Determination of the reference range of endogenous plasma carnitines in healthy adults

This version was published on 1 November 2008

Ann Clin Biochem 2008;45:585-592
doi:10.1258/acb.2008.008045
© 2008 Association for Clinical Biochemistry

 

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Original Articles


Stephanie E Reuter1,
Allan M Evans1,
Donald H Chace2 and
Gianfranco Fornasini3


1 Sansom Institute, University of South Australia, Adelaide, SA, Australia;
2 Pediatrix Screening, Bridgeville, PA, USA;
3 Sigma-Tau Pharmaceuticals Inc., Gaithersburg, MD, USA


Corresponding author: Prof Allan M Evans. Email: allan.evans{at}unisa.edu.au




Abstract

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Background: L-carnitine is an endogenous substance, vital in the transport of fatty acids across the inner mitochondrial membrane for oxidation. Disturbances in carnitine homeostasis can have a significant impact on human health; therefore, it is critical to define normal endogenous concentrations for L-carnitine and its estersto facilitate the diagnosis of carnitine deficiency disorders.This study was conducted to determine the normal concentrationsof a number of carnitines in healthy adults using three analyticalmethods. The impact of age and gender on carnitine concentrationswas also examined.

Methods: Blood samples were collected from 60 healthy subjects of bothgenders and various ages. Plasma samples were analysed for endogenouscarnitine concentrations by radioenzymatic assay, high-performanceliquid chromatography and electrospray tandem mass spectrometry.

Results: Precision and accuracy of results obtained for each assay were within acceptable limits. Average endogenous concentrations obtained from the three analytical methods in this study were in the range of 38–44, 6–7 and 49–50 µmol/L for L-carnitine, acetyl-L-carnitine and total carnitine, respectively. Comparison of results between the genders indicated that males had significantly higher endogenous plasma L-carnitine and totalcarnitine concentrations than females. Age was found to haveno impact on plasma carnitine concentrations.

Conclusion: These results are useful in the evaluation of biochemical ormetabolic disturbances and in the diagnosis and treatment ofpatients with carnitine deficiency.





Introduction

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L-carnitine (3-hydroxy-4-N-trimethylammonium butyrate) is an endogenous substance present in all mammalian species. A wide range of biological activities of L-carnitine have been described, including buffering of the ratio of free coenzyme A (CoA) to Acyl CoA and as a scavenger of unwanted acyl groups; however, the most important role of L-carnitine is in the transport of fatty acids across the inner mitochondrial membrane for subsequent β-oxidation.1 Mitochondrial fatty acid oxidation is a fundamental source of cellular energy, particularly in cardiac and skeletal muscle; therefore it is not surprising that approximately 98% of the total carnitine concentrations within the body are located in these tissues.2,3 Despite the fact that plasma comprises only approximately 1% of the total body carnitine pool, it is commonly used in studies as an indication of the total body carnitine status in patients and subjects.4,5

Disturbances in carnitine homeostasis have been shown to impact greatly on human health. Metabolic disorders resulting in low plasma L-carnitine concentrations are associated with cardiomyopathy, encephalopathy, muscle weakness and even early death if left untreated.6,7 The less severe, but more common, secondary carnitine deficiency may be the result of impaired renal or hepatic function, or may be induced by administration of certain therapeutic agents, such as pivampicillin and valproic acid.6,8,9 It is therefore critical to properly define normal endogenous values for L-carnitineand its esters so that these carnitine deficiency disordersmay be correctly and easily diagnosed.

Analytical methods used for the measurement of plasma carnitine concentrations can be categorized as enzymatic, chromatographic and mass spectrometric assays. Enzymatic assays represent the more traditional approach and most published papers of L-carnitine pharmacology have utilized this type of assay. High-performance liquid chromatography (HPLC) potentially has a wider application as it allows for the quantification of specific short-chain acylcarnitines, in addition to L-carnitine, which may be used as markers of metabolic diseases. Mass spectrometry methods are established in the diagnosis of metabolic disorders and have the added advantage of allowing the measurement of L-carnitine and an entire range of its esters in one analytical run. These assays have been reviewed in more detail elsewhere.10

While a large number of studies have reported a range of plasma L-carnitine concentrations in healthy adults (Table 1), most of these published reports have used modifications of early enzymatic assays.1114 With the advent of newer HPLC andmass spectrometry methods, it is not known whether utilizationof these methods has affected the interpretation of normal values.Consequently, the aim of this study was to determine normalconcentrations and reference intervals for a number of endogenouscarnitines in the healthy adult population using three analyticalapproaches – radioenzymatic assay (REA), HPLC and electrosprayionisation-tandem mass spectrometry (ESI MS/MS). In addition,the impact of gender and age on endogenous carnitine concentrationswas examined.



