Oxalates

Oxalates

Hello. Welcome back to the GPL-Blog.  My name is Jessica Bonovich, RN, BSN.  I’m the nurse consultant here at The Great Plains Laboratory.  Today I’m going to be discussing oxalates, which are one of the many things that are tested for in the Organic Acids Test (OAT). Oxalates are of particular interest to patients who have pain and in non-verbal children with behavioral issues. Frequently, these individuals are experiencing pain as the result of oxalate crystals precipitating with minerals in tissue, including the formation of kidney stones. The Organic Acid Test is well suited to determine if this is likely occurring. When determining the best course of action we look at the proportion of the oxalate, the metabolite of oxalate, and the patient’s symptoms.

As the nurse consultant at the lab, it is my primary job to review test results with people. and as a result, I see a lot of Organic Acids Tests. Doctors and patients are often surprised to learn that Candida and Aspergillus species can produce oxalates. These species have certain enzymes that allow them to use glyoxalate as a means of making energy (it is an intermediate in their TCA cycle).  Individuals with elevations in Candida or Aspergillus frequently have a subsequent elevation in oxalate metabolites. The degree of elevation may or may not be proportional to the yeast/mold overgrowth and this is an important distinction when evaluating the significance of the markers.  If the elevation is proportional, I can easily point toward yeast as the culprit. If the oxalates are disproportional, it can be related to several other factors.

To some extent, all individuals will obtain oxalates from three sources: liver cells (endogenously), yeast species (exogenously), and food (also exogenous). The reference ranges on our test show the typical accumulation of oxalate metabolites from all three sources.

In humans and in yeast, glyoxalate is the parent compound that can be converted into the three metabolites measured on the Organic Acids Test (OAT): glyceric, glycolic, and oxalic acid (Figure 1).

Figure 1

Figure 1

It can also be converted into glycine which is not measured on the OAT. Individuals with primary, secondary, or tertiary hyperoxaluria have genetic deficiencies in the enzymes that drive these pathways and cause the distinguishing features of the disease. People who are predisposed to stone formation may or may not have deficiencies in these enzymes. The degree to which a person will favor each pathway depends on a number of metabolic factors (including available precursor and pH of the cell). Elevations in all three metabolites can occur because of yeast and endogenous production. Food and Aspergillus on the other hand, produce oxalate in the body directly. So, when these are the source of excess, only oxalate will be elevated on the test.

Patient symptoms are a key component to all of this. It almost goes without saying that we treat the patient and not the number. Low oxalate values do not rule out an oxalate issue and extremely elevated values are not always equated with pain (though the potential certainly exists).  

Let’s get back to the disproportional oxalate scenario. If a patient has mildly elevated yeast and moderately to highly elevated oxalate, what do you think would be the most likely cause?

a.      Endogenous production

b.      Yeast

c.       Food

d.      A combination of b. and c.

The correct answer is d. Food is a direct source of oxalate and the most common cause of disproportionately elevated oxalates. Yeast is contributing to the oxalates in this scenario but is not likely to be the only cause of the elevation. Patients like these should introduce calcium and magnesium supplementation with meals to help bind up excessive oxalates in the food (so they can be eliminated in stool). Many conventional doctors falsely believe that calcium supplementation should be avoided when oxalate stones are a problem. They forget that calcium levels are maintained at precise levels in the blood no matter what the intake is. This is because without calcium, the heart will not pump. So, several mechanisms are in place to ensure adequate levels are maintained at all times. Avoiding calcium is only likely to increase osteopenia and not at all likely to reduce stone formation.

Let’s walk through another scenario. An individual presents with extreme pain in the muscles and history of stone formation. The patient has very elevated Candida and eats a high oxalate diet. All of the oxalate metabolites on the OAT are normal. What is the most likely scenario?

a.      Oxalates are not a problem

b.      Endogenous production

c.       Food and yeast are not a problem

d.      None of the above

The correct answer is d. This is a scenario that I refer to as hidden oxalate toxicity. This patient should have elevated oxalate metabolites.  Based on their history and lab results, oxalates would be expected. It is likely that oxalates are present in the body. However, they are precipitating in tissues before they ever make it into the urine. These patients are usually the most extreme cases of pain. They are also the people who do very well once all of the sources of oxalate have been eliminated. It is important to remember that when patients are in pain, removing oxalates should be done SLOWLY. Otherwise the patients are likely to experience an increase in pain as a result of “oxalate dumping”. When oxalate crystals are already in the tissues, mobilizing them can cause irritation. I recommend that patient introduce therapies one at a time, thoughtfully, over several weeks to months.

