Review of Clinical Guidelines in the Diagnosis of Pediatric Nonalcoholic Fatty Liver Disease

Abbreviations

ALT

alanine aminotransferase

CMV

cytomegalovirus

EBV

Epstein‐Barr virus

HAART

highly active antiretroviral therapy

IBD

inflammatory bowel disease

IgA

immunoglobulin A

MRI‐PDFF

magnetic resonance proton density fat fraction

NAFLD

nonalcoholic fatty liver disease

NAS

NAFLD Activity Score

NASH

nonalcoholic steatohepatitis

NASPGHAN

North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

PCOS

polycystic ovarian syndrome

TPN

total parenteral nutrition

ULN

upper limit of normal

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by accumulation of fat in the liver in the absence of metabolic or genetic causes, alcohol abuse, liver‐toxic medication use, infection, or malnutrition. It is defined as greater than 5% steatosis on imaging or histopathology. NAFLD is currently the most common liver disease in children and one of the most common causes of liver transplant in adults.¹, ², ³, ⁴ NAFLD in children is more severe than in adults, with up to 15% of cases diagnosed with stage 3 fibrosis. Long‐term follow‐up studies evaluating the natural history of NAFLD in children are limited, but progression of liver disease to advanced fibrosis and cirrhosis is well documented during childhood.⁵

NAFLD can be subdivided based on severity as follows:

1. NAFLD: presence of steatosis (>5% microvesicular or macrovesicular fat accumulation)

2. Nonalcoholic steatohepatitis (NASH): presence of steatosis with lobular inflammation and hepatocellular injury

3. NAFLD or NASH with fibrosis

4. NAFLD or NASH with cirrhosis

The prevalence of NAFLD varies by ethnicity and sex. NAFLD is often accompanied by obesity, dyslipidemia, and insulin resistance. Dyslipidemia presents with elevated triglycerides and low high‐density lipoprotein cholesterol. Risk factors for NAFLD are as follows, with obstructive sleep apnea, type 2 diabetes, hypothyroidism, and panhypopituitarism being independent risk factors¹, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰:

• Race: caucasian, Asian, Hispanic

• Sex: male

• Obesity

• Genetic predisposition

• Metabolic syndrome

• In utero environment

• Type 2 diabetes mellitus, prediabetes

• Hypothyroidism

• Panhypopituitarism

• Obstructive sleep apnea

Without validated NAFLD‐specific markers, NAFLD is a diagnosis of exclusion, and other causes of fatty infiltration of the liver need to be carefully considered (Fig. 1).

FIG 1.

Differential diagnosis of NAFLD.

Screening and Diagnosis

Screening for NAFLD is recommended for all obese children 9 years or older as defined by a BMI above the 95th percentile, and should also be considered for overweight children with a family history of NAFLD or the presence of risk factors. ALT is the recommended initial screening test for NAFLD, and interpretation should be based on sex‐specific reference ranges (normal ALT <26 U/L in males and <22 U/L in females). In a study by Schwimmer et al.,¹¹ the sensitivity for NAFLD of sex‐specific ALT of greater than two times the upper limit of normal (ULN) in obese and overweight children was 88% with a specificity of 26%. In addition, NASH was observed more commonly in obese children with an ALT >80 U/L (41% compared with 21% in children with ALT <80 U/L). As such, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) clinical guidelines recommend additional diagnostic evaluation for overweight or obese children with an ALT >80 U/L.¹ An algorithm for initiation of further evaluation in children with NAFLD is proposed in Fig. 2.

FIG 2.

Proposed algorithm for screening and initiating further evaluation in children with suspected NAFLD.

Review of NASPGHAN and European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines, as well as American Association for the Study of Liver Diseases guidance, offers the following summary of current recommended screening and diagnostic testing: although targeted testing is recommended based on the children’s clinical presentation and symptoms, additional testing for an underlying hepatic causative factor is recommended for overweight and obese children with an ALT greater than two times the sex‐specific ULN (Table 1). Screening tests for metabolic syndrome and other comorbidities associated with NAFLD also should be considered.

TABLE 1.

Diagnostic and Screening Tests for Consideration in the Screening and Evaluation of NAFLD

Screening for NAFLD and Comorbidities

Tests for Hepatic Cause

Hepatic function panel International normalized ratio Complete blood count Basic metabolic panel Fasting glucose and insulin Hemoglobin A1c Fasting lipid profile Thyroid function tests

Ceruloplasmin, 24‐hour urine copper excretion, serum copper Antibodies against tissue transglutaminase IgA and total IgA a1‐Antitrypsin levels and phenotype Autoimmune hepatitis labs (anti‐smooth muscle antibody, anti‐liver kidney microsome antibody, antinuclear antibody) Amino and organic acids Plasma‐free fatty acids and acyl carnitine profile Urinary steroid metabolites Serum lactate, uric acid, iron, ferritin, pyruvate Viral hepatitis panel (EBV, CMV, hepatitis A/B/C) Serum immunoglobulins Ferritin and total iron Apolipoprotein B

Liver Biopsy

Liver biopsy remains the gold standard for the diagnosis of NAFLD. However, the decision to perform a liver biopsy in NAFLD is a challenge because it is an invasive procedure. Liver biopsy is considered safe in children with a complication rate from percutaneous liver biopsy between 1% and 4%.¹, ², ¹², ¹³