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Table 1 Summary of previously reported healthy subject endogenous carnitine concentrations





Materials and methods

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This study was reviewed and approved by the Human Research EthicsCommittee of the University of South Australia. Subjects werecompletely informed of the study procedures and provided writteninformed consent prior to study initiation. The study was conductedin accordance with the Declaration of Helsinki and the NationalStatement on Ethical Conduct in Human Research issued by theNational Health and Medical Research Council (Australia).

Sixty healthy adult subjects were recruited for study participation and were divided into four categories according to gender and age, as outlined in Table 2. A single blood sample (20mL) was collected via venepuncture from each subject and transferredinto heparinized collection tubes. Samples were stored on iceand centrifuged within 30 minutes of collection for the separationof plasma. Plasma was divided into three aliquots for sampleanalysis, one each for analysis by REA, HPLC and ESI MS/MS.An additional aliquot was taken from each plasma sample andcombined to form a pooled plasma sample for use as a qualitycontrol.



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Table 2 Demographic data for each subject group

 

All plasma samples were stored at –20°C until sample analysis. Previous preliminary studies have demonstrated that L-carnitine and its esters are stable for four weeks under thecollection and storage conditions that were used.

All analytical laboratories were blinded to sample identificationcodes.


Quality control samples

Identical quality control samples were prepared for each of the three analytical methods and submitted for analysis with the subject samples. In order to test precision, 10 aliquots of a pooled plasma sample (QCP) were included in the sample set for each method. For assessment of accuracy, quality control samples with known concentrations were prepared with dialysed plasma and designated as QCA (L-carnitine 7.50 µmol/L, acetyl-L-carnitine 1.50 µmol/L, total carnitine 9.75 µmol/L), QCB (L-carnitine 30.0 µmol/L, acetyl-L-carnitine 6.00 µmol/L, total carnitine 39.0 µmol/L) and QCC (L-carnitine 150 µmol/L, acetyl-L-carnitine 30.0 µmol/L, total carnitine 195 µmol/L). Five aliquots of each of thesequality control samples were included for analysis by each analyticalmethod.


Radioenzymatic assay

Plasma samples were analysed for L-carnitine (free carnitine) concentrations by the Department of Chemical Pathology, Women’s and Children’s Hospital, Adelaide, South Australia. Samples were analysed by REA based on the method of Cederblad and Lindstedt,15 using the reaction:


Formula 08

 

Briefly, the analytical method comprised four steps: sample preparation, incubation, separation and quantification of the product. Samples were prepared by mixing 10 µL of plasma, 90 µL of water and 20 µL of carnitine acetyltransferase (1.25 mg/mL, F Hoffman La Roche Ltd, Basel, Switzerland). To this, 70 µL of a reagent solution was added, which consisted of 14C-acetyl-CoA (0.25 mCi/2.5 mL, NEN Life Science Products Inc., Boston, MS, USA) and acetyl-CoA (Sigma-Aldrich Pty Ltd.) in a combined concentration of 43 µmol/L and 0.025 mCi/3.5 mL in a potassium phosphate buffer (0.3 mmol/L, pH 7.6) containing 1.4 mmol/L N-ethyl maleimide (Sigma-Aldrich Pty Ltd., St Louis,MO, USA).

Each sample was incubated for 60 minutes at room temperature and then separated using an ion-exchange resin (BioRad AG2-X8, 20–50 mesh chloride form, BioRad Laboratories, Hercules, CA, USA). Radiolabelled product was quantified by scintillation counting. Standard curve samples were prepared using an L-carnitine chloride solution (Sigma-Aldrich Pty Ltd) over the range of 0–200 µmol/L and were processed according to thesame procedure as the subject plasma samples.


