Thyroid Disorder Laboratory Testing

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Thyroid Disorder Laboratory Testing

MOL.CS.320.X

v1.0.2022 Introduction

Laboratory testing for thyroid disorders is addressed by this guideline.

Procedures addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's

procedure code list for management requirements.

Procedure addressed by this guideline Procedure code TSH receptor antibodies (TRAb) 83519

TSH receptor antibodies (TRAb) 83520

Thyroglobulin 84432

Thyroxine (T4), Total 84436

Thyroxine (T4) requiring elution (e.g.

neonatal thyroxine)

84437

Free Thyroxine (free T4) 84439

Thyroxine Binding Globulin 84442 Thyroid Stimulating Hormone (TSH;

Thyrotropin)

84443 Thyroid Stimulating Immunoglobulins

(TSI)

84445 Thyroid hormone (T3 OR T4) uptake or

thyroid hormone binding ratio (THBR) 84479

Triiodothyronine (T3) 84480

Free Triiodothyronine (free T3) 84481

Reverse T3 84482

Microsomal (Thyroid peroxidase) antibodies

86376

Thyroglobulin antibody 86800

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What are thyroid diseases?

Definition

The two predominant forms of thyroid dysfunction are hypothyroidism and

hyperthyroidism. The clinical manifestations of hypothyroidism or hyperthyroidism are broad, common and nonspecific.

The American Association for Clinical Chemistry (AACC) describes the functioning and interaction of the following hormones and binding proteins:¹

 Thyroid hormones: thyroxine (T4) and triiodothyronine (T3) and their binding proteins, thyroglobulin in the thyroid and thyroxine binding globulin (TBG) in the circulation.

 Pituitary hormone: thyroid stimulating hormone (TSH also known as Thyrotropin).

 Hypothalamic hormone: thyrotropin releasing hormone (TRH).

The feedback loop controlling the hormones involves both the central nervous system and the thyroid gland.¹

 “The body has an elaborate feedback system to control the amount of T4 and T3 in the blood. When blood levels of the hormones decrease, the hypothalamus

releases thyrotropin-releasing hormone, which in turn causes the pituitary gland to release thyroid-stimulating hormone (TSH). TSH stimulates the thyroid gland to produce and secrete T4 (primarily) and T3. When the system is functioning normally, thyroid production turns on and off to maintain relatively stable levels of thyroid hormones. Inside the thyroid, most of the T4 is stored bound to a protein called thyroglobulin. When the need arises, the thyroid gland produces more T4 and/or releases some of what is stored. In the blood, most T4 and T3 are bound to a protein called thyroxine-binding globulin (TBG) and are relatively inactive. The small amounts that are unbound, called free T4 or free T3, are the active forms of the hormone. T4 is converted to T3 in the liver and other tissues. T3 is primarily responsible for controlling the rate of body functions.”

Hypothyroidism

Overt hypothyroidism affects approximately 0.5% of the population of the United States.^2-4 Subclinical hypothyroidism, which is defined as a normal free thyroxine (free T4) concentration despite an elevated thyroid stimulating hormone (TSH) concentration occurs in an estimated 3-5% of the population.^4,5 Individuals with subclinical

hypothyroidism are at enhanced risk for progression to overt hypothyroidism. This is the basis for clinically monitoring individuals with subclinical hypothyroidism.^4,6

There are several causes of hypothyroidism.^4,7 The most common in the United States is Hashimoto’s thyroiditis, an autoimmune disease that causes destruction of the thyroid. Hashimoto’s thyroiditis is associated with autoantibodies which were originally known as microsomal antibodies and which are now known to be anti-thyroid

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peroxidase antibodies (TPOAbs); identifying these antibodies is clinically helpful in confirming a diagnosis of hypothyroidism secondary to Hashimoto’s thyroiditis.^1,4,7-10 Other causes of hypothyroidism include surgical removal of all or part of the thyroid (as occurs in treatment of thyroid cancers), radiation therapy to the thyroid (which is also a treatment for cancer), treatment with antithyroid drugs for hyperthyroidism, and

medications such as lithium. Iodine deficiency is a rare cause of hypothyroidism in the United States but the most common cause in developing countries. Much less

commonly, hypothyroidism can be caused by disorders of the hypothalamus or pituitary; this is known as “secondary” hypothyroidism.⁴

Hyperthyroidism

The prevalence of hyperthyroidism in the United States is 0.5% for overt

hyperthyroidism and 0.7% for subclinical hyperthyroidism.¹¹ Subclinical hyperthyroidism is defined as a low serum TSH while both T3 and free T4 values are within the

reference range. The most common cause of hyperthyroidism in the United States is Grave’s disease followed by nodular thyroid disease. Grave’s disease is an

autoimmune disease usually caused by Thyrotropin Receptor Antibodies (TRAbs), also referred to as Thyroid Stimulating Immunoglobulins (TSI). These activate TSH

receptors leading to thyroid overstimulation. These autoantibodies are clinically useful in confirming a diagnosis of hyperthyroidism.^1,9-11 Nodular thyroid disease can cause hyperthyroidism when the nodule or nodules becomes autonomous and starts overproducing thyroxine.^11-13

Other less common causes of hyperthyroidism include iodine-induced hyperthyroidism and hyperthyroidism induced by a variety of medications, including lithium, cytokines, tyrosine kinase inhibitors and amiodarone. Disorders of the hypothalamus or pituitary, such as a TSH secreting tumor of the pituitary, are rare causes of hyperthyroidism and these are known as “secondary” hyperthyroidism.¹¹

