Table of contents
- 1. Introduction
- 2. Definitions
- 3. Amiodarone Induced Thyroid Dysfunction
- 4. Diagnostic Tests
- 5. Thyrotoxicosis
- 6. Hypothyroidism
- 6.1. Sx / Px
- 6.2. Labs
- 6.3. Treatment
- 6.4. Subclinical Hypothyroidism
- 6.5. Hypothyroidism in Elderly
- 7. Pregnancy and Thyroid Disease
- 8. NOTES
- 9. Hypothyroidism In Primary Care / Screening
.
Introduction
- HPA Axis controls thyroid release (TRH --> TSH --> Thyroxine (T4) and Tri-iodothyronine (T3))
- Thyroid produces T4, and small amount of T3
- 85% of biologically active T3 produced by extra-thyroidal peripheral conversion by 5'-deiodinaze enzymes (mainly liver and kidneys).
- Most patients with thyroid dysfunction have normal HPA axis, and have abnormal TSH.
- Very rarely, patient may have thyroid disease mediated by HPA
- Thyroid produces T4 and T3, but 85% of body's T3 is created by extra-thyroidal conversion
- T4-->T5 by 5′-deiodinase enzymes made in liver and kidney
- Only small unbound T4/T3 is biologically active (free T4/T3).
- Rest is bound to thyroxine-binding globulin (TBG) and to less extent transthyretin and albumin.
- When bound = Inactive, act as a storage reservoir.
- Iodide is required for thyroid synthesis (In US iodide deficiency is very rare)
Definitions
- Subclinical thyroid dysfunction defined as:
- Elevated or low Thyroid-Stimulating Hormone (TSH) (normal ref: 0.45-4.50 mIU/L) in the setting of normal thyroid levels.
- Overt Thyroid Disease
- Presence of abnormal thyroid hormone (free thyroxine +/- triodothyronine) levels.
- Hyperthyroidism
- Primary: TSH is low due to negative feedback of high levels of circulating T3 and T4
- Secondary: TSH is increased with increased T4/T3 levels.
- Hypothyroidism
- Primary: TSH is high due to low T4/T3 levels.
- Secondary: TSH is low or normal with variable response to TRH (depending on lesion site - pituitary or hypothalamic).
- Euthyroid Sick Syndrome [MKSAP]
- During recovery phase of severe illness (from non-thyroidal illness) can alter the results of thyroid function tests.
- This is called "euthyroid sick syndrome", which is more common in critically ill patients.
- Mechanisms are unknown, likely reated to cytokine release.
- Serum TSH level is not expected to increase to greater than 10 microunits/mL (10 milliunits/L), except perhaps in the recovery phase of a serious illness.
-
Thyrotoxicosis Hypothyroidism Graves Disease Hashimoto's Toxic Nodular Goitre Congenital Toxic Nodule Iatrogenic Thyroiditis Hypothyroid phase
of thyroiditis
Amiodarone Induced Thyroid Dysfunction
- Type 1
- Thyroid is abnormal - typically patients have previous thyroid disease - predisposed to hyperthyroidism.
- Extra iodine load from amiodarone causes increase in thyroid hormone production causing thyrotoxicosis.
- Order thyroid ultrasound: Will have increased sized, hypervascularity, etc..
- Jod-Basedow phenomenon (vs. Wolff–Chaikoff effect which is opposite)
- Type 2
- Thyroid is previously normal.
- Amiodarone causes thyroiditis - inflammation causing a release of
- Hypothyroidism
- Believed to be from a toxic effect of amiodarone
- Also decreased T4 to T3 peripheral conversion by amiodarone
Diagnostic Tests
Lab Tests
- TSH
- Most sensitive indicator in ambulatory patients of thyroid function
- First test used for patients for symptoms/signs
- If TSH is abnormal, measurement thyroid hormone levels is indicated.
- If TSH is HIGH
- Measurement of Free T4 for severity of hypothyroidism
- Do not measure T3 levels in hypothyroidism.
