Thyroid disorders Flashcards
Physiological functions regulated by THs
*increased oxygen consumption by most tissues -> increased basal metabolic rate
- Body temperature
- CNS
- Sleep
- Cardiac function
- GI function
- Muscle strength
- Breathing
- Menstrual cycle
- Skin dryness
- Increases lipid metabolism
- Increases uptake & utilisation of glucose
Regulation of thyroid hormones (homeostasis)
- Hypothalamus detects when circulating THs are low -> release Thyrotropin Releasing Hormone (TRH)
- TRH acts on pituitary to release Thyroid Stimulating Hormone (TSH) *aka thyrotropin
- TSH stimulates thyroid gland to secrete THs
- Elevated circulating levels of TH in blood sends a NEGATIVE FEEDBACK to hypothalamus to stop releasing TRH
Role of Thyroid Stimulating Hormone in thyroid disorders
Primary HYPOthyroidism: ELEVATED TSH levels
- Hypothalamus detects low circulating TH in blood, releases TRH to instruct pituitary -> release TSH. BUT TSH will unsuccessfully stimulate thyroid gland to secrete THs -> continuous secretion of TSH
Primary HYPERthyroidism: LOW levels of TSH
- Hypothalamus detects persistently elevated levels of TH, does not secrete TRH -> pituitary is not stimulated to secrete TSH -> low TSH levels
**thyroid gland functioning INDEPENDENTLY of TSH levels
Thyroid hormones (T4, T3) information
*Production of thyroid hormones: IODINE CONSUMPTION ESSENTIAL; obtained EXOGENOUSLY
*T3 more potent
T4:T3 present in circulation in ratio of 4:1
80% of T3 produced from peripheral conversion of T4 by deiodination via deiondinase
T4: t1/2 of 6-7days (>99% protein-bound) **USED AS SURROGATE MARKER TO EVALUATE THYROID STATUS
- free T4 unbound; measured
T3: t1/2 of 2d (>99% protein-bound)
not routinely ordered
Role of thyroxine binding globulin (TBG) in thyroid hormone regulation
*TBG as protein that TH binds to
if no thyroid issues, TBG ELEVATED (eg. pregnant, on estrogen) -> free T3 & T4 levels DECREASES (more T3/ T4 bound to extra TBG) -> TSH RELEASED, instruct thyroid gland to release MORE TH -> levels of free T3 & T4 return to normal *new equilibrium achieved
Antibodies present in thyroid disorders (Test of autoimunity)
Thyroglobulin Antibodies (ATgA)
Thyroperoxidase Antibodies (TPO) *significantly associated with HYPOthyroidism
Thyrotropin Receptor IgG antibodies (TRAb)
*specific & confirmatory for Graves’ disease BUT ex
Hashimoto’s (hypo): 95% (+) ATgA, (+) TPO
Graves’ (hyper): 60-70% (+) ATgA, (+) TPO
Compelling indications for screening of thyroid disorders
- Presence of autoimmune disease (eg. T1DM, cystic fibrosis)
- 1st-degree relative with autoimmune thyroid disease
- Psychiatric disorders
- Amiodarone/ Lithium consumers
- History of head/neck radiation for malignancies
- Symptoms of hypo/hyperthyroidism
**PEDIATRIC + PREGANT WOMEN: ROUTINE SCREENING REQUIRED
Possible causes of hypothyroidism
Primary causes:
1. Iodine deficiency *most common cause
2. Hashimoto disease: hypothyroid disorder in areas with iodine SUFFICIENCY (chronic autoimmune thyroiditis)
*(+) ATgA & TPO antibodies – disproportionate affects women
3. Iatrogrenic: Thyroid resection/ radioiodine ablative therapy for hyperthyroidism
Secondary causes:
1. Central hypothyroidism: hypothalamus unable to secrete TRH/ pituitary unable to secrete TSH
2. Drug induced (eg. amiodarone, lithium)
Clinical presentation of HYPOthyroidism
Signs/ symptoms
Cold intolerance
Dry skin
Fatigue, lethargy, weakness
Weight gain
Bradycardia
Slow reflexes
Coarse skin & hair
Periorbital swelling
Menstrual disturbances (MORE frequent/ MORE blood)
Goiter
Lab values/ clinical manifestation:
INCREASED total cholesterol, LDL, triglycerides
INCREASED atherosclerosis, MI risk
INCREASED creatine phosphokinase (CPK) levels
INCREASED miscarriage risk
IMPAIRED fetal cognitive development
Diagnosis of hypothyroidism
Signs & symptoms/ screening
+
Labs (TSH, free T4, antibodies TPO/ATgA)
*primary hypo: INCREASED TSH, DECREASED T4; (+) antibodies (ATgA, TPO)
Central hypo: DECREASED TSH, DECREASED T4
Goals of therapy (hypo/hyper)
- Minimise/ eliminate symptoms; improve QoL
- Minimise long-term damage to organs (HYPO: myxedema coma, heart disease)
(HYPER: heart disease, arrhythmias, sudden cardiac death, bone demineralisation, fractures) - HYPO: Prevent neurologic deficits in newborns & children
- Normalise free T4 & TSH concentrations
Overview of management of HYPOthyroidism with levothyroxine
Drug of choice: LEVOTHYROXINE **lifelong treatment
- synthetic T4
*initial dosing:
adults (young & healthy): 1.6mcg/kg/d (~100mcg)
