High homocysteine explained: what it signals and what to do

What homocysteine is

Your body makes homocysteine as a by-product of processing methionine, an amino acid found in protein. Normally it does not accumulate, because enzymes that depend on vitamins B12, B6 and folate convert it into other compounds. MedlinePlus notes that a shortfall in any of these vitamins can cause levels to rise.

That is why homocysteine is often used as a functional marker of B vitamin status: when B12 or folate is low at the tissue level, homocysteine tends to climb.

Where the ranges sit

Many laboratories report a reference range of roughly 5 to 15 micromoles per liter, although the exact range varies by lab and method. The NIH Office of Dietary Supplements notes that a level above 15 µmol/L can suggest B12 deficiency, but that the marker is nonspecific because low folate and reduced kidney function also raise it.

Levels also tend to be higher in men, increase with age, and rise in women after menopause.

Common causes of a raised level

A high result has a fairly predictable list of explanations.

• Low vitamin B12, which is more common with age, with plant-based diets, and with long-term metformin or acid-reducing medicines
• Low folate, from diet or alcohol use
• Low vitamin B6
• Reduced kidney function
• An underactive thyroid
• Smoking and heavy alcohol use
• Certain medicines, such as methotrexate
• Rarely, an inherited condition called homocystinuria

What the evidence shows about heart disease

Studies of large populations link higher homocysteine with heart attack, stroke and cognitive decline. That led to an obvious idea: lower homocysteine with B vitamins and reduce risk. Several large randomized trials tested exactly that. The ODS reports that B12 and folic acid supplements did lower homocysteine, but trials and a Cochrane review found they did not reduce cardiovascular events or deaths.

MedlinePlus reaches the same conclusion, noting that lowering homocysteine usually does not reduce heart attack or stroke risk and that routine screening for everyone is not recommended. The current view is that homocysteine is a marker of risk and of B vitamin status, not a treatment target in its own right.

The MTHFR question

MTHFR is an enzyme involved in processing folate. Common variants in the MTHFR gene are found in a large share of the population and can modestly raise homocysteine, particularly when folate intake is low. When folate intake is adequate, their effect on homocysteine and health is small.

Mainstream guidelines do not recommend routine MTHFR testing for heart disease, fatigue or mood, and having a common variant does not on its own explain symptoms. Special 'methylated' supplements are widely marketed for MTHFR, but evidence that they improve outcomes compared with ordinary folate and B12 is limited.

What to do with a raised result

The useful response is to find the cause.

• Check vitamin B12, and methylmalonic acid if B12 is borderline
• Check folate
• Review kidney function on a metabolic panel
• Check thyroid function
• Review medicines and alcohol intake
• Correct any deficiency that is found, then recheck

Food sources of the vitamins involved

Most people get enough of these vitamins from a varied diet. Folate is found in leafy greens, beans, lentils and fortified grains. Vitamin B12 comes almost entirely from animal foods, including meat, fish, eggs and dairy, and from fortified foods, so people following a vegan diet usually need a reliable supplement. Vitamin B6 is widespread in poultry, fish, potatoes, chickpeas and bananas.

Absorption of B12 falls with age, as stomach acid declines, which is one reason older adults are more likely to be low even with a good diet.

Is the test worth having?

For most people, homocysteine adds little on top of standard heart risk assessment. It can be helpful when a B12 or folate result is borderline and the clinical picture is unclear, when there are neurological symptoms such as numbness or tingling, or in specific situations such as unexplained blood clots or a strong family history of early vascular disease.

If it is ordered, fasting for 8 to 12 hours is often requested. HealifyMD's Comprehensive Lab Panel is $199, and the Methylation Health Panel is $549, with prices confirmed at your eligibility review; a clinician can help you decide whether either test would change your care.