Urinary Carnitine Excretion Research Articles

Enhanced lipid utilization in infants receiving oral l-carnitine during long-term parenteral nutrition

Fourteen infants requiring long-term total parenteral nutrition but able to tolerate small quantities of enteral feedings were randomized into carnitine treatment and placebo control groups. All infants had received nutritional support devoid of carnitine. Plasma carnitine levels and observed plasma lipid indices were not different before supplementation. Under standardized, steady-state conditions, 0.5 g/kg fat emulsion (intralipid) was administered intravenously over 2 hours both before and after infants received 7 days of continuous nasogastric or gastric tube L-carnitine (50 mumol/kg/day) or placebo. Plasma triglyceride, free fatty acid, acetoacetate, beta-hydroxybutyrate, and carnitine concentrations were observed at 0 (start of lipid infusion), 2, and 4 hours for pre- and post-treatment periods, and in addition at 6 and 8 hours after carnitine supplementation. Infants receiving carnitine had significantly greater beta-hydroxybutyrate plasma concentrations (P less than 0.05) and carnitine (P less than 0.001) at 0, 2, 4, 6, and 8 hours, and greater plasma acetoacetate concentrations (P less than 0.05) at 2, 4, 6, and 8 hours, compared with controls. Twenty-four-hour urinary carnitine excretion was very low for both groups before supplementation; after supplementation, excretion was higher (P less than 0.05) in the carnitine group. No significant differences were found between groups for plasma triglyceride or free fatty acid concentrations at any observation period. This study demonstrated enhanced fatty acid oxidation, as evidenced by increased ketogenesis, with L-carnitine supplementation in infants receiving long-term total parenteral nutrition.

Plasma carnitine and renal-carnitine clearance during pregnancy

This study assessed the time course of decrease in plasma carnitine during pregnancy and compared the renal clearance of carnitine during late pregnancy with nonpregnant women. As early as the 8th wk of pregnancy, the mean (±SD) value of total plasma-carnitine concentration in 19 women was significantly decreased from 39.0 ± 6.3 to 32.8 ± 4.6 µmol/l and the values continued to fall to 17.3 µmol/1 by the 36th wk. The pattern was due to a fall in free-carnitine level; acylcarnitine remained unchanged. In 12 other women examined during late pregnancy, the renal clearance of acylcarnitine was significantly higher than in nonpregnant women, 53.9 ± 29.4 versus 13.3 ± 3.0 ml/min, in contrast to free carnitine, 3.5 ± 2.8 versus 2.8 ± 1.9 ml/min. Urinary excretion of carnitine (expressed per mol creatinine) did not differ between the two groups. Pregnant women showed sustained excretion of carnitine in the presence of low plasma-carnitine concentrations.

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.

Potential role of carnitine in patients with renal insufficiency.

Carnitine metabolism is altered in renal insufficiency and influenced by the treatment modalities. Chronically uremic patients with end-stage renal disease under conservative therapy, hemodialysis, or peritoneal dialysis show low, normal, or elevated serum levels of TC and a distorted pattern of FC, SCAC, and LCAC. HD induces a marked depletion of FC, while predialytic elevated SCAC and LCAC are in the normal range at the end of dialysis treatment. All carnitine fractions rapidly return to predialysis levels 6 h after HD due to a transport of carnitine from muscle stores to plasma pool. Muscle carnitine content is elevated in chronic uremic patients under conservative therapy. Normal or decreased levels are observed in patients on long-term HD treatment. In addition, weekly losses of carnitine in patients undergoing HD or peritoneal dialysis do not exceed urinary carnitine excretion of CO. Supplementation with currently recommended doses (1-2 g L-carnitine i.v. at the end of each HD) is followed by a marked rise in plasma carnitine levels, suggesting limited carnitine utilization in uremia. Therefore, lower carnitine doses and modified application regimens should be considered to avoid exaggerated plasma levels of carnitine and carnitine esters. Furthermore, carnitine application has been reported to show beneficial, worsening, or no effect on the deranged lipid metabolism of the uremic patients. In patients undergoing CAPD or IPD predominantly normal serum carnitine levels have been reported. On the other hand, SCAC and LCAC esters are markedly elevated in these patients. After kidney transplantation the pattern of carnitine fractions is fully normalized in patients with plasma creatinine less than or equal to 120 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Carnitine in the Streptozotocin-Diabetic Rat

