Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation.
OBJECTIVE
Nonalcoholic steatohepatitis (NASH) is the most severe form of a hepatic condition known as nonalcoholic fatty liver disease (NAFLD). NASH is histologically characterized by hepatic fat accumulation, inflammation, and ballooning, and eventually coupled with fibrosis that, in turn, may progress to end-stage liver disease even in young individuals. Hence, there is a critical need for specific noninvasive markers to predict hepatic inflammation at an early age. We investigated whether plasma levels of cathepsin D (CatD), a lysosomal protease, correlated with the severity of liver inflammation in pediatric NAFLD.


METHODS
Liver biopsies from children (n=96) with NAFLD were histologically evaluated according to the criteria of Kleiner (NAFLD activity score) and the Brunt's criteria. At the time of liver biopsy, blood was taken and levels of CatD, alanine aminotransferase (ALT), and cytokeratin-18 (CK-18) were measured in plasma.


RESULTS
Plasma CatD levels were significantly lower in subjects with liver inflammation compared with steatotic subjects. Furthermore, we found that CatD levels were gradually reduced and corresponded with increasing severity of liver inflammation, steatosis, hepatocellular ballooning, and NAFLD activity score. CatD levels correlated with pediatric NAFLD disease progression better than ALT and CK-18. In particular, CatD showed a high diagnostic accuracy (area under receiver operating characteristic curve (ROC-AUC): 0.94) for the differentiation between steatosis and hepatic inflammation, and reached almost the maximum accuracy (ROC-AUC: 0.998) upon the addition of CK-18.


CONCLUSIONS
Plasma CatD holds a high diagnostic value to distinguish pediatric patients with hepatic inflammation from children with steatosis.
Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Sofie M A
SM
Walenbergh
Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Tom
T
Houben
Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Tim
T
Hendrikx
Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Mike L J
ML
Jeurissen
Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Patrick J
PJ
van Gorp
Department of Paediatrics and Nutrition, Maastricht University Medical Centre, Maastricht, The Netherlands.
Anita C E
AC
Vreugdenhil
Department of Paediatrics and Nutrition, Maastricht University Medical Centre, Maastricht, The Netherlands.
Marlou P
MP
Adriaanse
Department of Surgery and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands.
Wim A
WA
Buurman
Department of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Marten H
MH
Hofker
1] Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy [2] Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
Antonella
A
Mosca
Department of Population Genetics, Maastricht University, Maastricht, The Netherlands.
Patrick J
PJ
Lindsey
1] Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy [2] Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
Anna
A
Alisi
Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
Daniela
D
Liccardo
Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
Nadia
N
Panera
Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Ger H
GH
Koek
1] Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy [2] Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
Valerio
V
Nobili
Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
Ronit
R
Shiri-Sverdlov
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002402:Cathepsin D / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology; D053538:Keratin-18 / Q000097:blood; D008099:Liver / Q000473:pathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D012720:Severity of Illness Index
D015415:Biomarkers; D053538:Keratin-18; D000410:Alanine Transaminase; D002402:Cathepsin D