the role of endocrine disruptors by raphael kellman, m.d

THE THYROID AUTISM CONNECTION

THE ROLE OF ENDOCRINE DISRUPTORS

by Raphael Kellman, M.D.

• According 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, 2006

• Prevalence 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 DISORDERS

 • According 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 States

JAMA 297 (24): 2755- 9

EPIDEMIC TWOTHYROID DISEASE

According to the Colorado Thyroid Disease Prevalence Study in 2000• The 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 double

• 24% of women older than 60 have hypothyroidismG. Canaris et al

The Colorado Thyroid Disease Prevalence StudyArch Intern Med 2000; 160:526-534

•Thyroid cancer is rising in incidence faster than any other cancer in the United States•According to the NCI, thyroid cancer is increasing by 6.5% per year since 1997•Papillary carcinoma between 1999 and 2005, and 2003 and 2005 increased nearly 100%

Enewald V. et al

Rising Thyroid Cancer Incidence in the US by Demographic Tumor Characteristics 1980-2005

Cancer Epidemiology Biomarkers 2009; 18:784-791

•Increasing Incidence of elevated TSH levels in newborn screening in Northern England

Pearce MS et al

J. Thyroid Research, Jan 2010

•Thyroid auto-immune disease is the most common auto-immune disease 7-8% of the population, totaling 24 million

Dayan CM et al

Chronic Autoimmune Thyroiditis

New 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 million

NIH Autoimmune Coordinating Committee Autoimmune Research, 2005

US Dept. of Health and Human Services, NHI pub March 25

IS THE EPIDEMIC OF NEURO-DEVELOPMENTAL DISEASES LARGELY

REDUCIBLE TO A MORE PRIMARY DISORDER - HYPOTHYROIDISM?

•Many of the same chemicals that are associated with autism, also cause thyroid disease•Toxins thought to contribute to the development of autism and ASD mediate their effects via their adverse effects on the thyroid•Thyroid hormone known to play a critical role in orchestrating brain development•Thyroid dysfunction in utero, and neonates leads to many of the same symptoms associated with autism and ASD

EVIDENCE SUPPORTING THYROID-AUTISM CONNECTION

• Celiac disease/gluten intolerance is associated with hypothyroidism. Gluten-free diets known to help with autism, may mediate via its positive effects on the thyroid

• Autism and ASD frequently associated with auto-immune diseases. A percentage of thyroid disease is auto-immune in nature

• Mitochondrial dysfunction found to be associated with autism -hypothyroidism causes mitochondrial dysfunction

• Hypothyroidism contributes to methylation defects

THE CRITICAL ROLE OF THYROID HORMONEIN BRAIN DEVELOPMENT

Phase I• First trimester, before synthesis of fetal TH, fetus

dependent on maternal TH• Proliferation, migration and differentiation of neurons

that develop into the forebrain, orchestrated by TH

Phase II• Fetal TH production, some role of maternal TH• Proliferation, migration and differentiation of neurons

that develop into the cerebellum • Forebrain maturation and synapse formation• Orchestrated by TH

Phase III•After birth, continuation of proliferation, migration, and differentiation•Myelination, 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 conductor

S. 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

Low 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 dysfunction

 Zoeller RT et alTiming of Thyroid Hormone Function in the Developing Brain: Clinical

Observations and Experimental FindingsJ. Neuroendocrinol 16:809-818

HYPOTHYROXINEMIA 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 offspring

Lower performance in gross and fine motor coordinationLower performance in socialization

Delayed Neurobehavioral Development in Children Born to Pregnant Women with Mild Hypothyroxinemia During First Month of Gestation

The Importance of Early Iodine Supplementation

P.Berbel et al

Thyroid Number 6, December 19, 2009

Thyroid function can be damaged by the same toxins associated with autism and other developmental disorders:• PCBs• Dioxins• Perchlorate• Phthalates• PBDEs• Lead• Mercury• Cadmium• Insecticides• Bisphenol-A

