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Normal range of homocysteine levels: Levels, Tests, High Homocysteine Levels


Levels, Tests, High Homocysteine Levels

What is homocysteine?

Homocysteine is an amino acid. Amino acids are chemicals in your blood that help create proteins. Vitamin B12, vitamin B6 and vitamin B9 (folate) break down homocysteine to generate other chemicals your body needs.

What does homocysteine do?

When it interacts with the B vitamins, homocysteine converts to two substances:

  • Methionine, an essential amino acid and antioxidant that synthesizes (creates) proteins.
  • Cysteine, a nonessential amino acid synthesized from methionine that reduces inflammation, increases communication between immune cells and increases liver health.

What happens if I have too much homocysteine?

In a healthy person, homocysteine levels are around five to 15 micromoles per liter (mcmol/L). Nearly all that homocysteine converts to other proteins.

If you have more than 50 mcmol/L, the excess homocysteine may damage the lining of your arteries (blood vessels that carry oxygen-rich blood throughout your body). High levels of homocysteine can also lead to blood clots or blood vessel blockages. Artery damage or blood clots significantly raise your risk of heart attack.

Common Conditions & Disorders

What conditions and disorders affect homocysteine?

Typically, homocysteine breaks down into other substances, and only small amounts of homocysteine remain in your blood. Some conditions interfere with this process and leave you with high homocysteine levels.

You may have too much homocysteine in your blood if you have:

  • Deficiencies in vitamins B12, B6 or folate.
  • Heart disease.
  • Rare inherited diseases, such as homocystinuria (when your body can’t process methionine).

What are the risks of high homocysteine levels?

Without treatment, elevated homocysteine levels can lead to severe health complications. Too much homocysteine increases your risk for:

How do I know if I need a homocysteine test?

You may need a homocysteine test if you have a high risk of heart disease. You may also need a homocysteine blood test if you have symptoms of a vitamin B deficiency. Common symptoms of vitamin B deficiencies include:

  • Dizziness.
  • Fatigue.
  • Muscle weakness.
  • Pale complexion.
  • Tingling in your feet, arms or hands.
  • Tongue or mouth soreness.

What do the results of a homocysteine blood test mean?

Unusual homocysteine levels do not necessarily mean you have a medical condition. Other factors can affect your homocysteine blood levels, including:

Caring for Your Homocysteine Levels

How can I keep my homocysteine levels healthy?

If you have high homocysteine levels, your healthcare provider may recommend taking supplements of:

  • Vitamin B6.
  • Vitamin B12.
  • Folic acid (the human-made form of folate).

Increasing your vitamin intake alone does not reduce your risk of heart disease. You can lower your risk of heart disease by:

  • Avoiding or quitting smoking.
  • Consuming less than 2,300 milligrams of sodium daily.
  • Exercising at least three to five times weekly.
  • Managing your blood pressure.

When to Call a Doctor

What should I ask my doctor about homocysteine levels?

You may want to ask your healthcare provider:

  • What is the most likely cause of high homocysteine levels?
  • How can I lower my homocysteine?
  • How can I prevent my homocysteine levels from increasing again?
  • What are the risks of elevated homocysteine levels?

A note from Cleveland Clinic

Homocysteine is an amino acid. Vitamins B12, B6 and folate interact with homocysteine and create other proteins that your body needs. Typically, very little homocysteine stays in your blood. High homocysteine levels could mean you have an underlying condition such as heart disease or homocystinuria. Your healthcare provider may order a homocysteine blood test. Based on the test results, your healthcare provider can recommend the best treatment option.

How It Affects Your Blood Vessels

What is homocysteine?

Homocysteine is an amino acid (a building block of protein) that is produced in the body.

How is a high homocysteine level harmful?

High homocysteine levels in the blood can damage the lining of the arteries. High levels may also make the blood clot more easily than it should. This can increase the risk of blood vessel blockages. A clot inside your blood vessel is called a thrombus. A thrombus can travel in the bloodstream. From there, it can get stuck in your:

  • Lungs (called a pulmonary embolism).
  • Brain (which can cause a stroke).
  • Heart (which can cause a heart attack).

Some people have very high levels of homocysteine. They are at an increased risk for heart disease.

What causes a high homocysteine level?

Homocysteine is normally changed into other amino acids for use by the body. Vitamin B helps your body use the homocysteine. If your homocysteine level is too high, you may not be getting enough B vitamins.

Most people who have a high homocysteine level don’t get enough folate (also called folic acid), vitamin B6, or vitamin B12 in their diet. Replacing these vitamins often helps return the homocysteine level to normal. Other possible causes of a high homocysteine level include:

  • Low levels of thyroid hormone.
  • Kidney disease.
  • Psoriasis.
  • Some medicines.
  • When the condition is common in your family.

How is the homocysteine level measured?

Homocysteine is measured using a simple blood test. If your homocysteine level is too high, you need to lower it. This is especially important if you have blockages in your blood vessels. Sometimes your doctor may take a watchful waiting approach. This means he or she will monitor your level closely but not take steps to lower it. Your doctor may do this if you have no other major risk factors for cardiovascular disease and you don’t have atherosclerosis (a buildup of plaque in your arteries). If your homocysteine level increases further, you may need to lower it.

No studies have shown that lowering homocysteine levels helps reduce strokes, heart attacks, or other cardiovascular conditions. But a high homocysteine level is a risk for heart disease. So it’s a good idea to lower it if you can.

