Description
Thyroid hormones are necessary for both prenatal and postnatal development, as well as metabolic activity in adults (Brent, 2022).

Thyroid disease includes conditions which cause hypothyroidism, hyperthyroidism, goiter, thyroiditis (which can present as either hypo- or hyperthyroidism), and thyroid tumors (Rugge et al., 2015).

Thyroid function tests are used in a variety of clinical settings to assess thyroid function, monitor treatment, and screen asymptomatic populations for subclinical or otherwise undiagnosed thyroid dysfunction (Ross, 2022c).

Policy  
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

1. Thyroid function testing is considered MEDICALLY NECESSARY in the following situations:
   1. For individuals with signs and symptoms consistent with hypothyroidism (see Note 1):
      1. Thyroid stimulating hormone (TSH) to confirm or rule out primary hypothyroidism.
      2. Free T4 (fT4) as a follow up to abnormal TSH finding.
      3. TSH and fT4 in cases of suspected secondary hypothyroidism.
      4. For individuals being treated for hypothyroidism, monitoring with TSH and fT4 testing every 6 weeks upon dosage change and annually in stable individuals.  
   2. For individuals with signs and symptoms consistent with hyperthyroidism (see Note 2):
      1. TSH to confirm or rule out overt hyperthyroidism.
      2. fT4 as a follow up to abnormal TSH findings.
      3. Total T3 (TT3) or free T3 (fT3) to confirm a diagnosis of hyperthyroidism.
      4. fT4 to distinguish between overt and subclinical hyperthyroidism.
      5. Monitoring individuals after treatment for hyperthyroidism
         1. In patients being treated for hyperthyroidism, repeat testing of TSH and fT4 should occur every 8 weeks.
         2. Annual monitoring after first year even if asymptomatic for risk of relapse or late-onset hypothyroidism.
   3. For asymptomatic individuals at high risk for thyroid disease due to:
      1. A personal or family history of thyroid dysfunction.
      2. Personal or family history of type 1 diabetes or other autoimmune disorder.
      3. Prescribed drugs that can interfere with thyroid function:
         1.  Annually.
         2.  When dosage or medication changes.
         3. If symptoms consistent with thyroid dysfunction develop.
   4. For individuals capable of becoming pregnant who:
      1. Are undergoing evaluation for infertility.
      2. Have experienced two or more pregnancy losses.
   5. For individuals with disease or neoplasm of the thyroid or other endocrine glands.
   6. For individuals with chronic or acute urticaria.
   7. For individuals undergoing immune reconstitution therapy (IRT), TSH testing:
      1. Individuals with active relapsing remitting multiple sclerosis (MS) undergoing therapy with alemtuzumab (Lemtrada).
      2. Individuals with HIV undergoing highly active antiretroviral therapy (HAART).
      3. Individuals following allogeneic bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT).
   8. For individuals suspected of central hypothyroidism.
   9. For individuals diagnosed with primary mitochondrial disease, annual screening of TSH and fT4.
   10. For pediatric individuals diagnosed with short stature.
   11. For pediatric individuals with a clinical finding of failure-to-thrive.
2. For individuals who are pregnant or who are postpartum and who have symptoms of thyroid dysfunction (see Note 1 and Note 2), TSH and fT4 testing (once every 4 weeks) is considered MEDICALLY NECESSARY (see Note 3).
3. For individuals who are pregnant or who are postpartum and who have been diagnosed with hyperthyroidism, total T4 (TT4), antithyroglobulin antibody (Tg-Ab), thyrotropin receptor antibodies (TRAb), and anti-thyroid peroxidase antibody (TPOAb) is considered MEDICALLY NECESSARY (see Note 3).
4. For individuals with hypothyroidism or hyperthyroidism, testing for thyroid antibodies (once every three years) is considered MEDICALLY NECESSARY.
5. For individuals with thyroid cancer, testing for serum thyroglobulin and/or Tg-Ab levels for the detection of tumor recurrence, post-surgical evaluation, surveillance, and maintenance for differentiated thyroid carcinomas is considered MEDICALLY NECESSARY.
6. For the evaluation of the cause of hyperthyroidism or hypothyroidism, testing for thyrotropin-releasing hormone (TRH) or thyroxine-binding globulin (TBG) is NOT MEDICALLY NECESSARY.
7. For all other situations not mentioned above, testing of reverse T3, T3 uptake, and TT4 is NOT MEDICALLY NECESSARY.
8. For the assessment of hypothyroidism, measurement of TT3 and/or fT3 is NOT MEDICALLY NECESSARY.
9. To assess levothyroxine dose in hypothyroid patients, measurement of total or fT3 level is NOT MEDICALLY NECESSARY.
10. For asymptomatic nonpregnant individuals, testing for thyroid dysfunction during a general exam without abnormal findings is NOT CONSIDERED MEDICALLY NECESSARY.

NOTES:

Note 1: Signs and symptoms of hypothyroidism include:

• Fatigue
• Increased sensitivity to cold
• Constipation
• Dry skin
• Unexplained weight gain
• Puffy face
• Hoarseness
• Muscle weakness
• Elevated blood cholesterol level
• Muscle aches, tenderness, and stiffness
• Pain, stiffness or swelling in your joints
• Heavier than normal or irregular menstrual periods
• Thinning hair
• Slowed heart rate
• Depression
• Impaired memory

Note 2: Hyperthyroidism can mimic other health problems, which may make it difficult for doctors to diagnose. It can also cause a wide variety of signs and symptoms, including:

• Sudden weight loss, even when your appetite and the amount and type of food you eat remain the same or even increase
• Rapid heartbeat (tachycardia) — commonly more than 100 beats a minute — irregular heartbeat (arrhythmia) or pounding of your heart (palpitations)
• Increased appetite
• Nervousness, anxiety, and irritability
• Tremor — usually a fine trembling in your hands and fingers
• Sweating
• Changes in menstrual patterns
• Increased sensitivity to heat
• Changes in bowel patterns, especially more frequent bowel movements
• An enlarged thyroid gland (goiter), which may appear as a swelling at the base of your neck
• Fatigue, muscle weakness
• Difficulty sleeping
• Skin thinning
• Fine, brittle hair

Note 3: Due to significant changes in thyroid physiology during pregnancy, measurement of hormone levels should only be performed at labs that have trimester specific normal ranges for their assay(s). While fT4 is the preferred test, TT4 may be useful if the TSH and fT4 results are discordant or when trimester specific normal ranges for fT4 are unavailable.

