High homocysteine (hyperhomocysteinemia): causes, levels and what your result means

A high (elevated) homocysteine result is a message about your B vitamins, your kidneys or your medicines, and a few follow-up tests usually say which one within a single blood draw: vitamin B12, methylmalonic acid (MMA, a second B12 marker), folate, and eGFR (a kidney filtration score). Lowering the number itself has not been shown to prevent heart disease ³; finding the cause is what helps. Homocysteine is an amino acid your body makes from methionine in protein. Recycling it needs folate and B12, and clearing it needs B6 and working kidneys, so when any of those falls short it builds up in the blood. Doctors call this hyperhomocysteinemia. For the marker itself, see the homocysteine guide.

What counts as high

Most US labs set the upper limit of total homocysteine at about 15 µmol/L for adults, and the expert consensus led by Helga Refsum grades anything above that in three bands: moderate (15 to 30), intermediate (30 to 100) and severe (above 100) ¹. US reports and SI (international) reports use the same unit, µmol/L, so there is nothing to convert; a report in mg/L converts at 1 µmol/L = 0.135 mg/L. Limits run lower in children and in women before menopause, and pregnancy pushes homocysteine down, so a value of 13 means more in a 30-year-old woman than in a 75-year-old man ¹.

Homocysteine has no standard critical value, so the severe band above 100 µmol/L, which Refsum's group links to inherited homocystinuria and severe B12 deficiency, is the act-now line ¹.

When it is urgent

Is it really high?

Before reading a single high homocysteine as a vitamin or kidney problem, rule out the handling and timing effects that Refsum's expert group lists ¹.

• Unspun sample: red cells keep pushing homocysteine into the plasma, so a tube left at room temperature reads about 10% higher for every hour before it is spun ¹. This is why many labs want the sample on ice or spun within an hour.
• Not fasting: a protein-heavy meal raises homocysteine modestly for several hours; a fasting morning sample is the standard ¹.
• Age and sex: homocysteine climbs with age and runs higher in men; pregnancy lowers it ¹.
• Lab method: different labs measure it different ways and can differ by a few µmol/L, so compare repeats from the same lab ¹.

For a moderate result in someone who feels well, doctors usually repeat it fasting at the same lab with the sample spun promptly, and add B12 and folate. A useful way to put it to your clinician: "My homocysteine was 18. Can we repeat it fasting and add B12, MMA, folate and eGFR to find the cause?"

Causes of high homocysteine

Common

• Low vitamin B12: without B12 the body cannot recycle homocysteine back to methionine. Clues: age over 60, vegan diet, metformin, acid-blocking drugs, tingling, or large red cells (a high MCV). Confirm with vitamin B12 and methylmalonic acid ¹. As our B12 deficiency guide puts it, "nerve damage can start, and become permanent, while the blood count is still normal."
• Low folate: folate supplies a small chemical tag the same recycling step needs. Clues: few greens or legumes, heavy drinking, pregnancy, methotrexate. Confirm with serum folate or red cell folate ¹. See folate deficiency.
• Reduced kidney function: kidneys clear homocysteine, so it rises as filtration falls and is high in most people with advanced kidney disease. Clue: raised creatinine. Confirm with eGFR and creatinine ¹. See chronic kidney disease.
• Diet and habits: a diet low in folate (few greens, legumes or fortified grains), a vegan diet without a B12 source, heavy alcohol, smoking and very high coffee intake each push homocysteine up ¹. See alcohol and blood tests and vegan nutrient deficiencies.

Medicines that raise homocysteine

These drug effects are listed by Refsum's consensus ¹ and, for metformin and acid blockers, the NIH Office of Dietary Supplements ¹⁴. A raised homocysteine is never a reason to stop a prescribed medicine; the useful question for the prescriber is whether a B12 or folate check is due.

Less common

• Underactive thyroid: hypothyroidism slows homocysteine clearance and the level falls when thyroid levels are corrected. Clues: tiredness, weight gain, feeling cold. Confirm with TSH ¹. See hypothyroidism.
• Low vitamin B6: B6 drives the clearance route that turns homocysteine into cysteine, so low B6 mainly raises the level after a protein load. Confirm with vitamin B6 ¹.
• MTHFR C677T, two copies (TT): about 10 to 15% of people in many populations carry two copies, and the enzyme works less well, raising homocysteine mainly when folate is low ¹. Confirm with folate and homocysteine, not a gene test: the American College of Medical Genetics advises against MTHFR genotyping for clot risk or pregnancy loss ⁵.

MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss.American College of Medical Genetics and Genomics, Hickey et al, Genet Med 2013 ⁵

Must not miss

• Classical homocystinuria (cystathionine beta-synthase deficiency): an inherited enzyme defect that pushes homocysteine above 100 µmol/L. Clues: a clot or stroke before 40, a dislocated eye lens, tall thin build, learning difficulty. Confirm with plasma amino acids and genetic testing through a metabolic specialist ¹. Red flag: any clot in a young person with homocysteine over 100 needs same-day care.
• Severe B12 deficiency with nerve involvement, including nitrous oxide misuse: homocysteine often above 30 to 50 µmol/L with numbness, unsteady walking or confusion. Confirm with B12, MMA and a blood count ¹. Red flag: neurological symptoms mean same-day assessment.