Path to improved health

How can I lower a high homocysteine level?

Eating more fruits and vegetables can help lower your homocysteine level. Leafy green vegetables such as spinach are good sources of folate. Other good sources of folate include:

  • Many breakfast cereals.
  • Fortified grain products.
  • Lentils.
  • Asparagus.
  • Most beans.

You may need to increase the amount of vitamin B-6 in your diet. Foods that are rich in vitamin B-6 include:

  • Fortified breakfast cereals.
  • Potatoes.
  • Bananas.
  • Garbanzo beans (chickpeas).
  • Chicken.

You also may need to increase the amount of vitamin B-12 you eat. Good sources of vitamin B-12 include:

  • Dairy products.
  • Organ meats (such as liver).
  • Beef.
  • Some types of fish.

Adjusting your diet may not be enough to lower your homocysteine level. If it’s not, your doctor may suggest that you take a folate supplement. You may also need to take a vitamin B-6 and vitamin B-12 supplement.

Things to consider

If you start taking folate or vitamin B supplements, you should have your homocysteine level rechecked after 8 weeks. If your homocysteine level remains high, your doctor may have you try a higher dose. You may need to have some tests to see if you have another health condition that causes high homocysteine levels. If you have had a high homocysteine level, you may need to have your level checked more regularly (2 or 3 times a year).

Questions to ask your doctor

  • What is causing my homocysteine level to be high?
  • Could a high level be the sign of another condition?
  • Can I lower my homocysteine level through diet alone?
  • Should I take a supplement?
  • Can I ask my doctor to check my homocysteine level even if I have no symptoms?

Copyright © American Academy of Family Physicians

This information provides a general overview and may not apply to everyone. Talk to your family doctor to find out if this information applies to you and to get more information on this subject.

Gender- and age-related differences in homocysteine concentration: a cross-sectional study of the general population of China

This study was conducted to investigate the distribution of plasma Hcy concentrations in males and females in China and its change with age and to explore independent factors affecting the Hcy concentration. A total of 7872 individuals from among a total of 116,940 people participated in this study. The proportion of males participating was higher (63% of the cohort) than in the general Chinese population, which is about 51.1% according to the National Bureau of Statistics (https://www.stats.gov.cn). This may be because some of the people who visited the hospital for a routine health check-up were referred by their employers and men have higher employment rates than women.

The results of the data analysis showed that the plasma Hcy levels first decreased and then increased, in both males and females, being lowest at 30–50 years of age and increasing significantly after 50 years of age. The trend differs from studies of the white and black populations in the United States, which showed that Hcy concentrations increase with age throughout adulthood15. The mean Hcy concentration levels also showed racial and ethnic differences. The geometric mean plasma tHcy level (13.5 umol/L for males and 9.7 umol/L for females) for our subjects tended to be higher compared with the geometric mean values in the U. S. NHANES report15 (9.6 and 7.9 umol/L in non-Hispanic white males and females, respectively, 9.8 and 8.2 umol/L in non-Hispanic black males and females, respectively, and 9.4 and 7.4 mmol/L in Mexican American males and females, respectively), geometric means in the Hordaland Homocysteine Study for Norway5 (10.8 umol/L for men and 9.1 umol/L for women), and geometric means reported in Korean adults18 (11.18 umol/L for men and 9.20 umol/L for women). The data indicate that the reference range of Hcy concentration in Western countries may not be applicable to Chinese people.

Based on the analysis of Hcy levels in men and women in this study, the results showed definite differences by gender. In comparison with females, Hcy levels in males were significantly higher at each age range, and the trend did not abate with age. In addition, the percentage of males with hyperhomocysteinemia was also higher than that of females at all ages. Previous studies have reported possible associations between various endogenous sex hormones and Hcy levels. Studies have shown that males have higher concentrations of Hcy than females, but the difference diminishes after menopause19. However, our study shows that gender-related differences persist over the lifespan, eliminating the beneficial effects of estrogen. This is consistent with the results reported by Cohen et al.14, which indicates that these gender-related differences persisted in a subgroup analysis of the subjects above the age of 55 years. In another study on sex hormones and the Hcy level in older males, the results did not support a direct role of circulating sex hormone levels in regulating the fasting Hcy concentration in middle-aged and older males20. Our collinearity analysis showed independent effects of age and gender in the relationship with Hcy.

It is well known that vitamin B12 deficiency is a major contributor to elevated Hcy levels. Deficiency of vitamin B12, an important methyl-cobalamin synthesis enzyme, can lead to impaired Hcy re-methylation and Hcy accumulation17. Additionally, vitamin B12 deficiency was found to be significantly associated with gender, and the mean values of serum vitamin B12 concentration for men are lower than those for women21,22. The above suggest that vitamin B12 may explain the relationship between gender and Hcy concentration. The values of serum vitamin B12 in this study were not recorded, which limits the current study. However, according to one previous study, men still had a higher OR (3.44; 95% CI, 2.89–4.09) for hyperhomocysteinemia compared to women, after adjusting for vitamin B12 and some other related confounders (age, smoking status, kidney function and folate). Even if vitamin B12 plays a role in the relationship between gender and Hcy concentration, it seems that the findings of the current study cannot be explained solely by vitamin B12.

