• Clinical science

Hyperthyroidism (Thyrotoxicosis)

Abstract

The term hyperthyroidism refers to the symptoms caused by excessive amounts of circulating thyroid hormone. Hyperthyroidism typically results from thyroid gland hyperactivity, the most common causes of which are Graves' disease (most common), toxic multinodular goiter (MNG), and toxic adenoma. In rare cases, hyperthyroidism is caused by TSH-producing pituitary tumors (central hyperthyroidism), β-hCG mediated hyperthyroidism (gestational trophoblastic disease), or oral intake of thyroid hormones (factitious hyperthyroidism). Regardless of the cause, the characteristic symptoms of hyperthyroidism include fatigue, anxiety, heat intolerance, increased perspiration, palpitations, and significant weight loss despite an increased appetite. Serological thyroid hormone assay confirms hyperthyroidism, while measurement of antithyroid antibodies, thyroid ultrasonography, and radio-active iodine uptake tests help identify the etiology. Management, in general, includes the initial control of symptoms with beta-blockers and anti-thyroid drugs followed by definitive therapy either with radioactive iodine ablation of the thyroid gland or surgery.

Epidemiology

References:[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[3][5][6]

Pathophysiology

Hypothalamic-pituitary-thyroid axis

The hypothalamus, anterior pituitary gland, and thyroid gland, together with their respective hormones, comprise a self-regulatory circuit referred to as the hypothalamic-pituitary-thyroid axis.

Effects of hyperthyroidism

  • Generalized hypermetabolic state (increased substrate consumption)
  • Hyperstimulation of the sympathetic nervous system
  • Cardiac effects

References:[7][8]

Clinical features

References:[5][9]

Diagnostics

Overview of changes in hormone levels

Overt hyperthyroidism

Subclinical hyperthyroidism

Basal TSH
  • ↓/undetectable
  • ↓

FT3
  • ↑
  • Normal

FT4
  • ↑ in 90% of cases
  • Normal

Laboratory studies

Imaging

  • Thyroid ultrasonography: Can diagnose the etiology of hyperthyroidism (e.g., diffuse enlargement, solitary/multiple nodules, increased vascularity of the gland)

  • Thyroid scintigraphy: A nuclear medicine imaging technique, which demonstrates the structure and function of thyroid tissue based on its selective uptake of radioactive iodine (RAI).
    • Indications
    • Contraindications: pregnant or breast-feeding women
    • Procedure
      • Stop anti-thyroid drugs one week before the test
      • Oral administration of 123I (iodine) (100–400 microCi)
      • Scan performed after 24 hours
    • Interpretation of results
      • Only the functional part of the gland takes up RAI.
      • Normal thyroid tissue: normal sized gland with a diffuse uptake of RAI.
      • Most common findings
        • Graves disease: enlarged gland with diffusely increased RAI uptake
        • Toxic MNG: multiple nodular areas, both cold and hot, resulting in an overall heterogeneous appearance
        • Toxic adenoma: a hot nodule
        • Factitious hyperthyroidism: no uptake of RAI since there is no thyroid gland hyperfunction.

References:[5][10][9]

Differential diagnoses

Common differential diagnoses

Exogenous hyperthyroidism or factitious hyperthyroidism

  • Definition: hyperthyroidism due to excessive intake of thyroid hormone
  • Etiology
    • Intentional
    • Unintentional
      • Iatrogenic
      • Accidental ingestion (mostly children)
      • Dietary supplement overdose
  • Clinical features: symptoms of hyperthyroidism, but no goiter
  • Diagnostics
    • Low/undetectable TSH, high levels of T4/T3, low Tg levels
    • Low RAI uptake in scintigraphy
  • Treatment

Differential diagnosis of hyperhidrosis

References:[11][12][13]

The differential diagnoses listed here are not exhaustive.