Rats made moderately diabetic by streptozotocin (decreased growth without decreased body mass, blood glucose, 588–840 mg/dl) and nondiabetic rats were either fed a purified diet with no measurable carnitine (diet 1), the same diet supplemented with carnitine (44.5 nmol/g food, diet 2), or a closed formula, non-purified diet (3.3 nmol/g food, diet 3). Levels of total carnitine (free + acyl) were lower (P < 0.05) in plasma, heart, soleus, extensor digitorum longus and kidney of rats fed diet 1 compared to those fed diet 2. Liver carnitine in diabetic animals was 2.6- to 4.4-fold higher than in nondiabetic animals with urinary carnitine of rats fed diet 1 being four times greater in diabetic than in nondiabetic rats. Other changes in tissue total carnitine were less pronounced. Compared to diabetic rats, insulin-treated diabetics had lower urinary excretion of carnitine and blood glucose levels (P < 0.05), and tissue carnitine approximating nondiabetic levels. Significant catabolism of carnitine was not found. Apparent carnitine biosynthesis (diet 1) showed no difference between nondiabetic and diabetics (31.5 ± 1.6 and 31.2 ± 2.2 nmol/g of body weight per day, respectively) suggesting elevated liver levels resulted from redistribution.

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.

Postheparin plasma lipases and carnitine in infants during parenteral nutrition.

Lipoprotein lipase is the rate-limiting factor for hydrolyzing triglycerides to glycerol and fatty acids. Carnitine is a cofactor in the transport of long-chain fatty acids through the mitochondrial membrane for oxidation. To assess these determinants of fat utilization during total parenteral nutrition, lipoprotein and hepatic lipase activities and carnitine concentrations of nine newborn infants, operated on because of gastrointestinal anomalies during the first day of life, were measured with specific methods. Total parenteral nutrition was built up in 3 days whereafter the infants received 3 g/kg of fat at a constant rate of infusion for 24 h/day. Lipoprotein lipase activity of post-heparin plasma increased from 14 to 35 mumol free fatty acids/ml/h during parenteral nutrition whereas hepatic lipase activity remained unchanged at 40 mumol free fatty acids/ml/h. Serum free carnitine and acylcarnitine levels decreased significantly during parenteral nutrition; urinary excretion of carnitine decreased also. In addition, serum cholesterol and phospholipids increased markedly during parenteral nutrition whereas serum triglycerides, free fatty acids, and blood beta-hydroxybutyrate remained unchanged. Serum apolipoprotein A-I concentrations were unaltered, apolipoprotein A-II underwent a transient increase, and apolipoprotein B increased monotonically during parenteral nutrition. The results suggest that under the present circumstances neither lipoprotein lipase activity nor carnitine resources are rate-limiting for the utilization of fat in newborn infants during total parenteral nutrition.

Postheparin plasma lipoprotein and hepatic lipases and serum camitine in newborn infants during parenteral nutrition

Lipoprotein lipase hydrolyzes triglycerides in plasma and thus regulates the clearance of fat from the circulation. Liproprotein lipase activity has been estimated in infants during parenteral nutrition by measuring postheparin lipolytic activity (PHLA). PHLA is, however, an inadequate measure of lipoprotein lipase because a substantial part of PHLA results from hepatic lipase. Carnitine is essential for facilitated transport of long-chain fatty acids across the mitochondrial membrane. With specific methods we measured lipoprotein and hepatic lipase activities. Nine newborn infants were operated on because of gastrointestinal anomalies. Parenteral nutrition was built up in three days whereafter infants received 3/g/kg/day of fat (intralipid) at a constant rate. On the average, weight gain started at the age of 5 days and was 16 g/day. The duration of parenteral nutrition was 1-23 weeks. During the first week lipoprotein lipase activity increased from 14 to 35 μmol FFA/ml/h whereas hepatic lipase activity remained at 40 μmol FFA/ml/h during parenteral nutrition. Serum free carnitine decreased from 25 to 11 μmol/1 and acylcarnitine from 9 to 2 μmol/1 during the first three weeks of parenteral nutrition; urinary excretion of carnitine decreased from 114 to 68 nmol/mg of creatinine. Serum triglycerides, free fatty acids and blood beta-hydroxybutyrate remained, however, practically unchanged during parenteral nutrition. The results suggest that neither lipoprotein lipase activity nor carnitine availability are rate-limiting for the utilization of fat in newborn infants during parenteral nutrition.

