Integrative Treatments for Behavioral Problems in Children

By: James Greenblatt, MD

Attention deficit/hyperactivity disorder (ADHD) is a multifactorial condition that is influenced by genetic, biological, environmental, and nutritional factors. While there are numerous integrative therapies available including vitamins, minerals, herbs, neurofeedback, exercise, and meditation, individuals are unique and thus require personalized treatments based on their own biological needs identified through laboratory testing. In this article, we will discuss commonly overlooked mineral deficiencies and imbalances in the gastrointestinal flora that can exacerbate behavioral symptoms and impede the therapeutic effect of pharmacological treatment.

In the early 1960s, researchers discovered that zinc was an essential trace mineral necessary for normal growth and development. Zinc is also critical for immune function, and the activity of over 300 enzymes is dependent on zinc bioavailability. Zinc is a vital component of the central nervous system, maintaining neurotransmitter activity. This mineral enhances GABA, one of our main inhibitory/relaxation neurotransmitters. Moreover, zinc is needed as a co-factor to produce melatonin which helps regulate dopamine function.

Multiple studies have confirmed that not only are zinc levels lower in children with ADHD, but the extent of the deficiency is proportionately correlated with the severity of ADHD symptoms including inattention, hyperactivity, impulsivity, and conduct problems:

• Toren et al. (1996) found that almost one-third of 43 ADHD children aged 6-16 were severely deficient in serum zinc.

• Another study involving 48 ADHD children aged 5-10 demonstrated that most of the participants had serum zinc levels in the lowest 30% of the reference range.

• There is a highly significant inverse correlation between zinc level and parent and teacher ratings of inattention among children with ADHD (Arnold et al., 2005). A more recent study echoed the same findings, when researchers analyzed the zinc in the hair of 45 children with ADHD against 44 controls. They found that there was a relationship between hair zinc levels and worse overall ADHD symptoms (Shin et al., 2014).

• In a recent study, 70% of the 20 ADHD cases examined were zinc deficient. Those with lower hair zinc levels reported significantly increased symptoms of inattention, hyperactivity, and impulsivity (Elbaz et al., 2016).

• In a larger group of 118 children with ADHD, those with the lowest blood levels of zinc had the most severe conduct problems, anxiety, and hyperactivity as rated by their parents (Oner et al., 2010).

In children with ADHD, plasma zinc levels were shown to directly affect information processing via event related potentials which reflect brain activity. In ADHD children compared to controls, the amplitudes of P3 waves in frontal and parietal brain regions were significantly lower (worse working memory) and the latency of P3 in the parietal region was significantly longer (slower information processing). Unsurprisingly, plasma zinc levels were significantly lower in the ADHD children compared to the control children. When a low-zinc ADHD subgroup was compared to a nondeficient ADHD subgroup, the latencies of N2 in frontal and parietal brain regions were significantly shorter (worse information processing and inhibition) (Yorbik et al., 2008).

Supplementation with zinc is more effective at improving ADHD symptoms when compared to placebo, and can also be an effective adjuvant therapy to enhance the therapeutic effect of stimulant medication without increasing the dosage. When 400 ADHD children aged 6-14 were randomized to zinc sulfate 150 mg/day or placebo for 12 weeks, those taking zinc had significantly reduced symptoms of hyperactivity, impulsivity, and impaired socialization (Bilici et al., 2004). Similarly, when over 200 children were randomized to zinc 15 mg/day or to placebo for 10 weeks, those taking zinc saw significant improvement in attention, hyperactivity, oppositional behavior, and conduct disorder. And these children had normal zinc levels to begin with (Üçkardeş et al., 2009). In a small study of 18 boys with ADHD, higher baseline hair zinc levels predicted better behavioral response to amphetamine (Arnold et al., 1990). In a six-week double blind, placebo controlled trial, researchers assessed the effects of zinc in combination with methylphenidate (Ritalin). 44 children aged 5-11 were randomized to methylphenidate plus zinc sulfate 55 mg/day or methylphenidate plus placebo. At week 6, those taking zinc had significantly better scores on the Parent and Teacher ADHD Rating Scale (Akhondzadeh et al., 200452 children aged 6-14 with ADHD were randomized to zinc glycinate 15 mg/day or placebo for 13 weeks. For the first 8 weeks, they only took zinc then for the last 5 weeks they also took d-amphetamine. The optimal absolute mg/day amphetamine dose with zinc was 43% lower than with placebo (Arnold et al., 2011).

Copper is an essential trace mineral that plays an active role in the synthesis of dopamine and norepinephrine. However, excess copper can manifest as displays of aggression, hyperactivity, insomnia, and anxiety. Elevated copper levels can also cause low zinc levels and reduce the efficacy of medications commonly used to treat ADHD.

Copper may affect ADHD through its role in antioxidant status. Copper/Zinc superoxide dismutase (SOD-1) is a key enzyme in our antioxidant defense system. Both copper and zinc participate in SOD enzymatic activities that protect against free radical damage. In a study on 22 ADHD children and 20 controls, serum Copper/Zinc SOD levels of ADHD children were significantly lower in individuals with high serum copper when compared to controls. It is also hypothesized that excess copper can damage dopamine brain cells by destroying antioxidant defenses, such as lowering Copper/Zinc SOD levels (Russo, 2010).

In a randomized controlled trial on 80 adults with ADHD, lower baseline copper levels were associated with better response to treatment with a vitamin-mineral supplement (Rucklidge et al., 2014). Unfortunately, even copper levels that are considered normal can negatively affect cognition. In a group of 600 adolescents with normal copper levels, blood copper was associated with decreased sustained attention and short-term memory (Kicinski et al., 2015).

Magnesium is part of 300 enzymes that utilize ATP (cellular energy) and is important for nerve transmission. It is involved in the function of the serotonin, noradrenaline, and dopamine receptors. Magnesium has been progressively declining in our food supply due to increased consumption of processed foods. The use of medications, presence of stress, and caffeine and soft drink consumption also deplete magnesium, and it is estimated that 50% of Americans are deficient in magnesium (Mosfegh et al., 2009).

Symptoms of magnesium deficiency include irritability, difficulty with concentration, insomnia, depression, and anxiety. A prospective population-based cohort of over 600 adolescents at the 14- and 17-year follow-ups found that higher dietary intake of magnesium was significantly associated with reduced externalizing behaviors (attention problems, aggressiveness, delinquency) (Black et al., 2015). Because up to 95% of those with ADHD are deficient in magnesium, almost all ADHD children can benefit from magnesium supplementation (Kozielec & Starobrat-Hermelin, 1997).

In a recent study on 25 patients with ADHD aged 6-16, 72% of children were deficient in magnesium and there was a significant correlation between hair magnesium, total IQ, and hyperactivity. The magnesium deficient children were randomized to magnesium supplementation 200 mg/day plus standard medical treatment or to standard medical therapy alone for 8 weeks. Those taking magnesium saw a significant improvement in hyperactivity, impulsivity, inattention, opposition, and conceptual level while those taking medication alone did not see these improvements (El Baza et al., 2015).

