Download Endocrinology 2b – Hypothyroid Disorders

Endocrinology 2b – Hypothyroid Disorders
Anil Chopra
1. List the possible causes of hypothyroidism and differentiate between cretinism
and myxoedema.
2. Describe the clinical features of hypothyroidism.
3. Describe how myxoedema is diagnosed.
4. Describe the treatment for myxoedema. The following specific questions
highlight some important pharmacological considerations:5. Drugs and Hypothyroid Conditions.
i) Define hormone replacement therapy.
ii) Name two drugs used in the treatment of hypothyroidism and distinguish
between them on the basis of their principal applications and routes of
administration.
iii) Categorise the actions of thyroid hormones in terms of their effects on
metabolism, growth and development and the sympathetic nervous system.
iv) Describe the mechanisms of action of thyroid hormones at the cellular level.
v) List the major unwanted effects of replacement therapy with thyroid hormones.
vi) Explain the function of thyroxine binding globulin.
vii) How may pregnancy and treatment with certain drugs (e.g. oral
contraceptives, phenothiazines, phenytoin, salicylates) alter the free plasma
concentrations of thyroid hormones and what are the implications of these factors
for patients taking thyroxine.
6. Describe the radioisotopic imaging of the thyroid in normal and disease states.
7. Describe the possible effects of the immune system on the thyroid gland.
Revision of Hypothalamo-pituitary-thyroid (HPT)
axis:
 Hypothalamus releases TRH (Thyrotrophin
Releasing Hormone) → Adenohypohysis releases
Thyrotrophin (TSH – Thyroid Stimulating Hormone)
→ causes release of Iodothyronines (T3 and T4) from
thyroid. This negatively feeds back to the
hypothalamus and adenohypophysis
 Oestrogens have a positive effect on the
adenohypophysis and glucocorticoids a negative
effect
THE THYROID GLAND
Follicular
cells
trachea
colloid
FOLLICLES
Essentially bilobed
THYROID GLAND
Iodothyronine production in the follicular cells of the thyroid
 Thyroglobulin synthesis:
o The amino acid tyrosine is converted into the glycoprotein
thyroglobulin
 Iodine Trapping:
o Plasma iodide ions (I-) are actively transported from the plasma into
the follicular cells against a strong concentration gradient. This is the
rate limiting step.
 Iodide Oxidation:
o I- is rapidly oxidised into I2 by a peroxidase enzyme near the luminal
membrane, increasing its reactivity
 Iodination of thyroglobulin:
Parafollicular
cells
o Reactive iodine rapidly attaches to the tyrosine molecule using
thyroperoxidase, an enzyme on the luminal membrane of the follicle
cell. T1 and T2 are formed
 Coupling:
o Combinations of T1 and T2 are joined together as the tyrosine
molecules within thyroglobulin are coupled.
o T3 is made from T1 + T2
o T4 is made from T2 + T2
 Only a small number of coupling reactions form T3 (3 iodine molecules) and T4 (4
iodine molecules)
 Iodinated thyroglobulin is stored in the colloid tissue of the thyroid gland
Actions of T3 and T4:
 Metabolism – metabolism of carbohydrate, fat and protein is increased:
 Direct effects
 Indirect effects – via actions of insulin, glucagon, glucocorticoids,
catecholamines, adrenoceptor expression
 BMR (Basal Metabolic Rate increases)
 O2 consumption and heat production increases
 CO and HR Increase:
 Calorigenic and sympathetic nervous system effect
 Growth and Development:
 Skeletal development – direct action on cells, indirectly via increase in GH
production and responsiveness to its effects
 CNS development –
 Action of parathormone and calcitonin (produced by parafollicular cells)
 Effects on Sympathetic Nervous System:
 Sensitises β-adrenoceptors to ambient levels of NA and A
 This causes sympathetic activation
 Causes tachycardia, palpitations, tremor in hands and lid lag
TRH = thyroid releasing hormone
TSH = thyroid stimulating hormone
T3 – mono-idotyrosine with di-iodotyrosine
T4 – two molecules of di-iodotyrosine
Primary Hypothyroidism (myxoedema):




Immune system damages follicular cells of the thyroid glands.
Start to make less and less thyroxine
Thyroxine levels decline
TSH levels go up in order to compensate.
Can eventually result in a myxoedema coma. This normally occurs if the
hypothyroidism is undiagnosed (e.g. old people’s homes). They have confusion,
bradycardia, hypothermia, hypoventilation, and unconsciousness.
Can also result in abnormal brain development in neonates. This can result in
cretinism. Caused by lack of thyroxine in early life. Cretins are very small in stature
and will remain so if not treated in life.
Symptoms
 Deep voice.
 Depression
 Tiredness.
 Cold intolerance.
 Weight gain with reduced appetite
 Constipation
 Bradycardia






