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The triglyceride glucose-body mass index: a non-invasive index that identifies non-alcoholic fatty liver disease in the general Japanese population

Background By identifying individuals at high risk for non-alcoholic fatty liver disease (NAFLD), interventional programs could be targeted more effectively. Some studies have demonstrated that triglyceride glucose-body mass index (TyG-BMI) showed an independent positive association with NAFLD. However, research on its diagnostic value in patients with suspected NAFLD is limited. In this study, we aimed to evaluate whether TyG-BMI was accurate in detecting NAFLD in the general Japanese population. Methods A cross-sectional study of 14,280 individuals who underwent a comprehensive health examination was conducted. Standard protocols were followed to collect anthropometric measurements, lab data, and ultrasonography features. All participants were randomly stratified into the development group (n = 7118) and validation group (n = 7162). The TyG-BMI was calculated. Following this, the diagnostic value of the TyG-BMI was evaluated based on the area under the receiver-operating characteristic curve (AUROC). Two cutoff points were selected and used to rule out or rule in the NALFD, and the specificity, sensitivity, negative predictive value, and positive predictive value were explored, respectively. In order to verify the stability of the results, external verification was performed. Results There were 1272 and 1243 NAFLD participants in the development and validation groups, respectively. The area under the ROC curve (AUC) of TyG-BMI was 0.888 (95% CI 0.876–0.896) and 0.884 (95% CI 0.875–0.894) for the training and validation group, respectively. Using the low TyG-BMI (182.2) cutoff, NAFLD could be excluded with high accuracy (negative predictive value: 96.9% in estimation and 96.9% in validation). The presence of NAFLD could effectively be determined by applying the high cutoff of TyG-BMI (224.0), as the positive predictive value of the estimation and validation groups is 70.7% and 70.1%, respectively. As a result of applying this model, 9996 (70%) of the 14,280 participants would not have undergone ultrasonography, with an accurate prediction of 9308 (93.1%). AUC was 0.874 for external validation using 183,730 Chinese non-obese participants. TyG-BMI was demonstrated to be an excellent diagnostic tool by both internal and external validation. Conclusions In conclusion, the present study developed and validated a simple, non-invasive, and cost-effective tool to accurately separate participants with and without NAFLD in the Japanese population, rendering ultrasonography for identifying NAFLD unnecessary in a substantial proportion of people. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03611-4.


