Nor-ursodeoxycholic acid in hepatobiliary diseases: A narrative review

Table 1 Comparative efficacy of nor-ursodeoxycholic acid and ursodeoxycholic acid in patients with different hepatobiliary diseases

Properties	UDCA	Nor-UDCA
Chemical name[1]	3-α,7 β-dihydroxy-5 β-cholan-24-oic acid	3-α,7 β-dihydroxy-24-nor-5 β-cholan-23-oic acid
Molecular formula[1]	C24H40O4	C23H3804 (one methylene group less)
Synthesis[1,13]	Secondary bile acid formed by intestinal bacteria from primary bile acids and available synthetically	Synthetic sidechain shortened derivative of UDCA
Hydrophilicity[1,13,14]	Less	More hydrophilic than UDCA
Cytotoxicity[1,16]	Low cytotoxicity in healthy states; but may be toxic in obstructive cholestasis (e.g., bile duct ligated models)	Less cytotoxic; ameliorates injury even in obstructive conditions where UDCA is toxic
Dosage[2,9,44]	Typically, 13-15 mg/kg/day (e.g., for PBC or PSC)	1500 mg/day (approximately equimolar to high dose UDCA)
FXR agonism[1,14]	Negligible effects on FXR activation	No effects on FXR. Most Effects are independent of FXR or TGR5 receptors
Effects on TGF-β[19]	Reduces TGF levels (moderate anti-fibrotic effect)	Significantly reduces TGF-β expression more effectively than UDCA in fibrosis models
Chole-hepatic shunt[1,20]	No. It is conjugated with taurine/glycine and remains in the bile until it reaches the intestine	Yes. Resists conjugation, allowing it to be reabsorbed by bile ducts and return to the liver creating a shunt
Bicarbonate secretion[1,15,20]	Moderate increase in bicarbonate secretion	Significant increase (hypercholeresis); the “bicarbonate umbrella” hypothesis suggests efficient choleresis protects hepatocytes and cholangiocytes
Anti-inflammatory and antifibrotic activity on hepatocyte[18,19]	Moderate; established in PBC but less effective in other fibrosis models	Superior and more potent. Significantly reduces hydroxyproline and collagen in models like Mdr2-/- and TAA-induced fibrosis
Effects on bile duct ligated mice[16]	Detrimental as it increases biliary pressure and may lead to bile infarcts or necrosis	Protective. It reduces liver injury and markers of cholestasis compared to UDCA
Current indications[1]	FDA approved: PBC, gallstone dissolution and intrahepatic cholestasis of pregnancy	Investigational: MASLD and PSC. Approved in India for MASLD by Central Drugs Standard Control Organisation
Adverse events[2,9]	Generally well tolerated; diarrhea, weight gain, hair thinning	Similar safety profile in trials; mild gastrointestinal symptoms reported
Pregnancy safety[43,44]	Safe (category B); widely used for ICP	Unknown
Contraindications[1,44]	Complete biliary obstruction, acute cholecystitis, calcified gallstones	Hypersensitivity (theoretical: Complete obstruction, though animal models suggest it is safer than UDCA)

UDCA: Ursodeoxycholic acid; PSC: Primary sclerosing cholangitis; PBC: Primary biliary cholangitis; FXR: Farnesoid X receptor; TGR: Takeda-G-protein coupled receptor; TGF: Transforming growth factor; TAA: Thioacetamide; FDA: Food and Drug Administration; MASLD: Metabolic dysfunction-associated steatotic liver disease; ICP: Intrahepatic cholestasis of pregnancy.

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.