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 (TSH)
    • 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)
    • 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

Differential Diagnosis

Screening

  • Hypothyroidism
    • Neonatal – TSH test at 24 hours of age
      • Abnormal tests must be followed up with T4 test
    • Pregnancy – not recommended to screen all pregnant women
      • Women at risk should be screened using TSH (Endocrine Society Guidelines, 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
        • Miscarriage or preterm delivery
        • Women who are symptomatic  
    • At-large population screening for hypothyroidism not recommended

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

Clinical Background

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).

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
    • Toxic multinodular (Plummer disease) or uninodular goiter
      • Secrete hormone autonomously
    • Thyroiditis
      • Postpartum
      • Subacute
    • Other – TSH secreting tumors (rare); ingestion of T3, T4, drug-induced (amiodarone)

    Clinical Presentation

    • Hyperactivity, heat intolerance, fatigue, weakness, diarrhea, tachycardia, tremor, goiter, weight loss
    • Diffuse nontender enlargement of the gland – subacute thyroiditis
    • Ophthalmopathy – occurs in 30% of patients and consists of protrusion of the eyes and periorbital swelling (Graves disease)
  • Pregnancy-related
    • 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 – low energy, 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 mutations

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Assess thyroid function

Use in risk stratification of palpable thyroid nodule

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

   
Thyroxine 0070140
Method: Quantitative Electrochemiluminescent Immunoassay

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

 
Thyroid Stimulating Immunoglobulin 0099430
Method: Quantitative Bioassay/Quantitative Chemiluminescent Immunoassay

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

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

 
Thyroid Stimulating Hormone Receptor Antibody (TRAb) 2002734
Method: Quantitative Electrochemiluminescent Immunoassay

Acceptable testing for autoimmune thyroid disease

Aids 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

   
Thyroid Peroxidase (TPO) Antibody 0050075
Method: Quantitative Chemiluminescent Immunoassay

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

   
Thyroglobulin Antibody 0050105
Method: Quantitative Chemiluminescent Immunoassay

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)

   
Thyroid Antibodies 0050645
Method: Chemiluminescent Immunoassay

Test panel composed of TPO and TG antibody tests

See individual tests for recommended uses

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Triiodothyronine, Total (Total T3) 0070474
Method: Quantitative Electrochemiluminescent Immunoassay

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)

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

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

Thyroxine, Free (Free T4) 0070138
Method: Quantitative Electrochemiluminescent Immunoassay

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

Thyroxine, Free by Equilibrium Dialysis/HPLC-Tandem Mass Spectrometry 0093244
Method: Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry

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

Triiodothyronine, Reverse by Tandem Mass Spectrometry 2007918
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

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

Triiodothyronine, Free by Equilibrium Dialysis/HPLC-Tandem Mass Spectrometry 0093243
Method: Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry
Thyroxine Binding Globulin 0070410
Method: Quantitative Chemiluminescent Immunoassay

Not recommended for routine thyroid screening

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

Triiodothyronine, Free (Free T3) 0070133
Method: Quantitative Electrochemiluminescent Immunoassay

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

Thyroid Panel 0070141
Method: Quantitative Electrochemiluminescent Immunoassay

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

T3 Uptake 0070135
Method: Quantitative Electrochemiluminescent Immunoassay

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