Clinical Usefulness of IgG Food Allergy Testing

William Shaw Ph.D

Immunoglobulin G (IgG) food allergy testing has made vast advancements since the year 2003 when the American Academy of Allergy, Asthma, and Immunology published a statement that "Measurement of specific IgG antibodies to foods is also unproven as a diagnostic tool"(1) Most of the IgG food allergy throughout the world is done using the same immunochemical technique. First, soluble food proteins in solution are reacted to a solid phase that chemically binds to a variety of proteins. The use of plastic microtiter trays with one to several hundred wells has become the most common material used as the solid phase. Then these trays are washed, dried, and stored for later use. A sample of diluted serum is then added to each of the wells. Antibodies of all types in the diluted serum bind to the specific food molecules that are attached to the plastic wells of the tray. Next, the plates are washed to remove any nonspecific antibodies in the diluted serum. At this time, food antibodies from all of the five major immunoglobulin classes called G, A, M, E, and D may be attached to the food antigens on the plate. The next step confers specificity on the assay. Antisera from sheep, goats, rabbits, or other animals that specifically binds to IgG is added to microtiter wells and only binds to IgG, not to IgA, IgM, IgE, or IgD. This antibody to IgG has previously been modified by the attachment of an enzyme that can be measured conveniently. The amount of enzyme bound to food antigen-IgG complexes on the plate is directly related to how much IgG antibody is attached to a given food. The overall technique is termed Enzyme Linked Immuno Assay or ELISA. If IgG4 is measured, an antiserum specific for IgG4 only must be used for the final step.

The clinical usefulness of IgG testing in an array of illnesses is illustrated in an early article published by an otolaryngologist who reported that the majority of his patients had substantial health improvements after an elimination of foods positive by IgG food allergy tests (2). The overall results demonstrated a 71% success rate for all symptoms achieving at least a 75% improvement level. Of particular interest was the group of patients with chronic, disabling symptoms, unresponsive to other intensive treatments. Whereas 70% obtained 75% or more improvement, 20% of these patients obtained 100% relief. Symptoms most commonly improved 75%-100% on the elimination diets included asthma, coughing, ringing in the ears, chronic fatigue, all types of headaches, gas, bloating, diarrhea, skin rash and itching, and nasal congestion. The most common IgG food allergies were cow's milk, garlic, mustard, egg yolk, tea, and chocolate.

The usefulness of IgG food allergy to design customized elimination diets has now been documented in scientific studies. Irritable bowel syndrome (IBS) is a common, costly, and potentially disabling gastrointestinal (GI) disorder characterized by abdominal pain/discomfort with altered bowel habits (e.g., diarrhea, constipation). The major symptoms of IBS are (1) abnormality of bowel movement, (2) reduction in bowel sensitivity thresholds, and (3) psychological abnormality. Many IBS patients have psychological symptoms including depression, anxiety, tension, insomnia, frustration, hypochondria. psychosocial factors (3). Atkinson et al (4)evaluated a total of 150 outpatients with irritable bowel syndrome (IBS) who were randomized to receive, for three months, either a diet excluding all foods to which they had raised IgG antibodies (ELISA test) or a sham diet excluding the same number of foods but not those to which they had antibodies . Patients on the diet dictated by IgG testing had significantly less symptoms than those on the sham diet after 120 days on the diets. Patients who adhered closely to the diet had a marked improvement in symptoms while those with moderate or low adherence to the IgG test dictated diets had poorer response. Similar results were also obtained by Drisko et al (5). They used both elimination diet and probiotic treatment in an open label study of 20 patients with irritable bowel syndrome diagnosed at a medical school gastroenterology department. The most frequent positive serologic IgG antigen-antibody complexes found on the food IgG tests were: baker's yeast, 17 out of 20 (85%); onion mix, 13 out of 20 (65%); pork, 12 out of 20 (60%); peanut 12 out of 20 (60%); corn, 11 out of 20 (55%);wheat, 10 out of 20 (50%); soybean, 10 (50%); carrot, 9 out of 20 (45%); cheddar cheese, 8 out of 20 (40%); egg white, 8 out of 20 (40%). Only 5 out of 20 reacted by IgG antibody production to dairy; however the majority of patients reported eliminating dairy prior to trial enrollment presumably clearing antigen-antibody complexes prior to testing. Significant improvements were seen in stool frequency, pain, and IBS quality of life scores. Imbalances of beneficial flora and dysbiotic flora were identified in 100% of subjects by comprehensive stool analysis. There was a trend to improvement of beneficial flora after treatment but no change in dysbiotic flora. The one-year follow up demonstrated significant continued adherence to the food rotation diet, minimal symptomatic problems with IBS, and perception of control over IBS. The continued use of probiotics was considered less helpful.

IgG food allergy testing was also proved effective in the gastrointestinal disorder Crohn's disease. Bentz et al (6) found that an elimination diet dictated by IgG food allergy testing resulted in a marked reduction of stool frequency in a double blind cross-over study in which the IgG-dictated diet was compared to a sham diet in 40 patients with Crohn's disease. IgG food allergies were significantly elevated compared to normal controls. Cheese and baker's yeast (Saccharomyces cerevisiae) allergies were extremely common with rates of 83% and 84% respectively. Main et al (7), focusing on the baker's yeast allergy, also found extremely high prevalence of IgG allergy in patients with Crohn's disease. Titers of both IgG and IgA to S. cerevisiae in the patients with Crohn's disease were significantly higher than those in the controls. In contrast, antibody titers in the patients with ulcerative colitis were not significantly different from those in the controls. Among the patients with Crohn's disease there was no significant difference in antibody titers between patients with disease of the small or large bowel. Since IgG antibodies to S. cerevisiae cross react with Candida albicans (8), Candida species colonization might be a trigger for the development of Crohn's disease.

IgG food allergy to wheat, gluten, gliadin, rye, and barley are prevalent in the gastrointestinal disorder celiac disease. Virtually all patients with celiac disease have elevated IgG antibodies to gliadin if they currently have wheat or related grains in their diet. The confirmation of celiac disease is confirmed by the presence of flattened mucosa with a lack of villi when a biopsy sample of the small intestine is examined microscopically. Another confirmation test with equal sensitivity is a blood test for IgA transglutaminase antibodies. The antibody confirmation test is equal in accuracy to the biopsy test with the exception that individuals with IgA deficiency may have false negative results. However, I would estimate that only 1% of people with elevated IgG antibodies to gliadin and other grains related to wheat have celiac disease. If the individual is negative for the confirmation tests for celiac disease, many patients are frequently erroneously advised that that have no problem with wheat. Hadjivassiliou et al argued that it is a significant clinical error to classify wheat allergy through the filter of celiac disease (9) and argue that celiac disease is a subtype of wheat sensitivity. Many of their patients with wheat allergy but celiac disease negative had remission of severe neurological illnesses when they adopted a gluten free diet and expressed that in these patients the gluten molecule causes an autoimmune reaction in the brain rather than in the intestinal tract, likely against the Purkinje cells that are predominant in the cerebellum.

A wide range of additional studies has proven the clinical value of IgG antibodies in autism (10), bipolar depression (11), schizophrenia (12), migraine headaches (13), asthma (14), and obesity (15).

