Pediatric Hypothyroidism:

Implications for
Down Syndrome and Autism

DOWN SYNDROME TREATMENT CENTER OF OREGON

DR. ERICA PEIRSON

 Objectives

Basic Thyroid Physiologoy

Symptoms of Hypothyroidism
Labs
Hypothyroidism and Down syndrome
Hypothyroidism and Autism
Case Studies
Treatment
 Thyroid Basics

Hypothalamus
Pituitary
Thyroid Gland
Cellular Enzymes

http://adkblog.s3.amazonaws.com/wp-content/uploads/2012/09/thyroid-gland-092912.jpeg
 No other endocrine
hormone in the body
effects cellular function
in every organ of the
body like thyroid
hormone.

Thyroid hormone
production is a multi-
step process.
Requires proper brain,
thyroid and enzyme
function at the cellular
level
Hypothalamus & Pituitary
Sella Turcica
Hypophyseal Portal System

http://wps.aw.com/wps/media/tmp/labeling/7093936_dyn.jpg
Thyroid Histology
 Thyroid Hormone Synthesis

http://www.nature.com/nrendo/journal/v6/n1/images/nrendo.2009.225-f2.jpg
Thyroid
Hormone
Function
Every cell in the body
depends on thyroid
hormone to function
properly.

T3 regulates gene
expression, especially
genes involved in
growth and
development.

http://www.nature.com/nrendo/journal/v5/n4/images/nrendo.2009.19-f1.jpg
 Thyroid Hormone Function

http://corticoides.wordpress.com/2012/06/02/influencia-do-t3-e-t4-na-regulacao-da-
expressao-genica-e-do-metabolismo-basal/
Reverse T3
 Deiodinase Enzymes

D2 (IDII) converts T4 to active T3

D3 (IDIII) converts T4 to reverse T3 and active T3 to T2
 Light Bulb Analogy

Checking TSH only is

missing many steps in
the process
Using TSH only to
assess thyroid hormone
function is
DANGEROUS!
 Labs

TSH
Free T4
Free T3
Reverse T3
TPO/TgAb
Ferritin
CBC w/ diff and platelets
Diurnal Cortisol pediatric saliva collection through Neuroscience
DHEA - saliva
8-OHdg (oxidative stress)
Lipid Panel
 Reverse T3

Free T3 : Reverse T3 ratio must be calculated

A ratio below 20 indicates that reverse T3 is too high
compared to free T3
Elevated free T3 and reverse T3 can indicate T3
pooling
T3 is staying in the blood and not getting into the cell
Reverse T3 is blocking active T3
Support cell membranes while working on lowering reverse T3
Phosphatidylcholine
Fish oil (DHA/EPA)
Vitamin E
 Signs & Symptoms

http://upload.wikimedia.org/wikipedia/commons/9/9f/Signs_and_symptoms_of_hypothyroidism.png
 Signs & Symptoms

Others:
Delayed deep tendon reflexes, especially the Achilles tendon
Plantar fasciitis
Carpal tunnel syndrome
Difficulty swallowing (dysphagia)
Dry skin
Acne
Reflux
Sleep apnea
300+ Hypothyroidism Symptoms
Signs & Symptoms
 Maternal thyroid disease, thyroid medication use, and selected birth
defects in the National Birth Defects Prevention Study

Authors: Browne ML1, Rasmussen SA, Hoyt AT, Waller DK, Druschel CM, Caton AR, Canfield MA, Lin AE, Carmichael SL,
Romitti PA; National Birth Defects Prevention Study.
Journal: Birth Defects Res A Clin Mol Teratol. 2009 Jul;85(7):621-8. doi: 10.1002/bdra.20573.

