Serum Carnitine Concentrations Research Articles

Serum carnitine concentrations in patients with idiopathic hypertrophic cardiomyopathy: relationship with impaired myocardial fatty acid metabolism

We evaluated the clinical significance of serum carnitine concentrations in determining the severity of impaired myocardial fatty acid metabolism in idiopathic hypertrophic cardiomyopathy (HCM). We studied 56 asymptomatic or mildly symptomatic patients with HCM. Serum levels of free carnitine and acylcarnitine were measured by the enzymic cycling method. Myocardial scintigraphy with (123)I-labelled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) was performed, and the images were analysed quantitatively and semi-quantitatively. Serum free carnitine levels were significantly higher in HCM patients than in normal subjects (52. 5+/-9.5 and 42.3+/-5.5 nmol/ml respectively; P<0.0001). On the other hand, serum acylcarnitine levels and acyl/free carnitine ratios were lower in HCM patients than in normal subjects (10.2+/-4.0 nmol/ml and 0.19+/-0.08, compared with 13.2+/-3.9 nmol/ml and 0.32+/-0.11 respectively; P<0.0001). Clinical characteristics were not significantly different between the patients showing high and normal free carnitine levels, although female patients with high free carnitine levels were few (P=0.02). Both quantitative and semi-quantitative analyses revealed that the severity of decreased myocardial BMIPP uptake was significantly correlated with serum free carnitine levels (quantitative analysis: r=-0.422, P<0.0012; semi-quantitative analysis: r=0.633, P<0.0001). In the presence of reduced carnitine uptake into the myocardium in HCM, there may also be reduced transport of acylcarnitines out of the myocardium into the plasma. Although inborn errors of fatty acid metabolism and carnitine deficiencies are reported to provoke secondary HCM and are associated with low serum carnitine concentrations, this study has revealed that the levels of carnitine are, in contrast, increased in idiopathic HCM. Moreover, serum carnitine concentrations are a sensitive indicator of the severity of impaired myocardial fatty acid metabolism even in asymptomatic patients with HCM.

Serum Carnitine Levels in Centenarians

Objective and Study Participants: We evaluated serum carnitine concentrations in a group of 17 centenarians (six males, 11 females: mean age 102.35 ±2.21 years), and compared them with a control group that comprised 20 elderly volunteers (age range: 66 to 75 years). Results: The mean serum carnitine level in the centenarian group was 8.99 ±5.1 mg/L compared with 7.71 ±0.92 mg/L in the control group (p = NS). Serum carnitine levels were not significantly correlated with lipid pattern, kidney function, daily activity, body mass index and daily diet in the centenarians. Analysis of the lipid pattern revealed that the mean serum total cholesterol, low density lipoprotein (LDL) cholesterol, apoprotein B100 and triglyceride concentrations were higher in the controls than in the centenarians (p = 0.01 for total cholesterol, LDL cholesterol, and apoprotein B100; p = 0.05 for triglycerides). High density lipoprotein (HDL) cholesterol and apoprotein A levels were significantly lower in the controls than in the centenarians (p = 0.01). We postulated that an endogenous synthesis is responsible for the increased serum carnitine levels observed in the centenarians. Conclusion: In our study series, the association between a good lipid profile and elevated serum carnitine levels, although nonsignificant, might be considered an important factor in achieving longevity.

CSF levels of carnitine in children with meningitis, neurologic disorders, acute gastroenteritis, and seizure.

Carnitine concentrations in CSF, serum, and urine in normal febrile children and children with meningitis, neurologic disorders, and dehydration were studied. Carnitine levels in CSF were 1/10 compared with serum in normal febrile children. These levels increased two- to three-fold in the pathologic conditions studied. Since damage to the blood-brain barrier occurs in these conditions, higher blood-brain barrier permeability might explain CNS carnitine accumulation.

Successful lowering of epididymal carnitine by administration of pivalate to rats.