Thyroid nodules

The evaluation and management of thyroid nodules have been outlined by the American Thyroid Association (ATA) guidelines in adults and children.^12,13 These guidelines have summarized the prevalence of thyroid nodules, the frequency with which they are malignant, and the prevalence of various kinds of malignancy. In adults, thyroid nodules are common but rarely malignant. Children have nodules much less frequently than adults, but the nodules have a higher likelihood of malignancy. In general, in both children and adults, thyroid nodules of >1cm in diameter should be further evaluated and laboratory testing has an important role in this process. More than 95% of thyroid malignancies are differentiated thyroid cancers (DTCs) of the papillary or follicular type. These tend to be treatable and have an excellent long-term prognosis. There are three main treatments - surgery (thyroidectomy or partial

thyroidectomy), radioactive iodine, or anti-thyroid drugs—with surgery being primary and other treatments used as adjuncts or when necessary. Medullary or anaplastic carcinomas constitute <5% of thyroid cancers and have a worse prognosis. Laboratory testing plays an important role in managing thyroid cancers of all types.

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Test Information

Introduction

The laboratory tests discussed in this guideline play a foundational role in the diagnosis and monitoring of thyroid disease.4,7,8,11-14 Screening for thyroid disease is useful because hypothyroidism and hyperthyroidism are common; the laboratory tests used for screening are inexpensive, reasonably accurate and precise; and the

treatment is generally safe, effective and relatively inexpensive. Similarly, many of the tests are also useful for monitoring thyroid disease due to their safety and cost

effectiveness.

Thyroid Stimulating Hormone (TSH, Thyrotropin)

Although there are many laboratory tests to biochemically assess thyroid function and disease, by far the most useful and most frequently ordered is thyroid stimulating hormone (TSH), also known as thyrotropin.⁷ TSH is useful as the primary screening test and monitoring test for both hypothyroidism and hyperthyroidism, and it is also important in monitoring and risk stratifying thyroid cancer.¹² When screening, a TSH within the reference range, by itself, rules out hyperthyroidism and hypothyroidism in most cases.^4,11,15 In addition, the test is used to monitor the effectiveness of thyroid related therapy for both hyperthyroidism and hypothyroidism. These treatments include thyroid hormone replacement, partial or complete thyroidectomy, radioactive iodine, and pharmaceuticals to reduce or increase thyroid hormone production.^4,11-13,15 The test is performed by automated immunoassay and there are many FDA approved

laboratory instruments that can measure TSH accurately and precisely.

Thyroxine (T4)

After TSH, thyroxine is the most common and useful thyroid function test. Thyroxine is sometimes used with TSH as the primary screening and monitoring tests for both hypothyroidism and hyperthyroidism. In addition, like TSH, the test is used commonly to monitor the effectiveness of thyroid related therapies.^4,11-13,15 As a screening test, TSH and thyroxine within the reference range rule out hypothyroidism or

hyperthyroidism. In some cases of hyperthyroidism, a T3 within the reference range is also needed to rule out hyperthyroidism.¹¹ Elevated T4 with low TSH generally

suggests primary hyperthyroidism and reduced T4 with an elevated TSH indicates primary hypothyroidism. These findings are usually accompanied by characteristic symptoms. Secondary hypothyroidism or hyperthyroidism is rare and refers to thyroid dysfunction that is caused by pathology extrinsic to the thyroid gland. This is usually emanating from the central nervous system (CNS) as opposed to an ectopic location somewhere else in the body. The CNS pathology is most commonly a pituitary tumor and more rarely a tumor of the hypothalamus. In secondary hypothyroidism, the TSH and T4 are low, and in secondary hyperthyroidism the TSH and T4 are elevated. When monitoring therapies aimed at normalizing thyroid function, the overall goal is to

normalize TSH or T4 levels in or near the reference range.

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In non-pregnant individuals, serum free thyroxine (free T4) is the primary test used to confirm a suspected diagnosis of thyroid dysfunction and then monitor treatment.^4,11-13 This test is done by automated immunoassay and there are many FDA-approved laboratory instruments. In practice, the automated immunoassay for free T4 has

minimized the need for the T4 by elution test, which is a complex method for producing a free T4 result based on high performance liquid chromatography (HPLC) with mass spectrometry.

Thyroxine, with thyroid hormone (T3 or T4) resin uptake or thyroid hormone binding ratio

In pregnant individuals, total thyroxine (total T4) is generally more useful than free T4 unless trimester specific reference ranges for free T4 are available and the method of measurement remains constant throughout pregnancy.¹⁴ In pregnant individuals, the total T4 is often used to calculate a free thyroxine index (FTI). It is a calculated quantity that estimates free T4 by multiplying the total T4 by the result of the T3 resin uptake assay. A version of T3 resin uptake (based on normalization), known as a thyroid binding hormone ratio (THBR) can replace the T3 resin uptake in the calculation.⁸ The purpose of the T3 resin uptake or THBR test is to give an estimate of the number of binding sites available on thyroxine binding globulin, which is the main transport protein for T4. T3 resin uptake and THBR are measured by immunoassay.

