Press Release

Cindy J. Warren, MSN, RN

Prig Cardiovasc Nurs 17(1):35-41, 2002. © 2002 Le Jacq Communications, Inc.

April 26, 2002

Abstract and Introduction

Abstract

Homocysteine is an independent, modifiable risk factor for cardiovascular disease. It is an intermediate amino acid formed during the metabolism of methionine. Plasma homocysteine is normally </=12 µmol/L, but when elevated has many deleterious cardiovascular effects. This review explains homocysteine metabolism, the effects of elevated homocysteine, factors contributing to high homocysteine, and its measurement. Risk factors for elevated homocysteine and intervention with B vitamins are discussed. Cardiovascular nurses are encouraged to facilitate homocysteine awareness through a variety of educational means.

Introduction

In 1969 Dr. Kilmer McCully, a Harvard Medical School graduate, proposed the relationship between homocysteine and coronary artery disease. His work did not gain acceptance until recently.[1] Now, research demonstrates that homocysteine is an independent, modifiable risk factor for cardiovascular disease[2-6] and a strong predictor of mortality in patients with coronary artery disease.[6] Some studies have found hyperhomocysteinemia to be a higher risk factor for coronary artery disease than hypercholesterolemia or smoking[3] and that high homocysteine powerfully increases the risk of vascular disease when combined with smoking and hypertension.[6] Other studies have shown no relationship between plasma homocysteine and serum cholesterol.[3] Even though homocysteine research is still in progress, many researchers agree that there is a clear relationship between high plasma homocysteine and many vascular diseases.[2-6] This review will address the practical aspects of homocysteine screening and education, as well as describe how cardiovascular nurses can collaborate with physicians, fellow registered nurses (RNs), patients, and the community to increase awareness of this modifiable risk factor. The focus is on research findings, assessment criteria, and avenues of dissemination of this information by cardiovascular nurses.

"A 57-year-old man had a family history of premature coronary artery disease (his father died of a myocardial infarction at the age of 46 years), but he had no personal history or clinical symptoms of cardiovascular disease. His weight was normal, and his blood pressure was 124/82 mm Hg. He did not smoke, and he exercised approximately twice a week. In fact, beyond his family history, he had no other known risk factors for coronary artery disease. The patient's fasting plasma lipid levels were as follows: total cholesterol, 236 mg/dL (6.10 µmol/L); low-density lipoprotein (LDL) cholesterol, 133 mg/dL (3.45 µmol/L); high-density lipoprotein cholesterol, 88 mg/dL (2.30 µmol/L); and triglycerides, 74 mg/dL (0.84 µmol/L). The fasting glucose concentration was 90 mg/dL (5.0 µmol/L). Because of the patient's family history, his total plasma homocysteine concentration was checked and was found to be 29 µmol/L (optimal value: <12 µmol/L). The patient was given a multivitamin containing 400 µg of folic acid plus an additional 400 µg of folic acid per day for 2 months. His repeat homocysteine level was less than 2 µmol/L. The patient is currently taking 400 µg of folic acid and the multivitamin each day. Follow-up homocysteine testing is performed every 8 weeks or as often as necessary to ensure that he maintains a homocysteine level in the optimal range, thereby reducing or eliminating this atherosclerotic risk factor."[4] The preceding case study illustrates the process of identification and successful treatment of the homocysteine cardiovascular risk factor.

Research has shown that most patients with myocardial infarction or carotid stenosis have normal cholesterol levels.[2,4,7,8] An autopsy study[2] found that in two thirds of cases of severe arteriosclerosis, the disease developed without evidence of elevated serum cholesterol, diabetes, or hypertension. The presence of high plasma homocysteine levels has recently been accepted as an independent atherogenic and thrombotic factor,[3,4] yet homocysteine testing and education are not routinely being done. Careful assessment of homocysteine risk factors and intervention with effective therapies may help prevent cardiovascular disease.[4,9]

Since cardiovascular nurses are the primary educators for patients, it is increasingly important that nurses' knowledge of health information is current,[10] especially when Internet access provides easily ob-tainable medical information to the public. Patients are well informed and ask important health-related questions. This review proposes that cardiovascular nurses increase their awareness of hyperhomocysteinemia by discussing recent homocysteine re-search findings with physicians and other nurses, professionals in other disciplines, patients, and the general public. In addition, the assessment screening criteria that can be used to help identify those with increased risk of hyperhomocysteinemia will be presented.

