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A. Types navigator

  1. Hashimoto's Thyroiditis
    1. Most common cause of thyroiditis
    2. In developed nations, most frequent cause of goiter and hypothyroidism
  2. Painless (sporadic) Thyroiditis (form of Subacute Lymphocytic Thyroiditis)
  3. Postpartum (painless) thyroiditis (form of Subacute Lymphocytic Thyroiditis)
  4. Subacute Painful Thyroiditis, synonyms:
    1. De Quervain's
    2. Giant cell
    3. Subacute granulomatous
    4. Pseudogranulomatous
  5. Suppurative Thyroiditis, synonyms:
    1. Infectious
    2. Pyogenic
    3. Bacterial
  6. Drug Induced Thyroiditis
    1. Amiodarone
    2. Lithium
    3. Interferon alpha
    4. Interleukin-2
  7. Reidel's Thyroiditis (fibrous)
  8. Thyroiditis may occur with other autoimmune endocrinopathies
  9. Other Causes of Hypothyroidism
    1. Post-thyroidectomy: second most common cause of hypothyroidism (after autoimmune)
    2. Central hypothyroidism: Pituitary and/or Hypothalamic Insufficiency
    3. Congenital: ~1:3500 births, ~30% caused by thyroid oxidase 2 (THOX2) mutations [3]

B. Pathophysiology of Hashimoto's Diseasenavigator

  1. Autoantibodies
    1. Anti-mitochondrial antibodies against thyroid peroxidase enzyme (TPO) in 90%
    2. Non-stimulatory antibodies to thyroglobulin in 20-50%
    3. May coexist with other auto-antibodies (Abs)
    4. These include ANA (commonly), anti-parietal cell, anti-adrenal Abs
    5. Familial disease, with ~50% of first-degree relatives having anti-thyroid antibodies
    6. Increased risk of thyroiditis in hepatitis C virus (HCV) infected persons []
  2. Histopathology
    1. Interstitial lymphocytes and macrophage (mononuclear) infiltrates
    2. Eosinophilic changes in thyroid cells, fibrosis, and atrophy
    3. Some intact follicles, normal colloid, usually seen with dying areas
  3. Pathophysiology
    1. Believed to be initiated by autoimmune CD4+ helper cells
    2. Local overproduction of interferon-gamma leads to MHC class II expression on thyroid
    3. In addition, monocytes are induced to infilatrate and become activated
  4. Result is thyroid inflammation and destruction
    1. Initially, thyroid hormone is released and patient can be hyperthyroid
    2. After 1-2 months, hypothyroidism occurs
  5. Increased risk (67X) for thyroid lymphoma (which is very rare)

B. Presentation of Hashimoto's Disease [4]navigator

  1. Typically young women with large goiter: firm, bumpty, symmetric, painless
  2. Usually present with symptoms of hypothyroidism (see below)
  3. Often will have bout of hyperthyroidism, followed by waxing and waning hypothyroidism
  4. Older persons with hypothyroidism may have hoarseness, confusion, depression, hair loss
  5. Hypothyroid coma is very rare

C. Signs and Symptoms of Hypothyroidism [4]navigator

  1. Goiter
    1. Extremely large goiters are mainly found in Hashimoto's Disease
    2. Multinodular goiter, Graves' disease, lymphoma, thyroid cancer should also be considered
  2. Hypothyroidism, progressive with eventual complete loss of thyroid function
  3. Typical Symptoms of Hypothyroidism [5]
    1. Cold intolerance
    2. Fatigue
    3. Menstrual abnormalities
    4. Constipation
    5. Weight gain is an uncommon feature
  4. Severe Symptoms of Hypothyroidism [6]
    1. Dry skin
    2. Bradycardia
    3. Elevated blood pressure (frank hypertension, diastolic > systolic)
    4. Dilated cardiomyopathy, pericardial effusion
    5. Hoarseness and/or deafness
    6. Hyponatremia, abnormal renal function
    7. Confusion, ataxia
    8. Progression to coma if untreated
  5. True Myxedema
    1. Nearly always associated with Graves' disease (not thyroiditis)
    2. Most strongly associated with autoantibodies
  6. Vascular Disease
    1. Chronic hypothyroidism is associated with accellerated atherosclerosis
    2. Hypothyroidism is associated with deleterious lipid abnormalities [7]
    3. Hypothyroidism causes elevated homocysteine levels [8]
    4. Thyroxine replacement reduces the homocysteine levels [8]
    5. Subclinical hypothyroidism has a ~2X risk of atherosclerosis and myocardial infarction in women >60 years [9]
  7. Lymphoma
    1. There is an ~67X increased risk of thyroid lymphoma with autoimmune thyroiditis
    2. This is associated with the disease, not the treatment
    3. Likely related to diffuse immune activation in some patients with thyroiditis
    4. Patients with dominant thryoid nodule and goiter should have nodule biopsied

