Download THE THYROID AUTISM CONNECTION pp (1)

by Raphael Kellman, M.D.
EPIDEMIC ONE
AUTISM AND NEURO-DEVELOPMENTAL DISORDERS
•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 al
2007 Lifetime Prevalence of Learning Disability among US Children, 119; 77-83
•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 Children
Pediatrics 93 (3): 399-403
•According to an article in JAMA in 2007 developmental
disorders and chronic conditions in general is on the
rise.
Perrin JM
The Increase of Childhood Chronic Conditions in the United States
JAMA 297 (24): 2755- 9
EPIDEMIC TWO
THYROID 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 hypothyroidism
G. Canaris et al
The Colorado Thyroid Disease Prevalence Study
Arch 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 NEURODEVELOPMENTAL DISEASES LARGELY
REDUCIBLE TO A MORE PRIMARY
DISORDER - HYPOTHYROIDISM?
EVIDENCE SUPPORTING THYROID-AUTISM CONNECTION
•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
•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 HORMONE
IN 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 neurodevelopmental 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 al
Timing of Thyroid Hormone Function in the Developing Brain: Clinical
Observations and Experimental Findings
J. Neuroendocrinol 16:809-818
HYPOTHYROXINEMIA IN PREGNANCY AND NEURODEVELOPMENTAL DYSFUNCTION IN CHILDREN
 Children of mothers with low normal T4 (T4-0-10th
percentile) due to iodine deficiency from early
gestation to birth increases the risk of neurodevelopmental delay in their offspring
 Lower performance in gross and fine motor
coordination
 Lower 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. Landrigan
Curr Opin Pediatr 2010
What Causes Autism? Exploring the Environmental Contribution
HYPOTHYROIDISM AND
GLUTEN INTOLERANCE/CELIAC DISEASE
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 Sciences
February 2000; 45:403-406
HYPOTHYROIDISM AND
METHYLATION PATHWAY DEFECTS
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 al
Riboflavin Metabolism in the Hypothyroid Newborn
American Journal of Clinical Nutrition 1988; 47: 481-483
MITOCHONDRIAL DYSFUNCTION IN AUTISM
•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
Hypothyroidism Alters Mitochondrial Morphology
and Induces Release of Apoptogenic Proteins
R. Singh
J 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 development
Thyroid Hormone Action in Mitochondria
C. Wrutniak-Cabello et al
Journal Molecular Endocrinology 2001; 26: 67-70
AUTISM, ASD, PDD
AND AUTOIMMUNE DISORDERS
•Increased prevalence of familial autoimmune diseases
in families of a child with autism
Comi Am et al
J. 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 al
Pediatrics, Nov 2003, 112 (5) 420-426
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”.
ENDOCRINE DISRUPTOR THEORY
GENERAL CONCEPTS
•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 poison
Toxicology II – Endocrine disrupting chemicals
Plays 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 THEORY
GENERAL 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
“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. Porterfield
Vulnerability of Developing Brain to
Thyroid Abnormalities
Environmental Insults to the Thyroid
Systems
Environmental Health Perspectives 1994,
102 (2): 125-130
S. Porterfield
Thyroidal Dysfunction and Environmental
Chemicals-Potential Impact on Brain
Development
Environmental Health Perspectives,
Vol 108 Supplement 3 June 2000
Other effects of thyroid disruption on neurodevelopment 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
CHRONOLOGY OF KEY EVENTS IN THE DEVELOPMENT OF
THE ENDOCRINE DISRUPTOR THEORY
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
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 passed
Requires 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
MUTIPLE MECHANISMS
CHEMICAL
MECHANISM OF
ACTION
SOURCE
Perchlorates
Bromates
Thyocinate
Phthalates
Blocks Iodide Uptake
Blount BC 2007
Crofton KM 2008
PCB’s
Pentachlorophenol
Flame Retardants
Phthalates
Competitive Binding to
Thyroid Transport
Protein eg. TTR
Cheek D. 1999
Whitefield GR 1999
Purkey HR 2004
Pluim J 1993
Mancozeb
Amitrole
Benzophenone
Blocks Production of
Thyroid Hormone
Crofton KM 2008
THYROID DISRUPTING CHEMICALS
MUTIPLE MECHANISMS
CHEMICAL
MECHANISM OF
ACTION
SOURCE
PCBs
Bisphenol A
Flame Retardants
Dioxin
Phthalates
Binds to Thyroid
Receptor
Boas M. 2006
Shen O. 2009
Moriyama 2002
Lead
Cadmium
FD&C Red Dye #3
PCBs
PBDE
Octylmethoxycinnamate
Mercury
HCB
Inhibition of
Deoidinases
Santini 2003
Mori K. 2008
Boas M. 2006
Takser L 2005
THYROID DISRUPTING CHEMICALS
MUTIPLE MECHANISMS
CHEMICAL
MECHANISM OF
ACTION
SOURCE
DDT
PCBs
Binds to TSH Receptor
Santini F. 2003
Acetochlor
PCBs
PBDE
Enhanced Hepatic
Metabolism
Hosokawa S. 1992
Zhou T. 2001
PCB’s
TCDD
Chlorinated Pesticides
Mercury
PBDE
Direct Toxic Effect on
Thyroid Gland
Ness DK 1993
Porterfield S. 1994
Takser L. 2005
Zhou 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
PCBs
“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.”
