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THE THYROID AUTISM CONNECTIONTHE ROLE OF ENDOCRINE DISRUPTORS

by Raphael Kellman, M.D.1According to the CDC 1 in 110 US eight year olds have autism spectrum disorder.US Centers for Disease Control and Prevention (CDC) 2007. Counting Autism

According to US centers for disease control and prevention (CDC) approximately 4.5 million children have been diagnosed with ADHD.CDC 2007 Summary Health Statistics for US Children: National Health Interview Survey, 2006Prevalence of learning disabilities in United States children is approximately 9.7% according to a 2007 pediatrics article.Altakac M. et al2007 Lifetime Prevalence of Learning Disability among US Children, 119; 77-83 EPIDEMIC ONEAUTISM AND NEURO-DEVELOPMENTAL DISORDERS2According to a 1994 study 16% of US children have a developmental disability.Boyle CA et al Prevalence of Health Impact of Developmental Disabilities in US ChildrenPediatrics 93 (3): 399-403

According to an article in JAMA in 2007 developmental disorders and chronic conditions in general is on the rise.Perrin JMThe Increase of Childhood Chronic Conditions in the United StatesJAMA 297 (24): 2755- 9

3 EPIDEMIC TWOTHYROID DISEASEAccording to the Colorado Thyroid Disease Prevalence Study in 2000The prevalence of abnormal thyroid function is 9.5%If the upper level of TSH reference range is reduced to 2.5, as suggested by the National Academy of Clinical Biochemistry, this number will at least double24% of women older than 60 have hypothyroidismG. Canaris et alThe Colorado Thyroid Disease Prevalence StudyArch Intern Med 2000; 160:526-5344Thyroid cancer is rising in incidence faster than any other cancer in the United StatesAccording to the NCI, thyroid cancer is increasing by 6.5% per year since 1997Papillary carcinoma between 1999 and 2005, and 2003 and 2005 increased nearly 100%Enewald V. et alRising Thyroid Cancer Incidence in the US by Demographic Tumor Characteristics 1980-2005Cancer Epidemiology Biomarkers 2009; 18:784-791

Increasing Incidence of elevated TSH levels in newborn screening in Northern EnglandPearce MS et alJ. Thyroid Research, Jan 20105Thyroid auto-immune disease is the most common auto-immune disease 7-8% of the population, totaling 24 millionDayan CM et alChronic Autoimmune ThyroiditisNew England Journal of Medicine 1996; 335: 99-107

Because only one-third of those with autoimmune diseases are diagnosed, the statistics are estimated to be 3x higher than that, as high as 72 millionNIH Autoimmune Coordinating Committee Autoimmune Research, 2005US Dept. of Health and Human Services, NHI pub March 25

6IS THE EPIDEMIC OF NEURO-DEVELOPMENTAL DISEASES LARGELY REDUCIBLE TO A MORE PRIMARY DISORDER - HYPOTHYROIDISM?7Many of the same chemicals that are associated with autism, also cause thyroid diseaseToxins thought to contribute to the development of autism and ASD mediate their effects via their adverse effects on the thyroidThyroid hormone known to play a critical role in orchestrating brain developmentThyroid dysfunction in utero, and neonates leads to many of the same symptoms associated with autism and ASDEVIDENCE SUPPORTING THYROID-AUTISM CONNECTION8Celiac disease/gluten intolerance is associated with hypothyroidism. Gluten-free diets known to help with autism, may mediate via its positive effects on the thyroidAutism and ASD frequently associated with auto-immune diseases. A percentage of thyroid disease is auto-immune in natureMitochondrial dysfunction found to be associated with autism -hypothyroidism causes mitochondrial dysfunctionHypothyroidism contributes to methylation defects

9THE CRITICAL ROLE OF THYROID HORMONEIN BRAIN DEVELOPMENTPhase IFirst trimester, before synthesis of fetal TH, fetus dependent on maternal THProliferation, migration and differentiation of neurons that develop into the forebrain, orchestrated by TH

Phase IIFetal TH production, some role of maternal THProliferation, migration and differentiation of neurons that develop into the cerebellum Forebrain maturation and synapse formationOrchestrated by TH

