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Carnitine supplementation: an update.
Abstract
Carnitine is an essential nutrient for fat metabolism. This review summarizes fat metabolism and the important role of carnitine in beta-oxidation of fats. Causes of carnitine deficiency, signs and symptoms of deficiency states, and treatment strategies, including enteral and parenteral dosing, are presented.
... Carnitine is a quaternary ammonium compound, an amino acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, liver and adrenal glands) [692]. Its primary role is in fatty acid metabolism, but it is also involved in glucose metabolism [693]. ...
... Carnitine is the carrier molecule which transports long-chain fatty acid from the cytosol across the outer and inner membranes of the mitochondrial matrix for b-oxidation, i.e. for energy generation [693]. Fatty acid oxidation is controlled by the carnitine palmitoyltransferase system, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine palmitoyltransferase II (CPT II), and carnitine:acylcarnitine translocase (CACT) [694]. ...
... From these values the acyl-to-free carnitine ratio can be calculated: if the latter ratio ¼ 0.25, the status is normal, if the ratio >0.4, carnitine deficiency is present [693]. These determinations require access to specialist laboratory facilities. ...
Background
Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome.
Objective
This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words ‘deficiency’, “repletion”, “complement”, and ‘supplement’.
Methods
The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations.
Results
There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed.
Conclusion
This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.
... Micronutrients were assessed by serum lab assays drawn according to routine clinical care and not for research purposes at various time points during patients' hospitalization. The normal range for the micronutrients of interest are defined in Table 2. Micronutrient deficiencies were defined as below the normal range, while carnitine deficiencies were described as an ACFR >0.4 after post-hoc dividing acyl carnitine into free carnitine [14]. All micronutrient labs were taken during hospitalization and in the CRRT group and only micronutrient labs taken during or after CRRT were assessed for deficiencies. ...
Background & Aims
Continuous renal replacement therapy (CRRT) is essential to the management of acute kidney injury (AKI) in critical illness. Unfortunately, large quantities of micronutrients are shown to be lost in CRRT effluent. Current literature describes serum micronutrient values in CRRT patients to be below-reference range, yet seldom compares such values to other critically ill populations unexposed to CRRT. The aim of this study was to describe and compare the prevalence of micronutrient and carnitine deficiencies in critically ill patients at high malnutrition risk exposed to CRRT to a group of patient unexposed to CRRT.
Methods
A retrospective chart review was conducted at Duke University Hospital using the electronic medical record. The study group consisted of patients at high malnutrition risk requiring intensive care unit (ICU) admission from 01/01/2017-12/31/2018 with one or more of the following serum micronutrient levels checked: carnitine, copper, zinc, selenium, and vitamins B1, B6, B9, and C. Micronutrient deficiencies were defined as below the reference range and carnitine deficiencies were interpreted as an acyl to free carnitine ratio (ACFR) of >0.4.
Results
106 ICU patients met inclusion criteria and 46% were exposed to CRRT. At least one micronutrient deficiency was reported in 90% of CRRT patients compared to 61% patients unexposed to CRRT (p=0.002). A greater percentage of copper (p<0.001) and carnitine (p<0.001) deficiencies were found among patients exposed to CRRT, while more zinc deficiencies were noted among non-CRRT patients (p=0.001).
Conclusions
The vast majority of CRRT patients presented with micronutrient deficiencies. Clinicians should have a heightened awareness of the risk for serum copper, carnitine, and vitamin B6 deficiencies among CRRT patients. Further prospective and randomized-controlled trials are needed to better define this new category of malnutrition and test supplementation strategies to address and prevent these clinically-relevant deficiencies.
... 13 Carnitine is important in fat metabolism; deficiency may contribute to development of EFAD. 14 Ahmad and colleagues found that maintenance hemodialysis patients with signs of EFAD showed partial correction with L-carnitine supplementation alone. 15 The authors found that serum concentrations of LA and docosahexaenoic acid were significantly lower in patients who had severe CF transmembrane conductance regulator mutations, suggesting that the deficiency was associated with abnormal EFA metabolism. ...
Background:
Levocarnitine deficiency has been observed in patients receiving parenteral nutrition (PN) and can cause or worsen hypertriglyceridemia. The objective was to characterize use of levocarnitine supplementation in PN and evaluate its effect on triglyceride levels in hospitalized adults.
Methods:
This retrospective, single-center study included patients with triglyceride levels ≥175 mg/dl while receiving PN who had a subsequent reduction in lipid injectable emulsion dose. A piecewise linear regression was used to evaluate trends in triglyceride levels before and after the intervention, defined as initiation of levocarnitine in PN for the levocarnitine group, or reduction in lipid injectable emulsion alone for the control group.