“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
DIOXINS
PCDs AND PCDF
Widespread and persistent and highly toxic
environmental pollutants from:
•Industrial burning processes
•Production of herbicides
TCDD prototype and most toxic
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 al
Effects of dioxins on the thyroid function in newborn babies
Environmental Health Perspectives, vol 101 number 6 1993: 504-508
FLAME RETARDANTS TBBPA AND PBDEs
•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
INSECTICIDES AND DEVELOPMENTAL DISORDERS
•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
ORGANOCHLORINE PESTICIDES
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
BPA
•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 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.
ENDOCRINE DISRUPTORS AND
CHILDHOOD SOCIAL IMPAIRMENT
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
 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
continued
 Transition between situations
 Modulate emotional responses
 Initiate a task
 Retain information for task completion
 Set goals
ASSOCIATION BETWEEN
ORGANOCHLORINES AND ASD
 ASD risk increase with poundage of
organochlorine applied and decreased with
distance from field sites
 Mechanism of action thyroid disruption
 Binding of Gaba receptors
 Estrogenic 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 AUTISM
 Increase incidence associated with increased
iodine deficiency
 Iodine necessary for TH production
BMJ
2004; 328:226
PUTTING THE PIECES TOGETHER
•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 subbiochemical maternal hypothyroidism that either
preceded pregnancy or developed subsequently
due to the excessive need of TH and/or to a
decrease in available iodine
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 antithyroid 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
continued
 The complex effect of EDCs have on the HPT access
can elude routine thyroid blood tests
 A 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 STATUS
 Biologic variation is important for interpretation of
thyroid function tests
S.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 brain
 Adult 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% sensitivity
 In 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 – 1.87
Group one: 39 women ovulation disorders, PCOS
Group two: 48 women normal ovulation
Abnormal 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 test
 Stage 2: gradual elevations of TSH
 Researchers 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 test
 Profound improvement with thyroid hormone
treatment, some complete recovery
 Many mothers of such children show biochemical evidence of hypothyroidism
 If hypothyroidism is confirmed TH is the most
effective known treatment for autism
MY APPROACH TO THE TREATMENT OF AUTISM,
ASD AND NEURO-DEVELOPMENTAL DISORDERS
 TRH stimulation test thyroid hormone treatment
 Provide 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
continued
 We 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
Summary
Thyroid-Autism connection and the role of
endocrine disruptors:
 Reduces a variety of medical disorders and
epidemics to a more primary problem
 Provides a deeper explanation for the known
likely causes of autism
 Proves 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
continued
 TRH stimulation test detects hypothyroidism in
children with autism missed by routine test.
 When diagnosed with hypothyroidism, thyroid
hormone is the most effective treatment for autism
 TH 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 neurodevelopment we can also significantly reduce the
incidence of neuro-developmental disorders in the
future.
Message of Hope
We can change the course of autism and neurodevelopmental disorders by understanding and
treating a deeper cause so often missed.