10Phase IIIAfter birth, continuation of proliferation, migration, and differentiationMyelination, gliogenesis Thyroid hormones act as a time clock stimulating and subsequently terminating proliferation, migration and differentiation at the precise time with the precise dose and in the correct sequence Central Nervous System symphony, thyroid hormone the conductorS. Porterfield; Endocrine Reviews; 14 (1) 94-106; 1993

If TH plays such a critical role in neurodevelopment, that is the system where we should be concentrating our efforts to better understand the origins of neuro-developmental disorders

11Low thyroid function in the fetus and newborn associated with similar symptoms associated with ASD and ADHD General developmental delays Cognitive dysfunction Hyperactivity Attention disorders Speech delays Hypotonia/Fine motor dysfunction Repetitive behavior Social and communication dysfunctionZoeller RT et alTiming of Thyroid Hormone Function in the Developing Brain: Clinical Observations and Experimental FindingsJ. Neuroendocrinol 16:809-818

12HYPOTHYROXINEMIA IN PREGNANCY AND NEURO-DEVELOPMENTAL DYSFUNCTION IN CHILDRENChildren of mothers with low normal T4 (T4-0-10th percentile) due to iodine deficiency from early gestation to birth increases the risk of neuro-developmental delay in their offspringLower performance in gross and fine motor coordinationLower performance in socializationDelayed Neurobehavioral Development in Children Born to Pregnant Women with Mild Hypothyroxinemia During First Month of GestationThe Importance of Early Iodine SupplementationP.Berbel et alThyroid Number 6, December 19, 2009

13Thyroid function can be damaged by the same toxins associated with autism and other developmental disorders:PCBsDioxinsPerchloratePhthalatesPBDEsLeadMercuryCadmiumInsecticidesBisphenol-AP. LandriganCurr Opin Pediatr 2010What Causes Autism? Exploring the Environmental Contribution14According to research reported in Digestive Diseases and Sciences:Gluten sensitivity/celiac disease associated with thyroid diseaseCeliac disease can play a role in the etiology of thyroid diseaseWe believe that undiagnosed celiac disease can cause other disorders by switching on some as yet unknown immunological mechanism. Untreated celiac patients produce organ specific antibodies.Digestive Diseases and SciencesFebruary 2000; 45:403-406

HYPOTHYROIDISM ANDGLUTEN INTOLERANCE/CELIAC DISEASE15T4 regulates the conversion of riboflavin to FAD.Levels of FAD in the liver of hypothyroid rat is similar to rats on a riboflavin-deficient diet

Erythrocyte Glutathione Reductase (EGR) an FAD enzyme low in adults with hypothyroidism

Hypothyroidism - conversion of riboflavin to FAD and MTHFRJ Cimino et alRiboflavin Metabolism in the Hypothyroid NewbornAmerican Journal of Clinical Nutrition 1988; 47: 481-483

HYPOTHYROIDISM ANDMETHYLATION PATHWAY DEFECTS16Decreased NADHIncreased oxidative stressMitochondrial DNA over replication or deletion Whether the mitochondrial dysfunction in children with autism is primary or secondary to an as yet unknown event remains the subject of future work; however mitochondrial dysfunction could greatly amplify and propagate brain dysfunction, such as that found in autism. JAMA.2010; 304 (21):2389-2396.JAMA Dec 1, 2010

MITOCHONDRIAL DYSFUNCTION IN AUTISM 17Hypothyroidism Alters Mitochondrial Morphology and Induces Release of Apoptogenic Proteins R. SinghJ Endocrinol 2003; 176: 321-329

TH deficiency leads to extensive apoptosis during cerebellar development

TH maintains mitochondrial architecture and inhibits release of apoptogenic molecules to prevent excess apoptosis during cerebellar development18TH REGULATES MITOCHONDRIAL ACTIVITY