Results:
Two hundred sixty-one patients who received PN had an elevated triglyceride level and lipid injectable emulsion dose reduction, of which 97 (37.2%) received levocarnitine in PN. The median (IQR) levocarnitine dose added to PN was 8.0 (5.7-9.9) mg/kg. Triglyceride levels at 30 days post-intervention did not differ between groups (125 vs 176 mg/dl, P = .345). The addition of levocarnitine to PN was associated with a significantly greater rate of reduction in triglyceride levels pre-intervention to post-intervention compared with a reduction in lipid injectable emulsion alone (-11 vs -3 mg/dl per day; 95% CI, -15 to -2; P = .012).
Conclusion:
In hospitalized adults with hypertriglyceridemia who had a lipid injectable emulsion dose reduction, the addition of levocarnitine in PN was not associated with a difference in triglyceride levels at 30 days; however, a greater rate of improvement in pre-intervention to post-intervention triglyceride levels was observed.
Carnitine is an essential cofactor in mitochondrial fatty acid oxidation. Carnitine deficiency results in accumulation of non-oxidized fatty acyl-coenzyme A molecules, and this inhibits intra-mitochondrial degradation of ammonia. Hyperammonemia may lead to encephalopathy. This scenario has been previously reported.
We report the case of a 47-year-old Caucasian man who had sustained a remote motor vehicle accident injury and relied on long-term tube feeding with a commercial product that wascarnitine-free. He was also on phenytoin therapy for control of his chronic seizures. He developed significant acute psychological and behavioral changes superimposed on his chronic neurological impairment. His ammonia level was found to be elevated at 75 to 100μmol/L (normal <35μmol/L). Phenytoin was found to be at a supra-therapeutic level of 143μmol/L (therapeutic range 40-80μmol/L). After adjusting the dose of phenytoin, other pharmacological and hepatic causes of his hyperammonemia and subacute encephalopathy were excluded. His carnitine levels were found to be low. After initiating carnitine supplementation at 500mg twice daily, the patient's mental status improved, and his ammonia level improved to 53-60μmol/L.
This case illustrates the importance of avoiding carnitine deficiency and anti-convulsant toxicity in tube-fed patients encountered in hospital wards and nursing homes. These patients should have their carnitine levels assessed regularly, and supplementation should be provided as necessary. Manufacturers of enteral feeds and formulas should consider adding carnitine to their product lines.
In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine diminution was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete beta-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.
Plasma carnitine levels were studied in 14 uremic patients before, during, and after hemodialysis. The predialysis plasma carnitine levels were normal but fell during dialysis (half-life of 3.6 h). Plasma carnitine levels rose quickly in the first 6 h after dialysis, after which time the rise was more gradual. Muscle carnitine was significantly reduced in the dialyzed patients (p less than 0.005) compared with controls. In four patients lipid droplets were observed in muscle. Ten patients on maintenance hemodialysis exhibited plasma hyperlipidemia and low muscle carnitine. These individuals were given DL-carnitine (50 mg/kg body weight) intravenously after each dialysis. At the end of a 2-month carnitine treatment, plasma triglyceride levels were found to be reduced (p less than 0.001) and muscle carnitine content significantly increased (p less than 0.005). These findings suggest that carnitine may be useful in treatment of hypertriglyceridemia and muscle carnitine deficiency states induced during maintenance hemodialysis.
The objective of this article is to review primary and secondary causes of carnitine deficiency, emphasizing recent advances in our knowledge of fatty acid oxidation. It is now understood that the cellular metabolism of fatty acids requires the cytosolic carnitine cycle and the mitochondrial beta-oxidation cycle. Carnitine is central to the translocation of the long chain acyl-CoAs across the inner mitochondrial membrane. The mitochondrial beta-oxidation cycle is composed of a newly described membrane-bound system and the classic matrix compartment system. Very long chain acyl-CoA dehydrogenase and the trifunctional enzyme complex are embedded in the inner mitochondrial membrane, and metabolize the long chain acyl-CoAs. The chain shortened acyl-CoAs are further degraded by the well-known system in the mitochondrial matrix. Numerous metabolic errors have been described in the two cycles of fatty acid oxidation; all are transmitted as autosomal recessive traits. Primary or secondary carnitine deficiency is present in all these clinical conditions except carnitine palmitoyltransferase type I and the classic adult form of carnitine palmitoyltransferase type II deficiency. The sole example of primary carnitine deficiency is the genetic defect involving the active transport across the plasmalemmal membrane. This condition responds dramatically to oral carnitine therapy. The secondary carnitine deficiencies respond less obviously to carnitine replacement. These conditions are managed by high carbohydrate, low fat frequent feedings, and vitamin/cofactor supplementation (eg, carnitine, glycine, and riboflavin). Medium chain triglycerides may be useful in the dietary management of patients with inborn errors of the cytosolic carnitine cycle or the mitochondrial membrane-bound long chain specific beta-oxidation system.