High-performance liquid chromatography

Plasma samples were quantified for L-carnitine, acetyl-L-carnitine and total carnitine concentrations by the Centre for Pharmaceutical Research, University of South Australia, Adelaide, South Australia. Sample analysis was carried out using the fluorometric detection method described by Longo et al.16

In short, samples were purified by solid-phase extraction (Bond Elut SAX-Isolute cartridges 100 mg/mL, Varian, Palo Alto, CA, USA) followed by derivatisation with 1-aminoanthracene (Sigma-Aldrich Chemie GmbH) with 1-3-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Aldrich Chemical Company Inc., Milwaukee, WI, USA) present as a catalyst. Chromatography was carried out using a Shimadzu pump (LC-10AD), automatic injector (SIL-10AD), system controller (SCL-10A) and spectrofluorometric detector (RF-10AXL; Shimadzu Corporation, Kyoto, Japan) together with a Varian Res Elut-BD C18 analytical column (4.6 mm x 250 mm, with spherical particles of 5 µmol/L; Varian) and an Alltech column heater (Model 530, 220 V; Alltech Associates Inc., Deerfield, IL, USA). The mobile phase was run at a flow rate of 1 mL/min and consisted of 35% acetonitrile (HiPerSolv for HPLC, BDH Laboratory Supplies, Leicestershire, UK) and 65% ammonium acetate buffer (0.1 mol/L, pH 3.5). The detector wavelengths were 248 nm (excitation) and 418 nm (emission). The sample injection volume was 20 µLand run time was 20 minutes. Integration was carried out usingCLASS-VP software (Version 6.10, Shimadzu Corporation).

The standard curve was constructed using samples of dialysed human plasma spiked with aqueous solutions of L-carnitine, acetyl-L-carnitine and propionyl-L-carnitine. Calibration ranges for each of the analytes were: 2.5–160 µmol/L for L-carnitine, 0.5–32 µmol/L for acetyl-L-carnitine and 3.25–208 µmol/L for total carnitine (L-carnitine + acetyl-L-carnitine + propionyl-L-carnitine).


Electrospray tandem mass spectrometry

Subject plasma samples were analysed for L-carnitine, total carnitine and an array of 31 acylcarnitines (including acetyl-L-carnitine) by Pediatrix Screening, Bridgeville, PA, USA, based on the method described by Chace et al.17 (with modifications for plasma). Four 25 µL aliquots of each plasma sample were pipettedonto the designated target areas on purpose-prepared filterpaper (S&S grade 903, Schleicher & Schuell BioscienceInc., Keene, NH, USA) and allowed to dry for two to three hoursat room temperature. Once dry, the filter papers were sealedinside individual glassine envelopes (Westvaco number 10 stampenvelopes, MeadWestvaco Corporation, Glen Allen, VA, USA) andthen placed in plastic-covered foil zipper pouches containingdesiccant pillows. The filter papers were then shipped to PediatrixScreening for analysis.

The analysis involved extraction of plasma from a 3/16 in. punch of filter paper using 300 µL methanol containing stable isotopically labelled internal standards over a period of 30 minutes. Samples were then derivatized with 50 µL acidifiedbutanol for 15 minutes at 65°C to form butyl-esters of thecarnitines. The derivatized carnitines were then analysed byflow injection ESI MS/MS (API-Sciex 3000, Foster City, CA, USA)with a throughput of two minutes per sample. The modified methodutilized multiple deuterated internal standards, allowing forcorrection for any free carnitine produced during the derivatizationwith acidified butanol.

Calibration ranges for each of the analytes were: 0–80 µmol/L for L-carnitine, 0–50 µmol/L for acetyl-L-carnitine and 0–10 µmol/L for non-acetyl acylcarnitines.

Total acylcarnitine concentrations were determined as the sum of all 31 of the quantified acylcarnitines. Total carnitine concentrations were calculated as the sum of L-carnitine andtotal acylcarnitines.


Data analysis

Statistical comparisons were performed on Ln-transformed data using an analysis of variance with post hoc analysis (contrasts) if significance was detected. Statistical examination of the relationship between carnitine concentrations and age was conducted using linear regression. Significance was set at an {alpha} level of 0.05. WinNonlin® Professional Version 4.1 (Pharsight Corporation,Mountain View, CA, USA) was used for all statistical analyses.

Reference interval was defined as the range of values whichincluded 95% of the healthy population. As the distributionof carnitine concentrations within the population is slightlyskewed, the lower and upper limits of the reference intervalsfor each analyte were determined as the 2.5 and 97.5 percentilesof the data.





Results

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Sixty healthy adult subjects participated in the study and were partitioned into groups according to gender and age. The demographic details of each study group are outlined in Table 2.