- If TSH is LOW
- Measurement of Free T4 and T3 is indicated to measure degree of thyrotoxicosis
- Mostly T4 and T3 ("T3 thyrotoxicosis" is possible)
- Free T4 level
- Measure if risk of pituitary or thyroid disease is high.
- Esp if pts with cranial irradiation, pituitary surgery or massive head trauma.
- Total T4
- Reflects Free + Bound T4 (may not represent free T4 levels)
- Hashimoto Tyroiditis (Autoimmune Hypothyroidism)
- Anti-TPO (Anti-Thyroid peroxidase antibody)
- Antithyroglobulin Antibodies
- Autoimmune Hyperthyroidism (Graves Disease)
- aka "Anti-TSH receptor antibodies"
- Thyroid Stimulating Immunglobulins [TSIs]
- aka Thyrotropin-Binding Inhibitory Immunoglobulins [TBIIs]
- Only indicated if when dx of Graves cannot be made clinically (i.e. radioactive iodine uptake not available or contraindicated (i.e. pregnancy))
- If Antibodies found with normal TSH ==> NO TREATMENT (but increased risk of future thyroid problems)
- Repeat testing of antibodies not indicated --> titre does not correlate with disease (ONLY TSH)
- Only if women who want to become pregnant with positive anti-TPO antibody + normal TSH can have repeat serial measurements (high risk of infertility, preterm delivery, and miscarriage)
- Thyroglobulin
- Stores thyroid hormone in thyroid gland, released.
- Can be elevated in hyperthyroidism and destructive thyroiditis
- Decreased if patient taking exogenous thyroid hormone.
- Followed post resection or ablation in well-differentiated thyroid cancer (papillary or follicular thyroid cancer)
- Good tumor marker, used to detect cancer recurrence or persistence
- Should be absent post-thyroidectomy
- Should also measure serum anti-thyroglobulin levels (if present, can falsely drop thyroglobulin levels)
- Calcitoinin
- Secreted by C-cells (of thyroid gland).
- Routine measurement is not recommended (only recommended in "high risk" groups for medullary ca):
- Indications: family hx of medullary thyroid cancer, MEN-2, or biopsy suggestive of medullary ca.
- Tumor marker for medullary thyroid cancer
- Radioactive Iodine Uptake (RAIU)
- Measures iodine uptake over time period (4 and 24hrs after iodine injestion).
- Thyrotoxicosis pts (hyperthyroidism) have elevated >30% @24hrs, or high-normal RAIU
- Indicates endogenous production of thyroid hormones.
- Decreased in:
- Subacute, silent or post-partum thyroiditis
- Exposure to exogenous thyroid hormones
- Increased (Homogeneous) in:
- Graves Disease
- Increased (Focal):
- Toxic multinodular goiter
- Toxic adenoma
- Contraindicated in:
- Pregnacy
- Breastfeeding
- (Postpartum thyroiditis occurs in 1/3 of women with elevated thyroid peroxidase ab level).
Imaging
- Normal gland size 15-20g.
- Ultrasound
- Measure size of gland.
- Solid vs. cystic nodule.
- Facilitate fine needle aspiration biopsy (FNAB)
- Radioisotope scan (Technetium-99)
- Test of Structure - Order if thyroid nodule in a patient who is hyperthyroid with low TSH
- Differentiates between hot (excess hormone) and cold (non-functioning) nodules.
- Hot nodule --> Very low malignancy risk; treat hyperthyroidism.
- Cold nodule --> ~5% chance of malignancy; further workup (U/S, FNAB)
- Radioactive iodine uptake (RAIU)
- Test of Function - order if thyrotoxic.
- Measure iodine turnover in vivo.
- If increased uptake (Radioiodine incorporated) --> gland is overactive (hyperthyroid)
- If decreased uptake (not incorporated) --> gland is leaking thyroid hormone (thyroiditis), exogenous thyroid hormone use, excess iodine intake (amiodarone, contrast dye).
- Thyroid Biopsy
- Fine need aspiration (FNA) for cytology differentiates between benign and malignant disease.
Thyrotoxicosis
Graves Disease
- Most common cause of thyrotoxicosis, any age 3-4th decades peak.
