Thyroid disorders, Hypothyroidism Flashcards
What does the thyroid gland regulate?
Body’s physiological functions:
Development, growth, metabolism
Incr O2 consumption by most tissues, incr basal metabolic rate
- Body temp
- CNS
- Sleep
- Cardiac function
- GI function
- Muscle strength
- Breathing
- Menstrual cycle
- Skin dryness
- Lipid metabolism
- Uptake and utilization of glucose
Describe the release of thyroid hormones
Hypothalamus => TRH (thyrotropin-releasing hormone)
Pituitary => TSH (thyroid stimulating hormones)
Thyroid glands => TH (T3, T4)
Describe the two ways in which thyroid hormones are regulated
- Negative feedback
- Peripheral conversion of T4 to T3
=> T4:T3 released in a 4:1 ratio
=> T3 is more potent (80% T3 produced from peripheral conversion of T4 by deiodination via 5-deiodinases in liver, kidney, pituitary)
Describe the properties (half life, protein binding) of T4 and T3
T4:
- Longer half life of 6-7 days
- >99% protein bound
- FT4 is routinely ordered with TSH to evaluate thyroid status
T3:
- Shorter half life of 2 days
- >99% protein bound
- FT3 not routinely ordered as it degrades faster
What is the clinical significance of protein binding?
Which group of people may have elevated TBG levels?
Thyroxine binding globulin (*thyroxine is T4)
Elevated levels of TBG in pregnant women or on estrogen
=> FT3 and FT4 levels decrease due to more binding
=> Negative feedback cause more TSH to be released
=> More TH released to return to normal levels of FT3 and FT4 (new equilibrium)
*If thyroid gland not functioning well, unable to release TH, then primary hypothyroidism, need exogenous TH
What are the autoantibodies that can be present in thyroid disorders?
ATgA (thyroglobulin antibodies) - hyper/hypothyroidism
TPO (Thyroperoxidase antibodies) - hyper/hypothyroidism
- More a/w hypothyroidism
*Hashimoto and Graves can have positive ATgA and TPO
TRAb (thyrotropin receptor IgG antibodies) - Grave’s disease (hyperthyroidism)
What are compelling indications for screening for thyroid disorders?
Who requires ROUTINE SCREENING?
- Presence of autoimmune disease (e.g., T1DM, CF)
- 1st degree relative with autoimmune thyroid disease
- Psychiatric disorders (bc thyroid abnormalities can induce mood changes, psychiatric disorders)
- Taking amiodarone or lithium => affect TH levels
- Hx of head/neck radiation for malignancies
- Symptoms of hypo/hyperthyroidism
ROUTINE SCREENING
- pregnant
- pediatric
*bc thyroid abnormalities affect the development of the fetus and children
*impt to screen TBG levels in pregnant ladies, and check thyroid function
*hypothyroidism can incr miscarriage risk
Describe the changes in primary hypothyroidism
List examples
Primary failure of the thyroid gland
=> High TSH, low TH
E.g.,:
- Iodine deficiency
- Hashimoto disease - chronic autoimmune thyroiditis
- Iatrogenic - thyroid resection or radioiodine ablative therapy
Describe secondary hypothyroidism
Secondary hypothyroidism: Low TSH, Low TH
E.g.,
- Central hypothyroidism (hypothalamus unable to secrete TRH, or pituitary unable to secrete TSH)
- Drug-induced (amiodarone, lithium)
What are the signs and symptoms of hypothyroidism?
Intolerance to cold
Dry skin
Fatigue, lethary, weakness
Weight gain
Bradycardia
Slow reflexes
Coarse skin and hair
Periorbital swelling
Menstrual disturbances (more frequent, more bleeding and cramps)
Goiter (overstimulation of thyroid gland by TSH, e.g., iodine deficiency)
Others:
Obesity
Depression
Hair loss
Constipation
Joint pain
Explain why hypothyroidism causes menstrual disturbances (more bleeding)
Hypothyroidism
=> Estrogen does not get metabolised as quickly
=> More estrogen (builds up endometrium), low progestin
=> More periods, more blood, more cramps
What are the clinical manifestations of hypothyroidism?
- Incr total cholesterol, LDL, TGs => incr CVD risk
- Incr atherosclerosis, MI risk
- Incr levels of creatine phosphokinase (CPK) levels
- Incr miscarriage risk
- Impaired fetal development
*Statins also incr CPK - hence if pt on statin and CPK incr, check for thyroid issues
Explain the diagnosis of hypothyroidism
- Signs and symptoms
- Labs
- Primary hypothyroidism: incr TSH, dcr T4, positive autoantibodies (ATgb, TPO)
- Central hypothyroidism: low TSH, low T4
What are the goals of hypothyroidism therapy?
- Minimize or eliminate symptoms, improve QoL
- Minimize long-term damage to organs (myxedema coma, heart disease - CVD risk)
- Prevent neurological deficits in newborns and children
- Normalise FT4 and TSH concentrations
Describe the MOA of levothyroxine (Drug of choice for hypothyroidism)
Levo isomer of T4/Thyroxine
Mimics T4 and is converted by 5-deiodinase to active T3, which binds to TR in the nucleus to affect gene transcription, release mRNA, promote protein synthesis, affect metabolic pathways
What is the initial dosing for levothyroxine
Young healthy adults: 1.6mcg/kg/d
50-60yo w no cardiac issues: 50mcg daily
With CVD: 12.5-25mcg/d, and titrate up
*Available in 25ug, 50ug, 75ug, 100ug tablets
How should dose titration of levothyroxine be done?
