Homocysteine: Rethinking a Predictive Biomarker

In 1968, Dr. Kilmer McCully, a Harvard researcher, reported that a genetic defect that caused sharp elevations in homocysteine led to early, aggressive atherosclerosis and coronary heart disease. This was the first of many studies that pointed to homocysteine as an independent risk factor for heart disease.

Homocysteine and methionine are sulfur-based amino acids that differ by a transferable methyl group. They are abundant in meats, seafood, dairy, and eggs, as well as plant foods such as peas, beans and lentils. Homocysteine is 'remethylated' to methionine with the help of mainly folate and Vitamin B12.


Elevations in circulating homocysteine levels are strongly associated with increased cardiovascular risk in all age and ethnic groups. The homocysteine to methionine ratio, or set point, reflects how available each of these nutrients is to the cells.

In many clinicians' minds, homocysteine is strongly linked with cardiovascular disease. Fewer are aware that this biomarker is predictive of many other things. It reflects the functional status of bone and retinal tissue, as well as the ears. It is also indicative of a host of autoimmune conditions (Hermann et al. Clin Chem Lab Med. 2005; 43(10): 1111-1117). High homocysteine is also associated with refractory migraine headaches (Nelson et al. Arch Pediatr Adolesc Med. 2010; 164(4): 358-362)

Homocysteine measurements, combined with Hemoglobin A1c (HgbA1c), high-sensitivity C-Reactive Protein (hsCRP), and the Lymphocyte Response Assay (LRA) by ELISA/ACT immune tolerance test, become strong predictors of all-cause, 10-year survival and quality of life. Together, they cover 92% of modifiable lifetime health risks.

Debate remains on how to interpret usual homocysteine values. Various labs have different normal and typical values, ranging anywhere from 8-15 μmol/L. Commercial labs base these values on statistics, in some cases derived from fewer than 100 specimens.

It is better to take a 'least risk' approach based on the notion that it is healthier for people to maintain plasma homocysteine levels under 6 μmol/L. Risk increases geometrically as homocysteine levels in the plasma rise.

Elevated homocysteine levels will drop fairly quickly after a few weeks of supplementation with comprehensive Vitamin B complex and mineral cofactors. Further improvement occurs when phase 1, 2, and 3 detoxification supplements are added. Lower homocysteine levels are associated with improved tissue repair competence and reduced inflammation.

Simply put, low homocysteine levels correlate with longer and healthier life, elevated levels are indicators of high risk of debilitating (and expensive) chronic illness.

Four Combined Biomarkers

There are robust data to support homocysteine as a predictive biomarker for all cause 10-year morbidity and mortality across all ethnic groups and geographies. Plasma homocysteine levels under 6 μmol/L predict a 10-year survival rate of around 99%. On the other hand, 10-year survival in people with homocysteine levels greater than 18 μmol/L is around 40%.

Elevated homocysteine irritates the lining of the blood vessels, causing them to become scarred, hardened, furry and narrowed due to lack of repair caused by essential nutrient cofactor deficits.

This loss of homeostatic repair increases resistance to blood flow, thus increasing the work the heart must do. Increased propensity for blood clotting--especially in people consuming too much Omega 6 and not enough Omega-3 fatty acids--further decreases or blocks the flow of blood through blood vessels, resulting in greater risk of strokes and heart attacks.

Be aware, however, that very low homocysteine levels due to deficits in dietary sulfur, are also unhealthy, and may indicate a depletion of dietary sulfur amino acids. Loading these people with high-sulfur foods -- garlic, ginger, onions, brassica (broccoli) sprouts, and eggs (GGOBE for short)--for two weeks before repeating the homocysteine test can distinguish helpful from harmful low levels.

Epigenetic risk and resilience in connection with homocysteine levels is related to methylation capacity—the body's ability to move methyl groups around to make molecules more or less soluble as needed for cell functions and repair.

