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AbstrAct• Objective:Toreviewdiagnosticchallengesandman-

agementstrategiesinchildrenwithnonalcoholicfattyliverdisease(NAFLD).

• Methods:Reviewoftheliteraure.• Results:NAFLDiscommonintheUnitedStatesand

shouldbesuspectedinoverweightorobesechildrenwith an elevated serum alanine aminotransferaselevel.The differential diagnosis for these patients isbroad,however,andliverbiopsy—thegoldstandardtest—should be undertaken selectively after an ap-propriate workup. Patients should be counseled onlifestylemodifications,whereasvitaminEtherapycanbeinitiatedforthosewithbiopsy-provendisease.

• Conclusion: Providersshouldhaveahighdegreeofsuspicion for NAFLD, approaching the workup anddiagnosis inan incremental, step-wise fashion.Fur-therresearchisneededtostandardizethediagnosticapproach, identify reliable, noninvasive diagnosticmeasures,anddevelopnoveltreatmentmodalities.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, affecting approximately 10% of children

and a third of all adults in the United States [1–3]. It is a significant public health challenge and is estimated to soon be the number one indication for liver transplanta-tion in adults.

NAFLD is a generic term encompassing 2 distinct conditions defined by their histopathology: simple ste-atosis and nonalcoholic steatohepatitis (NASH). Simple steatosis is characterized by predominantly macrovesicu-lar—meaning large droplet—cytoplasmic lipid inclusions found in ≥ 5% of hepatocytes. NASH is defined as hepatic steatosis plus the additional features of inflammation, hepatocyte ballooning, and/or fibrosis. There are some adult data [4-6] and 1 retrospective pediatric study [7] demonstrating that over time, NAFLD may progress.

That is, steatosis may progress to NASH and some pa-tients with fibrosis will ultimately develop cirrhosis. If intervention is provided early in the histologic spectrum, NAFLD can be reversed [4,8] and late complications—such as cirrhosis, hepatocellular carcinoma, or liver trans-plantation—may be prevented.

It is important to highlight that the above definitions are based on histology and that a liver biopsy cannot be reasonably obtained in such a large percentage of the U.S. population. This case-based review will therefore focus primarily on the current diagnostic challenges facing health care providers as well as management strategies in children with presumed NAFLD.

CASE STUDYInitial Presentation

As you finish your charts at the end of a busy clinic day, you identify 3 patients who may have

NAFLD:

History

All 3 patients presented to your office for a routine annual physical before the start of the school year and are asymptomatic. None of the patients has a family history of liver disease and their previously diagnosed comor-bidities are listed in the table above. No patient is taking medications other than patient C, who is on metformin. All 3 children have a smooth, velvety rash on their necks

Recognition and Management of Children with Nonalcoholic Fatty Liver DiseaseBryan Rudolph, MD, and Debora Kogan-Liberman, MD

Case-based review

From the Albert Einstein College of Medicine, Division of Pediatric Gastroenterology and Nutrition, Children’s Hospital at Montefiore, Bronx, NY.

Pt

Age

Ethnicity/ gender

BMI, Percentile

Comorbidities

A 12 Hispanicmale 85th–95th Hypercholesterolemia

B 5 Caucasianmale >95th Obstructivesleepapnea

C 15 African-Americanfemale >95th Pre-hypertension,

diabetes

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NAFLD iN chiLDreN

consistent with acanthosis nigricans with an otherwise normal physical exam. The liver and spleen are difficult to palpate but are seemingly normal.

• What is the typical presentation for a childwithNAFLD?

Most children with NAFLD are asymptomatic, though some may present with vague right upper quadrant abdominal pain. It is unclear, however, if the pain is caused by NAFLD or is rather an unrelated symptom that brings the child to the attention of a physician. In addition, hepatomegaly can be found in over 30% to 40% of patients [9]. For children without abdominal pain or hepatomegaly, most are recognized by an elevated serum alanine aminotransferase (ALT) or findings of increased liver echogenicity on ultrasonography.

