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Jornal Vascular Brasileiro

Print version ISSN 1677-5449

J. vasc. bras. vol.8 no.4 Porto Alegre Dec. 2009 



Level of homocysteine in patients with peripheral arterial disease treated at a public health care facility



Luciene de Souza VenâncioI; Roberto Carlos BuriniII; Winston Bonetti YoshidaIII

INutricionista. Doutora, Bases Gerais da Cirurgia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), Botucatu, SP. Coordenadora, Curso de Graduação em Nutrição, Universidade Metodista de Piracicaba, Lins, SP
IIProfessor titular, Departamento de Saúde Pública. Coordenador, Centro de Metabolismo em Exercício e Nutrição, Faculdade de Medicina de Botucatu, UNESP, Botucatu, SP
IIIProfessor adjunto, Departamento de Cirurgia e Ortopedia, Faculdade de Medicina de Botucatu, UNESP, Botucatu, SP





Background: Recent studies have suggested that high level of homocysteine is an important and prevalent risk factor for coronary, cerebral and peripheral arterial disease.

Objective: In light of the lack of information on hyperhomocysteinemia in peripheral arterial disease (PAD) in Brazil and the peculiarities of its population, the objective of the present study was to evaluate the frequency of hyperhomocysteinemia in a sample of the Brazilian population by means of a clinical trial involving individuals with and without PAD being treated at a public health care facility.

Methods: A case-controlled clinical trial was conducted with 40 individuals with a PAD diagnosis confirmed by Doppler ultrasound (PAD group) compared with 20 volunteer individuals without PAD (control group).

Results: The predominant PAD was chronic limb ischemia (75%). Median fasting plasma levels of homocysteine were significantly higher in the PAD group than in the control group (16.7 vs. 12.9 μmol/L, p = 0.001), both in men (18.9 vs. 14.0 μmol/L, p = 0.005) and women (13.9 vs. 11.2 μmol/L, p = 0.025). As to the proportion of individuals with hyperhomocysteinemia, a tendency toward a higher frequency was observed in the PAD group (60%) in relation to the control group (30%) (p = 0.054). Individuals aged less than 60 years had significantly high median values of homocysteine in the PAD group (p = 0.041).

Conclusions: Hyperhomocysteinemia was a prevalent and important risk factor in individuals with PAD treated at a public health care facility in Brazil.

Keywords: Homocysteine, hyperhomocysteinemia, peripheral vascular diseases.




Risk factors for developing atherosclerotic disease are well known, including age, being male, dyslipidemia, smoking, hypertension, diabetes mellitus, obesity, sedentary lifestyle, and genetic factors or family history of atherosclerotic disease.1 Recently, other risk factors have been identified, such as homocysteine. Studying it might widen what we know about the pathophysiologic mechanisms of atherosclerosis and enable the development of new preventive or therapeutic measures.

Homocysteine is a sulphur amino acid, synthesized in physiological conditions from dietary methionine, metabolized in various manners. Hyperhomocysteinemia can be attributed to the occurrence of genetic defects in some of the enzymes related to homocysteine metabolism, or nutritional deficiencies and even other risk factors for atherosclerosis. Among nongenetic causes of hyperhomocysteinemia, nutritional status seems to be the most important parameter for the regulation of homocysteine concentrations. Nutritional alterations related to vitamins B12, B6 and especially folate, cofactors in homocysteine metabolism, stand out.2

Vitamin deficiencies are highly prevalent and can cause moderate hyperhomocysteinemia, with plasma homocysteine concentrations inversely proportional to blood folate, vitamins B6 and B12 levels and the ingestion of those vitamins.3,4 Countless epidemiological studies have shown that high homocysteine levels can be an additional risk factor for coronary,5 cerebral6 or peripheral7 vascular disease, as well as venous thrombosis.8 Hyperhomocysteinemia has been detected in 28 to 30 percent of patients with peripheral arterial disease (PAD),7 and the mean homocysteine levels of patients with various PAD manifestations are significantly higher than those of control subjects, intermittent claudication,9 ileo-femoral lesions,10 Leriche's syndrome,11 carotid stenosis,12 and abdominal aortic aneurysm.13

