THYROID DISORDERS

THYROID PHYSIOLOGY

Thyroid tissue has an avidity for iodide and is able to

trap (with a gradient of 100 : 1), transport, and
concentrate it in the follicular lumen for synthesis of
thyroid hormone.

Entry of iodide from the circulation into the thyroid is

carried out by the sodium–iodide symporter.
Iodide diffuses across the cell to the apical
membrane where it is transported into the
colloid via pendrin.

Before trapped iodide can react with

tyrosine, it must be oxidized; this reaction is
catalyzed by thyroidal peroxidase.
Dual oxidase maturation factor 2 (DUOXA2)
is required to express DUOX2 enzyme, which
is required for H2O2 generation, a crucial
step in iodide oxidation.

The thyroid cells produce thyroglobulin,

containing approximately 120 tyrosine units.
Iodination of tyrosine forms
monoiodotyrosine and diiodotyrosine;

2 molecules of diiodotyrosine then couple to

form 1 molecule of T4, or 1 molecule of
diiodotyrosine and 1 of monoiodotyrosine
to form T3.
Once formed, hormones are stored as
thyroglobulin in the lumen of the follicle
(colloid) until ready to be delivered to the
body cells.

T4 and T3 are liberated from thyroglobulin by

activation of proteases and peptidases.
The metabolic potency of T3 is 3-4 times that
of T4.

Only 20% of circulating T3 is secreted by the

thyroid; the remainder is produced by
deiodination of T4 in the liver, kidney, and
other extrathyroidal tissues by type I 5′-
deiodinase.
In the pituitary and brain, approximately 80%
of required T3 is produced locally from T4 by
a different enzyme, type II 5′-deiodinase.

The level of T3 in blood is one fiftieth that of

T4, but T3 is the physiologically active thyroid
hormone.
Thyroid hormones increase oxygen
consumption, stimulate protein synthesis,
influence growth and differentiation, and
affect carbohydrate, lipid, and vitamin
metabolism.

Specific thyroid hormone transporters, of

which the most important is
monocarboxylate transporter 8, facilitate
entry of T4 and T3 into cells.
Once into the cell, T4 is converted to T3 by
type I or II 5′-deiodinase.

Intracellular T3 then enters the nucleus,

where it binds to thyroid hormone receptors.
Binding of T3 activates the thyroid hormone
receptor response element, resulting in
production of an encoded messenger RNA
and protein synthesis specific for the target
cell.
Approximately 70% of the circulating T4 is
firmly bound to T4- binding globulin (TBG).

Less-important carriers are T4-binding

prealbumin, called transthyretin, and
albumin.

Only 0.03% of T4 in serum is not bound and

comprises free T4.
Approximately 50% of circulating T3 is bound
to TBG, and 50% is bound to albumin; 0.30%
of T3 is unbound, or free, T3.
DEFECTS OF THYROXINE BINDING
GLOBULINS

Abnormalities in levels of thyroxine-binding

globulin (TBG) are not associated with
clinical disease and do not require
treatment.
uncovered by a chance finding of abnormally
low or high levels of thyroxine (T4)

TBG deficiency occurs as an X-linked

dominant disorder.

low levels of total T4 and elevated resin

triiodothyronine uptake, but levels of free T4
and thyroid stimulating hormone are normal.
confirmed by the finding of absent or low
levels of TBG.

TBG excess also is a harmless X-linked

dominant anomaly
level of T4 is elevated, triiodothyronine is
variably elevated, thyroid-stimulating
hormone and free T4 are normal, and resin
triiodothyronine uptake is decreased.

The elevated levels of TBG confirm the

diagnosis.
Familial dysalbuminemic hyperthyroxinemia
is an autosomal dominant disorder

Markedly increased binding of T4 to an

abnormal albumin variant leads to increased
serum concentrations of T4.
The levels of free T4, free triiodothyronine,
and thyroid-stimulating hormone are
normal.

Levels of triiodothyronine are normal or only

slightly elevated. Affected patients are
euthyroid.
 HYPOTHYROIDISM

Hypothyroidism results from deficient

production of thyroid hormone, either from
a defect in the gland itself (primary
hypothyroidism) or a result of reduced
thyroid-stimulating hormone (TSH)
stimulation (central or hypopituitary
hypothyroidism).
The disorder may be manifested from birth
(congenital) or acquired.
When symptoms appear after a period of
apparently normal thyroid function, the
disorder may be truly acquired or might only
appear so as a result of one of a variety of
congenital defects in which the
manifestation of the deficiency is delayed.
CONGENITAL HYPOTHYROIDISM

Most cases of congenital hypothyroidism are

not hereditary and result from thyroid
dysgenesis.
ETIOLOGY
Clinical Manifestations
Most infants with congenital hypothyroidism
are asymptomatic at birth, even if there is
complete agenesis of the thyroid gland.