Nuclear pathwayDirect mitochondrial pathway stimulation of mitochondrial genome transcriptionBoth pathways mitochondriogenesisMitochondrial pathway involved in regulation of cell differentiationTH regulation of mitochondrial activity - link between metabolism and developmentThyroid Hormone Action in MitochondriaC. Wrutniak-Cabello et alJournal Molecular Endocrinology 2001; 26: 67-70

19Increased prevalence of familial autoimmune diseases in families of a child with autismComi Am et alJ. Child Neurol, June 14, 1999 (6) 388-94

Frequency of autoimmune disorders is significantly higher in families of children with PDD compared with families of both autoimmune and healthy control bandsHypothyroidism significantly increased in PDD families compared to autoimmune familiesSweeten TL et alPediatrics, Nov 2003, 112 (5) 420-426

AUTISM, ASD, PDDAND AUTOIMMUNE DISORDERS20WHAT IS THE CAUSE OFTHE EPIDEMIC OF THYROID DISEASE?

THE ROLE OF ENDOCRINEDISRUPTING CHEMICALS21Endocrine disrupting chemicals, EDCs are synthetic substances in environment, food and consumer products. According to the EPA, EDC is an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action or elimination of natural blood borne hormones that are present in the body and responsible for homeostasis reproduction and developmental processes.

22Growing list of chemicals now known to disrupt bodys communication network Blocks or impersonate hormone messages Scrambles messagesSows misinformation- fools the endocrine system to accept new instructions

Toxicology I Focus on cancer, dose makes the poisonToxicology II Endocrine disrupting chemicalsPlays by different rules:Even low doses can have devastating effectsHormones, mostly TH, orchestrate neurological development, even low doses of EDCs that have little effect on adults, can have devastating effects on the unborn, neonate and childENDOCRINE DISRUPTOR THEORYGENERAL CONCEPTS23Toxicology II continuedNormal development depends on the right hormone message at the right time and the right amount chemical balletWindows of vulnerabilityTiming makes the poisonENDOCRINE DISRUPTOR THEORYGENERAL CONCEPTS24Thyroid system is one of the most frequent targets of synthetic chemicalsLinda Birnbaum; Director of Environmental Toxicology Division at the US Environmental Protection Agency25ENDOCRINE DISRUPTORS AND ITS EFFECTS ON THE THYROID AND NEURO-DEVELOPMENT IN UTERO TO FIRST TWO YEARS OF LIFEEffects include:Learning disabilitiesBehavioral problemsFine motor dysfunctionPoor response to stressAttention problems and hyperactivity Language speech deficitsSocial development deficits

S. PorterfieldVulnerability of Developing Brain to Thyroid AbnormalitiesEnvironmental Insults to the Thyroid SystemsEnvironmental Health Perspectives 1994, 102 (2): 125-130

S. PorterfieldThyroidal Dysfunction and Environmental Chemicals-Potential Impact on Brain DevelopmentEnvironmental Health Perspectives,Vol 108 Supplement 3 June 2000

26Other effects of thyroid disruption on neuro-development in infants and children:Visuospatial deficitsMotor and visual motor delaysDecreased social and perceptual abilitiesDecreased auditory discriminating abilitiesJF RobetNeurodevelopment in Infants and Preschool Children with Congenital HypothyroidismEtiological and Treatment Factors Affecting OutcomeJournal of Pediatric Psychology 1990, vol 17: 187-213

27Wingspread Consensus Statement 1991We are certain of the following: a large number of man made chemicals have the potential to disrupt the endocrine system of animals including humans.

Endocrine disruptors cause:Thyroid dysfunction in birds and fishDecreased fertility in birds, fish and mammalsGross birth deformities in birds, fish and turtlesBehavioral abnormalities in animals

CHRONOLOGY OF KEY EVENTS IN THE DEVELOPMENT OF THE ENDOCRINE DISRUPTOR THEORY28May 1996 scientific conference in Erice, Sicily concluded:Endocrine disrupting chemicals at levels found in the environment and in humans threaten brain development

We are certain of the following: endocrine disrupting chemicals can undermine neurological and behavioral development and subsequent loss of potential of individuals exposed in the womb This loss of potential in humans and wildlife is expressed as behavioral and physical abnormalities. It may be expressed as reduced intellectual capacity and social adaptability, as impaired responsiveness to environmental demands.29The extreme sensitivity of the developing brain to chemical disruption of the endocrine system[can cause] reduced intelligence, learning disabilities, attention deficit problems and intolerance to stress.