- Familial (15% have close family member w/ Graves, 50% have family with positive antibodies)
- B-cells produce Thyroid Stimulating Immunoglobulin (TSI), binds TSH receptor, stimulates thyroid gland.
- Can be triggered by:
- Postpartum.
- Iodine excess
- Lithium therapy
- Viral/bacterial infections.
- Steroids withdrawal
- Can be triggered by:
- NOTE:
- Ophthalmopathy is common (Increased tissue volume due to inflammation and accumulation of glycosaminoglycans, stimulated by TSI, increase osmotic pressure in orbit, displacing eye forward).
- Opthalmopathy (5-10% of Graves)
- Varies Mid-to-Severe
- Lid Changes: Proptosis, Exopthalmos,
- Inflammation: Chemosis, Conjunctival Injection, Periorbital Edema, Iritis
- Extraocular: Double Vision
- Optic Nerve Compression: Visual Acuity (Blindness)
- Either hypothyroidism or hyperthyroidism can make ophthalmopathy worse!
- Dermopathy: cutaneous glycosaminoglycan deposition.
- Diagnosis:
- Low TSH, Increased free T4 (and/or increased T3)
- POSITIVE for TSI
- Increased radioactive iodine uptake.
- (Diffuse high uptake on thyroid scan [ONLY do this if nodule is present!]).
- Treatment
- See "Treatments".
- Often PTU or Methimazole (Methimazole preferred, but careful with BM suppression).
- Treat until remission (20-40% achieve spontaneous remission at 6-18mo of treatment).
- Small goitre and recent onset are good indicators for long-term remission with medical therapy.
- B-blockers for symptoms.
- Radioactive Iodine Ablation 131I if PTU or MMI trial does not produce remission.
- MAINSTAY!! (PREFERRED)
- However, contraindicated in pregnancy, and DO NOT do if ophthalmopathy is present
- Often became hypothyroid requiring lifetime supplementation.
- Surgery
- Rare - Risky (Hypoparathyroidism, vocal cord palsy)
- Indications:
- Severe Allergic/Intolerance to Iodine or antithyroid drugs
- Large/Obstructive Goitres
- Ophthalmopathy
- CA suspected
- Patient refusing RAI ablation
- Ophthalmopathy
- Methimazole initially
- Surgical decompression if optic nerve is impinged (visual loss)
- Radioactive Iodine WORSENS Graves Opthalmopathy (often surgery preferred)
- Another option is to pre-treat with steroids
- Medical Treatment:
- Local Measures
- Trial of Corticosteroids
- Thyroidectomy
- Smoking cessation, prevent drying, high dose prednisone if VERY severe, orbital radiation/surgical decompression.
Subacute Thyroiditis (Thyrotoxic Phase)
- Acute inflammatory disorder of the thyroid gland leading to initial thyrotoxic state and later on hypothyroidism, and eventually by euthyroidism in most cases.
- Categorized as Painful or Painless
- Inflammation causes disruption of thyroid follicles, leading to thyroid hormone release (NOT production).
- Therefore, Radioactive Iodine Uptake will be negative.
- Types:
- Painful -
- Viral (usually preceeded by URTI),
- De Quervain's (Granulomatous Thyroiditis) - acute anterior neck pain. Viral illness preceeding months. CT: patchy infiltrate, minimal lymphadenopathy
- Painless - postpartum, auto-immune, lymphocytic.
- Occurs in 5-10% of postpartum women, but only symptomatic in 1/3.
- Painful -
- Diagnosis
- Elevated T4, T3, low TSH, RAIU reduced.
- ESR elevation
- (Rise in RAIU reflects gland recovery)
- Treatment
- Painful - high dose NSAIDs, sometimes prednisone
- Iodinated contrast agents (iopanoid acid, ipodate) - inhibit peripheral conversion T4 to T3
- B-blockers usually effective for hypermetabolic and cardiac symptoms.
- (If hypothyroid - treat with thyroxine.)
Toxic Adenoma/Toxic Multinodular Goitre
- Functioning adenoma that is hypersecreting T3/4
- Can be:
- Single: toxic adenoma
- Multiple: Toxic Multinodular goitre (aka Plummer's disease).