These highlight that gender per se is a possible unique independent factor in Hcy concentration and perhaps the difference in Hcy concentration between males and females can be explained by gender-related differences in Hcy metabolism. We noticed that males need to produce creatine more often than females because they have more muscle mass23. Part of the methyl donor needed for creatine synthesis comes from s-adenosyl methionine conversion to s-adenosyl homocysteine. S-adenosyl homocysteine is the precursor of Hcy24, as shown in Fig. 4. Contrarily, studies have shown that females have a greater Hcy flux through the transsulfuration pathway, which lowers the Hcy concentration25.

Figure 4

Pathways of homocysteine metabolism.

According to the data analysis, age also has a significant effect on serum Hcy concentration. After 50 years of age, the Hcy concentration is significantly higher than in other age groups. We speculate there are two reasons for this: first, decreased liver and renal function induce decreased Hcy metabolism in the elderly, resulting in increased serum Hcy concentration; second, the digestive and absorption dysfunction of the elderly lead to vitamin B12 and folate deficiencies, which affects Hcy metabolism. This suggests that clinicians should pay special attention to elderly patients, especially those with cardiovascular and cerebrovascular diseases, as an elevated plasma Hcy level has been reported to be associated with major components of the cardiovascular risk profile5,26 and endothelial dysfunction27. However, it is worth noting that in the multivariate regression analysis of males and females, age is an independent risk factor for homocysteine only in females. In males, age is significant only before the confounders were adjusted, which seems inconsistent with the relationship between age and Hcy concentration shown in the figures.

Independent factors affecting the Hcy concentration in males and females were explored. The results showed that these factors were different in males compared to females. In males, factors associated with Hcy concentration were eGFR, BUN, cystatin C, DBP, smoking status, fT3 and K, while in females, factors associated with Hcy concentration were, cystatin C, albumin, fT4, fT3, age, and K. Additionally, a previous study found that high Hcy levels were negatively associated with cardiovascular health in females, but not in males28. This indicates that not only are the factors affecting Hcy in males and females different, but also, the effects on the body are different, which is very interesting and worth further study.

A previous study showed a negative linear association between the plasma Hcy level and GFR29. Hyperhomocysteinemia occurs when the GFR is about 60 mL/min, and the possibility of hyperhomocysteinemia in end stage renal disease is 85–100%30. Proposed mechanisms for the relationship between renal function and Hcy include reduced renal elimination of Hcy and damaged non-renal disposal31. Damaged non-renal disposal includes the inhibition of crucial enzymes in Hcy metabolism31 and abnormal folate metabolism when in renal failure30. There was one notable contradictory result in that BUN was negatively correlated with Hcy, which should be positively correlated according to the above theory. Urea is the main end product of protein metabolism and Hcy is a methionine metabolism intermediate, which mainly binds to albumin by the disulfide bond. We hypothesized that BUN levels increase when the body is in a high catabolic state, and Hcy levels decrease as a result of decreased protein levels. This assumption, however, was not confirmed.

fT3 was negatively correlated with Hcy in both men and women. Increased fT4 was associated with increased Hcy in women. Studies on thyroid function and Hcy have shown increased Hcy levels in patients with hypothyroidism and subclinical hypothyroidism32,33, and low Hcy levels in patients with hyperthyroidism34. A study35 reported negative correlations between Hcy and TSH and fT3, and a positive correlation between fT4 and Hcy. However, only the data exists and no theory was proposed. Whether there is a causal relationship between Hcy concentration and thyroid function needs further investigation. It is interesting that the average fT3 level of men is higher than that of women36, but the higher fT3 levels do not help men have a lower Hcy level than women. It may be that other factors that increase Hcy in men mask this effect.

In addition, multiple linear regression analysis showed that the Hcy concentration was positively correlated with albumin levels in females. Hcy is an intermediate product of methionine metabolism. In vivo, it is mainly bound to albumin by the disulfide bond, and very little Hcy is in the free state. Table 2 shows that the average albumin level in females is lower than in males. Whether the lower Hcy level is related to the low albumin level remains to be confirmed. Furthermore, according to the molecular studies on Hcy toxicity, protein N-homocysteinylation is one of the important pathogenic and toxic mechanisms of hyperhomocysteinemia37. It has been proved that Hcy and its derivatives can modify protein targets including albumin, hemoglobin, low density lipoprotein, cytochrome C, C-reactive protein, etc.38,39,40,41. Protein N-homocysteinylation provided another perspective for us to analyze the gender difference in hyperhomocysteinemia.

Serum potassium was negatively correlated with Hcy in both men and women. As far as we know, there is no research showing that serum potassium has a biological effect on Hcy concentrations. But when potassium was added to the multiple regression model, the regression coefficients of the other variables in the model changed greatly and the goodness of fit of the model improved. Even with a sample of such magnitude, significant associations might be random, particularly for associations which carry no biological plausibility. Considering that the inclusion of potassium to the model only affects the size of the regression coefficient of other variables, but not its significance, we displayed the results that contained potassium just in case there are biological processes associated with potassium and Hcy that we don’t know yet.

This study is the first statistical analysis of the Hcy concentration over the lifetime in males and females, separately, and the first investigation of the factors associated with the Hcy concentration. We found significant differences in Hcy level between males and females, which differences did not diminish in old age. At the same time, the relationship of thyroid function and albumin with Hcy was confirmed for the first time, providing abundant reliable data for further understanding Hcy and clues and ideas for further exploration of the effects of Hcy on the body.