Many of the endocrine disrupting chemicals can affect the thyroid which plays a key role in brain development.30August 1996 Food Quality Protection Act passedRequires the EPA to obtain data about the potential hormone disrupting effects of pesticides in food.

October 1996 EPA forms Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC)The EDSTAC establishes a comprehensive screening and testing program for pesticides and other chemicals

The EDSTAC decides program should focus on estrogen, testosterone and thyroid hormone disruptors

The EDSTAC charged to coordinate research in the field of endocrine disruptors to more accurately characterize the risks of endocrine disruptorsMarch 1996 publication of Our Stolen Future

31THYROID DISRUPTING CHEMICALS32THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMSCHEMICALMECHANISM OF ACTIONSOURCEPerchloratesBromatesThyocinatePhthalatesBlocks Iodide UptakeBlount BC 2007Crofton KM 2008PCBsPentachlorophenolFlame RetardantsPhthalatesCompetitive Binding to Thyroid TransportProtein eg. TTRCheek D. 1999Whitefield GR 1999Purkey HR 2004Pluim J 1993MancozebAmitroleBenzophenoneBlocks Production ofThyroid Hormone

Crofton KM 2008

33THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMSCHEMICALMECHANISM OF ACTIONSOURCEPCBsBisphenol AFlame RetardantsDioxinPhthalatesBinds to ThyroidReceptor Boas M. 2006Shen O. 2009Moriyama 2002LeadCadmiumFD&C Red Dye #3PCBsPBDEOctylmethoxycinnamateMercuryHCBInhibition of DeoidinasesSantini 2003Mori K. 2008Boas M. 2006Takser L 200534THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMSCHEMICALMECHANISM OF ACTIONSOURCEDDTPCBsBinds to TSH ReceptorSantini F. 2003AcetochlorPCBsPBDEEnhanced Hepatic MetabolismHosokawa S. 1992Zhou T. 2001 PCBsTCDDChlorinated PesticidesMercuryPBDEDirect Toxic Effect onThyroid Gland

Ness DK 1993Porterfield S. 1994Takser L. 2005Zhou T. 2001

35Endocrine disruptors may have similar or different effects on the thyroid. This can create a cumulative and/or synergistic effect.Crofton K.M. et alThyroid Hormone Disrupting Chemicals: Evidence for Dose Dependent Additivity or Synergism.Environmental Health Perspectives2005, 113; 1549-155436There is substantial evidence that polychlorinated biphenyls dioxins and furans cause hypothyroidism in exposed animals, and that environmentally occurring doses affect human thyroid homeostasis.

Thyroid disruption may be caused by a variety of mechanisms as different chemicals interfere with the hypothalamic-pituitary thyroid axis at different levels.PCBs37Growth and development in fetal life and childhood is highly dependent on normal levels of TH (thyroid hormone). Normal levels of THs are crucial for the development of the Central Nervous System. This critical phase may be vulnerable to even subtle effects of synthetic chemicals. Such developmental deficiencies may not be identifiable until late in life.European Journal of Endocrinology.Environmental Chemicals and Thyroid Function.Malene Boas et al2006, vol. 154 Issue 5: 599-61138PCBs in maternal blood during pregnancy.Negative correlation between maternal TT3 and PCBs, three pesticides (p--DDE, cis-nonachlor, hexachlorobenzene) and inorganic mercury at low levels of exposure.Positive correlation to fetal TSH L. Takser et al Thyroid Hormones in Pregnancy in Relation to Environmental Exposure to Organochlorine Compounds and MercuryEnvironmental Health Perspective 113: 1039-1045 (2005)

39PCBs interfere with HPT axis by producing a subnormal response of the pituitary to TRH stimulation.Khan & Hansen 2003. Orthosubstituted, PCB Congeners (95 or 101) Decrease Pituitary Response to Thyrotropen Releasing Hormone.Toxicol Lett. 144; 173-182