Treatment

Symptomatic therapy of thyrotoxicosis

Definitive therapy

There are currently three effective initial treatment options for Graves disease: antithyroid drugs, radioactive iodine ablation, or surgery. Toxic multinodular goiter (TMNG) and toxic adenoma (TA) are not generally treated with antithyroid drugs, but rather with ablation or surgery.Which form of therapy is chosen depends on the individual clinical situation and the patient preference.

Antithyroid drugs (ATDs)

  • Antithyroid drugs can effectively render a patient euthyroid; 20–75% of patients achieve permanent remission after 1–2 years of treatment. Some patient groups have a higher likelihood of remission than others.
  • Indications
    • Patients with high likelihood of remission (e.g., small goiter, negative or low TRab titer, women)
    • Active Graves ophthalmopathy
    • Children age ≤ 5 years
    • Pregnancy
    • Thyroid storm
    • Patient preference
    • Patients who need rapid disease control before further treatment, e.g., achievement of euthyroid state prior to surgery.
    • Patients with an inability to follow radiation safety regulations
  • Contraindications: history of adverse reactions to ATD
  • Adverse effects: see antithyroid drugs
  • Drugs used

Radioactive iodine ablation (RAIA)

  • Definition: destruction of thyroid tissue using radioactive iodine (iodine 131) through a sodium/iodine symporter
  • Indications
    • High surgical risk; limited life-expectancy
    • Liver disease
    • Major adverse reaction to ATDs
    • Previous operations or radiation of the neck
    • No access to a high volume thyroid surgeon
    • Failure to achieve euthyroidism with ATDs
    • Patient preference
    • Patients with congestive heart failure, right heart failure, pulmonary hypertension, or periodic hypokalemic paralysis
    • Recommended especially for TMNG and TA patients with high nodular radioactive iodine uptake
  • Contraindications
    • Pregnant/breastfeeding women
    • Children < 5 years
    • Confirmed or suspected thyroid malignancy
    • Patients with moderate to severe Graves ophthalmopathy
    • Patients with an inability to follow radiation safety regulations
      •
  • Procedure
    • Pre-treatment methimazole: in patients who are at high risk for complications due to worsening of hyperthyroidism
      • For 4–6 weeks to rapidly achieve a euthyroid state; must be discontinued 2–3 days before RAIA is begun.
      • Young or middle-aged patients with mild to medium symptoms of hyperthyroidism, who undergo RAIA do not routinely require pretreatment with methimazole.
    • Avoidance of excess iodine for 7 days prior to RAIA
    • Single oral dose of (131I) → isotope uptake by thyroid gland → emission of β-radiation that slowly destroys the thyroid tissue
  • Precautions
    • Patients treated with RAIA have the potential to expose others to radiation and are advised to avoid close contact (6 feet), especially to children/pregnant women.
    • The period of restricted contact depends on the dose received.
    • Women treated with RAI are advised to avoid becoming pregnant for a minimum of 4–6 months.
  • Post-procedural care

Thyroid surgery

References:[5][12][14][15][16][17][18][19][20]

Complications

Thyroid storm (thyrotoxic crisis)

If simultaneous heart failure occurs, the administration of beta blockers may worsen hemodynamics and is therefore contraindicated!
References:[12][21]

We list the most important complications. The selection is not exhaustive.

Special patient groups

Hyperthyroidism in pregnancy

Suspect a molar pregnancy or choriocarcinoma if severe hyperthyroidism manifests during pregnancy!

Neonatal hyperthyroidism

  • Occurs in ∼ 5% of babies born to mothers with Graves disease
  • Etiology: transplacental passage of maternal TRAbs
  • Clinical features
    • Hyperthyroidism: irritability, restlessness, tachycardia, diaphoresis, hyperphagia, poor weight gain, diffuse goiter (can cause tracheal compression), microcephaly (due to craniosynostosis)
    • May arise directly after birth or delayed up to 10 days later as a result of transplacental maternal antithyroid medication (including propylthiouracil or carbimazole)
  • Treatment
  • Complications: Untreated symptomatic hyperthyroidism in infants can cause cardiac failure, intellectual disability

References:[22][23]