Therapeutics of thyroid disease

Question 1

Where is the thyroid gland located?

Answer 1

• Located in the neck region on the anterior surface of the trachea (just below the larynx)

Question 2

Hormonal control pathway:

Answer 2

Hypothalamus –> pituitary –> thyroid gland –> T3 (most active) or T4 (given most in treatment, given in HYPOthyroidism)

Question 3

What is the drug for T3?

Answer 3

liothyrinine

Question 4

What is the drug for T4?

Answer 4

levothyroxine

Question 5

What type of thyroid disease is the hypothalamus associated with?

Answer 5

tertiary thyroid disease

Question 6

What type of thyroid disease is the pituitary gland associated with?

Answer 6

secondary thyroid disease (as a result of disease in the pituitary and is accompanied by a cohort of other diseases aswell)

Question 7

What type of thyroid disease is associated with the thyroid?

Answer 7

Primary thyroid disease (T3 and T4 not produced)

Question 8

Primary Hypothyroidism prevalence?

Answer 8

• At the level of the thyroid gland
• increased production of thyroid hormones
• Prevalence 2%, 10-20x more common in women (3.5% in women and 0.6% in men

Question 9

Causes of hypothyroidism?

Answer 9

• Autoimmune disease (Hashimoto’s thyroiditis)
• Result of previous treatment (e.g. surgery) for hyperthyroidism
• Iodine imbalance (uncommon in UK as it is put in bread)
• Congenital hypothyroidism – where a child is born without a thyroid gland or a very small one (1 in 4000 children affected) If untreated, major development problems.

Question 10

Symptoms of hypothyroidism?

Answer 10

• Lethargy, weakness
• Dry scaly skin
• Sensitive to cold weather
• Depression
• Hair loss
• Memory loss
• Weight gain
• Constipation
• Puffy face and gruff voice with untreated disease

Question 11

What is a Thyroid Function Tests (TFTs)?

Answer 11

• Thyroid Stimulating Hormone (TSH)
• Free (unbound) T4
• Thyroid peroxidase antibody (rarely measured outside secondary care because T4 levels and TSH are very good at measuring)
• Primary Hypothyroidism:
  •  TSH,  free (unbound) T4

Question 12

Initial treatment of hypothyroidism?

Answer 12

• Adults ≤50 years – initially 50-100 mcg thyroxine daily, adjusted 25–50 mcg every 3–4 weeks according to response
• Adults >50 years & in heart disease - initially 25 mcg once daily, adjusted 25 mcg every 4 weeks (Start at lower dose if CVD risk)
• Congenital hypothyroidism – initially 10-15 mcg/kg for neonates (max 50 mcg), adjusted 5 mcg/kg every 2 weeks
• Measure TSH after 8-12 weeks (T½ of T4 = 7days) and three monthly until stabilised

Question 13

hypothyroidism treatment – maintenance

Answer 13

• Usual maintenance dose
• 100-200 mcg adults
• 50-200 mcg children, depending on age
• Monitor TSH yearly for adults and every 4-6 months until puberty for children; aim for
• Lower half of reference range
• Symptom free
• Monitor for angina

Question 14

Combination treatments for hypothyroidism?

Answer 14

• Liothyronine (t3) and levothyroxine (t4)
• Evidence shows no evidence of benefit over monotherapy
• Rarely used, usually only by endocrinologist when patient not responding to monotherapy
• Natural thyroid extract
• Desiccated animal thyroid gland
• Not recommended as no evidence of benefit
• Long term adverse effects uncertain
• Source of much debate on patient forums as available in US

Question 15

Patient Counselling for hypothyroidism?

Answer 15

• Life-long treatment
• Single daily dose
• Do not take at same time as calcium or iron preparations or caffeine containing beverages – can effect absorption
• Three strengths of tablet – common cause of confusion as they look the same(25, 50, 100)
• Need for monitoring
• Entitled to medical exemption certificate for prescription charges (if primary or congenital)

Question 16

Prevalence of hyperthyroidism?

Answer 16

• Autoimmune (Grave’s disease)
• Toxic Nodules
• Antibodies to TSH receptor stimulate the gland
• increased production of thyroid hormones
• Prevalence of 2% in women & 0.2% in men

Question 17

What does a hyperthyroid patient look like?

Answer 17

• Anxious
• Palpitations
• Tremor
• Weight loss
• Tachycardia
• Goitre
• Heat intolerance
• Warm moist skin
• Difficulty sleeping
• Diarrhoea

Question 18

Thyroid Function Tests (TFTs) for hyperthyroidism?

Answer 18

 Thyroid Stimulating Hormone (TSH)
 Free (unbound) T4
• Primary Hyperthyroidism
•  TSH,  free T4

Question 19

Treatment Options – Drug Therapy for hyperthyroidism?

Answer 19

• Non-invasive
• Low risk of long term hypothyroidism
• Low long-term cure rate (<50%) for non-mild disease
• Rare but serious side effects requiring monitoring
• Drug treatment can be used either for suppression or to block and replace
• Carbimazole is the most common drug therapy used and is a pro-drug, with methimazole as the active drug

Question 20

Drug therapy (thionamides) preferred for _____?

Answer 20

• Children
• Pregnancy, breast feeding (propylthiouracil only)
• Uncomplicated, mild disease
• Acute phase, prior to surgery or 131I

Question 21

Carbimazole (active metabolite: methimazole) or propylthiouracil mode of action ?

Answer 21

• Interfere with thyroid hormone synthesis by inhibiting thyroperoxidase activity in follicular lumen

Question 22

Carbimazole for hyperthyroidism?

