Hypothyroidism

Jump to: navigation, search
In Process

Author / Curator: Jacob Mirsky MD MA

Faculty Advisor:

GUIDELINES:
The format of each page are recommended guidelines. They should be fluid as each topic will have a unique flow.

(1) Be concise.

(2) Be evidence-based. (Everything should have a reputable citation and resource)

(3) Be clinically relevant. (Avoid unnecessary discussion of pathophysiology and epidemiology if it does not help clinical decision-making).



Learning Objectives 

  • Understand the prevalence of hypothyroidism and its presentation in the community
  • Develop a framework for working-up newly diagnosed hypothyroidism
  • Appreciate the treatment choices for various etiologies of hypothyroidism

Top Teaching Points

  • Hypothyroidism is the deficiency of thyroid hormone that manifests in many and varied ways, however treatment is relatively straightforward except in a few special circumstances (e.g. pregnancy)
  • Subclinical hypothyroidism is mild thyroid failure demonstrated by an increase in TSH but with normal serum free T4 and T3. Treatment of patients with subclinical hypothyroidism whose TSH is under 7 to 10 mIU/L is debated.
  • Primary hypothyroidism accounts for >95% of cases of hypothyroidism and is due to a thyroid gland defect. Secondary (or central) hypothyroidism is due to a pituitary gland defect, and tertiary hypothyroidism is due to a hypothalamic defect.
  • Symptoms and exam findings will suggest the diagnosis of hypothyroidism, which is then confirmed by lab tests.
  • An abnormal TSH should be repeated and confirmed along with the serum free T4. In primary hypothyroidism, the TSH will be elevated and the free T4 will be decreased. In central hypothyroidism, free T4 will be decreased, and the TSH may be low or not appropriately elevated.
  • Routine testing for autoantibodies is not indicated, however an elevated TPO may help predict progression to overt hypothyroidism in subclinical hypothyroidism.
  • Treatment is with synthetic T4 (levothyroxine) to restore the euthyroid state, to improve hypothyroid symptoms, and to decrease goiter size if present.
  • Steady state is reached after 6 weeks of treatment. TSH should be checked every 4-6 weeks while adjusting the dose until the target TSH is reached. Thereafter, TSH can be followed yearly, provided the patient is stable and has not started any medications that affect T4 absorption/metabolism.


Background

- Epidemiology: The prevalence of overt hypothyroidism is approximately <1% and for subclinical hypothyroidism is 4-9%. Hypothyroidism increases with age, and is ten times more common in women. [1][2]

- Physiology / Pathophysiology [3]:

  • Sick euthyroid syndrome - transient abnormal TFTs (low TSH and T3, normal T4) after acute, severe non-thyroid illness due to caloric deprivation that normalizes after recovery
  • Primary Hypothyroidism (Thyroid Disease = High TSH, low T4)
    • Hashimoto's thyroiditis (chronic autoimmune hypothyroidism) - anti-TPO (usually not necessary for dx because so common), lymphoma of thyroid
    • Primary Idiopathic Hypothyroidism - may be atrophic form of chronic thyroiditis
    • Autoimmune polyendocrine syndromes (APS), also called multiple autoimmune endocrinopathies (MAE)
    • Thyroiditis (postpartum, postviral, subacute)
    • Subtotal thyroidectomy
    • Radioablative - common in patients with Graves disease)
    • Excessive iodidine intake
    • Iodine deficiency
    • Medications (tyrosine kinase inhibitors, lithium, amiodarone, anti-thyroid medications)
    • Congenital
    • Thyroid infiltration - amyloid, sarcoid, hemochromatosis, scleroderma
  • Secondary Hypothyroidism (Pituitary Disease = Low TSH, low T4)
    • Hypopituitarism - pituitary infarct, pituitary or suprasellar tumor, infilltrative disorders, congenital thyroid-stimulating hormone deficiency or receptor defect
  • Tertiary Hypothyroidism (Hypothatlamus Disease = Low TSH, low T4)
    • Hypothalamic dysfunction - tumor, infarct, infiltrative disorders

- Progression and Complications of Disease[4]:

  • Myxedema coma - severe hypothyroidism w/ altered mental status, hypothermia, parasympathetic symptoms
  • Hyperlipidemia - due to decreased LPL activity
  • Hyponatremia
  • Asymptomatic CK elevation - can be elevated for years before developing clinical symptoms
  • Asymptomatic transaminitis
  • Lymphoma of thyroid (in Hashimoto's)

Diagnosis

- History and Risk Factors - family history of hypothyroidism or other autoimmune diseases, postpartum state, history of thyroid resection, history of prior head or neck radiation, medication use (see above) [3][5][6]

