Clinical UM Guideline

This document addresses laboratory testing of thyroid function. Thyroid function tests include serum testing for thyroid stimulating hormone (TSH) and levels of specific thyroid hormones; including total and free thyroxine, thyroid hormone (T3 or T4) uptake, and thyroid hormone binding ratio (THBR). Thyroid gland hormones regulate the metabolic rate, affecting all body functions.

Medically Necessary:

Thyroid function testing is considered medically necessary for individuals who meet any of the following indications:

• For evaluation of signs or symptoms consistent with thyroid disease; or
• To evaluate, assess, or monitor confirmed or suspected thyroid disease; or
• To evaluate thyroid function when there are risk factors for thyroid disease.

Not Medically Necessary:

The use of thyroid function tests are considered not medically necessary when the criteria listed above are not met, including as a screening test in the absence of risk factors.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Medically Necessary:

When services are Not Medically Necessary:
For the procedure codes listed above, for all other diagnoses not listed.

Background

Thyroid stimulating hormone (TSH), also known as thyrotropin, thyrotropic hormone, is produced in the pituitary gland in response to low levels of serum free thyroxine, also known as T4, or triiodothyronine, also known as T3, in the bloodstream. TSH stimulates the thyroid gland to produce and secrete T4. T4 is converted to T3 by the removal of an iodine atom. Over 99% of the T3 and T4 are bound to transport proteins in circulation and are not metabolically available. Free T3 or T4 levels consists of the amount of hormone which is not bound to transport proteins and is available for uptake and use by body tissue.

Serum TSH levels are used as the first-line test to diagnose and monitor thyroid function. They are used to detect thyroid dysfunction, both overt and subclinical, in those with intact hypothalamic and pituitary function. Serum free T4 levels can be used to detect or monitor hypothyroidism. When T4 testing is combined with TSH testing, a low free T4 level can detect primary or central hypothyroidism. Serum T4 testing is also used to monitor for hypothyroidism during hyperthyroidism treatment. Free or total T3 levels can be used to evaluate those with suspected hyperthyroidism (Esfandiari, 2017).

Thyroid Disorders

Symptoms

The most common thyroid disease is hypothyroidism. The reported rate of subclinical disease varies from 4.3% to 8.5% and approximately 0.3% to 0.4% of overt disease. In the United States, the most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) (Garber, 2012). Hypothyroidism has multiple etiologies including treatment of hyperthyroidism, thyroid cancer, benign nodular thyroid disease or non-thyroid-related head and neck malignancy. The symptoms of hypothyroidism are varied and nonspecific including fatigue, cold intolerance, dry skin, constipation, myalgia, depression, edema, menstrual irregularities, hoarse or deep voice, muscle cramps, puffy eyes and weight gain. Hypothyroidism has been associated with an increased risk of developing a number of conditions, including decreased bone density, atrial fibrillation, premature atrial beats and elevated serum cholesterol levels (Canaris, 2000). Untreated congenital hypothyroidism in infants can lead to structural and intellectual impairments (Ortiga-Carvalho, 2016).

The American Thyroid Association (2016) defines thyrotoxicosis as “a clinical state that results from inappropriately high thyroid hormone action in tissues generally due to inappropriately high tissue thyroid hormone levels.” Hyperthyroidism is the most common form of thyrotoxicosis with a prevalence in the U.S. of approximately 1.2%. The most common causes of hyperthyroidism are Graves’ disease, toxic multinodular goiter, and toxic adenoma. The symptoms of hyperthyroidism can be widespread and vague including nervousness, irritability, anxiety, increased sweating, hand tremors, sleep problems, changes in menstrual cycle, thin skin, fine brittle hair or hair loss, upper extremity weakness, unexplained weight loss, frequent bowel movements, goiter, palpitations, heat intolerance, shortness of breath, vision changes and enlarged or bulging eyes.

In some cases, thyroid disorders can present with behavioral health symptoms, including psychosis. These symptoms can mimic intoxication, drug use or a psychotic break. The possibility of a thyroid etiology should be explored in those with altered mental status (Bennett, 2021; Carroll, 2010; Cota, 2017; Desai, 2018; Mohammed, 2021; Toloza, 2021; Ueno, 2015).

