Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment

Abstract

Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.

The therapeutic mechanisms and beneficial effects of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease: a systematic review

“…In recent decades, UDCA has been of interest for the treatment of NAFLD patients due to its hepatoprotective effects [ 90 ]. The beneficial effects of UDCA treatment have been studied by numerous authors [ 91 – 94 ], that demonstrated that UDCA intervenes in the process of hepatocytic apoptosis, which is a characteristic of patients with NASH, but also reduces the serum level of TNF-α, which is increased in these patients and aggravates IR.…”

Therapeutic Roles of Bile Acid Signaling in Chronic Liver Diseases

“…Furthermore, UDCA has recently emerged as a promising therapeutic medication for polycystic liver diseases. It has been confirmed that UDCA inhibits hepatic cytogenesis in experimental models of polycystic liver disease and improves symptoms in patients 32,33. However, up to 40% of PBC patients are nonresponders to UDCA therapy, who have poor prognosis despite full-dose UDCA medication.…”

Review: Pathogenesis of cholestatic liver diseases

“…Recently an open-label clinical trial tested UDCA effect in cystic liver diseases and reported a reduction of liver cyst volume growth after 24 wk of treatment[ 48 , 49 ]. This effect was expected as UDCA decreases the concentration of cytotoxic BA and therefore diminishes proliferation stimuli[ 50 ]. Additionally, more than 50% of patients may have fibrosis[ 51 ].…”