Introduction
A non-alcoholic fatty liver disease (NAFLD) is marked by hepatic steatosis without evidence of excessive alcohol use or other obvious factors that damage the liver [1]. In the 21st century, NAFLD remains an essential public health issue [2]. Globally, an estimated 20% of the general population is suffering from NAFLD, with a range from 6 to 35% based on multiple measurements [3]. There is a continuum of NAFLD, from simple steatosis to nonalcoholic steatohepatitis (NASH), with varying degrees of fibrosis that eventually progress to cirrhosis [4,5]. NASH may cause cirrhosis and hepatocellular carcinoma, while simple steatosis presents as a benign condition with slow progression over many years [3,6,7]. The extrahepatic form of NAFLD is characterized by its ability to aggravate the cardiovascular disease, kidney disease, and diabetes, resulting in adverse health effects [8][9][10]. Even though the prevalence of NAFLD is increasing and its adverse effects are seen throughout multiple systems in the body, there are no effective treatments except for lifestyle changes along with regular physical activity [11]. It is therefore extremely important to identify patients whose risk of NAFLD is high at an early stage.
As far as diagnosis of NAFLD is concerned, liver biopsy has always been the gold standard [12]. However, due to its invasiveness and high cost, it could not become a widely accepted diagnosis. It is also unreasonable to perform routine liver biopsies as a screening or risk assessment test for the general population. In addition, a liver biopsy analysis with poor inter-observer variability and modest intra-observer variability has suboptimal reliability for measuring a treatment effect in clinical trials [13]. Clinical practitioners use liver ultrasound as a valuable tool in their practice for detecting fatty liver in the early stages. Ultrasonography (US), nevertheless, depends on the operator's experience and technological sophistication [14]. Besides, Steatosis less than 20% [15] or steatosis in morbidly obese individuals could not be detected by ultrasound [16]. In addition, the accuracy of US for hepatic steatosis assessment is affected by the presence of severe fibrosis [17]. Moreover, there is a drawback in that dietary and pharmacological interventions are unable to be qualitatively evaluated [18]. With the development of ultrasonic transient elastography, the controlled attenuation parameters of the liver and the liver stiffness value can be used to assess the degree of hepatic steatosis and fibrosis quantitatively, but they are affected by the operator's skill level [19]. In addition, based on proton magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), which can accurately determine the amount of liver fat content and the degree of fibrosis, and play the role of similar liver biopsy, but their cost is high, and difficult to obtain, so it has not been widely used clinically [20]. In recent years, serum noninvasive diagnostic markers or models have attracted widespread clinical attention due to their advantages of non-invasiveness, low cost, simple operation, strong reproducibility, and low requirements for operators, especially for early screening and evaluation of NAFLD [20]. Therefore, effective noninvasive methods should be used in clinical practice to identify NAFLD, track disease processes, and monitor treatment effects [21].
Overweight, obesity, and insulin resistance strongly correlate with NAFLD due to excessive fat accumulation, especially triglycerides in hepatocytes [22]. NAFLD is characterized by oxidative stress and inflammation. An increase in reactive oxygen species (ROS) can lead to lipid peroxidation by damaging both membrane structure and function. In addition to oxidizing key proteins for cell metabolism and function, it may also cause the oxidation of nucleic acids [23]. Since the liver has a limited ability for triglyceride accumulation, lipid deposition under overfeeding conditions, as in the case of NAFLD, determines the accumulation of high levels of fatty acids, generally saturated ones, which are associated with cell dysfunction [24]. Indeed, the excess of fatty acids induces high rates of β-oxidation, increasing the production of ROS in the mitochondrial respiratory chain, which causes cellular damage and oxidative stress [25]. Oxidative damage markers rise in response to this circumstance, Kupffer cells become active, pro-inflammatory pathways activate, and circulating immune cells are drawn into the body [26,27].
An insulin resistance (IR) is characterized by decreased peripheral tissue insulin sensitivity, which is at the core of the pathogenesis of NAFLD by impairing glucose uptake and oxidation [11,28]. Triglyceride-glucose (TyG) is an index combining fasting blood glucose (FPG) with fasting triglyceride (TG) that could better reflect insulin resistance. It has been widely accepted and used in clinical applications due to its convenience and simple calculation [29][30][31]. Using a combination of body mass index (BMI) and TyG index, Er et al. found that the information imparted by a multitude of critical clinical indicators could be simultaneously reflected, such as blood lipids, blood glucose, and BMI, and could better reflect IR than the TyG index alone [32]. Given the importance of IR in NAFLD pathogenesis [11,28], TyG-BMI has been linked to an increased incidence of NAFLD, according to certain studies [33][34][35][36]. As a result, we hypothesized that the TyG-BMI might be an effective marker in identifying NAFLD in the general population. However, as a noninvasive and simple model, applying TyG-BMI to identify and evaluate NAFLD still needs further research. The objective of this study was to determine the diagnostic accuracy of the TyG-BMI in detecting NAFLD in the general Japanese population.

