Metabolic dysfunction-associated steatotic liver disease in children

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD), is the main chronic liver pathology in children and adolescents. The prevalence of MASLD in children is increasing with the obesity pandemic. Childhood obesity rates have increased significantly worldwide over the past three decades, rising from 5% to 19%, and exceeding 340 million in the highest income countries. This increase has occurred in all age groups, but is most pronounced in the teenage population, and it is estimated at around 20%. This increase is closely linked to metabolic disorders, especially insulin resistance, type 2 diabetes mellitus (T2DM) and the systematically evolving spectrum of MASLD [1].

Early detection and treatment of MASLD coexisting with obesity can prevent or alter the course of metabolic disease. The basis for the treatment of MASLD is lifestyle interventions focusing on a healthy diet and regular physical activity, but the prevalence of both MASLD and obesity still continues to rise. It seems that a number of factors influence the achievement of sustainable weight loss and effective treatment of MASLD, including genetic, epigenetic, environmental, social, financial, psychological, and endocrinological influences.

Sustained weight loss is particularly difficult to achieve, which suggests the potential validity of other

therapeutic options, including anti-obesity drugs or even bariatric surgery [2]. The increasing prevalence of MASLD and associated long-term health risks require appropriate clinical management as well as a consensus in the guidelines.

Epidemiology

In the study by Shi et al. among 1,446 adolescents in the USA, steatotic liver disease (SLD) was present in 291 (20.1%). Patients with SLD had a higher prevalence of clinically significant liver fibrosis (CSF) (p < 0.001). The MASLD criterion was met by 260/291 (89%) adolescents with SLD, but this was not associated with a higher prevalence of CSF [3].

Epidemiological studies have shown that MASLD affects almost 40% of children with obesity. The prevalence of obesity in the United States according to the Centers for Disease Control statistics for 2017-2020 was 12.7% among children aged 2-5 years and 20.7% among children aged 6-11 years [4]. An Italian study of pre-school children with obesity found that 39% had at least 1 metabolic comorbidity, including insulin resistance, steatohepatitis associated with metabolic dysfunction (MASLD), hypertension, or dyslipidaemia [5].

Criteria for diagnosis

The diagnostic criteria for paediatric MASLD are detailed in the Delphi consensus document and are very similar to those for adults [6]. They require a diagnosis of hepatic steatosis based on imaging studies or liver biopsy and the presence of at least one of five cardiometabolic risk factors:

New potential markers of screening MASLD in children

Identifying high-risk children with MASLD remains a major challenge, as most do not show clear symptoms of the disease. There is a need to develop a widely accepted, non-invasive prognostic indicator to facilitate early diagnosis and treatment of the disease. In recent years, several markers have been reported to have potential for routine diagnosis of MASLD in children.

Liu et al. developed a screening strategy for MASLD in children, tailored to the prevalence of obesity. They used data from 1018 children from schools in two cities in China to develop and validate a non-invasive predictive model for childhood MASLD. They identified waist-to-height circumference ratio (WHtR) as the optimal predictor of MASLD, with a proposed cut-off value of 0.48. In addition, they determined that the combination of WHtR and lipid accumulation product (LAP) with a LAP cut-off value ≥ 668.22 cm × mg/dl improves the positive predictive value of the test. WHtR appears to be a simple, efficient and cost-effective non-invasive indicator for predicting childhood MASLD worldwide. Further testing for MASLD is recommended for children with WHtR ≥ 0.48 in areas where the prevalence of obesity is ≥ 12% and for children with WHtR ≥ 0.48 accompanied by LAP ≥ 668.22 cm × mg/dl in areas of unknown obesity prevalence. Further testing for MASLD is unnecessary in children with WHtR < 0.48 who do not have abnormal liver enzyme values. The cost-effectiveness and efficacy of WHtR as a screening tool should be further validated in different populations and ethnic groups. Nevertheless, given the growing global challenge posed by childhood obesity and MASLD, the implementation of this screening tool could significantly improve the early identification and treatment of childhood MASLD, contributing to a reduction in the burden of MASLD in childhood and in later life [7].

Huneault et al., based on a retrospective analysis of data from 184 children, reported that fasting insulin concentrations and ALT activity were significantly higher in children with MASLD (p < 0.05). According to the authors, in paediatric patients, measurement of fasting insulin levels or in combination with assessment of ALT activity may be a non-invasive strategy for detecting MASLD [8].

De Boom et al. assessed the prevalence and the associated factors of MASLD in a group of severely obese adolescents using the hepatorenal index (HRI), ALT activity and fatty liver index (FLI). Fifty-six adolescents were included in the analyses, including 44 (79%) girls. Mean age was 15.75 (±1.01) years, and mean body mass index (BMI) was 44.08 (±5.16) kg/m². The hepatorenal index was abnormal in 35 (62.5%) patients. This group had a higher waist/hip ratio, elevated liver biochemical activity values and significantly lower leptin levels compared to the group with normal HRI. ALT activity was elevated in 32 (55.2%) patients and the hepatic steatosis index was abnormal in all (100%) participants. Linear regression analysis indicated associations between HRI and typical anthropometric and metabolic measures, and an inverse relationship between HRI and leptin, independent of sex- and age-adjusted BMI. MASLD was shown to be highly prevalent in severely obese adolescents, with the frequency depending on the tool used (HRI – 62.5%, ALT activity – 55.2%, FLI – 100%). Leptin may be a valuable biomarker to support the diagnosis of MASLD [9].

