PREVENTION AGAINST MICRONUTRIENT MALNUTRITIONIODINEFOLIC ACIDVITAMIN D

3RD SUMMER SCHOOLMANI, GREECE2014

Professor Steven C. BoyagesWestmead HospitalSydney, Australia

Sydney, Australia

Nutrition 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

PAMM

Iodine

Folic Acid

Vitamin D

Iodine Deficiency Disorders

Thyroid Thyroid autonomy Nodular thyroid

disease Goitre Thyroid

Malignancy

Brain Endemic cretinism Deafness Subclinical

deafness intellectual

disability ?Attention deficits ? Colour

perception deficitsIodine 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

Iodine 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 deficiency at critical stages during pregnancy and early childhood results in impaired development of the brain and consequently in impaired mental function.

Endemic Goitre

Pathogenesis of goitre

Adaptation to iodine deficiency

Iodine Deficiency Disorders

Early recognition of goitre with impaired mental ability"Hence while travelling in a

certain region in the County Tyrol, under the jurisdiction of the Bishop of Gurk, I was astonished at the very large number of madmen, fools and dolts; but when I considered the frigidity and the humidity of the air, and also perceived the crudity of the waters from the very frequent occurrence of goitre... all astonishment ceased entirely."

EUSTACHIUS RUDIUS, A PHYSICIAN FROM UTRECHT

(1551-1611)

Endemic Cretinism

Occurs in areas of severe iodine deficiency and almost universal endemic goitre

Geographic clustering

Two predominant clinical phenotypes

Endemic Cretinism: Clinical Phenotypes Neurological

Euthyroid Goitrous Severe mental

disability Deafness Neurological

abnormalities More frequent

Myxedematous Hypothyroid Thyroid atrophy Severe mental

disability Deafness Neurological

abnormalities Less frequent

Timing 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

Why are certain parts of brain predisposed? Timing of the insult and preferential sites for thyroid hormone action

Differential expression of TH receptors

ARE IODINE LEVELS FALLING?

Are we at risk?

Are iodine levels falling?

Figure 1. (A) Median U.S. urinary iodine concentrations in males and females, 1971-2002 (B) Median U.S. urinary iodine concentrations in pregnant and non-pregnant women of child-bearing age (15- 44 years old), 1971-2002.[Adapted from Hollowell et al, JCEM 1998; 83:3401-8 & Caldwell et al, Thyroid 2005;15:692-9]

Figure 1. (A) Median U.S. urinary iodine concentrations in males and females, 1971-2002 (B) Median U.S. urinary iodine concentrations in pregnant and non-pregnant women of child-bearing age (15- 44 years old), 1971-2002.[Adapted from Hollowell et al, JCEM 1998; 83:3401-8 & Caldwell et al, Thyroid 2005;15:692-9]

Pregnancy increases risk of iodine deficiency

Iodine Deficiency in Australia

TasmaniaUrine Iodine Distribution

Median UIE 84mcg/lMedian UIE 84mcg/l

Thyroid Size: Boys and Girls

24.6%24.6% 20.7%20.7%

Other States

NINS study Overall, children in mainland Australia are

borderline iodine deficient, with a national median UIE of 104 mcg/L.

On a state basis, NSW and Victorian children are mildly iodine deficient, with median UIE levels of 89 mcg/L and 73.5 mcg/L, respectively. South Australian children are borderline iodine deficient, with a median UIE of 101 mcg/L.

Both Queensland and Western Australian children are iodine sufficient, with median UIE levels of 136.5 mcg/L and 142.5 mcg/L, respectively.

There was no significant association between UIE and thyroid volume.

Just eat sushi! Is that ok?

What is normal intake?Too little and Too much can be a problem

ENDEMIC GOITRE IN CENTRAL CHINA CAUSED BY

EXCESSIVE IODINE INTAKE

Thyroid status was examined in children from two villages in China where the iodine concentrations in drinking water were 462.5 and 54 μg/1

Goitres were present in 65% (n = 120) and 15.4%

(n=51), respectively.

Children from the high-iodine village had a lower mean serum triiodothyronine and higher serum free thyroxine and serum thyroid-stimulating hormone concentrations than the children from the control village. 2 cases of overt hypothyroidism were detected in the high-iodine village.

TOPICAL IODINE-CONTAINING ANTISEPTICS AND NEONATAL HYPOTHYROIDISM IN VERY-LOW-BIRTHWEIGHT INFANTS: P. Smerdely, S. C. Boyages, et al. Lancet 1989

The thyroid function of very-low-birthweight (VLBW; below 1500 g) infants admitted to neonatal intensive-care units was studied at two hospitals; one routinely used topical iodinated antiseptic agents and the other used chlorhexidine-containing antiseptics.

Serial Urinary iodine excretion rose dramatically in the 54 iodine-exposed infants and was up to fifty times greater than in the 29 non-exposed infants.

Within 14 days, 25% (9 of 36) of the infants exposed to iodine had serum thyrotropin levels above 20 mIU/l, compared with none of the control group.

The mean serum thyroxine level in these 9 infants (44·1 nmol/l) was significantly lower than that in exposed infants with normal thyrotropin levels (83·1 nmol/l) and in the non-exposed control group (83·0 nmol/l), thyroxine levels fell before serum thyrotropin rose.