In human adults, adolescents and children from highly exposed areas: PCB levels correlated negatively to TH levels.Hagmar C. et alPCB toxicity in children:Positive correlation between PCB exposure and TSH levels.Osius N et alExposure to PCBs and Levels of Thyroid Hormones in Children.Environmental Health Perspectives 1999. 107 843-849 40Positive AssociationBetween PCB levels in breast milk and TSH levels in infantsKoopman-Esseboom et alEffects of Dioxins and Polychlorinated Biphenyls on Thyroid Hormone Status of Pregnant Women and TheirInfantsPediatric Research36:468-473,1994

1971 Women in Taiwan consumed cooking oil contaminated with PCBs and furans128 Children studied who were in womb:Impairment in mental and motor abilitiesBehavioral problemsHyperactivity Attention deficitsW Rogan et alCongenital Poisoning by PCBs and Their Contaminants in TaiwanScience 241: 334-336; 1998

41Widespread and persistent and highly toxic environmental pollutants from:Industrial burning processesProduction of herbicides

TCDD prototype and most toxic

DIOXINSPCDs AND PCDF42Single dose of TCDD in rats:dose-dependently decreased T4 and free T4 and increased TSHViluksela M. et alTissue Specifics Effects of TCDD on the Activity of 5-Deiodinases I and II in Rats. Toxicology letters 2004:147: 133-145

In offspring a single dose of TCDD to the dam during gestation was:Correlated to decreased T4A two-fold increase in TSHHyperplasia of the thyroid glandNishimura N. Rat Thyroid Hyperplasia Induced by Gestational and Lactational Exposure to TCDD.Endocrinology 2003; 144: 2075-2083 43Large study of Vietnam veteransGroup with highest TCDD levels showed a significant increase in TSHPavuk M. et alSerum TCDD Levels and Thyroid Function in Air Force Veterans of the Vietnam War.Annals of Epidemiology 2003 13:335-343

44PCBs and dioxins measured in human milk. Higher levels in human milk correlated significantly with:Lower plasma levels of maternal TT3 and TT4Higher TSH levels in the infants in the second week and third month after birth.

Similar study of breast-fed infants:Chlorinated dioxins and furans (dioxins) positively correlated with TSH levels in infants.Dioxins may interfere with transport of T4 into the cell and the conversion of T4 to T3 or binding of T3 to nuclear receptor.45Inhibition of enzyme 5-deiodinase and decreased conversion of T4 to T3.Decreased nuclear T-3 receptor occupancy.In pituitary gland decreased nuclear T-3 occupancy stimulates TSH secretion .Pluim J et alEffects of dioxins on the thyroid function in newborn babiesEnvironmental Health Perspectives, vol 101 number 6 1993: 504-50846PBDEs used as flame retardants in plastics, paints, electrical equipment and synthetic textilesTBPH used in electrical equipment such as televisions, computers, copying machines and video displays

Commercial PBDE mixture DE-7:Decreases levels of THInduces activity of hepatic enzymes UDPGTHigh doses DE-7 causes histopathological changesZhou T. et alEffects of Short-term in Vivo Exposure to Polybrominated Diphenyl Ethers (PBDE) Mixture on Thyroid Hormones and Hepatic Enzymes Activities in Weaning RatsToxicological Sciences 2001: 61; 26-82 FLAME RETARDANTS TBBPA AND PBDEs

47Maternal residence near agricultural pesticide applications during key periods of gestation could be associated with the development of autism spectrum disorder (ASD) in children

ASD risk increased with the poundage of organochlorine pesticides applied and decreased with distance from field sites.Roberts EMMaternal Residence Near Agricultural Pesticide Applications and ASD among Children in California of Central ValleyEnvironmental Health Perspectives 115 (10): 1482-1489