The purpose of this review is to describe the most common complications of home total parenteral nutrition, their identification, treatment and prevention. Data sources were manuscripts and abstracts published in the English literature since 1968. Studies were selected for summarization in this review on the basis of clinical relevance to the practicing clinician. Home total parenteral nutrition is a relatively safe, life-saving method for nutrient delivery in patients with compromised gastrointestinal function. However, numerous complications, with associated morbidity and mortality, involving the delivery system and the gastrointestinal, renal, and skeletal systems may develop. Catheter-related complications are often preventable and treatable when they occur, although renal and bone abnormalities have elusive etiologies.
In this study, our aim was to evaluate the effect of postdialysis administration of parenteral L-carnitine supplementations on hematological parameters and also on weekly requiring dose of the recombinant human erythropoietine (rHuEPO) in hemodialysis (HD) patients.
The stable 34 patients (17 male, 17 female) were enrolled in the study who were on rHuEPO therapy and a regular maintenance HD program at 5 h, three times a week with bicarbonate dialysate and with biocompatible membranes in HD Center of Medical Faculty Hospital in University of Dicle. rHuEPO was administered subcutanously at 80-120 U/kg/week. The patients were divided into two groups: Group 1, rHuEPO therapy (n=17) and Group 2, rHuEPO therapy + L-carnitine (n=17). L-carnitine (L-carnitine ampul, Santa Farma) 1 g was injected postdialysis intravenously via venous route of the dialytic set, three times a week. The patient's hemoglobin (Hgb), hematocrit (Hct), serum iron (Fe(+2)), total iron-binding capacity (TIBC), transferrin saturation index (TSI), and serum ferritin (Fer) levels were followed during the 16-week period. The weekly requiring doses of rHuEPO and hematological parameters of patients were recorded at the beginning of the study, at 8 weeks, and at 16 weeks of the study period.
In group 1 (n=17, 13 female, four male), the mean age was 38.8 +/- 12.1 years, mean period time on HD therapy was 18.1 +/- 14.9 months, and mean Kt/V value was 1.48 +/- 0.28. In group 2 (n=17, 13 male, four female), the mean age was 48.1 +/- 15.4 years, mean period time on HD therapy was 34.4 +/- 23.0 months, and mean Kt/V value was 1.29 +/- 0.20. The hematological parameters of the groups were found as follows: in group 1, Hgb: 7.9-10.8 g/dl, Hct: 25.3-32.5%; in group 2, Hgb: 10.2-11.8 g/dl, Hct: 30.6-35.4%, respectively (p < 0.05). The target Hgb/Hct values were achieved at the end of the study in both groups. Both groups were the same according to their serum Fe(+2) markers (p > 0.05). But unlike serum Fe(+2) markers, there were significant differences on weekly requiring doses of rHuEPO therapy between groups. While in group 1, the mean weekly requiring dose of rHuEPO was 6529 U/week (120 U/kg/ week) at the beginning of the study, and maintenance weekly requiring dose of rHuEPO was 3588 U/week (66 U/kg/week) at the end of the study, in group 2, they were 4882 U/week (80 U/ kg/week), and 1705 U/week (28 U/kg/week), respectively. According to these values, the total reduction in weekly requiring dose of rHuEPO was 45% in group 1, and 65% in group 2; the net gain was 20% in group 2 (p < 0.05).
If other factors related to anemia are excluded, the postdialysis parenteral L-carnitine therapy can be considered in selected stable patients, which may improve anemia and may reduce the weekly requiring dose of the rHuEPO and also be cost-effective.
The neonate receiving parenteral nutrition (PN) therapy requires a physiologically appropriate solution in quantity and quality given according to a timely, cost-effective strategy. Maintaining tissue integrity, metabolism, and growth in a neonate is challenging. To support infant growth and influence subsequent development requires critical timing for nutrition assessment and intervention. Providing amino acids to neonates has been shown to improve nitrogen balance, glucose metabolism, and amino acid profiles. In contrast, supplying the lipid emulsions (currently available in the United States) to provide essential fatty acids is not the optimal composition to help attenuate inflammation. Recent investigations with an omega-3 fish oil IV emulsion are promising, but there is need for further research and development. Complications from PN, however, remain problematic and include infection, hepatic dysfunction, and cholestasis. These complications in the neonate can affect morbidity and mortality, thus emphasizing the preference to provide early enteral feedings, as well as medication therapy to improve liver health and outcome. Potential strategies aimed at enhancing PN therapy in the neonate are highlighted in this review, and a summary of guidelines for practical management is included.
Although individual metabolic disorders are rare, collectively, inborn errors of metabolism are not uncommon and paediatricians should be alert to the possibility of such disorders. The presenting symptoms are frequently non-specific and may include lethargy, poor feeding, vomiting, coma, and seizures. After investigations, appropriate therapeutic options including exchange transfusion, peritoneal- and haemo-dialysis, forced diuresis, mega-dosing of vitamin cofactors, and special dietary therapy can be instituted, depending on the diagnosis. Somatic gene therapy may offer hope of a cure for inborn errors of metabolism in the future.