This study was designed to lower the epididymal content of carnitine in male rats and to examine subsequent effects on fertility and sperm motility. As carnitine is transported from serum into the epididymal lumen a method to lower serum carnitine was sought. Administration of 20 mmol/L sodium pivalate in the drinking water for up to 5 weeks substantially lowered serum carnitine (to 20% of control levels within 1 week) and reduced epididymal carnitine content (to 25% of control levels in the proximal and 52% of control in distal regions) within 2 weeks. Carnitine in distal cauda epididymal fluid was also reduced (to 30% of control levels) but no changes were observed in the sperm carnitine content. The percentage motility and kinematic parameters of spermatozoa released from four epididymal regions and diluted into artificial medium were unaltered by the treatment, and all males retained their fertility in mating tests performed at weekly intervals. Increasing the dose of sodium pivalate administered to 60 mmol/L for 2 weeks lowered serum carnitine concentration more but did not further decrease epididymal carnitine content and altered neither sperm motility nor male fertility. The rat epididymis secretes an excessive amount of carnitine into its lumen so that substantially lowering the tissue content does not reduce sperm carnitine or affect their motility or fertilizing ability.

Influence of sex and chronic haemodialysis treatment on total, free and acyl carnitine concentrations in human serum.

The influence of sex and haemodialysis treatment on serum total, free and acyl carnitine concentrations in healthy controls and chronic renal failure patients has been investigated. Patients on regular haemodialysis treatment generally displayed significantly decreased serum carnitine levels. The mean predialysis serum carnitine levels were not significantly different from the mean healthy control values. However, after dialysis a significant decrease in serum carnitine levels was observed compared to the predialysis and healthy control values. Moreover, serum ratio of acylated to free carnitine was significantly higher after haemodialysis as compared to both healthy controls and predialysis patients. Sex-related changes in serum total, free and acyl carnitine levels and ratios of acylated to free carnitine have been observed in healthy controls and patients on chronic haemodialysis treatment.

Long-chain 3-hydroxyacyl–coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients

Long-chain 3-hydroxyacyl—coenzyme A (CoA) dehydrogenase is one of three enzyme activities of the mitochondrial trifunctional protein. We report the clinical findings of 13 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. At presentation the patients had had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Seven patients had recurrent metabolic crises, and six patients had a steadily progressive course. Two patients had cholestatic liver disease, which is uncommon in β-oxidation defects. One patient had peripheral neuropathy, and six patients had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. All patients were homozygous for the common mutation G1528C. However, the enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities of the mitochondrial trifunctional protein were variably decreased in skin fibroblasts. Dicarboxylic aciduria was detected in 9 of 10 patients, and most patients had lactic acidosis, increased serum creatine kinase activities, and low serum carnitine concentration. Neuroradiologically there was bilateral periventricular or focal cortical lesions in three patients, and brain atrophy in one. Only one patient, who has had dietary treatment for 9 years, is alive at the age of 14 years; all others died before they were 2 years of age. Recognition of the clinical features of long-chain 3-hydroxyacyl-CoA deficiency is important for the early institution of dietary management, which may alter the otherwise invariably poor prognosis. J Pediatr 1997;130:67-76

Choline supplementation reduces urinary carnitine excretion in humans

Two experiments were conducted to determine the effects of supplementary choline and/or pantothenate on the carnitine and lipid status of free-living humans. Analyses of carnitine and cholesterol fractions, triacylglycerols, and creatinine were determined in serum and/or urine. In experiment 1, adults receiving 13.5 mmol choline plus 1.4 mmol pantothenate/d had a significant decline in urinary carnitine excretion and renal clearance with nonesterfied carnitine (NEC) declining the most dramatically, 84%. Additionally, serum NEC and total carnitine concentrations decreased significantly. No changes were observed in any of the serum lipids examined. In experiment 2, subjects took 0.20 mmol and 0.02 mmol/kg choline or pantothenate, respectively. Choline, but not pantothenate, supplementation significantly decreased urinary carnitine excretion, renal clearance, and fractional clearance of NEC. We conclude that supplementary choline maintained serum carnitine concentrations by conserving urinary carnitine. Moreover, these observations merit additional investigation to determine metabolic and functional consequences of choline and carnitine interactions in humans.

