Carnitine is an increasingly popular supplement used mainly by athletes to help improve performance. However, other individuals could benefit, including patients with heart disease and those on haemodialysis. This article reviews the latest research on this compound
|
|
Carnitine is an essential cellular component, which is sometimes referred to as vitamin BT, although it is not generally considered to be a vitamin. It is an amino acid derivative synthesised from the amino acids lysine and methionine in the liver and kidney, from where it is released into the systemic circulation. It is also synthesised in the brain.
Of the total carnitine in the human body, 98 per cent is found in cardiac and skeletal muscle. Carnitine can also be obtained from the diet, mainly from food of animal origin, and the amount ingested determines the absorption rate.1,2
Carnitine exists in two isomeric forms, the d- and l-forms. The two forms have different biochemical and pharmacological properties, the l-isomer being naturally occurring. The form often sold as a nutritional supplement is a mixture of the d- and l-forms, and this is claimed to be less safe than the l-form.2
For the purposes of this article, the l-isomer has been considered.
The main function of carnitine is in fatty acid metabolism. The biochemical reactions of this nutrient are based on the reaction between carnitine and acyl groups (carnitine + acyl-coA ¤ acylcarnitine + coenzyme A) and carnitine is therefore involved in many coenzyme A-dependent pathways.3
The first recognised function of carnitine was its involvement in long-chain fatty acid oxidation at the mitochondrial level, providing energy. Carnitine acts as a carrier of the acyl and acetyl groups across the mitochondrial membrane before b-oxidation can occur to provide energy.4 Indeed, this is the main energy source in skeletal and cardiac muscle, attesting to the important role of carnitine.5 It is now known that carnitine also has many other metabolic functions, such as branched chain a-ketoacid oxidation and detoxification of potentially toxic acyl-coA metabolites from other pathways.
Carnitine is excreted as free carnitine or as acylcarnitine by the kidneys, with more than 90 per cent being reabsorbed by the proximal renal tubule.6
Inadequate intake or excessive loss can result in very low carnitine levels, but this does not necessarily lead to clinical symptoms.7 In preterm infants, where carnitine synthesis is inadequate for the needs of the baby, carnitine supplementation may be of benefit.8 Deficiency in those on a normal diet is rare but can occur due to a primary cause, such as an inborn error of metabolism, or secondary either to another disease or to drug administration.
Clinical symptoms of deficiency can become manifest in two ways. In infants and young children, carnitine deficiency leads to repeated bouts of coma, hypoglycaemia and a Reye's-like syndrome. (Reye's syndrome involves acute encephalopathy and fatty degeneration of the liver and has been associated with giving aspirin to children.) There have been several reports of carnitine supplementation in these cases but due to the problems of setting up clinical trials for children with metabolic disorders, most accounts have been single case reports or anecdotal.9,10 In adults, carnitine deficiency usually presents as chronic muscle weakness.2
The history of carnitine is an interesting example of the problems facing nutraceuticals. Dr Stephen DeFelice, former chief of clinical pharmacology at the Walter Reed Army Institute of Research and director of Pfizer Inc, spent 35 years studying carnitine as a pharmaceutical. While doing so, he found that carnitine was already being sold in health food shops. The US Food and Drug Administration finally approved carnitine as an orphan drug to treat serious paediatric disease. (The US Orphan Drug Act offers companies tax and other incentives to develop substances for the treatment of rare diseases where the market is too small to make it cost-effective for a pharmaceutical company to carry out the required testing.)11,12
In Europe, l-carnitine is frequently prescribed, but in some countries, including Britain, it is available with or without a prescription as a nutritional supplement or nutraceutical.13
Since the 1970s, it has been known that carnitine levels are altered in chronic renal failure and in haemodialysis (HD) patients. Kletzmayr1 has reviewed much of the work in this field.
Anaemia is frequently a problem in chronic renal failure patients on HD.