Congest Heart Fail. 2011;17:199–203. © 2011 Wiley Periodicals, Inc.
Heart failure (HF) is a growing epidemic worldwide with a particularly large presence in the United States. Nutritional assessment and supplementation is an area that can be studied to potentially improve the outcomes of these chronically ill patients. There have been many studies reporting the effect of various nutrients on HF patients, often with mixed results. Amino acids such as taurine, which is involved in calcium exchange, has been reported to improve heart function. Coenzyme Q10, a key component in the electron transport chain, is vital for energy production. l-carnitine, an amino acid derivative, is responsible for transport of fatty acids into the mitochondria along with modulating glucose metabolism. Thiamine and the other B vitamins, which serve as vital cofactors, can often be deficient in HF patients. Omega-3 fatty acid supplementation has been demonstrated to benefit HF patients potentially through anti-arrhythmic and anti-inflammatory mechanisms. Vitamin D supplementation can potentially benefit HF patients by way of modulating the renin-angiotensin system, smooth muscle proliferation, inflammation, and calcium homeostasis. Although supplementation of all of the above nutrients has the potential to benefit patients with HF, more studies are needed to solidify these recommendations. Congest Heart Fail.
Carnitines are involved in mitochondrial transport of fatty acids and are of critical importance for maintaining normal mitochondrial function. This review summarizes recent experimental and clinical studies showing that mitochondrial dysfunction secondary to a disruption of carnitine homeostasis may play a role in decreased NO signaling and the development of endothelial dysfunction. Future challenges include development of agents that can positively modulate L-carnitine homeostasis which may have high therapeutic potential.
Several new functions or metabolic uses of carnitine and improvements in assessment of carnitine status impact carnitine dosing recommendations. Carnitine dosing will likely be customized for patients at different stages of the life cycle and for patients with dysfunction of different organs. Nutrition supplementation of carnitine should be 2-5 mg x kg(-1) x day(-1) and be administrated via the route used for administration of macronutrients. Pharmacologic supplementation of carnitine should be 50-100 mg x kg(-1) x day(-1) and be reserved for the removal of toxic compounds from the body.
Introduction:
Valproic acid (VPA) is a broad-spectrum antiepileptic drug that is now used commonly for several other neurological and psychiatric indications. VPA is usually well tolerated, but serious complications, including hepatotoxicity and hyperammonemic encephalopathy, may occur. These complications may also arise following acute VPA overdose, the incidence of which is increasing. Intoxication usually only results in mild central nervous system depression, but serious toxicity and death have been reported.
Valproic acid and carnitine:
As a branched chain carboxylic acid, VPA is extensively metabolized by the liver via glucuronic acid conjugation, mitochondrial beta- and cytosolic omega-oxidation to produce multiple metabolites, some of which may be involved in its toxicity. Carnitine is an amino acid derivative that is an essential cofactor in the beta-oxidation of fatty acids. It is synthesized endogenously from the essential amino acids, methionine and lysine. VPA inhibits the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se.
Carnitine supplementation:
Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy although a correlation between ammonia concentrations and the clinical condition was not always observed. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children, although the clinical benefit in terms of liver protection or hastening of recovery from unconsciousness has not been established clearly. Prophylactic carnitine supplementation is also advocated during VPA therapy in high-risk pediatric patients.
Conclusion:
Further controlled, randomized, and probably multicenter trials are required to better delineate the therapeutic and prophylactic roles of l-carnitine and the optimal regimen of administration in the management of VPA toxicity.
L-carnitine (LC) deficiency is commonly observed in chronic hemodialysis (HD) patients. As a result of this and other causes of secondary LC deficiencies, LC has been described as a "conditionally essential nutrient" or "conditional vitamin". Although a large number of clinical trials regarding the beneficial effects of LC administration in HD patients have been published, some controversy about its use in this indication persists. In this article, we will review the use of LC in dialysis patients, by focussing mainly on those experimental and clinical data supporting the notion that supra-physiological concentrations of LC in plasma and target organs may exert beneficial effects on several metabolic parameters that have derangements of a common origin (e.g. insulin resistance, type 2 diabetes, dyslipidemia) and which are frequently present in end-stage renal disease (ESRD) patients undergoing dialysis.
