Hypothyroidism

Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non–iodine-deficient regions. Primary hypothyroidism occurs with thyroid gland disorders, while the central type arises from pituitary and hypothalamic conditions. Thyroid hormones are integral in metabolic processes and in the development of the brain and other organs. Congenital hypothyroidism can result in significant mental disability due to the loss of thyroid hormones. The features of acquired hypothyroidism also reflect the effects of slowed organ function, such as fatigue, bradycardia, cold intolerance, and exertional dyspnea. Diagnosis is by thyroid function testing. Elevated thyroid stimulating hormone and low free thyroxine (T4) levels are noted. Treatment is with synthetic T4.

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Overview

Definition

Hypothyroidism is an endocrine disorder resulting from thyroid hormone deficiency.

Epidemiology

  • Prevalence: 0.1%–2%
  • More common in women than in men: range, 5–8 times higher
  • Congenital hypothyroidism: 
    • Annual incidence: 1 in 4000 births in the United States
    • High incidence in Down syndrome (trisomy 21)
  • Secondary hypothyroidism: 1 in 20,000–80,000 in the general population

Classification

By onset:

  • Congenital 
  • Acquired

By organs affected with disease:

  • Primary hypothyroidism (thyroid gland involved):
    • Low thyroxine/tetraiodothyronine (T4)
    • Low triiodothyronine (T3)
  • Central hypothyroidism:
    • Secondary (pituitary involved): low thyroid stimulating hormone (TSH)
    • Tertiary (hypothalamus involved): low thyrotropin-releasing hormone (TRH)

Etiology of congenital hypothyroidism

  • Primary hypothyroidism:
    • Thyroid dysgenesis (agenesis, hypoplasia or ectopy): approximately 85% of cases; majority are sporadic
    • TSH unresponsiveness: 
      • TSH receptor gene mutation
      • TSH signaling defect (in pseudohypoparathyroidism 1A)
    • Hereditary defects in hormone synthesis or secretion
  • Central hypothyroidism: 
    • Rare
    • Associated with congenital syndromes
  • Other rare causes (outside the hypothalamic–pituitary–thyroid axis):
    • Thyroid hormone transport disorder: mutation in transporter gene
    • Tissue resistance to thyroid hormone
  • Transient hypothyroidism:
    • Detected during newborn screening
    • Temporary decline in thyroid function for weeks to months, then recovery occurs in the natural course or with treatment up to a certain age
    • Causes:
      • Iodine deficiency
      • High-dose iodine exposure 
      • Gland in situ: normal-sized gland in normal location with some degree of dyshormonogenesis
      • Maternal intake of antithyroid drugs (which cross the placenta)
      • Maternal autoimmune thyroid disease (antibodies cross the placenta)
      • Hepatic hemangiomas
      • Loss-of-function mutations

Etiology of acquired hypothyroidism

  • Primary hypothyroidism: 
    • Hashimoto’s thyroiditis: most common cause in the United States and in areas with adequate iodine intake 
    • Iodine deficiency: most common cause worldwide
    • Iodine excess: inhibits hormone synthesis, and iodide organification (Wolff–Chaikoff effect)
    • Procedures: 
      • Thyroidectomy
      • Radiation therapy
      • Radioiodine (I-131) treatment
    • Drugs: 
      • Antithyroid drugs: propylthiouracil, methimazole
      • Lithium
      • Ethionamide
      • Amiodarone (iodine-containing)
      • Tyrosine kinase inhibitors such as sunitinib
    • Thyroid infiltration: 
      • Riedel’s thyroiditis
      • Amyloidosis
      • Hemochromatosis
      • Sarcoidosis
      • Scleroderma
    • Postpartum thyroiditis
    • Environmental exposure: flame retardants
  • Central hypothyroidism:
    • Pituitary disorders (secondary) such as adenoma, Sheehan’s syndrome
    • Hypothalamic disorders (tertiary) such as tumors, trauma

Pathophysiology

Hypothalamic–pituitary–thyroid axis

  • Hormones involved:
    • TRH from the hypothalamus
    • TSH from the anterior pituitary gland
    • T4 and T3 from the thyroid gland: 
      • T4 > T3 released
      • T4 is converted to T3 peripherally, predominantly in the liver (but also in other tissues).
      • Total thyroid hormones = bound + free T3/free T4 (FT3/FT4)
    • Bound T3 and T4:
      • Bound to thyroxine-binding globulins (TBGs) (cannot freely diffuse into cells)
      • 99% of hormones released into circulation 
    • FT4 and FT3
      • Bioavailable
      • Can bind to tissue thyroid receptors and exert their effects
  • Regulation of hormones:
    • Hypothalamus releases TRH → pituitary gland releases TSH (prolactin release is also stimulated) → thyroid gland produces T3/T4:
    • Level of FT3/FT4 → ↓ TSH and TRH
    • ↓ Level of FT3/FT4 → ↑ TSH and TRH
  • 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 system, 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)
Hypothalamic–pituitary–thyroid axis