Table of Terminology

Term	Definition
AAAAI	Academy of Allergy, Asthma & Immunology
AACE	American Association of Clinical Endocrinologists
AAFP	American Academy of Family Physicians
AAP	American Academy of Pediatrics
ACAAI	American College of Allergy, Asthma & Immunology
ACOG	American College of Obstetricians and Gynecologists
AITD	Autoimmune thyroid disease
ALPS	Autoimmune lymphoproliferative syndrome
Anti-TPO	Anti-thyroid peroxidase antibodies
ASCP	American Society for Clinical Pathology
ATA	American Thyroid Association
ATD	Antithyroid drug treatment
ATDs	Antithyroid drugs
BMI	Body mass index
BMT	Bone marrow transplantation
CeH	Central hypothyroidism
CFPC	College of Family Physicians of Canada
CLIA ’88	Clinical Laboratory Improvement Amendments of 1988
CMS	Centers for Medicare and Medicaid
CSEM	Canadian Society of Endocrinology and Metabolism
CTFPHC	Canadian Task Force on Preventive Health Care
DNA	Deoxyribonucleic acid
ELISA	Enzyme-linked immunosorbent assay
ES	Endocrine Society
ETA	European Thyroid Association
fT3/FT3	Free triiodothyronine
fT4/FT4	Free thyroxine
GD	Grave’s Disease
HAART	Highly active antiretroviral therapy
HDL	High-density lipoprotein
HIV	Human immunodeficiency virus
HSCT	Hematopoietic stem cell transplantation
IBM	Inclusion body myositis
IGF-1	Insulin-like growth factor 1
IGSF1	Immunoglobulin superfamily member 1
IRT	Immune reconstitution therapy
JCAAI	Joint Council of Allergy, Asthma & Immunology
JTFPP	Joint Task Force on Practice Parameters
LC	Liquid chromatography
LDL	Low-density lipoprotein
LDTs	Laboratory-developed tests
LT4	Levothyroxine
MMS	Mitochondrial Medicine Society
MR	Mendelian randomization
MS	Multiple sclerosis
NICE	National Institute for Health and Care Excellence
NSAID	Non-steroidal anti-inflammatories
ADEM	Acute disseminated encephalitis and encephalomyelitis
PPT	Postpartum thyroiditis
QT interval	The interval from the beginning of the QRS complex to the end of the T wave on an electrocardiogram
rhGH	Recombinant human growth hormone
RIA	Radioimmunoassay
RXR	Retinoid X Receptor
SBP2	Selenocysteine (Sec) insertion sequence-binding protein 2
SLE	Systemic lupus erythematosus
SMFM	Society for Maternal-Fetal Medicine
T3	Triiodothyronine
T4	Thyroxine
TBG	Thyroxine binding globulin
TC	Total cholesterol
Tg	Thyroglobulin
TG-Ab	Antithyroglobulin antibodies
THBR	Thyroid hormone binding ratio
TPO	Thyroid peroxidase
TPOAb	Anti-thyroid peroxidase antibody
TRAb	Thyrotropin receptor antibodies
TRAbs	T receptor antibodies
TRH	Thyrotropin-releasing hormone
TSH	Thyroid-stimulating hormone
TSHR	Thyroid stimulating hormone receptor
TSH-R-Ab	TSH-R-stimulating antibody
TSHRAbs	Thyrotropin receptor autoantibodies
TT3	Total T3
TT4	Total T4
USPSTF	United States Preventive Services Task Force

Rationale 
Metabolic homeostasis is regulated by the thyroid gland through production of thyroid hormones. Thyroid disease is estimated to occur in approximately 30 million Americans, much of which is undiagnosed (AACE, 2023). The thyroid gland is regulated by thyroid stimulating hormone (TSH). TSH is secreted by the anterior pituitary and stimulates thyroid gland to secrete two hormones, thyroxine (T4) and triiodothyronine (T3), and TSH secretion is controlled through a negative feedback loop by these thyroid hormones. Thyroid function is best assessed by measuring TSH (assuming steady-state conditions and the absence of pituitary or hypothalamic disease). However, direct measurement of all TSH and all other serum thyroid hormone levels (serum total T3 and total T4, serum free T3 (fT3) and free T4 (fT4) is still important, as it may be difficult in some patients to be certain about the state of pituitary and hypothalamic function (Ross, 2022c)

Thyroid hormones must be maintained within a carefully regulated range, as levels outside this range (both hypo- or hyperthyroid) can result in adverse clinical consequences. Hypothyroidism diagnosis depends heavily on laboratory tests because of the lack of specificity of the typical clinical manifestations. Primary hypothyroidism is characterized by high TSH and low fT4 concentrations. Subclinical hypothyroidism is defined biochemically as a patient having elevated TSH but a normal fT4 concentration and secondary (central) hypothyroidism is characterized by a patient having low serum T4 concentration but a normal serum TSH concentration. Symptoms include fatigue and weakness, cold intolerance, weight gain, cognitive dysfunction, dyspnea on exertion, hair loss, hoarseness, dry skin,  edema, decreased hearing, myalgia and paresthesia, depression, menorrhagia, arthralgia, or pubertal delay (Ross, 2022a). Another well-documented consequence of hypothyroidism during childhood is that of short stature, serving as presenting feature and is linked to delayed bone age, as those treated for hypothyroidism often resume their normal growth potential (Richmond & Rogol, 2022). Thus, newborns with undetected or untreated hypothyroidism will have both mental and physical developmental delay. Hypothyroidism during pregnancy increases the risk for miscarriage, preterm delivery and pre-eclampsia (Alexander et al., 2017). 