The mean precision and accuracy values for L-carnitine, acetyl-L-carnitine and total carnitine were within 9% for all the analyses; the accuracy for total acylcarnitines was slightly higher for QCA (23.0%). Precision and accuracy results for each of the analytes by each analytical method are outlined in Table 3. It shouldbe noted that the concentrations of each analyte quantifiedby ESI MS/MS for the high quality control samples (QCC) wereoutside the standard range and consequently these results wereexcluded in the calculation of accuracy values.



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Table 3 Precision (data expressed as %CV) and accuracy (data expressed as mean ± SD) results for L-carnitine, acetyl-L-carnitine, total acylcarnitine and total carnitine concentrations quantified by radioenzymatic assay (REA), high-performance liquid chromatography (HPLC) and electrospray ionisation-tandem mass spectrometry (ESI MS/MS)

 

Mean ± standard deviation (SD) and 95% confidence interval for L-carnitine, acetyl-L-carnitine, total acylcarnitine (defined as the sum of all acylcarnitines, including acetyl-L-carnitine) and total carnitine concentrations for each analytical method are detailed in Table 4. L-carnitine concentrations quantified by both HPLC and ESI MS/MS were significantly higher than those measured by REA. Both the L-carnitine and acetyl-L-carnitineconcentrations measured by HPLC were slightly, but significantly,higher than the concentrations quantified by ESI MS/MS. No significantdifferences were found between total carnitine concentrationsquantified by HPLC and ESI MS/MS.



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Table 4 Comparison of analytical methods: endogenous plasma L-carnitine, acetyl-L-carnitine, total acylcarnitine and total carnitine concentrations obtained by radioenzymatic assay (REA), high-performance liquid chromatography (HPLC) and electrospray ionisation tandem mass spectrometry (ESI MS/MS) (n = 60)

 

The effects of gender on carnitine concentrations were examined using the three analytical methods (Table 5). L-carnitine concentrations for the male subjects were shown to be significantly higher than those for females by all three analyses. Similarly, total carnitine concentrations were significantly higher in the males when compared with female subjects for both the HPLC and ESI MS/MS analyses, whereas no differences in acetyl-L-carnitine and acylcarnitine concentrations were found between the two genders. Average endogenous concentrations of L-carnitine and total carnitine were in the range of 35–40 µmol/L and 45–47 µmol/L for females and 41–47 µmol/L and 52–53 µmol/L for males.



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Table 5 Effect of gender: endogenous plasma L-carnitine, acetyl-L-carnitine, total acylcarnitine and total carnitine concentrations for females (n = 30) and males (n = 30) obtained by radioenzymatic assay (REA), high-performance liquid chromatography (HPLC) and electrospray ionisation-tandem mass spectrometry (ESI MS/MS)

 

Differences in carnitine concentrations between the two different age groups (18–40 and >40 years) were examined (Table 6)and age was found to have no impact on carnitine concentrationsquantified by any of the analytical methods. No significantdifferences between the age groups were found within each gendergroup. Similarly, statistical correlations between age and carnitineconcentrations resulted in no significant results (data notpresented).



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Table 6 Effect of age: endogenous plasma L-carnitine, acetyl-L-carnitine, total acylcarnitine and total carnitine concentrations for subjects aged 18–40 years (n = 30) and >40 years (n = 30) obtained by radioenzymatic assay (REA), high-performance liquid chromatography (HPLC) and electrospray ionization-tandem mass spectrometry (ESI MS/MS)

 

The reference intervals for L-carnitine (stratified into females and males), acetyl-L-carnitine, total acylcarnitine and total carnitine (stratified into females and males) for each analytical method are presented in Figure 1. The reference intervalsshow significant overlap between the analytical methods andare comparable in width for each analyte.



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Figure 1 Reference intervals for endogenous L-carnitine, acetyl-L-carnitine, total acylcarnitine and total carnitine concentrations obtained by radioenzymatic assay, high-performance liquid chromatography and electrospray ionisation-tandem mass spectrometry. Data are expressed as mean within reference interval





Discussion

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Numerous studies have reported plasma carnitine concentrations in healthy subjects with varying results 4,5,1839 (Table 1). Mean ± SD values for L-carnitine in healthy adults have been reported as low as 20.7 ± 0.97 µmol/L28 and as high as 49.8 ± 2.0 µmol/L.25 Similar variations have been observed in the reporting of total carnitine (26.6 ± 1.18 to 57 ± 2.3 µmol/L), acetyl-L-carnitine (0.84 ± 0.20 to 10.2 ± 0.368 µmol/L) and other carnitine concentrations.19,22,28 The variability appears to be independent of the assay used, with the majority of studies reporting values obtained from REA analysis. These inconsistencies present complexities in defining normal endogenous concentrations for carnitines in healthy adults and consequently the diagnosis of carnitine deficiency disorders becomes difficult. This study has therefore been designed to determine normal concentrations and reference intervals for endogenous L-carnitine, total carnitine and acetyl-L-carnitine in healthy adults using three differentanalytical methods.

