Background
Non-alcoholic fatty liver disease (NAFLD) seems to have become the most common chronic disease in the world. According to a recent epidemiological survey of more than 8 million people in 22 countries by Younossi et al., the current prevalence of NAFLD is 25.24% in the world and 27.37% in Asia [
1]. With the increasing prevalence of obesity and diabetes worldwide, the prevalence of NAFLD continues to go up and has become a global public health problem [
1,
2]. NAFLD contains a series of liver histological changes ranging from mild hepatic steatosis to severe necrotizing inflammation. Without any interventions, it will eventually develop into liver cirrhosis or even liver cancer, leading to serious adverse consequences [
3‐
5]. Additionally, many clinical studies have found that NAFLD also causes many adverse effects on other organs and systems outside the liver [
6‐
8]. The widespread adverse consequences caused by NAFLD in and out of the liver have further increased the global burden of chronic diseases. Therefore, both medical institutions and the general public should pay attention to the preventive screening and management of NAFLD.
Atherogenic dyslipidemia is closely related to NAFLD, in which characteristic changes of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) are common in NAFLD patients [
9,
10]. Therefore, monitoring atherosclerotic lipids is an important way to assess the risk of NAFLD [
9,
11]. Remnant cholesterol (RC) is an unconventional lipid that has been widely studied in recent years. It is a kind of lipoproteins rich in TG, that is, intermediate-density lipoprotein and very-low-density lipoprotein in fasting state, and in the nonfasting state also chylomicron remnants [
12]. It is a key lipoprotein of atherosclerosis [
13,
14]. Some previous clinical studies have also confirmed that RC is a major factor mediating the residual risk of major cardiovascular events and is independently related to the progression of atherosclerosis [
14‐
16]. In recent years, a growing number of studies have found that high levels of RC significantly increased the risk of diabetes complications, hypertension and NAFLD; additionally, high levels of RC can also be used to predict cardio-cerebrovascular events in patients with NAFLD [
17‐
20]. These pieces of evidence suggest that RC may be a good parameter for assessing the risk of metabolism-related disease. Recently, some scholars have pointed out that the parameter remnant cholesterol/high-density lipoprotein cholesterol ratio (RC/HDL-C ratio) after the combination of RC and HDL-C is a valuable independent predictor of myocardial injury in diabetic patients after receiving PCI; in addition, the RC/HDL-C ratio can also be used to evaluate intracranial atherosclerotic [
21,
22]. However, there are no epidemiological studies to investigate the relationship between RC/HDL-C ratio and NAFLD, and it remains unclear whether the RC/HDL-C ratio is a risk factor for NAFLD. Here, in order to solve these problems, this study retrospectively analyzed the population data of NAGALA (NAfld in Gifu Area, Longitudinal Analysis) cohort to examine the relationship between RC/HDL-C ratio and NAFLD.
Discussion
In this secondary analysis of the NAGALA cohort, we found that the higher RC/HDL-C ratio in the general population may be closely related to the increased risk of NAFLD. Additionally, our results show that the combination of atherosclerotic lipid HDL-C and RC improves the recognition ability of NAFLD (AUC:0.82), and is significantly better than the traditional lipid parameters. As far as we know, this study proves for the first time that there is a correlation between RC/HDL-C ratio and NAFLD. More importantly, the calculation of the RC/HDL-C ratio is very simple, and this simple new parameter may provide an effective monitoring means of preventing and managing the NAFLD risk in the general population.
Atherogenic dyslipidemia is an important feature of NAFLD and has been recognized as a risk factor for NAFLD [
9,
11]. RC is an unconventional lipid, calculated as non-HDL-C – LDL-C [
28]. In previous studies, RC has been shown to be a major lipid parameter mediating residual risk of cardiovascular disease, mainly due to its strong atherogenic effect [
14‐
16]. It is reported that RC can promote the formation of foam cells and cause atherosclerosis in many ways. In addition, RC is also involved in the inflammation of the arterial wall, resulting in vascular injury [
33‐
35]. Aside from being closely related to cardiovascular disease, several recent studies have found that higher levels of RC also significantly increase the risk of diabetic complications, hypertension and NAFLD [
17‐
20]. These results suggested that RC has the potential to be used as a predictor of metabolic diseases. HDL-C is an anti-atherosclerotic lipid parameter, and many studies in the past have shown that HDL-C is closely related to a variety of metabolic diseases [
9,
10,
36]. So can the combination of RC and HDL-C improve the discrimination ability of NAFLD? Can the combined parameters be used to assess NAFLD risk? In order to solve these problems, a series of analyses were carried out in this study. The study showed that the combination of RC and HDL-C significantly improved the ability of NAFLD identification, and was significantly better than other conventional lipid parameters. Additionally, this study revealed for the first time that RC/HDL-C ratio is an independent risk factor for NAFLD. At present, there are very few studies on RC/HDL-C ratio, and only a few studies have carried out some correlation analysis [
21,
22,
37]. As early as 1998, Masuoka et al. described RC/HDL-C ratio for the first time. They evaluated 124 patients who had received coronary angiography, and found that RC/HDL-C ratio was valuable as a predictor of coronary artery disease [
37]. Then, several recent studies specifically evaluated the value of the RC/HDL-C ratio in predicting intracranial atherosclerotic and diabetic complications [
21,
22]. Combined with our current research, these results suggest that RC/HDL-C ratio is a metabolic-related marker with good potential, which should be paid attention to by more researchers.
