Thyroid Flashcards
Describe the thyroid gland structure and function
Butterfly-shaped endocrine gland in the front of the neck
Responsible for synthesis, storage and release of the two thyroid hormones, T3 and T4
Hormones produce many physiological effects (almost every system in some capacity)
When doing a diagnostic workup, a physician is capable of doing what to the thyroid gland?
A physician can palpate the thyroid gland to determine structural abnormalities
Describe the thyroid gland anatomy? What type of cells are present?
Colloid
Follicular cells
Parafollicular cells
What is the most important cell of the thyroid gland?
Colloid is the most important cell in the thyroid – stores iodine, tyrosine, and thyroglobulin
Function of the Colloid
Colloid is the most important cell in the thyroid – stores iodine, tyrosine, and thyroglobulin
Follicular Cell Function
Follicular – transport cells, pumping susbtances into colloid and secretion
What hormones does the thyroid gland produce? How does it produce such hormones?
Synthesis and secretion of T3 and T4 controlled by thyroid stimulating hormone (TSH), which is controlled by thyrotropin-releasing hormone
Creation of T3 and T4 requires iodide, thyroglobulin and tyrosine
1) Iodide binds with tyrosine attached to thyroglobulin = mono or di-iodotyrosine (MIT or DIT) (metabolically inactive)
2) MIT + DIT = T3 or DIT + DIT = T4
3) Then secreted into circulation
4) Some T4 converted to T3 in peripheral tissue (kidney/liver)
Physiologic ratio of T4:T3 is ~13:1
What is the physiologic ratio of T3 and T4 conversion in the periphery?
Enables more mechanisms for homeostatic balance – T3 is 3x the potency of T4
If body is need, can produce t3
T3 is metabolically cheaper to produce and is more potent
What is the best signalling hormone for T3/T4 Production?
TSH best signalling hormone for T3 and T4 production and secretion
What enzymes is required for thyroid synthesis of T3 and T4?
Thyroid Perioxidase
Chemical steps of T3 and T4 production in the thyroid
Thyroglobulin synthesis
Iodide trapping
Oxidation of iodide
Iodination of tyrosine
Coupling of MIT and DIT
Secretion of hormones
What are some actions of T3 and T4?
Heart – chronotropic and inotropic (Affects Hr and CO)
Adipose tissue – catabolic
Muscle – catabolic (muscle cell turnover for building muscle)
Bone – developmental
Nervous system – developmental
Gut – metabolic
Other tissues - calorigenic
Describe the following:
a) T4 and T3 Circulation
b) T4 and T3 Potency
c) Conversion To Inactive Forms
T4 in circulation is 100% from thyroid
T3 in circulation is 20% directly from thyroid (rest of peripheral conversion)
T3 is ~4x more potent than T4
45% of T4 is converted to inactive rT3
The rest of T4 and T3 circulate in active free form or protein-bound inactive form
T3/T4 Protein Binding
99.5% is in the protein bound form
How is the thyroid hormone process regulated?
Regulated by a negative feedback loop
Describe the regulation process of thyroid hormone (What promotes release? What inhibits release?)
Hormone release promoted by:
Thyroid Stimulating Hormone – TSH
Release of TSH stimulated by low circulating T3/T4 levels
Low serum iodide (initially compensatory mechanism, increases T3 and T4 production, cannot go on for ever - chronically, low serum iodine leads to hypothyroid)
Hormone release inhibited by:
High circulating T3/T4 levels
Lithium (one of the main drug induced hypothyroidism)
Iodide excess (interferes with organocation of iodide; temporary inhibition by 7 days or so)
Draw out the process of thyroid hormone regulation?
What are some significant epidemiology statistics of thyroid disorders?
~10% of Canadians have overactive or underactive thyroid glands; >50% are undiagnosed
More than 8 out of 10 patients with thyroid disease are women
1 out of 50 women are diagnosed with hypothyroidism during pregnancy
Incidence of hypothyroidism increases with age (over the age of 65, rate incraeses by 25% plus)
Why are thyroid disorders often undiagnosed?
