Indications for Testing

• Symptoms of hyper- or hypothyroidism, family history of autoimmune thyroiditis, goiter on physical exam

Laboratory Testing

• Initial evaluation for thyroid disease – TSH
  • TSH elevated – suggests hypothyroidism
    • Order free T4
      • Low – hypothyroidism confirmed
        • Consider thyroid antibody testing
      • Normal – consider T3 testing
        • Low T3 – hypothyroidism confirmed
        • Normal T3 – subclinical hypothyroidism suspected if TSH minimally elevated
  • TSH low – suggests hyperthyroidism
    • Order free T4
      • High – hyperthyroidism confirmed
      • Normal – consider T3 testing
        • Normal – 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 normal; free T3, T4 may be low

Differential Diagnosis

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

• 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
    • However, 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

• 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 are 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 or cause gland destruction that subsequently leads to underproduction of hormones.

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
    • 1-2% 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

  Hypothyroidism – caused by underproduction of hormones Etiologies Autoimmunity – Graves disease, Hashimoto disease Iatrogenic (treatment of 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 is common Fatigue, depression, cold intolerance, weight gain, bradycardia, constipation, hair loss, alopecia, carpal tunnel syndrome, dry/coarse skin, skin thickening (myxedema) Most serious manifestation is myxedema coma Congenital disease Growth retardation Developmental delay/mental retardation

• Hyperthyroidism (thyrotoxicosis)

  Hyperthyroidism – caused by overproduction of thyroid hormones 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 – thyroid stimulating hormone (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) Treatment Usually required

• 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 have not been well established in pregnant patients – some research recommends use of total T4 in place of free T4 during pregnancy TSH falls – may be below the lower adult reference limit in 20% of pregnancies Hypothyroidism 0.3-0.7% of pregnancies Associated with infertility, low birth weight, low fetal IQ, fetal demise, hypertension, placenta abruptio and postpartum hemorrhage (fetus may be unaffected) Symptoms – low energy, inappropriate weight gain, constipation, goiter, cold intolerance and bradycardia Most common cause – chronic autoimmune thyroiditis Hyperthyroidism 0.2% of pregnancies Associated with spontaneous abortions, infertility, still births, low birth weight, pre-term delivery, fetal or neonatal hyperthyroidism, congestive heart failure in mother 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 and eye changes Causes Gestational transient thyrotoxicosis Hyperemesis gravidarum – frequently associated with gestational transient thyrotoxicosis Trophoblastic tumors such as choriocarcinoma TSH receptor mutations

Tests generally appear in the order most useful for common clinical situations

Guidelines

• ACOG Committee Opinion No. 381: Subclinical hypothyroidism in pregnancy. Obstet Gynecol. 2007; 110 (4) :959-960.PubMed
• ACR Appropriateness Criteria® neuroendocrine imaging. American College of Radiology - Medical Specialty Society. 1999 (Revised 2008). NGC:007007
• Demers Laurence M, Spencer Carol A. LABORATORY MEDICINE PRACTICE GUIDELINES Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. The National Academy of Clinical Biochemistry. [Accessed: 22 Jul 2009] 
• Routine Thyroid Screening Not Recommended for Pregnant Women. American College of Obstetricians and Gynecologists 2007 ACOG News Release. [Accessed: 29 Sep 2011] 

General

• Balestrieri GP. Primary or secondary hypothyroidism?. J Am Geriatr Soc. 2008; 56 (7) :1377-.PubMed
• DeBoer MD, Lafranchi SH. Pediatric thyroid testing issues. Pediatr Endocrinol Rev. 2007; 5 Suppl 1 :570-577.PubMed
• Dominguez LJ, Bevilacqua M, Dibella G, Barbagallo M. Diagnosing and managing thyroid disease in the nursing home. J Am Med Dir Assoc. 2008; 9 (1) :9-17.PubMed
• Gartner R. Thyroid diseases in pregnancy. Curr Opin Obstet Gynecol. 2009; 21 (6) :501-507.PubMed
• Glinoer D, Spencer CA. Serum TSH determinations in pregnancy: how, when and why?. Nat Rev Endocrinol. 2010; 6 (9) :526-529.PubMed
• LaFranchi SH. Newborn screening strategies for congenital hypothyroidism: an update. J Inherit Metab Dis. 2010; 33 (Suppl 2) :S225-S233.PubMed
• Lazarus JH. Thyroid function in pregnancy. Br Med Bull. 2011; 97 (1) :137-148.PubMed
• Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy. BMJ. 2008; 336 (7645) :663-667.PubMed
• Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab Clin North Am. 2007; 36 (3) :617-56, v.PubMed
• Nygaard B. Hyperthyroidism. Am Fam Physician. 2007; 76 (7) :1014-1016.PubMed
• Pantalone KM, Nasr C. Approach to a low TSH level: patience is a virtue. Cleve Clin J Med. 2010; 77 (11) :803-811.PubMed
• Shih JL, Agus MS. Thyroid function in the critically ill newborn and child. Curr Opin Pediatr. 2009; 21 (4) :536-540.PubMed
• Todd CH. Management of thyroid disorders in primary care: challenges and controversies. Postgrad Med J. 2009; 85 (1010) :655-659.PubMed
• Tonacchera M, Pinchera A, Vitti P. Assessment of nodular goitre. Best Pract Res Clin Endocrinol Metab. 2010; 24 (1) :51-61.PubMed
• Wilcken B, Wiley V. Newborn screening. Pathology. 2008; 40 (2) :104-115.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Baloch ZW, Cibas ES, Clark DP, Layfield LJ, Ljung BM, 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) :1658-1664.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) :442-448.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) :863-868.PubMed
• Lyon JL, Alder SC, Stone MB, Scholl A, Reading JC, Holubkov R, Sheng X, White GL Jr, Hegmann KT, Anspaugh L, Hoffman FO, Simon SL, Thomas B, Carroll R, Meikle AW. 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) :604-614.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
• Rawlins ML, Roberts WL. Performance characteristics of six third-generation assays for thyroid-stimulating hormone. Clin Chem. 2004; 50 (12) :2338-2344.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) :248-255.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) :1401-1402.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) :750-753.PubMed
• Yue B, Rockwood AL, Sandrock T, La'ulu SL, Kushnir MM, Meikle AW. Free thyroid hormones in serum by direct equilibrium dialysis and online solid-phase extraction--liquid chromatography/tandem mass spectrometry. Clin Chem. 2008; 54 (4) :642-651.PubMed

Autoimmune Thyroid Disease
Gestational Trophoblastic Disease
Hypopituitarism
Osteoporosis
Thyroid Cancer