Carnitine Intake Research Articles

Low carnitine intake and altered lipid metabolism in infants

We examined the effect of dietary carnitine on variables of lipid metabolism in human infants. Normal male full-term infants were fed an isolated soy-protein-based formula with or without added carnitine from age 6-9 d to age 112 d. Growth and food intake were measured throughout the study. At ages 56 and 112 d serum concentrations of carnitine, free fatty acids, and triglycerides and urinary excretion of carnitine and medium-chain dicarboxylic acids were measured. Serum carnitine concentrations were lower in all infants fed unsupplemented formula. There was no difference in growth or food intake between the two groups of infants. Serum free fatty acid concentrations were significantly higher in the infants not receiving dietary carnitine. Moreover, excretion of all three medium-chain dicarboxylic acids was significantly higher in infants not receiving dietary carnitine. We conclude that lack of dietary carnitine affects lipid metabolism of infants during the first 4 mo of life.

Changes of Plasma Free Amino Acids and Renal Clearances of Carnitines in Premature Infants During L‐Carnitine‐Supplemented Human Milk Feeding

SummaryEighteen breast‐fed infants with a mean postnatal age of 26 days (range 16–41 days) were studied. Following 1 control day, the infants were fed for 7 consecutive days with pooled human milk supplemented with 300 nmol L‐carnitine/ml milk. Both plasma fractions of acid‐soluble carnitines increased as a consequence of carnitine application. The level of β‐hydroxybutyrate also increased significantly. Of the circulating free amino acids, the levels of alanine (p < 0.025) and glutamine (p < 0.01) were found to be lower, with a decreased urea level (p < 0.005) by the last day of carnitine administration, compared with the control day. The urinary output of total nitrogen also decreased. There were no statistically significant changes in the level of free fatty acids and glucose. On the control day, the renal clearance rate of esterified carnitines significantly exceeded that of free fraction, thus the relative renal reabsorption calculated on the base of creatinine excretion rates was higher for free (mean 98.1%) than for acylated (mean 90.6%) carnitine. In response to enhanced carnitine intake, the clearance rates for each fractions of carnitines significantly exceeded the presupplementary values. The increased clearance rates was more pronounced for free (mean 13.2‐fold) than for esterified (mean 8.08‐fold) carnitines. Despite the increased clearance rates, considerable relative reabsorption was seen for free carnitines (mean 70.0%) as well as for acylcarnitines (mean 65.3%).

Changes of plasma free amino acids and renal clearances of carnitines in premature infants during L-carnitine-supplemented human milk feeding.

Eighteen breast-fed infants with a mean post-natal age of 26 days (range 16-41 days) were studied. Following 1 control day, the infants were fed for 7 consecutive days with pooled human milk supplemented with 300 nmol L-carnitine/ml milk. Both plasma fractions of acid-soluble carnitines increased as a consequence of carnitine application. The level of beta-hydroxybutyrate also increased significantly. Of the circulating free amino acids, the levels of alanine (p less than 0.025) and glutamine (p less than 0.01) were found to be lower, with a decreased urea level (p less than 0.005) by the last day of carnitine administration, compared with the control day. The urinary output of total nitrogen also decreased. There were no statistically significant changes in the level of free fatty acids and glucose. On the control day, the renal clearance rate of esterified carnitines significantly exceeded that of free fraction, thus the relative renal reabsorption calculated on the base of creatinine excretion rates was higher for free (mean 98.1%) than for acylated (mean 90.6%) carnitine. In response to enhanced carnitine intake, the clearance rates for each fractions of carnitines significantly exceeded the presupplementary values. The increased clearance rates was more pronounced for free (mean 13.2-fold) than for esterified (mean 8.08-fold) carnitines. Despite the increased clearance rates, considerable relative reabsorption was seen for free carnitines (mean 70.0%) as well as for acylcarnitines (mean 65.3%).

Lipoprotein lipase, hepatic lipase, and carnitine in premature infants.

