Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that, if left untreated or insufficiently treated, inexorably progresses toward cirrhosis and its potentially fatal ...complications. Alongside with the biochemical response to ursodeoxycholic acid therapy, advanced liver fibrosis and portal hypertension (PH) were shown to be major prognostic determinants in PBC. Therefore, one of the goals of noninvasive PBC evaluation should be to early diagnose compensated advanced disease and/or clinically significant PH. In this article, the main methods of noninvasive assessment of liver fibrosis and PH in PBC, and their clinical relevance, will be reviewed.
Backgrounds & Aims Under normal conditions, the biliary tract is a microbial-free environment. The absence of microorganisms has been attributed to various defense mechanisms that include the ...physicochemical and signaling actions of bile salts. Here, we hypothesized that bile salts may stimulate the expression of a major antimicrobial peptide, cathelicidin, through nuclear receptors in the biliary epithelium. Methods The expression of cathelicidin was analyzed in human liver samples by immunostaining and reverse-transcription quantitative polymerase chain reaction. The regulation of cathelicidin expression by the endogenous bile salt, chenodeoxycholic acid, and by the therapeutic bile salt, ursodeoxycholic acid (UDCA), was assessed in human biliary epithelial cells in which endogenous nuclear receptor expression was blunted by siRNA or dominant-negative strategies. Results In the human liver, biliary epithelial cells show intense immunoreactivity for cathelicidin and for the vitamin D receptor. In cultured biliary epithelial cells, chenodeoxycholic acid and UDCA induce cathelicidin expression through 2 different nuclear receptors: the farnesoid X receptor and the vitamin D receptor, respectively. Importantly, vitamin D further increases the induction of cathelicidin expression by both bile salts. In a prototypical inflammatory biliary disease (ie, primary biliary cirrhosis), we document that hepatic expressions of the vitamin D receptor and of cathelicidin significantly increased with UDCA therapy. Conclusions Our results indicate that bile salts may contribute to biliary tract sterility by controlling epithelial cell innate immunity. They further suggest that in inflammatory biliary diseases, which involve bacterial factors, a strategy systematically combining UDCA with vitamin D would increase therapeutic efficacy.
Primary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been ...established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.
Background & Aims:
We used a multistate modeling approach to assess the effect of ursodeoxycholic acid (UDCA) therapy on the natural course of primary biliary cirrhosis (PBC), which remains ...controversial.
Methods:
Our population included 262 patients with PBC who had received 13–15 mg/kg UDCA daily for a mean of 8 years (range, 1–22 years). Data were analyzed using a multistate Markov model, with histologic stage progression, death, and orthotopic liver transplantation (OLT) as main end points. Survival without OLT was compared with that predicted by the updated Mayo model and with the expected survival in the control population.
Results:
Forty-five patients developed cirrhosis, 20 underwent OLT, and 16 died by the censor date. Ten deaths were due to liver disease. The overall survival rates were 92% at 10 years and 82% at 20 years. Survival rates without OLT were 84% and 66% at 10 and 20 years, respectively, which were slightly lower than the survival rate of an age- and sex-matched control population (relative risk RR, 1.4;
P = .1) but better than the spontaneous survival rate as predicted by the updated Mayo model (RR, .5;
P < .01). The survival rate of patients in stage 1 and 2 was similar to that in the control population (RR, .8;
P = .5), whereas the probability of death or OLT remained significantly increased in treated patients in late histologic stages (RR, 2.2;
P < .05).
Conclusions:
Treatment with UDCA alone normalizes the survival rate of patients with PBC when given at early stages. However, there is a continued need for new therapeutic options in patients with advanced disease.
Summary Background and aim Fenofibrate is a potential novel therapy for primary biliary cirrhosis (PBC). We performed a systematic review and a meta-analysis of studies of fenofibrate in PBC. Methods ...Electronic database search was performed for relevant studies. A search of abstracts presented in the main scientific meetings in the field and articles in press was also performed. Random effect model was used to pool the effect size across studies for changes in alkaline phosphatase, GGT, bilirubin and IgM levels before and after treatment and the overall rate of complete response to fenofibrate therapy. Results Six studies with 102 patients met the inclusion criteria. All studies were case series and in all, patients who had no or incomplete response to UDCA had fenofibrate added at a dose of 100–200 mg daily. Treatment duration ranged from 8–100 weeks. Treatment with fenofibrate was associated with a significant decrease in alkaline phosphatase (–114 IU/L, 95% CI: –152 to –76, P < 0.0001); a significant decrease in GGT level (–92 IU/L, 95% CI: –149 to –43; P = 0.0004); significant decrease in total bilirubin (–0.11 mg/dL, 95% CI: –0.18 to –0.08; P = 0.0008); and a significant decrease in IgM level (–88 mg/dL, 95% CI: –119 to –58; P < 0.0001). The complete response rate was 69% (95% CI: 53–82%) with an odds ratio of 82.8 (95% CI: 21.6–317.2; P = 0.024) while on fenofibrate. Conclusions Fenofibrate at doses of 100–200 mg daily appears to be effective adjunctive therapy in PBC patients who had no or incomplete response to UDCA. There is a critical need for larger scale randomized trials to determine its effect on liver-related morbidity and mortality (or progression towards end-stage disease).