This situation is attributed to partial

transplacental passage of maternal T4, which
provides fetal levels that are approximately
33% of normal at birth.
Despite this maternal contribution of T4,
hypothyroid infants still have a low serum T4
and elevated TSH level and so will be
identified by newborn screening programs.

The clinician depends on neonatal screening

tests for the diagnosis of congenital
hypothyroidism.
Some babies escape newborn screening, and
laboratory errors occur, so awareness of
early symptoms and signs must be
maintained
It can be suspected and the diagnosis
established during the early weeks of life if
the initial, but less characteristic,
manifestations are recognized.
Birthweight and length are normal, but head
size may be slightly increased because of
myxedema of the brain.

The anterior and posterior fontanels are

open widely;
Prolongation of physiologic jaundice, caused
by delayed maturation of glucuronide
conjugation, may be the earliest sign.

Feeding difficulties, especially sluggishness,

lack of interest, somnolence, and choking
spells during nursing, are often present
during the 1st mo of life.
Respiratory difficulties, partly caused by the
large tongue, include apneic episodes, noisy
respirations, and nasal obstruction.

Some infants may develop respiratory

distress syndrome.
Affected infants cry little, sleep much, have
poor appetites, and are generally sluggish.

There may be constipation that does not

usually respond to treatment
The abdomen is large, and an umbilical
hernia is usually present.

The temperature is subnormal, often <35°C

(95°F), and the skin, particularly that of the
extremities, may be cold and mottled.
Edema of the genitals and extremities may
be present.

The pulse is slow, and heart murmurs,

cardiomegaly, and asymptomatic pericardial
effusion are common.
Macrocytic anemia is often present and is
refractory to treatment with hematinics.

Approximately 10% of infants with congenital

hypothyroidism have associated congenital
anomalies.
Cardiac anomalies are most common, but
anomalies of the nervous system and eye
have also been reported.

Infants with congenital hypothyroidism may

have associated hearing loss.
Specific mutations in genes involved in
thyroid gland development result in
“syndromic” congenital hypothyroidism.
If congenital hypothyroidism goes
undetected and untreated, these
manifestations progress.

Retardation of physical and mental

development becomes greater during the
following months, and by 3-6 mo of
age the clinical picture is fully developed.
The child’s growth will be stunted, the
extremities are short, and the head size is
normal or even increased.

The anterior fontanel is large and the

posterior fontanel may remain open.
The eyes appear far apart, and the bridge of
the broad nose is depressed.

The palpebral fissures are narrow and the

eyelids are swollen.
The mouth is kept open, and the thick, broad
tongue protrudes.

Dentition will be delayed.

The neck is short and thick, and there may be

deposits of fat above the clavicles and
between the neck and shoulders.
The hands are broad and the fingers are
short.

The skin is dry and scaly, and there is little

perspiration.

Myxedema is manifested, particularly in the

skin of the eyelids, the back of the hands,
and the external genitals.
The skin shows general pallor with a sallow
complexion.

Carotenemia can cause a yellow

discoloration of the skin, but the sclerae
remain white.

The scalp is thickened, and the hair is coarse,

brittle, and scanty.
The hairline reaches far down on the
forehead, which usually appears wrinkled,
especially when the infant cries.

Development is usually delayed.

Hypothyroid infants appear lethargic and are

late in learning to sit and stand.
The voice is hoarse, and they do not learn to
talk.
The degree of physical and intellectual delay
increases with age.

Sexual maturation may also be delayed or

might not take place at all.
The muscles are usually hypotonic, but in
rare instances generalized muscular
pseudohypertrophy occurs

Affected older children can have an athletic

appearance because of pseudohypertrophy,
particularly in the calf muscles.
Laboratory Findings

In developed countries, infants with

congenital hypothyroidism are identified by
newborn screening programs.

Blood obtained by heelprick between 2 and 5

days of life is placed on a filter paper card
and sent to a central screening laboratory.
The early approach to newborn screening
Levels of T4, followed by measurement of
TSH when T4 is low.

identifies infants with primary

hypothyroidism, some with central or
hypopituitary hypothyroidism, and infants
with a delayed elevation in
TSH levels.
Now switched to an initial TSH
measurement.

This approach will detect infants with

primary hypothyroidism and infants with
milder, subclinical hypothyroidism (normal
T4, elevated TSH), but it may not detect
infants with delayed TSH elevation or with
central or hypopituitary hypothyroidism.
Regardless of the approach used for
screening, some infants escape detection
because of technical or human errors
Serum levels of T4 or free T4 are low; serum
levels of T3 may be normal and are not
helpful in the diagnosis.

