C4OH-carnitine: an important marker of ketosis in patients with and without inborn errors of metabolism.

Background: Elevated C4OH (3-hydroxybutyryl-/3-hydroxyisobutyryl-) carnitine has been reported in physiologic ketosis, secondary to ketogenic diet, and is also observed in several Inborn Errors of Metabolism (IEMs). However, the reliability of plasma C4OH-carnitine as a marker of ketosis on routine acylcarnitine testing has not been extensively studied. The goal of this study was to correlate the plasma C4OH-carnitine levels with the measurements of plasma/serum β-hydroxybutyrate (BHB). We also investigated the prevalence of elevated C4OH-carnitine in different IEMs.

Methods: We conducted a retrospective analysis of >75,000 samples sent to our laboratory for plasma acylcarnitine analysis. The concentrations of C4OH-carnitine and BHB were correlated in 559 samples with concurrent BHB and acylcarnitine profile (ACP). BHB was also directly measured in 151 samples submitted for acylcarnitine analysis. The range of C4OH-carnitine concentrations and the frequency of elevated C4OH-carnitine was evaluated in >2000 samples from patients with known diagnosis of IEM.

Results: We observed a strong correlation between C4OH-carnitine and BHB concentration (Spearman coefficient r > 0.80, p < 0.0001). The overall concordance between C4OH-carnitine and BHB results in analyzed samples was 84 % with negative and positive predictive values of 74 % and 96 %, respectively. In the IEM cohort, isolated elevations of C4OH-carnitine were consistently present in a patient with L-3-hydroxyacyl-CoA dehydrogenase deficiency. A large number of samples from patients with beta-ketothiolase deficiency, methylmalonic acidemia (MMA) and propionic acidemia (PA) had high C4OH-carnitine (35 %, 21 % and 17 %, respectively) reflecting ketosis. Abnormal C4OH-carnitine was less commonly seen in multiple acyl-CoA dehydrogenase deficiency (7.7 %), very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 5.8 %), glutaric acidemia type 1 (4.6 %), and medium-chain acyl-CoA dehydrogenase deficiency (0.4 %). Significantly higher concentrations of diagnostic acylcarnitine species were observed in MMA, PA and VLCADD samples with elevated C4OH-carnitine vs samples with normal C4OH-carnitine even after correcting for free carnitine.

Conclusion: Plasma C4OH-carnitine concentration showed a strong positive correlation with plasma/serum concentrations of BHB, demonstrating that elevated C4OH-carnitine is a reliable marker of ketosis. Elevated C4OH-carnitine in individuals with IEMs could indicate catabolic state and should prompt additional metabolic and nutritional evaluations to prevent metabolic decompensation.