Graves’ Disease

Graves’ disease is an autoimmune disorder characterized by the presence of circulating antibodies against the thyroid-stimulating hormone (TSH) receptors, thereby causing the thyroid gland to hyperfunction. Clinical features include hyperthyroidism (of which Graves’ disease is the most common cause), orbitopathy, goiter, and dermopathy/pretibial myxedema. Manifestations reflect the muti-systemic effects of a hyperactive thyroid, including heat intolerance, sweating, palpitations, tremors, pretibial myxedema, and exophthalmos. Diagnosis is by thyroid laboratory tests showing a low TSH, elevated thyroid hormones (thyroxine (T4) and triiodothyronine (T3)) and thyrotropin-receptor antibodies (particularly the thyroid-stimulating immunoglobulins subtype). If initial tests are nondiagnostic, radioactive iodine uptake (increased uptake) and thyroid ultrasound (diffuse thyroid enlargement) provide diagnostic information. Treatment options include thionamides, radioiodine ablation, and surgery.

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Overview

Definition

Graves’ disease is an autoimmune disorder in which antibodies against the thyroid-stimulating hormone (TSH) receptors cause the thyroid gland to hyperfunction. The syndrome may have the following features:

  • Hyperthyroidism (most common)
  • Goiter: thyroid enlargement
  • Orbitopathy: Graves’ ophthalmopathy/thyroid eye disease
  • Dermopathy: pretibial myxedema

Epidemiology

  • Most common cause of hyperthyroidism, making up 60%–80% of all cases
  • Annual incidence of 20–50 cases per 100,000 persons
  • Female-to-male ratio of 8:1
  • Onset usually at 20–40 years of age
  • In children, the majority of cases occur after 11 years of age.

Etiology

Susceptibility to Graves’ disease is considered to be a combination of multiple factors.

Risk factors:

  • Genetic factors:
    • Family history of thyroid disease or other autoimmune disease (e.g., pernicious anemia, type 1 diabetes mellitus)
    • Polymorphisms identified in immunoregulatory genes: PTPN22, CTLA-4, IL2RA, gene encoding the TSH receptor (TSHR)
    • Associated with HLA-DR3 and HLA-B8
    • Increased risk of Graves’ disease in patients with trisomy 21 (Down’s syndrome)
  • Environmental and non-genetic factors:
    • Smoking
    • Stress
    • Sudden increases in iodine uptake
    • Pregnancy
    • Bacterial and viral infections

Pathophysiology

Hyperthyroidism and goiter

  • Thyroid-stimulating immunoglobulins (type II hypersensitivity reaction):
    • Synthesized in the thyroid gland, bone marrow, and lymph nodes
    • Stimulate TSH receptors on thyroid gland
    • Effects:
      • ↑ Autonomous secretion of thyroid hormones (T3/T4): hyperthyroidism
      • Thyroid follicular hypertrophy and hyperplasia: diffuse toxic goiter
    • Histologic findings in the thyroid gland:
      • Crowded tall follicle epithelial cells, which exhibit hypertrophy and hyperplasia
      • Lymphoid infiltrates also noted
  • Negative feedback: ↑ thyroid hormones → compensatory ↓ TSH

Hypothalamus-pituitary-thyroid axis feedback loop:
When the thyroid hormones are low, the hypothalamus releases thyrotropin-releasing hormone (TRH), which triggers the pituitary gland to secrete TSH. The effect of this process is that the thyroid gland produces thyroxine (T4) and triiodothyronine (T3) (more T4 is produced, as it gets converted to T3). The increase in thyroid hormones (free or unbound T3/T4) creates a negative feedback, inhibiting TRH and TSH release.

Image: “Classic Negative Feedback Loop” by OpenStax College. License: CC BY 3.0, edited by Lecturio.

Orbitopathy and myxedema

  • Believed to be an autoimmune response directed at an antigen (TSH receptor) shared by the thyroid and the orbit
  • The process in dermal tissues is considered to be similar, with TSH receptor protein expression noted in normal dermal fibroblasts.
    • Activation of T cells within the retro-orbital space and skin → ↑ cytokines → tissue activation and remodeling
    • Activated fibroblasts increase glycosaminoglycans (which trap water), leading to:
      • ↑ Fluid retention
      • Swelling and fibrosis of the muscles involved
      • Fatty infiltration (↑ adipocytes)
    • Effects:
      • Protrusion, and possible displacement, of the eyeball (Graves’ orbitopathy) 
      • Infiltration in the shin area or pretibial myxedema (unclear mechanism for this localization)

Clinical Presentation

Factors affecting presentation

  • Severity and duration of disease
  • Susceptibility to excess thyroid hormone
  • Patient’s age: In the elderly, features are subtle.

