Over the past 40 years, there has been a growing epidemic of pediatric obesity and obesity-related conditions. Among those, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have risen from an unnamed entity to the most common form of chronic liver disease in pediatrics.1 NASH was first named in 1980 by Ludwig et al.2 to describe the observed pattern of fatty changes, lobular hepatitis, focal necrosis, inflammatory infiltrates, and fibrosis found on biopsy in predominantly obese adults with no significant history of alcohol consumption. Since this initial description, NASH has been understood as a subtype of NAFLD, a consequence of obesity and metabolic syndrome.3 Whereas NAFLD refers to a spectrum of liver pathology involving hepatocyte lipid accumulation (steatosis found in >5% of hepatocytes) in the absence of alcohol abuse or other liver diseases, NASH is characterized by the histologic presence of inflammation with or without fibrosis on liver biopsy. NASH is differentiated clinically from NAFLD by its potential progression to fibrosis and ultimately cirrhosis associated with liver failure and hepatocellular carcinoma.4
NAFLD has grown into one of the predominant hepatic diseases internationally in the past several decades paralleling increasing rates of obesity worldwide. Unsurprisingly, given its association with obesity and metabolic syndrome, NAFLD now accounts for 75% of chronic liver disease (CLD) cases in the US population at a time when the prevalence of other CLD has remained relatively static.5 NASH is a histopathologic diagnosis, poorly assessed via noninvasive means. The resulting paucity of data, particularly among pediatric populations, makes the full prevalence of NAFLD and subsequently NASH difficult to determine. In the only study of its kind to date, the Study of Child and Adolescent Liver Epidemiology revealed NAFLD as the most common form of liver disease, occurring in 9.6% of children between ages 2 and 19 years.1 Prevalence increased with age (0.7% among 2- to 4-year-olds vs 17.3% among 15- to 19-year-olds), male gender (11.1% vs 7.9% for the female gender), and Hispanic ethnicity (11.8% vs 8.6% for non-Hispanic whites, 10.2% for Asians, and 1.5% among non-Hispanic blacks).1 Among those children with NAFLD, 23% (or 3% of the total population) exhibited features of NASH. This study translates into an estimated NAFLD prevalence of greater than 6.5 million children nationwide, including approximately 38% of obese children. More significantly, however, is that the prevalence of NAFLD among children has more than doubled over the past three decades despite nationwide efforts to diminish pediatric obesity and related risk factors.6
To date, the precise pathophysiology of NASH remains largely speculative. Historically, a “two-hit” hypothesis was used to describe the transition from NAFLD to NASH. Under the “two-hit” hypothesis, the initial process of steatosis (first hit) would increase susceptibility to hepatocyte injury. A second “hit,” such as oxidative stress resulting in lipid peroxidation, was theorized to initiate the progression to steatohepatitis.7 Recent theories suggest that the “two-hit” hypothesis may be an oversimplification and that a more complete mechanism would require lipid deposition as previously described, but necessitate distinct pathways consisting of various organ systems, hormonal influences, dietary patterns, intestinal flora, and genetic/epigenetic variability.8 These pathways, however, are not completely defined and are confounded by the difficulty in determining the direction of causality among the observed correlations and risk factors.