Mental slowing
Goitre
Muscle weakness
Coarse, thin hair,
Pale puffy face
Chronic oedema
Diagnosis:
 History in adults
o Diagnosed by signs and symptoms, and circulating TSH and Thyroxine
levels. Free thyroxine is low, TSH is high. Autoantibodies can also be
detected in Hashimoto’s thyroiditis
 Heel prick test at birth to test for TSH (along with Guthrie test for
phenylketonuria) at 5-10 days. If TSH is high, then thyroxine is given
immediately.
Pharmacology
Name
Thyroxine T4 - Levothyroxine sodium (a prohormone)
Tri-iodothyronine T3 - Liothyronine sodium (active hormone)
Usage
T4 Replacement used in treatment of
 Primary Hypothyroidism (Hashimoto’s Disease)
o Autoimmune response
o Anti-thyroglobulin, anti-thyroid peroxidase, and TSH blocking antibodies.
o Lymphocytes and macrophages invade the thyroid gland.
 Iatrogenic hypothyroidism
o Glucocorticoids
o Thiourylenes
o Lithium
 Thyroid gland destruction with radioiodine.
T3 Replacement used in the treatment of
 Myxoedema coma treatment (rare) given i.v. when rapid treatment is needed
o If the myxoedema coma is caused by an iodide deficiency, then replace
with iodine.
Mode of Action
Actions of T3 and T4
- metabolism of carbohydrate, fat, and protein is increased
- indirect effects on insulin, glucagon, glucocorticoids, catecholamines,
adrenoceptor expression
- Basal Metabolic Rates increases: O2 consumption, heat production increases,
kidney, gonads, spleen, brain.
- Cardiac output and heart rate increases.
- Promote adequate brain and skeletal development by increasing growth
hormone production and responsiveness, thus preventing cretinism, mental
retardation and dwarfism.
Intracellular receptors belong to families of nuclear receptors  causes transcription.
- hormone binds to the nuclear receptor (NB – normally it is T3 that binds to the
receptor, not T4. T3 is converted to T4 in the cells).
- the complex formed by this causes transcription of RNA (different for the
different cells).
Side Effects
- high basal metabolic rate, increased temperature, sweating e.t.c. (symptoms of
hyperthyroidism).
- Actions on the sympathetic nervous system activity. (e.g. risk of precipitating
angina pectoris, cardiac dysrhythmias or cardiac failure.)
Pharmacokinetics
 Administered Orally
 Accumulate if given daily
o T4: Half-life of 6 days (peak effect 9 days)
o T3: Half life of 2-5 days (peak effect 1-2 days)
 100% binds to plasma proteins, mainly thyroxine binding globulin (TBG)
 T3 and T4 are transported in the blood mostly bound to plasma proteins:
 Thyronine-binding globulin (TBG) approx 75% of T3 and T4
 Albumin approx 5%
 Pre-albumin 15-20% of T4 and very small amounts of T3
 Only the unbound hormones are bioactive (approx 0.05% of T4and 0.5% of T3)
 Plasma binding proteins increase in pregnancy and on prolonged treatment with
oestrogens and phenothiazines.
 Certain co-administered drugs (e.g. phenytoin, salicylates) compete for protein binding sites.
 10 times more T4 in plasma than T3.
 Hormone metabolised and secreted in bile (liver) and urine (kidney).
In the case of secondary hypothyroidism (pituitary disorder), a TRH test is done. This
is when patients are given Thyrotrophin releasing hormone (protirelin – given IV
with short half life) and their TSH levels are measured. If there is an exaggerated
response, then patient has primary hypothyroidism, if there is not, then the patient has
secondary hypothyroidism.
Altering Concs of Free Plasma Thyroxine
» Almost 100% of both forms in circulation is plasma protein bound (see above)
» By altering the TBG properties and quantities the dose of hormone needed is changed
o Plasma binding proteins increase in pregnancy and with prolonged treatment
with estrogens and phenothiazines – acts to decrease amount of active
unbound hormone
o Phenytoin and Salicylates compete for binding sites – acts to increase the
amount of active, unbound hormone
Radiosiotopic imaging of the thyroid in normal and diseased states
 Radioisotope scanning using radioactive iodine can show the size of the thyroid
gland and any abnormal “hot” areas such as toxic adenomas..
Possible effects of the immune system on the thyroid gland
 The immune system can either cause hyperthyroidism, or hypothyroidism in its
effects on the thyroid gland
Hyperthyroidism:
Grave’s Disease – auto-antibodies against TSH receptors in the thyroid gland
stimulate the receptors so thyroid hormones are released in excess. The most common
cause of hyperthyroidism Most common in middle-aged women and can also progress
to hypothyroidism with time
Hypothyroidism:
Hashimoto’s Thyroiditis – a destructive autoimmune disease common in middle aged
women. Auto-antibodies against the RER or against thyroglobulin. The initial destruction
of the thyroid gland can cause a release of thyroid hormones and initial hyperthyroidism.
The disease causes infiltration of lymphocytes and gland swelling (goitre).