thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development
DESCRIPTION
Iodine deficiency adversely effects fetal brain development via the actions of prenatal thyroid hormone levelsTRANSCRIPT
Thyroid hormone and the brain: Thyroid hormone and the brain: understanding the effects of understanding the effects of
iodine deficiency on brain iodine deficiency on brain developmentdevelopment
1111thth World Hellenic Biomedical Congress World Hellenic Biomedical Congress
Laconia, GreeceLaconia, Greece
Wednesday 21Wednesday 21stst May May
Professor Steven C. BoyagesProfessor Steven C. Boyages
Westmead HospitalWestmead Hospital
The university of Sydney, AustraliaThe university of Sydney, Australia
Early recognition of goitre with Early recognition of goitre with impaired mental abilityimpaired mental ability
"Hence while travelling in a "Hence while travelling in a certain region in the County certain region in the County Tyrol, under the jurisdiction of Tyrol, under the jurisdiction of the Bishop of Gurk, I was the Bishop of Gurk, I was astonished at the very large astonished at the very large number of number of madmen, fools and madmen, fools and doltsdolts; but when I considered ; but when I considered the frigidity and the humidity the frigidity and the humidity of the air, and also perceived of the air, and also perceived the crudity of the waters from the crudity of the waters from the very frequent occurrence the very frequent occurrence of of goitregoitre... all astonishment ... all astonishment ceased entirely." ceased entirely."
EUSTACHIUS RUDIUS, A EUSTACHIUS RUDIUS, A PHYSICIAN FROM UTRECHTPHYSICIAN FROM UTRECHT
(1551-1611)(1551-1611)
Iodine Deficiency DisordersIodine Deficiency DisordersSIGNIFICANCESIGNIFICANCE
One of the commonest nutritional disordersOne of the commonest nutritional disorders Over 1 billion people live in deficient Over 1 billion people live in deficient
environmentsenvironments Affects primarily the thyroid but secondarily Affects primarily the thyroid but secondarily
may impact on brain developmentmay impact on brain development Most preventable cause of mental Most preventable cause of mental disabilitydisability Not limited to developing countriesNot limited to developing countries Principles of food fortification to populationsPrinciples of food fortification to populations Structural basis of scientific thinking (Kuhn)Structural basis of scientific thinking (Kuhn)
OutlineOutline
Nutritional DisordersNutritional Disorders Principles of thyroid physiologyPrinciples of thyroid physiology Iodine physiologyIodine physiology What is a normal iodine level?What is a normal iodine level? How do we adapt to iodine deficiency?How do we adapt to iodine deficiency? Iodine Deficiency DisordersIodine Deficiency Disorders Are we at risk?Are we at risk?
Nutrition Related DisordersNutrition Related Disorders
MicronutritionMicronutritionUndernutrition PCMUndernutrition PCM
Minerals and VitaminsMinerals and VitaminsFolic AcidFolic Acid
Vitamin D deficiencyVitamin D deficiencyVitamin A deficiencyVitamin A deficiency
Fe deficiencyFe deficiencySelenium deficiencySelenium deficiency
Iodine deficiencyIodine deficiency
MicronutritionMicronutritionUndernutrition PCMUndernutrition PCM
Minerals and VitaminsMinerals and VitaminsFolic AcidFolic Acid
Vitamin D deficiencyVitamin D deficiencyVitamin A deficiencyVitamin A deficiency
Fe deficiencyFe deficiencySelenium deficiencySelenium deficiency
Iodine deficiencyIodine deficiency
MacronutritionMacronutritionObesityObesity
HyperlipidemiaHyperlipidemiaInsulin ResistanceInsulin Resistance
DiabetesDiabetesAlcoholAlcohol
MacronutritionMacronutritionObesityObesity
HyperlipidemiaHyperlipidemiaInsulin ResistanceInsulin Resistance
DiabetesDiabetesAlcoholAlcohol
Thyroid PhysiololgyThyroid Physiololgy
Thyroid Function TestsThyroid Function Tests
TSH, direct measure of thyroid TSH, direct measure of thyroid hormone actionhormone action– Different types of thyroid hormone Different types of thyroid hormone
receptorsreceptors Free T4, estimatesFree T4, estimates Free T3, estimatesFree T3, estimates
Iodine is essential for normal Iodine is essential for normal thyroid hormone synthesisthyroid hormone synthesis
Na Iodide TransporterNa Iodide Transporter
OutlineOutline
Nutritional DisordersNutritional Disorders Principles of thyroid physiologyPrinciples of thyroid physiology Iodine physiologyIodine physiology What is a normal iodine level?What is a normal iodine level? How do we adapt to iodine deficiency?How do we adapt to iodine deficiency? Iodine Deficiency DisordersIodine Deficiency Disorders Are we at risk?Are we at risk?
