Carnitine is a compound in the body that helps your body digest fats for energy. A carnitine deficiency is related to a number of different medical problems. A carnitine total and free plasma test is a blood test that measures the amount of carnitine in the blood. It examines that amount of usable, or free, carnitine and compares it with the total amount of carnitine.
The analysis of carnitines is indicated in people who exhibit the following:
- failure to thrive,
- hypotonia,
- chronic muscle weakness,
- cardiomyopathy,
- intermittent episodes of weakness and encephalopathy,
- renal Fanconi's syndrome,
- hypoglycemic episodes,
- metabolic acidosis,
- or hypoketotic dicarboxylic acidurias.
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Reference Ranges:
Carnitine is a quaternary, water-soluble ammonia compound biosynthesized from lysine and arginine. It serves as a mechanism for transport of long-chain fatty acids from the cytoplasm across the inner mitochondrial membrane and into the mitochondrial matrix, the site of b-oxidation of fatty acids for energy generation.
The reference range of carnitine depends on the laboratory being used;
Reference Range of Carnitine at a Single Laboratory
|
Age Range |
Serum Free Carnitine (µmol/L) |
Serum Total Carnitine (µmol/L) |
|
Neonate |
26-76 |
35-102 |
|
Child |
41.4±10.4* |
56.2±11.4* |
|
Adolescent female |
39.3±8.1* |
53.2±8.9* |
|
Adolescent male |
39.6±9.3* |
53.5±10.5* |
|
Adult female |
19.3-53.9** |
28.1-66.4** |
|
Adult male |
38.8-69.5 |
44.2-79.3 |
|
*Mean ± standard deviation (SD) **95% confidence interval (CI) |
||
Quest Laboratories reports the reference range of total carnitine as follows:
Men: 30-70 μmol/L
Women: 25-58 μmol/L
Male children (age ≤17 years): 32-62 μmol/L
Female children (age ≤17 years): 28-59 μmol/L
Quest Laboratories reports the reference range of free carnitine as follows:
Men: 23-59 μmol/L
Women: 19-48 μmol/L
Male children (age ≤17 years): 25-54 μmol/L
Female children (age ≤17 years): 19-51 μmol/L
The University of California San Francisco Laboratory reports the normal values of free and total carnitine in adults as 18-69 μmol/L and 20-71 μmol/L, respectively.
Chace et al (2003) examined free and total carnitine levels in newborns. The reference ranges depended both on technique used (radioenzyme vs tandem mass spectroscopy) and the sample type (whole blood vs serum).
Variations in the ratio of free to total carnitine may also be important; typically, normal is reported as 0.1-0.4.
References:
Minkler PE, Stoll MS, Ingalls ST, Kerner J, Hoppel CL. Validated Method for the Quantification of Free and Total Carnitine, Butyrobetaine, and Acylcarnitines in Biological Samples. Anal Chem. 2015 Sep 1. 87 (17):8994-9001. [QxMD MEDLINE Link].
Belay B, Esteban-Cruciani N, Walsh CA, Kaskel FJ. The use of levo-carnitine in children with renal disease: a review and a call for future studies. Pediatr Nephrol. 2006 Mar. 21(3):308-17. [QxMD MEDLINE Link].
Quest Diagnostics. Available at http://www.questdiagnostics.com/testcenter/%20BUOrderInfo.action?tc=5800&labCode=AMD.
Chace DH, Pons R, Chiriboga CA, et al. Neonatal blood carnitine concentrations: normative data by electrospray tandem mass spectometry. Pediatr Res. 2003 May. 53(5):823-9. [QxMD MEDLINE Link].
Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci. 2004 Nov. 1033:42-51. [QxMD MEDLINE Link].
Reuter SE, Evans AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet. 2012 Sep 1. 51(9):553-72. [QxMD MEDLINE Link].
Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006 May 15. 142C(2):77-85. [QxMD MEDLINE Link]. [Full Text].
Dahash BA, Sankararaman S. Carnitine Deficiency. StatPearls. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].
