Norursodeoxycholic acid as a candidate pharmacological therapy for nonalcoholic fatty liver disease
Editorial Commentary

Norursodeoxycholic acid as a candidate pharmacological therapy for nonalcoholic fatty liver disease

Masato Yoneda, Atsushi Nakajima

Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Kanazawa-ku, Yokohama, Japan

Correspondence to: Masato Yoneda, MD, PhD. Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Japan. Email: yoneda-ycu@umin.ac.jp.

Comment on: Traussnigg S, Schattenberg JM, Demir M, et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol 2019;4:781-93.


Received: 10 March 2020; Accepted: 17 April 2020; Published: 30 December 2020.

doi: 10.21037/dmr-20-15


Nonalcoholic fatty liver disease (NAFLD) has become one of the most frequent causes of chronic liver disease in the past 2 decades. Almost 25% of the adult population presently suffers from NAFLD worldwide (1,2). Especially, patients with nonalcoholic steatohepatitis (NASH), which is a more severe type of NAFLD, can progress to liver cirrhosis over time and associated with a high risk of hepatic failure and hepatocellular carcinoma (HCC). As mentioned previously, NALFD/NASH is rapidly becoming the foremost cause of liver-related morbidity (e.g., end-stage liver disease, HCC, and liver transplantation) as well as cardiovascular disease (1,3).

Improvement of lifestyle, such as low-calorie diet and exercise (aerobic and resistance), are currently the first-line therapy for NAFLD/NASH, but can be difficult to succeed and continue good condition, emphasizing the urgent issue for pharmacotherapy. Nevertheless, no established pharmacological therapies and no Federal Drug Administration (FDA)-approved drugs or European Medicines Agency (EMA)-approved drugs are available for the treatment of NASH despite numerous clinical trials to date. Ursodeoxycholic acid (UDCA), a secondary bile acid, has historically been one of the most general-purpose therapies for chronic hepatitis, however it has no histological benefit over a placebo in NAFLD/NASH patients (4). Therefore, UDCA is not recommended as a therapeutic medication for NAFLD/NASH (5).

In recent years, several innovative medicines have been developed in the drug pipeline for the treatment of NAFLD/NASH. Among them, obeticholic acid, a selective farnesoid X receptor (FXR) agonist, have entered phase 3 trials for NASH treatment and are thought to have potential for the treatment of NASH (6).

To overcome this background and these limitations, the medical need for an effective pharmacological treatment for NAFLD/NASH must be met. In their report on this issue, Traussnigg et al. showed a dose-dependent reduction in serum ALT in patients treated with norursodeoxycholic acid (norUDCA), a synthetic side chain-shortened C23 homologue of UDCA (7), versus a placebo in a phase 2, multicenter, double-blind, clinical trial (8). Although it is also well known that the serum ALT values may not always be well-correlated with the severity of liver disease (9), they also demonstrated a decrease in the hepatic fat fraction as measured using MRI or MRS in a group of receiving 1,500 mg of norUDCA, even if the number of patients in whom MRI/MRS was performed was too small to allow a definitive conclusion. NorUDCA is known not to activate FXR, but was reported to be relatively resistant to conjugation reaction with glycine or taurine, compared with UDCA. Furthermore, norUDCA goes through cholehepatic shunting, causing ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection (10).

NAFLD with Advanced fibrosis is associated with an increased all-cause mortality and liver-related mortality (11,12), and several trials evaluating anti-fibrotic agents have been withdrawn because of insufficient efficacies over a placebo. Hopefully, the anti-fibrotic effect of norUDCA will be evaluated by liver biopsy or recent MRI-based technologies or US-based elastography.


Acknowledgments

Funding: None.


Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Digestive Medicine Research. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/dmr-20-15). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


References

  1. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84. [Crossref] [PubMed]
  2. Li J, Zou B, Yeo YH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2019;4:389-98. [Crossref] [PubMed]
  3. Farrell GC, Wong VW, Chitturi S. NAFLD in Asia--as common and important as in the West. Nat Rev Gastroenterol Hepatol 2013;10:307-18. [Crossref] [PubMed]
  4. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770-8. [Crossref] [PubMed]
  5. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328-57. [Crossref] [PubMed]
  6. Ratziu V, Sanyal AJ, Loomba R, et al. REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis. Contemp Clin Trials 2019;84:105803. [Crossref] [PubMed]
  7. Yoon YB, Hagey LR, Hofmann AF, et al. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 1986;90:837-52. [Crossref] [PubMed]
  8. Traussnigg S, Schattenberg JM, Demir M, et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol 2019;4:781-93. [Crossref] [PubMed]
  9. Kallai L, Hahn A, Roeder V, et al. Correlation between histological findings and serum transaminase values in chronic diseases of the liver. Acta Med Scand 1964;175:49-56. [Crossref] [PubMed]
  10. Steinacher D, Claudel T, Trauner M. Therapeutic mechanisms of bile acids and nor-ursodeoxycholic acid in non-alcoholic fatty liver disease. Dig Dis 2017;35:282-7. [Crossref] [PubMed]
  11. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017;65:1557-65. [Crossref] [PubMed]
  12. Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 2017;67:1265-73. [Crossref] [PubMed]
doi: 10.21037/dmr-20-15
Cite this article as: Yoneda M, Nakajima A. Norursodeoxycholic acid as a candidate pharmacological therapy for nonalcoholic fatty liver disease. Dig Med Res 2020;3:108.