Homocysteine, Discovering Susceptibility To Many Chronic Health Problems

Homocysteine is made in the body from another amino acid, methionine. A high level is to do with fundamental processes within the human body apon which life depends. Methylation and methylation support through nutrition, B vitamins, and nutritional supplements is key to the prevention of a multitude of disease states such as heart disease, cancer, Alzheimer dementia, autoimmunity, bone density loss, stroke, etc.

Elevated homocysteine can speed up oxidative stress and aging, damage one’s arteries, weaken your immune system, damage your brain and lower your IQ, it may increase pain, inflammation and blood clotting risk, it increases a person’s risk for cancer and weakens detoxification, ages the brain faster, alters hormone metabolites and can lead to hormone related problems, it is also a marker of neurotransmitter or brain chemical metabolism.
I consider homocysteine testing critical for discovering susceptibility to many chronic health problems.

Everyone has homocysteine production within the body but when homocysteine levels get too high, as mentioned it can lead to many many health issues. Many lifestyles factors can influence your homocysteine levels, causing it to rise too high, including stress, poor diet, toxin exposure, and medications. Homocysteine can also increase with estrogen deficiency.

Your body has metabolic pathways to keep homocysteine levels in check – namely methylation. However, to have healthy methylation pathways, your body needs beneficial methyl donors – B vitamins in particular – from the foods you eat, which convert homocysteine to SAMe and glutathione. For this reason, high homocysteine levels can also be a consequence of poor absorption of B vitamins.

Two of my favourite supplements to increase and improve methylation are the new quatrefolic version of folate and emothion (S-acetyl-glutathione) delivered orally for elevation of glutathione levels. The S-acetyl-glutathione is the best version for oral absorption.

Having good methylation and glutathionation in place equates to high probability of longevity and health.

SAMe (sulphated methionine) is another wonderful supplement that increases the availability of the neurotransmitters serotonin and dopamine, and protects our nerves and mood. . Glutathione is your body’s strongest antioxidant. Both methylation and glutathionation are essential for putting autoimmune reactions into remission. When your methyl donors are lacking, homocysteine accumulates in the body and further increases with estrogen deficiency, as well as with some long-term medications given to autoimmune patients.

Furthermore factors that contribute to cognitive decline in women from midlife seem clearly to be associated with low estrogen levels and high homocysteine levels. Endogenous (produced in the body) and exogenous estrogen (as in bio-equivalent hormone replacement therapy) may influence homocysteine levels.

Strict vegetarians and vegans can also have a higher risk of methylation impairments

Strict vegetarians and vegans can also have a higher risk of methylation impairments due to a potential deficiency of vitamin B12. Evidence exists that well-planned vegetarian diets provide numerous health benefits and are appropriate for all stages of the life cycle. It is also known that animal foods provide micronutrients that are nonexistent or available only in limited amounts in plant foods. Restriction or exclusion of all animal foods may therefore result in low intake of certain micronutrients such as vitamin B-12, thereby affecting vitamin B-12 status and elevating plasma homocysteine concentrations.

Integrative and functional medicine tailors care to the individual, and this is why the term personalized medicine is gaining such popularity.Since everyone is different, the treatments may differ from person to person.

Methylation is sort of an antioxidant recycling process in your body, and it’s needed for optimal brain and immune system health. Proper methylation produces your body’s top disease-fighting antioxidant glutathione. When your glutathione levels are low, so is your immune function.
Depletion of glutathione is due to a multitude of factors including : Toxic exposure, antidepressant medications and other chronic pharmaceuticals, Birth control pills, Diabetic medications, Antacid medications, MTHFR gene mutations and glutathione polymorphism gene SNPS.

Methylation function in patients can be gauged by running a homocysteine test. Homocysteine is supposed to be converted to glutathione via methylation. If homocysteine levels are high, methylation isn’t functioning well. I honestly believe that everyone should have their homocysteine level;s checked. In order to have a healthy immune system, you need to have a healthy microbiome, and conditions associated with dysbiosis, or an imbalance between beneficial and pathogenic bacteria (such as SIBO and leaky gut syndrome) can drastically suppress healthy immune function.

Having optimal brain-immune-gut axis function overall is a crucial way to optimize your immune system, so tackle health from all sides to thrive. Managing stress is also key.