P. LandriganCurr Opin Pediatr 2010

What Causes Autism? Exploring the Environmental Contribution

According to research reported in Digestive Diseases and Sciences:•  Gluten sensitivity/celiac disease associated with

thyroid disease• Celiac disease can play a role in the etiology of

thyroid disease“We 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 DISEASE

T4 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 MTHFR

J Cimino et alRiboflavin Metabolism in the Hypothyroid Newborn

American Journal of Clinical Nutrition 1988; 47: 481-483

HYPOTHYROIDISM ANDMETHYLATION PATHWAY DEFECTS

• Decreased NADH• Increased oxidative stress• Mitochondrial 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

Hypothyroidism 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 development

TH REGULATES MITOCHONDRIAL ACTIVITY

• Nuclear pathway• Direct mitochondrial pathway –stimulation of

mitochondrial genome transcription• Both pathways –mitochondriogenesis• Mitochondrial pathway involved in regulation of

cell differentiation• TH regulation of mitochondrial activity - link

between metabolism and developmentThyroid Hormone Action in Mitochondria

C. Wrutniak-Cabello et alJournal Molecular Endocrinology 2001; 26: 67-70

• Increased prevalence of familial autoimmune diseases in families of a child with autism

Comi 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 bands

• Hypothyroidism significantly increased in PDD families compared to autoimmune families

Sweeten TL et alPediatrics, Nov 2003, 112 (5) 420-426

AUTISM, ASD, PDDAND AUTOIMMUNE DISORDERS

WHAT IS THE CAUSE OFTHE EPIDEMIC OF THYROID

DISEASE?

THE ROLE OF ENDOCRINEDISRUPTING CHEMICALS

Endocrine 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”.

• Growing list of chemicals now known to disrupt body’s communication network

• Blocks or impersonate hormone messages • Scrambles messages• Sows 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 effects• Hormones, 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 child

ENDOCRINE DISRUPTOR THEORYGENERAL CONCEPTS

Toxicology II continued• Normal development depends on the right hormone

message at the right time and the right amount – chemical ballet

• Windows of vulnerability• Timing makes the poison

ENDOCRINE DISRUPTOR THEORYGENERAL CONCEPTS

“Thyroid system is one of the most frequent targets of synthetic chemicals”Linda Birnbaum; Director of Environmental Toxicology Division at the

US Environmental Protection Agency

ENDOCRINE DISRUPTORS AND ITS EFFECTS ON THE THYROID AND NEURO-DEVELOPMENT IN UTERO

TO FIRST TWO YEARS OF LIFE

Effects include:• Learning disabilities• Behavioral problems• Fine motor dysfunction• Poor response to stress• Attention problems and

hyperactivity• Language speech deficits• Social 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 Development

Environmental Health Perspectives,Vol 108 Supplement 3 June 2000

Other effects of thyroid disruption on neuro-development in infants and children:• Visuospatial deficits• Motor and visual motor delays• Decreased social and perceptual abilities• Decreased auditory discriminating abilities

JF Robet

Neurodevelopment in Infants and Preschool Children with Congenital Hypothyroidism

Etiological and Treatment Factors Affecting Outcome

Journal of Pediatric Psychology 1990, vol 17: 187-213

Wingspread Consensus Statement 1991“We 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 fish• Decreased fertility in birds, fish and mammals• Gross birth deformities in birds, fish and turtles• Behavioral abnormalities in animals

CHRONOLOGY OF KEY EVENTS IN THE DEVELOPMENT OF THE ENDOCRINE DISRUPTOR THEORY

May 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.”

• “The 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.”