D. Laboratorynavigator

  1. Thyroid Stimulating Hormone (TSH) is best screening test
    1. Elevated TSH indicates hypothyroidism
    2. Elevated TSH with normal T4 is subclinical hypothyroidism
    3. Elevated TSH with reduced T4, particularly low FTI, indicates true hypothyroidism
    4. TSH is unreliable in critical illness
  2. High TSH and Low T4 or FTI
    1. Consider hypothalamic or pituitary disease
    2. Other indicators of pituitary insufficiency should be assessed
    3. TSH releasing hormone (TRH) levels used for hypothalamic versus pituitary disease
  3. T4 and Thyroid Binding Globulin (TBG)
    1. T4 (thyroxine) is the major circulating thyroid hormone
    2. TBG is main carrier protein for T4 (along with prealbumin)
    3. Thyroid Binding Globulin Levels (TBG) are useful for following disease (non-specific)
    4. However, TBG levels may be difficult to measure in presence of autoantibodies
  4. Free Thyroxine Index (FTI)
    1. Calculated from T4 and TBG and indicates active T4 level
    2. In many patients with elevated TSH and autoantibodies, FTI is normal
    3. These patients have "euthyroid" or subclinical hypothyroidism
    4. Such patients have a high rate of progression to frank hypothyroidism (2-4% per year)
    5. Subclinical hypothyroidism should generally be treated to prevent long term effects [10]
  5. Autoantibodies
    1. Formerly, anti-thyroglobulin antibodies were best test for Hashimoto's disease
    2. Now, anti-thyroid microsomal antibodies are used with ~95% sensitivity
    3. If TSH is elevated and anti-thyroid microsomal Abs are present, diagnosis is clear
    4. Anti-thyroid peroxidase Ab titers are not helpful in most cases
    5. Anti-TSH-receptor and anti-Na/I transporter Abs are also found
    6. Since autoimmune and surgical causes are most common, autoantibody panels are not required for diagnosis
  6. Radionucleide Imaging
    1. In Hashimoto Disease, radioidiodine uptake is low normal, normal or elevated
    2. Goiters usually show normal or elevated uptake
    3. In Subacute (De Quervain's) and Silent thyroiditis, uptake is low
    4. Therefore, if patient is hypothyroid, a radionuclide scan is not useful
    5. Uptake is diffusely elevated in Graves' Disease

E. Treatment of Hashimoto's Thyroiditis [11,12]navigator

  1. Thyroid hormone replacement
    1. T4 (thyroxine) alone is as good as T4 + T3 for treatment of primary hypothyroidism [17]
    2. Titrate T4 dose using TSH levels (monthly)
  2. T4 Preparations: Synthroid®, Levoxyl®, Levothyroid®, Unithroid®, others
  3. Risks of Long term treatment with T4
    1. Very low or no risk if TSH is maintained in mid to low normal range
    2. Osteoporosis - mainly with overdoses of T4
    3. Myocardial hypertrophy and ischemia
  4. Subclinical Hypothyroidism [10]
    1. Serum TSH >5 mU/L in the absence of symptoms
    2. Any patients with TPO antibodies and TSH >5mU/L should be treated
    3. Patients without TPO but with symptoms OR TSH >10mU/L should be treated
  5. Effects of not treating (subclinical) hypothyroidism [10]
    1. Increased risk of infertility / spontaneous abortion
    2. Decreased HDL levels; increased total cholesterol levels
    3. Myocardial dysfunction (reduced ejection fraction)
    4. Fatigue, malaise
    5. Symptoms of severe hypothyroidism (see above) [6]
    6. However, the extent to which symptoms are reversible with treatment are unclear

