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BASICS

  • Decreased free thyroid hormone levels or resistance to thyroid hormone action
  • Types:
  • Primary (thyroid gland pathology, >95% cases)
  • Central (pituitary or hypothalamus dysfunction)
  • Peripheral (tissue resistance)
  • Subclinical hypothyroidism: elevated TSH with normal free T4
  • Overt hypothyroidism: elevated TSH with low free T4

EPIDEMIOLOGY

  • Incidence per 1,000 persons/year:
  • Women: 3.5
  • Men: 0.6

ETIOLOGY AND PATHOPHYSIOLOGY

  • Primary hypothyroidism:
  • Worldwide: iodine deficiency (most common)
  • USA: Hashimoto thyroiditis (autoimmune destruction)
  • Postablative/posttherapeutic: post-radioiodine therapy or thyroidectomy
  • Transient hypothyroidism: de Quervain thyroiditis, postpartum, silent thyroiditis
  • Drug-induced: PTU, methimazole, lithium, amiodarone, antiepileptics, tyrosine kinase inhibitors, interferon-Ξ±
  • Central hypothyroidism: pituitary or hypothalamic dysfunction
  • Consumptive hypothyroidism: ectopic deiodinase production (rare)
  • Genetic and infiltrative causes

RISK FACTORS

  • Autoimmune disease history or family history
  • Head/neck irradiation, thyroid surgery, or radioiodine therapy
  • Abnormal thyroid exam or TPO antibody positivity
  • Use of medications (amiodarone, lithium, interferon-Ξ±, sunitinib, sorafenib)
  • Syndromes: Down syndrome, Turner syndrome

COMMONLY ASSOCIATED CONDITIONS

  • Pernicious anemia
  • Celiac disease
  • Addison disease
  • Rheumatoid arthritis, SLE
  • Depression

DIAGNOSIS

History

  • Fatigue, lethargy
  • Cold intolerance
  • Constipation
  • Dry skin
  • Muscle cramps, arthralgia, paresthesias
  • Modest weight gain (1.8–5.0 kg)
  • Menstrual irregularities, infertility
  • Depression, hoarseness
  • Sleep apnea
  • Carpal tunnel syndrome

Physical Exam

  • Dry, thickened skin
  • Hair loss, brittle hair
  • Periorbital edema, myxedema (nonpitting swelling)
  • Bradycardia; altered BP (reduced systolic, increased diastolic)
  • Delayed deep tendon reflex relaxation
  • Macroglossia
  • Goiter (iodine deficiency or Hashimoto thyroiditis)
  • Elderly may present with nonspecific symptoms

Differential Diagnosis

  • Chronic fatigue syndrome
  • Depression
  • Anemia
  • Congestive heart failure
  • Primary adrenal insufficiency

Diagnostic Tests

  • Primary hypothyroidism:
  • Elevated TSH (>4.5 mIU/L)
  • Low free T4
  • Central hypothyroidism:
  • Decreased or normal TSH
  • Low free T4 or free T4 index
  • Subclinical hypothyroidism:
  • Elevated TSH
  • Normal free T4
  • Antithyroid antibodies (TPO, antithyroglobulin) may help define etiology
  • TRH stimulation test if hypothalamic-pituitary pathology suspected
  • Imaging of hypothalamus/pituitary as indicated

TREATMENT

First Line

  • Levothyroxine (Synthroid, Levothroid)
  • Dose: 1.5–1.8 Β΅g/kg/day (ideal body weight)
  • Titrate by 12.5–25 Β΅g every 4–8 weeks until TSH normalizes
  • Start lower doses (12.5–25 Β΅g) in elderly, CAD, or multiple comorbidities
  • Take on empty stomach, 1 hour before breakfast or at bedtime (2 hours after last meal)
  • Avoid concurrent ingestion of iron, calcium, PPIs, bile acid sequestrants within 4 hours

Contraindications

  • Overt thyrotoxicosis
  • Uncorrected adrenal insufficiency
  • Acute MI
  • Preexisting TSH suppression

Precautions

  • Adjust hypoglycemics in diabetics
  • Monitor anticoagulant therapy closely
  • Monitor digoxin levels
  • Elderly at higher risk for atrial fibrillation, fractures

Pregnancy

  • Dose increases by 25–50%
  • Monitor TSH monthly in 1st half of pregnancy
  • Target TSH 2.0–2.5 mIU/L in 1st trimester, <3 in later trimesters
  • Postpartum TSH check at 6 weeks

Second Line

  • Liothyronine (T3) or desiccated thyroid hormone in intolerant patients

ISSUES FOR REFERRAL

  • Children, infants, pregnancy/planning conception
  • Goiter, nodules, structural abnormalities
  • Adrenal or pituitary disorders

ADDITIONAL THERAPIES

  • Limited evidence for alternatives

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

  • Myxedema coma: severe untreated hypothyroidism
  • Monitor for hypotension, arrhythmias, effusions

ONGOING CARE

  • Monitor TSH, free T4 every 4–8 weeks after initiation or dose change
  • Once stable, test TSH every 6–12 months
  • Monitor cardiac function in elderly
  • Monitor more frequently in pregnancy or major body weight changes
  • Free T4 preferred in central hypothyroidism (TSH unreliable)
  • Thyroid hormones not for obesity treatment in euthyroid patients

PATIENT EDUCATION

  • Explain symptoms of thyrotoxicosis
  • Instruct on medication timing and drug interactions

PROGNOSIS

  • Normalization expected with treatment
  • Relapse possible if treatment interrupted
  • Untreated severe cases may progress to myxedema coma

COMPLICATIONS

  • Similar surgical morbidity in euthyroid and mild/moderate hypothyroid patients
  • Myxedema coma mortality 30–60%
  • Increased infection susceptibility
  • Megacolon, sexual dysfunction, infertility
  • Organic psychosis, depression, apathy
  • Hypersensitivity to opiates
  • Long-term therapy: decreased bone mineral density
  • Iatrogenic thyrotoxicosis: atrial fibrillation, osteoporosis
  • Adrenal crisis if steroids not replaced prior to levothyroxine in adrenal insufficiency
  • Congestive heart failure risk in CAD patients

REFERENCES

  1. Chaker L, Razvi S, Bensenor IM, et al. Hypothyroidism. Nat Rev Dis Primers. 2022;8(1):30.
  2. Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists, American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults. Endocr Pract. 2012;18(6):988-1028.
  3. Chaker L, Bianco AC, Jonklaas J, et al. Hypothyroidism. Lancet. 2017;390(10101):1550-1562.
  4. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;379(9821):1142-1154.
  5. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat and how. Drugs. 2012;72(1):17-33.
  6. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism. Thyroid. 2014;24(12):1670-1751.
  7. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy. N Engl J Med. 2004;351(3):241-249.

Clinical Pearls

  • Initial screening: TSH test; free T4 only if TSH abnormal (2)[A]
  • TSH and free T4 should be monitored every 4–8 weeks after starting or changing therapy; once stable, monitor every 6–12 months
  • Take levothyroxine on empty stomach, avoid interacting medications close to dose time
  • Treat subclinical hypothyroidism if TSH >10 mIU/L or with iron deficiency anemia