Link between triglyceride to good cholesterol ratio and fatty liver disease and liver scarring in American adults

Nonalcoholic fatty liver disease (NAFLD), as a globally prevalent metabolic-related disease of the liver, affects approximately 38% of the world’s population, and as such, it significantly threatens public health (1). Most patients with NAFLD do not experience discomfort, whereas a small percentage may present with fatigue, epigastric discomfort, or vague pain (2). While its typical characteristic include excessive lipid accumulation in the liver without alcohol abuse, some NAFLD patients can further progress to nonalcoholic steatohepatitis, liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. The number of individuals at risk for this serious consequence is steadily increasing (3, 4). Although NAFLD involves complex risk factors, its prevalence is usually associated with obesity (5–7). NAFLD is associated with poor hepatic prognosis and an increased risk of extrahepatic metabolic abnormalities, including hyperlipidemia, hyperglycemia, insulin resistance (IR), and hyperuricemia (8, 9). Furthermore, cardiovascular events and extrahepatic tumorigenesis, the leading causes of extrahepatic death, are also more likely with this condition (8, 10). Despite ongoing efforts to determine drugs to treat NAFLD and liver fibrosis, there are no specific licensed drugs that can completely reverse NAFLD or liver fibrosis. The main goals of current treatment are to ameliorate metabolic sequelae and to control the risk of cardiovascular events to reduce associated mortality (11, 12). Therefore, it is of utmost importance to investigate novel treatment agents, targets, and interventional approaches for NAFLD and liver fibrosis.

The severity of hepatic steatosis and liver fibrosis is currently assessed by liver biopsy, but despite being an established standard, this practice is invasive and expensive, with limited acceptability, and hence, it is not only impractical for widespread screening of the general population but also requires caution in clinical practice (13). Therefore, there is an urgent need to identify new noninvasive tests to diagnose NAFLD. Serum markers and their combinations have several advantages. They are easy to access, low-cost, and offer high diagnostic accuracy, making them valuable for disease screening. A combination of lipids and lipoproteins proves to be more beneficial for predicting risks of NAFLD compared with individual lipid values as it captures interactions between lipid components (14, 15). Patients with NAFLD usually have lipid metabolism disorders and dyslipidemia, and serum markers may show reduced levels of high-density lipoprotein cholesterol (HDL-C) along with increased levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) (16). TG level is crucial for NAFLD development and progression. When TG level is elevated in the blood, there is an increase in the amount of TG celiac “debris” and free fatty acids transported to the liver through the bloodstream, which exceeds the liver’s ability to utilize these fatty acids, resulting in fatty infiltration of hepatocytes (17). In hepatocytes from patients with NAFLD, intracellular TG levels exceed 5% (18). As free fatty acids are oxidized in the mitochondria, hepatocytes experience oxidative stress. The excess reactive oxygen species generated in these reactions harm the hepatocytes, impairing their ability to metabolize free fatty acids and aggravating oxidative stress and lipid peroxidation, ultimately hastening the pathological process of NAFLD (19). The development of NAFLD impairs the ability of hepatocytes to oxidize, transport, and resynthesize lipids in the blood, exacerbating the increase in TG levels (20). HDL-C is essential for preventing atherosclerosis through the reverse cholesterol transport system that carries dietary cholesterol from peripheral tissues to the liver, where it is transformed into bile salts and expelled in the feces (21). HDL-C even possesses antioxidant and anti-inflammatory properties based on which it is called “good cholesterol.” Additionally, HDL-C levels showed a negatively correlated with NAFLD diagnosis (22).

