Elsevier

Metabolism

Volume 65, Issue 8, August 2016, Pages 1161-1171
Metabolism

Nonalcoholic Fatty Liver Disease: From Pathogenesis to Emerging Treatment
Similarities and differences between pediatric and adult nonalcoholic fatty liver disease

https://doi.org/10.1016/j.metabol.2016.01.008Get rights and content

Abstract

Nonalcoholic fatty liver disease (NAFLD) is highly common and potentially serious in children and adolescents. The term NAFLD refers to a spectrum of diseases ranging from accumulation of fat in the liver (simple steatosis or nonalcoholic fatty liver “NAFL”) to the potentially progressive form of nonalcoholic steatohepatitis (NASH) characterized by hepatocyte ballooning, inflammation, and often associated with fibrosis. While large prospective longitudinal studies in pediatric NAFLD are still lacking, growing evidence suggests that children with NAFL are at increased risk for cardiometabolic complications, while those with NASH and advance fibrosis are also at risk for significant liver-related morbidity including cirrhosis and its complications. Pediatric NAFLD shares features of adult NAFLD but also shows many different characteristics in terms of prevalence, histology, diagnosis and management. Translational studies suggest that NAFLD is a highly heritable disease in which genetic variations and environment closely interact to determine the disease phenotype and the progression to the more advanced forms of the disease. Changes in lifestyle, targeting gradual weight reduction, and physical exercise continue to be the mainstay of treatment for NAFLD in children. Recent advances in development of noninvasive diagnostic modalities and the potential for identifying effective pharmacological interventions may result in significant progress in the management of NAFLD in the pediatric population.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is defined as steatosis affecting more than 5% of the hepatocyte in the absence of significant alcohol consumption or other liver diseases. The histologic spectrum ranges from simple fatty deposition in the hepatocyte (simple steatosis or nonalcoholic fatty liver “NAFL”) to the potentially progressive form of nonalcoholic steatohepatitis (NASH) which is characterized by inflammation and hepatocyte injury leading to progression to fibrosis, cirrhosis, and potentially end-stage liver disease and hepatocellular carcinoma (HCC) [1].

From a historical perspective, scientists recognized an association between obesity and fatty liver more than 100 years ago. In 1884, Pepper was the first to describe the presence of fatty liver in a diabetic patient. Thereafter, several publications discussed the similarities between liver histology of patients with alcoholic liver disease and those with severe obesity and diabetes [2]. However, it was not until 1980, when Ludwig first used the term of NASH to describe the progressive form of liver disease in obese, diabetic female patients in the absence of alcohol intake [3]. At that time it was thought to be an adult disease. Three years later, the first three cases of NAFLD were described in children [4]. Obesity, insulin resistance, metabolic syndrome, and dyslipidemia are well known risk factors associated with NAFLD. Given the rapid rise of obesity rates and diabetes, NAFLD is the most common cause of chronic liver disease and it is of major public concern secondary to the increase in prevalence. The aim of this review article is to provide an understanding about current knowledge related to pediatric NAFLD and to highlight differences between the adult and pediatric disease.

Section snippets

Literature Search

An extensive structured keyword search using the PubMed database was performed to identify studies providing information about pediatric and adult NAFLD, NASH, epidemiology, natural history, genetics, diagnosis, and management. Studies published in English were included up to August 2015, focusing on studies published within the last 10 years. We also manually searched the references of retrieved articles to identify additional relevant studies. Further updates were performed whenever needed

Epidemiology and Risk Factors

Epidemiologic studies in adults have estimated that the prevalence of NAFLD in the Western countries ranges from 20% to 30% [5] with approximately 10–20% of these patients having NASH. The presence of type 2 diabetes is associated with an increased prevalence of NAFLD (ranging from 45% to 75%), and these patients are at a higher risk for NASH and developing liver-related complications [6].

Estimating the true prevalence of NAFLD in children is very challenging. An autopsy based study concluded

Natural History

The natural history of adult NAFLD is well established with NASH being considered the aggressive form of the disease. However, this concept has been recently challenged with a large longitudinal study that demonstrated that only fibrosis stage, and no other histological features, was the strongest predictor of long-term overall mortality and liver disease complications [19]. NAFLD-related cirrhosis is currently the second leading etiology of liver disease among adults awaiting liver

Pathogenesis of NAFLD: Multiple Parallel Hits

The pathogenesis of NAFLD has still to be fully elucidated. A two hit hypothesis was initially described involving the accumulation of triglycerides within the hepatocyte, also known as the first hit, followed by a second hit that leads to hepatocellular injury and inflammation [30]. Insulin resistance causes increased influx of free fatty acids (FFAs) to the liver, causing fatty infiltration and the increased levels are enough to induce liver damage via lipid peroxidation, formation of

Histologic Features of Pediatric NAFLD: Similarities and Differences from Adult NAFLD

As in adults, liver biopsy remains the ‘the gold standard’ for establishing the diagnosis of NAFLD in children and grading and staging the severity; in other words, distinguishing steatosis from steatohepatitis, and assessing the degree of fibrosis. The predictive value of liver enzymes for NASH and fibrosis is poor and as it was previously demonstrated in adults, in children the entire spectrum of NAFLD including NASH and fibrosis can be found in those with normal liver enzymes [43]. Moreover,

Diagnosis of NAFLD

Given the high prevalence of NAFLD and the serious limitations of liver biopsy in children, it is paramount to have a simple noninvasive method to screen for this disease. An expert committee for the prevention, assessment, and treatment of overweight and obese children and adolescents recommended that every child over the age of 10 years with a BMI ≥ 95th percentile or those with BMI between 85th percentile and 94th percentile with risk factors (family history of diabetes, cardiovascular

Role of Nutrition and Weight Loss Surgery

Change in lifestyle, targeting gradual weight reduction, and physical exercise continues to be the mainstay of treatment for NAFLD in children [32]. Weight reduction has been widely studied in adults and has been shown to improve not only the biochemical parameter but also the liver histology. Based on studies in adults, weight loss of 7–10% was associated with significant improvement in liver histology. The relative efficacy of weight loss and degree of weight loss needed to induce histologic

Conclusions

Pediatric NAFLD is now the most common cause of liver disease in children. Its incidence is predicted to continue to rise with the increase in pediatric overweight and obesity. The full spectrum of the disease can occur in children from isolated hepatic steatosis, the most common form that seems to be a relatively benign condition to NASH that may progress to advanced fibrosis and cirrhosis. At present, only a liver biopsy can differentiate hepatic steatosis from NASH and reliable noninvasive

Conflict of Interest

No conflict of interest for any of the authors.

Acknowledgements

Supported by the ACG Junior Faculty Development Award to NA and by NIH grants (DK076852 and DK082451) to AEF.

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