Recognition and Management of Children with Nonalcoholic Fatty Liver Disease
Ethnicity
NAFLD is most common in Hispanics, followed by Asians, Caucasians, and African Americans. Research suggests that genetics may be largely responsible for these ethnic disparities. For example, the I148M allele of PNPLA3 (a single nucleotide polymorphism) is strongly associated with steatosis, NASH, and fibrosis [21] and is most common in Hispanics, with a 50% carrier frequency in some cohorts [22]. Conversely, African Americans are more likely to carry the S453I allele of PNPLA3, which is associated with decreased hepatic steatosis [22]. There is also considerable variability within ethnic groups. For example, Mexican-American children appear to be at the highest risk for steatosis or NASH among Hispanics, whereas Filipino-American children are believed to have higher disease prevalence than Cambodian or Vietnamese Americans [1].
Comorbidities
NAFLD is associated with obesity, insulin resistance and diabetes, cardiovascular disease, the metabolic syndrome [23], decreased quality of life [24,25], and obstructive sleep apnea (OSA). These associations generally hold even after controlling for the other confounders listed. It is important to note that these data come largely from cross-sectional studies and direct causation has yet to be determined.
Insulin resistance in particular is strongly associated with NAFLD—so much so, in fact, that some consider it to be the hepatic manifestation of the metabolic syndrome. Additionally, children with features of the metabolic syndrome are more likely to have advanced histologic features of NAFLD [23]. There are also intriguing data from small pediatric studies to suggest that OSA may contribute to the development of hepatic fibrosis. In one study of 25 children with biopsy-proven NAFLD, for example, the presence of OSA and hypoxemia correlated with the degree of hepatic fibrosis [26]. In a slightly larger study of 65 children, OSA was also strongly associated with significant hepatic fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23–7.42; P < 0.001). The duration of hypoxemia also correlated with histologic findings of inflammation and circulating biomarkers of apoptosis and fibrogenesis [27].
Other Laboratory Tests
Several studies have documented an association between elevated gamma-glutamyl transferase (GGT) and hepatic fibrosis [28,29], though others have been conflicting [30,31]. Pediatric studies have also demonstrated an inverse correlation between NASH and total bilirubin [32], serum potassium [33], and serum ceruloplasmin [34]. In addition, there are a number of serum biomarkers or biomarker panels commercially available for use in adults. Because similar efficacy data are unavailable in children, however, serum biomarkers should be primarily used for research purposes only.
Who should be screened for NAFLD? And how?
Published professional society recommendations differ significantly with regards to screening. In 2007, the American Academy of Pediatrics suggested screening obese children over 10 years of age or overweight children with additional risk factors with biannual liver tests [35]. There were no management recommendations made for elevated aminotransferase levels other than for subspecialty referral. In 2012, the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recommended obtaining an ultrasound and liver tests in every obese child [36]. One month later, however, the American Gastroenterological Association, American Association for the Study of Liver Disease, and the American College of Gastroenterology published joint guidelines without screening recommendations “due to a paucity of evidence” [37].
Because these statements conflict and are based heavily on expert opinion, one should consider the risks, benefits, and costs to screening large numbers of patients. Until additional research clarifies this controversy, we suggest that providers individualize their screening practices to their population and the risks of each individual patient. For example, we would consider screening children who are obese; Hispanic or Asian; have multiple features of the metabolic syndrome; and/or those who have a family history of NAFLD. Further, we recommend screening children for NAFLD with serum liver enzymes only and not with ultrasonography.
Case Continued: Laboratory Results
ALT and GGT tests are ordered and the results are as follows:
What is the differential for children with suspected NAFLD?
Autoimmune Hepatitis (AIH)
AIH is a progressive necro-inflammatory disorder of the liver characterized by elevated aminotransferases, positive autoantibodies, and distinctive histologic features. AIH is believed to occur in genetically predisposed patients in response to an environmental trigger. There is a female predominance and it can present in any age or ethnic group.
AIH is divided in 2 subtypes. Type 1 disease is characterized by a positive antinuclear (ANA) antibody and anti-smooth muscle antibody. More commonly, it presents in adolescence with an indolent course—many patients are asymptomatic until they develop features of cirrhosis and portal hypertension. Conversely, type 2 AIH is characterized by a positive liver kidney microsomal (LKM) antibody and tends to present acutely in young children. It is important to note that antibody titers can be falsely positive in a significant percentage of patients and, in such cases, are often mildly elevated [38]. We strongly suggest children with positive autoantibody titers be evaluated by a specialist.
Treatment should be started promptly to avoid progression to cirrhosis and should also done so in consultation with a pediatric gastroenterologist or hepatologist. The prognosis of AIH with immunosuppression is favorable, with long-term remission rates of approximately 80%. Transplantation is typically required in the remaining 10% to 20% [39].
