36-Thyroid gland: disorders and treatment Flashcards
The thyroid gland
-Endocrine gland
-Synthesises, stores and secretes the thyroid hormones, T3 and T4
+T3= Tri-iodothyronine
+T4= Tetra-iodothyronine (thyroxine)
-Thyroid hormones increases basal metabolic rate
+Essential for growth and development: Cretinism= infant hypothyroidism
+Essential for healthy life
Essential stages of T3/T4 secretion
-See iodination (organification of tyrosine first
-Iodine uptake into cell
+Active transport by carrier
-Iodination of tyrosine residues on thyroglobulin (TG)
+By thyroperoxidase enzyme
+Called organic binding
-Formation of T3 and T4 from MIT and DIT
-Endocytosis of TG, enzymatic release of T3 and T4, secretion
Action of thyroid hormone
Affecting growth and development
-Direct and indirect action on cells
+Potentiates secretion and effects on growth hormone
-Needed for normal skeletal development and maturation of CNS
-Act by entering cell nucleus, T3 binds to receptor and switches it OFF
+Receptors normally STOPS transcription
+SO T3 causes increase mRNA and protein synthesis in cells
-NB because there work at the level of DNA it takes bit longer than receptor type responses
Transport and Action of thyroid hormones
-T3 and T4 transported bound to a protein carrier, TBG, little free
+TBG (thyroxine binding globulin)
-LARGE Pool T4, less active and mainly in circulation
-SMALL pool of T3, mainly intracellular
+T4 converted to T3 in target tissues, T3 is the active form
Metabolism
- Deiodination
- Deamination
- Conjugation with glucuronic and sulphuric acids
When the system goes wrong
-Hypersecretion- Too much
-Hyposecretion- Too Little
-For each:
What might causes it?
What would happen to the body
Disorders of the thyroid function (hyperthyroidism- Graves disease)
Hyperthyroidism (Graves disease)
-Occurs in 2% of women, which is 10x incidence observed in men
-Autoimmune disease
+Abs directed against proteins on surface of follicular cells
-Causes overproduction of thyroid hormones
-Possible involvement of environmental or emtional trigger factors
NB- always check what other drugs patient is on e.g. amiodarone can cause hyper and hypothyroidism
-Historical treatment: rest and sedation: 50% mortality rate
Diagnosis
-Physcial examination
-Family history
-Blood tests
+Hormones (T3,4 increase)
+TSH levels (increase)
+Thyroid Abs
-Thyroid scan (iodine uptake radioactive)
-Goitre
-Exophthalmos- eyes popping out
Clinical features (of hyperthyroidism)
Result from generalised over activity of thyroid gland
- Hot, flushed, heat intolerant
- Enlarged thyroid gland (goitre)
- Exophthalmos
- Weight loss
- Muscle weakness, tremor
- Pulse rate increase, palpitations, sweating
- Hair loss, menstrual changes
- This can cause more serious diseases including AF
Treatment of hyperthyroid
1) Drug treatment (aim and major side effects)
Anti-thyroid drugs: Decrease T3/T4 secretion: used for
-Prompt control: relieve symptoms
-Mild hyperthyroidism
-Children or young adults
-Temporary treatment
-Treatmeant for 12-18 months
+Prolonged remission in 20-30% patients
-Allergic reactions 5%, rashes, fever, pains
-Neutrophils decreased, infection risk= death
-Agranulocytosis: rare, possible fatal
+Patient develops infection, sore throat, fever, mouth ulcers, brusing . get a blood test MUST WARN PATIENT
Anti-thyroid drugs 1.
Drugs which inhibit organic binding of iodine
The thiourelynes (thionamides)
-Carbimazole: precursor of methimazole which inhibits oxidation of iodide and coupling to tyrosine
+1st line in UK
+Thought to act by inhibiting the thyroperoxidase enzyme
-Propylthiouracil (PTU): also inhibits peripheral de-iodination of T4 to T3
+(T4 pro-hormones, less active, more abundant)
+In UK kept for people unable to take carbimazole
How is carbimazole used
-Give in high doses till euthyroid
-Reduce to maintenance dose
-Withdraw after 1-2 years and monitor
Clinical effect note:
-Rapid action to inhibit organic binding BUT large stores of T3 and T4 must be ‘Used up’ before therapeutic effects
Anti-thyroid drugs 2
-Drugs which reduce the uptake of iodine
+Thiocyanate
+Perchlorate
-Reduce uptake of iodine ion
+Seldom used today because of danger of aplastic anaemia (bone marrow damage reduces haemotopoietic stem cells)
-Sensible drug target … but side effects mean not clinically useful
Drugs used to relieve the symptoms of hyperthyroidism
Beta-blockers (BB)
-Propranolol, nadolol (less common)
-Used to reduce symptoms of overactivity of the sympathetic nervous system
+Reduces tumor, tachycardia, and the anxiety associated with the condition
+Not anti-thyroid
-Used in many patients prior to and during initiation of other treatments to reduce distress while waiting for therapeutic effects
NB- C/I in some patient.. asthmatics
Non-drug treatment of hyperthyroidism: radioactive iodine
- 131-Iodine given as Aqueous solution or capsules
- Taken up by active transport and concentrated in gland by I pump (this is specific because the thyroid is the only cells that take up iodine)
- Local tissue destruction by X-ray and beta-particle emission
Normal follicle anatomy
- Gland is made up of lots of little follicles
- These contain the cells that are responsible for synthesising hormones
- Colliod is a storage area in the middle which stores hormone
- Lots of capillaries, lots of blood flow to take hormones and signals to and from
