Background
Pediatric nonalcoholic fatty liver disease (NAFLD) is defined as chronic hepatic steatosis in children (18 years or younger) that is not secondary to a genetic/metabolic disease, infection, use of steatogenic medications, ethanol consumption, or malnutrition [
1]. NAFLD is an inclusive term referring to the full spectrum of diseases from fatty infiltration of the liver, typically more than 5% of the liver analyzed using imaging, direct quantification, or histological estimation [
1]. Because obesity is strongly correlated with NAFLD, and the obese pediatric population has increased, the prevalence of NAFLD has increased and has become the most common cause of chronic pediatric liver disease in developed countries [
2]. In Korea, the estimated prevalence of adolescents with NAFLD also increased from 4.7% in 2010 to 5.9% in 2015, and an increased ALT level was associated with the male sex, obesity and truncal obesity [
3].
NAFLD tends to progress and could transit into the adult period; therefore, an early diagnosis and treatments are important [
4]. Although the data for the natural history of pediatric NAFLD are limited, pediatric NAFLD appears to be a more severe phenotype than the disease in adults, and 15% of the children with NALFD have stage 3 fibrosis or higher at diagnosis [
5,
6].
The gold standard of treatment for NAFLD is a nonpharmacological intervention, such as weight reduction and physical exercise [
7‐
9]. Therefore, nutrition is a key factor that affects the progression and development of NAFLD. Some efforts have attempted to reveal the relationship between dietary factors and fatty liver or liver fibrosis in adult populations [
10‐
19]. Although overnutrition is the main cause of NAFLD, each nutrient may function as a causative or protective factor. Fat- and carbohydrate-rich diets contribute to the pathogenesis of NAFLD [
10,
14,
16,
20]. In contrast, fiber and low-glycemic-index diets, as well as monounsaturated fatty acids (MUFAs) and omega-3 fatty acids, exert protective effects on NAFLD [
11,
14,
16].
Sodium intake positively correlates with metabolic syndrome and hypertension in children, adolescents and adults [
21‐
23]. One study revealed an independent association between high sodium intake and an increased risk of NAFLD and advanced liver fibrosis in healthy Korean adults [
19]. However, to date, only a few studies have examined the dietary risk factors for NAFLD or liver fibrosis in children and adolescents [
24‐
26].
In this study, we attempted to identify the dietary factors that affect suspected NAFLD in Korean children, and we further evaluated the factors associated with potential liver fibrosis in children with suspected NAFLD.
Results
The overall prevalence of suspected NAFLD was 8.2% in the current study. The characteristics of the study participants according to the presence of suspected NAFLD are presented in Table
1. The suspected NAFLD group exhibited a significantly higher height (
P < 0.001), BMI-SDS (
P < 0.001), SBP-SDS (
P < 0.001), DBP-SDS (
P < 0.001), WC (
P < 0.001), total cholesterol level (
P < 0.001), TG level (
P < 0.001), AST level (
P < 0.001), ALT level (
P < 0.001) and fasting glucose level (
P = 0.039) than the healthy control group.