Despite the increasing complexity, the most significant risk factors associated with NAFLD remain obesity and metabolic syndrome.9 Intrahepatic lipid accumulation has independently been shown to increase inflammatory cytokine production leading to hepatocellular injury and fibrosis. Elevated tumor necrosis factor-alpha and interleukin-6 levels, in particular, have been correlated with increased obesity and NASH severity.10,11 However, although obesity and metabolic syndrome have been recognized as the most significant risk factors, NAFLD has been reported in 5% of normal weight children, emphasizing that even though obesity remains the major risk factor, NASH does not exclusively occur in the obese population.1
Myriad genetic mutations resulting in metabolic abnormalities, alteration of normal hepatic lipid regulation, regulation of reactive oxygen species, and abnormal cytokine production may lead to hepatic steatosis or development of obesity and metabolic syndrome. However, it is important to note that although over 100 genes have been implicated in obesity, no single gene has been identified as integral to more than a small fraction of the obese or NASH population. This suggests that although genetic makeup may contribute, obesity, and similarly NASH, is a polygenetic, multifactorial disease reliant on epigenetic and environmental factors.8 Despite this, genetic variants may offer a means to differentiate risk factors between ethnic groups independent of environmental factors. Specifically, two variants within the patatin-like phospholipase 3 gene exemplify this idea. The I148M variant has been strongly associated with increased hepatic steatosis and consequently has been identified in nearly 50% of Hispanics in some studies, whereas the S453I variant associated with decreased hepatic steatosis has been found primarily in African American patients.12
The natural history of NAFLD and NASH is similarly complex, with a spectrum of the disease ranging from simple steatosis notable for its benign and reversible course to steatohepatitis (NASH) resulting in fibrosis and cirrhosis ultimately leading to end-stage-liver disease.13 The later stages of this progression are older age, increased obesity, elevated triglycerides, and worsening insulin resistance.3 This progression is variable, with the rate of progression currently believed to be a factor of histologic severity worsened by the presence of metabolic syndrome and insulin resistance.9 Longitudinal data on pediatric patients are limited, comprised of individual small-scale studies with varying reports regarding the progression of steatosis to NASH. One of the largest such studies followed 66 patients with NAFLD over 20 years and reported an approximately 14-fold increase in all-cause mortality or need for liver transplantation when compared to an age-/gender-matched population. In addition, progression from steatosis to NASH was seen in four patients without fibrosis on initial biospy.13 Histopathologically, the pediatric presentation of NASH differs from the adult presentation in the hepatocyte injury pattern and disease course.
Unlike adult populations, it appears that full progression to cirrhosis is not common within the pediatric presentation of NASH, often delaying until adulthood despite frequently observed hepatic fibrosis.14 This deviation from the natural history of adult NASH, when combined with the need for additional large-scale longitudinal pediatric studies, further complicates attempts to identify patients who may progress from benign NAFLD to NASH. Unfortunately, severity of fibrosis serves as one of the few recognized predictors of disease progression. The estimated 5% to 10% of patients with NAFLD who present with advanced fibrosis represent a stunning number of children at high-risk for progression to NASH and emphasizes the need for advances in early screening and diagnosis of NAFLD.8
NAFLD is an insidious disease and often times asymptomatic.8 Some patients may present with right upper quadrant pain. Signs of metabolic syndrome are often present, such as increased waist circumference and acanthosis nigricans. Hepatomegaly is not always present and is hard to appreciate on physical examination but can be detected by imaging studies. There are limited data on the progression of NAFLD in the pediatric population. Although some have persistent steatohepatitis, others can progress to cirrhosis rapidly8; therefore, it is difficult to identify those at high risk for progression.
Currently, conflicting screening guidelines for NAFLD have been published in the literature. Imaging techniques can be helpful in detecting liver diseases but are limited in the diagnosis of NAFLD because they cannot detect liver inflammation or fibrosis. Among them, liver ultrasound is a widely used method since it is inexpensive and noninvasive. On ultrasound, steatosis appears as a hyperechogenic image. The threshold of detection is 15% to 30% steatosis so it may miss early disease.8 Furthermore, ultrasound is an operator- and interpreter-dependent technique with variable sensitivity for detection. Computed tomography scans have greater specificity than ultrasound in detecting steatosis but are generally avoided if possible in the pediatric population due to radiation exposure. Magnetic resonance imaging (MRI) is a highly sensitive method for quantifying the degree of steatosis, detecting as little as 3% steatosis. However, it can be costly and time consuming, and in many pediatric patients requires sedation. Magnetic resonance spectroscopy is a noninvasive technique that has the highest accuracy among all imaging modalities in quantifying steatosis. However, limitations are similar to MRI due to cost and time. Elastography employs an ultrasound to measure the tissue vibrations caused by an impulse that passes through the liver. This method has the advantage of being noninvasive but its effectiveness in identifying inflammation and fibrosis is still under investigation in pediatrics.3
