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Endocrine System Internal Medicine

Hyperthyroidism

Clinical syndrome characterized by hypermetabolic state due to the increased free serum thyroxine (T4) and/or free triiodothyronine (T3).

Photography by Marta Pucci

Clinical syndrome characterized by hypermetabolic state due to the increased free serum thyroxine (T4) and/or free triiodothyronine (T3).

  • M/C cause of hyperthyroidism: Graves’ disease > toxic nodular goitre

Epidemiology

Graves disease is typically seen in younger patients and is the most common cause of hyperthyroidism in that demographic. Toxic multifocal goiter is typically seen in older individuals and is the most common cause of hyperthyroidism in this respective demographic.

Both Graves disease and toxic multifocal goiter have a female predilection and are typically seen in patients with pertinent family and personal medical histories.

Map of overt hyperthyroidism prevalence
Map of overt hyperthyroidism prevalence (selective populations used when representative data not available). | Taylor, P. N., Albrecht, D., Scholz, A., Gutierrez-Buey, G., Lazarus, J. H., Dayan, C. M., & Okosieme, O. E. (2018). Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews Endocrinology, 14(5), 301–316. https://doi.org/10.1038/nrendo.2018.18

Etiology

Hyperthyroidism is defined as elevated Thyroid Hormones (TH) in circulation. Thyroid hormones are important hormones in fetal development and also metabolism. So high thyroid hormone levels as you can imagine will amp up metabolism to a point where it becomes pathological. Hyperthyroidism and thyrotoxicosis refers to the same thing really. However some define hyperthyroidism specifically as increased synthesis of thyroid hormones where as thyrotoxicosis refers to the clinical syndrome of excess circulating thyroid hormones, irrespective of the source. In this video hyperthyroidism will mean high levels of thyroid hormones in circulation causing the signs and symptoms of hyperthyroidism.

Etiology & pathogensis of hyperthyroidism
Etiology & pathogensis of hyperthyroidism | Kravets I. (2016). Hyperthyroidism: Diagnosis and Treatment. American family physician, 93(5), 363–370.

Pathophysiology

  • Thyrotoxicosis: Clinical syndrome of excess circulating thyroid hormones, irrespective of the source

Thyrotoxicosis with hyperthyroidism “true hyperthyroidism”:

Normal/high radioactive iodine uptake
Effect of increased thyroid stimulators:
TSH-receptor antibodyGraves’ disease
Inappropriate TSH secretionTSH-secreting pituitary adenoma; pituitary resistance
to thyroid hormone
Excess hCG secretionTrophoblastic tumours (choriocarcinoma or
hydatidiform mole); hyperemesis gravidarum
Autonomous thyroid function:
Activating mutations in TSH receptor
or
Gsα protein		Solitary hyperfunctioning adenoma; multinodular
goitre; familial non-autoimmune hyperthyroidism

Thyrotoxicosis without hyperthyroidism:

Low radioactive iodine uptake
Inflammation and release of stored hormone:
Autoimmune destruction of thyroid glandSilent (painless) thyroiditis; post-partum thyroiditis
Viral infectionSubacute (painful) thyroiditis (De Quervain thyroiditis)
Toxic drug effectsDrug-induced thyroiditis (amiodarone, lithium,
interferon α)
Bacterial or fungal infectionAcute suppurative thyroiditis
RadiationRadiation thyroiditis
Extrathyroidal source of hormone:
Excess intake of thyroid hormoneExcess exogenous thyroid hormone (iatrogenic or
factitious)
Ectopic hyperthyroidism (thyroid hormone produced outside the thyroid gland)Struma ovarii; functional thyroid cancer metastases
Ingestion of contaminated foodHamburger thyrotoxicosis
Exposure to excessive iodine:
Jod-Basedow effectIodine-induced hyperthyroidism (iodine,
iodine-containing drugs, radiographic contrast agents)

Presentation

Hyperthyroidism
Hyperthyroidism

Adrenergic:

