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Carnitine is an amino acid which is available (i) in the diet, mainly from red (muscle) meats, and (ii) by synthesis in the body from lysine and methionine with the assistance of vitamin C and other secondary compounds produced in the body. The endogenous formation of carnitine occurs most readily in liver, kidney and the brain as a result of the occurrence there of the required enzyme 4-butyrobetaine hydroxylase (Lohninger et al, 1987). Tissue distribution and uptake are partly hormonally controlled (COMMENT: this might be defective in HIV disease), and most tissues have levels that are several times higher than that of blood serum; thus transport occurs against a large concentration gradient (Siliprandi & Ciman, 1986). Carnitine transport in the body depends partly on extracellular sodium concentrations. Storage of carnitine is primarily in muscle tissues. Estimated turnover time for carnitine is about 35 days. Carnitine is of particular importance to heart muscle since the heart gets about 80% of its energy from lipids (Lohninger et al, 1987) - see below. Excretion from the body is mainly in the urine (Ashbrook, 1987).
Due to endogenous formation, carnitine is not normally considered an essential amino acid under normal circumstances of health. However, even for healthy individuals, "whether tissues are able to synthesize carnitine in sufficient quantities in absence of an exogenous source is uncertain" (Hunt & Groff, 1990). In fact, L-carnitine has been called a conditionally essential nutrient (Rebouche, 1992), meaning an exogenous source may be necessary.
The amino acids lysine and either methionine or cysteine, are considered essential. Methionine and cysteine are sulphur-containing amino acids of which at least one is essential in the diet. Lysine is one of only two amino acids considered "totally indispensable". Both lysine and the sulphur containing amino acids are particularly subject to modification during food processing such that they may become no longer available for normal body metabolism. Furthermore, both cysteine and methionine have been reported to tend to be low in HIV disease (Singer et al, 1992).
Although methionine lowering could be secondary to cysteine deficiency since cysteine normally functions partly as a "methionine sparing" amino acid (Hunt & Groff, 1990), it is more likely that methionine would become deficient in any case in a disease, such as HIV, characterized by severe oxidant stress. Both cysteine and methionine are readily oxidized, reversibly under lower oxidation stress, but irreversibly under more severe oxidation. The irreversibly oxidized forms, cysteic acid and methionine sulphone, respectively, are not available for normal body metabolism.
Carnitine is found in the muscles of the body at high levels. This is particularly important for supply of energy to the body muscles. The carnitine transports long-chain fatty acids into the mitochondria where they are oxidized (called ß-oxidation) to provide energy. Production of this energy also requires vitamins B2, B3, B12, and biotin. Carnitine also aids in removing short- and medium-chain fatty acids that accumulate in the mitochondria as the result of abnormal metabolism. L-carnitine also helps normalize the redox state of the brain, and facilitates liver urea synthesis (Rebouche, 1992).
The main symptoms of carnitine deficiency are high triglycerides and muscular fatigue - see more on this below. It is likely that the phenomenon known as futile cycling (of free fatty acids) which occurs with HIV disease (Grunfeld, 1992) is either caused, or at least exacerbated, by carnitine deficiency. Futile cycling is the cyclical reformation of fat from free fatty acids with subsequent breakdown back to free fatty acids, and so on - thus fats are recycled burning up protein in the process. In HIV disease, the result is unusually high usage of protein to provide energy and relatively high storage of fat so that patients lose body lean mass and become fatty (about 44% increase in fat oxidation, but 300% increase in fat storage! a concomitant 250% increase in glucose formation (Hellerstein, 1992) is likely primarily from protein sources, hence the protein cannibalization). Since the immune system requires protein stores for its energy, this is devastating in a disease where the immune system is already under heavy siege.
In the absence of HIV infection, there have been several types of carnitine deficiency states observed. Systemic carnitine deficiency (SCD) occurs when deficiency occurs in several types of body tissue, and this is a source of acidosis, and acute encephalopathy (Lohninger et al, 1987), whose onset is usually characterized by vomiting followed by stupor and coma. SCD also results in muscular fatigue, and lipid accumulation, i.e., hypertriglyceridemia (Siliprandi & Ciman, 1986). Myopathic carnitine deficiency (MCD) occurs when deficiency is limited to muscle tissue, and muscular fatigue is a major symptom. One of the conditions of mitochondrial failure is observed in Reye's syndrome (Angelini et al, 1986). Heart disorders and respiratory distress syndrome (RDS) are two other manifestations of carnitine deficiency.
Carnitine supplementation has been routinely shown to help correct states of deficiency, although improvement has been noted to occur in 80% of SCD patients compared to 100% of MCD patients (Ashbrook, 1986). At supplementation levels of more than 4 grams per day, diarrhoea may occur. Otherwise, carnitine has an LD50 value about the same as for other amino acids, i.e., it is considered non-toxic (Lohninger et al, 1987).
Exercise helps increase carnitine levels (Braverman & Pfeiffer, 1987; Angelini et al, 1986) with resulting increase in utilization of fatty acids by the muscles.
What does this mean for those living with HIV?
In HIV disease, it is likely that hypertriglyceridemia occurs primarily, perhaps exclusively, from carnitine deficiency. Futile cycling and low cholesterol are similarly likely results. Contribution to fatigue and wasting is also highly likely, although there are other obvious sources for these. Those who require kidney dialysis are at increased risk since low carnitine results even in the absence of HIV (Lohninger et al, 1987).