Hyperthyroidism and goiter

  • General (increased basal metabolic rate):
    • Heat intolerance, sweating
    • Weight loss
  • Dermatologic:
    • Warm, moist skin (due to vasodilation)
    • Fine hair and onycholysis
  • Goiter: 
    • Diffuse and painless thyroid enlargement (2–3x normal)
    • +/- Thyroid bruit
  • Cardiac:
    • Tachycardia, palpitations, dyspnea, tachyarrhythmias
    • Increased blood pressure, widened pulse pressure
    • Aortic systolic murmur
    • Congestive heart failure
  • GI: 
    • Diarrhea due to increased GI motility
    • Nausea
  • Musculoskeletal:
    • Thyrotoxic (proximal) myopathy
    • Osteoporosis, higher fracture rate 
  • Reproductive:
    • Oligomenorrhea or amenorrhea
    • Gynecomastia (in males)
    • Reduced libido, and infertility
  • Neuropsychiatric:
    • Hyperactivity, restlessness, anxiety, insomnia
    • Fine tremors, overactive reflexes
  • Elderly patients:
    • Commonly lack most signs and symptoms
    • Often present with fatigue, depression, or weight loss (“apathetic hyperthyroidism”)

Orbitopathy and myxedema

  • Graves’ orbitopathy: 
    • Scleral injection
    • Periorbital edema
    • Lid retraction accompanied by lid lag (if ≥ 2 mm, graded as moderate to severe)
    • Exophthalmos/proptosis (if ≥ 3 mm, graded as moderate to severe)
    • Diplopia (noted in moderate-to-severe orbitopathy)
    • Severe corneal exposure, optic nerve compression (sight threatening)
  • Myxedema: 
    • Non-pitting edema
    • Well-demarcated papules and nodules in affected area (may be pigmented)
    • Most common in lower legs/shins (pretibial area)
    • Can affect feet, arms, elbows, face
  • Thyroid acropachy: soft-tissue swelling of the hands and clubbing of the fingers

Diagnosis

Initial evaluation

  • Clinical findings from history and examination
  • Laboratory tests:
    • Thyroid function tests: 
      • ↓ TSH
      • ↑ T3/T4
    • Thyrotropin receptor antibodies (TRAb), particularly thyroid-stimulating immunoglobulins:
      • Found in 90% of patients
      • Thyroid-stimulating immunoglobulins are rarely observed in other autoimmune thyroid diseases.
    • Antibodies against thyroid peroxidase and thyroglobulin: 
      • Usually present 
      • Also found in other autoimmune thyroid diseases (e.g., Hashimoto’s thyroiditis)
  • Nonspecific laboratory findings:
    • CBC: normocytic anemia
    • Lipid: ↓ cholesterol, ↓ triglycerides

Imaging

  • Additional diagnostic tests performed if presentation is ambiguous
    • Radioactive iodine uptake (RAIU):
      • Uptake is increased.
      • Uptake is diffusely distributed throughout the thyroid gland.
    • Thyroid ultrasound with Doppler:
      • Utilized if RAIU is contraindicated (e.g., pregnancy)
      • High thyroid blood flow in Graves’ disease
  • CT or MRI of the orbits obtained in the following situations:
    • In orbitopathy with nondiagnostic thyroid tests 
    • In unilateral orbitopathy (to rule out space-occupying lesions) 
    • In moderate-to-severe orbital changes (to determine complications or risks thereof)

Management

Principles of treatment

  • Goals: 
    • Reach euthyroid state by reducing thyroid hormone synthesis.
    • Control of symptoms and complications
  • Options to decrease thyroid hormones:
    • Thionamides
    • Radioiodine ablation
    • Surgery
  • Multiple options can be utilized with the same patient to reach goals.
  • Choice of treatment(s) dependent on individual clinical factors and preference
  • Untreated hyperthyroidism carries a mortality rate of up to 30%.

Thionamides

  • Reduce oxidation and organification of iodide by inhibiting thyroid peroxidase
  • May be used initially to achieve euthyroid state
  • Intake for up to 2 years may help reach remission (rate of remission: 40%).
  • May be followed by radioiodine ablation or surgery
  • Risks:
    • Teratogenicity (methimazole > propylthiouracil)
    • Hepatotoxicity (propylthiouracil > methimazole)
    • Agranulocytosis (check WBC count with any sign of infection!)
  • Baseline CBC count and hepatic panel required
  • Options:
    • Methimazole: 
      • Usual 1st choice
      • Longer acting
      • Fewer side effects
      • Associated with congenital aplasia cutis 
    • Propylthiouracil:
      • Used in the 1st trimester of pregnancy and in thyroid storm
      • Short acting

Radioiodine ablation and surgery

  • Radioiodine ablation:
    • Capsule or solution of sodium iodine-131 (I-131) taken orally
    • I-131 concentrates in the thyroid and progressive thyroid cell destruction follows.
    • Ablation is reached at about 6–18 weeks.
    • Some patients may require a second dose.
    • I-131 emits radiation (prolonged, close contact with other people, especially pregnant women and small children for up to a week should be avoided).
    • Contraindications:
      • Pregnant or breastfeeding
      • Those with moderate-to-severe orbitopathy
  • Surgery (thyroidectomy):
    • Rarely done
    • Choice of treatment in:
      • Severe active orbitopathy
      • Patients with goiters causing obstructive symptoms
      • Pregnant women with antithyroid drug allergy
      • Cases with a concomitant suspicious thyroid nodule

