Lifestyle Intervention as the Primary Treatment for Pediatric Nonalcoholic Fatty Liver Disease

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Abbreviations

ALT

alanine aminotransferase

BMI

body mass index

CRD

carbohydrate‐restricted diet

ESPGHAN

European Society of Pediatric Gastroenterology, Hepatology, and Nutrition

FFA

free fatty acid

HFF

hepatic fat fraction

hs‐CRP

high‐sensitivity C‐reactive protein

KIDMED

Mediterranean Diet Quality Index for children and adolescents

LDL

low‐density lipoprotein

MD

Mediterranean diet

MRS

magnetic resonance spectroscopy

NAFLD

nonalcoholic fatty liver disease

NAS

NAFLD activity score

NASPGHAN

North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition

NASH

nonalcoholic steatohepatitis

OSA

obstructive sleep apnea

SBP

systolic blood pressure

VLDL

very low density lipoprotein

Liver fat accumulation in nonalcoholic fatty liver disease (NAFLD) is the result of an imbalance between lipid deposition and removal, driven by hepatic synthesis of triglycerides and de novo lipogenesis (Fig. 1). ¹ , ² Weight loss is the most effective way to promote liver fat removal because it decreases the delivery of free fatty acids (FFAs) to the liver, increases extrahepatic insulin sensitivity, and reduces adipose tissue inflammation. ¹ , ² As such, intensive lifestyle intervention with dietary and physical activity modification supported by behavioral change strategies is the mainstay of therapy for pediatric NAFLD. Aspects of care, including behavioral therapy, dietary modification, and increased physical activity, are best carried out by a multidisciplinary team generally composed of a medical provider, registered dietician, exercise specialist, mental health professional, nurse, and social worker. This is the most effective treatment approach for pediatric NAFLD when executed appropriately.

FIG 1.

Pathophysiology of hepatic lipid accumulation. Dietary lipids, lipolysis of visceral fat, and de novo lipogenesis differently contribute to the pool of lipids stored in the liver. Hepatic FFAs are partly oxidized as energy sources, partly stored as triglycerides, and finally are excreted as components of VLDL. However, in NAFLD, the whole process is unable to dispose of excess fat, and triglycerides accumulate in the liver.

Lifestyle interventions with a total of 26 contact hours or more over a period of 2 to 12 months have been shown to result in weight loss in children and adolescents with obesity. ³ Both short‐term (12 weeks) and long‐term (12 months) multidisciplinary lifestyle interventions have demonstrated improvement in various pediatric NAFLD outcomes, including serological markers and liver histology. ⁴ , ⁵ , ⁶ In adult NAFLD, a 7% to 10% body weight reduction has been associated with histological improvement, specifically resolution of liver fat, necroinflammation, and fibrosis. ⁷ Although there is currently insufficient evidence to determine to what degree body mass index (BMI) reduction or weight loss is required for improvement in pediatric NAFLD, there is evidence to support the utility of weight loss achieved through combined dietary and physical activity changes in the treatment of pediatric NAFLD. ⁵ , ⁶

Dietary Treatment Options

Diet plays a key role in the development of NAFLD. The macronutrient composition of the diet is associated with NAFLD, independent of energy intake. Macronutrients such as saturated fatty acids, trans fats, simple sugars (sucrose and fructose), and animal proteins damage the liver. These modulate the accumulation of triglycerides and antioxidant activity in the liver, which affects insulin sensitivity and postprandial triglyceride metabolism. ⁸ In contrast, monounsaturated fatty acids, polyunsaturated omega‐3 fats, plant‐based proteins, and dietary fibers appear to be beneficial to the liver; however, studies have not shown that they are effective in reducing NAFLD. Although several diets have been shown to be effective in reducing NAFLD, data generally do not support one specific diet over another (Table 1), although avoidance of sugar‐sweetened beverages is often recommended. ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷

TABLE 1.