Liver biopsy remains the gold standard for diagnosis and is able to show the degree of hepatic fibrosis as well as evaluate for other potential causes of CLD. The disadvantage of liver biopsy is that it is an expensive procedure that is more invasive and carries a significant risk of morbidities. One can also run into sampling errors because hepatic fibrosis is not always evenly distributed. Therefore, liver biopsy is not a practical screening tool but should be considered in patients who are at increased risk for steatohepatitis, advanced fibrosis, or those whose diagnosis is unclear from serologic testing.15
The American Academy of Pediatrics in 2007 recommended biannual testing of liver functions in obese or overweight children older than age 10 years who have other risk factors. Serum aspartate transaminase and alanine transaminase (ALT) results of 2 times normal should raise suspicion.16 Traditionally, serum ALT is an inexpensive marker for screening. However, it is neither sensitive nor specific for NAFLD. The value of ALT to use for screening is also controversial. The SAFETY (Screening ALT For Elevation in Today's Youth) study examined the upper limit of ALT used in hospitals and found that it is variable across hospitals, with median sensitivity ranging from 32% to 48%. It additionally suggests that using a lower value of 25 U/L for boys and 22 U/L for girls increases detection for NAFLD (sensitivities are 72% in boys and 82% in girls and specificities are 79% in boys and 85% in girls).17 Gamma-glutamyl transpeptidase has also been found to be useful for the diagnosis of NAFLD and metabolic syndrome.3 Although these serologic markers are helpful in identifying patients at risk, NAFLD is a disease of exclusion. Therefore, it is critical to perform a comprehensive evaluation for other causes of liver disease, including various metabolic, infectious, pharmacologic, and genetic causes (Figure 1). Over the years, different organizations have made various recommendations for the diagnosis of NAFLD, including ultrasonography and screening liver tests for all children who are obese, but currently there is no consensus.
Approach to diagnosing nonalcoholic fatty liver disease. ALT, alanine transaminase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; INR, International Normalized Ratio; RUQ, right upper quadrant; TPN, total parenteral nutrition; US, ultrasound. Adapted from Fusillo and Rudolph.8
Treatment of NAFLD consists of managing the liver disease as well as comorbid metabolic diseases. Currently, weight loss is still the only effective intervention for NAFLD. Weight loss is associated with a significant improvement in liver function and liver histology. Specifically, it leads to decreased liver steatosis in pediatric NAFLD.15 Loss of as little as 5% to 10% of body weight is associated with long-term benefits. However, weight loss should be gradual to prevent worsening liver function. The initial approach to weight loss should consist of lifestyle modifications with diet and exercise. There is no specific dietary recommendation for treatment of NAFLD. In general, a well-balanced low-calorie diet with moderate physical activity is recommended for healthy weight loss. Bariatric surgery remains a controversial option. Although short-term follow up in adults who undergo gastric bypass shows reduction in weight and improvement in liver histology, long-term data as well as risk and benefits in the pediatric population are lacking.8
Pharmacologic management of NAFLD is still under development and investigation. Currently no one specific agent has been proven to effectively treat NAFLD in children. A large multicenter, randomized controlled trial comparing metformin, vitamin E, and placebo in pediatric NAFLD found no difference in the primary outcome (ALT reduction) among the subgroups. In the same trial, vitamin E was found to decrease the histologic activity of NAFLD in a subgroup of children, even though it did not improve liver function tests.18 Based on these results, some physicians may prescribe vitamin E (400 IU twice per day) for children with confirmed NAFLD on biopsy. In recent years, as the role of intestinal microbiota is being delineated, there are emerging studies that have promising results in preventing steatohepatitis using probiotics and prebiotics. Clinical application of probiotics and prebiotics in NAFLD warrants further studies, however, given the diversity of factors involved in delivery and duration.19
NAFLD has become the most common form of pediatric liver disease in the United States, and is heavily associated with obesity and metabolic syndrome. The high prevalence of this chronic disease and its potential to progress from a reversible state of steatosis to irreversible NASH resulting in fibrosis, cirrhosis, and ultimately liver failure marks it as a looming danger in public health. Given the nature of NAFLD, early identification and intervention are critical to the prevention and reversal of the disease. However, these efforts are often hindered by the insidious onset of the disease, its frequently asymptomatic presentation, and the relative difficulty of identifying the disease itself. As a histopathologic diagnosis, there are few methods to noninvasively screen for the disease, many of which are complicated by low sensitivities (such as ultrasound) that may miss early disease, or are cost prohibitory (such as MRI).