Epidemiological studies in Brazil show high prevalence levels, as much as 20 percent, of hyperhomocysteinemia among Japanese-Brazilian individuals with atherosclerotic peripheral arteriopathy, with progressively higher mean homocysteine values for males as their glycemic status worsens.14,15 The importance of hyperhomocysteinemia as an additional risk factor for PAD is well known, and its development has an odds ratio (OR) ranging from 6.83 to 1116. Hyperhomocysteinemia is also associated with increased PAD progression17,18 and risk of early death caused by cardiovascular disease4 and coronary artery disease among patients with symptomatic PAD.17,19 Based on those studies, blood homocysteine levels seem to be a key predictive marker for PAD, especially among individuals with premature atherosclerosis or severe family history of atherothrombosis and in the absence of other risk factors.20

Several pathophysiologic mechanisms have been suggested for the vascular lesion caused by increased plasmatic homocysteine, including a direct aggressive event to the endothelium, induction of oxidative stress to the vascular wall and oxidation of lipoproteins, changes to the production of nitric oxide and changes to antithrombotic properties.21.

Considering the scarcity of nutritional information for hyperhomocysteinemia in PAD in Brazil and the particularities of the Brazilian poor, users of the public Unified Health System (UHS), the objective of this study was to assess the frequency of hyperhomocysteinemia in the population in a case-control study with 40 Doppler ultrasound-confirmed PAD patients, compared to 20 volunteers who did not have PAD (controls).



The study was approved by the Research Ethics Committee (protocol number 087/99). All subjects taking part in this study were provided with detailed information about the procedures they would undergo and signed the consent form. This was a case-control study, with case group consisting of 40 individuals with symptomatic PAD (PAD group), arriving consecutively at the outpatient department of the Vascular Surgery Service between March 1999 and October 2001 with Rutherford ischemia grades 1 through 322 and ankle-brachial pressure index (ABPI) equal to or below 0.9023. Subjects were excluded from the PAD group if they had major surgery scheduled for the study period, if they had arterites or previous amputations, clinically diagnosed liver or kidney disease, were pregnant, had been diagnosed with HIV/AIDS, cancer or cell proliferation diseases, heart and/or respiratory failure, were receiving parenteral or enteral artificial feeding, were chronic users of folic acid supplements, polyvitamins, and/or medication that might interfere with homocysteine metabolism. The control group consisted of 20 healthy individuals without objectively confirmed PAD and ABPI above 0.9, originating from the same geographic region and patients at the same hospital, recruited between March 1999 and December 2000.

The following risk factors for atherosclerotic disease were investigated:

1) Past and current smoking habits;

2) overweight: Body Mass Index above 24.9 kg/m2, as per World Health Organization guidelines;24

3) excess abdominal fat: waist circumference greater than 88 cm for women and 102 cm for men;25

4) dyslipidemia: total cholesterol above 200 mg/dL, high-density lipoprotein (HDL-c) below 45 mg/dL and triglyceride above 150 mg/dL,25 automated enzymatic colorimetric assay (RA-XT Technicon, USA), and low-density lipoprotein (LDL-c) above 100 mg/dL,25 as calculated using the Friedewald method;

5) diseases with clinical and laboratory confirmation documented in patients' medical records, such as hypertension and diabetes mellitus.

Total fasting plasma homocysteine concentration assays have used Shimadzu's (LC-10AD) high performance liquid chromatography (HPLC), using pre-column derivatization with SBD-F and later detection by fluorescence, as per the standardization proposed by Araki & Sako26 and modified by Ubbink et al.27 Normal total homocysteine levels were defined as 5 to 15 µmol/L, following Ueland et al.28 Blood was harvested from peripheral veins after 8 to 12 hours of rest and fasting.

For statistical analysis, the study used the Sigma Stat for Windows version 3.5 computer application. Descriptive statistics such as medians and inter quartile ranges, with the medians of all variables compared for both the control and the PAD group using the unpaired t (Mann-Whitney) test and the chi-square test (or Fisher's exact test); differences were considered significant when p = 0.05. Odds ratios (OR) were also computed to predict the risk of developing PAD for subjects in the control group who suffered from hyperhomocysteinemia.



Table 1 compares the two groups. As compared to the PAD group, members of the control group had significantly lower age, waist circumference, serum creatinine, serum total cholesterol, LDL-c and triglyceride values, as well as higher ABPI, HDL-c, hypertension and diabetes mellitus values. There were also more patients suffering from chronic limb ischemia than other arterial diseases (p = 0.05) (Table 2).