Schematic diagram of the hypothalamic–pituitary–thyroid axis:
The hypothalamus produces TRH, which stimulates the pituitary gland to synthesize and secrete TSH, which then stimulates the synthesis and secretion of T3 and T4 by the thyroid gland. T4 is converted to T3 in the liver and other tissues. A fraction of T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine; some of this fraction in the intestine may be reabsorbed. If the hypothalamus senses low FT3 and FT4, there will be an increase in TRH and subsequently, TSH; conversely, in this negative feedback loop, T3 and T4 inhibit the release of TSH from the hypothalamus and the pituitary once normal levels are achieved.

Image by Lecturio.

Forms of hypothyroidism

  • Primary:
    • Thyroid disease → ↓ FT3/FT4 from the thyroid gland → compensatory ↑ TSH and TRH 
    • Types:
      • Subclinical: elevated TSH, but normal FT3/FT4
      • Overt: elevated TSH, low FT4/low-normal FT3
  • Secondary: pituitary disorders (unable to produce TSH; ↓ TSH → ↓ FT3/FT4 levels)
    • Pituitary adenomas are the most common cause of central hypothyroidism.
      • Can interfere with TSH production by their mass/compression effect on the TSH-producing cells, and/or by interrupting the hypothalamic–pituitary portal blood flow and blocking the TRH signal from the hypothalamus
      • Pituitary adenomas can also interfere with TSH production if they hemorrhage or become infarcted.
    • Mass lesions other than pituitary adenoma: cysts, abscesses, meningiomas, and dysgerminomas, metastatic tumors, and craniopharyngiomas
    • Effects of surgery or radiation therapy for pituitary adenomas or other masses
    • Infiltrative or inflammatory causes: tuberculosis, syphilis, sarcoidosis, fungal infections, toxoplasmosis, histiocytosis, hemochromatosis, lymphocytic hypophysitis
    • Traumatic brain injury with injury to the pituitary stalk
    • Stroke, subarachnoid hemorrhage
    • Sheehan’s syndrome (postpartum pituitary necrosis).
    • Checkpoint inhibitor–induced hypophysitis or other drug-induced cause
  • Tertiary: 
    • Hypothalamic disorder (unable to produce TRH): ↓ TRH → ↓ TSH → ↓ FT3/FT4 
    • Developmental abnormalities
    • Aneurysms, tumors (primary or secondary)
    • Effects of surgery or radiation therapy for brain tumors or other disorders
    • Ischemic or hemorrhagic stroke; traumatic brain injury

Clinical Presentation

Symptoms of hypothyroidism

Diagram of the most common signs and symptoms of hypothyroidism

Image: “Symptoms and signs of hypothyroidism” by Mikael Häggström. License: CC0

Underlying processes of manifestations

  • ↓ Metabolic rate: slow organ function and metabolic processes
  • Myxedema: deposition and accumulation of connective tissue elements such as glycosaminoglycans with water retention

Congenital hypothyroidism

  • Initially asymptomatic:
    • Due to maternal thyroid hormones
    • Weight and length within normal range, partly due to myxedema
  • General symptoms: 
    • Poor growth and weight gain
    • Poor feeding
    • Decreased activity/excessive sleeping
    • Constipation
    • Hoarse cry
  • Physical signs: 
    • General:
      • Hypotonia
      • Pallor
      • Dry skin
      • Prolonged jaundice
    • Head and neck: 
      • Large fontanelles
      • Macroglossia
      • Coarse facial features 
      • Goiter may be noted.
    • Abdomen:
      • Umbilical hernia
      • Protuberant abdomen
    • Myxedema
    • Central hypothyroidism can present with microgenitalia.
  • Cretinism:
    • Severe intellectual disability resulting from iodine deficiency–related maternal hypothyroidism
    • Maternal iodine intake, especially in the first 12 weeks of gestation, is needed for brain development.
    • Myxedematous cretinism:
      • Intellectual disability
      • Short stature
      • Hypothyroidism 
    • Neurologic cretinism:
      • Intellectual disability
      • Deaf mutism
      • Spasticity and gait problems
      • No hypothyroidism (when iodine intake is increased in the newborn)
    • Cretinism, remember the 6 Ps: 
      • Pale
      • Puffy face
      • Protuberant tongue
      • Poor brain development
      • Pot-bellied
      • Protruding umbilicus
Infant with congenital hypothyroidism

