Thyroid Disease

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.

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)

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.

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.