Overt hyperthyroidism refers to patients with elevated levels of fT4, fT3, or both, and subnormal TSH levels, while subclinical hyperthyroidism is defined as patients having normal T4 and T3 in the presence of subnormal TSH levels. Hyperthyroid symptoms are nonspecific, but can include tachycardia, heat intolerance, sweating, tremor, dyspnea on exertion, and weight loss. Because a number of these symptoms are so common and nonspecific, they may be subtle and unrecognized. Both hypothyroidism and hyperthyroidism conditions rely on laboratory testing to confirm diagnosis (Ross, 2022a, 2022b). 

Current assays for TSH are extremely sensitive at detecting changes in thyroid homeostasis prior to changes in T4 and T3 levels. Thus, TSH assessment is the most often used initial test for thyroid function.  In general, if serum TSH is normal, no further testing is needed; however, if serum TSH is high, fT4 is used to determine the degree of hypothyroidism. In contrast, if serum TSH is low, fT4 and fT3 are used to determine the degree of hyperthyroidism. If a pituitary or hypothalamic condition is suspected, both serum TSH and fT4 may be measured, and serum fT4 may be measured if symptoms of hyper- or hypothyroidism are present in a patient with normal TSH levels (Ross, 2022c). Measurement of fT4 is regarded as a better indicator of thyroid function than total T4 measurement for most situations, as it reflects the amount of available hormone. Presently, there is considerable controversy as to the appropriate upper limit of normal for serum TSH, with most labs using upper limits of approximately 4.5 to 5.0 mU/L (current “normal” range 0.4-5 mU/L) and there are debates on the cost effectiveness of screening asymptomatic patients. In addition, research has shown an age-related shift toward higher TSH concentrations in older patients (Ross, 2022c).

Thyroiditis may be caused by an autoimmune disorder, an infection, or exposure to certain drugs or toxic chemicals which can be either acute or chronic. The evaluation of possible autoimmune thyroid disorders includes testing for the presence of thyroid antibodies. Several antibodies against thyroid antigens have been described in chronic autoimmune thyroiditis. The antigens include thyroglobulin (Tg), thyroid peroxidase (TPO) and the thyrotropin receptor. However, different levels of antibodies correspond to different conditions—for example, nearly all patients with Hashimoto's thyroiditis (chronic autoimmune hypothyroidism) have high serum concentrations of antibodies to Tg and TPO (Ross, 2022a). Thyrotropin receptor antibodies (TRAb) can be classified as stimulating, blocking, or neutral. Stimulating TRAb cause Graves' disease and thyroid receptor-blocking antibodies can cause hypothyroidism. Some patients will have a mixture of both antibodies and may fluctuate between hyper- and hypothyroidism, depending on the relative titers of these stimulating and blocking antibodies. Although these antibodies are not routinely measured in evaluating thyroid function, measuring them may still be helpful for more specific goals, such as predicting progression of hypothyroidism (Ross, 2022c). 

Assessment of the thyroid is particularly important for pregnant individuals. Due to the metabolic changes during pregnancy, the levels of thyroid hormones differ dramatically. In pregnant individuals, total T4 and total T3 are higher than in nonpregnant individuals, thyroxine-binding globulin nearly doubles due to the increased estrogen, and in the first trimester, TSH concentrations are reduced due to high serum human chorionic gonadotropin (hCG) levels. Thyroid physiology changes during pregnancy, therefore trimester-specific ranges for TSH and fT4 should be utilized. Unfortunately, not all commercial laboratories provide these reference ranges. As such, when trimester-specific reference ranges for fT4 are not available and fT4 levels appear discordant with TSH, total T4 measurements may be superior to fT4 (Ross, 2022d).

The effects of thyroid problems during pregnancy may be dire. Luewan et al. (2011) performed a study comparing 180 pregnant women with hyperthyroidism to 360 controls. The authors found that the mean gestational age and mean birth weight were significantly lower in the study group. The incidence of fetal growth restriction, low birth weight, and preterm weights were 1.3, 1.4, and 1.3 times higher, respectively, in the study group compared to the control group (Luewan et al., 2011). 

An imbalance of thyroid hormones is not only harmful to pregnant individuals, it can negatively impact children, producing short stature. Thyroid hormone isoforms and thyroid hormones play an important role in bone development and growth, as defects associated with congenital hypothyroidism include delayed epiphyseal closure and widely spaced cranial sutures (Leung & Brent, 2016). During development, these effects extend to influence chondrocytes and growth plate cartilage in bones. Mediation of the chondrogenesis—the formation of cartilage from condensed mesenchyme tissue—by the endocrine system takes place through the action of hormones, including growth hormone, insulin-like growth factor 1 (IGF-1), androgens, glucocorticoids, and thyroid hormone. It is believed that the balance between proliferation and senescence of chondrocytes at the growth plate of bones plays a crucial role in both normal and pathologic variations of linear growth, though the pathways are unclear as of date (Leung & Brent, 2016; Richmond & Rogol, 2022).

Tests measuring levels of thyroid-related markers are widely available commercially, often as a panel. Many combinations of thyroid serum markers are available. For example, Testing.com offers thyroid tests which screen for individual thyroid hormones including TSH, fT4, and fT3 (Testing, 2023). EverlyWell offers a direct-to-consumer home-health panel testing for TSH, T3, T4, and thyroid peroxidase antibodies (EverlyWell, 2023). Other direct-to-consumer home-health panel tests include LetsGetChecked (LetsGetChecked, 2023), Paloma Health (Paloma_Health, 2023), myLABBOX Thyroid Health Screening (myLABBOX, 2023), and TellmeGEN (TellmeGEN, 2023). 