Supplements of magnesium plus vitamin B6, which increases magnesium absorption, have shown promise for reducing ADHD symptoms. One study on 52 children with ADHD found that 58% had low red blood cell magnesium levels. All the children were given preparations of magnesium plus vitamin B6 100 mg/day for a period of 1 to 6 months. In all patients, physical aggression, instability, attention at school, muscle rigidity, spasms, and twitching were improved. One of the treated children was a six-year old identified as “J”. Initially, J suffered from aggressiveness, anxiety, inattention, and lack of self-control. After taking magnesium supplements, he reported better sleep and concentration and no methylphenidate was needed (Mousain-Bosc et al., 2004). A later study by the same researchers also found that 40 children with ADHD had significantly lower red blood cell magnesium values than control children. Likewise, a magnesium-vitamin B6 regimen for at least 2 months significantly improved hyperactivity, aggressiveness, and school attention. The researchers concluded, “As chronic magnesium deficiency was shown to be associated to hyperactivity, irritability, sleep disturbances, and poor attention at school, magnesium supplementation as well as other traditional therapeutic treatments, could be required in children with ADHD” (Mousain-Bosc et al., 2006). In a larger study of 122 children with ADHD aged 6-11, 30 days of magnesium-vitamin B6 supplementation led to improved anxiety, attention, and hyperactivity. On a battery of tests, magnesium treatment increased attention, work productivity, task performance, and decreased the proportion of errors. The EEG of treated children showed positive changes as well, with brain waves significantly normalizing (Nogovitsina & Levitina, 2007).

There has also been a considerable amount of research illustrating the symbiotic, bidirectional relationship between the brain and the gut, and animal studies have demonstrated how certain strains of bacteria, or lack thereof, can alter cognitive and emotional processes. In the presence of dysbiosis, where “bad” bacteria outnumber the “good,” harmful strains of bacteria can proliferate and cause behavioral disturbances.

HPHPA is a harmful byproduct of some strains of the bacterium Clostridium that can disrupt the normal gut environment. Elevated urinary levels are commonly seen in ADHD children, especially those with poor response to stimulants. HPHPA inhibits the conversion of dopamine to norepinephrine. This causes dopamine to accumulate, resulting in decreased attention and focus. A patient should especially be tested for HPHPA if he or she experiences stimulant side effects such as irritability, agitation, or anxiety. ADHD medications work by increasing dopamine. But high HPHPA levels prevent the breakdown of dopamine, exacerbating symptoms. HPHPA must be cleared before medications will be helpful. Probiotics, good bacteria found in fermented food such as yogurt, or antibiotics can be used to lower HPHPA.

Intestinal overgrowth of Candida yeast is seen in some children with ADHD, mostly in those with a diet high in sugar that feed Candida, or in those who have received many rounds of antibiotics for recurrent ear infections. Antibiotics are effective at resolving infections by eradicating all bacteria, including the good bacteria. An early study found that children with the greatest history of ear infections (and presumably the greatest frequency of antibiotic use) had an increased chance for developing hyperactivity later (Hagerman & Falkenstein, 1987). Toxins produced by Candida can enter the bloodstream and then enter the brain where they can cause changes leading to hyperactivity and poor attention span. Fortunately, the presence of HPHPA and other yeast overgrowth can be easily detected with an organic acids test or with a stool sample. Candida can be treated with probiotics, antifungal foods (e.g. garlic, oregano, ginger), and a lower sugar diet. In some cases, a regimen of antibiotics and probiotics can be useful in reestablishing a healthy gut flora.

Nutritional augmentation strategies are frequently used as part of the integrative clinician’s toolbox to treat behavioral disorders in children. It is important for healthcare providers to collaborate and communicate with caregivers of children with behavioral disorders to discern whether other complementary therapies could be incorporated into treatment. By carefully assessing a patient’s whole health history and conducting appropriate laboratory testing, providers can make informed treatment recommendations that is tailored specifically for the individual.

---

References

Akhondzadeh, et al (2004). Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial ISRCTN64132371. BMC Psychiatry, 4, 9.

Arnold et al. (1990). Does hair zinc predict amphetamine improvement of ADD/hyperactivity? The International Journal of Neuroscience, 50(1-2), 103-7.

Arnold et al. (2005). Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 15(4), 628-36.

Arnold et al. (2011). Zinc for attention-deficit/hyperactivity disorder: Placebo-controlled double-blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology, 21(1), 1-19.

Bilici et al. (2004). Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 28(1), 181-190.

Black et al. (2015). Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutrition, 18(10), 1824-30.

Elbaz et al. (2016). Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egyptian Journal of Medical Human Genetics, Egyptian Journal of Medical Human Genetics, in press.

El Baza et al. (2016). Magnesium supplementation in children with attention deficit hyperactivity disorder. Egyptian Journal of Medical Human Genetics, 17(1), 63-70.

Hagerman & Falkenstein. (1987). An Association Between Recurrent Otitis Media in Infancy and Later Hyperactivity. Clinical Pediatrics, 26(5), 253.

Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.

Kozielec & Starobrat-Hermelin. (1997). Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 10(2), 143-148.

Moshfegh et al. (2009). What We Eat in America, NHANES 2005–2006: Usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. Department of Agriculture, Agricultural Research Service: Washington, DC, USA.

Mousain-Bosc et al. (2004). Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. Journal Of The American College Of Nutrition, 23(5), 545S-548S.

Mousain-Bosc et al. (2006). Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders. Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 19(1), 46-52.

Nogovitsina & Levitina. (2007). Neurological aspects of the clinical features, pathophysiology, and corrections of impairments in attention deficit hyperactivity disorder. Neuroscience and Behavioral Physiology, 37(3), 199-202.

Oner et al. (2010). Effects of Zinc and Ferritin Levels on Parent and Teacher Reported Symptom Scores in Attention Deficit Hyperactivity Disorder. Child Psychiatry and Human Development, 41(4), 441-447.

Rucklidge et al. (2014). Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Progress in Neuropsychopharmacology & Biological Psychiatry, 50, 163-171.

Russo, A. (2010). Decreased Serum Cu/Zn SOD Associated with High Copper in Children with Attention Deficit Hyperactivity Disorder (ADHD). Journal of Central Nervous System Disease, 2, 9-14.

Shin et al. (2014). The Relationship between Hair Zinc and Lead Levels and Clinical Features of Attention-Deficit Hyperactivity Disorder. Journal of the Korean Academy of Child and Adolescent Psychiatry, 25(1), 28-36.

Toren et al. (1996). Zinc deficiency in attention-deficit hyperactivity disorder. Biological Psychiatry, 40(12), 1308-1310.

Üçkardeş et al. (2009). Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children. Acta Paediatrica, 98(4), 731-736.

Yorbik et al. (2008). Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 32(3), 662-667.

Magnesium: The Missing Link in Mental Health?

by James Greenblatt, MD

Chief Medical Officer at Walden Behavioral Care in Waltham, MD
Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth College Geisel School of Medicine

Magnesium is a cofactor in more than 325 enzymatic reactions—in DNA and neurotransmitters; in the bones, heart and brain; in every cell of the body. Unfortunately, a deficiency of this crucial mineral is the most common nutritional deficiency I see in my practice as an integrative psychiatrist. Fortunately, supplementation with magnesium is the most impactful integrative treatment I use, particularly in depression and attention deficit hyperactivity disorder (ADHD).

Why is magnesium deficiency so common, and why is restoring the mineral so essential to mental and emotional well-being and behavioral balance? The rest of this article addresses those two questions, and presents aspects of my therapeutic approach.

Magnesium Deficiency

 The population is deficient in magnesium—found abundantly in whole grains, beans and legumes, nuts and seeds, and leafy greens, as well as cocoa and molasses—for several reasons.

Soil depletion. Intensive agricultural practices rob the soil of magnesium and don’t replace it. As a result, many core food crops—such as whole grains—are low in magnesium. A recent paper in Crop Journal put it this way: Magnesium’s “importance as a macronutrient ion has been overlooked in recent decades by botanists and agriculturists, who did not regard Mg deficiency in plants as a severe health problem. However, recent studies have shown, surprisingly, that Mg contents in historical cereal seeds have markedly declined over time, and two thirds of people surveyed in developed countries received less than their minimum daily Mg requirement.” [1]  

Food processing. Magnesium is stripped from foods during food processing. For example, refined grains—without magnesium-rich germ and bran—have only 16% of the magnesium of whole grains. [2]

Stress. Physical and emotional stress—a constant reality in our 24/7 society—drain the body of magnesium. In fact, studies show inverse relationships between serum cortisol and magnesium—the higher the magnesium, the lower the cortisol. Stress robs the body of magnesium—but the body must have magnesium to respond effectively to stress.