Triiodothyronine (T3)

T3 is produced from T4 in the liver and T3 is primarily what influences end organs and creates the clinical effects of hyperthyroidism and hypothyroidism. T3 is generally not used for screening for thyroid dysfunction.^4,9-11,15 However, in some less common cases of hyperthyroidism, a T3 within the reference range is also needed to rule out

hyperthyroidism.¹¹ In general, T3 is elevated in hyperthyroidism and decreased in hypothyroidism. The test comes in two forms. The first is a total T3, which is done by an automated immunoassay performed on a variety of FDA-approved instruments. The second test is a free T3 which measures the active unbound T3 and is done by a more cumbersome immunoassay. In practice, the tests can be used interchangeably in most, but not all, clinical situations and the total T3 is used preferentially for convenience.^9-11 TSH receptor antibodies (TRAb) and Thyroid Stimulating Immunoglobulins (TSI) The main purpose of TRAb testing is to confirm a diagnosis of Grave’s disease. TRAb can be measured by a number of laboratory techniques, some of which are coded as automated immunoassays, performed on a variety of FDA-approved platforms.⁷ Alternatively, an older but very useful measurement of TRAbs is called thyroid stimulating immunoglobulins (TSI) which is performed by immunoassay.¹¹ Microsomal Antibodies (also known as anti-Tissue Peroxidase antibodies (TPOAb))

TPOAb (microsomal antibodies) testing is not a recommended screening test for either hypothyroidism or hyperthyroidism.^4,11 A positive TPOAb test is used commonly to

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confirm a diagnosis of Hashimoto’s thyroiditis in individuals who have screened

positive for hypothyroidism by virtue of an elevated TSH and depressed T4.^4,9 Another common use of TPOAb is to identify individuals at risk for progression to overt

hypothyroidism caused by Hashimoto’s thyroiditis in those with subclinical

hypothyroidism based on the initial screening evaluation of an elevated TSH and T4 within the reference range.⁴ Other uses concern determining if thyroid nodules are due to an autoimmune process or if recurrent miscarriage is related to autoimmune

hypothyroidism.^4,14 A rare use is as a secondary marker in Grave’s disease if the clinical index of suspicion is high and the TRAb and TSI testing is indeterminate.^10,11 The test is performed by immunoassay.

Thyroxine Binding Globulin

Thyroxine binding globulin (TBG) is the main transport protein for the thyroid

hormones, T3 and T4. It is not used for screening for thyroid disease.^4,9-11 It is a rarely used test that can occasionally be useful in interpreting T3 or T4 values that do not match the clinical presentation and are therefore diagnostic conundrums.^9,10 Such situations can arise in inherited and other diseases that affect the level of thyroxine binding globulin. The test is performed by immunoassay.

Thyroglobulin (Tg) and Thyroglobulin Antibody (anti-Tg Ab)

The main use of Tg and anti-Tg Ab testing is in the staging and monitoring of differentiated thyroid cancers (DTC), over 97% of which are classified as papillary carcinoma (85%) or follicular thyroid carcinomas (12%).^12,13 Tg is a useful tumor marker for staging the cancer and monitoring treatment. Anti-Tg Ab must be measured prior to measuring Tg as Anti-Tg Ab occurs in up to 25% of individuals, and in their presence can interfere with the Tg assay. Individuals who have Anti-Tg Abs detected then are directed to use a more complex measurement of thyroglobulin based on mass spectrometry or radioimmunoassay (RIA) rather than usual first-line thyroglobulin measurement, which is by immunoassay when no Anti-Tg Abs are detected.^9,10,12,16 Tg or anti-Tg Ab testing has no role in screening for hypothyroidism or hyperthyroidism.^4,9-

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Reverse T3

The utility of reverse T3 remains controversial.¹⁷ Reverse T3 is not a recommended screening test for either hypothyroidism or hyperthyroidism.^4,11 In addition, reverse T3 does not appear as either a screening or confirmatory test in standard algorithms for evaluating thyroid dysfunction, nor does it appear in academic reviews of useful thyroid testing.^7-10 The test is performed by tandem mass spectrometry.

“Reverse T3 (rT3) is an inactive metabolite of thyroxine. It is widely measured by

alternative health practitioners to justify the use of T3 therapy and supplements thought to enhance the conversion of T4 to T3. It has extremely limited utility for conventional medical practitioners for assessing rare conditions such as consumptive

hypothyroidism, MCT8 or SBP2 mutations, or possibly distinguishing central hypothyroidism from nonthyroidal illness in critically ill hospitalized patients.” ⁸

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Guidelines and Evidence

Introduction

There are a number of guidelines, expert reviews, and algorithms from academic practices and professional societies related to the function, diagnosis and screening of thyroid disorders.1,4,5,7-15,18 These also discuss the evaluation and management of

thyroid nodules and associated malignancies and the further evaluation and monitoring of individuals who are confirmed to have overt or subclinical thyroid disease after

screening.

Screening for Thyroid Disease

There is a continuum of screening between population screening for thyroid disease and “aggressive case finding.”^18,19 In population screening, all of the population, or a large part of it, are screened by laboratory testing. In aggressive case finding, people are screened based on criteria indicating they are at risk for a disease.¹⁹

Garber and colleagues (2012) published guidelines for the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA), which were endorsed by the American Association of Diabetes Educators, the American Academy of Otolaryngology-Head and Neck Surgery, and the American College of Endocrinology (ACE).⁴ According to these guidelines, there is no consensus among panels of experts regarding population screening for thyroid dysfunction.⁴

 “expert panels have disagreed about TSH screening of the general population.”

The United States Preventive Services Task Force (USPSTF) concluded:¹⁸

 “that the current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant, asymptomatic adults.”

In contrast, the joint AACE/ATA guidelines recommend screening:⁴

 “Screening for hypothyroidism should be considered in patients over the age of 60.”

