Maimun ZA

Clinical Pathology Dept Medical

Faculty Brawijaya Univ

Structure of thyroid follicle Euthyroid follicle

Colloid
(glycoprotei
n)

Basal membrane of epithelial

cells
Apical membrane of epithelial
cells
Thyroid Ccell

Capillary
(Rich blood
supply)

Basemen
t
membran
e

Cuboidal epithelial
cells

Physiology
The thyroid follicles secretes tri-iodothyronine(T3)and
thyroxin(T4)synthesis involves combination of
iodine with tyrosine group to form mono and diiodotyrosine which are coupled to form T3 andT4.
The hormones are stored in follicles bound to
thyrogobulin .
When hormones released in the blood they are
bound to plasma proteins and small amount
remain free in the plasma .
The metabolic effect of thyroid hormones are due to
free (unbound)T3 and T4.
90%of secreted hormones is T4 but T3is the active
hormone so, T4is converted to T3 peripherally.

Synthesis and libration of T3 and T4 is

controlled by thyroid stimulating
hormone(TSH)secreted by anterior pituitary
gland.
TSH release is in turn controlled by thyrotropin
releasing hormone (TRH)from hypothalamus .
Circulating T3and T4 exert ve feedback
mechanism on hypothalamus and anterior
pituitary gland .
So, in hyperthyroidism where hormone level in
blood is high ,TSH production is suppressed
and vice versa

Characteristics of Circulating T4
and
T
Hormone properties 3
T
T
4

Total serum concentrations

8 g/dl

0.14
g/dl

Fraction of total hormone in

free form (serum)

0.02 %

0.3 %

Free (unbound hormone) in

serum

21 X 10-12
M

6 X 10-12
M

Serum half life

Fraction directly from the
thyroid

7d
100 %

0.75 d
20 %

Production rate, including

peripheral conversion

90 g/d

32 g/d

Intracellular hormone fraction

~ 20 %

~ 70 %

Functions
of
thyroid hormones

Functions of thyroid hormones

Generally, THs:
1. Increases metabolic rate.
Stimulates increased
consumption of glucose, fatty
acids and other molecules.
2. Increases metabolic heat, by
mitochondrial no & activity
ATP,
3. Stimulates rate of cellular
respiration by:
Production of uncoupling
proteins.
Increase active transport by
+

4. Necessary for normal growth &

maturation.
5. Promotes maturation of nervous
system.
6. Stimulates protein synthesis.
7. Help regulating lipid & CHO
metabolism.

Abnormal
thyroid hormones
secretions

I: Hyperthyroidism
(thyrotoxicosis)

Hyperthyoidism THs.

Could be:
1ry hyperthyroidism (diseases is
in the gland), e.g. Graves disease
Exerts TSH-like effects on thyroid.
Not affected by negative
feedback.
T3 & T4 reflex TSH.
2ry hyperthyroidism (disease is
higher up)
TRH TSH T3 & T4.

I: Hyperthyroidism Graves
disease

90% of hyperthyoidism is due to

Graves disease.
GD is an autoimmune disease
thyroid stimulating antibodies IgG
Symptoms of GD:
- Exophthalmous, due to retro-orbital
oedema (irreversible).
- Lid lag, due to weakness of
extraoccular muscles
(reversible).
- Anxiety & restlessness.
- Sleeplessness.
- appetite, weight &

Graves Disease
Diagnosis:
Low TSH, High FT4 and/or FT3
If eye signs are present, the diagnosis of Graves
disease can be made without further tests
If eye signs are absent and the patient is
hyperthyroid with or without a goitre, a radioiodine
uptake test should be done.
Radioiodine uptake and scan:
Scan shows diffuse uptake
Uptake is increased
TSH-R Ab (stim) is specific for Graves disease. May
be a useful diagnostic test in the apathetic
hyperthyroid patient or in the pt who presents with
unilateral exopthalmos without obvious signs or
laboratory manifestations of Graves disease

II: Hypothyroidism
Adult (Myxedema)

Hypothyroidism in adults THs.

Could be:
1ry hypothyroidism (diseases
is in the gland)
- autoimmune disease such as
Hashimotos throiditis.
- lack of iodine.
- absence of deiodination enzyme.
T3 & T4 reflex TSH.
2ry hypothyroidism (disease
is higher up)
TRH TSH T3 & T4.

