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11 January 2020
Follicular cells (thyrocytes) is the major cell type in the thyroid gland responsible for
the production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine
(T3). Thyroid follicular cells form a simple cuboidal epithelium and are arranged in
spherical follicles surrounding a fluid filled space known as the colloid.
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6. Organification of iodine and coupling of iodinated tyrosine molecules are catalyzed by
the rate-limiting enzyme, thyroid peroxidase (TPO), in a reaction dependent on
hydrogen peroxide.
7. Iodinated thyroglobulin within the lumen is reabsorbed from the colloid by pinocytosis
into the thyrocytes where it undergoes proteolysis, allowing T4 and T3 to be released
from the thyrocytes into the systemic circulation. The main iodinated by-products of
thyroid hormone synthesis, monoiodotyrosine and diiodotyrosine are deiodinated to
release iodide for recycling.
8. Formation of T3 from T4 in thyroid and the peripheral tissues occurs through the action
of 5’monodeiodinase (80 percent of T3 is formed from deiodination of T4)
THYROID HORMONES
Circulating T4 and T3 is more than 99% bound to carrier proteins. Thyroxine binding
globulin (TBG) binds 75% of circulating T4. It is a 54kD glycoprotein, which is synthesized
by the liver. TBG concentration increases in conditions in which estrogen levels are
increased (e.g. pregnancy). T4 and T3 are also bound to transthyretin (TTR), albumin and
lipoproteins. The free (not bound) T4 and T3 concentrations determine biological activity.
Binding proteins serve to maintain the serum free T4 and T3 within narrow limits and to
ensure that T4 and T3 are immediately and continuously available to the tissues.
Deiodinases
Thyroxine (T4)
D2, D1 D3
Activation Inactivation
D1: Liver, Kidney (Circulating T3)
D2: Brain, Pituitary (Brain T3)
D3
D1, D2
Inactivation
Diiodothyronine
2
Thyroxine, T4 is an inactive prohormone. Within the target cells, conversion of T4 to
the active hormone, T3, is catalyzed by the action of deiodinases. The iodothyronine
deiodinases are a group of three selenoenzymes, two of which, the types I (D1) and type II
(D2) enzymes, activate T4 by removing an iodine atom from its outer or phenolic ring,
converting it to the active hormone T3. The type III deiodinase (D3) inactivates both T4 and
T3 by removing an iodine atom from the inner (tyrosyl) ring. In humans 80 to 90% of the T3
is produced from T4 by these deiodinases in various tissues. D1 is principally found in liver,
kidney, and thyroid. D1 is susceptible to inhibition by the antithyroid drug, propylthiouracil
(PTU). Deiodinase D2, which is insensitive to PTU, is expressed in pituitary and
cerebrocortical tissue.
The regulation of type II deiodinase (D2), which predominates in brain and pituitary is
different. In hypothyroidism, the requirement for increased T3 is achieved by up-regulating
D2 and downregulating D3. In hyperthyroidism, this is reversed and T3 is decreased by
down-regulating D2 and upregulating D3.
Diverse tissues exert local control over thyroid hormone action by converting T4 to T3
through the actions of D1 and D2 or by deactivating T4 to rT3 (reverse T3) and T3 to T2
through the actions of D3. Thyroid hormone is primarily degraded through successive
deiodination.
Two genes, THRA and THRB, encode the thyroid hormone receptors. There are 3 α
and 3 β receptor isoforms. All β receptor isoforms (β1, β2, and β3) and the α1 isoform have
significant thyroid hormone binding. Thyroid hormone is typically found in a heterodimer
with the retinoid X receptor. In the absence of thyroid hormones, the receptors and
corepressors bind to the thyroid hormone response elements, thus suppressing
transcription. When thyroid hormone binds the thyroid hormone receptor, the corepressors
are displaced and coactivators bind, thereby activating the transcriptional effects of thyroid
hormone. b1 receptors are concentrated in the brain, heart, kidney and liver, while b2
receptors are found in the pituitary and hypothalamus. Separate functions for these
receptors have not been elucidated but a specific syndrome of thyroid hormone resistance,
associated with a mutation in the ligand- binding region of the b receptor, has been
identified.
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TSH stimulates iodide trapping by the thyroid follicular cells by regulating the activity
of the sodium-iodide symporter. It also regulates oxidation of inorganic iodine as well as the
coupling reactions to form T4 and T3.
Anti-thyroid drugs, carbimazole and propylthiouracil are actively transported into the
thyroid cells where they inhibit organification of iodine and coupling of iodotyrosines.
Propylthiouracil, but not carbimazole, also inhibits the activity of type I deiodinase (D1) but
not D2, to block the conversion of T4 to T3.