High homocysteine symptoms

Homocysteine in the moderate band (15 to 30 µmol/L) causes no symptoms of its own. What people feel with a high result is usually the cause: B12 deficiency, folate deficiency or an underactive thyroid. Only very high levels, mostly above 100 µmol/L in inherited homocystinuria, produce signs from homocysteine itself ¹.

If tingling or tiredness is what sent you for the test, see numbness and tingling in hands and feet, why you are tired all the time and vitamin deficiency symptoms.

Why it matters: heart, brain and pregnancy

Heart and stroke: in pooled observational studies, a 25% lower homocysteine went with about 11% less heart disease and 19% less stroke ². That link is why homocysteine was once tipped as a heart test, but the 2019 ACC/AHA prevention guideline does not list it among its risk enhancers, while apoB, Lp(a) and family history are ¹⁵.

Brain: in the Framingham study, people with homocysteine above 14 µmol/L had nearly double the risk of Alzheimer's disease over about 8 years ⁹. In the VITACOG trial of older people with mild memory problems, B vitamins slowed brain shrinkage on MRI by about 30%, most clearly when homocysteine started above 13 µmol/L ¹⁰; that is a scan result, not proof of less dementia.

Pregnancy and kidneys: high homocysteine is linked with placental problems and pregnancy complications ¹, and folic acid before conception cuts the risk of neural tube defects ⁶, so a high result in pregnancy, or while planning one, goes to the obstetric team (see blood tests for women). In advanced kidney disease, where homocysteine is almost always high, the HOST trial of 2,056 people lowered it with B vitamins but found no fewer deaths ¹¹.

Methylmalonic acid and homocysteine: telling B12 from folate

Homocysteine rises with low B12, low folate and slow kidneys alike, so it cannot name the cause alone. Methylmalonic acid (MMA) is the marker that splits them: MMA needs B12 to be cleared but does not need folate, so a high homocysteine with a high MMA points to B12, and a high homocysteine with a normal MMA and low folate points to folate ¹. Kidney disease raises both, which is why eGFR belongs in the same read.

CalculatoreGFR calculatorTurn your creatinine into an eGFR to see whether slow kidney clearance explains the homocysteine.Work it out

What usually happens next

How to lower homocysteine (and whether it helps)

Folic acid lowers homocysteine reliably, by about 25%, and adding B12 takes off roughly another 7% ⁷. Whether that prevents anything depends on what the high level was signalling. When the B-Vitamin Treatment Trialists pooled 8 randomized trials in 37,485 people, lowering homocysteine by about a quarter for about 5 years had no significant effect on heart attacks, strokes, cancer or death ³. A Cochrane review that took in more trials found the same for heart attacks and death, with a small reduction in stroke (risk ratio 0.90, about a tenth fewer) ¹³.

The China Stroke Primary Prevention Trial result matters because China does not fortify flour with folic acid, so the benefit appeared in people who started with lower folate ⁴. The US began fortifying grain in 1998, and in the Framingham cohort the share of people with homocysteine above 13 µmol/L fell from 18.7% to 9.8% within a few years ¹². Most of the pooled trials ran where folate intake was already adequate, which may explain the null result ³. Methylfolate and folic acid both lower homocysteine; no outcome trial has compared them.

In practice, the fix follows the cause and your doctor sets the dose. In trials, folic acid reached near-maximal lowering at 0.8 mg a day ⁸, and the upper limit for folic acid from supplements and fortified food is 1,000 µg a day for adults ⁶. High-dose B12 by mouth corrects most deficiencies, with injections used when absorption is the problem ¹⁴. B6 helps only if B6 is low, and betaine is reserved for inherited homocystinuria under a specialist ¹. On the food side, leafy greens, legumes and fortified grains supply folate ⁶; eggs, fish, meat and dairy supply B12, and vegans need a fortified food or supplement for it ¹⁴. Cutting heavy drinking and stopping smoking also help ¹.

What the research says about B vitamins and homocysteine

Strongest evidenceFolate and folic acidLowers homocysteine by about a quarter in meta-analyses; B12 status should be checked first, as folic acid can mask B12 deficiency

Strong when B12 is lowVitamin B12Corrects homocysteine when B12 is the cause; adds a little lowering on top of folic acidIn our shop

Mixed evidenceB complexLowers homocysteine, but pooled trials found no fewer heart attacks or deathsIn our shop

A lower homocysteine number does not replace the cardiovascular markers that do guide treatment. If heart risk is the worry, read high apoB and high Lp(a). If you are wondering what else to check, see what blood tests should I get.

Free, no accountRead your blood testRead the rest of your panel alongside this result, including the B12, folate and kidney markers.Read my results

Free, no accountDrop in your lab report and see every marker explained in plain words, placed on the body, against your lab's range. It's read on your device: nothing is uploaded and nothing is kept.

Read my results Download the app