What is normal intake?What is normal intake?Too little and Too much can be Too little and Too much can be
a problema problem
Recommended intakesRecommended intakes
The American Thyroid Association has recently recommended that all women receive 150 µg iodine supplements above their dietary intake during pregnancy and lactation, and that the iodine content in all prenatal vitamins should be standardized at 150 µg
The American Thyroid Association has recently recommended that all women receive 150 µg iodine supplements above their dietary intake during pregnancy and lactation, and that the iodine content in all prenatal vitamins should be standardized at 150 µg
Sources of iodineSources of iodine
SaltSalt MilkMilk BreadBread Other foods, eg kelp, seaweed, laverOther foods, eg kelp, seaweed, laver MedicationsMedications
Sources of iodineSources of iodine Dietary iodine Daily intake (µg)Dietary iodine Daily intake (µg) Dairy products Dairy products 5252 GrainsGrains 7878 Meat Meat 3131 Mixed dishes Mixed dishes 2626 Vegetables Vegetables 2020 Desserts Desserts 2020 Eggs Eggs 1010 Iodized salt Iodized salt 380380 Other iodine sourcesOther iodine sources(µg)(µg) Vitamin/mineral prep (per tablet) Vitamin/mineral prep (per tablet) 150150 Amiodarone (per tablet) Amiodarone (per tablet) 75,00075,000 Povidone iodine (per mL) Povidone iodine (per mL) 10,00010,000 Ipodate (per capsule) Ipodate (per capsule) 308,000308,000
OutlineOutline
Nutritional DisordersNutritional Disorders Principles of thyroid physiologyPrinciples of thyroid physiology Iodine physiologyIodine physiology What is a normal iodine level?What is a normal iodine level? How do we adapt to iodine deficiency?How do we adapt to iodine deficiency? Iodine Deficiency DisordersIodine Deficiency Disorders Are we at risk?Are we at risk?
Endemic GoitreEndemic Goitre
Adaptation to iodine deficiencyAdaptation to iodine deficiency
OutlineOutline Nutritional DisordersNutritional Disorders Principles of thyroid physiologyPrinciples of thyroid physiology Iodine physiologyIodine physiology What is a normal iodine level?What is a normal iodine level? How do we adapt to iodine deficiency?How do we adapt to iodine deficiency? Iodine Deficiency DisordersIodine Deficiency Disorders
– Iodine and brain damageIodine and brain damage Are we at risk?Are we at risk?
Iodine Deficiency DisordersIodine Deficiency Disorders
Iodine Deficiency Disorders (IDD) refers to all of the ill effects of iodine deficiency in a population that can be prevented by ensuring that the population has an adequate intake of iodine
Iodine DeficiencyIodine Deficiency
Iodine deficiency at critical stages during pregnancy and early childhood results in impaired development of the brain and consequently in impaired mental function.