- Classically seen in ederly people presenting with Afib (later find other hyperthyroid features).
- Diagnosis
- Low TSH, high T3/4
- Thyroid Scan (increased uptake in nodule(s), and remainder of gland is suppressed.
- Treatment
- PTU or MMI (make euthyroid)
- B-blockers for symptoms.
- Definitive:
- If PTU/MMI fail: Radioactive iodine to ablate tissues.
- Sometimes surgery also used, but rarely.
Thyrotoxic Crisis/ Thyroid Storm
- Acute exacerbation of all hyperthyroid symptoms presenting in life-threatening state.
- Rare, medical emergency, mortality 20-30%.
- Often precipitated by trauma/infection/surgery in pts who are already hyperthyroid.
- Symptoms:
- Hyperthyroid symptoms, but also tachyarrhythmias, hepati failure + jaundice, confusion, CHF, shock.
- Diagnosis
- Increased T3/4, undetectable TSH
- +/-: Anemia, WBC, hyperglycemia, hypercalcemia, elevated LFTs.
- Treatment
- Supportive: fluids, electrolytes, diuretics, vasopressors, cooling blanket, tylenol for hyperthermia.
(NOTE: LOTS of fluids! usually patients lose a lot through vomiting, diarrhea, insensible) - Propranolol IV for tachycardia and to decrease T4-->T3 conversion.
(1mg IV q5min until desired effect, PO 20-120mg q6h) - Methimazole
- Preferred - causes rapid decline in thyroxine levels, less S/E
- Start 10-30mg daily
OR:....
- Propylthiouracil
- Starting dose 75-100mg q8h
- Drug-induced agranulocytosis (limited popularity of this drug)
- Iodide (NaI, KI, Lugol's solution): inhibit thyroid hormone release after PTU given
- Orally as Lugol's Solution (4 drops q12h) or IV as sodium iodide (500-1000mg q12h)
- If Iodide allergy: Lithium (300mg PO q8h can be used)
- Hydrocortisone (300mg IV load then 100mg IV q8h)
- Thyroid storm can accelerate glucocorticoid metabolism, often get adrenal insufficiency.
- Iodinated radiocontrast solutions (iopanoic acid) to stop peripheral conversion and T3/4 release.
- Lithium: inhibits T3/4 release.
- Dexamethasone to block peripheral conversion, lower body temp, treat underlying autoimmune condition.
- Plasmapheresis/Dialysis: IF EXTREME, to remove high T3/4.
- Supportive: fluids, electrolytes, diuretics, vasopressors, cooling blanket, tylenol for hyperthermia.
Treatments
- Antithyroid drugs
- Thionamides
- Inhibit thyroid hormone synthesis by inhibiting peroxidase-catalyzed reactions. Inhibit organification of iodine, blocking coupling of iodotyrosines.
- PTU also inhibits peripheral deiodination of T4 to T3.
- propylthyouracil (PTU)
- methimazole (MMI) (for Graves)
- MMI is preferred over PTU due to longer duration of action (once daily), more rapid efficacy, less side-effects.
- MMI is contraindicated in pregnancy.
- CAUTION: induce permanent remission in 20-30% of patients with Graves.
- Can create euthyroid state before definitive management.
- Adverse effects: rash, teratogenicity, hepatitis?, agranulocytosis, hepatotoxicity, ANCA-positive vasculitis.
- Thionamides
- B-blockers for symptom control.
- Radioactive iodine ablation (for Graves).
- Surgery (hemi, subtotal, complete thyroidectomy)
Hypothyroidism
- Common (2% women vs. 0.2% men)
- Causes:
- Hashimodo Thyroiditis (most frequent)
- Iatrogenic Hypothyroidism (After ablation, external beam to thyroid, surgical removal)
- Surgical
- Radiation/Ablation
- Medications (Amiodarone (10% of pts), Lithium, Interferon, etc..)