  • Palpitations, tachycardia
  • Anxiety, tremor, jitteriness
  • Diaphoresis, heat intolerance
  • Stare, lid lag
  • Hyperdefecation (not diarrhoea)

Cardiovascular:

  • Tachycardia (atrial fibrillation in thyroid storm)
    • Irregular pulse (in atrial fibrillation)
  • Dyspnoea, orthopnoea
  • Peripheral oedema (heart failure)

Cutaneous:

  • Onycholysis (Plummer’s nails)
  • Patchy/generalised hyperpigmentation (esp on face & neck)
  • Pathognomic of Grave’s disease:
    • Pretibial myxedema (thyroid dermopathy) & thyroid acropachy (clubbing of fingers & toes + soft-tissue swelling of hands & feet)
Pretibial myxedema and thyroid acropachy
Pretibial myxedema and thyroid acropachy accompanying hyperthyroidism – This 33-year-old woman presented with painless swelling of her fingers and lower legs of about four months’ duration. | Herbert L. Fred, MD and Hendrik A. van Dijk – http://cnx.org/content/m14924/latest/, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5038257
Pretibial myxedema
Bilateral erythematous infiltrative plaques on lower extremities in 42-year-old man with Graves disease are consistent with pretibial myxedema. Myxedematous changes of skin usually occur in pretibial areas and resemble orange peel in color and texture. | Pr. (2020) What are the dermatologic manifestations of Graves disease?. Retrieved January 30, 2020, from https://www.medscape.com/answers/121865-25225/what-are-the-dermatologic-manifestations-of-graves-disease
Onycholysis
Onycholysis is a painless detachment of the nail from the nail bed. The detachment usually occurs at the free lateral margins of the nail. The onycholytic area is white owing to the presence of air, but it may acquire a green-brown color if the space if colonized by bacteria, such as Pseudomonas aeruginosa. | Dartmouth University and Dermnet Weekly Clinic, July 30, 2001

Hypermetabolism:

  • Weight loss in spite of increased appetite
  • Fever (in thyroid storm)

Neuromuscular:

  • Brisk peripheral reflexes with accelerated relaxation
  • Proximal muscle weakness

Neuropsychiatric:

  • Anxiety, rapid & pressured speech, insomnia,
  • Psychosis (severe cases)

Ocular:

  • Increased lacrimation
  • Incomplete closure of eyelids during sleep
  • Photophobia
  • Increased sensitivity to wind/smoke
  • Grittiness/foreign-body sensation in eyes
  • Pathognomic for Grave’s disease: Exophthalmos, periorbital oedema, diplopia, blurred vision, reduced colour perception
Classic severe Graves' ophthalmopathy
Severe proptosis, periorbital edema, and eyelid retraction from thyroid-related orbitopathy. This patient also had optic nerve dysfunction and chemosis (conjunctival edema) from thyroid-related orbitopathy. | Pr. (2020) What are the dermatologic manifestations of Graves disease?. Retrieved January 30, 2020, from https://www.medscape.com/answers/121865-25225/what-are-the-dermatologic-manifestations-of-graves-disease
Classic severe Graves' ophthalmopathy
Classic severe Graves’ ophthalmopathy demonstrating a widened palpebral fissure, periorbital edema, proptosis, chemosis, and conjunctival injection. | DeGroot LJ. Graves’ Disease and the Manifestations of Thyrotoxicosis. [Updated 2015 Jul 11]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285567/

Complications

Congestive heart failure:

Differences between hyperthyroid and nonhyperthyroid heart failure
Differences between hyperthyroid and nonhyperthyroid heart failure. | Osuna, P. M., Udovcic, M., & Sharma, M. D. (2017). Hyperthyroidism and the Heart. Methodist DeBakey cardiovascular journal, 13(2), 60–63. doi:10.14797/mdcj-13-2-60

Osteoporosis

Thyroid storm:

