It's the Homocysteine, Stupid!

By Anthony Rosner, PhD, LLD [Hon.], LLC

The celebrated sign that James Carville hung in Bill Clinton's campaign headquarters to keep his campaign workers "on message" back in 1992 was, "It's the economy, stupid!"

A mere 15 years later, I'd like to propose a variant of that celebrated phrase by substituting the word "homocysteine." Make no mistake about it: In the medical literature, homocysteine has appeared in so many places as a bad actor - an evildoer as was so commonly expressed by an American president not too long ago - that you would almost think that homocysteine has wreaked more havoc upon personal health than the 1918 flu pandemic, Hurricane Katrina and the December 2005 tsunami combined.

Atherosclerosis: Let us begin with a biggie - a clearly life-threatening condition.

The newer models of arterial disease center around inflammation as being just as important a determinant as elevated cholesterol and triglyceride levels, if not more so.¹ Plasma homocysteine has been identified as an independent risk factor for cardiovascular disease.^2-4 Numerous mechanisms have been proposed to account for this anomaly, including (a) promotion of endothelial dysfunction of coronary resistance vessels;⁵ (b) increasing oxidative stress, known to promote myocardial dysfunction;⁶ and (c) stimulating left-ventricular remodeling brought on by the increased cardiac fibrosis and activation of matrix metallopriteinases.⁷ Left-ventricular remodeling produced by homocysteine also has been linked to renal failure in humans.⁸

Arterial dissection, ischemia, stroke: The activation of matrix metalloproteinases is but a part of the sordid story of how homocysteine dismembers collagen and elastin, the basic building blocks of arterial walls. Homocysteine also interferes with the aldehyde groups that are indispensable for the cross-linking of the collagen and elastin networks which constitute the arterial wall. With high homocysteine levels having been correlated for years with strokes and arterial dissections, it is easy to imagine how elevated levels of this metabolite may have brought on many of the vertebral arterial dissections that have hounded the chiropractic profession for years. I have previously discussed the background and mechanisms of this chain of events, together with its implications for chiropractic, in some detail.⁹

Cognitive decline: An alarmingly large number of references are suggesting that individuals with high homocysteine levels suffer from impaired cognitive ability, usually demonstrated by significant declines in copying scores.^10-14 Why does this occur? One clue might be offered by a recent observation which demonstrates that each 1 mumuol/L increase of total plasma homocysteine is independently associated with a 7 percent increase of severe leukoaraoisis, otherwise known as white matter disease of the brain.¹⁵ This could be a manifestation of an autoimmune inflammatory reaction with obvious detrimental effects.

Bone resorption: In cultured blood mononuclear cells, one enzyme which quantifies osteoclast activity and another which reflects dentine-resorbing activity can be shown to increase specifically with increasing concentrations of homocysteine. No such increases are seen with the molecular analogues cysteine and glutathione. This experiment is thought to shed light upon how homocysteine might be involved in bone resorption.¹⁶ This observation is only reinforced by the finding that plasma levels of homocysteine are inversely related to bone mineral density in middle-aged and elderly women.¹⁷

Retinal occlusion: In a case-control study, it has been shown that the highest tertile of homocysteine is associated with greater than a twofold elevation of risk for retinal occlusion.¹⁸ To paraphrase a superb phrase put forward by Manny Ramirez¹⁹ of the World Series-victorious Boston Red Sox, when so many indicators are pointing in the same direction to one component that signifies clinical distress and, at times, life-threatening conditions, you know that homocysteine is definitely a bad man.

So, how does one deal with this state of affairs? From the genetic standpoint, the news is not encouraging. When you face the facts that such factors as defects or deficiencies of methylenetetrahydrofolate reductase [MTHFR]²⁰ or cystathione-beta-synthetase [CBS]²¹ lead to elevations of homocysteine levels, you have a formidable challenge indeed. But from the clinical point of view, the paths for escaping this dilemma are remarkably clear and attest to the fact that we must pay far more attention to our nutritional supplements.

For it is well-known that deficiencies of folate,^10,11,22,23 cobalamin [vitamin B₁₂]^22,23 and pyridoxal [vitamin B₆]²⁴ lead to elevations of homocysteine, supported by either multiple well-designed randomized controlled clinical trials, meta-analyses, or multiple well-designed cohort or case-control studies.²⁵ Therefore, it is not too far of a stretch of the mind to figure that taking these compounds as nutritional supplements will, in fact, lower plasma homocysteine levels and reverse the adverse effects described earlier.

