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Homocysteine & PAD Risk

What is homocysteine?

Homocysteine is a chemical found in the blood that is produced when the amino acid methionine (a building block for proteins) is broken down. High levels are linked to an increased risk of PAD, heart disease, and stroke.

The connection between homocysteine and heart and blood vessel disease was first suspected about 25 years ago. Doctors noticed that people with a rare genetic disease called homocystinuria, which causes very high levels of homocysteine to build up in the blood, often developed heart disease in their teens and twenties. Since then, studies have found that higher-than-normal levels of homocysteine increase the risk of developing heart and blood vessel disease in otherwise healthy people as well.

It is thought that homocysteine damages the linings of the blood vessels and makes the blood more likely to form clots (especially in the arteries).1 In patients with PAD, homocysteine reduces the ability of the blood vessels to expand (dilate) when muscles need more blood, and causes other problems with the artery lining.2 So far, trials have failed to show that lowering homocysteine levels can reduce a person’s risk of developing PAD or PAD complications.3

See also:

Homocysteine & Vein Disease Risk
Homocysteine & Heart Risk

How does homocysteine affect my risk of PAD?

Women with high homocysteine levels are twice as likely to develop PAD than with women with lower levels.4,5 However, it is still not clear if homocysteine is the cause of this increased risk, or if women with high homocysteine are simply more likely to have other conditions and characteristics that put them at risk for PAD.

One in five women with PAD have high homocysteine levels (see What do my homocysteine numbers mean?).6 PAD patients tend to have higher homocysteine levels than people without PAD.7 One study of 631 people (half were women) found that people with homocysteine levels about 50% above average had a 44% higher risk of developing PAD.8

However, homocysteine may be only a sign, rather than a cause, of artery problems. A large study in women found that the link between homocysteine and PAD disappears after other factors are taken into account. The Nurse’s Health Study examined 27,935 healthy women and monitored them for 12 years. Women who developed PAD had slightly higher homocysteine levels than women who stayed PAD-free. However, homocysteine levels were not linked to the risk of developing PAD after other PAD risk factors were taken into account.9 Another analysis that looked at a cross-section of the US population found that the link between homocysteine and PAD was explained by differences in smoking habits, kidney function, and levels of certain metals in the blood.10

In women who have already been diagnosed with PAD, higher homocysteine levels indicate your PAD is more likely to get worse, and to progress more quickly.11 In patients with leg symptoms of PAD, each 1-point rise in homocysteine corresponds to a 6% higher risk of dying from heart and blood vessel disease.12 Again, it is not clear whether homocysteine is a cause of worsening PAD, or simply an indicator of more severe disease.

How is homocysteine measured? Should I be tested?

Homocysteine is measured with a routine blood test. The homocysteine test is not widely available, costs about $100, and is not currently covered by insurance. In rare cases, your healthcare provider may order a methionine-load test, a more precise test that measures homocysteine before and after you swallow 100 mg/kg of methionine (dissolved in orange juice).

Since it has not been proven that lowering homocysteine levels reduces your risk of PAD and other problems, most women do not need to be tested. Your doctor may test your homocysteine level if you have a personal or family history of early heart or blood vessel disease, but you do not have any well-established risk factors (such as smoking, high cholesterol, high blood pressure, lack of exercise, obesity or diabetes).

What do my homocysteine numbers mean?

AHA Fasting Blood Homocysteine Levels13
Normal 5 to 15
Moderately High 16 to 30
Intermediately High 31 to 100
Very High More than 100
Levels are measured in micromoles of homocysteine per liter of blood (µmol/L)

What causes high homocysteine levels?

Homocysteine levels are determined by your diet and genetic makeup. Folic acid and other B vitamins, such as B6 and B12, break down homocysteine in the body. If you do not get enough of these vitamins, your homocysteine levels will go up.5 Click here to learn how to make sure you get enough B vitamins in your diet.

Your age, hormonal status, and other conditions and medications can also affect your homocysteine levels. See What causes high homocysteine levels? to learn more.

Can lowering homocysteine prevent future problems?

Because women with high homocysteine levels are at increased risk for PAD, it was thought that lowering homocysteine might reduce this risk. However, so far trials have failed to show that lowering homocysteine levels with B vitamins can reduce the risk of developing heart and blood vessel disease, including PAD.