Common variable immunodeficiency is one of the more common antibody deficiency disorders. In one large series of primary immunodeficiency (PID) in children diagnosed over a 10-year period, CVID made up 17 of 189 total PID cases and 20 percent of the 87 cases of antibody deficiency. Most patients with CVID present after puberty, and the disorder is usually diagnosed in the second or third decade of life. However, about 25 percent of all CVID patients present in childhood or adolescence and there is an earlier peak of diagnosis occurring around eight years of age. A diagnosis of CVID before six years of age should be considered preliminary because of immunologic immaturity and the persistence of transient hypogammaglobulinemia of infancy in some children. In addition, the possible presence of a monogenic defect that causes a CVID-like disorder should be considered in children who present at a very young age. Children with failure-to-thrive should be evaluated for thyroid function and growth hormone deficiency. Growth hormone replacement therapy should be offered if deficiency is identified (Hogan,2020). 

Analytical Validity
The current generation of assays measuring serum TSH is a chemiluminometric assay, which have detection limits of about 0.01 mU/L. This amount is sufficiently low enough to distinguish between euthyroidism and hyperthyroidism as well as providing superior sensitivity to the prior generation of assays whose detection limits were approximately 0.1 mU/L (Ross, 2022c). 

A study focusing on validating a new electrochemiluminescent assay for serum TSH, T4, and T3 found their intra-assay coefficient of variation to be under 8% for all three hormones and inter-assay coefficient of variation to be <2.9% for TSH, 2.3% for FT4, and 12.3% for T3. The correlation between this assay and the typical ELISA or RIA assays were all at least r = .8 with many correlations near or above .9 (Kazerouni & Amirrasouli, 2012).

Serum T4 and T3 are typically measured by automated competitive binding chemiluminometric assays. Older competitive binding radioimmunoassays are still available for serum total T4. Serum total T4 and total T3 measure both bound and unbound (free) T4 and T3, respectively. A large percentage of serum T4 is bound (99.97%) to TBG, transthyretin (also called TBPA [thyroxine0binding prealbumin]), and albumin. Serum T3 is less tightly bound to TBG and TBPA but more tightly bound to albumin than T4. Normal reference ranges do vary among laboratories; however, a typical reference range for total T4 is 4.6-11.2 mcg/dL (60-145 nmol/L) and for total T3, while more variable across laboratories even than total T4, a typical reference range is ~75-195 ng/dL (~1.1-3 nmol/L) (Ross, 2022c). 

The current immunoassays used to measure T3 do not always agree with other methods. For example, a study by Masika et al. (2016) compared immunoassay methods to LC/MS/MS and found that 45% of patients classified as “normal” by immunoassay were classified as “lower than 2.5th percentile” by LC/MS/MS. The authors also noted that in patients not receiving T4, 74% of their results were below the 2.5th percentile by LC/MS/MS whereas only 21% were under that mark by immunoassay. The authors speculate that this discrepancy may be due to deionidase polymorphisms, but overall conclude that because this is a significant method to diagnose thyroid issues, accuracy of T3 measurements should be paramount (Masika et al., 2016).

The measurement of reverse T3 may not be reliable. A study by Burmeister, focused on a total of 246 patients contributing 262 reverse T3 measurements, showed an inverse linear relationship between the log of TSH and reverse T3. However, Burmeister notes that hypothyroidism may cause reverse T3 to appear normal and euthyroidism may cause reverse T3 to appear low. Furthermore, it is possible that symptoms attributed to unusual reverse T3 levels are actually caused by hypothyroidism, despite normal TSH levels. Overall, Burmeister concludes that reverse T3 cannot differentiate between hypothyroidism and euthyroidism (Burmeister, 1995; Gomes-Lima & Burman, 2018). 

Clinical Utility & Validity
Li et al. (2017) conducted a preliminary study to investigate how certain dietary supplements could affect clinical assays. They examined 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays and found that ingesting 10 mg/d of biotin for 1 week was associated with a potentially clinically important interference with some biotinylated assays. These immunoassays use a biotin-strepavidin binding system, so excess biotin may influence the results of assays using this system. The time at which the biotin was ingested was also a factor in the magnitude of the distortion (Li et al., 2017). Repeating a thyroid test at least two days after biotin discontinuation may be considered (Ross, 2022c).

Livingston et al. (2015) assessed the impact of T3 testing and whether T3 testing provides clinically useful information to patients who are over-treated for hypothyroidism with levothyroxine. Out of 542 patients, 33 were placed in an over-treated group, 236 were placed in a control group, and the remaining 273 did not fulfill either group. None of the patients in the over-treated group had an increased T3 and the “most discriminant” T3 level was only at 58% sensitivity and 71% specificity. The authors concluded there is no reason to measure T3 in patients with hypothyroidism on levothyroxine therapy (Livingston et al., 2015).

Yazici et al. (2016) assessed three predictors of thyroid cancer: thyrotropin (TSH), thyroglobulin (Tg), and their ratio. A study of 242 patients (134 with benign thyroid conditions, 68 with malignancy) was performed. The authors found that preoperative Tg levels were significantly lower in the malignant group (64 ng/mL vs 20 ng/mL) and that the TSH to Tg ratio was significantly higher in the malignant group, as there was no major difference in TSH between groups despite the Tg changes. However, the authors note that only fine-needle aspiration biopsy was a significant factor (Yazici et al., 2016). Autoantibodies may also play a role in the diagnosis of cancer. A study by Gholve assessing 301 samples from differentiated thyroid cancer patients (compared to 37 euthyroid controls) found the prevalence of autoantibodies in the cancer patients to be significantly higher than the controls. The authors found the prevalence of the antibodies to be 17.3% by the Immunotech kit and 16.6% by the radioassay in patients with cancer, whereas the control group was found to be only 5.4% by both methods (Gholve et al., 2017).