Alterations of Remnant Liver Carnitine Palmitoyltransferase I Activity and Serum Carnitine Concentration after Partial Hepatectomy in Rats

Many authors agree that alteration of the energy substrate from glucose to free fatty acid occurs during the early stage after partial hepatectomy. An accelerative effect of carnitine on the early phase of liver regeneration was suggested in several reports, but much controversy prevails. Using male Wistar rats weighing about 200 g as subjects, we undertook partial hepatectomy with resection of the median and left lateral lobes (67%). Another group of rats undergoing a sham operation was compared. Rats were killed at 6, 24, 48, or 72 hr after the operation. The rate of synthesis of DNA and content of DNA in remnant Liver were chosen as regenerative indicators. Serum carnitine, free fatty acid and its metabolites, remnant liver carnitine palmitoyltransferase I (CPT-I) activity, high-energy phosphate (HEP), including adenosine triphosphate (ATP), and crestine phosphate (CP) were measured. The results showed a marked decrease of HEP, ATP, and CP with suddenly increased free fatty acid and total ketone body in serum that occurred during the early regenerating phase after partial hepatectomy. Serum L-carnitine also increased markedly in this early stage. The mitochondrial CPT-I activity in the remnant liver decreased significantly 24 hr after partial hepatectomy. Our data show that regenerating liver utilizes free fatty acids as an immediate main substrate. Mitochondrial respiration with a CPT-I effect could be an important reaction in this utilization.

Transient reduction of human left ventricular mass in carnitine depletion induced by antibiotics containing pivalic acid.

To study the effect of induced carnitine depletion on myocardial structure and function. 7 healthy adult volunteers given 1200 mg pivmecillinam per day for 7-8 weeks were studied by echocardiography before and after 7-8 weeks of treatment and a 15 months follow up after the treatment period. Teaching hospital. Carnitine concentration in serum, urine, and muscle and echocardiographic measurements. After 7-8 weeks of treatment the median free serum carnitine concentration was reduced to 7% and the median total muscle carnitine concentration to 46% of the pretreatment levels. The median diastolic interventricular septum thickness decreased by 14% (mean 26%, P = 0.028) and the median left ventricular mass by 10% (mean 20%, P = 0.018). Fifteen months later these dimensions had increased but not completely returned to pretreatment values. Extended treatment with pivalic acid containing antibiotics causes carnitine depletion which may lead to changes in cardiac structure.

Effect of Short-Term Treatment with Pivalic Acid Containing Antibiotics on Serum Carnitine Concentration - A Risk Irrespective of Age

Treatment with pivalic acid containing prodrugs has been shown to cause carnitine depletion by loss of pivaloyl carnitine in urine. A 7-day standard pivmecillinam treatment of adults lead to a marked decrease of the free serum carnitine concentration (44.6 to 12.9 μmol/liter), whereas no change was seen in those given norfloxacine (40.0 to 40.5 μmol/liter). In some patients irrespective of age the free serum carnitine concentration was decreased to levels (around 10 μmol/liter) at which an impaired ketone-body production may occur. Therefore, there is reason for cautious use of this type of drug irrespective of the age of the patients.

Rhabdomyolysis and acute encephalopathy in late onset medium chain acyl-CoA dehydrogenase deficiency.

A previously asymptomatic 30 year old man presented with rhabdomyolysis, muscle weakness, and acute encephalopathy after strenuous exertion in the cold without adequate food intake. Serum and muscle carnitine concentrations were decreased. Urinary excretion of carnitine and glycine esters and biochemical examination of skeletal muscle and fibroblasts led to the diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency. A point mutation at nucleotide position 985 of the coding region of the MCAD gene was found. The MCAD protein was synthesised in the patient's fibroblasts at a normal rate, but was unstable. In general, patients in whom the 985 point mutation has been established show much more severe clinical symptoms and other symptoms than those seen in this patient. The relation of the 985 point mutation and the residual MACD activity to the symptoms is not as straightforward as previously thought.

Relationships between muscle carnitine, age and oxidative status.

Muscle carnitine levels were examined in 31 younger [mean (SD), 27 (5) years] and 27 older [49 (8) years] men. Needle biopsies were obtained from the lateral gastrocnemius or vastus lateralis muscles and assayed for free and total carnitine concentrations via a 5,5'-Dithiobis-(2-nitrobenzoic acid) DTNB-linked spectrophotometric procedure. A subgroup of subjects (n = 28) were assessed for citrate synthase (CS) and succinate dehydrogenase (SDH) activity, and type I muscle fiber composition (% type I fibers). An additional sub-group of nine subjects was assessed for free and total serum carnitine levels. No mean (SEM) differences in free [21.6 (0.7) vs 20.3 (0.9) mumol.g dry weight-1] and total [26.4 (0.6) vs 26.1 (0.9) mumol.g dry weight-1) muscle carnitine levels were found between the younger and older subjects, respectively. Correlational data revealed no significant relationships between total muscle carnitine and CS (r = -0.36), SDH (r = -0.26), or % type I fibers (r = -0.16). In addition, there was a low non-significant relationship between serum and muscle total carnitine concentrations (r = -0.44). These findings suggest that muscle carnitine levels are similar between younger and older males, and there does not appear to be any relationship between muscle carnitine and markers of muscle oxidative potential (i.e., oxidative enzymes, % type I fiber). Since serum carnitine is often used as an indicator of body carnitine status, it is noteworthy that we found a low negative relationship between blood and muscle carnitine concentrations.