Our study has some limitations that deserve mentioning. First, we were unable to infer causality because this was a retrospective cross-sectional study. However, the examined association implies causation. Second, important parameters (vitamin B12 and folate levels, sex hormones, etc.) should be framed as residual confounding to avoid a false positive (Type I) error. However, we can only discuss confounding factors qualitatively rather than quantify their effects because they were not recorded during the health checks. The third limitation concerns the external validity of the study. Because Hcy tests are only given to individuals or groups that have purchased more expensive medical checkup packages, the subjects in this study may not be a good representation of different socioeconomic classes. However, although the external validity of the study is limited, it is not expected to influence the examined associations. Last, the relationship between serum potassium and Hcy concentration may be only at the analytical level.

Why High Homocysteine is Bad + Should You Decrease It? SelfDecode Labs

High homocysteine can be a marker of vitamin deficiency. It has been linked to many health problems including heart disease, dementia, and Alzheimer’s. However, studies have shown that lowering homocysteine with vitamin supplements doesn’t necessarily produce desired health benefits and may even be harmful. This post explains homocysteine, reviews the factors that influence its levels, including diet, lifestyle, and genetics (i.e. MTHFR mutation), and discusses the best ways to optimize your levels in ways that are actually conducive to better health.

What is Homocysteine?

Homocysteine is a sulfur-containing amino acid that the body produces from another amino acid, called methionine. Foods that are high in methionine include meat, egg whites, and seafood.

Homocysteine is usually found in very small amounts in your body. That’s because your body converts it efficiently into other products with the aid of B vitamins. Higher homocysteine levels can indicate a deficiency of these vitamins [1].

Apart from vitamin deficiency, higher homocysteine levels have been linked to heart disease, cognitive dysfunction, and dementia.

The Breakdown of Homocysteine

Homocysteine is converted into less toxic and more useful amino acids via two biochemical pathways, i.e. remethylation or transsulfuration:

  • Remethylation – A methyl group from 5-MTHF, a breakdown product of dietary folate, or betaine is added to homocysteine to convert it back to methionine. Vitamin B12 is needed in this process, as are the enzymes methionine synthase MTHFR [2, 3].
  • Transsulfuration – Homocysteine is converted to cystathionine by cystathionine β-synthase. Vitamin B6 is needed for this conversion [2, 3]. Cystathionine can then be converted into cysteine and subsequently glutathione (a very powerful antioxidant) [4].

When homocysteine can not be converted to other compounds, it builds up in the body and may cause damage. B vitamins play a very important role in this balance.

Homocysteine Blood Test

A doctor may order a homocysteine test to:

  • Find out if there is vitamin B12, folate, or vitamin B6 deficiency
  • Check for heart disease in people at high risk
  • Help diagnose homocystinuria, a rare genetic disorder

Homocysteine is not a commonly used test. It’s relatively expensive and rarely covered by insurance. Ranges and results may slightly vary from lab to lab, due to differences in equipment, techniques, and chemicals used.

A high-protein meal can significantly increase homocysteine levels. Therefore, fasting throughout the night before a blood test is recommended to ensure the most accurate results [5].

Reference Ranges

The normal range of homocysteine is usually below 15 micromoles per liter (µmol/L).

Elevation in homocysteine can be [2]:

  • Moderate: 15 – 30 µmol/L
  • Intermediate: 30 – 100 µmol/L
  • Severe: > 100 µmol/L

High Homocysteine Levels

Factors That Increase Homocysteine Levels

A result that is higher than normal doesn’t necessarily mean that you have a medical condition needing treatment. Your doctor will interpret a high homocysteine result together with your medical history, signs and symptoms, and other test results.

Causes listed below are commonly associated with elevated homocysteine. Work with your doctor or another health care professional to get an accurate diagnosis.

1) B Vitamin Deficiency

Homocysteine levels increase if there is:

  • Vitamin B12 deficiency [6, 7]
  • Vitamin B6 deficiency [6]
  • Folate (vitamin B9) deficiency [6, 7]

Several studies that looked at people with different dietary patterns, found that people who were on a vegetarian or a vegan diet had significantly higher homocysteine levels, likely due to lower vitamin B12 levels [8, 9, 10, 11].

2) Smoking

Studies suggest that both smoking and exposure to second-hand smoke can increase homocysteine levels [12, 13].

3) Alcohol

Daily alcohol consumption can increase homocysteine levels, likely by lowering vitamin B12 and folate levels [14, 15].

4) Stress

Several studies suggest that stress may increase homocysteine levels [16, 17, 18].

5) Medication

Several drugs can increase homocysteine levels, including:

  • Methotrexate, an immunosuppressant [19, 20]
  • Metformin, used in diabetes [21]
  • Cholestyramine, used to lower cholesterol [22]
  • Antiepileptics [23, 24, 25]
6) Kidney Disease

Kidneys help transform homocysteine into other amino acids [26]. Therefore, a decrease in kidney function can cause an accumulation of homocysteine.

This explains why those with kidney disease have high homocysteine levels [27, 28, 29].

7) Hypothyroidism

Several studies have found higher homocysteine levels in hypothyroidism [30, 31, 32].