Twenty six preterm infants were studied at the age of 2, 7, and 26 days. The activities of lipoprotein and hepatic lipase in plasma taken 15 minutes after a heparin bolus of 100 IU/kg had been given and the concentrations of carnitine in serum and urine were measured. The mean gestational age was 31 weeks (range 26-35 weeks) and birth weight 1580 g (range 840-2280 g). Thirteen infants weighed under 1500 g at birth (very low birth weight), 20 were of appropriate weight for gestational age and six were small for gestational age. Lipoprotein lipase activity was higher in the preterm infants of appropriate weight than in the infants of very low birth weight and those who were small for gestational age. At the age of 2 or 7 days the activity of lipoprotein lipase in the preterm infants (mean (SEM) 46.2 (4.3) mumol free fatty acid/ml/hour) was, however, higher than in term infants and adults. Multivariate regression analyses showed that weight and relative birth weight together explained 58% of the variance of lipoprotein lipase activity but only 3% of the variance of hepatic lipase activity. Serum carnitine concentration was lower in the preterm infants than in term infants. Urinary excretion of carnitine increased progressively with age but was independent of serum concentration and carnitine intake. Urinary excretion of total carnitine was significantly greater in the infants who were small for gestational age (mean (SEM) 754 (203) nmol/mg of creatinine, n = 6) than in the infants of appropriate weight (161 (22.0) nmol/mg of creatinine, n = 12) but acyl/free carnitine ratio was smaller in the infants who were small for gestational age than in infants of appropriate weight (0.56 v 5.5). The results indicate that the slow elimination of fat from the circulation in preterm infants less mature than 32 weeks of gestation can hardly be explained by low lipoprotein lipase activity.

Carnitine during prolonged breast feeding.

To assess carnitine levels during prolonged sole breast feeding we measured serum and breast milk carnitine concentrations in 37 lactating mothers and their healthy term infants from birth to the age of 1 yr. The number of solely breast-fed infants decreased to 31 at 2 months of age, to 28 at 6 months, and to seven at 9 months, because formula and/or solid food was added when there was not enough breast milk. In mothers the mean serum carnitine increased from 35 to 50 mumol/liter during the first 2 months after delivery and remained unchanged thereafter. Irrespective of the type of feeding, the mean serum carnitine in infants increased from 29 to 59 mumol/liter during the first 2 months, remained unchanged during 2-9 months, and decreased to the mean level of mothers thereafter. The mean carnitine concentration of breast milk was high (106 mumol/liter) immediately after delivery. During the first 2 months the mean carnitine concentration of milk decreased to the mean serum level of mothers and remained unchanged thereafter. The carnitine concentrations of serum and breast milk did not correlate, however. The mean daily carnitine intake of the breast-fed infants was 5.7 mumol/kg at 4 months of age, 4.7 mumol/kg at 6 months, and 6.0 mumol/kg at 9 months whereas the mean daily carnitine intake of the infants receiving formula was 28.9 mumol/kg at 1 month of age and 30.7 mumol/kg at 2 months. The serum concentration of carnitine in our infants did not correlate with carnitine intake. Our results indicate that serum carnitine concentrations are maintained during prolonged sole breast feeding.

Plasma Carnitine and Breast Milk Carnitine Intake in Premature Infants

SummaryTen premature infants with a mean gestational age of 29 weeks (range, 27–32) and a mean birth weight of 1,294 g (range, 930–2,300) and without complications at birth were studied during the first 14 days after birth. Their breast milk intake was recorded and the carnitine content determined in each daily portion. During the first week, the daily mean carnitine intake was low and increased to 6–7 μmoles/kg and day during the second week. Breast milk carnitine concentration ranged from 17 to 148 n, moles/L. Plasma carnitine and its derivatives did not change during the observation period. No relationship was found between the individual cumulative breast milk carnitine intake and total plasma carnitine levels or between carnitine and its derivatives and nonesterified fatty acids or 3‐OH‐butyrate. The urinary carnitine excretion, in millimoles of carnitine per mole of creatinine, was higher during the second week. In other studies, declining plasma carnitine levels have been observed in premature infants on total parenteral nutrition. The results from this study indicated that premature infants without complicating disorders were able to maintain their plasma carnitine levels.

