Report of Liver Dysfunction or Damage Associated With Creatine/Whey Protein Ingestion: Potential Relation to the Urea Cycle

This article [Whitt et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18452122)] discusses a case of reversible liver dysfunction/damage associated with creatine intake. I can't get the full text of the article at the moment, but there's also a study showing liver damage in animals on high-dose creatine [Tarnopolsky et al., 2003: (http://ajpregu.physiology.org/cgi/content/full/285/4/R762)(http://www.ncbi.nlm.nih.gov/pubmed/12959920?dopt=Abstract)]. I do think it might be possible for creatine to produce liver dysfunction at excessive dosages, in the long term, but that's just my opinion. The articles on the "alternate urea cycle" that occurs in people with chronic renal failure suggest that creatine or other guanidino compounds that have sometimes been shown to accumulate, at relatively low levels in humans taking 5 grams/d of creatine [Derave et al., 2004: (http://jap.physiology.org/cgi/content/full/97/3/852)(http://www.ncbi.nlm.nih.gov/pubmed/15107411?dopt=Abstract)], could inhibit urea cycle enzymes or interfere with the transport of urea cycle intermediates, etc., and produce liver dysfunction, in my opinion. This doesn't mean that creatine is "toxic" or "bad" but just means that there tends to be a therapeutic dosage range for a physiological substrate, such as creatine, and then a dosage range across which derangements in the transport or utilization of substrates with similar structures may begin to occur. That's just my opinion, but I discussed research, in a past posting, showing that high levels of glutamine, for example, could reduce endothelial nitric oxide production from eNOS, and the effect was thought to be due to the inhibition, by glutamine, of citrulline uptake or reutilization [Kawaguchi et al., 2005, cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/03/inhibition-of-nitric-oxide-dependent.html)]. Citrulline is a urea cycle intermediate, and so it's conceivable, in my opinion, that abnormally-high levels of glutamine or a guanidino compound derived from the transamination of arginine could, in the liver, interfere with the metabolism of citrulline in the urea cycle, etc. Glutamine, citrulline, and creatine are structurally similar, to some extent, and there's a lot of research showing competition for transport among those compounds or competitive inhibitory effects on enzymes, etc. I don't have time to get into the research on guanidinosuccinate, which has been shown to decrease in response to creatine supplementation, or argininic acid and the other guanidino compound that can accumulate during creatine supplementation (Derave et al., 2004, cited above). This could be another reason to consider using the lower end of the dosage range of creatine monohydrate used in clinical trials (~3-10 grams/d), as discussed previously, and to discuss this with one's doctor.