August 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 disruptors

March 1996 publication of Our Stolen Future

THYROID DISRUPTING CHEMICALS

THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMS

CHEMICAL MECHANISM OF ACTION

SOURCE

PerchloratesBromatesThyocinatePhthalates

Blocks Iodide Uptake Blount BC 2007Crofton KM 2008

PCB’sPentachlorophenolFlame RetardantsPhthalates

Competitive Binding to Thyroid TransportProtein eg. TTR

Cheek D. 1999Whitefield GR 1999Purkey HR 2004Pluim J 1993

MancozebAmitroleBenzophenone

Blocks Production ofThyroid Hormone

Crofton KM 2008

THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMS

CHEMICAL MECHANISM OF ACTION

SOURCE

PCBsBisphenol AFlame RetardantsDioxinPhthalates

Binds to ThyroidReceptor

Boas M. 2006Shen O. 2009Moriyama 2002

LeadCadmiumFD&C Red Dye #3PCBsPBDEOctylmethoxycinnamateMercuryHCB

Inhibition of Deoidinases

Santini 2003Mori K. 2008Boas M. 2006Takser L 2005

THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMS

CHEMICAL MECHANISM OF ACTION

SOURCE

DDTPCBs

Binds to TSH Receptor

Santini F. 2003

AcetochlorPCBsPBDE

Enhanced Hepatic Metabolism

Hosokawa S. 1992Zhou T. 2001

PCB’sTCDDChlorinated PesticidesMercuryPBDE

Direct Toxic Effect onThyroid Gland

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

• Endocrine disruptors may have similar or different effects on the thyroid. This can create a cumulative and/or synergistic effect.

Crofton K.M. et al

Thyroid Hormone Disrupting Chemicals: Evidence for Dose Dependent Additivity or Synergism.

Environmental Health Perspectives

2005, 113; 1549-1554

“There 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.”

PCBs

“Growth 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 al

2006, vol. 154 Issue 5: 599-611

PCBs in maternal blood during pregnancy.•Negative correlation between maternal TT3 and PCBs, three pesticides (p-ṕ-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 Mercury

Environmental Health Perspective 113: 1039-1045 (2005)

•PCBs 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 al

PCB toxicity in children:•Positive correlation between PCB exposure and TSH levels.

Osius N et al

Exposure to PCB’s and Levels of Thyroid Hormones in Children.

Environmental Health Perspectives 1999. 107 843-849

Positive Association• Between PCB levels in breast milk and TSH levels in

infants• Koopman-Esseboom et al

Effects of Dioxins and Polychlorinated Biphenyls on Thyroid Hormone Status of Pregnant Women and Their Infants

Pediatric Research 36: 468-473, 1994

1971 Women in Taiwan consumed cooking oil contaminated with PCBs and furans

128 Children studied who were in womb:• Impairment in mental and motor abilities• Behavioral problems• Hyperactivity – Attention deficits

W Rogan et al

Congenital Poisoning by PCBs and Their Contaminants in Taiwan

Science 241: 334-336; 1998

Widespread and persistent and highly toxic environmental pollutants from:•Industrial burning processes•Production of herbicides

TCDD prototype and most toxic

DIOXINSPCDs AND PCDF

Single dose of TCDD in rats:•dose-dependently decreased T4 and free T4 and increased TSH

Viluksela M. et al

Tissue 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 T4•A two-fold increase in TSH•Hyperplasia of the thyroid gland

Nishimura N. Rat Thyroid Hyperplasia Induced by Gestational and Lactational Exposure to TCDD.

Endocrinology 2003; 144: 2075-2083

Large study of Vietnam veterans•Group with highest TCDD levels showed a significant increase in TSH

Pavuk M. et al

Serum TCDD Levels and Thyroid Function in Air Force Veterans of the Vietnam War.

Annals of Epidemiology 2003 13:335-343

PCBs and dioxins measured in human milk. Higher levels in human milk correlated significantly with:•Lower plasma levels of maternal TT3 and TT4•Higher 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.