II: Hypothyroidism (myxedema)

cont.
If No Iodine T3 & T4 TRH
TSH
growth (size) of the gland simple
goiter.

How goiter swollen neck is

formed?
With lack of iodine
COL
D

Hypothalamu
s
TR
H

Anterio
r
pituitar
TSH y +
NO or low
feedback
inhibition

Lack of
iodine

Thyroi
d
gland

Poo
r

Low T3 or T4
release

+++

Growth of
the gland

II: Hypothyroidism (myxedema)

cont.

If there is absence of
deionization enzyme
NO recycle synthesis of DIT & MIT
accumulate.

DIT & MIT will not be used for new

THs formation
THs.

II: Hypothyroidism (myxedema)

cont.

Symptoms of Hypothyroidism:
- Decreased metabolic rate.
- Slow heart rate & pulse.
- Slow muscle contractions
- appetite, weight gain, &
constipation.
- Prolonged sleep, & dizziness.
- Coarse skin.
- Slow thinking, lethargy, & mask face.
- Intolerence to cold ( ability to adapt
cold).
- Myxoedema swollen & puffy
appearance of body, due to deposition of

Hypothyroidism
Diagnosis:
A iFT4 and hTSH is diagnostic of primary hypothyroidism
Serum T3 levels are variable (maybe in normal range)
+ve test for thyroid autoantibodies (Tg Ab & TPO Ab) PLUS
an enlarged thyroid gland suggest Hashimotos thyroiditis
With pituitary myxedema FT4 will be i but serum TSH will
be inappropriately normal or low
TRH test may be done to differentiate pituitary from
hypothalamic disease. Absence of TSH response to TRH
indicates pituitary deficiency
MRI of brain is indicated if pituitary or hypothalamic
disease is suspected. Need to look for other pituitary
deficiencies.
If TSH is h & FT4 & FT3 are normal we call this condition
subclinical hypothyroidism

II: Hypothyroidism
Children (Cretinism)

Hypothyroidism in children THs.

Hypothyroid from end of 1st
trimester to 6 months
postnatally, or in the 1st few
years of life.

T3 & T4 reflex TSH.

Additional Signs & Symptoms:
- Severe mental retardation.
- Short stature (due to growth of
bones, muscle, & brain).

Thyroid Nodule

Very common
30 60 years old ; 4.2% ( Palpation)
19 67% by ultrasound
Autopsy ; 50%

Thyroid Cancer is rare ; 4 / 100,000

Ocult thyroid cancer in 6 24 %
autopsy

Thyroid Nodule 2
Thyroid nodule very common
Thyroid cancer very rare but
curable
AIM IS NOT MISS THYROID CANCER

Thyroid nodule Risk factors

Exposure to radiation as child

Family history
Under 20 years
Over 60 years
? male sex
Hourseness
Fixed hard nodule
Similar risk for multinodular and
single nodule

Thyoid Nodule
Invesigations
TFTs
Ultra sound scan
Thyroglobulin and Calcitonin not
recommended ( US Guidelines)
Fine needle Aspration(FNA)

Hashimotos Thyroiditis
Symptoms & Signs:
Usually presents with goitre in a patient who is
euthyroid or has mild hypothyroidism
Sex distribution: four females to one male
The process is painless
Older patients may present with severe
hypothyroidism with only a small, firm atrophic
thyroid gland
Transient symptoms of thyrotoxicosis can occur
during periods of hashitoxicosis (spontaneously
resolving hyperthyroidism)

Hashimotos Thyroiditis
Lab:
Normal or low thyroid hormone
levels, and if low, TSH is elevated
High Tg Ab and/or TPO Ab titres
FNA bx reveals a large infiltration
of lymphocytes PLUS Hurthle cells
Complications:
Permanent hypothyroidism (occurs
in 10-15% of young pts)
Rarely, thyroid lymphoma

Thyroid Function Tests

TSH
Thyroxine (T4) (free / total)
Ttriiodothyronine (T3) (free / total)
Thyroid Antibodies: Autoimmune
thyroid disease is detected by
circulating antibodies against TPO and
Tg.
Imaging
Thyroid Ultrasound scan
Thyroid Isotope Scan