Other factors. Many medications—such as medications for ADHD—deplete magnesium. So does the intake of alcohol, caffeine and soft drinks.

The result: In 1900, the average intake of magnesium was 475 to 500 mg daily. Today, it’s 175 to 225 mg daily. Which means that only one-third of adult Americans get the daily RDA for magnesium—320 mg for women, and 420 mg for men. (And many researchers consider the RDA itself inadequate.)  And that magnesium deficit causes deficits in health. Magnesium deficiency has been cited as contributing to atherosclerosis, hypertension, type 2 diabetes, obesity, osteoporosis and certain types of cancer. [4] But detecting that deficiency in laboratory testing is difficult, because most magnesium in the body is stored in the skeletal and other tissues. Only 1% is in the blood, so plasma levels are not a reliable indicator. That means a “normal” magnesium blood level may exist despite a serious magnesium deficit. An effective therapeutic strategy: Assume a deficit is present, and prescribe the mineral along with other appropriate medical and natural treatments. That’s particularly true if the patient has symptoms such as anxiety, irritability, insomnia and constipation, all of which indicate a magnesium deficiency.

The Mind Mineral

Some of the highest levels of magnesium in the body are found in the central nervous system, with studies dating back to the 1920s showing how crucial magnesium is for a balanced brain…

It’s known, for example, that magnesium interacts with GABA receptors, supporting the calming actions of this neurotransmitter. Magnesium also keeps glutamate—an excitatory neurotransmitter—within healthy limits. Patients with higher magnesium levels also have healthy amounts of serotonin in the cerebrospinal fluid. And the synthesis of dopamine requires magnesium.

In summary, the body needs magnesium to create neurotransmitters (biosynthesis) and for those neurotransmitters to actually transmit. Magnesium also acts at both the pituitary and adrenal levels. In the pituitary gland, it modulates the release of ACTH, a hormone that travels to the adrenal glands, stimulating cortisol release. In the adrenal gland, it maintains a healthy response to ACTH, keeping cortisol release within a normal range. As a result, magnesium is a must for maintaining the homeostasis of the HPA axis. Given all these key mechanisms of action, it’s not surprising that a lack of the mineral can produce psychiatric and other types of problems. The patient may have: Difficulty with memory and concentration. Depression, apathy and fatigue. Emotional lability. Irritability, nervousness and anxiety. Insomnia. Migraine headaches. Constipation. PMS. Dysmenorrhea. Fibromyalgia. Autism. ADHD. Fortunately, studies show that magnesium repletion—restoring normal levels of the mineral—produces positive changes in mood and cognition, healthy eating behavior, healthy stress responses, better quality of sleep, and better efficacy of other modalities, such as medications. Let’s look at two areas in which magnesium supplementation is particularly effective: Depression and ADHD.

Depression

A cross-sectional, population-based data set—the National Health and Nutrition Examination Survey—was used to explore the relationship of magnesium intake and depression in nearly 9,000 US adults. Researchers found significant association between very low magnesium intake and depression, especially in younger adults. [5] And in a recent meta-analysis of 11 studies on magnesium and depression, people with the lowest intake of magnesium were 81% more likely to be depressed than those with the highest intake. [6] In a clinical study of 23 senior citizens with depression, low blood levels of magnesium and type 2 diabetes, magnesium was compared to the standard antidepressant medication imipramine (Tofranil)—one group received 450 mg of magnesium daily and one group received 50 mg of imipramine. After 12 weeks, depression ratings were equally improved in both groups. [7] In my practice, I nearly always prescribe magnesium to a patient with diagnosed depression. You can read more about the integrative approach to depression in Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention (CRC Press), which I co-edited, and in Breakthrough Depression Solution: Mastering Your Mood with Nutrition, Diet & Supplementation (Sunrise River Press, 2nd Edition).

Attention Deficit Hyperactivity Disorder

Magnesium deficiency afflicts 90% of all people with ADHD and triggers symptoms like restlessness, poor focus, irritability, sleep problems, and anxiety. These symptoms can lessen or vanish one month after supplementation starts. Magne­sium can also prevent or reverse ADHD drug side effects. That’s why all of my ADHD patients get a prescription for magnesium. For adolescents, I typically prescribe 200 mg, twice daily. For children 10 to 12, 100 mg, twice daily. For children 6 to 9, 50 mg, twice daily. Typically, I recommend magnesium glycinate, using a powdered product. I describe my entire approach to magnesium and ADHD (and to the disorder’s overall integrative treatment) in my book Finally Focused: The Breakthrough Natural Treatment Plan for ADHD That Restores Attention, Minimizes Hyperactivity, and Helps Eliminate Drug Side Effects. (Forthcoming from Harmony Books in May 2017)

Dosage and Form

I have found that 125 to 300 mg of magnesium glycinate at meals and a bedtime (four times daily) produces clinically significant benefits in mood. (This form of magnesium is gentle on the digestive tract.) 200 to 300 mg of magnesium glycinate or citrate before bed supports sleep onset and duration through the night. You can also find magnesium in powder or liquid form, which are effective alternatives to capsules, particularly for children with ADHD. Ways to increase the bioavailability of magnesium include: Supplementing with vitamin D3, which increases cellular uptake of the mineral. Vitamin B6 also helps magnesium accumulate in cells. Taking the mineral in divided doses instead of a single daily dose. Taking it with carbohydrates, with improves absorption from the intestine. And taking an organic form, such as glycinate or citrate, which improves absorption by protecting the mineral from antagonists in the digestive tract. Avoid giving magnesium in enteric-coated capsules, which decreases absorption in the intestine.

Magnesium oxide is poorly absorbed and tends to cause loose stools. Magnesium-l-threonate has been shown to readily cross the blood-brain barrier, and animal studies show that it supports learning ability, short and long-term memory and brain function, I don’t typically prescribe it, however, because of its higher cost, and the clinical effectiveness of other forms. The therapeutic response to magnesium typically takes several weeks, as levels gradually increase in the body.

CITATIONS

[1] Guo W., et al. Magnesium deficiency in plants: An urgent problem. The Crop Journal, Volume 4, Issue 2, April 2016, Pages 83-91.

[2] http://www.ancient-minerals.com/magnesium-sources/dietary/

[3] https://www.washingtonpost.com/national/health-science/magnesium-is-essential-to-your-health-but-many-people-dont-get-enough-of-it/2017/06/09/77bc35b4-2515-11e7-bb9d-8cd6118e1409_story.html?noredirect=on&utm_term=.b92d507bf92a

[4] Volpe, SL. Magnesium in Disease Prevention and Overall Health. Advances in Nutrition, 2013 May; 4(3): 378S-383S.

[5] Tarleton EK, at al. Magnesium Intake in Depression in Adults. Journal of the American Board of Family Medicine, 2015 Mar-Apr;28(2):249-56.

[6] Li B, et al. Dietary magnesium and calcium intake and risk of depression in the general population: A meta-analysis. Australian and New Zealand Journal of Psychiatry, 2016 Nov 1. [Epub ahead of print].

[7] Barragan-Rodriquez L, et al. Efficacy and safety or oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. Magnesium Research, 2008 Dec;21(4):218-23.

Response to Article on the Lack of Oxalate Dangers in the Green Smoothie Diet

William Shaw, PhD

In response to the inaccurate, unscientific article by Thomas Lodi, M.D. on oxalates1 in the December 2015 issue of Townsend Letter, I will make the following point by point responses:

(1)Cartoons about Popeye.
I will not use any cartoons in my response. Anyone interested in cartoons should immediately stop reading this article and start reading their local paper’s comic section.