Study population and design
In this study, the TyG-BMI was tested for its ability to detect NAFLD in the general Japanese population in a cross-sectional design. As a secondary analysis, we used data derived from a published article shared by Takuro Okamura et al. [37]. We obtained the data from the 'DATADRYAD' database (https:// datad ryad. org/ stash/). This website permitted users to freely download the raw data. Dryad is a nonprofit membership organization that is committed to making data available for research and educational reuse now and into the future. According to Dryad Terms of Service, we cited the Dryad data package in the present study. (Dryad data package: Okamura, Takuro et al. Data from: ectopic fat obesity presents the greatest risk for incident type 2 diabetes: a populationbased longitudinal study, Dryad, Dataset, https:// doi. org/ 10. 5061/ dryad. 8q0p1 92) [38]. From 2004 to 2015, the original study enrolled 20,944 participants ≥ 18 years of age who had at least two routine physical examinations at Murakami Memorial Hospital.
Exclusion criteria of the original study included: (1) participants diagnosed with type 2 diabetes (n = 323) or with fasting plasma glucose (FPG) over 6.1 mmol/L (n = 808); (2) participants with known liver disease, such as hepatitis B or C virus (n = 416); (3) anyone who took medication (n = 2321); (4) participants with heavy drinking habits (more than 40 g per day for women and more than 60 g per day for men) (n = 739); (5) participants with a missed value of covariates, including abdominal ultrasonography, exercise, alcohol intake or laboratory variables (n = 863) [37]. A total of 15,464 participants were included in the raw study for the final analysis. 1184 participants in the present study were further excluded for excessive alcohol consumption (in males > 210 g/week and in females > 140 g/week) [39]. Figure 1 showed the process of selecting participants. Finally, 14,280 subjects (7440 males and 6840 females) were included in this secondary analysis.
Murakami Memorial Hospital's Ethics Committee approved the research ethics, and all subjects provided informed consent in the original study [37].

Health check-ups and laboratory measurement
A standard and unified questionnaire was used by trained medical staff to gather basic health information about the subjects, including height, habit of exercise, weight, blood pressure (SBP and DBP), WC, age, smoking and drinking status. Biochemical analysis of blood samples was conducted after at least 8 h of fasting. Analysis indicators included HbA1c, ALT, FPG, TG, HDL-c, GGT, TC, and AST [37].

Definitions and calculations
BMI = weight divided by height 2 . TyG = Ln [(FPG (mg/ dL)/2) × TG (mg/dL)] [30]. TyG-BMI = BMI × TyG [32]. Ethanol consumption was evaluated by the mean ethanol intake of participants per week during the prior month. The smoking status was categorized into current smokers, ex-smokers, or non-smokers. According to World Health Organization 2020 guidelines on physical activity, regular exercise was defined as follows: adults should undertake 150-300 min of moderate-intensity, or 75-150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vigorous-intensity aerobic physical activity, per week [40].

Diagnosis of NAFLD by abdominal ultrasonography
An abdominal ultrasound was used to assess NAFLD, and gastroenterologists, without knowledge of the participants' personal information, reviewed the ultrasound images. The final diagnosis was made based on the evaluation of four ultrasound findings: liver brightness, liver, and kidney echo contrast, vessel blurring, and depth attenuation [41]. This was a new scoring system of ultrasonographic findings in apparently healthy Japanese adults. The AUC to diagnose NAFLD was 0.980. The sensitivity was 91.7% (95% CI 87.0-95.1), and the specificity was 100% (95% CI 95.4-100.0).

Statistical analysis
A random stratification process was used to divide participants into training and validation groups. For continuous variables, the mean (standard deviation) was given for normal distribution, the median (range) for non-normal distribution, and the number (%) for categorical variables. The authors used the student's t-test (normal distribution), the χ 2 (categorical variables), or the Mann-Whitney's U-test test (non-normal distribution) to test for differences between development and validation groups. Stratified by the presence of NAFLD, the authors also showed the characteristics of the validation and training groups, respectively. Using the area under the receiver operating characteristic (ROC) curve (AUC) and its 95% confidence intervals, the overall diagnostic accuracy of the TyG-BMI was determined in the development and validation groups, respectively. Using 500 bootstrap resamplings, the authors computed the AUC with a 95% CI with TyG-BMI to evaluate its discriminatory properties and validate its diagnostic accuracy [42].
Through the ROC curve, 2 cutoff points were selected according to the deciles of TyG-BMI and considering the specificity (SP), sensitivity (SE), negative predictive value (NPV), and positive predictive value (PPV) of the two cutoff points. The two cutoff points were used to rule out or rule in the NALFD, respectively. The authors calculated specificity, sensitivity, NPV, PPV, positive likelihood ratios (PLR), and negative likelihood ratios (NLR) to determine the diagnostic accuracy of the two cutoff points. The authors also explored the cutoff points' diagnostic values for different NAFLD prevalence or different gender and age subgroups.
Moreover, the authors used a database of 183,730 general Chinese populations for external validation. The data were also taken from the DATADRYAD database (https:// datad ryad. org/ stash), shared by Sun et al. [43]. Data from: association of low-density lipoprotein cholesterol within the normal range and NAFLD in the non-obese Chinese population: a cross-sectional and longitudinal study, Dryad, Dataset, https:// doi. org/ 10. 5061/ dryad. 1n6c4. All participants were non-obese people with a normal range of Low-density lipoprotein cholesterol (LDL-c), as described in the original article [43]. Decision curve analysis was performed to explore the clinical use of TyG-BMI for the diagnosis of NAFLD: the proportion of people who showed a true positive result was first subtracted from those who showed a false positive result, then weighed against the relative risks of falsepositive and false-negative results, and finally, obtained the net benefit of making a decision [44].
All results were reported according to the STARD statement [45]. All analyses were carried out using statistical packages from the R (http:// www.r-proje ct. org, The R Foundation) and EmpowerStats packages (http:// www. empow ersta ts. com, X and Y Solutions, Inc, Boston, MA). P values less than 0.05 were considered statistically significant (two-sided).