Infant with congenital hypothyroidism displaying typical signs and symptoms, such as hypotonia (A), myxedematous facies and macroglossia (B), and an umbilical hernia (C)

Image: “Infant with congenital hypothyroidism” by Department of Pediatrics, Division of Endocrinology, Oregon Health & Science University, 707 SW Gaines Street, Portland, OR, USA. License: CC BY 2.0

Acquired hypothyroidism

Common signs and symptoms:

  • General:
    • Tiredness, weakness
    • Weight gain with poor appetite
    • Cold intolerance
    • Slow movement
  • Integumentary:
    • Dry skin
    • Hair loss
    • Decreased sweating
  • Neurologic and musculoskeletal:
    • Difficulty concentrating and poor memory
    • Paresthesia
    • Delayed relaxation of deep tendon reflexes
    • Carpal tunnel syndrome
  • Cardiac:
    • Bradycardia
    • Pericardial effusion
    • Decreased cardiac output
  • Pulmonary:
    • Dyspnea on exertion
    • Pleural effusion
  • Gastrointestinal: 
    • Constipation
    • Decreased taste
  • Reproductive: 
    • Menorrhagia (later, oligomenorrhea or amenorrhea)
    • Infertility
    • Decreased libido
    • Erectile dysfunction
  • Other:
    • Nonpitting edema (myxedema) 
    • Periorbital edema
    • Macroglossia
    • Hoarse voice
    • Impaired hearing
    • Increased triglycerides
  • Because prolactin also can increase, effects can include:
    • Galactorrhea and amenorrhea (females)
    • Sexual dysfunction and infertility (males)

In the elderly:

  • Depression
  • Psychosis/delusions/hallucinations

Myxedema coma:

  • Severe hypothyroidism is characterized by slowing function of multiple organs.
  • A medical emergency: 
    • Can lead to shock and death 
    • Mortality rate up to 50%
  • Elderly women most often affected
  • Presentation:
    • Illness (e.g., infection, surgery, myocardial infarction)
    • Decreased mental status
    • Hypothermia
    • Hypoglycemia
    • Hyponatremia
    • Hypotension
    • Hypoventilation
    • Bradycardia
Ascites due to hepatic cirrhosis

A man with myxedema due to hypothyroidism:
Note the expressionless face, periorbital puffiness, pallor, peripheral edema, and massive ascites. Because it is curable, myxedema should be considered in every patient with conspicuous ascites, except perhaps those with widespread or terminal malignancy. The patient shown received thyroid replacement therapy, and all of his physical abnormalities resolved. If ascites persists after treatment, a coexisting cause should be sought.

Image: “57-year-old bartender” by Herbert L. Fred, MD and Hendrik A. van Dijk. License: CC BY 2.0

Diagnosis

Congenital hypothyroidism

Mandatory screening in all newborns:

  • Measurement of TSH and/or T4 24–48 hours after birth
  • Sample obtained via heel prick
  • Elevated TSH  → confirm with venous TSH and T4
  • ↑ TSH, ↓ FT4: confirms diagnosis

Imaging:

  • Not routine
  • Ultrasonography or radionuclide uptake imaging are options.
  • Performed if results are borderline and indication for treatment is unclear (e.g., if imaging shows thyroid agenesis, treatment is initiated)
  • Performed if transient hypothyroidism is suspected

Early diagnosis and treatment can prevent long-term mental disability.

Acquired hypothyroidism

Thyroid function tests:

  • Initial test: 
    • Obtain TSH
    • If elevated, repeat and check FT4
  • Primary hypothyroidism:
    • ↑ TSH 
    • ↓ FT3/FT4
  • Secondary/tertiary hypothyroidism:
    • ↓ TSH 
    • ↓ FT3/FT4
  • Subclinical hypothyroidism:
    • ↑ TSH 
    • Normal FT3/FT4

Antibody testing:

  • Thyroglobulin and thyroid peroxidase antibodies (TPOs):
    • Consistent with autoimmune hypothyroidism 
    • Not routinely measured in typical cases of hypothyroidism, unless active thyroiditis is suspected, since > 90% of cases of hypothyroidism are due to “burned-out” Hashimoto’s thyroiditis in non–iodine-deficient regions.
  • Helpful in subclinical hypothyroidism or goiter:
    • Antibodies (indicating immunologically mediated disease) may predict the progression to overt hypothyroidism.
    • Monitoring TSH regularly in these cases helps assess the need for pharmacotherapy.

Imaging studies:

  • Ultrasonography: rarely used but can help in distinguishing asymmetric goiter in Hashimoto’s thyroiditis from a nodule/multinodular goiter
  •  Brain imaging: 
    • CT or MRI
    • Part of workup for central hypothyroidism
    • Assess pituitary gland, hypothalamus, and surrounding areas.

