Iodine deficiency adversely effects fetal brain development via the actions of prenatal thyroid hormone levels

2. Thyroid hormone and the brain:Thyroid hormone and the brain:
understanding the effects ofunderstanding the effects of
iodine deficiency on brainiodine deficiency on brain
developmentdevelopment
1111thth
World Hellenic Biomedical CongressWorld Hellenic Biomedical Congress
Laconia, GreeceLaconia, Greece
Wednesday 21Wednesday 21stst
MayMay
Professor Steven C. BoyagesProfessor Steven C. Boyages
Westmead HospitalWestmead Hospital
The university of Sydney, AustraliaThe university of Sydney, Australia

3. Early recognition of goitre withEarly recognition of goitre with
impaired mental abilityimpaired mental ability
"Hence while travelling in a"Hence while travelling in a
certain region in the Countycertain region in the County
Tyrol, under the jurisdictionTyrol, under the jurisdiction
of the Bishop of Gurk, I wasof the Bishop of Gurk, I was
astonished at the very largeastonished at the very large
number ofnumber of madmen, fools andmadmen, fools and
doltsdolts; but when I considered; but when I considered
the frigidity and the humiditythe frigidity and the humidity
of the air, and also perceivedof the air, and also perceived
the crudity of the watersthe crudity of the waters
from the very frequentfrom the very frequent
occurrence ofoccurrence of goitregoitre... all... all
astonishment ceasedastonishment ceased
entirely."entirely."
 EUSTACHIUS RUDIUS, AEUSTACHIUS RUDIUS, A
PHYSICIAN FROM UTRECHTPHYSICIAN FROM UTRECHT
 (1551-1611)(1551-1611)

4. Iodine Deficiency DisordersIodine Deficiency Disorders
SIGNIFICANCESIGNIFICANCE
 One of the commonest nutritional disordersOne of the commonest nutritional disorders
 Over 1 billion people live in deficientOver 1 billion people live in deficient
environmentsenvironments
 Affects primarily the thyroid but secondarilyAffects primarily the thyroid but secondarily
may impact on brain developmentmay impact on brain development
 Most preventable cause of mentalMost 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)

5. 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?

6. Nutrition Related DisordersNutrition Related Disorders
MicronutritionMicronutrition
Undernutrition PCMUndernutrition PCM
Minerals and VitaminsMinerals and Vitamins
Folic AcidFolic Acid
Vitamin D deficiencyVitamin D deficiency
Vitamin A deficiencyVitamin A deficiency
Fe deficiencyFe deficiency
Selenium deficiencySelenium deficiency
Iodine deficiencyIodine deficiency
MicronutritionMicronutrition
Undernutrition PCMUndernutrition PCM
Minerals and VitaminsMinerals and Vitamins
Folic AcidFolic Acid
Vitamin D deficiencyVitamin D deficiency
Vitamin A deficiencyVitamin A deficiency
Fe deficiencyFe deficiency
Selenium deficiencySelenium deficiency
Iodine deficiencyIodine deficiency
MacronutritionMacronutrition
ObesityObesity
HyperlipidemiaHyperlipidemia
Insulin ResistanceInsulin Resistance
DiabetesDiabetes
AlcoholAlcohol
MacronutritionMacronutrition
ObesityObesity
HyperlipidemiaHyperlipidemia
Insulin ResistanceInsulin Resistance
DiabetesDiabetes
AlcoholAlcohol

7. Thyroid PhysiololgyThyroid Physiololgy

8. Thyroid Function TestsThyroid Function Tests
 TSH, direct measure of thyroidTSH, direct measure of thyroid
hormone actionhormone action
– Different types of thyroid hormoneDifferent types of thyroid hormone
receptorsreceptors
 Free T4, estimatesFree T4, estimates
 Free T3, estimatesFree T3, estimates

9. Iodine is essential for normalIodine is essential for normal
thyroid hormone synthesisthyroid hormone synthesis

10. Na Iodide TransporterNa Iodide Transporter

11. 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?

12. What is normal intake?What is normal intake?
Too little and Too much can be aToo little and Too much can be a
problemproblem

13. 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

14. Sources of iodineSources of iodine
 SaltSalt
 MilkMilk
 BreadBread
 Other foods, eg kelp, seaweed, laverOther foods, eg kelp, seaweed, laver
 MedicationsMedications

15. Sources of iodineSources of iodine
 Dietary iodine Daily intake (µg)Dietary iodine Daily intake (µg)
 Dairy productsDairy products 5252
 GrainsGrains 7878
 MeatMeat 3131
 Mixed dishesMixed dishes 2626
 VegetablesVegetables 2020
 DessertsDesserts 2020
 EggsEggs 1010
 Iodized saltIodized 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

16. 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?

17. Endemic GoitreEndemic Goitre

18. Adaptation to iodine deficiencyAdaptation to iodine deficiency

19. 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?

20. 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

21. 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 hormoneModel of prenatal thyroid hormone
action on fetal brain developmentaction on fetal brain development

22. Iodine Deficiency DisordersIodine Deficiency Disorders
 ThyroidThyroid
 Mild to ModerateMild to Moderate
– Thyroid autonomyThyroid autonomy
– Nodular thyroidNodular thyroid
diseasedisease
– GoitreGoitre
– Thyroid MalignancyThyroid Malignancy
 BrainBrain
 SevereSevere
– Endemic cretinismEndemic cretinism
– DeafnessDeafness
– Subclinical deafnessSubclinical deafness
– intellectual disabilityintellectual disability
– ?Attention deficits?Attention deficits
– ? Colour perception? Colour perception
deficitsdeficits
Iodine Deficiency Disorders (IDD)Iodine Deficiency Disorders (IDD)
1000 million people at risk for the1000 million people at risk for the
development of IDDdevelopment of IDD

