Thyroid disorders (including Pharmacology)

Question 1

State the populations that should be routinely screened for thyroid disorders

Answer 1

Pediatric patients and pregnant women

Question 2

What are some compelling indications for thyroid disorder screening (6 total)

Answer 2

1) Presence of autoimmune disease (e.g. T1DM, cystic fibrosis) -> High risk of developing autoimmune disease in another organ

2) First degree relative with autoimmune thyroid disease

3) Psychiatric disorders
* Thyroid abnormalities can induce mood swings, anxiety psychosis

4) Taking amiodarone or lithium
* Affect thyroid hormone levels

5) History of head / neck radiation for malignancies
* Predisposed to thyroid conditions

6) Symptoms of hypothyroidism / hyperthyroidism

Question 3

What thyroid protein is affected by certain conditions (e.g pregnancy, estrogen therapy)?

Answer 3

Thyroxine Binding Globulin (TBG)

Question 4

Tests for autoantibodies in thyroid screening test for which antibodies?

Answer 4

1) ATgA: Thyroglobulin antibodies

2) TPO: Thyroid peroxidase antibodies

3) TRAb: Thyrotropin receptor IgG antibodies

Question 5

Which antibody is specific and confirmatory for Graves Disease?

Answer 5

TRAb

Question 6

State the respective lab trends for Primary hypothyroidism vs Central hypothyroidism

Answer 6

Primary Hypothyroidism
o ↑TSH, ↓ T4
o Positive antibodies (TPO, ATgA)

Central Hypothyroidism (pituitary is the issue)
o ↓ TSH, ↓ T4

Question 7

State how you would initiate and subsequently titrate Levothyroxine in a young, healthy adult.

Answer 7

Initiation: 1.6 mcg/kg/day (can remember as 1.5mcg/kg)

Titration: titrate up/down by 25mcg/day

Question 8

State how you would initiate Levothyroxine in a patient who is 50-60 years old who has no cardiac issue

Answer 8

50 mcg/day

Question 9

How would you initiate Levothyroxine in a patient with CVD

Answer 9

12.5-25 mcg/day and titrate up

Question 10

State how you would counsel a patient who is starting Levothyroxine.

Answer 10

1) Take this 30-60 minutes before breakfast or 4 hours after dinner (take on empty stomach/ when you just wake up) Space apart from foods containing metal cations by at least 2 hours (e.g milk and tofu)

2) Space apart from all other medications especially calcium or iron supplements and antacids (metal cations) need to space at least 2 hours apart

Question 11

What are the side effects of Levothyroxine?

Answer 11

1) Cardiac abnormalities (tachyarrhythmias, angina, myocardial infarction, Atrial fibrillation)

2) Risk of fractures

3) Signs of hyperthyroidism (e.g diarrhea, anxiety, increased appetite, insomnia)

4) Hair loss

Question 12

State the monitoring parameters for someone with primary hypothyroidism, including frequency of monitoring

Answer 12

TSH levels

4-8 weeks after initiation/titration. Once thyroid hormone levels stable, once semi-annually to once annually

Question 13

State the monitoring parameters for patient with Central hypothyrodism, including frequency of monitoring

Answer 13

Free T4 levels (recall: pituitary spoil in central hypothyroid)

4-8 weeks after initiation/titration. Once thyroid hormone levels stable, once semi-annually to once annually

Question 14

When would Liothyronine use be considered? (3 situations)

Answer 14

1) Normalisation of TSH but still having symptoms of hypothyroidism

2) Myxoedema coma

3) Going for diagnostic procedure and needs to stop Levothyroxine but still need short term control of hypothyroidism (Liothyronine can be stopped 1-2 days before procedure, start Levo again after procedure)

Question 15

State how you would adjust Levothyroxine therapy for pregnant women and why this adjustment may be needed

Answer 15

May need a 30-50% increase in pre-pregnant dosage to maintain euthyroid status (due to TBG ↑-> lower free T3 and T4)

Question 16

What is the definition of subclinical hypothyroidism?

Answer 16

Elevated TSH with normal T4. Often the result of early Hashimoto disease

Question 17

In general, when would treatment of subclinical hypothyroidism be considered?