There is widespread agreement that “aggressive case finding” is useful to detect thyroid dysfunction. This means that screening is considered useful in a large variety and number of individuals with enhanced risk for either hyperthyroidism or

hypothyroidism based on their history and physical.^4,19

Hennessey and colleagues wrote the official position of the AACE and ACE regarding the importance of aggressive case finding for both hypothyroidism and

hyperthyroidism.¹⁹ This was in response to the USPSTF conclusion regarding insufficient evidence to support population screening.¹⁸ They emphasized the

importance of laboratory testing for aggressive case finding in thyroid dysfunction since the testing is effective and inexpensive treatments are often available.

 “Given the lack of specificity of thyroid-associated symptoms, the appropriate diagnosis of thyroid disease requires biochemical confirmation. The Thyroid

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Scientific Committee of the AACE has produced this White Paper to highlight the important difference between screening and case-based testing in the practice of clinical medicine. We recommend that thyroid dysfunction should be frequently considered as a potential etiology for many of the nonspecific complaints that physicians face daily. The application and success of safe and effective

interventions are dependent on an accurate diagnosis. We, therefore, advocate for an aggressive case-finding approach, based on identifying those persons most likely to have thyroid disease that will benefit from its treatment.”

The ATA guideline on thyroid nodules in adults and children strongly supports laboratory testing with TSH in individuals with a thyroid nodule >1cm in diameter.^12,13

 “Serum thyrotropin (TSH) should be measured during the initial evaluation of a patient with a thyroid nodule.”¹²

The joint AACE/ATA task force completed an exhaustive literature review and provided a list of findings that support aggressive case finding with laboratory testing for

hypothyroidism. These findings include, but are not limited to:⁴

 A history of coexisting autoimmune disorders such as Type 1 Diabetes or pernicious anemia

 A family history of autoimmune thyroid disease in a first-degree relative

 Abnormal thyroid exams

 Previous thyroid surgery or thyroid disease

 History of radiation treatment to the thyroid (beam radiotherapy and/or radioactive iodine)

 Current treatment with lithium or amiodarone

 Presence of a psychiatric disorder

 Infertility

 A large and varied list of ICD codes describing alopecia, fatigue and malaise, weight gain, skin texture changes, vitiligo, disorders of menstruation, and a number of cardiac findings including rhythm abnormalities, EKG changes such as a

prolonged QT interval, or the presence of congestive heart failure.

The joint AACE/ATA guideline goes on to state:⁴

 “Aggressive case finding” should be considered in those at increased risk for hypothyroidism.”

The recommendations for aggressive case finding in pregnant individuals or individuals seeking to become pregnant are quite similar in the joint AACE/ATA guideline, as well as in a separate guideline from the ATA that is specific to thyroid disease in pregnancy and the postpartum period.^4,14 These guidelines recommend against universal

screening of pregnant individuals or those planning pregnancy, but recommend

aggressive case finding in pregnant individuals with any of the many signs, symptoms,

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and comorbid conditions associated with hypothyroidism. This recommendation also includes any individuals seeking care for infertility.^4,14

Guidelines from the American College of Obstetricians and Gynecologists (ACOG) have similar guidance recommending against universal screening of thyroid disease in pregnant individuals:²⁰

 “Universal screening for thyroid disease in pregnancy is not recommended because identification and treatment of maternal subclinical hypothyroidism has not been shown to result in improved pregnancy outcomes and neurocognitive function in offspring.”

In addition, the ATA guideline regarding thyroid disease in pregnancy and the postpartum period recommends universal newborn screening:¹⁴

 “All newborns should be screened for hypothyroidism by blood spot analysis typically 2-5 days after birth.”

Based on the guidance of expert panels, testing for an initial diagnosis of a thyroid disease (whether it be hypothyroidism, hyperthyroidism, or the evaluation of thyroid nodules) will be fairly common given the high prevalence of treatable disease in the population and the wide variety of signs, symptoms, and comorbid conditions

associated with thyroid diseases. However, one clinical guideline has recommended against treatment of subclinical hypothyroidism in most persons, citing no clinical benefit.²¹

Specific thyroid tests for screening for and monitoring thyroid disease Thyroid Stimulating Hormone (TSH, Thyrotropin)

Thyroxine (T4)

 Thyroxine T4, Total

 Thyroxine T4 requiring elution

 Free Thyroxine (free T4)

Thyroid Hormone (T3 or T4) Uptake or Thyroid Hormone Binding Ratio (THBR) Triiodothyronine (T3)

 Triiodothyronine (T3)

 Free Triiodothyronine (T3)

Judicious test use in the screening for thyroid disease

The joint ASCP-Choosing Wisely guidance regarding screening for thyroid dysfunction states:¹⁵

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 "Don't order multiple tests in the initial evaluation of a patient with suspected non- neoplastic thyroid disease. Order thyroid-stimulating hormone (TSH), and if abnormal, follow up with additional evaluation or treatment depending on the findings. The TSH test can detect subclinical thyroid disease in patients without symptoms of thyroid dysfunction. A TSH value within the reference interval excludes the majority of cases of primary overt thyroid disease. If the TSH is abnormal,

confirm the diagnosis with free thyroxine (T4)."

According to the current ATA guideline for hyperthyroidism screening, TSH is the best single test to diagnose hyperthyroidism, and in some cases with higher pretest

probability of disease, the diagnosis is aided by adding measurement of free T4 and T3.¹¹ The guideline makes the following statements regarding initial biochemical evaluation by laboratory testing:¹¹

 “Serum TSH measurement has the highest sensitivity and specificity of any single blood test used in the evaluation of suspected thyrotoxicosis and should be used as an initial screening test. However, when thyrotoxicosis is strongly suspected,

diagnostic accuracy improves when a serum TSH, free T4, and total T3 are assessed at the initial evaluation.”

