Triglyceride-glucose index is associated with gastroesophageal reflux disease and erosive reflux disease: a health checkup cohort study

To the best of our knowledge, this is the first study to demonstrate an association between the GERD, ERD, and TyG index. To evaluate IR, various methods, such as the hyperinsulinemic-euglycemic clamp and the insulin tolerance test, have been used18,19. Since these methods are expensive and invasive, the homeostasis model assessment for IR (HOMA-IR) was introduced as an alternative method20. Recently, the TyG index, a simple and cost-effective marker from routine laboratory results, was identified as a useful marker for IR in recent studies13,21. Despite its simplicity, the TyG index has substantial clinical importance owing to its metabolic significance.

Although the precise mechanism underlying the relationship between the TyG index and GERD is unclear, it may be explained by the metabolic syndrome, which is a complex of various metabolic conditions such as IR, obesity, dyslipidemia, and hypertension22. Among these conditions, IR, which is the inability of insulin to transport glucose into optimal cells, is closely associated with metabolic syndrome23,24.

The relationship between GERD and IR is explained by changes in esophageal motility resulting from hyperglycemia, which increases the peristaltic wave duration and decreases peristaltic velocity in the distal esophagus, decreases lower esophageal sphincter (LES) pressure, and eventually delays gastric emptying25,26,27. Pro-inflammatory cytokines have also been suggested to explain the relationship between GERD and IR. They involved disruptions in insulin transport and insulin sensitivity via cellular pathways linked with insulin receptor substrate serine phosphorylation-1 and nuclear factor-kappa B in adipocytes, hepatocytes, and macrophages28. Previous studies have reported that hyperglycemia is associated with a prolonged LES relaxation period compared with euglycemic conditions25,27, and high IR is associated with increased severity and prevalence of GERD29.

Several recent studies reported that serum TG levels are associated with GERD mediated via several mechanisms30. Intraduodenal administration of long-chain TG after meals influences the contraction and relaxations of the lower esophageal sphincter31, and cholesterol of dietary nutrients enhances perception of the esophagus following intraesophageal acid reflux32.

In addition to the glucose and TG, metabolic factors such as obesity and hypertension were significantly associated with GERD and ERD both in this study. Inflammation is involved in the association between obesity and IR. Obesity-associated inflammation in the adipose tissue and liver induces an increase in macrophage infiltration and the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha and IL-6. These cytokines, and other inflammatory mediators are involved in the insulin signaling pathway and the induction of IR. IR, with compensatory hyperinsulinemia, is an important proposed mechanism in the pathophysiology of hypertension. IR induces increased blood pressure through various mechanisms, including stimulating sympathetic nervous system activity and renal tubular sodium reabsorption. Thus, various metabolic factors and GERD are interlinked by IR.

The strength of this study was that we analyzed patients who received laboratory tests two times during the study period. The median TyG indices for the first and second tests increased in both the GERD and control groups. This result may be associated with the aging process between the first and second tests. However, the increase was more obvious in the GERD group than in the control group. This tendency was maintained after adjusting for metabolic factors, H. pylori infection, smoking, and alcohol consumption. An upper endoscopy may be recommended if a patient has GERD-related symptoms and shows a noticeable increase in the TyG index compared with the previous test.

GERD diagnoses are based on heterogeneous clinical symptoms such as regurgitation, heartburn, and dyspepsia33. Since our checkup center questionnaire did not have questions to evaluate these symptoms, GERD was diagnosed via endoscopic findings based on the LA classification34. To overcome this limitation, we set the “ERD group (LA grades B to D reflux esophagitis),” which is a more conclusive endoscopic finding for GERD35, and performed additional analysis. In addition to the TyG index, metabolic components such as obesity and hypertension were significantly associated with GERD. The TyG index and these metabolic factors were also independent predictive factors for ERD. Notably, regarding the other metabolic components and TyG index, the OR was more potent in the patients with ERD, which has a more definitive mucosal injury and is more specific than GERD. This can be also explained with the other study on GERD patients in Moscow, which found that proinflammatory cytokines levels such as IL-8 and Transforming growth factor-α (TNF-α) in serum patients with ERD were higher than those without esophagitis or normal subjects36.

We are also aware of several unresolved issues that should be addressed. First, because of the retrospective nature of this study, we might have collected some incomplete data. Although we handled it using a complete case analysis that excluded all patients with missing data (n = 41), it could have led to biased estimates and reduced statistical power. Second, due to the study’s cross-sectional design, there was a selection bias regarding individuals’ socioeconomic status, dietary habits, and physical activity. Furthermore, as we could not assess these data, confounding variables still needed to be considered to determine the relationship between GERD and TyG index. Third, since the enrolled patients of this study were Korean from a single center, it is hard to generalize our findings. Prospective, well-designed, longitudinal studies are required to elucidate the precise correlations between GERD, ERD, and the TyG index. Forth, GERD and ERD were diagnosed based on endoscopic findings via a retrospective review of endoscopic images in our electronic medical records. To overcome this limitation, we performed an additional analysis in the ERD group, which is a more specific mucosal injury for GERD. Finally, since the laboratory tests performed at our health checkup center did not include a test for the insulin level, the HOMA-IR was not considered. Further studies are needed to measure insulin levels and to compare the TyG index with the HOMA-IR.

In conclusion, the TyG index may be a novel predictive biomarker for GERD. Notably, the amount of the increase in the TyG index between the first and second tests was prominent for GERD. Therefore, the TyG index from routine laboratory tests could help diagnose GERD in clinical practice. Moreover, treatment of high TG or glucose levels, which are determinants of the TyG index, may be important for preventing and treating GERD.

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