Homocysteine Metabolism

Homocysteine is a naturally occurring intermediate amino acid formed during the complex metabolism of the amino acid methionine. Homocysteine can either enter the trans-sulfuration pathway to eventually be excreted as a sulfate in the urine, or it can enter the remethylation pathway whenever there is a relative methionine deficiency.[3] The remethylation ability of homocysteine ensures an adequate supply of methionine for protein synthesis.[3] Under normal conditions, about 50% of homocysteine irreversibly enters the trans-sulfuration pathway.[3] The homocysteine concentration in the blood is an important reflection of the status of intracellular methionine metabolism.[3] The metabolic pathway that homocysteine takes can be influenced by alterations in the concentrations of folic acid, vitamin B6, and vitamin B12, and by activities of the various enzymes that participate in metabolic processes.[3] Research correlations have been made that attribute cardiovascular or peripheral vascular occlusive disease to elevations of plasma homocysteine.[1-7]

Deleterious Effects of High Homocysteine

Homocysteine, in elevated amounts, is toxic to endothelial cells.[2,7,11] The toxicity is associated with hydrogen peroxide formation, in the presence of copper ions.[2,3] Copper concentrations have been reported to be lower in patients with coronary artery disease than in other subjects, although the association of homocysteine with copper remains unclear.[3] In the presence of circulating homocysteine, blood vessels lose their elasticity and ability to dilate,[2,3,10] causing intimal injury.[2] Especially in areas of high pressure and turbulent blood flow, calcium, cholesterol, and collagen adhere to sites of intimal injury to form fibrous atherosclerotic plaques.[2] Reactive oxygen radicals accumulate in the intimal cells, releasing growth factors and promoting hyperplasia of these cells.[2] Fibrin is deposited within and over the surface of the plaques.[2] In animal models, in vitro studies, and human investigations, elevated homocysteine also affects a number of other factors important to the atherosclerotic process. It promotes platelet aggregation,[2,3,12] impairs endogenous tissue-type plasminogen activator activity,[12] increases smooth muscle cell proliferation,[2,3] stimulates the oxidation of LDL,[2] increases the binding of lipoprotein(a) (Lp[a]) to fibrin,[11,12] inhibits natural anticoagulants, such as antithrombin III and factor C,[2,12] and stimulates clotting factors V, X, and XII.[3,11,12] Homocysteine increases the likelihood of atherosclerotic aneurysms, thrombus formation, and the progression of narrowing arteries.[2]

Factors Contributing to High Homocysteine

Homocysteine concentration is influenced by age, gender, and medication and by genetic, nutritional, and pathologic factors.[3,4] Plasma homocysteine increases with age, possibly due to renal impairment.[3] There is a positive correlation between creatinine levels and plasma homocysteine.[3] In general, men have higher levels of homocysteine than women, most likely due to higher creatinine values and greater muscle mass.[3] Women, before menopause, have lower levels of homocysteine than do postmenopausal women.[3]

Use of some medications raises homocysteine levels. Methotrexate, nitrous oxide, phenytoin (Dilantin), and carbamazepine (Tegretol) all increase homocysteine levels.[3,12] Azaribine, which also raises homocysteine, was prohibited by the Food and Drug Administration in 1976 because it was associated with increased risk of thromboembolism.[3] Estrogen-containing oral contraceptives may alter the metabolism of homocysteine. Usually, women taking oral contraceptives have lower homocysteine, but higher levels have been seen in some.[3] The lipid-lowering agents colestipol and niacin, in combination with thiazide diuretics, may raise homocysteine levels.[3,12]