•Inhibition 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 babies

Environmental Health Perspectives, vol 101 number 6 1993: 504-508

•PBDEs used as flame retardants in plastics, paints, electrical equipment and synthetic textiles•TBPH used in electrical equipment such as televisions, computers, copying machines and video displays

Commercial PBDE mixture DE-7:•Decreases levels of TH•Induces activity of hepatic enzymes UDPGT•High doses DE-7 causes histopathological changes

Zhou T. et al

Effects of Short-term in Vivo Exposure to Polybrominated Diphenyl Ethers (PBDE) Mixture on Thyroid Hormones and Hepatic Enzymes Activities in Weaning Rats

Toxicological Sciences 2001: 61; 26-82

FLAME RETARDANTS TBBPA AND PBDEs

•Maternal 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 EM

Maternal Residence Near Agricultural Pesticide Applications and ASD among Children in California of Central Valley

Environmental Health Perspectives 115 (10): 1482-1489

INSECTICIDES AND DEVELOPMENTAL DISORDERS

Neuro-developmental effects include:•Decreased psychomotor function•Decreased mental function: depressed memory, attention and verbal skills•Mechanism of action: thyroid disruption

Jurewicz J 2008: Prenatal and Childhood Exposure to Pesticides and Neurobehavioral Development: Review of Epidemiological Studies.

International Journal of Occupational Medicine. Environmental Health 21 (2): 121-132

Korrick S. et al

2008: PCBs Organochlorine Pesticides and Neuro-development

Current Open Pediatric 20 (two): 178-204

Ribas-Fito N et al

2006

In utero Exposure to Background Concentrations of DDT and Cognitive Functioning among Preschoolers

AM J P. Epidemiol 164:955-962

ORGANOCHLORINE PESTICIDES

•BPA levels correlated with increased weight of thyroid •Positive finding between increasing BPA and activity of hepatic enzyme UDPGT.

Tan BL et al

Assessment of Pubertal Development in Juvenile Male Rats after Sub-acute Exposure to Bisphenol and Nonylphenol

Toxicology letters 2003, 143; 261-270

BPA

BPA 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 effect

Endocrinology. 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 brain

Zoeller RT, Bansal R, Parris C.

Miodouinik A. et al

Neurotoxicology 2010 Dec 20

Mt. 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 awareness•Mechanism of action thyroid disruption

ENDOCRINE DISRUPTORS ANDCHILDHOOD SOCIAL IMPAIRMENT

Prenatal Phthalate exposure is associated with childhood behavior and executive function

S.M. Engel

Environmental Health Perspectives April 2010

Urine of mothers collected on third trimester from Mt. Sinai Environmental Health Study

Their children evaluated at ages 4-9 for behavioral issues and executive function

Phthalate levels correlate with poor executive function and decreased ability to:Control impulses

continuedTransition between situationsModulate emotional responsesInitiate a taskRetain information for task completionSet goals

ASSOCIATION BETWEEN

ORGANOCHLORINES AND ASDASD risk increase with poundage of

organochlorine applied and decreased with distance from field sites

Mechanism of action thyroid disruptionBinding of Gaba receptorsEstrogenic effects

Eric Roberts

Maternal Residence near Agricultural Pesticide Application and ASD among Children in the California Central Valley

Environmental Health Perspectives

2007 October: 115 (10):1482-1489

IODINE DEFICIENCY AS A CAUSE OF AUTISMIncrease incidence associated with increased

iodine deficiencyIodine necessary for TH production

BMJ

2004; 328:226

•If autism is an environmental disease, then based on the overwhelming evidence, hypothyroidism is likely to be a underlying metabolic state significantly contributing to its pathophysiology•Hypothyroxinemia 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 TOGETHER

continued•Reported 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 Agents-“The 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 autism

G Roman

Journal of the Neurological Sciences 262 (2007) 15-26

continued• Although the etiology of autism is multi-factorial, hypothyroidism at any point during neurodevelopment can be a central cause of autism•Therefore treating hypothyroidism place a vital role in the treatment of autism

IF THERE IS SUCH A PROFOUND THYROID-AUTISM CONNECTION,WHY IS IT NOT BEING DETECTED

BY ROUTINE BLOOD TESTS?

