Carnitine Deficiency E-mail
Thursday, 21 January 2010 16:15

Carnitine is a meta-vitamin: ie. a food substance required for life but also made within the human body to a limited extent and therefore not a vitamin. A true vitamin is a substance ESSENTIAL FOR LIFE that must be gotten from food--or by pills or injection thanks to modern science. Because carnitine can be produced within our own body it is not considered medically important except in rare cases of genetic defects, in which babies die because of their inability to perform the synthesis of this substance. In everyday practice, health professionals are unlikely to think of carnitine at all. This is a dangerous oversight because deficiency of this essential molecule can be disastrous. As this case report illustrates, symptoms of weakness, muscle pain and mental impairment are almost certainly commonplace due to the frequency with which all of us face conditions of inadequate diet, illness and chemical or medication exposures. It is only in the past two years that case reports are beginning to appear in line with this prediction, especially in epileptic patients on long-term medication.

Were it not for the fact that about 25 percent of the adult daily requirement for carnitine is normally synthesized in the liver and kidney it would be considered a true vitamin. There is a dietary paradox here: vegetarians depend almost entirely on synthesis of carnitine within their own body chemistry, so it is not a vitamin for vegetarians as it is for meat and dairy eaters, who get over 75 percent of their carnitine from food. For those on an omnivourous diet carnitine is about 75 percent a vitamin, one might say. The paradox is that the vegetarians, for whom it is not a vitamin, have 15 percent lower blood levels.[1] This has not been identified as a carnitine deficiency so far but I am suspicious that there might be a connection to the fact that vegetarians are known to be more vulnerable to adverse effects and nerve damage after toxic chemical exposure. Likewise the fact that Americans are consuming less red meat and dairy products these days has not been associated with reports of carnitine deficiency but one might suspect a connection in some cases of Chronic Fatigue Syndrome[2]., especially if the patient complains of fibromyalgia.

There is reason to suspect carnitine deficiency in those who eat wheat and other gluten containing grains if they have signs of intestinal irritation. Gluten sensitivity interferes with carnitine absorption [3] Deficiency has also been recognized in infants and children because they are unable to make it at birth and are at risk . It has been added to all infant soy formulas since 1985; but before that time there must have been a lot of tired and cranky babies with muscle pain and poor muscle tone. They may have had some risk of delayed brain development and lowered intelligence as well. If this is so we can expect improvement in school achievement tests starting within the next few years.

Lately athletes and others interested in peak performance have discovered carnitine, for it is an enhancer of endurance and speed.[4] Its effects are most likely to be recognized in long distance runners who use up more raw materials but weight lifters and body builders are among the most avid customers. Advertisements for carnitine appear in popular body building magazines, where it is a familiar name at the same time it is almost unknown in the medical journals!

Carnitine was isolated from meat in 1905 and its chemical structure identified in 1927; however it was not until the work of Irwin Fritz in 1952 that the function of carnitine was determined to be related to the oxidation of long chain fatty acids. Carnitine is itself water soluble but it acts as a carrier for fatty acids to gain entrance into the mitochondria, an assembly of membranes carrying enzymes that oxidize the fatty acids. In the absence of carnitine, fatty acids are stuck in the cytoplasm of cells, thus not available for energy production and resulting in a syndrome of fatigue and fat deposition, particularly in the liver, heart, muscle and kidneys. Way back in 1952 researchers discovered that carnitine is a vitamin or "growth factor" for the mealworm, Tenebrio molitor. Deficiency of carnitine caused the larvae to die. Since they were lacking a nutrient this was death by starvation, but the worms died fat!

I was impressed 20 years ago by the amazing protection carnitine provided against heart damage. Dogs that otherwise died within a few minutes lived up to an hour after surgical closure of the coronary artery, if they were given carnitine in advance. Carnitine wasn't available commercially in 1980 at the time of publication of my book, MegaNutrition, or I would have written about this. Because it is expensive, about 30 dollars per month for a therapeutic dose, I have reserved it for cases where the results could be easily measured, eg. in lowering triglyceride levels. A dose of a 2400 mg. per day lowers triglyceride by about 30 percent and also raises HDL about a third, thus improving these well known cardiovascular risk predictors.[5]

That's about as far as I went into the use of carnitine until recently. It took a dramatic case example to open my eyes to new possibilities. Mary G. is a 57 year old woman who has been afflicted with chronic and recurrent spells of insomnia and mania for almost 40 years. Unfortunately her illness had proved unusually drug resistant and no treatment controlled her manic attacks: not lithium, haloperidol, clonazepam or megavitamin nor injectable doses of vitamins C, B6 and B3 and many others. She averaged over 3 manic attacks a year and was hospitalized over 130 times over the years.

