Current Therapies for Cholestatic Diseases

Abstract

Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.

Keywords: FXR agonist; PXR agonist; bile acids; cholestasis; fibreates; fibrosis; ursodeoxycholic acid.

Figure 1

Pathophysiology of cholangiopathies. In general, patients with CLD are in a proinflammatory state due to an exposition to a microbial and immunogenic environment with mitochondrial autoantigens in the form of apoptotic blebs that induce an immune response. (1) Dysregulation of the innate and adaptive immune response results in directed damage to cholangiocytes. (2) Small cholangiocytes act as antigen presenting cells and produce a variety of cytokines such as IL-6 and IL-8 and increase the expression of CXCL10. The latter will allow an increase in the production of IFNγ and other chemoattractants that result in T-cell infiltration and production of anti-mitochondrial antibody by B cells that ultimately increase production of bile. On the other hand, (3) there is a failure of biliary transporters (AE2, BSEP and the HCO3 umbrella) due to direct damage of cytotoxic T cells with mitochondrial injury on biliary cells. Hence, cholangiocytes lose their protection against toxic hydrophobic BAs and reduce BAs transportation in the context of bile overproduction. (4) Inflammation and injury lead to ductular reaction (DR), infiltration of leukocytes and lymphocytes that activate liver progenitor cells, thus increasing matrix protein levels through different proteins such as TGFβ1/2. Moreover, bile salts will be acidified becoming hydrophobic; eventually these toxic bile salts cross the membrane leading to apoptosis. (5) In addition, the constant bile duct insult led to retention of hydrophobic Bas promoting local injury and altering the enterohepatic circulation of bile. Finally, there is a dysregulation in FXR activation that may lead to a profibrotic state. (6) Apoptosis and cell injury promotes formation of reactive oxygen species (ROS) both in liver cells and cholangiocytes. Furthermore, apoptosis releases apoptotic blebs that perpetuate a proinflammatory state. All those processes induce cells to evolve toward an exhausted, profibrogenic phenotype which can contribute to the development of hepatic stellate cell-mediated liver fibrosis.

Figure 2

Treatments and molecular targets. In the liver, FXR agonists, PPAr agonist and FGF agonist improve cholestasis by decreasing BAs production and output via CYP7A1 inhibition. PPAr agonist and FRX also modulate the proinflammatory state by suppression of inflammatory pathways such as NF-kB. This results in ROS and interleukin reduction as well as decrease in hepatic stellate cells and immune cells activation. Immunomodulatory therapies, such as Rituximab or Baricitinib are aimed at blocking antigen presentation and the direct damage to liver cells. It is important to note that apoptosis releases apoptotic blebs which perpetuates a proinflammatory state and the formation ROS both in liver cells and cholangiocytes. Among other mechanisms, * UDCA serves as a partial agonist of FXR, improves BAs flow and enhances ions channels. Its effects on the biliary HCO³⁻ umbrella, near the apical surface, prevents the permeation of hydrophobic BAs; hence, contributing to the reduction in cell injury. Intestinal FXR agonists enhance the alleviation of cholestasis in the digestive system by reducing the overall size of the BAs pool that is reabsorbed. The events triggered by FXR in the gut liver axis probably represent a therapeutic option through the decrease in the excess of BAs in the liver. Finally, about 90–95% of BAs are reabsorbed into the terminal ileum via ASBT. Hence, the inhibition of ASBT reduces the overload of BAs in the liver. The decrease in ASBT expression increases the excretion of fecal BAs and the total concentration of BAs in liver.