Homocysteine above or below the reference range

Elevated homocysteine in the analysis form is often alarming because of its reputation as a "heart attack marker." In fact, most often it has a completely understandable and correctable cause - a lack of folate or vitamin B12. But there are other explanations that cannot be overlooked. The editors systematized the causes of deviations in people who train and explained how to act rationally, without panic and without uncontrolled "vitamin cocktails".

When the result is considered a deviation

Reference limits of homocysteine depend on the laboratory, age and gender. According to the expert statement of Refsum et al., in fasting adults, typical values ​​are approximately 5–15 μmol/L, and above 15 μmol/L usually indicate varying degrees of hyperhomocysteinemia. Some laboratories use lower upper limits.

Before looking for the cause, it is important to make sure that the result is correct. Homocysteine ​​is one of the tests most sensitive to sample processing: if the blood has been standing for a long time at room temperature before centrifugation, the indicator artificially increases. Eating protein food before the test or intense training the day before can also have an effect.

Therefore, with a moderate increase without obvious reasons, it is advisable to repeat the analysis, following the rules: in the morning on an empty stomach, without heavy training for a day or two, in a laboratory that processes samples correctly. If the result is confirmed, the search for the cause begins.

The degree of deviation indicates the direction of the search. A moderate increase is most often associated with nutrition, vitamin status, lifestyle and kidney function. Very high values, especially in young people, make the doctor think about hereditary metabolic disorders or severe B12 deficiency.

The main causes of elevated homocysteine

The reasons for the increase can be conveniently divided into several groups. There are often several of them at the same time, and each adds its own contribution.

B12 deficiency deserves special attention. It develops slowly, can be manifested by fatigue, anemia, numbness in the limbs, memory impairment, and in advanced cases - irreversible neurological disorders. Risk groups are vegans without supplements, people with atrophic gastritis, after gastric surgery and those who take metformin or PPIs for a long time.

Folate deficiency is more often associated with nutrition: not enough leafy greens, legumes, vegetables, as well as excessive alcohol consumption. In countries without mandatory enrichment of flour with folic acid, it occurs more often.

The MTHFR C677T variant is often overestimated. It is common, and in homozygous carriers homocysteine ​​is higher mainly with low folate status. The fact of carrier itself is not a disease, and genetic testing without clinical indications does little to change tactics: the main thing is adequate intake of folate.

Special situations in athletes

Sports nutrition often has specific distortions. A diet built around meat, eggs, milk protein, and simple carbohydrates with a minimum of vegetables is high in methionine but low in folate. This is a classic prerequisite for elevated homocysteine.

The opposite situation is plant-based nutrition without B12 supplements. The popularity of veganism among endurance athletes makes B12 deficiency a real problem. In such cases, homocysteine ​​often increases earlier than changes in the complete blood count appear.

Training factors also matter. After prolonged or very intense loads, homocysteine ​​may temporarily increase, so the analysis taken the next morning after the competition may be overestimated. The review by Joubert and Manore emphasizes that the effects of physical activity are mixed and highly dependent on nutrition.

We will separately mention hormonal drugs and stimulants. Data on the effect of anabolic steroids on homocysteine ​​are limited and contradictory, so the editors cannot draw conclusions about a direct connection. At the same time, in people using such drugs, cardiovascular risk increases through other mechanisms—lipids, pressure, hematocrit—and elevated homocysteine ​​in this context must be evaluated as part of the overall picture.

Finally, large amounts of coffee and energy drinks common among athletes may modestly increase homocysteine. Smoking and alcohol increase the effect.

Low homocysteine: Is it a problem?

Low homocysteine values are usually of no clinical significance and most often reflect good vitamin status. They are especially common in people who regularly take multivitamins or B vitamin complexes.

In women, the level is lower on average, and during pregnancy it further decreases. Lower values ​​can also be observed with hyperthyroidism, as well as with very low protein intake, when the supply of methionine is limited.

Very low homocysteine ​​is sometimes discussed as a possible sign of insufficient intake of sulfur-containing amino acids or impaired methionine metabolism, but there is no convincing evidence of the clinical significance of such conditions in healthy people. No "vitamin" or other action is needed just because of the low number.

A practical nuance: if a person takes high doses of folic acid, low homocysteine ​​does not guarantee that everything is fine with B12. Excess folate may mask hematologic signs of B12 deficiency while neurologic damage continues to develop. Therefore, with relevant symptoms, B12 should be tested separately.

What to do: examination and correction plan

The rational approach to elevated homocysteine is not to "reduce the number at any cost", but to find and eliminate the cause. The editors suggest the following sequence of actions, which should be discussed with the doctor:

1. Repeat the test under standardized conditions to exclude a preanalytical error.
2. Check B12 and folate; for "borderline" B12, the doctor can prescribe methylmalonic acid or holotranscobalamin.
3. Assess kidney function (creatinine, GFR) and thyroid gland (TSH).
4. Review medicines, diet, coffee and alcohol intake, and smoking.
5. For a confirmed deficiency — correction of nutrition and/or supplements in doses determined by the doctor; follow-up analysis after a few months.

Regarding nutrition, the editors advise first of all to increase the diet of leafy greens, legumes, vegetables, citrus fruits (sources of folate), and for a plant-based diet, to ensure a reliable source of B12 (fortified foods or supplements). For people without medical contraindications, standard doses of B vitamin complexes are generally safe, but it is better to select them after examination.

It is important to keep realistic expectations. B vitamins reliably lower homocysteine, but large randomized trials, including HOPE-2, and a Cochrane review have shown that it does not reduce the risk of heart attack. Correction is needed primarily to eliminate the deficiency itself and its consequences — anemia, neurological disorders, and not as a "shield" against atherosclerosis.

Editorial conclusions

Elevated homocysteine in athletes is most often associated with insufficient folate or B12, diet and lifestyle features; kidney, thyroid, and medications are must-check points.

Correct pre-analysis is critical: incorrect sample processing or post-competition analysis can easily give a false positive.

Low homocysteine ​​usually does not require action. If it is elevated, treat the cause, not the number, remembering that vitamins do not replace the control of the main cardiovascular risk factors.

We also advise you to read the editorial materials about what the homocysteine ​​analysis shows, about lipoprotein(a) above or below the norm, and about urea in athletes.

References

1. 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.
2. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999;19:217–246.
3. Joubert LM, Manore MM. Exercise, nutrition, and homocysteine. Int J Sport Nutr Exerc Metab. 2006;16(4):341–361.
4. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354(15):1567–1577.
5. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8:CD006612.
6. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–113.
7. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015–2022.