- Signs and Symptoms - fatigability, weakness, cold intolerance, weight gain, constipation, depression, menstrual irregularities (menorrhagia/oligomenorrhea/infertility), muscle cramps, memory changes, hoarseness, dry skin, alopecia, proximal muscle weakness

- Physical Exam Findings: weight, pulse rate, blood pressure, temperature, cool/dry skin, slowed relaxation phase of reflexes, hoarse husky voice, non-pitting edema, depressed affect, thyroid gland abnormalities (e.g. goiter)

- Differential diagnosis[7][8][9]: sick euthyroid syndrome, anemia, adrenal insufficiency, liver failure

- Recommended Work-up [10][11][12][13][14][15][16][17]: TSH and free T4 are generally sufficient in making the diagnosis of hypothyroidism:

  • TSH is the most sensitive test for detecting primary hypothyroidism. Upon detection of an elevated TSH, it should be repeated along with the free T4, the active form of thyroxine.
    • Primary = high TSH usually > 10 mu/L; low-normal FT4
    • Secondary and Tertiary = low-normal or slightly elevated TSH; low-normal FT4
  • Total T4 and T3 levels can vary through changes in binding globulins and albumin, however free T4 in theory will remain unaffected (in extreme situations such as critically ill patients, the free T4 assays may not be reliable). However, in pregnancy, the direct immunoassay of free T4 levels will be reduced, and the serum total T4 is preferable.
  • Findings in primary hypothyroidism are an elevated TSH, decreased free T4, and decreased total T3.
  • If central hypothyroidism is suspected, it is important to check free T4 regardless of TSH which may be low or just not appropriately elevated; occasionally TSH is slightly elevated in central hypothyroidism due to abnormal glycosylation which produces an immunoreactive but not bioactive hormone.
  • Confirmation of an abnormal TSH is important as there may be up to a 30% diurnal variation in the TSH level, with the trough in the afternoon, and acute illness can also alter testing characteristics. In addition, free T4 should ideally be checked before thyroxine medication dosing. There is also some variability in different laboratory assays and reference ranges.
  • Anti-thyroid peroxidase antibodies (anti-TPO) are usually not necessary for diagnosis of Hashimoto's because it is such a common cause of primary overt hypothyroidism but may be helpful in patients with subclinical hypothyroidism (elevated TSH with normal T4)
  • Anti-thyroglobulin (anti-TG) antibodies are elevated in Hashimoto's
  • Ultrasound can be used to assess for pseudocystic pattern in Hashimoto's
  • FNA and possible cone biopsy are performed by endocrinology, although it may miss Hashimoto's
  • MRI of brain/pituitary can be considered in suspected central hypothryoidism

Management

- Pharmacological treatments[18][19][20][21][22][23]

  • Treatment goals - to restore the euthyroid state (based on TSH), to improve hypothyroid symptoms, and to decrease goiter size if present.
  • Most patients require lifelong treatment with thyroid hormone replacement (synthetic thyroxine; T4; levothyroxine). Patients with transient subacute thyroiditis or drug-induced hypothyroidism need only be treated during their hypothyroid phase.
    • It is possible that a subset of patients with a polymorphism in the type 2 deiodinase might benefit from a combination of synthetic T4 and T3.  The pace of T4 repletion depends on severity of hypothyroidism, as well as age, weight, and cardiac status of the patient. For most patients, the full daily dose of levothyroxine is about 1.6 μg/kg body weight. This is roughly 100 mcg daily for the average-sized woman and 125 mcg for the average-sized man.
  • Levothyroxine should be ideally taken on an empty stomach 30-60 minutes before breakfast or at bedtime 4 hours after the last meal. The half-life of levothyroxine is about 7 days, so steady state is reached in about 6 weeks.
  • TSH should be checked every 4-6 weeks while adjusting the dose until the target (a normal TSH) is reached. After target is reached, TSH can be followed yearly, provided that the patient is stable and has not started any medications that affect T4 absorption/metabolism.
    • Drugs that interfere with levothyroxine absorption:
      • Cholestyramine
      • Ferrous sulfate
      • Sucralfate
      • Calcium salts
      • Antacids with aluminum hydroxide 
    • Drugs that increase levothyroxine metabolism:
      • Rifampin
      • Sertraline hydrochloride
      • Phenytoin
      • Carbamazepine
      • Phenobarbitol 
    • Drugs that increase thyroid binding globulin:
      • Estrogen therapy 
  • The various generics and brands of levothyroxine may not be bioequivalent and TSH should be checked after 6 weeks if a switch in brand must be made. In those patients where TSH requires precise titration (e.g. patients with thyroid cancer, and patients with cardiovascular disease), the use of a brand should be considered.
  • In patients older than 60 years of age, it is best to start conservatively at 50 mcg of levothyroxine daily. In the very elderly, or in patients with coronary artery disease and ischemia, even lower doses should be used. The normal range for TSH is shifted upwards in older patients; the 97.5%-ile in 80 year olds is > 7.0 mIU/L.
  • In treatment in Central Hypothyroidism, targets for T4 therapy are mid- to upper-normal range of FT4.