(2)Inaccurate references.
The tone for accuracy of the author is set in the very first paragraph of his article in which his first reference, #23, has nothing to do with my green smoothie article, which is reference #24. A better reference would actually be #2 from my article2.  When the clock strikes 13, the accuracy of the other 12 hours of the clock is in serious question.

(3)Inaccuracy about the contribution of endogenous production to total oxalate load.
Lodi states that 80-90% of oxalates in the body are endogenously produced. Unfortunately, the best scientific study refutes his assertion. According to Holmes et al3, who did extremely well-controlled studies on every aspect of oxalate metabolism and has publishedforty-one scientific articles on oxalates in the peer reviewed literature, the mean dietary oxalate contribution to total oxalate in the diet is 52.6 % on a high oxalate diet which was defined as a diet of 250 mg oxalate per day. The person drinking a green smoothie with 2 cups of raw spinach ingests 1312 mg of oxalates or over five times the level of what Holmes considers a high-oxalate diet, just in the spinach consumption alone and over 26 times the amount of oxalates in a low oxalate diet (50 mg per day)4. The estimated human production of oxalates is 40 mg per day3. On a green smoothie diet with two cups of spinach, the diet in normal humans contains 33 times the endogenous human production of oxalates just based on the spinach alone.

All of Lodi’s assertions about the benefits of a vegetarian diet are meaningless since there is no single vegetarian diet; there are as many vegetarian diets as there are vegetarians.

 (4)Inaccuracy about the availability of calcium and magnesium in spinach.
Lodi states that “every plant, green and otherwise (including spinach) has abundant magnesium and calcium and potassium”. Unfortunately, none of the calcium and magnesium in spinach or other high oxalate plants is bioavailable since it is strongly bound to oxalates. Furthermore, the average oxalate value of spinach is 7.5 times its calcium content, making spinach a very poor choice for someone to maintain adequate calcium stores5. According to Kohmani, who added a good deal of spinach, similar to the diet of a person ingesting a daily green smoothie or a large daily spinach salad, to the diet of rats to determine its effects5:

“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 considerable of that of the other foods. Considerable of the oxalate appears in the urine, much more in the feces.”

(5)Lodi argues that his patients haven’t complained about kidney stones while drinking a lot of green smoothies so oxalates must not be problematic.
Lodi’s contention that his patients on a high oxalate diet don’t have kidney stones is anecdotal. He presents no data from active chart review of his patients to determine if questions about kidney stones were ever asked. Furthermore, it is doubtful that his patients would have even have connected their diet with their kidney stones. I have had numerous seminars on the connection between oxalates and kidney stones and it is common to get feedback from the audience members that they had kidney stones shortly after starting either a diet including a spinach green smoothie or a large spinach salad on a regular basis.  Since these comments were not even solicited, it is likely that even a larger number of individuals may have experienced kidney stones but were shy to voice their experiences. A neurologist friend attributes his recent severely-disabling stroke to the dietary changes encouraged by his wife that placed him on a daily green spinach smoothie for a considerable time.

Furthermore, Lodi seems to think that a lack of kidney stones indicates a lack of oxalate problems. However, oxalates may form in virtually every organ of the body including the eyes, vulva, lymph nodes, liver, testes, skin, bones, gums, thyroid gland, heart, arteries, and muscles6-7. Oxalates may occur in these other organs without appearing in the urinary tract at all and in individuals without genetic hyperoxalurias7. Oxalates have been implicated in heart disease7, stroke, vulvodynia, and autism8-10. Women of child-bearing age need to be especially careful of the spinach green smoothie diet because of the autism oxalate connection and the negative effects of spinach containing oxalates on fertility5. Prisoners in the state prisons in Illinois were encouraged by the Weston-Price Nutrition Foundation to file a lawsuit against the state because of their deteriorating health due to a high amount of soy protein in the prison diet11. Soy protein is tied with spinach as the highest oxalate foods4. Oxalates are especially toxic to the endothelial cells of the arteries, leading to atherosclerosis12. Oxalate crystals are concentrated in the atherosclerotic lesions7.  Such lesions have commonly been overlooked by the use of stains of atherosclerotic lesions that make the oxalate crystals difficult to visualize.  The relatives of people consuming the green smoothie diet would only know of their loved ones’ oxalate deposits throughout their organs on the day of their autopsies which employed pathological examinations that can detect oxalates.

Primary genetic hyperoxaluria is not the major cause of kidney stones in adults since 80% of individuals died of this disorder before age 20 and it is so rare that it could not possibly be the cause of most cases of oxalate kidney stones13.  However, a genetic polymorphism present in up to 20% of Caucasian groups called P11L codes for a protein with three times less activity of alanine: glyoxylate aminotransferase (AGT) than the predominant normal activity polymorphism, leading to excessive endogenous production of oxalates14. This substantial group of individuals would be even more susceptible to the harm of a high oxalate diet. Kidney stones were rampant in the United Kingdom during the World Wars when rhubarb, another high oxalate food, was recommended as a substitute for other low oxalate but unavailable vegetables13.

In summary, those who do not care for their health can eat or drink whatever they want. But they should realize that their diets are fad-based and/or based on quasi-religious ( “feasts” as part of the “awakening” according to Lodi) reasons, not based on hard scientific evidence. Furthermore, they should be aware that their diet may kill them15. The green smoothie fad will go down in medical history with the AMA journal allowing cigarette advertising with physician endorsements and the use of mercury-containing teething powder for babies as one of the greatest health follies in a considerable time.

---

References

1.       Lodi, T. Green smoothie bliss: Was Popeye secretly on dialysis?  Townsend Letter for Doctors. Dec 2015 pgs 28-39

2.       Shaw, W.  The Green Smoothie Health Fad: This Road to Health Hell is Paved with Toxic   Oxalate Crystals.  Townsend Letter for Doctors. Jan 2015 Available online at: http://www.townsendletter.com/Jan2015/green0115.html

3.       Holmes RP, Goodman HO, and Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney International, Vol. 59 (2001), pp. 270–276

4.       Harvard T.H. Chan School of Public Health Nutrition Department's File Download Site on oxalates in the diet. https://regepi.bwh.harvard.edu/health/Oxalate/files Accessed December 1,2015

5.       Kohmani,EF. Oxalic acid in foods and its fate in the diet. Journal of Nutrition 18(3):233-246,1939

6.       Jessica N. Lange, Kyle D.Wood, John Knight, Dean G. Assimos, and Ross P. Holmes. Glyoxal Formation and Its Role in Endogenous Oxalate Synthesis. Advances in Urology Volume 2012, Article ID 819202, 5 pages doi:10.1155/2012/819202

7.       G.A. Fishbein, R. G. Micheletti, J. S. Currier, E. Singer, and M. C. Fishbein, Atherosclerotic oxalosis in coronary arteries, Cardiovascular Pathology, vol. 17, no. 2, pp. 117–123, 2008.

8.       Giuseppe Di Pasquale, , Mariangela Ribani, Alvaro Andreoli, , Gian Angelo Zampa, and Giuseppe Pinelli,  Cardioembolic Stroke in Primary Oxalosis With Cardiac Involvement. Stroke 1989, 20:1403-1406

9.       Solomons CC, Melmed MH, Heitler SM.Calcium citrate for vulvar vestibulitis. A case report. J Reprod Med. 1991 Dec;36(12):879-82.

10.   Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela-Olech H, Kulak W, Owens SC, Piotrowska-Jastrzebska J, Kaczmarski M. A potential pathogenic role of oxalate in autism. Eur J Paediatr Neurol. 2012 Sep;16(5):485-91.

