Thyroid Disease

Thyroid disease frequently arises from autoimmune processes that stimulate overproduction of hormones (hyperthyroidism) or causes gland destruction that subsequently leads to underproduction of hormones (hypothyroidism).

Quick Answers for Clinicians

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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

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
    • 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

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

ARUP Lab Tests

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Thyroid stimulating hormone (TSH) status should be known to properly interpret serum thyroglobulin levels

Reflex pattern: if the TSH is outside the reference interval, then free T4 testing will be added

Not recommended for routine thyroid screening

Less sensitive and specific than free T4 (FT4) test

May not be useful in monitoring treatment in individuals receiving T4 replacement therapy

Preferred testing for autoimmune thyroid disease (eg, GD) based on ARUP analytical sensitivities (versus TRAb sensitivities)

Prognostic marker for relapse of GD or remission following drug therapy

Support GD diagnosis in difficult (euthyroid) cases

Predict risk of thyroid dysfunction in newborns of mothers with GD

Blocking antibodies specific to TSHR may decrease TSI antibody levels; net response is most likely physiologic

TSH serum levels ≥6 mU/L may cause a false-positive result

Acceptable testing for autoimmune thyroid disease

Aid in the differentiation of GD from factitious thyrotoxicosis, postpartum thyroiditis, or toxic nodular goiter

Prognostic marker for relapse of GD or remission following drug therapy

Predict risk of thyroid dysfunction in newborns of mothers with GD

Evaluate for the presence of euthyroid GD ophthalmopathy

Analytical sensitivity: 0.9 IU/L limit of detection

Analytical specificity: 88.9%

Primary testing for Hashimoto thyroiditis

Secondary testing for Graves disease (GD); aids in the differentiation of GD from factitious thyrotoxicosis, postpartum thyroiditis, or toxic nodular goiter

Predict progression to hypothyroidism in individuals with subclinical hypothyroidism

Evaluate individuals with recurrent miscarriage, with or without infertility issues

Clinical sensitivity

  • GD: ~75%
  • Hashimoto thyroiditis: >90%

Analytical sensitivity: 0.25 IU/mL limit of detection

Not recommended in the initial evaluation of autoimmune thyroid disease

Diagnose autoimmune thyroid disease when TPO antibody measurements are negative and a high clinical suspicion exists for autoimmune thyroid disease

Predict progression to hypothyroidism in individuals with subclinical hypothyroidism (eg, Hashimoto thyroiditis)

Most often used to evaluate potentially unreliable thyroglobulin measurements in thyroid carcinomas

Not the preferred initial test for evaluation of autoimmune thyroid disorder; consider ordering thyroid peroxidase (TPO) antibody

Test panel composed of TPO and TG antibody tests

See individual tests for recommended uses

Related Tests

Not recommended for routine thyroid screening

Indications for ordering are rare cases of suppressed serum thyroid stimulating hormone (TSH) with normal free thyroxine (FT4) (eg, suspected T3 toxicosis, subclinical T3 hyperthyroidism, rare pituitary conditions)

Preferred test for screening and monitoring thyroid function, but does not include T4 reflex testing.

Aid in the diagnosis of primary hyperthyroidism and differential diagnosis of hypothyroidism

Monitor individuals on thyroid hormone replacement therapy

Confirm suppression during thyroxine therapy for thyroid carcinoma

Not the preferred initial thyroid disorder screening test

Order following abnormal thyroid stimulating hormone (TSH) result 

Order in conjunction with TSH if pituitary (secondary) hypothyroidism is suspected

Assess thyroid status in pregnant women or those on estrogen supplementation, phenytoin, or salicylates

Monitor thyroid hormone replacement therapy during pregnancy and treatment of secondary hypothyroidism

Not recommended for routine evaluation of thyroid disorders; order free T4 instead

Generally not recommended for routine evaluation of thyroid disorders, although may be considered in pregnant women

  

Not recommended for routine thyroid screening

Aid in interpreting T3 and T4 levels that do not correlate with clinical findings

Not recommended for routine thyroid screening

Indications for ordering are rare cases of suppressed serum thyroid stimulating hormone (TSH) with normal free thyroxine (FT4) (eg, suspected T3 toxicosis, subclinical T3 hyperthyroidism, rare pituitary conditions)

Second-line test in evaluating individuals during pregnancy, those receiving steroids, or individuals with dysalbuminemia

Do not order for individuals with abnormal total T3 values

False positives may result from thyrotoxicosis or excess replacement therapy

Not recommended for routine thyroid screening

Total T4, T3 uptake, and estimation of free thyroxine (FT4) index have limited clinical utility

Replaced by the combination of more sensitive TSH and FT4 tests that provide direct measurements

Not recommended for routine thyroid screening

Replaced by the combination of more sensitive TSH and FT4 tests that provide direct measurements

Little clinical value as stand-alone test

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References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®