Other Teaching Pearls

  • In the elderly, high normal or slightly elevated TSH is a reasonable target, since overtreatment increases the risk of osteoporosis and atrial fibrillation. 
  • Patient illness and recovery may also affect TSH secretion, therefore routine measurement of TFTs is not recommended in hospitalized patients.

Trial Summaries

Ongoing controversies / New updates

  • Subclinical thyroid dysfunction is common in the adult population, however screening is generally currently not recommended[24][25][26][27][28]
  • There is considerable controversy as to the appropriate upper limit of normal for serum TSH[29]

Teaching Resources

Blogs:

Videos:

Podcast episodes:

Core review articles / Guidelines:

Other links:

References

Hypothyroidism

  1. Hollowell et al.: Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J. Clin. Endocrinol. Metab. 2002;87:489-99.
  2. Tunbridge et al.: The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. (Oxf) 1977;7:481-93.
  3. 3.0 3.1 Vaidya & Pearce: Management of hypothyroidism in adults. BMJ 2008;337:a801.
  4. McDermott &: In the clinic. Hypothyroidism. Ann. Intern. Med. 2009;151:ITC61.
  5. Stagnaro-Green et al.: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-125.
  6. Garber et al.: Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22:1200-35.
  7. Topliss et al.: Significance of thyrotropin excess in untreated primary adrenal insufficiency. J. Clin. Endocrinol. Metab. 1980;50:52-6.
  8. Kahn et al.: Factitious elevation of thyrotropin in a new ultrasensitive assay: implications for the use of monoclonal antibodies in "sandwich" immunoassay. J. Clin. Endocrinol. Metab. 1988;66:526-33.
  9. Loh et al.: Macro-thyrotropin: a case report and review of literature. J. Clin. Endocrinol. Metab. 2012;97:1823-8.
  10. Roberts & Ladenson: Hypothyroidism. Lancet 2004;363:793-803.
  11. Surks & Hollowell: Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 2007;92:4575-82.
  12. Valdés et al.: Reference values for TSH may be inadequate to define hypothyroidism in persons with morbid obesity: Di@bet.es study. Obesity (Silver Spring) 2017;25:788-793.
  13. Samuels & Ridgway: Central hypothyroidism. Endocrinol. Metab. Clin. North Am. 1992;21:903-19.
  14. Lania et al.: Central hypothyroidism. Pituitary 2008;11:181-6.
  15. Beck-Peccoz et al.: Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N. Engl. J. Med. 1985;312:1085-90.
  16. Mariotti et al.: Antithyroid peroxidase autoantibodies in thyroid diseases. J. Clin. Endocrinol. Metab. 1990;71:661-9.
  17. Adler & Wartofsky: The nonthyroidal illness syndrome. Endocrinol. Metab. Clin. North Am. 2007;36:657-72, vi.
  18. Jonklaas et al.: Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid 2014;24:1670-751.
  19. Adler & Wartofsky: The nonthyroidal illness syndrome. Endocrinol. Metab. Clin. North Am. 2007;36:657-72, vi.
  20. Allahabadia et al.: Diagnosis and treatment of primary hypothyroidism. BMJ 2009;338:b725.
  21. Wartofsky &: Myxedema coma. Endocrinol. Metab. Clin. North Am. 2006;35:687-98, vii-viii.
  22. Stagnaro-Green et al.: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-125.
  23. Garber et al.: Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22:1200-35.
  24. Danese et al.: Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. JAMA 1996;276:285-92.
  25. Surks et al.: Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-38.
  26. Gharib et al.: Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J. Clin. Endocrinol. Metab. 2005;90:581-5; discussion 586-7.
  27. Rugge et al.: Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 2015;162:35-45.
  28. LeFevre & U.S. Preventive Services Task Force: Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 2015;162:641-50.
  29. Waise & Price: The upper limit of the reference range for thyroid-stimulating hormone should not be confused with a cut-off to define subclinical hypothyroidism. Ann. Clin. Biochem. 2009;46:93-8.