SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease.
OBJECTIVE
The appropriate alanine aminotransferase (ALT) threshold value to use for diagnosis of chronic liver disease in children is unknown. We sought to develop gender-specific, biology-based, pediatric ALT thresholds.


METHODS
The Screening ALT for Elevation in Today's Youth (SAFETY) study collected observational data from acute care children's hospitals, the National Health and Nutrition Examination Survey (NHANES, 1999-2006), overweight children with and without non-alcoholic fatty liver disease (NAFLD), and children with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. The study compared the sensitivity and specificity of ALT thresholds currently used by children's hospitals vs study-derived, gender-specific, biology-based, ALT thresholds for detecting children with NAFLD, HCV, or HBV.


RESULTS
The median upper limit of ALT at children's hospitals was 53 U/L (range, 30-90 U/L). The 95th percentile levels for ALT in healthy weight, metabolically normal, liver disease-free, NHANES pediatric participants were 25.8 U/L (boys) and 22.1 U/L (girls). The concordance statistics of these NHANES-derived thresholds for liver disease detection were 0.85 (95% confidence interval [CI]: 0.74-0.96) in boys and 0.91 (95% CI: 0.83-0.99) in girls for NAFLD, 0.80 (95% CI: 0.70-0.91) in boys and 0.79 (95% CI: 0.69-0.89) in girls for HBV, and 0.86 (95% CI: 0.77-0.95) in boys and 0.84 (95% CI: 0.75-0.93) in girls for HCV. Using current children's hospitals ALT thresholds, the median sensitivity for detection of NAFLD, HBV, and HCV ranged from 32% to 48%; median specificity was 92% (boys) and 96% (girls). Using NHANES-derived thresholds, the sensitivities were 72% (boys) and 82% (girls); specificities were 79% (boys) and 85% (girls).


CONCLUSIONS
The upper limit of ALT used in children's hospitals varies widely and is set too high to reliably detect chronic liver disease. Biology-based thresholds provide higher sensitivity and only slightly less specificity. Clinical guidelines for use of screening ALT and exclusion criteria for clinical trials should be modified.
Schwimmer
Jeffrey B
JB
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics University of California, San Diego School of Medicine, San Diego, California 92103-8450, USA. jschwimmer@ucsd.edu
Dunn
Winston
W
Norman
Gregory J
GJ
Pardee
Perrie E
PE
Middleton
Michael S
MS
Kerkar
Nanda
N
Sirlin
Claude B
CB
D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood*; D002648:Child; D002908:Chronic Disease; D005234:Fatty Liver / Q000175:diagnosis; D019694:Hepatitis B, Chronic / Q000175:diagnosis; D019698:Hepatitis C, Chronic / Q000175:diagnosis; D006801:Humans; D008107:Liver Diseases / Q000175:diagnosis*; D012016:Reference Values
D000410:Alanine Transaminase