Dietary carnitine intake related to skeletal muscle and plasma carnitine concentrations in adult men and women

The purpose of this investigation was to determine if there was any relationship between dietary carnitine intake and the concentrations of carnitine in skeletal muscle and blood plasma in healthy adult men and women. Subjects (14 men, 14 women, fasted 8 h) reported to the Biodynamics Laboratory where they completed a 24-h diet recall questionnaire. Resting muscle biopsy (vastus lateralis) and blood plasma samples were taken and assayed for free, short-chain, and long-chain acyl carnitine concentrations. Dietary carnitine intake was estimated from data on concentrations in food. There was no significant relationship between either protein or carnitine intake with skeletal muscle carnitine concentrations. There was a significant relationship between both dietary carnitine (r = 0.50) and protein (r = 0.48) intake with blood plasma total acid soluble carnitine concentrations (p < 0.01) in all subjects.

Changes in erythrocyte and plasma carnitine concentrations in preterm neonates

Erythrocyte and plasma total, free, and acyl carnitine concentrations in 13 low birthweight, preterm infants were determined between birth and 21 days of age. Although erythrocytes contributed 73.6 ± 4% (mean ± SD) of total blood carnitine at birth, the contribution by day 14 declined to 42.2 ± 14.1. Linear regression analysis showed no significant correlation between plasma and erythrocyte concentrations. At 3 wk erythrocyte total carnitine concentrations were similar to adult values, but erythrocyte acyl carnitine concentrations were markedly lower. Although a significant (p < 0.05) positive correlation between plasma carnitine concentrations and mean daily intake from birth was found at 7, 14, and 21 days of age (r = 0.66, 0.87, and 0.88, respectively), no significant relationships between erythrocyte carnitine concentrations and carnitine intake could be demonstrated by linear regression analysis. It appears that the carnitine present in plasma and erythrocytes represents two separate pools which are influenced by different factors in preterm infants.

Carnitine as an essential nutrient.

Carnitine performs a critically important role in energy metabolism and is synthesized in the healthy adult predominantly in the liver and kidney. The typical well balanced American diet contains significant amounts of carnitine as well as the essential amino acids and micronutrients needed for carnitine biosynthesis. Thus carnitine is an infrequent problem in the healthy, well nourished adult population in the United States. However, carnitine can be a conditionally essential nutrient for several different types of individuals. Preterm infants require carnitine for life-sustaining metabolic processes but have a carnitine biosynthetic capability that is not fully developed. There is an increasing number of documented problems with carnitine metabolism in preterm infants not receiving an exogenous source of carnitine indicating that endogenous biosynthesis of carnitine is not adequate to meet the infant's need. Children with different forms of organic aciduria appear to have a greatly increased need for carnitine to function in the excretion of the accumulating organic acids. This need exceeds their dietary carnitine intake and carnitine biosynthetic capability. Renal patients treated with chronic hemodialysis appear to lose carnitine via the hemodialysis treatment, and this loss cannot be repleted simply by endogenous biosynthesis and dietary intake. Treatment with drugs such as valproic acid and metabolic stresses such as trauma, sepsis, organ failure, etc, can also result in a requirement for exogenous carnitine. Accurate assessment of the carnitine status of patients at risk for carnitine deficiency is fundamental to the identification of those patients who require carnitine as the result of altered metabolism.

Plasma carnitine levels and urinary carnitine excretion during sepsis.

