Thyroid Disease

Diagnosis

Indications for Testing

• Symptoms of hyper- or hypothyroidism
• Family history of autoimmune thyroiditis
• Goiter on physical exam

Laboratory Testing

• Initial evaluation for thyroid disease – thyroid stimulating hormone (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
  • Thyroid stimulating hormone (TSH) and T4 normal – thyroid disease unlikely
  • TSH elevated – suggests hypothyroidism
    • Order free T4 (thyroxine)
      • Low – hypothyroidism confirmed
        • Consider thyroid antibody testing
      • Normal – consider T3 (triiodothyronine) testing
        • Low T3 – hypothyroidism confirmed
        • Normal T3 – hypothyroidism unlikely, but if indicated by clinical presentation, could be subclinical hypothyroidism
  • TSH low – suggests hyperthyroidism
    • Order free T4
      • High – hyperthyroidism confirmed
      • Normal – consider T3 testing
        • Normal T3 – if TSH levels 0.1-0.4, subclinical hyperthyroidism
        • High T3 – hyperthyroidism
      • Low – central hypothyroidism or severe illness
• Hypothyroidism during pregnancy may cause fetal demise and low IQ in liveborn infants (endemic cretinism)
  • Different reference ranges based on trimester
  • Order TSH and thyroid peroxidase (TPO) antibody testing for patients who have a prior diagnosis or family history of hypothyroidism
  • Elevated TPO antibodies associated with postpartum thyroiditis
• Euthyroid sick syndrome
  • Low levels of thyroid hormone in clinically euthyroid patients who have systemic illnesses
  • Diagnosis – TSH variable; free T3, T4 may be low

Imaging Studies

Only order ultrasound in patients with abnormal thyroid function tests if palpable abnormality is present (ASCP's Pathology-Related Choosing Wisely Recommendations, 2015; The Endocrine Society, American Association of Clinical Endocrinologists).

Differential Diagnosis

• Hyperthyroidism
  • Drug-induced (amiodarone)
  • Thyrotoxicosis factitia
  • Trophoblastic tumors
  • Anxiety
  • Sepsis
• Hypothyroidism
  • Depression
  • Cushing disease
  • Obesity
  • Polycystic ovarian syndrome
  • Metabolic syndrome

Screening

• At-large population screening for thyroid dysfunction not recommended in nonpregnant, asymptomatic adults (USPSTF, 2015)
  • The American Thyroid Association and American Association of Clinical Endocrinologists (Garber, 2012) recommend consideration of screening patients >60 years and “aggressive” case findings
• Neonatal – TSH at 24 hours of age
  • Abnormal tests must be followed up with T4 test
• Pregnancy
  • Universal screening is not recommended (ACOG, 2015; AACE, 2012; Endocrine Society, 2012)
  • Women at risk should be screened using TSH (Endocrine Society Guidelines, 2007; ACOG, 2007)
  • Risk factors include the following
    • Personal or family history of thyroid disease
    • Pregestational diabetes mellitus or other known autoimmune diseases
    • Prior head and neck irradiation
    • Previous infertility
    • History of miscarriage or preterm delivery
    • Women who are symptomatic

Monitoring

• Hyperthyroidism
  • Initial monitoring – TSH and free T4 testing 6 weeks after initiation of therapy until euthyroid
    • Don’t order free T3 or total T3 level when assessing levothyroxine dose (Choosing Wisely, 2013, Endocrine Society)
  • Patients eventually develop hypothyroidism in autoimmune disease as the gland burns out
  • Monitor TSH and free T4 every year
  • Pregnancy-related hyperthyroidism – check TSH 6 weeks postpartum
• Hypothyroidism – TSH and free T4 useful in monitoring thyroid replacement therapy
  • Monitor TSH in pregnant women to assess adequacy of therapy screening

Background

Epidemiology

• Incidence
  • Hypothyroidism
    • 4-6% of the population
    • Increases with age – 1 of 4 nursing home patients has hypothyroidism
    • Primary congenital hypothyroidism – 1/3,000 infants
  • Hyperthyroidism
    • 2-3% of the population
    • 2/1,000 pregnancies
• Age – onset is 40s-50s for both hypo- and hyperthyroidism
• Sex – M<F, 1:5-8 for both types

