Laboratory Evaluation of Thyroid Function

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FEATURE: LAURA M. GUNDER, DHSC, MHE, PA-C,AND SARA HADDOW, MSA, PA-C Laboratory evaluation of thyroid function Blood tests can detect thyroid dysfunction, which can result in cardiac, GI, and menstrual disturbances as well as abnormalities in fetal neural development.

lood tests to measure thyroid function are Myxedema is a skin readily available and widely used.To un- condition caused derstand a test’s scientific basis and what it by the deposition B of hyaluronic acid in can tell us, a quick review of the thyroid gland’s patients with pathophysiology is in order.The major hormone thyroid disease. secreted by the thyroid is thyroxine,also called T4 because it contains four iodine atoms.1 To e xe r t

its effects, T4 is converted to triiodothyronine

(T3) by the removal of an iodine atom.This occurs mainly in the liver and in certain tissues

where T3 acts,such as the brain.The amount of T4 produced by the thyroid is controlled by thyroid- stimulating hormone (TSH), which is produced and released by the pituitary gland.As is the case with many endocrine glands, regulation of the thyroid occurs through a negative feedback loop.

If the pituitary detects very little T4 in the blood, it produces more TSH, which then signals the

thyroid to produce more T4. Once the T4 in the bloodstream rises above a certain level, the pituitary’s production of TSH is shut off,thereby sig-

naling the thyroid to produce less T4.Conditions that interfere with this normal process are cate- gorized as influencing the thyroid either directly or indirectly.Whichever the case, simple blood tests are useful in identifying the most common causes of thyroid dysfunction.

Evaluating thyroid function The serum TSH is the best initial test of thyroid function.The latest generation of this assay has high sensitivity and is an excellent screening tool for those patients with a low pretest probability 2,3 © ISM / PHOTOTAKE of thyroid disease. A TSH of 0.5-4.0 mU/L is

26 THE CLINICAL ADVISOR • DECEMBER 2009 • www.clinicaladvisor.com THYROID FUNCTION A high TSH indicates that the thyroid is failing because of a problem directly affecting the gland. This is known as primary hypothyroidism.

4 highly diagnostic for normal thyroid function.A high TSH thyroid function than FT4. Because the FTI corrects for (>5.0 mU/L is an indication for further testing,such as a free changes in TBGs,it can be used to diagnose thyroid disorders

T4 (FT4) determination or a free thyroxine index (FTI). in patients with protein abnormalities and to monitor their When there is a high pretest probability for thyroid disease, therapy. For example, women who are pregnant have in- e.g.,in the presence of risk factors or clinical signs and symp- creased globulin levels, while persons on certain globulin- toms,initial testing should include a serum TSH as well as an binding drugs,e.g.,phenytoin (Dilantin),may have decreased 2,3 FT4 or an FTI. A patient who has a TSH in the gray zone levels of available globulin.

(4.1–5.0 mU/L) is very likely to develop hypothyroidism and An elevated FT4 or FTI indicates hyperthyroidism, while a 1,4 should be screened regularly.Treatment for subclinical hypo- low FT4 or FTI indicates hypothyroidism. Combining the thyroidism in asymptomatic individuals with TSH <10 mU/L TSH test with the FT4 or FTI accurately determines how the is controversial.2 thyroid is functioning.The finding of an elevated TSH and low