Carnitine is an indispensable factor for the beta-oxidation of medium- and long-chain fatty acids, and it plays a possible role in the oxidation of branched-chain amino acids. Plasma and urinary levels of free carnitine and short-chain acyl-carnitines were studied in 67 surgical patients, after non-septic surgical procedures or during sepsis. The septic state was associated with increased urinary excretion of free carnitine (p less than 0.001), as well as with lower plasma levels of short-chain acyl-carnitines (p less than 0.001); the latter feature correlated with the level of hypermetabolism, as evaluated by the metabolic rate and by the arterial-mixed venous O2 difference. In 26 patients during total parenteral nutrition D, L-acetyl-carnitine was administered (100 mg/kg/24 hrs, in continuous iv infusion) and was associated, in septic patients only, with a significant decrease in the respiratory quotient, suggesting enhanced oxidation of low respiratory quotient substrates (fatty acids and/or branched-chain amino acids). Carnitine supplementation during total parenteral nutrition might be of theoretical benefit in some clinical conditions, such as sepsis, in which the following conditions coexist enhanced utilization of substrates whose oxidation is partially or totally carnitine dependent; prolonged absence of exogenous intake of carnitine (as in long-term total parenteral nutrition); eventual impairment of carnitine synthesis due to hepatic dysfunction; increased, massive urinary loss of carnitine.

Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport.

The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and "other tissues") was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.

Urinary excretion of carnitine in multiply injured patients on different regimens of total parenteral nutrition

Carnitine derives from intake of preformed exogenous carnitine and synthesis from lysine and methionine, but is absent in parenteral fluids. Urinary excretions of carnitine and its derivatives was measured in 30 patients 2–8 days after severe multiple injuries and compared with controls. The patients received five different isocaloric parenteral nutritional regimens; group 1 glucose and fat, group 2 glucose, fat and amino acids, group 3 glucose and insulin, group 4 glucose and amino acids, and group 5 branched-chain amino acids. The mean total carnitine excretion in healthy men was 420 μ mol 24 h ± 57 (SEM), and in women 266 μ mol 24 h ± 29 , 41% of which was free carnitine. Mean excretion of total carnitine during days 2–8 after trauma for the five groups was: 900 ± 100, 1169 ± 112, 1251 ± 102, 1023 ± 117, and 668 ± 128 μ mol 24 h , being significantly higher in groups 1–4 than in healthy men. The free carnitine fraction in the patients was significantly higher than in controlled healthy subjects. Total carnitine excretion was unaffected by different nutritional regimens in the very first days. During days 6–8, group 5, receiving branched-chain amino acids had lower excretion of total carnitine (compared to groups 2–4) and free carnitine (compared to groups 3–4). Groups 3 and 4 excreted a higher percentage as free carnitine compared to the other groups. A significant correlation was found between total carnitine and net nitrogen losses during the whole observation period and between total carnitine and 3-methylhistidine during days 6–8 after trauma.

Tissue carnitine concentrations after total parenteral nutrition with and without L-carnitine supplementation

The concentrations (μmoles/g dry weight) of total carnitine (TC), free carnitine (FC) and acylcarnitine (AC) were determined in skeletal muscle, heart, liver, kidney and brain cortex of male mini pigs (4000–5000 g) after seven days of total parenteral nutrition (TPN) with amino acids 5% (3.0g/kg/d), glucose (25g/kg/d) and lipids 20% (4g/kg/d). This regime was administered with L-carnitine supplementation (1.5 mg/kg/d; n = 7) (group 1) and without it (n = 5) (group 2). Orally alimented animals (n = 5) served as controls (group 3). (Average carnitine intake: 3 mg/d) Carnitine free TPN affected only the concentrations in muscle. TC was markedly reduced (3.6 ± 0.8) when compared with oral controls (5.8 ± 0.7) (p<0.01). This decrease was exclusively due to AC, whereas FC concentrations remained almost unchanged. In group 1 the concentrations of TC in skeletal muscle, heart and brain cortex were higher than in both the other groups. The increase was mainly due to AC and FC remained unchanged in heart and brain. The concentrations in liver and kidney were not affected by either carnitine free or carnitine supplemented TPN. AC, determined as described, consists almost entirely of acid soluble acetyl-carnitine, the major product of fatty acid oxidation. Since the AC concentrations were almost exclusively altered by the two TPN-regimes we conclude that the observed changes reflect regulatory changes of fatty acid oxidation. Thus the decrease of muscle TC in group 2 is considered a consequence of an insulin induced down regulation (plasma insulin: mean 20 μU/ml; maximum: 60 μU/ml) of fatty acid oxidation in consequence of high glucose intake (25 g/kg/d). The increased TC concentrations after carnitine supplemented TPN are discussed to reflect an enhancement of oxidative degradation of fatty acids as a pharmacological effect of L-carnitine.