Some rare genetic disorders that include deficiencies of cystathionine b-synthase, methionine synthase, and 5-methyltetrahydrofolate reductase (enzymes necessary for the metabolism of methionine) result in elevated homocysteine.[3,12] In 1962 a group of children in northern Ireland with thromboembolic disease and neurologic, skeletal, and ocular abnormalities were found to have a rare autosomal recessive trait that was characterized by elevated homocysteine levels.[3,11] Men who have high homocysteine and factor V Leiden, an inherited blood clotting disorder, have a much greater risk of developing venous thrombosis than men who have either condition alone.[13] Hormonal abnormalities, such as thyroid deficiency and decreased estrogen levels, can also raise homocysteine. In studies of normal subjects there is a strong genetic influence on plasma homocysteine concentration.[3]

Environmental toxins, such as tobacco smoke and carbon disulfide, can raise homocysteine levels. Carbon disulfide is used in the manufacture of cellophane and pesticides, and as solvent for fats, resins, and rubber.[2]

Nutritional deficiencies of folic acid or vitamin B12 raise homocysteine levels. Deficiency of vitamin B6 may also be associated with high homocysteine, but less commonly than folic acid.[3,4] The more coffee consumed, decaffeinated or regular, and especially unfiltered, the higher the levels of homocysteine.[14,15]

Certain diseases, such as breast, ovarian, and pancreatic cancers, acute lymphoblastic leukemia, and severe psoriasis, are also linked to high homocysteine levels. Chronic renal failure contributes to high homocysteine, which increases when creatinine increases.[3] Both heart and kidney transplant recipients have very high homocysteine levels.[16,17]

The Role of Vitamins

The three vitamins necessary to metabolize homocysteine are folic acid, vitamin B6, and vitamin B12. When homocysteine levels are elevated, a deficiency of folic acid, vitamin B12, and to a lesser extent, vitamin B6 may be indicated.[4] Folic acid can be found in citrus fruits, tomatoes, green leafy vegetables, asparagus, broccoli, yeast, lentils, beans, eggs, beef, organ meats, whole grains, and enriched cereals. Vitamin B6 is found in meat, poultry, fish, legumes, peanuts, walnuts, oats, brown rice, and whole wheat. Vitamin B12 is found only in animal products and supplements. It is abundant in organ and muscle meats, fresh shrimp and oysters, fish, milk, eggs, and cheese.[4] Dietary consumption of these vitamins should be evaluated to ensure adequacy.[4] If a patient does not consume adequate B vitamins or has risk factors that predispose to a high homocysteine level, then supplementation is recommended.[4,12]

On January 1, 1998, the Food and Drug Administration mandated that grains and cereals be fortified with folic acid.[4] At the November, 1998 American Heart Association 71st Scientific Sessions, Jacques Genest, Jr., MD, Cardiovascular Genetics Laboratory, Montreal, Canada, was one of the speakers.[18] He recommended the following regimen to reduce homocysteine levels: rule out secondary causes of high homocysteine and treat with a multivitamin containing 400 µg of folic acid. If, after 4-8 weeks of therapy, plasma homocysteine is still elevated, a daily regimen of 1-2 mg of folic acid, 1 mg of vitamin B12, and 100 mg of vitamin B6 is recommended. If his patients remain unresponsive to this regimen, he increases folic acid to 15 mg daily. Despite his own recommendations for treatment, he said the position of the American Heart Association was to recommend that people eat foods rich in B vitamins and folic acid to lower homocysteine levels, but did not recommend vitamin supplementation for therapy of hyper-homocysteinemia.[18] He named six ongoing studies, scheduled to be completed in 5 years, that will likely provide a consensus on the value of treating elevated total plasma homocysteine. Those studies are: VISP (Vitamin Intervention for Stroke Prevention), NORVIT (NORwegian study of total plasma homocysteine lowering with B-VITamins), SEARCH (Study of the Effect- iveness of Additional Reduction in Cholesterol and Homocysteine), WACS (Women Antioxidant and Cardiovascular disease Study), CHAOS-2 (Cambridge Heart Attack AntiOxidant Study), and PACIFIC (Prevention with A Combined Inhibitor and Folate in Coronary artery disease).[18] No other information is currently available about these studies.