Table 1
Characteristics of study participants according to the presence of suspected NAFLD in Korean children and adolescents aged 10–18 years
Age | 14.34 ± 0.21 | 13.77 ± 0.06 | 0.011 |
Sex | Male (n = 932) | 92 (66.7%) | 840 (54.7%) | 0.007 |
Female (n = 742) | 46 (33.3%) | 696 (45.3%) |
Ht (cm) | 163.96 ± 0.87 | 160.01 ± 0.29 | < 0.001 |
BMI (kg/m2) | 28.12 ± 0.31 | 19.29 ± 0.06 | < 0.001 |
BMI-SDS | 2.35 ± 0.08 | −0.49 ± 0.02 | <0.001 |
Hypertension (n, %) | 47 (34.1%) | 221 (14.4%) | <0.001 |
SBP (mmHg) | 115.70 ± 0.91 | 107.16 ± 0.24 | <0.001 |
SBP-SDS | 0.33 ± 0.08 | −0.27 ± 0.02 | <0.001 |
DBP (mmHg) | 69.99 ± 0.77 | 65.28 ± 0.22 | <0.001 |
DBP-SDS | 1.08 ± 0.09 | 0.52 ± 0.03 | <0.001 |
WC (cm) | 89.35 ± 0.85 | 66.60 ± 0.18 | <0.001 |
Hemoglobin A1c (%) | 5.51 ± 0.06 | 5.37 ± 0.01 | 0.023 |
Hypercholesterolemia (n, %) | 26 (18.8%) | 135 (8.8%) | <0.001 |
Total cholesterol (mg/dL) | 174.22 ± 2.38 | 161.39 ± 0.68 | <0.001 |
Hypertriglyceridemia (n, %) | 38 (27.5%) | 178 (11.6%) | <0.001 |
TGs (mg/dL) | 113.68 ± 5.17 | 81.42 ± 1.28 | <0.001 |
AST (IU/L) | 32.41 ± 2.50 | 19.32 ± 0.17 | <0.001 |
ALT (IU/L) | 49.64 ± 4.52 | 13.37 ± 0.32 | <0.001 |
Fasting glucose (mg/dL) | 94.56 ± 1.44 | 91.53 ± 0.18 | 0.039 |
U-Na-to-SGU ratio | 55.47 ± 1.96 | 51.21 ± 0.56 | 0.029 |
The U-Na-to-SGU ratio was significantly higher in the suspected NAFLD group than in the healthy control group (55.47 ± 1.96 vs. 51.21 ± 0.56,
P = 0.029). Higher dietary sodium intake was also recorded in the suspected NAFLD group, but the difference was not significant (3692.58 ± 195.47 vs. 3462.63 ± 51.32,
P = 0.204, Table
2). In this population, the sodium intake of both groups was much higher than the recommended reference daily intake. Regarding the other dietary factors, only cholesterol intake was noticeably different between the suspected NAFLD group and the control group (366.60 ± 27.13 vs. 302.11 ± 6.10,
P = 0.022, Table
2). We also compared dietary intake to the recommended reference daily intake between the suspected NAFLD group and control group after stratification by gender and age. For boys, overall dietary intake was higher in the potential NAFLD group. The intake of cholesterol (412.19 ± 36.78 vs. 334.32 ± 9.04,
P = 0.042) and polyunsaturated fatty acids (PUFAs; 17.51 ± 1.48 vs. 14.10 ± 0.33,
P = 0.027) was significantly higher in boys with suspected NAFLD. Total water intake was significantly higher in healthy controls than participants with suspected NAFLD among girls aged 12–18 years (1723.86 ± 81.81 vs. 1909.79 ± 28.16,
P = 0.003).