Answer 17

1) TSH > 10mIU/L (widely accepted)

2) TSH 4.5-10 mIU/L AND
o I. Symptoms of hypothyroidism OR
o II. TPO antibody present OR
o III. History of cardiovascular disease, heart failure, or risk factors for such

Question 18

What are the signs and symptoms of hyperthyroidism? (9 total)

Answer 18

1) Weight loss or increased appetite

2) Heat intolerance

3) Goiter
* Not as common compared to hypothyroidism; goiter is more due to the fact that nodules get bigger and bigger

4) Fine, weak hair

5) Heart palpitations or tachycardia

6) Nervousness, anxiety, insomnia

7) Menstrual disturbances (lighter or more infrequent menstruation, amenorrhea)
* High T3, T4 -> higher metabolism of estrogen + higher progestin

8) Sweating or warm, moist skin

9) Exophthalmos in Graves disease

Question 19

What are the usual indications for pharmacological treatment of hyperthyroidism? (4 total)

Answer 19

1) Those awaiting ablative therapy or surgical resection (Minimizes risk of post-ablation hyperthyroidism caused by thyroiditis by depleting thyroid stores)

2) Not ablative or surgical candidates / failed to normalize thyroid [e.g: pregnant (give drug until give birth) or too young, too old, cannot be temporarily isolated (patient will not be able to interact with people for awhile)]

3) Mild disease / small goiter / low or negative antibody titers / women (tend to respond better to drugs)

4) Limited life expectancy

Question 20

What is the MOA of Thionamides (Carbimazole and Propylthiouracil)?

Answer 20

(C+P): Inhibits thyroid peroxidase (TPO) which normally iodinates tyrosyl residues in thyroglobulin (Tg-Tyrosine) to give precursors of T3 and T4 (MIT and DIT). Inhibition of iodination step leads to gradual ↓ of T3 and T4 synthesis

P: PTU can additionally block T4/T3 conversion in the periphery at high doses

Question 21

What are the adverse effects of Thionamides? (7 total)

Answer 21

1) Rashes

2) Joint pain

3) Nausea

4) Hepatotoxicity (one sign is Jaundice; PTU > Carbimazole)

5) Hypothyroidism (due to overtreatment)

6) Agranulocytosis (rare)

7) Fever

Question 22

What lab values are used to titrate Thionamide treatment?

Answer 22

For first 1-2 years of therapy, look at T4 instead of TSH as marker to titrate

Question 23

What are some disadvantages of using Thionamides? (3 total)

Answer 23

1) Slow onset in reducing symptoms (weeks). Maximal effect may take 4–6 months

2) Remission rates low: 20%–30%. Remission is defined as normal TSH and T4 for 1 year after discontinuing antithyroid therapy

3) Does not solve root cause (symptomatic treatment)

Question 24

How is Carbimazole metabolised?

Answer 24

Metabolised by CYP450 and FMO (Flavin-containing monooxygenase) enzymes

Question 25

What are symptoms of hyperthyroidism in pregnancy? (2 main symptoms)

Answer 25

1) Failure to gain weight despite good appetite

2) Tachycardia

Question 26

State how you would treat a pregnant woman with Thionamide (which one would you use at which trimester(s) and why)

Answer 26

1st Trimester: Use PTU as Carbimazole have higher risk of congenital malformations

2nd and 3rd Trimesters: Use Carbimazole as PTU have higher risk of hepatotoxicity and yet less potent

Use lowest possible dose; keep T4 at upper-normal limit

Question 27

What is the MOA of beta-blockers in treating hyperthyroidism?

Answer 27

Blocks many hyperthyroidism manifestations mediated by β-adrenergic receptors; also may block T4 conversion to T3 when used at high dose

Question 28

What are beta blockers place in therapy for hyperthyroidism?

Answer 28

1) Symptomatic relief (does not solve root cause)

2) Bridging therapy for Thionamides effects to kick in/ before ablation /surgery
o Use to suppress symptoms before Carbimazole starts working

3) PRN for high-risk patients e.g elderly with CVS disease

4) Treatment of thyroiditis, which is usually self-limiting

Question 28

What is the MOA of Iodides?

Answer 28

Inhibits the release of stored thyroid hormones + Helps decrease vascularity and size of gland.

Minimal effect on hormone synthesis.

Question 29

When are Iodides typically used?

