Thyroid

Dr Nafiu Amidu
• Thyroxine (T4) + tri-iodothyroxine (T3) = Thyroid
hormone
• TH are synthesized in the thyroid gland by iodination
& coupling of 2 tyrosine molecules whilst attached to
a complex protein called THYROGLOBULIN
• Thyroid gland secrets mostly T4 i.e. about 100
mmol/l in plasma
• Peripheral tissues (e.g. liver and kidney) deiodinate
T4 to produce approx. 2/3 of T3 (active)
• It is T3 that binds to receptors and trigger the end-
organ effects of the TH
• Also, T4 can be metabolized to reversed T3 (rT3)
(biological inactive) when T3 synthesis is impaired
 Thyroid hormones
NH3+ NH3+ NH3+

HC COO- HC COO- HC COO-

CH2 CH2 CH2

I I I I I

O O O

I I I I I

OH OH OH
Tetraiodothyronine 3,5,3´ Triiodothyronine 3,3´,5´ Triiodothyronine
(T4, Thyroxine) (T3) (reverse T3)
 Effects of thyroid hormones
• Stimulate fetal neural & Skeletal development
• ↑ bone formation & resorption
• Promote conversion of carotene to Vitamin A
• ↑ RBC production
• Calorigenic ( O2 consumption)
• Growth, development, sexual maturation, CNS
maturation
• ↑ basal body temperature
• ↑ metabolism and clearance of steroid hormone
  HR and contraction
  Protein synthesis, C(H2O)n metabolism, lipid turnover
  Sensitivity of -adrenergic receptors to catecholamines
• Brain, retina, lungs, spleen, testes appear to be unaffected
by thyroid hormones
 Regulation of TH Secretion
• The component of the hypothalamic-pituitary-
thyroid axis are TRH, TSH and TH
• TRH - tripeptide and TSH – glycoprotein
• TSH production is feedback regulated by circulation
unbound TH i.e.
• ↑ in TH leads to ↓ in TSH and
• ↓ in TH production leads to ↑ TSH in an attempt to
stimulate thyroid gland to secret more
• Thyroid function test normally includes TSH, T4
and sometimes T3
• T4 ½ life is 7 days compare to T3 of 1 day
 Goitre
• A goitre is an enlarged thyroid gland
• May be caused by hypofunction, hyperfunction or
normal concentration of of thyroid hormone
• Biochemistry laboratory can confirm if a patient is
hypothyroid, hyperthyroid or euthyroid
• NB: There is a diurnal rhythm with the serum TSH
peaking around midday when the concentration is
approx. 30% higher than midnight, when it is at its
nadir.
• Things that affect the transport protein would affect
TH. So no TH in sick person
Regulation of thyroid hormones

TRH

TSH

T4 T3
(T3)
(rT3)
 Synthesis of TH
• Thyroid gland use energy-requiring process to
transport dietary iodide (I-) from circulation into the
thyroid

• Iodide is oxidized to iodine (I2) by thyro-peroxidase

(TPO) and then combine with tyrosyl residue within
the thyroglobulin to form thyroid hormone
(iodothyronines)

• TH are formed & stored within thyroglobulin protein

for release into circulation
• Coupling of two iodinated tyrosine molecules
yields T4, which, still part of the thyroglobulin
molecule.
• T4 is stored as colloid in the thyroid follicle.
• Proteolysis of thyroglobulin by follicular cells
yields the free hormone, which is released into the
bloodstream.
• Rarely, congenital hypothyroidism is due to a
defect in one of these metabolic steps.
• Also, several of these biosynthetic steps are targets
for anti-thyroid drugs (eg carbimazole), used to
treat thyroid overactivity.
 Thyroid hormone production
Follicle Colloid
TPO
T1 T2
Iodide (I ) - NIS *
I-
(40X) Thyroglobulin