In 1992 however she had experienced a therapeutic breakthrough in response to a new combination of medications, valproic acid 500 mg and lithium 800 mg daily. These worked for her better than anything ever had before. Her sleep and mood improved to the point that she could cope with the occasional spells of hyperactivity and loudness by taking Ativan and a rest period or nap. Before long she became confident enough to travel extensively and did so without incident, ie. without getting arrested due to mania. She also moved into a residential hotel where she got along well with everyone for three months.

Then one day in December she appeared confused as she appeared for lunch in her bathing suit. An ambulance was called and she was hospitalized. The hospital physician doubled her dose of valproic acid to 1000 mg a day and discharged her in three days. Two weeks later she began to feel weak and she lost control of her legs, falling down several times. She staggered so badly that she looked drunk and her speech was slurred. Her friends knew she had NOT been drinking alcohol and they were puzzled and frightened by her condition. They literally had to carry her into my office and I noticed her feet dragging helplessly as she tried to hold her weight. When she was seated, her head listed to the side with her chin on her shoulder. She rambled a bit, no worse than usual for her--but she was oriented and lucid. She was not depressed or manic; in fact she was in rather good humor considering the extreme disability that had overtaken her. Her grip was too weak even to register on a hand grip dynamometer but she did not complain of difficulty breathing and her heart rate, 80 beats per minute, was not unusual. However, she did cough and I thought she had rales, crackling sounds from small amounts of fluid accumulation at the base of her lungs If so it could have been due to weakness of the heart muscle, an early sign of heart failure.

It came down to a single symptom: myasthenia, acute muscle weakness. It was not relapse of mania and it was not due to alcohol excess. She had been on an increased dose of valproic acid but not an overdose. I was sure she did not have myasthenia gravis, because that is a chronic disease and it would have surfaced before now. I had heard of carnitine depletion in a case report of an epileptic child treated with valproic acid[6] so why not expect it in an adult? This seemed plausible because of the increased dose of valproic acid for the preceding 3 weeks, during which time she had poor appetite and ate no meat or dairy products, ie. a low carnitine diet. In addition after she began coughing she treated herself with aspirin twice a day for about a week, during which time she got weaker. Aspirin liberates valproic acid from serum albumin, thus increasing free valproic acid, which binds to carnitine. Also aspirin, otherwise known as acetyl-salicylic acid, may bind to carnitine via the acetyl group, thus directly depleting carnitine a step further.

I took blood and urine samples for testing of total carnitine and acyl-carnitine levels as measured by bio-assay, using a carnitine-dependent yeast culture.[7] The results were far below normal: the plasma free carnitine was 1.6, the fat-linked acyl carnitine 0.3 and the total plasma carnitine was 1.9 mcg per ml. This is about half the normal minimum (3.5) and less than 15 percent of the high normal (13.4 mcg per ml). Urine carnitine was even more depleted, registering only 4.9 mcg per ml of urine (4.9 mg per liter). This was a random sample but her daily urine output is known to be between 1 and 2 liters. Assuming a 2 liter output this would amount to 9.8 mg of total carnitine, which is less than half the normal reference level of 25 mg at the Vitamin Diagnostics Laboratory.

She recovered her muscle strength after taking 1000 mg of carnitine, twice in the next 10 hours. In fact she felt so well she did not return for her appointment next morning! I advised her to maintain that dose twice a day for a week and then lower the dose to 500 mg.

Three weeks later She had a normal blood level of 12 mcg per ml despite continued treatment with valproic acid and Ativan but no aspirin. A gram a day of carnitine is evidently sufficient for her.

She did not have any other abnormal laboratory findings that could offer an alternative diagnosis. Case reports of carnitine deficiency have described low blood sugar, a condition that can cause irritability and mental confusion. In retrospect it seems plausible that this was the cause of symptoms leading to her hospitalization a few weeks before. However the blood sugar reading at the hospital was normal and the blood test of valproic acid at the time was actually 50 percent below the therapeutic range, which is why the doctor raised the dose. This must have caused the depletion in her carnitine and the eventual onset of muscle weakness even though the level of valproic acid in her blood was not above the accepted therapeutic range on the day she was carried into my office. Her blood sugar was not low at that time either, but it was already mid-afternoon and one must keep in mind that by the time the sample is taken, the blood sugar may have self-corrected by means of adrenal hormones or by eating food

The first cases of carnitine deficiency were seen in patients on long-term intravenous feedings in the 1970s, a time before the solutions contained carnitine. Over two dozen cases were reported and this spawned interest in the possibility that a low carnitine diet, ie. a vegetarian diet, might cause deficiency. However no such case has yet been reported. Deficiency symptoms have been observed in patients with liver disease, which decreases synthesis, as well as in patients on kidney dialysis or suffering from chronic renal disease, which both increases excretion and curtails synthesis of carnitine by the kidney.