Recombinant human erythropoietin (rHuEPO) is often used to treat these patients. Several factors can affect the dose of rHuEPO required, including blood loss, inflammation, iron deficiency and aluminium toxicity.14 However, because the treatment is so expensive, rHuEPO is not usually started until the anaemia reaches dangerous levels. Many patients receiving rHuEPO have low carnitine levels, and this has been shown to affect the amount of rHuEPO needed.14
In one study,1 40 HD patients were given either carnitine or placebo after each dialysis session for eight months. For the first four months, 20mg intravenous iron was also administered after each session, as iron deficiency has also been implicated in failure of rHuEPO. The rHuEPO dose was adjusted according to the patient's blood profile. Results showed that at the end of the study period most of the subjects still had free carnitine levels below the reference range for healthy subjects. The rHuEPO dose was reduced as a result of carnitine administration in the first four months, but when iron therapy was discontinued the rHuEPO requirement increased in both groups, suggesting that iron as well as carnitine is necessary to improve the anaemia of HD.
Ageing may lead not only to chronic renal impairment but also to a reduction of carnitine and erythropoietin, both of which are synthesised in the kidney. A randomised, double-blind study15 was carried out to determine the benefit of carnitine in 31 elderly dialysis patients. They received either 1g intravenous carnitine or placebo at the end of each dialysis session for six months. The rHuEPO dose was adjusted every two weeks, corresponding to the patient's blood profile. The results showed a reduced need for rHuEPO in the patients receiving carnitine supplementation, and/or improved blood profile without the need for increasing the rHuEPO dose, with the best results in those patients over 65 years of age. Although this was a small study, these findings could be quite significant, as decreasing rHuEPO dosage with the use of carnitine therapy could lead to considerable financial savings for the NHS.
Carnitine deficiency in dialysis patients can also lead to cardiac problems, which can be severe. A small clinical study was carried out comparing oral carnitine in HD patients, and controls with neither renal nor cardiac disease.16 Before the study was started the carnitine levels in the dialysis patients were lower than in the controls, as expected. After the two months of carnitine supplementation, plasma levels increased significantly in the patients and exceeded those of the controls. The defective myocardial fatty acid metabolism observed before the treatment period, which can eventually lead to heart failure in chronic renal patients, was corrected, suggesting another advantage for carnitine supplementation in HD patients.
Long-term HD often leads to a reduced quality of life resulting from weakness, tiredness, and a general decrease in energy metabolism. Since carnitine is involved in energy metabolism, a trial was carried out to determine whether carnitine supplementation would alter patients' perceived quality of life.17 The placebo-controlled crossover study involved 101 patients. Every six weeks the patients had to fill out a questionnaire assessing various parameters associated with quality of life. These included body pain, emotional role (emotional limits to daily activities), general health, mental health, physical function, physical role (limits to physical activities), social function and vitality. Since diabetes and hypertension are often causes of renal disease, results in the study population were compared with these populations.
A questionnaire was also completed at the end of each dialysis session reporting any symptoms associated with the dialysis itself, such as chest pain, headache, nausea, muscle cramps, etc, but these were found to be unaffected by the carnitine therapy. Except for physical limits to daily activities (physical role), quality of life assessments were perceived as low in the HD patients compared with healthy subjects or those with diabetes or hypertension before the study was started. By three months, carnitine patients reported an increase in vitality and general health, and by six months physical function also improved, but some patients' perceptions of mental health and vitality were again lower. This could be due to the plateau reached, which is perceived as a decrease in some subjects simply because they are expecting an improvement. Alternatively, long-term carnitine therapy may cause a reduced perception of vitality and mental health. Most effects had occurred within three months of starting carnitine supplementation.
It may be too soon to recommend routine carnitine therapy for all HD patients, but when there is an unexplained low response to rHuEPO, carnitine may be worth considering.18 Large clinical studies are required to provide unequivocal results as well as optimal dose and duration, but there certainly seems to be a role for carnitine in some patients on dialysis, especially the elderly, those with cardiac disease or those whose quality of life is perceived as very low.
Carnitine is found in high concentrations in heart muscle, where it has important functions, including the prevention of lactic acid formation, which is damaging to the myocardium. The increasing amount of research in this area, including many clinical trials, points to the beneficial use of this supplement for many heart conditions.