Thyroid disorders may contribute to or result in a number of cardiac disorders and may exhibit in the form of cardiac arrhythmias. Hypothyroidism can cause abnormal systolic and diastolic performance (Yancy, 2013). The American College of Cardiology (ACC) /American Heart Association (AHA) and the Heart Rhythm Society (HRS) guideline on the management of atrial fibrillation (2014) notes that atrial fibrillation is the most common arrhythmia in individuals with hyperthyroidism, affecting 5% to 15% of the population. The treatment of atrial fibrillation with the long-term use amiodarone therapy has infrequently caused hyperthyroidism and thyrotoxicosis and these individuals should be monitored. The 2018 ACC/AHA/HRS guideline on the evaluation and management of bradycardia and cardiac conduction delay lists hypothyroidism as a potential reversible cause of sinus bradycardia. Both hypothyroidism and hyperthyroidism can result in an atrioventricular block. Hyperthyroidism may also play a role in the development of dilated cardiomyopathy in some cases. The 2013 ACC/AHA guideline on heart failure recommends that the diagnostic testing of individuals presenting with heart failure should include TSH levels.

In the absence of new symptoms, thyroid testing is used to monitor thyroid levels during various therapies. TSH levels are also used to monitor both thyroid hormone replacement therapy to treat primary hypothyroidism and suppressive therapy to treat follicular, papillary or Hürthle cell thyroid cancer (Esfandiari, 2017; National Comprehensive Cancer Network^® [NCCN], V2.2024; Ross; 2016). For pregnant individuals who are currently being treated for hypothyroidism, thyroid levels are typically evaluated every 4 to 6 weeks, while adjusting medications (ACOG, 2020). The 2016 ATA guidelines recommend “an assessment of free T4, total T3 and TSH” within 1 to 2 months following radioactive iodine therapy for hyperthyroidism. In addition, the recommendation continues:

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 hormone replacement. Strong recommendation, low-quality evidence

The hypothalamus-pituitary-thyroid axis is a hormone regulatory system which sets the baseline level thyroid hormone production. Dysregulation within the complex system can influence the function of both central and peripheral mechanisms. Hypothalamus or pituitary gland dysfunction can lead to central hypothyroidism which is associated with vague and nonspecific clinical symptoms usually milder than symptoms of primary hypothyroidism (Feldt-Rasmussen, 2021). A deficiency of thyroid hormones during the neonatal period is associated with impaired neurologic development, including decreased vascularity, dendritic and axonal growth, astrocyte proliferation and differentiation. Thyroid hormone deficiency also interferes with the normal development of cellular processes.

Conditions Associated with Increased Risk of Thyroid Disorder

There is an increased prevalence of thyroid disorders in survivors of adolescent/childhood cancers and individuals who have undergone irradiation of the thyroid region for the treatment of cancer. Hodgkin’s lymphoma survivors, who are typically treated with thyroid region irradiation, may experience thyroid disease, with the risk rising along with the radiation dose (Jensen, 2018). The pathophysiology behind this increased incidence is thought to be caused by radiation-related disturbances of the thyroid hormonal axis. These disturbances result in both secondary dysfunction (central pituitary axis) and primary dysfunction (thyroid gland) (Nome, 2021; Vogelius, 2011). The NCCN Clinical Practice Guideline (CPG) on cancer related fatigue (V2.2024) recommendation assessment of endocrine dysfunction as part of the primary evaluation due to the high incidence of thyroid dysfunction in normal individuals and those receiving thyroid medication or immunotherapy.

Endocrine complications are one of the most common late effects in childhood cancer survivors, particularly thyroid disorders. Approximately 7.5% to 9.2% of childhood survivors of brain tumors and those exposed to HP radiotherapy are later diagnosed with TSH deficiency. Risk increases with time and with the presence of other central endocrinopathies (Chemaitilly, 2018). The Childhood Oncology group recommendations regarding long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers recommend testing thyroid function in several situations including individuals with:

• Any cancer experience who report fatigue or sleep problems
• Head or brain radiation history who report poor growth
• Head, brain, neck or spine radiation history in individuals attempting pregnancy and periodically throughout pregnancy
• Head, brain, neck or spine radiation history with thyroid nodules

Central hypothyroidism is categorized as congenital or acquired. Feldt-Rasmussen and associates (2016) noted that acquired central hypothyroidism can be associated with:

• Invasive and/or compressive lesions of the pituitary sella region, such as pituitary macroadenomas, craniopharyngiomas, meningiomas, gliomas, Rathke cleft cysts, metastatic seeding or carotid aneurysm
• Iatrogenic causes, such as cranial surgery or irradiation or drugs
• Injuries, such as head traumas or traumatic delivery
• Vascular accidents, such as pituitary infarction, Sheehan syndrome or subarachnoid hemorrhage
• Autoimmune diseases/immunologic lesions, such as postpartum hypophysitis, lymphocytic hypophysitis, IgG4-related hypophysitis, treatment with anti-CTLA4 antibodies and treatment of anti-PIT1 antibody
• Infiltrative lesions, such as iron overload, sarcoidosis and histiocytosis X
• Infective diseases, such as tuberculosis, mycoses and syphilis

While obesity is often associated with thyroid dysfunction, the exact mechanism of action is unknown. It has been theorized that obesity has an impact on the hypothalamic-pituitary-thyroid axis which may result in thyroid dysfunction (Garber, 2012; Laurberg, 2012; Walczak, 2021). In individuals with thyroid cancer, the presence of obesity may be associated with a more aggressive type of cancer (Laurberg, 2012). Thyroid hormones regulate the energy balance aid in the control of energy expenditure and nutrient metabolism, including cholesterol synthesis (Ortiga-Carvalho, 2016).