Homocysteine levels above 7 UMOL/L have been shown to cause brain inflammation, destruction of the blood-brain barrier, and decreased immune health. The good news is that in the presence of methyl-donors like vitamin B6, B9, B12 homocysteine is converted to glutathione. TMG, SAMe are other supplements that can be used.

Homocysteine levels protect your DNA

Homocysteine and Autoimmunity :
Healthy methylation pathways and balanced homocysteine levels protect your DNA. Methylation helps keep good genes “”turned on”” and bad genes “”turned off””, but when methylation is impaired, it can result in an autoimmune response.

Homocysteine and Brain Function:
Homocysteine levels above 7 UMOL/L have been shown to damage the protective blood-brain barrier (leaky brain syndrome), and are linked to neurologically-based autoimmune spectrum diseases like multiple sclerosis, Parkinson’s disease, and Alzheimer’s.

Preventing and reversing autoimmune decline is essential for protection of the brain, neurotransmitter function, and myelin rep[air and myelin health, which is the sheath protecting nerve fibers. This all depends on healthy methylation pathways.

Homocysteine and Heart Function:
High homocysteine levels are linked with heart or cardiovascular damage. Heart disease is the leading cause of death for both men and women, so everyone should be concerned about their homocysteine levels. Many autoimmune conditions, such as lupus and autoimmune thyroid disease (Hashimoto’s or Graves), also increase the risk for heart attack and stroke, as all these systems and processes are connected by a web-like interconnection of bodily systems.

Elevated homocysteine 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 homocysteine levels and increased risk of cardiovascular disease. Lowering homocysteine levels by administration of folate and vitamins B6 and B12 is associated with a significant decrease in vascular risk but remains the subject of ongoing debate Although some lipid-modifying treatments have been shown to increase homocysteine levels, there is no evidence that this attenuates or compromises the beneficial effects of such treatments on cardiovascular risk according to some studies.

What to do about high homocysteine

If you have high homocysteine levels, there are a couple of things you can do to lower your health risks and restore homocysteine to normal levels. One thing I suggest is running another lab, to get more information. This is the methylation gene mutation tests (MTHFR, COMT) which can shed light on specific genetic reasons why your homocysteine level might be higher than normal.

The more gene polymorphisms you have, the more methylation impairments you’re likely to experience, which can lead to higher homocysteine levels. For example MTHFR gene mutations has been associated in many cases with autoimmunity, such as Hashimoto’s 9an autoimmune thyroid condition). . Knowing your risk factors is the first step to optimizing your health and personalizing your therapies.

In addition to homocysteine and MTHFR mutation tests, there are other functional and Integrative medicine doctors that will probably recommend for optimal DNA health. So a visit to a functional or Integrative medicine practitioner can help you find solutions. One thing you can do on your own right now, however, if you have high homocysteine levels or an autoimmune condition, is to optimize your B vitamin levels, to support methylation.

The type of B vitamins you take is important. Be sure to go for the activated forms of folate, B6, and B12:

L-5-MTHF Folate: Methylfolate
B6: Pyridoxyl-5-Phosphate (P5P)
B12: Methylcobalamine

Quatrefolic is the newest best form of folic acid/folate, but if not available methylated forms of folic acid are superior to non-methylated forms of folic acid.

Elevated plasma total homocysteine is a marker of folate and cobalamin deficiency and a strong independent risk factor for coronary artery, cerebrovascular and peripheral arterial disease. More recently it was also implicated in pregnancy complications and birth defects, as well as in vascular dementia and Alzheimer’s disease.

METABOLISM AND DETERMINANTS OF HOMOCYSTEINE
Homocysteine is a sulphur amino acid derived from metabolism of the essential amino acid methionine. It lies at the branch point in one-carbon metabolism between two metabolic pathways (remethylation and trans-sulphuration). Folate, vitamins B2, B6 and B12 are essential cofactors and deficiencies result in hyperhomocysteinemia.