Answer 22

• First choice drug
• Start with 15-40 mg daily (depends on severity of symptoms – can be higher)
• Maintain high doses until TFTs normal (4-8 weeks)
• Maintenance for 12-18 months
•  by 25-30% monthly, until 5-15mg
• Longer-term treatment may be required if relapse – occurs in up to 50% of patients with non-mild disease

Question 23

Blocking-replacement regimen (make the person completely hypothyroid)

Answer 23

• Carbimazole 40-60 mg for approx 4 weeks
• THEN Carbimazole 40-60 mg PLUS thyroxine 50-100 mcg
• Makes patient temporarily hypothyroid
• Not eligible for free prescriptions
• Treat for up to 18 months
• Thyroid gland returns to normal function when stop treatment
• Not in pregnancy as only carbimazole crosses the placental barrier

Question 24

Pregnancy and carbimazole?

Answer 24

• “Carbimazole is associated with an increased risk of congenital malformations when used during pregnancy, especially in the first trimester and at high doses (daily dose of 15 mg or more).
• Women of childbearing potential should use effective contraception during treatment with carbimazole. It should only be considered in pregnancy after a thorough benefit-risk assessment, and at the lowest effective dose without additional administration of thyroid hormones—close maternal, fetal, and neonatal monitoring is recommended.” BNF

Question 25

Propylthoiuracil regimen?

Answer 25

* 200-400 mg daily initially, in divided doses * 50 mg three times a day maintenance * Preferred in pregnancy, particularly in first trimester * Intolerant of carbimazole (rash, agranulocytosis) Carbimazole is associated with an increased risk of foetal nail abnormalities

Question 26

CSM warning from BNF for Propylthoiuracil and Carbimazole:

Answer 26

* Both can cause bone marrow suppression * decreased white cell count and increased infection * 0.3-0.5% – abrupt onset & not dose related * CSM warning BNF - “Doctors are reminded of the importance of recognising bone marrow suppression induced by carbimazole and the need to stop treatment promptly. - Patient should be asked to report symptoms and signs suggestive of infection, especially sore throat. - A white blood cell count should be performed if there is any clinical evidence of infection. - Carbimazole should be stopped promptly if there is clinical or laboratory evidence of neutropenia.”

Question 27

Patient Counselling (carbimazole)?

Answer 27

* Carbimazole as a single daily dose and Propylthiouracil in divided doses * Duration of treatment & tapering to maintenance dose * Report signs of agranulocytosis: sore throat, mouth ulcer, bruising * Report signs of hepatic dysfunction with Propylthiouracil: pruritis, jaundice, dark urine * Advise on contraception if on carbimazole * Need for regular review, tests * Patients with hyperthyroidism ARE NOT entitled to medical exemption certificate for prescription charges * Patients on carbimazole who come into community pharmacies with a sore throat or mouth ulcers should be referred immediately to their GP, rather than sold over-the-counter treatments * If on blocking-replacement regimen, then need counselling for both treatments

Question 28

Radioactive iodine as treatment?

Answer 28

``` Radioactive iodine (131I) – Non-invasive – Excellent cure rate – Likelihood of long term hypothyroidism – Can worsen eye disease – Avoid pregnancy/fatherhood ``` ``` Preferred for: – First-line treatment except for mild disease or if radioactivity means is unsuitable – Failure to respond to drug treatment – Relapse after drugs – Comorbid cardiac disease – Toxic nodular goitre ```

Question 29

Surgery for hyperthyroidism? (preferred for)

Answer 29

``` – Excellent and rapid cure rate – High likelihood of long term hypothyroidism – Invasive – Risk of damage to parathyroid gland – Scarring and possible swallowing difficulties • Surgery preferred for – Oesophageal obstruction – Intolerance to drug treatment – Young adults ```

Question 30

131I or surgery??

Answer 30

• Do not use either of these immediately after diagnosis • Make patient euthyroid first using drugs for several weeks • Prevent thyrotoxic crisis (thyroid storm) due to dangerously high levels of T4 released into system – Hyperpyrexia, dehydration. – Heart rate greater than 140 beats per minute, hypotension – Nausea, vomiting, diarrhoea, abdominal pain. – Confusion, agitation, delirium, psychosis, seizures or coma

Question 31

Hyperthyroidism – adjuvant therapy?

Answer 31

Beta-blockade • rapid relief of symptoms within 4 days: palpitations, anxiety, tremor • C/I in asthma • Propranolol, nadolol • May need to be given 3-4 times per day as metabolism increased in hyperthyroidism • Usually only needed for initial stages of treatment, when still symptomatic

Question 32

Drug-induced Thyroid Disease. Iodine:

Answer 32

* Overdose e.g. Radiographic contrast media * Acute - inhibits release of T3/T4 from thyroid * Prolonged – suppress T3/T4 production * Rarely, can cause thyrotoxicosis if there is an underlying defect in autoregulation * Iodine deficiency (very rare in UK) can cause hypothyroidism due to inability to produce T3/T4

Question 33

Drug-induced Thyroid Disease. Amiodraone? How?

Answer 33

• Contains organic iodine Hypothyroidism • Can occur at anytime in treatment – 1-10% of patients • Inhibition of synthesis & release of T4 & T3 • usually continue amiodarone and start replacement T4 therapy if necessary Mild Hyperthyroidism • Blocks conversion of T4 to T3, therefore increases TSH & T4 • Transient when start treatment – normalises in 3-4 months Severe hyperthyroidism • Increased production of T4 because of iodine content • Direct thyroiditis – excessive release of T4 into circulation • Withdraw therapy, if possible or may use carbimazole

Question 34

Drug-induced Thyroid Disease. Lithium? How?

Answer 34

Hypothyroidism • inhibits iodine uptake and prevents T3 & T4 release • can be transient & subclinical • monitor TSH • start replacement T4 therapy if clinical Hyperthyroidism • Rare, paradoxical effect