Other drugs and chemicals can bind to carnitine, just as valproic acid does, tying up the vitamin and increasing its excretion. The list of known trouble-makers is still very incomplete but includes cancer chemotherapy drugs, many tranquilizers, especially Valium derivatives, and some antibiotics. Any molecule that contains a benzene ring is likely to bind to carnitine.[8]

Vitamin B12 deficiency causes methyl malonic acid excretion, which binds to carnitine and carries it out via the urine. Biotin deficiency has a similar outcome by provoking the excretion of isovaleric acid. I think it is very likely that thyroid supplements can aggravate carnitine deficiency by increasing the oxidation of fat, thus using up more carnitine. This would explalin why some patients get weaker and more tired when taking thyroid supplements. Physical exercise increases carnitine utilization and can deplete reserves. Does it also increase carnitine synthesis? Presumably so as long as the dietary precursors are sufficient. Carnitine synthesis depends on amino acids lysine and methionine as well as vitamins C, B12, folic acid and B6.

Carnitine deficiency is particularly dangerous in infancy because it takes several months after birth before the baby is able to synthesize the vitamin. Breast milk contains adequate carnitine; but until now the infant feeding formulas have been devoid of it. This can be particularly dangerous in babies that are medicated with valproic acid and also certain antibiotics.

Was valproate involved in the deficiency status of my patient? I think so and this is the first report ever of confirmed valproate induced carnitine deficiency in an adult. Evidently valproate binds to carnitine; however urinary excretion is not increased. The current view is that valproate interferes with the normal production of carnitine, perhaps by inhibiting methylation of lysine, from which carnitine is derived.

The important implication of this case report is that carnitine deficiency does occur in adults and must be considered in all sick patients, especially those exposed to anticonvulsants, tranquilizers and in cancer chemotherapy, since all of these drugs can link up with carnitine and carry it out of the body. This is especially significant in patients with coronary artery disease. The presence of angina pectoris or electrocardiograph evidence of ischemia, especially PVC (premature ventricular contractions) is a strong indication for carnitine supplementation.[9] Carnitine supplements have been demonstrated to prevent ventricular fibrillation in early cardiac ischemia, such as occurs due to coronary atherosclerosis or blockage[10]. Another exciting application is in the treatment of senile brain disease. Acetyl-carnitine in particular has produced improvement of mental acuity in some of these Alzheimer's patients.[11]

A recent essay in Lancet[12] concluded that the results of medical treatment are unpredictable and beyond our control and that "the practice of medicine will remain fundamentally stochastic, as it always was." In plainer English the word, stochastic, means "a guess." It may be true that much of medicine has been and continues to be highly educated guess-work. However the authors of this featured essay in a major medical journal did not include any mention of nutrition. And nutrient deficiency disorder is not guess-work because nutrient deficiency produces specific syndromes, which can be precisely diagnosed by specific and exact laboratory measurement from which diagnosis and prognosis can be predicted with more authority than in any other field of medicine. We just have to be ready for them when the time comes. Keep that in mind next time you hear anyone liken vitamins to quackery or labels nutrition medicine as an "alternative."

©2010, Richard A. Kunin, M.D.

[1] Lombard KA, Olson AL et al: Carnitine status of lactoovovegetarians and strict vegetarian adults and children. Am J Clin Nutr 1989; 50:301-6.

[2] Grau JM, Casademont J, et al: Chronic fatigue syndrome: studies on skeletal muscle. Clin Neuropath 1992; 11(6): 329-32

[3] Ceccarelli M, Cortigiani L, et al: Plasma L-carnitine levels in children with celiac disease. Minerva Pediatrica 1992; 44(9):401-5.

[4] Vecchiet L, Di Lisa F, et al: Aerobic processes enhanced by L-Carnitine. Eur J Appl Physiol 1990; 611:486-490.

[5] Maebashi M: Lipid lowering effect of carnitine in patients with type IV hyperlipoproteinemia. Lancet, 1978; xxxi: 805.

[6] Murakami K, Sugimoto T et al: Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy. Brain & Development, 1992; 14 (3) 178-182.

[7] Baker H, DeAngelis B, et al: Routine microbiological assay for carnitine activity in biological fluids and tissues. Food Chemistry 43 (1992) 141-146.

[8] Quistad GB, Staiger LE and Schooley DA: The role of carnitine in the conjugation of acidic xenobiotics. Drug Metabolism and Disposition. (1986) 14 (5) 521-524.

[9] Pepine CJ. The therapeutic potential of carnitine in cardiovascular disorders. Clin Ther 1991; 13:2-21.

[10] Opie LH: Role of carnitine in fatty acid metabolism of normal and ischemic myocardium. Am. Heart J. 1977; 3:375. 1977.

[11] Spagnoli A: Acetyl L-carnitine impvoes attention and memory in Alzheimer's disease. Neurology 1991; 41:1726-1732.

[12] Ierodiakonou K, Vandenbroucke JP: Medicine as a stochastic art. Lancet 1993; 341, 542-543.