Genetic factors:	Effect on tHcy
Congenital homocystinuria (homozygous CBS defect)¹
Heterozygosity for CBS defect
MTHFR C677T homozygosity²
Methionine synthase deficiency
Physiologic determinants:
Increasing age, male sex
Pregnancy/ premenopausal	¯
Lifestyle determinants:
Smoking, coffee, alcohol
Exercise	¯
Clinical conditions:
Vitamin deficiency (folate, B12, B6)	–
Renal failure
Hyperproliferative disorders (eg psoriasis, solid tumors, leukaemia)
Hypothyroidism
Drugs:
Folate antagonists, eg methotrexate, trimethoprim, anticonvulsants (phenytoin), cholestyramine
Cobalamin antagonists eg nitrous oxide, metformin
Vitamin B6 antagonists eg niacin, isoniazide, theophylline
Other: cyclosporin A, fibrates, diuretics

*1 CBS: Cystathionine B-synthase, incidence of homozygous defect 1/200 000
*2 MTHFR C677T: Methylene tetrahydrofolate reductase thermolabile variant, homozygosity associated with increased CVD risk in association with folate deficiency, incidence 12% of Caucasian population

SAMPLING, REFERENCE LIMITS AND CLASSIFICATION

The preferred sample for determination of plasma total homocysteine (tHcy) is a single EDTA-sample on ice (falsely elevated in serum), fasting or within 3 hours following a light breakfast (protein-rich meal increase tHcy by 10-15% after 6-8 h), preferably ambulatory (lower if supine).
In adults with good vitamin status the upper reference limit is generally regarded as 12 umol/L. according to our conventional laboratory testing. The use of separate reference limits for children, adults, the elderly and pregnant women is advocated.
In integrative medicine we target a value of 6.3 – 7umol/L for ideal health.

Upper reference limits for tHcy according to conventional lab testing
Basal tHcy (umol/L)	Folate supplemented	Nonsupplemented
Pregnancy	8	10
Children < 15 years	8	10
Adults 15-65 years	12	15
Elderly > 65 years	16	20
Post-methionine (100 mg) load tHcy (4-6h)	5 times basal or 40 umol/L increase above fasting	Clinical value is uncertain – not recommended for routine use
American Heart Association Classification of hyperhomocysteinemia
Moderate ()	Intermediate ()	Severe ()
15-30	30-100	>100

HYPERHOMOCYSTEINEMIA AND FOLATE/COBALAMIN DEFICIENCIES

otal homocysteine is a good screening test for folate/cobalamin deficiencies.
The combination of an increased tHcy and low vitamin concentration improves patient identification.
With absent/non-specific symptoms, tHcy is superior to vitamin measurements as primary screening test.
If tHcy is elevated or borderline with symptoms, both of the specific vitamins (B12/RBC-folate) should be determined to establish a diagnosis.
Treatment of pernicious anaemia by folate only in the presence of B12-deficiency may result in irreversible neurological damage.

HYPERHOMOCYSTEINEMIA AND PREGNANCY COMPLICATIONS

Increased tHcy is associated with an increased risk of placental vasculopathy, which is related to preeclampsia, recurrent early pregnancy loss, premature delivery, low birth weight, and placental abruption or infarction.
Maternal hyperhomocysteinemia is also related to the following birth defects: neural tube defects (NTDs), orofacial clefts, clubfoot, and Down syndrome.
Folic acid supplements in the periconceptual period and the first few weeks of pregnancy reduce the risk of NTDs and other complications. In addition, the MTHFR 677TT genotype and cobalamin deficiency have also been implicated as risk factors.

My personal favourites include methylated folate instead of ordinary folic acid and the newer generation quatrefolic are the best choices

HYPERHOMOCYSTEINEMIA AND COGNITIVE IMPAIRMENT

A dose dependent association has been noted between tHcy and Alzheimer’s disease. Increased tHcy or low folate often precedes cognitive decline. There are as yet no randomised trials that have assessed the effects of tHcy-lowering therapy on cognitive function.
Because of the contributory effect of folate/cobalamin deficiencies in patients with psychiatric disorders, cognitive impairment or dementia, assessment of vitamin status (tHcy and/or vitamin levels) should always be done in these patients and treated appropriately.

WHO SHOULD ESPECIALLY BE TESTED FOR HOMOCYSTEINE?