A meta-analysis of 17 studies found that hypothyroid people not treated with levothyroxine (synthetic T4) had increased homocysteine levels, associated with the severity of hypothyroidism. Further, levothyroxine treatment was effective in reducing homocysteine levels [33].

8) Dental Health

Chronic periodontitis (inflammation of the teeth and gums) has been linked to elevated homocysteine levels in studies. This elevated homocysteine level returns to normal after the periodontal diseases are treated [34, 35].

9) Genetics

Homocysteine levels increase in a rare inherited condition called homocystinuria [36, 37]. If severely elevated homocysteine levels are found, your doctor will usually do more testing to rule out or confirm a diagnosis.

Other than homocystinuria, slight elevations in homocysteine can be caused by relatively common mutations in the MTHFR gene [38, 39, 40].

Every individual has 2 MTHFR alleles (1 from each parent). Mutation in just one MTHFR alleles is referred to as “heterozygous”; mutations of both is called “homozygous”. Approximately 10% of people of European descent have two mutations in this gene (homozygous form).

The two most common MTHFR mutations (polymorphisms) found in humans are:

  • MTHFR C677T (Rs1801133). This mutation (the A allele) is associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate [41]. People with one “A” allele for this mutation have a 35% lower and people with “AA” genotype 68% lower enzyme activity [42].
  • MTHFR A1298C (rs1801131). This mutation also impacts the MTHFR activity and homocysteine levels but to a lesser extent than C677T [41].

In a study of 872 healthy people, those who were homozygous for the MTHFR mutation (MTHFR 677TT genotype) were 10 times more likely to have high homocysteine levels compared to those with normal MTHFR [40].

Other genes that can impact homocysteine levels are genes that encode methionine synthase (MTR; rs1805087) and cystathionine-β-synthase (CBS; rs5742905, rs121964962) [40].

Diseases Associated with High Homocysteine

Elevated homocysteine levels have been linked to a number of diseases.

However, if you have high homocysteine levels it doesn’t mean you have any of the below-listed diseases!

High homocysteine levels are also encountered in:

  • Sleep apnea [43]
  • Autism [44, 45]
  • Gut disorders [6]

It is important to correct your homocysteine levels if possible. High homocysteine increases the risk of:

  • Heart disease [6]
  • Hardening of the arteries [6, 46]
  • Cognitive decline and dementia [46, 47]
  • Alzheimer’s [6]
  • Osteoporosis and bone fractures [6, 48, 49]
  • All-cause mortality [50, 51, 52, 53, 54, 55]

1) Heart Disease

High homocysteine (hyperhomocysteinemia) has been suggested as a potential risk factor for heart diseases since the early 90s [56, 57].

Studies have shown that higher fasting blood homocysteine levels are linked to a higher risk of heart disease and stroke [56, 58, 59].

However, the exact role homocysteine plays in heart disease has not yet been confirmed. Some scientists suggest that higher levels of homocysteine contribute to the narrowing and hardening of the arteries (atherosclerosis) [6, 60, 61, 59].

On the other hand, a large study of over 115k people suggests that lifelong moderate homocysteine elevation (based on genetics) had little or no effect on heart disease and calls previously published studies into question [62].

In addition, there is some controversy when it comes to lowering homocysteine levels using supplements. Large-scale studies have shown that using combined vitamin B supplements to lower homocysteine was ineffective in preventing heart disease, and even harmful in some cases [63, 64, 65]!

A meta-analysis of 15 studies with over 71k people has found that homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination had no effect on preventing heart attack or all-cause mortality compared to placebo, although there was a very small benefit when it came to preventing stroke [66].

Therefore, homocysteine may not actually be a risk factor but a risk marker for heart disease, harmful when elevated due to other factors that increase heart disease risk, such as a diet rich in red meat and low in fruits and vegetables or smoking [67].

Because of the discrepancies listed above, the American Heart Association doesn’t consider homocysteine a major factor for heart disease. That’s also why routine testing is not recommended [68, 67].

Technical: Homocysteine may cause an inflammatory response in vascular smooth muscle cells by stimulating CRP production. However, this is based on animal research and has yet to be confirmed in humans [69]. CRP or C-reactive protein is a well-known marker of chronic inflammation that can increase the hardening of the arteries and heart disease risk.

2) Insulin Resistance

A study has found that people with insulin resistance tend to have higher homocysteine, likely due to the effects of insulin exerts on homocysteine metabolism and kidney clearance [70].

3) Depression

A study with 924 men found that those in the upper third of homocysteine levels were more than twice as likely to be depressed than those in the lowest third [71].

A second study found that individuals with the highest homocysteine levels (>12 µmol/L) tended to have lower levels of SAMe, a nutrient that is vital for the production of neurotransmitters associated with mood-enhancement [72].

In a study in 236 hospitalized acutely ill older patients, supplementation with vitamins B2, B6, B12, and folic acid decreased homocysteine levels and reduced depressive symptoms [73].

4) Cognitive Function, Dementia, and Alzheimer’s Disease

A systematic review and meta-analysis of 111 articles found an association between cognitive decline and increased plasma homocysteine levels. However, treatment with vitamin supplements failed to prevent cognitive decline [74].

Similarly, a meta-analysis of 10 studies with 1.9k people with cognitive impairment and 21 studies with over 15k people without cognitive impairment found that higher homocysteine was associated with an increased risk of cognitive impairment and dementia. But there was no obvious cognitive benefit of lowering homocysteine using B vitamins [75].