Studies are revealing the complexity of the ways in which endocrine disruptors may interfere with TH signaling

Some endocrine disruptors can cause decreased T4 and yet normal TSH

Other endocrine disruptors due to its effects on receptors can cause increased T4 and TSH normal or slightly increased

Endocrine disruptors can also affect diodinase, for example organochlorines can cause over-expression of D3 causing high reverse T3 and low T3

continuedThe 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 revealing

“The 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 population”

Thomas Zoeller

Environmental Chemicals Targeting Thyroid

Hormones 2010, 9 (1): 28-40

TSH VALUES ARE OFTEN UNRELIABLE AND MISLEADING AND MAY NOT ADEQUATELY

REPRESENT THYROID STATUSBiologic variation is important for interpretation of

thyroid function testsS.Anderson et al

Thyroid, Vol 13 number 11 2007

Individual set point for normal thyroid function-unique for each individual

“Some 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 individual”

“Subclinical thyroid disease may be defined in purely biochemical terms…under 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.”

Many studies shed doubt on validity of reference range of TSH

Subclinical 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 al

Int. J Cardiol 2007

Treatment of patients with subclinical hypothyroidism and hyperlipidemia with thyroid hormone resulted in significant reduction in LDL cholesterol and improved endothelial function.

Razvi S et al

Endocrinol Metab 2007; 92:1715-1723

Depressed patients with normal TSH could have an exaggerated response to TRH

Kraus RP et al

Exaggerated TSH Response to TRH in Depressed Patients with “Normal Baseline” TSH

J 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 al

Sub-biochemical Hypothyroidism: An Exaggerated TSH response to TRH

J Assoc Physicians India 1999; 47:275-279

Landmark 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

continued

seldom 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 al

Clinical Medicine and Research Volume 8 Number 3 145-148

Dr. 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 hypothyroidism

DeRosa et al

Comparison between TRH Stimulation Test and Basal TSH Measurement by a Commercial Immunoradiometric Assay in the Management of Thyroid Disease

J. Nucl Med 1996; 40:182-187

Subclinical Hypothyroidism in Infertile Women the Importance of Continuous Monitoring and the Role of Thyrotropin Releasing Hormone Stimulation Test

T. Ldar-Geva et al

Journal of Clinical Endocrinology June 2007; 23 (6):332-337

87 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%

Baseline-Individual set point normal TSH and TH, TRH test normal

Stage 1: Normal T4, TSH slightly above patients individual’s 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”

My Findings Based on the Use of the TRH Stimulation Test:Approximately 70% of children with autism, ASD

and other neuro-developmental disorders have hypothyroidism

Most 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

MY 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, DHA- Phosphatidyl Serine, Choline- CDP Choline- GPC- Galantamine- Carnosine

continued- Aniracetam- Melatonin- Gaba- Huperizine- Vinpocitene- Inositol- Amyloban- etc

b. Hyperbaric Oxygen Therapy

Immune Modulation

Anti-inflammatory compounds: Curcumin Boswellia Luteolin Transfer-factors Glutathione LDN Liposomal Vitamin C Lipoic Acid etc

Methylation Pathway Improvement Vitamin B6- P5P Folinic Acid MB12 / Glutathione Taurine Creatine etc

Mitochondrial Repair NADH Ubiquinol A.L. – Carnitine PQQ

Detoxification Clay baths Chelation Infrared sauna Liver detoxification

Infectious Disease GI bacterial infections Lyme disease Strep Viral infections

Dietary Changes GF/Diet Remove allergens

Implications for the Treatment and Prevention of Neuro-Developmental Disorders

All children with neurodevelopment disorders should be tested with the TRH stimulation test

Mothers of such children should be tested with the TRH stimulation test

Women should be tested with the TRH stimulation test before pregnancy

All pregnant mothers should take Iodine 250mcg p/day

continuedWe 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 damage

We 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

SummaryThyroid-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 neonates

First to connect endocrine disruptors to autism and ASD

continuedTRH 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.

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