Regarding testing in addition to TSH that can be useful for screening individuals at risk for hypothyroidism, the joint recommendation of AACE/ATA concluded the following for individuals who are not pregnant:⁴

 “Apart from pregnancy, assessment of serum free T4 should be done instead of total T4 in the evaluation of hypothyroidism. An assessment of serum free T4 includes a free T4 index or free T4 estimate and direct immunoassay of free T4 without physical separation using anti-T4 antibody.”

The AACE/ATA task force goes on to declare that T3 measurements are not normally indicated in screening for hypothyroidism:⁴

 “Serum total T3 or assessment of serum free T3 should not be done to diagnose hypothyroidism.”

In addition, for pregnant individuals, the AACE/ATA guidelines make the following modifications for screening for hypothyroidism because of the difficulty of accurately measuring free T4 during some pregnancies:⁴

 “In pregnancy, the measurement of total T4 or a free T4 index, in addition to TSH, should be done to assess thyroid status. Because of the wide variation in the results of different free T4 assays, direct immunoassay measurement of free T4 should only be employed when method-specific and trimester-specific reference ranges for serum free T4 are available.”

Monitoring thyroid function and disease

TSH is the most commonly used test for monitoring therapy for thyroid diseases. T4 and T3 play a less frequent but important role. A variety of guidelines explain the

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plethora of uses of these tests for monitoring the thyroid in the context of treatments for thyroid diseases.

For example, in non-pregnant individuals who have hypothyroidism:⁴

 “Patients being treated for established hypothyroidism should have serum TSH measurements done at 4-8 weeks after initiating treatment or after a change in dose. Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise.”

 “Assessment of serum free T4, in addition to TSH, should be considered when monitoring L-thyroxine therapy.”

In non-pregnant individuals with hyperthyroidism caused by Grave’s disease (GD) and being treated with radioactive iodine (RAI):¹¹

 “Follow-up within the first 1-2 months after RAI therapy for GD should include an assessment of free T4 and total T3 and TSH. Biochemical monitoring should be continued at 4-to-6 week intervals for 6 months, or until the patient becomes hypothyroid and is stable on thyroid replacement.”

In hypothyroidism of pregnancy being treated by L-thyroxine:

 “Maternal serum TSH (and total T4) should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation and L- thyroxine dosages adjusted as indicated.”⁴

 “In parallel to the treatment of hypothyroidism in the general population, it is reasonable to target a TSH in the lower half of the trimester specific range. When this is not available, it is reasonable to target maternal TSH concentrations below 2.5 mU/L.”¹⁴

In Grave’s Disease (GD) related hyperthyroidism of pregnancy being treated by anti- thyroid drugs (ATD):¹¹

 “GD during pregnancy should be treated with the lowest possible dose of ATD needed to keep the mother’s thyroid hormone levels at or slightly above the reference range for total T4 and T3 values in pregnancy (1.5 times above nonpregnant reference ranges in the second and third trimesters), and the TSH below the reference range for pregnancy. Similarly, free T4 levels should be kept at or slightly above the upper limit of the pregnancy trimester reference range for the assay. Thyroid function should be assessed at least monthly, and the ATD dose adjusted, as required.”

Lastly, in thyroid cancer, the most common therapy for differentiated thyroid cancers is full or partial thyroidectomy. The standard of care, as expressed in the ATA guideline, is chronic monitoring of TSH and, to a lesser extent, T4 with the goal of establishing and maintaining adequate thyroid function with levothyroxine therapy after surgical treatment.¹² In addition, TSH measurement is part of the risk stratification strategy in

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the guideline. The risk stratification is carried out multiple times over the course of cancer monitoring.

Antibody tests

TSH receptor antibodies (TRAb)

Thyroxine Stimulating Immunoglobulins (TSI) Microsomal Antibodies (also known as TPOAbs)

TRAb/TSI

As described above, the current ATA guideline for hyperthyroidism screening states TSH is the best single test to diagnose hyperthyroidism.¹¹ In some cases with higher pretest probability of disease, the diagnosis is aided by adding

measurements of free T4 and T3. The guideline goes on to recommend confirmatory laboratory testing for Grave’s Disease using TRAb and other confirmatory diagnostics if:

o “the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation”

Besides its use in confirmatory testing, TRAb is also used to monitor Grave’s disease.

For example, in individuals with Grave’s disease being treated with anti-thyroid drugs (ATD), the ATA guideline states:¹¹

o “Measurement of TRAb levels prior to stopping ATD therapy is suggested

because it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission.”

And for pregnant women, the ATA guideline states:¹⁴

o “If a patient is taking ATDs for treatment of Grave’s hyperthyroidism when pregnancy is confirmed, a maternal serum determination of TRAb is recommended.”

o “If the patient requires treatment with ATDs for GD through midpregnancy, a repeat determination of TRAb is again recommended at weeks 18-22." This aforementioned guidance is also supported by the European Thyroid

Association.²² TPOAb

The AACE/ATA guideline for hypothyroidism states the main use of TPOAb, which is now incorporated in published algorithms is to identify the inciting event.^4,9,10 o “in patients with documented hypothyroidism, TPOAb identifies the cause”⁴ In addition, the guideline recommends using TPOAb as a confirmatory diagnostic test in individuals who have subclinical hypothyroidism, based on the initial screening

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evaluation with TSH and free T4, since TPOAb identifies individuals at risk for progression to overt hypothyroidism caused by Hashimoto’s thyroiditis. The recommendation states:⁴

o “Anti-thyroid peroxidase antibody (TPOAb) measurements should be considered when evaluating patients with subclinical hypothyroidism.”