Hypothalamus
TRH
Pituitary gland
Negative
feedback
TSH
Thyroid gland
Thyroid hormones
(T3, T4)
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The hypothalamic-pituitary-thyroid axis provides a classic example of feedback
loops. The dominant effects on TSH secretion are produced through negative feed- back by
thyroid hormone at the pituitary and hypothalamic levels, and stimulation by TRH (TSH
releasing hormone) directly on the thyrotroph (TSH producing cell).
Refs:
Cooper DS Synthesis of thyroxine and triiodothyronine N Engl J Med 2005 453:905-917
Larsen R Editorial J Clin Endo Metab 2009 94(6):1893-1895
Heemstra KA et al J Clin Endo Metab 2009 94(6):2144-2150
Burch HB Review Drugs Effects on the Thyroid N Engl J Med 2019 381(8):749-761
Jod-Basedow phenomenon
Wolff-Chiakoff Effect
Refers to the reduction in synthesis and release of T4 and T3 by follicular cells when
presented with excess iodine. Caused by:
• Reduction in sodium-iodine symporters resulting in down-regulation of iodine
transport into the thyroid
• An acute decrease in activity of thyroid peroxidase which results in cessation of
thyroid hormone synthesis
• Inhibition of thyroglobulin proteolysis which reduces release and secretion of
thyroid hormones
During the next 2 to 4 weeks of continued exposure, the iodide trap adapts by
functioning at greatly reduced efficiency. This results in a decrease in intrathyroidal iodide to
normal concentrations and resumption of thyroid hormone production. This new steady
state is known as adaptation or escape from the acute Wolff-Chiakoff effect. Thus in
normal subjects, exposure to high serum iodide causes only a small and transient decrease
in serum T4 and T3 concentrations. Because escape from this effect often occurs after 10 to
14 days, iodine is generally used only after anti-thyroid drugs (ATDs) have been started to
prepare a patient rapidly for surgery or as an adjunctive measure in patients with “thyroid
storm.” Iodine is also used to decrease the vascularity of the thyroid before thyroidectomy
for Graves’ disease. Typical doses are Lugol’s solution (8 mg iodide/drop) 5 to 7 drops
(0.25–0.35 mL) or SSKI (50 mg iodide/drop) 1 to 2 drops (0.05–0.1 mL) three times daily
mixed in water or juice for 10 days before surgery.
1. Thyroxine binding globulin (TBG) increases 2.5 fold with peak levels at 15-20 weeks
gestation because of estrogen-induced sialylation, decreased hepatic clearance and
TBG saturation
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2. Total T4 and T3 increase through mid-gestation through compensatory increase in
thyroidal secretion, restoring equilibrium between bound and free hormone.
3. The production of hCG begins in the first days of pregnancy and peaks at 9-11
weeks gestational age; levels then decline until approximately 20 weeks of gestation
and remain stable for the remainder of the pregnancy. hCG shares alpha subunit
with TSH and is a thyroid stimulator
4. Free T4 and T3 remain in normal range except for late 1st trimester when a transient
increase may occur – peaking at 10-13 weeks, the time of peak hCG levels.
5. In first trimester, TSH is suppressed below 0.4 mIU/l in 9% of normal pregnancies.
6. First trimester free T4 positively correlates with hCG levels
7. Trimester specific serum TSH in women with healthy pregnancies without preexisting
thyroid disease
1st 0.8 mIU/l (0.03-2.3)
2nd: 1.1 mIU/l (0.03-3.1)
3rd: 1.3 mIU/l (0.13-3.5)
8. Pregnant L-T4-replaced hypothyroid women require a dosage increase of about 45%
9. Euthyroid women with positive TPO antibodies have progressively higher TSH
values during pregnancy
10. Women in areas of borderline iodine insufficiency have relative hyperthyroxinemia,
increased T3/T4 ratios and high normal TSH as pregnancy progresses
11. Thyroid autoantibodies if present during first trimester in euthyroid women –
associated with increased miscarriage rate, and not related to presence of anti-
phospholipid antibodies
12. There are ethnic differences in maternal thyroid parameters during pregnancy
(Korevaar 2013)
13. Persistently low FT4 concentrations throughout pregnancy were associated with
higher birth weight and an increased risk of large for gestational age (LGA) (Zhang
2019).
Iodine in pregnancy
The U.S. Institute of Medicine’s recommended dietary allowance for iodine is 220
µg/d for pregnant women, higher than the 150 µg/d recommended for non-pregnant adults
and adolescents. Similarly, recent World Health Organization guidelines suggest an intake of
200–300 µg/d iodine daily for pregnant women, and the Endocrine Society has recently
recommended an average daily intake of 250 µg iodine daily for pregnant women.