Propionylcarnitine excretion in propionic and methylmalonic acidurias: a cause of carnitine deficiency

Two patients with propionic acidemia (PA) and two patients with methylmalonic aciduria (MMA) had low plasma free carnitine and increased short-chain acylcarnitines. Urinary excretion of free carnitine was decreased, while the excretion of short-chain acylcarnitines, mostly propionylcarnitine, was increased. Carnitine supplementation markedly increased the short-chain acylcarnitine fractions of both plasma and urine. Total carnitine content was decreased in skeletal muscle biopsies obtained from two of the patients. It is suggested that in these organic acidurias mitochondrial propionylcarnitine, formed from free carnitine and excess propionylCoA, exchanges with free cytosolic carnitine: propionylcarnitine is then lost in the urine, causing secondary carnitine deficiency in the tissues.

Muscle and plasma carnitine levels and urinary carnitine excretion in multiply injured patients on total parenteral nutrition

Carnitine is necessary for the transport of long-chain fatty acids across the mitochondrial membrane. Thirteen severely injured patients on total parenteral nutrition were studied during days 2–8 post injury. Initially plasma and skeletal muscle carnitine values were within the range earlier found for normal subjects, whereas the urinary carnitine excretion was markedly increased. On day 4 there was a simultaneous decrease in the carnitine concentration in plasma (α < 0.01) and urine (α < 0.05) as well as in skeletal muscle tissue (α < 0.05 using only the values that could be paired i.e. from eight subjects), whereas no difference was found between day 2 and 8. One explanation of this pattern might be that a redistribution of carnitine occurs to other organs not measured, for example the liver. In skeletal muscle tissue, statistically significant positive correlations were found between the carnitine level and ATP (α < 0.01) and phosphocreatine (α < 0.02) as well as between carnitine and glycogen (α < 0.05).

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.

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 and creatine content of tissues of normal and alloxan-diabetic sheep and rats

1. 1. The concentration of carnitine in liver increased 28-fold and urinary carnitine excretion 5-fold in alloxan-diabetic sheep. In contrast there were no similar increases in alloxan-diabetic rats. 2. 2. The creatine content of liver decreased 3-fold and creatine excretion decreased 2-fold in diabetic sheep. In contrast the creatine content of liver increased nearly 4-fold in diabetic rats with no change in creatine excretion. 3. 3. The marked increased in production of carnitine by the liver of the diabetic sheep appears possible because of decreased production and excretion of creatine.

Carnitine deficiency presenting as familial cardiomyopathy: A treatable defect in carnitine transport

We studied a boy who presented at age 3 1/2 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 1/2 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with L-carnitine (174 mg/kg/da) was begun at age 5 1/2 years and continued to the present (age 6 1/2 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with L-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder.

Plasma and urine carnitine in children with diabetes mellitus

l-Carnitine is essential for the transport of long chain fatty acids into mitochondria and, hence, in ketoacid production. Total, free and acylcarnitine in plasma and urine have been determined in 52 children and adolescents with insulin-dependent juvenile diabetes and compared with 72 controls. The subjects were divided into three age groups, 8–10, 11–15 and 16–20 years. In plasma, total and free carnitine were significantly lower in diabetic patients than in controls in all age groups. Acylcarnitine was significantly higher in the diabetic patients than in the controls in the two younger age groups. No sex-related differences in plasma carnitine and its derivatives were found in the two younger groups. A statistically significant correlation coefficient was noted between glycosylated hemoglobin and the plasma acyl/free carnitine ratio, 2 p < 0.05. The daily urinary excretion and renal clearance of carnitine and its derivatives showed few significant differences between the diabetic and the control subjects.