Studies of Dietary Intervention in Pediatric NAFLD

First Author (Year)	Type of Study	Patients	Experimental Diet (Time)	Main Outcome Measures	Key Results
Vos (2009) 9	Randomized controlled study, pilot	10 children with NAFLD (7 children with biopsy‐proved NASH, 3 children diagnosed based on serology and laboratory tests)	Low‐fructose diet or low‐fat diet (6 months)	Oxidized LDL, ALT	Oxidized LDL significantly lower in low‐fructose group but unchanged in low‐fat group; ALT levels did not change in either group
Ramon‐Krauel (2013) 10	Randomized controlled study	17 obese children with HFF > 9% via MRS	Low‐glycemic‐load diet or low‐fat diet (6 months)	HFF via MRS, visceral fat, BMI, ALT, insulin resistance	8%‐10% reduction in HFF in both groups; significant decreases in ALT in both groups; no between‐group differences
Jin (2014) 11	Randomized controlled study	24 overweight Hispanic American adolescents with HFF > 8% via MRS, regular consumers of sugar‐sweetened beverages	Calorie‐matched study provided fructose‐only or glucose‐only beverages (4 weeks)	HFF via MRS, lipid measurements, insulin resistance, oxidative stress	No change in HFF, body weight, or ALT in either group; improved adipose insulin sensitivity, hs‐CRP, oxidized LDL in glucose beverage group
Mager (2015) 12	Controlled cohort study, pilot	12 children with NAFLD (4 NASH, 8 simple steatosis) compared with 14 healthy lean controls	Combination low‐fructose, low‐glycemic‐index, low‐glycemic‐load diet (6 months)	Plasma markers of liver dysfunction, cardiometabolic risk, insulin resistance, inflammation, anthropometrics, blood pressure	Significant reductions in SBP, percent body fat, ALT, and cardiometabolic risk in children with NAFLD at 3 and 6 months
Cakir (2016) 13	Prospective survey study	106 obese children with NAFLD, 21 obese children without NAFLD, 54 healthy children with normal BMI	MD (indigenous diet in the Black Sea region of Turkey)	KIDMED index (compliance to MD), anthropometrics, insulin, triglyceride, total cholesterol, ALT, glucose, insulin resistance	Significantly lower KIDMED index scores in obese children with NAFLD; KIDMED index score negatively correlated with BMI
Della Corte (2017) 14	Prospective survey study	243 obese children (166 with NAFLD [53 NASH], 77 without NAFLD)	MD (indigenous diet in Italy)	KIDMED index (compliance to MD)	Significantly lower KIDMED index scores in NASH; poor adherence to MD correlated with NAS > 5, grade 2 fibrosis
Schwimmer (2019) 15	Randomized controlled study	40 adolescent (11‐16 years) boys with clinicopathological diagnosis of NAFLD	Diet low in free sugars (those sugars added to foods and beverages and naturally occurring in fruit juices) or usual diet (8 weeks)	Change in HFF via MRS; 12 secondary outcomes, including change in ALT and diet adherence	Mean decrease in HFF significantly greater for diet low in free sugar group (25% to 17%) versus usual diet group (21% to 20%); greater ALT decrease and better diet adherence in intervention diet group
Goss (2020) 16	Randomized controlled study	32 children/adolescents with obesity and NAFLD	CRD or fat‐restricted diet (8 weeks)	HFF via MRS, body composition by X‐ray absorptiometry, insulin resistance	Change in HFF did not differ with diet; greater decreases in insulin resistance, abdominal fat mass, and body fat mass in CRD group

There are several diets that have been shown to be effective in reducing NAFLD in obese children. Generally, one specific diet has not been shown to be better than another, except for potentially a diet low in free sugars when compared with a usual diet.

Diets high in fructose are known to increase plasma lipids and oxidative stress. The liver is the primary site of fructose metabolism, with nearly 60% oxidation of fructose ingestion. ⁸ The metabolism of fructose in the liver is much higher than that of glucose. The hepatic metabolism of fructose stimulates de novo lipogenesis in the liver, increasing liver fat. ¹ , ⁸ Two large randomized, controlled clinical trials in children showed reduced weight gain in experimental groups of either decreased consumption of sugar‐sweetened beverages or replacement with noncaloric beverages versus control groups. ¹⁸ , ¹⁹ Notably, these two studies did not evaluate children with NAFLD. A recent open‐label randomized trial study by Schwimmer et al. ¹⁵ demonstrated a diet in low free sugars (restricted free sugar intake to <3% of daily caloric intake) for 8 weeks resulted in greater reduction in hepatic fat compared with the usual diet. It is important to note that patients on the low free sugar diet did lose more weight during the study compared with those consuming their usual diet.

Based on the best evidence‐based data available at this time, pediatric NAFLD consensus guidelines (North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition [NASPGHAN] and European Society of Pediatric Gastroenterology, Hepatology, and Nutrition [ESPGHAN]) recommend avoidance of sugar‐sweetened beverages and consumption of a healthy, well‐balanced diet as the best dietary approach in NAFLD. ²⁰

Exercise and Physical Activity

Studies have shown that exercise affects NAFLD through various pathways that regulate triglyceride turnover and, indirectly, liver fat, independent of weight loss. ¹ , ² , ²¹ Improved peripheral insulin resistance achieved through exercise reduces the excess delivery of FFAs and glucose for FFA synthesis to the liver. ² , ²¹ While in the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through reduction of the release of damage‐associated molecular pathways. ² , ²¹ The benefits of exercise (aerobic versus resistance) for reducing hepatic fat in obese adolescents have been supported by two randomized, controlled clinical trials. ²² , ²³ Interestingly, in obese adolescent boys, both aerobic and resistance exercise were effective in reducing hepatic fat measured by magnetic resonance spectroscopy (MRS) and in improving visceral adiposity. An identical study in obese adolescent girls showed that aerobic, but not resistance, exercise was effective in reducing hepatic fat measured by MRS and in improving visceral adiposity. ²² , ²³ Very few children (12 boys and 5 girls) in the aforementioned studies had sufficient hepatic fat to have been considered as having NAFLD; therefore, it is unclear whether the small changes seen in hepatic fat are clinically relevant for children with NAFLD. ¹⁷

