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Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Oct 30, 2014

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Iodine deficiency adversely effects fetal brain development via the actions of prenatal thyroid hormone levels
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Page 1: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development
Page 2: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 3: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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)

Page 4: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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)

Page 5: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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?

Page 6: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 7: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Thyroid PhysiololgyThyroid Physiololgy

Page 8: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 9: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Iodine is essential for normal Iodine is essential for normal thyroid hormone synthesisthyroid hormone synthesis

Page 10: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Na Iodide TransporterNa Iodide Transporter

Page 11: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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?

Page 12: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 13: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 14: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Sources of iodineSources of iodine

SaltSalt MilkMilk BreadBread Other foods, eg kelp, seaweed, laverOther foods, eg kelp, seaweed, laver MedicationsMedications

Page 15: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 16: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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?

Page 17: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Endemic GoitreEndemic Goitre

Page 18: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

Adaptation to iodine deficiencyAdaptation to iodine deficiency

Page 19: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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?

Page 20: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 21: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 22: Thyroid hormone and the brain: understanding the effects of iodine deficiency on 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

Page 23: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 24: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 25: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 26: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development
Page 27: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 28: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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)

Page 29: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 30: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 31: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 32: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 33: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 34: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 35: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 36: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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

Page 37: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development
Page 38: Thyroid hormone and the brain: understanding the effects of iodine deficiency on brain development

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