A high TSH indicates that the thyroid is failing because of a FT4 or FTI indicates primary hypothyroidism due to disease in 1 1,4 problem directly affecting the gland. This direct relationship the thyroid itself. A low TSH and low FT4 or FTI indicates is known as primary hypothyroidism. Occasionally, a low secondary hypothyroidism, i.e., a problem outside the thyroid, 1,4 TSH may result from an abnormality in the pituitary that likely involving the pituitary. A low TSH with an elevated FT4 prevents it from making enough TSH to stimulate the thy- or FTI is found in individuals who have hyperthyroidism.1,4 roid.This indirectly caused state is known as secondary hy- (Table 1 summarizes the interpretation of various test results.) pothyroidism. The opposite situation, in which the TSH Continues on page 30 level is low,usually indicates that the person has an overactive thyroid that is producing too much thyroid hormone (hy- TABLE 1.Thyroid function test interpretation perthyroidism).1 In most healthy individuals, a normal TSH Subsequent value means that the thyroid is functioning well and the pa- TSH result Possible diagnoses FT4 result* tient’s condition is considered to be euthyroid.The newest Elevated TSH Low FT Primary hypothyroidism version of the TSH assay is sensitive enough to distinguish (>5 mU/L) 4 hyperthyroidism from the below-normal TSH values ob- Normal FT served in transient circumstances (such as euthyroid sick 4 Subclinical hypothyroidism syndrome).2-4 The TSH is likewise useful for following pa- TSH-mediated hyperthyroidism 2-4 tients on thyroid medication. High FT4 (secondary or tertiary hyperthyroidism) Generally,the serum T4 represents about 90% of circulating 4 Low TSH thyroid hormone. T4 circulates in the blood in two forms:T4 Low FT4 Central hypothyroidism (rare) bound to proteins which prevent the hormone from entering (<0.1 mU/L) Subclinical hyperthyroidism the various tissues that need it and FT4 (not bound to protein), Normal FT4 Check T4; may recheck FT4 and T4 which enters the various target tissues and exerts its effects. every two to three months The FT4 fraction represents only about 5% of total T4 but is Hyperthyroidism or thyrotoxicosis the most important for determining how the thyroid is func- High FT 4 Check RAIU to identify cause tioning since it is the metabolically active form of the hor- 4 mone. Abnormal protein levels can have significant effect on *In some patients, an freethyroxine index (FTI) may provide more information. See text 4 for discussion of FTI. the total T4 results. For example, an increase in thyroxine- FT4=free thyroxine, RAIU=radioactive iodine uptake;TSH=thyroid-stimulating hormone binding globulins (TBGs) will raise the level of total T4,while 4 a decrease in TBG will lower total T4. Note that while Sources: Baskin HJ et al2;Wilson GR and Curry RW8; Demers LM, Spencer CA. Laboratory changes in TBGs,which transport T4 and T3,can affect the lev- Support for the Diagnosis and Monitoring of Thyroid Disease.American Association for Clinical Chemistry; 2002.Available at www.aacc.org/members/nacb/Archive/LMPG els of circulating T4, such alterations may not affect the patient’s metabolic state. /ThyroidDisease/Pages/ThyroidDiseasePDF.aspx.Accessed October 26, 2009; Supit EJ, Peiris AN. Interpretation of laboratory thyroid function tests for the primary care physi- Variations among laboratory test methods and variance in cian. South Med J. 2002;95:481-485. patients’globulin status make the FTI a better indicator of true

www.clinicaladvisor.com • THE CLINICAL ADVISOR • DECEMBER 2009 29 THYROID FUNCTION Consideration of subclinical thyroid disorders is crucial in the presence of abnormal test results regardless of clinical presentation.

T3 tests are often useful to diagnosis hyperthyroidism or to patient with clinical hyperthyroidism, suspect autoimmune determine its severity.Patients who are hyperthyroid will have thyroid disease.1,4 an elevated T3 level.In some patients with a low TSH,only the A summary of the tests used to evaluate thyroid function 1,4 T3 is elevated and the FT4 or FTI is normal. T3 testing rarely appears in Table 2. is helpful in the hypothyroid patient, since it is the last test to become abnormal.1,4 Clinically, this raises the possibility for Which tests to order and when patients to be severely hypothyroid with a high TSH,low FT4 In clinical practice, three basic scenarios indicate a need for or FTI,and a normal T3. laboratory evaluation of thyroid function: (1) suspicion of Some persons produce antibodies against their thyroid that thyroid disease based on clinical signs and symptoms,1-4 either stimulate or damage the gland.The two major anti- (2) screening for thyroid disease,1-6 and (3) evaluation of treat- bodies that interfere with thyroid function are antithyroid ment for thyroid disease.1,4,7,8 peroxidase (anti-TPO) and antithyroglobulin.1,4 Both anti- Working up symptomatic patientsWhen clinical signs bodies are readily detected in the serum. The presence of and symptoms of hypothyroidism or hyperthyroidism (Ta bl e anti-TPO and/or antithyroglobulin antibodies in a patient 3) are present, evaluation of a serum TSH and FTI or FT4 is with clinical hypothyroidism is diagnostic for Hashimoto’s indicated.1,4 Because thyroid dysfunction may develop insidi- thyroiditis.1,4 When these same antibodies are detected in a ously over a long period,consideration of subclinical thyroid

TABLE 2. Summary of blood tests to evaluate thyroid function and their clinical utility

Entity Description Clinical utility tested

TSH Thyroid-stimulating hormone or thyrotropin • Best thyroid function screening test • Initial test for suspected thyroid disease • Used to follow patients on thyroid hormone therapy

• Used in conjunction with T4 to manage patients with Graves’ disease

T4 Serum total thyroxine • Used to make diagnosis of underactive or overactive thyroid when TSH is abnormal • Used with TSH for monitoring patients with Graves’ disease • Newborn screening test for hypothyroidism • Fairly accurate in patients with no protein abnormalities and not pregnant

Free thyroxine is the metabolically active thyroid • Should be ordered when TSH is abnormal to determine thyroid hyperfunction FT 4 hormone – not bound to protein or hypofunction.