Patients with primary sclerosing cholangitis (PSC) develop progressive liver fibrosis and end-stage liver disease. Non-invasive and widely available parameters are urgently needed to assess disease ...stage and the risk of clinical progression. Transient elastography (TE) has been reported to predict fibrosis stage and disease progression. However, these results have not been confirmed in an independent cohort and comparison of TE measurement to other non-invasive means is missing.
In a retrospective study we collected data from consecutive PSC patients receiving TE measurements from 2006 to 2014 (n = 139). Data from 62 patients who also underwent a liver biopsy were used to assess the performance of TE and spleen length (SL) measurement for the staging of liver fibrosis. Follow-up data from this cohort (n = 130, Hamburg) and another independent cohort (n = 80, Paris) was used to compare TE and SL as predictors of clinical outcome applying Harrel's C calculations.
TE measurement had a very good performance for the diagnosis and exclusion of higher fibrosis stages (≥F3: AUROC 0.95) and an excellent performance for the diagnosis and exclusion of cirrhosis (F4 vs. < F4: AUROC 0.98). Single-point TE measurement had very similar predictive power for patient outcome as previously published. In a combined cohort of PSC patients (n = 210), SL measurements had a similar performance as TE for the prediction of patient outcome (5 x cross-validated Harrel's C 0.76 and 0.72 for SL and TE, respectively).
Baseline TE measurement has an excellent performance to diagnose higher fibrosis stages in PSC. Baseline measurements of SL and TE have similar usefulness as predictive markers for disease progression in patients with PSC.
The recent phase 3 trials of peroxisome proliferator-activated receptor (PPAR) agonists in primary biliary cholangitis (PBC) patients with incomplete response to ursodeoxycholic acid (UDCA) ...demonstrated very promising short-term biochemical responses. However, long-term outcomes, crucial in chronic diseases like PBC, remain uncertain. While real-world data (RWD) support surrogate endpoints, there's a need to validate long-term efficacy especially with combination therapies. Bezafibrate, an off-label option with extensive RWD, demonstrated short-term response, reduced patients’ pruritus, and improved long-term outcomes. Therefore, the therapeutic choice between new selective PPAR agonists and old bezafibrate poses a challenge. Undoubtedly further investigations into new PPAR agonists in terms of long-term efficacy are warranted, but prospective, randomized trials in post-approval settings are very unlikely to be successfully conducted, necessitating alternative approaches using RWD rather than traditional trial design. Finally, it will be essential to identify patients who may be intolerant and/or unresponsive to PPAR agonists.
Background/Aims In primary biliary cirrhosis (PBC), pathogenesis is influenced by genetic factors that remain poorly elucidated up to now. We investigated the impact of sequence diversity in ...candidate genes involved in immunity ( CTLA-4 and TNFα ), in bile formation (10 hepatobiliary transporter genes) and in the adaptative response to cholestasis (three nuclear receptor genes) on the susceptibility and severity of PBC. Methods A total of 42 Ht SNPs were identified and compared in 258 PBC patients and two independent groups of 286 and 269 healthy controls. All participants were white continental individuals with French ancestry. Results Ht SNPs of CTLA-4 and TNFα genes were significantly associated with susceptibility to PBC. The progression rate of liver disease under ursodeoxycholic acid (UDCA) therapy was significantly linked to SNPs of TNFα and SLC4A2 /anion exchanger 2 (AE2) genes. A multivariate Cox regression analysis including clinical and biochemical parameters showed that SLC4A2 /AE2 variant was an independent prognostic factor. Conclusions These data point to a primary role of genes encoding regulators of the immune system in the susceptibility to PBC. They also demonstrate that allelic variations in TNFα and SLC4A2 /AE2 have a significant impact on the evolutive profile of PBC under UDCA therapy.
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