J Nutr. 1988 May;118(5):541-7.
Role of carnitine in human nutrition.
Feller AG, Rudman D.
Medical Service, Veterans Administration Medical Center, North Chicago, IL 60064.
[ Free full text ]

From the full text article:

Functions

The oxidation of long-chain fatty acids in animal tissues is dependent on carnitine because it allows long-chain acyl-CoA esters to cross the mitochondrial membrane, which is otherwise impermeable to CoA compounds. This function of carnitine is carried out in four steps: formation of a long-chain acyl-CoA ester by the CoA synthetase located outside the mitochondrion; formation of a long-chain fatty acylcarnitine ester at the outer face of the inner mitochondrial membrane by the enzyme carnitine palmitoyltransferase A (CPT A); transport of the carnitine ester to the inside of the membrane; and regeneration within the mitochondrion by CPT B of the long-chain fatty acyl-CoA and free carnitine (1).

Another role of carnitine may be to protect cells against toxic accumulation of acyl-CoA compounds of either endogenous or exogenous origin by trapping such acyl groups as carnitine esters, which may then be transported to the liver for catabolism or to the kidney for excretion in the urine (2). This speculation is based on the existence of three different types of carnitine transferase (carnitine acetyltransferase, carnitine octanoyltransferase and CPT), which collectively provide a broad range of substrate specificity.

The more rapid renal clearance of acylated carnitine than of free carnitine (3), and the inhibitory effect of acyl-CoA accumulations on many enzymatic activities (2), support this postulated protective role of the compound against metabolic acidosis. If carnitine indeed functions physiologically as a buffer for endogenous acyl groups of varying chain length, then in states of elevated acyl-CoA concentrations, when the ratio of acylcarnitine to free carnitine tends to rise, its availability to transport long-chain fatty acids into mitochondria may be reduced. Stumpf, Parker and Angelini (2) have proposed that the depletion of free carnitine under such circumstances signifies cellular carnitine deficiency.

Two Sources of Carnitine in the Body

Dietary. The average nonvegetarian American diet provides about 100-300 mg of L-carnitine daily. The highest concentrations of L-carnitine are found in red meat and dairy products. Vegetables, cereals and fruits contain little or no carnitine. Strict vegetarians, therefore, have negligible sources for this nutrient, except for the fermented soybean product tempeh (4).

Endogenous synthesis of carnitine. Like the distribution of carnitine in animal tissues, the biosynthetic capacity for this compound is virtually ubiquitous in the animal kingdom. The four-carbon chain comes from lysine; the methyl groups come from methionine. The biosynthesis is accomplished by a sequence of five enzymes (Fig. 1) (5). Of importance in clinical nutrition is the role of four other micronutrients, vitamin C, niacin, vitamin B-6 and iron, as cofactors required by various enzymes of the pathway (4). Thus deficiencies of lysine, methionine, vitamin C, vitamin B-6 and iron have all been shown to lead to reduced fluid and/or tissue levels of carnitine, presumably due to impaired biosynthesis (4, 6).

Transport of Carnitine

For carnitine to carry out its principal function in mitochondrial fatty acid oxidation, the molecule must enter the cell. Most cell types possess a stereospecific mechanism for transporting carnitine across the cell membrane, with a resulting 10- to 100-fold gradient between extracellular and intracellular concentrations 17).

Cells can also release carnitine into the plasma. The different turnover times of carnitine in different organs in the rat (kidney, 0.4 h; liver, 1.3 h; heart, 21 h; skeletal muscle, 105 h; brain, 220 h) (8) presumably reflect the variable relationship of cellular uptake and release mechanisms in these locations.

The transport process is stimulated by fasting, diabetes, glucagon and glucocorticoids. Thus, in fasting or diabetes, liver carnitine concentration in rats is substantially increased (9).

The rapid release capabilities of liver, gut and kidney reflect the roles of these three organs in the synthesis of endogenous carnitine, in the absorption of exogenous carnitine and in the renal tubular reabsorption and renal conservation of circulating carnitine.