Medications

Amiodarone related thyroid disease

FOLIC ACID

Sources of folate intake

Folate sources Folate Folic acid

(FA)Dietary Folate Equivalents

(DFE)

Food (natural) + - 1 DFE = 1 μg food folate

Food (fortified): ECGP + RTE

cereals+ + 1 DFE = 1 μg food folate or 0.6 μg

FA from fortified food

Supplements - + 1 DFE = 0.6 μg FA taken with food or 0.5 μg FA on empty stomach

Association of folate with health outcomes

• NTD’s and other birth defects

• Cardiovascular disease• Cognition• Cancer

• Acceleration of cancerous growth • Masking of vitamin B12 deficiency• Twinning• Immunity• Epigenetic changes

Cause and effect has not been proven

Potential adverse

effects; basis is observational

data

Proven effectiveness of folic acid intervention

Monitoring of the impact of folic acid fortification

Changes in dietary intake

Changes in blood levels

Changes in NTD rates

Folic acid fortification

policy

Changes in other health outcomes

Benefits Risks

anes

Changes in biomarker levels of folate status

How much did folate blood levels change after the

introduction of fortification?

What are the challenges associated with assessing

folate status through biochemical measurements?

Serum folate levels have nearly tripled

• Serum folate levels have increased much more than expected from FDA intake modeling and short-term FA supplementation trials – demonstrating the value of biomonitoring.

• Post-fortification serum folate levels have stabilized after several years.

http://www.cdc.gov/nchs/data/databriefs/db06.htm

http://www.cdc.gov/nutritionreport

Prevalence of low RBC folate levels has decreased

Red blood cell folate levels have also stabilized after fortification and the prevalence of low levels in women of childbearing age was ~5% compared to ~40% at pre-fortification.

http://www.cdc.gov/nchs/data/databriefs/db06.htm

RBC folate <140 ng/mL

Folate dietary intake data

Strengths ChallengesNon-invasive Self-reported data; flawed with

multiple errors

Relatively easy and inexpensive to conduct

Various sources of intake need to be captured

Easier to compare between countries

Computation of data is complex (DFE)

Requires two 24-h dietary recalls to calculate usual intakes

VITAMIN D

Health benefits of vitamin D

Low 25(OH)D levels linked to Osteoporosis and osteopenia Cancer Diabetes Cardiovascular disease Autoimmune disease Multiple sclerosis Respiratory Illness Mental Health

Adequate vitamin D statusVitamin D (nmol/L*)Conventional guidelines

Newer recommendations+

Severe Deficiency <12.5

Moderate deficiency 12.5-25

Mild deficiency 25-50 <50

Insufficiency 50-75

Sufficiency >50 >75

*2.5 nmol/L = 1 ng/ml

+Bischoff Ferrari, AJCN 2006

Australian Studies

46974697

31131 25(OH)D assays1 July 2008 and 30 July 2010

31131 25(OH)D assays1 July 2008 and 30 July 2010

Primary test, complete data available for gender, age, patient setting, date of test, postcode**, known breast cancer case, 25(OH)D ≤400 nmol/L

Sample type

1083910839 1397913979

Diagnostic referralOutpatientPrivate outpatientEmergency

InpatientPrivate hospital patientPublic hospital patientPrivate patient

2951629516

2481924819

Yes

680668061801218012Female Male

6201620162516251Summer Winter

6121612162456245Autumn Spring

16151615

QC sampleResearchMiscellaneousUnknown

* *Matched to ARIA, SEIFA, Latitude, Longitude

Mean 25(OH)D by gender

37% reductio

n by June

Mean 25(OH)D by patient setting

Mean 25(OH)D by gender and patient setting

Supporting Women with Breast Cancer Today and Every Day

Mean 25(OH)D by age group

Mean 25(OH)D by remoteness

Results

Bilinski & Boyages MJA 197 (2) · 16 July 2012

Requests per 100000 for FBC, bone densitometry and vitamin D

Bilinski & Boyages BMJ Open 2013;3: e002955

Frequency of repeated testing

Bilinski & Boyages BMJ Open 2013;3: e002955

Vitamin D intake recommendations

*Recommendations based on maintaining serum vitamin D > 75 nmol/L (30ng/ml)

Recognition that individuals who are obese or on certain medications be give 2-3 times more vitamin D

40 IU = 1 µg

Age NHMRC IOM US Endo Society*

0-1 200 400 1000

1-18 200 600 1000

19-49 200 600 1500-2000

50-69 400 600 1500-2000

70 and over

600 800 1500-2000

Health Implications

Public health messages required to address high prevalence of vitamin D deficiency

Australians are not adequately supplementing - suitable guidelines are required

Implications regarding frequency and timing of testing

Percentage of households with access to iodised salt

Food Fortification

Eradication of iodine deficiency has always the highest priority.

Optimal prevention of thyroid disease by modification of

iodine intake in the population is achieved by keeping iodine intake in individuals within a relatively narrow interval around the recommended level.

To run an optimal iodization program it is necessary to have information on dietary habits in the population, and on iodine contents of different food items.

Iodine used for enrichment of food should be well distributed in different food items, e. g. by universal or nearly universal iodization of salt. Optimal methods may differ between European countries depending on dietary habits.

Risks of iodisation programmes Sudden increase in the prevalence of

hyperthyroidism Jod Basedow phenomenon

Development of hypothyroidism in those with pre-existing autoimmune thyroid disease Positive anti-TPO antibodies

Change in the pattern of thyroid disease, rise in the prevalence of thyroid autoimmunity

CONCLUSION

Thyroid hormone is essential for normal somatic and neurological development.

Iodine deficiency leads to thyroid hormone deficiency at critical periods of brain development that leads to irreversible neurological damage.

Prevention of iodine deficiency is essential

Acknowledgements Australia

CJ Eastman JP Halpern John K Collins Li Mu

China Indonesia The Netherlands

Hemmo Drexhage USA, Atlanta

GF Maberly Italy, Pisa

Alessandro Antonelli