In a study of 1.9k people without dementia, higher homocysteine levels were associated with an increased risk of developing dementia and Alzheimer’s disease over the following 8 years. Homocysteine levels above 14 µmol/L were associated with nearly twice higher Alzheimer’s disease risk [76].

Cell and animal models suggest that homocysteine may be able to trigger neuronal damage through oxidative stress, DNA damage and activation of pro-apoptotic (pro-cell death) factors in cell and animal models [77]. However, these findings don’t necessarily apply to humans.

5) Autoimmune Disease

Homocysteine levels can be higher in some autoimmune diseases such as

  • Rheumatoid arthritis patients [78]
  • Lupus [79, 80]
  • Psoriasis [81]

Homocysteine levels are only elevated in some cases of multiple sclerosis, but not others [82].

6) Osteoporosis

Higher homocysteine has been associated with a higher risk of osteoporosis [6, 83].

However, treating high homocysteine with vitamin B supplements is unlikely to help. A study in over 75k women found that vitamin B6 and B12 supplements, alone or combined, increased the risk of hip fractures by up to 50% [84].

7) Migraine

While we still don’t completely understand the causes of migraines, some clinicians speculate that homocysteine may cause migraines by inflaming the blood vessels and contributing to the blood clotting cascade (thrombosis).

The concentration of homocysteine in cerebrospinal fluid that bathes the brain is increased in migraine patients [85].

People who have mutations in genes that are involved in homocysteine metabolism, such as MTHFR mutation rs1801133, are more likely to get a migraine [86].

B vitamin supplementation decreased the severity and frequency of migraine attacks in some studies [85, 87, 88].

However, the association between migraine and homocysteine levels is speculative and further research is needed to confirm it.

Low Homocysteine

Although much rarer, and generally less of an issue than high levels, low homocysteine levels may also cause problems.

For example, adequate homocysteine levels are necessary for the production of factors important for detoxification (e.g. glutathione production), such as cysteine, taurine, and sulfate. Thus, low homocysteine levels can restrict detoxification pathways that respond to oxidative stress [89].

Low homocysteine has been associated with nerve damage of unknown cause (idiopathic peripheral neuropathy) [90].

How to Decrease Homocysteine Levels

The most important thing is to work with your doctor to find out what’s causing your high homocysteine levels and to treat any underlying conditions.

Discuss the lifestyle changes listed below with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes!

1) A Healthy Diet

The best way to prevent homocysteine from increasing is to ensure your diet contains adequate amounts of folate (vitamin B9), vitamin B12, and vitamin B6.

Folate is abundant in fresh fruits and vegetables, while vitamin B12 is found in animal products, including meat, fish, cheese, and milk. The richest sources of vitamin B6 include fish, beef liver, potatoes and other starchy vegetables, and fruit (other than citrus).

Studies suggest that simply supplementing with these vitamins to lower homocysteine levels doesn’t prevent diseases and disorders associated with high homocysteine, such as heart disease, impaired cognitive function, dementia, and osteoporosis. In fact, taking combined vitamin B supplements may even be harmful [84, 65].

In other words, homocysteine is likely a marker of a healthy diet and lifestyle, and not a target to address in its own right. So it’s important to check your vitamin levels and correct any deficiencies, but ultimately, it’s best to prevent deficiencies by having a healthy balanced diet.

However, in some cases, vitamin deficiencies can have non-dietary causes, such as bleeding or gut issues (malabsorption), in which case they can’t be corrected by simple dietary adjustments. Work with your doctor to address such underlying issues.

And if you do need to take supplements, it’s best if you can take active forms of vitamins, such as methylcobalamin, or 5-MTHF.

2) Regular Exercise

Although exercise increases homocysteine short-term, in the long term, it is associated with lower homocysteine levels.

A systematic review of 34 studies found that regular exercise may be able to decrease homocysteine levels [91].

A study in Parkinson’s disease patients found that those who regularly engage in exercise had lower homocysteine levels [92].

3) Managing Stress

Although the link between stress and homocysteine is not quite clear, several studies have found that stress can increase homocysteine levels [16, 17, 18].

Therefore, finding ways to avoid or cope with stress can be beneficial to decrease homocysteine but also to improve health in general.

A study has shown that yoga may help reduce elevated homocysteine levels [93].

4) Quitting Smoking

Both smoking and exposure to second-hand smoke can increase homocysteine levels [12, 13].

If smoking, quitting may help decrease homocysteine levels.

5) Alcohol

Daily alcohol increases homocysteine levels [14, 15].

Discuss your alcohol consumption with your doctor. Avoid heavy drinking.

6) Supplements

The following supplements have been found to decrease homocysteine in small-scale clinical trials:

  • Omega-3 [94, 95]
  • N-acetylcysteine [96, 97]
  • Probiotics (L. plantarum) [98]
  • Beta-carotene [99]
  • Betaine [100]

However, as lowering homocysteine with vitamins has shown little clinical benefit, using other supplements for the same purpose will likely also be clinically ineffective.

Remember, always speak to your doctor before taking any supplements, because they may interfere with your health condition or your treatment/medications!

Homocysteine – Lab Tests Online AU

How is it used?