Thyroid disorders cause non-specific sx that are hard to pinpoint on the thyroid
Define hyperthyroidism
Disease caused by excess synthesis and secretion of thyroid hormone
Causes of Hyperthyroidism
Toxic diffuse goiter (Graves disease)
Toxic multi-nodular goiter (Plummers disease)
Acute phase of thyroiditis
Toxic adenoma
- Can be many causes
What is a goiter?
enlargement of the thyroid
Hyperthyroidism Sx
Causes a constellation of symptoms
Sx can change over time for the same individual
What type of disease is toxic diffuse goiter?
Autoimmune disorder
What is the most common cause of hyperthyroidism?
Toxic diffuse goiter (AKA Graves disease)
Who is toxic diffuse goiter more common in? Explain the pathology of the condition?
More common in younger, female patients (ages 20-50)
Most common cause of hyperthyroidism
Autoimmune disorder
Immune system creates antibodies against the TSH receptor
Can result in hyperplasia of thyroid gland, leading to a goiter
–> Antibodies bind to receptor and cause secretion of T3 and T4
–> Negative feedback does not work – TSH levels will be low; but does not cause anything as it is the antibodies doing the elevation
Is toxic multi-nodular goiter an autoimmune disease?
NO - NOT AN AUTOIMMUNE DX
Describe the epidemiology of toxic-multi nodular goiter?
Most common in older, female patients (>50)
Second most common cause of hyperthyroidism
Temprrary iodine deficiency (not chronic) most common trigger for nodules to grow, but can be many others
Develops slowly over several years
Describe the pathology of toxic multi-nodular goiter?
Iodine deficiency –> less T4 production –> thyroid cells grow larger (multi-nodular goiter) –> TSH receptors mutate –> continually active
Describe acute phase of thyroiditis
Causes inflammation and damage to the thyroid gland
Damage causes excess hormone to be released (passive diffusion type mechanism)
Eventually leads to hypothyroidism once T3/T4 stores exhausted
What is toxic adenoma?
Benign tumours growing on thyroid gland
Become active and act just like thyroid cells, secreting T3/T4 but not responding to negative feedback (no TSH receptors)
What are some causes of acute phase of thyroiditis?
Infection
Physical Trauma
Pregnancy During the Delivery Phase
What are some common non-specific symptoms of hyperthyroidism?
What are some less common non-specific symptoms of hyperthyroidism?
When analyzing a patients symptoms (non-specifc sx), how many can a patient have?
Can vary from person to person
A person may only have one of the symptoms listed
What are some specifc symptoms of toxic diffuse goiter?
Exophthalmos (or proptosis) (slow processes to reverse)
Peri-orbital edema
Diplopia
Diffuse Goiter
Pre-tibial myxedema (rash on the shins, not severe consequences but uncomfortable)
In toxic diffuse goiter, are the ocular symptoms permenant?
Ocular sx are often reversible
What are some specific symptoms of toxic multi-nodular goiter?
Same general hyperthyroidism symptoms
Individual thyroid nodules may be palpable (only difference)
What is unique to toxic multi-nodular goiter hyperthyroidism?
Individual thyroid nodules may be palpable (only difference)
How is hyperthyroidism diagnosed?
a) Subclinical Hyperthroidism
b) Toxic Diffuse
c) Toxic Multi-nodular
Diagnosis based on clinical symptoms and lab tests
T3 and T4 are inverse to TSH in toxic diffuse and toxic multi-nodular - Differentiate the two on an imaging exam
When diagnosing hyperthyroidism, an important consideration is to….
Treat the patient (sx) and not the number
Can drugs influence lab tests of hyperthyroidism? If so, how? Which ones?
Are these significant? If so, in who?
Some drugs can influence lab tests
If someone has healthy thyroid, these should not matter
Only really effects people if they have hyperthyroid or undiagnosed hyperthyroid issues
What are the treatment options for hyperthyroidism?
I. Drugs
Thioamides
Beta-blockers
II. Radioactive iodine (RAI)
III. Surgery (thyroidectomy)
Thioamide Examples
Anti-thyroid drugs:
Methimazole (MMI)
Propylthiouracil (PTU)
What are the clinical indications for thioamides?
Toxic diffuse goiter
Toxic multi-nodular goiter
Pre-treatment before Radioactive Iodine
In regards to hyperthyroidism, remission refers to?
Bring thyroid levels into normal range and are sx free
What is the goal of therapy for thioamides?