At the University of Wisconsin, Patrick McBride, MD, MPH, and James H. Stein, MD, have created an algorithm for the management of patients with hyperhomocysteinemia.[12] They conservatively recommend measurement of Vitamin B12 levels in all patients with hyperhomocysteinemia (total plasma homocysteine of 14 µmol/L or higher). If the vitamin B12 level is low and treated, that may reverse the homocysteine elevation. After vitamin B12 deficiency has been excluded or treated, and offending medications eliminated if possible, folic acid may be started as primary therapy. They start with a folic acid supplement (400-1000 µg) and a high-potency multivitamin (without iron for men and postmenopausal women) that contains at least 400 µg of folic acid and the US recommended daily allowance of vitamin B6 and vitamin B12. They remeasure the homocysteine level 6-8 weeks after beginning treatment. If the level remains high, they increase the amount of folic acid to 2000 µg per day and repeat the homocysteine measurement in another 6-8 weeks. In patients with end-stage renal disease, or in others with high amounts of folic acid loss, up to 5000 µg per day may be needed. If folic acid supplementation is unsuccessful and the homocysteine level is >/=24 µmol/L, vitamin B6 deficiency should be considered. If high homocysteine levels persist, patient compliance should be evaluated or other possible causes should be considered. They noted that this algorithm may need to be modified when the results of prospective clinical trials become available.[12] No other treatment algorithms were found in the literature.

Some researchers have found that B vitamins, taken as a dietary supplement or consumed in fortified cereals and grains, lower homocysteine levels to the normal range.[4,19] Boushey's meta-analysis of 27 studies[19] states that the largest potential reduction of coronary artery disease mortality occurs with folic acid fortification of grains, rather than supplementation with folic acid. Most studies have shown that high homocysteine levels can be lowered by vitamin B supplementation, especially folic acid,[4,5,12,19-21] but it has not been proved that taking B vitamins decreases the risk of occlusive vascular disease.[4,5,19,20,22] Folic acid supplementation is considered safe.[4,5,12,19-21] Only when folic acid has been given in doses of 10 mg/day or greater have there been reports of exacerbation of vitamin B12 deficiency.[12]

At the Chinese University of Hong Kong, Woo et al. recruited healthy volunteers aged 40-70 who had no history of hypertension, diabetes mellitus, hyperlipidemia, or ischemic heart disease and no family history of premature atherosclerosis.[21] Seventeen of the 89 subjects with fasting total plasma homocysteine levels above the 75th percentile (mean, 9.8±2.8 µmol/L) consented to participate in a double-blind, randomized, crossover study of oral folic acid and placebo. The researchers assessed flow-mediated, endothelium-dependent dilation of the brachial artery using high-resolution ultrasound, before and after folic acid or placebo supplementation. Compared with placebo, folic acid supplementation resulted in higher serum folate levels, lower total plasma homocysteine, and significant improvement in arterial endothelium-dependent dilation. Endothelium-independent responses to nitroglycerin were unchanged. They concluded that folic acid supplementation significantly improves arterial endothelial function in adults with asymptomatic elevations of homocysteine.[21]

How Homocysteine is Measured

Fasting blood tests are usually the manner in which homocysteine is measured.[3] For standard reference purposes, total fasting plasma homocysteine is recommended.[3] A patient who has had a serious illness, such as a myocardial infarction or cerebrovascular accident, should not be tested for 8-12 weeks after the event because there is a potential for the homocysteine level to be abnormal during that time period.[12] The reason for this effect has not been elucidated. Before a blood sample is taken, the patient should be advised to fast for 10-12 hours.[23] Between 0.6 and 1.2 mL of blood is collected in a green-top or purple-top tube for total homocysteine assay. The blood should be centrifuged within 30 minutes[12] to 1 hour[23] of collection, and must be refrigerated[12] or frozen until the time of analysis.[23] Some studies with negative results have been criticized for using plasma samples that were stored in liquid nitrogen for extended periods.[18] Storing blood at room temperature may cause homocysteine levels to be falsely elevated due to the export of homocysteine from red blood cells[2] or hemolysis.[23] If the sample is sent to an outside laboratory for analysis, the serum should be shipped on dry ice, via overnight delivery.[23] The cost of fasting homocysteine analysis ranges from $50-$110. It is advisable to check with individual insurance and managed care companies to ask if they will pay for the screening test.

