Drinking artificially sweetened beverages was not associated with an increased risk for liver cancer, but consumption of sugar-sweetened beverages (SSBs) was linked to two types of liver cancer, a new study found.

The authors adjusted for confounders like demographics and lifestyle factors, and they determined that drinking one additional artificially sweetened beverage per day was not tied to any liver cancer. In contrast, each additional SSB consumed per day was associated with a 10% increased risk for hepatocellular carcinoma (HCC) and a 15% increased risk for intrahepatic cholangiocarcinoma.

“We need a high-quality long-term study to study the effect of artificial sweeteners on cancer risk,” but that doesn’t mean they are safe, said Xuehong Zhang, MBBS, ScD, co-author of the combined analysis of 11 prospective cohort studies, and a professor and an associate dean of research at Yale School of Nursing in West Haven, Connecticut.

The results contribute to the growing research investigating sweetened beverages and liver cancer risk.

The most common risk factors for liver cancer include hepatitis B and C infections, excessive alcohol consumption, smoking, food contaminated with aflatoxin, and metabolic disorders, particularly diabetes, obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD).

A strong body of evidence has linked SSBs to all three of those metabolic disorders. For example, a 2023 systematic review and meta-analysis of 85 articles confirmed the risk for obesity from SSBs, and a 2010 meta-analysis similarly linked SSBs to type 2 diabetes. A 2022 Framingham Heart Study paper showed an association between SSBs and MASLD, and a 2012 interventional study demonstrated potential mechanisms for SSBs impact on the liver.

But the evidence on artificially sweetened beverages and metabolic conditions is less clear. Previous studies have found links between the sweeteners and type 2 diabetes, but others show no association or mixed findings. A 2015 systematic review that found evidence linking both SSBs and sweeteners to type 2 diabetes also noted high levels of bias and potential confounding only for the artificial sweeteners studies. Evidence for a link between artificial sweeteners and obesity is similarly mixed.

Given the risk for liver cancer from metabolic disorders, questions about potential links between artificial sweeteners and those conditions has contributed to investigation into sweeteners’ risk for liver cancer.

In the new study, the researchers assessed findings from one European and 10 US prospective cohort studies that included a total of 1,518,411 participants, with 2811 incident liver cases having occurred, including 1699 HCC cases, over a median of 17.8 years of follow-up. The researchers calculated the association between risk for liver cancers and both SSBs and artificial sweeteners.

What have studies examining artificial sweeteners and liver cancer risk found?

The International Agency for Research on Cancer classified the sweetener aspartame as “possibly carcinogenic to humans” in 2023 based on “limited evidence” linking it to HCC in humans as well as “limited evidence” in experimental animals and mechanistic studies.

“The evidence was not strong enough to draw a convincing conclusion, so that’s why the topic is still being debated in the scientific community,” Longgang Zhao, PhD, a co-author of the new study and who is also a postdoctoral researcher at Yale School of Nursing, told Medscape Medical News.

Essentially, studies have not been able to rule aspartame out as a risk yet, Namrata Vijayvergia, MD, an associate professor of hematology/oncology and section chief of gastrointestinal medical oncology at Temple Health’s Fox Chase Cancer Center in Philadelphia, told Medscape Medical News.

“At this point in time, what we have is the possibility of it because it’s not something that has been studied in detail and we don’t have a lot of data,” Vijayvergia said. Further research could end up clearing aspartame of any risk, as happened with saccharin and bladder cancer when that sweetener was investigated after studies showed it caused bladder cancer in rodents.

A 2022 study found a link between artificial sweeteners and liver cancer only in individuals with diabetes, suggesting that preexisting conditions may influence the level of risk, but not enough research has been done to confirm or refute that possibility.

What does the evidence show about SSBs and liver cancer risk?

Prior to this study, evidence had been building that supported a link between SSBs and liver cancer, such as a 2022 study showing an 18% increased risk for liver cancer specifically with sugar-sweetened soda consumption, though not sugar-sweetened beverages overall (such as fruit juices). One of Zhao’s previous studies similarly showed a higher risk for liver cancer from SSBs.

Overall, the relationship between sugar-sweetened beverages and liver cancer has been pretty consistent, said Zhang, and the new analysis confirms that. What’s less clear are the reasons driving that association.

The authors tried to adjust for BMI and diabetes, but they acknowledged potential for residual confounding and could not control for all metabolic conditions.

It’s likely that “the sugar consumption leads to obesity and inflammation in the body” that then may play a role in liver cancer, Vijayvergia said. Though there could be other mechanisms involved, said Zhao.

“A higher fructose intake can hurt the liver cell and its function,” potentially contributing to liver fat accumulation and liver damage, he said. “The high sugar may also affect the microbiome, which may produce harmful agents that transfer to the liver.” He also noted links between sugar and increased inflammation biomarkers, among other potential mechanisms.

How should clinicians counsel their patients about sweetened beverages?

Despite a good understanding of the most significant risk factors of liver cancer, an estimated 35% of HCC cases are not explained by known risk factors, the authors of the study noted in their paper. Given the popularity and overall high consumption of sweetened beverages in the US and globally, they may be a potentially modifiable risk factor for liver cancer, Vijayvergia said.

“That small step of stopping the sugar-sweetened beverages can ultimately improve their overall health, decrease risk of diabetes and obesity, and then ultimately hopefully decrease risk of cancer too,” though the risk reduction would be modest based on this evidence, she said. As for artificially sweetened beverages, Vijayvergia would not recommend, for example, a child start drinking aspartame-sweetened beverages, but if switching from SSBs to artificially sweetened beverages “can help people become healthier by improving their metabolic profile, I think it’s a reasonable thing to do,” she said.

Zhang agreed that the benefit of limiting sugary drinks is clear but added that it’s also important to focus on the larger established risk factors for liver cancer.

“We know that 60% liver cancer can be prevented from remaining a healthy weight, being physically active, not smoking, consuming low-to-moderate alcohol, and maintaining healthy lifestyle.”

Support for the research came from the Canadian Institutes of Health, the National Institutes of Health, and a Boston University Peter Paul Career Development Professorship.

One author of the new research reported receiving personal fees from Merck, and another reported holding equity options from Convergent Therapeutics, both unrelated to this study. Zhao and Zhang reported having no disclosures. Vijayvergia reported receiving honoraria from Guidepoint Global; advisory fees from Exelixis, Pfizer, and RayzeBio; and institutional grants from Bristol Myers Squibb/Medarex, ITM, Oryzon Genomics, Puma Biotechnology, and Zymeworks.

Tara Haelle is a science/health journalist based in Dallas.