Carnitine metabolism in thyroid hormone treated rats and mice.

This study was undertaken to investigate the changes in carnitine metabolism in rats and mice injected with T4 for 3 days and 10 days, respectively, and in rats fed a T3 and T4-supplemented diet for 6 weeks. Thyroid hormone administration brought about a significant increase in urinary excretion of total carnitine. In T3 + T4-treated rats urinary esterified-carnitine to free-carnitine ratio increased significantly in the later phase of administration. Carnitine pool size in the body was significantly decreased in both T4-injected mice and T3 + T4-fed rats. In the latter animals, this decrease was due to the reduced carnitine contents in organs other than the liver, especially in skeletal muscle. The amount of carnitine synthesized by control and T3 + T4-treated rats was calculated from the data on carnitine intake, urinary carnitine excretion and carnitine pool size in the body over the 6-week period. Values obtained were 66.2 +/- 3.2 (mean +/- SEM) mumol/rat and 28.5 +/- 4.9 mumol/rat, respectively, and the difference was significant (p less than 0.05). These results indicate that carnitine synthesis is depressed by thyroid hormone, however, some possibilities that thyroid hormone may increase carnitine synthesis were also discussed.

Carnitine blood concentrations and fat utilization in parenterally alimented premature newborn infants

To investigate the relationships among carnitine intake, carnitine blood concentrations, and the ability to utilize exogenous fat, total carnitine, free carnitine, acylcarnitine, beta-hydroxybutyrate, free fatty acid and triglyceride plasma concentrations were measured in 26 parenterally alimented appropriate-for-gestational-age premature infants before and at the end of a four-hour infusion of Intralipid, 1 gm/kg body weight. There was an increase in plasma levels of AC, BOB, FFA, and TG, but a decrease of FC, TC was unaffected by the infusion, but strongly correlated with calculated carnitine intake. At the end of the fat infusion, AC and BOB were positively correlated, and FFA negatively correlated with TC. The results demonstrate the proportion of AC to FC to be an additional indicator of fatty acid utilization and suggest that decreased carnitine intake in premature infants may impair fatty acid oxidation and ketogenesis.

Carnitine intake and excretion in neuromuscular diseases

Free and total carnitine serum concentrations and urinary excretion were examined in patients with various neuromuscular diseases. On a measured, low carnitine diet and during fasting, the patients did not differ from controls. Carnitine excretion in patients (3.09 +/- 1.87 mumol/kg/day) and controls (2.99 +/- 1.12) exceeded carnitine intake (patients, 2.35 +/- 0.94 mumol/kg/day; controls, 1.33 +/- 0.70). Because of heterogeneity in the patient population, carnitine excretion was assessed according to creatinine excretion, chosen as an indicator of muscle mass. Those patients with daily creatinine excretion less than 1 g/day had significantly lower carnitine excretion (106 +/- 47 versus 205 +/- 95 mumol/day, p less than 0.05), and there was a positive correlation between creatinine excretion and carnitine excretion (r = 0.82) and between muscle carnitine and carnitine excretion (r = 0.67). Urinary clearances for acylcarnitine were 10 and 20 times higher than those for free carnitine. Two patients with carnitine palmityl transferase deficiency were similar to the other patients, but the carnitine-deficient patient lost excessive carnitine during fasting, probably secondary to elevated acylcarnitine fraction in the blood.

Urinary carnitine excretion in surgical patients on total parenteral nutrition.