Most commonly seen in the context of underlying Graves’ hyperthyroidism but can complicate thyrotoxicosis of any aetiology.
  • Occurs when hyperthyroid patient stops treatment/develops infection/has surgery
  • Clinical features represent manifestations of organ decompensation, with fever seen almost universally.
Causes of death in Japanese patients with TS
Causes of death in Japanese patients with TS. CHF, congestive heart failure; DIC, disseminated intravascular coagulation; GI, gastrointestinal; MOF, multiple organ failure. | Akamizu T. (2018). Thyroid Storm: A Japanese Perspective. Thyroid : official journal of the American Thyroid Association, 28(1), 32–40. doi:10.1089/thy.2017.0243

Diagnosis

Algorithm for the diagnostic workup of hyperthyroidism
Algorithm for the diagnostic workup of hyperthyroidism. (T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.) | Kravets I. (2016). Hyperthyroidism: Diagnosis and Treatment. American family physician, 93(5), 363–370.

Thyroid function tests:

HormoneReference Range
TSH0.4 – 4.5 µU/ml
Total thyroxine (total T4)4.0 – 12.0 µg/dl
Free thyroxine (free T4)0.7 – 1.8 ng/dl
Total triiodothyronine (total T3)100 – 200 ng/dl
Free triiodothyronine (free T3)208 – 596 pg/dl
ConditionTSHTotal T4Free T4Total T3

Overt hyperthyroidism

Suppressed

Elevated

Elevated

Elevated

Subclinical hyperthyroidism*

Suppressed or low

Normal

Normal

Normal

TSH-secreting pituitary adenoma

Normal or elevated

Elevated

Elevated

Elevated

Estrogen excess

Normal

Elevated

Normal

Elevated

Nonthyroidal illness syndrome

Low

Normal or mildly decreased

Normal

Low (and reverse T3 is elevated)

Glucocorticoid and/or dopamine therapy

Low

Normal

Normal

Normal

Radioactive Iodine Uptake and Scan:

ConditionRadioactive iodine uptake (normal = 15% to 25%)Radiotracer distribution in the thyroid gland

Graves disease

High

Homogeneous

Toxic adenoma

High

Iodine 123 is concentrated in one spot

Toxic multinodular goiter

High

Iodine 123 is concentrated in multiple spots

Thyroiditis

Low

Not applicable

Iodine 123 (123I) nuclear scintigraphy
Iodine 123 (123I) nuclear scintigraphy: 123I scans of normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D) | Pr. (2020) What are the dermatologic manifestations of Graves disease?. Retrieved January 30, 2020, from https://www.medscape.com/answers/121865-25225/what-are-the-dermatologic-manifestations-of-graves-disease

Management

Treatment for Grave's disease
Treatment for Grave’s disease | Ginsberg, J. (2003). Diagnosis and management of Graves’ disease. Canadian Medical Association Journal, [online] 168(5), pp.575-585. Available at: http://www.cmaj.ca/content/168/5/575.full [Accessed 24 May 2017]

Antithyroid drugs (ATDs):

Not effective in toxic adenoma or toxic multinodular goitre. In toxic nodular goitre, ATDs are generally used to restore euthyroidism before definitive treatment with surgery/radioactive iodine, and infrequently used as long-term treatment when the other two therapies are contraindicated or the patient has a short life expectancy.
  • Propylthiouracil
  • Thiamazole (DOC in Grave’s disease)
  • Methimazole (DOC for initial treatment in Grave’s disease in children): As use of propylthiouracil in children associated with fetal hepatotoxicity
  • Carbimazole

Radioactive iodine ablation:

First-line treatment for Graves’ disease, toxic adenoma, and toxic multinodular goitre
  • Absolute contraindications:
    • Pregnancy, breastfeeding, planning pregnancy
    • Inability to comply with radiation safety recommendations
  • Side effects: Acute thyroiditis (1% cases)

Thyroidectomy:

M/successful treatment for Graves’ hyperthyroidism.
  • Recommended in:
    • Large goitres or low uptake of radioactive iodine (or both)
    • Suspected/documented thyroid cancer
    • Moderate-to-severe ophthalmopathy (radioactive iodine therapy contraindicated)
    • Preference for surgery

Summary

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