THYROID DISEASES

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 THE THYROID GLAND
The largest endocrine gland Internally, composed of
Greek thyreos = shield - 20-25 g hollow follicles
(adults) Separated by areolar CT rich
Sits on thyroid cartilage of the in capillaries
Walls are formed of cuboidal
larynx
Butterfly-like appearance or squamous epithelial cells
(follicular cells)
Two lobes joined by the isthmus Lying within the epithelium
May have a pyramidal lobe are parafollicular (C) cells
Lies in front upper trachea (2nd/3rd Central lumen filled with
rings) colloid (‘gluelike’) consisting
Posterior – 2 pairs of parathyroid of thyroglobulin (protein
glands precursor to thyroid hormone)
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 THYROID ANATOMY
ARTERIES VEINS
Superior thyroid Superior thyroid
artery vein

Inferior thyroid
artery* Middle thyroid
vein

COMMON
CAROTID Inferior thyroid
vein
INTERNAL
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The thyroid gland has an abundant blood supply-5 ml/g of thyroid
tissue
Although the thyroid represents about 0.4% of body weight it
accounts for 2% of total blood flow.
In disease the flow through the gland may be increased up to 100-
fold.

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Anatomy and Histological Organization of the Thyroid Gland 6
FOLLICLES : The functional units of the
thyroid gland
Follicles Are the
Sites Where Key
Thyroid Elements
Function:
Thyroglobulin (Tg)
Tyrosine
Iodine
Thyroxine (T4)
Triiodotyrosine (T3)

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The follicles are the functional, secretory units of the thyroid
gland.
Follicular cells produce thick, proteinaceous colloid that fills the
lumen.
Colloid is composed primarily of thyroglobulin (Tg).
Thyroglobulin is a high-molecular weight glycoprotein that
facilitates the assembly of thyroid hormones within the thyroid
follicular lumen.
The amino acid tyrosine, which is incorporated within the
molecular structure of Tg, becomes iodinated.
Iodine is bound to tyrosyl residues in Tg at the apical surface of the
follicle cells to form, in turn, monoiodotyrosine (MIT) and
diiodotyrosine (DIT).
MIT and DIT combine to form the 2 biologically active thyroid
hormones, thyroxine (T4) and triiodothyronine (T3).
In addition to providing the matrix for thyroid hormone synthesis, 8
 THYROID HORMONES

T4 is the major secretory product of the thyroid

T3 is the active form of thyroid hormone
Binds to the thyroid hormone receptor
T3 is produced from T4 by the deiodinases
Type I (liver, kidney, thyroid)
Type II (nonhepatic tissues, including brain and pituitary)
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 T4 T3
Potency 1 10
Protein Bound 10-20 1
Half-Life 5-7d < 24h
Secreted by thyroid 100 µg/d 6 µg/d

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 THYROID-STIMULATING
HORMONE (TSH)
Thyroid stimulating hormone (TSH; also called thyrotropin)
A glycoprotein hormone with  and  subunits
Is secreted by the anterior pituitary gland
Thyroid stimulating hormone is inhibited by thyroid hormone in a
classic endocrine negative feedback loop.
Its synthesis and release is stimulated by thyrotropin-releasing
hormone (TRH), which is the major positive regulator of TSH
secretion.
TSH is the major regulator of the thyroid gland.

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Physiological roles of TSH include:
Stimulation of various thyroid functions, eg, iodine uptake &
organification
Production & release of thyroid hormone from the gland, and
Promotion of thyroid growth
TSH-cyclic adenosine monophosphate (cAMP) is the prime
regulator of iodide uptake and concentration and T 3/T4 formation.
TSH-cAMP induces the expression and activation of the 3
necessary genes encoding proteins involved in iodide uptake and
thyroid hormone formation:
The sodium-iodide symporter (NIS)
Thyroglobulin (Tg), and
Thyroperoxidase (TPO)

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 BIOSYNTHESIS OF T4 AND T3
The major steps in the synthesis, storage, and release of thyroid
hormones are:
Ingestion of iodine with the diet
Active transport & uptake of iodide ion (I-) by the thyroid gland
The oxidation of iodide & the iodination of tyrosyl groups of
thyroglobulin (Tg)
Coupling of iodotyrosine residues monoiodotyrosine (MIT) &
diiodotyrosine (DIT) to generate iodothyronines
Storage of iodinated Tg containing MIT, DIT, T4 & T3; and
The proteolysis of Tg and the release of T4 & T 3 into the blood