T4 T3 T4

TBG Thyroglobulin
T4 T3
T4
Alb Thyroglobulin

T4
TSH
TBPA

*
Sodium/Iodide Symporter protein
 Thyroid hormone synthesis

OH OH

I I I I

OH OH O O

I I I I Thyroglobulin I I
Tyrosyl
I-
residue protease

TPO TPO

CH2 CH2 CH2 CH2

HOOC NH2

Thyroglobulin Free
thyroxine
Peripheral T4 metabolism
OH

I I

I I

5'-(3'-) Deiodinase 5-(3-) Deiodinase

OH CH2 Three types OH
Type I or II
I I I
HOOC NH2
40% 45%
T4
O O

I I I

CH2 CH2

HOOC NH2 HOOC NH2

T3 reverse T3
Peripheral thyroxine metabolism
• T4 production is exclusively thyroidal
• 70-90% of T3 is produced extrathyroidally
• 95-98% of rT3 is produced extrathyroidally
• Most peripheral de-iodination occurs in the liver
• T3 accounts for most of the thyroid hormone activity
in peripheral tissues
– 3-4 times more potent than T4
– Some researchers have questioned whether T4 has any
intrinsic biological activity
– rT3 is biologically inactive
 TH Circulation
• TH are circulated bound to 4 protein:
• Majority to thyroxine-binding globulin
• The rest to thyroxine-binding prealbumin (TBPA or
transthyretin), albumin and apolipoprotein
• Only about 0.02% of T4 & 0.2% of T3 circulate
unbound, free to diffuse into tissue
• The free form is the metabolically active form
• Total and free hormone exist in an equilibrium state
• The bound form serve as a reservoir for making the
free fraction available to tissue
• Because it is the free, biologically active, form of
the hormone that is regulated by TSH, factors that
increase (oestrogens) or decrease (protein
malnutrition, nephrotic syndrome) TBG will lead
to an increased or decreased total T4, respectively,
while the patient remains euthyroid with a normal
level of freeT4.
• Measurement of the free hormone levels directly
(freeT4 and freeT3). TSH assay also helps by
providing a useful independent marker of free
thyroid hormone status at the tissue level.
Circulating thyroid hormones
99.97% T4
T3 T4
TBG

T3 T4 fT4 (0.03%)
Alb fT3 (0. 3%)

T3 T4
TBPA
Only free hormone is active!

99.7% T3
 Affinities of thyroid binding
proteins

TBG >>> TBPA >> Alb

68% of T4 11% of T4 20% of T4

80% of T3 9% of T3 11% of T3
Low conc. (0.27 M) Low conc. (4.6 M) High conc. (640 M)
High affinity (K=1010) Low affinity (K=107) Low affinity (K=105)
54 kDa 15.5 kDa 66 kDa

A small fraction of thyroid hormones is bound to lipoproteins

 Increased protein binding

  TBG
– Genetic, Nonthyroidal illness (HIV, hepatitis,
estrogen-producing tumors, autoimmune
pancreatitis), pregnancy, drugs
  Prealbumin (TBPA) (euthyroid thyroxine
excess)
• Albumin variant (familial dysalbuminemia
hyperthyroxinemia)
• T4 autoantibodies
 Decreased protein binding

  TBG
– Genetic, NTI (NS), drugs, nephrosis
  Prealbumin or TRANSTHYRETIN
(TBPA)
  TBG binding capacity (competing drugs
such as salicylate and phenytoin)
 Thyroglobulin (TG)

• 660 kd protein that is the intra-thyroidal

carrier of thyroid hormones
• Synthesized in the thyroid follicular cells;
secreted into the lumen
• Stored mostly in the colloid
• Synthesis, colloidal uptake, and proteolysis
(to release T4 and T3) regulated by TSH
 Thyrotropin (TSH)
• One of several hormones synthesized in the
anterior pituitary
– Others are LH, FSH, Prolactin, ACTH, GH
  (common with LH, FSH, hCG) and  subunits
• MW=30 kDa
• Binds to a TSH receptor on the thyroid
follicular cells to activate adenylyl
cyclase/cAMP protein kinase A and Ca++
protein kinase C pathways
 Thyroid disorders
• Patients with a normally functioning TG are said
to be in a euthyroid state
• When this is disrupted thyroid disease may result
• It occurs 4 times more often in women than men
and may occur at any age
• It peaks at 3rd and 6th decades of life
• There is often a family history, especially for the
autoimmune disease
• Thyroid disease often involve change in the
quantity or quality of thyroid hormone secretion
TESTS OF THYROID FUNCTION
 Sick Euthyroid