Total IgG Versus IgG4 Food Allergy

Immunoglobulin G (IgG) is classified into several subclasses termed 1, 2, 3, and 4. IgGs are composed of two heavy chain–light chain pairs (half-molecules), which are connected via inter–heavy chain disulfide bonds situated in the hinge region (Figure 1). IgG4 antibodies usually represent less than 6% of the total IgG antibodies. IgG4 antibodies differ functionally from other IgG subclasses in their lack of inflammatory activity, which includes a poor ability to induce complement and immune cell activation because of low affinity for C1q (the q fragment of the first component of complement). Consequently, IgG4 has become the preferred subclass for immunotherapy, in which IgG4 antibodies to antigens are increased to reduce severe antigen reactions mediated by IgE. If antigens preferentially react with IgG4 antibodies, the antigens cannot react with IgE antibodies that might cause anaphylaxis or other severe reactions. Thus, IgG4 antibodies are often termed blocking antibodies. Another property of blood-derived IgG4 is its inability to cross-link identical antigens, which is referred to as "functional monovalency". IgG4 antibodies are dynamic molecules that exchange half of the antibody molecule specific for one antigen with a heavy-light chain pair from another molecule specific for a different antigen, resulting in bi-specific antibodies that are unable to form large cross-linked antibodies that bind complement and thus cause subsequent inflammation(16). In specific immunotherapy with allergen in allergic rhinitis, for example, increases in allergen-specific IgG4 levels indeed correlate with improved clinical responses. IgG4 antibodies not only block IgE mediated food allergies but also block the reactions of food antigens with other IgG subclasses, reducing inflammatory reactions caused by the other IgG subclasses of antibodies to food antigens.

In IgG mediated food allergy testing, the goal is to identify foods that are capable of causing inflammation that can trigger a large number of adverse reactions. IgG1, IgG2, and IgG3 all are capable of causing inflammation because these antibodies do not exchange heavy and light chains with other antibodies to form bispecific antibodies. Thus, IgG1, IgG2, and IgG3 antibodies to food antigens can and do form large immune complexes or lattices that fix complement and increase inflammation. The presence of IgG4 antibodies to food antigens indicates the presence of antibodies to foods that will not usually cause inflammation even though high amounts of these antibodies do indicate the presence of immune reactions against food antigens. Testing only for IgG4 antibodies in foods limits the ability of the clinician to determine those foods that are causing significant clinical reactions that are affecting their patients. The importance of measuring other subtypes of IgG antibodies is highlighted in an article by Kemeny et al. (17). They found that IgG1 antibodies to gluten were elevated in all 20 patients with celiac disease but none of the patients had elevated IgG4 antibodies to gluten.

Clinical References

  • 1. Statement of the AAAAI Work Group Report: Current Approach to the Diagnosis and Management of Adverse Reactions to Foods, October 2003. http://www.aaaai.org/ask-the-expert/usefulness-of-measurements-of-IgG-antibody.aspx (Accessed October 27,2013).
  • 2. Dixon H, Treatment of delayed food allergy based on specific immunoglobulin G RAST testing relief. Otoloryngol Head Neck Surg 2000;123:48-54.
  • 3. Nagisa Sugaya N and Nomura S, Relationship between cognitive appraisals of symptoms and negative mood for subtypes of irritable bowel syndrome. BioPsychoSocial Medicine 2008;2:9-14
  • 4.Atkinson, W et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial Gut 2004;53:1459-1464
  • 5. Drisko J, Bischoff B, Hall M, McCallum R, Treating Irritable Bowel Syndrome with a Food Elimination Diet Followed by Food Challenge and Probiotics. Journal of the American College of Nutrition 2006; 25: 514–522
  • 6. Bentz S, et al. Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double-blind cross-over diet intervention study. Digestion. 2010;81:252-64.
  • 7.Janice Main, Hamish McKenzie, Grant R Yeaman, Michael A Kerr, Deborah Robson, Christopher R Pennington, David Parratt Antibody to Saccharomyces cerevisiae (bakers' yeast) in Crohn's disease BMJ 1988;297:1105-1106
  • 8. Thomas Schaffer, Stefan Mueller, , Beatrice Flogerzi, , Beatrice Seibold-Schmid,Alain M. Schoepfer, and Frank Seibold Anti-Saccharomyces cerevisiae Mannan Antibodies (ASCA) of Crohn's Patients Crossreact with Mannan from Other Yeast Strains, and Murine ASCA IgM Can Be Experimentally Induced with Candida albicans Inflamm Bowel Dis 2007;13:1339 –1346
  • 9. M Hadjivassiliou, R A Grünewald, G A B Davies-Jones Gluten sensitivity as a neurological illness. Neurol Neurosurg Psychiatry 2002;72:560–563
  • 10. Vladimir T et al Higher Plasma Concentration of Food-Specific Antibodies in Persons With Autistic Disorder in Comparison to Their Siblings. Focus Autism Other Dev Disabl 2008; 23: 176-185
  • 11. Severance EG et al Immune activation by casein dietary antigens in bipolar disorder. Bipolar Disord 2010;12: 834–842
  • 12. Severance EG, et al Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res. 2010;118:240-7.
  • 13.Huber A, et al Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial. Int Arch Allergy Immunol. 1998; 115:67-72.
  • 14.Vance G. et al. Ovalbumin specific immunoglobulin G and subclass responses through the first five years of life in relation to duration of sensitization and the development of asthma. Clia Exp Allergy 2004;34:1452-1459
  • 15.Wilders-Truschnig M et al. IgG Antibodies Against Food Antigens are Correlated with Inflammation and Intima Media Thickness in Obese Juveniles. Exp Clin Endocrinol Diabetes 2008;116:241-5.
  • 16. Marijn van der Neut Kolfschoten, et al Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange. Science 2007;317:1554-1555
  • 17. Kemeny DM, et al Sub-class of IgG in allergic disease. I. IgG sub-class antibodies in immediate and non-immediate food allergy. Clin Allergy. 1986; 16:571-81.


The Green Smoothie Health Fad: This Road to Health Hell is Paved with Toxic Oxalate Crystals

William Shaw, PhD.

Recent internet news indicated the conviction of an oncologist who attempted to kill her boyfriend who was involved with another woman. The weapon of choice was ethylene glycol, popularly known as antifreeze, which had been placed in his coffee just after coitus. Although emergency measures saved the boyfriend's life, extensive deposits of oxalate crystals, the main toxic metabolite of ethylene glycol, had caused extensive kidney and liver damage, reducing the man's lifespan by about half.

Similar results in sabotaging your own health can occur through the regular consumption of a popular concoction called a "green smoothie". A recent Google search for "green smoothie" yielded 609,000 hits. In addition, a recent "improving your diet" seminar I attended promoted this same idea. Interestingly, on the same day, I reviewed test results of a urine organic acid test of a woman with oxalate values three times the upper limit of normal. A conversation with the patient indicated that she had recently turned to consuming daily "green smoothies" to "clean up her diet". The most common "green" components of the most popular green smoothies are spinach, kale, Swiss chard, and arugula. Each of these greens is loaded with oxalates. A typical internet recipe advises that two cups of packed raw spinach leaves is a good starting point for a good smoothie. In addition to the high oxalate greens added to the blender, green smoothie proponents frequently recommend adding a variety of berries or almonds, also containing high oxalate amounts. Similar high urine oxalate results were found in organic acid tests of a number of patients with kidney stones who had decided to eat large spinach salads daily as a "move to clean up my unhealthy diet". Unfortunately kidney stones are not the only health problems that people who regularly consume green smoothies and large spinach salads will experience with their new "clean" diet.