Results
In the present study, 14,280 participants (52.1% men and 47.9% women) were eligible. Figure 1 depicted the subjects' selection and grouping process. The mean age of all participants was 43.53 ± 8.89 years. A total of 2515 (17.6%) participants were diagnosed with NAFLD. The mean BMI was 22.07 ± 3.14 kg/m 2 . The mean FPG and TG were 92.74 ± 7.42 and 79.03 ± 56.07 mg/dL, respectively. The mean TyG and TyG-BMI were 8.01 ± 0.64 and 177.74 ± 34.53, respectively. Table 1 illustrated the eligible participants' basic demographic and clinical information. The authors randomly divided all participants into the development group (n = 7118) and the validation group (n = 7162). 1272 and 1243 participants were diagnosed with NAFLD in the development and validation groups, respectively. In all baseline characteristics, the development group did not differ statistically from the validation group (all P > 0.05).

Baseline characteristics of participants
By NAFLD status, Table 2 showed the characteristics of the 2 groups. The participants with NAFLD had higher BMI, WC, alcohol consumption, SBP, age, FPG, DBP, TG, HbA1c, ALT, TC, AST, BUN, GGT, and higher rates of males and ever or current smokers in the development and validation groups. In contrast, participants in the NAFLD group had lower levels of HDL-c.
TyG-BMI levels were distributed in a normal distribution, as shown in Fig. 2 and Additional file 1: Fig. S1. They ranged from 97.49 to 421.35 in the total population. The TyG-BMI values of all the participants from the NALFD and non-NAFLD groups were shown in Fig. 3. As a result, the distribution level of TyG-BMI was higher in the NALFD group than in the non-NALFD group. Men were found to have a higher prevalence of NAFLD in age-stratified by 10 intervals than women, regardless of age group (Fig. 4). Meanwhile, the study also found that the prevalence of NAFLD increased stepwise in both male (except for those older than 50) and female (except for those older than 60) participants with increasing age ( Fig. 4). All participants were divided into four groups according to quartiles of TyGBMI, and we found that participants with a high TyGBMI had higher prevalence rates of NAFLD compared to the group with the lowest TyGBMI (P < 0.0001 for trend) (Additional file 2: Fig. S2).

