thyroid Flashcards
Thyroid gland
○ Endocrine gland (secrete hormones directly into bloodstream)
○ Located in middle of lower neck
○ “butterfly” shape
Releases THYROID HORMONE
TH regulates
Regulate body physiological functions
Relate to development, growth, metabolism
physiological functions of thyroid hormone
body temp
CNS
sleep
cardiac
GIT
muscle strength
breathing
menstrual cycle
skin dryness
lipid metabolism
ulitlisation of glucose
Mechanisms negative feedback
1) Hypothalamus detect circulating TH low
a) Hypothalamus release thyrotropin-releasing hormone (TRH)
2) TRH instruct pituitary to release TSH
3) TSH instruct thyroid gland to secrete TH
4) Elevated lvl of circulating TH in blood
a) Hypothalamus sense incr in TH, stop release of TRH
TSH is ___ in 1* hypothroidism
ELEVATED
- Hypothalamus detect persistently low lvl of TH
◊ Hypothalamus secretes TRH - Instruct pituitary to secrete TSH
- Unsuccessfully stimulate thyroid gland to secrete TH
TSH is ___ in 1* hyperthroidism
LOW
-Hypothalamus detect persistently high lvl of TH
◊ Hypothalamus STOP secrete TRH
- No instruct pituitary to secrete TSH
- Independently functioning thyroid gland that continues to secrete TH
TH exists in
4:1 ratio (T4:T3)
T3 is
more potent
◊ 80% of T3 is peripheral converted from T4
◊ T1/2 of 2 days
◊ 99% protein bound
Not routinely ordered
T4 is
◊ T1/2 of 6-7 days
◊ 99% protein bound
- FreeT4 unbound (that carry out metabolic effect), routinely ordered with TSH – evaluate thyroid stores in pt
what is needed for TH
idoine (Obtained exogenously), thyroglobulin, tyrosine
Peripheral conversion – TBG
§ 80% of T3 is peripheral converted from T4
§ Affected by binding to proteins
□ Eg: pregnant (elevated TBG - thyroxine binding globulin)
- Decr T3, T4 (free unbound), more bound to extra TBG
- TSH released. Instruct thyroid gland release more THs for FT3, FT4 to normal
* Risk hypothyroidism
test for autoimmunity
1) antibodies
(ATgA, TPO, TRAb)
ATgA
thyroglobulin Ab
TPO
thyroperoxidase Ab (sig associated with hypothyroidism)
□ 95% of pt Hashimoto (inflammation): ATgA + TPO
□ 60-70% Graves (hyperthy): ATgA + TPO
TRAb
thyrotropin receptor IgG Ab
□ Specific, confirmatory for Graves
□Expensive test
ranges
T4 = 0.8-2.7
TSH = 0.4 - 4.2
When to screen:
APR Li RS
1) Presence of autoimmune disease (T1DM, cystic fibrosis)
2) 1st degree relative w/ autoimmune thyroid disease (genetics)
3) Psychiatric disorders
a) TH abnormality affects psychiatric
4) Take amiodarone/ lithium
5) History of head/ neck radiation for malignancies
a) Radiation predisposes
6) Symptoms of hypo/ hyperthyroidism
ROUTINE TEST FOR ONLY
(risk developmental risk)
1) Preg
2) Pediatric pt
hypothyroidism
TSH Elevated in 1* hypothyroidism
- Hypothalamus detect persistently low lvl of TH
◊ Hypothalamus secretes TRH
- Instruct pituitary to secrete TSH
-Unsuccessfully stimulate thyroid gland to secrete TH
HIGH TSH, LOW TH
1* hypothroidis:
- Iodine deficiency **
- Hashimoto disease
○ If no iodine insuff
○ Chronic autoimmune thyroiditis - Iatrogenic
○ Thyroid resection for HYPER
○ Radiation ablative therapy for HYPER
2nd causes of hypothyroidism
- Central hypothyroidism
Not thyroid gland issue
○ Hypothalamus unable to secrete TRH
○ Pituitary unable to secrete TSH - Drug induced
○ Amiodarone, Li
hypothyroidism Signs and symptoms
Cold intolerance
Dry skin
