The treatment of primary biliary cholangitis: from shadow to light

Abstract

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease characterized by the destruction of the small intrahepatic bile ducts, which can progress to liver cirrhosis. The gold standard in the treatment of PBC is ursodeoxycholic acid (UDCA), which is indicated in all patients with PBC because it improves not only biochemical parameters but also patients' survival. An important milestone in the identification of patients at risk is the assessment of biochemical response to UDCA. Patients who respond to treatment have a lower incidence of hepatic events and better prognosis than patients who do not. Several scoring systems can be used to assess the response and identify non-responders who will benefit from second-line treatment. Obeticholic acid (OCA) is currently the only approved second-line treatment for PBC, which is effective for non-responders to UDCA therapy or patients, who have not tolerated UDCA therapy. However, OCA is contraindicated in advanced liver cirrhosis and portal hypertension. Moreover, pruritus may be a limiting factor for the administration of OCA. Fibrates have shown promising data supporting their use in non-responders to UDCA because they improve the biochemical parameters and elastographic findings and have possible antipruritic effects. Therefore, the idea of a triple treatment seems interesting. Clinical research is focusing on several other groups of drugs: peroxisome proliferator-activated receptor (PPAR) δ- and α/δ agonists, non-steroidal farnesoid X receptor agonists, fibroblast growth factor 19 modulators, and inhibitors of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4.

Keywords: biochemical response; fibrates; obeticholic acid; primary biliary cholangitis; ursodeoxycholic acid.

Figure 1.

Factors involved in PBC pathophysiology. PBC, primary biliary cholangitis.

Figure 2.

Mechanism of UDCA action. Source: Adapted from Pinyopornpanish. Potential mechanisms of the action and anti-fibrosis effects of UDCA: alteration of the bile acid pool by replacing toxic, hydrophobic bile acids with non-toxic, more hydrophilic UDCA; stimulation of impaired hepatocyte and cholangiocyte secretion; cytoprotection and anti-apoptotic effects; inhibition of cholangiocyte apical uptake of hydrophobic bile acids. The mechanisms illustrate the anticholestatic effect of UDCA resulting in a decrease in hepatic inflammation and a decrease in hepatic fibrosis in cholestatic liver disease. UDCA may also cause a decrease in the production of collagen by hepatic stellate cells, therefore providing primary anti-fibrosis activity. UDCA, ursodeoxycholic acid.

Chart 1.

Comparison of transplant-free survival in PBC patients treated and untreated with UDCA. Source: Adapted from Harms et al. Chart constructed by Cox proportional hazards model adjusted to inverse probability of treatment weight. A 95% confidence interval is visualized by gray lines. PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid.

Chart 2.

Comparison of survival between PBC responders to treatment with UDCA and the general population. Source: Adapted from Pares et al. PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid.

Chart 3.

Changes in the stage of fibrosis in PBC responders and non-responders to UDCA treatment. Source: Adapted from Kumagi et al. Histological progression is significantly less frequent in biochemical responders to UDCA treatment (p < 0.005). PCB, primary biliary cholangitis; UDCA, ursodeoxycholic acid.

Figure 3.

Mechanism of OCA action. Source: Adapted from Keshvani et al. OCA crosses the cell membrane in the liver and enterocytes to activate FXR which can form a heterodimer with the RXR, a homodimer with FXR, or bind to DNA as a monomer. This can activate various signaling pathways, decreasing bile acid synthesis, fatty acid and cholesterol metabolism, glucose metabolism, inflammation, and fibrosis. FXR activation causes the release of FGF-19 which acts as an endocrine signaling molecule released from enterocytes to the liver causing decreased bile acid. LRH1 and SHP levels are increased due to FXR activation, which also decreases bile acid synthesis via inhibition of CYP7A1, cholesterol utilization, and fatty acid metabolism. This all improves cholestasis in patients with PBC. CYP7A1, cholesterol 7 alpha-hydroxylase; DNA, deoxyribonucleic acid; FGF-19, fibroblast growth factor 19; FXR, farnesoid X receptor; LRH1, liver-related homolog 1; OCA, obeticholic acid; PBC, primary biliary cholangitis; RXR, retinoid X receptor; SHP, small heterodimer protein.

Chart 4.

Comparison of survival in PBC patients from the Global PBC Study Group and UK-PBC Research Cohort POISE registries. Source: Adapted from Murillo Perez et al. PBC, primary biliary cholangitis; POISE, phase III study of obeticholic acid in patients with primary biliary cirrhosis.

Figure 4.

Targets for PBC treatment. BA, bile acids; FGF-19, fibroblast growth factor 19; FXR, farnesoid X receptor; HCO₃, bicarbonate; NOX, nicotinamide adenine dinucleotide phosphate oxidase; OCA, obeticholic acid; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; UDCA, ursodeoxycholic acid.