Homeostasis of Carnitine

The total body pool of carnitine in a normal 70-kg human adult is approximately 100 mmol (10). Of this quantity, 98% is found in muscle and only about 1.5% in liver and kidney. In the rat, about one-fifteenth to one-twentieth of the body pool turns over each day, consistent with the slow rate of turnover in muscle, where most of the body carnitine is stored (7, 8).

There are two sources for appearance of carnitine in the body and only one route for removal. Entrance is either by the absorption of exogenous dietary carnitine from the consumption of animal or dairy products or by endogenous biosynthesis. The only known route for removing carnitine from the body is excretion in the urine. Renal clearance reflects to some degree the plasma concentration: When the plasma carnitine level falls, the urinary excretion of carnitine diminishes. Carnitine is filtered at the same rate as creatinine through the glomeruli. Over 90% of filtered carnitine is then reabsorbed by the renal tubules (11), a degree of conservation similar to that for the circulating amino acids.

The proposal that esterification with carnitine provides a way of storing, transporting or excreting endogenous acyl groups (at the expense of free carnitine) adds another dimension to carnitine homeostasis. To maintain a capability for long-chain fatty acid oxidation, a sufficient level of extramitochondrial unesterified carnitine must be available. As mentioned above, a "trapping" of unesterified carnitine by the formation of acyl esters has the potential to lower the intracellular level of the free compound (2).

Theoretical Causes of Cellular Deficiency of Carnitine or Impairment of Carnitine Function

Theoretically, there are at least seven different causes for impairment of carnitine function within cells: 1) A reduced capacity for biosynthesis. There are several potential causes of such reduced synthetic capacity: deficient intake of lysine, of methionine or of the cofactors vitamin C, niacin, vitamin B-6 or iron; advanced disease of either of the two main organs involved in carnitine biosynthesis, skeletal muscle and liver; prematurity of the biosynthetic pathway in neonates; a congenital block in the biosynthetic pathway. 2) Subnormal CPT A. 3) Subnormal transport of carnitine across the cell membrane. 4) Subnormal transport of carnitine across the mitochondrial membrane. 5) Subnormal transepithelial transport (small intestine, renal tubule). 6) Excess losses (renal tubular disease, hemodialysis, acidosis, drugs). 7) Raised tissue requirement for carnitine: rapid growth of the infant; nutritional repletion of the undernourished child or adult; pregnancy and lactation; increased acyl loads.

The seven theoretical disorders listed above can be categorized according to whether they would be associated with low plasma carnitine or with low tissue carnitine and whether they would be benefited by the presence of carnitine in the diet. Thus in 1} and 5) but not in 3), plasma carnitine would be low; in 2) but not in 2) or 4], dietary carnitine would correct the problem.

Theoretical Consequences of Impaired Carnitine Function

If the carnitine defect involves the liver, the supply of ketones and the utilization of long-chain fatty acids during starvation are cut off; all tissues become glucose dependent. When hepatic carnitine is depleted, therefore, starvation tends to cause nonketotic, insulinopenic hypoglycemia. Because hepatocytes depend on fatty acids for their energy requirements during fasting, carnitine depletion may also cause clinical liver dysfunction, shown by hyperammonemia, encephalopathy and hyperbilirubinemia.

Skeletal muscles are generally involved, with weakness, lipid myopathy and myoglobinuria often aggravated or precipitated by fasting or exercise.

Cardiac muscle, like skeletal muscle, is dependent on fatty acids for energy during fasting, and cardiomegaly, cardiac failure and arrhythmias are frequent manifestations of systemic carnitine deficiency.

Primary Congenital Disorders of Carnitine Metabolism

According to the tissue distribution of the carnitine abnormality, these autosomal recessive disorders are classified as either myopathie or systemic (12). The myopathie disease features muscle weakness with elevation of plasma enzymes of muscle origin. Type I muscle fibers are extensively infiltrated by fat. Carnitine concentrations in muscle are low, plasma levels are normal and both the carnitine acyltransferase system and the enzymes of fatty acid oxidation are normal. As the cause, a defective transport system for carnitine uptake has been proposed (7, 13).