F. Levothyroxine (T4) Therapy [12,13]navigator

  1. Drug of choice for hypothyroidism
  2. Absorption
    1. Gastrointestinal (oral) absorption is ~90% with normal stomach acid
    2. Cholestyramine, colestipol, aluminum, sucralfate, iron block absorption
    3. Patients with impaired acid secretion have reduced absorption [21]
    4. Active Helicobacter pylori infection associated with reduced absorption [21]
  3. Serum t1/2 ~ 7 days due to protein binding (thyroid binding globulin)
  4. L-Thyroxine and Triiodothyronine (T3)
    1. T4 is metabolized to T3 and other products
    2. No demonstrable benefit to adding T3 to T4 therapy
    3. T3 replacement not required if T4 therapy is used [22]
  5. Mechanism of action [5]
    1. Binds nuclear thyroid hormone receptors as homo- or heterodimer
    2. Action on muscle cell (including cardiac), liver cells, most other cell types
    3. Increase heat production by increasing ATP turnover
  6. Drug Interactions
    1. Hypothyroidism decreases drug metabolism
    2. Phenytoin (Dilantin®), rifampin, carbamazepine, phenobarbital speed metabolism
    3. Dialysis increases clearance rate
    4. Estrogen replacement may increase need for thyroxine [14]
    5. Propylthyiouracil, amiodarone, ß-blockers, glucocorticoids block T4 to T3 conversion
  7. Single dose of L-thyroxine required per day
    1. Causes little change in serum levels of T4 OR T3
    2. Do not initiate full dose in older patient (due to decreased hepatic metabolism)
    3. Missed doses may be made up
    4. Possibility of weekly doses
  8. Dosing
    1. Normal dose is ~1.6µg/kg/day; Iniate at 50-100 µg/d in uncomplicated hypothyroidism
    2. Initiate at 12.5-25µg/day in patients with coronary artery or other heart disease
    3. After 3-4 weeks, reassess clinical status and serum TSH
    4. Note that serum TSH levels are really a functional assay (body's perception of T4 status)
    5. Serum free T4 also may be useful; TSH not useful in pituitary disease
    6. Reassess dose requirement on yearly basis
    7. Levothyroxine requirements increase during pregnancy by up to 30% [19]
    8. Levothyroxine dose adjustments should be made from 5th week gestation onward [19]
  9. Determinants of Dose
    1. Weight of patient - 0.8µg/lb/day (1.6-1.8µg/kg/day)
    2. Age of patient - children may need 5µg/kg/day
    3. Begin at 25-50% of weight based dose in patients with heart disease
    4. Minimize dose to maintain TSH in normal range
    5. High normal TSH may improve symptoms quickly, but longer term risks increased
    6. Eradication of Helicobacter pylori leads to improved absorption, reduced TSH levels [21]
  10. Thyroxine Formulations
    1. Generic and brand names available and learly not identical
    2. TSH must be checked 6-8 weeks after change [13]
    3. Not clear that all formulations are equivalent
    4. Branded: Levothroid®, Levoxyl®, Synthroid®, Unithroid®
    5. At least 3 generic formulations available
  11. Liothyronine (T3) Combined with L-thyroxine (T4)
    1. Partial substitution of T3 for thyroxine may improve neuropsychiatric function and mood in patients with hypothyroidism [15]
    2. Minimal effect on mood in another study but with overall patient preferance for adding T3 to standard T4 [20]
    3. However, at this time, combined T4+T3 thyroid replacement is not recommended [16]

G. Painful Subacute (De Quervain's) Thyroiditisnavigator

  1. Typically 40-50 year olds, 80% females
  2. Etiology
    1. Nearly all cases with viral upper respiratory syndrome
    2. May be due to lytic viral effects, or immune destruction of thyroid cells
    3. Immune cells may mistake thyroid cells for infection
    4. No chronic autoimmune association
    5. Typically in summer at peak of enterovirus season, but no specific virus found to date
  3. Symptoms
    1. Prodrome of myalgias, pharyngitis, low-grade fever, fatigue
    2. Neck pain very common (most common cause of thyroid pain)
    3. Tender and hard thyroid with swelling
    4. Fever prominant
    5. Thyrotoxicosis occurs for several weeks
    6. Hypothyroidism typically develops for 4-6 months
    7. Thyroid function then typically normalizes (95% of cases)
  4. Laboratory
    1. ESR > 50mm/hr nearly all cases
    2. C-reactive protein (CRP) elevated as well
    3. High TBG
    4. Peripheral blood thyroid hormone levels elevated, with T4:T3 <20
    5. Serum thyrotropin (TSH) low or undetectable
    6. 24 hour 123-I update is low (<5%) in toxic phase (distinct from Graves' disease)
  5. Treatment
    1. Self limited disease
    2. Treat with NSAIDs
    3. Glucocorticoids for severe symptoms: 40mg/d prednisone provides immediate relief
    4. Taper glucocorticoids over 406 weeks
    5. ß-adrenergic blockers for hyperthryoidism symptoms
  6. ~5% will have residual hypothyroidism
  7. Recurs in ~2% of cases

H. Postpartum (Lymphocytic) Thyroiditisnavigator

  1. Postpartum in up to 10% of women
  2. Probably autoimmune
    1. Lymphocytic infiltrates
    2. Often in women with high serum TPO antibody levels
    3. Increased incidence in patients with Type I diabetes mellitus
    4. Increased incidence with family history of autoimmune thyroid disease
  3. Painless
  4. Symptomatic thyrotoxicosis may occur, usually mild (see below)
    1. Typically begins 1-6 months after delivery
    2. May last 1-2 months
  5. 50% with thyroid enlargement
  6. Laboratory
    1. Normal ESR
    2. Serum T4>T3
    3. May have elevated ANA (antinuclear antibody) titers
    4. Erythrocyte sedimentation rate (ESR) usually normal
  7. Treatment
    1. Only treat symptomatic disease
    2. Evaluate for Graves' Disease and other autoimmune endocrinopathies
    3. Thyrotoxicosis symptoms treated with ß-blockers
  8. 70% chance of recurrence with subsequent pregnancies