Autoimmune thyroid diseases (AITDs) are characterized by infiltration of the thyroid by sensitized T lymphocytes and thyroid auto-antibodies, resulting in either an abnormal regulation of the immune response or in an alteration of presenting antigen in the thyroid (Garber, 2012). Autoimmune diseases are associated with a higher incidence of thyroid disorders and are the most common form of thyroid failure (Garber, 2012). Other disorders, such as type 1 diabetes, Addison’s disease, Down’s or Turner’s Syndrome, rheumatoid arthritis, pernicious anemia, myasthenia gravis, celiac disease and systemic lupus erythematosus are associated with an increased frequency of hypothyroidism. (ACOG, 2019; Garber, 2012; Huang, 2022).

Thyroid disease has been implicated as a cause of ovulatory dysfunction. The American College of Obstetricians and Gynecologists (ACOG) and the American Society for Reproductive Medicine (ASRM) committee opinion regarding an infertility workup (2020) recommend measuring TSH levels in individuals with ovulatory dysfunction, infertility or with signs of thyroid disease. Thyroid function abnormalities, either hypothyroidism or hyperthyroidism, are associated with increased risk of pregnancy induced hypertensive disorders (Toloza, 2022). Thyroid testing should be performed in pregnant individuals for several indications including: a personal or family history of thyroid disease, a diagnosis of type 1diabetes mellitus, clinical suspicion of thyroid disease or an increased risk of overt hypothyroidism (ACOG, 2020).

Thyroid Disorder Screening

The United States Preventive Services Task Force (USPSTF) concluded that there is insufficient evidence to recommend screening for thyroid dysfunction in nonpregnant, asymptomatic adults.

Central hypothyroidism: Hypothyroidism caused by damage to the hypothalamus or pituitary gland which result in low TSH, T3 and T4 levels.

Graves’ disease: Overproduction of thyroid hormone by the entire thyroid gland.

Primary hypothyroidism: Hypothyroidism caused by a damaged or absent thyroid gland which results in a high TSH level and low T3 and T4 levels.

Peer Reviewed Publications:

1. Baumgartner C, da Costa BR, Collet TH, et al; Thyroid Studies Collaboration. Thyroid function within the normal range, subclinical hypothyroidism, and the risk of atrial fibrillation. Circulation. 2017; 136(22):2100-2116.
2. Bennett B, Mansingh A, Fenton C, Katz J. Graves' disease presenting with hypomania and paranoia to the acute psychiatry service. BMJ Case Rep. 2021; 14(2):e236089.
3. Burch HB. Drug Effects on the Thyroid. N Engl J Med. 2019; 381(8):749-761.
4. Carroll R, Matfin G. Endocrine and metabolic emergencies: thyroid storm. Ther Adv Endocrinol Metab. 2010; 1(3):139-145.
5. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017; 390(10101):1550-1562.
6. Chemaitilly W, Cohen LE, Mostoufi-Moab S, et al. Endocrine Late Effects in Childhood Cancer Survivors. J Clin Oncol. 2018; 36(21):2153-2159.
7. Cota E, Lentz J. Gland new pyschosis: new onset adult psychosis with suicidal ideation and attempt in the setting of thyroid storm. Case Rep Psychiatry. 2017; 2017:7402923.
8. Desai D, Zahedpour Anaraki S, Reddy N, et al. Thyroid storm presenting as psychosis. J Investig Med High Impact Case Rep. 2018; 6:2324709618777014.
9. Ebert EC. The thyroid and the gut. J Clin Gastroenterol. 2010 ;44(6):402-406.
10. Esfandiari NH, Papaleontiou M. Biochemical testing in thyroid disorders. Endocrinol Metab Clin North Am. 2017; 46(3):631-648.
11. Feldt-Rasmussen U, Effraimidis G, Klose M. The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions. Mol Cell Endocrinol. 2021; 525:111173.
12. Jensen MV, Rugbjerg K, de Fine Licht S, et al. Endocrine late effects in survivors of cancer in adolescence and young adulthood: A Danish population-based cohort study. JAMA Netw Open. 2018; 1(2):e180349.
13. Laurberg P, Knudsen N, Andersen S, et al. Thyroid function and obesity. Eur Thyroid J. 2012; 1(3):159-167.
14. Lee HJ, Li CW, Hammerstad SS, et al. Immunogenetics of autoimmune thyroid diseases: A comprehensive review. J Autoimmun. 2015; 64:82-90.
15. Mohammed S, Siepmann M, Barlinn K, et al. Myxedema psychosis: Systemic review and pooled analysis. Neuropsychiatr Dis Treat. 2021; 18;17:2713-2728.
16. Nome RV, Småstuen MC, Fosså SDet; al. Thyroid hypofunction in aging testicular cancer survivors. Acta Oncol. 2021; 60(11):1452-1458.
17. Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, Wondisford FE. Hypothalamus-Pituitary-Thyroid Axis. Compr Physiol. 2016; 6(3):1387-1428.
18. Ruggeri RM, Trimarchi F, Giuffrida G, et al. Autoimmune comorbidities in Hashimoto's thyroiditis: different patterns of association in adulthood and childhood/adolescence. Eur J Endocrinol. 2017; 176(2):133-141.
19. Toloza FJK, Derakhshan A, Männistö T, et al. Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis. Lancet Diabetes Endocrinol. 2022; 10(4):243-252.
20. Toloza FJK, Mao Y, Menon L, et al. Association of thyroid function with suicidal behavior: A systematic review and meta-analysis. Medicina (Kaunas). 2021; 57(7):714.
21. Ueno S, Tsuboi S, Fujimaki M, et al. Acute psychosis as an initial manifestation of hypothyroidism: a case report. J Med Case Rep. 2015; 9:264.
22. Vogelius IR, Bentzen SM, Maraldo MV, Petersen PM, Specht L. Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis. Cancer. 2011; 117(23):5250-5260.
23. Walczak K, Sieminska L. Obesity and Thyroid Axis. Int J Environ Res Public Health. 2021; 18(18):9434.

Government Agency, Medical Society, and Other Authoritative Publications:

1. 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.
2. ACOG and ASRM.
   • ACOG Committee Opinion No. 762: Prepregnancy counseling. Obstet Gynecol. 2019; 133(1):e78-e89. Reaffirmed 2020.
   • Thyroid Disease in Pregnancy. Practice Bulletin Number 223. Obstet Gynecol. 2020; 135(6):e261-e274.
3. Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer. Thyroid. 2021; 31(3):337-386.
4. Childrens Oncology Group. Long-term follow-up for survivors of childhood, adolescent, and young adult cancers. Version 5.0 (October 2018). Available at: http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf. Accessed on December 14, 2023.
5. 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. Thyroid. 2012; 22(12):1200-1235.
6. Gharib H, Papini E, Garber JR, et al; AACE/ACE/AME Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules--2016 update. Endocr Pract. 2016; 22(5):622-639.
7. January CT, Wann LS, Alpert JS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014; 64(21):e1-e76.
8. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid. 2014; 24(12):1670-751.
9. Kusumoto FM, Schoenfeld MH, Barrett C. et al. 2018 ACC/AHA/HRS Guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019; 140(8):e382-e482.
10. Lin JS, Aiello Bowles EJ, Williams SB, Morrison CC. Screening for Thyroid Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2017 May. Report No.: 15-05221-EF-1.
11. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2023 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on December 15, 2023.
    • Cancer-Related Fatigue (V2.2024). Revised October 30, 2023.
    • Thyroid Cancer (V4.2023). Revised August 16, 2023.
12. 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.
13. United States Preventive Services Task Force (USPSTF). Thyroid Dysfunction Screening. March 24, 2015. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/thyroid-dysfunction-screening. Accessed on December 14, 2023.
14. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62(16):e147-e239.

1. American College of Obstetricians and Gynecologists (ACOG). Thyroid Disease Frequently Asked Questions. Available at: https://www.acog.org/womens-health/faqs/thyroid-disease. Accessed on December 14, 2023.
2. American Thyroid Association.
   • Hyperthyroidism (Overactive). Available at: https://www.thyroid.org/hyperthyroidism/. Accessed on December 14, 2023.
   • Hypothyroidsim (Underactive). Available at: https://www.thyroid.org/hypothyroidism/. Accessed on December 14, 2023.
   • Thyroid Function Tests. Available at: https://www.thyroid.org/thyroid-function-tests/. Accessed on December 14, 2023.
3. National Institute of Health (NIH). National Institute of Diabetes and Digestive and Kidney Diseases. Graves Disease. Last reviewed November 2021. Available at: https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease. Accessed on December 14, 2023.

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