1.81-2.87, P < 0.001). The interaction between baseline GLOBE score and ΔGLOBE 0-1 was not statistically significant ( P = 0.296). The ΔGLOBE 1-2 was associated with LT or death (adjusted hazard ratio 2.19, 95% confidence interval 1.67-2.86, P < 0.001), independently from the baseline GLOBE score and the change in GLOBE score during the first year of UDCA. DISCUSSION: UDCA-induced changes in the GLOBE score were significantly associated with LT-free survival in patients with PBC. While the relative risk reduction of LT or death was stable, the absolute risk reduction was heavily dependent on the baseline prognosis of the patient