A normal iodine status is important in lactating women, as iodine within breast milk is
the sole source of iodine for breastfed infants. The iodine supplementation recommended
by the American Thyroid Association during lactation is 150 mcg daily
Refs:
Korevaar TIM Ethnic Differences in Maternal Thyroid Parameters during Pregnancy: The
Generation R Study 2013 J Clin Endocrinol Metab 98(9):3678-3686
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Pearce, E. Iodine in pregnancy: Is salt iodization enough? Editorial 2008 J Clin Endocrinol
Metab 93(7):2466-2468.
Pearce E. What do we know about iodine supplementation in pregnancy? Editorial 2009 J
Clin Endocrinol Metab 94(9):3188-3190
Optimal iodine nutrition in the pregnant woman is required for full development of the
foetus. For the developing foetus or infant, untreated maternal hypothyroidism due to
severe iodine deficiency is a catastrophe because thyroid hormone is essential for normal
maturation of the central nervous system, particularly its myelination. For the first 12 weeks
of gestation, the foetus is completely dependent upon maternal T4. During the 10th to 12th
week of gestation, foetal TSH appears, and the foetal thyroid is capable of concentrating
iodine and synthesizing iodothyronines. However, little hormone synthesis occurs until the
18th to 20th week. Thereafter, foetal thyroid secretion increases gradually. The maternal
contribution persists until birth and may still play a critical role in the preferential protection of
the foetal brain from T3 deficiency. Hypothyroidism during these critical periods of
development and that which continues after the foetal thyroid develops in the setting of
ongoing maternal iodine deficiency leads to permanent intellectual disability, which, in its
most severe form, is known as cretinism.
Cretinism
How are the actions of deiodinases II and II in the brain coordinated to ensure
adequate levels of T3 in the right place and at the right time?
In the brain, triiodothyronine (T3) plays a critical role in the development and
differentiation of the brain. The cerebral cortex develops before mid-gestation while the
cerebellum, midbrain, basal ganglia, brain stem, spinal cord and hippocampus develops
after mid-gestation.
Type II deiodinase, D2, controls conversion of T4 to T3. Type III deiodinase, D3,
inactivates T4 by converting T4 to reverse T3 (rT3). The appropriate spatial and temporal
expression of T3 in the cerebral cortex and cerebellum respectively, is achieved by:
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• Elevated expression of type III deiodinase (D3) in the cerebellum, midbrain, basal
ganglia, hippocampus, brain stem and spinal cord. This protects those regions from
excessive T3 before mid-gestation.
From mid-gestation:
• Reduced expression of type III deiodinase in the cerebellum and other parts of the
brain to allow increase in T3 levels from mid-gestation when such differentiation is
required.
Liothyronine (T3) does not cross the placenta in sufficiency quantity to be available for the
fetus.
Timing is everything
Refs:
Editorial Zoeller 2004 JCEM 89:3114-3116
Kester M et al 2004 Iodothyronine levels in the human developing brain: Major regulatory
roles of iodothyronine deiodinases in different areas. JCEM 89:3117-3128
Treat to target
• Use the lowest dose of antithyroid drug (ATD) to maintain maternal thyroid hormone
levels in the high normal to slightly elevated range for pregnancy (FT4 2-2.5 ng/dl;
25.8-32.25 pmol/l). Antithyroid drug dosages that normalize maternal thyroid
function are generally excessive for the foetus and lead to foetal hypothyroidism.
Surgery
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• Subtotal thyroidectomy if consistently high levels of ATD (PTU >450 mg, carbimazole
>40 mg) are required; if the patient is non-compliant or allergic to ATD, or if
compressive symptoms exist because of goitre size. Surgery should be performed
during the second trimester because of teratogenic effects associated with
anaesthetic agents and increased risk of foetal loss in the first trimester and high risk
of preterm labour in the third trimester.
Radioactive iodine
• Absolutely contraindicated (see supplementary question Q3)
Postpartum
• Women with Graves' disease who have been in remission are at risk for having a
relapse during this period. The risk of relapse appeared to be related to the
postpartum period, occurring four to eight months postpartum.
• Women with Graves' disease who have been treated during pregnancy need careful
monitoring during the postpartum period as they may experience an exacerbation.
Measure thyroid function tests (TSH, free T4) six weeks postpartum, then every six
weeks if dose adjustment is needed or every four months if thyroid tests remain
normal
• Maternal ATD use during lactation is safe for doses of carbimazole, doses up to 20
mg daily or PTU doses up to 450 mg daily
• Use of 131I is contraindicated during lactation because of its relatively long half-life (8
days). If required for diagnostic purposes, 123I can be used if breast milk is pumped
and discarded for 3 to 4 days before breastfeeding is resumed. 99mTc pertechnetate
administration requires breast milk to be pumped and discarded during the day of
testing (ESAP 2019 Q68).