Table 2
Dietary factors of study participants according to the presence of suspected NAFLD in Korean children and adolescents aged 10–18 years and reference daily intake
Total energy intake (kcal) | 2214.74 ± 90.84 | 2172.17 ± 23.01 | 0.601 | 1900 ~ 2700 |
Total water intake (g) | 953.76 ± 48.12 | 960.57 ± 14.02 | 0.891 | 900 ~ 2600 |
Carbohydrate intake (g) | 311.65 ± 12.79 | 323.14 ± 3.26 | 0.319 | 247.5 ~ 438.75 |
Protein intake (g) | 87.99 ± 4.81 | 79.16 ± 1.15 | 0.076 | 40 ~ 65 |
Fat intake (g) | 64.90 ± 3.70 | 61.40 ± 1.00 | 0.320 | 15 ~ 30 |
Cholesterol intake (mg) | 366.60 ± 27.13 | 302.11 ± 6.10 | 0.022 | < 300 |
SFA intake (g) | 20.18 ± 1.19 | 20.48 ± 0.36 | 0.807 | 16 ~ 24 |
MUFA intake (g) | 20.96 ± 1.33 | 20.36 ± 0.37 | 0.647 | |
PUFA intake (g) | 14.92 ± 1.07 | 12.95 ± 0.24 | 0.074 | |
Fiber intake (g) | 18.77 ± 0.89 | 19.05 ± 0.29 | 0.785 | 20 ~ 25 |
Calcium intake (mg) | 514.38 ± 34.39 | 513.40 ± 8.19 | 0.973 | 650 ~ 1000 |
Phosphorus intake (mg) | 1155.95 ± 48.45 | 1119.61 ± 13.34 | 0.438 | 1000 ~ 1200 |
Iron intake (mg) | 15.61 ± 0.94 | 15.65 ± 0.53 | 0.981 | 7 ~ 16 |
Sodium intake (mg) | 3692.58 ± 195.47 | 3462.63 ± 51.32 | 0.204 | 1400 ~ 1500 |
Potassium intake (mg) | 2686.12 ± 116.95 | 2628.61 ± 33.49 | 0.623 | 3000 ~ 3500 |
Vitamin A intake (ngE) | 611.75 ± 53.50 | 627.55 ± 36.37 | 0.897 | 550 ~ 850 |
Vitamin B1 intake (mg) | 1.94 ± 0.10 | 1.90 ± 0.03 | 0.753 | 0.9 ~ 1.3 |
Vitamin B2 intake (mg) | 1.66 ± 0.09 | 1.55 ± 0.02 | 0.214 | 1.0 ~ 1.7 |
Vitamin C intake (mg) | 65.69 ± 6.46 | 72.01 ± 2.19 | 0.403 | 70 ~ 105 |
Niacin intake (mg) | 16.21 ± 0.85 | 15.39 ± 0.23 | 0.310 | 12 ~ 16 |
The characteristics of the participants in the suspected NAFLD subgroup according to PNFI are shown in Table
3. In addition to age, WC, and TG levels, which are the variables necessary for measuring PNFI, a significantly larger proportion of subjects in the PNFI > 3 group were male and significantly larger proportions exhibited a higher BMI, BMI-SDS, AST and ALT levels than participants in the NAFLD without liver fibrosis group (
P < 0.001). Regarding nutritional factors, total water intake (
P = 0.004), carbohydrate intake (
P = 0.034), protein intake (
P = 0.021), calcium intake (
P = 0.015), phosphorus intake (
P = 0.048), iron intake (
P = 0.006) and vitamin B2 intake (
P = 0.015) were higher in the PNFI > 3 group (Table
4). We also compared dietary intake to the recommended reference dietary intake between the PNFI≤3 group and PNFI>3 group after stratification by gender and age. Higher niacin intake was recorded in all age subgroups of the PNFI≤3 group among girls, but the difference was not statistically significant (14.29 ± 1.21 vs. 13.13 ± 1.57,
P = 0.554).