The TG/HDL-C ratio exhibits a strong association with IR (23, 24). Indeed, in a study involving a multiethnic primary prevention cohort, a stronger relationship was noted between TG/HDL-C and a homeostasis model assessment of IR in comparison with other lipid parameters (25). Moreover, it can predict cardiovascular diseases, hypertension, and type 2 diabetes (26–28). Limited evidence has recently suggested that this ratio could also be linked to NAFLD, with an observational study noting an increased likelihood of developing NAFLD in children and adolescents having higher TG/HDL-C ratios (29). Similarly, in Japan, a population-based cohort study demonstrated that TG/HDL-C ratios could predict NAFLD incidence (30). Nonetheless, the relationship between the rate and NAFLD and liver fibrosis in American adults remains unclear.

To the best of the current authors’ knowledge, no epidemiological studies have explored the above association in American adults. Therefore, based on information of 6495 participants from the National Health and Nutrition Examination Survey (NHANES) 2017–2020.03, a cross-sectional study was performed for investigating how TG/HDL-C ratio was linked to NAFLD and liver fibrosis. It is expected that this study will provide new understanding of NAFLD that will guide treatment and management of the condition.

NAFLD is recently prevalent worldwide, and timely and effective assessment of NAFLD risk is critical for patients, with efforts to stop disease progression to advanced fibrosis or hepatocellular carcinoma (37). Currently, liver biopsy remains the established standard to assess the extent of liver steatosis and fibrosis is; however, being a harmful and invasive procedure, liver puncture should therefore be cautiously applied in clinical practice (38). LUTE is widely used for evaluating the extent of liver fibrosis and steatosis; its main advantage is that it is noninvasive, and the results are comparable to those of a liver biopsy (39, 40). Despite limited evidence on the relationship between TG/HDL-C ratio and NAFLD (29, 30, 41), it remains unclear how this ratio is linked to NAFLD and liver fibrosis in American adults. The current study examined this association in American adults, with the results demonstrating a positive correlation between TG/HDL-C ratios and NAFLD in all models. Grouping the ratios into quartiles revealed a consistent correlation that strengthened with increasing TG/HDL-C. However, although the TG/HDL-C ratios were positively correlated with liver fibrosis in all models, this positive correlation was not statistically significant in Model 3. Our findings could assist healthcare professionals in identifying high-risk patients for NAFLD and liver fibrosis, thereby enabling more informed decisions regarding patient management.

Recently, increasing evidence has suggested that TG/HDL-C ratios were linked to more unfavorable metabolic diseases, such as atherosclerosis, obesity, diabetes, and dyslipidemia (41). Our results were consistent with previous results and also showed that for participants with higher TG/HDL-C ratios, LDL-C, AST, ALT, TC, GGT, Alb, TG, CRP, blood pressure, BMI, and ferritin levels were significantly higher compared with those who presented lower TG/HDL-C ratios.

However, the mechanism underlying the link between TG/HDL-C ratio and NAFLD and liver fibrosis have not been fully elucidated. IR is an important feature of NAFLD and may, therefore, be a potential mediator. IR and lipid disorders are the starting links and the core of NAFLD. When the effector organs of insulin action (e.g., liver, skeletal muscle, adipose tissue) become less sensitive to insulin, there is a compensatory increase in insulin, eventually leading to hyperinsulinemia. Compensatory elevation of insulin can promote hepatic synthesis of TC, which also elevates LDL-C levels and leads to inactivation of lipoprotein lipase, which reduces clearance of TG. Consequently, large amounts of TG accumulate in the liver (42). Additionally, when the concentration of TG is elevated in the bloodstream, the “debris” and free fatty acids of TG celiacs transported to the liver through the bloodstream will increase, which exceeds the liver’s ability to utilize these fatty acids, ultimately triggering the development of NAFLD (43–46). Moreover, IR leads to decreased fat metabolism and increased catabolism, and the liver takes up large amounts of free fatty acids. However, the β-oxidation of fatty acids is inhibited by hyperinsulinemia, and a large amount of free fatty acids accumulates in the liver, exacerbating hepatocellular steatosis (47). As NAFLD progresses, oxidative stress and excessive lipid deposition aggravate the impairment of hepatocyte mitochondrial function, which further attenuates the metabolism of lipid pairs, thereby leading to further increases in the levels of TG, TC, and other markers (47). IR induces the secretion of larger and TG-overconcentrated very low-density lipoprotein particles while decreasing HDL-C concentration (48, 49). Therefore, IR contributes to an increase in TG/HDL-C ratio.