INSECTICIDES AND DEVELOPMENTAL DISORDERS48Neuro-developmental effects include:Decreased psychomotor functionDecreased mental function: depressed memory, attention and verbal skillsMechanism of action: thyroid disruptionJurewicz J 2008: Prenatal and Childhood Exposure to Pesticides and Neurobehavioral Development: Review of Epidemiological Studies.International Journal of Occupational Medicine. Environmental Health 21 (2): 121-132Korrick S. et al2008: PCBs Organochlorine Pesticides and Neuro-developmentCurrent Open Pediatric 20 (two): 178-204Ribas-Fito N et al2006In utero Exposure to Background Concentrations of DDT and Cognitive Functioning among PreschoolersAM J P. Epidemiol 164:955-962ORGANOCHLORINE PESTICIDES49BPA levels correlated with increased weight of thyroid Positive finding between increasing BPA and activity of hepatic enzyme UDPGT.Tan BL et alAssessment of Pubertal Development in Juvenile Male Rats after Sub-acute Exposure to Bisphenol and NonylphenolToxicology letters 2003, 143; 261-270BPA50BPA acts as a TH antagonist on specific TR in the pituitary, which mediates the negative feedback of TH on the pituitary, causing: T4, TSH normal to borderline high

BPA does not antagonize peripheral TR receptors Result: Hyperthyroidism in certain neurons in the developing brain leading to a mosaic effectEndocrinology. 2005 Feb;146(2):607-12. Epub 2004 Oct 21.Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brainZoeller RT, Bansal R, Parris C.

51Miodouinik A. et alNeurotoxicology 2010 Dec 20Mt. Sinai Children's Environmental Health Study between 1998-2002 evaluated relationship between phthalates and bisphenol-A (BPA) exposure in mothers collected during third trimester of pregnancy and neuro-developmental disorders in their children when they reach ages 7-9.Increasing phthalates associated with:Greater social deficits:Poorer social cognition, social communication and social awarenessMechanism of action thyroid disruption ENDOCRINE DISRUPTORS ANDCHILDHOOD SOCIAL IMPAIRMENT52Prenatal Phthalate exposure is associated with childhood behavior and executive functionS.M. EngelEnvironmental Health Perspectives April 2010

Urine of mothers collected on third trimester from Mt. Sinai Environmental Health StudyTheir children evaluated at ages 4-9 for behavioral issues and executive functionPhthalate levels correlate with poor executive function and decreased ability to:Control impulses53continuedTransition between situationsModulate emotional responsesInitiate a taskRetain information for task completionSet goals54ASSOCIATION BETWEENORGANOCHLORINES AND ASDASD risk increase with poundage of organochlorine applied and decreased with distance from field sites Mechanism of action thyroid disruptionBinding of Gaba receptorsEstrogenic effectsEric RobertsMaternal Residence near Agricultural Pesticide Application and ASD among Children in the California Central ValleyEnvironmental Health Perspectives2007 October: 115 (10):1482-148955IODINE DEFICIENCY AS A CAUSE OF AUTISMIncrease incidence associated with increased iodine deficiencyIodine necessary for TH production

BMJ2004; 328:22656If autism is an environmental disease, then based on the overwhelming evidence, hypothyroidism is likely to be a underlying metabolic state significantly contributing to its pathophysiologyHypothyroxinemia may have began in a percentage of children with autism as early as the first trimester in utero; this may be caused by sub-biochemical maternal hypothyroidism that either preceded pregnancy or developed subsequently due to the excessive need of TH and/or to a decrease in available iodine

PUTTING THE PIECES TOGETHER57continuedReported in the Journal of the Neurological Sciences 2007 Autism: Transient in utero Hypothyroxinemia Related to Maternal Flavonoid Ingestion During Pregnancy and to Other Environmental Anti-thyroid AgentsThe current surge of autism could be related to transient maternal hypothryoxinemia resulting from dietary and/or environmental exposure to anti-thyroid agents.Decrease TH in utero causes alterations of cerebral cortical architecture by affecting neuronal migration reminiscent of those observed in brains of patients with autismG RomanJournal of the Neurological Sciences 262 (2007) 15-26

