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Abstract Details
Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases
Hepatol Commun. 2024 Jan 5;8(1):e0361. doi: 10.1097/HC9.0000000000000361.eCollection 2024 Jan 1.
1Section of Clinical Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado, USA.
2Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
3Section of Endocrinology, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado, USA.
4Department of Molecular Biology and Department of Medicine, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA.
5Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
6Broad Institute, Cambridge, Massachusetts, USA.
7Department of Neurosciences, University of California San Diego, San Diego, California, USA.
8Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
9Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California, USA.
10Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
11Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University and Riley Hospital for Children, Indianapolis, Indiana, USA.
12Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, USA.
13Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois, USA.
14Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Spencer F. Eccles School of Medicine, University of Utah, Salt Lake City, Utah, USA.
15Intermountain Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
16Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
17Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital Philadelphia, Philadelphia, Pennsylvania, USA.
18Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
19Departments of Pediatrics and Surgery, University of California San Francisco, San Francisco, California, USA.
20Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
21Division of Gastroenterology and Hepatology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.
22Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
23Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado, USA.
Abstract
Background: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children.
Methods: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls.
Results: GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01).
Conclusions: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.