1. Risk factor for Cardiovascular disease :

Until the results of randomised clinical trials proving that lowering of homocysteine levels are indeed associated with reduction in CVD risk, widespread screening cannot be justified. According to the American Heart Association the following individuals should be tested:
a. Family history of cardiovascular disease
b. Premature atherosclerosis (< 40y)
c. Atherosclerosis with no known conventional risk factors (hypertension or hyperlipidemia)

2. Thrombo-embolic disease:

Part of routine hypercoagulability profile.

3. To diagnose homocystinuria:

a. Children/young adults with unexplained thrombotic disease, failure to thrive, mental retardation, psychiatric disease, lens dislocation, progressive myopia, or connective tissue disorders.
b. Any person with severe hyperhomocysteinemia not explained by vitamin deficiency or renal failure.

4. Screening test for individuals with or at risk of developing cobalamin or folate deficiency:

a. Symptoms suggestive of vitamin deficiency:
i. Hematological: Anemia, macrocytosis
ii. Neurological: peripheral neuropathy/myelopathy
iii. Psychiatric diseases: mood changes, asthenia, memory problems, dementia.
iv. Adverse pregnancy outcome: measure tHcy with adverse early pregnancy outcome or 3 months post-partum if birth defect.

b. Patients at high risk of vitamin deficiency:
i. Elderly (> 75y): screening every 3-5 years recommended
ii. Newborns/infants: Vegetarian mothers, exclusively breastfed > 6 m
iii. Poor diet: Vegetarians (no cobalamin supplements), alcohol/drug addicts, elderly, psychiatric disease, dementia
iv. GIT disease causing malabsorption/achlorhydria
v. Chronic use of certain drugs.

TREATMENT OF HYPERHOMOCYSTEINEMIA

Exclude folate and cobalamin deficiencies and treat appropriately.
If vitamin levels are normal, consider other common secondary causes (eg drugs, renal impairment, hypothyroidism).
Consider genetic causes, depending on level of tHcy elevation (if severe congenital homocystinuria , if moderate consider testing for MTHFR C677T polymorphism).
Patients with CVD and increased tHcy (> 15 umol/L): Treat as above PLUS promote healthy lifestyle AND optimal treatment of known causal risk factors (eg lipids and hypertension).

Supplements to consider : B vitamins, homocysteine like lowering formulas, TMG, SAMe, quatrefolic, emothion (S-acetyl glutathione if glutathione levels are lower than expected as well)

QUATREFOLIC® VS FOLIC ACID

In the recent years increasing evidence of the advantages of reduced folate vs folic acid have been found. The rational use of reduced folate (particularly reduced and methylated such as Quatrefolic®) is derived from the inability of a part of world population to assimilate and metabolize folic acid from food or supplements (the most of folate assumption is coming from folic acid man-made version in supplements and added to foods).

Folic acid and also food folate are not biologically active and need to be converted to the metabolically active 5-methyltetrahydrofolate (5-MTHF) through a multi-steps process where the enzyme methylenetetrahydrofolate reductase (MTHFR) owns a key role. Some individuals, due to their unique genetic patterns and expression, have polymorphic forms of this enzyme and do not produce adequate or effective MTHFR (references 5,6,7)

Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, deficiencies in production or function of this enzyme have been associated with increased risk of different diseases.

Quatrefolic® is the glucosamine salt of (6S)-5-methyltetrahydrofolate and is structurally analogous to the reduced and active form of folic acid so Quatrefolic® completely bypasses the “damaged” MTHFR conversion step and delivers a “finished” folate the body can immediately use without any kind of metabolization.

References

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Welch GN, Loscalzo J. Homocysteine and atherothrombosis. Review article. NEJM 1998; 338(15): 1042-1050.
Patanwala I et al. Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 2014
Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014
Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev. 2006
Pietrzik K et al. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010
Lawrence, Kripalani et al. “Profiling National Mandatory Folic Acid Fortification Policy Around the World.” New York: Springer; 2012
Kelly et al. “Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements.” Am J Clin Nutr 1997:65:1790-5
Jamil K. Clinical Implications of MTHFR Gene Polymorphism in Various Diseases. Biol Med. 2014
Wilcken B et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide. J Med Genet. 2003
Morris MS et al. “Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors”. Am J Clin Nutr. 2010

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