In the systemic form, carnitine levels are low not only in plasma but also in skeletal and heart muscle and in liver. In addition to muscle weakness, the following abnormalities of the liver, central nervous system and heart are prominent: encephalopathy, hyperbilirubinemia, hyperammonemia, elevated liver enzymes, impaired ketogenesis and hypoglycemia during fasting and cardiomyopathy (14). Both skeletal muscle and liver are infiltrated with fat. It is not known what biochemical defect in these individuals leads to low body carnitine in the face of adequate dietary carnitine.

In both the myopathie and the systemic forms, many patients have responded dramatically to carnitine supplements given by either the intravenous or the oral route (12, 15). Some individuals with systemic carnitine deficiency, however, have not improved even when carnitine was given for long periods.

Carnitine Status of Vegetarians

Strict vegetarian diets contain less than 10% as much carnitine as typical omnivorous diets of the developed nations, and ovolactovegetarian diets contain about 20% as much. Nevertheless, vegetarian diets furnishing adequate lysine, methionine and micronutrients for carnitine biosynthesis should theoretically maintain normal carnitine nutrition in the healthy individual, consistent with the concept that carnitine is nutritionally dispensable.

Three studies have tested this prediction. 1) Healthy well-nourished individuals in the United States eating either ovolacto- or strict vegetarian diets for prolonged periods showed normal plasma carnitine levels (16). 2) In a population of Indian adult males consuming preponderantly cereal-based diets, only those individuals with protein malnutrition (edema and hypoalbuminemia) had subnormal plasma carnitine (17). 3) Slightly lower plasma total carnitine levels were found in a vegetarian rural population in Thailand than in an omnivorous urban population, which may be attributed to poor nutritional status (18).

Noncongenital Hypocarnitinemic Clinical States

A nutritionally dispensable compound is one that can be removed from the diet of healthy individuals in an ordinary environment without causing illness or dysfunction. A conditionally essential nutrient is a nutritionally dispensable compound for which, under a particular conditioning circumstance, dietary removal causes a demonstrable adverse effect (19).

The studies with healthy vegetarian adults indicate that carnitine is nutritionally dispensable for such individuals. A series of noncongenital conditions have been reported, however, in which infants or sick adults tend to become hypocarnitinemic, especially if the diet contains little or no carnitine. Several such conditions will be discussed below. If the hypocarnitinemia signifies tissue carnitine depletion, it should be accompanied by the hepatic, skeletal muscle and cardiac muscle abnormalities discussed earlier. Unfortunately the occurrence of such abnormalities and their correlation with level of tissue carnitine have not been thoroughly described in the majority of reports on noncongenital hypocarnitinemic states. Usually, however, the circumstances surrounding the hypocarnitinemia provide a logical cause for increased carnitine requirement or impaired carnitine biosynthesis. Accordingly, these situations represent suspected but as yet unproven, in stances of "conditional carnitine essentiality" (19).

The neonate and the premature infant. Shenai and Borum (20) studied 22 neonates who died within 24 h of birth, prior to any intervention that might have affected carnitine status. In comparison to adult controls, tissue carnitine concentrations (muscle, heart and liver) were significantly lower, especially in the premature infants. Penn, Schmidt-Sommerfeld and Pascu (21)found liver and heart carnitine concentrations to be low in 13 premature infants who had received more than 15 d of carnitine-free total parenteral nutrition (TPN). Schmidt-Sommerfeld, Penn and Wolf (22) studied 29 premature infants during TPN; 15 received carnitine supplementation and 14 were not supplemented. Plasma total carnitine was normal in the supplemented group and reduced in the unsupplemented group.

At birth, the neonate tends to shift from glucose to fatty acids as the main metabolic fuel. It is a matter of concern, therefore, that neonates, particularly if premature, frequently have low plasma and tissue carnitine concentrations. Conventional TPN solutions contain no carnitine. Human milk appears to be the major source of carnitine to meet the neonate's metabolic needs. It has been suggested, therefore, that all infant diets, including TPN solutions, should contain adequate carnitine (23).