Seventy-five years ago, a food scientist of the Campbell Soup Company (1) reported: "Only a few foods, notably spinach, Swiss Chard, New Zealand spinach, beet tops, lamb's quarter, poke, purslane, and rhubarb have high oxalate content. In them, expressed as anhydrous oxalic acid, it is often considerably over 10% on a dry basis. In fifty-three samples, including practically all commercial and many experimental varieties grown in California and in Maryland as well as those shipped from Texas, Florida and Carolina, the average anhydrous oxalic acid content was 9.02% on the dry basis (maximum 12.6, minimum 4.5). Whereas spinach greatly increases the calcium content of the low calcium but well performing basal diet, it decidedly interferes with both growth and bone formation. If to a diet of meat, peas, carrots and sweet potatoes, relatively low in calcium but permitting good though not maximum growth and bone formation, spinach is added to the extent of about 8% to supply 60% of the calcium, a high percentage of deaths occurs among rats fed between the age of 21 and 90 days. Reproduction is impossible. The bones are extremely low in calcium, tooth structure is disorganized and dentine poorly calcified. Spinach not only supplies no available calcium but renders unavailable a considerable amount of the calcium in the other foods. Considerable amounts of the oxalate appear in the urine, much more in the feces."

The author also discovered that in addition to leading to excessive death and defective reproduction in the rats, high oxalate foods also cause soft and pliable bones and defective teeth.

Oxalate and its acid form oxalic acid are organic acids that come from three sources: the diet, fungus infections such as Aspergillus and Penicillium and possibly Candida (2-10), and also human metabolism (11).

Oxalic acid is the most acidic organic acid in body fluids and is used commercially to remove rust from car radiators. Antifreeze (ethylene glycol) is toxic primarily because it is converted to oxalate. Two different types of genetic diseases are known in which oxalates are high in the urine. The genetic types of hyperoxalurias (type I and type II) can be determined from the organic acid test done at The Great Plains Laboratory. Foods especially high in oxalates include spinach and similar leafy vegetables, beets, chocolate, soy, peanuts, wheat bran, tea, cashews, pecans, almonds, berries, and many others. Oxalates are not found in meat or fish at significant concentrations. Daily adult oxalate intake is usually 80-120 mg/d but it can range from 44-1000 mg/d in individuals who eat a typical Western diet. I estimate that the person who consumes a green smoothie with two cups (about 150 grams) of spinach leaves is consuming about 15 grams or 15,000 mg of oxalates or about 150 times the average daily oxalate intake. A complete list of high oxalate foods is available on the Internet at http://www.upmc.com/patients-visitors/education/nutrition/pages/low-oxalate-diet.aspx

High oxalate in urine and plasma was first found in people who were susceptible to kidney stones. Most kidney stones are composed of calcium oxalate. Stones can range in size from the diameter of a grain of rice to the width of a golf ball. It is estimated that 10% of males may have kidney stones some time in their lives. Because many kidney stones contain calcium, some people with kidney stones think they should avoid calcium supplements. However, the opposite is true. When calcium and magnesium are taken with foods that are high in oxalates, oxalic acid in the intestine combines with these minerals to form insoluble calcium and magnesium oxalate crystals that are eliminated in the stool. These forms of oxalate cannot be absorbed into the body. When calcium and/or magnesium are low in the diet, oxalic acid is soluble in the liquid portion of the contents of the intestine (called chyme) and is readily absorbed from the intestine into the bloodstream. If oxalic acid is very high in the blood being filtered by the kidney, it may combine with calcium and other metals, including heavy metals like lead and mercury to form crystals that may block urine flow, damage the kidney, and cause severe pain. These oxalate crystals can also form in the bones, skin, joints, eyes, thyroid gland, blood vessels, lungs, and even the brain (11-14). Oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression (14). In addition to individuals with autism and kidney disease, individuals with fibromyalgia and women with vulvar pain (vulvodynia) may also suffer from the effects of excess oxalates (15-18).

Recent evidence also points to the involvement of oxalates in stroke, atherosclerosis, and in endothelial cell dysfunction (19-21). High amounts of oxalates were found concentrated in atherosclerotic lesions of the aortas and coronary arteries of a number of individuals at autopsy. These individuals did not have oxalate deposits in the kidney but did have oxalate deposits in other organs such as the thyroid gland and testis. Since the stains used by most pathologists examining atherosclerotic lesions cannot readily determine the presence of oxalates in diseased arteries, it seems possible that this cause of atherosclerosis may be much more common than previously realized. I suspect that oxalates are a much more common cause of atherosclerosis than high cholesterol. Furthermore, since ethylenediaminetetraacetic acid (EDTA) is effective in the removal of oxalate crystals deposited in the tissues (22,23), the benefits of intravenous EDTA in the treatment of cardiovascular disease may be mediated largely by the removal of oxalate crystals and their associated heavy metals from the tissues in which they are deposited.

Oxalate crystals may cause damage to various tissues due to their sharp physical structure and they may increase inflammation. Iron oxalate crystals may also cause significant oxidative damage and diminish iron stores needed for red blood cell formation (11). Oxalates may also function as chelating agents and may chelate many toxic metals such as mercury and lead. However, unlike common chelating agents like EDTA and DMSA that cause metals to be excreted, a reaction of oxalate with heavy metals like mercury and lead leads to the precipitation of the heavy metal oxalate complex in the tissues, increasing the toxicity of heavy metals by delaying their excretion (24).

What steps can be taken to control excessive oxalates?

  • Use antifungal drugs to reduce yeast and fungi that may be causing high oxalates. Children with autism frequently require years of antifungal treatment. I have noticed that arabinose, a marker indicating yeast/fungal overgrowth on the organic acid test at The Great Plains Laboratory, is correlated with high amounts of oxalates (Figure 1). Candida albicans produces high amounts of the enzyme collagenase (25), which breaks down collagen in the gastrointestinal tract to form the amino acid hydroxyproline, which in a series of reactions is converted to oxalates, especially in people with low vitamin B6. Candida organisms have also been found surrounding oxalate stones in the kidney (10).
  • Give supplements of calcium citrate and magnesium citrate to reduce oxalate absorption from the intestine. Citrate is the preferred calcium form to reduce oxalate because citrate also inhibits oxalate absorption from the intestinal tract. The best way to administer calcium citrate would be to give it with each meal. Children over the age of 2 need about 1000 mg of calcium per day. Of course, calcium supplementation may need to be increased if the child is on a milk-free diet. The most serious error in adopting the gluten-free, casein-free diet is the failure to adequately supplement with calcium.
  • Give chondroitin sulfate to prevent the formation of calcium oxalate crystals (26).
  • Vitamin B6 is a cofactor for one of the enzymes that degrades oxalate in the body and has been shown to reduce oxalate production (27).
  • Consume a low-oxalate diet, avoiding high-oxalate foods such as leafy greens, beans, berries, nuts, tea, chocolate, wheat germ, and soy. Dr. Clare Morrison, a general practitioner from the U.K. who has fibromyalgia found relief from symptoms after changing to a low-oxalate diet. In a 2012 article in the Daily Mail, she said, "I cut these out of my diet and overnight my symptoms disappeared — the disabling muscle pains, tingling legs, fatigue and inability to concentrate all went" (28).
  • Increase water intake to help eliminate oxalates.