Okay, last one. This is a patient with moderately high yeast metabolites, a diet rich in fruits and veggies, and severely elevated oxalate metabolites.  To give this some perspective, the reference range for oxalates is 100 mmol/mol. This patient has close to 1000. The patient has symptoms of yeast overgrowth and fatigue as the chief complaints. What is the most likely cause of the extremely elevated oxalates?

a.      Yeast

b.      Diet

c.       Endogenous production

d.      All of the above

If your answer was d, you are correct. This patient has disproportional oxalates beyond what would be expected in diet. The patient certainly has the potential to accumulate oxalates in the tissues. However, since she is eliminating it effectively, it is not causing her pain at this time. Measures should still be taken to decrease the oxalate burden. We have much more to learn about the tendency for a person to form oxalate crystals.  Several genes (AGXT, GRPHR, and HOGA1) have been implicated (all of which are identified on the GPL SNP1000 test). Even if these genes are not mutated, some individuals still have a tendency toward oxalate stone formation. The high glyoxalate production is only one factor. 

Remediation of high oxalates is a multi-step process. Elimination of yeast is always important and not only because of excessive production. Pathogenic yeast can also cause an imbalance in beneficial bacteria that help to degrade oxalates.  Many studies have demonstrated that oxalobacter can reduce oxalate stone formation (hence the name). As of right now, testing for oxalobacter is available primarily in research settings and supplements are not widely available to the public (though I expect that they will be soon). Fortunately, there are other beneficial bacteria species shown to reduce oxalic acid. Many of these are already available probiotic form. These include Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium breve, and Bifidobacterium lactis all of which are available in Lactoprime and Ther-biotic Complete probiotic formulas.

Awareness of oxalates in food and elimination of those foods highest in oxalate (like spinach, soy, almonds, sweet potatoes, and raspberries) is important. Keep in mind that a low oxalate diet should only be done with the help of a practitioner and only when there is a clear need. The foods that contain oxalate are healthy and provide many nutrients that our bodies need to maintain healthy homeostasis. People forget that the oxalate content alone is not the only factor in oxalate absorption. The oxalate to calcium/magnesium ratio should be taken into account when we consider the potential for oxalate accumulation. If a food has equal amounts of both calcium and oxalate, it is likely that neither one will be absorbed very well. Plenty of bile acid needs to be available to prevent fats from binding with calcium. Both taurine and glycine strengthen bile acid but glycine increases oxalate. Glycine is where our endogenous production of glyoxalate starts. Keep this in mind when you are choosing supplements.

Lastly, sufficient B6 is required to help with the conversion of glyoxalate to glycine in the body. Maintaining sufficient levels of vitamin B6 will help with the endogenous production. However, the active form (P5P) is poorly absorbed.  I recommend that patients in pain start with low doses of pyridoxine hydrochloride (10 mg) and work up to higher doses as tolerated. The upper limit is 100 mg per day. Patients without pain can usually safely start at 50 mg per day.   

Wow, so that was a lot. Oxalates are a topic of much interest in our patient population so I want to be as thorough as possible. If in doubt, call the lab and speak with a consultant. We have lots of experience looking at tests results and can provide insight into the patterns that are occurring on the results.


References:

Finkielstein, V., Goldfarb, D., (2006). Strategies for preventing calcium oxalate stones. Canadian Medical Association Journal , 174 (100). Published online doi: 10.1503/cmaj.051517

Herb, Nutrient, and Drug Interactions. (1st edition). (2008). St. Louis, MO, Mosby, Elsevier

Liebman, M., Costa, G. (2000). Effects of calcium and magnesium on urinary oxalate excretion after oxalate loads. Journal of Urology, 163(5): 1565-1659.

Matkovic, V., Heaney, R.P., (1992). Calcium balance during human growth: evidence for threshold behavior. The American Society for Clinical Nutrition, 55(5): 992-996.

Pennistion, K., Nakada, S. (2009). Effect of Dietary Changes on Urinary Oxalate Excretion and Calcium Oxalate Supersaturation in Patients With Hyperoxaluric Stone Formation. Urology, 73(3):484-489.

Physicians Desk Reference for Nutritional Supplements. (2nd edition). (2008). Montvale, NJ: Thomson PDR

Rushton, HG., Spector, M. (1982). Effects of magnesium deficiency on intratublar calcium formation and crystalluria in hyperoxaluric rats. Journal of Urology, 127(3): 598-604.

Poore, R.E., Hurst, C.H., Assimos, D.G., Holmes, R.P. (1997). Pathways of hepatic oxalate synthesis and their regulation. Cell Physiology. 272(1), C289-C294

Shaw, W. (2009). Autism: Beyond the Basics. Self Published, USA.

Weaver, C. (1994). Age related calcium requirements due to changes in absorption and utilization. Journal of Nutrition, 124(8): 1418S-1425S.

Genetic Testing and Organic Acids Testing: A Dynamic Duo of Diagnostics

Today I have two words for you:  Personalized medicine.  What does this phrase mean to you?  When I think of personalized medicine I think of treatments that are custom designed for each individual patient, and I believe this is the ultimate goal for all of us in the field of functional medicine.  To make this happen, we will have to work together as a team - the healthcare practitioner, the lab, and the patient.  If we do so effectively, the result should be better health and improved lives of our patients.  The only way to get there is to design a treatment plan that addresses the underlying cause(s) of our patient’s ailments and not try to just suppress the symptoms. 