Abstract:
BACKGROUND:
Although thyroid disorders are present in approximately 3% of pregnant women, little is known about the association
between maternal thyroid disease and birth defects.
METHODS:
We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among
14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control
study. Infants in this study were born between October 1997 and December 2004. Information on exposures including
maternal diseases and use of medications was collected by telephone interview.
RESULTS:
We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract
obstruction heart defects (1.5; 95% CI, 1.0-2.3), hydrocephaly (2.9; 95% CI, 1.6-5.2), hypospadias (1.6; 95% CI, 1.0-2.5), and
isolated anorectal atresia (2.4; 95% CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine
and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use
CONCLUSIONS:
was rare, we could not adequately assess risks for their use for most case groups.
CONCLUSIONS:
Our
Our results
results are
are consistent
consistent with
with the
the positive
positive associations
associations between
between maternal
maternal thyroid
thyroid
disease
disease or
or thyroid
thyroid medication
medication use
use and
and both
both hydrocephaly
hydrocephaly andand hypospadias
hypospadias
observed
observed inin some
some previous
previous studies.
studies. New
New associations
associations with
with left
left ventricular
ventricular outflow
outflow
tract
tract obstruction
obstruction heart
heart defects
defects and
and anorectal
anorectal atresia
atresia may
may be
be chance
chance findings.
findings.
 Thyroid Basics

Schmaltz C., Thyroid hormones in the neonate: an overview of physiology and

clinical correlation., Adv Neonatal Care. 2012 Aug;12(4):217-22
 Signs of Hypothyroidism in Infants

Schmaltz C., Thyroid hormones in the neonate: an overview of physiology and

clinical correlation., Adv Neonatal Care. 2012 Aug;12(4):217-22
 Beta Carotenemia

The Carotenemia of Hypothyroidism

The occurrence of carotenemia in hypothyroidism, long known, is confirmedIt is regularly associated with lipemiaand
cholesterolemia, but the carotene tends to be relatively more increased than the lipids or cholesterol.

(Josephs, HW, J Pediatr. 1952 Dec;41(6):784-91)

 Beta Carotenemia

The characteristic yellow tint of the skin in hypothyroidism

is due to hyper-beta-carotenemia. Both in hyper- and
hypothyroidism in a retinol deficiency has been observed in
literature.

Aktuna D, etal , Beta-carotene, vitamin A and carrier proteins in thyroid diseases.

Acta Med Austriaca. 1993;20(1-2):17-20
 Beta Carotenemia

The interrelationship between the retinoids and

triiodothyronine and thyroxine hormones has been
established

Goswami UC, etal, The status of retinoids in women suffering from hyper- and
hypothyroidism: interrelationship between vitamin A, beta-carotene and thyroid
hormones. Int J Vitam Nutr Res. 1999 Mar;69(2):132-5
 Beta Carotenemia

Carotenemia does not hurt children.

Gregory Gordon, MD
No treatment is necessary for
carotenemia, although you can perhaps
offer fewer foods high in beta-carotene
if you like. -Vincent Iannelli, MD on
About.com

http://gregorygordonmd.com/carotenemia.html
Incidence rate of CH in the United States, 19912000, based on a national data set provided by the
NNSGRC (odds: 1.03 [95% CI: 1.021.04]; P < .0001).

Hinton C F et al. Pediatrics 2010;125:S37-S47

 The Increased Incidence of Congenital Hypothyroidism

Marvin L. Mitchell, Ho-Wen Hsu, Clin Endocrinol. 2011;75(6):806-810.

 Congenital hypothyroidism.

Authors: Abduljabbar MA, Afifi AM.

Journal: J Pediatr Endocrinol Metab. 2012; 25(1-2):13-29.