Guidelines
The diagnosis of primary hypothyroism
requires the measurement of both TSH and
T4
Patients with type-1 diabetes should have a
check of thyroid function included in their
annual review. Patients with type-2 diabetes
should have their function checked at
diagnosis but routine annual thyroid function
testing is not recommended
Patients stabilised on long term thyroxine
treatment should have TSH checked annually

Guidelines
The thyroid status of hypothyroid patients
should be checked with TSH + T4 during each
trimester
Ideally the following sequence of TFT should be
performed in the hypothyroid women during
pregnancy
Before conception
At time of diagnosis of pregnancy
At antenatal booking
At least once in 2nd and 3rd trimester
Again after delivery at 2 4 weeks post partum
Newly diagnosed hypothyroid will need testing
every 4 6 weeks until stable

Thyroid Antibodies
Thyroid Peroxidase(thyroid microsomal)
100% in Hashimato thyroiditis
87% with graves disease
Thyroglobulin Antibody
76% of Graves Disease
Thyroid receptor antibody
Normally present in 12 18 % of
female population

Measure TSH
Elevate
d
Measure unbound T4
Normal

Pituitary disease
suspected
No
yes

Low

Mild
hypothyroidi
sm
TPO Ab
(+)
or
symptom
atic

Normal

TPO Ab
(-)
or no
sympto
ms

Primary
hypothyroidi
sm
TPO
Ab
(+)

TPO
Ab (-)

No
further
test

Measure
unbound
T4
Lo
Norm
w
al

No
Rule out other
further
causes of
test
hypothyroidism
Autoimmune
Rule out drug effects,
T4 treatment
hypothyroidism
sick euthyroid
syndrome, then
Annual follow T treatment
4
Evaluate anterior
up

Application of TSH examination

Bioassay
Vary in
sensitivity
Inconvinient

RIAs
Sensitivity 1mu/L
Cross reaction < 1
%
Hypothyroid

Hyperthyroid
TSH 0.05 - 0.11mu/L

Detecti
on

ICMAs
< 0.1

Euthyroid
0.4 4.0

IRMAs
Sensitivity
10 - 200 x RIAs
Hypo +
euthyroid

Hypothyroid
4 m U/L

II

Immunoassay
I : 5 7 mU/L
II: 0.1 0.2

Immunoassay
III: 0.01 0.02
IV: 0.001 0.002

Autoimmune Thyroiditis (AIT)

Anti Tg
Cytoplasma
follicular
Complemen
t activation
(-)

Anti TPO
105 kDa, microsomal
Thyroid peroxidase
enzyme
Pos correlation: anti TPO
& PPTD
Complement activation

AntiTSH-R

Hyperthyroid

Hypothyroid
!! In GD

Ab bispecific: Ab
(+) TPO more frequent & higher than anti
Only anti TPO (+): rare
Anti TPO & anti Tg in GD: not established (discussion)

Routine detection Ab thyroid: only anti TPO

Prevalence of anti

Ab
bispecific

TPO

PPTD: 16 %

PPTD (post partum

N population: 1.4

thyroiditis): 16 %

Graves disease: 34.6 %

Anti TPO Hasimoto

& AIT thyroiditis: 40.5 %
Clinical relevancy: not clearly
Correlation with active clinical
disease
Strong correlation with risk of

Anti TPO for predict PPTD

Variation of sensitivity & specificity
Depend on when anti TPO examined

PPTD (-) when anti TPO (-)

Screening anti TPO in early pregnancy

Anti Tg
Iodium Deficiency
Detection AIT (Goiter +)
Monitoring jodium Tx

Tiroglobulin (Tg)
Precursor of thyroid H
Produced in thyroid gland

IHA > 1: 1000

Secretion to colloid

T Hashimoto: 80 %

Thyroid H reserved

GD : 60 %

Receptor apical Tg for

Thyroid carcinoma: 30 %
IHA < 1: 1000
Normal: 3-18 %
Anemia Perniciosa
Syogren Syndrome

traffic intracellular Tg
Early indicator of PPTD
Rise in GD
Target anti Tg

Serum Tg Examination
Not distinguished: PPTD & GD
Interference: serum anti Tg
(reaction of anti Tg + anti Tg
antibody in immunoassay kit),
examination simultaneously Tg
+ anti Tg