Median fasting plasma concentrations of homocysteine in control group individuals were normal (12.9 µmol/L) and significantly below the PAD group (16.7 µmol/L) (p = 0.001) (Figure 1). Men (p = 0,005) and women (p = 0.025) in the PAD group had significantly higher levels of homocysteine than those in the control group (Figure 2). Considering hyperhomocysteinemia classification in terms of form, 30 percent of individuals in the control group had mild hyperhomocysteinemia, defined as plasma levels of up to 30 µmol/L; in the PAD group, a majority (50 percent) had mild mild hyperhomocysteinemia. Ten percent of individuals with PAD had moderate hyperhomocysteinemia (31 to 100 µmol/L) (Figure 3). Therefore, in terms of ratio of individuals with hyperhomocysteinemia, the PAD group had higher rates than the control group (p = 0.054).







In terms of age, groups were classified as younger or older than 60. Individuals below the age of 60 had significantly higher homocysteine values in the PAD group than in the control group: 14.9 µmol/L (12.5-18.1) for the PAD group versus 12.8 µmol/L (10.5-15.2) for the control group, p = 0.041.

Odds ratio calculations identified healthy individuals with homocysteine levels above 15 µmol/L as 3.5 times more likely to develop PAD than individuals with homocysteine below 15 µmol/L (OR 3.5; 95% confidence interval: 1.45-8.57; p = 0.003).



This survey of PAD patients in the Brazilian Unified Health System (SUS) is important, since most have unique socioeconomic conditions, education levels, and dietary and lifestyle habits typical of their geographic regions, thus clearly distinguishing their behavior from that of other Brazilian and international populations in terms of risk factors for homocysteine-related atherosclerosis.

The importance of hyperhomocysteinemia as a risk marker for PAD is well known. Plasma homocysteine concentrations above 10 µmol/L, or else 5 µmol/L increases, represent a 6.8 increase in the risk of developing PAD.3,29 Hyperhomocysteinemia is also associated with higher risk of dying from cardiovascular disease4 and progression of coronary artery disease in patients with symptomatic PAD.17,18 Clinical analysis of blood homocysteine as a predictive marker for PAD is considered critical, especially in individuals with premature atherosclerosis or severe family history of atherothrombosis, in the absence of other risk factors.20 However, results from other epidemiological prospective studies involving populations without past history of cardiovascular disease disagree about the presence of high blood homocysteine concentrations as a risk factor for coronary artery disease mortality after a few years of follow-up.30.

As in this study, others with symptomatic PAD patients (manifestations include intermittent claudication, carotid stenosis, abdominal aortic aneurysm, and ileo-femoral and aortoiliac lesions31,32), show blood homocysteine concentrations, as well as prevalence of hyperhomocysteinemia (20 to 78 percent) were significantly higher among cases than controls, even after adjusting for other risk factors for vascular disease. In this study, hyperhomocysteinemia was found in 60 percent of patients with confirmed PAD, predominantly in moderate form. Other Brazilian studies also show high prevalence of hyperhomocysteinemia among individuals suffering from abdominal aortic aneurysms (11%) and abdominal aortic occlusive disease (33%).33 Among Japanese-Brazilians with atherosclerotic peripheral arteriopathy, mean homocysteine levels were positively correlated with glycemic status14 and male gender.15,34 Homocysteine concentration is correlated to age and gender as well. Though the control group had lower median age than the PAD group, the results of this study agree with results from others,35,36 which also found higher homocysteine levels among men than among women and progressive increase with age. In analyzing sex-related differences in stable isotope methionine cycles, Fukagawa et al.37 found transmethylation and remethylation rates for homocysteine were higher for women than for men. The authors suggest the difference between men and women can be explained by the fact that different requirements and uses for certain amino acids lead to increased remethylation in women. The authors also suggest homocysteine metabolism could be influenced by female sex hormones, such as estrogen; however, there are known mechanisms through which estrogen might lead to decreased homocysteine levels.38 Decreased production or enzymatic activity of homocysteine metabolism, physiological decay in renal function and diminished bioavailability of vitamins such as folate, B6 and B12 might explain why homocysteine concentrations rise with age.3,36 According to Hernanz,39 higher homocysteine in older subjects would negatively impact the pro-oxidative state of cells by increasing reactive oxygen species levels, consequently favoring higher risk for noncommunicable chronic diseases, especially those involving the endothelium.

