Folate, Vitamin B6, and Vitamin B12 Intake in Relation to Hyperuricemia

If you suffer from gout, or you know someone who has, you’ll be well aware of how painful and debilitating it can be.

Gout doesn’t strike randomly. It’s usually a consequence of another serious condition: hyperuricemia.

Hyperuricemia (HU) is a metabolic disorder affecting around 21% of American adults and is fast becoming a serious public health problem.

Hyperuricemia occurs in people who have excess levels of uric acid in their blood. It can lead to a range of health issues including not only gout but heart disease, diabetes, and various kidney problems.

It’s considered to be a major risk factor for gout arthritis, cardiovascular diseases, type 2 diabetes, hypertension, and chronic kidney disease.

Although the exact cause of HU is not entirely certain, a number of dietary factors are thought to contribute. Uric acid is a waste product formed in the body following the breakdown of purines (adenine, guanine, and xanthine), which are naturally present within the body's cells and in certain foods.

While gout is often associated with poor diet and being overweight, hyperuricemia itself isn’t necessarily a disease that “unhealthy people” get. Cases of hyperuricemia have increased dramatically over the last 50 years. It’s estimated that around 43.3 million Americans are now affected.

What’s more, recent research suggests that the risk of developing hyperuricemia could be as simple as a B vitamin deficiency, which is more common than most people realize.

A 2018 study published in the Journal of Clinical Medicine sought to identify the impact that folate, B6, and B12 could have on hyperuricemia.¹ It was the first study to show an association between intakes of folate, vitamin B6, and vitamin B12 with hyperuricemia.

The study included 24,975 US adults aged 20 between 85 years, which was the largest population-based study using a nationally representative sample in the US.

The results provided important insights into just how valuable B vitamins are to our overall health.

What the researchers found was this: supplementation with folate and vitamin B12 could be the key to preventing and treating excess uric acid levels in both men and women. 

The study used data from National Health and Nutrition Examination Survey (NHANES), an ongoing survey administered by the Centers for Disease Control and Prevention, to represent the total civilian population of the US.

Uric acid samples were taken from a total of 3,215 adults aged between 20–85 years provided UA samples for NHANES 2001–2014. This included 12,218 women and 12,757 men.

The participants were interviewed about their daily diet to gauge their overall nutritional intake. Daily folate intake referred to both food folate and folic acid, and was measured against the RDA of 400mcg.

Prior to the current study, there was little research into the relationships between folic acid and serum uric acid, and no known studies investigating the link between intakes of folate, vitamin

B6, vitamin B12, and hyperuricemia.

While overall nutrient intake is crucial for the maintenance of healthy uric acid levels, the most important of these nutrients appears to be folate. There are many reasons for this.

Firstly, folate and its derivatives has been found to inactivate the enzyme xanthine oxidoreductase (XOR), which is responsible for two important processes:

1. The oxidation from hypoxanthine to xanthine
2. And the oxidation from xanthine to uric acid

XOR converts hypoxanthine to xanthine and then xanthine to uric acid. These are the last two steps in the breakdown of purines in the body.²

Folate helps to reduce uric acid levels by inhibiting XOR. It does this by slow binding with high affinity at the molybdenum site, which is where purines interact. Folic acid disrupts the interaction of the enzyme with xanthine and hypoxanthine.

Several studies have shown a significant link³ between elevated homocysteine levels (hyperhomocysteinemia) and hyperuricemia . Hyperhomocysteinemia is particularly prevalent in patients with gout.

Folate not only helps to lower homocysteine, but lower homocysteine levels are also associated with a lower risk of hyperuricemia.

This link is believed to be due to the fact that long-term elevated levels of homocysteine result in a simultaneous increase in intracellular S-adenosylhomocysteine (SAH). SAH is known to cause serious damage to DNA, as well as releasing purine nucleotides. The breakdown of these purine nucleotides ultimately results in the production of uric acid.

This means that lowering homocysteine levels is likely to be highly beneficial in also lowering serum uric acid levels.