23. Endemic CretinismEndemic Cretinism
 Occurs in areas ofOccurs in areas of
severe iodinesevere iodine
deficiency anddeficiency and
almost universalalmost universal
endemic goitreendemic goitre
 GeographicGeographic
clusteringclustering
 Two predominantTwo predominant
clinical phenotypesclinical phenotypes

24. Endemic Cretinism: ClinicalEndemic Cretinism: Clinical
PhenotypesPhenotypes
 NeurologicalNeurological
– EuthyroidEuthyroid
– GoitrousGoitrous
– Severe mentalSevere mental
disabilitydisability
– DeafnessDeafness
– NeurologicalNeurological
abnormalitiesabnormalities
– More frequentMore frequent
 MyxedematousMyxedematous
– HypothyroidHypothyroid
– Thyroid atrophyThyroid atrophy
– Severe mentalSevere mental
disabilitydisability
– DeafnessDeafness
– NeurologicalNeurological
abnormalitiesabnormalities
– Less frequentLess frequent

25. HypothesisHypothesis
 That a combination of maternal andThat a combination of maternal and
fetal hypothyroidism accounts for thefetal hypothyroidism accounts for the
neurological manifestations of endemicneurological manifestations of endemic
cretinism; ipsi facto all cretins shouldcretinism; ipsi facto all cretins should
display evidence of neurological damagedisplay evidence of neurological damage
 That postnatal factors determine theThat postnatal factors determine the
final “phenotypic” appearancefinal “phenotypic” appearance

27. Findings: Neurological FeaturesFindings: Neurological Features
 We found a similar pattern of neurological involvementWe found a similar pattern of neurological involvement
in nearly all cretins from both endemias, regardless ofin nearly all cretins from both endemias, regardless of
type (myxoedematous or neurological), and of currenttype (myxoedematous or neurological), and of current
thyroid functionthyroid 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; BrainHalpern JP, Boyages SC et al; Brain Brain, Vol 114, Issue 2 825-841,Brain, Vol 114, Issue 2 825-841,
Copyright © 1991 by Oxford University PressCopyright © 1991 by Oxford University Press

28. Neuroimaging: CT scanningNeuroimaging: CT scanning
 Cerebral CT scanning demonstrated only minorCerebral CT scanning demonstrated only minor
abnormalities which did not contribute to theabnormalities which did not contribute to the
localization of the clinical deficitslocalization of the clinical deficits
 DiffuseDiffuse
 CT scanning in the majority of cretins wasCT scanning in the majority of cretins was
normalnormal
 Basal ganglia calcification (15 of 50)Basal ganglia calcification (15 of 50)
 Cochlear malformation (petrous temporalCochlear malformation (petrous temporal
bone)bone)

29. The pattern of neurologicalThe pattern of neurological
damage reflects time anddamage reflects time and
regional sensitivity to thyroidregional sensitivity to thyroid
hormone deficiencyhormone deficiency
 Damage to:Damage to:
– CochleaCochlea
– Cerebral cortexCerebral cortex
– Basal gangliaBasal ganglia
– Disordered thalamic projectionsDisordered thalamic projections

30. Mechanism of damageMechanism of damage
 Thyroid hormone is essential for normal brainThyroid hormone is essential for normal brain
gene expressiongene expression
– NeurogenesisNeurogenesis
– MyelinationMyelination
– MigrationMigration
– DifferentiationDifferentiation
 Classical sensitive window in the developingClassical sensitive window in the developing
brainbrain
 Timing and Region dependent gradient ofTiming and Region dependent gradient of
sensitivitysensitivity

31. Postnatal thyroid functionPostnatal thyroid function
modifies the clinical phenotypemodifies the clinical phenotype
 Neurological cretinsNeurological cretins
– GoitrousGoitrous
 MyxoedematousMyxoedematous
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

32. Brain Damage: Shift in the IQBrain Damage: Shift in the IQ
distribution to the leftdistribution to the left
 The neurological sequelae are not an all orThe neurological sequelae are not an all or
none phenomenonnone phenomenon
 The population distribution of cognitiveThe population distribution of cognitive
function shows a marked shift to the leftfunction shows a marked shift to the left
towards lower IQ scorestowards lower IQ scores
 10 to 15 IQ points10 to 15 IQ points

33. 20-29
30-39
40-49
50-59
60-69
70-79
80-89
90-99
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 IODISED
SALT PROPHYLAXIS

34. Timing of insultTiming of insult
Timing ofTiming of
insultinsult
PrenatalPrenatal PostnatalPostnatal
TargetTarget Fetal brainFetal brain
Fetal thyroidFetal thyroid
MaternalMaternal
thyroidthyroid
Child andChild and
AdultAdult
ThyroidThyroid
OutcomeOutcome EndemicEndemic
cretinismcretinism
Impaired IQImpaired IQ
EndemicEndemic
GoitreGoitre
ShortShort

35. 

Normal
Maternal
Hypothyroidism
Sporadic
cretinism
Sporadic
cretinism (TBII
positive)
Endemic
cretinism
Normal
Normal
Normal
Normal
Maternal
Thyroid
Function
Foetal Thyroid
Function
Neurological
Outcome
Normal
? Normal
? Normal
Severe deficit
Severe deficit

36. CONCLUSIONCONCLUSION
 Thyroid hormone is essential for normalThyroid hormone is essential for normal
somatic and neurological development.somatic and neurological development.
 Iodine deficiency leads to thyroidIodine deficiency leads to thyroid
hormone deficiency at critical periods ofhormone deficiency at critical periods of
brain development that leads tobrain development that leads to
irreversible neurological damage.irreversible neurological damage.
 Prevention of iodine deficiency isPrevention of iodine deficiency is
essentialessential

38. 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