If one looks more deeply at the biochemical pathways involved, a better test to measure sulfur metabolism and methylation status, it would be the methionine / homocysteine ratio or the S-AdenosylMethionine / S-AdenosylHomocysteine (SAM/SAH) ratio.

However, for usual clinical situations, plasma homocysteine measurement alone is sufficient, cost effective, and actionable.

High-Sensitivity Tests on Horizion

Homocysteine deserves to be a routine measurement in any primary care practice. Until now, however, it has been limited by an important pre-analytic variable: if proper cell preservatives are not used in the testing process, homocysteine may leak out of dead red cells into the plasma, giving a false increase in plasma levels that does not really reflect the patient's actual inflammation status.

Better labs require that specimens be processed within 30 minutes of drawing blood in order to return an accurate assessment of actual plasma levels. In practice, this has limited the utility of the test.

In the near future, look for emergence of high sensitivity homocysteine (hsHCY) tests that use better cell preservatives thus providing a more precise, accurate and predictive homocysteine measurement, with less variance at the important low end of the range.

The hsHCY would then join hsCRP and perhaps hsHbA1c along with LRA immune tolerance tests as the quartet of more predictive biomarkers that can be used initially to measure risk and then later, are to monitor therapeutic responses, and to guide nutritional supplementation strategies.

Homocysteine in Clinical Practice

Available methods, properly used, can still give important information. The first step in getting a handle on homocysteine and the inflammation it reflects, is to simply measure plasma levels. If someone's value is above the goal value of 6 µmol/L, there's an opening for nutrition-based interventions.

The following nutrients, available in a single sublingual lozenge, are extremely helpful:

Vitamin B12: I recommend 2,000 mcg of hydroxocobalamin, a more stable form of B12 that easily converts to methylcobalamin where and as needed, to be used quickly where it is made. Do not use the cyanocobalamin form at these therapeutic levels (Elian KM, Hoffer LJ. Metabolism. 2002; 51(7): 881-886).

Folate: Use 2.5 mg of mixed natural folinate or methylfolate rather than synthetic folic acid, which is not recommended. The folic acid used to fortify our food supply, and the one used in most studies is a fully oxidized, synthetic compound. It costs less and is more stable than the natural eight forms of this nutrient. But it cannot be easily converted or metabolized, and may increase cancer and disease risk. Excess folic acid becomes oxidized and promotes free radical production and genetic oxidative stress.

People who carry the MTHFR genetic variant need more natural folate. We do not recommend the leucovorum factor that was developed to prevent folate deficiency in people receiving 5-FU chemotherapy because it does not inter-convert as do natural folates. Indeed, it was designed to allow chemotherapy to block folate metabolism without creating downstream folate deficiency in recipients of 5-FU.

Vitamin B6: As 10 mg of pharmaceutical grade pyridoxine, which facilitates the transferase reactions needed for production of glutathione among other metabolically important molecules.

Magnesium ascorbate: As 50 mg of a fully buffered, fully reduced, 100% l-ascorbate with a balance of potassium, calcium, magnesium and zinc. Magnesium works with B6 in certain methyl transfer reactions. Ascorbates protect the other nutrients and help reduce oxidative stress as well.

We suggest increasing the intake of garlic, ginger, onions, brassica (broccoli) sprouts, and eggs as dietary staples, assuming immune function tests like LRA confirm a patient to be immune-tolerant and not at risk of inflammation repair deficit from delayed hypersensitivity reactions to antigens in any of these foods.

Russell Jaffe received his MD and PhD from Boston University School of Medicine in 1972. He is a Senior Fellow of Health Studies Collegium (www.HealthStudiesCollegium.org) and founding chairman of the Scientific Committee of the American Holistic Medical Association. Dr. Jaffe developed the lymphocyte response assays (LRA) that enable physicians to rule in/out 491 common allergenic substances based on delayed hypersensitivity by functional LRA by ELISA/ACT. He is also founder of PERQUE, a practitioner-only nutraceuticals company (www.PERQUE.com).