Development phase
The median TyG-BMI was elevated among participants with NAFLD (214.5). For participants without NAFLD, the median level was 166.2 (Fig. 5A). The authors applied the ROC method to analyze the diagnostic accuracy of the TyG-BMI for detecting NAFLD in the development group. TyG-BMI had an AUC of 0.888 (95% CI 0.879, 0.897) (Fig. 6, Additional file 7: Table S1). Using 500 bootstrap resamplings, TyG-BMI had an average AUC of 0.886 (95% CI 0.876, 0.896). The AUROC remained high and almost unchanged in the development set (Additional file 3: Fig. S3). Table 3 described the diagnostic accuracy of TyG-BMI in predicting NAFLD at decile intervals. In the development group, when the cut-off point of the TyG-BMI was set at 182.2 to discriminate NAFLD, it would meet the relatively high Youden's index (0.605) and the diagnostic accuracy of sensitivity (89.4%)/specificity (71.  (Table 3).
Using a low cutoff point (below 182.2), 4156 (71.1%) of the 5846 individuals without NAFLD were correctly identified, whereas 135 (3.3%) of 4289 individuals with a low cutoff point were incorrectly identified (Table 4).   (Table 4). Significant differences in NAFLD prevalence were found in age and gender stratification. The diagnostic performance of the TyG-BMI in different gender and age strata for NAFLD was also evaluated using ROC analysis. TyG-BMI showed a larger AUC for distinguishing NAFLD in females, young, and middle-aged people ( Table 5).
In the development group, when the cut-off point of the TyG-BMI was set at 182.   Men were found to have a higher prevalence of NAFLD in age-stratified by 10 intervals than women, regardless of age group. Meanwhile, the study also found that the prevalence of NAFLD increased stepwise in both male (except for those older than 50) and female (except for those older than 60) participants with increasing age  (Table 3). By applying the low cutoff point (below 182.2), 4148 (70.1%) of the 5919 participants without NAFLD were correctly identified, whereas 134 (3.1%) of 4279 with a low cutoff point were incorrectly staged (Table 4). Thus, this low cutoff point could also exclude the absence of NAFLD with high accuracy (NPV of 96.9%).
By applying the high cutoff point (greater than 224.0), 519 (41.8%) of the 1243 participants with NAFLD were correctly identified, whereas only 221 (29.9%) of the 742 participants with a high cutoff point were incorrectly staged (Table 4) The authors also found that TyG-BMI had a larger AUC to distinguish NAFLD in female and young and middleaged people in the validation group (Additional file 7: Table S2).

Predictive values of the TyG-BMI for different prevalence of NAFLD
The worldwide prevalence of NAFLD ranges from 6 to 35% [3]. As a result, the authors calculated the positive and negative predictive values of the two cutoff    points using a range of prevalences of NAFLD ranging between 5 and 50%. The NPV of the low cutoff point to rule out NAFLD decreased as the prevalence of NAFLD increased, but it remained high (≥ 87.8%, Table 6) when the prevalence of NAFLD was less than 30%. The PPV of the high cutoff point to diagnose NALFD increased as the prevalence of NAFLD increased. It also remained high, particularly for the prevalence of 20% or more (≥ 73.7%, Table 6). Thus, these two cutoff points may be helpful in diagnosing NAFLD in participants with different prevalences of NAFLD.

External validation
The external validation was performed on a database of 183,730 Chinese non-obese participants with a normal range of LDL-c.  Table S3). The AUC of the external validation was 0.874 (Additional file 5: Fig.  S5). The NPV, sensitivity, and specificity rate of the low cutoff point to rule out NAFLD were 98.5%, 94.1%, and 60.0%, respectively. While the PPV, specificity, and sensitivity rate of the high cutoff point to diagnose NALFD   Table 7). The external validation revealed that TyG-BMI's ability to diagnose NAFLD could be promoted to some extent.

Clinical use of the model
The decision curve analysis of the TyG-BMI was demonstrated in Fig. 7 in the training and validation groups.
As it could see from the graph, the black line represented the net benefit when no participants had been diagnosed with NALFD. In contrast, the light gray line represented the net benefit when everyone had been diagnosed with NALFD. A model's diagnostic utility was defined as the distance between the "no treatment line" (black line) and the "all treatment line" (light gray line) in its curve. In terms of clinical application, the further the model curve was from the black and light gray lines, the better. Specifically, in the training cohort, the net benefit was equal to performing 50 additional NAFLD screenings (such Presence of NAFLD (64% certainty) as abdominal ultrasonography) per 100 Japanese adults if the threshold probability was 30% in the model when without a significant change in the prevalence of NAFLD (Fig. 7A). Similar results could be obtained in the internal and external validation participants (Fig. 7B, Additional file 6: Fig. S6).