Measuring oxalate toxicity

The organic acid test (Table 1) is one of the best measures for determination of both genetic and nutritional factors that lead to toxic oxalates. The organic acid test includes two additional markers, glycolic and glyceric acids, that are markedly elevated in genetic causes of excessive oxalate, the hyperoxalurias I and II. In addition, the organic acid test includes factors such as high fungal and Candida markers that make oxalate (fungus) or their precursors (Candida). Finally, although vitamin C poses little risk of excess oxalates at doses up to 2000 mg per day, I have measured marked increases in oxalates (more than ten times the upper limit of normal) in a child with impaired kidney function after a 50,000 mg intravenous vitamin C megadose. The organic acid test also includes the main vitamin B6 metabolite pyridoxic acid that diminishes the body's own production of oxalates.

Clinical References:

  • Kohmani EF. Oxalic acid in foods and its behavior and fate in the diet. Journal of Nutrition. (1939) 18(3):233-246,1939
  • Tsao G. Production of oxalic acid by a wood-rotting fungus. Appl Microbiol. (1963) May; 11(3): 249-254.
  • Takeuchi H, Konishi T, Tomoyoshi T. Observation on fungi within urinary stones. Hinyokika Kiyo. (1987) May;33(5):658-61.
  • Lee SH, Barnes WG, Schaetzel WP. Pulmonary aspergillosis and the importance of oxalate crystal recognition in cytology specimens. Arch Pathol Lab Med. (1986) Dec;110(12):1176-9.
  • Muntz FH. Oxalate-producing pulmonary aspergillosis in an alpaca. Vet Pathol. (1999) Nov;36(6):631-2.
  • Loewus FA, Saito K, Suto RK, Maring E. Conversion of D-arabinose to D-erythroascorbic acid and oxalic acid in Sclerotinia sclerotiorum. Biochem Biophys Res Commun. (1995) Jul 6;212(1):196-203.
  • Fomina M, Hillier S, Charnock JM, Melville K, Alexander IJ, Gadd GM. Role of oxalic acid overexcretion in transformations of toxic metal minerals by Beauveria caledonica. Appl Environ Microbiol. (2005) Jan;71(1):371-81.
  • Ruijter GJG, van de Vondervoort PJI, Visser J. Oxalic acid production by Aspergillus niger: an oxalate-non-producing mutant produces citric acid at pH 5 and in the presence of manganese. Microbiology (1999) 145, 2569–2576.
  • Ghio AJ, Peterseim DS, Roggli VL, Piantadosi CA. Pulmonary oxalate deposition associated with Aspergillus niger infection. An oxidant hypothesis of toxicity. Am Rev Respir Dis. (1992) Jun;145(6):1499-502.
  • Takeuchi H, Konishi T, Tomoyoshi T. Detection by light microscopy of Candida in thin sections of bladder stone. Urology. (1989) Dec;34(6):385-7.
  • Ghio AJ, Roggli VL, Kennedy TP, Piantadosi CA. Calcium oxalate and iron accumulation in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. (2000) Jun;17(2):140-50.
  • Ott SM, Andress DL, Sherrard DJ. Bone oxalate in a long-term hemodialysis patient who ingested high doses of vitamin C. Am J Kidney Dis. (1986) Dec;8(6):450-4.
  • Hall BM, Walsh JC, Horvath JS, Lytton DG. Peripheral neuropathy complicating primary hyperoxaluria. J Neurol Sci. (1976) Oct;29(2-4):343-9.
  • Sahin G, Acikalin MF, Yalcin AU. Erythropoietin resistance as a result of oxalosis in bone marrow. Clin Nephrol. (2005) May;63(5):402-4.
  • Sarma AV, Foxman B, Bayirli B, Haefner H, Sobel JD. Epidemiology of vulvar vestibulitis syndrome: an exploratory case-control study. Sex Transm Infect. (1999) Oct;75(5):320-6.
  • http://wisewitch.blogspot.com/2006/07/guaifenesinfibromyalgia-and-oxalates.html
  • http://www.diagnoseme.com/cond/C510175.html
  • http://www.vulvarpainfoundation.org/Lowoxalatetreatment.htm
  • Fishbein GA, Micheletti RG, Currier JS, Singer E, Fishbein MC. Atherosclerotic oxalosis in coronary arteries. Cardiovasc Pathol. (2008) ; 17(2): 117–123.
  • Levin RI, PW Kantoff, EA Jaffe. Uremic levels of oxalic acid suppress replication and migration of human endothelial cells. Arterioscler Thromb Vasc Biol (1990), 10:198-207
  • Di Pasquale G, Ribani M, Andreoli A, Angelo Zampa G, Pinelli G. Cardioembolic stroke in primary oxalosis with cardiac involvement. Stroke (1989), 20:1403-1406.
  • Ziolkowski F, Perrin DD. Dissolution of urinary stones by calcium-chelating agents: A study using a model system. Invest Urol. (1977) Nov;15(3):208-11.
  • Burns JR, Cargill JG 3rd. Kinetics of dissolution of calcium oxalate calculi with calcium-chelating irrigating solutions. J Urol. (1987) Mar;137(3):530-3.
  • http://www.greatplainslaboratory.com/home/eng/oxalates.asp
  • Kaminishi H, Hagihara Y, Hayashi S, Cho T. Isolation and characteristics of collagenolytic enzyme produced by Candida albicans. Infect Immun. (1986) August; 53(2): 312–316.
  • Shirane Y, Kurokawa Y, Miyashita S, Komatsu H, Kagawa S. Study of inhibition mechanisms of glycosaminoglycans on calcium oxalate monohydrate crystals by atomic force microscopy. Urol Res. (1999) Dec; 27(6):426-31.
  • Chetyrkin SV, Kim D, Belmont JM, Scheinman JI, Hudson BG, Voziyan PA. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Kidney Int. (2005) Jan;67(1):53-60.
  • Morrison C. Ditch healthy berries to beat muscle pain: The eating plan that helped me cure my aches and pains. The Daily Mail Online. August 13, 2012. http://www.dailymail.co.uk/health/article-2187890/Ditch-healthy-berries-beat-muscle-pain-The-eating-plan-helped-cure-aches-pains.html. (Accessed November 21, 2014)

    Great Plains Announces New Test for Phospholipase A2 (PLA2)

    William Shaw, Ph.D., Lab Director and Matt Pratt-Hyatt, Ph.D., Associate Lab Director

    The Great Plains Laboratory is excited to announce a new test for PLA2 activity, and we are the only commercial lab currently offering this particular test in urine. PLA2 is elevated in a wide range of inflammatory disorders from multiple sclerosis to cancer. This test can be easily added to the organic acids test to provide powerful new clinical insights and treatments for a variety of serious illnesses.

    PLA2 Overview:

    Chronic diseases are caused by many different biological imbalances, but they almost all create and have inflammation as a cornerstone. Inflammation plays a major part in most of the disorders that we spend billions of dollars to combat, searching for relief from the pain, swelling, and other symptoms that inflammation causes. Inflammation is the immune system's natural response to infection and injury. Phospholipase A2 (PLA2) is one of the key biochemical factors produced in the inflammation response. It is commonly found in human tissues, as well as insect and snake venom. In normal amounts, PLA2 is involved in remodeling cell membranes and changing cell architecture. In infections, PLA2 can break down the phospholipids in the membranes of bacteria, fungi, and parasites leading to their death. However, inflammation, like many other biological processes often has negative effects. The same phospholipase that attacks infectious agents may also attack the cell membranes of the human host, damaging or killing those cells. In addition, the products of the PLA2 reaction, lysolecithins and free fatty acids (Figure 1) are powerful detergents that have the ability to denature proteins and destroy their biological functions. The lysolecithins produced by PLA2 initiate the pain response.

