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Basic Information ⬇

AUTHOR: Fred F. Ferri, MD

Definition

Hypothyroidism is a disorder caused by the inadequate secretion of thyroid hormone.

Synonym

Myxedema

ICD-10CM CODES
E00.9Congenital iodine-deficiency syndrome, unspecified
E02Subclinical iodine-deficiency hypothy-roidism
E03.0Congenital hypothyroidism with diffuse goiter
E03.1Congenital hypothyroidism without goiter
E03.2Hypothyroidism due to medicaments and other exogenous substances
E03.3Postinfectious hypothyroidism
E03.8Other specified hypothyroidism
E03.9Hypothyroidism, unspecified
E89.0Postprocedural hypothyroidism
Epidemiology & Demographics
Incidence & Prevalence

1.5% to 2% of women and 0.2% of men. Overall, about 1 in 300 persons in the U.S. has hypothyroidism.

Predominant Age

Incidence of hypothyroidism increases with age; among persons older than 60 yr, 6% of women and 2.5% of men have laboratory evidence of hypothyroidism (thyroid-stimulating hormone [TSH] more than twice normal level).

Physical Findings & Clinical Presentation

  • Hypothyroid patients generally present with the following signs and symptoms: Fatigue, lethargy, weakness, constipation, weight gain, cold intolerance, muscle weakness, slow speech, slow cerebration with poor memory
  • Skin: Dry, coarse, thick, cool, sallow (yellow color caused by carotenemia); nonpitting edema in skin of eyelids and hands (myxedema) secondary to infiltration of subcutaneous tissues by a hydrophilic mucopolysaccharide substance (Fig. E1, A and B)
  • Hair: Brittle and coarse; loss of outer third of eyebrows
  • Face: Dulled expression, thickened tongue, thick and slow-moving lips
  • Thyroid gland: May or may not be palpable (depending on the cause of the hypothyroidism)
  • Heart sounds: Distant, possible pericardial effusion
  • Pulse: Bradycardia
  • Neurologic: Delayed relaxation phase of the deep tendon reflexes, cerebellar ataxia, hearing impairment, poor memory, peripheral neuropathies with paresthesia
  • Musculoskeletal: Carpal tunnel syndrome, muscular stiffness, weakness

Figure E1 A and B, Typical Appearance of Patients with Moderately Severe Primary Hypothyroidism or Myxedema

Notice the Dry Skin and Sallow Complexion; Absence of Scleral Pigmentation Differentiates the Carotenemia from Jaundice. Both Individuals Demonstrate Periorbital Myxedema. The Patient in B Illustrates the Loss of the Lateral Aspect of the Eyebrow, Sometimes Termed Queen Anne Sign. That Finding is Not Unusual in the Age Group that is Commonly Affected by Severe Hypothyroidism and Should Not Be Considered a Specific Sign of the Condition.

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Etiology (Table 1

  • Primary hypothyroidism (thyroid gland dysfunction): The cause of >90% of the cases of hypothyroidism
    1. Hashimoto thyroiditis is the most common cause of hypothyroidism after age 8 yr
    2. Idiopathic myxedema (nongoitrous form of Hashimoto thyroiditis)
    3. Previous treatment of hyperthyroidism (radioiodine therapy, subtotal thyroidectomy)
    4. Subacute thyroiditis
    5. Radiation therapy to the neck (usually for malignant disease)
    6. Iodine deficiency or excess
    7. Drugs (lithium, paraaminosalicylate, sulfonamides, phenylbutazone, amiodarone, thiourea). Box E1 summarizes medications that may cause iatrogenic hypothyroidism.
    8. Congenital (approximately one case per 2000 to 4000 live births)
    9. Prolonged treatment with iodides
  • Secondary hypothyroidism: Pituitary dysfunction, postpartum necrosis, neoplasm, infiltrative disease-causing deficiency of TSH
  • Tertiary hypothyroidism: Hypothalamic disease (granuloma, neoplasm, or irradiation causing deficiency of thyrotropin-releasing hormone)
  • Tissue resistance to thyroid hormone: Rare