Correlation between long-chain acylcarnitine in serum and myocardium after heart transplantation in humans

The concentrations of free, short-chain, and long-chain acylcarnitine were determined in 19 right ventricular endomyocardial biopsies and in serum from 14 patients after orthotopic heart transplantation and 3 nontransplanted control patients with normal cardiac function. Coronary angiography was normal in all patients. Left ventricular ejection fraction as measured by radionuclide ventriculography was not different between heart-transplanted and control patients (60.3 +/- 6.7% and 61.7 +/- 10.7%, respectively). Myocardial and serum carnitine concentrations in heart-transplanted patients were not different from control patients (myocardium: free carnitine 11.8 +/- 4.8 vs 7.1 +/- 7.1, short-chain acylcarnitine 4.5 +/- 2.1 vs 5.8 +/- 2.0, long-chain acylcarnitine 4.9 +/- 3.8 vs 3.9 +/- 3.2 mumol/g noncollagen protein; serum: free carnitine 32.6 +/- 11.2 vs 32.0 +/- 9.9, short-chain acylcarnitine 7.3 +/- 5.2 vs 5.1 +/- 1.3, long-chain acylcarnitine 4.1 +/- 2.7 vs 4.8 +/- 4.0 mumol/L). There was a highly significant correlation between myocardial and serum long-chain acylcarnitine (r = 0.76, P < 0.001). The data suggest that carnitine metabolism is not altered after heart transplantation.

Serum carnitine concentrations in coeliac disease.

Carnitine is essential for muscle energy production and is required for the transport of long chain fatty acids and acyl co-enzyme A derivatives across the inner mitochondrial membrane. Recently, an absorptive transport mechanism was discovered at the small bowel level suggesting the possibility of a carnitine deficient state in patients with mucosal damage. Therefore, this study investigated carnitine concentrations in serum of patients with coeliac disease. Serum samples were obtained from 12 patients with active coeliac disease and seven with non-active disease, and compared with serum samples of 17 children with gastrointestinal symptoms but with a small bowel normal on biopsy examination and 33 normal controls. Total serum carnitine concentration was significantly lower in the patients with coeliac disease compared with the other two groups and to reference values. When the degree of atrophy of coeliac intestinal mucosa was numerically graded, serum carnitine concentrations did not correlate to the degree of the intestinal lesion but were significantly lower in the damaged intestine compared with the group with normal mucosa. It is suggested that coeliac disease should be considered as a potential cause of secondary carnitine deficiency.

Carnitine function and requirements during the life cycle

L-Carnitine has been described as a "conditionally essential" nutrient for humans. Segments of the human population suggested as having a requirement for carnitine include infants (premature and full-term), patients on long-term parenteral nutrition, and perhaps children. The evidence to support these claims includes 1) low circulating carnitine concentrations; 2) abnormal (or at least different) circulating metabolite concentrations (free fatty acids, triglycerides, ketone bodies), and 3) very limited and inconsistent growth data. A number of subjective observations and anecdotal case reports have been offered in support of a requirement for carnitine. Exogenous carnitine is required to maintain "normal" (in the epidemiologic sense) plasma or serum carnitine concentrations in humans of all ages. But "functional carnitine deficiency," defined by abnormal clinical presentation correctable by carnitine administration, has not been demonstrated in an otherwise normal (nonpathologic) population. On the other hand, nutritional or pharmacological intervention with carnitine or its esters may be beneficial for very premature infants, infants and children with various clinical conditions associated with low circulating carnitine concentrations, and in some chronic diseases associated with the aging process.

The effect of carnitine on the metabolism of valproic acid in epileptic patients.

The half-life of valproic acid (VPA) was studied in 8 epileptic and severely mental retarded patients before and after one month of carnitine supplementation. Serum carnitine concentration was significantly decreased and VPA half-life was prolonged especially in adult patients before carnitine supplementation. After the treatment with carnitine, serum carnitine concentration was increased, and prolonged half-lives of VPA were corrected near to the normal range (from 12.2 +/- 4.2 hr to 9.7 +/- 2.2 hr; p < 0.05). Controlled state of epilepsy was unchanged during the short period of observation.