TPN in adults. Hahn, Allardyce and Frohlich(24) studied 47 surgical patients undergoing TPN. In contrast to neonates, these adult patients usually main tained normal plasma carnitine concentrations for 2 or 3 wk; thereafter, however, there was a gradual decline. On initiation of oral feedings, levels rapidly returned to normal.

More recently, Bowyer et al. (25) studied 37 patients receiving long-term home TPN. Thirteen patients had low total and free plasma carnitine levels. One of five patients who underwent liver biopsy had low liver carnitine concentration. No association was found be tween plasma carnitine and liver enzymes.

Worthley, Fishlock and Snoswell (26) described an adult male who, after 1 yr of TPN, developed hyperbilirubinemia, hypoglycemia and generalized skeletal muscle weakness. Plasma and urinary carnitine were low. Intravenous administration of L-carnitine corrected the plasma carnitine deficiency, the hypoglycemia and the hyperbilirubinemia. Skeletal muscle strength was also restored. The same authors (27) reported decreased levels of plasma and urinary carnitine in two patients requiring TPN for 34 and 37 mo, respectively. Recently Palombo et al. (28) reported a patient on home TPN who developed abnormal liver function tests in the presence of low plasma and liver carnitine concentrations. This patient who had shortgut syndrome, did not respond to oral DL-carnitine but was benefited by intravenous L-carnitine.

The question of whether adult patients on long-term TPN should be routinely supplemented with carnitine is unresolved (29). The amount of functional bowel and whether the patient is eating probably influence the carnitine status in this group of patients.

Enteral feedings with protein hydrolysate formulas in adults. Feller et al. (30) described 19 elderly subjects in a nursing home who were chronically tube-fed with a protein hydrolysate formula (Isocal, Mead-Johnson, Evansville, IN). In more than one-half of these individuals both free and total plasma carnitine concentrations were below the normal range. Carnitine concentrations were lowered to a similar degree as during long-term TPN. These observations indicate that endogenous synthesis in some elderly patients fed carnitine-free diets may not be adequate to maintain normal body carnitine content.

Chronic renal failure and hemodialysis. In patients with chronic renal failure, plasma carnitine is normal or high. In 14 uremic patients, Bertoli et al. (31) found that carnitine levels fell sharply during hemodialysis. In 10 of the 14 patients, muscle carnitine was significantly reduced; in four patients, lipid droplets were found in muscle.

Gusmano, Oleggini and Perfumo (32) studied seven children who had undergone hemodialysis for more than 4 mo. Postdialysis plasma carnitine concentration was significantly reduced. Rodriguez-Segade et al. (33) recently reported that in 54 chronic renal failure patients undergoing chronic hemodialysis, both total and free serum carnitine declined progressively during 25 wk of observation.

The causes of carnitine deficiency during chronic hemodialysis are probably multifactorial. Renal failure may impair the endogenous synthesis of carnitine, removal of carnitine from the body may be accelerated by the dialytic procedure and the diet fed to uremic patients may be limiting not only in carnitine but also in the micronutrients required for carnitine biosynthesis (34).

Renal tubular defect. In 19 children with nephropathic cystinosis, the plasma concentrations of free and total carnitine were subnormal (35). Nevertheless three patients who underwent a fasting study had normal ketogenesis. In contrast to the apparent lack of hepatic involvement, they had moderate depression of free and total carnitine in skeletal muscle, where lipid droplet accumulation and myopathie changes were also present. Excessive loss of carnitine in the urine, because of impaired renal tubular reabsorption, probably explains carnitine deficiency in these individuals.

Malnutrition. Khan and Bamji (36) analyzed plasma carnitine levels in 35 children between 1 and 5 yr of age. Of these, 13 had kwashiorkor, 12 had marasmus and 10 were underweight. All showed significantly depressed carnitine levels. A positive correlation was found between carnitine and serum albumin. During 4 wk of treatment with a high protein diet, carnitine and albumin levels improved.