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 PRODUCTION OF T4 AND T3
The thyroid gland is the sole source of endogenous T 4, while only
about 20% of T3 is produced in the thyroid.
T4 is the most abundant iodothyronine in Tg and is about 10-20
times more abundant than T3.
The thyroid secretes T4 and T3 in a proportion determined by the
T4/T3 ratio in thyroglobulin (Tg), which is 15:1 in humans with
minimal thyroidal conversion of T4 to T3.
Normally, the ratio of secreted T4 to T3 is about 11:1
The serum concentrations and daily production rates of T 4 are
higher than those of any other iodothyronine.

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The estimated range of normal daily production of T 4 is 70-90 g;
for T3 the estimated range is about 15-30 g.
Normal circulating concentrations of T 4 in plasma range from 4.5-
11.0 g/dL, while those for T3 are 100-fold less (60-180 ng/dL).
One third to one half of the T4 that is secreted is converted to T3.
The production of T4 and its extrathyroidal conversion to T3 provide
a more constant source of T3 than were T3 to be solely produced
by the thyroid.
T3 is produced by 2 different and relatively independent
processes:
About 20% via direct thyroid secretion and
About 80% by extrathyroidal 5' deiodination of T4
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CARRIERS FOR CIRCULATING
THYROID HORMONES
Thyroid hormones are transported in the blood by carrier plasma
proteins, which bind more than 99% of serum T4 and T3.
Together, the carrier proteins keep the concentration of thyroid
hormone constant over a wide range and provide a means for
equal distribution of hormone among the tissues.
Thyroxine-binding globulin (TBG) is the major carrier of thyroid
hormones in the circulation because of its extremely high binding
affinity, even though it represents only a small fraction of the total
serum proteins.
TBG binds 75% of T4, and has 10-20 times greater affinity for T4
than T3. 17
Transthyretin (TTR), also called thyroxine-binding prealbumin
(TBPA), binds about 10%-15%
Transthyretin (TTR) binds T4, but does not significantly bind T3.

In spite of its low binding affinity, albumin carries about 7% of T4

because of its high serum concentration.

The thyroid hormones also bind to plasma lipoproteins, with high-

density lipoproteins (HDL) being the major binders.
HDL transports about 3% of T4 and about 6% of T3 in serum.

The transport proteins are affected by physiological changes,

pharmacologic agents, and disease.
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 T4 DISPOSITION
In healthy individuals:
About 41% of T4 is converted to T3
About 38% is converted to reverse T3 (rT3), and
About 21% is metabolized via other pathways, such as conjugation
in the liver and excretion in the bile

Reverse T3, which is metabolically inactive, results from removal

of the iodine on position 5 of the inner ring.

The normal circulating concentration of T 4 is 4.5-11 g/dL.

The normal circulation concentration of T 3 is about 100-fold less

(60-180 ng/dL).
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REGULATION OF Environmental stimuli (e.g., cold,
THYROID stress)
Hypothalam
SECRETION us
TRH
Depends on a negative feedback
system between: Anterior
pituitary
Anterior pituitary gland and
Thyroid gland TSH

Thyroid
gland

Thyroid hormones (T3

& T4 )
Metabolis Growt 20
 FUNCTION OF THYROID
HORMONES
Increase BMR (O2 consumption & heat production – body temp)

Growth/development = all tissues (brain)

Carbohydrate metabolism = hyperglycemia (glucose

absorption/production/utilization)

Fat metabolism = decrease (Chol., TG, Phospholipids)

Protein metabolism (both protein anabolism & catabolism –

excess = catabolism)
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Bone turnover

Cardiovascular = HR, muscle contraction, cardiac output, SBP,

wide pulse pressure (DBP)

GI tract = appetite, GI motility, diarrhoea

CNS = essential for normal brain development : memory,

mentation, reflexes, tremor

Gonadal function

Vitamin A synthesis stimulation from the liver

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 BLOOD TESTS
Thyroid Function Test
Measure serum TSH
Free T4 & free T3

Thyroid Autoantibody Estimation

Antithyroid Ab
 Thyroid microsomal Ab (TMAb)  95% of patients with
Hashimoto.D
 Thyroglobulin Ab (TGAb)  60% of patients with Hashimoto.D