Abstract
Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birth. Babies with
CH who are not identified and treated promptly develop severe mental retardation. Most of the babies
with CH do not manifest the typical known signs and symptoms of hypothyroidism, and this is most likely
due to transplacental passage of some maternal thyroid hormone in addition to some residual neonatal
thyroid function, as might be seen with thyroid hypoplasia, an ectopic gland, or mild dyshormonogenesis.
Screening for CH has enabled the virtual eradication of the devastating effects of mental retardation due
to sporadic CH in most developed countries of the world. CH is classified into permanent and transient
forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Permanent CH
refers to a persistent deficiency of thyroid hormone that requires life-long treatment. Transient CH refers
to a temporary deficiency of thyroid hormone that is discovered at birth but recovers to normal in the first
few months or years of life. In the last several decades, there have been exciting advances in our
However,
understanding
However, many
many questions
of fetal
questions and
and neonatal
and challenges
thyroid are
areInstill
physiology.
challenges not
not answered.
addition,
still advances
answered. For
For example,
in molecular the
biology have
example, the
helped in
increasing understanding
numbers the early events
of surviving in thyroid
small and gland embryogenesis, mechanisms of thyroid action
increasing numbers
in the brain, the molecularofbasis
surviving
for manysmall and premature
of the inborn premature neonates
neonates
errors of thyroid
with
with abnormalities
hormonogenesis,abnormalities
and thyroid
in
in thyroid
thyroid
hormone function
function
action. However,need
need
manydefinite
definite diagnostic
questionsdiagnostic criteria
criteria
and challenges and
are stilland whether
whetherFor
not answered. they
they require
require
example, the
medical
increasingtherapy.
medical numbers ofAnother
therapy. Another challenge
challenge
surviving small is
and prematureis the
the dilemma
dilemma
neonates of
of finding
finding
with abnormalities the
the best
in thyroid best
function
screening
need definite
screening methodology
diagnostic criteria
methodology that
and
that is
whether
is sensitive
they require
sensitive and
medical
and cost effective.
therapy.
cost Another
effective. challenge is the
dilemma of finding the best screening methodology that is sensitive and cost effective.
Hypothyroidism and
Down Syndrome
 Signs & Symptoms

Down syndrome Hypothyroid

Delayed Growth Delayed Growth
Slow Cognition Slow Cognition
Low Muscle Tone Low Muscle Tone
Protruding tongue Protruding tongue
Delayed dentition Delayed dentition
Delayed fontanel closure Delayed fontanel closure
Dry skin Dry skin
Elevated cholesterol and triglycerides Elevated cholesterol and triglycerides
Elevated platelets Elevated platelets
Elevated MCV Elevated MCV
Constipation/Hirschprungs Disease Constipation/Hirschprungs Disease
Low hippocampal volume Low hippocampal volume
http://www.downsyndrometreatment.net/uploads/6/0/5/5/6055321/thyroid_questionnaire.pdf
 Trisomy 21 causes persistent congenital
hypothyroidism presumably of thyroidal origin.

Authors van Trotsenburg AS, Kempers MJ, Endert E, Tijssen JG, de Vijlder JJ, Vulsma T.
Journal Thyroid. 2006 Jul;16(7):671-80.

Abstract
OBJECTIVE AND DESIGN: Lowered neonatal plasma thyroxine (T(4)) and mildly elevated
thyrotropin concentrations together with developmental benefits from neonatally started T(4) treatment
in a randomized clinical trial demonstrated Down syndrome (DS) neonates to be mildly hypothyroid, at
least during their first weeks of life. To prove that this hypothyroid state persists beyond this period in all,
and to elucidate its etiology, we evaluated the course of the thyroid function determinants in all DS
infants participating in this 24-month trial.
MAIN OUTCOME: Mean plasma thyrotropin concentrations and thyrotropin frequency distributions of
97 placebo-treated infants were persistently shifted to substantially higher concentrations, while free T(4)
frequency distributions were in the lower two thirds of the reference interval. Mean thyroglobulin
concentrations were normal. To normalize plasma thyrotropin, T(4)-treated DS infants (N = 99) needed
rather high free T(4) concentrations, like T(4)- treated non-DS children with thyroidal congenital
hypothyroidism. At ages 12 and 24 months, thyroid peroxidase antibodies were detected in 1.1% and 5.4%
of all DS infants.
CONCLUSIONS:
These findingsThese findings
suggest suggest
that as athat as a group
group DSDS infants have
infants havea novel type oftype
a novel persistent
of mild
congenital hypothyroidism, presumably of thyroidal origin. The group character suggests a direct relation
persistent mild
with the trisomic statecongenital
of chromosome hypothyroidism, presumably
21, hypothetically through genomic dosageof imbalance
thyroidal origin.
of dosage-
sensitive genes interfering with thyroid hormone production.
 Sleep Apnea

59 percent of DS children in the

current series were found to
have OSA and they were more
likely to develop OSA than
controls.