I. Suppurative Thyroiditisnavigator

  1. Rare disease, more common in women and with underlying thyroid disease
  2. Bacterial infection: Streptococcus pyogenes > S. pneuoniae > Staph. aureus
  3. Fungal infection can occur, typically in AIDS or other immunocompromise
  4. Symptoms
    1. Acute onset, painful, toxic appearing
    2. Tender and erythematous thyroid
  5. Evaluation
    1. Fine needle aspiration required for diagnosis; rule out tumor, cyst infection, others
    2. Leukocyte counts usually elevated
    3. TFT's usually normal
    4. hyroid scan usually cold
  6. Antibiotic Treatment
    1. Empiric: Oxacillin or nafcillin OR
    2. Alternative: first generation cephalosporin
    3. Culture organism(s) and treat accordingly

J. Reidel's Thyroiditisnavigator

  1. Rare disease, local manifestation of systemic fibrotic process
  2. Progressive fibrosis of thyroid leading to hard, "woody" gland
  3. Euthyroid; nontender, fixed, "rock-hard" gland in most cases
  4. Fibrosis may extend into parathyroid tissue
  5. Open biopsy is required with fibrosis found
  6. Surgical resection usually required with thyroid hormone replacement
  7. Glucocorticoids, methotrexate or tamoxifen may be effective early in disease

K. Thyrotoxicosis (Thyroid Storm) [1] navigator

  1. Can occur in association with the following:
    1. Painless sporadic Thyroiditis
    2. Postpartum Thyroiditis
    3. Painful subactue Thyroiditis
  2. Preformed thyroid hormone released on Inflammatory destruction of thyroid gland
  3. Biochemical Processes
    1. First biochemical change with thyroid destruction is increase in serum thyroglobulin
    2. Serum concentration of thyrotropin is suppressed
    3. Total and free T3 and T4 are elevated
    4. Serum T4 levels proportionally higher than T3
  4. Signs and symptoms of thyroiditis associated thyrotoxicosis are usually not severe

References navigator

  1. Pearce EN, Farwell AP, Braverman LE. 2003. NEJM. 348(26):2646 abstract
  2. Cooper DS. 2003. Lancet. 362(9382):459 abstract
  3. Moreno JC, Bikker H, Kempers MJE, et al. 2002. NEJM. 347(2):95 abstract
  4. Roberts CG and Ladenson PW. 2004. Lancet. 363(9411):793 abstract
  5. Silva JE. 2003. Ann Intern Med. 139(3):205 abstract
  6. Klein I and Ojamaa K. 2001. NEJM. 344(7):501 abstract
  7. Bauer DC, Ettinger B, Browner WS. 1998. Am J Med. 104(6):546 abstract
  8. Hussein WI, Green R, Jacobsen DW, Faiman C. 1999. Ann Intern Med. 131(5):348 abstract
  9. Hak AE, Pols HAP, Visser TJ, et al. 2000. Ann Intern Med. 132(4):270 abstract
  10. Cooper DS. 2001. NEJM. 345(4):260 abstract
  11. Singer PA, Cooper DS, Levy EG, et al. 1995. JAMA. 273(10):808 abstract
  12. Levothyroxine. 2001. Med Let. 43(1108):57 abstract
  13. Levothyroxine. 2004. Med Let. 46(1191):77
  14. Arafah BM. 2001. NEJM. 344(23):1743 abstract
  15. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. 1999. NEJM. 340(6):424 abstract
  16. Woeber KA. 1999. Ann Intern Med. 131(12):959 abstract
  17. Clyde PW, Harari AE, Getka EJ, Shakir KMM. 2003. JAMA. 290(22):2952 abstract
  18. Antonelli A, Ferri C, Pampana A, et al. 2004. Am J Med. 117(1):10 abstract
  19. Alexander EK, Marqusee E, Lawrence J, et al. 2004. NEJM. 351(3):241 abstract
  20. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, et al. 2005. Ann Intern Med. 142(6):412 abstract
  21. Centanni M, Gargano L, Cenettieri G, et al. 2006. NEJM. 354(17):1787 abstract
  22. Jonklaas J, Davidon B, Bhagat S, Soldin SJ. 2008. JAMA. 299(7):769 abstract