The same authors (17) studied 17 Indian adult males with anthropometric evidence of malnutrition but normal serum albumin levels, and six patients with nutritional edema and hypoalbuminemia. Only subjects with nutritional edema had markedly reduced plasma carnitine, which improved after 3 wk of a high energy, high protein diet. These authors and others (37, 38) have also observed in malnourished children and adults a reduced plasma carnitine level, which generally improved after dietary intervention.

Thus the low carnitine, low protein vegetarian diet that is common in the developing nations, and that is also sometimes used to treat patients with advanced liver or renal disease, appears to cause hypocarnitinemia and perhaps carnitine depletion.

Organic acidemias. The organic acidemias are in born errors of metabolism in which fatty and organic acids accumulate, causing growth retardation, muscle hypotonia, protein intolerance, hyperammonemia and ketoacidosis. Many of these features are similar to the manifestations of systemic carnitine deficiency (2).

Roe and Bohan (39) described a 6-mo-old child with propionic acidemia, lacking free urinary carnitine (plasma carnitine was not measured), who responded to L-carnitine supplementation with increased protein intake, weight gain and improved muscular tone. Seccombe, Snyder and Parsons (40) reported an 8-yr-old boy with methylmalonic aciduria. Free and total serum carnitine were low. Metabolic improvement was observed with oral L-carnitine.

A case of methylmalonic aciduria was studied in greater detail by Roe et al. (41). This 21-mo-old girl had normal plasma free carnitine but considerably raised short-chain acylcarnitines. Supplementation with carnitine resulted in a marked increase in propionylcarnitine urinary excretion. Allen, Hansch and Wu (42) reported an infant with homocystinuria and severe encephalomyopathy, who had reduced plasma and muscle carnitine levels. This patient had a dramatic clinical response to carnitine supplementation. Stumpf et al. (43) demonstrated that propionate toxicity on isolated hepatic mitochondria was neutralized by carnitine, supporting the clinical observations that carnitine therapy may benefit patients with organic acidemias. Chalmers et al. (44) concluded that most patients with or ganic acidurias are either deficient in carnitine or fail to synthesize adequate amounts to meet their increased needs. Urinary studies have shown a carnitine leak in the form of acylcarnitine.

Thus patients with organic acidemias may have either normal or decreased total plasma carnitine concentrations, but the proportion of acylcarnitine is usually elevated. Carnitine is believed to trap acidic groups (41), such as the propionyl groups that accumulate in both propionic and methylmalonic aciduria, thereby releasing CoA and restoring ATP synthesis. Carnitine supplementation of the diet may benefit some children with organic acidemias.

Reye's syndrome. This acute illness is encountered mostly in children below 15 yr of age. Its incidence varies in direct relationship to viral epidemics, especially those due to influenza B and varicella (45). A strong association has also been demonstrated with salicylate use (46). Its clinical manifestations, namely, acute liver injury with fatty infiltration, hyperammonemia, encephalopathy and hypoglycemia, resemble those of systemic carnitine deficiency. Therefore patients with Reye's syndrome have been treated with carnitine. A lack of clinical progression of the disease was observed in six such patients (47). However, a recent report described a 15-wk-old infant with severe Reye's syndrome who died in spite of treatment with intravenous L-carnitine (48).

Willner, Chutorian and DiMauro (49) studied skeletal muscle and liver carnitine content in six children during and after attacks of Reye's syndrome. No consistent abnormality was found. Nevertheless Roe et al. (47) showed that the urinary excretion of both free and acylcarnitine increased 40-fold in Reye's syndrome. It has been speculated that as carnitine is lost in the urine, the acyl buffering capacity deteriorates and excessive levels of acyl-CoA metabolites accumulate, causing mitochondrial damage (2). The role of carnitine in Reye's syndrome, however, is still uncertain.

Drugs. Valproic acid, a short-chain fatty acid, is an anticonvulsant widely used in pediatrie practice. Its most serious complication is a Reye's-like syndrome with hepatic dysfunction, hyperammonemia and encephalopathy.

