Endocrinology 3a – Hyperthyroid Disorders 2Anil Chopra

1. List the different possible causes of hyperthyroidism.2. Describe the clinical features of hyperthyroidism, Graves’ disease and thyroid

storm.3. List and explain the different treatments available for hyperthyroidism and thyroid

cancer. The following specific questions highlight some important pharmacological considerations:-

4. Drugs and Hyperthyroid Conditions.i) To which class of drugs does carbimazole belong?ii) Name another drug of the same class used to treat hyperthyroidism.iii) Using a labelled diagram of the steps in the synthesis of thyroid hormones (see

diagram in handout) explain the mechanisms of action of the thiourylenes.iv) Using carbimazole as an example, explain the term 'pro-drug'.v) Describe the signs and symptoms which will disappear after treatment with

thiourylenes.vi) Describe two situations in which hyperthyroid patients may be given large

doses of potassium iodide.vii) Why is radioactive iodine an effective therapy for hyperthyroidism?viii) Name two drugs used in thyroid function tests.

Hyperthyroidism

Graves Disease Autoimmune (IgG) Antibodies bind to stimulate to the TSH receptor in the thyroid. Causes smooth goitre

Plummer’s DiseaseDifferent from Grave’s disease in that: There is a toxic nodular goitre It is NOT autoimmune There is a benign adenoma that is overactive and makes thyroxine No pretibial myxoedema present. No exophthalmos seen. There will be low TSH

Thyroid Storm – a medical emergency. Any 2 of the following results in thyroid storm - 50% death if untreated. Heart rhythm becomes irregular Hyperpyrexia (body temperature above 41oC) Accelerated tachycardia Arrhythmia Cardiac failure Delirium/frank psychosis Hepatocellular dysfunction; jaundice

Symptoms: Antibodies also bind to the muscles behind the eyes causes exophthalmos

(forward protrusion of eyeballs). Pretibial myxoedema – thickening of skin on anterior lower leg. Thyroid is larger – can cause goitre (smooth in Grave’s disease). Palpitations Sweating Diarrhoea Weight loss despite increased appetite. Muscle wasting. Breathlessness Tachycardia Heat intolerance due to increased temperature. Lid lag – (Von Graefe's sign) lagging of upper eyelid in downward movement of

eye Tremor Oligomenorrhoea / amenorrhoea in women. Gynaecomastia in men. Emotional liability Feeling of fatigue Hair loss

Effects of Thyroxine: Increases basal metabolic rate. Weight loss despite increased appetite Increase in temperature Sensitises beta adrenoceptors to ambient levels of adrenaline and noradrenaline. Thus there is apparent sympathetic activation Tachycardia, palpitations, tremor in hands, lid lag e.t.c.

Treatment Options- Surgery (thyroidectomy)

o Removal of thyroid glando Risk of loss of parathyroids causing hypocalcaemiao Have to take calcium every dayo Damage to recurrent laryngeal nerve

- Radioiodine (capsule of radioactive iodine)o Irradiates thyroid gland.

- Drugso Propanolol (β-blocker)o Carbimazole, Propylthiouracil (anti-thyroid drugs)

- Some people have relapsing hyperthyroidismo Lifelong antithyroid drugs forevero Surgeryo Radioiodine

Viral (de Quervain’s) Thyroiditis

A virus attacks the thyroid gland resulting in: Painful dysphagia Tenderness Hyperthyroidism – the thyroid stops making thyroxine and makes virus instead Pyrexia Raised ESRThe thyroid gland is no longer visible on a thyroid scan because of the lack of thyroxine being produced. There is no iodine uptake and so no thyroxine is going to be synthesised. After around 4 weeks, patients have hypothyroidism.

After a month, when the virus is resolved, patients return back to normal thyroid function.

Normal 1 month hyperthyroidism 1 month hypothyroidism normalThyroid Cancers Papillary (takes up radioiodine) Follicular (takes up radioiodine) Anaplastic (bad news) Medullary (rare)Both papillary and follicular cancers can be encouraged to grow by TSH. In this case a total thyroidectomy is needed with a large dose of radioiodine. Large amounts of thyroxine should also be given to stop the TSH production.

Pharmacology Thiourylenes

Names carbimazole & propylthiouracil

UsageThese are use to treat hyperthyroidism conditions such as diffuse toxic goitre/Graves disease/exophthalmic goitre. They are also used in treatment before surgery or during thyroid irradiation with radioiodine.

Mode of ActionTheir mechanism of action is not clearly understood but it is thought that they work by inhibiting thyroperoxidase, inhibiting the action and production of antibodies in Grave’s disease and reducing conversion of T4 to T3 in peripheral tissues.

Their clinical effects may take weeks because of hormone store in colloid.

Side Effects agranulocytosis/ granulocytopenia (reduction or absence of granular leukocytes) -

rare and reversible on withdrawal of drug. rashes (relatively common) headaches Tachycardia and tremor nausea jaundice joint pain Can be give with a β-blocker to stop the tachycardia and tremor

Pharmacokinetics Administered orally Carbimazole is a pro-drug which first has to be converted to methimazole Half life of 6-15 hours Crosses placenta and is secreted in milk Metabolised in liver and secreted in urine

Name – Iodide

UsageThese are used mainly in thyrotoxicosis, thyroid storm and in preparation before surgery.

Mode of ActionIodide is given in large doses (30 times that normally taken) and can inhibit the production of thyroid hormones. Inhibits the secretion of thyroid hormones in thyrotoxic patients. Inhibition of iodination of thyroglobulin by swamping with iodine. Also inhibits H2O2 generation.

Side effects Allergic reaction e.g. rashes, fever, angio-oedemaPharmacokinetics Given orally, maximum effects after 10 days’ continuous administration

Radioiodine

Name - Radioiodine – 131I:

UsageUsed in hyperthyroidism to kill tumours. It is also used in very small doses to assess thyroid function. It works in that it imitates the action of iodine, but the radioisotope is selectively cytotoxic for thyroid cells.

Mode of Action Body processes isotope as for stable iodide; isotope concentrates in thyroid gland

and becomes incorporated into thyroglobulin Cytotoxic, almost selectively on thyroid follicular cells by virtue of irradiating β-

particles which have a very short rage (γ- particles have a long range and pass straight through the tissue)

Negligible cytotoxicity when used as tracer doses for thyroid function tests

Pharmacokinetics Give as a single dose (orally in Grave’s, orally or IV in tracer tests) Half life = 8 days Radioactivity negligible by 2 months Maximum effect after 2-3 months

Side Effects Hypothyroidism Avoid in children and pregnant patients

50% of patients presenting with hyperthyroid Grave’s disease will go into remission after 18 months of treatment with drugs. In the 50% that do not go into remission there are 3 choices:

Life long anti-thyroid drugs Radioiodine therapy Surgery – subtotal thyroidectomy. Risk of loss if parathyroids and associated hypocalcaemia and risk of damage to recurrent laryngeal nerve and voice damage