11.   Monica Eng, Chicago Tribune reporter. Soy in Illinois prison diets prompts lawsuit over health effects. December 21, 2009. http://articles.chicagotribune.com/2009-12-21/news/0912200121_1_soy-protein-soy-cheeses-soyfoods-association. Accessed December 2,2015

12.   RI Levin, PW Kantoff and EA Jaffe Uremic levels of oxalic acid suppress replication and migration of human endothelial cells. Arterioscler Thromb Vasc Biol 1990, 10:198-207

13.   A. J. Chaplin Histopathological occurrence and characterization of calcium oxalate: a review. J. Clin. Path., 1977, 30, 800-811

14.   Michael J. Lumb and Christopher J. Danpure.  Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations.  Journal of Biological Chemistry Vol. 275, No. 46, November 17, pp. 36415–36422, 2000

Sanz P, Reig R: Clinical and pathological findings in fatal plant oxalosis. Am J Forensic Med Pathol 13:342–345, 1992

Urine Calcium and Magnesium in Adults: Recommended Test for Nutritional Adequacy

William Shaw, PhD

Calcium
Calcium is one of the most tightly regulated substances in the body. In addition to the role of calcium as a structural element in bones and teeth (99% of the body’s calcium is in the bones), calcium is critically needed for nerve function. When calcium in the plasma drops about 30%, the person may develop tetany, a condition that is often fatal due to overstimulation of the nerves in both the central nervous system and peripheral nervous system, leading to tetanic contraction of the skeletal muscles. The concentration of calcium in the plasma is one of the most constant laboratory values ever measured. In the great majority of normal people, calcium only varies from 9-11 mg per dL, regardless of the diet (1). The reason is a complex hormonal system that utilizes the bones as a source of calcium. This regulatory system employs the parathyroid gland that secretes parathyroid hormone or parathormone to digest the bones and release calcium when there is only a small decrease in the plasma calcium. Parathormone also increases the absorption of calcium from the gastrointestinal tract and the kidney tubules. When calcium rises in the plasma, parathormone secretion decreases, depositing more calcium in the bones while renal and gastrointestinal absorption are decreased.  Calcitonin, a polypeptide hormone produced by the thyroid gland, opposes the effects of parathyroid hormone. In addition, vitamin D increases the absorption of calcium from the gastrointestinal tracts and the kidney tubules like parathyroid hormone but has little effect on digesting bones to release calcium. One of the most controversial and misunderstood topics is what is the optimum nutritional intake of calcium and vitamin D. In the center of the controversy is the role of calcium in the initiation of plaque in the arteries, leading to atherosclerosis and cardiovascular disease. 

An average adult ingests about 750 mg per day of calcium and secretes about 625 mg of calcium in the intestinal juices. If all the ingested calcium is absorbed, there would be a net absorption of 125 mg per day of calcium. Since the average person excretes about 125 mg calcium per day in the urine, the average person has a zero net calcium balance except when bone is being deposited. If bone is being deposited due to the stress of exercise or following a fracture, the regulation of the amount of urinary calcium excretion is the major factor to allow for bone growth. One of the major factors that prevents calcium absorption is the presence of high amounts of oxalates in the diet. The human body has the ability to make some oxalate endogenously, perhaps about 40 mg per day in individuals with a favorable genetic makeup. A low oxalate diet contains less than 50 mg per day of oxalates while a high oxalate diet with two cups or more of spinach, nuts, and berries in a smoothie or salad per day could easily contain 1500 mg per day of oxalates. Such high amounts of oxalates readily use up the 125 mg of available calcium, forming insoluble calcium oxalate salts which can deposit in every organ of the body. These deposits can easily initiate endothelial damage that can lead to strokes and myocardial infarctions (heart attacks) and such oxalate deposits have been detected in atherosclerotic lesions. The person on a high oxalate diet will have a much greater need for calcium and/or magnesium than the person on a low oxalate diet.       

Since urine is the major controlling element for maintaining calcium balance that is under tight hormonal control, it appears to me that urine calcium is the best indicator of adequate dietary calcium. The most common reasons for low urine calcium are inadequate dietary calcium and/or a high oxalate diet.  Other reasons for calcium deficiency include hypoparathyroidism, pseudohypoparathyroidism, vitamin D deficiency, nephrosis, nephritis, bone cancer, hypothyroidism, celiac disease, and malabsorption disorders.

The most common reason for high urine calcium is a diet high in calcium. Other reasons for calcium excess are vitamin D intoxication, hyperparathyroidism, osteolytic bone metastases, myeloma, excessive immobilization, Cushing’s syndrome, acromegaly, distal renal tubular acidosis, thyrotoxicosis, Paget’s disease, Fanconi’s syndrome, schistosomiasis, breast and bladder cancers, and sarcoidosis.

Magnesium
Magnesium is an essential element like calcium and is also in the bones (66% of the body’s magnesium is in the bones). It is a cofactor with many enzymatic reactions especially those requiring vitamin B6. Like extremely low calcium, extremely low magnesium can also cause tetany of the muscles.

Low magnesium
The most common reason for low urine magnesium is low magnesium in the diet. Low magnesium in the diet may increase the incidence of oxalate crystal formation in the tissues and kidney stones. Less common causes of low magnesium include celiac disease, other malabsorption disorders, dysbiosis, vitamin D deficiency, pancreatic insufficiency, and hypothyroidism. Early signs of magnesium deficiency include loss of appetite, nausea, vomiting, migraine headaches, fatigue, and weakness. As magnesium deficiency worsens, numbness, tingling, muscle contractions and cramps, seizures, personality changes, anxiety, depression, attention deficit, abnormal heart rhythms, and coronary spasms can occur. Low urinary magnesium for long time periods is associated with increased risk of ischemic heart disease.

High magnesium
The most common reason for high urine magnesium is high magnesium in the diet. Less common causes of high urine magnesium include alcoholism, diuretic use, primary aldosteronism, hyperthyroidism, vitamin D excess, gentamicin toxicity, and cis-platinum toxicity.  Increased urinary magnesium excretion can occur in people with insulin resistance and/or type 2 diabetes. Symptoms of marked magnesium excess can include diarrhea, hypotension, nausea, vomiting, facial flushing, retention of urine, ileus, depression, lethargy before progressing to muscle weakness, difficulty breathing, extreme hypotension, irregular heartbeat, and cardiac arrest.

---

REFERENECS

1. Guyton, Arthur. Textbook of Medical Physiology,3rd edition. WB Saunders Co, Philadelphia, 1966,pgs1100-1118.

2. Fleming, CR, et al. The importance of urinary magnesium values in patients with gut failure. Mayo Clinic Proceedings. 1996 Jan;71(1):21-4.

Rickets and dangerous eye-poking behavior in autism associated with calcium deficiency: Preventing and detecting deficiency with a simple urine test for calcium and magnesium

William Shaw, PhD

Failure to provide adequate calcium to persons on the autistic spectrum is very dangerous and could lead to the loss of the eyes due to severe eye-poking behavior. This is an especially important topic because some individuals like Amy Yasko warns that calcium may cause overstimulation of neurons. Every element in our food and drink including water may cause death with excess intake but you will not find skull and cross-bone warnings on bottled water at the supermarket. The most relevant question is: How much calcium in the diet and in supplements is excessive?

 Calcium deficiency can be a severe problem in normal children on a milk-free and dairy-free diet since milk is a significant source of protein, vitamin D, and calcium needed for strong bones and teeth. Some physicians have reported that rickets (1), a severe bone deformity, occurred in children with autism on the gluten and casein-free diet who did not receive added calcium supplements. Calcium and vitamin D supplementation is essential to children on a casein-free diet since most children with autism do not eat substantial amounts of other calcium-rich foods. Failure to provide adequate calcium to children on casein-free diets leads physicians to view such parents as negligent and ignorant and leads to skepticism about other nonstandard treatments for autism.