Sex steroid regulation of urinary excretion of carnitine in rats

The concentration of acid soluble carnitine was determined in several body tissues and fluids in rats under various conditions of sex steroid regulation. Intact female rats had significantly greater liver carnitine concentrations and urinary excretion rates, and lower blood plasma and heart carnitine concentrations than intact male rats. Ovariectomy increased blood plasma carnitine concentrations ( P < 0.01) and the excretion of carnitine in the urine ( P < 0.05). The administration of either estradiol or testosterone to ovariectomized rats did not alter blood plasma concentrations or urinary excretion of carnitine. Orchidectomized rats had similar blood plasma carnitine concentrations when compared to intact males but excreted significantly ( P < 0.01) greater quantities of carnitine in their urine. Administration of testosterone to orchidectomized rats reduced ( P < 0.01), whereas estradiol stimulated ( P < 0.05) the excretion rate of carnitine in the urine; however, blood plasma carnitine concentrations were not affected by these hormones. These data suggest that a major site for modulation of body carnitine concentration in the male resides in the control of kidney excretion by androgens. Liver, heart and skeletal muscle carnitine concentrations were not altered by the administration of either estradiol or testosterone to orchidectomized or ovariectomized rats.

Urinary excretion of carnitine and its derivatives in newborns

The inclusion of an SH-trapping compound in the radioenzymatic carnitine method based on the conversion of radioactive acetyl-CoA to acetylcarnitine in the presence of carnitine acetyltransferase results in linear standard curves. N-Ethylmaleimide was preferred since the amount of free carnitine was less overestimated when acetylcarnitine was present compared to tetrathionate. Urinary excretion of carnitine and its derivatives was determined in 13 healthy fullterm boys. On Days 3 and 6 after delivery, total carnitine excretion was similar, 7.5 μmol/24 hr ± 0.90 (SE) and 7.0 μmol 24 hr ± 1.16 (SE) despite the ingestion of more breask milk on Day 6. Regarding the distribution of free, acyl, and total carnitine, the variation between individuals was large. Weak but significant differences were noted pointing at a higher degree of carnitine acylation on Day 3. It was shown by a comparison of these variables between the newborns and healthy boys, 8–15 years, that the newborns had a markedly increased acylation degree of carnitine. The changes may be consistent with the fact that lipids are the major energy source in the neonatal period.

Effect of aging on lipid and carnitine metabolism.

In healthy subjects aged 20 to 50 years, the urinary excretion of carnitine and its serum concentration increased rapidly and markedly after synthetic beta 1-24 ACTH-Z was injected. Their serum triglyceride levels changed inversely. In contrast, healthy subjects older than 70 and patients aged 45 to 50 with atherosclerosis exhibited lower and delayed changes of carnitine excretion and serum concentrations of carnitine and lipid after ACTH injection. When the aged subjects and the atherosclerotic patients were administered with triiodothyronine prior to ACTH, their metabolic responses to ACTH improved towards normal. The results suggest that the aging process impairs the homeostatic regulation of serum lipid through a "lipid-carnitine" system and that thyroid hormone plays a contributory role in the activation of this system.

Urinary excretion of carnitine in burned patients

Urinary excretion of carnitine was studied in 14 patients with burns. Both free and total carnitine were monitored during an 8-day period following the burn and in some of the patients during a longer period of time. The mean value of total urinary carnitine was increased six-fold on day 2 compared with controls. The mean values decreased during the 8-day period post burn although they were still significantly higher on the eighth day compared to the mean value of controls. Increased carnitine excretion was also observed after the first post-traumatic week. A significant relationship was found between the percentage burned surface area and the individual mean value of carnitine excretion during the 8-day period. The percentage of free carnitine in urine was higher in the patients than in the normal subjects. A significant negative correlation was found for the regression of the ratio of acyl carnitine to free carnitine and total carnitine in urine both in the patients and in the controls.

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.