Titration is based on response (symptoms, normalization of FT4 and TSH)
=> Incr or dcr in 12.5-25mcg/day increments, or in 10-15% of weekly dose
Describe the absorption and administration of levothyroxine
Oral, 1 injection formulation
Take on empty stomach with water, 30-60min before breakfast or 4h after dinner
- erratic absorption with food, esp dietary fiber
Do not take with antacids, PPIs, milk, calcium or iron supplements (multivalent ions)
- Space 2h apart
- Affected by gastric pH, chelation
*Mainly absorbed in duodenum and jejunum
Describe distribution of levothyroxine
Highly protein bound >99%
Describe the metabolism of levothyroxine
Liver is the major site for T4 deiodination (via 5-deiodinase) - also in kidney, pituitary, peripheral
Liver phase 2 glucuronidation and sulphation
Describe the elimination of levothyroxine
Feces and urine
Metabolites - bile
What DDI and FDI to consider when taking levothyroxine?
Drugs that affect pH, absorption, GI motility, plasma protein binding, liver enzyme inducers and inhibitors
Describe the monitoring parameters for Levothyroxine treatment
- Primary hypothyroidism VS Secondary hypothyroidism
- Monitoring when euthyroid stage achieved
IN PRIMARY HYPOTHYROIDISM: use TSH (should dcr)
- 4-8 weeks (2-3months) to assess response in TSH after initial or changing therapy
General target for TSH: 0.4-4 mIU/L (normal range: 0.4-4.2) - 2-3 weeks for symptomatic relief
- If FT4 normalize but TSH remain high => non-adherence, inadequate dose, malabsorption, drug/food interactions
- *AFTER EUTHYROID STATE ACHIEVED: TFT recommended semiannually (6m) to annually (1y) in nonpregnant adult patients
IN SECONDARY HYPOTHYROIDISM: use FT4 (should incr)
- Use FT4 instead of TSH - FT4 should incr, TSH remains low due to pituitary failure
Treatment for hypothyroidism with levothyroxine is _______ as thyroid gland cannot function/due to thyroid resection
Lifelong
Need exogenous T4 as thyroid gland cannot release TH
Comment on the monitoring parameters for Levothyroxine in elderly
No consensus on appropriate upper limit of TSH
TSH levels rise in older adults despite normal T4 levels
For adults >70yo, TSH can be still WNL up to 6.9mIU/L
What are the adverse effects of Levothyroxine?
Risk of fracture
Reduced appetite
Anxiety
Diarrhea
Difficulty sleeping
Hair loss
Weight loss
RARE and SERIOUS:
- Heart issues (AF, tachyarrhythmias, angina, MI, high BP, incr HR)
- Seizures
Levothyroxine is contraindicated in?
- Patients with heart problems
- Epilepsy
- Hyperthyroidism
What are the adverse effects/signs of over replacement with Levothyroxine?
- Cardiac abnormalities (AF, tachyarrhythmias, angina, MI)
- Risk of fractures
- Signs of hyperthyroidism
Explain the MOA and properties of Liothyronine
Synthetic T3
- Half-life 1-2.5 days
- Higher incidence of adverse effects
When is Liothyronine considered?
- Combi of T4 and T3 can be considered if normalized TSH, but still complain of symptoms of hypothyroidism
- Pt needs to undergo diagnostic therapy (e.g., CT scan), need to discontinue replacement thyroids => may switch from levo to liothyronine and stop 1-2 days before procedure (since lio has shorter half life)
- Myxedema coma (severe hypothyroidism) - since T3 is more potent (but IV levo typically used)
Explain Myxedema coma and its treatment
Severe form of hypothyroidism with thyroid enlargement, multiple organ abnormalities and progressive mental deterioration
In myxedema coma, there is reduced blood flow and this affects the gut absorption of levothyroxine into the blood circulation
Hence IV levothyroxine or IV liothyronine can be given instead to directly enter systemic circulation
What is the risk of hypothyroidism in pregnancy?
- Incr miscarriage risk, spontaneous abortion
- Congenital defects, impaired cognitive development of fetus
*Maternal TH provides fetus with TH for up to 6 weeks until fetus forms their own thyroid gland
Hypothyroidism in pregnancy
- Explain the dose adjustment that is required for a mother on levothyroxine
Increase levothyroxine by 30-50% from pre-pregnant dose to maintain euthyroid status
*Recall elevated TBG in pregnancy, hence FT3 and FT4 levels decrease (need exogenous TH to replace)
TSH targets in pregnancy (do not memorise):
1st trimester <2.5mIU/L
2nd trimester <3.0mIU/L
3rd trimester <3.5mIU/L
*In general targets lower part of the range
Describe the TSH and TH levels in subclinical hypothyroidism
High TSH, Normal T4
*Often a result of early Hashimoto disease
Explain the risks associated with subclinical hypothyroidism
TSH >7.0mIU/L in older adults => elevated risk of HF
TSH >10mIU/L => elevated risk of coronary heart disease
When should subclinical hypothyroidism be treated?
What is the treatment for subclinical hypothyroidism?
Consider treating if:
TSH >10mIU/L
OR
TSH 4.5-10mIU/L, with one of the following:
1. Symptoms of hypothyroidism
2. TPO autoantibody present
3. History of CVD, HF, or risk factors for such
Treatment: initial daily doses of 25-75mcg recommended
If untreated, screen regularly for development of overt hypothyroidism