50-60y.o + NO cardiac issues: 50mcg daily
WITH CVD -> 12.5 - 25mcg daily, titrate up
**titration: depends on response (control of symptoms, normalisation of TSH & T4) – can INCREASE or DECREASE in 12.5 - 25mcg/day increments OR 10-15% of weekly dose
eg. 100mcg daily, reduce by 10-15%: 2 separate days of 50mcg, 5 days of 100mcg
Counseling points: take 30-60mins BEFORE breakfast or 4h AFTER dinner *EMPTY STOMACH - INCLUDES OTHER MEDICATIONS (esp Ca/ Fe supplements & antacids -> SPACE AT LEAST 2H APART)
Monitoring: 4-8 weeks (assess response in TSH after intiating/ changing therapy)
- general target TSH: 0.4 - 4mIU/L
*older adults: unclear on ULN, can be within normal limit up to 6.9mIU/L (higher TSH conc in older adults)
- symptomatic relief (2-3 weeks)
- AFTER euthyroid state achieved -> thyroid function tests (TFT) SEMIANNUALLY to ANUALLY in nonpregnant adult pts
**normalisation of free T4 with consistently RAISED TSH –> non-adherence
**IF CENTRAL HYPO: use free T4 to monitor instead
A/E: Cardiac abnormalities (tachyarrhythmias, angina, MI) // Risk of fractures // Signs of HYPERthyroidism
- considered drug of choice: A/E profile, cost, LACK OF ANTIGENICITIY, UNIFORM POTENCY
Overview of management of HYPOthyroidism with Liothyronine
*synthetic T3
t1/2: 1-2.5d (MUCH shorter than T4) *T3 t1/2: 2d
HIGH incidence of adverse effects
Starting dose: 25mcg (UNLESS elderly/ CVD -> 5mcg)
*generally not recommended by organisations/ guidelines
-> can be considered in myxedema coma (MORE potent)
**Combination T4 with T3 can be considered if NORMALISED TSH, BUT STILL complain of symptoms of HYPOthyroidism
Management of HYPOthyroidism in pregnancy
*effect of maternal HYPOthyroidism: [ maternal] miscarriage, spontaneous abortion // [fetus] congenital defects, impaired cognitive development
*fetus receives maternal THs UP TO 12wks before fetus forms their own thyroid gland
IF MOM ON LEVOTHYROXINE: may need 30-50% increase of pre-pregnant dosage to maintain euthyroid status
Targest TSH:
1st trimester: <2.5mIU/L
2nd trimester: <3mIU/L
3rd trimester: <3.5mIU/L
what is subclinical HYPOthyroidism?
elevated TSH with NORMAL T4
*often the result of EARLY Hashimoto disease
Risk:
TSH > 7mIU/L in OLDER adults -> ELEVATED risk of HEART FAILIURE
TSH > 10mIU/L -> ELEVATED risk of CORONARY HEART DISEASE
treatment: CONTROVERSIAL
- Consider treating when TSH > 10mIU/L
OR
- TSH 4.5 - 10mIU/L AND
1) symptoms of HYPOthyroidism
2) TPOAb present
3) History of CVD, HF, or RISK FACTORS for such
-> initial daily dose: 25-75mcg
*IF UNTREATED: screen REGULARLY for development of OVERT HYPOthyroidism
Possible causes of HYPERthyroidism
*overabundance of circulating thyroid hormone -> mimics effects of an activated sympathetic nervous system
- Graves disease (toxic diffuse goiter) *most common hyperthyroid disorder (~80%): TSH receptor antibodies (TRAb) mimics TSH binding (GD: Thyroid Stimulating Immunoglobulin TSI subtype stimulates TH production
- Pituitary adenomas
- Toxic adenoma (hot nodule): Solitary functioning nodule that secretes T3
- Toxic multi-nodular goiter (Plummer’s Disease): Multiple nodules that secrete T3
- Drug induced (eg. amiodarone, lithium)
- Subacute thyroiditis: infections, drug induced, early Hashimoto’s disease etc. -> release of STORED hormones
Signs & symptoms of HYPERthyroidism
THYROIDISM-E:
Tremor
Heart rate up
Yawning (fatigability)
Restlessness
Oligomenorrhea & amenorrhea
Intolerance to heat
Diarrhea
Irritability
Sweating
Muscle wasting & weight loss
Exophthalmos
Diagnosis of HYPERthyroidism
signs & symptoms (THYROIDISM-E)
+
labs:
- free T4 serum (elevated)
- TSH conc (suppressed EXCEPT in TSH-secreting adenomas)
- Radioactive iodine uptake (RAIU) - CAN BE USED FOR BETTER ETIOLOGY
–> uptake ELEVATED: if gland is ACTIVELY SECRETING TH (graves disease, TSH-secreting adenoma, toxic adenoma, multinodular goiter)
–> uptake SUPPRESSED: disorders caused by thyroiditis/ cancer
- Presence of TRAb, ATgA, TPO
- Biopsy
Treatment options for HYPERthyroidism
- Surgical resection (destroy certain parts of thyroid) *often results in HYPOthyroidism
- Radioactive iodine (RAI) ablative therapy *often results in HYPOthyroidism (>80%)
- 1st line option if no CI for Graves’ Disease
- Colourless, tasteless liquid in a capsule that concentrates in thyroid tissue -> destroys OVERACTIVE thyroid cells
*CI: PREGNANCY - Thyroidectomy (WHOLE thyroid removed) -> leads to HYPOthyroidism
- Antithyroid pharmacotherapy: thionamides/ iodides/ NSBB
indication for antithyroid pharmacotherapy in HYPERthyroidism?
