Evaluating Overweight and Obese Children for Suspected NAFLD
We studied a large clinical sample of overweight and obese children who were identified as having suspected NAFLD by screening in primary care following paediatric guidelines and referred to paediatric gastroenterology. Children were evaluated by a paediatric gastroenterologist and those with evidence of chronic liver disease underwent liver biopsy, which was well-tolerated. NAFLD was the most common diagnosis established. However, many children with suspected NAFLD were shown to have liver disease other than NAFLD. Amongst children with NAFLD, approximately half had steatohepatitis. Furthermore, many overweight and obese children were determined to have previously unrecognised advanced fibrosis.
Society recommendations to screen overweight and obese children for NAFLD were based in part on the asymptomatic nature of chronic liver disease that evades diagnosis without a screening effort. The paediatric guidelines as applied by primary care providers identified many children with liver disease, most commonly NAFLD. In addition, the current data demonstrated that not all overweight and obese children with a positive screening ALT will have liver disease. Thus, one major challenge is the interpretation of ALT values. As shown in the SAFETY study, there is wide institution-to-institution variability in the definition of the normal range for ALT and controversy over whether or not to use multipliers of the ULN. This creates confusion for paediatricians, gastroenterologists and endocrinologists as well as for the children themselves and their families. The current data show the strengths and limitations of various thresholds for ALT in children. The paediatric guidelines suggest using two times the ULN as the criterion for referral to paediatric gastroenterology. However, our data suggest that primary care providers vary greatly in their choice of threshold used for referral. Although the use of two times the ULN would improve the specificity for NAFLD, many children with NAFLD would be missed including some with NASH and advanced fibrosis. In addition, contrary to conventional wisdom, children with liver disease other than NAFLD had lower ALT than children with NAFLD. Thus, national standardisation of ALT thresholds is needed, but no single ALT threshold will be sufficient to be considered diagnostic.
Once the possibility of liver disease has been detected by screening, it is important to make an accurate diagnosis. One important lesson from this study is that physicians should not tell children that they have fatty liver based solely on the finding of elevated ALT in the context of obesity. Determining whether a child has NAFLD or another form of liver disease has important therapeutic implications, as many of the possible aetiologies have specific therapies. Although it is true that some diseases, such as hepatitis C, can be detected by serologic testing, many other diseases, such as autoimmune hepatitis, require liver biopsy to distinguish from NAFLD. In fact, the screening test for autoimmune hepatitis, auto-antibodies, has been reported to be positive in approximately 20% of patients with NAFLD. Indeed, in this study, a positive ANA did not sufficiently distinguish between those with NAFLD and those with autoimmune hepatitis. Because there are no alternative tests with satisfactory diagnostic accuracy, liver biopsy remains the clinical standard to determine the aetiology and stage of liver disease. Liver biopsy is not without risk; however, the current data show that when performed by experienced personnel, it can be performed with minimal adverse events.
The rationale for detecting NAFLD, and especially NASH, is based in part on the risk for progression to cirrhosis. In a national multi-centre study, advanced fibrosis was reported at the time of diagnostic liver biopsy in nearly one of seven children with NAFLD. Our study had similar findings, with 17% of children with NAFLD having advanced fibrosis. The detection of advanced fibrosis is important because these are the children who in the short-term are at risk for portal hypertension and its consequences, and in the long-term may require liver transplant and/or develop hepatocellular carcinoma. Beyond the hepatic consequences, obese children with NAFLD are phenotypically distinct from obese children without NAFLD. NAFLD is an independent risk factor for diabetes and cardiovascular disease. In addition, children with NAFLD also have substantially lower bone mineralisation than age- and adiposity-matched peers. Thus, the early identification of NAFLD has the potential to be clinically important.
The current study is notable for its large sample size of overweight and obese children identified by screening in primary care as having suspected NAFLD based on prevailing national clinical guidelines and referred to paediatric gastroenterology. In addition, data were available for detailed diagnostic outcomes based on history, physical examination, laboratory evaluation, liver biopsy and histology. These data represent children identified by screening and not those tested based on symptoms, thus may not reflect all overweight or obese children with elevated liver chemistry. Moreover, given the influence of race and ethnicity, there are likely to be differences in findings depending upon the demographics of the community being considered.