To evaluate the therapeutic efficacy of l-carnitine in heart failure, the myocardial carnitine levels and the therapeutic efficacy of l-carnitine were studied in cardiomyopathic BIO 14.6 hamsters and in patients with chronic congestive heart failure and ischemic heart disease. BIO 14.6 hamsters and patients with heart failure were found to have reduced myocardial free carnitine levels (BIO 14.6 vs FI, 287 +/- 26.0 vs 384.8 +/- 83.8 nmol/g wet weight, p less than 0.05; patients with heart failure vs without heart failure, 412 +/- 142 vs 769 +/- 267 nmol/g p less than 0.01). On the other hand, long-chain acylcarnitine level was significantly higher in the patients with heart failure (532 +/- 169 vs 317 +/- 72 nmol/g, p less than 0.01). Significant myocardial damage in BIO 14.6 hamsters was prevented by the intraperitoneal administration of l-carnitine in the early stage of cardiomyopathy. Similarly, oral administration of l-carnitine for 12 weeks significantly improved the exercise tolerance of patients with effort angina. In 9 patients with chronic congestive heart failure, 5 patients (55%) moved to a lower NYHA class and the overall condition was improved in 6 patients (66%) after treatment with l-carnitine. L-carnitine is capable of reversing the inhibition of adenine nucleotide translocase and thus can restore the fatty acid oxidation mechanism which constitutes the main energy source for the myocardium. Therefore, these results indicate that l-carnitine is a useful therapeutic agent for the treatment of congestive heart failure in combination with traditional pharmacological therapy.
Severe tissue carnitine deficiency impairs fatty acid oxidation. In explanted hearts from patients with end stage heart failure a 57% carnitine decrease was found in comparison with healthy donor hearts (p less than 0.05). The reduction of myocardial carnitine levels affected all areas of the explanted hearts to a comparable extent. Carnitine decreases in patients with dilated cardiomyopathy or coronary artery disease were similar. Endomyocardial biopsies from patients with less severe heart failure due to cardiomyopathy (n = 28) or other myocardial diseases (n = 8) showed a 42% decrease of total myocardial carnitine (in nmol/mg non-collagen protein) in comparison with biopsies from patients with normal cardiac function (controls) (heart failure: 5.7, confidence interval 4.2-7.0; controls 9.3, confidence interval 7.6-12.0, p less than 0.005). Free myocardial carnitine in heart failure was also different from controls (heart failure: 4.2, confidence interval 3.7-5.3; controls 10.3, confidence interval 7.5-12.2, p less than 0.001). The decrease of free and total myocardial carnitine was comparable in dilated cardiomyopathy and heart failure due to other diseases. Alterations in myocardial carnitine content represent therefore non-specific biochemical markers in heart failure with yet unknown consequences for myocardial function.
We studied the effects of intravenous L-carnitine on the metabolism of fatty acids, ketone bodies, glucose, and branched-chain amino acids in four normal volunteers and four patients on long-term home parenteral nutrition (HPN) with low plasma carnitine concentrations. Substrate kinetics were determined by use of [1-14C]palmitate, [3,4-13C2]-acetoacetate, [6,6-2H2]glucose, and [5,5,5-2H3]leucine before and during a 3-h intravenous infusion of L-carnitine. HPN patients were restudied after 1 mo of nightly intravenous carnitine administration. HPN patients tolerated the short-term fast well, exhibiting neither hypoglycemia nor hypoketonemia. Intravenous carnitine had no effect on rates of fatty acid oxidation, ketone body production, glucose production, or leucine kinetics in either group. Routine addition of carnitine to the HPN regimen does not appear to be necessary. The failure of L-carnitine administration to have discernable effects on intermediary metabolism in normal volunteers casts doubt on its role in the treatment of a variety of medical conditions.
Low levels of plasma carnitine and reduced urinary carnitine excretion with persistently elevated plasma bilirubin levels, reactive hypoglycemia and generalized skeletal muscle weakness are described in a patient requiring long-term total parenteral nutrition (TPN). Intravenous administration of L-carnitine at 400 mg/day for 7 days and subsequently a maintenance dose of 60 mg/day corrected the plasma carnitine deficiency and reactive hypoglycemia and was associated with a return to normal plasma bilirubin levels and a restoration of skeletal muscle strength.
Twenty-nine hemodialyzed patients with hypertriglyceridemia were given L-carnitine (20 mg/kg iv at the end of each dialysis) for 120 days and then placebo for the same duration in order to evaluate the lipid-lowering effects of the metabolite. A dramatic reduction in triglyceride levels was observed only in the group of patients (n = 12) with high basal triglyceride values, low levels of high-density lipoprotein-cholesterol, and with apoprotein A at the lower limit of normal range. During L-carnitine treatment these patients exhibited significantly increased high-density lipoprotein-cholesterol and apoprotein A. No rebound effects were observed. L-Carnitine did not provoke changes in the lipid parameters in the group (n = 17) with high basal triglyceride values, and normal high-density lipoprotein-cholesterol and apoprotein A. Hematocrit values increased in all the 29 patients during L-carnitine treatment. At the end of the experimental protocol, L-carnitine dosage was increased to 60 mg/kg iv (at the end of each dialysis) in four patients of the group of nonresponders and prolonged for 60 days. This produced a considerable reduction in triglyceride levels. The above results suggest that L-carnitine can be effective in the management of hypertriglyceridemia in the hemodialyzed patient especially when low high-density lipoprotein-cholesterol levels are present.