Effect of carnitine loading on long-chain fatty acid oxidation, maximal exercise capacity, and nitrogen balance.

Carnitine has a potential effect on exercise capacity due to its role in the transport of long-chain fatty acids into the mitochondria for beta-oxidation, the export of acyl-coenzyme A compounds from mitochondria and the activation of branched-chain amino acid oxidation in the muscle. We studied the effect of carnitine supplementation on palmitate oxidation, maximal exercise capacity and nitrogen balance in rats. Daily carnitine supplementation (500 mg.kg-1 body mass for 6 weeks) was given to 30 rats, 15 of which were on an otherwise carnitine-free diet (group I) and 15 pair-fed with a conventional pellet diet (group II). A control group (group III, n = 6) was fed ad libitum the pellet diet. Palmitate oxidation was measured by collecting 14CO2 after an intraperitoneal injection of [1-14C]palmitate and exercise capacity by swimming to exhaustion. After carnitine supplementation carnitine concentrations in serum were supranormal [group I, total 150.8 (SD 48.5), free 78.9 (SD 18.4); group II, total 170.9 (SD 27.9), free 115.8 (SD 24.6) mumol.l-1] and liver carnitine concentrations were normal in both groups [group I, total 1.6 (SD 0.3), free 1.2 (SD 0.2); group II, total 1.3 (SD 0.3), free 0.9 (SD 0.2) mumol.g-1 dry mass]. In muscle carnitine concentrations were normal in group I [total 3.8 (SD 1.2), free 3.2 (SD 1.0) mumol.g-1 dry mass] and increased in group II [total 6.6 (SD 0.5), free 4.9 (SD 0.9) mumol.g-1 dry mass].(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children.

Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over pivalic acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain pivalic acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.

Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children

We determined four carnitine constituents (total and free carnitine and short- and long-chain fatty acid carnitine esters) in serum from 471 patients treated for convulsions with phenobarbital, valproic acid, phenytoin, and/or carbamazepine. The 471 patients were in eight treatment groups; four were treated with monotherapy and four with polytherapy. The means of all four carnitine constituents were significantly reduced in all treatment groups (except for free carnitine in four groups). Total carnitine was reduced by 23% to 48%, free carnitine by 9% to 45%, short-chain fatty acid carnitine by 46% to 64%, and long-chain fatty acid carnitine by 6% to 29%. Patient frequency of reduction for total carnitine was 20% of all patients (10% for free carnitine), 23% of patients receiving valproate (9% for free carnitine), 36% of those receiving phenobarbital (21% for free carnitine), 12% of those receiving phenytoin (8% for free carnitine), and 8% of those receiving carbamazepine (1% for free carnitine). Only for phenobarbital was there an inverse correlation between the serum concentration of the drug and that of carnitine concentration. One patient receiving carbamazepine had a 59% reduction in the total and a 65% reduction in the free carnitine concentration and a fivefold increase in long-chain fatty acid carnitine, values similar to those seen in neonatal lethal carnitine palmitoyl transferase II deficiency. It remains to be determined whether a reduction in serum carnitine values in patients receiving anticonvulsant therapy is of clinical consequence, whether the reduction is present in some patients before the start of therapy, when and by what mechanism carnitine levels may become reduced during therapy, and whether the reduction exists in the solid tissues of these patients.

Renal carnitine concentration decreases in endotoxic dogs

Renal cortical and serum carnitine concentrations were studied in seven anesthetized beagle dogs in which acute circulatory collapse was induced by an iv injection of Escherichia coli endotoxin, 0.5 mg/kg given over 15 mins. Four controls received normal saline. The endotoxin injection resulted in cardiac depression, renal hypoperfusion, acidosis with a decrease in urinary output, and hematuria. Arterial and renal venous free carnitine concentrations increased significantly in endotoxemia during the 5-hr experiment, but remained low and unchanged in the controls. Circulating acyl-carnitine concentrations underwent no essential changes in either group. Total, free, and acyl-carnitine concentrations decreased in endotoxic renal tissue. These data suggest that endotoxemia decreases carnitine concentrations in the renal cortex, but increases free carnitine concentrations in the circulation.