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An important pathway for health



What is Homocysteine?

Is similar [[a homologue] to the amino acid cysteine. It can be converted to methionine or cysteine with the aid of B-Group vitamins. 

Homocysteine is not obtained directly from the diet but reflects protein status of an individual and in particular how much methionine is available.The tutorial 'Homycysteine Metabolism' provides a detailed explanation of this important pathway.

How do we know homocysteine is a cardiovascular risk?

So how do we know that homocysteine is a cardiovascular risk? The answer is in rare diseases such as homocysteinuria or genetic polymorphisms of enzymes such as methylene-tetrahydrofolate-reductase [MTHFR] polymorphisms which result in hereditary disorders that cause elevations in homocysteine in the body. Such individuals suffer from an increased risk of thrombosis [clotting] and cardiovascular disease [heart attacks, strokes, peripheral vascular disease].

Many laboratories have normal ranges between 6 - 14 umol/L. However,risk may start with levels around 6 umol/L.

It has been estimated that 2/3 [67%] of elevated homocysteine is due to suboptimal intake of B-group vitamins114.

Many studies have also shown an association with high homocysteine levels and Alzheimer's and Parkinson's diseases, diabetes, rheumatoid arthritis, miscarriages, pregnancy-induced hypertension [PIH], chronic fatigue syndrome and fibromyalgia probably due to the increased oxidative stress and increased inflammatory potential as a result of raised homocysteine levels.

What is the risk?

Approximated Risks

[Reference Range: 0.0  - 15 umol/L]

Plasma Homocysteine Level Cardiovascular Risk Average
Below 9.0 No Increase
9.0 - 14.9 x 2
15.0 - 19.9 x 3
20.0 or greater x 4.5

Approximations from New England Journal of Medicine [NEJM] 1997 (337:230 - 236)

Genetic factors in raised homocysteine

Dietary factors, are cited as the principal cause for elevated homocysteine levels however, dietary factors are not the only cause there are genetic causes as well.

There is a rare hereditary disease called homocystinuria which is characterized by elevated blood homocysteine levels accompanied by an increased rate of excretion in the urine hence the term homocystinuria. It is known that close to 25 percent of people with this genetic disorder will eventually die prematurely from cardiovascular complications and this happens usually before the age of thirty.

A high percentage - in fact ten percent [10%] of the general population have a related predisposition to elevated homocysteine levels where these individuals are unable to effectively metabolize homocysteine and as a result will be predisposed to cardiovascular complications such as blood clots, heart and vascular disease. This genetic disorder is known as a methylenetetrahydrofolate-reductase (MTHFR) polymorphism genetic trait.

Single Nucleotide Polymorphisms

  • In humans, the enzyme is coded by the gene with the symbol MTHFR on chromosome 1 location p36.3 in humans.
  • A report in 2000 indicated that up to 24 polymorphisms of the MTHFR gene exists. 

Two of the most investigated single nucleotide polymorphisms (SNPs) are:

  • C677T (rs1801133) and
  • A1298C (rs1801131) .

How does homocysteine cause damage?

Reduced Glutathione Synthesis

Increased homocysteine levels also indicate that glutathione synthesis may be impaired. Glutathione [3D diagram shown] is a powerful antioxidant produced by the body in response to oxidative stress. Thus free radical damage and inflammation will occur  in many organ systems as a result of impaired glutathione synthesis. There is also an increased risk of viral infections if glutathione synthesis is impaired.

The free NutriDesk tutorial shows how glutathione is synthesized from the methionine - homocysteine pathway. See below.

Fast Facts: How does homocysteine damage the body

  1. Homocysteine binds to certain proteins and inhibits both repair and maintenance of these proteins. This in turn affects protein structure and function. The three main vascular connective tissue [protein] structures —collagen, elastin and proteolgycans are affected by homocysteine  making them more susceptible to disease processes, which includes the chronic changes of vascular disease.
  2. 'Homocysteine harms the vascular endothelium in a variety of ways, impairing the ability of the endothelium to maintain homeostasis. Homocysteine increases platelet aggregation and thrombosis through enhanced thromboxane synthesis and inactivation of anticoagulant substances. Homocysteine increases oxidative stress by increasing superoxide production. It also increases leukocyte-endothelium interactions and was found to be toxic at high concentrations. In addition, homocysteine down-regulates nitric-oxide production and acts as a mitogen to increase vascular smooth muscle proliferation. Impaired endothelium-dependent, flow-mediated vasodilation was documented in hyperhomocysteinemic subjects and in healthy subjects with oral methionine load–induced hyperhomocysteinemia127.'
  3. Homocysteine leads to increased endothelial asymmetric dimethylarginine [ADMA] resulting in impaired nitric oxide synthesis as ADMA competes with arginine for nitric oxide [NO] synthesis. Please view the Flash tutorial 'Arginine, ADMA & Nitric Oxide'.This affects the ability of blood vessels to dilate. Nitric Oxide is important for blood vessel homeostasis and acts by inhibiting vascular smooth muscle contraction and smooth muscle growth, platelet aggregation [decreases clotting], and leukocyte adhesion to the endothelium decreasing the risk of white blood cell migration,  activation and inflammation.
  4. 'A 5-mmol/L tHcy [total homocysteine] increment elevates CAD [Coronary Artery Disease] risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL)' [Boushey et al 1995]
  5. Numerous estimates have shown that 40% or more of all heart attacks and strokes are caused by elevated homocysteine levels.
  6. Raised homocysteine levels are seen in sufferers of chronic fatigue syndrome [CFS]
  7. Homocysteine also accelerates the aging process by shortening telomeres.
  8. If you have a high cholesterol level then it is important to know that raised homocysteine oxidizes cholesterol. Why is this important? because the central theory of atherosclerosis and plaque formation is the oxidization of LDL cholesterol in blood vessel walls leading to an inflammatory process and eventually plaque rupture and a heart attack, stroke, DVT ischaemic peripheral vascular disease.
  9. If you have rheumatoid arthritis [RA] it is important to know that sufferers of RA are 20-30% more likely to have higher homocysteine levels than the normal population.
  10. Research has shown links between raised homocysteine levels contributing to the onset and to the progression of Alzheimer’s Disease, Schizophrenia, Dementia, MS, Depression and Parkinson’s Disease.

