Review: Pathogenesis of cholestatic liver diseases

Table 1 Potential pathways as targets for existing antibodies

Drug	Primary role of the pathway in specific cholestatic liver disease	Previous disease of drug-testing	Ref.
Anti-CD40 (dacetuzumab/lucatumumab)	T-cell-B-cell interactions in primary biliary cholangitis	Multiple sclerosis (pre-clinical)	[53]
Anti-CXCL10 (MDX-1100)	CXCR3-CXCL9/10/11 CXCR3 is upregulated on liver-infiltrating Th1 and Th17 in primary biliargy cholangitis	Rheumatoid arthritis	[54]
Anti-CXCL13 (Mab 5261)	T- and B-cell migration to germinal centers in primary biliary cholangitis	Preclinical development	[55]
Anti-CCR6	Recruitment of Th17 cells around inflamed biliary epithelial cells in primary biliary cholangitis	Preclinical development	[56]
Anti-GRP35	Activation of GPR35 reduces IL-4 release from natural killer T cells in primary sclerosing cholangitis	Antibody recently developed	[57]
Anti-PRKD2	SIK2 pathway in PSC, AMPK-related kinase PRKD2 polymorphism are seen in early inflammatory bowel disease in primary sclerosing cholangitis	Preclinical development	[58]

PSC: Primary sclerosing cholangitis.

Table 2 Preclinical research cholestatic liver diseases

Area of concern	Findings	Approach	Ref.
Mitochondrial damage by GCDCA	Mitofusin 2 protects hepatocyte mitochondrial function	In vitro (LO2 cell lines)	[59]
Immunomodulation in primary biliary cholangitis with CTLA-4-Ig (immunoglobulin) as an immunotherapeutic agent	Signaling by CTLA-4 can modulate costimulation and induce inhibitory signals	In vivo (murine models)	[60]
Immunomodulation in primary biliary cholangitis with anti-CD40L	Reduced liver inflammation significantly initial lowering of anti-mitochondrial antibodies was observed but non-sustained.	In vivo (murine models)	[61]
Action of nuclear bile acid receptor FXR in cholestasis	Hepatoprotection from cholestasis by inducing FGF-15	In vivo (murine model)	[9]
Immunomodulation Anti-CCR5/CCR2 in combination with all-trans-retinoic acid	Significant reduction in plasma liver enzymes, bilirubin, liver fibrosis, bile duct proliferation and hepatic infiltration of neutrophils and T cells and expression of cytokines	In vivo (murine model)	[62]
Curcumin acts through FXR signaling	Protection against alpha-naphthylisothiocyanate ANIT-induced cholestasis	In vitro and in vivo (murine model)	[63]
Modulation of bile duct proliferation, with Melatonin	GnRH stimulated fibrosis gene expression in Hepatic stellate cells; melatonin may improve outcomes of cholestasis by suppressing GnRH.	In vivo (murine model)	[64]
Apamin, an apitoxin (bee venom) derivate prevented tetrachloride-induced liver fibrosis	Apamin suppressed the deposition of collagen, the proliferation of BECs and expression of fibrogenic genes	In vivo (murine model)	[65]
Toxic bile acids induce mitochondrial fragmentation. Preventing fragmentation improved outcome	Decreasing mitochondrial fission substantially diminished ROS levels, liver injury, and fibrosis under cholestatic conditions	In vivo Knockout mouse models	[66]
Epigenetic approach Histone deacetylase 4 (HDAC4) restores prohibitin-1 (PHB1)	Genomic reprogramming, with regression of the fibrotic phenotype	In vivo Knockout mouse models	[67]
Anti-γ-glutamyl transpeptidase antibody for osteodystrophy in cholestatic liver disease	GGT inhibited mineral nodule formation and expression of alkaline phosphatase and bone sialoprotein in osteoblastic cells.	In vivo (murine model)	[68]
EGFR signaling protects from cholestatic liver injury and fibrosis.	STAT3 is a negative regulator of bile acids synthesis and protects from bile acid-induced apoptosis. Additionally, it regulates EGFR expression	In vivo Knockout mouse models	[69]
Necroptosis pathway in primary biliary cholangitis	Necroinflammatory pathways regulated by receptor-interacting protein 3 (RIP3), with deleterious progress in cholestatic diseases. RIP3 deficiency blocked bile-duct-ligation-induced (BDL) necroinflammation at 3 and 14 d post-BDL	In vivo Knockout mouse models	[70]
Tauroursodeoxycholic acid modulates apoptosis in mice	Significant reduction of liver fibrosis, accompanied by a slight decrease of liver damage	In vivo (murine model)	[71]