Fat in the diet must supply essential fatty acids, required in the synthesis of a number of important metabolites such as arachidonic acid - more on this below. These essential fatty acids are long-chain and some sources of them are essential. Such sources include corn, peanut, regular sunflower and safflower oils. The second requirement from fat is as a source of energy. Fats exist in a more reduced state than carbohydrates and therefore represent a highly concentrated form of energy (more energy is produced during oxidation to CO2 and H2O) from the body (if the body is able to extract it) and saturated fats contain more energy per gram than do the unsaturated fats.
In addition to contributing to wasting, lack of energy and hypertriglyceridemia, errors in fat metabolism may also upset the body's regulatory system. Fat derived hormone-like substances include the prostaglandins, thromboxanes and leucotrienes, including the eicosanoids. Prostaglandins and thromboxanes often exhibit antagonistic effects, e.g., in vasodilation by PGE2 and vasoconstriction by PGF2 - there seems to be no current research into whether these are involved in KS development. Other functions of these 'hormones' are regulation of blood pressure, diuresis, blood platelet aggregation, modulation of immune and nervous system effects, helping regulate gastric secretions, stimulation of smooth muscle contraction, etc. They affect only the cells in which they are synthesized. More specifically, leukotrienes contract respiratory, vascular, intestinal smooth muscle, modulate control of mucous etc. It is also significant that the formation of the leucotrienes involves glutathione in a cascading sequence of syntheses that produces a series of leucotrienes. Another significant feature may be that aspirin blocks the cyclooxygenase thus inhibiting prostaglandins and thromboxanes.
It is quite likely that those who supplement with NAC have less severe carnitine deficiency since cysteine levels are more likely to be maintained at an adequate level. If these same people also maintain red meat in their diet, this also ensures at least an exogenous source. For now we don't know how effective manoeuvres to replenish diminished carnitine supplies will be. There is still a possibility that the body's use of carnitine is impaired. Supplementation would seem a good idea in any case. Since there may be still a tendency for high cannibalization of protein as a source of energy, diets should not be abnormally high in fat, but instead should ensure adequate protein and carbohydrate contents, perhaps with an emphasis on elevated protein and starch contents. For those not taking NAC nor supplemental carnitine, it would seem best to keep dietary fat somewhat low, while maintaining intake of essential fatty acids. If serum triglycerides are normal, this is a good sign that "futile cycling" is not present.
An additional advantage will be achieved if part of the dietary fat is fat composed of medium-chain length fatty acids, i.e., medium-chain glycerides of which the most common is the product called medium chain triglycerides (MCT). Use of these by the body is possible without the presence of carnitine. Coconut oil/fat is the source of the commercial MCT product. An alternative to using the purified MCT product is to use coconut fat directly. Also, a nectar of coconut fat and pineapple is available and this is useful as a fat source in blender drinks. An added advantage is that coconut fat is not immunosuppressive, in contrast to polyunsaturated fats. A rule of thumb may be to make about 50% of the fat intake from the medium-chain length fatty acid variety.
References
Angelini, C., Vergani, L., Costa, L., Martinuzzi, A., Dunner, E., Marescotti, C., Nosadini, R., "Use of Carnitine in Exercise Physiology", Adv. Clin. Enzymol. 4(1986)103-110.
Ashbrook, D. W., "Carnitine Supplementation in Human Carnitine Deficiency", pp 120-134 in Clinical Aspects of Human Carnitine Deficiency, ed. P. R. Borum, Pergamon Press, 1986.
Braverman, E. R., Pfeiffer, C. C., The Healing Nutrients Within, Keats Publishing, Inc., 1987.
Grunfeld, C., "Metabolic Disturbances, Anorexia, and Wasting in HIV/AIDS", Proc. 1992 Internat. Symp. on Nutrition and HIV/AIDS, including the Nutrition Algorithm and Nutrition Initiative of the Physicians Association for AIDS Care, Nutrition and HIV/AIDS 1(1992)9-15.
Hellerstein, M. K., "Pathophysiology of Lean Body Wasting and Nutrient Unresponsiveness in HIV/AIDS: Therapeutic Implications", Proc. 1992 Internat. Symp. on Nutrition and HIV/AIDS, including the Nutrition Algorithm and Nutrition Initiative of the Physicians Association for AIDS Care, Nutrition and HIV/AIDS 1(1992)17-25.
Hunt, S. M., Groff, J. L., Advanced Nutrition and Human Metabolism, West Publishing Co., 1990.
Lohninger, A., Kaiser, E., Legenstein, E., Staniek, H., "Carnitine, Metabolism and Function", pp 1-25 in Carnitine -It s Role in Lung and Heart Disorders, ed. E. Kaiser, A. Lohninger, Karger, 1987.
Rebouche, C. J., "Carnitine Function and Requirements during the Life Cycle", FASEB J. 6(1992)3379-3386.
Siliprandi, N., Ciman, M., "Carnitine: Transport and Function", Adv. Clin. Enzymol. 4(1986)93-102.
Singer, P., Katz, D. P., Dillon, L., Kirvelä, O., Lazarus, T., Askanazi, J., "Nutritional Aspects of the Acquired Immunodeficiency Syndrome", Amer. J. Gastroent. 87(1992)265-273.
extra:
De Simone, C., Famularo, G., Tsantsoglou, S., Trinchieri, V., Moretti, S., Sorice, F., "Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine", AIDS 8(1994)655-660.
Seminomora, M. C., Leonmonzon, M. E., Dalakas, M. C., "Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. 1. L-carnitine prevents the myotoxicity of AZT in vitro", Lab. Invest. 71(1994)102-112.
De Simone, C., Tzantzoglou, S., Famularo, G., et al "High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients", Immunopharm. Immunotox. 15(1993)1-12.
De Simone, C., et al, "L-carnitine deficiency in AIDS", AIDS 6(1992)203-205.
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