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.