Goal of therapy is to achieve remission
Relapses are common
About 30% remain in remission after 1-2 years of therapy with either drug (some people can see long term success; may not be necessary to pursue curative options)
Describe the mechanism of action of thioamides?
Interferes with thyroid peroxidase-mediated processes in T3/T4 production
PTU also inhibits peripheral conversion T4 to T3
Of the thioamides, which drug is considered the most potent?
PTU
What is an issue with the mechanism of action of the thioamides?
Not targeting the route cause – likely to not be effective lifelong – temporary relief until permanent treatment
Draw out the mechanism of action of drugs used to treat hyperthyroidism
Methimazole – Not clinically significant effect on peripheralnversion to T3
Describe the dosing/administration of the thioamides
High initial dose –> lower maintenance doses
Titrate dose if TSH and T4 does not improve in 4-6w
Decrease dose gradually once euthyroid
Why does the MD of the thioamides decrease with continual usage?
Goiter should shrink so lower MD as we continue
When can thioamide doses be adjusted? Why?
Do not alter doses no more than every 4-6 weks
When a new homeostatic set point is established
What is the dosing of the thioamides?
Explain the dose to s/e relationship of the thioamides
Meth – Dose related s/e
PTU – same rates of s/e no matter the dose
Can the thioamides be taken with food?
Take with or without food
Onset of effect of the thioamides
Symptom improvement within 1-4 weeks
Euthyroid in 2-3 months
Duration of therapy with the thioamides
12-18 months common
May taper to d/c and see if relapse occurs
How can dosing of the thioamides be altered for:
a) Convenience
b) S/e Management
If convenience is a priority, may give both as a single daily dose
If lowered naseau more important, divide the doses
Which thioamide has higher rates of s/e? Are they dose related?
Higher rates with PTU
Dose related for MMI, but not PTU
How common are side-effects with the thioamides?
Occur in 5-10% of patients
Most of these side-effects improve over 4 weeks
What are some common side effects of thioamides?
GI upset
Rash
Arthralgia
Abnormal taste/smell
A patient is on a thioamide and the dose was just increased. Would you expect this individual to have s/e with the dose increase?
Dose escalations may cause s/e to reappear for a few weeks before disappearing
An individual is complaining of s/e from thioamide therapy. As a pharamacist, should you encourage the patient to continue the thioamide or stop the thioamide?
No other options for drugs that work on the thyroid, so really want people to push through these s/e
What are some serious side effects of thioamides?
Neutropenia
Agranulocytosis
Hepatotoxicity
Vasculitis
Describe thioamide neutropenia and agranulocytosis. When does it occur? Symptoms? Is frequent monitoring required?
Small decline in neutrophils common (transient decrease is common)
Agranulocytosis in 0.3 – 0.4% of patients
higher with PTU
Usually occurs within the first 90 days
Fever, malaise, sore throat most common symptoms
Abrupt onset
Regular monitoring of WBC not cost-effective
Lab value definition of neutropenia and agranulocytosis?
How much a decline is required to lead to agranulocytosis?
Sig decline over 30-40% of baseline may lead to agranulocytosis
Monitoring of thioamides frequenyc?
Only monitoring suggested – baseline and week later but no more often
Important counselling tip for thioamides
Feel any illness lasting beyond a few days, go see physician
Hepatoxocity and thioamides. Frequency? Type of injury? Does it resolve? Lab Findings?
0.1-0.2% incidence (higher with PTU)
MMI – reversible cholestatic jaundice
PTU – allergic type hepatocellular damage
Resolves once drug d/c, but can result in death
Both can increase AST/ALT, concern if >3x upper limit normal, or alcoholic
When monitoring for hepatoxicity in the thioamides? Watch for? Which drug primarily?
Watch for fatigue, darker urine, yellowing of skin/eyes, ruq pain – Definetely for PTU would warn someone about these s/e
Abrupt onset, so regular testing unlikely to catch it happening
Testing of hepatoxcity thiamoides?
Baseline and a week later
Thioamides vasculitis? More common with….. What type of condition is it? What does it lead to?