Table 3
Characteristics of the participants in the suspected nonalcoholic fatty liver disease group according to the pediatric NAFLD fibrosis index
Age (y) | 15.16 ± 0.33 | 13.89 ± 0.26 | 0.003 |
Sex | Male (n = 92) | 23 (46.9%) | 69 (77.5%) | <0.001 |
Female (n = 46) | 26 (53.1%) | 20 (22.5%) |
Ht (cm) | 163.40 ± 1.29 | 164.28 ± 1.16 | 0.634 |
BMI (kg/m2) | 26.74 ± 0.37 | 28.87 ± 0.41 | <0.001 |
BMI-SDS | 1.97 ± 0.10 | 2.57 ± 0.10 | <0.001 |
SBP (mmHg) | 114.67 ± 1.63 | 116.27 ± 1.11 | 0.403 |
SBP-SDS | 0.26 ± 0.15 | 0.36 ± 0.08 | 0.481 |
DBP (mmHg) | 69.18 ± 1.31 | 70.43 ± 0.97 | 0.445 |
DBP-SDS | 0.93 ± 0.17 | 1.17 ± 0.11 | 0.229 |
WC (cm) | 82.17 ± 0.82 | 93.30 ± 1.03 | <0.001 |
Platelet count (×103 /μL) | 312.41 ± 9.01 | 320.93 ± 6.34 | 0.433 |
Hemoglobin A1c (%) | 5.42 ± 0.05 | 5.56 ± 0.09 | 0.289 |
Total cholesterol (mg/dL) | 171.73 ± 3.97 | 175.60 ± 2.98 | 0.439 |
TGs (mg/dL) | 85.57 ± 5.89 | 129.16 ± 6.81 | <0.001 |
AST (IU/L) | 23.65 ± 0.97 | 37.24 ± 3.75 | <0.001 |
ALT (IU/L) | 32.73 ± 2.07 | 58.96 ± 6.73 | <0.001 |
Fasting glucose (mg/dL) | 92.65 ± 1.65 | 95.61 ± 2.04 | 0.329 |
U-Na-to-SGU ratio | 50.95 ± 3.69 | 57.95 ± 2.22 | 0.087 |
Table 4
Dietary factors of the suspected nonalcoholic fatty liver disease group according to the pediatric NAFLD fibrosis index and reference daily intake
Total energy intake (kcal) | 1986.38 ± 112.07 | 2340.47 ± 125.06 | 0.062 | 1900 ~ 2700 |
Total water intake (g) | 788.37 ± 56.15 | 1044.98 ± 66.15 | 0.004 | 900 ~ 2600 |
Carbohydrate intake (g) | 275.14 ± 15.96 | 331.75 ± 17.48 | 0.034 | 247.5 ~ 438.75 |
Protein intake (g) | 75.23 ± 4.91 | 95.01 ± 6.87 | 0.021 | 40 ~ 65 |
Fat intake (g) | 59.03 ± 4.46 | 68.13 ± 5.17 | 0.185 | 15 ~ 30 |
Cholesterol intake (mg) | 317.86 ± 32.99 | 393.43 ± 37.78 | 0.184 | < 300 |
SFA intake (g) | 18.90 ± 1.53 | 20.89 ± 1.64 | 0.424 | 16 ~ 24 |
MUFA intake (g) | 19.24 ± 1.70 | 21.91 ± 1.84 | 0.340 | |
PUFA intake (g) | 12.98 ± 1.20 | 15.99 ± 1.51 | 0.179 | |
Fiber intake (g) | 17.36 ± 1.48 | 19.55 ± 1.11 | 0.241 | 20 ~ 25 |
Calcium intake (mg) | 417.31 ± 37.18 | 567.82 ± 48.46 | 0.015 | 650 ~ 1000 |
Phosphorus intake (mg) | 1039.88 ± 60.58 | 1219.85 ± 66.59 | 0.048 | 1000 ~ 1200 |
Iron intake (mg) | 12.56 ± 1.05 | 17.29 ± 1.31 | 0.006 | 7 ~ 16 |
Sodium intake (mg) | 3321.73 ± 296.53 | 3896.75 ± 253.96 | 0.160 | 1400 ~ 1500 |
Potassium intake (mg) | 2379.48 ± 148.32 | 2854.94 ± 159.68 | 0.051 | 3000 ~ 3500 |
Vitamin A intake (ngE) | 499.98 ± 57.20 | 673.29 ± 76.20 | 0.071 | 4550 ~ 850 |
Vitamin B1 intake (mg) | 1.77 ± 0.14 | 2.03 ± 0.13 | 0.194 | 0.9 ~ 1.3 |
Vitamin B2 intake (mg) | 1.38 ± 0.11 | 1.82 ± 0.12 | 0.015 | 1.0 ~ 1.7 |
Vitamin C intake (mg) | 63.98 ± 10.98 | 66.63 ± 8.03 | 0.845 | 70 ~ 105 |
Niacin intake (mg) | 15.09 ± 2.88 | 16.82 ± 1.22 | 0.251 | 12 ~ 16 |
The adjusted ORs of risk factors for potential liver fibrosis are presented in Table
5.After adjusting for confounding factors, males had an 8.036-fold higher risk of potential liver fibrosis (
P < 0.001) than females in the NAFLD group. As BMI-SDS and AST levels were increased, the risk of potential liver fibrosis also increased independently (BMI-SDS: OR 3.321,
P < 0.001, AST: OR 1.059,
P = 0.022). Regarding dietary factors, protein and carbohydrate intake increased the risk of potential liver fibrosis (protein intake: OR 1.053.
