Thyroid function

HPTh axis
Hormone action (post-receptor
mechanisms)
Thyroid follicle
Iodide & Hormonogenesis
Dyshormonogenesis
Endemic goitre
Thyroid hormones
Sick euthyroid syndrome
Actions of the thyroid hormones
Control of TSH secretion
Effect of TRH
Transport of thyroid hormones
TBPs

Protein bound iodine
Total thyroxine, TT
4
Total tri-iodothyronine, TT
3
Free thyroxine, FT
4
Free thyroxine index, FTI
TT
4
:TBG ratio
Free tri-iodothyronine, FT
3
Thyroid stimulating hormone, TSH
Tests of H-P-Th axis, TSH and TRH
tests
In vivo radio-active uptake tests
131
I

132
I
99
Tc
Thyroid auto-antibodies, TSI, LATS,
LATSP, colloid antibodies


.
.
ACTH, TSH, GH, LH
SEX/ STEROID HORMONES
THYROID HORMONES
.
.
Thyroid hormones
NB: Thyroid hormones act
via intracellular nuclear
receptors
.
.
thyroglobulin
Follicular cell
Para follicular cell
interstitium
(glycoprotein)
colloid
Main sources of iodide
Sea food
Fish
Iodated salt
Iodide.1
Daily requirement 20 g
Daily intake 70-200 g
Deficiency endemic goitre / cretinism
High concentrations of I- in saliva, milk
Prevention of iodine deficiency: addition
of Na+ I- to table salt
Iodide.2
Normally one-third of absorbed iodide is
taken up by the thyroid gland and the other
two-thirds excreted by the kidneys
Gland : plasma iodide ratio is normally 20: 1
(can go up to 100:1 or more)
Other glands that concentrate iodide are:
salivary glands, gastric mucosa and
mammary glands
Formation and release of thyroid
hormones
Steps:
Trapping of iodide
Oxidation of iodide to iodine
Incorporation of iodine into tyrosyl
residues
Coupling of iodo-tyrosyl residues
Release of T
3
and T
4
from thyroglobulin


.
.
Thyroid hormonogenesis

Thyroid hormonogenesis

Closer view
Dyshormonogenesis
Enzyme/process Inhibitor/Goitrogen
Trapping enzyme Perchlorate, thiocyanate
pertechnetate
Peroxidase Thiourea, methimazole,
carbimazole
Iodinase Carbimazole, propylthiouracil,
sulphonamides
Coupling enzyme Thiouracil
Blocks or difficulty in making thyroid hormones
Endemic goitre
Iodine deficiency+T
3
and +T
4
|TSH
TSH stimulates all physiological
processes of the thyroid gland
hyperplasia / hypertrophy of the thyroid
.
.
.
.
o |
Mono deiodination of T
4
in the
peripheral tissues (liver & kidney)


T
3
(35%)

RT
3
(40%)

T
4

Sick euthyroid syndrome
In the very old, starving, severely ill, acutely
ill and after trauma (e.g. surgery) and drugs:
(propranolol, amiodarone, radio contrast
media), there is:
Increased metabolism of T
4
to RT
3
Plasma T
3
level falls

There is minimization of BMR
NB: 20% of T
3
is made by the thyroid gland
and 80% is made by mono-deiodination of T
4


Actions of the thyroid
hormones.1
They speed up metabolic processes
(tissue oxidation)
They are essential for normal growth,
mental development and sexual
maturation
They increase the sensitivity of the CVS
and CNS to catecholamines (influence
cardiac output and heart rate)
Actions of the thyroid
hormones.2
In physiological concentrations thyroxine is a
protein anabolizer
In excess, thyroxine is protein catabolic (can
cause negative nitrogen balance)

Thyroxine stimulates gluconeogenesis

The abnormally high glucose tolerance test
curve found in thyrotoxicosis is primarily due
to rapid absorption of carbohydrate from the
intestine
Actions of the thyroid
hormones.3
Thyroxine lowers plasma concentration
of cholesterol and lipoproteins
Thyroxine also directly stimulates the
breakdown of bone
Control of TSH secretion.1
Circulating FT
4
and FT
3
reduce TSH
secretion by negative feedback
T
3
binds to pituitary nuclear receptors
as it does in other cells
Most of the intracellular T
3
in the
pituitary is derived from circulating FT
4