Plasma levels of total carnitine remained unaltered in surgical patients fed intravenously up to about the 20th day of feeding. After that day there was a gradual decline in the levels. When oral feeding was recommended, levels rapidly returned to normal. It is concluded that adult patients can maintain plasma levels of carnitine much longer than newborns when no exogenous carnitine is supplied.
Experimental evidence from several investigators suggests that carnitine is a conditionally essential nutrient for neonates. If carnitine is a conditionally essential nutrient for the neonate, most neonates on total parenteral nutrition in the United States are not receiving adequate nutritional support. The metabolic functions of carnitine are varied and important in several aspects of neonatal physiology. All neonates receiving breast milk receive dietary carnitine and most neonates receiving enteral infant formulas receive dietary carnitine at a level similar to that of the breast-fed neonate. However, most neonates on total parenteral nutrition receive no dietary carnitine. Investigators have been testing the working hypothesis that carnitine is a conditionally essential nutrient for the neonate for many years. This review discusses (1) data supporting the hypothesis, (2) reasons why it has not been either proved or disproved by now, and (3) the author's view of a prudent approach to dietary carnitine supplementation of neonates.
It has been reported that cumulative carnitine losses through dialysis membranes may worsen hyperlipidemia during long-term hemodialysis. However, carnitine supplementation has not shown a consistent beneficial response. We undertook the present study to determine if there is any hypolipidemic effect of L-carnitine on Greek dialysis patients in concert with the dialysate buffer composition (acetate or bicarbonate). A total of 28 patients (16 male, 12 female), mean age 43 years (range 21-61), with end-stage renal disease on maintenance hemodialysis for a mean period of 25 months (range 7-84) were studied. The dialysis schedule was 4 h, 3 times/week using cuprophane hollow-fiber dialyzers and acetate (n = 14) or bicarbonate (n = 14) dialysate. In all patients L-carnitine (5 mg/kg body weight) was infused intravenously 3 times/week at the end of each hemodialysis session. Blood samples for carnitine and lipid determinations were obtained before treatment, and 3 and 6 months following treatment. Even though L-carnitine did not modify most of the serum lipid levels, a significant decrease in serum triglycerides was evident in the whole group of patients (from 225 +/- 76 to 201 +/- 75 mg/dl, p = 0.03). Furthermore, L-carnitine could decrease serum triglycerides only in hypertriglyceridemic patients (from 260 +/- 64 to 226 +/- 82 mg/dl, p < 0.05). L-Carnitine resulted in a reduction of serum triglycerides in both patients on bicarbonate and on acetate dialysis, while there were no significant differences in the changes of lipid parameters after L-carnitine between the two groups of hemodialysis patients. We conclude that relatively low doses of L-carnitine supplementation could contribute to the management of some hypertriglyceridemic hemodialysis patients.
L-carnitine (LC) plays an essential metabolic role that consists in transferring the long chain fatty acids (LCFAs) through the mitochondrial barrier, thus allowing their energy-yielding oxidation. Other functions of LC are protection of membrane structures, stabilizing a physiologic coenzyme-A (CoA)-sulfate hydrate/acetyl-CoA ratio, and reduction of lactate production. On the other hand, numerous observations have stressed the carnitine ability of influencing, in several ways, the control mechanisms of the vital cell cycle. Much evidence suggests that apoptosis activated by palmitate or stearate addition to cultured cells is correlated with de novo ceramide synthesis. Investigations in vitro strongly support that LC is able to inhibit the death planned, most likely by preventing sphingomyelin breakdown and consequent ceramide synthesis; this effect seems to be specific for acidic sphingomyelinase. The reduction of ceramide generation and the increase in the serum levels of insulin-like growth factor (IGF)-1, could represent 2 important mechanisms underlying the observed antiapoptotic effects of acetyl-LC. Primary carnitine deficiency is an uncommon inherited disorder, related to functional anomalies in a specific organic cation/carnitine transporter (hOCTN2). These conditions have been classified as either systemic or myopathic. Secondary forms also are recognized. These are present in patients with renal tubular disorders, in which excretion of carnitine may be excessive, and in patients on hemodialysis. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and particularly by the loss through dialytic membranes, leading, in some patients, to carnitine depletion with a relative increase in esterified forms. Many studies have shown that LC supplementation leads to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia, normalizing the reduced carnitine palmitoyl transferase activity in red cells.