Ng DK, et al, Obstructive sleep apnoea in

children with Down syndrome. Singapore
Med J. 2006 Sep;47(9):774-9.
 Sleep Apnea

Sleep apnea episodes are common in persons with

untreated hypothyroidism, even with normal lung
function. Thyroxine replacement therapy decreases
apnea frequency, even without change in body
weight.

Rajagopal KR, et al. Obstructive sleep apnea in hypothyroidism. Ann Intern Med. 1984 Oct;101(4):491-4.
 Sleep Apnea

Our experience suggests that there is high incidence of sleep

apnea among hypothyroid patients. Thyroxine treatment
could achieve disappearance of these apneas in majority of
them. Few hypothyroids may develop sleep apnea despite the
achievement of euthyroid state. Central respiratory drive
probably plays an insignificant role in the pathogenesis of
sleep apnea among hypothyroids.

Hira HS, Sibal L. Sleep apnea syndrome among patients with hypothyroidism. J
Assoc Physicians India. 1999 Jun;47(6):615-8
 Neurodevelopment

Thyroid in Brain Development and Function by Juan

Bernal, M.D., Ph.D. (ThyroidManager.org)

Postnatal morphological changes in the rodent

cerebellum after neonatal hypothyroidism.
 Reflux/Gut Motility

Down syndrome (DS) is often accompanied by

gastrointestinal disease, occurring mainly in early
infancy and frequently requiring therapy. Among
motility disorders, the most frequent is
gastroesophageal reflux disease (GERD), which may
often be misdiagnosed because of its atypical
manifestations.

Francesco Macchini, Ernesto Leva, Maurizio Torricelli, and Alberto Valad. Treating acid reflux disease
in patients with Down syndrome: pharmacological and physiological approaches. Clin Exp
Gastroenterol. 2011; 4: 1922.
 Reflux/Gut Motility

Hypothyroidism prominently reduces esophageal and

gastric motor activity and can cause gastrointestinal
dysfunction. (Olga Yaylali, et al. Does Hypothyroidism Affect Gastrointestinal Motility?
Gastroenterol Res Pract. 2009)

Euthyroid Hypothyroid
 Delayed Growth

Delayed growth
Low Muscle Tone
Aberrant platelet parameters1
Elevated MCV
Elevated cholesterol
Elevated Triglycerides

1. Erikci AA, et al. The effect of subclinical hypothyroidism on platelet parameters. Hematology. 2009
Apr;14(2):115-7
 Sonic Hedgehog

Essential for
Embryonic development
Cell growth
Cell specialization
Development of brain and spinal cord
Development of many other parts of the body
Given its very broad range of effects in development, it is
not surprising that many of the structures affected by a
disruption in Shh signaling are also affected in Down
syndrome (DS).

Currier DG1, Polk RC, Reeves RH. A Sonic hedgehog (Shh) response deficit in trisomic cells may be a common
denominator for multiple features of Down syndrome. Prog Brain Res. 2012;197:223-36
 Sonic Hedgehog

Our results indicate that maternal and adult-onset

perturbations of euthyroid status cause robust and region-
specific changes in the Shh pathway in the embryonic and
adult forebrain, implicating Shh as a possible mechanistic
link for specific neurodevelopmental effects of thyroid
hormone.
Sonic Hedgehog genes are regulated by thyroid hormone.

Desouza LA, et al. Thyroid hormone regulates the expression of the sonic hedgehog
signaling pathway in the embryonic and adult Mammalian brain. Endocrinology.
2011 May;152(5):1989-2000
 Elevated rT3 in Down syndrome?