This in fact is the case, clearly shown by taking folate in the neighborhood of 0.8 mg/day.^26,27 Vitamin B₆ enters the picture as well in a study which clearly demonstrates the reversal of cognitive decline with dietary intakes exceeding 2-3 mg/day.¹¹ And vitamin B₁₂ gets into the act also to complete the triumvirate of supplements capable of depressing elevated levels of homocysteine. The Homocysteine Lowering Trialists' Collaboration has shown that including vitamin B₁₂ enhances the ability of folate to decrease elevated homocysteine levels.²⁷

How can all this be succinctly summed up? Starting from the premise that a picture is worth 1,000 words, you can simply consult the pathways of homocysteine metabolism, which clearly demonstrate the abilities of folate, vitamin B₁₂ and vitamin B₆ to reduce homocysteine levels by converting this obnoxious amino acid to other products.²⁸ With this discussion, hopefully, it should then become obvious how important nutritional research and a few biochemical principles are to understanding and gaining control of personal health. By connecting the dots, therefore, we need to appreciate how essential approaches such as these are to future endeavors to all health care research, not just chiropractic.

References

1. Libby P. Atherosclerosis: The new view. Scientific American, 2002;286(5):46-55.
2. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Ann Rev Med, 1998;49:39-62.
3. Homocysteine and the risk of ischemic heart disease and stroke: a meta-analysis. JAMA, 2002;288:2015-22.
4. Vasam RS. Beiser A, D'Agostino RB, et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA, 2003;289(10):1251-7.
5. Lentz SR. Homocysteine and vascular dysfunction. Life Sciences, 1997;95:522-8.
6. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest, 1996;98:5-7.
7. Miller A, Mujumdar V, Palmer L, et al. Reversal of endocardial endothelial dysfunction by folic acid in homocysteinemic hypertensive rats. Am J Hypertension, 2002;15:157-63.
8. Blacher J, Demuth K, Guerin AP, et al. Association between plasma homocysteine concentrations and cardiac hypertrophy in end-stage renal disease. J Nephrol, 1999;12(4):248-55.
9. Rosner A. Spontaneous cervical artery dissections: another perspective. JMPT, 2004;27(2):124-32.
10. Arauz A, Hoyos L, Cantu C, et al. Mild hyperhomocysteinemia and low folate concentrations as risk factors for cervical artery dissection. Cerebrovasc Dis, 2007;24:210-4.
11. Tucker KL, Qiao N, Scott T, et al. High homocysteine and low vitamins predict cognitive decline in aging men: The Veterans Affairs Normative Aging Study. Am J Clin Nutr, 2005;82(3): 627-35.
12. Elias MF, Sullivan LM, D'Agostino RB, et al. Homocysteine and cognitive performance in the Framingham Offspring Study: age is important. Am J Epidemiol, 2005;162(7):644-53.
13. Nurk E, Refsum H, Tell GS, et al. Plasma total homocysteine and memory in the elderly: The Hordaland Homocysteine study. Ann Neurol, 2005;58(6):847-57.
14. Clarke R, Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr,2007;86(5):1384-91.
15. Censori B, Partziguian T, Manara O, Poloni M. Plasma homocysteine and severe white matter disease. Neurologic Sci, 2007;28(5):259-63.
16. Herrmann M, Widmann T, Colaianni G, et al. Increased osteoclast activity in the presence of increased homocysteine concentrations. Clin Chem, 2005;51(12):2348-53.
17. Gjesdal CG, Vollset SE, Ueland PM, et al. Plasma homocysteine level and bone mineral density. Arch Intern Med, 2006;166:88-94.
18. Sofi F, Marcucci R. Atherosclerosis 2007; Oct. 16 [Epub ahead of print].
19. Lamothe D. Red Sox monster. Posted Oct. 6, 2007. blog.masslive.redsoxmonster/2007/ manny_doesnt_want_to_be_a_bad.html.
20. Ueland PM, Hustad S, Schneede J, et al. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci, 2001;22:195-201.
21. Guttormsen AB, Ueland PM, Kruger WD, et al. Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathione-beta synthetase deficiency: relationship between genotype and phenotype. Am J Med Genet, 2001;100(3):204-13.
22. Klee GG. Cobalamin and folate evaluation: Measurement of methylmalonic acid and homocysteine vs vitamin B12 and folate. Chin Chem, 2000;46:1277-83.
23. Stabler SP, Marcell PD, Podell ER, et al. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest, 1988;81:466-74.
24. Ubbink JB, van der Merwe A, Delport R, et al. The effect of a subnormal vitamin B6 status on homocysteine metabolism. J Clin Invest, 1996;98(1):177-84.
25. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem, 2004;50(1):3-32.
26. Durga J, van Tits LJH, Schouten EG, et al. Effect of lowering of homocysteine levels on inflammatory markers. Arch Intern Med, 2005;165:1388-94.
27. Homocysteine Lowering Trialists' Collaboration: Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. J Clin Nutr, 2005;82(4):806-12.
28. Please see http://ipi.oregonstate.edu/infocenter/vitamins/fa/ fig02-2.jpg.

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