Ohtani, Endo and Matsuda (50) reported that 14 patients treated with this drug had lower plasma carnitine levels and higher blood ammonia concentrations in the absence of other manifestations of liver injury, than age-matched controls. A significant inverse relationship was observed between carnitine levels and dosage of valproic acid and between carnitine and blood ammonia levels. Oral supplementation with DL-carnitine corrected both the hypocarnitinemia and the hyperammonemia.

Bohles et al. (51) reported a 3-yr-old child who died from a Reye's-like syndrome during valproate therapy. Plasma carnitine was reduced. Murphy, Marquardt and Shug (52) reported a 6-mo-old infant with valproate hepatotoxicity whose plasma carnitine was reduced to levels seen in systemic carnitine deficiency; after with drawal of valproate, the patient recovered and his plasma carnitine returned to normal. In this study, 13 asymptomatic children on valproate treatment also had lower plasma carnitine than controls, but their carnitine levels were higher than that of the symptomatic child.

More recently, Laub, Paetzke-Brunner and Jaeger (53) demonstrated low serum free carnitine concentrations and a high ratio of acylcarnitine to free carnitine in 21 children receiving valproic acid. Valproylcarnitine has been detected in the urine of these patients (54). This finding supports the view that the mechanism leading to reduction of plasma free carnitine and elevation of acylcarnitines is similar to that of the organic acidurias, namely, an augmented urinary loss of carnitine excreted as acylcarnitines.

Animal studies have shown that other xenobiotic acids are conjugated with carnitine (55). The role of carnitine in xenobiotic metabolism could be more general than presently appreciated.

Pregnancy and lactation. Scholte, Stinis and Fennekens (56) reported a gradual decrease in plasma carnitine during pregnancy in 12 women; at delivery, the average value was only 50% of control. Bargen-Lockner, Hahn and Wittman (57) also demonstrated a significant reduction of plasma free and total carnitine during pregnancy. Levels of total and free carnitine were significantly higher in the fetal circulation than in the maternal circulation. Cederblad et al. (58) recently reported a study of 19 pregnant women. The mean maternal carnitine value was lower than the mean infant value and lower than that of the nonpregnant, fertile woman. As has been mentioned before, milk is a source of carnitine loss in lactating women. Women with primary systemic carnitine deficiency have been reported to deteriorate during the third trimester of pregnancy or the immediate postpartum period. In two cases the outcome was fatal; a third case, a 16-yr-old girl, recovered in association with oral DL-carnitine supplementation (59). Thus the loss of carnitine during pregnancy and lactation can trigger acute decompensation in those patients whose stores have already been depleted because of an inborn error of carnitine metabolism.

Conclusions

Carnitine serves a physiologically indispensable function in mitochondrial fatty acid oxidation. How ever, the compound is nutritionally dispensable in healthy adults in conventional environments because of their adequate endogenous synthetic capacity.

Several clinical circumstances have been described that either increase the tissue requirements for carnitine or diminish the synthetic capacity and that therefore may tend to create a nutritional dependence. Requirement is increased by rapid growth (infancy, or the repletion of protein-calorie undernutrition), pregnancy, lactation, metabolic acidosis, certain drugs excreted in acidic form, renal dialysis and renal tubular disorders. Synthetic capacity is reduced by undernutrition for protein, iron, vitamin C, niacin or vitamin B-6 and by prematurity and infancy.

Diets containing little or no carnitine are common, i.e., vegetarian diets and the synthetic formulas widely used in pediatrie and adult medicine. When patients with increased carnitine requirements or impaired synthetic capacity are exposed to low carnitine diets, the potential for carnitine depletion arises. Several such examples of noncongenital hypocamitinemic states have been discussed. The case of valproic acid-induced hypocarnitinemia and recent experimental animal data raise the possibility of a widespread role of carnitine in the metabolism of foreign acidic compounds.

Categories: 1998, Carnitine, Fatty acid metabolism, Fatty acid oxidation, Acylcarnitines, Carnitine deficiency, Urinary organic acids, Organic acidemias, Inborn errors of metabolism, Malnutrition