Novel therapies targeting bile acid-triggered pathways may benefit children with NASH
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Key takeaways:
- Youths with obesity and NASH may need medications in addition to lifestyle intervention.
- Novel medications targeting bile acid signaling pathways could be developed for NASH.
Medications that target bile acid-triggered pathways and combination therapies could be the key for treating nonalcoholic steatohepatitis for young people with obesity and type 2 diabetes, according to a speaker.
During a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease, Rohit Kohli, MBBS, MS, division chief of gastroenterology, hepatology and nutrition at Children’s Hospital Los Angeles, discussed how weight loss following bariatric surgery is associated with increased circulating bile acid levels. He said medications focused on bile acid pathways could provide novel therapies for treating NASH.
“Bariatric procedures clearly increase serum bile acid levels and improve NASH,” Kohli said during the presentation. “Bile acid-triggered pathways are important in the hepatic benefits of anti-obesity surgeries. Murine data says that it’s probably not just the bile acids, it’s probably the bile acid signaling that is more important and, therefore, opens up opportunities for us to study those pathways and produce pharmacotherapies.”
Lifestyle intervention should serve as the foundation for treating NASH and obesity among children, Kohli said. In a study analyzing children who attended a NASH-focused clinic and received lifestyle modification advice, participants had decreases in BMI z score, alanine transaminase and aspartate transaminase at 1 year. However, only 47% of children who attended the clinic at baseline returned for the 1-year follow-up. Kohli said the struggles with retention reveal why other therapies, such as medications or bariatric surgery, may be needed.
In 2013, Kohli and colleagues published a study that took a look at the mechanisms behind bariatric surgery. The study found that people who underwent Roux-en-Y gastric bypass had increases in circulating serum bile acids post-surgery. Kohli said a separate study published in 2013 also found a similar post-surgery increase in serum bile acids among adults who underwent sleeve gastrectomy.
“In gastric banding, there was a decrease in circulating bile acids,” Kohli said. “We now know with hindsight that gastric banding, nobody does it anymore because it never works really well. So the two procedures that worked had a common signal: bile acids.”
Kohli said the farnesoid X receptor, or FXR, in the liver may be a target for future medications to treat NASH. In 2014, a study published in The Lancet examined the effect of obeticholic acid, a farnesoid X nuclear receptor ligand, among a group of adults with NASH. The study found obeticholic acid improves histologic features of NASH, but there were also safety concerns in the form of decreased HDL cholesterol and increased LDL cholesterol among the participants.
Researchers are continuing to investigate many types of therapeutic targets with NASH, some of which involve bile acid synthesis, such as FXR agonists or fibroblast growth factor (FGF) 15/19 analogues, while other pathways may involve targeting insulin sensitivity. However, Kohli noted, treatments targeting a single pathway may not be the solution.
“My prediction, if we’re looking into the future, is that combination therapies might be more important than individual therapies in the long run, especially when we’re looking at specific disorders of liver disease,” Kohli said.
References:
- DeVore S, et al. J Pediatr Gastroenterol Nutr. 2013;doi:10.1097/MPG.0b013e318290d138.
- Kohli R, et al. J Clin Endocrinol Metab. 2013;doi:10.1210/jc.2012-3736.
- Neuschwander-Tetri BA, et al. Lancet. 2014;doi:10.1016/S0140-6736(14)61933-4.
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Kohli R. Novel treatments on the horizon for youth with obesity, fatty liver and type 2 diabetes. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 7-9, 2023; Los Angeles.
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