A doctor may order a homocysteine test to determine if a person has B12 or folate deficiency. The homocysteine concentration may be elevated before B12 and folate tests are abnormal. Some doctors may recommend homocysteine testing in malnourished patients, the elderly, who often absorb less vitamin B12 from their diets, and those with drug or alcohol addictions.

A doctor may order both a urine and blood homocysteine to help diagnose homocystinuria if there is suspicion that an infant may have this inherited disorder. In some states, babies are tested for excess methionine as part of their newborn screening. If a baby’s test is positive, then urine and blood homocysteine tests are often performed to confirm the findings.

Homocysteine may also be ordered as part of a screen for people at high risk for heart attack or stroke. It may be useful in someone who has a family history of coronary artery disease but no other known risk factors. Its utility for this purpose, however, continues to be questioned because the role, if any, that homocysteine plays in the progression of cardiovascular disease (CVD) has not been established. Routine screening, such as that done for total cholesterol, is not yet recommended.

When is it requested?

This test may be ordered when a doctor suspects that a person may have a B12 and/or folate deficiency or when a baby has signs or symptoms that suggest that he or she may have homocystinuria.

Homocysteine may be ordered as part of a cardiac risk assessment, depending on the patient’s age and other risk factors. It may also be used following a heart attack or stroke to help guide treatment.

What does the test result mean?

In cases of suspected malnutrition or vitamin B12 or folate deficiency, homocysteine levels may be elevated. If you do not get enough B vitamins and/or folate through diet or supplements, then your body may not be able to convert homocysteine to forms that can be used by your body. In this case, levels of homocysteine in the blood can increase.

In newborn testing, greatly increased concentrations of homocysteine in the urine and blood mean that it is likely that an infant has homocystinuria and indicates the need for further testing to confirm the cause of the increase.

Older studies (1995 to 1999) suggested that people who have elevated homocysteine levels have a much greater risk of heart attack or stroke than those with average levels. At present, however, the use of homscysteine levels for risk assessment of cardiovascular disease (CVD), peripheral vascular disease and stroke is uncertain given that several trials investigating folic acid and B vitamin supplementation indicate no benefit or lowering of CVD risk. The American Heart Association does acknowledge strong evidence of a relationship between homocysteine levels and heart attack/stroke survival rates but stops short of calling elevated homocysteine a major risk factor for cardiovascular disease. Blockage of a coronary artery, a precursor to a heart attack, occurs with more than double the average frequency in people with homocysteine levels in the highest 25% as compared to those in the lowest 25%.

At present, a direct correlation between homocysteine levels and heart attacks has not been established but there does seem to be strong evidence of a relationship between homocysteine levels and heart attack/stroke survival rates.

Since measuring homocysteine levels to determine cardiac risk is a relatively new use for the test, the exact reference range has yet to be determined.

Is there anything else I should know?

There is a hereditary (genetic) form of homocystinuria – an increase of homocysteine in the urine – that causes a form of mental retardation, skeletal abnormalities, and premature cardiovascular disease. A prevents an enzyme from breaking down homocysteine into products that can be excreted through the kidneys. The build-up of homocysteine thus becomes toxic to the body. The most common hereditary form results in both an increase in homocysteine and a decrease in folic acid. When test results suggest homocystinuria, liver or skin samples are sometimes tested to determine whether the enzyme cystathionine beta synthase (CBS) is present. The absence of this enzyme is the most common cause of homocystinuria. Genetic tests may be ordered to test for one or more of the most common gene . If the patient has a strong family history of early atherosclerosis or a family member has been diagnosed with homocystinuria, then the patient should be tested for the gene mutation that was found in the family member.

Homocysteine levels can increase with age, when a patient smokes, and with the use of drugs such as carbamazepine, methotrexate and phenytoin. Homocysteine levels are lower in women than in men. Women’s concentrations increase after menopause, possibly due to decreased estrogen production.

Homocysteine Levels: What They Mean + Why They Matter

What your homocysteine level means for your health

Homocysteine is regulated during a biochemical process known as methylation. Methylation acts like a big biochemical superhighway, influencing and helping to regulate your immune system, brain, hormones, and gut. The methylation process occurs about a billion times every second in your body, and if it isn’t working as well as it should, chances are, you will feel it. Methylation gene mutations, such as the MTHFR variation, are closely associated with autoimmune-inflammation spectrum issues, and keeping homocysteine at a healthy level (not too high).

If you have one or two mutations at the MTHFR C677t gene, your body is not as efficient at managing homocysteine. For example, I have a double mutation of this gene, so I have to be extra diligent in supporting that genetic weakness. Fortunately there are some things you can do to keep your homocysteine in check, even if you are genetically predisposed to have problems in this area.

When homocysteine is too high

In addition to the influence of genetic mutations, such as the MTHFR mutation, that can cause elevated homocysteine levels, (1) homocysteine can also rise too high due to lifestyle. Certain medications, a poor diet, toxin exposure, hormone imbalances, and stress can all influence homocysteine. Another major contributor is a deficiency in B vitamins.

B vitamins from food and supplements act as methyl donors that help keep your body’s homocysteine at a healthy level and methylation working optimally. Homocysteine will use these methyl donors to produce the über-beneficial compounds SAMe and glutathione, which is extremely important for your health. Your body needs SAMe and glutathione to put autoimmune symptoms into remission. This happens through glutathione’s role as the body’s most powerful antioxidant and SAMe’s ability to protect nerves and support neurotransmitters like serotonin and dopamine. When methyl donors are inadequate, homocysteine can build up and continue to increase.