Thyroid antibodies play a role in autoimmune thyroiditis. A study performed by Biktagirova et al. (2016) found that 97% of patients with autoimmune thyroiditis had a high antibody-to-denatured DNA ratio compared to healthy controls. Most of these patients also had a thyroid condition (euthyroidism, hypothyroidism, hyperthyroidism) (Biktagirova et al., 2016). Another study performed by Diana investigated the prevalence of thyroid stimulating hormone receptor (TSHR) blocking antibodies (TBAb) in autoimmune thyroid disease. 1079 patients with autoimmune thyroid disease (AITD) were compared to 302 controls. The authors found that about 10% of patients with AITD were positive for TBAb (82/1079). TBAb also correlated positively with TSHR binding inhibiting immunoglobulins and negatively with TSHR stimulatory antibodies. The authors concluded that TBAb was a useful and important tool to identify hypothyroidism (Diana et al., 2017).

Kluesner et al. (2018) analyzed current thyroid function test ordering practices. The authors examined 38,214 tests (encompassing TSH, fT4, TSH + fT4, fT3, Total T4, and total T3). Overall, TSH alone comprised 52.14% of tests, TSH + fT4 26.72%, fT3 alone 10.63%, fT4 alone 4.26%, and TSH + fT4 + fT3 2.74%. Free thyroid hormone testing amounted to 36% of all tests. The authors estimated the annual cost of free thyroid hormone testing to be $107,720, with savings of up to $120,000 (Kluesner et al., 2018).
Jin (2018) investigated the prevalence of subclinical hypothyroidism in obese children and its association with thyroid hormone. The study included 1,104 children and 27 of 111 (24.3%) obese children were found to have subclinical hypothyroidism, compared to 127 of 993 (12.8%) non-obese children. Body mass index was found to positively correlate with serum concentrations of TSH and negatively correlate with serum concentrations of fT4. Total cholesterol and triglyceride concentration were found to positively correlate with TSH concentrations, with fT4 negatively correlating with total cholesterol. Jin concluded that TSH is correlated with lipid profiles (Jin, 2018). .

In a 2018 study, Muraresku et al. (2018)reviewed mitochondrial disease and  recent advances in clinical diagnosis, management, therapeutic development, and preventative strategies. They noted that routine screening of individuals with mitochondrial diseases is imperative. Screening should include examining the “multitude of symptoms known for diabetes mellitus, adrenal insufficiency, thyroid hormone insufficiency, hearing loss, cardiac arrhythmias, and other disease related symptoms, with appropriate multi-specialist management provided.” They also noted that “primary mitochondrial disease encompasses an impressive range of inherited energy deficiency disorders having highly variable molecular etiologies as well as clinical onset, severity, progression, and response to therapies of multi-system manifestations” (Muraresku et al., 2018).

Sarkar (2012) examined literature surrounding recurrent pregnancy loss in patients with thyroid dysfunction. Disturbances in thyroid function and thyroid hormone levels are common in women during their reproductive years and that dysfunction can interfere with reproductive physiology, can reduce the likelihood of pregnancy, and can adversely affect pregnancy outcome. They note that “universal screening for thyroid hormone abnormalities should be conducted in females with fetal loss or menstrual disturbances. Practitioners providing health care for women should be alert to thyroid disorders as an underlying etiology for recurrent pregnancy loss.” However, universal screening for thyroid hormone abnormalities is not routinely recommended at present. In individuals capable of pregnancy and of reproductive age, hypothyroidism can be reversed by thyroxine therapy and this can improve fertility and help individuals avoid needing to use assisted reproduction technologies (Sarkar, 2012). 

Korevaar et al. (2019)performed a meta-analysis focusing on thyroid function test abnormalities and thyroid autoimmunity with preterm birth. They assessed 19 cohorts encompassing 47,045 pregnant individuals and found that 1,234 of these individuals had subclinical hypothyroidism, 904 had isolated hypothyroxinemia (“decreased fT4 concentration with normal thyrotropin concentration”), 3,043 were thyroid peroxidase (TPO) antibody positive, and 2,357 had preterm birth. Risk of preterm birth was found to be higher for individuals with subclinical hypothyroidism than with euthyroidism (odds ratio = 1.29), as well as higher for individuals with isolated hypothyroxinemia (odds ratio = 1.46). The authors also found that a one standard deviation increase in maternal serum thyrotropin concentration increased risk of preterm birth by an odds ratio of 1.04. Finally, TPO antibody positive individuals were found to have a higher risk of preterm birth compared to TPO antibody negative individuals by an odds ratio of 1.33 (Korevaar et al., 2019).

In a population-based study by Kiel et al. (2020) the use of thyroid hormone measurements in ambulatory care was assessed. Measurement of serum TSH, fT3, and fT4 within the 1-3 years prior to the study was reported. A total of 5,552 participants were included in the analysis, with 25% (1,409/5,552) having a diagnosed thyroid disorder or treatment. Of these, 30% (1626/5552) received at least one TSH measurement and 6.8% (378/5552) received at least one thyroid ultrasound. In the study, “TSH measurement rates were 1.7 times higher than the highest reported rate (438/1000), fT4 measurement rates were within the reported range (89/1000), and fT3 was measured at a 10- fold higher rate than the highest reported (89/1000).” The study results are in accordance with current guidelines, which recommend measuring TSH levels rather than fT4/fT3 both for patients with suspected hypo- and hyperthyroidism as well as for monitoring purposes. However, the data also suggests that fT4 and fT3 were tested at the same rate, even though fT4 is recommended as sufficient to distinguish between overt and subclinical hypothyroidism. Despite overuse of thyroid hormone testing, there is possible underuse in patients with diagnosed thyroid disorders who are taking thyroid medication. In the study, 40% did not receive a monitoring TSH test within 1 year, and 16% did not receive a TSH test within 3 years. The authors suggest that “Given the frequency of patients with thyroid disorders, diagnostic and monitoring tests should be used rationally with regard to costs. TSH levels should be monitored regularly in patients on thyroid medication” (Kiel et al., 2020).