58continued Although the etiology of autism is multi-factorial, hypothyroidism at any point during neurodevelopment can be a central cause of autismTherefore treating hypothyroidism place a vital role in the treatment of autism59IF THERE IS SUCH A PROFOUND THYROID-AUTISM CONNECTION,WHY IS IT NOT BEING DETECTED BY ROUTINE BLOOD TESTS?60Studies are revealing the complexity of the ways in which endocrine disruptors may interfere with TH signalingSome endocrine disruptors can cause decreased T4 and yet normal TSHOther endocrine disruptors due to its effects on receptors can cause increased T4 and TSH normal or slightly increasedEndocrine disruptors can also affect diodinase, for example organochlorines can cause over-expression of D3 causing high reverse T3 and low T361continuedThe complex effect of EDCs have on the HPT access can elude routine thyroid blood testsA reason of why hypothyroidism is frequently overlooked is because routine thyroid blood tests are often conflicting and not very revealingThe current clinical strategy of evaluating thyroid disease (measurement of blood levels of hormones) is not sufficient to identify EDC action or thyroid hormone signaling that may well be associated with disease in the human populationThomas ZoellerEnvironmental Chemicals Targeting ThyroidHormones 2010, 9 (1): 28-40 62TSH VALUES ARE OFTEN UNRELIABLE AND MISLEADING AND MAY NOT ADEQUATELY REPRESENT THYROID STATUSBiologic variation is important for interpretation of thyroid function testsS.Anderson et alThyroid, Vol 13 number 11 2007Individual set point for normal thyroid function-unique for each individualSome individuals with TSH within reference range have a TSH outside the individual reference range Laboratory reference ranges are relatively insensitive to aberrations from normality in the individual63Subclinical thyroid disease may be defined in purely biochemical termsunder certain conditions such as pregnancy where normal thyroid function is of importance for fetal brain development subclinical thyroid disease should be treated. Even TSH within reference range may be associated with slightly abnormal thyroid function in the individual. 64Many studies shed doubt on validity of reference range of TSHSubclinical and sub-biochemical hypothyroidism can adversely affect target organs and systems: Developing brainAdult brain (depression studies)Cardio-vascular system: angina patients who underwent cardiac cath: those with TSH levels above 2.1 were more likely to have multiple vessel disease. Yun KH et alInt. J Cardiol 2007

65Treatment of patients with subclinical hypothyroidism and hyperlipidemia with thyroid hormone resulted in significant reduction in LDL cholesterol and improved endothelial function.Razvi S et alEndocrinol Metab 2007; 92:1715-1723

66Depressed patients with normal TSH could have an exaggerated response to TRHKraus RP et alExaggerated TSH Response to TRH in Depressed Patients with Normal Baseline TSHJ Clin Psychiatry 1997; 58: 266-270

Concept of Sub-biochemical Hypothyroidism coined by Sheth J 1999. TH and TSH within normal range yet TRH test is abnormal.Sheth J et alSub-biochemical Hypothyroidism: An Exaggerated TSH response to TRHJ Assoc Physicians India 1999; 47:275-279

67Landmark study 2007 demonstrates routine thyroid test frequently fails to detect hypothyroidism.

Patients with normal TSH and TH with suggestive clinical symptoms of hypothyroidism evaluated with TRH test.

Conclusion of researchers:We document that an exaggerated TRH response indeed occurs in many subjects with normal biochemistry Even though the TRH test is 68continuedseldom used in clinical practice at present, a larger prospective study is in order. Until then physicians may once again need access to TRH for diagnostic use.

TRH Stimulation When Basal TSH is within normal reference range: Is there Sub-Biochemical Hypothyroidism?Suhail A.R Doi et alClinical Medicine and Research Volume 8 Number 3 145-148

69Dr. Rosa and colleagues compared TRH stimulation testing with sensitive 2nd generation TSH testing Basal TSH frequently failed to exclude hypothyroidism 35.3% sensitivityIn conclusion, after the introduction of the current 2nd generation TSH assay the diagnostic role of the TRH test can provide additional information to that obtained with simple basal TSH measurement in the diagnosis of subclinical hypothyroidismDeRosa et alComparison between TRH Stimulation Test and Basal TSH Measurement by a Commercial Immunoradiometric Assay in the Management of Thyroid DiseaseJ. Nucl Med 1996; 40:182-187