Discussion
This cross-sectional study aimed to develop and validate a non-invasive index that uses routinely measured and readily accessible clinical and laboratory variables to discriminate between the presence or absence of NAFLD. This index, called the "TyG-BMI", accurately distinguished the populations with or without NAFLD. The absence or presence of NAFLD was diagnosed in 9996 (70%) of the 14,280 patients using values below or above the lower or upper cutoff points. Of these 9996 individuals, 9308 (93.1%) were diagnosed correctly. Only 4284 participants (30%) of the 14,280 participants with TyG-BMI in the range of 182.2-224 were considered "indeterminate". According to this, 70 percent (9996 out of 14,280) of participants in the whole population were able to avoid ultrasonography by applying the TyG-BMI. Both internal and external validations demonstrated that TyG-BMI was highly accurate in diagnosing patients. In addition, the authors summarized the positive and negative predictive values of the two cutoff points using a wide range of prevalence of NAFLD, ranging from 5 to 50%. TyG-BMI's clinical application was demonstrated by the decision curve analysis. A number of non-invasive and simple models have been developed to detect and evaluate NAFLD [18,46]. Due to their calculation based on anthropometric and biochemical parameters, these could be easily obtained in clinical practice. Hepatic steatosis has been identified and managed with these models because they are cost-effective, practical, and reliable [46]. Several studies have shown that the fatty liver index (FLI), which is derived from a population of fewer than 8000 individuals in an Italian municipality [47], is acceptable for detecting NAFLD [48]. Based on a survey of nearly 10,000 Korean patients, the hepatic steatosis index (HSI) has also been shown to be an accurate and simple method for predicting NAFLD [49]. A few other indicators may be used to determine central lipid accumulation, including lipid accumulation product (LAP) and visceral adiposity index (VAI) [50,51]. The underlying cause of NAFLD is a complex combination of environmental factors, heredity, and dietary habits [52]. Several dietary habits contribute to the development of NAFLD, such as excessive calorie consumption, fructose consumption, and physical inactivity [53]. Moreover, Western and Asian countries differ significantly in genetic backgrounds, dietary habits, and lifestyles [54]. It is possible, however, that these indices may not be appropriate for Asian populations since they were most originally designed for western populations. Furthermore, most centers do not have external validation of these models, making it challenging to apply the proposed scoring system daily.
In a Japanese population, Wang et al. developed a novel model called the TyG-BMI index that could help predict NAFLD [34]. After adjusting for confounding variables, according to the study, NAFLD was positively associated with TyG-BMI (OR: 3.90 per SD increase; 95% CI 3.54 to 4.29). Analysis of ROC showed that the TyG-BMI was more effective at predicting NAFLD risk than other tra-  Table S4), the results of the present study were consistent with Wang et al. [34]. However, hepatic steatosis commonly occurs in obese individuals. We consider the reasons for this phenomenon as follows. After further analysis of the baseline information of subjects for BMI stratification, we found that there were more non-obese women than men in this study. Sex differences in non-obese NAFLD have also been noted in some previous studies [55,56]. There is a general tendency for females to have more subcutaneous and visceral fat [57,58], and the BMI alone does not provide a complete picture of this information [56]. According to recent studies, people with non-obese NAFLD are more likely to develop metabolic diseases [59].
Wang et al. [59] carried out a receiver operating characteristic analysis that showed that the TyG-BMI could better predict the risk of NAFLD than other traditional indicators and obtained the optimal threshold for TyG-BMI. However, the performance of TyG-BMI has not been validated in an external population in the study of Wang et al. [34]. In addition, they did not explore two cut-off values of TyG-BMI to identify or exclude NAFLD and the corresponding positive and negative predictive values. It is essential to point out that although the optimal threshold had the largest Youden index, it is not associated with the greatest positive or negative predictive value. Therefore, a diagnostic and exclusion model of a disease requires 2 cut-off values, and the optimal threshold is not the best choice. To address this question, the present study developed and validated a simple, non-invasive, and cost-effective tool, TyG-BMI, to accurately separate participants with and without NAFLD in the Japanese population. A total