02. Hypothyroidism and Myxedema

Definition 

  • Primary hypothyroidism: dysfunction of the thyroid gland. High TSH and a low FT4.
  • Secondary (central) hypothyroidism: dysfunction of the pituitary and/or hypothalamus. Low FT4 and a TSH that is not appropriately elevated.
  • Subclinical hypothyroidism: high TSH with a normal FT4.
  • Myxedema coma: severe hypothyroidism causing multi-organ dysfunction. A medical emergency with a high mortality rate.

Presentation

  • Early: usually asymptomatic, but may have fatigue, weight gain, cold intolerance, menorrhagia or amenorrhea, constipation, dry skin, thin hair, delayed DTRs, diastolic HTN and hyperlipidemia.
  • Late: slow speech, brawny edema, hoarseness, loss of outer third of eyebrows, puffy face/eyelids, thickened tongue, myxedema, bradycardia, hypotension, and hypothermia.
  • Myxedema coma: an endocrine emergency with mortality exceeding 30%. Can present with altered mental status, hypothermia, hypoventilation, hyponatremia, hypoxia, hypercapnia, hypotension, convulsions, confusion, lethargy, and coma. Consider infectious insult or acute illness, and remember that the hypothyroid patient may not mount fever in the face of infection.

Etiology

  • Primary: autoimmune (Hashimoto thyroiditis), post-therapy (post-thyroidectomy or radioiodine ablation), antithyroid drugs (methimazole, PTU), iodine deficiency, infiltrative disease (e.g., sarcoid), and medications (e.g., lithium, iodide, check-point inhibitors and amiodarone).
  • Secondary: signs of other pituitary hormone abnormalities are common. DDX: mass effect (primary pituitary adenoma, metastasis, meningioma and other intracranial masses), hemorrhage (pituitary apoplexy), ischemic (post-partum pituitary necrosis/Sheehan’s syndrome, shock).
  • Myxedema coma: often induced by underlying infection, cardiac, respiratory or CNS illness, cold exposure, or drugs.

Evaluation

  • FT4 low to normal, TSH increased (except in pituitary disease, when TSH can be low or inappropriately normal). 
  • With significant disease, there may be increased cholesterol (especially LDL), elevated transaminases, increased CK, increased prolactin, hyponatremia, hypoglycemia, and anemia. Anti-thyroperoxidase (anti-TPO) antibodies are often positive in autoimmune thyroiditis.

Management

  • Levothyroxine: in general, full replacement is approximately 1.6mcg/kg/day. Patients not requiring full replacement may require a lower dose. Starting doses are dependent on the situation and duration of hypothyroidism (see below for special populations).
  • Monitoring and dose adjustment: based on TSH every 4-8 weeks until stable dose achieved.

Special populations

  • Pregnancy: goal TSH varies by trimester, consultation with Endocrinology is indicated.
  • Elderly, with CAD or high risk for CAD, long standing untreated hypothyroidism: start levothyroxine 25mcg/day.
  • Subclinical hypothyroidism: although controversial, treatment is generally not necessary unless TSH is >10 mU/L, anti-thyroperoxidase (anti-TPO) antibody level is positive, presence of a goiter, pregnancy or other compelling complications. Typically, lower doses of levothyroxine are needed: can start with 25-50mcg. Must get follow up in 4-8 weeks regardless of treatment initiation.
  • Thyroid cancer: patients who had total thyroidectomy for thyroid cancer need higher doses of thyroid hormone to suppress TSH and growth of residual thyroid tissue.
  • Myxedema coma: immediate endocrine consult to help guide therapy. Associated with a very high mortality rate.
    • Draw cortisol level first and administer glucocorticoids (hydrocortisone 50-100mg q6-8h) until adrenal insufficiency can be ruled out. Thyroid hormone therapy can increase cortisol clearance, precipitating adrenal insufficiency.
    • Thyroid replacement: 200-400mcg IV load followed by 50-100mcg IV daily. Consider lower IV load doses in elderly patients or patients with cardiac conditions. No good data showing benefit of T3 therapy.

Complications and precautions

  • Decreased metabolism of other medications, such that patients will often require lower doses (e.g., pain meds or sedatives).
  • Higher doses of warfarin may be required because of decreased clearance of vitamin K-dependent clotting factors.
  • Precipitation of ischemia or arrythmias by aggressive thyroid replacement.
  • Increased susceptibility to infection.

Patient counseling

  • Thyroid hormone should be given on an empty stomach. Iron, soy, calcium and resin binders may interfere with absorption. Remember that most enteral feeding formulas are soy-based.
  • Recommend taking levothyroxine 30-60 minutes prior to breakfast or 4 hours after dinner.

Garbe J. Cobin R, Gharib H, Hennessey J, Et al. Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice: November 2012, Vol. 18, No. 6, pp. 988-1028. https://doi.org/10.4158/EP12280.GL

Jonklaas, J, et al. Guidelines for the Treatment of Hypothyroidism. Thyroid. 2014. 24(12): 1670-1751.

Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med. 2007. Jul-Aug;22(4):224-31.

Peeters RP. Subclinical Hypothyroidism. N Engl J Med 2017; 376:2556-2565. DOI: 10.1056/NEJMcp1611144.

Roos, A, et al. The Starting Dose of Levothyroxine in Primary Hypothyroidism Treatment: A Prospective, Randomized, Double-Blind Trial. Arch Intern Med. 2005. 165:1714-1720.