Nor-ursodeoxycholic acid in hepatobiliary diseases: A narrative review

Table 2 Nor-ursodeoxycholic acid in pre-clinical animal studies and randomised controlled trials on patients with metabolic dysfunction-associated steatotic liver disease and primary sclerosing cholangitis

Ref.	Study subjects	Patient phenotype	Treatment	Outcome
Buko et al[19]	Thioacetamide-induced liver fibrosis in rat model	Experimental in animal model of liver fibrosis	Fibrotic rats were administered UDCA (80 mg/kg) and nor-UDCA (equimolar 80 mg/kg)	Nor-UDCA decreased liver hydroxyproline content and TGF-β expression. Liver fibrosis regression was more pronounced in UDCA-treated rats
Fickert et al[16]	Bile duct ligated mice	Experimental animal model of cholestasis	0.5% UDCA vs nor-UDCA in Abcb (-/-) mice with bile duct ligated mice	UDCA is toxic to bile duct ligated mice however, nor-UDCA ameliorated liver injury
Marchianò et al[23]	Western diet-fed rat model with hepatic steatosis	Experimental animal study in liver steatosis	UDCA vs nor-UDCA in rat model with steatosis	UDCA and nor-UDCA both protected against steatosis and fibrosis but failed to ameliorate hepatic ballooning and nor-UDCA use was associated development of dyslipidemia
Sombetzki et al[22]	Murine model of schistosomiasis	Experimental animal study with liver fibrosis	UDCA vs nor-UDCA in schistosoma mansoni infected liver	Nor-UDCA affected surface expression of MHC in macrophage and exerts anti-fibrotic property
Traussnigg et al[2]	NAFLD	A double-blind, randomised, placebo-controlled, phase II dose-finding trial	198 patients randomised to 1:1:1 to receive 500 mg/day nor-UDCA vs 1500 mg/day nor-UDCA vs placebo in patients with NAFLD	A dose-dependent reduction in ALT between baseline and end of treatment was observed with nor-UDCA vs placebo, with a significant effect in the 1500 mg group (mean change -27.8%, 95%CI: -34.7 to -14.4; P < 0.0001). Ninety nine and 112 side effects were reported in 63 subjects and 64 subjects, respectively
Panuganti et al[9]	MASLD	Phase III double blind randomised controlled trial	110 received nor-UDCA (1500 mg/day) and 55 received placebo	At 12 weeks: ALT normalization in nor-UDCA group: 89% vs 76% in placebo group (P = 0.022). Fibrosis improvement: 57% in nor-UDCA group vs 40% in placebo (P = 0.035). Major limitations of this study include the absence of established parameters of liver fibrosis and steatosis as a trial endpoint, i.e., paired liver biopsy, and MR-PDFF. The effects on metabolic parameters were not elaborated in the study and they included a small number of patients. Impact of de-novo hyperglycemia and dyslipidemia during the study deserved a special mention and discussion in the trial
Fickert et al[10]	PSC	Randomised control trial	161 patients PSC with or without UDCA randomized for 12 weeks of nor-UDCA with 4 weeks follow-up	Nor-UDCA group showed significant reduction in ALP levels as compared to the placebo: -12.3%, -17.3%, and -26.0% in the 500, 1000, and 1500 mg/day groups (P = 0.029, P = 0.003, and P < 0.0001 respectively)

UDCA: Ursodeoxycholic acid; TGF: Transforming growth factor; MHC: Major histocompatibility complex; NAFLD: Nonalcoholic fatty liver disease; CI: Confidence interval; MASLD: Metabolic dysfunction-associated steatotic liver disease; MR-PDFF: Magnetic resonance proton density fat fraction; PSC: Primary sclerosing cholangitis; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase.