Erythritol and metabolic dysfunction‐associated steatotic liver disease: A sweet friend, bitter foe, or reliable fellow traveler?

In a recent article published in Diabetes, Buziau et al. ¹ investigated the role of pentose phosphate pathway (PPP) activity, using urinary erythritol as a proxy, in liver fat accumulation. The study included 1,494 individuals from the Maastricht Study, a large population‐based cohort study, and found that 24‐h urinary erythritol levels were significantly associated with intrahepatic lipid (IHL) content on 3T Dixon magnetic resonance imaging (MRI), after adjusting for age, sex, smoking status, body mass index (BMI), type 2 diabetes and intake of erythritol‐containing food items. To overcome the limitations of observational studies on causal inference, Buziau et al. ¹ also conducted Mendelian randomization (MR) analysis and revealed that genetically determined 24‐h urinary erythritol level was not associated with liver fat, suggesting that erythritol per se was not causal in the pathogenesis of IHL accumulation but rather a biomarker of heightened PPP activity which may be a cause or consequence of de novo lipogenesis in the liver.

Metabolic dysfunction‐associated steatotic liver disease (MASLD), defined as liver fat accumulation of 5% or more, together with the presence of at least one cardio‐metabolic risk factor (overweight/obesity, prediabetes, type 2 diabetes, hypertension, and dyslipidaemia), is a pressing global health problem currently affecting around one third of the world adult population and more than two thirds of patients with type 2 diabetes. While Buziau et al. ¹ concluded a biomarker role of 24‐h urinary erythritol in reflecting liver fat accumulation from a cross‐sectional study and MR analysis ¹ , previous preclinical studies had shown that treatment with erythritol could ameliorate liver steatosis, oxidative damage and endoplasmic reticulum stress through activation of nuclear factor E2‐related factor 2 (NrF2) with anti‐oxidant effects ² . Consistently, in another preclinical study, it was demonstrated that 12 weeks of erythritol supplementation in drinking water improved liver histology in high fat diet (HFD)‐fed mice, with reduced liver fat, non‐alcoholic fatty liver disease (NAFLD) activity score (NAS) and liver fibrosis compared to vehicle treatment, suggesting potential beneficial effects of erythritol not only in alleviating liver steatosis, but also progression to steatohepatitis and liver fibrosis ³ . The interplay between erythritol and liver steatohepatitis is summarized in Figure 1. Notably, the median IHL content in the Maastricht cohort was only 2.4% (interquartile range 1.4–4.8%), which was far lower than the 5% threshold used to define liver steatosis in MASLD. Therefore, further large‐scale prospective studies should be conducted to validate urinary erythritol level as a more sensitive biomarker for early MASLD screening and diagnosis. In addition, interventional studies to evaluate the direct effects of exogenous erythritol on MASLD development and progression are also eagerly required.

Figure 1.

The interplay between erythritol and liver steatosis.

Indeed, despite the benefits of erythritol as a well‐tolerated, non‐caloric artificial sweetener, its potential role in the development of cardio‐metabolic diseases has gained considerable attention recently following earlier reports of elevated cardio‐metabolic risks in epidemiological studies. In particular, Witkowski et al. ⁴ demonstrated that circulating erythritol levels were associated with incident major adverse cardiovascular events, independent of conventional cardiovascular risk factors, and their mechanistic studies showed the ability of erythritol to enhance platelet aggregation and clot formation ⁴ . However, similar to the relationship between erythritol and liver fat reported by Buziau et al. ¹ , a subsequent MR study also could not demonstrate any evidence to support a causal link between circulating erythritol levels and several cardio‐metabolic conditions including glycaemia, type 2 diabetes, coronary artery disease, kidney function, and chronic kidney disease (CKD) ⁵ .

Erythritol is a 4‐carbon sugar alcohol widely used as an artificial sweetener. Since the majority of dietary erythritol is unmetabolized and excreted unchanged in the urine, its circulating and urinary levels reflect erythritol originated from both endogenous and exogenous sources via PPP and diet, respectively. It is therefore crucial to determine their relative contributions to the circulating and urinary levels in order to accurately assess the potential health risks associated with erythritol consumption. Accordingly, Buziau et al. ¹ attempted to make this distinction in their study by several methods, such as adjusting for intake of erythritol‐containing food items, performing sensitivity analyses to assess the effect of erythritol‐containing beverages on 24‐h urinary erythritol levels, as well as an MR analysis. However, a few limitations remain to be addressed. Despite the widespread culinary application of erythritol in the real world, only four erythritol‐containing food items (cheese, mushroom, grapes and pears) were considered for adjustments in their study, and data on the dietary intake of erythritol from other food sources including tabletop sweeteners were not available. Furthermore, although the MR findings refuted a linear relationship between 24‐h urinary levels and liver fat content, it remains possible that the risk of liver fat accumulation increases only when 24‐h urinary levels rise above a certain threshold, especially with high consumption of erythritol‐containing food products and sweeteners.

Prized by the food industry as a non‐caloric substitute for table sugar which does not elicit short‐term glycaemic and insulinaemic responses, erythritol has been considered ‘generally recognized as safe (GRAS)’ by regulatory authorities, including the US Food and Drug Administration (FDA) and the European Union (EU). As MASLD is an important risk factor of type 2 diabetes and cardiovascular diseases (CVD), and users of artificial sweeteners including erythritol are often individuals harboring or at risk of these cardio‐metabolic conditions, the findings from Buziau et al. ¹ that erythritol was not directly causal to liver fat accumulation in this population‐based cohort was at least reassuring ¹ . However, since most study cohorts of erythritol consisted exclusively of participants from the Western population, and the fact that this artificial sweetener has been gaining popularity in parallel with the global diabesity epidemic, future studies should involve a more diverse, multi‐ethnic population with different genetic backgrounds, dietary patterns and metabolic risks to further decipher the interplay between erythritol and liver fat metabolism. Moreover, given the potential differences in health risks of the various compounds under the large umbrella of artificial sweeteners, policymakers and stakeholders should consider specification of individual artificial sweetener in food labelling not only to better inform the public, but also to facilitate further research into the long‐term cardio‐metabolic, or even oncological safety of individual artificial sweetener.

DISCLOSURE

C.H.L. is a member of the editorial board of Journal of Diabetes Investigations. He received advisory board and lecture honorarium from AstraZeneca, AusMed, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, Novo Nordisk, and Sanofi Aventis. The remaining authors have no conflicts of interest.

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.