Why has research failed to show the benefit of lowering homocysteine?

Important Research: The B-Vitamin Atherosclerosis Intervention Trial (BVAIT)

The BVAIT study is an important one and the conclusion was:

"High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin "replete" individuals at low risk for cardiovascular disease with a fasting tHcy ≥9.1 µmol/L."

Many studies have found no association between B-group supplementation, lowering of homocysteine and decreases in cardiovascular disease. For those that believe that supplementation has no place in the treatment of individuals or those that see diet and nutrition as remote to disease processes and as having no place in clinical medical practice, these results seemed to provide confirmation of these misplaced beliefs.

Timing - the critical factor

One factor that seems to be left out of research is the timing of an intervention whether this is hormonal, pharmaceutical or nutraceutical.

Many of the studies done in the past on vitamin intervention for raised homocysteine levels were carried out on individuals who already had advanced cardiovascular disease. These individuals were given sub-optimal doses of the vitamins involved in homocysteine metabolism and were often given some but not all the biochemical factors involved. This often resulted in mild decreases in homocysteine levels and the research was deemed to show how futile it was to use vitamin therapy to alter cardiovascular risk by lowering homocysteine levels.

It is truly a far stretch of the imagination to think that mild lowering of homocysteine was going to have any impact on individuals with advanced atherosclerotic disease. The authors of the BVAIT study stated the following with regard to their findings and that past negative studies---

"may be the result of different timing of B vitamin supplementation according to the stage (early versus advanced) of atherosclerosis." The conclusion was, "Further studies to determine whether reducing total homocysteine levels prevents plaque rupture and clinical events in a population similar to BVAIT are warranted."

Reference - Stroke

  • Howard N. Hodis, Wendy J. Mack, Laurie Dustin, Peter R. Mahrer, Stanley P. Azen, Robert Detrano, Jacob Selhub, Petar Alaupovic, Chao-ran Liu, Ci-hua Liu, Juliana Hwang, Alison G. Wilcox, Robert H. Selzer for the BVAIT Research Group High-Dose B Vitamin Supplementation and Progression of Subclinical Atherosclerosis. A Randomized Controlled TrialStroke, Dec 2008; doi:10.1161/STROKEAHA.108.526798

Methionine - Homocysteine Pathway

SAMe and Methylation

  • The Methionine - Homocysteine pathway is important for many reasons and one important compound generated in this cycle is S-Adenosyl-L-methionine (SAMe)
  • SAMe is the body’s principal methyl donor.
  • It is required for the transmethylation reactions essential to synthesis of a wide range of important biochemical compounds including neurotransmitters for the regulation of mood.

Click to enlarge

Oxidative Stress

Increased riskfor inflammatory damage


Laboratory testing takes away the guess work

If you have a chronic illness or if you are feeling constantly unwell, especially so if you have a disease with an underlying inflammatory process such as arthritis, heart disease, vascular disease, diabetes. asthma, chronic lung disease, macular degeneration, Parkinson's disease nd Alzheimer's disease.

Checking essential fatty acid status may be that important step you need to take towards good health. 

Testing takes the guesswork out of the equation in terms of your dietary needs, treatment  or supplementation.

Possible tests to investigate your potential for chronic inflammation

  • The AA/EPA Ratio --- the Arachidonic Acid [AA] to Eicosapentaenoic acid [EPA] ratio is an early marker of inflammation. Recent studies have shown that individuals taking statin medications have have increased levels of the very inflammatory AA in their blood [Harris et al 2004].
  • The EPA/DGLA Ratio ---can be used to fine-tune the good [anti-inflammatory] Series-1 and Series-3 eicosanoids.
  • The Omega-3 Index --- this particular test is a major advance on assessing essential fatty acid testing as results are comparable between laboratories. This test measures the percentage of the omega-3 essential fatty acids DHA and EPA in erythrocytes [Red Blood Cells]. A good Omega-3 Index is regarded as being greater than or equal to 8. A 'healthy' Western population has an average Omega-3 Index of 4.9 +/- 2.1 and individuals with coronary artery disease [blocked heart vessels] have an Omega-3 Index of 3.9 +/- 1.1. [Curr Opin Nutr Metab Care 2008; 11[2]:94-91

Tests for Oxidative Stress for risk of worsening inflammation include:

  • Hydroxyl radical markers – Catechol and 2,3 DHB
  • Urine lipid peroxides
  • Reduced Glutathione (GSH)
  • Glutathione peroxidase (GSH-Px)
  • Superoxide dismutase (SOD)

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