Thyrotoxicosis and Hyperthyroidism

Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves’ disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Subacute thyroiditis is an example of thyrotoxicosis without hyperthyroidism, and a pituitary adenoma, which secretes thyroid-stimulating hormone (TSH) is an example of secondary hyperthyroidism. Clinical features of thyrotoxicosis are mostly due to an increase in the metabolic rate and overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic “tone”). Thyrotoxicosis is diagnosed by measuring the levels of TSH produced by the anterior pituitary gland and unbound T4 and T3. Depending on the etiology and clinical presentation, it may be treated pharmacologically, surgically, or with radioiodine.

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Overview

Definition

Thyrotoxicosis is a condition characterized by the classic physiologic manifestations of excess thyroid hormones regardless of the cause or hormonal source. If the excessive hormones are produced and released by the thyroid gland, the condition is called hyperthyroidism.

Epidemiology

Thyrotoxicosis due to hyperthyroidism:

  • De novo synthesis of hormone, with normal or high radioactive iodine uptake
  • Much more common in women than in men (5:1)
  • Prevalence: approximately 1.3% overall in the United States; 0.8% in Europe
    • 4%–5% in older women
    • Graves’ disease: 
      • Most common cause of thyrotoxicosis (80%) in iodine-sufficient areas
      • More common in younger women, with incidence of 4.6 per 1000 women per 10 years of observation
    • Toxic multinodular goiter (15% of cases) and toxic adenoma (approximately 5% of cases):
      • Higher in iodine-deficient areas
      • More common in elderly people
      • More common in smokers
    • Pituitary adenoma (< 1% of cases)

Thyrotoxicosis without hyperthyroidism:

  • Less common, generally transient
  • No new synthesis of hormone in thyroid and, therefore, low radioactive iodine uptake
  • 3 major categories: 
    • Inflammation and release of stored hormone, most commonly: 
      • Initial phase or exacerbations of Hashimoto’s thyroiditis (incidence: 3.5/1000/year in women and 0.8/1000/year in men)
      • Subacute thyroiditis
    • Extrathyroidal source of hormone
    • Exposure to excessive iodine

Etiology

Table: Thyrotoxicosis due to hyperthyroidism
PathologyCondition
Thyroid-stimulating hormone (TSH)–receptor antibodyGraves’ disease (diffuse hyperplasia)
Inappropriate TSH secretion
  • TSH-secreting pituitary adenoma
  • Pituitary resistance to thyroid hormone
Excess hCG secretion
  • TSH-secreting pituitary adenoma
  • Pituitary resistance to thyroid hormone
Mutations in TSH receptor or Gsα protein (G-protein alpha subunit) results in autonomous thyroid function.
  • Solitary hyperfunctioning adenoma
  • Multinodular goiter
  • Familial non-autoimmune hyperthyroidism
Table: Thyrotoxicosis without hyperthyroidism
Category of causesPathologyCondition
Inflammation and release of stored thyroid hormoneAutoimmune destruction of thyroid gland
  • Silent (painless) thyroiditis
  • Postpartum thyroiditis
  • Initial phase or exacerbations of Hashimoto’s thyroiditis
Viral or postviral infection (etiology not definitive)Subacute (painful) thyroiditis (De Quervain thyroiditis, granulomatous thyroiditis)
Toxic drug effectsDrug-induced thyroiditis (amiodarone, lithium, interferon-α, checkpoint inhibitors)
Bacterial or fungal infectionAcute suppurative thyroiditis
RadiationRadiation thyroiditis
Extrathyroidal source of hormoneExcess intake of thyroid hormoneExcess exogenous thyroid hormone (iatrogenic or factitious)
Ectopic hyperthyroidism (thyroid hormone produced outside the thyroid gland)Struma ovarii (functioning thyroid tissue in an ovarian teratoma); functional thyroid cancer metastases
Ingestion of contaminated foodHamburger thyrotoxicosis (meat containing thyroid tissue)
Exposure to excessive iodineJod–Basedow effectIodine-induced hyperthyroidism (iodine, iodine-containing drugs (e.g., amiodarone), radiographic contrast agents)