The long‐term effects of aerobic exercise versus aerobic plus resistance exercise have been evaluated in postpubertal obese adolescents with NAFLD finding that combined aerobic and resistance exercise was more effective than aerobic exercise alone in improving noninvasive biomarkers of NAFLD progression. ²⁴ A systematic review and meta‐analysis of supervised exercise training intervention on hepatic fat content and on NAFLD prevalence in children and adolescents showed that both aerobic and resistance exercise, at vigorous or moderate‐to‐vigorous intensities, with a volume of ≥60 minutes/session and a frequency of ≥3 sessions/week, aiming to improve cardiorespiratory fitness and muscular strength, had benefits on hepatic fat content reduction in youth. ²⁵ The general consensus based on the available data at this time is to recommend moderate‐ to high‐intensity exercise of any modality daily in conjunction with other lifestyle changes for the treatment of pediatric NAFLD. ²⁰ Any volume and intensity of physical activity, including leisure time and nonexercise activity, is important to decrease the burden of triglycerides to and in the liver, compared with the time spent sedentary. ¹

Additional Lifestyle Considerations

Additional lifestyle considerations should include screen time, sleep, and counseling for high‐risk behaviors. Screen time activities, inclusive of social media, should be limited to less than 2 hours/day for all children, including those with NAFLD, ²⁰ with the American Academy of Pediatrics recommending no screen time in those younger than 2 years. ²⁶ Sleep is an essential part of a child’s routine and an indispensable part of a healthy lifestyle. Poor sleep is increasingly common in children, and the association between short sleep duration and obesity or adiposity during early childhood has emerged in numerous studies over the past decade. ²⁷ Sleep duration is now considered a well‐established modifiable risk factor for early obesity and persistence into adulthood. Cross‐sectional studies in adults have revealed that short sleep duration has a close relationship with the presence of NAFLD, with a recent study using a historical cohort of >12,000 participants showing that sleep duration of less than or equal to 5 hours in both men and women was a significant risk factor for incident NAFLD, compared with those with sleep duration greater than 7 hours. ²⁸ Although such studies are lacking in pediatric NAFLD, it is a fair assumption that appropriate sleep hygiene should be recommended as part of lifestyle modification. Certain comorbidities have been associated with an increased risk and/or severity of NAFLD. One example being obstructive sleep apnea (OSA), which has been associated with nonalcoholic steatohepatitis (NASH) in pediatric studies, independent of BMI and standard metabolic risk factors. ²⁹ As such, OSA should be considered an important clinical risk factor for NAFLD. Lastly, increased participation in high‐risk behaviors needs to be considered in adolescents with NAFLD. In addition to standard counseling of adolescents, health care providers should counsel adolescents regarding the potential effects of increased fibrosis progression with binge drinking. ²⁰ Families of children with NAFLD should be counseled about the risks of secondhand smoke exposure, and adolescents with NAFLD should be counseled against smoking, including use of electronic nicotine delivery devices. ²⁰

Conclusion

The comprehensive health benefits of a healthier diet and increased physical activity are clear, and these remain the first‐line approach for treatment of NAFLD in children. Lifestyle recommendations for the treatment of pediatric NAFLD currently endorsed by governing organizations (NASPGHAN and ESPGHAN) are avoidance of sugar‐sweetened beverages, consumption of a healthy and well‐balanced diet, moderate‐ to high‐intensity exercise daily, and less than 2 hours/day of screen time (Table 2). ²⁰

TABLE 2.

Lifestyle Modification is the Primary Treatment Modality for Pediatric NAFLD

Lifestyle Modifications	Modification Details
Dietary Changes	Avoidance of sugar‐sweetened beverages Healthy well‐balanced diet
Exercise and Increased Physical Activity	Moderate‐ to high‐intensity exercise, of any modality, daily
Other Lifestyle Interventions	Less than 2 hours per day of screen time, including social media Adequate sleep hygiene/duration Counseling for high risk behaviors
Multidisciplinary Approach	Intensive behavioral interventions with frequent contact hours and follow up at least every 3 months Delivered by multidisciplinary team

A combination of lifestyle interventions, including dietary changes, exercise and increased physical activity, and other behavioral interventions, to promote weight loss is the best therapeutic approach in pediatric NAFLD. A multidisciplinary team approach has been shown to be most effective for pediatric weight management.