Control of TSH secretion.2
The pituitary gland is more sensitive to
plasma T
4
than to T
3
levels
In early hypothyroidism T
4
levels are low but
T
3
levels are normal
The effect of T
3
on peripheral tissues
minimizes the clinical effect of low T
4
levels.
But TSH may be elevated in response to
the low T
4
levels
Effect of TRH
TSH secretion is stimulated by
hypothalamic TRH
The TRH stimulatory effect can be
overriden by abnormally high circulating
FT
4
levels
Exogenous TRH has little or no effect
on TSH secretion in hyperthyroidism,
and can be used to test for this
condition
.
.
20%
80%
Transport of thyroid hormones
Transported as protein-bound and free
hormone in equilibrium
99.95% T4 and 99.5% T3 is protein
bound
Protein binding is so strong that only
0.05% of T
4
and 0.5% T
3
is free
hormone

Thyroid hormone binding proteins
Protein
(TBPs)
Amount of T
3
and
T
4
bound (%)

Thyroxine binding
globulin (TBG)
75
Thyroxine binding
pre-albumin (TBPA)
15
Albumin (Alb) 10
Hereditary TBG excess
Causes an increase in TT
4
and TT
3
levels
Benign
Needs to be recognized to prevent
unnecessary treatment
Factors that increase the TBPs
Pregnancy (30-40% higher than in the
non-pregnant)
Oestrogens (including high levels in the
newborn)
Oestrogen containing contraceptives
Hereditary TBG excess
Factors that decrease the TBPs
Chronic liver disease
Nephrotic syndrome
Malnutrition
Drugs that displace T
3
and T
4
from TBPs
Intake of androgens or danazol
Severe or chronic illness especially in the
elderly
Inherited TBG deficiency (rare)
Importance of free T
3
& free T
4

They are diffusible
They are responsible for the metabolic
effects of thyroid hormones
They regulate the output of TSH
Thyroid function tests1
Protein bound iodine
Total thyroxine, TT
4
Total tri-iodothyronine, TT
3
Free thyroxine, FT
4
Free thyroxine index, FTI
TT
4
:TBG ratio
Free tri-iodothyronine, FT
3
.
.
a: hyperthyroidism, b: hypothyroidism c: increased TBG, d: decreased TBG,
e: drug binding


Thyroid function tests2
Thyroid stimulating hormone, TSH
Tests of H-P-Th axis, TSH and TRH
tests
In vivo radio-active uptake tests
131
I
132
I

99
Tc
Thyroid auto-antibodies, TSI, LATS,
LATSP, colloid antibodies


Total thyroxine
Measured by RIA, EMIT, IMA
Changes in the levels of TBPs can cause
misleadingly high or low results
TBP-T
4
FT
4
+ U-TBP
>99.9% of T
4
is present as TBP-T
4

TT
4
effectively measures TBP-T
4
Other causes of low TT
4
Increased peripheral metabolism of T
4

Androgens
Corticosteroids
Some anticonvulsants (e.g. phenytoin)

Inhibition of secretion of thyroid hormones
Lithium
Phenylbutazone

Total tri-iodothyronine (TT
3
)

Measured by RIA, EMIT, IMA
Little cross-reaction with T
4
Main use is in the diagnosis of
hyperthyroidism
In most cases of thyrotoxicosis TT
4
|,

TT
3
|
In a few cases of thyrotoxicosis TT
4
,
FT
4
, TT
3
|, FT
3
|, (T
3
toxicosis)
Total tri-iodothyronine (TT
3
)
Total tri-iodothyronine (TT
3
) usually + in
hypothyroidism
Less sensitive for hypothyroidism than plasma
TT
4

Hypoactive thyroid glands produce an |
proportion of T
3

+ levels of T
3
in the old, severely ill, after
trauma and in certain acute illnesses (e.g.
MI)

Hyperthyroidism.1
TT
4
is usually |, >150 qmol /L
A few patients have normal TT
4
but
with an |TT
3
(T
3
toxicosis)
|Radio-iodine uptake
|Resin uptake
Low urine iodine excretion
|BMR
Hyperthyroidism.2
Lag-storage or diabetic type GTT curve
Low plasma cholesterol
|urinary creatine excretion
Demineralisation of bone with |urinary
calcium excretion
Hypercalcaemia especially with renal
damage
Hypothyroidism.1
TT
4
is usually +, <70 qmol /L
Sensitive test for hypothyroidism
Less sensitive than plasma TSH (||)
+Radio-iodine uptake
|Urine iodine excretion
+BMR, hypothermia
Flat GTT curve
Hypothyroidism.2
| Plasma cholesterol
|Protein content of interstitial fluid
||-lipoproteins
+ Resin uptake
+Decreased urinary ketosteroids
Free thyroid hormones: FT
3,
FT
4
More accurate, (i.e. sensitive and specific)
tests of thyroid status than TT
3,
and TT
4
Measured by:
Equilibrium dialysis , RIA, EMIT, IMA
Estimated by:
Free thyroxine index (FTI)
Total T
4
: TBG ratio
Because FT
4
can now readily be measured
few laboratories still determine FTI and TT
4
:
TBG ratio
Thyroid stimulating hormone (TSH)
Measured by RIA, EMIT, IMA
Some methods cannot distinguish between
subnormal and low normal TSH levels (cannot
be used in diagnosing hyperthyroidism)
Valuable measurement in 1 hypothyroidism:
Plasma T
3
,T
4
and in vivo radio-active
uptake tests normal in early 1
hypothyroidism (TSH |)
Also important in 2 hypothyroidism: TSH +
TSH response to TRH
stimulation
.
The TRH Test
T4 levels may be high-normal
Low T4 levels
The TRH test.1
In hyperthyroidism due to increased
plasma T
4
levels, increased negative
feedback overrides the TRH stimulation
No response to TRH may be
demonstrable when plasma T
4
levels are
still within the upper reference limit
A normal response to TRH excludes the
diagnosis of hyperthyroidism
The TRH test.2
In hypopituitarism with secondary
hypothyroidism the anterior pituitary is
unable to respond normally to TRH
Plasma T
4
levels will tend to be low
There is an exaggerated TSH response
in primary hypothyroidism because of
the reduced negative feedback due to
low T
4
levels

