December 7, 2007

Homocysteine Levels and Peripheral Arterial Occlusive Disease: a Prospective Cohort Study and Review of the Literature

By Asfar, S Safar, H A

Aim. The aim of this study was to determine the prevalence of hyperhomocysteinemia in a population with peripheral vascular occlusive disease in Kuwait. Methods. From November 2000 to May 2002, total serum homocysteine levels were measured in 172 consecutive patients admitted to the vascular surgery unit because of peripheral vascular arterial disease. A fluorescence polarization immunoassay was used for measuring total serum homocysteine levels. Serum homocysteine levels over 15 mol/L were considered as high.

Results. The mean ankle-brachial index was 0.59+-0.2 and 0.55+- 0.2 for right and left legs, respectively. The mean serum homocysteine level was 14.9+-4.7 mol/L (range, 4.2-50.0). High homocysteine levels were found in 70 out of 172 patients (40.7%). The prevalence of hyperhomocysteinemia was significant in patients with hypertension (P=0.03) and ischaemic heart disease (P=0.04). Binary logistic regression model showed that male gender, diabetes mellitus and hypertension were significant independent predictors for high levels of homocystinemia in peripheral vascular occlusive disease [adjusted odds ratio (OR) 2.90; 95% confidence interval (CI); 1.18-7.12; P-0.02]; [ 0.35 OR; 95% CI; 0.15-0.79; P=0.01] and [2.12 OR; 95% CI; 0.98-4.59; P=0.05], respectively. Diabetes was significant but appeared to protect for peripheral vascular occlusive disease in patients with high levels of serum homocysteine.

Conclusion. Elevated homocysteinemia was found in 40.7% of patients suffering from peripheral vascular disease. In this cohort, male gender, diabetes and hypertension were found to be risk factors along with elevated homocysteine levels.

KEY WORDS: Homocysteine - Peripheral vascular disease - Atherosclerosis - Diabetes.

Homocysteinemia was first identified in the 1960s:1 in 1969 McCully described a clinical correlation between elevated plasma homocysteine (Hcy) and vascular disease in two children with extensive arterial thrombosis and atherosclerosis, elevated plasma Hey and homocystinuria.2 Hey is either re-methylated to methionine or undergoes transsulfuration to cystathionine; these steps require co-enzymes like folate, vitamin B6 and B12.

Hyperhomocysteinemia is a rare inborn metabolism alteration that results in abnormal increase of Hey in plasma and urine.3 It is caused by defects in genes encoding enzymes involved in Hey metabolism. A common mutation gene, C677T, responsible for the methylenetetrahydrofolate reductase enzyme, is associated with increased plasma Hey levels.4.5 High Hey levels are associated with dietary deficiencies in folic acid, vitamins B6 and B12,4,6,7 tobacco smoking,8 coffee and black tea consumption,9 and in obese patients.10 It is considered a risk factor for coronary artery, cerebrovascular, and peripheral vascular diseases.11 A methionine metabolite, Hey damages endothelial cells owing to its atherogenic and thrombotic properties. Patients with a high Hey level have marked decreased levels of folate and vitamins B6 and B12.

The aim of this study was to determine the prevalence of hyperhomocysteinemia in a population presenting with peripheral arterial occlusive disease (PAOD) in Kuwait and to investigate the association between high serum Hey levels and other risk factors in this patient cohort. Ours is probably the first report from the Middle East to address this correlation.

Table I.-Hyperhomocysteinemia with different risk factors in patients with PAOD.

Materials and methods

The aim of this prospective study was to investigate the correlation between serum Hey levels and other risk factors in patients suffering from peripheral arterial occlusive disease (PAOD).