Discussion
We studied a large clinical sample of overweight and obese children who were identified as having suspected NAFLD by screening in primary care following paediatric guidelines and referred to paediatric gastroenterology. Children were evaluated by a paediatric gastroenterologist and those with evidence of chronic liver disease underwent liver biopsy, which was well-tolerated. NAFLD was the most common diagnosis established. However, many children with suspected NAFLD were shown to have liver disease other than NAFLD. Amongst children with NAFLD, approximately half had steatohepatitis. Furthermore, many overweight and obese children were determined to have previously unrecognised advanced fibrosis.
Society recommendations to screen overweight and obese children for NAFLD were based in part on the asymptomatic nature of chronic liver disease that evades diagnosis without a screening effort. The paediatric guidelines as applied by primary care providers identified many children with liver disease, most commonly NAFLD. In addition, the current data demonstrated that not all overweight and obese children with a positive screening ALT will have liver disease. Thus, one major challenge is the interpretation of ALT values. As shown in the SAFETY study, there is wide institution-to-institution variability in the definition of the normal range for ALT and controversy over whether or not to use multipliers of the ULN. This creates confusion for paediatricians, gastroenterologists and endocrinologists as well as for the children themselves and their families. The current data show the strengths and limitations of various thresholds for ALT in children. The paediatric guidelines suggest using two times the ULN as the criterion for referral to paediatric gastroenterology. However, our data suggest that primary care providers vary greatly in their choice of threshold used for referral. Although the use of two times the ULN would improve the specificity for NAFLD, many children with NAFLD would be missed including some with NASH and advanced fibrosis. In addition, contrary to conventional wisdom, children with liver disease other than NAFLD had lower ALT than children with NAFLD. Thus, national standardisation of ALT thresholds is needed, but no single ALT threshold will be sufficient to be considered diagnostic.
Once the possibility of liver disease has been detected by screening, it is important to make an accurate diagnosis. One important lesson from this study is that physicians should not tell children that they have fatty liver based solely on the finding of elevated ALT in the context of obesity. Determining whether a child has NAFLD or another form of liver disease has important therapeutic implications, as many of the possible aetiologies have specific therapies. Although it is true that some diseases, such as hepatitis C, can be detected by serologic testing, many other diseases, such as autoimmune hepatitis, require liver biopsy to distinguish from NAFLD. In fact, the screening test for autoimmune hepatitis, auto-antibodies, has been reported to be positive in approximately 20% of patients with NAFLD. Indeed, in this study, a positive ANA did not sufficiently distinguish between those with NAFLD and those with autoimmune hepatitis. Because there are no alternative tests with satisfactory diagnostic accuracy, liver biopsy remains the clinical standard to determine the aetiology and stage of liver disease. Liver biopsy is not without risk; however, the current data show that when performed by experienced personnel, it can be performed with minimal adverse events.
The rationale for detecting NAFLD, and especially NASH, is based in part on the risk for progression to cirrhosis. In a national multi-centre study, advanced fibrosis was reported at the time of diagnostic liver biopsy in nearly one of seven children with NAFLD. Our study had similar findings, with 17% of children with NAFLD having advanced fibrosis. The detection of advanced fibrosis is important because these are the children who in the short-term are at risk for portal hypertension and its consequences, and in the long-term may require liver transplant and/or develop hepatocellular carcinoma. Beyond the hepatic consequences, obese children with NAFLD are phenotypically distinct from obese children without NAFLD. NAFLD is an independent risk factor for diabetes and cardiovascular disease. In addition, children with NAFLD also have substantially lower bone mineralisation than age- and adiposity-matched peers. Thus, the early identification of NAFLD has the potential to be clinically important.
The current study is notable for its large sample size of overweight and obese children identified by screening in primary care as having suspected NAFLD based on prevailing national clinical guidelines and referred to paediatric gastroenterology. In addition, data were available for detailed diagnostic outcomes based on history, physical examination, laboratory evaluation, liver biopsy and histology. These data represent children identified by screening and not those tested based on symptoms, thus may not reflect all overweight or obese children with elevated liver chemistry. Moreover, given the influence of race and ethnicity, there are likely to be differences in findings depending upon the demographics of the community being considered.
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