In vivo radio-active uptake tests
Measure the uptake of an oral dose of
radioactive iodine (
131
I; half-life 8 days
132
I; half-life 140 min)
I.V. Technetium 99m (
99m
Tc; half-life,
6h)
In vivo radio-active uptake tests
Uses :
Help with calculation of dose of radio-activity
required in treatment of hyperthyroidism
(
99m
Tc unsuitable)
Monitor thyroid function in patients treated
with anti-thyroid drugs
With scanning of the thyroid to determine if a
nodule is hot or cold
Determine if there is extra-thyroidal
functioning thyroid tissue
Thyroid auto-antibodies
Complement-fixing antibodies specific
for thyroid tissue
Present in >80% of patients with
Hashimotos disease
(anti-TPO, anti-Tg, TSH receptor
blocking antibodies)
Thyroid auto-antibodies
Antibodies to thyroglobulin
Can be detected in most cases of early or incipient
hypothyroidism
80% of hyperthyroid patients also have antibodies to
thyroglobulin in the serum
Found in a small proportion of healthy individuals
Thyroid microsomal antibodies in Graves and
Hashimotos diseases
Antibodies to a second colloid antigen reported in all
forms of auto-immune thyroiditis and in de
Quervains thyroiditis
Thyroid auto-antibodies
Thyroid stimulating immunoglobulins (TSI
formerly known as LATS)
In Graves disease IgG antibodies directed
against TSH receptors are present: binding to
receptors thyroxine production
Others; thyroid growth immunoglobulins (TGI)
stimulate thyroid growth but not hormone
production
Miscellaneous tests
Basal metabolic rate (BMR)
Glucose tolerance tests
Plasma calcium
Plasma LDL-cholesterol
Plasma creatine kinase
Reference intervals
MIT + DIT < 0.5g /100 ml
PBI = 4 -7.5g /100 ml
PBI in thyrotoxicosis =7-20g /100 ml
PBI in myxoedema =0-3g /100 ml




Reference intervals
Thyroid function
Reference intervals
Thyroid function
Reference intervals
FT3 3.0-8.6 pmol/L
TT3 1.2-3.4 nmol/L
FT4 9-23 pmol/L
TT4 55-140 nmol/L
TSH 0.2-5.5 mU/L
Thyroid hormonogenesis
You can skip this
diagram if it
appears too
complex for you
PBI
Screening test
An estimate of TT
4

90% of PBI is T
4
Unspecific: measures T
4,
T
3,
MIT, DIT,
Tetrac, Triac
Measures iodine containing drugs

(Cough mixtures and X-ray contrast
media)
FreeThyroxine Index
(TBP-T
4
FT
4
+ U-TBP)
.
(Put the unknowns together): [FT4]/K= [TT4]/[U-TBP]=FTI
Measurement of U-TBP: Serum & resin uptake:
X-resin uptake = serum uptake
.
Resin uptake
Serum uptake
Radioactive T3
Patients sample
.
FTI..1
If there is any change in levels of
binding proteins e.g. |, the measured
T
4
and U-TBP change in the same
direction.
The FTI corrects the abnormal total T
4

levels
FTI..2
In thyroid disorders if levels of binding
proteins are unchanged the measured
T
4
and U-TBP change in opposite
directions (vary inversely)
The FTI exaggerates the abnormal
total T
4
levels
Total T
4
: TBG ratio
TBG measured by RIA
Total T
4
: TBG ratio; better index than
FTI
Has not gained wide acceptance
because it still requires two
measurements
It does not make allowance for changes
in [TBPA] and [Albumin]