If the defect is primarily in the thyroid, levels

of TSH are elevated, often to >100 mU/L.
Serum levels of thyroglobulin are usually low
in infants with thyroid agenesis or defects of
thyroglobulin synthesis or secretion, whereas
they are elevated with ectopic glands and
other inborn errors of T4 synthesis
Retardation of osseous development can be
shown radiographically at birth

The distal femoral and proximal tibial

epiphyses, normally present at birth, are
often absent.
X-rays of the skull show large fontanels and
wide sutures; intersutural (wormian) bones
are common.
The sella turcica is often enlarged and round;
in rare instances, there may be erosion and
thinning.

Formation and eruption of teeth can be

delayed
Cardiac enlargement or pericardial effusion
may be present.

Scintigraphy can help to pinpoint the

underlying cause in infants with congenital
hypothyroidism, but treatment should not be
unduly delayed for this study.
A normally situated thyroid gland with a
normal or avid uptake of radionuclide
indicates a defect in thyroid hormone
biosynthesis.
Ultrasonographic examination of the thyroid
is helpful, butit can miss some ectopic glands
shown by scintigraphy.

Demonstration of ectopic thyroid tissue is

diagnostic of thyroid dysgenesis and
establishes the need for lifelong treatment
with T4.
The electrocardiogram may show low-
voltage P and T waves with diminished
amplitude of QRS complexes and suggest
poor left ventricular function and pericardial
effusion.

Echocardiography can confirm a pericardial

effusion.
The electroencephalogram often shows low
voltage.

In children older than 2 yr of age, the serum

cholesterol level is usually elevated.
Treatment

Levothyroxine (l-T4) given orally is the

treatment of choice.

The recommended initial starting dose is 10-

15 μg/kg/day (totaling 37.5-50.0 μg/day for
most term infants).
The starting dose can be tailored to the
severity of hypothyroidism.

Rapid normalization of thyroid function has

been demonstrated to be important in
achieving optimal neurodevelopmental
outcome.
Newborns with more severe hypothyroidism,
as judged by a serum T4 <5 μg/dL and/or
imaging studies confirming aplasia, should be
started at the higher end of the dosage
range.
Although it is recommended to administer l-
T4 on an empty stomach and avoid food for
30-60 min, this is not practical in an infant.

As long as the method of administration is

consistent day to day, dosing can be adjusted
based on serum thyroid test results to
achieve the desired treatment goals.
Levels of serum T4 or free T4 and TSH should
be monitored at recommended intervals
(every 1-2 mo in the 1st 6 mo of life, and
then every 2-4 mo between 6 mo and 3 yr of
age).
The goals of treatment are to maintain the
serum free T4 or total T4 in the upper half of
the reference range for age, with serum TSH
in the reference range for age, optimally 0.5-
2.0 mU/L.
The only untoward effects of l-T4 are related
to its dosage.

Overtreatment can risk craniosynostosis and

temperament problems.
Prognosis

Delay in diagnosis, failure to correct initial

hypothyroxinemia rapidly, inadequate
treatment, and poor compliance in the 1st 2-
3 yr of life result in variable degrees of brain
damage.
Without treatment, affected infants are
profoundly intellectually challenged and
growth retarded.

When onset of hypothyroidism occurs after 2

yr of age, the outlook for normal
development is much better even if diagnosis
and treatment have been delayed, indicating
how much more important thyroid hormone
is to the rapidly growing brain of the infant.
ACQUIRED HYPOTHYROIDISM
ETIOLOGY
CLINICAL FEATURES

Deceleration of growth
Goiter
Weight gain (myxedema)
Myxedematous changes of the skin,
constipation, cold intolerance, decreased
energy, and an increased need for sleep
bradycardia, muscle weakness or cramps,
nerve entrapment, and ataxia
Osseous maturation is delayed
delayed puberty
adolescent girls manifest menometrorrhagia
galactorrhea or pseudoprecocious puberty
headaches and vision problems
Abnormal laboratory studies include
hyponatremia, macrocytic anemia,
hypercholesterolemia, and elevated creatine
phosphokinase.
Diagnostic Studies
serum free T4 and TSH
antithyroglobulin and antiperoxidase
antibodies
ultrasound examination
radioactive iodine uptake scan
bone age x-ray
Treatment and Prognosis

l-T4 is the treatment of choice in children with

hypothyroidism.

For children age 1-3 yr, the average l-T4 dosage is 4-6
μg/kg/day;

for age 3-10 yr, 3-5 μg/kg/day;

for age 10-16 yr, 2-4 μg/kg/day

Treatment should be monitored by
measuring serum free T4 and TSH every 4-6
mo as well as 6 wk after any change in
dosage.

In central hypothyroidism the goal

should be to maintain serum free T4 in the
upper half of the normal reference range for
age
During the 1st yr of treatment, deterioration
of schoolwork, poor sleeping habits,
restlessness, short attention span, and
behavioural problems might ensue, but
these are transient;

forewarning families about these

manifestations enhances appropriate
management.
Periodic bone age x-rays are useful to
monitor treatment and future growth
potential.