In 2021, Degrandi et al. (2021) examined the prevalence of thyroid autoimmunity in children with developmental dyslexia. Serum TSH, fT3, and fT4 were measured and thyroid autoimmunity was evaluated by measuring TPOAbs and antithyroglobulin antibodies (TG-Abs). The authors also performed thyroid ultrasonography in the subjects with developmental dyslexia. The study enrolled 51 subjects with developmental dyslexia (M : F = 39 : 12, mean age 12.4 ± 9 years) and 34 controls (M : F = 24 : 10, mean age 10.8 ± 4 years) and found a significant increase in TPOAb positivity in subjects as compared to controls (60.8% vs 2.9%, p<0.001) but no significant change in TG-Ab positivity (16% vs 5.8%). Additionally, in the subjects with developmental dyslexia who received ultrasonography (49 of 51 subjects), 60% of them had a thyroiditis pattern. Overall, this study showed a high prevalence of thyroid autoimmunity in children with developmental dyslexia and while further research is needed to confirm these initial findings, these results may change the approach to developmental dyslexia and eventually lead to a systematic determination of thyroid autoimmunity in affected children (Degrandi et al., 2021).

Wang et al. (2021) examined the association between thyroid function and serum lipid metabolism, utilizing a genetic analysis termed Mendelian randomization (MR). While thyroid dysfunction is known to be associated with cardiovascular disease, the role of thyroid function in lipid metabolism is still partly unknown. “The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial” and for this study, the authors performed a two-sample MR to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). TSH, fT3 and fT4 levels, the fT3:fT4 ratio, and the concentration of TPOAb were all used to get a clinical measurement of thyroid function. Serum lipid metabolism traits included total cholesterol (TC) and triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels. To assess the association between thyroid function and serum lipid metabolism, the MR estimate and MR inverse variance-weighted method were used. The authors found that increased TSH levels were significantly associated with higher TC and LDL levels, as was the fT3:fT4 ratio. However, they observed no significant differences between genetically predicted fT4 and TPOAb and serum lipids. They concluded that their results suggest an association between thyroid function and serum lipid metabolism, “highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility” (Wang et al., 2021).

Toloza et al. (2022) performed a systematic review and meta-analyses of data collected from pregnant patients (excluding pre-existing thyroid disease and multifetal pregnancies) to analyze the primary outcomes of gestational hypertension and pre-eclampsia; data was taken from cohort studies that included maternal concentrations of TSH, FT4, and TPO antibodies as well as data regarding maternal gestational hypertension, pre-eclampsia, or both. The study comprised 46,528 pregnant individuals, of which 39,826 individuals had enough data to be classified by thyroid function status. Individuals who had subclinical hypothyroidism made up 3.2% of the cohort (1,275 individuals).  After analyses, a total of 933 individuals had isolated hypothyroxinemia, 619 had subclinical hyperthyroidism, and 337 had overt hyperthyroidism. The authors concluded that “compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia…In a continuous analysis, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia” (Toloza et al., 2022).

United States Preventive Services Task Force  (USPSTF)
The USPSTF states that “current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in non-pregnant, asymptomatic adults” (Rugge et al., 2015). In addition, USPSTF recommends against screening for thyroid cancer in asymptomatic adults (USPSTF, 2017).

American College of Obstetricians and Gynecologists (ACOG)
ACOG published an updated guideline regarding Thyroid Disease in Pregnancy in June 2020. The following recommendations are based on good and consistent scientific evidence (Level A): 

• “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.
• If indicated, the first-line screening test to assess thyroid status should be measurement of the TSH level.
• The TSH level should be monitored in pregnant women being treated for hypothyroidism, and the dose of levothyroxine should be adjusted accordingly with a goal TSH level between the lower limit of the reference range and 2.5 milliunits/L. Thyroid-stimulating hormone typically is evaluated every 4–6 weeks while adjusting medications.
• Pregnant women with overt hypothyroidism should be treated with adequate thyroid hormone replacement to minimize the risk of adverse outcomes.
• The level of free T4 should be monitored in pregnant women being treated for hyperthyroidism, and the dose of antithyroid drug (thioamide) should be adjusted accordingly to achieve a free T4 at the upper end of the normal pregnancy range. Among women who also have T3 thyrotoxicosis, total T3 should be monitored with a goal level at the upper end of normal pregnancy range.
• Pregnant women with overt hyperthyroidism should be treated with antithyroid drugs (thioamides).”

The following recommendation is based on limited or inconsistent scientific evidence (Level B):

• “Either propylthiouracil or methimazole, both thioamides, can be used to treat pregnant women with overt hyperthyroidism. The choice of medication is dependent on trimester of pregnancy, response to prior therapy, and whether the thyrotoxicosis is predominantly T4 or T3.”

The following recommendations are based primarily on consensus and expert opinion (Level C):

• “Indicated testing of thyroid function should be performed in women with a personal or family history of thyroid disease, type 1 diabetes mellitus, or clinical suspicion of thyroid disease.
• Measurements of thyroid function are not recommended in patients with hyperemesis gravidarum unless other signs of overt hyperthyroidism are evident.”

Other miscellaneous, relevant comments from ACOG include:

• “Indicated testing of thyroid function should be performed in women with a personal or family history of thyroid disease, type 1 diabetes mellitus, or clinical suspicion of thyroid disease… In a pregnant woman with a significant goiter or with distinct thyroid nodules, thyroid function studies are appropriate…”
• “In cases of suspected hyperthyroidism, total T3 also is measured...Total T3 is used preferentially over free T3 because assays for estimating free T3 are less robust than those measuring free T4…”
• “Routine testing for antithyroid peroxidase antibodies in women who are euthyroid (eg, no history of thyroid disease and normal thyroid function tests) is not recommended because thyroid hormone replacement for antithyroid peroxidase antibodies alone has not been found to improve pregnancy outcomes… Identification of thyroid antibodies including thyroid receptor antibodies and thyroid stimulating immunoglobulin in women with Graves disease may establish those at an increased risk for fetal or neonatal hyperthyroidism” (ACOG, 2020).