More common with PTU
Auto-immune process
Damages vascular tissue causing inflammation and destruction of blood vessels
Leads to:
Acute renal dysfunction
Arthritis
Skin ulcers/rashes
Respiratory problems
OVERALL COUNSELLING TIPS OF THIOAMIDES
Discuss common side-effects, management strategies, and reassurance they usually improve after 1 month
Discuss risk of severe side-effects are low, but watch for:
Signs of infection: fever, headache, malaise, sore throat
Depending on severity of symptoms, may need to see doctor immediately
PTU: Liver related issues (fatigue, weakness, RUQ pain, yellowing of eyes/skin, dark urine)
Should be seen by doctor immediately for evaluation
Drug Interactions of Thioamides
Warfarin: Decrease in INR
Digoxin: Increase in digoxin levels
Methimazole weakly inhibits 2D6, 2C9, 2E1 – Clinically insignificant
How should the effectiveness of thioamides be monitored? What if discontinuing a thioamide?
1-4 weeks for symptom improvement
Assess TSH, T3 and T4 at 4-6 week intervals until stable; then q2-3 months for 6-12m, then q4-6 months
If discontinuing, must watch for relapse:
TSH at 3 months –> 6 months –>12 months –> anually
Relapse most likely within first 3 months
If suppressed TSH and normal T4/T3 seen, relapse likely
How can thioamides safety be monitored?
CBCs: baseline and 1 week later
LFTs: baseline and 1 week later
watch for AST/ALT >3x ULN and symptoms of hepatotoxicity
Compare methimazole and PTU
a) Onset of euthyroid
b) Clinical Response
c) S/e and toxicity
d) Compliance
e) C.I.
f) Pregnancy
In hyperthyroidism, beta-blockers are used for….
Reduces symptoms of hyperthyroidism:
Palpitations
Tachycardia
Tremors
Anxiety
Heat intolerance
Just related to cardiovascular symptom improvement
What beta-blocker should be used in hyperthyroidism?
Choose propranolol if no other compelling indication for a beta-blocker – short acting and easy to titrate and withdraw – can use on PRN basis if not constant cardiovascular indication
Most beta-blockers effective
When can a beta-blo0cker be started for hyperthyroidism?
Can be started as soon as hyperthyroidism suspected and added to other treatment
- If other beta-blocker on board, just continue to use it
What conditions should be watched for in hyperthyroidism and beta-blocker usage? Which beta-blocker should be used?
COPD or Asthma – propranolol not recommended as a short acting beta-blocker, use atenolon OD beta-blocker that is cardioselective
Radioactive Iodine Usage in Hyperthyroidism
Radioactive Iodine 131 (I131)
Used commonly
I131 is taken up by the thyroid in its normal process, but the I131 causes tissue damage and ablation of gland
Is a definitive treatment compared to thioamides
When is radioactive iodine given in hypethyroidism?
Only give when:
Mild hyperthyroidism (tx with thioamides prior to radioactive iodine)
Normal or only slightly enlarged gland
No exopthalmous
What are some downsides/complications of radioactive iodine?
Permanent hypothyroidism (Treating hypo is easier and safer lifelong than hyper)
Can trigger thyroid storm / thyrotoxicosis
Worsen exopthalmous
Radioactive Iodine C.I.
In pregnancy / lactation
Severe hyperthyroidism / exopthalmous
What are some adverese effects of hypothyroidism
Initial hyperthyroidism exacerbation likely
Followed by hypothyroidism symptoms
What is the most common usage of radioactive iodine?
Pre-treatment with thioamides
Given to achieve euthyroid status and avoid thyroiditis
Recommended for all, but must pretreat: Elderly patients, cardiac disease or severe hyperthyroidism
A permenant solution of hyperthyroidism is….
Surgery (thyroidectomy)
How should radioactive idoine be given to patients persuing pre-tx in hyperthyroidism?
Initiate 4-6 weeks before RAI
Stop three days prior to RAI
Restart three days after RAI
Taper and discontinue once thyroid hormone levels decline
A thyroidectomy should be pursued be used as an option in individuals when….
Pregnant patients who cannot tolerate medication
Patients who want “curative” therapy, but not RAI
Patients with large goiters (resistant to RAI)
Complications of thyroidectomy
Hypoparathyroidism (parathyroid located on back side of thyroid) – rates are low
Vocal cord paralysis
Thyrotoxicosis
What is subclinical hyperthyroidism?