The study was carried out in the Vascular surgery department of Mubarak Al Kabeer Hospital; the sample was 172 consecutive patients with severe PAOD (i.e. critical limb ischaemia and disabling claudication) admitted to the department from November 2000 to May 2002. Patient demographics, symptoms, and risk factors were recorded. Oral consent was obtained before collecting blood samples. Total serum Hey levels were measured by fluorescence polarization immunoassay at the laboratories of the Department of Surgery, Faculty of Medicine, Kuwait University. The mean Hey level was 7.2 [mu]mol/L (range, 3.6-21.6 [mu]mol/L; central 95% range 4.4-12.4 [mu]mol/L). According to the literature, a range of 5-15 [mu]mol/L is considered normal, thus levels over 15 [mu]mol/L are considered high.12

Statistical analysis

Binary logistic regression was performed using SPSS -10.01 (SPSS Inc., Chicago IL) and ORs were calculated. Pearson chi^sup 2^ and two-tailed t tests were used where appropriate with GraphPad Instat 301 (GraphPad Software, San Diego CA). A P-value of 0.05 or less was considered significant. All means are expressed as standard deviation, medians with lowest and highest values, and effect size with 95% CI. We considered levels over 15 mol/L as high serum Hcy levels.


The patients (76% men) were admitted to the department because of severe PAOD (critical limb ischaemia and disabling claudication), the mean anklebrachial index was 0.59+-0.2 and 0.55+-0.2 for right and left legs, respectively.

The mean age in the younger age group was 56.9+-12.6 years and 59.6+-12.4 years in the older age group (P=0.84), with no statistical significance in HCY levels between the two age groups. The distribution in percent of risk factors for this cohort were: diabetes 74%, hypertension 53%, smoking 60%, stroke 13%, ischaemic heart disease 51%, hyperlipidaemia 27%, and chronic renal failure 7%. The mean serum Hcy level was 14.9+-4.7 mol/L (range, 4.2-50.0). Seventy out of 172 patients (40.7%) presented a high level of Hcy.

Table I shows the association between different risk factors and hyperhomocysteinemia. The prevalence of high Hey (>15 [mu]mol/L) was compared with the presence or absence of different risk factors for PAOD: only hypertension (P=0.03) and ischaemic heart disease (P=0.04) were statistically significant. Although the proportion of men and diabetics was high in this patient cohort, the prevalence of hyperhomocysteinemia in women and non-diabetics was 29.3% and 51.1%, respectively.

Binary logistic regression model showed that significant independent predictors for high levels of homocysteinemia were male gender [2.90 OR; 95% CI; 1.18-7.12; P-0.02]; diabetes mellitus [0.35 OR; 95% CI; 0.15-0.79; P-0.01] and hypertension [2.12 OR; 95% CI; 0.98-4.59; P=0.05L Diabetes was significant but appeared to protect for peripheral vascular occlusive disease in those patients with high levels of Hey (37% of diabetics with high Hey levels us 51% of non-diabetics). There was no statistical difference with the other risk factors, i.e. age, stroke, tobacco smoking, ischaemic heart disease, hyperlipidaemia and renal failure (Table II).


Metabolism of methionine results in the formation of Hey, a thiol- containing amino acid. A demethylated derivative of methionine, Hey is normally either remethylated to methionine or undergoes transsulfuration to cystathionine. Re-methylation requires a methyl group, which is normally transferred from 5-methyltetrahydrofolate. This step is catalyzed by two enzymes, one is pyridoxine (vitamin B^- dependent and the other is cobalamin (vitamin B12)-dependent. Transsulfuration of Hey is catalyzed by another pyridoxine- dependent enzyme called cystathionine ocsynthase (CBS). Deficiency of the latter enzyme is the cause of the most common form of inherited hyperhomocysteinaemia.13-21

Acquired causes of hyperhomocysteinaemia include chronic renal failure, psoriasis, acute lymphoblastic leukaemia and some drugs: methotrexate, nitrous oxide, 6-azauridine triacetate and phenytoin are known to interfere with folate; theophylline and phosphodiasterase inhibitors interfere with vitamin B6); carbamazepine22-24 tamoxifen lowers the level of Hey.25-26 In addition, high levels of Hey have also been found in the following conditions: dietary vitamin deficiencies (folic acid, B6 and B12),4.6.7 tobacco smokers,8 coffee and black tea consumers,9 obese people.10

High Hey levels seem to have a direct toxic effect on the vascular endothelium: they cause proliferation of vascular smooth muscle, activate platelets, promote lipid peroxidation (responsible for the lipid accumulation in atherosclerotic lesions) and activate the coagulation cascade.27-29

TABLE II.-OR associated with various risk factors and hyperhomocysteinemia.