TABLE 1 Causes of Hypothyroidism

Primary Hypothyroidism
Acquired
  • Hashimoto thyroiditis
  • Iodine deficiency (endemic goiter)
  • Drugs blocking synthesis or release of T4 (e.g., lithium, ethionamide, sulfonamides, iodide)
  • Drug-induced thyroid destruction (e.g., interferon alpha, interleukin 2, tyrosine kinase inhibitors, blockers of CTLA4 or PD1)
  • Amiodarone (reversible or permanent)
  • Goitrogens in foodstuffs or as endemic substances or pollutants
  • Thyroid infiltration (amyloidosis, hemochromatosis, sarcoidosis, Riedel struma, cystinosis, scleroderma)
  • Postablative thyroiditis due to 131I, surgery, or therapeutic irradiation for nonthyroidal malignancy
  • Transient hypothyroidism following painless thyroiditis (including postpartum) or painful subacute thyroiditis
Congenital
  • Iodide transport or utilization defect (NIS or pendrin mutations)
  • Iodotyrosine dehalogenase deficiency
  • Organification disorders (TPO deficiency or dysfunction)
  • Defects in thyroglobulin synthesis or processing
  • Thyroid agenesis or dysplasia
  • TSH receptor defects
  • Thyroidal Gs protein abnormalities (pseudohypoparathyroidism type 1a)
  • Idiopathic TSH unresponsiveness
Consumptive Hypothyroidism
  • Rapid destruction of thyroid hormone due to D3 expression in large hemangiomas or hemangioendotheliomas
Defects of Thyroxine to Triiodothyronine Conversion
  • Selenocysteine insertion sequence-binding protein 2 (SECISBP2) defect
Central Hypothyroidism
Acquired
  • Pituitary origin (secondary)
  • Hypothalamic disorders (tertiary)
  • Bexarotene (retinoid X receptor agonist)
  • Dopamine or severe illness
Congenital
  • TSH deficiency or structural abnormality
  • TSH receptor defect
Resistance to Thyroid Hormone
  • Generalized
  • “Pituitary” dominant

NIS, Sodium-iodide symporter; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone (thyrotropin).

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier.

BOX E1 Medications That May Cause Iatrogenic Hypothyroidism

IV, Intravenous; T4, thyroxine; TSH, thyroid stimulating hormone.

Inhibition of Thyroid Hormone Synthesis or Secretion

  • Aminoglutethimide
  • Lithium
  • Perchlorate
  • Thalidomide
  • Thionamides (methimazole, propylthiouracil)
  • Iodine-containing medications
    1. Amiodarone
    2. Iodinated IV contrast
    3. Guaifenesin
    4. Kelp
    5. Potassium iodide
    6. Topical antiseptics

Immune Dysregulation

  • Interferon alfa
  • Interleukin-2
  • Alemtuzumab
  • Ipilimumab
  • Nivolumab
  • Pembrolizumab

TSH Suppression

  • Dopamine

Destructive Thyroiditis

  • Sunitinib

Increased Type 3 Deiodinase Activity

  • Sorafenib

Increased T4 Clearance and TSH Suppression

  • Bexarotene

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Depression
  • Dementia from other causes
  • Systemic disorders (e.g., nephrotic syndrome, congestive heart failure, amyloidosis)
Laboratory Tests (Table 2

  • TSH, free T4, thyroid peroxidase antibodies (TPOAB)
  • Increased TSH: TSH may be normal if patient has secondary or tertiary hypothyroidism, is receiving dopamine or corticosteroids, or the level is obtained after severe illness
  • Decreased free T4 in hypothyroidism, normal free T4 in subclinical hypothyroidism
  • Other common laboratory abnormalities: Hyperlipidemia, hyponatremia, and anemia
  • Increased antimicrosomal and antithyroglobulin antibody titers: Useful when autoimmune thyroiditis is suspected as the cause of the hypothyroidism. The American Thyroid Association recommends treatment of pregnant patients with subclinical hypothyroidism and antithyroid peroxidase (anti-TPO) antibody positivity
  • Fig. 2 describes a strategy for the laboratory evaluation of patients with suspected hypothyroidism
Figure 2 Strategy for the Laboratory Evaluation of Patients with Suspected Hypothyroidism

!!flowchart!!!!flowchart!!

The principal differential diagnosis is between primary and central hypothyroidism. The serum thyrotropin (TSH) concentration is the critical laboratory determination that in general allows recognition of the cause of the disease. An exception is the individual with a recent history of thyrotoxicosis (and suppressed TSH) in whom a low free thyroxine (T4) level may be associated with a reduced TSH level for several months after relief of the thyrotoxicosis. In patients with primary hypothyroidism, the absence of thyroid peroxidase (TPO) antibodies raises a possible diagnosis of transient hypothyroidism following an undiagnosed episode of subacute or postviral thyroiditis. In such patients, a trial of levothyroxine in reduced dosage after 4 mo may reveal recovery of thyroid function, thus avoiding permanent levothyroxine replacement. MRI, Magnetic resonance imaging; TRH, thyrotropin-releasing hormone; T4I, thyroxine index.