Carboxylesterase 1 (CES1) is a key serine hydrolase located in liver parenchymal cells and adipocytes and acts to hydrolyse endogenous lipids, including cholesterol esters and triglycerides, and promotes lipid storage. Increased expression of the gene for CES1 was observed in adult patients with MASLD. Wang et al. evaluated the association between CES1 levels and metabolic syndrome (MetS) and MASLD in Chinese children with obesity. Seventy-two children aged 6-13 years were included in the study, including 25 (35%) with a diagnosis of MetS and 36 (50%) with a diagnosis of MASLD. Higher serum CES1 concentrations were found among children with MASLD (p < 0.001). Serum CES1 concentrations were positively correlated with ALAT, AspAT activity, triglyceride levels, cholesterol, LDL cholesterol, GDF15, and leptin and negatively correlated with HDL cholesterol, adiponectin and IGF1. The combination of CES1, sex, age and BMI showed a sensitivity and specificity of 92.7% for MASLD; hence CES1 can be considered a biomarker of metabolic syndrome and MASLD in obese children [10].

A non-invasive and potentially effective alternative for identifying MASLD risk in overweight or obese adolescents is offered by bioelectrical impedance analysis (BIA). Song et al. evaluated the usefulness of BIA for screening for MASLD in 206 overweight and obese children. Pearson correlation analysis showed that waist-hip ratio (WHR), percentage body fat (PBF) and BIA parameters in combination with anthropometric measurements were correlated with ALAT activity. WHR, PBF-WHR and visceral fat area (VFA)-WHR were positively correlated with MASLD in the overall population after adjusting for age, sex and pubertal characteristics. PBF-WHR and VFA-WHR were also correlated with MASLD in adolescents with normal ALAT activity. The utility of combining BIA and WHR parameters in identifying MASLD risk in overweight and obese children, even in those with normal ALAT activity, has been highlighted, facilitating early detection and intervention in adolescents at risk of MASLD [11].

Zdanowicz et al. evaluated serum uric acid (UA) concentrations in 194 children and adolescents with overweight/obesity and suspected liver disease and the association of this parameter with MASLD and metabolic disorders. In children with MASLD, they observed statistically significantly higher ALAT, AspAT activities, GGTP levels, total cholesterol, triglycerides, UA and carotid intima-media thickness (IMT). They suggested that UA levels could be a potential additional and readily available marker of metabolic dysfunction in children with MASLD [12].

Kopiczko et al., based on a study of dihomo-g-linolenic acid (DGLA), linoleic acid (LA) and arachidonic acid (AA) concentrations together with estimated desaturase activity in 25 obese children diagnosed with MASLD, concluded that serum DGLA concentrations could be considered a potential new non-invasive biomarker for detecting hepatic steatosis in children [13].

Treatment

Treatment options for steatohepatitis associated with metabolic dysfunction (MASLD) in children, remain limited. Despite the recent approval of drugs targeting weight loss in adolescents that may facilitate treatment of MASLD in children, lifestyle interventions such as diet and physical activity remain the cornerstone of the therapeutic approach.

A systematic review and meta-analysis by Jamil et al. showed that the Mediterranean diet improves liver function in children with MASLD. However, further randomised trials of longer duration are needed to develop evidence with high confidence [14].

Weight loss following dietary intervention in children with obesity and MASLD has a beneficial effect regardless of the diet used. The combination of diet and physical activity appears to be beneficial, as several studies have shown improvements in surrogate markers of MASLD, such as serum ALAT activity and liver fat fraction assessed by imaging [15].

Lifestyle modifications through physical activity, combating a sedentary lifestyle, including limiting screen time, and diet remain the cornerstones of treatment for MASLD in children. All patients with MASLD should perform aerobic exercise for at least 60 minutes a day, preferably resistance training three times a week and moderate-intensity aerobic training (e.g. walking, cycling), which are recommended to improve metabolic parameters and mobility. Education of children at school, including knowledge of healthy eating and physical activity, is also essential [16].

Conclusions

MASLD in children is a growing public health problem. Liver steatosis can be caused by genetic disorders, nutritional deficiencies, medications, intestinal microbiota disorders, endocrine disorders, and alcohol; therefore, it is important to rule out causes of liver steatosis other than obesity. ALT activity assessment remains the standard screening tool, and further research is needed to determine the usefulness of other biomarkers. Advanced imaging methods, such as magnetic resonance elastography (MRE), will play an increasingly important role in the non-invasive assessment of MASLD in children. Liver biopsy remains crucial in cases of suspected advanced disease to rule out other causes of liver steatosis. Lifestyle interventions, focusing on a healthy diet and regular physical activity, are the basis for treatment of MASLD. It is also suggested that clinical trials of drugs used in MASLD and MASH in adults should be conducted in children in order to apply them at a younger age.