    The most common free fatty acid produced by PLA2 is arachidonic acid which can increase the production of powerful mediators of inflammation called prostaglandins, leukotrienes, and thromboxanes, collectively known as eicosanoids. These mediators play an important role in the generation and maintenance of inflammation in neural cells. In addition, arachidonic acid can be converted to 4-hydroxynonenal (4-NE), which can be very toxic due to covalent modification of important biomolecules including proteins, DNA, and phospholipids containing amino groups. In addition to PLA2 causing local damage, it may be transported by the blood vessels to other parts of the body, causing widespread tissue damage.


    Diseases Associated with PLA2

    Increased levels of PLA2 have been observed in most systemic inflammatory diseases. Studies have linked elevated PLA2 activity with multiple sclerosis, rheumatoid arthritis, Crohn's disease, pancreatitis, ulcerative colitis, allergies, atherosclerosis and cardiovascular disease, lung, prostate, small intestine, and large intestine cancers, with increased susceptibility to metastases, Candida infection, asthma, autism, chronic pulmonary obstructive disorder (COPD), and sepsis.

    What Causes Elevated PLA2?

    Phospholipase A2 is produced by the pancreas and released into the small intestine following a fatty meal. Infection or trauma of the pancreas may result in the release of phospholipase into the circulation, causing widespread damage or even death. Activation by viruses of proenzymes of PLA2 within the pancreas instead of, as normally, in the intestine, may cause pancreatitis. Phosholipase may be produced by cells of the immune system in response to bacterial antigens, especially those containing certain lipopolysaccharides (LPS). Allergies, especially those to house dust and cats, have been implicated as a trigger for PLA2 synthesis and release. Venoms from snakes, spiders, and bees contain high amounts of PLA2, which is responsible for much of the toxicity of these venoms. In addition, microorganisms such as Candida albicans and certain Clostridia species produce PLA2 which increases the ability of the microorganism to infect the host. Trauma may also cause significant increases in PLA2 and result in brain injury.

    PLA2 and Inflammatory Disease

    Research has implicated PLA2 in the pathophysiology of neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD). Multiple sclerosis involves both antigen-specific mechanisms and components of the innate immune system that result in inflammatory response. Elevated PLA2 activity was found to be ongoing among MS patients, with the highest levels measured in patients with progressive disease. In the development of Alzheimer's disease, the abnormal PLA2 levels appear to be related to oxidative signaling pathways involving NADPH oxidase and production of ROS species that lead to impairment and destruction of neurons and inflammation of glial cells.

    Inflammation is the hallmark of rheumatoid arthritis (RA), a joint-destructive autoimmune disease. PLA2 is found in synovial fluid of RA-affected individuals and in the cartilage of RA patients as compared to cartilage from osteoarthritic and normal individuals.

    Measurement of PLA2 is emerging as an important tool for evaluating the chance of cardiovascular disease (CVD), including future stroke, myocardial infarction, heart failure, and other vascular events. PLA2 appears to be more specific than hsCRP for CVD risk and may also have a pivotal role as a mediator of cardiovascular pathology. In atherosclerosis, PLA2 not only activates macrophages and formation of foam cells, but it also hydrolyzes LDL and HDL, spawning increased numbers of pro-atherogenic small LDL particles, and impairing anti-atherogenic HDL. PLA2 activity may even precipitate bleeding from atherosclerotic plaques.

    PLA2 is expressed normally in pancreatic, gall bladder, and GI epithelial cells, but is significantly increased in inflammatory gastrointestinal disorders. In ulcerative colitis and Crohn's disease, all intestinal cell types increase expression of PLA2, which increases gut permeability and may actually contribute to infectivity.

    PLA2 and Cancer

    Elevations of PLA2 have been found in gastrointestinal cancers including colonic adenomas and carcinomas and pancreatic ductogenic carcinomas, among others. Patients with lung tumors positive for PLA2 had a greatly increased tumor growth rate and a markedly reduced survival rate. Patients with lung cancer also had higher plasma levels of PLA2 than patients with benign nodules. A similar pattern has been observed in prostate cancer, although metastatic tumors expressed lower PLA2 than primary tumors. As PLA2 releases arachidonic acid and other fatty acids from cell membranes, they initiate downstream production of tumor-promoting eicosanoids. In cancer, the spread of tumor cells from a primary tumor to the secondary sites within the body is a complicated process involving cell proliferation and migration, degradation of basement membranes, invasion, adhesion, and angiogenesis. Continued research on PLA2 expression in cancer will certainly reveal valuable new insights.

    What lowers PLA2?

    There has been a great deal of research done by both academia and pharmaceutical companies to find chemical inhibitors to PLA2. However, there has also been research on more natural methods for inhibiting PLA2. Glucocorticoids such as the natural hormone cortisol and pharmaceutical agents such as dexamethasone inhibit the production of phospholipase, decreasing harm caused by the enzyme but also decreasing the benefits of the enzyme in killing harmful microorganisms. Thus, excess glucocorticoids can reduce inflammation in a patient with tuberculosis while reducing the effects of PLA2 against the bacteria resulting in spread of the illness. Lithium at pharmacological doses, carbamazepine, and the antimalarial drug chloroquine are all PLA2inhibitors. Vitamin E is also an inhibitor of PLA2. In addition, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (belonging to the omega-3 class of fatty acids) inhibit PLA2. Analysis has shown that treatment with supplements of Cytidine 5'-Diphosphocholine (CDP-choline) can limit the ability of PLA2 to promote inflammation. CDP-choline is a precursor in the formation of phospholipids and has been used as a nutritional supplement at doses ranging from 500-4000 mg per day in the treatment of patients with a variety of disorders including Parkinson's disease, memory disorders, vascular cognitive impairment, vascular dementia, senile dementia, schizophrenia, Alzheimer's disease (especially effective in those with the epsilon-4 apolipoprotein E genotype), head trauma, and ischemic stroke. A trial in patients with Alzheimer's disease indicated that CDP-choline (1,000 mg/day) is well tolerated and improves cognitive performance, cerebral blood perfusion, and the brain bioelectrical activity pattern. No side effects were noticed at the lower doses of CDP-choline and only some mild gastrointestinal symptoms were found using higher doses. No abnormal blood chemistry or hematology values were found after the use of CDP-choline.

    Testing for PLA2

    Because PLA2 is a relatively small enzyme (about 14 KD), it is able to be excreted in urine. 10 mL of the first morning urine before food or drink is suggested for testing. There are no dietary restrictions. This test is convenient to include with other urine tests such as organic acids, amino acids, and peptides. Since chelating agents might interfere with the test, they should not be used for at least 48 hours prior to testing. PLA2 testing is recommended for the following disorders:

    • Multiple sclerosis
    • Rheumatoid arthritis
    • Crohn's disease
    • Pancreatitis
    • Ulcerative colitis
    • Allergies
    • Cardiovascular disease including atherosclerosis
    • Neurodegenerative diseases
    • Schizophrenia
    • Bipolar depression, subtype with psychosis
    • Candida infection
    • Sepsis
    • Long term depression
    • Asthma
    • Chronic obstructive pulmonary disease (COPD)

    Inflammation plays such a key role in so many diseases, and we believe this new PLA2 test will be a valuable tool in the treatment of patients suffering from numerous disorders. The test is now available and we hope you will integrate it into your practice. For more information about PLA2 and possible treatments, please see the references below.