Pathophysiology

Hypothalamic–pituitary–thyroid axis

  • Hypothalamus releases thyrotropin-releasing hormone (TRH) → pituitary gland releases TSH (prolactin release is also stimulated) → thyroid gland produces triiodothyronine (T3) and tetraiodothyronine (T4)
  • Feedback mechanisms:
    • When free T3 and/or T4, then ↓ TSH and TRH
    • When ↓ free T3 and/or T4, then ↑ TSH and TRH
  • Hormone secretion by the thyroid gland:
    •  93% T4 and 7% T3; synthesized from tyrosine
    •  T4 is converted in the tissues to the much more metabolically active T3.
  • Normal function of thyroid hormones:
    • Increased metabolism:
      • Increased transcription of cell membrane Na+/K+-adenosine triphosphatase (ATPase) → oxygen consumption
      • Enhanced fatty acid oxidation and heat generation
      • Gluconeogenesis, glycolysis, lipolysis
    • Growth and development:
      • Protein synthesis 
      • Regulates cholesterol and triglyceride metabolism
      • Affects brain, reproductive and bone development, and growth 
    • Interrelated actions with catecholamines:
      • Thyroid hormones enhance responsiveness to catecholamines (producing inotropic and chronotropic cardiac effects).
      • ↑ Expression of catecholamine receptors
    • Regulates pituitary hormone synthesis (feedback loop)

Schematic diagram of the hypothalamic–pituitary–thyroid axis and the negative feedback loops

Image by Lecturio.

Thyrotoxicosis

Patients with high levels of T3/T4 will exhibit a compensatory decrease of TSH and a variable uptake of radioactive iodine depending on the source or cause of excessive T3/T4.

With low TSH and high radioactive iodine uptake (RAIU):

  • Graves’ disease has an autoimmune pathology characterized by overstimulation of the thyroid gland by thyroid receptor antibodies.
  • Toxic multinodular goiter (TMG) and toxic adenoma (TA):
    • A spectrum of disease ranging from a single hyperfunctioning nodule (TA) to a gland with multiple hyperfunctioning areas (TMG)
    • Scintiscan shows hot nodules (high RAIU) and suppression of uptake in the rest of the thyroid gland.
    • The suppression of the nontoxic portion of the gland is caused by the absence of TSH (negative feedback produced by the excess thyroid hormones).
    • Diffuse nontoxic (simple) goiter causes enlargement of the entire gland without producing nodularity; most often due to dietary iodine deficiency.
  • Chorionic gonadotropin–induced: hCG has a structure similar to that of TSH and can stimulate thyroid hormone production.

With low TSH and low RAIU:

  • Iodide-induced hyperthyroidism (Jod–Basedow effect): 
    • Hyperthyroidism in a patient with endemic iodine deficiency goiter or other underlying thyroid disorder after iodine administration 
    • The thyroid gland becomes independent of the TSH regulatory mechanism.
  • Amiodarone treatment (very common cause): Amiodarone contains iodine, which stimulates the production of thyroid hormones and may cause thyroiditis.
  • Thyroiditis:
    • Hashimoto’s thyroiditis: autoimmune disease, with antibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg), which may result in transient thyrotoxicosis initially and during exacerbations.
    • Subacute (painless) lymphocytic thyroiditis: autoimmune disease with anti-TPO antibodies
    • Granulomatous (painful) thyroiditis: most likely viral
    • Acute thyroiditis (rare): due to bacteria and fungi
  • Exogenous thyroid hormone intake: high levels of circulating T3/T4 lead to a compensatory decrease of TSH.

Pathology of the thyroid gland

  • Graves’ disease: 
    • Thyroid: diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells, with heterogeneous lymphoid infiltrates
    • Ophthalmopathy and dermopathy: glycosaminoglycan deposition and heterogeneous lymphoid infiltrates
  • TMG and TA:
    • Toxic multinodular goiter can be very large (2 kg), with irregular enlargement, and with gelatinous colloid, hemorrhage, degeneration, fibrosis, cystic change, and calcification.
    • Toxic adenoma may appear to be a prominent nodule.
    • Microscopic: many follicles filled with colloid and lined by flat, inactive epithelium alternating with areas of follicular hyperplasia
  • Hashimoto’s thyroiditis: 
    • Extensive infiltration of the gland by lymphoplasmacytic infiltrates, with germinal centers
    • Atrophic thyroid follicles lined by Hürthle cells (large eosinophilic epithelial cells, reflecting metaplastic response to chronic injury caused by autoimmune attack) 
    • Variable fibrosis
  • Subacute lymphocytic (painless) thyroiditis: lymphocytic infiltrates
  • Granulomatous (De Quervain, painful) thyroiditis: granulomatous inflammation of the thyroid, with multinucleated macrophages around extrafollicular colloid

Clinical Presentation

The most common signs and symptoms of hyperthyroidism: Exophthalmos is a 
specific sign of Graves disease.

