Cholestatic liver diseases: new targets, new therapies

Abstract

Cholestatic liver diseases result from gradual destruction of bile ducts, accumulation of bile acids and self-perpetuation of the inflammatory process leading to damage to cholangiocytes and hepatocytes. If left untreated, cholestasis will lead to fibrosis, biliary cirrhosis, and ultimately end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the two most common chronic cholestatic liver diseases affecting adults, and their etiologies remain puzzling. While treatment with ursodeoxycholic acid (UDCA) has significantly improved outcomes and prolonged transplant-free survival for patients with PBC, treatment options for UDCA nonresponders remain limited. Furthermore, there is no available medical therapy for PSC. With recent advances in molecular biochemistry specifically related to bile acid regulation and understanding of immunologic pathways, novel pharmacologic treatments have emerged. In this review, we discuss the standard of care and emphasize the various emerging treatments for PBC and PSC.

Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches

“…The FXR agonist also plays an important role in downregulating inflammatory signaling, which reduces inflammation and cholestasis in the liver. 72 Overall, OCA is well tolerated and has been shown to decrease ALP and total bilirubin. 65,73,74 In the landmark phase 3 Perioperative Ischemic Evaluation Study (POISE) trail, the primary endpoint of an ALP level of less than 1.67 times the ULN range, with a reduction of at least 15% from baseline and a normal total bilirubin level met in an intention-to-treat analysis.…”

“…fibrates), which is found in the liver, muscle, and kidneys, is involved in the beta oxidation of fatty acids and regulation of lipid metabolism. In addition, both PPAR-a and PPAR-d are important regulators of bile acid homeostasis 72. Both PPAR-a and PPAR-d work by acting on transcription factors which reduce inflammation (thus lowering IgM) and increase bile acid excretion.…”

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

“…Cholestasis often occurs as a result of chronic liver and biliary diseases, such as hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, and graft-versus-host disease. (52) Accumulation of toxic bile acids can induce apoptosis of both hepatocytes and cholangiocytes and is strongly associated with hepatocarcinogenesis as was shown in a rodent model. (53) Unfortunately, potent caspase inhibitors could only moderately alleviate liver injury after bile duct ligation, which implies that apoptosis is not the only type of cell death in cholestasis.…”

Precision medicine in primary sclerosing cholangitis

“…One of the downstream mediators of FXR activation is FGF19, an enteral hormone shown to suppress bile acid synthesis via the downregulation of CYP7A1 . FGF19 is upregulated in PSC, potentially representing a protective mechanism in progressive disease .…”