Among the various metabolic abnormalities documented in dialysis patients are abnormalities related to the metabolism of fatty acids. Aberrant fatty-acid metabolism has been associated with the promotion of free-radical production, insulin resistance, and cellular apoptosis. These processes have been identified as important contributors to the morbidity experienced by dialysis patients. There is evidence that levocarnitine supplementation can modify the deleterious effects of defective fatty-acid metabolism. Patients receiving hemodialysis and, to a lesser degree, peritoneal dialysis have been shown to be carnitine deficient, as manifested by reduced levels of plasma free carnitine and an increase in the acyl:free carnitine ratio. Cardiac and skeletal muscles are particularly dependent on fatty-acid metabolism for the generation of energy. A number of clinical abnormalities have been correlated with a low plasma carnitine status in dialysis patients. Clinical trials have examined the efficacy of levocarnitine therapy in a number of conditions common in dialysis patients, including skeletal-muscle weakness and fatigue, cardiomyopathy, dialysis-related hypotension, hyperlipidemia, and anemia poorly responsive to recombinant human erythropoietin therapy (rHuEPO). This review examines the evidence for carnitine deficiency in patients requiring dialysis, and documents the results of relevant clinical trials of levocarnitine therapy in this population. Consensus recommendations by expert panels are summarized and contrasted with present guidelines for access to levocarnitine therapy by dialysis patients.
Previously, we demonstrated that selected groups of hemodialysis patients might be more likely to have abnormalities of carnitine metabolism. The purpose of the present study was to examine the effects of carnitine therapy in these selected groups of hemodialysis patients on quality-of-life measures and erythropoietin dose.
This was a double-blind, randomized, controlled trial, in which 50 hemodialysis patients were treated with either 2 g i.v. carnitine or placebo. The treatment period was for 24 weeks.
Thirty-four patients (15 in the treatment group) completed the study. The mean age was 69 +/- 15 years, 35% were women, and 44% had diabetes. Mean initial plasma total, free, short-chain acyl and long-chain acyl carnitine concentrations (micromol/L; mean +/- SEM) were 35.9 +/- 1.8, 18.2 +/- 1.1, 11.6 +/- 0.6, and 6.0 +/- 0.3, whereas the plasma acyl-to-free-carnitine ratio was 1.02 +/- 0.05. With respect to the Medical Outcomes Short Form-36 (SF-36), improvements from baseline were noted in the treatment group (n = 13) for role-physical (33.9 +/- 1.9 to 43.2 +/- 3.0, p < .05) and the SF-36 physical component summary score (36.1 +/- 2.7 to 39.7 +/- 2.3, p = .09) relative to changes in the control group (n = 14). The erythropoietin dose over the 24-week period was reduced from baseline in the treatment group relative to the placebo group (-1.62 +/- 0.91 vs 1.33 +/- 0.79 units erythropoietin/dry weight/hemoglobin concentration, respectively, p < .05).
After 24 weeks of i.v. carnitine therapy, SF-36 scores were improved and erythropoietin doses were reduced in hemodialysis patients, relative to the control group.
Trimethylamine (TMA) is a short-chain tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods high in TMA or by the intake of food high in precursors to TMA, such as trimethylamine-N-oxide (TMNO), choline and L-carnitine. The clinical significance of TMA may be related to its potential to contribute to neurological toxicity and 'uraemic breath' in patients with end-stage renal disease (ESRD).
Concentrations of TMA and TMNO in plasma from 10 healthy adults (not on haemodialysis) and 10 adults with ESRD undergoing haemodialysis (pre- and post-dialysis) were determined by gas chromatography-mass spectrometry.
The concentrations of TMA and TMNO in pre-dialysis plasma (1.39+/-0.483 and 99.9+/-31.9 microM, respectively) were significantly (P<0.05) higher than the corresponding levels in healthy subjects (0.418+/-0.124 and 37.8+/-20.4 microM, respectively). However, there were no significant differences between post-dialysis and healthy subject plasma concentrations. In the ESRD patients, there was a significant (P<0.05) reduction in plasma TMA (from 1.39+/-0.483 to 0.484+/-0.164 microM) and TMNO (from 99.9+/-31.9 to 41.3+/-18.8 microM) during a single haemodialysis session.
TMA and TMNO accumulate between haemodialysis sessions in ESRD patients, but are efficiently removed during a single haemodialysis session.
Carnitine plays an essential role in the transfer of long-chain fatty acids across the inner mitochondrial membrane. This transfer requires enzymes and transporters that accumulate carnitine within the cell (OCTN2 carnitine transporter), conjugate it with long chain fatty acids (carnitine palmitoyl transferase 1, CPT1), transfer the acylcarnitine across the inner plasma membrane (carnitine-acylcarnitine translocase, CACT), and conjugate the fatty acid back to Coenzyme A for subsequent beta oxidation (carnitine palmitoyl transferase 2, CPT2). Deficiency of the OCTN2 carnitine transporter causes primary carnitine deficiency, characterized by increased losses of carnitine in the urine and decreased carnitine accumulation in tissues. Patients can present with hypoketotic hypoglycemia and hepatic encephalopathy, or with skeletal and cardiac myopathy. This disease responds to carnitine supplementation. Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia. The heart and the muscle, which express a genetically distinct form of CPT1, are usually unaffected. These patients can have elevated levels of plasma carnitine. CACT deficiency presents in most cases in the neonatal period with hypoglycemia, hyperammonemia, and cardiomyopathy with arrhythmia leading to cardiac arrest. Plasma carnitine levels are extremely low. Deficiency of CPT2 present more frequently in adults with rhabdomyolysis triggered by prolonged exercise. More severe variants of CPT2 deficiency present in the neonatal period similarly to CACT deficiency associated or not with multiple congenital anomalies. Treatment for deficiency of CPT1, CPT2, and CACT consists in a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from carnitine, carnitine supplements, and avoidance of fasting and sustained exercise.