Image by Lecturio.

Goiter

  • Diffusely enlarged thyroid gland in Graves’ disease; prominent nodule in TA or irregular with multiple nodules in TMG
  • Usually smooth borders and nontender; tenderness suggestive of thyroiditis
  • A bruit may be audible at the superior poles of the gland due to increased blood flow.

Multinodular goiter and symptoms of hyperthyroidism:
This is a 36-year-old woman who presented with a multinodular goiter and symptoms of hyperthyroidism for five years, with tachycardia and tremors in the extremities.
Increased sweating, a common sign in hyperthyroidism, was only present on the right side of the face in this rare case because the left sympathetic nerve trunk, which innervates the sweat glands and blood vessels of the left side of the face, was compressed and compromised by a dilated and tortuous left inferior thyroid artery. This is called “Harlequin syndrome” and is associated with multiple conditions. In this case it was due to an indirect consequence of the increased vascularity which accompanies an enlarged and metabolically active thyroid gland.

Image: “Harlequin syndrome” by Department of Endocrine Surgery, Narayana Medical College & Superspeciality Hospital, Chinthareddypalem, Nellore, Andhra Pradesh 524002, India. License: CC BY 3.0

Cardiovascular system alterations

Cardiovascular system alterations are caused by increased circulatory demand generated by hypermetabolism/heat production:

  • Decreased peripheral vascular resistance through increased NO production
  • Cardiac output increased through increased heart rate and stroke volume
  • Thyroid hormones have a positive inotropic effect.
  • Increased sympathetic and decreased vagal tone
  • Widening of pulse pressure

Metabolism alterations

  • Protein, carbohydrate, and lipid metabolism:
    • Increased basal metabolic rate
    • Increased appetite
    • Heat intolerance
    • Severe cases have a decrease in tissue protein:
      • Muscle wasting
      • Weight loss
      • Hypoalbuminemia
    • Accelerated turnover of insulin due to lack of control of preexisting diabetes mellitus
    • Increased lipolysis:
      • High levels of free fatty acids
      • High glycerol levels
      • Low cholesterol levels
  • Calcium and phosphorus metabolism:
    • Increased excretion of calcium and phosphorus in urine and stool
    • Demineralization of bone
    • Increased total and ionized serum calcium concentrations

Nervous system alterations

  • Sympathetic nervous system and catecholamines:
    • Epinephrine and norepinephrine levels are not increased.
    • Thyroid hormones increase sensitivity to catecholamines.
  • Neuropsychiatric symptoms:
    • Nervousness
    • Emotional lability
    • Hyperkinesia
    • Insomnia
    • Fatigue
    • Mental disturbances in severe cases (manic depressive, schizoid, and paranoid reactions)

Musculoskeletal alterations

  • Weakness in proximal muscles of the limbs
  • Muscle wasting (thyrotoxic myopathy)
  • Skin and hair symptoms:
    • Warm, moist skin (vasodilation)
    • Easy blushing
    • Palmar erythema
    • Friable hair and nails, increased hair loss

Ocular alterations

  • Retraction of the upper and/or lower eyelids
  • Lid lag and globe lag
  • Caused by increased adrenergic tone

Respiratory alterations

  • Dyspnea
  • Reduced vital capacity owing to muscle weakness

Gastrointestinal alterations

Gastrointestinal alterations manifest in hepatic dysfunction:

  • Hypoproteinemia
  • Increased ALT
  • Hepatomegaly and jaundice in severe cases
  • Liver failure in untreated Graves’ disease

Reproductive/hormonal alterations

  • Delayed sexual maturation
  • Low or absent menstrual flow
  • Reduced fertility with a high risk of miscarriage
  • Decreased libido
  • Gynecomastia

Clinical manifestations of hyperthyroidism specific for Graves’ disease

Orbitopathy and dermopathy:

  • Caused by increased content of hyaluronic acid and chondroitin sulfates secondary to cytokine activation of fibroblasts
  • Patients with severe orbitopathy have the highest levels of thyroid receptor antibodies (TRAbs).
  • In the skin, there is compression of dermal lymphatics and nonpitting edema, especially in the pretibial region (myxedema).