Angina During myocardial ischaemia, when blood flow to the heart is reduced, carnitine levels in myocardial muscle may decrease by as much as 40 per cent.19 Supplementation with carnitine may therefore be of use in patients with ischaemic heart disease. In one study,20 200 patients suffering from exercise-induced stable angina were recruited. Half of the patients were treated with 2g/day carnitine orally for six months in addition to their normal therapy. The control patients continued their usual medication. Heart measurements, including heart rate, blood pressure, electrocardiogram (ECG) and cycle exercise testing were performed in both groups of patients. In the carnitine group significant and progressive improvements were seen in cardiac function and quality of life, and there was also a significant reduction of cardioactive drug consumption.
Congestive heart failure One trial21 investigated 160 patients, all of whom had suffered recent acute myocardial infarction. On discharge from hospital the patients were randomly assigned to group A or B. Group A received 2g carnitine twice daily, for one year, in addition to the standard medication. Group B acted as the control. Throughout the study, at set intervals, heart measurements were carried out. Positive results were seen in group A in terms of cardiac events and life expectancy with significant differences for nearly all the parameters studied. Particularly striking were the differences in mortality of 1.2 per cent in the carnitine group (one death by thromboembolism) and 12.5 per cent in the control group (reinfarction and sudden death in eight cases and two extracardiac deaths). In a similar study involving 101 patients with suspected acute myocardial infarction, 2g carnitine was compared with placebo. After 28 days' treatment, the mean infarct size was significantly reduced in the carnitine group, as was angina, left ventricular enlargement and total arrhythmias.19 More recently, carnitine was used to shorten recovery time in 24 children with heart failure who received 50mg/kg carnitine orally for 15 days, compared with controls.22
Cardiogenic shock Carnitine has been shown to be protective in cardiogenic shock, a condition which has been defined as "a state of severe tissue hypoperfusion resulting from underlying pump dysfunction".23 In a pilot study, carnitine was administered to 27 patients in addition to their usual therapy. An intravenous bolus was given initially, followed by a continuous infusion for the duration of the cardiogenic shock conditions. Results showed that those patients given carnitine had an improvement in their condition with a marked increase in survival time.
In view of these and many other reports, which have been reviewed by Kelly,5 the role of carnitine in heart disease seems promising. The reduction in mortality in post-myocardial infarction patients is encouraging, as are the many other significant improvements to cardiac parameters seen with carnitine supplementation.
Other effects of carnitine may become clinically relevant as research continues. The role of carnitine in glucose metabolism and insulin deficiency has been studied.4 In healthy volunteers, carnitine reduced insulin secretion and blood sugar levels with an improvement in glucose metabolism. Insulin resistance was also improved in chronic renal patients.24
Acetyl-l-carnitine has been used as a neuroprotective agent in Alzheimer's disease and other dementias as it crosses the blood-brain barrier when administered by both oral and intravenous routes. In several clinical trials, reviewed by Calvani,25 acetyl-l-carnitine improved cognitive and behavioural areas. This requires further investigation but seems to be a promising use of carnitine.
Carnitine has also been investigated in Rett syndrome (a neurological disorder, affecting girls, which involves the progressive loss of intellectual and motor skills, resulting in severe mental retardation). A small, randomised, placebo-controlled, double-blind trial was carried out, in which the subjects were treated with carnitine for eight weeks in a crossover design. Parents reported an improvement in their daughters' conditions while they were on carnitine. However, owing to the side effect of diarrhoea experienced by some subjects, the carnitine period was identified by the parents, and this may have affected results. In addition, the short duration of the trial did not uncover any long-term benefits (or drawbacks) of carnitine supplementation in these patients.26
A group of researchers found that carnitine is beneficial in patients with the human immunodeficiency virus (HIV). Their results suggest that carnitine acts on the immune system, rather than directly on the virus and may be of use in combination with antiviral drugs.27 Other studies have found that carnitine can correct secondary carnitine deficiency in HIV patients.28
It has also been suggested that the muscle weakness in chronic fatigue symptom is associated with carnitine deficiency. Periods of muscle weakness are related to low carnitine levels, which can be corrected with carnitine supplementation.28
Carnitine has also been given to transfusion-dependent beta thalassemia major patients, who suffer from a genetic abnormality in which there is continued production of foetal haemoglobin, resulting in clinical symptoms of haemolytic anaemia.29 Other indications for carnitine therapy include anorexia, diphtheria and male infertility.5
To date the evidence for all of these uses is not conclusive and studies in these areas have been small scale. Large, controlled trials are necessary to determine the clinical relevance of these findings.