of 2 cut-off values of TyG-BMI were found in this study, one for excluding  [33] focuses on the association between TyG-BMI and NAFLD in the non-obese Chinese population with normal blood lipid levels. In their study, TyG-BMI had a good prediction value (0.85 area under ROC; 95% CI 0.84-0.86) for NAFLD incidence. The AUROCs of the two studies were a bit smaller than the present study. Besides, the AUROC of TyG-BMI was less than TyG for detecting NAFLD in the study of Mohammad E. et al. [36]. Several factors might explain the difference: (1) the study populations differed. The present study was performed on the general Japanese, while the above two studies focused on Iranian with overweight/obesity or the non-obese Chinese population with normal blood lipid levels. (2) The diagnosis method of NAFLD was different. There was a difference between ultrasonography and transient elastography. (3) The prevalence of NAFLD varied significantly by gender, age, dietary habits, and ethnicity [54]. Japanese dietary pattern is also different from Chinese dietary pattern. In the Japanese diet, the total energy is lower, and essential fatty acids (e.g., N-3 fatty acids) are higher because of more seafood consumption compared to the Chinese diet. NAFLD is a multifactorial disease related to a complex living environment, heredity, and dietary habits [52]. In patients with NAFLD, dietary n-3 polyunsaturated fatty acids (PUFAs) can reduce hepatic inflammation, fibrosis, and steatosis, lower plasma TG levels, and improve hepatic fatty acid metabolism [60]. Different dietary habits affected the prevalence of NAFLD in Chinese and Japanese populations, and the prevalence could affect the effectiveness of TyG-BMI in diagnosing NAFLD. However, our results validated in the Chinese population suggest that the AUC was 0.874. The results indicate that TyG-BMI has an excellent ability to identify NAFLD in both Chinese and Japanese people.
Applying the TyG-BMI index, the results of the present study suggested that ultrasonography would only be needed to identify NAFLD in 30 percent of participants, i.e., those considered "indeterminate" (TyG-BMI in the range of 182.2-224). Most importantly, since most persons seen in clinical practice were not suffering from NAFLD [82.4% (11,765/14280) of the study cohort], the lower cutoff point was exceptionally accurate in ruling it out. In both estimation and validation, the NPV was 97% and 97%, respectively, and ranged from 75.6 to 98.3% for a prevalence of NAFLD of 5-50%. Among 14,280 patients, 8568 (60%) had a negative diagnosis of NAFLD through TyG-BMI (TyG-BMI below 182.2), and thus, using the TyG-BMI would have prevented the need for ultrasound. Of these 8568 participants diagnosed as not having NAFLD by TyG-BMI, 8304 (97%) were confirmed by ultrasound to have non-NAFLD indeed.
It should be pointed out that, clinically, US is the preferred imaging test for individuals with suspected NAFLD [61], with a typical appearance of a hyperechogenic liver. In a recent meta-analysis, ultrasound showed 85% sensitivity and 94% specificity in diagnosing moderate-to-severe steatosis compared to histology [14]. In contrast, US could not detect steatosis of less than 20% [15] or steatosis in individuals with morbid obesity [16]. Moreover, ultrasound cannot determine how severe NAFLD steatosis is [17]. Using computed-assisted US hepatic/renal ratios and US hepatic attenuation rates, it is possible to detect NAFLD early [17,62]. Compared to the conventional US, both measurements are excellent in detecting hepatic steatosis, with a sensitivity of 95% and specificity of 100%. However, the NPV is still low (72% for US H/R ratio and 67% for US hepatic attenuation rate) [17,63]. In addition, by standardizing it with a tissue-mimicking phantom, this quantitative US model can improve its reliability and reproducibility, while these findings are needed to verify in further studies [63]. Above all, it is still recommended by current guidelines that US be used to diagnose moderate and severe steatosis [64]. Vibration-controlled transient elastography (TE) is one of the available non-invasive assessment tools for NAFLD. By generating vibrations of low frequency and mild amplitude, elastic shear waves propagate through liver tissues and are used for measuring stiffness [65]. With newer models, liver fibrosis can now be measured by liver stiffness measurement (LSM), and liver steatosis can be measured by controlled attenuation parameter (CAP) [66]. There are several benefits of TE, including its low cost, fast procedure time, immediate result availability, good reproducibility, and ability to be performed in an outpatient setting [67]. Several cross-sectional studies have investigated how it helps diagnose NAFLD and assess its severity [63,65,68]. In conclusion, the quantitative US model and transient elastography will become a good