Answer 29

1) Before Surgery (7–10 days) to shrink the gland

2) After ablative therapy (3–7 days) to inhibit thyroiditis thyroiditis-mediated release of stored TH

3) Thyroid storm

Question 30

When should Iodides not be used?

Answer 30

1) Limited efficacy after 7–14 days of therapy as TH release will resume

2) Do NOT use before ablative RAI (may reduce uptake of radioactive iodine).

Question 31

How does Radioactive Iodine treat hyperthyroidism?

Answer 31

Radioactive Iodine gets taken up by thyroid cells and destroys them

Question 32

What are the absolute contraindications for Radioactive Iodine Ablative Therapy?

Answer 32

Pregnancy

Question 33

What are the signs and symptoms of hypothyroidism? (10 total)

Answer 33

1) Cold intolerance

2) Dry skin

3) Fatigue, lethargy, weakness

4) Weight gain

5) Bradycardia

6) Slow reflexes

7) Coarse skin and hair

8) Periorbital swelling

9) Menstrual disturbances (more frequent, more blood)
* Low level of T3 and T4 -> estrogen levels are high (doesn’t get metabolised that quickly) and low progestin (cause more painful cramps)

10) Goiter
* Thyroid gets bigger because it cannot get enough iodine to try and absorb iodine

Question 34

What are clinical manifestations of hypothyroidism?

Answer 34

1) ↑ Total cholesterol, LDL, Triglycerides

2) ↑ CV risk (e.g Atherosclerosis, MI risk, Stroke risk)

3) ↑ Creatine phosphokinase (CPK) levels
* Other drugs that may increase CPK: Statins
o Check for thyroid problems as well if patient on statin and CPK increase

4) ↑ Miscarriage risk

5) Impaired fetal development

Question 35

State starting dose of Levothyroxine for subclinical hypothyroidism that is required to be treated

Answer 35

25-75mcg/day

Question 36

What is the definition of subclinical hyperthyroidism?

Answer 36

Low or undetectable TSH with normal T4

Question 37

What are patients with subclinical hyperthyroidism at risk of?

Answer 37

1) higher risk of AFib in patients > 60 y.o

2) higher risk of fractures in postmenopausal women

Question 38

What are some drugs that may cause thyroid diseases?

Answer 38

Amiodarone, Lithium, Interferon alfa

Question 39

What are patients with subclinical hypothyroidism at risk of?

Answer 39

CV problems

Question 40

How is Levothyroxine metabolised?

Answer 40

1) Liver (major site for T4 deiodination to T3)
- Glucuronidation and sulphation also occur

2) Deiodination in kidney and peripheral tissues

Question 41

What are some DDIs/DFIs of Levothyroxine?

Answer 41

• Drugs (inducers/inhibitors) affecting pH, absorption, GI motility, plasma protein binding, liver enzyme
• Food: fiber, grapefruits, pomelo
  o Fibre -> interfere with absorption of levothyroxine from the GI tract

Question 42

Explain the negative feedback principle of thyroid hormone regulation

Answer 42

Low [free T3, T4] -> ↓negative feedback signal -> ↑ release of TRH from hypothalamus -> ↑ TSH -> ↑ binding to TSH receptor -> ↑ T3, T4 synthesis -> ↑ negative feedback signal -> ↓ release of TRH and TSH

Question 43

Is Carbimazole an active or prodrug?

Answer 43

Prodrug. Converted into active Methimazole in serum.

Question 44

State the 2 ways in which thyroid hormones are regulated

Answer 44

1) Negative feedback
2) Conversion of T4 to T3 in the periphery via 5-deiodinase

Question 45

Compare and contrast the 2 thyroid hormones (T3 and T4)

Answer 45

T3 more potent but shorter half life (2 days vs T4: 6-7 days)

T3’s shorter half-life is also why its levels are more erratic and hence not usually measured when evaluating thyroid function

Question 46

What is MOA of Levothyroxine?

Answer 46

Undergoes deiodination by 5-deiodinase to form active T3 -> binds to Thyroid hormone receptors in cell nucleus and exert its effects (activate gene transcription of proteins responsible for metabolism)

Question 47

What should you do if a patient on thyroid hormone replacement therapy presents with normal T4 but persistently high TSH?

Answer 47

Enquire about adherence