Children with autism may have an even more severe problem with calcium deficiency. Mary Coleman, M.D. (2) reported that children with autism who are calcium deficient are much more likely to poke out their eyes and a substantial number of children with autism have done so. I have talked to numerous parents of children with autism that began to touch their eyes after starting the casein-free diet. This abnormal behavior is associated with low urine calcium; blood calcium levels were usually normal. Parathyroid hormone, calcitonin, and vitamin D were all normal in patients with autism but all of them had low urine calcium. Treatment with calcium supplementation prevents this behavior but dietary supplementation with high calcium foods does not. (I suspect that this behavior is due to increased eye pain due to high deposits of oxalate crystals in the eye. Oxalates are high in urine samples of children with autism and can deposit in many tissues including the eyes.  Low calcium may act to intensify this pain and poking out the eye relieves the pain.) Dr. Coleman also found that speech developed very quickly after calcium supplementation in a portion of mute children with autism who had low urine calcium. In one case, according to a parent who contacted me, her child with autism persisted in poking at the eyes even after one eye had been partially poked out and surgically re-implanted. Calcium supplementation stopped this behavior immediately. I am aware of many other children with eye-poking behavior in which calcium supplements stopped this behavior in less than two days. Verbal autistic children say that their eye pain is severe and that calcium supplementation stopped their pain quickly. In Coleman’s study of 78 children with autism, 20% had urine calcium values two standard deviations below the normal child’s range for urine calcium. Clearly, this extremely low group requires supplementation with calcium. I would recommend calcium supplementation for any child below the mean value urine calcium for normal children of the same age.

Magnesium research in autism is often combined with research on vitamin B6 since the two nutritional factors work together in a host of biochemical reactions. In one study in France (4), children on the autistic spectrum were given 6 mg per kilogram of body weight per day of magnesium and 0.6 mg per kilogram body weight of vitamin B6. This supplementation improved autistic symptoms including the following: social interactions (23/33), communication (24/33), stereotyped restricted behavior (18/33), and abnormal/delayed functioning (17/33). When the Mg-B6 treatment was stopped, autistic symptoms reappeared in a few weeks. Low magnesium levels may be associated with restlessness, sensitivity to noise, poor attention span, poor concentration, irritability, aggressiveness, and anxiety.

From a parent- “Our daughter also used to look in the mirror all the time - really up close and wanting to look at herself and poke her eyes. I was so worried about it that I finally put pepper juice on her fingers so she would stop. I know that sounds awful - but she had really gotten bad. Dr. Shaw said that their eyes are hurting so much from lack of calcium. He recommended 1000mg. daily - our daughter was about 43 pounds at the time. I started giving it to her and her eye poking stopped and I noticed that so many of her other stimming behaviors also decreased.”

---

REFERENCES

1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856

2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994

3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.

4. M. Mousain-Bosc et al Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6 II. Pervasive developmental disorder-autism. Magnesium Research 2006;19(1): 53-62

5. Fleming, CR, et al.  The importance of urinary magnesium values in patients with gut failure.  Mayo Clinic Proceedings. 1996 Jan;71(1):21-4

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)

OXALATES CONTROL IS A MAJOR NEW FACTOR IN AUTISM THERAPY

Test Implications for Yeast and Heavy Metals
William Shaw, Ph.D.

What are Oxalates?

Oxalate and its acid form oxalic acid are organic acids that are primarily from three sources: the diet, from fungus such as Aspergillus, Penicillium, and possibly Candida (1-9), and also from human metabolism (10).

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 Acids Test (OAT) done at The Great Plains Laboratory. Foods especially high in oxalates include spinach, beets, chocolate, 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; it can range from 44-1000 mg/d in individuals who eat a typical Western diet.  A complete list of high oxalate foods is available at  http://patienteducation.upmc.com/Pdf/LowOxalateDiet.pdf.

High oxalate in the urine and plasma was first found in people who were susceptible to kidney stones. Many 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 life. Because many kidney stones contain calcium, some people with kidney stones think they should avoid calcium supplements. However, the opposite is true. When calcium is taken with foods that are high in oxalates, oxalic acid in the intestine combines with calcium to form insoluble calcium oxalate crystals that are eliminated in the stool. This form of oxalate cannot be absorbed into the body. When calcium is 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 to form crystals that may block urine flow and cause severe pain.

Such crystals may also form in the bones, joints, blood vessels, lungs, and even the brain (10-13). In addition, oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression (13). In addition to autism and kidney disease, individuals with fibromyalgia and women with vulvar pain (vulvodynia) may suffer from the effects of excess oxalates (14,15).

Oxalate crystals may cause damage to various tissues. The sharp crystals may cause damage due to their physical structure and may also increase inflammation. Iron oxalate crystals may also cause significant oxidative damage and diminish iron stores needed for red blood cell formation (10). Oxalates may also function as chelating agents and may chelate many toxic metals such as mercury and lead. Unlike other chelating agents, oxalates trap heavy metals in the tissues.

Many parents who told me of adverse vaccine reactions of their children reported that their child was on antibiotics at the time of vaccination. Yeast overgrowth, commonly associated with antibiotic usage, might lead to increased oxalate production and increased combination with mercury, slowing mercury elimination if oxalates were so high that they deposited in the bones with attached mercury. It would be interesting to see if increased elimination of heavy metals occurs after oxalate elimination by antifungal therapy and low oxalate diet. In addition, oxalates from the diet or from yeast/fungus in the gastrointestinal tract bind calcium, magnesium, and zinc, perhaps leading to deficiencies even when dietary sources should be adequate.

Oxalates and Autism

Oxalates in the urine are much higher in individuals with autism than in normal children (Figure 1). As a matter of fact, 36% of the children on the autistic spectrum had values higher than 90 mmol/mol creatinine, the value consistent with a diagnosis of genetic hyperoxalurias while none of the normal children had values this high. 84% of the children on the autistic spectrum had oxalate values outside the normal range (mean ± 2 sd). None of the ± 2 sd).  None of the children on the autistic spectrum had elevations of the other organic acids associated with genetic diseases of oxalate metabolism, indicating that oxalates are high due to external sources.

As shown in the table, both mean and median values for urine oxalates are substantially higher  in autism compared to the normal population. As a matter of fact the mean oxalate value of 90.1 mmol/mol creatinine is equal to the lower cutoff value for the genetic hyperoxalurias. The median value in autism is six times the normal median value and the mean value in autism is five times the normal mean value.

A brand new diet is being extensively used to treat children with autism and other disorders. Researcher named Susan Owens discovered that the use of a diet low in oxalates markedly reduced symptoms in children with autism and PDD. For example, a mother with a son with autism reported that he became more focused and calm, that he played better, that he walked better, and had a reduction in leg and feet pain after being on a low oxalate diet. Prior to the low oxalate diet, her child could hardly walk up the stairs. After the diet, he walked up the stairs very easily. Many hundreds of children with autism throughout the world are now being placed on this diet with good results.

Benefits Reported By Parents Using Low Oxalate Diet

Improvements in gross and fine motor skills
Improvements in expressive speech
Better counting ability
Better receptive and expressive language
Increased imitation skills
Increased sociability
Speaking in longer sentences
Decreased rigidity
Better sleep

Reduced self-abusive behavior
Increased imaginary play
Improved cognition
Loss of bed wetting
Loss of frequent urination
Improved handwriting
Improved fine motor skills
Improvement in anemia

... and many others

How Can High Oxalates Be Treated?

Use antifungal drugs to reduce yeast and fungi that may be causing high oxalate. Children with autism frequently require years of antifungal treatment. I have noticed that arabinose, a marker used for years for yeast/fungal overgrowth on the Organic Acids Test (OAT) at The Great Plains Laboratory, is correlated with high amounts of oxalates (Table 2 and Figure 2) and arabinose has been found to be an important fuel for fungal oxalate production (5). Candida organisms have been found surrounding oxalate stones in the kidney (9).