    Clinical References:

    • Green, .J.A., Smith, G.M., Buchta, R., et al. (1991) Circulating phospholipase A2 activity associated with sepsis and septic shock is indistinguishable from that associated with rheumatoid arthritis. Inflammation 15: 355-367
    • Lilja, I., Smedh, K., Olaison, G., et al. (1995) Phospholipase A2 gene expression and activity in histologically normal ileal mucosa and in Crohn's ileitis. Gut. 37: 380-385.
    • Mounier, C.M., Wendum, D., Greenspan, E., et al. (2008) Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate. Br J Cancer 98: 587-595.
    • Nicolas, J.P., Lin, Y., Lambeau, G., et al. (1997). Localization of structural elements of bee venom phospholipase A2 involved in N-type receptor binding and neurotoxicity. J Biol Chem. 272: 7173-7181.
    • Pinto, F., Brenner, T., Dan, P., et al. (2003) Extracellular phospholipase A2 inhibitors suppress central nervous system inflammation. Glia 44(3):275-282.
    • Pruzanski. W., Scott, K., Smith, G., et al. (1992) Enzymatic activity and immunoreactivity of extracellular phospholipase A2 in inflammatory synovial fluids. Inflammation 16: 451-457.
    • Sawada, H., Murakami, M., Enomoto, A., et al. (1999) Regulation of type V phospholipase A2 expression and function by proinflammatory stimuli. Eur J Biochem 263:826–835.
    • Adibhatla, R.M. and Hatccher, J.F. (2005). Cytidine 5'-Diphosphocholine (CDP-Choline) in Stroke and Other CNS Disorders. Neurochemical Research. 30: 15-23.
    • Shaw, W. Possible synergistic effects of nonesterified fatty acids and lysolecithins, a toxic methionine metabolite, and ammonia in the production of hepatic encephalopathy and schizophrenia. Orthomolecular Medicine. 1988.3: 87.
    • Shaw, W. Possible role of lysolecithins and nonesterified fatty acids in the pathogenesis of Reye's syndrome, sudden infant death syndrome, acute pancreatitis, and diabetic ketoacidosis. Clin. Chem. 1985. 31:1109.
    • Alvarez, X.A., Mouzo, R., Pichel, V., Pérez P., et al. Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin Pharmacol. 1999 Nov;21(9):633-44.
    • Fioravanti, M. and Yanagi, M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD000269.
    • Rosenson, R.S. and Gelb, M.H. Secretory phospholipase A2: A multifaceted family of proatherogenic enzymes. Current Cardiology Reports 2009, 11:445–451
    • Farooqui, A.A., Ong, W., and Horrocks, L.A. Inhibitors of brain phospholipase A2 activity: Their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev 58:591–620, 2006
    • Wang, M., Hao, F.Y., J.G. Wang, and Xiao, W. Group IIa secretory phospholipase A2 (sPLA2IIa)and progression in patients with lung cancer. European Review for Medical and Pharmacological Sciences 2014; 18: 2648-2654
    • Pniewska, E., Sokolowska, M., Kupry-Lipinska, I., et al. The step further to understand the role of cytosolic phospholipase A2 alpha and group X secretory phospholipase A2 in allergic Inflammation: pilot study. Biomed Red Int. Volume 2014, Article ID 670814, 9 pages
    • Touqui, L. and Alaoui-El-Azher, M. Mammalian secreted phospholipases A2 and their pathophysiological significance in inflammatory diseases. Current Molecular Medicine 2001, 1, 739-754 739
    • Putignano, S., Gareri, P., Castagna, A., et al. Retrospective and observational study to assess the efficacy of citicoline(CDP-choline) in elderly patients suffering from stupor related to complex geriatric syndrome. Clinical Interventions in Aging 2012:7 113–118.
    • Farooqui, A.A. and Horrocks, L.A. Phospholipase A2-generated lipid mediators in the brain: The good, the bad, and the ugly. The Neuroscientist, Vol. 12, No. 3, 245-260 (2006)
    • Mahmoudabadi, A.Z., Zarrin, M., and Miry, S. Phospholipase activity of Candida albicans isolated from vagina and urine samples. Jundishapur J Microbiol. 2010; 3(4): 169-73.
    • Bell , J.G., MacKinlay , E.E., Dick, J.R., et al. Essential fatty acids and phospholipase A-2 in autistic spectrum disorders. Prostaglandins, Leukotrienes and Essential Fatty Acids Volume 71, Issue 4 , October 2004, Pages 201-204
    • Tavares, H., Yacubian, J., Talib, L.L., et al. Increased phospholipase A2 activity in schizophrenia with absent response to niacin. Schizophr Res. 2003 May 1;61(1):1-6.
    • Ross, B.M. , Hughes, B. , Kish, S.J. , and Warsh, J.J. Serum calcium-independent phospholipase A2 activity in bipolar affective disorder. Bipolar Disord. 2006 Jun;8(3):265-70.
    • Eckert, G.P. , Schaeffer, E.L., Schmitt, A., et al. Increased brain membrane fluidity in schizophrenia. Pharmacopsychiatry 2011 Jun;44(4):161-2.
    • Titsworth, W.L., Liu, N.K., and Xu, X.M. Role of Secretory phospholipase A2 in CNS inflammation: Implications in traumatic spinal cord injury. CNS Neurol Disord Drug Targets 2008 June ; 7(3): 254–269
    • Funakoshi, A., Yamada, Y., Migita, Y., and Wakasugi, H. (1993). Simultaneous determinations of pancreatic phospholipase A2 and prophospholipase A2 in various pancreatic diseases. Dig Dis Sci 38: 502-506

    Vitamin D and Depression

    James Greenblatt, M.D.

    Vitamin D was thought to be of use only in preventing rickets and osteomalacia. Accumulating evidence, however, has demonstrated that vitamin D does much more, influencing the health and function of tissues and organs throughout the body. Vitamin D is an important nutrient for our physical health, but many people are unaware of how critical this vitamin is for maintaining our mental health. In this article, we will explore the evidence-based research on vitamin D and depression. The next article will explore the effects of vitamin D on psychosis and schizophrenia.

    Vitamin D is categorized as a hormone because of its paracrine, autocrine, and endocrine functions, and it can be acquired through food or exposure to the sun. Vitamin D can be found in high amounts in fatty fish and also in milk, yogurt, orange juice and cereals, and dietary supplements. A sufficient amount of vitamin D can also be produced from 5-15 minutes of daily exposure to sunlight.

    Vitamin D2, or ergocalciferol, is only made by plants and vitamin D3, or cholecalciferol, is created when ultraviolet light hitting the skin photochemically converts cholesterol to vitamin D. Serum 25-hydroxyvitamin D [25(OH)D] is a biological marker used to reliably measure the levels of both forms of vitamin D. Among its many functions, vitamin D is important for absorbing calcium, maintaining calcium homeostasis in tissues, growth of bones and teeth, properly functioning neurons and glial cells, preventing rickets and osteomalacia, influencing tissues and organs, preventing psoriasis, muscle pain, weakness, elevated blood pressure, some forms of cancer, and autoimmune disease, and preserving mental health.