Santra S, Hendriksz C. How to use acylcarnitine profiles to help diagnose inborn errors of metabolism. Arch Dis Child Educ Pract Ed. 2010 Oct. 95(5):151-6. [QxMD MEDLINE Link].
Scaglia F. Carnitine Deficiency. Medscape Drugs & Diseases. Updated 2019 Dec 13. [Full Text].
Magoulas PL, El-Hattab AW. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012 Sep 18. 7:68. [QxMD MEDLINE Link]. [Full Text].
Tein I. Metabolic myopathies. Swaiman KF, Ashwal S, Ferriero DM. Swaiman’s Pediatric Neurology Principles and Practice. 5th ed. Schor NF: Elsevier Sanders; 2012. 1627-40.
Crefcoeur LL, Visser G, Ferdinandusse S, Wijburg FA, Langeveld M, Sjouke B. Clinical characteristics of primary carnitine deficiency: A structured review using a case-by-case approach. J Inherit Metab Dis. 2022 May. 45 (3):386-405. [QxMD MEDLINE Link]. [Full Text].
Berardo A, DiMauro S, Hirano M. A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep. 2010 Mar. 10(2):118-26. [QxMD MEDLINE Link]. [Full Text].
Bernardini I, Rizzo WB, Dalakas M, Bernar J, Gahl WA. Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome. J Clin Invest. 1985 Apr. 75(4):1124-30. [QxMD MEDLINE Link]. [Full Text].
Gahl WA, Bernardini I, Dalakas M, et al. Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome. J Clin Invest. 1988 Feb. 81(2):549-60. [QxMD MEDLINE Link]. [Full Text].
Determination of Free and Total Carnitine and Choline in Infant Formulas and Adult Nutritional Products by UHPLC-MS/MS: Single-Laboratory Validation, First Action 2014.04. J AOAC Int. 2015 Jun 24. [QxMD MEDLINE Link].
El-Hattab AW. Systemic Primary Carnitine Deficiency. 1993. [QxMD MEDLINE Link].
Rinaldo P, Cowan TM, Matern D. Acylcarnitine profile analysis. Genet Med. 2008 Feb. 10(2):151-6. [QxMD MEDLINE Link].
Dietzen DJ, Rinaldo P, Whitley RJ, et al. National academy of clinical biochemistry laboratory medicine practice guidelines: follow-up testing for metabolic disease identified by expanded newborn screening using tandem mass spectrometry; executive summary. Clin Chem. 2009 Sep. 55(9):1615-26. [QxMD MEDLINE Link].
Johns Hopkins University Clinical Lab.
National Newborn Screening Status Report 2012.
Stanley CA. Carnitine disorders. Adv Pediatr. 1995. 42:209-42. [QxMD MEDLINE Link].
Mamedov I, Zolkina I, Nikolaeva E, Glagovsky P, Sukhorukov V. Carnitine insufficiency in children with inborn errors of metabolism: prevalence and treatment efficacy. J Pediatr Endocrinol Metab. 2015 Jul 18. [QxMD MEDLINE Link].
Sgambat K, Moudgil A. Carnitine deficiency in children receiving continuous renal replacement therapy. Hemodial Int. 2015 Aug 11. [QxMD MEDLINE Link].
Primary carnitine deficiency is caused by an autosomal-recessive defect in the SLC22A5 gene, resulting in a lack of OCTN2, which is a high-affinity carnitine-uptake transporter expressed in muscle, kidney, and heart.
Laboratory values in primary carnitine deficiency show markedly decreased free and total carnitine levels, since 90-95% of filtered carnitine is lost in the urine. Analysis of urine organic acids, serum amino acids, and acylcarnitine panels can be used to distinguish this condition from other causes of carnitine deficiency.
Individuals with primary carnitine deficiency usually present with cardiomyopathy and skeletal weakness or with episodic hypoketotic hypoglycemia and encephalopathy when stressed at around age 2-4 years. This results from the inability to oxidize fatty acids and generate ketones to provide energy during catabolic states. The disorder is fatal without treatment, but supplementation with oral carnitine results in elevated carnitine levels and prevents progression of the disease.