- Hyperthyroidism (to high levels of hormone), the cells get bigger and swell so they pump out more hormone, they also have a smaller colloid so there is less storage- the swelling seen is known as a goitre
- Hypothyroidism the cells become smaller meaning there ability to pump out hormone is reduced- the increased signal to produce more hormone with no results can cause the swelling fo the glands known as a goitre
See iodination (organification of tyrosine first
- 2 molecules of Tyrosine binds to thyroglobulin
- Thyroid peroxidase places 2 iodide groups (on the aromatic ring) on each tyrosine forming diiodotyrosine (DIT)
- Thyroid peroxidase takes Off one tyrosine the benzene group with -OH and 2 iodide groups come and and bind to the other tyrosine forming thyroxine
- The reaction is known as iodination of tyrosine
- You can also have the same process with just one iodide group this is monoiodotyrosine (MIT)
- MIT+ DIT= T3
- DIT+DIT= T4
Synthesis and secretion of thyroid hormone
-Iodine active pump- brings iodine into the cell (if we block iodine pump no synthesis of thyroxine)
-T3 and T4 are produced
proteins are bound to it, and placed in thyroglobulin precursors in secretory vesicles
-Through pinocytosis occurs to bring more T3 and T4 in, proteolysis occurs to remove proteins from the hormones
-T3 and 4 are secreted into the blood
Action of thyroid hormones: metabolism
- Regulate metabolism in most tissue
- Modulate effects of other hormones (glucagon)
- T3 more potent than T4
- Increase metabolism of carbohydrates, proteins and fat
- Increase O2 use and heat production (due to increased metabolism in tissue)
- Increased basal metabolic rate
Control of thyroid hormone secretion
HPT AXIS
- HPT (hypothalamus, anterior pituitary, Thyroid gland) axis
- Other brain centres (e.g. cold outside)- must increase metabolism therefore increase thyroid hormone
- Hypothalamus release TRH (thyrotropin releasing hormone) to act on the anterior pituitary
- Anterior pituitary releases TSH (thyroid stimulating hormone) which acts on thyroid gland
- Thyroid gland then releases thyroid hormone into target cells throughout the body
- Thyroid hormone gives negative feedback to the pituitary and hypothalamus to inhibit them to prevent over secretion
Radioactive iodine
- Slow progressive effect, difficult to control
- May produce hypothyroidism due to more destruction (need replacement therapy)
- 1st line treatment
- Or after failure of anti-thyroid drugs
- Or after failure of thyroidectomy
- Or a standard procedure for some thyroid cancers
Non drug treatment of hyperthyroidism: Surgery
-Thyroidectomy
+For patients where 131-I and drugs have failed
+Patients with large goitre: cosmetic effects, swallowing or breathing difficulties
-Ideally: sub-total thyroidectomy leaving patient with enough gland to be euthyroid
+BUT possibility of recurrent thyrotoxicosis or developing hypothyroidism is great
-Hypothyroidism: Need thyroid replacement therapy
Aim of all of these treatments
- Patient is euthyroid- normal hormone levels
- BUT what if they become hypothyroid
Hypothyroidism (symptoms and potential causes)
-Syndrome cause by deficiency of thyroid hormones
+weakness, fatigue, cold intolerance
+Weight gain, skin thickness
+Intellectual deterioration, mental and physical lethargy
+Goitre (increased TSH)
-Possible causes
+Congenital
+Autoimmune disease: Abs to thyroglobulin
+Inflammation of thyroid (hashimotos thyroiditis)
+Dietary iodine deficiency
Names for types of hypothyroidism
-Hashimotos thyroiditis (Auto-immune)
+Inflammatio, fibrosis and decreased function of thyroid gland. goitre evident
-Myxoedema
+Hypothyroidism developing in adult life
+Adult onset slow and insidious, confused with normal ageing process. increase in women
+In rare cases, becomes medical emergency, requires treatment by T3
-Cretinism: affects children from birth
+Mental retardation, pot belly, dwarfism
+Prevented by rapid treatment with T4 at birth
(Maternal I deficiency and congenital dysfunction in hormone biosynthesis)
Thyroid replacement therapy
-Thyroxine used to replace deficiency
-Aim of therapy
+replace thyroid hormone function
+Normal physical and mental development
=Reduced goitre (Suppress raised TSH levels
-optimum dose determined individually
+Single dose before breakfast
+Empty stomach, 30 mins before food
+Counsel re drug interactions which can impair absorption or metabolism
+Antacids, Fe drugs affecting CYP450 enzymes MUST MONITOR
Thyroid replacement therapy
-Life long therapy, monitor effects
-Signs of overdose
+Tremor, agitation, weakness
-Insomnia
-Weightloss, flushing
-Arrhythmias, anginal pain
-Diarrhoea
NON compliance leading to increased doses
-Check TSH levels if raised then not taking tablets
Drugs for thyroid replacement therapy
-Levothyroxine
+treatment of choice for maintenance
+Once daily dose
-Liothyronine
+similar action but more rapidly metabolised
+May be used in severe hypothyroid states
+Used IV as part of supportive treatment of thyroid coma
Monitoring of replacement therapy
-Monitor TSH levels
+Within 8 weeks of starting levothyroxine
+After a dose change
+Annually once established
Organification (iodination of tyrosine)
- 2 Tyrosine molecules binds to thyroglobulin
- Thyroid peroxidase that places iodine onto the tyrosines
- Thyroidperoxidase then combines the 2 tyrosines to form thyroxine leaving (H2)C=