Model of prenatal thyroid hormone Model of prenatal thyroid hormone action on fetal brain developmentaction on fetal brain development
Iodine Deficiency DisordersIodine Deficiency Disorders
ThyroidThyroid Mild to ModerateMild to Moderate
– Thyroid autonomyThyroid autonomy– Nodular thyroid Nodular thyroid
diseasedisease– GoitreGoitre– Thyroid MalignancyThyroid Malignancy
BrainBrain SevereSevere
– Endemic cretinismEndemic cretinism– DeafnessDeafness– Subclinical deafnessSubclinical deafness– intellectual intellectual
disabilitydisability– ?Attention deficits?Attention deficits– ? Colour perception ? Colour perception
deficitsdeficitsIodine Deficiency Disorders (IDD)Iodine Deficiency Disorders (IDD)1000 million people at risk for 1000 million people at risk for
the development of IDDthe development of IDD
Iodine Deficiency Disorders (IDD)Iodine Deficiency Disorders (IDD)1000 million people at risk for 1000 million people at risk for
the development of IDDthe development of IDD
Endemic CretinismEndemic Cretinism
Occurs in areas of Occurs in areas of severe iodine severe iodine deficiency and deficiency and almost universal almost universal endemic goitreendemic goitre
Geographic Geographic clusteringclustering
Two predominant Two predominant clinical phenotypesclinical phenotypes
Endemic Cretinism: Clinical Endemic Cretinism: Clinical PhenotypesPhenotypes
NeurologicalNeurological– EuthyroidEuthyroid– GoitrousGoitrous– Severe mental Severe mental
disabilitydisability– DeafnessDeafness– Neurological Neurological
abnormalitiesabnormalities– More frequentMore frequent
MyxedematousMyxedematous– HypothyroidHypothyroid– Thyroid atrophyThyroid atrophy– Severe mental Severe mental
disabilitydisability– DeafnessDeafness– Neurological Neurological
abnormalitiesabnormalities– Less frequentLess frequent
HypothesisHypothesis
That a combination of maternal and That a combination of maternal and fetal hypothyroidism accounts for the fetal hypothyroidism accounts for the neurological manifestations of neurological manifestations of endemic cretinism; ipsi facto all endemic cretinism; ipsi facto all cretins should display evidence of cretins should display evidence of neurological damageneurological damage
That postnatal factors determine the That postnatal factors determine the final “phenotypic” appearancefinal “phenotypic” appearance
Findings: Neurological FeaturesFindings: Neurological Features
We found a similar pattern of neurological We found a similar pattern of neurological involvement in nearly all cretins from both involvement in nearly all cretins from both endemias, regardless of type (myxoedematous or endemias, regardless of type (myxoedematous or neurological), and of current thyroid functionneurological), and of current thyroid function
Characteristic and specificCharacteristic and specific Mental retardationMental retardation DeafnessDeafness Pyramidal disturbancePyramidal disturbance Extrapyramidal dysfunctionExtrapyramidal dysfunction Gait disorderGait disorder
– Halpern JP, Boyages SC et al; Brain Halpern JP, Boyages SC et al; Brain Brain, Vol 114, Issue 2 825-Brain, Vol 114, Issue 2 825-841, Copyright © 1991 by Oxford University Press 841, Copyright © 1991 by Oxford University Press
Neuroimaging: CT scanningNeuroimaging: CT scanning
Cerebral CT scanning demonstrated only Cerebral CT scanning demonstrated only minor abnormalities which did not minor abnormalities which did not contribute to the localization of the clinical contribute to the localization of the clinical deficitsdeficits
DiffuseDiffuse CT scanning in the majority of cretins was CT scanning in the majority of cretins was