Most guidelines recommend a liver biopsy if the diagnosis is unclear, if there is concern for multiple diagnoses, or if there is persistent elevation of ALT despite lifestyle modifications.¹, ², ¹⁴, ¹⁵ The decision to pursue a liver biopsy in a child with suspected NAFLD should be based on clinical judgment and discussion with the patient and family. The role of liver biopsy in NAFLD is to exclude other causes of chronic liver disease while also allowing for assessment of severity of steatosis, steatotic hepatitis, and degree of fibrosis. A major limitation of liver biopsy is sampling variability due to lack of uniformity in liver disease involvement in NAFLD, and recommendations are for a liver biopsy length of >2 cm to ensure an adequate sample.¹

The NAFLD Activity Score (NAS) is a commonly used tool to assess liver involvement in NAFLD. The NAS was designed as a research tool and is not intended to confirm a clinical diagnosis. The NAS uses a semiquantitative scale to assess steatosis (0‐3 score), lobular inflammation (0‐3 score), and hepatocyte ballooning (0‐2 score). The majority of patients with NASH have an NAS score ≥5. Fibrosis in NAFLD is assessed separately and staged using a semiquantitative scale of 0 to 4.¹⁶, ¹⁷

Pediatric NAFLD and NASH histology has been found to have distinct features not seen in adults with the disease. This pattern is characterized by steatosis that is most prominent in zone 1, forming around the portal areas. Mild lobular and portal inflammation is present. Ballooned hepatocytes are mostly absent and, if present, are the same size as nonballooned cells. Fibrosis begins around the portal areas, with hepatocyte trapping by collagen and extension of short septations into the surrounding parenchyma. When bridging fibrosis develops, the bridges connect the portal areas, leaving the central veins alone. This pattern has been termed zone 1 borderline pattern (Fig. 3). By contrast, NAFLD histology in adults is typically characterized by zone 3 centered ballooning injury, inflammation, steatosis, and perisinusoidal fibrosis (Fig. 4).¹⁵, ¹⁸

FIG 3.

Pediatric‐type (type 2) NASH. Hematoxylin and eosin stain, original magnification 10×. Moderate hepatic steatosis with portal inflammation and portal tract expansion with an absence of perisinusoidal fibrosis and hepatocyte ballooning.

FIG 4.

Adult‐type (type 1) NASH. Hematoxylin and eosin stain, original magnification 10×. Mild hepatic steatosis with zone 3 distribution with lobular inflammation, hepatocyte ballooning, and perisinusoidal fibrosis.

The natural history of NAFLD in children undergoing dietary and lifestyle counseling is variable. Resolution of NASH has been observed in up to 28% of children, with 40% of children having improved fibrosis or steatosis.¹⁹ Progression of liver disease occurs in up to one‐third of children with NAFLD undergoing dietary and lifestyle modification, and it is marked by advancement of steatosis or fibrosis. This histological progression of liver disease is associated with loss of glucose homeostasis, worsening obesity, and an increasing ALT.²⁰

Imaging

Ultrasound is an inexpensive modality to detect hepatic steatosis. However, there are limitations of using ultrasound to quantify steatosis because although ultrasound has a reported sensitivity of 79.7% and specificity of 86.2% in the detection of hepatic steatosis for moderate‐to‐severe steatosis,²¹ ultrasound is not sensitive in children with a low percentage of steatosis (<30%).²² Given this limitation of low sensitivity and specificity of ultrasound at detecting and quantifying steatosis, the European guidelines and NASPGHAN guidelines differ in the use of ultrasound as a screening tool for NAFLD. Whereas the NASPGHAN guidelines recommend against the use of ultrasound because of low sensitivity and specificity, the European guidelines recognize ultrasound as an effective screening tool for steatosis in obese children with elevated ALT or signs of insulin resistance.², ¹⁶ Ultimately, the clinician should be aware of the limitations of ultrasound in NAFLD.

Advances in imaging technology have allowed for quantification of steatosis and fibrosis via other imaging modalities. Magnetic resonance proton density fat fraction (MRI‐PDFF) can be used to quantify hepatic steatosis,²³ and in children with NAFLD, MRI‐PDFF has a sensitivity of 74% at distinguishing between histological grade 1 and grade 2 and 3 hepatic steatosis.²⁴ In adults, magnetic resonance spectroscopy has also been used for the detection and quantification of hepatic steatosis, but magnetic resonance spectroscopy has not yet been validated in children.¹, ¹⁶

Vibration‐controlled transient elastography is validated as a method to assess for liver stiffness and hepatic fibrosis in children with NAFLD.²², ²⁵ Vibration‐controlled transient elastography reports hepatic stiffness in kilopascals, and in children with NAFLD, a liver stiffness of >9 kPa is associated with advanced histological fibrosis.²⁵ Noninvasive biomarkers, such as the enhanced liver fibrosis score, and scoring systems, such as the Fibrosis‐4 index, have been developed to trend fibrosis in NAFLD, but these are not currently validated in children.

Overall, the diagnosis of NAFLD in children remains a challenge. Pediatric NAFLD should be suspected for any child 9 years or older with obesity or if overweight with risk factors for NAFLD. Sex‐specific reference ranges of ALT should be used in determining elevation of ALT. Based on current recommendations, additional diagnostic evaluation should be initiated if a child has clinical symptoms of liver disease or if ALT is >80. Hepatic steatosis can occur in the absence of elevated ALT, and additional workup to assess for hepatic inflammation and fibrosis should be considered, especially with newer noninvasive screening modalities. Although the natural history of NAFLD is variable, dietary and lifestyle counseling should be initiated with close monitoring of ALT.