The optimal range for homocysteine in functional medicine is less than 7 μmol/L. When homocysteine is higher than this, you can see it play out in a multitude of seemingly unrelated health problems, including those related to autoimmunity and chronic inflammation.

The homocysteine-autoimmunity connection

One of the most important things methylation does is keep the good genes turned on, and keep the bad genes turned off. When methylation isn’t working correctly, genes that can trigger autoimmune issues can get turned on, leading to serious health problems. High homocysteine levels are associated with incredibly common autoimmune diseases like Hashimoto’s disease, rheumatoid arthritis, and psoriasis. So to avoid a higher risk of these conditions, it’s best to keep methylation working and homocysteine in normal range.

The homocysteine-heart disease connection

Homocysteine is most notorious for its link to an increased risk of cerebrovascular, heart, coronary, and peripheral artery diseases. (2) Especially high homocysteine levels have been connected to coronary artery disease and higher risk of hardening of the arteries. Even moderate levels can increase risk.

Heart attack and stroke can be brought on by autoimmune conditions—lupus and autoimmune thyroid disease, in particular—which we have seen are also affected by homocysteine levels, creating a double whammy of dysfunction. I’ve written many articles before about how low cholesterol is not a good indicator of a healthy cardiovascular system, but homocysteine is. In fact, research shows that not only is it more important than cholesterol, but inflammatory markers like homocysteine are actually a better indicator of heart disease than other well-known risks like smoking and high blood pressure. (3)

The homocysteine-cognitive decline connection

If you are like most people, you fear dementia, and high homocysteine levels can affect the brain because it can be toxic to neurons (4) and other cells. (5) Normally, old and damaged cells do get flushed out of our systems from the autophagy process (which is our cells’ way of self-cleaning) to keep our brains healthy and avoid the premature death of healthy cells associated with cognitive decline. But did you know that many diseases that cause cognitive decline also have an autoimmune component?

Parkinson’s disease, Alzheimer’s, and multiple sclerosis are all neurological autoimmune spectrum diseases and can be linked to high homocysteine levels. As homocysteine rises, it can start to destroy the blood-brain barrier, which can cause “leaky brain syndrome.” According to recent research, when homocysteine levels increase to 14 µmol/L or higher, the risk of Alzheimer’s doubles. (6) This is especially important considering the growing rate of Alzheimer’s in the U.S.: Over 5.7 million Americans suffer from Alzheimer’s today, and that number is expected to rise to 14 million by 2050. But you can decrease your chances of succumbing to cognitive decline, dementia, and the epidemic of Alzheimer’s disease by keeping methylation pathways healthy. Lowering homocysteine is crucial to protect your brain from dementia.

The homocysteine-depression connection

Homocysteine can also affect the brain in less severe but debilitating ways, particularly by increasing the risk of depression. Various studies have connected depressive thoughts to higher homocysteine levels. High homocysteine has been correlated with low serotonin levels, which are a known contributor to depression. According to some experts, the high homocysteine levels present in women after giving birth contribute to postpartum depression. (7) Men are not immune, however. A recent study involving a large group of men showed that those with the highest homocysteine levels (in the top third of those studied) were twice as likely to struggle with depression than those in the lowest third.

Getting your homocysteine tested

If you think high homocysteine levels could be an issue you deal with, the first step is to ask your doctor to run a homocysteine lab test, along with a methylation genetic test. Note that conventional doctors and laboratories have a higher number for what they consider to be a normal homocysteine level than what is considered healthy in functional medicine. If your homocysteine level is elevated, the genetic test can give you and your doctors more insight into why your homocysteine levels might be higher than normal.

The more gene polymorphisms you have, the more susceptible you will be to methylation issues. When you know that you’re at a higher risk for autoimmune disorders from genetic predisposition, you and your doctor can understand your health case better and take more targeted and personalized steps to overcome your particular deficiencies. This can include making sure you’re correcting any nutrient deficiencies, supporting the health of your immune system by eating an anti-inflammatory diet, getting plenty of sleep, moving your body regularly, and repairing your gut health.

Another helpful step is to see a functional medicine practitioner. Along with the homocysteine and methylation labs, a functional medicine practitioner will find out all about your health history and lifestyle, and will order additional labs that seem appropriate for your unique situation, to get a better understanding of your entire health case. Lab testing will help bring any other underlying health issues to light, to help you reach optimal health.

But you don’t have to wait for an appointment with your doctor. If you want to start lowering your homocysteine levels right away, you can begin by ensuring that you’re consuming enough B vitamins. Activated forms of folate (methylfolate), B6 (oyridoxyl-5-phosphate), and B12 (methylcobalamine) are the best options to ensure healthy methylation pathways. The best way to get these vitamins is through food, so focus on  vitamin-B-rich, methylation-supporting foods like green leafy vegetables, sulfur-rich vegetables like cabbage and broccoli sprouts, wild-caught fish, grass-fed beef, and organ meats like grass-fed liver. (8) The healthier your diet and lifestyle, the lower your homocysteine, and the lower your homocysteine, the better that all-important methylation process will work for you.

As one of the first functional medicine telehealth clinics in the world, we provide webcam health consultations for people around the globe. 

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Homocysteine Blood Test | Walk-In Lab