Other recommendations from the guideline regard using TPOAb to help determine if an autoimmune hypothyroidism, either subclinical or overt, is causing thyroid nodules or recurrent miscarriage.⁴

o “TPOAb measurement should be considered in order to identify autoimmune thyroiditis when nodular thyroid disease is suspected to be due to autoimmune thyroid disease.”

o “TPOAb measurements should be considered when evaluating patients with recurrent miscarriage.”

In the treatment of primary hypothyroidism, the ATA guideline focuses on TSH levels as a therapeutic endpoint with selected use of T4. TPOAb are not mentioned regarding monitoring autoimmune hypothyroidism because once a person has TPOAb, they persist throughout life despite successful treatment.⁴

o “Once present, these antibodies generally persist, with spontaneous disappearance occurring infrequently.”

Thyroglobulin and Thyroglobulin Antibody Thyroglobulin

Thyroglobulin Antibody

Thyroglobulin is not a recommended screening test for either hypothyroidism or hyperthyroidism.^4,11 In addition, thyroglobulin is not recommended in the initial

evaluation of a thyroid nodule by the ATA guidelines regarding thyroid nodules in adults or children.^12,13

 “Routine measurement of serum thyroglobulin (Tg) for initial evaluation of thyroid nodules is not recommended.”

 “Serum Tg levels can be elevated in most thyroid diseases and are an insensitive and nonspecific test for thyroid cancer.”

The ATA guidelines regarding thyroid nodules for adults and children summarize the characteristics and uses of thyroglobulin (Tg) and thyroglobulin antibody (TgAb) testing.^12,13 The main use of thyroglobulin is in the postoperative staging and risk stratification of thyroid malignancies, which can guide future disease monitoring and treatment. The guideline in children regarding differentiated thyroid cancer (DTC) states:¹³

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 “..the measurement of serum Tg is a critical component in the management of the pediatric DTC patient, both at the time of the initial postoperative staging…as well as during long term surveillance and subsequent restaging…”

Similarly, the adult guideline for DTC also addresses using Tg for surveillance:¹²

 “Postoperative serum Tg (on thyroid hormone therapy or after TSH stimulation) can help in assessing the persistence of disease or thyroid remnant and predicting potential future disease recurrence. The Tg should reach its nadir by 3–4 weeks postoperatively in most patients.”

The adult guideline states that measurement of Tg and TgAb (anti-Tg) should be paired with TgAb analyzed first to determine Tg methodology:¹²

 “Serum Tg should be measured by an assay that is calibrated against the CRM457 standard. Thyroglobulin antibodies should be quantitatively assessed with every measurement of serum Tg. Ideally, serum Tg and anti-Tg antibodies should be assessed longitudinally in the same laboratory and using the same assay for a given patient.”

The guideline in children emphasizes a similar point:¹³

 “TgAb are detected in up to 20%-25% of patients with DTC….and they interfere with Tg measurements in a qualitative, quantitative, and method-dependent manner, rendering the Tg level uninterpretable…All specimens sent for Tg measurement require concomitant TgAb testing…”

Reverse T3 and Thyroxine Binding Globulin

Reverse T3 is not a recommended screening test for either hypothyroidism or hyperthyroidism.^4,11 The use of the test is controversial and the majority of the test orders in the United States come from the workup of thyroid disease by alternative practitioners.¹⁷

Thyroxine Binding Globulin (TBG) is not used for screening for thyroid disease or in the workup of thyroid nodules or cancer.^4,11-13 It is a rarely used test that can occasionally be useful in interpreting T3 or T4 values that do not match the clinical presentation and are therefore diagnostic conundrums.^9,10 Such situations can arise in inherited and other diseases that affect the level of thyroxine binding globulin.

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Criteria

Introduction

This guideline outlines coverage criteria for in-vitro testing of blood or other body fluids in the evaluation and management of thyroid disease. It does not address molecular (i.e. nucleic acid) testing such as BRAF, and TERT mutations; anatomic pathology examinations of fine needle aspirates or biopsies; imaging by any modality; or other assessments of the thyroid besides in-vitro chemistry and antibody testing.

Thyroid Stimulating Hormone (TSH; Thyrotropin) Test name and procedure code(s)

Test Name Procedure Code

Thyroid Stimulating Hormone (TSH;

Thyrotropin)

84443

Medical necessity requirements

TSH testing is indicated in the following circumstances:

o Signs and symptoms of hyperthyroidism or hypothyroidism

o Abnormal thyroid exam (e.g., enlarged thyroid) or thyroid imaging study o Suspected iodine deficiency

o History of thyroid surgery, radiation treatment to thyroid, or treatment with anti- thyroid drugs

o Monitoring thyroid treatment of overt or subclinical hypothyroidism, including but not limited to levothyroxine therapy, watchful waiting, or immune modulating therapies

o Monitoring treatment of overt or subclinical hyperthyroidism, including but not limited to surgery, radioactive iodine, thyroid modifying drugs, or watchful waiting o Monitoring and risk-stratifying treatment of thyroid cancers, including but not

limited to watchful waiting, surgery, radioactive iodine, and anti-thyroid drugs o History of a disorder that may be associated with thyroid disease (e.g., other autoimmune conditions besides Grave’s disease or Hashimoto’s thyroiditis) o Use of medications that may compromise thyroid function, such as lithium or

amiodarone

o Family history of thyroid disease in a first-degree relative o Infertility

o Psychiatric disorder(s)

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Population-based thyroid disease screening with TSH is indicated for newborns and people over age 60. Outside of these populations, population screening is not indicated in the absence of symptoms or increased risk.