Fatigue, lethargy, weak
Weight gain
Bradycardia
Slow reflex
Coarse skin, hair
Periorbital swelling
Menstrual disturbances (more freq, more blood)
- Less thyroid, less estrogen, progestin
- More painful cramps
Goiter
- Enlarged thyroid gland
hypothyroidism Clinical manifestations
- HIGH total cholesterol, LDL, TG
- HIGH atherosclerosis, MI risk
- HIGH creatine phosphokinase (CPK) lvls
- DDI statins (will cause CPK to rise too)
- Incr miscarriage risk
*Impaired fetal development
Diagnosis for hypothyroidism
1) Signs and symptoms
2) Labs
- hypothyroidism (thyroid gland issue) * HIGH TSH, LOW T4 * +ve Ab (TPO, ATgA) - Central hypothyroidism (pituitary gland issue) * LOW TSH, LOW T4
Goals of therapy for hypothyroidism
- Eliminate symptoms, improve QOL
- Minimise LT damage to organs
- Myxedema coma
- Heart Disease
- Prevent neurologic deficits in newborns, children
- Normalise FT4, TSH conc
2 drugs for hypothyroidism
Levothyroxine (synthetic T4 )
Liothyronine (synthetic T3)
dose of levothyroxine
a. Young, healthy adults: 1.5-1.6 mcg/kg/d
b. 50-60 yrs (no CVS): 50mcg daily
c. 50-60 yrs (w/ CVS): 12.5 - 25 mcg/d
i. Titrate up
admin of levothyroxine
- 30-60mins before bfast
- 4hrs after dinner (empty stomach)
○ For meals, meds - If Ca/ Fe suppl/ antacids/ milk
○ Space 2 hrs apart
titrate levothyroxine
a. Response
i. Control of symptoms
ii. Normalisation of TSH, T4
b. Incr/ decr by 12.5-25 mcg/ day increments
c. Incr/ decr by 10-15% of wkly dose
Monitor levothyroxine
- 2-3mnths assess response in TSH (after start/ change in therapy)
○ Target TSH: 0.4-4mIU/L (WNL)
○ Symptomatic relief (within 2-3wks)
§ Negative feedback takes time to regulate (TSH, T4 to normal)
*euthyroid state: TFT semiannual - annually in non preg - Normal FT4 + HIGH TSH
○ = non-adherence - If central hypo (use FT4, no TSH)
ADR/ sign of over replacement of T4
- Cardiac abnormalities
○ Techy, angina, MI - Risk of fractures
- Signs of hyperthyroidism
Liothyronine, synthetic T3
T1/2 = 1-2.5 days (much shorter than T4)
Liothyronine ADR
- High risk of ADR
○ Not recc
when liothyronine is used
1) Combi T3, T4 — if normal TSH, but still symptoms of hypothyroidism
2) Myxedema coma — Very low TH, in coma
3) diagnostic criteria, CT scan, contrast media exposure
§ Stop T4, put on T3, stop 1-2 days before
§ Shorter t1/2
Monitoring hypothyroidism
- Upper limit normal of TSH in older adults continue to rise
- Age-related shift
- Adults > 70 yrs (TSH ~ 6.9mIU/L)
- After euthyroid state achieved
- TFT recc semiannually –> annually in nonpreg adults
Hypothyroidism & preg EFFECTS
- Miscarriage, spontaneous abortion
- Congenital defects, impaired cognitive development
- Maternal TH provide fetus with TH for up to 6wks
Until fetus forms own thyroid gland
- Maternal TH provide fetus with TH for up to 6wks
mother alr on levo before preg
○ Incr dose 30-50% in pre-preg dose
- To maintain euthyroid status: incr in thyroid binding proteins
* Target TSH: 1) Trimester: <2.5mIU/L 2) Trimester: <3.0mIU/L 3)Trimester: <3.5 mIU/L
Subclinical hypothyroidism (early stage)
- HIGH TSH, normal T4 –> early Hashimoto disease
- Risk:
○ TSH > 7.0mIU/L
§ Older adults = risk of HF
○ TSH > 10mIU/L
§Risk of coronary HD
Treatment for subclinical hypothyroidism??
(may risk incr TSH further, incr HF risk) ONLY TREAT:
○ TSH > 10mIU/L
○ TSH 4.5 - 10mIU/L
-Symptoms of hypothyroidism?