TSH of 0.1-0.3, normal FT3/FT4, asymptomatic
Subclinical hypothyrodism is ________. Tx shoudl occur in those who…
Clinically important! Tx those such as:
Osteoporosis risk increase
Cardiac abnormalities
Increase in mortality
Treatment and monitoring of subclinical hyperthyroidism?
If at risk for complications: strongly consider treatment, or check levels again in 3 months (then treat if confirmed result)
If at low risk for complications: recheck levels in 3-6 months unless TSH <0.1 (then consider treating)
Thyroiditis Management?
Self-limiting
B-blocker for Symptom control
NSAIDs for pain
Course of steroids for severe cases
DO NOT USE THIOAMIDES
What are some causes of hypothyroidism?
Results from a defect anywhere on the HPT axis
Chronic autoimmune thyroiditis (Hashimoto’s)
Drug induced
Iatrogenic disease (e.g. thyroidectomy/RAI)
Post-partum thyroiditis
Chronic iodine deficiency
Central hypothyroidism
Hypopituitarism
What is the most common cause of hypothyrpoidism?
Chronic autoimmune thyroiditis (Hashimoto’s)
Whis is chronic autoimmune thyroiditis?
Most common cause of hypothyroidism
Autoimmune disorder where antibodies form
Antibodies bind to TSH receptors which directly destroy thyroid cells
Other antibodies may form that interfere with production of T3 and T4
What are some drug-induced causes of hypothyroidism?
Lithium
Blocks iodine transport into the thyroid & prevents hormone release
May cause subclinical or overt hypothyroidism (~20%)
Patients with history of thyroid dysfunction at risk, elderly
Monitor at 3m, then q6-12m
Amiodarone
Can cause hyper (<5%) or hypothyroidism (5-25%)
Increased risk if history of thyroid dysfunction
Monitor q1m x 3 m, then q3m x 6 m, then q6-12m
What is the most common presentation of hypothyroidism?
Weight gain and fatigue
What are some signs of early hypothyroidism and advanced hypothyroidism?
Hypothyroidism presentation in the elderly?
Elderly patients – atypical presentation – cognitive related signs and symptoms
What are some lab tests for sub-clinical hypothyroidism and hashimoto’s?
What are some drugs that can influence the lab results in hypothyroidism? Management?
Don’t panic if you see someone on one of these and is being treated for hypothyroidism. It can be managed.
Not a contraindication if start one of these meds if someone has hypo.
What is the treatment of hypothyroidism? What are the treatment options?
Treatment
Replacement of thyroid hormone necessary
Options:
Desiccated thyroid
Liothyronine
Levothyroxine
Combined T3/T4
What was the first agent available for hypothyroidism?
Desiccated thyroid
First agent available
What is dessicated thyroid?
Prepared from thyroid glands of animals
Contains T3 and T4
Causes high peak T3
Not well standardized batch to batch
Short t1/2
What is the ratio of dessicated thyroid concerning T3 and T4?
Dessicated has a ration of 4 T4 : 1 T3 – more potent than body would prefer
What is a PK parameter of dessicated thyroid? Implication?
Short t1/2 – tends to cause rollercoaster effect – high than low, repeat – prefer more stable levels of thyroid hormones – increase risk of CV effect; however, no long term studies
Effectivenesss of dessicated thyroid
People do have positive effects quickly – questions about long term
What is liothyronine?
Contains T3, no effect on T4
Short half-life - causes wide fluctuations in serum levels
Costly
Higher incidence of cardiac adverse effects
Try to dose close to physiologic ratio of T4:T3
When should liothyronine be considered?
Some people who take levothyroxine, some people will not get control of hypo.
In rare cases, adding it here it may be added – May not convert in person, add on to levothyroxine
- Only comes in 5 mcg increments
- 100 mg of levothyroxine, add on 10 mcg of liothyronine
What are some issues with liothyronine?
Wherever possible prefer body handles conversion of T4 to T3 to ensure homeostatic setpoint
Not family physician territory
What is levothyroxine?
Analogue of T4
Standard 1st therapy
Half life of 7 days
Conversion to T3 regulated by body
What PK parameter is important for levothyropxine? Whast does it allow us to do?