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier.

TABLE 2 Laboratory Evaluation of Patients With Suspected Hypothyroidism or Thyroid Enlargementa

TSH, Free T4TPOAbDiagnosis
TSH >10 mU/L
Low+Primary hypothyroidism due to autoimmune thyroid disease
Low-normal+Primary “subclinical” hypothyroidism (autoimmune)
Low or low-normal–Recovery from systemic illness
External irradiation, drug-induced, congenital hypothyroidism
Iodine deficiency
Seronegative autoimmune thyroid disease
Rare thyroid disorders (amyloidosis, sarcoidosis, etc.)
Recovery from subacute granulomatous thyroiditis
Normal+, –Consider TSH or T4 assay artifacts
Elevated–Thyroid hormone resistance
Blockade of T4 to T3 conversion (amiodarone) or a congenital 5′-deiodinase deficiency
Consider assay artifacts
TSH 5-10 mU/L
Low, low-normal+Early primary autoimmune hypothyroidism
Low, low-normal–Milder forms of nonautoimmune hypothyroidism (see earlier)
Central hypothyroidism with impaired TSH bioactivity
Elevated– (+)Consider thyroid hormone resistance
T4 to T3 conversion blockade (e.g., amiodarone)
TSH 0.5-5 mU/L
Low, low-normal– (+)Central hypothyroidism
Salicylate or phenytoin therapy
Desiccated thyroid or T3 replacement
TSH <0.5 μU/L
Low, low-normal– (+)“Post-hyperthyroid” hypothyroidism (131I or surgery)
Central hypothyroidism
T3 or desiccated thyroid excess
Following excess levothyroxine withdrawal

TgAb, Antithyroglobulin antibody; TPOAb, thyroid peroxidase autoantibody; TSH, thyroid-stimulating hormone (thyrotropin); +, present; –, not present.

a Initial tests: Serum TSH, serum free T4, TPO, or TgAb.

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

Patients should be educated regarding hypothyroidism and its possible complications. Patients should also be instructed about the need for lifelong treatment and monitoring of their thyroid abnormality. Patients should also be informed about potential drug and food interactions. Levothyroxine is best taken with water on an empty stomach 60 min before breakfast or at bedtime 3 h after last meal.

Acute General Rx

Start replacement therapy with levothyroxine (L-thyroxine) 25 to 100 μg/day, depending on the patient’s age and the severity of the disease. Physiologic combinations of L-thyroxine plus liothyronine do not offer any objective advantage over L-thyroxine alone. The levothyroxine dose may be increased every 6 to 8 wk, depending on the clinical response and serum TSH level. Elderly patients and patients with coronary artery disease should be started with 12.5 to 25 μg/day (higher doses may precipitate angina). The average maintenance dose of levothyroxine is 1.7 μg/kg/day (100 to 150 μg/day in adults). The elderly may require <1 μg/kg/day, whereas children generally require higher doses (up to 3 to 4 μg/kg/day). Pregnant patients also have increased requirements. Estrogen therapy may also increase the need for thyroxine. Women with hypothyroidism should increase their levothyroxine dose by approximately 30% as soon as pregnancy is confirmed. Close monitoring of serum thyrotropin levels and adjustment of levothyroxine dose to maintain a TSH level of a <2.5 mU/L before conception and during the first trimester and a TSH level of 4.0 mU/L as upper limit during the second and third trimester. Table E3 summarizes conditions that alter levothyroxine requirements.

TABLE E3 Conditions That Alter Levothyroxine Requirements

Increased Levothyroxine Requirements
Pregnancy
Gastrointestinal Disorders
Mucosal diseases of the small bowel (e.g., sprue)
After jejunoileal bypass and small-bowel resection
Impaired gastric acid secretion (e.g., atrophic gastritis)
Diabetic diarrhea
Drugs That Interfere With Levothyroxine Absorption
Cholestyramine
Sucralfate
Aluminum hydroxide
Calcium carbonate
Ferrous sulfate
Drugs That Increase the Cytochrome P450 Enzyme (CYP 3A4) Activity
Rifampin
Carbamazepine
Estrogen
Phenytoin
Sertraline
Drugs That Block T4-to-T3 Conversion
Amiodarone
Conditions That May Block Deiodinase Synthesis
Selenium deficiency
Cirrhosis
Decreased Levothyroxine Requirements
Aging (≥65 yr)
Androgen therapy in women

T3, Triiodothyronine; T4, thyroxine.