Many studies confirm the association between high levels of plasma Hey and risk factors for atherosclerosis. 30,31 High Hey levels were found to be associated with an increased risk of coronary artery (26%),15. 31-39 cerebrovascular (20%),40-42 peripheral arterial (4 fold),43-50 carotid artery diseases,51 arterial and venous thrombosis (2-3 fold)52-55 and renal failure or endstage renal artery disease.7.55-59 Premenopausal women have a high methionine transamination rate that results in low Hey levels. This may be one of the protective factors against vascular disease in women.60

In this prospective study, 40.7% of the patients presenting with severe PAOD had high plasma Hey levels.

Our results strenghten the findings of the Swiss Heart Study in which 29% of the patients admitted for coronary angioplasty were found to have high Hey levels.47 In addition, we found that ischaemic heart disease (P=0.04) and hypertension (P=0.03) were significant independent predictors for high Hey levels. Ours is probably the first clinical report to investigate the association between Hey and PAOD in the Middle East, where dietary habits and lifestyles differ considerably from Western societies.

Plasma Hey can be reduced by 5-fold with the administration of vitamins.61 The aim of therapy is to reduce Hey levels to less than 10 (imole/L.47 Excess folic acid enhances the re-methylation of Hey to methionine.61 In a randomized study in which healthy children were compared with siblings of patients with premature atherothrombotic disease, Hcy-lowering treatment with folic acid plus vitamin B^sub 6^ was associated with a decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic coronary events.63

Dietary supplementation with vitamin B-complex and fortified foods effectively reduces Hey concentration and may reduce the risk of cardiovascular and end-stage renal diseases.57,64

In a double blind placebo-controlled trial involving 553 patients, Schnyder et al. reported that Hcy-lowering therapy with folic acid and vitamins B12 and B6 significandy decreased the incidence of major adverse events after percutaneous coronary angioplasty. 29

These findings and the results of our study led to the prescription of folic acid and vitamin B complex to all our patients presenting with PAOD. The effect of this policy on the natural history of the disease may be difficult to document, since different factors play a role in the pathogenesis of the atherosclerosis process - i.e. optimum control of diabetes and hyperlipidaemia, cessation of tobacco smoking and lifestyle change.


Elevated hyperhomocysteinemia was found in 40.7% of patients suffering from PAOD. In this crosssectional study, male gender and hypertension were found to be significant risk factors associated with elevated Hey levels in patients with PAOD. While diabetes is also a significant risk factor, it appears to protect against elevated Hey. Treatment with folic acid and vitamin B-complex in patients presenting with PAOD may help in preventing the progression of the disease.


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1 Vascular Surgery Unit

Department of Surgery

Mubarak Al-Kabeer Hospital, Kuwait

2 Department of Surgery

Faculty of Medicine

Kuwait University Health Sciences Centre, Kuwait

Acknowledgments.-The authors wish to thank Dr. Joseph C. Longenecker, Assistant Professor, Department of Community Medicine, Faculty of Medicine, for his help in the final correction of the statistics Mr Ali Hussein Khaja, Department of Surgery Laboratories, Faculty of Medicine, Kuwait University, for his assistance in starting and standardizing the Hey immunoassay in the department.

Address reprint requests to: S. Asfar, Professor and Chairman, Department of Surgery, Faculty of Medicine, Kuwait University, P.O.Box 24923, Safat-13110, Kuwait. E-mail: [email protected]

Copyright Edizioni Minerva Medica Oct 2007

(c) 2007 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.