- TPO present
- Hist of CVS, HF, risk factors (genetics)
Start with: 25-75mg
If left untreated, screen regularly for development of OVERT hypothyroidism [HIGH TSH, LOW T4]
hyperthyroidism definition
TSH low lvl in 1* hyperthyroidism
- Hypothalamus detect persistently high lvl of TH
◊ Hypothalamus STOP secrete TRH
- No instruct pituitary to secrete TSH
- Independently functioning thyroid gland that continue to secrete TH
LOW TSH, HIGH TH
cause of hyperthyroidism
- Toxic diffuse goiter (GRAVES disease)**
○ Thyroid receptor Ab (TRAb) mimics TSH
○ Stimulate TH production - Pituitary adenomas
- Toxic adenomas (HOT NODULE)
○ Singular nodule
○ Oversecrete TSH –> T4 - Toxic multi-nodular goiter (Plummer’s disease)
○ Multi nodules that secrete T3 - Drugs induced
○ Amiodarone, Li - Subacute thyroiditis
○ Infections/ drug induced
○ Early HASHIMOTO’s disease
○ Release of STORED hormone
- HYPER –> HYPO (after explode)
signs and sx of hyperthyroidism
Weight loss, incr appetite
heat intolerance
Goiter
Fine hair
Heat palpitations/ tachycardia
Nervousness, anxiety, insomnia
Menstrual disturbances
(lighter/ infreq menstraution/ none)
Sweating, moist, warm skin
Exophthalmos (graves): bulging eyes (oedema, cytokines promote inflam)
Diagnosis of hyperthyroidism
- Signs and symptoms
- HIGH FREE T4
- LOW TSH (except in TSH-secreting adenomas)
- RAIU (radioactive iodine uptake)
- Used to better see if the gland is ACTIVELY secreting TH
- INCR UPTAKE:
○ Graves, TSH-secreting adenomas, toxic adenoma, multinodular goiter - DECR UPTAKE:
○ Thyroiditis, cancer
- Presence of TRAb, ATgA, TPO
*Biopsy
goals of treating hyperthyroidism
- Minimise/ eliminate symptoms, improve QOL
- Minimise LT damage to organs
- Heart disease, arrhythmias, cardiac death, bone demineralization, fractures
- Normalise free T4, TSH conc
non pharm therapy of hyperthyroidism
1) Surgical resection
- Causes hypothyroidism
- Cut out part
2) Radioactive iodine (RAI)
- Ablative therapy
- Conc in thyroid tissue
- Destroys overactive thyroid cells
-Preg is CI
3) Thyroidectomy
- Complete removal
- Results in hypothyroidism
Antithyroid pharmacotherapy (hyperthyroidism) used in which pop
1) Those awaiting ablative/ surgical resection
* Depletes stored T4, T3
*Minimise risk of post-ablation hyperthyroidism caused by thyroiditis
2) Pt that cannot undergo ablation (not candidates) // failed to normalise thyroid
○ Preg, old, young
○ Cannot go radiation therapy
○ leave radioactive reminants
3) Mild disease/ small goiter/ low or neg Ab titers/ women
4) Limited life expectancy too old
NOT LONG TERM
eg of antithyroid pharm
Thionamides (carbimazole & propylthiouracil)
Iodides
Non-selective beta blockers (propanolol)
Thionamides (carbimazole & propylthiouracil)
Inhibit iodination and synthesis of TH
i. PTU blocks T4/T3 conversion in periphery at high dose
Thionamides dose
i. PTU: 50-150mg TDS
1) Euthyroid: reduce to 50mg BD/ TDS
ii. Carbi: 15-60mg daily (split BD/ TDS)
1) Euthyroid: reduce to 5-15 mg OD
Thionamides ADR
i. Hepatotoxic risk *PTU
ii. Rash, SJS
iii. Agranulocytosis (early therapy, 3mnths)
iv. Fever
Efficacy of thionamides
i. Slow onset in reducing symptoms, max effect 4-6mnths
ii. Remission rates is low (20-30%)
1) Normal TSH, T4 for 1 yr after stop antithyroid therapy
iii. Monthly dose titration
1) Based on symptoms, FT4
2)TSH remain supp for mnths, FT3, FT4 better markers
Iodides MOA
Lugol’s sol (sat sol of KI)
inhibit release of stored TH
Minimal effect on hormone synthesis
Decr vascularity and size of gland
place in therapy of iodides
i. Before surgery (7-10 days) = shrink
ii. After ablation (3-7days) = inhibit thyroiditis mediated release of stored TH (BURST)
iii. Thyroid storm (too much TH)
considerations when using iodides
i. Limited efficacy after 7-14 days of therapy. TH release will resume
ii. NOT BEFORE ablative RAI (reduce uptake of radioactive I-)
Non-selective beta blockers – propanolol MOA
block hyperthyroidism manifestations mediated by b-adrenergic receptors
Block T4 conversion –> T3 (at high dose)