Table 3 Clinical trials and translational research

Area of concern and specific cholestatic liver disease	Findings	Phase, study description	Clinical trial number	Ref.
IL12/IL23 Inflammatory pathway and loss of self-tolerance (Primary biliary cholangitis)	After 28 wk of treatment modest decreases in alkaline phosphatase	Phase 2, open-label proof of concept using Ustekimunab for ursodeoxycholic acid non-responsive patients	NCT01389973	[72]
Ileal bile acid transporter (IBAT) (Primary biliary cholangiti, Alagille syndrome, progressive familial intrahepatic cholestasis)	Bile acid transporter inhibitor A4250 interrupts enterohepatic bile acid circulation at the terminal ileum	Phase 1 (40 individuals) completed Bile acids A4250 either as monotherapy or in combination with colonic release cholestyramine	NCT02963077	[73]
Modified bile acid and FXR agonist derived from chenodeoxycholic acid Obeticholic acid (OCA) (Primary biliary cholangitis)	Durable treatment response; the drug was approved by FDA in May 2017 for non-UDCA responders	Phase 4, double-blind, randomized, placebo-controlled, multicenter (428 patients) estimated completion by 2025 (COBALT study)	NCT02308111	[34]
IBAT inhibition by GSK2330672	After 14 d, GSK2330672 demonstrated to be safe, well tolerated and reduced pruritus severity	Phase 2 double-blind, randomized, placebo-controlled	NCT01899703	[74]
Bile acids	Significantly reduced ALT and the bile acid intermediate C4	Phase I: Combination of UDCA and ATRA	NCT01456468	[75]
Bile acids Obeticholic acid monotherapy (Primary biliary cholangitis)	With ursodiol or as monotherapy for 12 mo decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the placebo. observed changes	Phase 3, double-blind, placebo-controlled trial and long-term safety extension of obeticholic acid (217 patients) (POISE study)	NCT01473524	[76]
Bezafibrate 400 mg alternative	PBC patients with inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy	Phase 3 multi-center, randomized, placebo-controlled, parallel-group (100 patients) (BEZURSO study)	NCT01654731	[77]
Different doses of UDCA in primary sclerosing cholangitis	Significantly reduced ALP values dose-dependently	Phase 2 double-blind, randomized, multi-center, placebo-controlled (159 patients) (NUC3)	NCT01755507	[78]
Pentoxifylline as immunomodulator for primary biliary cholangitis	The study is small, and results were in clinicaltrials.gov, but due to study size no conclusion can be safely achieved	Phase 2, pilot study, open-label Pentoxifylline 400 mg TID for six months (20 participants)	NCT01249092	Results at clinicaltrials.gov
Umbilical cord-derived mesenchymal cells (UC-MSC)	A significant decrease in alkaline phosphatase	Phase1/2 study, randomized, parallel group (100 participants) 12 wk of treatment	NCT01662973	[79]
Mitomycin C in primary sclerosing cholangitis	Final results awaited	Phase 2, double-blind, randomized, parallel group (130 participants)	NCT01688024	-
Curcumin in primary sclerosing cholangitis	Final results awaited	Phase1/2 open-label pilot study Evaluating the safety and efficacy of curcumin (15 participants)	NCT02978339	-
Human monoclonal antibody (BTT1023) that targets the vascular adhesion protein (VAP-1) in primary sclerosing cholangitis	Recruiting	Phase 2, a single arm, two-stage, multicenter, open-label (41 participants)	NCT02239211	[80]
Cenicriviroc a CCR2/CCR5 inhibitor proof of concept in primary sclerosing cholangitis	Results awaited	Phase 2, proof of concept, open-label (24 participants) (PERSEUS study)	NCT02653625	-
Bile acids Maralixibat Apical bile acids transporter inhibition (ASBTi) in primary sclerosing cholangitis	Although results are online, complete information is still awaited	Phase 2, pilot, open-label	NCT02061540	Results available at clinicaltrial.gov
Immunomodulation Simtuzumab in primary sclerosing cholangitis Monoclonal antibody against lysyl oxidase-like 2 (LOXL2)	Results awaited	Phase 2b, dose-ranging, randomized, double-blind, placebo-controlled (235 participants)	NCT01672853	-
Bile acids Obethicolic acid in primary biliary cholangitis	Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event	Phase 2, double-blind, placebo-controlled trial. Dose-Finding (AESOP)	NCT02177136	[80]

PSC: Primary sclerosing cholangitis.