Healthy Sick

T3 T3

Peripheral T4

rT3 rT3
 Sick Euthyroid
rT3
Concentration 

TSH

Normal
fT4
T4 range

T3
Mild Moderate Severe Recovery

Phase of illness
 Hypothyroidism

• A deficiency in thyroid hormone activity

– Occurrence as high as 15%, with ♀preference
– Myxedema is severe form
– Untreated congenital hypothyroidism results in
severe developmental deficits
• Can be structural or functional
– 1° = deficiency in thyroid hormone production
– 2° (or “central) = pituitary or hypothalamic failure
• Hypothalamic failure sometimes called “3°”
 Clinical feature
• Lethargy and tiredness
• Cold intolerance
• Weight gain
• Dryness and carsening of skin and hair
• Slow relaxation of muscles & tendon reflexes
• Hoarseness
• Anaemia, demantia, constipation, subfertility and
galactorrhoea
 Primary Hypothyroidism

• Iodine deficiency (most common worldwide)

• Hashimoto’s thyroiditis (most common in
developed countries)
– Autoimmune (α-TG or α-TPO)
• Non-goitrous causes
– Radioactive I2 therapy/exposure; surgical ablation
– Congenital (1 per 3500 to 4000 live births)
 Secondary Hypothyroidism

• Pituitary (TSH) or hypothalamic (TRH)

failure.
• Isolated TSH deficiency is rare; usually
associated with panhypopituitarism.
– Sheehan’s Syndrome
– Endocrine-inactive adenomas
– Other space-occupying lesions
 Stages of Hypothyroidism

Stage of disease TSH fT4 T3

Sub-clinical  nl nl

Early   nl

Mature   
 Treatment
• Replacement therapy with T4 is the treatment of
choice

• Monitoring is essential for adequacy of treatment

• Once the dosage is established patient would be

required to take it for life

• Delay in treatment in neonate results in

CRETINISM
 Hyperthyroidism (thyrotoxicosis)

• Increased thyroid hormone production

– Graves’ Disease (most common; α-TSH receptor)
– Toxic multi-nodular goiter
– Solitary toxic adenoma or pituitary adenoma
• Normal thyroid hormone production
– Thyroiditis (thyroid hormone leakage)
– Thyrotoxicosis facticia
– Metastatic thyroid carcinoma or struma ovarii
 Clinical features
• Weight gain despite normal appetite
• Sweating and heat intolerance
• Fatigue
• Palpitation – sinus tachycardia or atrial fibrilation
• Agitation and tremor
• Generalized muscle weakness
• Angina and heart failue
• Diarrhoea
• Oligomenorrhoea and subfertility
• Goitre
• Eyelid retraction and lid lag
 Stages of Hyperthyroidism

Stage of disease TSH fT4 T3

Sub-clinical  nl nl

T3 toxicosis  nl 

Classic pattern   
 Treatment
• There are 3 methods:
• Antithyroid drug e.g. carbamazole,
propylthiouracil for younger patient
• Radioactive therapy (sodium 131I) in older patient
• Surgery. Many patients who have subtotal
thyroidectomy may later require thyroxine
replacement
• Thyroid function test are important in the
monitory of all three treatment
 Summary of thyroid autoantibodies

Autoantibody Target antigen HT GD

Thyroid microsomal Thyroperoxidase  
autoantibody (TMA) (TPO)
Thyroglobulin autoantibody Thyroglobulin  
(TGA) (TG)
TSH receptor autoantibody TSH receptor 
(TRAb)
Thyroid-stimulating TSH receptor 
immunoglobulin (TSI) (agonist)
Thyrotropin-binding inhibitory TSH receptor 
immunoglobulin (TBII) (inhibitory)
 Effects of Drugs on Thyroid
Hormones

Effect Drugs TSH fT4 T3

Inhibit TSH secretion dopamine, glucocorticoids   

Inhibit synthesis iodine, lithium   

Inhibit T4  T3 amiodarone, propranolol   

glucocorticoids
Inhibit protein binding salicylate, NSAIDs nl  
phenytoin, carbamazepine
Laboratory Evaluation of Thyroid
Function
nl
TSH Euthyroid
ND
 
Hyperthyroid? Hypothyroid?

Borderline

fT4 fT4, T3
fT4
if N, T3 TRH?