When I talk to both practitioners and patients, they often ask “Where do we start?” or “What is your most important test?”, and until recently I would have always said that the Organic Acids Test (OAT) is the obvious place to start.  The reason for this is that the OAT provides more information than any other test.  The OAT gives us a metabolic snapshot of multiple pathways in the body, offering insight into possible underlying causes of symptoms, as well as what kind of nutritional support is needed.  However, now the OAT by itself is no longer the obvious choice.  I am now recommending the OAT + GPL-SNP1000 combo because these two tests, one metabolic and one genetic, work so well together.   Today I would like to share some of the markers in each of these tests that work really well in tandem.    The primary pathways where we see overlap between the two tests are methylation, mental health, detoxification, and oxalate metabolism. 

The first pathway that GPL-SNP1000 covers is the DNA methylation pathway, also called the MTHFR pathway.  This pathway is a process by which carbons are added onto folic acid from amino acid and redistributed onto other compounds throughout the body.  This process is responsible for the formation of methionine, S-Adenosyl methionine (SAMe), and thymidylate monophosphate (dTMP).  These compounds are then used in neurotransmitter metabolism, detoxification, nucleotide synthesis, and multiple other processes.  I can’t say enough about how important neurotransmitter metabolism and detoxification of chemicals are to everyone’s health.  We have so many patients for whom the majority of their symptoms result from the upset of these two processes.  Since the methylation pathway is so important we decided to make it a high priority in our new genetic test.   GPL-SNP1000 looks at 105 different methylation SNPs (single-nucleotide polymorphisms).   Next week I plan on going more in-depth on the methylation pathway and how GPL-SNP1000 can be useful.

So what markers in the OAT are important for patients with MTHFR mutations?  The first one we have is vitamin B12.  We evaluate B12 levels by measuring the amount of methylmalonic acid (see Figure 1).  B12 is an important cofactor for many of these methylation enzymes.  The second important marker is pyridoxic acid, which is a form of vitamin B6. I have counted over 50 enzymes that require B6 in the body.  It is an important cofactor in the methylation pathway.  It is directly involved with the function of CBS enzyme and indirectly involved with MTHFR, BHMT, and SHMT.  Another marker involved with the MTHFR pathway is uracil.  Having an elevated uracil level can be indicative of folate pathway malfunction.

The next pathway that is helpful to analyze in both the OAT and GPL-SNP1000 is the mental health pathway, which involves the synthesis and breakdown of neurotransmitters in the brain.  The combination of measuring the neurotransmitter metabolites and knowing if the enzymes involved are functional will help guide us to the best treatment options.  GPL-SNP 1000 covers 14 different mental health genes, which I will cover next week (I’m trying not to make these blog posts too long).  Three of the best markers in the OAT for measuring neurotransmitter metabolism are homovanillic acid (a dopamine metabolite), vanilymandelic acid (epinephrine/norepinephrine), and 5-HIAA (serotonin, marker).  These markers are the metabolites of the neurotransmitters by the enzymes MAOA and COMT (see Figure 2), the genes for which are analyzed in GPL-SNP1000.  Deficiencies in these enzymes due to faulty SNPs  may cause low neurotransmitter levels, which may also be caused by low amounts of precursors, cofactors, or increased inhibitors which is why information from both the OAT and GPL-SNP1000 is so incredibly useful.   

The third pathway that I will briefly touch on today is the detoxification pathway, and specifically for glutathione (GSH).  Detoxification is so important in today’s industrial, polluted, and toxic world.  Every day we are inundated by hundreds of chemicals.  We are exposed to many through the environment and some by choice (like medications).  Our bodies have to process these chemicals in some way.  GPL-SNP1000 looks at dozens of genes that are important for detoxification.  A good marker in the OAT for how well the body is detoxifying is pyroglutamic acid.  Elevated values of pyroglutamic acid are indicative of glutathione deficiency due to excessive toxic exposure or a genetic issue. 

The final pathway I’m going to discuss today is oxalate metabolism.  Oxalates are crystalline molecules that we absorb from our diet (high oxalate foods) or are produced by an infection, like yeast/fungal overgrowth.  These oxalates can accumulate in the body and cause inflammation.  The symptoms of oxalate accumulation include pain, nephrolithiasis, and neurological symptoms. Oxalates are known to cause/create kidney stones.  Children with autism who exhibit eye-poking behavior have been shown to have a build-up of oxalates behind their eyes, causing tremendous pain, and thus the eye-poking.  GPL-SNP1000 covers five different genes involved with the production and elimination of oxalates.  The OAT has three oxalate markers:  glyceric, glycolic, and oxalic acids. (Figure 3)  In addition, low B6 and increased yeast or fungal markers are associated with increased oxalates. 

I think that is all I’ll cover today.  In the future I will cover the methylation pathway and the neurotransmitter pathway a little more in-depth.  If there is another pathway you want me to cover in greater detail, please let me know.  I want to be a part of your healthcare team as we all work together for the better well-being of our patients.

Email gplblog@gpl4u.com if you have any questions about this blog post.