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Evaluation of Nutrient Levels in Children with ASD vs. Controls – Preliminary Results

Evaluation of Nutrient Levels in Children with ASD vs. Controls – Preliminary Results. James B. Adams Arizona State University www.eas.asu.edu/~autism. Collaborators. Tapan Audhya Stephen Coburn Liz Geis Julie Ingram Sanford Newmark Dena Goldberg Warren Tripp Marie Adams

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Evaluation of Nutrient Levels in Children with ASD vs. Controls – Preliminary Results

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  1. Evaluation of Nutrient Levels in Children with ASD vs. Controls – Preliminary Results James B. Adams Arizona State University www.eas.asu.edu/~autism

  2. Collaborators • Tapan Audhya • Stephen Coburn • Liz Geis • Julie Ingram • Sanford Newmark • Dena Goldberg • Warren Tripp • Marie Adams Funded by Autism Research Institute, Greater Phoenix Chapter of the ASA, BHARE, Arizona State University Special thanks to Vitamin Diagnostics, Doctor’s Data, and Great Plains Labs for discounted/free testing

  3. Outline • Vitamins and Minerals • Amino Acids • Essential Fatty Acids

  4. Basics of Nutrition The essential major components of human nutrition are: • water • carbohydrates (for fuel) • vitamins and minerals • amino acids (from protein) • essential fatty acids A deficiency of any of these results in disease, or even death in extreme cases

  5. Examples of Nutritional Deficiencies • Lack of vitamin C -> scurvy • Lack of iron -> anemia; mental retardation in children • Lack of calcium or vitamin D -> rickets Children with autism are not classically deficient, but most are low in some essential vitamins, minerals, amino acids, and fatty acids . “Children with Starving Brains” by J. McCandless

  6. Why consider vitamin/mineral supplements for people with autism? 1) vitamin/mineral deficiencies common in general population 2) often restricted diets (“picky eaters”) -> limited vitamin/mineral intake 3) poor digestion (25% have chronic diarrhea, 25% chronic constipation); Endoscopies by Wakefield, Buie, Krigsman show damage to gut -> limited absorption of nutrients? 4) Rosseneu, Shaw research: overgrowth of harmful bacteria in GI tract: fewer “good” bacteria which actually produce several vitamins 5) 18 studies demonstrated benefits of vitamin B6/Mg 6) 1 study showed vitamin C was beneficial in autism 7) Prof. Megson: cod liver oil (with high levels of vitamin A, D, and essential fatty acids) helped with gaze aversion, behavior 8) Dr. Rimland’s set of parent-reported case studies on benefits of vitamins/minerals

  7. Goals:1) Evaluate nutritional status of unsupplemented children with ASD vs. unsupplemented typical children, age and gender matched.2) Check for correlations of symptoms of autism with nutritional levels Participants: Enrolled: 48 ASD, 35 controls Age: 3-9 years All children from Arizona. No use of vitamin/mineral supplements in 2 months prior to sample collection.

  8. Tests • Vitamins, minerals, essential fatty acids, amino acids (blood, urine) – Vitamin Diagnostics • Vitamin B6 variants and enzymes – Stephen Coburn (Purdue Un.) • Toxic elements and essential minerals in hair – Doctor’s Data • Urinary Organic Acid Testing – Great Plains Lab • Dietary Assessment of Nutrient Intake (1 week food diary) All samples sent blinded to labs.

  9. Vitamins Ref Range (RR) defined as between bottom 15% and top 15% Only small differences in vitamin levels between autism and controls (not statistically significant)

  10. % Worse % No Change % Better Number of Reports Vitamin A 2% 58% 41% 618 Folic Acid 3% 54% 42% 1437 Vitamin B3 4% 55% 41% 659 Vitamin B12 4% 33% 63% 192 Vitamin C 2% 57% 41% 1706 ARI Survey of Parent Ratings of Treatment Efficacy

  11. Why do children with autism benefit from vitamins if levels not very different from typical children? • Typical children do not eat 5 servings of fresh fruit and vegetables each day, so the level of vitamins in typical children is not optimal. • Several studies show children with autism are under increased oxidative stress, suggesting a need for increased levels of antioxidants.

  12. Vitamin B6 and Magnesium • Over 20 studies, including 11 double-blind, placebo-controlled studies, found that high dose vitamin B6 (8 mg/pound bodyweight) with Magnesium (3-4 mg/pound bodyweight) resulted in wide range of behavioral improvements • Only 2 negative studies: one with very few subjects, and one with half dose • Overall, very safe, and helps 50% of children and adults.

  13. Vit B6 – Coburn data • Urinary excretion of pyridoxic acid is low in autism • Oxidase activity low but not significant

  14. Vitamin B6 levels First Study Autism (n=35) 56 +/- 13 ng/ml Controls (n=11) 36 +/- 9 ng/ml ttest = 0.00002 Second Study Autism (n=47) 62 +/- 41 Controls (n=33) 53 +/- 27 not significant Combined First and Second Study Autism (n=82) 72 +/- 32 Controls (n=44) 52 +/- 25 p= 0.05 Conclusion: Some children with autism have unusually high levels of B6, and a few have unusually low levels of B6 - Explanation: study by Dr. Tapan Audhya found that 4 enzymes for conversion of B6 are defective in autism, such that conversion rate is much lower than normal

  15. Substrate Requirement for Maximal Activity of P5P-Dependent Enzymes Autistics often have weak B6-dependent enzymes, so may need very high B6

  16. Substrate Requirement for Maximal Activity of P5P-Dependent Enzymes Some autistics need high-dose B6 to make important neurotransmitters

  17. Autism Treatment Study: Effect of B6 (10mg/kg/day) + Zn (25mg) + Mg (400mg) on Kryptopyrrole Levels Conclusion: High-dose B6 very helpful for treating pyroluria

  18. High-dose B6 + multivitamin treatment study (Audhya) 184 Volunteers 1. Unsuccessful with Diet Intervention • Given Daily one centrum advanced formula Multivitamin Tablet with food, 25 mg Zn++ (as Gluconate and Citrate) and 400 mg Mg ++ (as Gluconate & Oxide) 128 (A) (95:33) 56 (B) (41:15) Pyrindoxine -HCℓ 5 mg/kg/day Pyridoxine – HCℓ & Pyridoxal – PO4 1 mg +4.7 mg/kg/day

  19. Outcome of the study 89 Volunteers Substantial Improvement; Almost normal 86 Volunteers No perceptible change; Behaviorally or physically 9 Volunteers No improvement; and additional adverse reaction

  20. % Worse % No Change % Better Number of Reports Vitamin B6 alone 8% 63% 30% 620 Magnesium 6% 65% 29% 301 Vitamin B6 with Magnesium 4% 49% 47% 5780 P5P (Vit. B6) 13% 37% 51% 213 ARI Survey of Parent Ratings of Treatment Efficacy

  21. Summary re. Vitamin B6 Some children and adults with autism benefit from high-dose B6, to make neurotransmitters, glutathione, and many other important substances Simple measurement of kryptopyroles in urine determines if high-dose vitamin B6 (or zinc) is needed (caution – destroyed by light, so collect in dark). Doses up to 10-15 mg/kg may be needed (1000 mg max); takes about 6 months to lower kryptopyroles in urine Always give at least half as much magnesium (400 mg max).

  22. Vitamin B12 • Methyl cobalamin (methyl form of vitamin B12) is most active form of vitamin B12 • Vitamin B12 is very hard for body to absorb orally • Injectable form of methyl-B12 may help up to 70% of autistics per informal reports by Dr. Jim Neubrander, at doses of 75 mcg/kg bodyweight, 2x/week, for 6+ weeks • Safe, but needs research to verify effectiveness • Research by Prof. Richard Deth shows it is needed to produce glutathione, and to help Dopamine 4 receptor function (important for attention)

  23. Low Cysteine and Glutathione • Studies by Jill James and Tapan Audhya find low cysteine and extremely low glutathione in children with autism; glutathione is important antioxidant and for detoxification • Treatment study by Jill James finds that 800 mcg of folinic acid and 1000 mcg of TMG over 8 weeks improve cysteine and glutathione levels somewhat • Addition of 75 mcg/kg of methyl B12 injections helps more • Informal reports of improvement in behavior

  24. Minerals Zinc slightly high in whole blood, but average in RBC Copper results mixed – slightly high in RBC, slightly low in serum, not statistically significant Disagrees with results by Walsh (possibly due to LabCorp Ref Range and age of controls?)

  25. Minerals (cont.) Iron: slightly slow in serum, but serum ferritine is more relevant and is “normal” However, many children with exceptionally low serum ferritine (10 with < 10 mcg/l) Calcium: low in urine, possibly due to low intake (GFCF diet)

  26. Toxic Elements in Hair • Most toxic elements are lower in autism, suggesting an overall problem with excretion; aluminum, tin, and possibly nickel are statistically significant

  27. Essential Minerals in Hair Manganese, molybdenum, and lithium are low in hair. Manganese slightly low in blood, partially consistent with hair. Low lithium is consistent with previous study.

  28. Essential Minerals in Hair (cont.) Low iron and possibly low cobalt. (iron not reliable in hair) Slightly low selenium. Possibly slightly high sulfur.

  29. Lithium – previous ASU study The only abnormality in mothers of children with ASD was low levels of lithium: all ages: -40%, p=0.05 mothers of children ages 3-8: -56%, p=0.005 (highly significant!) Similarly, children with ASD had lower levels of lithium all ages: -15%, not significant ages 3-6 yr: -30%, p=0.04

  30. Importance of Lithium • Hair is a reliable measure of lithium • Lithium is probably an essential mineral (not well studied) • Study of goats on lithium-deficient diet found: • decreased activity of monoamino oxidase, which is of particular importance to manic-depression, chronic schizophrenia, and unipolar depression. • lowered immunological status, and suffered from more chronic infections (may explain why children with autism had more ear infections) • Lithium concentrations highest during first trimester, and highest in the brain, so a deficiency of it could affect early fetal development, including early brain development

  31. Lithium - continued Several studies have show low lithium correlates with: • schizophrenia • neurosis • suicide • behavior problems • crime (homicide, rape, burglary, theft, drug use, juvenile runaways) Finally, a four-week placebo-controlled study of 24 former drug users found that 400 mcg/day of lithium resulted in steady increases in mood scores, especially in subcategories reflecting happiness, friendliness, and energy.

  32. Lithium • Not included in most nutritional supplements, or in prenatal supplements • An estimated RDA is 1000 mcg/day, and people in the US consume only about 500 mcg/day • Extremely high doses of lithium (1,000,000 mcg/day) are used as a psychiatric medication, primarily for “calming/mood stabilization”, especially for bipolar disorder; nearly toxic at that dose • RECOMMENDATION: a dosage of 200-1000 mcg/day should be safe, and may be beneficial to younger children with autism and their mothers • More research needed

  33. Essential Minerals - Iodine • Iodine: 45% lower in ASD than controls, p=0.005 (highly significant!) • in 3-6 yr old group, similar value (-47%) • Caution: no data showing that iodine in hair correlates with level in body (blood is standard measurement) • iodine is an essential mineral • major role of iodine in body is in thyroid function • a deficiency of iodine causes goiter (enlarged thyroid) and mental retardation (Cretinism) • worldwide, the leading cause of mental retardation is iodine deficiency, affecting roughly 20 million children

  34. Iodine - continued • In early 1900’s, iodine deficiency was up to 30% in some parts of the US • iodine in salt is believed to be sufficient to make iodine deficiency very rare in the US/western world • however, iodine levels in blood have declined 50% from 1970’s to 1990’s per NHANES I and III, possibly due to decreased salt intake • many fast foods (fries, chips) use non-iodinized salt • CAUTION: too much iodine can also decrease thyroid function • RECOMMENDATION: measure iodine in blood, supplement at modest level if low

  35. % Worse % No Change % Better Number of Reports CalciumE: 2% 62% 36% 1378 Magnesium 6% 65% 29% 301 Zinc 2% 51% 47% 1244 ARI Survey of Parent Ratings of Treatment Efficacy

  36. Summary of Minerals Low iron in some children – supplement only if low. Low calcium in some children (esp. if dairy-free) Low lithium in children and mothers, which can affect behavior Low iodine is a leading cause of mental retardation, and should be supplemented Low toxic metals in hair suggests problem with excretion of toxic metals.

  37. Research Study of Multivitamin/mineral supplement • 3 month study of Spectrum Support (by Brainchild Nutritionals) • Double-blind, placebo-controlled • Dosage is slowly increased to maximum over first 2 months, then held constant • parent ratings of changes • small study - 20 children only

  38. Vitamin C results (at end of study) range average Placebo: 0.9-1.4 1.03 Suppl. 1.0-2.0 1.33 typical child (age 3-8) 1.45 Placebo children are 2 standard deviations below average value 500 mg raised vitamin C to near-normal levels, but more may be better (1000 mg)

  39. Overall Results Based on parent evaluations on final day of study 7 point scale 1=much worse 2=worse 3=slightly better 4=same 5=slightly better 6=better 7=much better

  40. Overall Results Category Placebo Supplement Difference Sociability 5.1 5.3 +0.1 Expr. Language 5.6 5.9 +0.3 Rec. Language 4.9 5.8 +0.9 Eye Contact 4.9 5.5 +0.6 General Behavior 4.3 5.1 +0.8 Sleep 3.9 5.4 +1.5 Gastrointest. 3.9 5.4 +1.5 Overall 5.1 5.5 +0.4 Sleep and GI results are statistically significant (p<0.005); other results positive, and worth further investigation

  41. My recommended daily dose per 20 pounds of bodyweight, up to 100 pounds (i.e., for a 60 pound child, multiply by 3)Take with food, split into 3 doses Chromium 20 mcg Copper 0 mg (most autistics don’t need) Iodine 30 mg Lithium 0.2 mg Magnesium 120 mg Manganese 1 mg Molybdenum 40 mcg Selenium 25 mcg Vanadium 13 mcg Zinc 5-15 mg Calcium: Dosing independent of bodyweight: 400 mg for ages 2-5, 500-600 mg for older children Potassium from fruits and vegetables (esp. potatoes, avocados), esp. for low muscle tone Vitamin A 1000 IU Vitamin B1 7.5 mg Vitamin B2 7.5 mg Vitamin B3 25 mg (10 mg niacin, 15 mg niacinamide) Vitamin B5 20 mg Vitamin B6 80 mg Vitamin B12 200 mcg Folic Acid 50 mcg Folinic Acid 100 mcg Biotin 100 mcg Choline 70 mg Inositol 30 mg PABA 5 mg Vitamin C 300 mg Vitamin E 60 mg Mixed Carotenes 3000 IU

  42. Recommended Vitamin/Mineral Supplements • Kirkman’s Super Nu Thera – the original high-B6/Mg supplement for autism; contains many vitamins/minerals, but not a complete formulation; www.kirkmanlabs.com • Kirkman’s Spectrum Complete: broad-spectrum formulation, with moderate B6 • Brainchild’s Spectrum Support: broad-spectrum liquid vitamin/mineral supplement with moderate B6; www.brainchildnutrionals.com • D-Plex: broad-spectrum vitamin/mineral supplement with some amino acids; www.danplex.com • Awaken Nutrition: broad-spectrum liquid multivitamin/mineral with high B6; www.awakennutrition.com Need extra Calcium with most of above products.

  43. Amino Acids • Protein is composed of long strands of many amino acids • The body needs to digest protein to small peptides or individual amino acids • Amino acids can be measured in plasma (fasting) or urine (24-hr best) • Caution – high level in urine sometimes indicates wasting, resulting in low levels in body

  44. Essential Amino Acids in Urine • Lysine high and possibly significant; • Methionine slightly low but not significant; • Histidine slightly high but not significant Note: high level in urine may mean low level in body

  45. Conditionally Essential Amino Acids in Urine High glycine and high cystine in urine suggests low level in body; Worrisome that cystine excretion is high

  46. Metabolic Amino Acids in Urine Taurine and beta aminoisobutyric high but not statistically significant; high taurine probably suggests wasting, and hence a need for taurine

  47. Summary of Amino Acids • Some children with autism have low levels of amino acids in body • Recommendation: measure levels, and supplement if low • Also, consider measuring neurotransmitter levels in platelets, and then supplement with precursors if low (neurotransmitters made from amino acids) – more research needed

  48. Essential Fatty Acids Essential Fatty Acids are termed “essential” because they are necessary for human life. The major types of essential fatty acids are Omega-3 and Omega-6. Ancient human diets contained a roughly 1:1 ratio of Omega-3 to Omega-6 fatty acids. However, since Omega-3 fatty acids spoil much faster than Omega-6, commercial food processors usually remove them or “hydrogenate” them to increase shelf life. Today, American diets contain a roughly 1:15 ratio of Omega 3 to Omega-6; in other words, most people in the US are very low in Omega 3 fatty acids.

  49. EFA’s in Autism A recent study in France found that children with autism had normal levels of Omega-6, but their levels of Omega-3 were 25% below “normal”, and even “normal” is probably far from “optimal”. A small preliminary study by Gordon Bell (Un. Stirling) of 7 children with ASD also found less EPA and DHA, and sometimes more arachidonic acid, than control subjects.

  50. Sources of Omega-3 Fatty Acids In human diets, the major source of omega-3 fatty acids is fish. Fish contain two important types of Omega-3 fatty acids, EPA and DHA. Some fish contain much more omega-3’s than others.

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