Other therapies

  • For hyperthyroidism and goiter:
    • β-blockers:
      • Antagonizes β-receptor–mediated actions of catecholamines
      • Improve palpitations, tremors, tachycardia, anxiety, heat intolerance
    • Iodine elixirs (saturated solution of potassium iodide):
      • Used before surgery
      • Reduces vascularity of the thyroid gland
  • For orbitopathy:
    • With hyperthyroidism treatment, irritation and periorbital edema usually subside; proptosis and extraocular muscle disorders persist.
    • Artificial tears to improve eye symptoms
    • Selenium may help.
    • Moderate-to-severe orbitopathy:
      • Pulse therapy with intravenous methylprednisolone
      • Surgical decompression or external orbital radiation 
      • Teprotumumab
  • For dermopathy:
    • Pretibial myxedema may persist even when normal thyroid function is achieved.
    • Use of compression stockings
    • Lymphedema physiotherapy
  • Additional recommendations:
    • Smoking cessation
    • Calcium supplementation due to risk of osteoporosis

Differential Diagnosis

  • Granulomatous thyroiditis (De Quervain’s syndrome): thyroid inflammation usually associated with a previous viral infection and the most common cause of thyroid pain. Presentation includes neck tenderness with goiter. Work-up shows low TSH, elevated free T4, increased sedimentation rate, and a low or absent radioactive iodine uptake. Often a self-limited course that can go through a hyperthyroid state and then a euthyroid state followed by hypothyroidism. Recovery to normal thyroid function takes months.
  • Subacute lymphocytic thyroiditis (painless thyroiditis): an autoimmune disease with diffuse enlargement of the thyroid gland. The same process occurs in postpartum thyroiditis. Laboratory tests depend on the phase of the disease but the initial hyperthyroidism shows low TSH and elevated T4. The condition is associated with a low radioactive iodine uptake. The disease pattern is a transient hyperthyroid state and then hypothyroid followed by recovery. Some cases do not become euthyroid, however.
  • Multinodular toxic goiter: multiple nodules in an enlarged thyroid gland, producing excess thyroid hormones. Commonly found in elderly patients in iodine-deficient areas. Work-up demonstrates elevated thyroid hormones with high radioactive iodine uptake showing multiple spots of iodine concentration.
  • Toxic adenoma: a condition in which the thyroid gland contains a solitary nodule that actively secretes thyroid hormones. Tests are consistent with hyperthyroidism, with radioactive iodine uptake showing 1 spot of iodine concentration.
  • Factitious thyrotoxicosis: occurs with the intake of excessive amounts of thyroid hormone (most common preparation is levothyroxine). Separate outbreaks of so-called hamburger thyroiditis, which was caused by the ingestion of bovine thyroid tissue (i.e., ground-up neck muscle), occurred in 1984-85 in Minnesota, South Dakota, and Nebraska. Manifestations show hyperthyroidism with no exophthalmos or goiter. Features include low TSH, normal/elevated T4, low thyroglobulin level, and low radioiodine uptake.

References

  1. Davies, T., Burch, H. (2020). Treatment of Graves’ orbitopathy (ophthalmopathy). UpToDate. Retrieved February 11, 2021, from https://www.uptodate.com/contents/treatment-of-graves-orbitopathy-ophthalmopathy
  2. Davies, T., Burch, H. (2020). Clinical features and diagnosis of Graves’ orbitopathy (ophthalmopathy). UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-graves-orbitopathy-ophthalmopathy
  3. Davies, T. (2019). Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease. UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/pretibial-myxedema-thyroid-dermopathy-in-autoimmune-thyroid-disease
  4. Fitzgerald P.A. (2021). Hyperthyroidism (thyrotoxicosis). Papadakis M.A., & McPhee S.J., & Rabow M.W. (Eds.). Current Medical Diagnosis & Treatment 2021. McGraw-Hill. 
  5. Jameson J, & Mandel S.J., & Weetman A.P. (2018). Hyperthyroidism. Jameson J, & Fauci A.S., & Kasper D.L., & Hauser S.L., & Longo D.L., & Loscalzo J(Eds.). Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.
  6. Maitra, A. (2021). The Endocrine System. Kumar V., Abbas, A., Aster, J. , Robbins & Cotran Pathologic Basis of Disease, 10e. Elsevier.
  7. Smith M.A. (2019). Graves disease and goiter. Usatine R.P., & Smith M.A., & Mayeaux, Jr. E.J., & Chumley H.S. (Eds.). The Color Atlas and Synopsis of Family Medicine, 3e. McGraw-Hill.
  8. Ross, D. (2020). Graves’ hyperthyroidism in nonpregnant adults: Overview of treatment. UpToDate. Retieved February 10, 2021, from https://www.uptodate.com/contents/graves-hyperthyroidism-in-nonpregnant-adults-overview-of-treatment
  9. Yeung, S., Habra, M. (2020). Graves Disease. Medscape. Retrieved January 24, 2021, from https://emedicine.medscape.com/article/120619-overview

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