Urinary free and total carnitine excretions were measured in 41 normal adults and seven surgical patients on fat-free total parenteral nutrition for 8 to 45 days. The means (+/-SEM) of urinary free and total carnitine excretion in normal adults were 162 +/- 19 and 328 +/- 28 micrometers/days, respectively. All of the patients exhibited protein-calorie malnutrition with a mean carnitine intake of 11.6 +/- 1.5 micrometers/day. Under this stringent carnitine economy with the adequate supply of lysine and methionine, urinary total carnitine excretion significantly reduced to 127 to 162 micrometers/day. This probably reflects the carnitine biosynthetic rate. However, during the periods of operation and/or infection, urinary total carnitine excretion significantly increased 2- to 7-fold that of normal levels. Significant positive correlation was found between the two forms of urinary carnitine and total nitrogen excretions. Serum free and total carnitine levels in patients were significantly higher than normal adults. Such findings can be explained by the endocrine responses to the stress phenomenon and indicate a catabolic response of skeletal muscle in which most of the body carnitine resides. This can impair their carnitine status.

Plasma free carnitine levels in premature and full-term newborns, infants and children

The free carnitine plasma level was assayed in 142 healthy children from birth (minimum 28 weeks of gestation) to 10 years of age according to the radiochemical method of Cederblad and Lindstedt. All data were statistically analyzed using the Mann-Whitney test. Plasmatic data show a low concentration in the premature (34.9±2.6 S.E.nmoles/ml) and full-term newborns (31.2±2.5), probably caused by an immature hepatic synthesis and/or reduced oral intake of carnitine. However, the carnitine concentration is higher in premature (30-33 weeks of gestation) than in full-term newborns as also found by Novak et al. (Pediat.Res. 13:10, 1979) for the acetyl-carnitine determined in the funicular blood. These data seem to suggest that fetal carnitine storage mainly occurs in the first 30-33 weeks of gestation. Adult levels (44.7±1.7) are reached by the end of the first 6 months (44.1±1.7), possibly as a consequence of increased hepatic synthesis and/or of increased carnitine intake associated with a diet containing meat.

Carnitine status in Thai adults

Plasma carnitine and urinary carnitine levels were measured in Thai adults living in Bangkok city and Ubol villages. The mean plasma carnitine and urinary carnitine levels expressed in micromoles per liter in Bangkok adults were higher than those in Ubol adults. Their mean plasma carnitine levels were 56.6 +/- 1.8 and 50.3 +/- 1.7 whereas urinary carnitine levels were 161 +/- 19 and 127 +/- 18 micromole/liter, respectively. The nutritional status in Ubol adults was inadequate. This was evidenced by the significant decrease in urinary creatinine excretion, serum albumin, and hematocrit levels. The dietary assessment agreed with the biochemical findings. Since rice, limiting in carnitine, was the main protein and energy source consumed by Ubol adults their inadequate carnitine status could be due to the low carnitine intake. Sex affects plasma carnitine levels in Bangkok adults and urinary carnitine excretion in both groups. This could be related to the lean body mass in which most of the body carnitine resides. This is supported by the higher urinary creatinine excretion in males and the significant positive correlation between carnitine excretion and creatinine-height index.

Carnitine deficiency in premature infants receiving total parenteral nutrition.

Carnitine plays a significant role in fatty acid utilization and ketone body production. Its availability is especially important during the immediate postnatal period. To determine whether low birth weight infants who cannot be orally fed are at risk of developing carnitine deficiency, we compared the carnitine blood levels and urinary excretion of 12 premature infants (Group A) receiving total parenteral nutrition (TPN) with those of 8 infants of similar gestational age and birth weight (Group B) who received carnitine-containing milk formulas. In Group A, serum levels of total and free carnitine fell after 5 days of carnitine-deficient parenteral nutrition, and urinary excretion was significantly reduced. Serum levels and urinary excretion increased after the onset of oral feedings. The control Group B exhibited no significant changes in carnitine blood levels between the first and fifth days of life, but did show a later increase. Children in Group A had lower carnitine blood levels compared to those in Group B on the fifth day of life. These findings suggest that premature infants are not able to synthesize enough carnitine to maintain blood levels, and that carnitine deficiency can occur following TPN. Further investigation of metabolic consequences secondary to deficient carnitine intake in premature infants is necessary before carnitine supplementation should be considered.