Nearly all of my patients with Ds have an elevated rT3

(reference range is 8-25 ng/dL. I typically see 20-45+)
Nearly all have a free T3:reverse T3 ratio well below 20
However, Jerome Lejeune, MD, PhD reported in 1992
that rT3 was lower in children ages 6mo 16yo with Ds
than age matched controls
I see elevated rT3 primarily in newborn 4 year olds
with Ds, have seen it in one 18 yo with Ds.

JRME LEJEUNE, MD, PHD; et al, Down Syndrome and 3,3,5-Triiodothyronine. Am J Dis Child. 1990;144(1):19
 Circulating 3,3', 5'-triiodothyronine (reverse T3) in
the human newborn

Authors: Chopra IJ, Sack J, Fisher DA.

Journal: J Clin Invest. 1975 Jun;55(6):1137-41.

Abstract

The mean serum rT3 level in 5-7-day-old

infants was higher than that in normal adults,
but in 9-11 day and 20-30-day-old infants,
mean rT3 values were statistically similar to
the adult value.
 Reverse T3

We suggest that in patients on T4 replacement

treatment the peripheral thyroid homeostatic
mechanisms produce larger amounts of rT3, thereby
preventing high T3 values where serum T4 values are
raised. This may explain why the 'overtreated' children
showed no clinical evidence of hyperthyroidism. These
findings emphasise the protective and selective role of
peripheral monodeiodination.

M Desai, et al. The importance of reverse triiodothyronine in hypothyroid children on replacement

treatment. Arch Dis Child. Jan 1984; 59(1): 3035
 Causes for Elevated Reverse T3

Low iron1
High or low cortisol levels as a sign of stress2
Inflammation3
Oxidative Stress4

1. Smith SM, Johnson PE, Lukaski HC. In vitro hepatic thyroid hormone deiodination in iron-deficient
rats: effect of dietary fat. Life Sci. 1993;53(8):603-9.
2. Peeters RP, et al, Reduced activation and increased inactivation of thyroid hormone in tissues of
critically ill patients. J Clin Endocrinol Metab. 2003 Jul;88(7):3202-11.
3. Holtdorf, K. : Understanding Local Control of Thyroid Hormones: Deiodinases Function and Activity
4. Lamirand A. Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat
astrocytes. Endocrinology. 2008 Jul;149(7):3713-21
Oxidative
Stress &
Adrenals
Oxidative stress
increases cortisol
release from the adrenal
glands

http://www.nature.com/nrendo/journal/v9/n4/images/nrendo.2013.29-f1.jpg
Hypothyroidism and Autism
Regression was significantly associated with a family
history of autoimmune disorders. The only specific
autoimmune disorder found to be associated with
regression was autoimmune thyroid disease.

Molloy CA, et al, Familial autoimmune thyroid disease as a risk factor for regression in children with Autism
Spectrum Disorder: a CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):317-24
 Maternal Thyroid Status

Five children (three boys and two girls) with autism

or autistic-like conditions are described. Three of them
had congenital hypothyroidism and two had mothers
who had probably been hypothyroid in pregnancy. It is
suggested that hypothyroid hormone deficiency in
early development might cause central nervous system
damage such that autistic symptoms are likely to
ensue. An alternative explanation might be
autoimmune factors linking hypothyroidism and
autism.
Gillberg IC, et al, Hypothyroidism and autism spectrum disorders. J Child Psychol Psychiatry. 1992
Mar;33(3):531-42
Case Studies

MILES
NORAH
SAM
MICAH
 Miles
Symptoms:
oProlonged jaundice

oConstipation

oLow muscle tone

oPoor feeding

oSlow growth

Symptoms that remain:

oSensitive to loud noise

oDifficulty
understanding social
cues
oDelayed gross motor
skills
 Norah
Symptoms on
Levothyroxine:
oGrowth dropped from
50% to 25% (1 inch in 1
year)
oCold hands and feet

