Finding the cure for primary biliary cholangitis – Still waiting

Abstract

The introduction of ursodeoxycholic acid (UDCA)may well have contributed to some of the improvements in morbidity and mortality of primary biliary cholangitis (PBC). Yet nearly 40% of PBC patients are unresponsive to UDCA. Further the data on UDCA is confounded by the changes in the goepidemiology and particularly the earlier diagnosis of PBC. In this regard we welcome the addition of obeticholic acid (OCA) as an alternative therapeutic option forthe treatment of PBC in those patients refractory to UDCA. However, OCA is intellectually disappointing.There is no data on OCA that reflects dynamic and critical endpoints, for example death or liver transplantation; only surrogate endpoints have been used in the clinical trials. A nested study with liver histology wouldbeanideal surrogate marker,including intensive use of immunohistochemistry to define cellular infiltrates and cytokine/chemokine activity. More importantly, the clinical characteristics of PBCmay vary among patients and progression is not always predictable. We need to identify more appropriate and specific biomarkers that predict the clinical course, and we need to know which therapies are applicable at different stages, since treatmentfor PBC should be individualized. We need to know more about the etiology of PBC,and we want a cure for PBC.

SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model

“…And it increases the risk of hepatitis, liver cirrhosis, or other hepatic and gall-bladder diseases (Stone et al, 2012; Hirschfield et al, 2013; Geenes et al, 2014; Ji et al, 2014; Meng et al, 2015a). Recently, standard treatment for cholesteric diseases is limited to the use of ursodeoxycholic acid (UDCA) for primary biliary cholangitis (PBC), while there are no accepted treatments for other adult cholesteric disorders (Tanaka and Gershwin, 2017) Therefore, looking for new targets and developing new drugs for the treatment of cholestasis are necessary.…”

18β-Glycyrrhetinic acid protects against alpha-naphthylisothiocyanate-induced cholestasis through activation of the Sirt1/FXR signaling pathway

“…Activating Nrf2 may ameliorate bile duct ligation (BDL)-or ANITinduced cholestasis [7,42,43]. Recent studies have reported that Mrp2, Mrp3, and Mrp4 are direct Nrf2 target genes whose expression was increased by prototypical Nrf2 chemical activators in rodent livers and decreased to basal expression levels in Nrf2knockout mice [44][45][46].…”

“…The etiology of cholestasis is more complex, but cholestatic disease due to any cause can lead to the retention of toxic substances, such as BA, leading to liver damage and cholestatic liver disease [3][4][5][6]. Currently, obeticholic acid and ursodeoxycholic acid (UDCA) are two FDAapproved therapeutic drugs used as single agents or in combination for primary biliary cholangitis (PBC) treatment in adults, while there are no approved drugs for other cholesteric diseases that are found throughout the world [7,8]. Therefore, novel therapeutic strategies for the treatment of cholestasis are needed.…”

Reciprocal interactions between bile acids and gut microbiota in human liver diseases

“…However, the etiology of these diseases remains obscure and effective treatments are lacking. [88][89][90][91] Several studies present evidence to indicate the role of BAs in these autoimmune cholestatic liver diseases, 92 by reporting about reducing anion exchange 2 (AE2), 93 modulation of the immune system, 94 adaptive response of BA transporters, 95 and the activation of receptors such as FXR 96 and TGR5. 97 Furthermore, a series of studies indicated that dysbiosis is associated with autoimmune cholestatic liver disease.…”