Clinical manifestations of thyrotoxicosis of various forms of thyroiditis

  • Hashimoto’s thyroiditis:
    • Painless enlargement of the thyroid in middle-aged woman
    • Usually with variable degree of hypothyroidism
    • Transient thyrotoxicosis may occur: due to disrupted thyroid follicles and release of hormones (hashitoxicosis) → increased T4, T3 and decreased TSH and RAIU
    • After transient thyrotoxicosis → T4 and T3 decrease and TSH increases
    • Hashimoto’s thyroiditis is the most common cause of hypothyroidism in the United States.
  • Subacute (painless) lymphocytic thyroiditis: 
    • Most patients have circulating anti-TPO antibodies or a family history of other autoimmune disorders.
    • Similar thyroiditis in postpartum women (postpartum thyroiditis)
    • Mild, transient hyperthyroidism and/or painless goiter
    • Most recover, but up to ⅓ evolve into overt hypothyroidism over a 10-year period, with pathologic features that resemble Hashimoto’s thyroiditis.
  • Granulomatous (painful) thyroiditis:
    • The most common cause of thyroid pain
    • Variable enlargement of the thyroid gland
    • Glandular inflammation and hyperthyroidism are transient, usually diminishing in 2–6 weeks, and are associated with high T4 and T3 and low TSH and RAIU.
    • After recovery, normal thyroid function returns.

Diagnosis

Diagnostic algorithm for patients with symptoms suggesting thyrotoxicosis

Image by Lecturio.

Testing

Measurement of TSH levels is the best test for thyroid disease screening and function assessment.

  • Normal range: 0.4–4.2 mU/L (variable, based on the lab providing the results)
  • Thyrotoxic patients will have a TSH < 0.1 mU/L and ↑ T4.
  • If thyrotoxicosis is caused by hyperthyroidism, serum levels of T3 are higher than those for T4.
  • The primary differential diagnosis is between hyperthyroidism and thyroiditis.
    • Thyroiditis will have increased ESR and high thyroglobulin levels.
    • The most critical differentiating test is RAIU:
      • High or high normal uptake in hyperthyroidism (active synthesis)
      • Very low uptake in thyroiditis (no synthesis, just release of hormones)
  • Thyrotoxicosis with high TSH is a rare situation caused by TSH-producing pituitary tumor.

Thyrotoxicosis caused by autoimmune diseases requires additional tests:

  • Antibodies against:
    • TPO
    • Tg
    • TSH receptor
  • Thyroid antibodies should be tested in suspected Graves’ disease and Hashimoto’s thyroiditis.

Imaging

  • Ultrasonography of thyroid gland will detect diffuse enlargement, solitary or multiple nodules, and increased vascularity of the gland.
  • RAIU testing: nuclear medicine procedure that produces a visual display of functional thyroid tissue based on the selective uptake of 131I radionuclides

Radioactive iodine uptake (RAIU) of the thyroid of a patient with transient thyrotoxicosis:
The patient’s RAIU shows a reduced 24-hour uptake and little uptake throughout the thyroid gland.

Image: “Transient thyrotoxicosis as an initial presentation of rheumatoid arthritis: a case report” by Makdsi F, Brit M. License: CC BY 3.0

Management

Medical therapy

  • Thionamides (propylthiouracil, methimazole):
    • Inhibit oxidation and organic binding of thyroid iodide and produce intrathyroidal iodine deficiency, thus reducing hormone secretion
    • Decrease thyroid antigen expression
    • Decrease prostaglandin and cytokine release
  • Iodide transport inhibitors (thiocyanate, perchlorate)
  • Lithium: temporary control
  • Dexamethasone: inhibits conversion to T3 (the more active form)
  • Beta-blocking agents (adjunct in treatment): very useful in those with impending thyroid storm
  • Radioiodine therapy (nonsurgical ablation): 
    • 131I actively accumulates within the thyroid gland, causing cell destruction and permanent cure
    • Contraindicated during pregnancy and in children < 5 years old
    • Risk of aggravating orbitopathy; should be coupled with glucocorticoids

Surgical therapy

Thyroidectomy is indicated when medical treatment fails or is contraindicated owing to side effects, pregnancy, or age or in the case of malignancy.

