Sometimes we see highly unusual laboratory results that cause us to rethink our recommendations for nutritional interventions. The use of individualized amino acid formulas based on levels of plasma amino acids enjoys the support of two publications showing clinical efficacy. Single therapy with such free-form amino acids has been shown to produce reductions in symptoms of chronic fatigue[1], and a later report showed similar intervention produced significant symptom reduction in patients with major depression.[2] However, we would like further validation for cases of extremely low amino acid levels where unusually high amino acid levels are calculated for the individualized formula. For example, recently a case was found where the plasma histidine (His) level was very low, resulting in a calculated addition of 89 g to the monthly amino acid supplement formula, resulting in 2.9 g of supplemental His per day. Is this too much histidine for such a case?

One justification for the current formulation algorithms is the absence of any negative feedback about adverse symptoms produced, even when the amino acid powder has an unusually high amount of any one amino acid. Many thousands of amino acid profiles have been reported since the 2007 introduction of the current formulas where the amounts of each amino acid added is calculated with an exponential function that results in only small additions for results slightly below the mean, but steeply increasing amounts for very low levels. The parameters for those formulas were carefully adjusted to produce levels that closely approximated those from the previous ones over a broad range of levels. The original formulas were developed in 1995, and small adjustments were made in 1999.

Early in 2010 limits were added to the amount for arginine that would be recommended. This was done because of the evidence that members of the Calorie Restriction Society of America who maintain diets and lifestyles that produce very high states of wellness verified by extensive laboratory testing and clinical evaluations have very low plasma arginine levels[3]. We established the high limit for routine arginine supplementation to keep from over-recommending arginine based solely on finding very low plasma levels. There are ongoing discussions about how to establish optimum plasma arginine ranges and about interpreting levels of plasma arginine because of these unique observations in very healthy people.

In the case previously mentioned plasma histidine (His) level was very low (10 mcg/L; 1st decile limit: 31) lysine and phenylalanine were near their low limits (1st decile) and the other EAA were in mid-to-upper deciles (Figure 1). We don’t know much about the causes of such a pattern, but it may be that the patient has chronic histamine-mediated allergic reactions. At any rate, something appears to be causing abnormal utilization or a loss of specifically His that is essential for protein synthesis. That means that all tissue maintenance and repair functions will be impaired by lack of available His. Such an effect has been reported for several conditions where demand for amino acids is particularly high, producing depleted levels of histidine-rich glycoprotein (HRG).[4] HRG, an adaptor protein that modulates immune, vascular and coagulation systems, has unique structural and biological properties.[5] It’s unique acute phase inflammation negative response could be due to its concentrations being closely tied to circulating His levels.

Thus, it can be argued that the laboratory data give evidence that this patient may benefit from a course of aggressive His supplementation as shown in Figure 2. The RDI for His is about 1 gm. and the formula would deliver a total of 2.9 gm of His per day. Any time a single free-form amino acid is used at more than RDA levels, it is prudent to do a follow up test in 90 days to assess the need for such further use of the formula with high His content. An algorithm might be implemented to insert such a statement when added amounts are greater than a specified limit.

There is a paucity of information about high-dose specific amino acid therapies based on results of amino acid testing. We would be interested in hearing from anyone who has had experience in management of patients with such therapies. ~Richard S. Lord, Ph.D.

 References

1. Bralley, J. and R. Lord, Treatment of chronic fatigue syndrome with specific amino acid supplementation. J App Nutr, 1994. 46(3): p. 74-8.
2. Ille, R., et al., "Add-On"-therapy with an individualized preparation consisting of free amino acids for patients with a major depression. Eur Arch Psychiatry Clin Neurosci, 2007. 257(4): p. 222-9.
3. Lord, R. and A. Bralley, Nutritional and metaboli marker levels in humans using balanced caloric restriction for life extension. 1999: Duluth, GA. p. 15.
4. Morgan, W.T., Serum histidine-rich glycoprotein levels are decreased in acquired immune deficiency syndrome and by steroid therapy. Biochem Med Metab Biol, 1986. 36(2): p. 210-3.
5. Jones, A.L., M.D. Hulett, and C.R. Parish, Histidine-rich glycoprotein: A novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Immunol Cell Biol, 2005. 83(2): p. 106-18.