- Those awaiting ablative therapy/ surgical resection: depletes stored hormones + minimises risk of POST-ablation HYPERthyroidism caused by thyroiditis
- NOT ablative/ surgical candidates OR failed to normalise thyroid
- MILD disease/ SMALL goiter/ LOW or -ve antibody titers/ WOMEN
- limited life expectancy
Use of thionamides in HYPERthyroidism (dose, MOA, AE, monitoring)
Thionamides: Carbimazole (preferred for Graves for most patients), Propylthiouracil (PTU)
MOA: INHIBITS IODINATION & synthesis of thyroid hormones by acting as substrates for TPO
*PTU: blocks T4/T3 conversion in periphery @ HIGH doses
Dosing:
Carbimazole: initial 15-60mg daily (in 2-3 divided doses); once euthyroid can reduce to 5-15mg OD
PTU: initial 50-150mg PO TDS; once euthyroid can reduce to 50mg BD-TDS daily
A/E:
Hepatotoxicity risk *boxed warning for PTU -> carbimazole usually 1st line
Rash (risk for SJS)
Agranulocytosis early in therapy (usually <3months) [neutrophil count <100/uL]
Fever
Monitoring
- SLOW onset in reducing symptoms (weeks); MAX effect may take 4-6 MONTHS *MOA
- LOW remission rates (20-30%) [remission: normal TSH & T4 for 1y AFTER DISCONTINUING antithyroid therapy]
- Monthly dosage titrations as needed (depending on symptoms & free T4 conc): TSH may remain suppressed for months after therapy begins; total T3 may be better marker of efficacy EARLY IN THERAPY (vs free T4)
management of HYPERthyroidism using THIONAMDIES in PREGNANCY
*2 main symptoms:
- Failure to gain weight despite good appetite
- Tachycardia
*IF UNTREATED: FETAL LOSS
**but thionamides: risk of embryopathy
Treatment: use LOWEST possible dose; keep T4 at UPPER NORMAL LIMIT
- 1st trimester: use PTU (carbimazole higher risk of congenital malformation)
- 2nd & 3rd trimester: use Carbimazole (PTU: higher risk of hepatotoxicity)
use of Non-selective Beta Blockers in HYPERthyroidism
*primarily PROPANOLOL in SG
MOA: blocks hyperthyroidism MANIFESTATIONS mediated by beta-adrenergic receptors
*may also block T4 conversion to T3 when used @ high dose
- provides SYMPTOMATIC relief
- BRIDGING therapy for thionamide effects to kick in/ before ablation/ surgery
- PRN for HIGH RISK pts (elderly with CV disease)
- treatment of THYROIDITIS (usually self-limiting)
use of IODIDES in HYPERthyroidism
Lugol’s solution, saturated solution of potassium iodide
MOA: inhibits release of STORED THs
- Minimal effect on hormone synthesis
- Helps decrease vascularity & size of gland
- Before surgery (7-10d) to SHRINK THE GLAND
- After ablative therapy (3-7d) to INHIBIT thyroiditis-mediated release of stored TH
- Thyroid storm
**LIMITED EFFICACY AFTER 7-14d of therapy as TH release will resume
*** DO NOT use BEFORE ablative RAI (may REDUCE uptake of radioactive iodine)
Management of subclinical HYPERthyroidism
*Low/ undetectable TSH with NORMAL T4
Risk:
- Elevated risk of AF in patients >60y/o
- Elevated risk of BONE FRACTURE in postmenopausal women
*conflicting data about mortality risk
Treatment: (NO SURGERY)
- similar to overt hyperthyroidism, except oral therapy alternative to ablative therapy in young patients
- MORE COMPELLING if TSH <0.1mIU/L
- Beta blocker ESPECIALLY if AF
**IF UNTREATED: screen REGULARLY for development of OVERT HYPERthyroidism
which drugs cause drug-induced thyroid disease?
- Amiodarone
- Contains IODINE in chemical structure
- affects iodine UPTAKE, SECRETION, PRODUCTION -> causes THYROIDITIS
- may cause HYPO- or HYPER-thyroidism - Lithium
- INHIBITS thyroid hormone SECRETION & RELEASE -> signals INCREASE in TSH -> possible goiter development (hypo)
- causes THYROIDITIS (HYPO) - Interferon alfa
- Thyroiditis (HYPER THEN HYPO)