Although the complete pathogenesis of this disease remains a subject of debate, its risk factors and epidemiology have been well-documented in the literature.1,6,7 Understanding the risk factors associated with NAFLD including obesity, metabolic syndrome, Hispanic ethnicity, male gender, and increasing age allows physicians to identify high-risk people and guide further screening when prompted by clinical suspicion. Among screening methodologies, serum ALT serves as the most accessible and recommended first step in assessing a pediatric patient with suspected NAFLD. As evidenced in the SAFETY study, using threshold ALT values of 25 U/L in boys and 22 U/L in girls, the sensitivity of ALT screening can be increased by approximately 2-fold with minimal loss of specificity. Unfortunately, at the current time, only weight loss and prevention of metabolic syndrome are recognized treatments for NAFLD, although some studies suggest the use of vitamin E therapy among children with NAFLD proven on biopsy. However, through recognition of risk factors, appropriate diagnostic methods, and a high index of suspicion, pediatricians have the tools at their disposal to prevent and possibly even reverse the rise of the most common liver disease among our children.
- Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–1393. doi:10.1542/peds.2006-1212 [CrossRef]
- Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55(7):434–438.
- Biank V, Alemzadeh R. Pediatric non-alcoholic fatty liver disease. In: Voung MK, Sung JS, eds. Liver Disease and Peritonitis: Causes, Treatment and Prevention. 1st ed. New York, NY: Nova Science Publishers Inc; 2012.
- Anderson ML. Treating NASH. J Gastroenterol Hepatol. 2006;21(1 Pt 1):14. doi:10.1111/j.1440-1746.2005.04216.x [CrossRef]
- Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524–530.e1; quiz e60. doi:10.1016/j.cgh.2011.03.020 [CrossRef]
- Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J Pediatr. 2013;162(3):496–500.e1. doi:10.1016/j.jpeds.2012.08.043 [CrossRef]
- Day CP, James OFW. Steatohepatitis: a tale of two “hits”?Gastroenterology. 1998;114(4):842–845. doi:10.1016/S0016-5085(98)70599-2 [CrossRef]
- Fusillo S, Rudolph B. Nonalcoholic fatty liver disease. Pediatr Rev. 2015;36(5):198–205; quiz 206. doi:10.1542/pir.36-5-198 [CrossRef]
- Patton HM, Yates K, Unalp-Arida A, et al. Association between metabolic syndrome and liver histology among children with nonalcoholic fatty liver disease. Am J Gastroenterol. 2010;105(9):2093–2102. doi:10.1038/ajg.2010.152 [CrossRef]
- Park EJ, Lee JH, Yu G-Y, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208. doi:10.1016/j.cell.2009.12.052 [CrossRef]
- Hassan K, Bhalla V, El Regal ME, A-Kader HH. Nonalcoholic fatty liver disease: a comprehensive review of a growing epidemic. World J Gastroenterol. 2014;20(34):12082–12101. doi:10.3748/wjg.v20.i34.12082 [CrossRef]
- Speliotes EK, Butler JL, Palmer CD, et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. 2010;52(3):904–912. doi:10.1002/hep.23768 [CrossRef]
- Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–1544. doi:10.1136/gut.2008.171280 [CrossRef]
- Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42(3):641–649. doi:10.1002/hep.20842 [CrossRef]
- Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592–1609. doi:10.1053/j.gastro.2012.04.001 [CrossRef]
- Barlow SEExpert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(Suppl):S164–S192. doi:10.1542/peds.2007-2329C [CrossRef]
- Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology. 2010;138(4):1357–1364, 1364.e1–e2. doi:10.1053/j.gastro.2009.12.052 [CrossRef]
- Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659–1668. doi:10.1001/jama.2011.520 [CrossRef]
- Kelishadi R, Farajian S, Mirlohi M. Probiotics as a novel treatment for non-alcoholic fatty liver disease; a systematic review on the current evidences. Hepat Mon. 2013;13(4):e7233. doi:10.5812/hepatmon.7233 [CrossRef]