P = 0.007, carbohydrate intake: OR 1.028,
P = 0.049). Niacin intake exerted a protective effect on potential liver fibrosis (OR 0.862,
P = 0.019).
Table 5
Adjusted ORs (95% CI) of risk factors for potential liver fibrosis in Korean children and adolescents aged 10–18 years with suspected nonalcoholic fatty liver disease
Sex (1: male, 2: female) | 8.036 (2.62–24.61) | <0.001 |
BMI-SDS | 3.321 (1.75–6.31) | <0.001 |
AST | 1.059 (1.01–1.11) | 0.022 |
Protein intake | 1.053 (1.01–1.09) | 0.007 |
Carbohydrate intake | 1.028 (1.00–1.06) | 0.049 |
Niacin intake | 0.862 (0.76–0.98) | 0.019 |
Discussion
To our knowledge, few published studies have examined dietary factors associated with NAFLD and fibrosis in a pediatric population, although fibrosis is the most important concern of NAFLD. Therefore, we performed this study to analyze the dietary factors associated with suspected pediatric NAFLD and potential liver fibrosis.
Children with suspected NAFLD had higher U-Na-to-SGU ratios and cholesterol intake than healthy controls. High dietary sodium intake is a well-known risk factor for metabolic syndrome and hypertension [
21,
42,
43], and even NAFLD in the adult population [
18,
19,
44]. However, data on the association between sodium intake and pediatric NAFLD are lacking. Along with metabolic syndrome, hypertension and diabetes, NAFLD is one of the most important complications of obesity. Our result is clinically meaningful to confirm the harmful effects of a high level of dietary sodium intake in children. The average sodium intake of both the suspected NAFLD and healthy control groups was higher than the recommended reference daily intake, which has been widely reported in studies of adult subjects [
45,
46]. The possible underlying cause is the Korean preference for high sodium food such as soup, ramen, pickled food and kimchi [
45,
46].
Although the gold standard for the assessment of sodium intake is a 24-h urine collection, a spot urine sample is widely used in large population studies such as KNHANES and in the clinic because of its convenience. Furthermore, an applicable formula for estimating 24-h urinary sodium excretion in children is unavailable. Based on other studies, we used the U-Na-to-SGU ratio as a surrogate marker of sodium intake [
21,
36,
37].
In our study, significantly higher cholesterol intake was observed in the suspected NAFLD group than in the healthy controls. Fat intake is a well-known risk factor for hepatic steatosis, but some types of fat may prevent the development of NAFLD. MUFAs and PUFAs, including omega-3 fatty acids, protect against NAFLD by increasing fatty acid oxidation and reducing de novo lipogenesis [
13,
47], whereas saturated fatty acids (SFAs) induce hepatocyte injury [
20]. Cholesterol intake was significantly higher and PUFA intake was significantly lower in nonobese patients with NAFLD than in obese with NAFLD [
44]. Therefore, he consumption of MUFA-rich foods (nuts, olive oil and avocado) and PUFA-rich foods (sea fish and green leafy vegetables) rather than SFA-rich foods (meats and dairy products) might improve NAFLD [
16]. However, in the current study, PUFA intake was significantly higher in boys with suspected NAFLD. As the overall dietary intake of boys with suspected NAFLD was higher than healthy boys, we postulated that overnutrition potentially explained the differences in the results.