Refs:
Yoshihara A et al 2012 JCEM 97(7):2396-2403
ESAP 2013 Q15
ESAP 2019 Q68
UptoDate: Hyperthyroidism during pregnancy
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• Inability to compensate for increased TBG
• Increased renal iodine losses
The magnitude of the increased dosage requirement varies between 20% and 40%,
although some patients may require increases of as much as 80%. Factors specific to
patients include the preconception serum TSH value, schedule and timing of levothyroxine
administration, the presence of a singleton vs multiple gestation, and the aetiology of the
patient’s hypothyroidism.
All pregnant women are recommended to take a prenatal multivitamin that contains
150 mcg iodine to ensure that a total of 250 mcg iodine is ingested daily. Prenatal
multivitamins contain iron and calcium, and co-ingestion of either calcium or iron with
levothyroxine could potentially impair levothyroxine absorption. A separation of at least 4
hours is traditionally recommended between ingestion of levothyroxine and either calcium or
iron.
A relatively low serum thyroxine may be associated with a normal serum TSH in
iodine deficiency when the thyroid preferentially secretes T3, but maternal triiodothyronine
cannot be used by the foetal brain during early pregnancy.
(B) Recommendations
Normally, there is an increased demand for L-T4 during pregnancy that occurs very
early in gestation at 4 to 6 weeks, which increases through midgestation (16 to 20 weeks)
and then is sustained until delivery
• Optimise T4 dosage prior to conception (TSH 0.5-2.5 mIU/l) and FT4 within the upper
third of the reference range
• Check TSH as soon as pregnancy confirmed.
• Check TSH every 4 weeks
• If T4 dosage increased, re-check TSH in 4 weeks
• Requirement for increased LT4 peaks midway through pregnancy and remains
constant thereafter, until delivery
• Surveillance of thyroid function can be more relaxed after the 20th week of gestation,
during which time one addition test is probably sufficient
• Separate T4 ingestion from prenatal vitamins containing iron, iron and calcium
supplements and soy milk ingestion by at least 4 hr
• L4 dosage may be reduced to pre-pregnancy amount immediately after delivery, and
serum TSH should be re-checked at 6-week postpartum visit
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Recommended patient profiles for targeted thyroid disease case finding in women
seeking pregnancy or are newly pregnant
Over age 30 yr
Family history or autoimmune thyroid disease or
hypothyroidism
Goitre
Thyroid antibodies, primarily thyroid peroxidase antibodies
Symptoms or clinical signs suggestive of thyroid
hypofunction
Type 1 DM or other autoimmune disorders
Infertility
Prior history of miscarriage or preterm delivery
Prior therapeutic head or neck irradiation or prior thyroid
surgery
Currently receiving levothyroxine replacement
Living in a region with presumed iodine deficiency
Prior history of postpartum thyroiditis
Refs:
Männistö T et al 2013 J Clin Endocrinol Metab 98(7):2725-2733
Henrichs J et al 2010 J Clin Endocrinol Metab 95(9):4227-4234
Negro R et al 2010 J Clin Endocrinol Metab 95(9):E44-E48
Alexander et al Timing and magnitude of increases in levothyroxine requirements during
pregnancy in women with hypothyroidism 2004 N Engl J Med 351:241-249
Yassa L et al 2010 J Clin Endocrinol Metab 95(7):3234-3241
Endocrine Society Clinical Practice Guideline 2012. J Clin Endocrinol Metab
97(8)2543-2565
Stagnaro-Green A Editorial: Optimal care of the pregnant woman with thyroid disease. 2012
J Clin Endocrinol Metab 97(8):2619-2622
Negro R Editorial: Thyroid dysfunction and pregnancy: where are we five years later? 2012 J
Clin Endocrinol Metab 97(8):2629-2631
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CASE HISTORIES
A 51 year old man presents with palpitations, nervousness and a 4 kg weight loss in
the past 6 weeks despite a normal appetite. During the past several weeks, he has also
noticed a feeling of pressure in the lower anterior neck, particularly when he swallows.
Pulse rate is 92 bpm, and BP is 148/60. His oral temperature is 98.80F. He weighs
73 kgs and is 176 cm tall (BMI 23.6 kg/m2). He is hyperkinetic. He has a stare and bilateral
lidlag, but there are no signs of Graves orbitopathy. His thyroid gland is enlarged, firm and
nontender. Cardiac examination reveals a forceful apical impulse with normal heart sounds
and no murmur. Tremour is absent. The deep tendon reflexes are brisk. The rest of the
physical examination findings are normal.
Results of complete blood cell count and routine blood chemistries are normal.
Which one of the following tests would you order first to determine the aetiology of the
patient’s hyperthyroidism
Supplementary questions
Q1) What is the difference between a thyroid scan and a radioactive iodine uptake
test?
Q2) How long after 131I treatment should women wait before becoming pregnant or
resuming breastfeeding?
Q3) Why is radioactive iodine ablation absolutely contraindicated in a pregnant
woman with thyrotoxicosis
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