70Subclinical Hypothyroidism in Infertile Women the Importance of Continuous Monitoring and the Role of Thyrotropin Releasing Hormone Stimulation TestT. Ldar-Geva et alJournal of Clinical Endocrinology June 2007; 23 (6):332-33787 patients with infertility no other symptoms of hypothyroidism TH Normal, TSH 1.72 1.87Group one: 39 women ovulation disorders, PCOSGroup two: 48 women normal ovulationAbnormal TRH test 13.8%Abnormal TRH significantly more prevalent among women in group one 20%

71Baseline-Individual set point normal TSH and TH, TRH test normalStage 1: Normal T4, TSH slightly above patients individuals set point yet within normal range (such as from 1.7 to 2.1)Abnormality only detected by TRH testStage 2: gradual elevations of TSHResearchers conclude: we recommend performing TRH stimulation testing in women suffering from ovulations disorders, who have normal basal TSH levels

72My Findings Based on the Use of the TRH Stimulation Test:Approximately 70% of children with autism, ASD and other neuro-developmental disorders have hypothyroidismMost missed by routine testProfound improvement with thyroid hormone treatment, some complete recoveryMany mothers of such children show bio-chemical evidence of hypothyroidismIf hypothyroidism is confirmed TH is the most effective known treatment for autism

73MY APPROACH TO THE TREATMENT OF AUTISM, ASD AND NEURO-DEVELOPMENTAL DISORDERSTRH stimulation test thyroid hormone treatmentProvide enriched brain environment and a second chance for brain organization and development.a. Nutraceuticals, herbs that improve brain function:EPA, DHAPhosphatidyl Serine, CholineCDP CholineGPCGalantamineCarnosine74continuedAniracetamMelatoninGabaHuperizineVinpociteneInositolAmylobanetc

75b. Hyperbaric Oxygen Therapy

Immune ModulationAnti-inflammatory compounds:CurcuminBoswelliaLuteolinTransfer-factorsGlutathioneLDNLiposomal Vitamin CLipoic Acidetc

76Methylation Pathway ImprovementVitamin B6- P5PFolinic AcidMB12 / GlutathioneTaurineCreatineetc

Mitochondrial RepairNADHUbiquinolA.L. CarnitinePQQ

77DetoxificationClay bathsChelationInfrared saunaLiver detoxification

Infectious DiseaseGI bacterial infectionsLyme diseaseStrepViral infections

78Dietary ChangesGF/DietRemove allergens

79Implications for the Treatment and Prevention of Neuro-Developmental Disorders

All children with neurodevelopment disorders should be tested with the TRH stimulation testMothers of such children should be tested with the TRH stimulation testWomen should be tested with the TRH stimulation test before pregnancyAll pregnant mothers should take Iodine 250mcg p/day80continuedWe must move beyond the cancer paradigm in order to properly understand the effects of the hormone disrupting chemicals and the threats they pose to human health. We need to bring new concepts to our understanding of toxic chemicals. Our past assumptions about toxicity act as obstacles to understanding a different kind of damageWe must change our understanding of testing and treatment of thyroid disease. Routine thyroid testing can be misleading and frequently prevents us from uncovering the root cause of so much suffering

81SummaryThyroid-Autism connection and the role of endocrine disruptors:Reduces a variety of medical disorders and epidemics to a more primary problemProvides a deeper explanation for the known likely causes of autismProves clinically what researchers are theorizing and finding in animal studies and some human studies in neonatesFirst to connect endocrine disruptors to autism and ASD

82continuedTRH stimulation test detects hypothyroidism in children with autism missed by routine test.When diagnosed with hypothyroidism, thyroid hormone is the most effective treatment for autismTH together with other brain-enhancing compounds can provide the necessary enriched environment for brain re-organization and development.With the understanding of the effects of endocrine disruptors on thyroid function and neuro-development we can also significantly reduce the incidence of neuro-developmental disorders in the future.

83Message of HopeWe can change the course of autism and neuro-developmental disorders by understanding and treating a deeper cause so often missed.

84