Give supplements of calcium 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.

Try N-Acetyl glucosamine to stimulate the production of the intercellular cement hyaluronic acid to reduce pain caused by oxalates (16).

Give chondroitin sulfate to prevent the formation of calcium oxalate crystals (17).

Vitamin B6 is a cofactor for one of the enzymes that degrade oxalate in the body and has been shown to reduce oxalate production (18).

Increase water intake to help to eliminate oxalates.

Excessive fats in the diet may cause elevated oxalate if the fatty acids are poorly absorbed because of bile salt deficiency. Non-absorbed free fatty acids bind calcium to form insoluble soaps, reducing calcium’s ability to bind oxalate and reduce oxalate absorption (19). If taurine is low in the Amino Acids Test, supplementation with taurine may help stimulate bile salt production (taurocholic acid), leading to better fatty acid absorption and diminished oxalate absorption.

Probiotics may be very helpful in degrading oxalates in the intestine. Individuals with low amounts of oxalate-degrading bacteria are much more susceptible to kidney stones (20). Both Lactobacillus acidophilus and Bifidobacterium lactis have enzymes that degrade oxalates (21).

Increase intake of essential omega-3 fatty acids, commonly found in fish oil and cod liver oil, which reduces oxalate problems (22). High amounts of the omega-6 fatty acid, arachidonic acid, are associated with increased oxalate problems (23). Meat from grain fed animals is high in arachidonic acid.

Take supplements of vitamin E, selenium, and arginine which have been shown to reduce oxalate damage (24, 25).

Undertake a low oxalate diet. This may be especially important if the individual has had Candida for long periods of time and there is high tissue oxalate buildup. There may be an initial bad reaction lasting several days to a week after starting the diet since oxalates deposited in the bones may begin to be eliminated as oxalates in the diet are reduced.

Evaluate vitamin C intake. Vitamin C can break down to form oxalates. However, in adults, the amount of oxalate formed did not increase until the amount exceeded 4 g of vitamin C per day (26). A large study of more than 85,000 women found no relation between vitamin C intake and kidney stones (27). In addition, an evaluation of 100 children on the autistic spectrum at The Great Plains Laboratory revealed that there was nearly zero correlation between vitamin C and oxalates in the urine (Table 2). Megadoses (more than 100 mg/Kg body weight per day) of vitamin C were shown to markedly reduce autistic symptoms in a double blind placebo controlled study (28) so any restriction of vitamin C needs to be carefully weighed against its significant benefits.

Oxalate Metabolism

In the genetic disease hyperoxaluria type I and in vitamin B-6 deficiency, there is a deficiency in the enzyme activity of alanine glyoxylate amino transferase (AGT), leading to the accumulation of glyoxylic acid. The high glyoxylic acid can then be converted to glycolate by the enzyme GRHPR or to oxalate by the enzyme LDH. Thus, glycolate, glyoxylate, and oxalate are the metabolites that are then elevated in the Organic Acids Test (OAT) in hyperoxaluria type I and in vitamin B-6 deficiency.

In the genetic disease hyperoxaluria type II, there is a deficiency in an enzyme (GRHPR) that has two biochemical activities:  glyoxylate reductase and hydroxypyruvic reductase. This enzyme converts glyoxylate to glycolate and glycerate to hydroxypyruvate. When this enzyme is deficient, glycerate cannot be converted to hydroxypyruvate and glyoxylate cannot be converted to glycolate. In this disease, glyoxylate is increasingly converted to oxalate and glycerate is also very elevated.

External sources of oxalates include ethylene glycol, the main component of antifreeze. Antifreeze is toxic mainly because of the oxalates formed from it. In addition, some foods also contain small amounts of ethylene glycol. Vitamin C (ascorbic acid or ascorbate) can be converted to oxalates but apparently the biochemical conversion system is saturated at low levels of vitamin C so that no additional oxalate is formed until very large doses (greater than 4 g per day) are consumed. It is interesting that fungi can also produce vitamin C which may explain why many children with autism have high vitamin C even though they do not take supplements containing vitamin C. The high correlation between arabinose and oxalates indicate that intestinal yeast/fungal overgrowth is likely the main cause for elevated oxalates in the autistic spectrum population. The deposition of oxalates in critical tissues such as brain and blood vessels, the oxidative damage caused by oxalate salts, and the deposition of oxalate mercury complexes in the tissues may all be important factors in the core etiology of autism.

  [Insert OAT Sample Test Result – Oxalate Section]
 

Oxalate Interconversions

Oxalic acid undergoes many conversions depending on the acidity of the environment in which it is present. The acidity of a water solution is usually indicated by a value called the pH. A very low pH like 0 or 1 indicates a very acidic solution while a pH of 13 or 14 would represent a very alkaline solution. A pH of 7 indicates a condition of neutrality. Blood has a pH of 7.4 which is very slightly alkaline. The pH of urine varies between 4.5 to 8 with an average of 6. Oxalic acid can lose a positively charged hydrogen ion or proton at a very low pH. The first pK value for oxalic acid (1.27) indicates the pH in which there are equal amounts of oxalic acid and its form missing a proton called monobasic oxalate. At a higher pH, the monobasic oxalate converts to a dibasic oxalate form with two negative charges. The second pK value for oxalate (4.28) indicates the pH at which there are equal values of monobasic and dibasic oxalates.  At the pH of blood, which is extremely constant, virtually all oxalate is in the dibasic form. Because the pH of urine varies greatly, oxalate is mainly in the dibasic form in average urine while it is in both the monobasic and dibasic form in very acidic urine samples. When oxalates are tested, they are all converted to the same form before testing so they may be termed oxalates, oxalate, or oxalic acid.

Insolubility is a Key Factor in Oxalate Toxicity

Solubility of oxalate at body temperature is only approximately 5 mg/L at a pH of 7.0. The solubility of oxalic acid in water, in contrast, is approximately 106,000 mg/L. Thus, the oxalate form of oxalic acid is extremely insoluble. At most physiological pH values, oxalate salts are predominant. Oxalate has the ability to form salts with a wide variety of metals but each of these salts has a different solubility. A yardstick for measuring solubilities of different salts is called the solubility product constant or Ksp. The smaller the value of the Ksp, the greater the insolubility of a salt. Another way to express this is that the lower the Ksp, the greater the tendency of that salt to form insoluble crystals that may form in tissues. The table below lists the Ksp salts of oxalic acid in their order of solubility with the most insoluble salts listed at the top.

What is the importance of these solubility product numbers?

First, the Ksp for calcium oxalate indicates that whenever the product of the concentration of calcium and oxalate concentrations in blood exceeds the Ksp, calcium oxalate crystals may form and deposit in the tissues. Since the calcium concentration in blood hardly varies because of homeostatic mechanisms, it is the oxalate concentration in blood that varies widely and that determines whether or not calcium oxalate crystals form and deposit in the tissues. Zinc oxalate also has a very small Ksp so that if oxalates are present in high quantities in the intestinal tract, most of the zinc oxalate formed will not be absorbed because it is highly insoluble.

Second, mercury oxalate had the lowest Ksp of any oxalate salt that I could find. If an individual is exposed to inorganic mercury and has high oxalates in the blood or tissues, insoluble mercury oxalates may form in the blood and tissues that are unable to be eliminated.

The mercury used in vaccines as a preservative is an organic form that is converted to inorganic mercury. If an individual who is vaccinated is on antibiotics or was on antibiotics in the past, they may have extensive yeast/fungal overgrowth of the intestinal tract. They would absorb significant amounts of oxalates from these organisms that would trap mercury in the tissues and prevent its elimination. Many parents who talked with me indicated that their children had bad vaccine reactions while on antibiotics at the time of vaccination.