In this study, there were some special findings in the subgroup analysis. Subgroup analysis showed that there was a significant interaction between sex and the risk of NAFLD related to the RC/HDL-C ratio, and when the RC/HDL-C ratio was higher, the risk of NAFLD in men was significantly lower than that in women. However, according to the comparison of baseline information in Table
1, it can be seen that the proportion of men was about 5 times higher than that of women in the higher RC/HDL-C ratio group. It may seem odd that there were fewer women in the group with the higher RC/HDL-C ratio but the risk of developing NAFLD is higher. To clarify this particular association, we summarized the baseline characteristics of NAFLD patients according to sex in the highest RC/HDL-C ratio (Q4). As shown in Table
5, women with NAFLD were significantly older than men in Q4, and dyslipidemia appeared more severe in women with NAFLD than in men. Older age in women means aging of the ovaries and decreased estrogen secretion, which leads to a higher risk of NAFLD [
38,
39]. In addition, estrogen deficiency in women promotes atherosclerotic lipid abnormalities, visceral weight gain and insulin resistance (IR), which increases the risk of liver disease and heart metabolism [
40,
41].
Table 5
Baseline characteristics of NAFLD patients in Q4 group of RC/HDL-C ratio
No. of patients | 184 | 1368 | |
Age, years | 50.00 (42.00–54.00) | 43.00 (38.00–50.00) | < 0.001 |
Weight, kg | 64.74 (10.07) | 75.47 (10.46) | < 0.001 |
Height, cm | 156.77 (5.03) | 170.64 (5.93) | < 0.001 |
BMI, kg/m2 | 26.31 (3.60) | 25.87 (2.95) | 0.070 |
WC, cm | 84.79 (9.21) | 87.54 (7.10) | < 0.001 |
ALT, U/L | 21.50 (16.00–29.00) | 31.00 (23.00–44.00) | < 0.001 |
AST, U/L | 19.00 (16.00–22.00) | 21.50 (17.00–27.00) | < 0.001 |
GGT, U/L | 16.00 (13.00–21.00) | 26.00 (19.00–37.00) | < 0.001 |
HDL-C, mmol/L | 1.13 (0.18) | 1.03 (0.18) | < 0.001 |
Non-HDL-C, mmol/L | 4.73 (4.21–5.30) | 4.52 (4.04–5.03) | < 0.001 |
TC, mmol/L | 5.91 (0.88) | 5.59 (0.83) | < 0.001 |
LDL-C, mmol/L | 3.85 (3.47–4.35) | 3.67 (3.20–4.13) | < 0.001 |
TG, mmol/L | 1.48 (1.21–1.92) | 1.60 (1.25–2.16) | 0.043 |
RC, mmol/L | 0.81 (0.74–0.95) | 0.83 (0.71–0.98) | 0.725 |
RC/HDL-C ratio | 0.70 (0.61–0.86) | 0.78 (0.65-1.00) | < 0.001 |
FPG, mmol/L | 5.35 (0.37) | 5.43 (0.35) | 0.003 |
HbA1c, % | 5.46 (0.32) | 5.28 (0.34) | < 0.001 |
SBP, mmHg | 124.58 (18.16) | 124.67 (14.42) | 0.937 |
DBP, mmHg | 77.37 (11.08) | 79.08 (10.01) | 0.032 |
Habit of exercise | 24 (13.04%) | 185 (13.52%) | 0.858 |
Drinking status | | | < 0.001 |
Non or small | 179 (97.28%) | 1110 (81.14%) | |
Light | 5 (2.72%) | 177 (12.94%) | |
Moderate | 0 (0.00%) | 81 (5.92%) | |
Smoking status | | | < 0.001 |
Non | 157 (85.33%) | 485 (35.45%) | |
Past | 9 (4.89%) | 391 (28.58%) | |
Current | 18 (9.78%) | 492 (35.96%) | |
The underlying mechanism of the association between RC/HDL-C ratio and NAFLD is still uncertain, but IR may be involved in the association. Previous studies have found that TG to HDL-C ratio was an effective substitute marker for IR and had good IR prediction performance [
42,
43], while RC is TG-rich cholesterol, and previous studies have also found that RC was closely related to IR [
44]. Therefore, we speculated that RC/HDL-C ratio may be closely related to IR. However, IR information was not measured in this study and therefore could not be evaluated. Further studies are needed to clarify the correlation between RC/HDL-C ratio and IR.
This observational study has several strengths: (1) This study provides the first evidence that RC/HDL-C ratio is independently positively correlated with NAFLD. (2) In this study, a relatively strict statistical model
adjustment strategy is implemented, and the
sample size is large, so the conclusion of the study can be considered to be reliable. (3) The participants in this study are all people who have undergone physical examination, and the results of the study are very suitable for promotion in the general population.
Several limitations are also worth mentioning: (1) As mentioned above, IR was not measured in this study, so the association mechanism between RC/HDL-C ratio and NAFLD needs to be confirmed by further studies. (2) In this study, NAFLD was diagnosed by ultrasound, and some mild hepatic steatosis may be missed compared with liver biopsy. In addition, the current study excluded people who were taking oral drugs at baseline and people with abnormal blood glucose, which may also lead to the underestimation of the prevalence of NAFLD in the current sample and a certain selection bias. But from another point of view, this study found a correlation between RC/HDL-C ratio and NAFLD in the case of low prevalence, which further suggests that there is a strong correlation between them. (3) In this study, there is a lack of dietary information and some measurement parameters (such as neck and chest circumference), which may help to further understand the relationship between the two. (4) Since this study was designed as a cross-sectional investigation type, it could not prove whether there is a causal relationship between the two, and further prospective studies are needed.
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