Diabetic Retinopathy - Treatment

Homocysteine - updated: 15 March 2008

Discovered in 1932, homocysteine is a sulfur-containing amino acid normally found in small amounts in the blood of healthy persons. Homocysteine is derived from dietary protein (meat, milk, eggs) and is metabolized in the liver using vitamins B6 and B12. High levels of homocysteine can result from genetic disease (homocystinuria); kidney disease; hyperthyroidism; psoriasis; systemic lupus erythemotosus; drug treatment for chronic diseases; and dietary vitamin deficiencies (folic acid, B6, B12) .

As early as 1969, researchers began to make clinical observations linking elevated homocysteine to vascular diseases. Subsequent investigations confirmed these observations. In CVD, there is evidence that elevated levels of homocysteine are related to arterial wall damage, but the mechanism is unclear. It may be that homocysteine has a toxic effect on the endothelial (cellular) lining of blood vessels.

For some time, physicians have recognized the danger of homocysteine and they recommend use of vitamin supplements to lower homocysteine levels. The "normal range" used by commercial laboratories is 5-15 micromoles/L of blood. However, epidemiological data reveal that homocysteine levels above 6.3 result in a steep, progressive risk of heart attack, with each three-unit increase equaling a 35% increase in risk for heart attack. There may be no safe "normal range" for homocysteine. A survey in Cardiologia reported that the average American's level of homocysteine is 10.

Homocysteine and diabetic retinopathy

Diabetes Care. 2007 Sep 26

Brazionis L Research F, Rowley K Senior Res, Itsiopoulos C Research F, Harper CA, O'dea K Professor.

Background: Homocysteine is an emerging risk factor for cardiovascular and non-diabetic ocular vaso-occlusive diseases. However, studies of the relationship between homocysteine and diabetic retinopathy have reported inconsistent results. Objective: The purpose of this study was to evaluate the relationship between plasma total homocysteine concentration and diabetic retinopathy. Design: We assessed the homocysteine-retinopathy relationship in 168 men and women with type 2 diabetes in a community-based, cross-sectional study. We photodocumented diabetic retinopathy status and measured plasma total homocysteine concentration using a commercial FPIA enzymatic kit. Data for selected clinical/demographic variables and established risk factors for diabetic retinopathy were obtained from fasting blood samples and an interviewer-assisted lifestyle questionnaire. Results: A higher mean (95% CI) plasma total homocysteine concentration was observed in diabetic individuals with retinopathy than in those without retinopathy (11.5 [10.4- 12.5] umol/L vs. 9.6 [9.1-10.2] umol/L, p = 0.001). Furthermore, the relationship between homocysteine and diabetic retinopathy was not explained by renal dysfunction and was independent of the other major risk factors for diabetic retinopathy [duration of diabetes, HbA1c, systolic blood pressure] and determinants of higher homocysteine concentrations [age, gender, red cell folate], (OR 1.20 [1.023-1.41], p = 0.024). Conclusion: Plasma total homocysteine concentration may be a useful biomarker and/or a novel risk factor for increased risk of diabetic retinopathy in people with type 2 diabetes.

Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study

J Intern Med. 2005 Nov;258(5):450-

Soedamah-Muthu SS, Chaturvedi N, Teerlink T, Idzior-Walus B, Fuller JH, Stehouwer CD; Eurodiab ProspectivE Complications Study Group.

