Can B12 and Folate Help Detoxify Oxalate?

This may explain why high-dose biotin causes "oxalate dumping" symptoms in some people but not others.

Last week I had two consulting clients who reported having to cut back on high-dose biotin (in these cases, in excess of ten milligrams per day) because it was causing oxalate dumping symptoms, including crystals exuding from skin in one case and from the eyes in another.

In the comments on my previous article, Can Biotin Help Detoxify Oxalate?, David Barker MD reported low-dose biotin eliminated oxalate-related symptoms:

Muscle spasms that have plagued me for 6 months were gone by day two. Exercise tolerance and energy level have improved dramatically. Dude you are on to something. Everything else in my diet has been exactly the same. I eat the exact same low oxalate diet every day and I measure everything down to the gram. The only change in my regimen has been adding 75mcg per day of biotin initially, now up to 225 mcg per day in three divided doses. Dude, I really think you are on to something.

Together with the comments I highlighted in the original article from JenP and KattyGirlYo suggesting that “oxalate dumping” symptoms can be elicited from 2 milligrams per day in some, and in 10 milligrams but not 5 milligrams per day in others, these stories collectively suggest that biotin may have an extremely context-dependent ability to eliminate or elicit oxalate-related symptoms with a dose dependency that is widely variable between individuals.

My suspicion is that if biotin causes dumping symptoms instead of eliminating them, this is because the first step in the putative detoxification of oxalate is exceeding the capacity of the second step.

Recall my proposed two-step detoxification process:

1. Pyruvate carboxylase converts oxalate to formate.

2. Formate is joined to tetrahydrofolate to enter the methylation cycle, be used for the synthesis of purines or DNA, or be converted to carbon dioxide and exhaled in the breath.

I now further propose that when the rate of the first step exceeds the rate of the second, “oxalate dumping” symptoms are precipitated in a five-step process:

1. At first, circulating oxalate concentrations are reduced because the oxalate converts to formate and then becomes joined to folate.

2. The lowered concentration of circulating oxalate elicits a dissolution of calcium oxalate crystals. This is a result of Le Chatlier’s principle. Assume the reversible reaction calcium + oxalate ←→ calcium oxalate crystals. If this reaction is at equilibrium but then the concentration of oxalate is reduced, the equilibrium shifts leftward to favor dissolution of the calcium oxalate crystals.

3. If the pyruvate carboxylase reaction proceeded indefinitely to formate, there would be net drainage of crystals without the oxalate ever rising back to the original equilibrium concentration. However, if the utilization of formylated folate becomes limiting, then the concentration of formate rises. This reduces the rate at which oxalate is converted to formate through Le Chatlier’s principle. For the reaction oxalate ←→ formate + CO2, an increase in formate shifts the equilibrium leftward.

4. The concentration of oxalate now rises again, and this reverses the equilibrium shift that occurred in step 2. This favors the reformation of oxalate crystals.

5. These crystals may now deposit wherever they wind up, with the net result being a mobilization and redeposition of crystals. Perhaps in some cases these exude through the skin or mucous membranes, as reported by two of my clients.

There may be more regulation layered on top of this to prevent excessive formate accumulation. It would certainly be preferable to have oxalate crystals cause pain or disrupt the skin than to have formate accumulate beyond the capacity to clear it.

Formate accumulation is the principle mechanism of methanol toxicity. Part of its toxicity is driven by inhibiting cytochrome oxidase, complex IV of the mitochondrial respiratory chain, which would inhibit the clearance of sulfite and hydrogen sulfide and block the production of ATP.

Nourishing the first step of oxalate detoxification, according to my model, requires biotin and manganese.

Nourishing the second step requires above all else a sufficient amount of tetrahydrofolate (THF).

This is the unmethylated form of folate. This first of all requires having enough folate. It also requires having enough B12, because B12 removes the methyl group from 5-methyl-THF to regenerate THF.

Formate is joined to THF using the enzyme MTHFD1, which has a common polymorphism, rs2236225, where the risk allele has an “A,” where each copy reduces the rate of the enzyme by 22%. This enzyme depends on magnesium-ATP and is activated by potassium.

This forms 10-formyl-THF, which has four principle fates:

• Use in purine synthesis.

• Use in methylation.

• Use in DNA synthesis.

• Conversion to carbon dioxide.

10-formyl-THF can be used in a series of ten reactions to synthesize purines, which make up half the building blocks in our DNA, and which make up the base of important energy carriers such as ATP and the derivatives of niacin and riboflavin, NADH, NADPH, and FADH2. This pathway requires the amino acids aspartate, glutamine, and glycine, and it requires magnesium-ATP, carbon dioxide, 5-carbon sugars made in the pentose phosphate pathway, and enzymes that depend on iron, sulfur, and potassium. The pathway will be most active on a low-purine diet, such as would be prescribed for gout.