The analytical methods employed in this study are validatedtechniques and are commonly used for diagnostic and/or researchpurposes. The precision and accuracy results obtained in thisstudy for each of the assays were well within acceptable limits.

Comparison of carnitine concentrations obtained from each analytical method indicated that there were significant differences in the concentrations of L-carnitine and acetyl-L-carnitine quantified. However, examination of the data reveals that the average plasma concentrations are similar and in the range of 38–44 µmol/L. Analysis of samples by HPLC and ESI MS/MS resulted in average plasma concentrations which differed by only 4.8%, whereas assay by REA produced lower average concentrations than the other analytical methods (7.8% lower than ESI MS/MS and 12.2% lower than HPLC). Endogenous acetyl-L-carnitine concentrations quantified by HPLC and ESI MS/MS were approximately 6–7 µmol/L, with 3.3% difference in average concentrations between the assays. There were no significant differences in total carnitine concentrations between the methods (49–50 µmol/L, 1.4% difference). The concentrations of carnitines obtained in the present study are comparable with those previously reported in healthy adult subjects in several studies.5,18,23,26,2931,35,36

Examination of the effect of gender on plasma carnitine concentrations indicated that concentrations of L-carnitine and total carnitine are significantly higher in adult males than females in each of the analytical methods utilized. In this study, average L-carnitine concentrations were in the range of 35–40 µmol/L for females and 41–47 µmol/L for males, whereas total carnitine concentrations were in the range of 45–47 µmol/L for females and 52–54 µmol/L for males. Similarly, Lombard et al.27 has previously demonstrated significantly higher plasma L-carnitine and total carnitine concentrations in males than in females with L-carnitine concentrations of 39.9 ± 4.9 µmol/L and 32.5 ± 5.3 µmol/L and total carnitine concentrations of 49.4 ± 7.3 µmol/L and 43.3 ± 5.5 µmol/L in males and females, respectively. Niu et al.30 also reported significantly higher concentrations of L-carnitine and total carnitine in plasma of healthy male subjects than females; however, it was also noted that acetyl-L-carnitine concentrations were significantly different between genders, a result which was not demonstrated in the present study. Differences between the genders in plasma total carnitine concentrations were also noted by Borum et al.20 Harper et al.23 also examined the effect of gender on plasma carnitine concentrations and although a significant difference was observed in L-carnitineconcentrations, no differences between males and females werenoted for total carnitine. The average plasma carnitine concentrationsfor males and females calculated in the present study are similarto those reported in the above studies.

A limited number of studies have examined the effect of age on plasma carnitine concentrations in healthy subjects. Age was found to have no impact on any of the analytes quantified in the present study, neither with significant differences between the two age groups examined, nor differences between the age groups within the genders. Similarly, no significant correlations between age and carnitine concentrations were observed. Borum et al.20 previously demonstrated a significant correlation betweenage and endogenous plasma total carnitine concentrations inhealthy females (but not males), a result which could not bereplicated in the present study.

The reference intervals calculated from the three analytical methods in this study are very similar, with significant overlap in the intervals for each of the analytes and similar interval widths (Figure 1). However, there were slight differences in the upper and lower limits of the reference intervals obtained in this study, illustrating the importance of the development of laboratory-specific reference intervals for use in the diagnosis of primary and secondary carnitine deficiencies. In doing so, gender should be taken into consideration in the determination of reference intervals for L-carnitine and total carnitine;however, age is shown to have no impact. Laboratory-specificreference intervals are expected to be similar to those obtainedfrom our laboratories.

 

 

 

 

 

 

 




ACKNOWLEDGEMENT

 

This project was supported by an unrestricted research grantfrom Sigma-Tau Pharmaceuticals Inc.

(Accepted May 25, 2008)



REFERENCES

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 REFERENCES


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S. E. Reuter, R. J. Faull, E. Ranieri, and A. M. Evans
Endogenous plasma carnitine pool composition and response to erythropoietin treatment in chronic haemodialysis patients
Nephrol. Dial. Transplant.,

March 1, 2009;
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