• Used for making the diagnosis of thyroid disease in patients with protein Free thyroxine index – measure of free T determined 4 abnormalities and in pregnant patients FTI by measuring thyroxine level and either thyroid- • Used for monitoring therapy in above patient groups with hyperthyroidism binding globulin or hormone-binding ratio

T3 Serum total triiodothyronine • Used to diagnose hyperthyroidism when TSH is low and T4 is still normal

• Antithyroid peroxidase (antimicrosomal) • Used to diagnose suspected Hashimoto’s thyroiditis in hypothyroidism Thyroid antibodies • Used to diagnose autoimmune thyroiditis or Graves’ disease in hyperthyroidism antibodies • Antithyroglobulin antibodies

Sources: Baskin HJ et al2;Wilson GR and Curry RW8; Demers LM, Spencer CA. Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease.American Association for Clinical Chemistry; 2002.Available at www.aacc.org/members/nacb/Archive/LMPG/ThyroidDisease/Pages/ThyroidDiseasePDF.aspx.Accessed October 26, 2009; Supit EJ, Peiris AN. Interpretation of laboratory thyroid function tests for the primary care physician. South Med J. 2002;95:481-485.

30 THE CLINICAL ADVISOR • DECEMBER 2009 • www.clinicaladvisor.com disorders is crucial in the presence of abnormal test results re- TABLE 3. Signs and symptoms of thyroid disease gardless of clinical presentation. Subclinical hyperthyroidism and subclinical hypothyroidism are exclusively laboratory di- Hypothyroidism Hyperthyroidism 7,8 agnoses. Subclinical hypothyroidism should be suspected • Cold intolerance • Heat intolerance when the serum TSH is increased above the upper limit of the • Fatigue • Muscle weakness reference range (>5.0 mU/L) in combination with a normal • Depression • Fine resting tremor 1,5,7,8 T4. Conversely,subclinical hyperthyroidism is likely when • Memory impairment/ • Tachycardia TSH is decreased below the lower limit of the reference range decreased concentration • Palpitations/ 1,5,7,8 (<0.10 mU/L) in the presence of a normal T4 (Table 1). • Weight gain irregular heart rate Screening Patients not previously diagnosed or treated for • Dry skin and dry hair • Fatigue thyroid disease should be screened if they are older than 60 years • Hair loss with increasing • Weight change or if they have a personal history of surgery or irradiation of the coarseness • Increased frequency of stool thyroid or neck, any family history of autoimmune disease, or • Constipation • Irritability an existing thyroid nodule or goiter.3,6 Screening is also indi- • Myalgias • Anxiety cated for those patients who are currently using or who have • Menstrual irregularities • Sleep disturbance a history of long-term use of amiodarone or lithium.3,6 New- • Hoarseness • Ophthalmopathy borns are screened to detect hypothyroidism in infancy by per- • Goiter • Menstrual irregularities • Bradycardia • Myxedema forming a serum T4 level on the blood spot collected shortly after birth;hypothyroidism that is detected early can be treated • Myxedema • Hyperreflexia • Hyperlipidemia and mental retardation or cretinism prevented.2-4 • Delayed return of deep Subclinical hyperthyroidism is estimated to occur in 2% of tendon reflexes the adult population.1,5,7,8 The condition may be due to TSH suppression from an exogenous source or to endogenous pro- Sources: Baskin HJ et al2;Wilson GR and Curry RW8; Fitzgerald PA. Endocrine disorders. In: McPhee SJ, Papdakis MA, eds. Current Medical Diagnosis and Treatment. duction of thyroid hormone that suppresses pituitary TSH 48th ed. New York, NY: McGraw-Hill; 2009:976-1003. 1,2,7,8 production and keeps FT4 and T3 levels normal. Such circumstances may represent the early stages of clinical hyperthyroidism and should be considered a risk factor for the Hypothyroid patients who are started on levothyroxine development of osteoporosis and adverse cardiac manifesta- should have their TSH measured every six to eight weeks to tions, such as atrial fibrillation.1,2 Once the suppressed TSH is guide dose adjustments.2,4 Dosing is considered therapeutic detected, repeat evaluation is needed to document that the once TSH levels reach normal ranges and the patient is no low level is persistent.The American Academy of Clinical En- longer symptomatic.1-4 docrinologists (AACE) recommends that TSH, FT4, and T3 Female patients who become pregnant while taking determinations be repeated two to four months after the ini- levothyroxine should have a TSH level assessed immediately tial discovery of low TSH.1,2 While treatment guidelines for after pregnancy is diagnosed, since the replacement dose of subclinical hyperthyroidism have not been established, pa- levothyroxine will typically increase during pregnancy.1-4 tients who have persistently low TSH levels should be re- These patients will also need TSH assessment at regular inter- evaluated at six-month intervals thereafter.1 Subclinical hypothyroidism occurs in about 5% of the adult AT A GLANCE population, but prevalence may be as high as 20% in women ● 1,5,7,8 The serum thyroid-stimulating hormone is the best initial test older than 60 years. Approximately 5% of patients with of thyroid function. subclinical hypothyroidism will progress to clinical hypothyroidism each year.5,8 Subclinical hypothyroidism increases the ● Abnormal protein levels can have significant effect on the total thyroxine (T ) results. risks for hyperlipidemia, atherosclerosis, and possibly neu- 4 robehavioral disorders.2,5,7,8 Patients with subclinical hypothy- ● Subclinical hyperthyroidism and subclinical hypothyroidism roidism (TSH >5.0 mU/L) should be re-evaluated within are exclusively laboratory diagnoses. three months and then every six months.8 ● Re-evaluate patients with subclinical hypothyroidism within Treatment monitoring The same tests that are used for three months of detection and then every six months. diagnosis of thyroid disease can be used to follow treatment.