SerumAlanineAminotransferase

Serum aminotransferases are one of the more common screening tests for NAFLD. However, ALT is highly insensitive at commonly used thresholds and is also non-specific. As documented in the SAFETY study, the upper limit of normal for ALT in healthy children should be set around 25 U/L in boys and 22 U/L in girls [10]. Yet even at these thresholds, the sensitivity of ALT to diagnose NAFLD is 80% in boys and 92% in girls, whereas specific-ity is 79% and 85%, respectively [10]. These findings are largely consistent with adult studies [11–14]. Furthermore, ALT does not correlate well with disease severity and chil-dren may still have NASH or significant fibrosis with nor-mal values. In a well-characterized cohort of 91 children with biopsy-proven NAFLD, for example, early fibrosis was identified in 12% of children with a normal ALT (≤ 22 U/L for girls and ≤ 25 U/L in boys) [15]. Advanced fibrosis or cirrhosis was seen in 9% of children with an ALT up to 2 times this upper limit [15]. Thus, reliance on the serum ALT may significantly underestimate the prevalence and severity of liver injury.

Ultrasonography

Children with NAFLD typically have findings of increased hepatic echogenicity on abdominal ultrasonography. How-ever, there are multiple limitations to sonography. First, ultrasound is insensitive for identifying mild steatosis if less than 30% of hepatocytes are affected [16,17]. Second,

increased hepatic echogenicity is nonspecific and may be caused by inflammation, fibrosis, or intrahepatic accu-mulation of iron, copper, or glycogen. Third, there can be considerable inter- and intra-operator variability. And lastly, there is some evidence that ultrasounds do not add benefit to diagnosing children with NAFLD [18].

• Which patients are at risk for developing hepaticsteatosisandNASH?

Weight,Age,andGender

There is a strong, direct correlation between body mass index (BMI) and NAFLD. The Study of Child and Adolescent Liver Epidemiology (SCALE)—a sentinel pediatric autopsy study of 742 children—found that 5% of normal weight children, 16% of overweight children, and 38% of obese children had NAFLD. The SCALE study also demonstrated an increasing prevalence with age, such that NAFLD was present in 17.3% of 15- to 19-year-olds but only in 0.2% of 2- to 4-year-olds [1]. With regards to gender, NAFLD is roughly twice as prevalent in males [18–20]. While the exact etiology of this difference is unclear, hormonal differences are a lead-ing hypothesis.

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 Vietnam-ese Americans [1].

Comorbidities

NAFLD is associated with obesity, insulin resistance and diabetes, cardiovascular disease, the metabolic syn-

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drome [23], decreased quality of life [24,25], and obstruc-tive 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 syn-drome. Additionally, children with features of the meta-bolic 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 con-tribute 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 signifi-cant hepatic fibrosis (odds ratio, 5.91; 95% confidence inter-val, 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].

OtherLaboratoryTests

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 biomark-ers 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.

• WhoshouldbescreenedforNAFLD?Andhow?

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 chil-dren 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.

CaseContinued:LaboratoryResults

ALT and GGT tests are ordered and the results are as follows:

• Whatisthedifferential forchildrenwithsus-pectedNAFLD?

The differential for NAFLD is remarkably broad and includes any condition that could lead to an elevated ALT or hepatic steatosis. Several of the more common etiologies in the differential are listed in the proceeding section. A list of “red flags” is shown in the Table and, if any are present, should alert the practitioner to the pos-sible presence of alternative disease.

AutoimmuneHepatitis(AIH)

AIH is a progressive necro-inflammatory disorder of the liver characterized by elevated aminotransferases, positive

Case-based review

Pt

Age

Ethnicity/gender

BMI, Percentile

Comorbidities

ALT (U/L)

GGT (U/L)

A 12 Hispanicmale 85th–95th Hyper-

cholesterolemia49 52

B 5 Caucasianmale >95th Obstructivesleep

apnea51 26

C 15African-

Americanfemale

>95th Pre-hypertension,diabetes 36 18

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NAFLD iN chiLDreN

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 micro-somal (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 pro-gression to cirrhosis and should also done so in consulta-tion with a pediatric gastroenterologist or hepatologist. The prognosis of AIH with immunosuppression is favor-able, with long-term remission rates of approximately 80%. Transplantation is typically required in the remain-ing 10% to 20% [39].