Disorders

Hypothyroidism

• Etiologies
  • Autoimmunity – Graves disease, Hashimoto disease
  • Iatrogenic – treatment hyperthyroidism
  • Iodine deficiency most common cause worldwide – predominantly in underdeveloped countries
  • Drugs – amiodarone, androgens, aspirin, cholestyramine, estrogens, furosemide, glucocorticoids, levodopa, lithium, neuroleptics, phenytoin, propranolol
• Clinical presentation
  • Insidious onset common
  • Fatigue, depression, cold intolerance, weight gain, bradycardia, constipation, hair loss, alopecia, carpal tunnel syndrome, dry/coarse skin, skin thickening (myxedema)
  • Myxedema coma – most serious manifestation
  • Congenital disease
    • Growth retardation
    • Developmental delay/mental retardation

Hyperthyroidism (Thyrotoxicosis)

• Etiologies
  • Graves disease accounts for 60-80% of cases
    • Autoimmune – thyroid stimulating immune globulins (TSI IgG) bind to thyrotropin receptors on the thyroid gland leading to overproduction of thyroid hormones
  • Toxic multinodular goiter
    • Secrete hormone autonomously due to activating TSH receptor mutation
  • Toxic adenoma (Plummer disease)
    • Mutation in TSH receptor or Gs alpha gene in athyroid nodule
  • Thyroiditis
    • Hyperemesis gravidarum – high level of βHCG stimulates TSH receptors
    • Postpartum – increased risk in women with DM1, or women with antibodies to thyroglobulin, or TPO
    • Subacute granulomatous (de Quervain)
    • Drug induced (eg, amiodarone)
  • Other (rare) – TSH secreting tumors, factitious (ingestion of T3, T4), struma ovarii, germ cell tumors
• Clinical presentation
  • Hyperactivity, heat intolerance, fatigue, weakness, diarrhea, tachycardia, tremor, goiter, weight loss
  • Subacute thyroiditis – diffuse nontender enlargement of the gland
  • Ophthalmopathy – occurs in 30% of patients and consists of protrusion of the eyes and periorbital swelling (Graves disease)

Pregnancy-Related Thyroid Disorders

• Thyroid binding globulin (TBG) levels are elevated as estrogen increases
• Increased TBG causes a shift in T3 and T4 reference ranges 1.5 times the nonpregnant state – always use trimester-specific reference values
• Reference intervals for free T4 not well established in pregnant patients – some research recommends use of total T4 in place of free T4 during pregnancy
• TSH range is lower – due to crossreactivity of alpha subunit of hCG with TSH-receptor
  • May be below the lower adult reference limit in 20% of pregnancies
• Hypothyroidism
  • 0.3-0.7% of pregnancies
    • Higher for subclinical disease – likely similar to overt disease but risks not as well documented
  • Associated with decreased fertility, low birth weight, low fetal IQ, fetal demise, hypertension, placental abruption, and postpartum hemorrhage
  • Symptoms – fatigue, inappropriate weight gain, constipation, goiter, cold intolerance, bradycardia
  • Most common cause – chronic autoimmune thyroiditis
• Hyperthyroidism
  • ~0.2% of pregnancies
  • Associated with spontaneous abortions, infertility, still births, low birth weight, preterm delivery, fetal or neonatal hyperthyroidism, maternal heart failure, placental abruption, preeclampsia
  • In 2% of pregnancies, T4 is supranormal around 10-12 weeks because hCG is at its peak and TSH is at its nadir
  • Symptoms – weight loss, goiter, muscle weakness, palpitations, onycholysis, tachycardia, eye changes
  • Causes
    • Graves disease – most cases
    • Gestational transient thyrotoxicosis
    • Hyperemesis gravidarum – frequently associated with gestational transient thyrotoxicosis
    • Trophoblastic tumors such as choriocarcinoma
    • TSH receptor mutation