On Armour:
oGrew 1 inch in 1 month

oFine motor improved

oSpeech improved

oAble to put shoes on by

herself
oNo cold hands and feet
 Sam
Symptoms:
oLow muscle tone

oBeta-carotenemia
(orange skin)
oCold hands and feet

oDry skin

oDelayed growth (no

weight gain in 6-8 mo,
20 lb at 24 mo)
oDifficulty swallowing

oDelayed speech
 Sam
Symptoms:
oFontanel closure after
2yo
oDelayed dentition

oFamily history of
hypothyroid
oReflux (hx of Zantac)

oTemps: warm (99.2)

and sweaty
oMottled skin
 Sam
o April 13, 2014
o Before Nature
Throid
o TSH: 7.33

o Free T4: 1.42

o Free T3: 4.8

o Reverse T3: 23.8

o Ratio: 20.2

o MCV: 87

o Plt: 576

o Ferritin: 26
 Sam
May 4, 2014
3 weeks of
Nature Throid
(1/4 grain BID)
Recheck of labs
pending
 Sam has made AMAZING progress in the 3-1/2 weeks hes been
Sam on the meds! I dont know if he was on the verge of a
developmental leap anyway or if this is all a result of the thyroid,
but we are stunned! After starting the meds, he took his first
steps and almost immediately began walking 10-15 steps
(unassisted!) at a time! His EI program ...commented that his
strength seems much better. He added a new word to his
vocabulary, bringing him up to four spoken words! We think hes
trying to say three or four others, too, though theyre not clear
yet. Hes signing more and combining multiple signs to make
short sentences. Hes drinking out of a sippy cup. (I know, I
knowsippy cups are horrible. But given that he wouldnt drink
from ANYTHING before, this is progress!) And his play is more
mature than it wasinstead of just banging toys, hes actually
engaging in pretend play and imitation."
 Micah
TSH at Birth:

30!

No intervention because
at time of birth the cut
off for Congenital
Hypothyroid diagnosis
in MI was 33

No other thyroid testing

was ever done until he
was 2.5 years old!

Incidentally his
brothers CH was caught
because his TSH was 35.
Hes very healthy and
neurotypical.
 Micah
Symptoms
oExtreme GERD

oBad skin rashes

oDelayed growth

oLow muscle tone

oStrabismus

oNon-verbal

oMany sick visits

oTSH tested at 2.5 yo was

11 with low T4
oPut on Synthroid

oGERD immediately
disappeared
 Micah
Now:
oDiagnosed with
Autism
oNon-verbal

oSmall stature

oSwitched to Armour in
June 2013
o(need current photo)
 Treatment

Thyroid Hormone Replacement

Nature Throid
Armour
Do not use T4-only medication
Start child on grain by mouth, crushed, in AM
Increase by grain in two weeks if no improvement in
symptoms.
Re-check labs in 4 weeks after dose that alleviates
symptoms is achieved.
For overt hypothyroidism start on dose appropriate for age
and weight
Address underlying causes for elevated reverse T3
Nature Throid
Armour
 T3 medication

If reverse T3 increases after using Nature Throid or Armour

all underlying causes for elevated reverse T3 must be
diligently addressed.
Consider T3-only medication, frequent dosing, sublingual
Administration of T3 in slow-release form is ideal
Slow-release capsules cannot be swallowed by many
children
Use slow release T3 as soon as child is able to swallow
capsules
Ratio of T4:T3 dose is 2:1 or 3:1 for elevated reverse T3 (ex:
30mcg T4 given with separate capsule of 15 mcg SRT3)
 Supplements

Selenium
Zinc
Iodine
Adrenal Cortex (for low diurnal cortisol levels)
Phosphatidylserine (for high cortisol levels)
Pantothenic Acid
Vitamin C
 Herbs

Ashwagandha
Licorice Root (for low diurnal cortisol levels)
Coleus forskohlii
Gugulu (Commiphora mukul)
Kelp, Bladderwack - iodine

1. Laurberg P. Forskolin stimulation of thyroid secretion of T4 and T3. FEBS Lett. 1984 May 21;170(2):273-
6.
2. Panda S1, Kar A. Gugulu (Commiphora mukul) induces triiodothyronine production: possible
involvement of lipid peroxidation. Life Sci. 1999;65(12):PL137-41