OBJECTIVES. To examine the independent relationship between plasma total homocysteine (tHcy) and microvascular and macrovascular complications. DESIGN. We performed a cross-sectional nested case-control study from the EURODIAB Prospective Complications Study. SETTING. A hospital-based multicentre study at 24 centres in 13 European countries. SUBJECTS. A total of 533 type 1 diabetic patients, diagnosed at <36 years of age. Cases (n=359) were defined as those with one or more complications of diabetes and control subjects (n=174) were all those with no evidence of any complication. Main outcome measures. Retinopathy, albumin excretion rate (AER), glomerular filtration rate (GFR) estimated by Cockcroft-Gault formula, hypertension and cardiovascular disease (CVD) were assessed. RESULTS. In unadjusted models, tHcy (per 5 micromol L(-1)) was significantly associated with nonproliferative retinopathy (OR=1.45, 95% CI: 1.10-1.91), proliferative retinopathy (OR=1.74, 95% CI: 1.34-2.27), macroalbuminuria (OR=1.90, 95% CI: 1.49-2.42), hypertension (OR=2.23, 95% CI: 1.69-2.93) and CVD (OR=1.59, 95% CI: 1.18-2.14). In multivariate models, tHcy was significantly related to macroalbuminuria (OR=1.66, 95% CI: 1.24-2.24) and hypertension (OR=1.57, 95% CI: 1.19-2.07), independent of age, sex, diabetes duration, GFR, microvascular and macrovascular complications and cardiovascular risk factors. There was a significant relationship between tHcy and decreased GFR, independent of established risk factors. The relationship between tHcy and retinopathy was not independent of albuminuria or GFR. The initial positive relationship with CVD was explained by cardiovascular risk factors. CONCLUSION. In this large study of European type 1 diabetic subjects, increased concentrations of tHcy were independently related to macroalbuminuria, renal function and hypertension, which suggests that tHcy might play an important role in the pathogenesis of vascular complications in type 1 diabetes.

Publication Types:

• cross-sectional nested case-control study

Prevention with Folic Acid, B6 and B12

Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplemen

Semin Thromb Hemost. 2000;26(3):341-8

Clarke R, Armitage J.

Epidemiological studies have shown that higher blood homocysteine levels appear to be associated with higher risks of coronary, cerebral, and peripheral vascular disease and are inversely related to blood levels of folate and of vitamin B12 and vitamin B6. However, observational studies cannot exclude the possibility that elevated homocysteine levels may be associated with some other factor, rather than being causally related to vascular disease. Large-scale clinical trials of sufficient dose and duration of treatment are required to test this hypothesis, but there was substantial uncertainty about the optimal vitamin regimen to test in such trials. A meta-analysis of 12 randomized trials of vitamin supplements to lower homocysteine levels was carried out to determine the optimal dose of folic acid required to lower homocysteine levels and to assess whether vitamin B12 or vitamin B6 had additive effects. This meta-analysis demonstrated that reductions in blood homocysteine levels were greater at higher pretreatment blood homocysteine levels and at lower pretreatment folate concentrations. After standardization for a pretreatment homocysteine concentration of 12 micromol/L and folate concentration of 12 nmol/L (approximate average concentrations for western populations), dietary folic acid reduced homocysteine levels by 25% (95% confidence interval [CI]: 23 to 28%) with similar effects in a daily dosage range of 0.5 to 5 mg. Vitamin B12 (mean 0.5 mg) produced an additional reduction in blood homocysteine of 7%, whereas vitamin B6 (mean 16.5 mg) did not have any significant effect. Hence, in typical populations, daily supplementation with both 0.5 to 5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce homocysteine levels by one quarter to one third (from about 12 micromol/L to about 8 to 9 micromol/L). Large-scale randomized trials of such regimens are now required to determine whether lowering homocysteine levels by folic acid and vitamin B12, with or without added vitamin B6, reduces the risk of vascular disease.

Publication Types:

• Review

Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women

JAMA. 1998 Feb 4;279(5):359-6

Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ.

CONTEXT: Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE: To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN: Prospective cohort study. SETTING AND PATIENTS: In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE: Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS: During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION: These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.

Publication Types:

• Prospective cohort study

Homocysteine and cardiovascular disease: a review of the evidence

Diab Vasc Dis Res. 2007 Jun;4(2):143-50

Wierzbicki AS.

Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence, as well as data from retrospective and prospective studies, supports an association between elevated HCY levels and increased risk of cardiovascular disease (CVD). However, whether lowering HCY levels by administration of folate and vitamins B6 and B12 is associated with any significant decrease in vascular risk remains the subject of ongoing debate. Although the major studies that have reported to date show that vitamin supplementation was associated with a decrease in HCY levels, this failed to have any significant effect on cardiovascular risk. Furthermore, although some lipid-modifying treatments have been shown to increase HCY levels, there is no evidence that this attenuates or compromises the beneficial effects of such treatments on cardiovascular risk. Taken together, these data suggest that HCY is a marker, rather than a cause, of CVD and therefore do not provide support for routine screening for and treatment of elevated HCY to prevent CVD. Data from ongoing clinical trials are awaited to clarify this issue.

Publication Types:

• Review

Publication Types:

• Review