www.clinicaladvisor.com • THE CLINICAL ADVISOR • DECEMBER 2009 31 THYROID FUNCTION

vals throughout the pregnancy and postpartum period even if they had stable TSH levels prior to pregnancy.1-4 Left un- treated,maternal hypothyroidism can cause defects of the fetal neural development. Patients with low TSH who are treated for Graves’ disease, thyroid nodules, and thyroiditis may also be monitored using 1-4 TSH and T4 levels at four-week intervals during treatment. Monitoring of such patients should continue until thyroid levels normalize and symptoms resolve.■

Dr.Gunder and Ms.Haddow are assistant professors in the School of Allied Health Sciences at the Medical College of Georgia in Augusta.

References 1. Ladenson P,Kim M.The thyroid. In: Goldman L,Ausiello D, eds. Cecil Medi- “I wasn’t texting.I was building cine. 23rd ed. Philadelphia, Pa.: Saunders; 2007: chap 244. this ship in a bottle.” 2. Baskin HJ, Cobin RH, Duick DS, et al;American Association of Clinical Endocrinologists Thyroid Task Force.American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002; 8:457-469. 3. American Academy of Family Physicians (AAFP). Summary of recommen- dations for clinical preventive services. Revision 6.8. Leawood, Kan.:Ameri- can Academy of Family Physicians (AAFP); October 2009.Available at www.aafp.org/online/etc/medialib/aafp_org/documents/clinical/CPS /rcps08-2005.Par.0001.File.tmp/Oct2009RCPSwithedits.pdf. 4. Wu A, ed. Teitz Clinical Guide to Laboratory Tests.4th ed. Philadelphia, Pa.: Saunders; 2006. 5. U.S. Preventive Services Task Force. Screening for thyroid disease: recom- mendation statement. Ann Intern Med. 2004;140:125-127.Available at www.annals.org/cgi/reprint/140/2/125.pdf. “You smell like a chimney.” 6. Vanderpump MP,Tunbridge WM, French JM, et al.The incidence of thyroid disorders in the community: a twenty-year follow up of the Wickham Sur- vey. Clin Endocrinol (Oxf). 1995;43:55-68. 7. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228- 238.Available at jama.ama-assn.org/cgi/content/full/291/2/228. 8. Wilson GR, Curry RW.Subclinical thyroid disease. Am Fam Physician. 2005; 72:1517-1524.Available at www.aafp.org/afp/20051015/1517.html.

All electronic documents accessed November 10, 2009.

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