We describe a 21-year-old male with previously normal plasma total and free carnitine levels who developed a deficiency manifest by decreased plasma and muscle total and free carnitine, decreased urine carnitine, severe hepatic steatosis, mediastinal lipomatosis, progressively impaired triglyceride clearance, myopathy and intermittent hypoglycemia. This case demonstrates that systemic carnitine deficiency may occur in some patients receiving long term carnitine-free TPN. Carnitine may be an essential element of the diet in this patient population.
Carnitine is synthesized endogenously from methionine and lysine in the liver and kidney and is available exogenously from a meat and dairy diet and from human milk and most enteral formulas. Parenteral nutrition (PN) does not contain carnitine unless it is extemporaneously added. The primary role of carnitine is to transport long-chain fatty acids across the mitochondrial membrane, where they undergo beta-oxidation to produce energy. Although the majority of patients are capable of endogenous synthesis of carnitine, certain pediatric populations, specifically neonates and infants, have decreased biosynthetic capacity and are at risk of developing carnitine deficiency, particularly when receiving PN. Studies have evaluated for several decades the effects of carnitine supplementation in pediatric patients receiving nutrition support. Early studies focused primarily on the effects of supplementation on markers of fatty acid metabolism and nutrition markers, including weight gain and nitrogen balance, whereas more recent studies have evaluated neonatal morbidity. This review describes the role of carnitine in metabolic processes, its biosynthesis, and carnitine deficiency syndromes, as well as reviews the literature on carnitine supplementation in pediatric nutrition.
Carnitine is an essential co-factor in fatty acid metabolism. Carnitine deficiency can impair fatty acid oxidation, rarely leading to hyperammonemia and encephalopathy. We present the case of a 35-year-old woman who developed acute mental status changes, asterixis, and diffuse muscle weakness. Her ammonia level was elevated at 276 microg/dL. Traditional ammonia-reducing therapies were initiated, but proved ineffective. Pharmacologic, microbial, and autoimmune causes for the hyperammonemia were excluded. The patient was severely malnourished and her carnitine level was found to be extremely low. After carnitine supplementation, ammonia levels normalized and the patient's mental status returned to baseline. In the setting of refractory hyperammonemia, this case illustrates how careful investigation may reveal a treatable condition.
A review of carnitine deficiency in a tertiary care hospital [abstract]
- Mg Staniec
- Er Bell
Staniec MG, Bell ER. A review of carnitine
deficiency in a tertiary care hospital
[abstract]. Nutr Clin Pract. 2003;18:194.
Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility
- Dm Muoio
- Rc Noland
- Jp Kovfalik
Muoio DM, Noland RC, Kovfalik JP, et
al. Muscle-specific deletion of carnitine
acetyltransferase compromises glucose
tolerance and metabolic flexibility. Cell
Metab. 2012;15;764-777.
In: King Guide to Parenteral Admixtures
- Jc King
- Pn Catania
- Levocarnitine
King JC, Catania PN. Levocarnitine. In: King
Guide to Parenteral Admixtures. 7th ed. Napa,
CA: King Guide Publication, Inc; 2012.
Carnitor® (levocarnitine) Tablets, Oral Solution, and Sugar-Free Oral Solution Prescribing Information
Carnitor® (levocarnitine) Tablets, Oral
Solution, and Sugar-Free Oral Solution
Prescribing Information. 2007. Sigma-Tau
Pharmaceuticals, Inc. http://www.
carnitormetabolic.com/tabs_oral_pi.html.
Accessed July 2013.
Clinical practice guidelines for nutrition in chronic renal failure
National Kidney Foundation. KDOQI. Clinical
practice guidelines for nutrition in chronic
renal failure. Am J Kid Dis. 2000;35(suppl
2):S1-S140.
A review of carnitine deficiency in a tertiary care hospital
- M G Staniec
- E R Bell
Staniec MG, Bell ER. A review of carnitine
deficiency in a tertiary care hospital
[abstract].
Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility
- D M Muoio
- R C Noland
- J P Kovfalik
Muoio DM, Noland RC, Kovfalik JP, et
al. Muscle-specific deletion of carnitine
acetyltransferase compromises glucose
tolerance and metabolic flexibility. Cell
Metab. 2012;15;764-777.