Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice

Abstract

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients’ FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway.

Omics Insights into Metabolic Stress and Resilience of Rats in Response to Short‐term Fructose Overfeeding

“…Similarly, here, fibroblast growth factor 21 (FGF21), an endocrine hormone that regulates energy homeostasis, also showed significant upregulation. FGF21 concentration in plasma is increased in patients with obesity, insulin resistance, and metabolic syndrome . Our finding coincided with the aforementioned literature that revealed that fructose can activate hepatic transcription factor ChREBP, resulting in stimulation of hepatic FGF21 expression .…”

Plasma FGF‐21 and GDF‐15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders

“…reported comparable correlation between FGF‐21 and GDF‐15 in the plasma of patients with mitochondrial diseases. Absence of age differences in FGF‐21 concentrations could be explained by a small number of samples within the control group, although other authors found age differences in comparable groups . We also did not find any associations between the evaluated cytokines and body mass index, lactate, creatine kinase, organic acids pattern in the urine (data not shown).…”

Molecular basis of Leigh syndrome: a current look

“…et al reported raised levels of FGF-21 in mitochondrial translation defects and mtDNA deletions and correlated positively with disease severity being a possible biomarker to follow up [74]. Morovat A. et al demonstrated that FGF-21 displays considerable overlapping values between mitochondrial and nonmitochondrial diseases, increased levels in other conditions yet stability in repeated measurements to follow up procedures and important positive correlation in ophthalmoplegia in adults even suggesting to dismiss muscle assessment to produce a definite diagnosis [75]. Given the disagreement, a Russian group recently published results comparing mitochondrial disease groups with nonmitochoindrial controls for each biomarker and had no significant results in their cohort studies pointing raised levels in metabolic nonmitochondrial group, though mitochondrial group had higher values, which require further investigation of these biomarkers [76].…”