Additional workup:

  • Aside from TSH and T4, in myxedema coma: 
    • Obtain cortisol level (as adrenal insufficiency needs to be treated).
    • Obtain metabolic panel (may show low sodium) and electrocardiogram (bradycardia).
  • In central hypothyroidism: Obtain other pituitary hormone levels, especially in cases suspicious for hypopituitarism.

Management

Congenital hypothyroidism

  • Thyroid replacement therapy:
    • L-thyroxine: synthetic form of T4 that is peripherally converted to T3
    • Dosage: initially 10–15 µg/kg/day
    • Absorption reduced by antacids, iron, calcium, soy formula
  • For subclinical hypothyroidism: 
    • Monitor thyroid function tests
    •  Treat if TSH is > 10 mU/L after 4 weeks
  • For central hypothyroidism:
    • Thyroid replacement
    • Treat other concomitant hormone deficiencies, if present.
  • In endemic areas, where iodine deficiency is common, iodine supplementation is advised; iodized salt is commonly used in the United States but is not mandated, as in some other countries.

Acquired hypothyroidism

  • Goals: 
    • Attain euthyroid state
    • Correct metabolic derangements
    • Improve symptoms
    • Reduce goiter size (if present)
  • Thyroid replacement therapy:
    • L-thyroxine
    • Dosage: 
      • 1.6 µg/kg of body weight per day in young and healthy patients
      • Starting dose of 25 µg per day in the elderly
    • Measure TSH after 6 weeks and adjust the dose as necessary.
  • Myxedema coma:
    • Thyroid hormone (T3 and T4 given IV) with monitoring of thyroid function tests
    • Glucocorticoids (until adrenal insufficiency is ruled out)
    • Supportive therapy

Case-specific treatments

  • Discontinue use of medication in drug-induced hypothyroidism.
  • Surgery for pituitary–hypothalamic tumors in secondary and tertiary hypothyroidism

Differential Diagnosis

  • Euthyroid sick syndrome: abnormal thyroid function tests in the setting of nonthyroidal illness in clinically euthyroid patients: Low T3 with normal FT4 and TSH is commonly noted. There is impaired T4 conversion to T3 (removal of iodine atom normally in the outer ring, occurs in the inner ring). This produces reverse T3 (rT3), which is an inactive form of T3. Monitoring thyroid function until recovery is recommended.
  • Resistance to TSH or thyroid hormone: will have an elevated serum TSH level: This disorder may be associated with 1 or more abnormalities in the TSH receptors, and the patient may be euthyroid or hypothyroid. The thyroid gland is not enlarged. The diagnosis is made in infancy if a child is symptomatic, especially if other family members are affected. Finding an inactivating mutation in the TRH receptor confirms the diagnosis.
  • Recovery from nonthyroidal illness: will have an elevated serum TSH level but only elevated during recovery period: Repeat measurement of TSH and FT4 should be performed 4–6 weeks after recovery; rarely true hypothyroidism.
  • TSH-secreting pituitary adenoma: will have an elevated serum TSH level, but this is a rare disease: Suspect TSH-secreting pituitary adenoma when T4 and T3 are also high.
  • Adrenal insufficiency (AI): will have an elevated serum TSH level, usually caused by prolonged treatment with exogenous corticosteroids: Adrenal insufficiency may coexist with hypothyroidism but should be suspected if symptoms (lethargy, hypotension) persist after treatment with thyroxine and/or if there are associated laboratory findings of AI, such as hyponatremia, hyperkalemia, or hypoglycemia. Diagnosis involves a multistep approach, which includes the determination of low cortisol levels, measuring ACTH, and determining if it is primary or secondary.

References

  1. Jameson J, et al. (Eds.). (2018). Harrison’s Principles of Internal Medicine, 20th ed. New York: McGraw-Hill.
  2. LaFranchi S. (2020). Clinical features and detection of congenital hypothyroidism. UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/clinical-features-and-detection-of-congenital-hypothyroidism
  3. Molina P. (2013). Thyroid gland. Endocrine Physiology, 4th ed. Chapter 4. New York: McGraw-Hill.
  4. Orlander P, Varghese J. (2019) Hypothyroidism. Medscape. Retrieved January 8, 2021, from https://emedicine.medscape.com/article/122393-overview
  5. Ross D. (2019). Central hypothyroidism. UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/central-hypothyroidism
  6. Ross D. (2020). Disorders that cause hypothyroidism. UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/disorders-that-cause-hypothyroidism
  7. Ross D. (2019). Myxedema coma. UpToDate. Retrieved February 7, 2021, from https://www.uptodate.com/contents/myxedema-coma

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