non-invasive method for diagnosing NAFLD in the future, as an essential improvement of traditional ultrasonography. Lipotoxicity in hepatocytes and immune-mediated inflammation play a crucial role in the development and progression of NAFLD. Hepatocellular injury caused by the lipotoxicity of accumulated lipids and free fatty acids (FFAs) is characterized by oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, and subsequent expression of pro-inflammatory cytokines and inflammatory factors [69]. Apoptotic and immune pathways are activated as a consequence of cellular injury, which represents a distinctive feature of NASH pathophysiology. The lipotoxic lipids can activate both the intrinsic-and extrinsic-mediated (death receptor) apoptotic pathway in hepatocytes through the transcriptional up-regulation of proapoptotic and downregulation of antiapoptotic proteins [70]. It is believed that apoptosis or other forms of hepatocyte cell death play a crucial role in promoting immune responses associated with the progression of NAFLD to a more severe stage, e.g., fibrosis and cirrhosis development [71].
Since oxidative stress is a significant feature of NAFLD, antioxidant therapy is of great value for NAFLD [23]. The Mediterranean diet, Silymarin and berberine could play an antioxidant role, thereby protecting liver cells [72][73][74]. In humans, only a small amount of oral antioxidants are absorbed because they are easily destroyed by acids and enzymes. Consequently, the development of effective methods for efficiently delivering antioxidants is urgently needed. Nano-antioxidants, created as a sponge-like polymer, act as a protective vehicle to prevent antioxidants from being degraded in the human gut and promote improved absorption in the digestive tract. A nanocapsule binds itself to the intestinal wall and releases antioxidants right into the intestinal cells, where they are absorbed directly into the bloodstream. Numerous antioxidant units are connected in a branched pattern to form nano-antioxidants. It could provide numerous possible sites to couple with an active species and have enhanced free radical scavenging potency [75].
The current study has some strengths, as follows: (1) the present study included a sizable sample size and diverse individuals, making it simple to publicize outside of the study. (2) TyG-BMI is determined using objective clinical and easily accessible lab variables routinely measured during health checkups, without requiring any other tests. (3) The authors explored two cutoff points used to identify or exclude NAFLD and used a wide range of prevalence of NAFLD varying from 5 to 50% to study the changes in positive and negative predictive values. (4) Using our decision curve analysis, TyG-BMI's clinical effectiveness was demonstrated, and individuals with low-risk NAFLD would not require additional screening (such as ultrasonography). (5) The authors validated the results both internally and externally to make sure they were reliable.
Despite TyG-BMI's good performance, the study still has some potential limitations. First, due to its imperfect sensitivity, ultrasonography is not a gold standard in diagnosing NALFD. The liver biopsy in asymptomatic people was typically not available in this considerable population-based investigation. Besides, patients with BMI on extreme ends of the spectrum may skew the ratio and can lead to decrease sensitivity and predictive value for the NAFLD. In the future, we could design our studies to diagnose NAFLD with more appropriate methods, such as the quantitative US model and transient elastography. We could also compare TyG-BMI against liver biopsy, a definitive test to establish the diagnosis of NAFLD. Second, the authors did not receive information about the severity of hepatic steatosis, so we could not evaluate the ability of TyG-BMI to quantify hepatic steatosis. Third, in this study, the development and validation of the diagnostic value of TyG-BMI for NAFLD were conducted in Asians. The diagnostic effect of NAFLD in non-Asian populations may be limited. However, some other western-derived indices for diagnosing NAFLD, such as FLI, Framingham steatosis index (FSI), and LAP, have been validated in Asians. And they were valuable indices for identifying the presence of NAFLD [76][77][78][79]. So, we tend to believe that the TyG-BMI index could help predict NAFLD in populations other than Asians. Fourth, this was a cross-sectional study, and we could not explore the predictive value of TygBMI for the occurrence of NAFLD in the future.

Conclusion
TyG-BMI, constructed from routine clinical and laboratory variables, is able to accurately diagnose NAFLD, thus rendering ultrasonography unnecessary for the vast majority of populations. TyG-BMI, therefore, could be used to identify candidates for hepatic ultrasound and those who need lifestyle modifications.