Thyroxine (T4) Testing

Test name and procedure code(s)

Test Name Procedure Code

Thyroxine (T4), Total 84436

Thyroxine (T4) requiring elution (e.g.

neonatal thyroxine) 84437

Free Thyroxine (free T4) 84439

Thyroid hormone (T3 OR T4) uptake or

thyroid hormone binding ratio (THBR) 84479

Thyroxine (T4) testing is indicated in the following circumstances:

o Signs and symptoms of hyperthyroidism or hypothyroidism

o Abnormal thyroid exam (e.g., enlarged thyroid) or thyroid imaging study o Suspected iodine deficiency

o History of thyroid surgery, radiation treatment to thyroid, or taking anti-thyroid drugs

o Monitoring thyroid treatment of overt or subclinical hypothyroidism, including but not limited to levothyroxine therapy, watchful waiting, or immune modulating therapies

o Monitoring treatment of overt or subclinical hyperthyroidism, including but not limited to surgery, radioactive iodine, thyroid modifying drugs, or watchful waiting o Monitoring treatment of thyroid cancers, including but not limited to watchful

waiting, surgery, radioactive iodine, and anti-thyroid drugs

o History of a disorder that may be associated with thyroid disease (e.g., other autoimmune condition besides Grave’s disease or Hashimoto’s thyroiditis) o Use of medications that may compromise thyroid function, such as lithium or

amiodarone

o Family history of thyroid disease in a first-degree relative o Infertility

o Psychiatric disorder(s)

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Population-based thyroid disease screening is indicated for people over age 60.

Outside of these populations, population screening is not indicated in the absence of symptoms or increased risk.

Only one form of thyroxine (T4) testing should be necessary per date of service and the treating provider should select the single most informative test for the

circumstances. The only exception is when thyroid hormone (T3 or T4) uptake (CPT 84479) is performed with total thyroxine (CPT 84436) to generate a free T4 index in pregnant women.

Billing and reimbursement

When testing is medically necessary:

o Because only one form of thyroxine testing is necessary per date of service, the following billing limitations apply:

 When CPT 84439 is billed with 84436 or 84437 or 84479, only 84439 will be payable.

 When CPT 84437 is billed with 84436 or 84479, only 84437 will be payable.

 CPT 84436 is payable with CPT 84479.

Triiodothyronine (T3)

Test Name Procedure Code(s)

Triiodothyronine (T3) 84480

Free Triiodothyronine (free T3) 84481

Triiodothyronine (T3) testing is indicated in the following circumstances:

o Signs or symptoms of hyperthyroidism when T4 measurements are normal o Monitoring treatment of overt or subclinical hyperthyroidism from any cause T3 testing is not indicated for hypothyroidism screening and monitoring, or for population-based thyroid disease screening.

Only one form of triiodothyronine (T3) testing should be necessary per date of service and the treating provider should select the single most informative test for the circumstances.

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T3 testing will not be payable when billed with a diagnosis of hypothyroidism, including ICD E02 (Subclinical iodine-deficiency hypothyroidism), E03.X (Other hypothyroidism), E89.0 (Postprocedural hypothyroidism).

o Because only one form of T3 testing is necessary per date of service, when CPT 84480 is billed with 84481, only 84481 will be payable.

TSH Receptor Antibodies (TRAb/TSI) Test name and procedure code(s)

TSH receptor antibodies (TRAb) 83519 TSH receptor antibodies (TRAb) 83520 Thyroid Stimulating Immunoglobulins

(TSI)

84445

Medical necessity requirements TRAb or TSI testing is indicated for:

o Testing for Grave’s disease when screening results suggest hyperthyroidism o Monitoring treatment of Grave’s disease

TRAb or TSI testing has no role in screening for hypothyroidism or hyperthyroidism and is therefore not coverable in the absence of a specific indication.

Only one form of TRAb or TSI testing should be necessary per date of service and the treating provider should select the single most informative test for the

circumstances.

TRAb or TSI testing will be payable when billed with a diagnosis code in the E05.X range (Thyrotoxicosis [hyperthyroidism]).

o TRAb or TSI is allowed once per year to confirm or rule out a diagnosis of Grave’s disease in a patient with hyperthyroidism.

o TRAb or TSI is allowed up to 4 times per year for monitoring Grave’s disease.

o Because only one form of TRAb or TSI testing is necessary per date of service, only one of the following codes is allowed for such testing per date of service:

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 CPT 83519

 CPT 83520

 CPT 84445

Microsomal antibodies (anti-tissue peroxidase antibodies (TPOAb)) Test name and procedure code(s)

Microsomal (Thyroid peroxidase) antibodies

86376

Medical necessity requirements TPOAb is indicated to:

o Confirm Hashimoto’s thyroiditis when screening results suggest hypothyroidism o As a secondary confirmatory test for Grave’s Disease if the primary confirmatory

test, TRAb/TSI, is equivocal and the index of suspicion for Grave’s Disease remains high

TPOAb is not indicated for monitoring the treatment of either Hashimoto’s thyroiditis or Grave’s Disease.

TPOAb has no role in screening for hypothyroidism or hyperthyroidism and is therefore not coverable in the absence of a specific indication.