    Recent studies have advanced our understanding of vitamin D and its effect on the brain. There are vitamin D receptors in neurons and glial cells in the brain. Specifically, research suggests vitamin D may act on particular regions of the brain important in the development of depression, including the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra. Moreover, it has also been discovered that genetic variations of vitamin D receptors are associated with depression. Recent research shows vitamin D controls the transcription of over one thousand genes involved in neurotrophic and neuroprotective effects, including the maintenance and development of neurons. In addition, vitamin D may also stimulate the release of neurotrophins, a family of proteins that function to protect and stimulate the growth of neurons.

    In a recent study, Polak et al. investigated the association between vitamin D levels and depressive symptoms in 615 young adults. Subjects in the lowest quartile of vitamin D levels were more likely to report having symptoms of depression than those in the highest quartile, suggesting that vitamin D deficiency is a potential predictor of depression. Similarly, in a study on previously deployed military personnel who committed suicide, Umhau et al. found that subjects in the lowest octile of vitamin D levels had the highest risk of suicide. Milaneschi et al. found a comparable effect in the elderly population, with low levels of vitamin D correlating with a significantly higher risk of developing depression. In another study with adolescent participants, Toppanen et al. measured vitamin D levels and depressive symptoms in the same group of children at 9.8, 10.6, and 13.8 years old. Interestingly, higher levels of vitamin D at age 9.8 predicted lower levels of depression at age 13.8, suggesting an association between low levels of vitamin D and early onset depression.

    Bertone-Johnson et al., performed a cross-sectional study on 81,189 older women and found an inverse association between vitamin D levels and depressive symptoms in the postmenopausal women. In another study, Lee et al. found that lower vitamin D levels were associated with depression in a population of 3,369 European men. A study by Black et al. came to the same results in a population of young adult males.

    Vitamin D supplements have also been found to enhance positive moods. In a study by Allen et al., healthy subjects were given 800 IU, 400 IU, or no vitamin D during five days of winter. The results of their study showed that vitamin D was able to significantly enhance positive affect and also reduce negative affect. Taken together, these diverse studies suggest an indisputable connection between vitamin D deficiency and depression across all age groups and genders.

    Biochemical individuality plays a substantial role in vitamin D status. Although environmental factors, such as nutrition and sun exposure, are considered the major determinants of vitamin D status, genetics are responsible for a large portion of the variation seen in serum 25-hydroxyvitamin D. A Swedish study involving 204 same-sex twins between the ages of thirty-nine and eighty-five years living at northern latitude 60 degrees found that genetic factors were responsible for one-fourth of the variation in serum 25-hydroxyvitamin D, independent of season. During the summer season alone, genetics was responsible for half of the variability in 25-hydroxyvitamin D.

    Vitamin D levels between 20 and 30 ng/mL have been traditionally accepted as normal and healthy. We now know that this range is too low, and even people who were thought to be safely in the middle of range may need vitamin D supplementation. Given the quirks of biochemical individuality, some people in the upper reaches may need even more. I prefer to see a 25-hydroxyvitamin D between 40 and 60 ng/mL in my patients. The best way to determine vitamin D deficiency is through serum blood testing which should also be done twice a year.

    Research literature supports a link between vitamin D and depression; however, the exact mechanisms are unclear. The research has not yet established whether low levels of vitamin D cause depression, or whether depression causes low levels of vitamin D. New research is continually emerging on the importance of vitamin D in sustaining mental health. In one 2012 study, adolescents in a mental health facility who were vitamin D deficient were 3½ times more likely to have psychotic features when compared to those with sufficient vitamin D levels. We'll explore the exciting research implicating vitamin D's role in other mental illnesses such as psychosis and schizophrenia in the next newsletter.

    Clinical References


    • Anglin R, Samaan Z, Walter S et al. Vitamin D deficiency and depression in adults: systematic review and meta analysis. British Journal of Psychiatry, 2013.
    • Bertone-Johnson ER, Powers SI, Spangler L et al. Vitamin D Supplementation and Depression in the Women's Health Initiative Calcium and Vitamin D Trial. Am J Epidemiol 2012; 176(1):1-13.
    • Bertone-Johnson ER, Powers SI, Spangler L, et al. Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women. Am J Clin Nutr. 2011 Oct;94(4):1104-12.
    • Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr Rev. 2009 Aug;67(8):481-92.
    • Black LJ, Jacoby P, Allen KL, et al. Low vitamin D levels are associated with symptoms of depression in young adult males. Aust N Z J Psychiatry 2014 May;48(5):464-71.
    • Dean A J, Bellgrove M A, Hall T et al. Effects of vitamin D supplementation on cognitive and emotional functioning in young adults–a randomised controlled trial. PLoS One. 2011;6(11):e25966
    • Gracious, BL, Finucane, TL, Friedman-Campbell, M. et al. Vitamin D deficiency and psychotic features in mentally ill adolescents: A cross-sectional study. BMC Psychiatr. 2012; 12: 38.
    • Han B, Lyu Y, Sun Y et al. Low serum levels of vitamin D are associated with post-stroke depression. European Journal of Neurology Dec 2014. [E-pub ahead of print].
    • Jorde, M. Sneve, Y. Figenschau, J et al. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264(6):599-609.
    • Lansdowne AT & Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl) 1998 Feb;135(4):319-23
    • Lee DM, Tajar A, O'Neill TW, et al. Lower vitamin D levels are associated with depression among community-dwelling European men. J Psychopharmacol 2011 Oct;25(10):1320-8.
    • Polak MA, Houghton LA, Reeder AI, et al. Serum 25-hydroxyvitamin D concentrations and depressive symptoms among young adult men and women. Nutrients 2014 Oct 28;6(11):4720-30.
    • Toffanello ED, Sergi G, Veronese N, et al. Serum 25-hydroxyvitamin d and the onset of late-life depressive mood in older men and women: the Pro.V.A. study. J Gerontol A Biol Sci Med Sci 2014 Dec;69(12):1554-61.
    • Tolppanen AM, Sayers A, Fraser WD, et al. The association of serum 25-hydroxyvitamin D3 and D2 with depressive symptoms in childhood--a prospective cohort study. J Child Psychol Psychiatry 2012 Jul;53(7):757-66.
    • Umhau JC, George DT, Heaney RP, et al. Low Vitamin D Status and Suicide: A Case-Control Study of Active Duty Military Service Members. PLoS One 2013;8(1):e51543.
    • Yue W, Xiang L, Zhang YJ, et al. Association of serum 25-hydroxyvitamin D with symptoms of depression after 6 months in stroke patients. Neurochem Res. 2014 Nov;39(11):2218-24.

    Toxic Crumb Rubber: Nothing to Play Around With

    Matt Pratt-Hyatt, Ph.D.


    As a parent of two young children I understand that parents have a long list of things to worry about. We parents worry if our children are eating right, getting enough sleep, or if they're making friends. Unfortunately, we now also have to worry about the toxic environment to which our children may be exposed, be it the toys they are playing with or the cups they use for drinking. The latest data shows that the playgrounds and artificial turf fields they play on may be quite toxic and hazardous to their health.

    In the last two decades, many playgrounds, soccer fields, and football fields have been replacing their natural surfaces with a synthetic surface of rubber granules made up of ground up tires. Despite the popularity of these types of surfaces many different activist groups have expressed concern that these synthetic materials may be a toxic burden on our children.