We also investigated the factors associated with liver fibrosis, which is the most important clinical issue for patients with NAFLD. Although a liver biopsy is the most accurate way to confirm fibrosis, because of its invasiveness, noninvasive markers such as the PNFI, fibrosis-4 index (FIB-4), AST-to-platelet ratio index (APRI) and pediatric NAFLD fibrosis score are usually used [
41,
48]. Because the subjects included in the KNHANES data were young adolescents, only a few patients with significant fibrosis were identified in this population based on the FIB-4 and APRI. The PNFI is commonly used in patients with pediatric NAFLD to indirectly confirm the presence of liver fibrosis [
38‐
41]. One study performed in 111 Italian children with NAFLD showed that PNFI value less than 3 points, confidently excluded fibrosis with a high sensitivity (93.4%) [
39]. Another pediatric study evaluated the rs641738 polymorphism in the membrane-bound O-acyltransferase domain containing the protein 7 gene, which is associated with an increased risk of NAFLD. The authors also defined a PNFI score between 3 and 8.9 points as a potential marker of early fibrosis [
38]. We also used a PNFI cutoff scorer of 3 points to distinguish subjects with potential fibrosis from subjects without fibrosis.
Protein and carbohydrate intake were risk factors for potential liver fibrosis. This finding is supported by previous studies showing that the ingestion of a diet excessively rich in carbohydrates, particularly fructose, causes de novo lipogenesis, which may induce hepatic fat accumulation [
10,
49]. The consumption of sugar-sweetened beverages is associated with metabolic syndrome and fatty liver in adult and pediatric patients [
50,
51]. In contrast, protein intake exerts a positive effect on NAFLD by reducing fat deposition and plasma cholesterol levels [
17,
20]. According to the results of an animal study, a high-protein and low-carbohydrate diet prevents hepatic steatosis by reducing de novo lipogenesis [
52]. However, unlike previous studies, protein intake increased the risk of liver fibrosis in our study. Although each nutrient plays its own role in NAFLD, overnutrition is the main problem of patients with NAFLD, which might explain the different findings.
In addition, niacin intake was a protective factor against potential liver fibrosis. Niacin is one of the vitamin B complexes that is present in tuna, mushrooms, peanuts, avocado, and green peas. Although the precise mechanism is not completely known, niacin inhibits lipolysis by acting on the hydroxy-carboxylic acid receptor 2 in peripheral adipose tissue, ultimately reducing the reflux of free fatty acids to the liver [
53]. Recent studies reported beneficial effects of a higher level of niacin intake on improving hepatic steatosis in patients with NAFLD [
12,
54]. In one randomized controlled trial of 39 patients treated with niacin for 23 weeks, the liver fat content decreased significantly after treatment [
55]. Moreover, a mechanistic study comparing human hepatocytes treated with niacin to untreated control hepatocytes found that niacin prevented fat accumulation in hepatocytes by reducing hepatocyte diacylglycerol acyltransferase 2 and NADPH oxidase activity [
15]. However, the protective effect of niacin should be interpreted with caution until it has been confirmed in a large-scale study.
The present study has several limitations. First, the causal relationship between dietary factors and NAFLD or liver fibrosis cannot be proven because this study employs a cross-sectional design. Second, as nutritional surveys are based on 24-h dietary recall, differences between actual nutritional intake and the survey responses might exist, depending on the participant’s memory. Third, although we used the U-Na-to-SGU ratio to estimate sodium intake, daily variability may exist. Fourth, the study defined suspected NAFLD and potential liver fibrosis using a noninvasive method without hepatic imaging or biopsies.
To our knowledge, this epidemiological study is the first to evaluate the various dietary factors associated with suspected NAFLD and potential fibrosis in the general pediatric population. Although our results were unable to provide strong evidence because of some limitations of the study, our study produced some meaningful results. Because of a lack of data, very limited dietary guidance is available to provide to patients with NAFLD. We expect that the current study will be a useful reference for further studies on dietary factors and may be helpful for developing dietary guidelines for children with NAFLD in the future.
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