Several studies have established a relationship between body composition and homocysteine levels. These studies used the Body Mass Index (BMI) as a body composition indicator; there was positive correlation between BMI and homocysteine levels, especially among obese individuals,35 particularly those with BMI 30.7 kg/m2 or higher, according to Jacques et al.36 Among patients in this study, BMI and waist circumference were significantly higher in the PAD group than in the control group, and most patients suffering from hyperhomocysteinemia had were overweight and had excess body and abdominal fat, especially female subjects. This pattern of body composition, associated with higher levels of homocysteine, might contribute to greater risk of atherosclerotic disease.35.

Some authors report a significant positive correlation between homocysteine, total cholesterol and triglyceride levels.35 Also, high homocysteine concentrations in PAD patients lead to a twofold increase in PAD risk for hypercholesterolemic patients (relative risk reported, 2.1).4 Keep in mind that there is a possible interaction between low-density lipoprotein (LDL) and homocysteine as part of the pathophysiologic mechanism of atherosclerosis, since the PAD patient group in this study presented hypertriglyceridemia, hypercholesterolemia and increased LDL.

Therefore, the relationship between high plasma homocysteine levels and risk of atherosclerotic disease, especially PAD, has already been established. In addition, hyperhomocysteinemia would increase the risk of atherosclerotic disease when combined with other factors, causing vascular lesions.

Though high blood homocysteine levels are associated with endothelial dysfunction, thrombosis, and more severe atherosclerosis, there is still no consensus in terms of treatment options. A meta-analysis by Clarke et al.40 indicates that, among vitamins studied (B6, B12 and folic acid), folic acid led to decreases of up to 25 percent in blood homocysteine when supplemented with 50 to 500 µg per day. Another meta-analysis, this by Boushey et al.,3 indicates an increase of 200 µg in daily dietary folate intake would lead to a 4 µmol/L decrease in fasting plasma homocysteine concentrations in patients suffering from cardiovascular, cerebrovascular, and peripheral artery disease. Other authors also report folic acid vitamin supplements are beneficial and inexpensive, as well as a possible adjunctive therapy for patients with symptomatic or asymptomatic atherosclerotic disease and as an alternative for PAD prevention.41.

In summary, PAD patients who took part of this study were mostly elderly and male, predominantly suffering from both acute and chronic peripheral arterial insufficiency. Risk factors for atherosclerosis included systemic hypertension, diabetes mellitus, smoking,obesity, altered lipid metabolism and high plasma homocysteine concentrations. The findings underline the interest and importance of studying homocysteine in PAD patients, since nutritional factors are involved with the risk and treatment of atherothrombotic events.



Hyperhomocysteinemia, an important risk factor, was found in 60 percent of individuals suffering from PAD in a Brazilian public health care facility. Prospective and controlled clinical trials are particularly important in these cases, since we need to accurately assess the impact of blood homocysteine reductions in terms of risk, incidence and natural history of atherosclerotic disease, preventing the progression of atherosclerotic lesions. and perhaps even causing them to regress.



To Dr. Maria Dorotéia Borges dos Santos, for homocysteine dosage; to the physicians clinically responsible for the patients (professors Dr. Francisco H. A. Maffei, Dr. Sidnei Lastória, Dr. Hamilton A. Rollo, Dr. Regina Moura, Dr. Mariangela Giannini); to mathematician professor Dr. Adalberto Crocci (in memoriam), for assisting statistical analysis; and to the employees of the Vascular Surgery Service of Clinical Assay Laboratory and Center for Metabolism in Exercise and Nutrition at Hospital das Clínicas da Faculdade de Medicina de Botucatu - UNESP.



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Luciene de Souza Venâncio
Av. Floriano Peixoto, 240
Caixa Postal 334
CEP 18603-970 - Botucatu, SP - Brazil

Manuscript received Jun 22 2009, accepted for publication Oct 02 2009.



Apoio financeiro concedido pela Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) e pela Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (processo nº 98/16098-8130).

No conflicts of interest declared concerning the publication of this article.

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