Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases

Johan L K Van Hove; Marisa W Friederich; Dana K Strode; Roxanne A Van Hove; Kristen R Miller; Rohit Sharma; Hardik Shah; Jane Estrella; Linda Gabel; Simon Horslen; Rohit Kohli; Mark A Lovell; Alexander G Miethke; Jean P Molleston; Rene Romero; James E Squires; Estella M Alonso; Stephen L Guthery; Binita M Kamath; Kathleen M Loomes; Philip Rosenthal; Krupa R Mysore; Laurel A Cavallo; Pamela L Valentino; John C Magee; Shikha S Sundaram; Ronald J Sokol; Childhood Liver Disease Research Network (ChiLDReN)

doi:10.1097/HC9.0000000000000361

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.

Authors

Johan L K Van Hove^{1

2}, Marisa W Friederich^{1

2}, Dana K Strode¹, Roxanne A Van Hove¹, Kristen R Miller³, Rohit Sharma^{4

5

6}, Hardik Shah⁴, Jane Estrella^{1

7}, Linda Gabel², Simon Horslen⁸, Rohit Kohli⁹, Mark A Lovell², Alexander G Miethke¹⁰, Jean P Molleston¹¹, Rene Romero¹², James E Squires⁸, Estella M Alonso¹³, Stephen L Guthery^{14

15}, Binita M Kamath¹⁶, Kathleen M Loomes^{17

18}, Philip Rosenthal¹⁹, Krupa R Mysore²⁰, Laurel A Cavallo²⁰, Pamela L Valentino²¹, John C Magee²², Shikha S Sundaram²³, Ronald J Sokol²³; Childhood Liver Disease Research Network (ChiLDReN)

Affiliations

¹ Section 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.
² Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
³ Section of Endocrinology, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, Colorado, USA.
⁴ Department of Molecular Biology and Department of Medicine, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Broad Institute, Cambridge, Massachusetts, USA.
⁷ Department of Neurosciences, University of California San Diego, San Diego, California, USA.
⁸ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁹ Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁰ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University and Riley Hospital for Children, Indianapolis, Indiana, USA.
¹² Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, USA.
¹³ Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois, USA.
¹⁴ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Spencer F. Eccles School of Medicine, University of Utah, Salt Lake City, Utah, USA.
¹⁵ Intermountain Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
¹⁶ Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁸ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Departments of Pediatrics and Surgery, University of California San Francisco, San Francisco, California, USA.
²⁰ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
²¹ Division of Gastroenterology and Hepatology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.
²² Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
²³ Section 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.

MeSH terms

Alagille Syndrome* / diagnosis
Biliary Atresia* / diagnosis
Biomarkers
Child
Growth Differentiation Factor 15* / blood
Growth Differentiation Factor 15* / chemistry
Humans
Mitochondrial Diseases / diagnosis
Non-alcoholic Fatty Liver Disease*

Substances

Biomarkers
fibroblast growth factor 21
GDF15 protein, human
Growth Differentiation Factor 15

Abstract

MeSH terms

Substances

Grants and funding