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Chronic Rx

  • Periodic monitoring of TSH level is an essential part of treatment. Patients should be evaluated initially with office visit and TSH levels every 6 to 8 wk until the patient is clinically euthyroid and the TSH level is normalized. The frequency of subsequent visits and TSH measurement can then be decreased to every 6 to 12 mo. Pregnant patients should be checked every trimester.
  • For monitoring therapy in patients with central hypothyroidism, measurement of serum free thyroxine (free T4 level) is appropriate and should be maintained in the upper half of the normal range.
Referral

Admission to the hospital intensive care unit is recommended in all patients with myxedema coma. Additional information on the diagnosis and treatment of this life-threatening complication of hypothyroidism is available under “Myxedema Coma” in Section I.

Pearls & Considerations ⬆ ⬇

Comments

  • Subclinical hypothyroidism occurs in as many as 20% of elderly patients and is characterized by an elevated serum TSH and a normal free T4 level. Subclinical hypothyroidism is not associated with typical symptoms of overt hypothyroidism.1 Subclinical hypothyroidism can progress to overt hypothyroidism, especially if antithyroid antibodies are present. It is associated with an increased risk of coronary heart disease events and mortality, particularly in those with a TSH concentration of 10 mU/L or greater. Treatment is individualized and controversial. Some trials have shown that levothyroxine provides no apparent benefit in older persons (≥80 yr of age) with subclinical hypothyroidism. The management of subclinical hypothyroidism should be individualized on the basis of TSH level, comorbid conditions, risk factors, and patient preference. In general, replacement therapy is recommended by most physicians for patients with serum TSH >10 mU/L and with presence of goiter or thyroid autoantibodies or patient has risk factors. Subclinical thyroid dysfunction is not associated with cognitive decline or dementia and treatment of subclinical thyroid dysfunction is unlikely to improve cognitive function.2
  • Congenital hypothyroidism is a pediatric disorder with an observed prevalence of one in 2000 to 4000 live births in the U.S. Screening is conducted in all newborns in all states and accomplished by measuring TSH from dried whole blood spots collected on a newborn by heel stick within the first 24 to 48 hr of life. Currently 14 states perform a routine second screen at approximately 2 wk of age. A two-screen approach is preferred because retrospective analysis found that 20% of congenital hypothyroidism cases were in infants who had normal TSH on the first screen but elevated TSH concentrations on the second screen.
  • Switching among FDA-approved generic levothyroxine preparations in patients with stable doses and normal TSH levels is safe and not associated with changes in TSH.3
Related Content

Hypothyroidism (Patient Information)

Myxedema Coma (Related Key Topic)

Related Content ⬆

    1. Carlé A. : Does subclinical hypothyroidism add any symptoms? Evidence from a Danish population-base studyAm J Med. ;134(9), 2021.
    2. van Vliet N.A. : Association of thyroid dysfunction with cognitive function: an individual participant date analysisJAMA Intern Med. ;181(11):1440-1450, 2021.
    3. Brito J.P. : Association between generic-to-generic levothyroxine switching and thyrotropin levels among US adultsJAMA Intern Med. ;182(4):418-425, 2022.doi:10.1001/jamainternmed.2022.0045
    4. Azim S., Nasr C. : Subclinical hypothyroidism: when to treat, CleveClin J Med Off. ;86(2):101-110, 2019.
    5. Bekkering G.E. : Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guidelineBMJ. ;365, 2019.
    6. Burch H.B. : Drug effects on the thyroidN Engl J Med. ;381(8):749-761, 2019.
    7. Casey B.M. : Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancyN Engl J Med. ;376:815-825, 2017.
    8. Gaitonde D.Y. : Hypothyroidism: an updateAm Fam Physician. ;86(3):244-251, 2012.
    9. Jones D.E. : Identification of primary congenital hypothyroidism based on two newborn screens - Utah, 2010-16MMWR Morb Mortal Wkly Rep. ;67(28):782-785, 2018.
    10. Mooijaart S.P. : Association between levothyroxine treatment and thyroid-related symptoms among adults aged 80 years and older with subclinical hypothyroidismJAMA. ;322(20):1977-1986, 2019.
    11. Peeters R.P. : Subclinical hypothyroidismN Engl J Med. ;376:2556-2565, 2017.
    12. Rodondi N. : Subclinical hypothyroidism and the risk of coronary heart disease and mortalityJAMA. ;304(12):1365-1374, 2010.
    13. Rugge J.B. : Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task ForceAnn Intern Med. ;162:35-45, 2015.
    14. Stott D.J. : Thyroid hormone therapy for older adults with subclinical hypothyroidismN Engl J Med. ;376:2534-2544, 2017.