Folate, vitamin B6, and vitamin B12 all play crucial roles in lowering homocysteine, as has been shown in numerous studies. Normally, homocysteine is broken down by the body’s stores of vitamin B12, vitamin B6, and folate. It is then converted into substances that the body can use.

But if the body is lacking in any of these nutrients, homocysteine won’t be converted. This results in elevated homocysteine levels and fewer of the beneficial compounds the body requires.

Previous studies have also demonstrated that it is possible to reduce homocysteine levels by increasing intake of folate, vitamin B6, and vitamin B12.

A previous clinical trial showed that folic acid therapy can be effective in reducing uric acid levels in adults with high blood pressure.⁴ In addition, a study from Taiwan showed that high folate intake may protect against gout, while other studies have suggested that high doses of supplemental folate may help in both preventing gout and its recurrence.⁵

But if the body is lacking in any of these nutrients, homocysteine won’t be converted. This results in elevated homocysteine levels and fewer of the beneficial compounds your body needs.

Excess homocysteine levels can lead to one of two serious health issues: inflammation of the blood vessels, and/or oxidative stress.

A study published in the British Medical Journal showed that elevated homocysteine levels in blood plasma increased the risk of death from cardiovascular disease⁶ in older people even more than high cholesterol, blood pressure or smoking.

As explained above, high levels of homocysteine may cause vascular damage due to toxic accumulation in endothelial cells and the generation of free radicals.

Numerous studies have indicated that correct doses of vitamins such as folic acid, vitamin B6, vitamin B12, and betaine may control or alleviate the risk of elevated⁷ homocysteine.

Elevated homocysteine is strongly linked to low levels of plasma folate. There are also links between blood levels of vitamin B12 and pyridoxal-5-phosphate (the active form of B6). Previous studies have also found that elevated homocysteine levels in plasma was an independent risk factor for ischemic stroke.

Unsurprisingly, varying degrees of hyperhomocysteinemia are detectable in all inflammatory diseases. Hyperhomocysteinemia is also considered as a risk factor for inflammatorydiseases including life-threatening cardiovascular disease, stroke, renal failure and cancer.

In many cases, inflammation occurs when white blood cells rush to a site of infection or injury in order to fight off pathogens. Chronic inflammation results in a buildup of white blood cells and damage to the surrounding tissues, along with excess deposits inside the blood vessels.This buildup can ultimately lead to interruption of normal blood flow in the brain: a stroke.

Raised homocysteine affects the way cells use oxygen, causing a buildup of oxidized fats and proteins within developing arterial plaques. This oxidation injury - along with methylation defects and hindered DNA repair due to poor folate metabolism - has also been linked to the development of cancer.

It has also been shown that hyperhomocysteinemia not only is produced from inflammation, but the oxidative stress generated from hyperhomocysteinemia will again promote inflammation. As a result, elevated homocysteine and inflammation markers are frequently being detected at the same time,⁸ even if they are not correlated.

Oxidative damage also causes injury to blood vessels, making them more likely to catch sticky material and blood. This increases the risk of blood clots and bleeding.

As found by the researchers in this study, men who were otherwise healthy (i.e. no history of cardiovascular disease or diabetes) were able to reduce their risk of ischemic stroke by taking higher levels of folate and vitamin B12. This finding is supported by other epidemiological and experimental studies on the benefits of folate in preventing ischemic stroke.

But taking any old multivitamin won’t do. There’s another factor at play in the homocysteine pathway: genetics and MTHFR.

A mutation in the MTHFR gene - particularly SNP (single nucleotide polymorphism) C677T not only contributes to elevated homocysteine, but also to the risk of Vitamin B12 deficiency. MTR and MTRR variants are other genetic SNPs which may significantly impact the conversion and absorption of B12 in the body as well as folate and other nutrients.

It’s for this reason that only a bioactive form of folate and vitamin B12 is crucial to overall wellbeing and prevention of chronic disease.

