What is the role of Norursodeoxycholic acid (NorUDCA) in the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)?

Norursodeoxycholic Acid in NAFLD

Norursodeoxycholic acid (NorUDCA) is NOT recommended for the treatment of NAFLD or NASH based on current clinical practice guidelines, despite emerging research showing potential benefits. The confusion arises because NorUDCA is a distinct compound from standard ursodeoxycholic acid (UDCA), which has been definitively proven ineffective.

Guideline Position on Standard UDCA

Standard ursodeoxycholic acid (UDCA) is explicitly not recommended for NAFLD or NASH treatment. Multiple major guidelines consistently state this:

• The American Association for the Study of Liver Diseases states that UDCA is not recommended for the treatment of NAFLD or NASH, based on a large multicenter RCT that convincingly showed UDCA offers no histological benefit over placebo 1
• The European Association for the Study of the Liver confirms that UDCA showed only some biochemical but no histological improvements in trials lasting up to 2 years 1
• All major gastroenterology societies (AGA, AASLD, ACG) provide strong recommendations against UDCA use (Strength 1, Quality B) 1

The NorUDCA Distinction

NorUDCA is a side-chain shortened homologue of UDCA with fundamentally different biochemical properties that may explain its divergent effects:

• NorUDCA is relatively resistant to conjugation with glycine or taurine compared to standard UDCA, undergoes cholehepatic shunting, and demonstrates hepatoprotective, anti-inflammatory, and antifibrotic activity in preclinical models 2
• A phase 2 randomized controlled trial (2019) demonstrated that NorUDCA 1500 mg daily for 12 weeks produced a significant dose-dependent reduction in serum ALT (-27.8%, p<0.0001) compared to placebo in 198 NAFLD patients 3
• NorUDCA was safe and well-tolerated with adverse event profiles similar to placebo, with the most common being headache, gastrointestinal disorders, and infections 3

Current Clinical Recommendation

Do not prescribe NorUDCA for NAFLD outside of clinical trials. While research data are promising, no regulatory agency has approved NorUDCA for NAFLD treatment, and it is not mentioned in any current clinical practice guidelines 4. The 2019 phase 2 trial used only surrogate endpoints (ALT reduction) rather than histological outcomes, which are the gold standard for NAFLD treatment efficacy 3.

Established First-Line Treatments Instead

Prioritize lifestyle modification as the cornerstone of NAFLD management:

• Achieve 7-10% weight loss through gradual reduction (500-1000g per week maximum) to improve steatohepatitis and achieve fibrosis regression 4, 5, 6
• Implement a Mediterranean diet pattern with vegetables, fruits, whole grains, legumes, olive oil, and moderate fish consumption 4, 5, 6
• Prescribe 150-300 minutes of moderate-intensity or 75-150 minutes of vigorous-intensity aerobic exercise weekly 5, 6

For biopsy-proven NASH with fibrosis, consider pharmacotherapy:

• Vitamin E (800 IU daily) in non-diabetic, non-cirrhotic patients with biopsy-confirmed NASH improves liver histology and should be considered first-line pharmacotherapy 1
• Pioglitazone (30 mg daily) in patients with biopsy-confirmed NASH without cirrhosis, with or without diabetes 4

Critical Pitfall to Avoid

Never confuse standard UDCA with NorUDCA. Standard UDCA has been definitively proven ineffective through large multicenter trials and carries a strong recommendation against its use 1. NorUDCA is an investigational agent with different pharmacological properties that requires further phase 3 trials with histological endpoints before clinical use can be recommended 3, 2.