    In 2006 a commentary was written in Environmental Health Perspectives detailing how little we knew about the material we are having our children play on (Anderson et al, 2006). In the years since, there have been some insightful studies performed that give clues into how harmful prolonged exposure to these playing fields may be. In 2007, a study from the nonprofit organization Environment and Human Health, Inc. and the Department of Analytical Chemistry at the Connecticut Agricultural Experimental Station produced one of the first reports about chemicals found leaching from artificial surfaces made from rubber tires. This report indicated that benzothiazole, butylated hydroxyanisole, n-hexadecane, 4-(t-oxtyl) phenol, and zinc were found leaching from the tires. These chemicals are known carcinogens and neurotoxicants (Brown et al., 2007).

    A second report in 2008 in the Journal of Exposure Science and Environmental Epidemiology provided some additional data on the chemicals that could affect children. The report indicated that the rubber granules have a much higher amount of polycyclic aromatic hydrocarbons (PAHs) than soil. Zinc and chromium were also found to be much higher in the artificial surfaces than in soil. The report also stated that although lead was not found to be much higher than in soil the bioaccessibility was much higher (Zhang et al, 2008). PAHs are known neurotoxic chemicals which have been found in air pollution from fossil fuel combustion. A recent study published in PLOS One from the University of Columbia discovered a link between PAH exposure and the development of attention deficit and hyperactivity problems (Perera et al., 2014).

    In the last several years many alternatives to crumb rubber have emerged. One drawback to these alternatives is that they will add cost to the play area project. However, these costs do not calculate the damage these surfaces may be inflicting on our children. In light of the new data, any new playground or school field should reconsider the use of crumb rubber.

    Candida: A Factor in Depression and Mental Health

    Jessica Bonovich, R.N.

    One of the first psychiatrists to publish findings about the connection between Candida and depression is Dr. Orian Truss. His compelling work has been cited in numerous books and helped countless patients to date. Interestingly, his discovery in 1981 did not generate much interest from the psychiatric community who had just begun to see the effects of MAO inhibitors. While these and other modern antidepressants remain an important tool for treating psychiatric patients, studies have demonstrated that their efficacy rate is only about 20-30 percent (Kroenke, Hansen). Clearly, we do not have sufficient understanding of the complex spectrum of mental disorders that plague millions of individuals. To this end, we should leave no stone unturned. Especially if that stone has already shown to provide helpful information.

    Dr. Truss hypothesized that where Candida is merely a nuisance for some, it causes chronic illness (including mental illness) in others. People with weakened immune systems are particularly at risk however they need not have HIV or leukemia to suffer. At the Huxley symposium (1981), he presented 6 case studies he believed to encompass the so-called Candida syndrome that he discovered. All individuals had been exposed to multiple rounds of antibiotics or other immune lowering agents. These individuals were often female. Depression was almost always one of many vague symptoms. Loss of memory, difficulty concentrating, sensitivity to chemicals and other symptoms were also noted. Dr. Truss began to incorporate treatment with antifungal therapy for patients with chronic mental illness. Interestingly, all of the individuals responded to the treatment and their symptoms of depression lifted.

    More recently, a double blind placebo controlled study in 2001, under the direction of Heiko Santelmann found the antifungal drug nystatin to be significantly more effective at reducing symptoms of depression in polysymptomatic patients. In fact, the authors of the study noted that some of the most dramatic improvements reported were from individuals who had mental complaints. While nystatin is not specific to Candida, it is a compelling study that demonstrates yeast can affect mental health.

    Dr. Truss noted the difficultly of testing for Candida since nearly everyone has had exposure to the organism. Determining the degree to which each individual suffers is based on a set of vague symptoms that often ends with the patient being labeled as psychosomatic or psychiatric. Fortunately, today we have more robust methods of detecting Candida and a better understanding of the mechanism which may be causing symptoms.

    Genetic coding has helped determine the mechanisms that pathogens employ to help increase virulence. In the case of Candida albicans, a specific gene that codes for Immunogenic Alcohol Dehydrogenase was detailed in 1994 (Bertryam). This enzyme produces acetylaldehyde from glucose or ethanol (Gainza-Cirauqui). This acetylaldehyde creates an environment that is not conducive to most microbes which effectively decreases the competition. In humans, acetylaldehyde is a carcinogenic compound that easily passes the blood brain barrier where it interferes with neurotransmission (Correa). Depression and acetylaldehyde both cause a reduction in natural killer cell cytotoxicity (Irwin). Since nearly everyone has Candida in the body, it is plausible that a brief episode of depression may increase the possibility of developing a chronic condition.

    For years, a yeast culture with sensitivity has been the mainstay of Candida testing. The benefit to this test is that it can determine the exact species of yeast so that appropriate treatment can be instituted. The problem with this method is that it is notorious for producing false negatives (Maaroufi). Metabolites of yeast detected in The Great Plains Laboratory Organic Acids Test are a very reliable method of detecting Candida overgrowth (Shaw). While this test cannot determine the exact organism, this is less important. Most prescriptive antifungal agents are effective at killing Candida albicans, which is the most common yeast species (Shaw).

    Armed with correct information, the latest in diagnostic testing, and viable treatment options, psychiatric and primary care physicians can exercise multiple options for patients with symptoms of depression and other mental health disorders. As more and more physicians are looking outside the box to find solutions to psychiatric diseases as complex as the patients themselves, many are turning to comprehensive testing for yeast (and other pathogens) for answers. If a patient presents with a recent onset of chronic depression in the absence of major trauma, it makes sense to ask the question: Could this be related to Candida or another pathogen? Doing so may save your patient's life, or at least the life they once knew!

    Clinical References

    • Hansen, R. et al. (2005). Efficacy and Safety of Second-Generation Antidepressants in the Treatment of Major Depressive Disorder. Annals of Internal Medicine, 143(6); 415-426.
    • Kroenke, K., et al. (2001). Similar Effectiveness of Paroxetine, Fluoetine, and Sertaline in Primary Care. JAMA, 286(23); 2947-2955
    • Truss, O. (1981). The Role of Candida in Human Illness. Presented that the Huxley symposium, September, Birmingham, AL.
    • Bertryam, G., et al. (1995). Structure and Regulation of the Candida albicans ADH1 Gene Encoding an Immunogenic Alcohol Dehydrogenase. Yeast, 12:115-127.
    • Santelmann, H et al. (2001). Effectiveness of nystatin in polysymptomatic patients. A randomized, double-blind trial with nystatin versus placebo in general practice. Family Practice, 18; 258-265.
    • Gainza-Cirauqui, ML., et al. (2013). Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders. Journal of Oral Pathology and Medicine, 42(3); 243-9.
    • Correa, M., et al. (2011). Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neuroscience and Biobehavioral Reviews, 36; 404-430.
    • Irwin, M., et al. (1990). Major Depressive Disorder, Alcoholism, and Reduced Natural Killer Cell Cytotoxicity: Role of Severity of Depressive Symptoms and Alcohol Consumption. JAMA Psychiatry, 47(8); 713-719.
    • Maaroufi, Y., Heymans, C., De Rune, J., Duchateau, H. (2003). Rapid Detection of Candida albicans in Clinical Blood Samples by Using a TaqMan-Based PCR Assay. Journal of Clinical Microbiology, 41; 3293-3298.
    • Shaw ,W., (2008) Biological Treatments for Autism and PDD. Publisher: Author.