Similar to a glucose tolerance test for metabolic abnormality, a methionine loading test can be performed to assess methionine metabolism. In some laboratories a granulated form of 100 mg/kg of methionine is dissolved in a glass of fruit juice and given orally after 10 hours of fasting. Blood samples are obtained before and at 4, 8, 12, and 24 hours after loading.[24] In other laboratories, the post-loading sample is taken once at 6 hours and compared to the fasting value.[25] The methionine loading test is more expensive; however, the fasting homocysteine test can be made more sensitive by lowering the normative range criterion.[25] A methionine loading test is used by van der Griend et al.[25] to diagnose hyperhomocysteinemia because a considerable number of people with high homocysteine would remain undiagnosed with the determination of a fasting homocysteine level alone.[25] This test is not conducted on patients whose creatinine levels exceed 1.5 mg/dL, because elevated creatinine levels indicate malfunctioning kidneys that cannot effectively filter protein (in this case, methionine).[17] Comparisons of serum folic acid, vitamins B6 and B12, and creatinine should be measured at the same time as homocysteine.[17]

A total plasma homocysteine level of </=12 µmol/L is considered optimal,[4] but the algorithm used by Drs. McBride and Stein[12] starts secondary prevention at >/=11 µmol/L and considers >/=14 µmol/L to require primary prevention.[12] Those numbers vary somewhat, depending on which study is being followed.[3] A concentration above 15 µmol/L is associated with a high risk of occlusive vascular disease.[4] If the homocysteine level is >/=100 µmol/L, the patient should be referred to a geneticist, especially if several members of the same family have hyperhomocysteinemia.[4]

The Role of Nurses

Cardiovascular nurses, armed with information about homocysteine, are well positioned to discuss hyperhomocysteinemia as an emerging risk factor for coronary artery disease with physicians, nurses, dietitians, patients, and the general public. While doing health assessments, patients can be identified who may be at risk of hyperhomocysteinemia. Assessment of dietary history for the adequacy of B vitamin intake is also important. A health history can help identify patients with diseases or who are taking medications known to elevate homocysteine. There are also other predisposing factors of high homocysteine that need to be recognized. For example, any person who has atherosclerotic vascular disease (ASVD) without conventional risk factors–a mother, father, brother, or sister younger than 60 with ASVD, multiple risk factors for ASVD, chronic renal failure, severe psoriasis, kidney or heart transplant–is at risk of having high homocysteine.[12] In addition, thyroid or estrogen deficiencies, inherited metabolic deficiencies, factor V Leiden, smoking, drinking excessive amounts of coffee,[14] inadequate intake of B vitamins, and epilepsy treated with antiseizure medication, may increase the risk of high homocysteine.[3,12] Once a patient at risk has been identified, referral to his or her physician would be appropriate (Table 2).

Nurses and physicians discuss disease processes and patient outcomes frequently. Physicians may not have the time to discuss homocysteine, or may not test for homocysteine for a variety of reasons, such as cost. A discounted price for laboratory homocysteine testing may be negotiated if large numbers of samples are assayed for homocysteine. It is often less expensive if laboratories can process a large number of samples at once.

Dietitians, as members of the health care team, can also provide information about homocysteine and its relationship to B vitamins. They can individualize dietary counseling and design diets for those at risk of high homocysteine. Dietitians can collaborate with physicians and nurses by assessing dietary habits and making recommendations concerning nutritional approaches to prevent hyperhomocysteinemia. Discharge information can be prepared for patients identified at risk of high homocysteine, with examples of different kinds of foods containing B vitamins, and recommendations about taking B vitamin supplements (except in patients with pernicious anemia). Other important content would include suggestions about how to shop and prepare meals with rich sources of B vitamins.

In their roles as educators, cardiovascular nurses are often speakers at nursing conventions and seminars. In an effort to increase awareness about hyperhomocysteinemia, those who enjoy public speaking could offer to teach about homocysteine to groups of nurses in their own facilities and in other institutions that provide health care. Education about homocysteine can also include other hospital personnel, such as administrators, dietary and office personnel, and housekeeping staff.