Ab against thyroid TSH receptors (TRAbs)  seen in pts with

Graves . D
Serum Thyrogloublin
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
 TSH
Depends on negative feedback
Nl range: 0.5–5.0 mU/L
RAI, Immunometric, Chemiluminescent
1st generation, sens to 1 mU/L
2nd generation, sens to 0.1 mU/L
3rd generation, sens to  0.05 mU/L
The single best TFT
Only erroneous in secondary thyroid disease

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 FREE THYROID HORMONE
No assays actually measure free hormone directly
Free T4 and T3 by equilibrium dialysis
Expensive, not done routinely
Current commonly used free hormone assays are competitive
binding assays
Convenient but still depend on competitive reversible binding, like T3RU

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T4 radioimmunoassay FTI
measures bound and unbound product of T3RU and T4
hormone good initial determination of
hyper or hypo thyroidism
T3RU
determines TBG capacity T3 radioimmunoassay
radiolabeled T3 given reflects peripheral metabolism
bound to TBG open sites not thyroid function
resin given 25-35% normally T3 thyrotoxicosis
binds to resin
increased TBG decreased T3RU

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 RAIU
Normal 4h RAIU = 5-15 %
24h RAIU:
>25% Hyperthyroid
20-25% Equivocal (check TSH)
9-20% Normal
5-9% Equivocal (check TSH)
<5% Hypothyroid
Dependent on dietary iodine intake!
Must be: not pregnant! (ß-hCG), no ATD x 7d, no LT4 x 4d, no large
doses of iodine or radiocontrast for 2 wk (prefer 4-6 wk)

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 ANTI-THYROID ANTIBODIES
Antithyroglobulin and Antiperoxidase
Markers for autoimmune thyroid disease
Highest in Hashimoto’s but not specific
Markers for future hypothyroidism
Thyroid stimulating immunoglobulin—TSI
Against the TSH receptor
The cause of Graves’ disease
Predict neonatal hyperthyroidism

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 RADIOLOGY &
ENDOCRINOLOGY
ANATOMY FUNCTION
Radiography Radionuclide Imaging
Ultrasound Scintigraphy

CT PET

MRI

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 THYROID - RADIOGRAPHY
Little role
Thyroid mass diagnosed incidentally on chest radiograph
Thoracic inlet views may demonstrate tracheal compression

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 THYROID - CT/MRI
Not as good as US at resolving lesions within the thyroid
Best tests for assessing mediastinal disease
CT better than MRI for calcification
MRI better than CT for distinguishing between fibrosis and
residual tumour

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 RADIOISOTPE SCAN
Single or multiple nodules .
Over functioning (hot nodules) or non-functioning (cold nodules)
20% of cold nodules are malignant
Hot nodules ….rarely malignant

Hot n Cold n

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 ULTRASOUND
Provides considerable anatomic information but no functional
information
Determine the volume of a nodule, multicentricity and whether it
is cystic or solid- often performed before FNA
Extremely useful in also following patients being managed
conservatively for possible increasing size of lesion
Unable, however, to accurately predict the diagnosis of solid
nodules

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 FNA
Simple, safe office procedure
Tissue sample obtained by 25 gauge needle
With experience adequate sample may be obtained in 90 -97% of
aspirates of solid nodules
False negative rate (FNA benign but nodule turn out malignant) is
0-5% usually due to sampling error
False positive rates (malignant but turns out benign) <5% due to
focal hyperplasia in a macrofollicular adenoma or cellular atypia in
a degenerating adenoma

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 LABORATORY DIAGNOSIS OF
THYROID DISEASE
Division of hyperthyroidism and hypothyroidism into 1, 2, and 3
1 thyroid disease is abnormality in the thyroid gland
 Then TRH and TSH level just reflect normal feedback response
2 thyroid disease is really an abnormality in pituitary gland which
cause error in amount of TSH produced
 Then T4 and T3 concentration just reflect normal feedback

response
3 thyroid disease is abnormality in hypothalamus causing error of
TRH produced
 Then both TSH and T4 & T3 levels just reflect normal feedback
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 INTERPRETATION OF TFTS
Primary hypothyroidism: ↓TSH, ↑T or T .
4 3
↑TSH, ↓T
4.
Sick euthyroid:
Everything low’
Compensated or subclinical
hypothyroidism: Pituitary disease:
↑ TSH, normal T Everything low’
4.

