To the Editor:

We read with interest the recent review by Wieckowska et al. on noninvasive diagnosis and monitoring of nonalcoholic fatty liver disease (NAFLD) by measuring biomarkers and correlating their values with the severity of the liver disease.1 In 2006, a well-designed study by Wieckowska and colleagues showed that measuring the level of caspase 3–generated cytokeratin-18 (CK-18) fragments in plasma of adults with NAFLD could potentially be used as a noninvasive diagnostic technique to predict the severity of the disease. They showed that the level of CK-18 fragments is markedly increased in patients with nonalcoholic steatohepatitis (NASH), confirming their histological findings.2

Lack of similar data in children led us to study the value of CK-18 fragments in pediatric NAFLD. We measured the level of CK-18 fragments in serum samples obtained from 21 children (14 male; median age 13.3 years [range: 4.5-16.8 years]) with biopsy-proven NAFLD and 13 normal control children (11 male; median age 14.4 years [range: 8.4-18.6 years]) using the M30-Apoptosense enzyme-linked immunosorbent assay (ELISA) kit (Peviva AB, Bromma, Sweden).2 The diagnosis of NAFLD was established by clinical, biochemical, and liver histology analysis while other causes of liver disease were excluded. The control samples were retrieved from our research bank obtained from normal children. A single hepatopathologist (A.Q.) scored liver tissue steatosis (0-3), inflammation (0-3), hepatocellular ballooning (0-2), and fibrosis (0-4), and calculated NAFLD activity score (NAS) for each patient.3 CK-18 fragments values were correlated with NAS to predict the severity of liver disease.

We found that children with NAFLD had median body mass index z-score of 2.8 standard deviations (range: −0.67 to 5 standard deviations), serum aspartate aminotransferase levels of 64 U/L (25-175 IU/L), and NAS of 3 (0-6). Median serum level of CK-18 fragments was 255 U/L (range: 148-2614 U/L) in children with NAFLD compared to controls with 172 U/L (83-238 U/L; P = 0.002). There was a statistically significant correlation between level of CK-18 fragments and steatosis (P = 0.001, Spearman's test). Serum CK-18 levels in patients with NAS of ≥4 (median: 477 U/L; range: 157-2614 U/L) were significantly higher than patients with NAS of ≤3 (median: 209 U/L; range: 148-494 U/L; P = 0.049 Mann-Whitney test).

Our data support the findings of Wieckowska et al.2 in demonstrating that measuring serum CK-18 fragments level could potentially be used as a noninvasive diagnostic test to predict the severity of NAFLD; however, before the liver biopsy is abandoned altogether, verification of the noninvasive diagnostic in a bigger cohort of children is warranted.


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  • 1
    Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. HEPATOLOGY 2007; 46: 582589.
  • 2
    Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in non-alcoholic fatty liver disease. HEPATOLOGY 2006; 44: 2733.
  • 3
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for non-alcoholic fatty liver disease. HEPATOLOGY 2005; 41: 13131321.

Ragai R. Mitry Ph.D.*, Ruth De Bruyne M.D.*, Alberto Quaglia Ph.D.*, Robin D. Hughes Ph.D.*, Anil Dhawan M.D.*, * Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK.