Detoxification & Methylation

March 15th, 2013

Detoxification & Methylation important information for individuals on the Autism Spectrum

By Dr. David Berger, Pediatrician and TACA Physician Advisory Board member

Introduction

Detoxification, methylation and anti-oxidants continue to play an important role in the biomedical treatment of Autism and other chronic medical conditions. A main player in this is glutathione, a small peptide derived from the amino acids glutamic acid, glycine and cysteine. Although it is critical for maintaining good health, it is not considered an “essential protein” since the human body can make it, as opposed to needing to get it through the diet.  

Cysteine is the most important factor for the body to make glutathione. Primary food sources for cysteine include broccoli, red peppers, eggs, poultry, oats, garlic, onions and Brussel sprouts. It is also available in a supplement form as N acetyl cysteine (NAC).

Methylation refers to the process of the movement of methyl groups (A carbon with 3 hydrogens) which is involved in how genes are expressed, how enzymes function, and how heavy metals are metabolized.

Glutathione

Glutathione helps defend the body against damage from cigarette smoking, heavy metals, alcohol, and other toxins, exposure to radiation, and cancer chemotherapy. Glutathione protects cells in several ways. It neutralizes oxygen molecules before they can harm cells. Together with selenium, it forms the enzyme glutathione peroxidase, which neutralizes hydrogen peroxide. It is also a component of another antioxidant enzyme, glutathione-S-transferase, which is a broad-spectrum liver-detoxifying enzyme.

Glutathione protects not only individual cells but also the tissues of the arteries, brain, heart, immune cells, kidneys, lenses of the eyes, liver, lungs, and skin against oxidant damage. It plays a role in preventing cancer, especially liver cancer, and may also have an anti-aging effect.  Most glutathione is found in the liver where it detoxifies many harmful compounds to be excreted through the bile. Some glutathione is released directly by the liver into the bloodstream where it helps to maintain the strength of red blood cells and also protects white blood cells.

Glutathione can also be found in the lungs and intestinal tract. It is required for carbohydrate metabolism. Glutathione also appears to have anti-aging effects by aiding in the breakdown of oxidized fats that may contribute to atherosclerosis. As people age, glutathione levels in the body decrease and this can speed up the aging process.

Research on Glutathione

Neurotoxicology – Volume 26, Issue 1, January 2005, Pages 1-8

*Thimerosal Neurotoxicity is Associated with Glutathione Depletion:
Protection with Glutathione Precursors * *S.J. James, William Slikker III, Stepan Melnyk, Elizabeth New, Marta Pogribna and Stefanie Jernigan *

1 Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute, Little Rock, AR 72202, USA

2 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA

Abstract

Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (single bondSH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 /?/M glutathione ethyl ester or /N/-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 /?/M Thimerosal. Although Thimerosal has been recently removed from most children’s vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations.

An Important Related Study to Dr. Jill James

Read Dr. Richard Deth’s studies as it relates to detoxification and metals and other research at the Autism Research Institute website.

More Important Research Papers On This Topic

[1] Wu, J et al. Mercaptoethanol and N-acetylcysteine enhance T-cell colony formation in AIDS and ARC. Clin Exp Immunol 77:7-10, 1989.

[2] Lund, ME et al. Treatment of acute methylmercury ingestion by hemodialysis with N-acetylcysteine. Toxicol Clin Toxicol 22:31-49, 1984.

[3] Henderson, P et al. N-Acetylcysteine therapy of acute heavy metal poisoning in mice. Vet Hum Toxicol 27:522-5, 1985.

[4] Keith RL, et al. Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney. Toxicology 1997 Jan 15;116(1-3):67-75.

[5] Zalups RK, et al. Interactions between glutathione and mercury in the kidney, liver and blood. In: Chang, LW, ed. Toxicology of Metals. Boca Raton: CRC Press, 1996; 145-63.

[6] Shenker BJ, et al. Mercury-induced apoptosis in human lymphoid cells: evidence that the apoptotic pathway is mercurial species dependent. Environ Res 2000 Oct;84(2):89-99.

[7] Thompson SA, et al. Modulation of glutathione and glutamate-L-cysteine ligase by methylmercury during mouse development. Toxicol Sci 2000 Sep;57(1):141-6.

[8] Gong Z, et al. Effect of chelation with meso-dimercaptosuccinic acid (DMSA) before and after the appearance of lead-induced neurotoxicity in the rat. Toxicol Appl Pharmacol1997;144:205-214.

[9] Witschi Z, et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43(6):667-669.

Testing for  glutathione deficiency and other helpful markers

Although there are labs that will report on total glutathione levels, these labs to not differentiate between active (reduced) and inactive (oxidized) forms. If a total glutathione level is low, it would indicate that there is insufficient glutathione in the body. But a normal total glutathione level could be misleading since this could be mostly as the oxidized form.

Genova Diagnostics can test for cysteine levels. If cysteine is low, then improving the amount of cysteine in the body can help the body make glutathione.  But a normal or high cysteine level does not ensure that glutathione levels in the body are accurate. The cysteiene test can be run at the same time as a sulfate level. Low levels of sulfate can lead to toxic accumulation and inflammation, and can be corrected by taking an Epsom salt bath or taking oral sulfates.

An elevated whole blood histamine level or basophil count on a CBC can indicate under methylation.

Methylation/Methyl B12/Methylfolate/MTHFR

This is a rather complex chemical cycle (illustrated below). A simplified description is that our body takes a form of folic acid (called tetrahydrofolate), and then using an enzyme called MTHFR, this is converted to 5 methyltetrahyrofolate (5-MTFR). The 5-MTFR then gives it’s methyl group (a carbon with 3 hydrogens)  to  B12, to form Methyl B12. Methyl B12 then give up this  methyl group  to join with homocysteine to form methionine. Methionine is an amino acid that can either be used to build a protein, or it can give up its methyl group so that methylation can occur. Methylation refers to the process of the movement of methyl groups which are involved in how genes are expressed, how enzymes function, and how heavy metals are modified. After the methyl group is donated from the methionine, eventually homocysteine is formed again. Then homocysteine can meet up with another Methyl B12 to repeat the above, or with the aid of vitamin B6, it from cysteine and then glutathione.

Dr Jill James has demonstrated that children with autism have lower blood levels of methionine, cysteine and glutathione (Am J Clin Nutr. 2004 Dec;80(6):1611-7.) compared to typical children. She also found that the use of Methyl B12 (injected at 75mcg/kg every 3 days)  and folinic acid (at 400mcg twice a day)  can significantly improve cysteine and glutathione levels, though not fully up to the levels shown in typical children (Am J Clin Nutr. 2009 Jan;89(1):425-30)

In non published data, Dr Jim Neubrander (the most experienced physician using Methyl B12 in people with autism), by using his detailed patient questionnaire, reports 90% of ASD children showed at least one area of clinical improvement within 3 months with using injected Methyl B12. As of this writing he has patients have now taken over 1 million doses of Methyl B12!

Testing for MTHFR

All insurance-covered clinical laboratories should be able to run a test for MTHFR mutations. These mutations (one called C677T and one called A1298C) have a single DNA switch in the gene (so for instance at the 677th position on the gene, there is a T where there should be a C), which leads to an abnormal MTHFR enzyme being produced.  This leads to a decreased ability for the body to make the 5-MTHF, with a subsequent slow down in the methylation pathway.  Currently there are no commercial labs that can measure blood methylfolate, so we can not determine how much is naturally being produced in the body or the response to treatment.  But it is felt that by administering one of the two forms of activated folate (folinic or 5-MTHF, at doses of 400-1000mcg twice a day, with some doctors giving ½ as each form), along with Methyl B12, that the body should be able to mostly overcome the faulty MTHFR.

As MTHFR is a gene, and everyone has two copies (one from each parent), knowing the MTHFR status is also important because it can help identify other family members who may be at risk. When a person has either a double copy of C677T  or one copy each of C677T/A1298C, this can lead to an increase over time  in the homocysteine level, which is a significant risk factor for having either a heart attack or stroke (especially at a young age). Autoimmune conditions may be more common in those with MTHFR mutations.  Women with the abnormal MTHFR are also at risk of miscarriage, and there may also be an association with spina bifida in their children.  So checking others in the family for this gene, and treating with folinic/5-MTHF and Methyl B12 may be helpful in minimizing many chronic diseases.

One copy only of C677T is believed to cause some slowing of the MTHFR, but not as severe as if the pattern is either of the 2 abnormal copies as mentioned above. It is less clear as to the clinical significance of having 1 or 2 of the A1298C mutations without the C677T.

For a more information about MTHFR, see Dr Ben Lynch’s webpage, www.mthfr.net.

Cerebral Folate Receptor Antibodies:

Dr Quadros at State University of New York -Downstate Medical Center has identified the presence of autoimmune antibodies directed against some people’s cerebral folate receptors. These receptors are what transports folate into the brain. The presence of these antibodies can lead to a cerebral folate deficiency if the folate transport is inhibited or slowed down by the antibodies.

When these antibodies are present, it is felt that significantly higher amounts of activated folate  (1mg/kg or more) can overcome the deficiency.

For a detailed, simplified discussion on Cerebral Folate Deficiency, read  the article written by Dr. Dan Rossignol and Dr Richard Frye, TACA Medical Advisory Board Members, http://www.rossignolmedicalcenter.com/app/download/5857490604/Cerebral+Folate+Deficiency+ASD.pdf

Glutathione Administration

Supplementing with glutathione does not always solve methylation and detoxification problems. But with a doctor’s assistance with dosage and various forms of glutathione, it can help many children.

Some doctors recommend glutathione in several forms: Oral (liquid or capsule), topical (a lotion or cream), nebulized (similar to an asthma treatment), or via IV (intravenous drip.) Please note: FOR SOME CHILDREN ORAL GLUTATHIONE CAN EXACERBATE YEAST AND GUT IMBALANCE. But there is also concern expressed by many biomedical doctors that most orally consumed glutathione may be metabolized before it enters the blood stream. If so, this will not raise the blood reduced glutathione levels.

Be sure to work with your doctor on the right form for your child, and to use reliable products. It is important to find sources that meet dietary restrictions (gluten-free, casein-free, dye-free, additives-free, etc.). Sometimes these additives can mask any benefits of glutathione supplementation.

Typical glutathione dosing strategies:

A physician needs to prescribe these doses, and an experienced practitioner may use different doses than those listed here. These are for reference:

IV Glutathione: start small, around 300mg per dose as a slow push. Younger children often do well with doses in the 600-800mg range, and older children and adults often take doses in the 1000-1200mg range. This is often given every 1-2 weeks.

Nebulized glutathione: at a 200mg/ml concentration, 1 vial once to twice a day

Transdermal glutathione: 250-500mg once to twice a day. Those mixed in Emu oil appear to be well tolerated and absorbed.

As long as there are no side effects from glutathione, it probably cannot be overdosed, and much higher doses than those listed above have been needed in some people.

Typical N acetyl Cysteine (NAC) dosing strategies:

Oral/Transdermal NAC: (for oral use be very careful, or consider avoiding all together, in those with chronic intestinal yeast issues). A recent randomized trial at Stanford showed NAC reduced irritability is children with autism, working up to 900mg 3x a day by mouth http://www.ncbi.nlm.nih.gov/pubmed/22342106. Lower doses are more often used by biomedical doctors.

IV NAC: typically start at 10mg/kg and if fine go to20mg/kg. This is often given every 1-2 weeks.

Typical   Methyl B12 dosing strategies:

Methyl B12 has low effectiveness if swallowed, as it seems to lose it’s methyl group before being absorbed into the blood stream (which will subsequently provide regular B12 but not Methyl B12). Although some children get overstimulated with this treatment, there does not seem to be any toxic effect. Often the overstimulation will be reversed if folinic acid is added.

Subcutaneous injections: It is felt that this is the best way to give Methyl B12. When this tiny injection is given at an angle to deposit the vitamin in the fat between the skin and muscle, the vitamin is then slowly released into the bloodstream and this provides a steadier amount through the day(s) between shots. Most children receive one injection every 3 days. If a child seems overstimulated on the first day, he/she may benefit from less frequent dosing (such as every 5 or 7 days, a regression may be seen to know when the next dose should be given). If a child seems to do well right after an injection but then it seems to wear off before the 3rd day, some children need it every 2 days or even daily. Doses of 65-75 mcg/kg are typically given.

Nasal Spray: this is usually compounded to provide 625mcg or 1250mcg of methyl B12 per spray. Typically, the smaller amount is given one to two times a day for younger children and the larger dose once or twice a day for older kids and adults.

Lollipop: This can be an effective way to provide Methyl B12, but only if the pop is sucked and not chewed. Each pop has 3600mcg of Methyl B12, though a good amount of this will be swallowed in the saliva.  But some should get absorbed through the oral lining. Young children typically will do 1 a day and older children/adults will do 1 twice a day

Ways to increase sulfate

Epsom salt baths seem to be the best way to increase sulfate in the body. In water as hot as possible without burning the skin (the heat opens up the skin pores and capillary beds, allowing for better absorption) work up to 2 cups of the salt in a standard sized bath (3 cups if a garden sized bath). If tolerated, the water should go up to the neck, thereby maximizing the absorption surface. If this can be done lying down, then less water will be used and the salt will be more concentrated. Bubble baths can be used if needed, as the bubbles will stay on top of the water. If there are jets such as in a jacuzzi tub, do not run them as the salt may affect the motor over time If the child has a tendency towards try skin, such as with eczema, over time the anti-inflammatory properties of the sulfate can help treat the eczema. But a high quality, hypoallergenic skin moisturizer, especially to problem skin areas, should be applied right after the bath to prevent the drying of the skin from the salt bath that may be seen during the first few weeks of treatment. Due to the calming effects of the magnesium, Epsom salt baths often promote better sleep if done before bedtime

For patients who cannot, or do not have time to take an Epsom salt bath, there are topical magnesium sulfate creams. Parents often report that even better response is seen if the salt is dissolved in a small amount of hot water and rubbed on the skin, as described here http://wholisticpeds.com/uploads/Epsom%20Salt%20Application.pdf

Disclaimer: Talk About Curing Autism (TACA) provides general information of interest to the autism community. The information comes from a variety of sources, and TACA does not independently verify any of it. The views expressed herein are not necessarily TACA’s. Nothing in this document should be construed as medical advice. Always consult your child’s doctor regarding his or her individual needs.

 

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