propanolol Place in therapy:
i. SYMPTOMATIC RELIEF
ii. Bridge for thionamides effect to kick in, before ablation, surgery
iii. PRN for high risk pt (elderly + CVS)
Treatment of thyroiditis (self-limit)
preg and hyperthyroidism sx
- Failure to gain weight, despite good appetite
- Tachycardia
- Fetal loss if untreated
but if use Thionamides: risk of embryopathy
tx for preg + hyperthyroidism
- Lowest dose
- Keep T4 at upper-normal limit
- 1st trimester:
○ Impt organs formation
○ Use PTU > carbi (Risk of congenital malformation) - 2nd, 3rd trimester:
○ Use Carbi > PTU (Risk of hepatotoxic, also less potent)
Subclinical hyperthyroidism
- Definition: low/ undetectable TSH + normal T4
- Risk:
○ Incr risk of AF (pt > 60yrs)
○ Incr risk of bone fracture (Post menopausal women)
Conflict data about mortality risk
Subclinical hyperthyroidism tx
○ Overt hyperthyroidism except ORAL therapy alternative > to ablative
§ In young patients
○ TSH <0.10mIU/L
○ BB if AF
Untreated: screen regularly for development of overt hyperthyroidism (LOW TSH, HIGH T4)
Drug induced thyroid disease 3 eg
Amiodarone
lithium
interferon alfa
Amiodarone
○ Contains iodine in chemical structure
○ Affects iodine uptake, secretion, production —> thyroiditis
HYPO/ HYPER
lithium
○ Inhibit TH secretion, release
○ Signal incr TSH –> goiter development (due to hypo)
○ leads to HYPER thyroiditis
- Interferon alfa
○ Thyroiditis (HYPER then HYPO)
Carbimazole MOA
1) Inhibit thyroid peroxidase
- Iodinates tyrosyl residues in thyroglobulin
- For T3,T4
2) Reduce synthesis of thyroid hormones
carbimazole function
- Inhibit thyroid hormone synthesis
- Gradual decr thyroid hormones (T3,4) output
- Reduce signs & sx of thyrotoxicosis
- Hyperthyroidism
- Control disease before surgery
- Excised part of enlarged thyroid gland
- Clinical response: takes 3-6wks
- T4 long half life
- Thyroid stores to deplete
- T4 long half life
carbimazole PK
A: PO
- OD dosing
- converted to active methimazole in serum (after absorption)
D: clinical effect lasts a day – concentrated in thyroid
(methimazole: T1/2 ~ 4-6hr)
* No bind to plasma proteins
* Produce 90% inhibition of thyroid organification of iodine within 12hr
M: liver – CYP450, FMO enzyme
- oxidation of xeno-substrates
E: 90% excreted in urine. 10% feces
ADR of carbimazole
- Rashes
- Joint pain
- N
- Jaundice
- Agranulocytosis (rare)
- Hypothyroidism (over treat)
Monitor: thyroid size, TSH levels (to normal levels)
CI of carbimazole
- Liver insuff
- Prevent hypothyroidism
levothyroxine MOA
Synthetic thyroid hormone (T4)
1) Taken up by cell
2) De-iodination to active T3
3) Hormone enter nuclues
a. Affect metabolic pathway in body
4) Incr protein synthesis for
a. Proteins, enzymes, pumps that incr T3,T4 levels in blood
levothyroxine function
- Restore body normal lvl of T4
Special case: myxoedema coma
* Severe form of hypothyroidism
* Reduce blood flow
* Affect gut absorption of LEVOTHYROXINE
- IV Liothyroxine (synthetic T3)/ IV levothyroxine used
PK of levothyroxine
A: PO (empty stomach with water. 30min before meal)
- erratic is dietary fibre (affect absorption)
F~ 70-80%
D: T1/2 ~ 7days (OD dose)
* 99% High bind to plasma proteins
M: deiodination site (T4–>T3)
* Main: LIVER
○ Also phase 2: Glucuronidation, sulphation
* Kidney, peripheral
E: feces, urine
Bile – metabolites
levothyroxine F affected by
Mainly absorbed in duodenum, jejunum (affected by gastric pH)
- antacids, PPI decr
ADR of levothyroxine
- LOA
- ANX
- Diarrhea
- Difficulty sleeping
- Hair loss
Serious:
* Heart issues
○ Arrhy, high
* BP, pain, HF
Seizures
monitor for levothyroxine
- Serum TSH measure to monitor adequate treatment
- TSH measure 2-3mnths after initiation// change dose
- If TSH persistently high
a. Inadequate dose
b. Poor compliance
c. Malabsorption
d. Drug/ food interaction
CI for levothyroxine
- pH
- absorption
- GI motility
- plasma protein binding
- liver enzyme (induce/ inhibit)
Food - Fiber
- Grapefruit
- Pomelo
FIBRE, antacids, PPI decr absorption