- Pituitary Disease (central hypothyroidism)
- Congenital (rare)
- Thyroid Agenesis
- Dyshormonogenesis (genetic defect)
- Celiac Disease (poor L-thyroxine absorption -> may require higher doses)
Sx / Px
- Symptoms
- Not one in particular diagnostic (look at all symptoms)
- Fatigue! / Reduced Endurance
- Weight Gain
- Cold intolerance
- GI: Constipation
- Neuro:
- Impaired Concentration/ Short Term Memory
- Mood Changes (Depression)
- Psychomotor Retardation
- Skin: Dry Skin
- Muscles:
- Cramps
- Myalgias
- Edema
- Physical Exam:
- Vitals:
- Reduced basal temperature
- Diastolic HTN
- Bradycardia
- Enlarged thyroid gland
- Inspection: Dry/Cold Skin, Brittle Hair
- MSK: Delayed recovery phase in deep tendon reflexes
- Vitals:
Labs
- Serum TSH & Total/Free T4 Levels
- NOTE: Serum T3 is not needed
- Anti-TPO (Anti-Thyroglobulin antibodies) - Hashimoto Thyroiditis?
- NOT USEFUL: Thyroid Scan & Radioactive Iodine Uptake Scans
- If Goitre Palpated:
- Ultrasound (May have nodules to biopsy)
Treatment
- Oral levothyroxine is mainstay (daily dose of 50-200 mcg)
- Take on empty stomach (1hr before or 2-3hr after food or calcium/iron containing supplements)
- Initial dose is 50 mcg/day, increased in 50 mcg/day increments q3-5w until TSH level normalizes (usually 100-200 mcg/day)
- Target TSH 0.5-4.3 mU/L
- Patients >80 --> Can use higher range (i.e. 1-7 mU/mL)
- IV levothyroxine used initially for severe hypothyroidism (reduced GI absorption of PO meds)
- Initial dose: 250 mcg on 1st day, then 100 mcg on 2nd day, 50 mcg daily until oral therapy possible.
- Liothyronine & combinations of T3/T4 therapy --> Most evidence shows no benefit over traditional
- T3 has very short thalflife, causes spikes to T3 (concern for cardiac pts).
Subclinical Hypothyroidism
- TSH is above normal, and T3/T4 normal.
- VERY COMMON
- Mild or no symptoms of hypothyrodism
- Causes (The same as overt)
- Labs:
- Mild elevation in total cholesterol, LDLC, CRP.
- Meta Analysis: Increased risk of atherosclerosis and cardiac events
- Minimal evidence that L-thyroxine improves these outcomes when TSH < 10
- When to treat?
- TSH 5-10 --> Unclear (may treat if symptomatic)
- TSH > 10 --> Treat (clear benefit)
-
Indication for Treating Subclinical Hypothyroidism - TSH > 10
- Elevated TSH > ULN and:
- Markedly symptomatic
- If pregnant OR Planning pregnancy
- Goitre
- Positive Anti-TPO antibodies
Hypothyroidism in Elderly
- The effects appear to be different in older patients.
- >70yo do not experience mortality benefit of 40-70yo for treating subclinical hypothyroidism (above).
- Some emerging studies that subclinical hypothyroidism can be protective in older patients:
- (Gussekloo et al. 2004 JAMA)
- Followed 599pts 85years to 89 years.
- Plasma TSH and free thyroxine were not associated with disability, depression, cognitive impairment.
- Increasing TSH levels are associated with lower mortality rate.
- Less mortality in higher TSH levels (2.71 mIU/L assocated with 0.77 hazard ratio of death [0.63-0.94].
- Followed 599pts 85years to 89 years.
- (Gussekloo et al. 2004 JAMA)
- Some emerging studies that subclinical hypothyroidism can be protective in older patients:
- Patients to that live to 100 (centenarians) have slightly higher TSH levels.
- Other studies propose similar associations....
- >70yo do not experience mortality benefit of 40-70yo for treating subclinical hypothyroidism (above).
- May change reference range in pts > 80yo to 1-7mU/mL
- Do not place patients >80 on exogenous L-thyroxine only for elevated for TSH level, consider patient & clinical context.