A literature review by Crefcoeur et al found that in individuals with primary carnitine deficiency, the most prevalent symptoms were cardiac (23.8% of patients), with cardiomyopathy being the predominant manifestation of these. Neurologic, hepatic, and metabolic symptoms developed in 7.1%, 8.4%, and 9.2% of persons with primary deficiency and occurred most often in early childhood. The condition was asymptomatic in 55.1% of patients with primary deficiency.
Carnitine-acylcarnitine translocase deficiency (CACT) typically presents in an autosomal-recessive fashion with seizures, apnea, and an irregular heart beat in the neonatal period (although presentation can occur as late as age 15 months) and results from mutations in the CACT protein (SLC25A20 gene), a carnitine-acylcarnitine exchanger on the inner mitochondrial membrane. Crisis is triggered by fasting, viral illness, or stress (an in other fatty-acid disorders). In addition to low carnitine levels, laboratory studies also show hypoketotic hypoglycemia; elevated levels of ammonia, creatine kinase (CK), liver enzymes, and long-chain acylcarnitines in the blood; and dicarboxylic aciduria in urinary organic acids. CACT is treated with frequent feedings of carbohydrates, medium-chain triglycerides, and carnitine.
The autosomal-recessive disorder carnitine palmitoyltransferase 2 (CPT-2) deficiency is also characterized by low carnitine levels. The CPT-2 protein is essential for removing carnitine from long-chain fatty acids after translocation into the mitochondrial matrix is and thus essential for fatty acid oxidation. Although it typically presents as a myopathy in adolescents or adults, CPT-2 deficiency can also present as severe fatal neonatal and hepatocardiomuscular infantile forms. The difference in presentation relates to the amount of residual function (genotype-phenotype correlation).
Neonates with CPT-2 deficiency present within days of birth with encephalopathy, cardiomegaly, hepatomegaly, seizures, cardiac arrhythmias, and respiratory distress, and the condition is rapidly fatal. The infantile form presents between ages 6 and 24 months as episodes of encephalopathy, liver failure, seizures, hypoketotic hypoglycemia, metabolic acidosis, elevated CK levels, reversible hepatomegaly, and, in some cases, cardiomyopathy and arrhythmias, precipitated by infection, fasting, or fever.
The adolescent and adult form of CPT-2 deficiency presents with myopathic pain precipitated by exercise, cold, fever, or prolonged fasting and may be associated with myoglobinuria and kidney damage/failure.
Elevated long-chain acylcarnitine levels are detected in all forms of CPT-2 deficiency, and neonatal screening can be useful in determining the cause of death in the neonatal form.
Secondary carnitine deficiency can result from numerous conditions, such as chronic renal failure, end-stage renal disease, renal Fanconi syndrome, Lowe syndrome, cystinosis, and valproate therapy, all of which cause impaired carnitine reuptake from the kidneys. Carnitine-free diets (such as in those receiving intravenous nutrition), organic acidurias, and urea-cycle defects can also cause deficiency.
Transient falsely low carnitine levels have been reported in infants born to mothers with primary carnitine deficiency.
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Elevated carnitine levels are seen in carnitine palmitoyltransferase 1 (CPT-1) deficiency. The CPT-1 protein conjugates carnitine to long-chain fatty acids, and mutations in the CPT1A gene (expressed in liver cells) present as encephalopathy, seizures, and hypoketotic hypoglycemia in children younger than 18 months, usually triggered by a minor viral illness or fasting.
Blood testing shows low levels of long-chain acylcarnitines (long-chain fatty acid linked to carnitine) and elevated ratios of carnitine: C16+C18. Prevention involves avoidance of fasting (with nighttime feedings of cornstarch) and enrichment of diet with medium-chain triglycerides, which do not require conjugation to enter the mitochondrial matrix for oxidation.
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Carnitine levels are highest during a well-fed state (eg, not in a starvation or catabolic state)
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