Hyperthyroidism Flashcards
What is hyperthyroidism?
Overabundance of TH, mimics effect of activated sympathetic nervous system
Describe the changes in primary hyperthyroidism
High levels of TH secretion of thyroid gland (function independently)
=> Low TSH, high TH
List the possible causes of hyperthyroidism
- Grave’s disease - TRAb (thyrotropin receptor ab) mimics TSH & stimulates TH production
- Pituitary adenomas
- Toxic adenomas (hot nodule) - nodule secretes T3
- Toxic multi-nodular goiter (plummer’s disease) - nodules secrete T3
- Drug induced (amiodarone, lithium) - affect TH levels
- Subacute thyroiditis (may be due to infection, drug induced, early hashimoto) - inflamed thyroid bursts and release stored TH (result in hypothyroidism later on)
What are the signs and symptoms of hyperthyroidism?
- Weight loss, increased appetite (incr metabolism)
- Heat intolerance
- Goiter (due to nodules)
- Fine hair
- Heart palpitations, tachycardia
- Nervousness, anxiety, insomnia, tremor (*think sympathomimetic and CV effects)
- Menstrual disturbances (lower levels of E, higher levels of P, lighter and more infrequent menstruation, amenorrhea)
- Sweating, warm, moist skin
- Exophthalmos (bulging eyes) in Grave’s
- Fatigue
- Diarrhea
- Irritability
- Insomnia
Explain the diagnosis of hyperthyroidism
- Signs and symptoms
- Labs
- Radioactive iodine uptake (RAIU)
- Biopsy
- Signs and symptoms
- Labs
- Elevated FT4 concentrations
- Suppressed TSH concentrations (except in TSH-secreting adenomas, or secondary to excess TRH or TSH)
- Positive autoantibodies (TRAb, ATgA, TPO)
- Radioactive iodine uptake (RAIU)
- Uptake is elevated if gland is actively secreting TH (e.g., Grave’s toxic adenoma, multinodular goiter, TSH-secreting adenoma)
- Uptake is suppressed in disorders caused by thyroiditis or cancers (thyroiditis - thyroid gland burst, cancer - cancer cells proliferate and produce TH without iodine uptake)
- Biopsy (invasive)
What are the goals of hyperthyroidism therapy?
- Minimize or eliminate symptoms, improve QoL
- Minimize long-term damage to organs (heart disease, arrhythmia, sudden cardiac death, bone demineralization, fracture)
- Normalise FT4 and TSH concentrations
What are the 4 types of treatment options for hyperthyroidism?
- Surgical resection
- able to get rid of root cause (e.g., nodule)
- often results in hypothyroidism
- Radioactive iodine (RAI) ablative therapy
- colorless, tasteless liquid in a capsule that will concentrate in thyroid tissue and destroy overactive thyroid cells
- often results in hypothyroidism
- Thyroidectomy
- remove whole thyroid gland
- hypothyroidism - need to be on lifelong Levothyroxine
- Antithyroid Pharmacotherapy
- Thionamides
- Iodides
- Non-selective BBs
Antithyroid pharmacotherapy is last line in hyperthyroidism treatment
What are the situations in which antithyroid pharmacotherapy is considered?
- Those awaiting ablative therapy or surgical resection
- Antithyroid pharmacotherapy can be used to deplete stored hormones to minimize risk of post-ablative hyperthyroidism as a result of thyroiditis (thyroid gland burst)
- E.g., BB as bridging therapy, iodides to shrink gland before surgery, thionamides before surgery
- Those that cannot undergo ablative therapy or surgical resection
- RAI ablation is an absolute contraindication in pregnancy - risk of RAI entering fetus
- Pregnant ladies, young children, elderly may be unsuitable
- People who cannot isolate after RAI ablation (radioactive material ingested - potential exposure to others)
- Those who failed to normalize thyroid despite ablative or surgical intervention
- Mild disease / small goiter / low or negative antibody titers / women
- Limited life expectancy
What is the MOA of thionamides (carbimazole and propylthiouracil)
Inhibit iodination and synthesis of thyroid hormones via inhibiting thyroid peroxidase (TPO)
*TPO - oxidizes I- to active iodide, and attaches iodide to tyrosine within thyroglobulin (Tg) molecule to give MIT + DIT (precursors to T3 and T4)
PTU can additionally block T4 to T3 conversion in the periphery at high doses
Describe the absorption of Carbimazole
Oral, once daily dosing (FYI: initially 15-60mg daily in 2-3 divided doses, once euthyroid, can reduce to 5-15mg once daily)
Converted into active methimazole in serum after absorption
Describe the distribution of Carbimazole
Methimazole
- clinical effects last a day because it concentrates in the thyroid
- no binding to plasma protein
- produces >90% inhibition of thyroid organification of iodine (into thyroglobulin) within 12h
Describe the metabolism of Carbimazole
Metabolised in the liver by CYP450 and FMO enzymes
*FMO: flavin-containing monooxygenase
Describe the elimination of Carbimazole
Metabolites mainly excreted in urine ~90% and feces ~10%
What are the adverse effects of Thionamides (Carbimazole, PTU)
- Hepatotoxicity risk (Carbomazole can cause jaundice, PTU has Black Box Warning)
- Rash - risk for SJS
- Agranulocytosis (low WBC) early in therapy, usually within 3 months
- Fever
Others:
- Joint pain
- Nausea
- Overtreatment - hypothyroidism (thus dose should be decreased once euthyroid)
Describe the efficacy of Thionamide therapy
EFFICACY:
Slow onset in reducing symptoms - weeks
=> Clinical response may take 3-6w after initiating
Maximal effect may take up to 4-6 months
*Why? T4 has long half-life and the thyroid stores of hormone need to be depleted
How is remission defined, and what is the remission rate with Thionamide therapy?