Pregnancy and Thyroid Disease
- Levothyroxine dose increased 30 in first (and sometimes 2nd) trimester
- I.e. Get patient to take 2 extra doses each week (i.e. Tuesday and Friday)
- Fetus depends on maternal thyroid hormone supply in first 12w of gestation
- Failure to supply adequate thyroid hormones raises risk of:
- Neurocognitive impairment
- Premature birth
- Low birth weight
- Miscarriage
- Fetal death
- Targets:
-
Trimester Goal TSH 1st Trimester 0.1 - 2.5 mU/L Shown = fewer maternal/fetal complications 2nd Trimester 0.2 - 3.0 mU/L 3rd Trimester 0.3 - 3.0 mU/L - Thyroid testing q4w (TSH + T4) and q2-4w if TSH has been uncontrolled.
NOTES
- Methimazole prefered to PTU
- Methimazole is once daily, less agranulocytosis, faster response
- Contraindicated in 1st trimester pregnancy (cranial closure defects)
Hypothyroidism In Primary Care / Screening
- Subclinical hypothyroidism is associated with increased risk of:
- coronary artery disease (CAD)
- CHF
- Subclinical hyperthyroidism
- Increased risk of all-cause mortality.
- CV mortality
- Atrial Fibrillation
- Decreased Bone Density
- Overt Thyroid disease is assocated with negative:
- CV
- MSK
- Dermatologic
- GI
- Other...
- Thyroid Screening could identify undiagnosed overt thyroid disease.
- In 2004 - U.S. Preventative Services Task Force (USPSTF) found insuficient evidence to recommend for or against thyroid screening in asymptomatic non-pregnant patients.
Questions
- Do we screen?
- As of 2014: no study compared screening vs. not-screening for thyroid disease.
- What are the harms of screening?
- No good studies.
- Potential harms: anxiety, false positives, harms of treatment.
- Two prospective cohort studies: ~40% of persons with subclinical hypothyroidism were euthyroid after 3 years of watchful waiting. (suggesting overdiagnosis and overtreatment)
- Do we treat subclinical hypothyroidism?
- As of 2014: Two trials tested this, but were too low quality, and tested for intermediate outcomes.
- Do we treat overt hypothyroidism
- As of 2014: No study addressed treatment vs. no treatment in screening-detected overt hypothyroidism.
Is there benefit in treating hypothyroidism?
- Subclinical Hypothyroidism
- Mortality?
- One retrospective cohort study published (4735ppl >40yo) with subclinical hypothyroidism:
- Levothyroxine vs. no treatment
- Levothyroxine group:
- Less fatal and non-fatal Ischemic Heart Disease (IHD) (4.2% vs. 6.6%)
- Less death due to circulatory causes (1.4 vs. 2.4%)
- Less cancer mortality (1.2 vs. 2.2%)
- These effects are only present in 40-70 year olds.
- >70yo: no benefit.
- One retrospective cohort study published (4735ppl >40yo) with subclinical hypothyroidism:
- Levothyroxine vs. no treatment
- Levothyroxine group:
- Less fatal and non-fatal Ischemic Heart Disease (IHD) (4.2% vs. 6.6%)
- Less death due to circulatory causes (1.4 vs. 2.4%)
- Less cancer mortality (1.2 vs. 2.2%)
- These effects are only present in 40-70 year olds.
- >70yo: no benefit.
- But it's an observational study.
- One retrospective cohort study published (4735ppl >40yo) with subclinical hypothyroidism:
- Quality of Life and Cognitive function?
- 5 Trials tested this
- Not associated with clear improvement in quality of life or cognitive function.
- Intermediate outcomes? (BP, bone mineral density, BMI)
- No clear benefit was found in trials to this point (2014)
- Blood Lipids?
- Treatment of sublinical hypothyroidism may have some beneficial effects on total cholesterol and LDL cholesterol levels.
- Differences were small and of uncertain clinical significance
- Total Cholesterol: (-0.7 to 0 mmol/L)
- LDL Cholesterol (-0.6 to 0 mmol/L).
- Mortality?
- Overt hypothyroidism??
- Unclear.. no studies.
Comments