normalnormal Basal ganglia calcification (15 of 50)Basal ganglia calcification (15 of 50) Cochlear malformation (petrous temporal Cochlear malformation (petrous temporal
bone)bone)
The pattern of neurological The pattern of neurological damage reflects time and damage reflects time and
regional sensitivity to regional sensitivity to thyroid hormone deficiencythyroid hormone deficiency
Damage to:Damage to:– CochleaCochlea– Cerebral cortexCerebral cortex– Basal gangliaBasal ganglia– Disordered thalamic projectionsDisordered thalamic projections
Mechanism of damageMechanism of damage Thyroid hormone is essential for normal Thyroid hormone is essential for normal
brain gene expressionbrain gene expression– NeurogenesisNeurogenesis– MyelinationMyelination– MigrationMigration– DifferentiationDifferentiation
Classical sensitive window in the Classical sensitive window in the developing braindeveloping brain
Timing and Region dependent gradient of Timing and Region dependent gradient of sensitivitysensitivity
Postnatal thyroid function Postnatal thyroid function modifies the clinical phenotypemodifies the clinical phenotype Neurological cretinsNeurological cretins
– GoitrousGoitrous
Myxoedematous Myxoedematous cretinscretins– Thyroid atrophyThyroid atrophy
Exhaustion atrophyExhaustion atrophy Goitrogenic effect eg SCNGoitrogenic effect eg SCN Selenium deficiencySelenium deficiency Autoimmune effect, blocking antibodiesAutoimmune effect, blocking antibodies Combination of factorsCombination of factors
Brain Damage: Shift in the IQ Brain Damage: Shift in the IQ distribution to the leftdistribution to the left
The neurological sequelae are not an all or The neurological sequelae are not an all or none phenomenonnone phenomenon
The population distribution of cognitive The population distribution of cognitive function shows a marked shift to the left function shows a marked shift to the left towards lower IQ scorestowards lower IQ scores
10 to 15 IQ points10 to 15 IQ points
20-2
9
30-3
9
40-4
9
50-5
9
60-6
9
70-7
9
80-8
9
90-9
9
100-
109
110-
119
120-
129
130-
139
140-
149
0
10
20
Iodine deficient (pre-prophylaxis)
Rural control (old)
City controls
City controls
Intelligence Quotient (IQ)
Frequency (%)
BEFORE IODISEDSALT PROPHYLAXIS
Timing of insultTiming of insult
Timing of Timing of insultinsult
PrenatalPrenatal PostnatalPostnatal
TargetTarget Fetal brainFetal brain
Fetal thyroidFetal thyroid
Maternal Maternal thyroidthyroid
Child and Child and AdultAdult
ThyroidThyroid
OutcomeOutcome Endemic Endemic cretinismcretinism
Impaired IQImpaired IQ
Endemic Endemic GoitreGoitre
Short Short StatureStature
Normal
Maternal
Hypothyroidism
Sporadic
cretinism
Sporadic
cretinism (TBII
positive)
Endemic
cretinism
Normal
Normal
Normal
Normal
Maternal Thyroid
FunctionFoetal Thyroid
FunctionNeurological
Outcome
Normal
? Normal
? Normal
Severe deficit
Severe deficit
CONCLUSIONCONCLUSION
Thyroid hormone is essential for Thyroid hormone is essential for normal somatic and neurological normal somatic and neurological development. development.
Iodine deficiency leads to thyroid Iodine deficiency leads to thyroid hormone deficiency at critical periods hormone deficiency at critical periods of brain development that leads to of brain development that leads to irreversible neurological damage.irreversible neurological damage.
Prevention of iodine deficiency is Prevention of iodine deficiency is essentialessential
AcknowledgementsAcknowledgements AustraliaAustralia
– CJ EastmanCJ Eastman– JP HalpernJP Halpern– John K CollinsJohn K Collins– Li MuLi Mu
ChinaChina IndonesiaIndonesia The NetherlandsThe Netherlands
– Hemmo DrexhageHemmo Drexhage USA, AtlantaUSA, Atlanta
– GF MaberlyGF Maberly Italy, PisaItaly, Pisa
– Alessandro AntonelliAlessandro Antonelli