Carnitine Deficiency

Carnitine deficiency refers to low levels of carnitine in the body. Carnitine is a water-soluble molecule found naturally in many food sources, especially of animal origin like red meat, poultry, and dairy products, as well as dietary supplements. About one-fourth of the available carnitine in the body is synthesized endogenously in the liver, kidneys, and brain from the amino acids lysine and methionine. It is essential in energy production as it helps transport long-chain fatty acids into the mitochondria to oxidize them and produce energy through adenosine triphosphate (ATP). Carnitine also helps transport some toxic compounds out of the mitochondria. L-carnitine is the most common form of carnitine in the human body and most supplements. There are also several other forms of carnitine including acetyl L-carnitine and propionyl-L-carnitine. 

Carnitine is stored in tissues that oxidize fatty acids as an energy fuel. About 95% of total body carnitine is reserved in skeletal muscles, like the biceps and abdominal muscles; most of the remaining carnitine is concentrated in the liver and kidney. Circulating plasma contains only about 0.5% of the body’s carnitine. About 90% to 99% of the filtered carnitine is usually reabsorbed by the renal tubules to maintain the plasma carnitine levels within the normal range. Excess plasma carnitine is excreted in the urine.  

The signs and symptoms of carnitine deficiency vary depending on the underlying cause. In primary carnitine deficiency, symptoms usually present during infancy or early childhood. Infants may present in the first 2 years with episodes of irritability, fatigue, and abnormal enlargement of the liver (i.e., hepatomegaly). Infants with carnitine deficiency may also present with epilepsy and encephalopathy. Adolescents and younger adults usually experience seizures, irregular heartbeat (i.e., arrhythmia), and breathing problems (e.g., shortness of breath, wheezing, recurrent respiratory tract infections). Individuals with increased age may have myopathy (i.e., muscle weakness); rhabdomyolysis (i.e., damage of the muscle tissue releasing proteins and electrolytes into the blood); cardiomyopathy (i.e., a condition that makes it difficult for the heart to pump blood effectively); or sudden death. Although some individuals with primary carnitine deficiency do not have symptoms, all affected people have an increased risk of heart failure, hepatic disorders, and coma. 

Signs and symptoms of secondary carnitine deficiency are usually less severe than in primary deficiency and may include hypoglycemia (i.e., low level of glucose in the blood), muscle weakness, and hypotonia, (i.e., reduced muscle tone) as well as cardiomyopathy which can lead to sudden death. Developmental delays may also be observed in children. Weakness, seizures, and decreased consciousness can be caused by elevated ammonia levels in individuals with severe liver failure (e.g., hyperammonemia encephalopathy). Lastly, dicarboxylic aciduria (i.e., increased concentrations of dicarboxylic acids in the urine), hyperuricemia (i.e., excess uric acid in the blood), and myoglobinuria (i.e., excess myoglobin in the urine) can be identified in individuals with renal damage. 

Carnitine deficiency diagnosis begins with a detailed clinical evaluation and physical exam, looking for suggestive signs and symptoms. The diagnosis is confirmed by measuring plasma carnitine levels. Low plasma-free carnitine levels (i.e., < 5 μmol/L, average range 20–50 μmol/L) are suggestive of carnitine deficiency. Additionally, genetic testing may be performed to assess alterations of the SLC22A5 gene when primary carnitine deficiency is suspected, however, sequence analysis is not always conclusive. If genetic testing fails to confirm primary carnitine deficiency, the preferred diagnostic test is a functional assay, such as the cultured skin fibroblast carnitine assay. In individuals with primary carnitine deficiency, the activity of the OCTN2 transporter is typically less than 10% of typical control values.  

Once the diagnosis of either primary or secondary carnitine deficiency is confirmed, the individual may be advised to undergo a series of investigations including an echocardiogram, electrocardiogram (EKG), serum creatine kinase (CK), serum creatinine (Cr), serum transaminases (i.e., AST, ALT), electrolytes (e.g., sodium, potassium, chloride) and blood sugar levels. Other biochemical tests such as urine testing may be done to measure carnitine levels or carnitine-related metabolites, which can provide additional information about carnitine status and metabolism. Functional tests, such as carnitine loading tests, may be conducted to assess the body's ability to absorb and utilize carnitine. This involves administering a dose of carnitine and measuring carnitine levels in the blood or urine over a specific period. An endoscopy (e.g., gastroscopy, colonoscopy) may be suggested if gastrointestinal disorders are suspected.  

In the US, the newborn screening test includes evaluation for carnitine deficiency. However, due to carnitine's ability to cross the placenta, low fetal plasma creatinine levels shortly after birth can reflect the maternal plasma carnitine levels. Some mothers are diagnosed after their infants are detected with carnitine deficiency in their neonatal screening tests. Therefore, if the newborn screening detects low carnitine levels, both the baby and the mother are re-tested after two weeks to determine who has carnitine deficiency. 

Primary and secondary carnitine deficiency can be treated with the administration of high doses of supplemental L-carnitine (i.e., 20–200 mg/kg/day) along with intravenous dextrose infusions that can address hypoglycemic episodes during L-carnitine supplementation. Increasing dietary intake of carnitine-rich foods, such as meat, fish, poultry, and dairy products, may also help maintain adequate carnitine levels in individuals with mild deficiency. However, dietary modifications alone may not be sufficient to correct severe carnitine deficiency. Individuals receiving carnitine supplementation should undergo regular monitoring of carnitine levels in the blood to ensure therapeutic efficacy and safety. Monitoring may also include assessing clinical symptoms and evaluating any potential adverse effects of treatment.  

In addition to carnitine supplementation, addressing the underlying cause of carnitine deficiency is essential for optimal management. This may involve treating conditions such as gastrointestinal disorders impairing carnitine absorption, or renal failure, specifically for those requiring dialysis who have excessive loss of carnitine. In more detail, Celiac disease can be treated by excluding foods that contain gluten from the diet. Crohn disease can be regulated with aminosalicylates (e.g., balsalazide mesalamine), a medication containing 5-aminosalicylic acid (5-ASA), which helps control inflammation; corticosteroids (e.g., budesonide, hydrocortisone), immunomodulators (e.g., 6-mercaptopurine, azathioprine), which help modulate immune system activity; and biologic therapies (e.g., anti-tumor necrosis factor-alpha therapies, such as adalimumab), which target proteins made by the immune system decreasing inflammation in the intestines. When renal function is impaired, hemodialysis or peritoneal dialysis can be initiated to remove waste products and excess fluid from the blood. When these procedures are not sufficient kidney transplantation is recommended.