Clinical Utility in Hospital-Wide Use of GDF15 as a Biomarker for Mitochondrial DNA Encoded Primary Mitochondrial Disorders
Biochemical/Metabolic and Therapeutics
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Introduction:
Clinical recognition of primary mitochondrial disorders (PMD) is difficult due to the clinical and genetic heterogeneity. Whereas lactate and pyruvate have low sensitivity and specificity, new protein biomarkers GDF15 and FGF21 have shown promise in structured clinical studies, elevated particularly in mitochondrial DNA (mtDNA) encoded PMD (deletions, tRNA mutations), but the specificity has been questioned.
We aim to retrospectively review the clinical utility of GDF15 when used hospital-wide by clinicians in the recognition of mtDNA-encoded PMD.
Methods:
In a tertiary care hospital setting, medical records were reviewed of all patients in whom GDF15 had been measured on a clinical basis in inpatient or outpatient setting, and classified into patients with PMD due to mtDNA defects, PMD due to nuclear defects, definite or unlikely non-mitochondrial disease. Patients with liver disease or systemic inflammatory illness were excluded. GDF15 was assayed in a clinical laboratory (Mayo) with cutoff of 750 ng/mL.
Results:
Of 418 identified patients (213 male, 205 female) that had GDF15 clinically measured, there were 38 mtDNA-encoded PMD (GDF15 >750 pg/mL in 76%), 37 nuclear DNA-encoded PMD or structural subunits (66% elevated GDF15), 97 definite non-mitochondrial disorders (20% elevated GDF15), 213 unlikely mitochondrial disorders (10% elevated GDF15). The sensitivity was 76.3% and specificity 85. Based on the highest Youden J-index, the optimal cut-off value was 815 pg/mL, with sensitivity 76.3%, specificity 87.8%, PPV of 40% and NPV of 97%. At this optimized cutoff level, mtDNA-encoded PMD patients had elevated GDF15 in 76%, nuclear DNA-encoded PMD in 26%, and non-mitochondrial disorders in 11% of patients.
Conclusion:
In a real-life hospital-wide clinical setting, outside structured studies, after excluding abnormal liver function and critical illness, GDF15 had good clinical utility in predicting mtDNA-encoded PMD, but less nuclear encoded PMDs.
Clinical recognition of primary mitochondrial disorders (PMD) is difficult due to the clinical and genetic heterogeneity. Whereas lactate and pyruvate have low sensitivity and specificity, new protein biomarkers GDF15 and FGF21 have shown promise in structured clinical studies, elevated particularly in mitochondrial DNA (mtDNA) encoded PMD (deletions, tRNA mutations), but the specificity has been questioned.
We aim to retrospectively review the clinical utility of GDF15 when used hospital-wide by clinicians in the recognition of mtDNA-encoded PMD.
Methods:
In a tertiary care hospital setting, medical records were reviewed of all patients in whom GDF15 had been measured on a clinical basis in inpatient or outpatient setting, and classified into patients with PMD due to mtDNA defects, PMD due to nuclear defects, definite or unlikely non-mitochondrial disease. Patients with liver disease or systemic inflammatory illness were excluded. GDF15 was assayed in a clinical laboratory (Mayo) with cutoff of 750 ng/mL.
Results:
Of 418 identified patients (213 male, 205 female) that had GDF15 clinically measured, there were 38 mtDNA-encoded PMD (GDF15 >750 pg/mL in 76%), 37 nuclear DNA-encoded PMD or structural subunits (66% elevated GDF15), 97 definite non-mitochondrial disorders (20% elevated GDF15), 213 unlikely mitochondrial disorders (10% elevated GDF15). The sensitivity was 76.3% and specificity 85. Based on the highest Youden J-index, the optimal cut-off value was 815 pg/mL, with sensitivity 76.3%, specificity 87.8%, PPV of 40% and NPV of 97%. At this optimized cutoff level, mtDNA-encoded PMD patients had elevated GDF15 in 76%, nuclear DNA-encoded PMD in 26%, and non-mitochondrial disorders in 11% of patients.
Conclusion:
In a real-life hospital-wide clinical setting, outside structured studies, after excluding abnormal liver function and critical illness, GDF15 had good clinical utility in predicting mtDNA-encoded PMD, but less nuclear encoded PMDs.