Elevations of C14:1 and C14:2 Plasma Acylcarnitines in Fasted Children: A Diagnostic Dilemma

Abstract

Objectives: To test whether follow-up testing for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency uncovers a diagnosis in patients with elevations of C14:1 and C14:2 plasma acylcarnitines after a controlled fasting study performed for clinically suspected hypoglycemia and to compare the acylcarnitine profiles from fasted patients without VLCAD deficiency vs patients with known VLCAD deficiency to determine whether metabolite testing distinguishes these groups.

Study design: We performed a retrospective chart review and identified 17 patients with elevated C14:1 and C14:2 plasma acylcarnitine levels after a controlled fast and with testing for VLCAD deficiency (ACADVL sequencing or fibroblast fatty acid oxidation studies). The follow-up testing in all patients was inconsistent with a diagnosis of VLCAD deficiency. We compared the plasma acylcarnitine profiles from these fasted patients vs patients with VLCAD deficiency.

Results: C14:1/C12:1 was significantly lower (P < .001) in fasted patients vs patients with VLCAD deficiency. Metabolomics analysis performed in 2 fasted patients and 1 patient with VLCAD deficiency demonstrated evidence for up-regulated lipolysis and β-oxidation in the fasted state.

Conclusions: Elevations of plasma C14:1 and C14:2 acylcarnitines appear to be a physiologic result of lipolysis that occurs with fasting. Both metabolomics analysis and/or C14:1/C12:1 may distinguish C14:1 elevations from physiologic fasting-induced lipolysis vs VLCAD deficiency.

Figure 1

A. Plasma acylcarnitine profiles after fasting show elevation of long chain acylcarnitines. The z-scores for plasma acylcarnitines (C8 and higher) are shown for patients (n=17) with elevated C14:1 and C14:2 after a fasting study. Follow-up studies for VLCAD deficiency were performed and were negative in each of these patients. B. Repeat plasma acylcarnitine profiles in subjects (n=10) are normal in the fed state. One or more repeat plasma acylcarnitine profiles in the non-fasted state were available for 10 of the 17 subjects for whom data were presented in A, and the mean z-scores were normal. C. Plasma acylcarnitine profiles from patients with VLCAD deficiency. The z-scores for the plasma acylcarnitines (C8 and higher) are plotted for five patients with VLCAD deficiency who were identified from our center.

Figure 2

Z-scores for plasma acylcarnitines (including short chains) for patients (n=17) with elevated C14:1 and C14:2 after a fasting study. The line indicates z-score of 0.

Figure 3

Z-scores for plasma acylcarnitines (including short chains) for patients with VLCAD deficiency (n=5 patients with repeated measures in some patients). The dark line represents a z-score of 0.

Figure 4

A. C14:1/C12:1 may distinguish elevations of C14:1 from fasting vs. VLCAD deficiency. C14:1/C12:1 is plotted for subjects with normal VLCAD testing (fasting) and subjects with VLCAD deficiency (VLCAD). The y-axis was log₂ transformed. The dashed line indicates separation between the groups. A Mann-Whitney Test was used for statistical analysis. B. Global lipid metabolism upregulation in fasted individuals but not patients with VLCAD deficiency. The heat map shows z-score values for important lipid biomarkers uncovered by metabolomic profiling. Pat1 is a known patient with VLCAD deficiency, whereas Pat2 and Pat3 are fasted individuals. VLCADD = VLCAD deficiency.

Figure 5

C14:1 (nmol/L) to C2 (umol/L), C3 (nmol/L), C4 (nmol/L), and C5 (nmol/L).

Figure 6

C14:1 (nmol/L) to C6 (nmol/L) C8 (nmol/L), C10 (nmol/L), and C12 (nmol/L).