Recently, a strong association between IR and leptin secretion has been reported (50). Leptin is a protein-like hormone secreted by adipose tissue, and the degree of hepatic steatosis is positively correlated to its expression level (50). Persistent hyperleptinemia has therefore been linked to steatosis, liver fibrosis, and hepatocellular cancer in several observational clinical investigations, indicating that hyperleptinemia is a reliable indicator of the onset or development of NAFLD (51–53). It is currently believed that leptin promotes the development of NAFLD by centrally suppressing dietary intake and increasing sympathetic nerve activity, metabolic rates, and gluconeogenesis (54, 55).

This study has significant clinical value, as it reliably assesses hepatic steatosis and fibrosis in American adults with an adequate and representative sample size. However, certain limitations were also noted. Firstly, being a cross-sectional study, the causal association between TG/HDL-C ratio and NAFLD and liver fibrosis could not be elucidated. A longitudinal study in the future is necessary to better investigate the potential causal relationships. Secondly, the findings may not be applicable to individuals aged < 18 years since all included participants were over 18 years old. Therefore, further studies are required for investigating the association between TG/HDL-C ratios and NAFLD and liver fibrosis in this population. Thirdly, despite the fact that 6,495 participants have been included in this research, there is still a risk of insufficient sample size for a specific group, and therefore it is necessary for future studies to include more participants to demonstrate our results. Fourthly, the inherent limitations of the NHANES database resulted in several confounders that may have had an effect on the results that were not adjusted for. Finally, there are several potential influences on the occurrence and development of NAFLD and liver fibrosis. Despite including as many covariates as possible in this study and making adjustments to the models, the possibility that unaccounted confounders could have led to biased results cannot be excluded. Therefore, additional prospective studies would be required to validate the findings of this investigation and address the above limitations.

In the American adult population, the TG/HDL-C ratio was nonlinearly and positively associated with the prevalence of NAFLD; however, this relationship was not present in liver fibrosis.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

National Center for Health Statistics Ethics Review Committee gave approval for the NHANES survey protocol, with written informed consent also obtained from all participants. Since the NHANES database is publicly available, this study was exempted from ethical review. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

JW: Writing – review & editing, Writing – original draft, Validation, Funding acquisition, Formal analysis, Data curation. HLi: Writing – original draft, Investigation, Data curation, Conceptualization. XW: Writing – original draft, Visualization, Validation, Software, Resources, Project administration, Conceptualization. RS: Writing – original draft, Supervision, Software, Methodology, Investigation, Data curation. JH: Writing – original draft, Validation, Software, Project administration, Investigation, Formal analysis, Conceptualization. XZ: Writing – review & editing, Visualization, Validation, Supervision, Resources, Methodology, Data curation. HAL: Writing – review & editing, Validation, Project administration, Methodology, Formal analysis, Data curation. PY: Writing – review & editing, Software, Methodology, Investigation, Data curation, Conceptualization. HWL: Writing – original draft, Project administration, Methodology, Data curation. YC: Writing – original draft, Software, Investigation, Conceptualization. XC: Writing – original draft, Data curation. SC: Writing – original draft, Supervision, Investigation, Funding acquisition, Formal analysis. DW: Writing – review & editing, Writing – original draft, Conceptualization.

We are grateful to the NHANES participants and staff. We appreciate all the reviewers who participated in the review, as well as MJEditor (www.mjeditor.com↗) for providing English editing services during the preparation of this manuscript.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital) (Grant No.2023HYX032), Incubation Project of Mianyang Central Hospital (2022FH010, 2023FH002, 2023FH005) and Talent Introduction Project of Mianyang Central Hospital (2023RCYJ-001).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.