Folate is the natural active form of vitamin B9 in food. Folate is vital to your health no matter what age you are or what stage of life you’re at. It’s required for many different functions within the human body, particularly the production of red blood cells. Folate occurs naturally in many foods such as legumes and leafy greens.

Deficiency or low levels of folate can be caused by genetics, certain diseases, medications, or by not obtaining folate from your food.

One of folate’s most crucial roles is in ridding the body of excess homocysteine. Ordinary folic acid supplements will not provide the full spectrum of effects if an individual is unable to convert folate to its biologically active form called 5-methyltetrahydrofolate (5-MTHF) or L-Methylfolate.

Because a large proportion of the population has the genetic enzyme deficiency that prevents the proper conversion of folate to 5-MTHF,many people are vulnerable to low blood folate levels and subsequently, higher than desired homocysteine (even if they take a folic acid supplement daily).

For this reason, taking bioactive folate 5-MTHF directly has been shown to significantly increase blood serum folate levels compared with folic acid supplementation.

Key point: This form of folate is vital for people who have a genetic enzyme deficiency because it requires no conversion to become metabolically active.

Folic acid, on the other hand, is the synthetic (man-made) form of folate that is added to fortified foods or dietary supplements.

Some of the best methylfolate supplements for vegans, those with cardiovascular risks, or MTHFR mutations include Methyl-Life™ products (B-Methylated II, Methylated Multivitamin, also Methylfolate 7.5+ or Methylfolate 15+ if you suffer from depression).

These have been created by a team of natural health experts and used successfully by hundreds of people all over the world. It’s worth noting that Methyl-Life™ recently received data from a study that showed theirs to be the purest, stable, and most potent of four of the world’s industry-leading, patented L-Methylfolates. Check out the study comparison details to learn more.

B12 works closely alongside folate to help make red blood cells which are required for carrying oxygen to all parts of your body. It’s also required to keep homocysteine levels from becoming elevated.

Normally, homocysteine is broken down by your body’s stores of vitamin B12, vitamin B6, and folate and changed into substances that your body actually needs. However, a lack of any particular nutrient can lead to an undesirable elevation in homocysteine levels and a lowering of the ‘good and necessary’ compounds your body requires.

Vitamin B12 also plays a major role as a cofactor in the methylation process of L-methylfolate, and is then required for the conversion of homocysteine to methionine. The conversion of homocysteine to cysteine also requires B-6 (specifically pyridoxal-5-phosphate).

Vitamin B12 is also crucial for proper brain development and the one-carbon metabolism required for transmethylation reactions in the recovery of methionine from homocysteine. It’s also involved in the formation of S-adenosylmethionine (SAMe) which we know to be the neurotransmitter generator - so this is a key nutrient to take along with L-Methylfolate for maximum effect against mood disorders, particularly depression.

Vegans are especially at risk of high homocysteine due to their low B12 intake (since dietary B12 comes mainly only from animal-based foods). The good news is that taking the right B12 supplements can effectively reduce homocysteine levels. One study showed⁸ that taking 500 mcg/day of vitamin B12 for two months was able to reduce elevated homocysteine levels to less than 5 µmol/.

Similarly, another study showed that vegans whose intake of B12 averaged 5.6 mcg/day had homocysteine levels of 7.9 µmol/l, which was slightly lower than those with normal B12 levels⁹.

Supplementation with a highly bioavailable form of vitamin B12 5,000 mcg is the most efficient way to ensure optimal levels quickly. This is particularly important for vegans/vegetarians, the elderly, and anyone who is unable to absorb B12 efficiently.

Methy-Life’s™ B12 Complete is ideal for people who have MTR, MTRR, COMT, or other gene mutations that may be affecting B12 absorption. B12 Complete contains a combination of the 3 most bioactive forms of B12 (hydroxocobalamin, methylcobalamin and adenosylcobalamin) for maximum delivery and absorption.

The B12s within this supplement have already been converted into forms that can be absorbed and used by the body’s cells immediately. This truly is a full-spectrum B12 product.