Thyroid Storm

Thyroid storm is a rare, acute complication of thyrotoxicosis that constitutes a life-threatening emergency with a high mortality rate.

  • Mortality: 
    • 10%–20% with treatment
    • 100% if left untreated
  • Precipitated by:
    • Infection, trauma, surgical emergencies, or planned surgeries
    • Less commonly by radiation thyroiditis, diabetic ketoacidosis, toxemia of pregnancy
  • Clinical presentation: 
    • Fever
    • CNS effects:
      • Mild: agitation
      • Moderate: delirium, psychosis, extreme lethargy
      • Severe: seizures, coma
    • GI dysfunction:
      • Moderate: diarrhea, nausea, vomiting, abdominal pain
      • Severe: unexplained jaundice
    • Cardiovascular dysfunction:
      • Tachycardia 
      • Atrial fibrillation
      • Congestive heart failure
  • Diagnosis/labs: Serum thyroid hormone levels are not higher during the crisis. 
  • Management: 
    • Rehydration
    • Beta blockers
    • Iodide
    • Antithyroid drugs
    • Sedatives for agitation
    • Antipyretics
    • Cooling blankets

Differential Diagnosis

  • Generalized anxiety disorder and panic disorder can also present with tachycardia, palpitations, tremor or shakiness, and neuropsychiatric symptoms, such as anxiety, agitation, depression, insomnia, and emotional instability and are differentiated by thyroid-specific symptoms, such as goiter and lid retraction, and with blood tests showing normal levels of T3, T4, and TSH.
  • Cocaine use disorder can also present with weight loss, psychomotor agitation, tachycardia, hypertension, and palpitations and is differentiated by the presence of psychiatric symptoms, such as increased self-esteem, hallucinations, psychosis, paranoia, etc.
  • Diabetes mellitus can also present with weight loss and blurred vision and is differentiated by polydipsia, polyuria, and polyphagia.
  • Malignancy can also present with weight loss, weakness, and fatigue and is differentiated by normal levels of thyroid hormones (unless the malignancy is metastatic functioning thyroid carcinoma) and imaging to locate masses.
  • Congestive heart failure also presents with tachycardia, palpitations, irregular pulse, hypertension, edema, and dyspnea and is differentiated by normal hormone levels, ECG, and chest X-ray.
  • Thyroid carcinoma also presents with weight loss and signs of mass effects, such as dysphagia, hoarseness, and Horner’s syndrome and is differentiated by imaging tests that show signs of malignancy (irregular borders, calcifications, etc.).
  • Pheochromocytoma also presents with diaphoresis, palpitations, tachycardia, weight loss, and anxiety and is differentiated by normal levels of thyroid hormones and the presence of metanephrines in plasma.

References

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  2. Hershman JM. (2020). Hyperthyroidism (thyrotoxicosis). MSD Manual Professional Version. Retrieved December 20, 2020, from https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/thyroid-disorders/hyperthyroidism
  3. Melmed S, Koenig R, Rosen C, Auchus R, Goldfine A. (2019). Williams Textbook of Endocrinology, 14th ed. Elsevier. 
  4. Jameson JL, Mandel SJ, Weetman AP. (2018). Hyperthyroidism. In Jameson JL, et al. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed., Vol. 1, pp. 2703–2710. 
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  6. Algahtani H, Shirah B, Algahtani R, Alkahtani A. (2017). Idiopathic harlequin syndrome manifesting during exercise: A case report and review of the literature. Case Reports in Medicine, Article ID 5342593. https://doi.org/10.1155/2017/5342593
  7. Yeung SC. (2020). Graves disease: practice essentials, pathophysiology, epidemiology. https://emedicine.medscape.com/article/120619-overview#a5
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