Nurses can reach people with homocysteine information by other means, too. They can make posters about the topic to display on a bulletin board near the employee and visitor lunchrooms. Articles about homocysteine can be posted on bulletin boards in employee lounges. Cardiac rehabilitation nurses can also discuss homocysteine and the importance of B vitamins with patients and provide discharge information. Another approach for nurses to increase awareness about hyperhomocysteinemia would be to encourage the nursing education departments in hospitals to include the topic in orientation for new nurses.

Cardiovascular nurses can also be influential in the community. They can write editorials in local newspapers, give speeches at American Association of Retired Persons meetings, be guest speakers at local schools, and teach about homocysteine as parish nurses. Nurses can have a decisive impact on the dissemination of knowledge about homocysteine. They should also watch for the newest research findings as as they are published. Until the current intervention trials have been completed, nurses should encourage everyone to eat foods rich in B vitamins and encourage the use of supplemental B vitamins, especially persons identified as having a greater risk of having high homocysteine. Homocysteine awareness could be facilitated through the efforts of cardiovascular nurses.

Hyperhomocysteinemia is an emerging risk factor for coronary artery disease that can be easily identified with appropriate testing, and treated by dietary modification. Cardiovascular nurses, in partnership with physicians and dietitians, can assess, identify, and provide interventions for patients at risk for hyperhomocysteinemia. As educators, cardiovascular nurses can also increase awareness about hyperhomocysteinemia in their own practice settings as well as the community.

Tables

Table 1. Definitions

Table 2. Factors contributing to elevated homocysteine levels

	Increased age[3,10,12]
	Being male or postmenopausal female[3,10,12]
	Medications: anticonvulsants, lipid-lowering agents in combination with thiazide diuretics, estrogen-containing oral contraceptives, nitrous oxide, methotrexate[3,4,10-12]
	Low estrogen levels[3]
	Tobacco smoke and exposure to carbon disulfide[2,6]
	Nutritional vitamin deficiencies of folic acid, vitamin B6, and vitamin B12[3,4,11,12]
	Excessive coffee consumption[14,15]
	Chronic diseases: severe psoriasis, some cancers, systemic lupus erythematosus, renal failure, hypothyroidism, heart or kidney (recipients) transplantation[3,4,10-12]
	Inherited errors of methionine metabolism: cystathionine b-synthase deficiency, methionine synthase deficiency, 5-methyltetrahydrofolate reductace deficiency[2,3,11,12]

Table 3. Sources of Information About Homocysteine

	For information concerning laboratory tests involving the cystathionine b-synthase pathway or cardiovascular risk factor assessment, direct questions to Dr. Michael Tsai by e-mail: tsaix001@maroon.tc.umn.edu
	There is a web site, The Homocysteine File, that has a bulletin board on which Dr. Glen Tisman answers posted questions: http://www.homocysteine.com/
	The Lipid Nurse Task Force is a newsletter published four times a year. For information email: lntf@tmahq.com.

References

1. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332(5):286-291.

2. McCully K. Chemical pathology of homocysteine. I. Atherogenesis. Anal Clin Lab Sci. 1993;23(6):477-493.

3. Mayer EL, Jacobsen D, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-527.

4. Fallest-Strobl PC, Koch DD, Stein JH, et al. Homocysteine: a new risk factor for atherosclerosis. Am Fam Phys. 1997; 56(6):1607-1612.

5. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268(7):877-882.

6. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease: the European concerted action project. JAMA. 1997;277(22):1775-1781.

7. Stampfer MJ, Malinow MR. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med. 1995;332(5): 328-329.

8. Drown DJ. Homocysteine: an independent risk factor associated with coronary disease and other arterial occlusive diseases in adults. Prog Cardiovasc Nurs. 1995;10(4):37-38.

9. Frishman WH. Biologic markers as predictors of cardiovascular disease. Am J Med. 1998;104(6A):18S-27S.

10. Hughes S, Robinson K. Homocysteine: an emerging risk factor for coronary heart disease. Lipid Nurse Task Force. 1998;4(1):1-2.

11. Hughes S, Berra K. Emerging risk factors for coronary heart disease. Nurse Practitioners' Prescribing Reference: Clinical Management of Dyslipidemia. New York, NY: Philips Healthcare Communications; 1998:65-72.