American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) 
The ATA and AACE support TSH testing for individuals with the following conditions: adrenal insufficiency, alopecia, unexplained anemia, unexplained cardiac dysrhythmia, skin texture changes, congestive heart failure, constipation, dementia, type 1 diabetes, dysmenorrhea, hypercholesterolemia, hypertension, mixed hyperlipidemia, malaise and fatigue, unexplained myopathy, prolonged QT interval, vitiligo, or weight gain. The guidelines also recommend assessing serum fT4 instead of total T4 to diagnose hypothyroidism except with pregnant patients. 
The ATA and AACE also provide recommendations for thyroid antibody testing including: 

• “Anti-thyroid peroxidase antibody (TPOAb¬) measurements should be considered when evaluating patients with subclin¬ical hypothyroidism.”
• TPOAb measurement should be considered in evaluation of patients with recurrent miscarriage, regardless of fertility. 
• “Measurement of [Thyrotropin receptor autoantibodies] TSHRAbs should be con¬sidered in hypothyroid pregnant patients with history of Graves’ disease if treated with radioactive iodine or thyroidectomy before pregnancy. This should be done either at 20-26 weeks of gestation or during the first trimester and if they are elevated, again at 20-26 weeks of gesta¬tion” (Garber et al., 2012).

The guidelines recommend against testing serum T3 or fT3, as well as use of clinical scoring systems to diagnose hypothyroidism. In patients with central hypothyroidism, the guidelines recommend assessing either fT4 or its index and to avoid testing for TSH (Garber et al., 2012). 

American Thyroid Association (ATA) 
Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum
In 2011, the ATA stated that it does not recommend “universal” TSH or free T4 screening of pregnant women or during the preconception period. It also included the following recommendations: 

Thyroid Function Tests in Pregnancy: Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake, should be applied. The ATA recommends these reference ranges: first trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L. 

The best method to assess serum fT4 during pregnancy is measurement of T4 in the dialysate or ultrafiltrate of serum samples employing LC/MS/MS. If this is not available, clinicians should use the next best method available. However, serum TSH is a more accurate indication of thyroid status in pregnancy than any of these alternative methods. Method-specific and trimester-specific reference ranges of serum fT4 are required. 

Thyrotoxicosis in Pregnancy: If the first trimester serum TSH appears low (<0.1 mIU/L), a history and physical examination are indicated. fT4 measurements should be obtained in all patients. Measurement of serum total T3 (TT3) and thyrotropin receptor antibodies (TRAb) may be helpful in establishing a diagnosis of hyperthyroidism. If the patient has a history of Graves' disease, a maternal serum sample of TRAb should be obtained at 20–24 weeks gestation. 

Thyroid Nodules and Thyroid Cancer: Treatment of thyroid nodules during pregnancy will depend on risk assessment. However, all women should have the following: a complete history and clinical examination, serum TSH testing, and ultrasound of the neck. Thyroid hormone therapy may be considered in pregnant women who have deferred surgery for well-differentiated thyroid carcinoma until postpartum. The goal of levothyroxine (LT4) therapy is a serum TSH level of 0.1–1.5 mIU/L. Furthermore, a preconception TSH goal (determined by risk assessment) should be set in women with differentiated thyroid cancer. This goal should be maintained during pregnancy with monitoring every 4 weeks until 16-20 weeks of gestation followed by once between 26 and 32 weeks of gestation.

Postpartum Thyroiditis (PPT): Women with postpartum depression should have TSH, fT4, and TPOAb tests performed. Women who are symptomatic with hypothyroidism in PPT should either have their TSH level retested in 4–8 weeks or be started on LT4 in certain situations (such as if symptoms are severe). Women who are asymptomatic with hypothyroidism in PPT should have their TSH level retested in 4–8 weeks. Finally, women with a history of PPT should have an annual TSH test to evaluate for permanent hypothyroidism.

Thyroid Function Screening in Pregnancy: There is insufficient evidence regarding universal TSH screening at the first trimester visit. Serum TSH values should be obtained early in pregnancy in the following women at high risk for overt hypothyroidism:

• History of thyroid dysfunction or prior thyroid surgery
• Age >30 years
• Symptoms of thyroid dysfunction or the presence of goiter
• TPOAb positivity
• Type 1 diabetes or other autoimmune disorders
• History of miscarriage or preterm delivery
• History of head or neck radiation
• Family history of thyroid dysfunction
• Morbid obesity (BMI ≥40 kg/m²)
• Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast
• Infertility
• Residing in an area of known moderate to severe iodine insufficiency (Stagnaro-Green et al., 2011)

The ATA published an update in 2017 for thyroid function testing during pregnancy. Recommendations include:

• Total T4 measurement (with a pregnancy-adjusted reference range) is reliable for estimating concentration late in pregnancy. A free thyroxine index can also estimate fT4 well.
• Euthyroid and TPO or Tg antibody positive pregnant women should have serum TSH concentration measured at the start of pregnancy and every 4 weeks through mid-pregnancy.
• All women seeking care for infertility are recommended to have serum TSH levels measured.
• Pregnant women with TSH concentrations >2.5 mU/L should be evaluated for TPO antibodies.
• Women with hypothyroidism or those at risk for hypothyroidism (e.g. patients who are euthyroid but TPO or TGAb positive) should be monitored with a serum TSH measurement every 4 weeks until mid-gestation, and at least once near 30 weeks.
• “When a suppressed serum TSH is detected in the first trimester (TSH less than the reference range), a medical history, physical examination, and measurement of maternal serum FT4 or TT4 concentrations should be performed. Measurement of TRAb and maternal TT3 may prove helpful in clarifying the etiology of thyrotoxicosis”
• In women being treated with antithyroid drugs [ATDs] in pregnancy, fT4/TT4 and TSH should be monitored every 4 weeks.
• “All patients with depression, including postpartum depression, should be screened for thyroid dysfunction.”
• “Evaluation of serum TSH concentration is recommended for all women seeking care for infertility.”
• “If the patient has a past history of GD [Graves Disease] treated with ablation (radioiodine or surgery), a maternal serum determination of TRAb is recommended at initial thyroid function testing during early pregnancy. If maternal TRAb concentration is elevated in early pregnancy, repeat testing should occur at weeks 18–22.
• “If the patient requires treatment with ATDs for GD through mid-pregnancy, a repeat determination of TRAb is again recommended at weeks 18–22. If elevated TRAb is detected at weeks 18–22 or the mother is taking ATD in the third trimester, a TRAb measurement should again be performed in late pregnancy (weeks 30–34) to evaluate the need for neonatal and postnatal monitoring.”
• “The utility of measuring calcitonin in pregnant women with thyroid nodules is unknown. The task force cannot recommend for or against routine measurement of serum calcitonin in pregnant women with thyroid nodules.”
• “All newborns should be screened for hypothyroidism by blood spot analysis typically 2–5 days after birth.”
• “Following the resolution of the thyrotoxic phase of PPT, serum TSH should be measured in approximately 4–8 weeks (or if new symptoms develop) to screen for the hypothyroid phase.”
• “Women with a prior history of PPT should have TSH testing annually to evaluate for the development of permanent hypothyroidism”
• “There is insufficient evidence to recommend for or against universal screening for abnormal TSH concentrations in early pregnancy.
• “There is insufficient evidence to recommend for or against universal screening for abnormal TSH concentrations preconception, with the exception of women planning assisted reproduction or those known to have TPOAb positivity”
• “Universal screening to detect low FT4 concentrations in pregnant women is not recommended” (Alexander et al., 2017).