Remission: normal TSH and T4 for 1 year after discontinuing antithyroid therapy
Remission rate is low 20-30%
What is the monitoring parameter for Thionamide therapy?
Look at FT4 instead of TSH as TSH may remain suppressed for months
Also note that early in therapy, total T3 is a better marker of efficacy than FT4 since T3 is more representative due to its short half-life. However, this is rarely done as it is more expensive to assay T3.
How frequent is dose adjustment done for Thionamide therapy?
Monthly dosage titrations can be done depending on symptoms and FT4 levels
What are the 2 main symptoms of hyperthyroidism in pregnancy?
- Failure to gain weight despite good appetite
- Tachycardia
What are the risks associated with hyperthyroidism in pregnancy?
Fetal loss if untreated, yet thionamides have risk of embryopathy
Explain the treatment choices for hyperthyroidism in pregnancy
Also state the T4 target
1st trimester: PTU
- Because Carbimazole has higher risk of congenital malformations
2nd and 3rd trimester: Carbimazole
- PTU has higher risk of hepatotoxicity and is less potent
*Always use the lowest possible dose, and keep T4 at upper-normal limit
Describe the MOA of non-selective Beta Blockers (propanolol), and explain its place in therapy in hyperthyroidism.
MOA: blocks many hyperthyroidism manifestations mediated by B-adrenergic receptors, may also block T4 conversion to T3 at high doses
Place in therapy:
- Sympathetic relief
- Bridging therapy for thionamides effects to kick in / before ablation / before surgery
- PRN for high risk patients - elderly with CVS disease
- Treatment of thyroiditis, which is usually self-limiting (temporary incr in TH)
Describe the MOA of iodides, and explain its place in therapy in hyperthyroidism.
Lugol’s solution, saturated solution of potassium iodide
MOA: inhibit release of stored TH, minimal effect on hormone synthesis, helps decrease vascularity and size of gland
Place in therapy:
- Before surgery (7-10 days) to shrink gland
- After ablative therapy (3-7 days) to inhibit thyroiditis-mediated release of stored TH
- Thyroid storm (life-threatening - rapid HR, high BP, fever) - iodide can further inhibit release of TH
Clinical pearls:
- Limited efficacy after 7-14 days as TH release will resume
- Do not use before ablative RAI as it may reduce uptake of RAI
Describe the TSH and TH levels in subclinical hyperthyroidism
Low/undetectable TSH, normal FT4
What are the risks associated with subclinical hyperthyroidism?
Elevated risk of AF in patients >60yo
Elevated risk of bone fracture in postmenopausal women
Conflicting data about mortality risk
When should subclinical hypothyroidism be treated?
What is the treatment for subclinical hyperthyroidism?
More compelling if TSH <0.10 mIU/L
Treatment:
- Similar to overt hyperthyroidism but oral therapy is preferred over ablative therapy in young patients
- BB especially if AF
If untreated, screen regularly for development of overt hyperthyroidism
Drug induced thyroid disease can cause both hypo and hyperthyroidism
Explain how Amiodarone (anti-arrhythmic) can cause thyroid disorder
Contains iodine in its structure, may affect iodine uptake, secretion, and production; cause thyroiditis
=> hyper or hypothyroidism
Drug induced thyroid disease can cause both hypo and hyperthyroidism
Explain how Lithium (psychiatric drug) can cause thyroid disorder
Inhibitis TH secretion and release, thus signaling increase in TSH and possible goiter, hence cause hypothyroidism (incr TSH, low TH)
Thyroiditis (cause hyperthyroidism)
Drug induced thyroid disease can cause both hypo and hyperthyroidism
Explain how Interferon-alpha can cause thyroid disorder
Thyroiditis (hyper or hypothyroidism)
Hashimoto disease can cause…
Hashimoto disease is a chronic autoimmune thyroiditis
Hashimoto can present with positive ATgA and TPO
Early Hashimoto disease:
- Subacute thyroiditis - hyperthyroidism (temporary incr in TH)
- Subclinical hypothyroidism (high TSH, normal T4)
Hashimoto disease:
- Primary hypothyroidism