As already described, carnitine is involved in fatty acid oxidation, which provides energy. It is, therefore, logical to hypothesise that carnitine may be of value as a supplement in healthy sportsmen. These individuals are constantly looking for new (and legal) ways to enhance their performance. A review of recent clinical trials3 demonstrated that although some studies have shown beneficial results, this is not so in most cases.
There have been some promising reports of the use of carnitine in aerobic sports,30 but at present carnitine cannot be recommended as an ergogenic agent. Further clinical trials involving large groups of subjects and long periods of carnitine therapy (months rather than weeks) are required in order to determine whether carnitine will have a role as an ergogenic agent in the future.
It has been known for several years that anticonvulsant drugs, whether taken alone or in combination regimens, cause a decrease in total and/or free carnitine levels.31 In one study it was found that carnitine levels were affected by valproate (23 per cent of patients) and also, but to a lesser extent, by phenobarbital, phenytoin, and carbamazepine.32 (However, a drawback with this study was that baseline values were not taken, so it is not definite that the reduced levels were entirely due to the antiepileptic therapy.)
Long-term valproate therapy has particularly been associated with reduced levels of carnitine, and a panel of nine paediatric neurologists has reviewed much of the recent work in this area.6 Clinically, this work is important as valproate toxicity is associated with hepatotoxicity and can be fatal, especially in infants. The panel concluded that the valproate toxicity is related to a reduction of carnitine and intravenous, high-dose carnitine therapy may be life-saving in some cases, where there is hepatotoxicity due to either valproate overdose or a secondary carnitine deficiency. However, it is interesting to note that valproate-induced toxicity is not always due to carnitine deficiency, as was demonstrated in a case of a three-year-old girl who died from hepatic failure while on valproic acid, despite carnitine supplementation.33
Oral carnitine supplementation may be valuable in valproate patients, especially those under two years of age who are receiving multiple anticonvulsant therapy or those with renal disease or in other high-risk groups for hepatotoxicity (eg, failure to thrive, malnutrition, chronic illness, etc).
Carnitine has also been tested in acne patients on isotretinoin therapy.34 Musculoskeletal disturbances are often reported in patients receiving isotretinoin and can be severe enough to discontinue treatment. Such symptoms are also often the result of carnitine deficiency and carnitine supplementation was tested in 230 isotretinoin patients. Of these, 16 per cent showed muscular symptoms after approximately two weeks. Half these patients received carnitine supplementation and the rest acted as the control group and received placebo. In the carnitine group symptoms disappeared after five to six days, whereas in the placebo group symptoms continued, resulting in two patients discontinuing treatment and a further four receiving analgesics.
Carnitine has also been administered to avoid side effects, including decreased energy metabolism, which often occur in patients on pivampicillin therapy.35
In general, the side effects of carnitine are few. As stated above, diarrhoea can be a problem and other gastrointestinal effects have also been reported.5 A fishy body or urine odour has been noticed in some subjects.26 A few neurological patients taking carnitine have experienced agitation and aggression.28 In spite of these side effects, carnitine remains a safe supplement. However, dl-carnitine should be avoided as the d-isomer can lead to toxic effects.
Carnitine seems to be a semi-essential component of the human body with many promising uses. Although primary deficiency is rare, depletion due to a secondary cause, whether as a side effect of medication or as a result of another disease, can occur. As the research and evidence for this nutraceutical increase, pharmacists should become increasingly aware of its functions and use.
The authors are from the School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL. Lisa Rapport is also a practising community pharmacist. Correspondence to Dr Lockwood (e-mail Lockwood@fs1.pa.man.ac.uk)