Celiac Disease
Celiac disease is an autoimmune, inflammatory enteropathy caused by exposure to gluten in genetically susceptible individuals. Up to a third of all children presenting with celiac will have an elevated serum ALT [40]. Additional symptoms/features are both variable and nonspecific: abdominal pain, poor growth, diarrhea, or constipation, among others. Celiac is diagnosed by duodenal biopsy or a sufficiently elevated tissue transglutaminase antibody level [41]. Treatment with a strict gluten-free diet will resolve the enteropathy and normalize the serum aminotransferases.
Wilson’s Disease
Wilson’s disease is a metabolic disorder leading to copper deposition in the liver, brain, cornea, and kidneys. It is caused by an ATP7B gene mutation and inherited in an autosomal recessive fashion. Patients may present with asymptomatic liver disease, chronic hepatitis, acute liver failure, or with symptoms of portal hypertension. Neuropsychiatric symptoms may also be prominent. Screening tests include a serum ceruloplasmin and 24-hour urinary copper quantification. Because diagnosing Wilson’s disease can be challenging, however, further testing should occur in consultation with a pediatric gastroenterologist or hepatologist.
Viral Hepatitis
Chronic viral infections such as hepatitis B and C are still common etiologies of liver disease in the United States. However, universal vaccination and blood donor screening have reduced the risk of transmission; new antiviral agents will likely further decrease the prevalence and transmission risk over time. Acute viral hepatitis—cytomegalovirus, Epstein-Barr virus, hepatitis A, or hepatitis E—should also be considered in children who present with appropriate symptoms and an elevated ALT.
Drug-Induced
Drug-induced liver injury (DILI) can present with elevated serum aminotransferases (hepatocellular pattern), an elevated bilirubin (cholestatic pattern), or a mixed picture. Idiosyncratic DILI in children is commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. Substance abuse, including alcohol, is common and should also be investigated as the source of underlying liver disease.
Muscle Disease
Aspartate aminotransferase (AST) and ALT are present in hepatocytes, myocytes, and red blood cells, among other tissues. Thus, children with congenital myopathies or myositis can have elevated aminotransferases, typically with the AST higher than the ALT. In these patients, checking a creatine phosphokinase (CPK) level may lead to the correct diagnosis and limit unnecessary testing.
Other Metabolic Disorders
Myriad metabolic disorders present with liver disease and/or elevated serum aminotransferase levels. Individually, these conditions are rare but, collectively, are relatively common. Two of the more occult conditions—lysosomal acid lipase deficiency (LAL-D) and alpha-1 antitrypsin (A1A) deficiency—are discussed in further detail below.
LAL-D is an autosomal recessive disease resulting in the accumulation of cholesterol esters and triglycerides in lysosomes. Patients typically present with hepatomegaly and mildly elevated aminotransferases, an elevated LDL, low HDL cholesterol, and increased hepatic echogenicity on ultrasound. If a biopsy is obtained, microvesicular steatosis is predominant as opposed to macrovesicular steatosis found in NAFLD. The diagnosis of LAL-D can be made on a commercially available dry blood spot enzymatic assay or genetic testing and treatment has recently been FDA approved.
A1A deficiency is an autosomal recessive disease diagnosable by an alpha-1-antitrypsin phenotype. The clinical presentation is characterized by neonatal cholestasis in the infantile form and by hepatitis, cirrhosis and portal hypertension in older children. Classic symptoms of emphysema and chronic lung disease present in adulthood.
What further testing should be performed in children with suspected NAFLD?
For obese children with an elevated ALT or evidence of increased hepatic echogenicity, ESPGHAN recommends targeting the workup according to the child’s age [36]. According to their consensus statement, they recommend an upfront, thorough laboratory evaluation in children less than 10 years of age and consideration of a liver biopsy upon completion. For children over 10 years of age at low risk for NASH or fibrosis, additional laboratory evaluation is suggested 3 to 6 months after failed lifestyle interventions. In general, the recommended workup includes testing for conditions discussed in the section above such as viral hepatitis, AIH, Wilson’s disease, and others. If negative, ESPGHAN states that a liver biopsy should be “considered.”
The question of whether or not to obtain a liver biopsy is controversial, though there are several clear advantages to doing so. First, biopsy is the gold standard test for diagnosing NAFLD and there are no highly accurate, noninvasive tests currently approved for use in children. Second, biopsy is a more definitive means of ruling out competing diagnoses such as AIH. Third, biopsy may provide prognostic data. In a retrospective adult study of 136 patients, for example, those who presented with simple steatosis had a roughly 3% chance of progressing to cirrhosis within 10 years. If a patient within this cohort presented with NASH, however, the progression risk was approximately 30% within 5 years [42,43]. Fourth, due to potential side effects of medications, position papers recommend obtaining a liver biopsy prior to the initiation of pharmacotherapy [37]. Lastly, the risk for serious morbidity from a liver biopsy is low [44,45]. Alternatively, one must acknowledge the risks of liver biopsy: morbidity, sampling bias, invasiveness, cost, and sedation risks in children.
