Carnitine, Total

Carnitine is crucial for energy production, facilitating the transport of long-chain fatty acids into the mitochondria for oxidation and energy release. It is naturally present in animal-based foods and synthesized in the liver, kidneys, and brain from lysine and methionine, with about 95% of the body's carnitine stored in heart and skeletal muscles.

While carnitine supplementation is generally considered safe, excessive intake can lead to side effects such as gastrointestinal discomfort and a fishy body odor. Additionally, interactions with certain medications and potential health risks associated with elevated levels of metabolites like TMAO in relation to cardiovascular disease highlight the importance of careful consideration and consultation with healthcare professionals regarding carnitine intake, especially for individuals on specific medications or with underlying health conditions.

Elevated levels of total carnitine could mean:

→ Increased Dietary Intake: A diet high in carnitine-rich foods might temporarily increase blood levels.

→ Supplementation: Use of carnitine supplements can raise blood levels.

→ Liver Dysfunction: Since the liver plays a role in carnitine synthesis and regulation, liver disorders may affect carnitine levels.

→ Kidney Dysfunction: Normally, the kidneys regulate carnitine levels by excreting excess carnitine. Impaired kidney function can lead to elevated carnitine levels.

→ Metabolic Disorders: Certain metabolic disorders can cause an accumulation of carnitine.

→ Increased Muscle Mass or Physical Activity: Since carnitine is involved in energy metabolism, individuals with high muscle mass or those engaged in intense physical activity might have higher levels.

→ Medications: Some medications can increase carnitine levels.

Carnitine levels are highest during a well-fed state (eg, not in a starvation or catabolic state).

Carnitine palmitoyltransferase 1 (CPT-1) deficiency:

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.

Elevated carnitine levels alone do not diagnose a condition but may prompt further investigation or evaluation by a healthcare provider. If there are concerns about the results, it is advisable to discuss them with a healthcare professional who can provide personalized insights and recommendations.

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.

Serum carnitine analysis is useful in the diagnosis and monitoring of patients with carnitine deficiency (either primary or secondary). Primary carnitine deficiency is an autosomal recessively inherited genetic condition that affects carnitine uptake by cells and tissues through a defect in the plasma membrane carnitine transporter. Secondary carnitine deficiency can be seen in some disease states or in patients on carnitine-poor diets, but is also seen in a number of metabolic disorders. In these disorders, carnitine complexes with the accumulated substrate of the blocked metabolic step, and the resulting acylcarnitine ester is excreted in the urine, leading to a depletion of carnitine in the patient.