CeliacDisease

Celiac disease is an autoimmune, inflammatory enteropa-thy 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]. Addition-al 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’sDisease

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. Neuro-psychiatric symptoms may also be prominent. Screening tests include a serum ceruloplasmin and 24-hour urinary copper quantification. Because diagnosing Wilson’s dis-ease can be challenging, however, further testing should occur in consultation with a pediatric gastroenterologist or hepatologist.

ViralHepatitis

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 screen-ing have reduced the risk of transmission; new antiviral agents will likely further decrease the prevalence and transmission risk over time. Acute viral hepatitis—cyto-megalovirus, 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 pat-tern), an elevated bilirubin (cholestatic pattern), or a mixed picture. Idiosyncratic DILI in children is com-monly 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 underly-ing liver disease.

MuscleDisease

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.

OtherMetabolicDisorders

Myriad metabolic disorders present with liver disease and/or elevated serum aminotransferase levels. Indi-

Table. RedFlags

ALT>100U/L

AST>ALT

BMI<85thpercentile

Directhyperbilirubinemia(≥0.5mg/dL)

Splenomegaly

Symptomatic(eg,fever,jointpains)

Youngage(≤3yearsold)

www.jcomjournal.com Vol. 23, No. 3 March 2016 JCOM 139

vidually, 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 diag-nosable 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 adult-hood.

• What further testing should beperformed inchildrenwithsuspectedNAFLD?

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 bi-opsy 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 progress-ing 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, posi-tion 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.

Our suggested approach to these patients is shown in the Figure. Specifically, for older, asymptomatic, over-weight or obese children with a mildly elevated ALT and normal direct bilirubin level, we believe that a trial of life-syle modification can be safely initated prior to initiation of extensive laboratory testing or referral for biopsy. With that said, for children with any of the other “red flags” listed in the Table, early referral to an expert should be strongly considered.

CaseContinued:BiopsyResults

You refer your patients to a gastroenterologist. Tests for viral hepatitis, A1A deficiency, celiac dis-

ease, muscle disorders, Wilson’s disease, and AIH are nega-tive. Ultimately, a liver biopsy is performed on all 3 children without complications. The results are presented below.

• WhatisthetreatmentofNAFLD?

LifestyleModification

Lifestyle modifications are the mainstay of treatment for NAFLD. In adult studies, weight loss of more than 5% reduces hepatic steatosis whereas weight loss of more than 9% improves or eliminates NASH [47]. We recom-

Case-based review

Pt

Age

Ethnicity/Gender

BMI

Comorbidities

ALT (U/L)

GGT (U/L)

Pathology

A 12 Hispanicmale

85th–95th

Hyper-cholesterolemia 49 75 NASH,grade

2fibrosis

B 5 Caucasianmale >95th OSA 51 26 NASH,

nofibrosis

C 15African-

Americanfemale

>95th Pre-hypertension,diabetes 36 18 Steatosis,

nofibrosis

140 JCOM March 2016 Vol. 23, No. 3 www.jcomjournal.com

NAFLD iN chiLDreN

mend that children engage in age-appropriate, enjoyable, moderate- or vigorous-intensity aerobic activity for 60 minutes a day [48]. In addition, there should be a focus on reducing sedentary behavior by limiting screen time and a concerted effort to engage the family in lifestyle modifications.

Dietary interventions to treat NAFLD are less con-crete but there is a growing body of literature to suggest that dietary fructose is particularly harmful. In adults, for example, fructose consumption is associated with the development of NAFLD [49] and hepatic fibrosis [50]. Recent data in adolescents has similarly documented

Figure.DiagnosticalgorithmforchildrenwithpresumedNAFLD.Adaptedfromreference46.