Third, magnesium oxalates are much more soluble than calcium oxalates. Thus, if magnesium supplements are given by themselves, oxalates from food or yeast/fungal sources that combine with magnesium are much more likely to be absorbed than calcium oxalates. However, transdermal magnesium or magnesium from Epsom salts baths that enters the blood and tissues through the skin might help to dissolve calcium or mercury oxalate crystals that had already formed in the blood or tissues.

Testing for Oxalates

The most convenient way of testing oxalates is with the Organic Acids Test (OAT) from The Great Plains Laboratory, Inc.

The Organic Acids Test checks for the presence of:

• Oxalic acid (oxalates) -Tests for all forms of oxalic acid and its salts or conjugate bases, oxalates

• Arabinose - Important Candida indicator which strongly correlates with oxalates

• Glycolic acid (glycolate)- Indicator of genetic disease of oxalate metabolism called Hyperoxaluria type I due to a deficiency in the enzyme activity of alanine glyoxylate amino transferase (AGT).

• Glyceric acid (glycerate) - Indicator of genetic disease of oxalate metabolism called Hyperoxaluria type II due to a deficiencyin an enzyme (GRHPR) that has two biochemical activities: glyoxylate reductase (GR) and hydroxypyruvic reductase (HPR).

• Ascorbic acid (ascorbate, vitamin C) - Indicates nutritional intake of vitamin C and/or excessive destruction. Vitamin C can be excessively converted to oxalates when free copper is very high. Evaluate further with copper/zinc profile from The Great Plains Laboratory.

• Pyridoxic acid - Indicator of vitamin B-6 intake. The enzyme activity alanine glyoxylate amino transferase (AGT) requires vitamin B-6 to eliminate glyoxylic acid or glyoxylate, a major source of excess oxalates.

• Furandicarboxylic acid, hydroxy-methylfuroic acid - Markers for fungi such as Aspergillus infection, one of the proven sources of oxalates

• Bacteria markers - A high amount of bacterial markers may indicate low values of beneficial bacteria such as Lactobacilli species that have the ability to destroy oxalates.

High Oxalate Food List

The foods below contain more than 10 mg oxalate per serving. A more detailed list is available online from the University of Pittsburgh Schools of the Health Sciences website.

Drinks
- Dark or "robust" beer
- Black tea
- Chocolate milk
- Cocoa
- Instant coffee
- Hot chocolate
- Juice made from high oxalate fruits (see below for high oxalate fruits)
- Ovaltine
- Soy drinks

Dairy
- Chocolate milk
- Soy cheese
- Soy milk
- Soy yogurt

Fats, Nuts, Seeds
- Nuts
- Nut butters
- Sesame seeds
- Tahini
- Soy nuts

Starch
- Amaranth
- Buckwheat
- Cereal (bran or high fiber
- Crisp bread (rye or wheat)
- Fruit cake
- Grits
- Pretzels
- Taro
- Wheat bran
- Wheat germ
- Whole wheat bread
- Whole wheat flour

Condiments
- Black pepper (more than 1 tsp.)
- Marmalade
- Soy sauce

Miscellaneous
- Chocolate
- Parsley

Fruit
- Blackberries
- Blueberries
- Carambola
- Concord grapes
- Currents
- Dewberries
- Elderberries
- Figs
- Fruit cocktail
- Gooseberry
- Kiwis
- Lemon peel
- Orange peel
- Raspberries
- Rhubarb
- Canned strawberries
- Tamarillo
- Tangerines

Vegetables
- Beans (baked, green, dried, kidney)
- Beets
- Beet greens
- Beet root
- Carrots

Vegetables Continued...

- Celery
- Chicory
- Collards
- Dandelion greens
- Eggplant
- Escarole
- Kale
- Leeks
- Okra
- Olives
- Parsley
- Peppers (chili and green)
- Pokeweed
- Potatoes (baked, boiled, fried)
- Rutabaga
- Spinach
- Summer squash
- Sweet potato
- Swiss chard
- Zucchini

---

REFERENCES

1. Tsao, G. Appl Microbiol. 1963 May; 11(3): 249-254. Production of Oxalic Acid by a Wood-Rotting Fungus.

2. Takeuchi H Konishi T, Tomoyoshi T. Observation on fungi within urinary stones. Hinyokika Kiyo. 1987 May;33(5):658-61.

3. 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.

4. Muntz FH. Oxalate-producing pulmonary aspergillosis in an alpaca. Vet Pathol. 1999 Nov;36(6):631-2.

5. 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.

6. 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.

7. Ruijter, G.J.G., van de Vondervoort, P.J.I. & Visser, J. (1999) Oxalic acid production by Aspergillus niger: an oxalate-non-producing mutant produces citric acid at pH 5 and in the presence of manganese. Microbiology 145, 2569–2576.

8. 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.

9. 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.

10. 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.

11. 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.

12. Hall BM, Walsh JC, Horvath JS, Lytton DG. Peripheral neuropathy complicating primary hyperoxaluria. J Neurol Sci. 1976 Oct;29(2-4):343-9.

13. Sahin G, Acikalin MF, Yalcin AU. Erythropoietin resistance as a result of oxalosis in bone marrow. Clin Nephrol. 2005 May;63(5):402-4.

14. 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.

15. http://www.thevpfoundation.org/effective_treatment.htm

16. 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.

17. 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.

18. Sangaletti O, Petrillo M, Bianchi Porro G. Urinary oxalate recovery after oral oxalic load: an alternative method to the quantitative determination of stool fat for the diagnosis of lipid malabsorption. J Int Med Res. 1989 Nov-Dec;17(6):526-31.

19. Kumar R, Mukherjee M, Bhandari M, Kumar A, Sidhu H, Mittal RD. Role of Oxalobacter formigenes in calcium oxalate stone disease: a study from North India. Eur Urol. 2002 Mar;41(3):318-22.

20. Azcarate-Peril MA, Bruno-Barcena JM, Hassan HM, Klaenhammer TR. Transcriptional and functional analysis of oxalyl-coenzyme A (CoA) decarboxylase and formyl-CoA transferase genes from Lactobacillus acidophilus. Appl Environ Microbiol. 2006 Mar;72(3):1891-9.

21. Baggio B, Gambaro G, Zambon S, Marchini F, Bassi A, Bordin L, Clari G, Manzato E. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996 Apr;7(4):613-20.

22. Gambaro G, Bordoni A, Hrelia S, Bordin L, Biagi P, Semplicini A, Clari G, Manzato E, Baggio B. Dietary manipulation of delta-6-desaturase modifies phospholipid arachidonic acid levels and the urinary excretion of calcium and oxalate in the rat: insight in calcium lithogenesis. J Lab Clin Med. 2000 Jan;135(1):89-95.

23. Santhosh Kumar M, Selvam R. Supplementation of vitamin E and selenium prevents hyperoxaluria in experimental urolithic rats. J Nutr Biochem. 2003 Jun;14(6):306-13.

24. Pragasam V, Kalaiselvi P, Sumitra K, Srinivasan S, Varalakshmi P. Pragasam V, Kalaiselvi P, Sumitra K, Srinivasan S, Varalakshmi P. Counteraction of oxalate induced nitrosative stress by supplementation of l-arginine, a potent antilithic agent. Clin Chim Acta. 2005 Apr;354(1-2):159-66. Epub 2005 Jan 19.

25. Takenouchi KAso K, Kawase K, Ichikawa H, Shiomi T. On the metabolites of ascorbic acid, especially oxalic acid, eliminated in urine, following administration of large amounts of ascorbic acid. J Vitaminol (Kyoto). 1966 Mar 10;12(1):49-58.

26. Curhan, G. C., Willett, W. C., Speizer, F. E., Stampfer, M. J. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 10:4:840-845, Apr 1999

27. Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog. Neuropsycho-pharmacol Biol Psychiatry. 1993 Sep;17(5):765-74.