From the Guidelines
Homocysteine plays a crucial role in several biochemical pathways, and elevated levels are associated with increased risk of cardiovascular disease, stroke, and other conditions, with normal levels typically between 5-15 μmol/L, and treatment focusing on addressing underlying causes, including supplementation with B vitamins and dietary modifications 1.
Pathways and Pathology of Homocysteine
Homocysteine is an amino acid produced in the body during protein metabolism, specifically during the breakdown of methionine. It plays a role in several important biochemical pathways, primarily the methionine cycle and the transsulfuration pathway. In the methionine cycle, homocysteine can be remethylated back to methionine with the help of vitamin B12 and folate, while in the transsulfuration pathway, it converts to cysteine using vitamin B6.
Conditions Causing Abnormal Homocysteine Levels
Elevated homocysteine levels (hyperhomocysteinemia) can occur due to:
- Genetic defects in metabolizing enzymes
- Nutritional deficiencies of B vitamins (B6, B12, and folate)
- Certain medications
- Renal disease
- Hypothyroidism
- Lifestyle factors like smoking and excessive coffee consumption High levels are associated with increased risk of:
- Cardiovascular disease
- Stroke
- Venous thrombosis
- Neurodegenerative disorders like Alzheimer's disease
- Pregnancy complications
- Neural tube defects
Treatment and Management
Treatment for high homocysteine focuses on addressing underlying causes and often includes:
- Supplementation with B vitamins, particularly folate (400-1000 mcg daily), vitamin B12 (500-1000 mcg daily), and vitamin B6 (25-100 mg daily)
- Dietary modifications to increase consumption of B vitamin-rich foods
- Lifestyle changes like reducing alcohol intake and quitting smoking can also help normalize homocysteine levels, as supported by studies such as the Vitamin Intervention for Stroke Prevention (VISP) trial and the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) 1.
Some key points to consider:
- The relationship between homocysteine levels and carotid IMT was eliminated after adjustment for other cardiovascular risk factors or renal function, as found in several recent investigations 1.
- A meta-analysis of epidemiological studies found a 19% (95% CI, 5–31) reduction in odds of stroke per 25% lower homocysteine concentration after adjustment for smoking, SBP, and cholesterol 1.
- The results of trials that have examined the effect of homocysteine-lowering therapy with B-complex vitamins on risk of stroke are inconsistent, with stroke reduction generally found in trials in which the duration of treatment exceeded 3 years, the decrease in plasma homocysteine concentration was >20%, the region did not fortify diet with folate, and participants had no prior history of stroke 1.
From the Research
Role and Pathways of Homocysteine
- Homocysteine is a sulfur-containing amino acid that arises during methionine metabolism 2
- Its metabolism stands at the intersection of two pathways: remethylation, which requires folic acid and vitamin B12 coenzymes; and transsulfuration, which requires pyridoxal-5'-phosphate, the vitamin B6 coenzyme 3
- Pyridoxal, folic acid, riboflavin, and Vitamin B(12) are all required for methionine metabolism, and deficiency of each of these vitamins result in elevated plasma homocysteine 2
Pathology of Homocysteine
- Elevated homocysteine levels are an independent risk factor for cardiovascular disease, stroke, and Alzheimer's disease 4, 5, 6, 3
- Hyperhomocysteinemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven 5
- Elevated plasma homocysteine is associated with increased total and cardiovascular mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer's disease, increased incidence of bone fracture, and higher prevalence of chronic heart failure 3
Conditions that Can Cause Abnormal Homocysteine Levels
- Vitamin deficiencies, particularly folate, vitamin B6, and vitamin B12 4, 5, 2, 6, 3
- Polymorphisms of enzymes of methionine metabolism, such as the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene 5, 2
- Renal disease, which impairs homocysteine removal 2
- Lifestyle factors, such as inadequate nutrient status and various drugs 5
- Genetic predisposition, such as individuals with the MTHFR 677TT genotype 5