Most studies of homocysteine-lowering have looked at heart disease, rather than PAD. One study examined at 5,442 women aged with a history of heart or blood vessel disease or at least three major heart disease risk factors. A B vitamin pill lowered homocysteine by about 20% over 7 years, but did not lower the risk of heart attack, stroke, procedures to treat heart disease, or dying of heart and blood vessel disease.14 No randomized clinical trials (the gold standard way to determine if a treatment is effective) have examined whether lowering homocysteine can reduce the risk of developing PAD.

Despite this lack of success, it is possible that these studies did not lower homocysteine enough, or that the populations studied did not have high enough homocysteine levels to see a benefit. For now, it is not recommended that women take B vitamin supplements to prevent PAD or heart disease by lowering homocysteine.4,15

If you are at high risk for heart and blood vessel disease (calculate your risk here) and have had a homocysteine test that showed very high levels, your doctor may advise you to take B vitamin supplements.

How can I lower my homocysteine levels?

Although it has not been proven that lowering homocysteine levels reduces your risk of PAD and its complications, you are strongly advised to get enough folic acid in your diet, especially if you have risk factors for PAD. This means eating at least five servings of fruits and green, leafy vegetables daily.

Recommended intakes of

homocysteine-related vitamins13

Micronutrient Recommended
Daily Allowance
Good Sources
Vitamin B6 1.3 to 1.7 mg Beef, chicken, milk, tuna, potatoes, corn, bananas, watermelon, avocados, pork, fatty fish, sunflower seeds, soybeans, wheat germ, and fortified cereals
Vitamin B12 2.4 µg Fortified cereals, fish, liver, kidney, salmon, tuna, pork, eggs, beef, cheese, and chicken
Folic acid 400 µg (same for pregnant women*) Citrus fruit, orange juice, beans, liver, green leafy vegetables (such as turnip greens, broccoli, or spinach), peas, chicken giblets, and nuts. Many breads, cereals, flours, pasta, and rice have been fortified with folic acid to add at least 100 micrograms of folic acid to a person’s daily diet
*Folic acid supplements are recommended for women who may become pregnant to prevent neural tube defects (such as spina bifida) in their babies

Hearty-healthy lifestyle choices such as the DASH Diet (Dietary Approaches to Stop Hypertension) and quitting smoking can also help lower homocysteine levels.16 Even if homocysteine is not the culprit, quitting smoking and sticking to a heart-healthy diet are proven ways to lower your risk for PAD.

For more on how to lower your PAD risk, see Preventing PAD: The Basics.


  1. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. Sep 12 2007;298(10):1163-1170.
  2. Stuhlinger MC, Oka RK, Graf EE, et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation. Aug 26 2003;108(8):933-938.
  3. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. N Engl J Med. March 12, 2006 2006:NEJMoa060900.
  4. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic): A Collaborative Report from the American Association for Vascular Surgery/Society for Vascular Surgery,* Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation. March 21, 2006 2006;113(11):e463-465.
  5. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation. Feb 10 1998;97(5):437-443.
  6. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. Dec 8 1993;270(22):2693-2698.
  7. Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg. Sep 2009;38(3):316-322.
  8. Hoogeveen EK, Kostense PJ, Beks PJ, et al. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non- insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol. Jan 1998;18(1):133-138.
  9. Pradhan AD, Shrivastava S, Cook NR, Rifai N, Creager MA, Ridker PM. Symptomatic peripheral arterial disease in women: nontraditional biomarkers of elevated risk. Circulation. Feb 12 2008;117(6):823-831.
  10. Guallar E, Silbergeld EK, Navas-Acien A, et al. Confounding of the relation between homocysteine and peripheral arterial disease by lead, cadmium, and renal function. Am J Epidemiol. Apr 15 2006;163(8):700-708.
  11. Taylor LM, Jr., DeFrang RD, Harris EJ, Jr., Porter JM. The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg. Jan 1991;13(1):128-136.
  12. Taylor LM, Jr., Moneta GL, Sexton GJ, Schuff RA, Porter JM. Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vasc Surg. Jan 1999;29(1):8-19; discussion 19-21.
  13. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. Jan 5-12 1999;99(1):178-182.
  14. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. May 7 2008;299(17):2027-2036.
  15. Blinc A, Poredos P. Pharmacological prevention of atherothrombotic events in patients with peripheral arterial disease. Eur J Clin Invest. Mar 2007;37(3):157-164.
  16. O'Callaghan P, Meleady R, Fitzgerald T, Graham I, European COMAC group. Smoking and plasma homocysteine. Eur Heart J. October 2, 2002 2002;23(20):1580-1586.

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