Thyroid Disease

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    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.

     

    DiagnosticTestsThyroid.png

    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
    • 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:
    1. Local Measures
    2. Trial of Corticosteroids
    3. 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.
    • 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.

    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.
    • 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

     

    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].
      • Patients to that live to 100 (centenarians) have slightly higher TSH levels.
      • Other studies propose similar associations....
    • 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.
      • 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).
    • Overt hypothyroidism??
      • Unclear.. no studies.
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