Use in methylation requires two more sequential reactions using MTHFD1, using electrons and energy carried by niacin in the form of NADPH, taken from glucose in the pentose phosphate pathway. The pentose phosphate pathway, in turn, requires thiamin, calcium, and magnesium, and the enzyme glucose 6-phosphate dehydrogenase, an impairment of which is the most common genetic defect in the world. These reactions form 5,10-methylene-THF, which the enzyme MTHFR converts to 5-methyl-THF using riboflavin and yet more NADPH carrying electrons and energy from the pentose phosphate pathway. The enzyme methionine synthase then uses B12 to move the methyl group from 5-methyl-THF to homocysteine, forming methionine. Finally, the methionine is activated using energy and adenosine from magnesium-ATP and the enzyme methionine adenosyltransferase. The resulting S-adenosyl-methionine is then used for any of hundreds of methylation reactions.

An alternative use of 5,10-methylene-THF is to synthesize thymidylate, an intermediate in the synthesis of thymidine, one of the four bases used in DNA, the one designated as “T.” This pathway is blocked by antifolate medications such as methotrexate, used as a chemotherapy or immunosuppressive drug. The folate-mediated portion of this pathway requires the enzymes thymidylate synthase, dihydrofolate reductase, and serine hydroxymethyltransferase, which in turn depends on vitamin B6 as well as the amino acid serine. More broadly, thymidine synthesis depends on magnesium-ATP and NADPH from the pentose phosphate pathway, and will be tied to the synthesis of other DNA bases with similar requirements for magnesium-ATP and NADPH.

The enzymes aldehyde dehydrogenase 1 and 2 will oxidize the formyl group of 10-formyl-THF and release it as CO2, which we exhale in the breath. These enzymes require riboflavin in the form of FAD, niacin in the form of NAD+ or NADP+, magnesium, and iron.

If biotin causes “oxalate dumping symptoms” at a dose that exceeds the dose needed for maximal benefit of whatever else the biotin is being used for, the most rational starting place is to cut back on the dose of biotin.

However, I would look next at deficiencies that could limit the second step of my proposed system of oxalate detoxification.

Chief among these would be the supply of tetrahydrofolate, which is best assessed with urinary formiminoglutamate (FIGlu).

However, the full scope of nutrient statuses to test for is thiamin, riboflavin, niacin, B6, folate, B12, calcium, magnesium, iron, sulfur, and potassium.

ATP is featured ubiquitously throughout all aspects of the second step, so any limitation of energy metabolism could be catastrophic to the second step, regardless of the status of the above nutrients. Such limitations could be caused by many nutrient deficiencies or toxins. While I have often said they could be caused by common metabolic impairments such as disorders of the thyroid or adrenals, or diabetes, I am increasingly thinking these disorders are far more likely to be effects rather than causes of problems with energy metabolism. Common contributors would be overweight and obesity, junk food, indoor sedentary lifestyles, and toxic environments, while rare contributors would be hundreds of different idiosyncratic bottlenecks in energy metabolism caused by rare genetic mutations. While having a diagnosable disease due to homozygous status for one of these mutations is exceedingly rare, having heterozygous status for one or more of these hundreds of different disorders is collectively common.

The role of ATP in the putative second step of oxalate detoxification is one small subset of “everything,” and, as I have written recently, Energy Metabolism Governs Everything.

Thus, the low-hanging fruit of this problem is to eat a healthy diet, get good exercise, both in proportions that lead to healthy body composition, get outdoor sunlight, and take reasonable precautions against common toxins, like filtering water, minimizing plastic, and so on. And, finally, to avoid doses of biotin that provoke oxalate dumping symptoms.

The fruit a little further up on the tree is to use information such as my Vitamins and Minerals 101 (premium features for Masterpass members here) and my The Vitamins and Minerals 101 Cliff Notes (free for Masterpass members here) to make sure the diet is an optimal source of micronutrients.

The fruit mid-way up on the tree is to do nutritional status testing, with an emphasis on thiamin, riboflavin, niacin, B6, folate, B12, calcium, magnesium, iron, sulfur, and potassium.

The following constitutes comprehensive testing for nutritional status.

A Genova ION + 40, Vibrant America Micronutrient Panel, and, from Labcorp or Quest, the following:

• Complete Blood Count (CBC) 

• Comprehensive metabolic panel

• Vitamin B7 (biotin)

• Parathyroid Hormone

• 1,25(OH)2D

• Uric Acid

• Iron panel

• Serum transferrin

• Serum copper AND ceruloplasmin

• Serum iodine

The Cheat Sheet (free to Masterpass members here) can be used for the interpretation of these tests, and can also be used to narrow down the testing by consulting the individual testing sections for each of the nutrients that are especially relevant: thiamin, riboflavin, niacin, B6, folate, B12, calcium, magnesium, iron, sulfur, and potassium.

Oxalate is a metabolic toxin that decreases activity of the citric acid cycle by up to 48%, and formate is a respiratory chain poison.

You can get my oxalate protocol here:

Have you experienced any oxalate-related issues when taking biotin? Or have you found any of the other nutrients discussed here to help with oxalate-related symptoms? If so, let me know in the comments!

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