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Updated: Dec 9 2021

Graves Disease

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  • Snapshot
    • A 27-year-old woman with vitiligo presents to her primary care physician with progressive fatigue and weight loss despite a good appetite. On exam, her blood pressure is 170/110 mmHg, pulse is 110/min, diaphoretic, displays brisk reflexes, and has bilateral exophthalmos.
  • Introduction
    • Clinical definition
      • autoimmune hyperthyroidism
    • Genetics
      • HLA-DRB1 and HLA-DQB1
      • PTNP22
    • Associated conditions
      • polyglandular autoimmune syndrome
      • pernicious anemia
      • vitiligo
      • diabetes
  • Epidemiology
    • Demographics
      • the most common cause of hyperthyroidism in the United States
      • female dominant
      • typically 20-40 years of age
    • Pathogenesis
      • triggered by stress
        • e.g. childbirth, infection, steroid withdrawal, and trauma to the thyroid
      • stimulating autoantibodies against the TSH receptor leading to the overproduction of thyroid hormone
        • type II hypersensitivity
      • pituitary TSH is suppressed via negative feedback from elevated thyroid hormone
  • Presentation
    • Symptoms
      • tachycardia and/or palpitations
        • thyroid hormone increases heart rate and contractility and decreases systemic vascular resistance
      • fatigue and muscle weakness
      • weight loss
      • hyperactivity and/or tremulousness
      • diarrhea
      • warm moist skin and sweating
      • heat intolerance
      • eye pain and/or double vision
    • Physical exam
      • hypertension and/or arrhythmias
      • enlargement ophthalmopathy (proptosis and exophthalmos)
        • the hallmark of Graves disease but not always present
        • often worsens after radioiodine ablation
      • symmetrical, non-tender thyroid enlargement
      • myxedema
        • dermal accumulation of mucopolysaccharides
        • non-pitting
      • hyperreflexia
  • imaging
    • Radioactive iodine (123I) thyroid scan
      • contraindicated in pregnancy
        • defer to autoantibody assays
    • Computed tomography (CT) scan or magnetic resonance image (MRI) of the orbits
      • evaluation of ophthalmopathy
  • Studies
    • Diagnostic testing
      • diagnostic approach
        • screening for patients with clinical suspicion
        • autoantibody titers are diagnostic
        • imaging to differentiate etiologies of hyperthyroidism
        • ancillary laboratory tests for associated dysregulation
      • studies
        • TSH level
          • initial test of choice
        • thyroid hormone level
          • start with T4 level (total or free)
          • if T4 level is normal, T3 level may be helpful
        • autoantibody assays
          • anti-TSH antibodies are almost always positive
          • diagnostic for Graves
        • complete blood count
          • would demonstrate associated normocytic anemia, low-normal leukocytes, and low-normal platelets
        • lipid profile
          • would demonstrate associated low total cholesterol and triglyceride
      • biopsy
        • not routinely indicated but would show lymphocytic infiltrates and follicular hypertrophy
  • Differential
    • Multinodular toxic goiter
      • distinguishing factors
        • patchy uptake on 123I thyroid scan
        • more common in elderly patients
    • Toxic thyroid adenoma
      • distinguishing factor
        • single nodule with uptake on 123I thyroid scan
    • Iatrogenic
      • distinguishing factors
        • excessive levothyroxine intake
        • no increase in uptake on 123I thyroid scan
    • Diagnostic criteria
      • ↓ TSH and ↑ T4
        • if T4 is normal, then possibly ↑ T3
      • positive anti-TSH antibodies
      • radioactive iodine (123I) thyroid scan
        • diffusely increased uptake differentiates Graves from other etiologies of hyperthyroidism
  • Treatment
    • Medical treatment
      • first-line
        • propranolol
          • indication
            • sympathetic symptoms such as palpitations, muscle weakness, and/or anxiety
            • wean when thionamides take effect
            • not definitive treatment
            • indicated for atrial fibrillation secondary to hyperthyroidism (metoprolol)
      • second-line
        • thionamides
          • methimazole and propylthiouracil
          • mechanism
            • inhibits thyroid hormone synthesis
          • indication
            • propylthiouracil during pregnancy
          • adverse effects
            • agranulocytosis
              • discontinue and obtain CBC with differential if any signs of infection
            • hepatotoxicity
          • long-term remission in a minority of patients
          • not definitive treatment
      • third-line
        • radioiodine ablation (131I)
          • most common treatment
          • definitive treatment
          • mechanism
            • destruction of thyroid follicular cells
              • patients transition to hypothryoidism 3-6 months post-ablation, and subsequently require life-long thyroid replacement medication
            • release of thyroid hormone secondary to destruction may lead to a transient worsening of symptoms
              • pretreat with glucocorticoids
          • indication
            • failed antithyroid drugs
          • contraindication
            • pregnancy and breastfeeding
    • Surgical treatment
      • thyroidectomy
        • indication
          • cannot tolerate medical therapy
            • pregnancy
              • can be safely performed in the 2nd trimester 
            • allergy
          • very large goiter
    • Special considerations
      • in pregnancy
        • first line of treatment
          • propranolol
          • propylthiouracil
      • with ophthalmopathy
        • steroids
        • surgical decompression
        • orbital radiation
  • Complications
    • Thyroid storm
      • can be life-threatening with fatal arrhythmia
    • Pregnancy complications
      • anti-TSH receptor antibodies may cross placenta and lead to fetal hyperthyroidism
      • cretinism from contraindicated radioiodine ablation
    • Thyroidectomy complications
      • hypothyroidism
      • laryngeal nerve palsy
      • hypoparathyroidism and hypocalcemia ‘
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