Half-life – Miss a dose (not a big deal), can take totally week dose as one dose – not as effective but can be done to improve adherence
How is the dosage and administration of levothyroxine determined?
Depends on age, weight, cardiac status, severity and duration of hypothyroidism
Higher baseline TSH usually predicts higher T4 dose
AVERAGE DOSE OF LEVOTHYROXINE
Average replacement (target) dose is 1.6mcg/kg/d
Starting dose ranges from 12.5mcg/day to max wt. based
Often give 100mcg empirically to young, healthy patients (not CV)
If subclinical, 25-50mcg empirically
Why is a high empirical dos eof 100 mg of levothyroxine given to young healthy patients and not elderly patients?
Hypothyroidism for long time – CV system not use to higher amounts of stimulation – theoretical risk of causing too much stress on CV system
Levothyroxine should be started slow and titrated up if: Recommended Dose?
Any CVD (eg. ischemic heart disease)
Rhythm disorders (e.g a-fib)
>50 years old
Severe, long-standing hypothyroidism
Start low (12.5-25mcg) and titrate up by 12.5 – 25mcg q4-6 weeks
How should levothyroxine be administered?
Administer on empty stomach, 30 min before meals or 1 hour after, QAM best (small bioavailability) – spaced away from other meds
If someone does meet the criteria for starting slow, what dose should be started of levothyroxine?
Not this criteria – anyone else, higher empiric of max weight based – achieve control faster
Consistency is best here
-Unsure of what dose to start someone one
- If non-urgent, start slow and go slow
- Often not life threatning condition
What are some side effects of levothyroxine? Are these common?
Hyperthyroidism symptoms
Cardiac risk increase
Aggravate existing CVD
BMD reduction
If initiate appropriately, should not notice anything – NO s/e with medications unless dosed too high
What are some drug interactions with levothyroxine absorption? How are these drug interactions managed?
Antacids / H2 blockers / PPIs
Iron
Calcium / mineral supplements
Cholestyramine / colestipol
Manage by spacing levothyroxine 2-4 hours away from these meds
Raloxifene –> space by 12h
A patient just started a PPI and is on levotyhyroxine, what is the cocnern? What6 should be monitored?
PPI’s – mechanism of impairment changes pH of levothyroxine – PPI is okay on with levothyroxine (small effect), newly initiated be aware and dose change may be necessary for levothyroxine
Drug interactions of levothyroxine clerance?
Drug Interactions
Potent CYP inducers increases thyroid hormone metabolism
Ciprofloxacin (short term, so clinically significance is low)
Phenytoin
Carbamazepine
Rifampin
Pregnancy
TCAs: increased risk of arrhythmias
Monintroing of levothyroxine TFT’s
TSH –> aim for low normal value (~<2.5mIU/L)
Lower values can increase risk of cardiac toxicity (younger patient, may be better for more aggressive)
May take 4-6 weeks to stabilize with each dose change
Free T4 –> normal to slightly elevated
Free T3 –> normal
Symptoms –> improvement in 2-3 weeks, maximum effect in 4-6 weeks
Once stable and symptom free, monitor TSH q6-12-24m
Subclinical Hyothyroidism Test Diagnosis and TX
TSH of 4.5 - 10 mIU/L, normal T3/T4, “asymptomatic”
Treatment is controversial (often do not treat)
Subclinical hypothyroidism can be potentially clinically relevant when….
Potentially clinically relevant. Increased risk of:
Atherosclerosis
Heart failure
MI
Depression
Low BMD
Metabolic syndrome
When is subclinical hypothyroidism often treated?
Treat if patient develops symptoms, planning pregnancy, heart failure, very young patient
When treatment with levothyroxine fails, one should consider?
Decreased bioavailability
Poor adherence
Malabsorption (PPI therapy, gastritis, H.pylori, Celiac)
Improper administration (taking with food, milk, other meds)
Increased need
Recent weight gain
Pregnancy
New medications that increase metabolism of T3/T4
Other conditions:
Addison’s disease
Altered hypothalamic-pituitary-thyroid axis
Insufficient peripheral conversion of T4 to T3
Comapre leveothyroxine and thioamides?
a) Expect/Sx Improvement
b) Monitoring
c) S/e
d) When to see MD
e) Meds to Watch For
