This week we continue our theme of highlighting this year's award winners. Dr. Peggy Borum, the 2013 Pediatric and Maternal Fetal Medicine Division Award winner and an expert in nutritional sciences, discusses the recent controversy related to carnitine supplementation.
Carnitine was isolated from meat more than a century ago. Since then it has been studied as a nutrient, an endogenously synthesized metabolite, a pharmaceutical agent, an over the counter supplement, a vitamin for the mealworm, and a conditionally essential nutrient for some patient populations.
The good news scientifically is that it has been clearly shown that many carboxylic acids get to where they need to be in the body through the action of a small number of enzymes that esterify the acids to carnitine, transport the ester to either a place where the carboxylic acid is needed or away from a place where it is causing problems, and then release the acid. Since carboxylic acids play such an important role in metabolism, carnitine’s action is critically important in many aspects of metabolism. The good news clinically is that supplementation of carnitine or one of its esters at either nutritional supplementation dosages or at high pharmaceutical dosages have had dramatic positive impacts on symptoms and quality of life for many patients.
The scientific bad news is that we really know very little about all the metabolic functions of carnitine. We know it is synthesized in the body from the essential amino acids lysine and methionine. We know that it is consumed in many diets with the highest sources being animal products. We know that bacteria in the gastrointestinal tract metabolize carnitine in a very different way than we do with the side effect that some people experience a fishy smell of trimethylamine when supplementing with carnitine. As we advance one more step in understanding carnitine metabolism and function in our body or in our gastrointestinal microbiota, this good news can be sometimes misinterpreted or over-interpreted resulting in the clinical bad news that patient care can suffer. An example is flurry of sensational headlines in the public press and social media referring to the recent paper (1) that expanded on the knowledge that dietary betaines are metabolized by some bacteria in the gastrointestinal tract to trimethylamine and then to trimethylamine-N-oxide. It has been known for some time that products of trimethylamine can be toxic especially with chronic exposure. Since choline and carnitine are betaines, foods with higher concentrations will have a greater production of trimethylamine-N-oxide when provided to certain bacteria than when the bacteria are given foods with low concentrations of choline or carnitine. Likewise if choline or carnitine containing foods are provided to bacteria that produce little trimethylamine–N-oxide from choline or carnitine, one will see little production of it. The bad news is that although recent papers have added to our knowledge database about carnitine degradation by bacteria within our gastrointestinal tract, it has resulted in headlines that carnitine-containing foods are bad for you and worried many patients and their families who are benefiting from carnitine supplementation. The concern is to the point that some consider stopping their carnitine treatment.
The real world is that although we need to know more about carnitine metabolism and function, we must utilize the knowledge we do have to supplement carnitine wisely. We in the clinical laboratory have the opportunity and responsibility to facilitate this. Work is ongoing to better understand the microbial ecology in our gastrointestinal tract. The food we eat, the medications that we take, and the environment in which we live helps to create and maintain that microbial community. Our lack of knowledge about it has resulted in us simply not including it in our thought process as we design experiments or therapies for specific patients. We must change this. Characterization of the fecal microbiome in humans is being done every day and soon should be more readily available for clinical purposes of diagnosing patients and monitoring their progress on treatment. When it comes to carnitine, some of us have taken the approach that too little is of great concern, but we do not have to worry about giving too much because it is simply an innocuous compound that will be peed out if more is available than needed. We must change this. To change this we must have a better way to monitor the metabolites in bodily fluids. Acylcarnitine profiling has been used in diagnosing several inborn errors of metabolism, but we have not used targeted metabolomics of the blood or urine with an emphasis on acylcarnitines and bacterial metabolites of carnitine to help us monitor treatment of those patients.
Carnitine is very good for healthy individuals when a healthy diet is consumed (excessive meat consumption brings many more problems that high carnitine intake). Carnitine supplements taken in amounts several fold greater than any human population has ever eaten are likely bad for healthy people (although good for the bank accounts of companies selling them). Carnitine supplementation at nutritional dosages is very good for individuals who simply do not have adequate carnitine for normal metabolism. Pharmaceutical dosages of carnitine are life saving for patients who need carnitine to remove compounds from the body that are at toxic concentrations, but we must not simply give the same dose to all patients and not monitor what is happening inside their body. The clinical laboratory needs to make more readily available the carnitine metabolite concentrations in blood and urine and characterization of the gastrointestinal microbiome for the purpose of monitoring patients receiving carnitine supplementation.