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. 2024 Jan 5;8(1):e0361.
doi: 10.1097/HC9.0000000000000361. eCollection 2024 Jan 1.

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

Johan L K Van Hove  1   2 , Marisa W Friederich  1   2 , Dana K Strode  1 , Roxanne A Van Hove  1 , Kristen R Miller  3 , Rohit Sharma  4   5   6 , Hardik Shah  4 , Jane Estrella  1   7 , Linda Gabel  2 , Simon Horslen  8 , Rohit Kohli  9 , Mark A Lovell  2 , Alexander G Miethke  10 , Jean P Molleston  11 , Rene Romero  12 , James E Squires  8 , Estella M Alonso  13 , Stephen L Guthery  14   15 , Binita M Kamath  16 , Kathleen M Loomes  17   18 , Philip Rosenthal  19 , Krupa R Mysore  20 , Laurel A Cavallo  20 , Pamela L Valentino  21 , John C Magee  22 , Shikha S Sundaram  23 , Ronald J Sokol  23 ; Childhood Liver Disease Research Network (ChiLDReN)
Affiliations

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

Johan L K Van Hove et al. Hepatol Commun. .

Erratum in

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.

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Conflict of interest statement

Ronald J. Sokol is on advisory committees of Mirum and Albireo and consults with Astellas. Johan L.K. Van Hove has been an advisor to Stealth Biotherapeutics. Philip Rosenthal receives research support from Abbvie, Albireo, Arrowhead, Gilead, Merck, Mirum, Takeda, and Travere, and is a consultant for Albireo, Ambys, Audentes, BioMarin, Dicerna, Encoded, MedinCell, Mirum, Takeda, and Travere. Kathleen M. Loomes participated in advisory committees for Mirum and Albireo, and is a consultant for Travere Therapeutics. Binita M. Kamath is a consultant of Mirum, Albireo, and Audentes, and has unrestricted education grants from Mirum and Albireo. Rene Romero is a consultant for Mirum and Albireo and has a clinical trial with Gilead. Jean P. Molleston receives research funding from Albireo, Abbvie, Mirum, Gilead, and the CF Foundation. Rohit Sharma has equity in bluebird bio. Simon Horslen consults for Albireo, Ipsen and iEcure and received grants from Mirum. Rohit Kohli consults and advises Mirum, Albireo, Sanofi, Epigen, and Intercept. Alexander G. Miethke consults and received grants from Mirum. Pamela L. Valentino is on the speakers’ bureau for Mirum. Shikha S. Sundaram advises Mirum and Albireo. The remaining authors have no conflicts to report.

Figures

FIGURE 1
FIGURE 1
Biomarkers by age in normal controls. Values of biomarkers (A) GDF15 and (B) FGF21 in normal controls as a function of age (months). Inserts illustrate an increase in values in infants aged <6 months. Occasional outliers are also noted. Abbreviation: GDF15, growth differentiation factor 15.
FIGURE 2
FIGURE 2
Biomarkers in different categories of study participants ages 6 months to 18 years. Levels of biomarkers for patients ages 6 months to 18 years. (A) The levels of GDF15 (ng/L) are significantly increased in patients with MH compared to all other diagnostic groups and controls. (B) The log10-transformed GDF15 levels better visualize the moderate increase of GDF15 levels in patients with Alagille syndrome and biliary atresia from PROBE. (C) The levels of FGF21 (ng/L) are significantly increased in patients with MH compared to all other diagnostic groups and controls. (D) The log10-transformed FGF21 levels better visualize the moderate increase of FGF21 levels in patients with NASH. Abbreviations: A1AT, α1-antitrypsin deficiency; ALGS, Alagille syndrome; BA-BASIC=biliary atresia from the BASIC study; BA-PROBE, biliary atresia from the PROBE study; GDF15, growth differentiation factor 15; MITOHEP, mitochondrial hepatopathies. *p<0.05, **p<0.01, ***p≤0.001.
FIGURE 3
FIGURE 3
Biomarkers in different categories of study participants ages <6 months. Levels of biomarkers for patients aged <6 months. (A). Levels of GDF15 are significantly increased in patients with MH and (B) log10 of GDF15 shows a moderate increase in other liver diseases. (C) Levels of FGF21 are significantly increased in patients with MH and (D) log10 of FGF21 shows that no significant increase was present in other liver diseases. Abbreviations: GDF15, growth differentiation factor 15; MITOHEP, mitochondrial hepatopathies. *p<0.05, **p<0.01, ***p≤0.001.
FIGURE 4
FIGURE 4
Receiver operating curve analysis of the biomarkers. The receiver operating curves of both GDF15 and FGF21 are shown for (A) mitochondrial hepatopathies compared to all other liver diseases and patients, and (B) the genetically confirmed mitochondrial hepatopathies compared to all other subjects. Abbreviation: GDF15, growth differentiation factor 15.
FIGURE 5
FIGURE 5
Kaplan-Meier plot of survival without liver transplantation in patients with mitochondrial hepatopathy. Kaplan-Meier plots are shown for survival without liver transplantation (EFS) for participants with mitochondrial hepatopathy. (A) EFS is worse in patients with acute (blue, N=6, 5 events) vs. chronic presentation (red, N=30, 10 events). (B) EFS is worse for patients with a known genetic diagnosis (blue, N=17, 11 events) vs. those without a known genetic diagnosis (red, N=19, 4 events). (C) Significantly decreased EFS was demonstrated for patients with a GDF15 >2000 ng/L (blue, N=21, 14 events) vs. patients with GDF15 <2000 ng/L (red, N=15, 1 event). (D) Significantly decreased EFS was demonstrated for patients with FGF21 >2000 ng/L (blue, N=18, 13 events) vs. those with <2000 ng/L (red, N=16, 2 events). Abbreviations: EFS, event-free survival; GDF15, growth differentiation factor 15.
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