Thyroid Disease

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: 5 Things Physicians and Patients Should Question, 2015; 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

Thyroid Disorders Testing Algorithm

Read more about Thyroid Disorders Testing Algorithm

Thyroid Nodules Testing Algorithm

Read more about Thyroid Nodules Testing Algorithm

At-large population screening for thyroid disfunction not recommended in nonpregnant, asymptomatic adults (USPSTF, 2015; AAFP, 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

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

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
  - 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

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.

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Use to 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

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

Thyroxine 0070140
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Not recommended for routine thyroid screening

Less sensitive and specific than free T4 (FT4) test

Limitations

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

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

Recommended Use

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

Limitations

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

Recommended Use

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%

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

Recommended Use

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

Thyroglobulin Antibody 0050105
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

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

Thyroid Antibodies 0050645
Method: Chemiluminescent Immunoassay

Recommended Use

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

Guidelines

American College of Obstetricians and Gynecologists. Practice Bulletin No. 148: Thyroid disease in pregnancy. Obstet Gynecol. 2015; 125(4): 996-1005. PubMed

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

American Society for Clinical Pathology. Choosing Wisely - Pathology-Related Choosing Wisely Recommendations. An initiative of the ABIM Foundation. [Initial posting Feb 2015; Accessed: Nov 2015]

Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee C, Klein I, Laurberg P, McDougall R, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN, American Thyroid Association, American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011; 17(3): 456-520. PubMed

Clinical Preventive Service Recommendation - Thyroid. Am Fam Physician. Leawood, KS [Accessed: Jun 2015]

Committee on Patient Safety and Quality Improvement, Committee on Professional Liability. ACOG Committee Opinion No. 381: Subclinical hypothyroidism in pregnancy. Obstet Gynecol. 2007; 110(4): 959-60. PubMed

De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; 97(8): 2543-65. PubMed

Endocrine Society. Five Things Physicians and Patients Should Question. Endocrine Society. [Accessed: Jan 2016]

Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012; 18(6): 988-1028. PubMed

LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015; 162(9): 641-50. PubMed

Routine Thyroid Screening Not Recommended for Pregnant Women. News release. American College of Obstetricians and Gynecologists. [Accessed: Sep 2011]

Rugge B, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015; 162(1): 35-45. PubMed

General References

Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am. 2012; 96(2): 203-21. PubMed

Carney LA, Quinlan JD, West JM. Thyroid disease in pregnancy. Am Fam Physician. 2014; 89(4): 273-8. PubMed

Casey B, de Veciana M. Thyroid screening in pregnancy. Am J Obstet Gynecol. 2014; 211(4): 351-353.e1. PubMed

DeBoer MD, LaFranchi SH. Pediatric thyroid testing issues. Pediatr Endocrinol Rev. 2007; 5 Suppl 1: 570-7. PubMed

Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012; 379(9821): 1155-66. PubMed

Kravets I. Hyperthyroidism: Diagnosis and Treatment. Am Fam Physician. 2016; 93(5): 363-70. PubMed

Kundra P, Burman KD. The effect of medications on thyroid function tests. Med Clin North Am. 2012; 96(2): 283-95. PubMed

LaFranchi SH. Approach to the diagnosis and treatment of neonatal hypothyroidism. J Clin Endocrinol Metab. 2011; 96(10): 2959-67. PubMed

Menconi F, Marcocci C, Marinò M. Diagnosis and classification of Graves' disease. Autoimmun Rev. 2014; 13(4-5): 398-402. PubMed

Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011; 25(6): 927-43. PubMed

Samuels MH. Subacute, silent, and postpartum thyroiditis. Med Clin North Am. 2012; 96(2): 223-33. PubMed

Seigel SC, Hodak SP. Thyrotoxicosis. Med Clin North Am. 2012; 96(2): 175-201. PubMed

Shih JL, Agus MS. Thyroid function in the critically ill newborn and child. Curr Opin Pediatr. 2009; 21(4): 536-40. PubMed

Sweeney LB, Stewart C, Gaitonde DY. Thyroiditis: an integrated approach. Am Fam Physician. 2014; 90(6): 389-96. PubMed

Vaidya B, Pearce SH. Diagnosis and management of thyrotoxicosis. BMJ. 2014; 349: g5128. PubMed

Wilcken B, Wiley V. Newborn screening. Pathology. 2008; 40(2): 104-15. PubMed

Yazbeck CF, Sullivan SD. Thyroid disorders during pregnancy. Med Clin North Am. 2012; 96(2): 235-56. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Baloch ZW, Cibas ES, Clark DP, Layfield LJ, Ljung B, Pitman MB, Abati A. The National Cancer Institute Thyroid fine needle aspiration state of the science conference: a summation. Cytojournal. 2008; 5: 6. PubMed

La'ulu SL, Roberts WL. Second-trimester reference intervals for thyroid tests: the role of ethnicity. Clin Chem. 2007; 53(9): 1658-64. PubMed

Layfield LJ, Abrams J, Cochand-Priollet B, Evans D, Gharib H, Greenspan F, Henry M, LiVolsi V, Merino M, Michael CW, Wang H, Wells SA. Post-thyroid FNA testing and treatment options: a synopsis of the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008; 36(6): 442-8. PubMed

Lockwood CM, Grenache DG, Gronowski AM. Serum human chorionic gonadotropin concentrations greater than 400,000 IU/L are invariably associated with suppressed serum thyrotropin concentrations. Thyroid. 2009; 19(8): 863-8. PubMed

Lyon JL, Alder SC, Stone MB, Scholl A, Reading JC, Holubkov R, Sheng X, White GL, Hegmann KT, Anspaugh L, Hoffman O, Simon SL, Thomas B, Carroll R, Meikle W. Thyroid disease associated with exposure to the Nevada nuclear weapons test site radiation: a reevaluation based on corrected dosimetry and examination data. Epidemiology. 2006; 17(6): 604-14. PubMed

McDonald SD, Walker MC, Ohlsson A, Murphy KE, Beyene J, Perkins SL. The effect of tobacco exposure on maternal and fetal thyroid function. Eur J Obstet Gynecol Reprod Biol. 2008; 140(1): 38-42. PubMed

Pierce M, Sandrock R, Gillespie G, Meikle AW. Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor-guanine nucleotide-binding protein, (GNAS) fusion bioassay. Clin Exp Immunol. 2012; 170(2): 115-21. PubMed

Rawlins ML, Roberts WL. Performance characteristics of six third-generation assays for thyroid-stimulating hormone. Clin Chem. 2004; 50(12): 2338-44. PubMed

Roberts RF, La'ulu SL, Roberts WL. Performance characteristics of seven automated thyroxine and T-uptake methods. Clin Chim Acta. 2007; 377(1-2): 248-55. PubMed

Sandrock T, Terry A, Martin JC, Erdogan E, Meikle WA. Detection of thyroid-stimulating immunoglobulins by use of enzyme-fragment complementation. Clin Chem. 2008; 54(8): 1401-2. PubMed

Silvio R, Swapp KJ, La'ulu SL, Hansen-Suchy K, Roberts WL. Method specific second-trimester reference intervals for thyroid-stimulating hormone and free thyroxine. Clin Biochem. 2009; 42(7-8): 750-3. PubMed

Yue B, Rockwood AL, Sandrock T, La'ulu SL, Kushnir MM, Meikle W. Free thyroid hormones in serum by direct equilibrium dialysis and online solid-phase extraction--liquid chromatography/tandem mass spectrometry. Clin Chem. 2008; 54(4): 642-51. PubMed