ElevatedALTorincreasedechogenicityonultrasound

Thoroughhistoryandphysical

NAFLDlikelyif:•Asymptomatic,otherthanright

upperquadrantabdominalpain•Overweight/obese•Normalbilirubin/INR•Olderpatients(>3years)•ALT≤100U/L•Evidenceofmetabolicsyndrome

NAFLDlesslikelyif:•Symptomatic•Normal/underweight•Elevatedbilirubin/INR•Youngerpatients(<3years)•ALT>100U/L•Signs/symptomsofunderlying

liverdisease

Totalparenteralnutrition,hepatotoxicmedications,drugs,oralcoholuse?

WorkupandreferralasindicatedLiverbiopsymightbeindicated

Lifestylemodification,weightloss,andrepeatlivertests

No

IfrepeatALTremainselevated,performrightupperquadrantultrasoundandtestforthefollowing:

1)Fullhepaticpanel:INR, GGT, platelet count2)Viralhepatitis:HBsAg, HCV Ab3)α-1antitrypsindeficiency:A1A phenotype4)Celiacdisease:total IgA, tTG IgA5)Muscledisorders:CPK6)Wilson’sdisease:serum ceruloplasmin7)Autoimmunehepatitis:ANA, anti-smooth muscle Ab,

liver kidney microsomal Ab, total IgG

Referralforpossibleliverbiopsy

Screeningtestsnegative

Screeningtestspositive

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an association between NAFLD incidence and energy-adjusted fructose intake [51]. It is worth highlighting that these clinical findings are also biologically plausible, as fructose is primarily metabolized within hepatocytes and has recently been shown to increase de novo lipo-genesis [52,53]. In general, we suggest a well-balanced diet of unprocessed foods—that is, with limited added sugars—sufficient to induce gradual weight loss in older children or body weight maintenance in younger children.

Medications

Vitamin E is the only medication with proven efficacy in children, as demonstrated in the TONIC trial [20]. TONIC was a double-blind, multicenter, placebo-con-trolled study with 3 treatment arms: 800 IU of vitamin E daily, 1000 mg of metformin daily, or placebo. Met-formin did not reduce the serum ALT or significantly improve liver histology and should therefore not be used for these indications. However, patients treated with vi-tamin E had a statistically significant improvement in the NAFLD activity score (a histologic grading system com-prising steatosis, inflammation, and hepatocyte balloon-ing) and resolution of NASH when compared to placebo. For these reasons—as well as a paucity of other viable treatment options—vitamin E is routinely prescribed for children with biopsy-proven NASH. However, the long- term risks of high-dose vitamin E therapy in children are largely unknown.

Polyunsaturated fats such as docosahexaenoic acid (DHA) [54] and probiotics such as VSL #3 [55] have showed efficacy reducing hepatic steatosis in small, randomized clinical trials. Both medications need to be further validated before they can be recommended for use in children. Conversely, ursodeoxycholic acid has not been found to be efficacious in children with NAFLD [56], whereas phase IIb data on cysteamine is expected soon. There are currently insufficient data to recommend bariatric surgery as treatment for NAFLD in adolescence.

CaseContinued:Follow-up

After their biopsies, both patients with NASH (patients A and B) are started on vitamin E ther-

apy. All 3 patients continue to report for follow-up visits without short-term complications, though they have still been unable to significantly reduce their body mass index and have a persistently elevated serum ALT.

summary

NAFLD is a common condition in the United States with serious personal and public health ramifications. This case-based review highlights the diagnostic and management challenges in children with NAFLD and the unique role primary care providers play in caring for these patients.

Corresponding author: Bryan Rudolph, MD, Albert Ein-stein College of Medicine, Division of Pediatric Gastroen-terology and Nutrition, Children’s Hospital at Montefiore, 3415 Bainbridge Ave., Bronx, NY 10467, brudolph@mon-tefiore.org.

Financial disclosures: None.

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