TPOAb is allowed once per year to confirm or rule out a diagnosis of Hashimoto’s thyroiditis.

TPOAb is allowed once per year to confirm or rule out a diagnosis of Grave’s disease.

Thyroglobulin (Tg) and Thyroglobulin Antibody (anti-Tg Ab) Test name and procedure code(s)

Thyroglobulin 84432

Thyroglobulin antibody 86800

Medical necessity requirements:

Tg is indicated to:

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o Monitor the treatment of invasive or metastatic thyroid cancer o Help risk stratify thyroid cancers

Anti-Tg Ab is indicated as an aid for interpreting the Tg test.

Tg and anti-Tg Ab have no role in screening for hypothyroidism or hyperthyroidism and are therefore not coverable in the absence of a specific indication.

Tg and/or anti-Tg Ab testing will be payable when billed with a diagnosis code in Table: Thyroglobulin (CPT 84432) and Thyroglobulin Antibody (CPT 86800) Indications.

o Tg and anti-Tg Ab are allowed up to 6 times per year to monitor the treatment of invasive or metastatic thyroid cancer and provide an aid to risk stratification of the cancer.

o Anti-Tg Ab should be measured prior to Tg measurement to determine whether typical immunoassay measurement of Tg is appropriate, or if the presence of anti-Tg Ab necessitates measurement of Tg by an alternate method (e.g. mass spectrometry, RIA).

Reverse T3

Reverse T3 84482

There are no indications for reverse T3 testing that are supported by current guidelines or the medical literature. Therefore, reverse T3 testing is considered experimental/investigational/unproven.

Thyroxine Binding Globulin Test name and procedure code(s)

Thyroxine Binding Globulin (TBG) 84442

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TBG is indicated as a secondary test for interpreting T4 results that are diagnostic conundrums and where a binding globulin disorder is suspected as an explanation for the unexpected T4 result.

TBG has no role in screening for hypothyroidism or hyperthyroidism and is therefore not coverable in the absence of a specific indication.

Table: Thyroglobulin (CPT 84432) and Thyroglobulin Antibody (CPT 86800) Indications

ICD10 Codes and Descriptions

ICD Code(s) ICD Description(s)

C73 Malignant neoplasm of thyroid gland

D49.7 Neoplasm of unspecified behavior of

endocrine glands and other parts of nervous system

Z08 Encounter for follow-up examination after

completed treatment for malignant neoplasm

Z51.0 Encounter for antineoplastic radiation

therapy

Z51.11 Encounter for antineoplastic

chemotherapy

Z51.12 Encounter for antineoplastic

immunotherapy

Z85.850 Personal history of malignant neoplasm of

thyroid

Z85.858 Personal history of malignant neoplasm of

endocrine glands

References

Introduction

These references are cited in this guideline.

1. Thyroid Diseases (2020). Lab Tests Online. American Association for Clinical Chemistry. https://labtestsonline.org/conditions/thyroid-diseases

2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and

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Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab.

2002;87:489-99.

3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526-34.

4. Garber JR, Cobin RH, Gharib H, et al. 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.

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www.ahrq.gov/downloads/pub/prevent/pdfser/thyrser.pdf.

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stimulating hormone testing-optimizing pre-conception health or generating toxic knowledge? Hum Reprod. 2017;2(9):1779-1785.

7. Ross DS (2017a). Diagnosis of and screening for hypothyroidism in

nonpregnant adults. In JE Mulder (Ed.), UpToDate. Retrieved August 31, 2018.

8. Ross DS (2017b). Laboratory assessment of thyroid function. In JE Mulder (Ed.), UpToDate. Retrieved August 31, 2018.

9. Thyroid function ordering algorithm (2020). Mayo Foundation for Medical Education and Research. https://www.mayomedicallaboratories.com/it-mmfiles/

Thyroid_Function_Ordering_Algorithm.pdf

10. Thyroid disorders testing algorithm (2020). ARUP Consult, an ARUP test selection tool for healthcare professionals.

https://arupconsult.com/algorithm/thyroid-disorders-testing-algorithm 11. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association

guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.

12. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;6(1):1-133.

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2015;25(7):716-59.

14. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315-389.

15. Twenty things physicians and patients should question (2015). Choosing Wisely and the American Society for Clinical Pathology. Available at:

http://www.choosingwisely.org/wp-content/uploads/2015/02/ASCP-Choosing- Wisely-List.pdf

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16. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and

differentiated thyroid cancer: the American Thyroid Association (ATA) guidelines taskforce on thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Nov 1;19(11):1167-214.

17. Schmidt RL, LoPresti JS, McDermott MT, et al. Does reverse triiodothyronine testing have clinical utility? An analysis of practice variation based on order data from a national reference laboratory. Thyroid. 2018;28(7):842-848.

18. LeFevre ML. Screening for thyroid dysfunction. U.S. Preventive Services Task Force Recommendation Statement. Ann Int Med. 2015;162:641-652. Available at:

https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummar yFinal/thyroid-dysfunction-screening?ds=1&s=thyroid

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20. American College of Obstetricians and Gynecologists. Thyroid Disease in Pregnancy: ACOG Practice Bulletin, Number 223. Obstet Gynecol. 2020 Jun;135(6):e261-74.

21. Bekkering GE, Agoitsas T, Lytvyn L, et al., Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365:I2006.

22. Kahaly GJ, Bartalena L, Hegedüs L, et al. 2018 European thyroid association guideline for the management of Graves’ hyperthyroidism. Eur Thyroid J.

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