Resident Editor: Jessica Valente, MD 

Faculty Editor: Michelle Guy, MD

Background

• Overt primary hypothyroidism: High serum TSH and a low serum FT4. Most of these patients will have signs and symptoms of hypothyroidism.
• Subclinical hypothyroidism (SCH): High serum TSH and a normal-range serum FT4. Patients may experience mood or cognitive symptoms; likely has negative effect on cardiovascular function (especially in elderly with TSH >10). Approximately 10% of elderly. TPO antibody positivity might help predict progression to overt hypothyroidism. 
• Central hypothyroidism: Low serum FT4 and a serum TSH that is not appropriately elevated 
• Euthyroid sick syndrome: T3 and T4 levels low and TSH normal or low
• Prevalence of hypothyroidism approximately 3-7% in the USA
• Risk factors: female gender (5-8x more common), age > 65, white race, autoimmune disease (Celiac, T1DM, adrenal insufficiency)

Signs and Symptoms

*Signs and symptoms may be subtle or absent in elderly patients

Differential Diagnosis

• Chronic autoimmune thyroiditis (Hashimoto’s): Most common cause in developed world; 5-10 times more common in women; >90% have high autoantibodies to thyroglobulin, anti-TPO, or Na/I transporter antibodies (often don’t check given high prevalence of Hashimoto’s)
• Iatrogenic: Thyroidectomy, radioiodine therapy, external neck irradiation
• Drugs: propylthiouracil, methimazole, lithium, amiodarone (14% develop hypothyroidism), interferon-alfa, interleukin-2, tyrosine kinase inhibitors (measure TSH q6-12 months in people on these drugs), propranolol, glucocorticoids, estrogens
• Thyroiditis: Often preceded by a period of hyperthyroidism
  • Painful: subacute viral (de Quervain’s), infectious, radiation, trauma-induced
  • Painless: postpartum, drug induced (see above), fibrous
• Iodine deficiency (or excess): Most common worldwide
• Lymphoma (tumor replacing the thyroid gland)
• Infiltrative disease: hemochromatosis, sarcoidosis 
• Central Hypothyroidism: pituitary (i.e., surgery, radiation, adenomas, head trauma, apoplexy, Sheehan’s) or hypothalamic disease; TSH may be low, inappropriately normal, or insufficiently elevated in presence of low T4
• Other conditions: adrenal insufficiency, recovery from nonthyroidal illness

Evaluation

• In patients with symptoms or signs concerning for hypothyroidism, serum TSH is the initial test. If the serum TSH is high, repeat the serum TSH with a serum FT4.
• High TSH and low FT4 indicates primary hypothyroidism
• In patients with diffuse, firm goiter, measure anti-TPO antibodies to identify autoimmune thyroiditis. If no goiter, no need to routinely measure anti-TPO antibodies.
• No current recommendation for routine screening in asymptomatic patients by USPSTF
• AACE (American Association of Clinical Endocrinologists) recommend measuring TSH in any patient at risk for hypothyroidism, including patients with: 
  • Personal history of autoimmune disease (e.g. Type 1 DM, pernicious anemia)
  • First-degree relative with autoimmune thyroid disease
  • History of head or thyroid/neck radiation
  • History of thyroid surgery
  • Abnormal thyroid exam
  • Psychiatric or cognitive disorders
  • Infertility or dysmenorrhea
  • Medical therapy with drugs affecting thyroid function (i.e., amiodarone or lithium)
• For subclinical hypothyroidism, first repeat TSH and free T4 in 2-3 months to rule out transient abnormality. If confirmed SCH, recommendation is to repeat testing every 6-12 months given risk of developing overt disease
  • 2-6% of people per year progress to overt hypothyroidism (higher rate if anti-TPO Ab present). Approximately 50% with SCH normalize within 2 years.
  • Recommend checking anti-TPO antibodies to help predict patients high risk of progression to overt disease.
• For patients who are critically ill, avoid testing for thyroid disease unless primary or central hypothyroidism is suspected; acute illness causes changes in thyroid hormone metabolism.

Treatment

• Therapy consists of thyroid hormone replacement unless transient (thyroiditis) or reversible (drug-related)
• Pregnant women will usually require 30% dose increase
• Levothyroxine (LT4): starting dose is 1.6 mcg/kg/day (typical dose 75-100 mcg) except in older patients or those with heart disease, then start 25 mcg daily 
  • Try to stick with one formulation given subtle differences in bioavailability between T4 preparations; if change is necessary then recheck TSH 6 weeks afterwards and retitrate
  • Ideally LT4 is taken on an empty stomach 30-60 minutes before breakfast with no other medications; avoid taking interacting meds for 4 hours (iron, calcium, PPI, sulcrafate)
  • Titrate dose by 12.5-25 mcg/day every 6 weeks until TSH normalizes
  • Takes 6 weeks to achieve steady state
  • Check TSH at 6 months after treatment onset and then annually for maintenance therapy
  • Goal = normalization of TSH, improved symptoms, and avoidance of under/overtreatment (induced hyperthyroidism can reduce bone mass and increase risk of afib)
    • In patients who are hypothyroid from surgical management of thyroid cancer, goal is TSH less than or near 1.

• Persistent elevation of TSH despite adequate repletion should prompt evaluation for poor absorption in diseases like Celiac, pernicious  anemia, or  interacting meds. Persistent fatigue despite adequate treatment should cause PCP to consider adrenal insufficiency.
• Subclinical hypothyroidism: RCT demonstrated no change in symptoms, mood, or quality of life for older adults with SCH treated with levothyroxine.
  • Indications to treat:
    • TSH > 10 (increased risk of heart failure)
    • Patients age < 70 and TSH > 7
    • Goiter or patients with elevated anti-TPO antibody titers
    • Pregnancy or women attempting to conceive 
  • Discontinue treatment if adverse effects or no symptom improvement after 3-6 months

Drug interactions with Levothyroxine

When to refer

• Patients of age 18 years or younger
• Patients unresponsive to therapy or in whom achieving a euthyroid state is difficult 
• Those with special conditions such as pregnancy, women attempting conception, or severe cardiovascular disease
• Presence of goiter, nodule, or other structural changes in the thyroid gland
• Presence of other endocrine disease such as adrenal and pituitary disorders 
• Unusual constellation of thyroid function test results
• Suspected myxedema coma

References

Chaker L, Bianco AC, Janklaas J,  Peetres RP. Hypothyroidism. Lancet. 2017; 390: 1550-62.

Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice. 2012; 18(6). 

LeFevre ML. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Int Med. 2015; 162(9): 642-651.

McDermott MT. In the clinic – Hypothyroidism. Ann Int Med. 2009; 151 (11): ITC61.

Nygaard B. Clinical evidence handbook: Primary hypothyroidism. AAFP. 2015; 91(6): 359-360.

Peeters RP. Subclinical hypothyroidism. NEJM. 2017; 376: 2556-65.

Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. NEJM. 2017; 376:2534-44.

Ross DS, Cooper DS, Mulder JE. Diagnosis and screening for hypothyroidism in nonpregnant adults. UpToDate. Nov 7, 2017.