Are they taking their thyroxine? Pregancy (or other state where
(Perhaps they have a rare TSH- ↑ TIBG):
secreting tumour…): Normal TSH & abnormal T
4
↑ TSH, ↑T [Check free T and T to confirm
4 3 4

Thyrotoxicosis: actual euthyroid status.]

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 TSH

High Low

FT4 FT4 & FT3

High Low Low High

1° Hypothyroid Central Hypothyroid 1° Thyrotoxicosis

If
2° thyrotoxicosis equivocal
TRH Stim. RAIU

• Endo consult
• FT3, rT3 MRI, etc.
• MRI, α-SU
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FACTORS WHICH AFFECT TFT
Mild-moderate illness…
T3 decreases as a result of reduced conversion of T4 to T3 in
peripheral tissues
Serum free T4 usually normal
TSH normal or elevated
rT3 increases

Severe illness…
T3 levels decrease further
T4 also decreases
 Because of decreased binding proteins & decreased TSH secretion
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How can euthyroid sick be distinguished from hypothyroidism?
In hypothyrodism
Both T4 and T3 will be low
rT is low
3
In euthyroid sick
T <<T4 and
3

rT is elevated
3

Repeat approximately 6 weeks after discharge

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Changes in TBG Concentration Determine Binding and
Influence T4 and T3 Levels.
Because of the high degree of binding of thyroid hormones to

serum carrier proteins, such as TBG, quantitative or qualitative

changes in either the concentrations of the proteins or molecular
changes in the binding affinity of the hormones for the protein have
significant effects on the total serum hormone levels.

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Increased TBG For example, the alterations in
Total serum T4 and T3 levels total thyroid hormone levels in
pregnancy are the direct result
increase
of the marked increase in
Free T4 (FT4), and free T3
serum TBG.
(FT3) concentrations remain
Total T4 and T3 levels
unchanged
Decreased TBG increase significantly during
the first half of gestation,
Total serum T4 and T3 levels
while there is a transient drop
decrease in FT4.
FT4 and FT3 levels remain

unchanged 41
Drugs and Conditions That Increase Serum T4 and T3 Levels by
Increasing TBG.
Drugs that increase TBG Conditions that increase TBG
Oral contraceptives and other Pregnancy
sources of estrogen Infectious/chronic active
Methadone hepatitis
Clofibrate HIV infection
5-Fluorouracil Biliary cirrhosis
Heroin Acute intermittent porphyria
Tamoxifen Genetic factors

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Only the unbound thyroid hormone has metabolic activity.

Because of the high degree of binding of thyroid hormones to

plasma proteins, changes in the protein concentrations or the

binding affinity of the hormones for the proteins can greatly affect
total serum hormone levels.

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Drugs and Conditions That Decrease Serum T4 & T3 by
Decreasing TBG Levels or Binding of Hormone to TBG.
Drugs that decrease serum T4 Conditions that decrease
and T3 serum T4 and T3
Glucocorticoids Genetic factors
Androgens Acute and chronic illness
L-Asparaginase
Salicylates
Mefenamic acid
Antiseizure medications, eg,
phenytoin, carbama-zepine
Furosemide
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Because the pituitary responds to & regulates circulating free

hormone levels, minimal changes in free hormone concentrations

are seen.
Therefore, laboratory tests that measure only total hormone levels

may be subject to misinterpretation.

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 SUBCLINCAL
HYPOTHYROIDISM
 TSH, normal FT4
Most asymptomatic & don’t need Rx (monitor TSH q2-5y)
Rx Indications:
Increased risk of progression
 TSH > 10, Female > 50 y.o.
 Anti-TPO Ab titre > 1:100,000 ?
 Goitre present ?

Dyslipidemia?
 Total cholesterol (TC)  6-8% if TSH > 10 and TC > 6.2 nM

Symptoms?
Pregnancy, Infertility, Ovulatory Dysfn.
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 SUBCLINICAL
HYPERTHYROIDISM
 TSH, Normal FT4 and FT3
Progression to overt hyperthyroidism low:
Men 0% per year
Women 1.5% per year
TMNG or toxic adenoma present 5% per year
Indications to Rx:
Any cardiac disease (CAD, AFIB, etc.)
Age > 60 (10 year risk AFIB 32%, 10% if normal TSH)
TMNG or toxic adenoma
Osteoporosis

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