The guideline also lists certain populations of pregnant women that should have serum TSH measured “as soon as pregnancy is confirmed” due to presence of risk factors of thyroid disease. These risk factors include “history of thyroid dysfunction, symptoms or signs of thyroid dysfunction, presence of a goiter, and known thyroid antibody positivity…age >30 years, history of diabetes mellitus type 1, or other autoimmune disorders, history of pregnancy loss, preterm delivery or infertility, history of head or neck radiation or prior thyroid surgery, family history of autoimmune thyroid disease or thyroid dysfunction, morbid obesity, use of amiodarone, lithium, or recent administration of iodinated radiologic contrast, two or more prior pregnancies, and residing in area of moderate to severe iodine deficiency” (Alexander et al., 2017).

ATA, Task Force on Thyroid Hormone Replacement for Hypothyroidism Treatment (2014)
The ATA recommended LT4 as the primary treatment of choice for hypothyroidism due to overall efficacy, low cost, and lack of side effects. The ATA also states that great care should be taken to monitor dose diligently especially in pregnant women, as excessive LT4 can have dangerous side effects (Jonklaas et al., 2014).

ATA, Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016)
The ATA recommends that the cause of the thyrotoxicosis should be determined. Initial diagnostic tests include measurement of TRAb, radioactive iodine uptake, or measurement of thyroidal blood flow on ultrasonography. The guidelines also note that serum TSH is the most accurate and should be the first screening test done, but if thyrotoxicosis is suspected, it is helpful to test fT4 and T3. 

The ATA recommends treatment of subclinical hyperthyroidism (persistent TSH <0.1 mU/L) for the high-risk populations such as those with cardiac risk factors or those older than 65. Treatment of asymptomatic and otherwise healthy individuals may be considered. The ATA also recommends testing TRAb in pregnant women with unknown hyperthyroidism. A diagnosis of hyperthyroidism should made with the serum TSH values and trimester-specific reference ranges for T4 and T3 (Ross et al., 2016).

American Academy of Family Physicians (AAFP)
The AAFP has recommended this diagnostic workup for hyperthyroidism: “measuring TSH, free (T4), and total T3 levels to determine the presence and severity of the condition, as well as radioactive iodine uptake and scan of the thyroid to determine the cause.” The level of this evidence is C which is a consensus, disease-oriented evidence, usual practice, expert opinion, or case series (Kravets, 2016). The AAFP also recommends using TSH testing to diagnose primary hypothyroidism (Level C) (AAFP, 2012). 
In the case of subclinical thyroid disease, the AAFP recommends that “Physicians should not routinely screen for subclinical thyroid disease” (Donangelo & Suh, 2017). Moreover, the AAFP reaffirms its support for the USPSTF stance on thyroid dysfunction, stating that there is no evidence that population screening is beneficial and that “Screening for thyroid dysfunction in nonpregnant, asymptomatic individuals has uncertain risks and benefits” as there has been a dearth of studies comparing the benefits of harms of screening against no screening (AAFP, 2018; Wilson et al., 2021). 

American Academy of Pediatrics - Section on Endocrinology 
The American Academy of Pediatrics recommends against routinely measuring thyroid function or insulin levels in obese children, as well as screening healthy children for thyroid problems (AAP, 2017).

American Thyroid Association 
The American Thyroid Association recommends that “the appropriate management of abnormal maternal thyroid tests attributable to gestational transient thyrotoxicosis and/or hyperemesis gravidarum includes supportive therapy, management of dehydration, and hospitalization if needed. Antithyroid drugs are not recommended, though β-blockers may be considered.  In women being treated with antithyroid drugs in pregnancy, FT4/TT4 and thyroid hormone secretion should be monitored approximately every 4 weeks. Antithyroid medication during pregnancy should be administered at the lowest effective dose of MMI or PTU, targeting maternal serum FT4/TT4 at the upper limit or moderately above the reference range. A combination regimen of LT4 and antithyroid drugs should not be used in pregnancy, except in the rare situation of isolated fetal hyperthyroidism” (Alexander et al., 2017). 

Australian Journal of General Practice 
The Australian Journal of General Practice recommends “couples with two of more pregnancy losses     should have thyroid antibody and function testing performed. Abnormal results should be managed by a specialized clinic. There is evidence that suggests hypothyroidism and even subclinical hypothyroidism is associated with recurrent pregnancy loss. All guidelines recommend testing for thyroid-stimulating hormone (TSH) levels, but there is contention about what is considered a ‘normal’ TSH. Current guidelines suggest treating all women with overt hypothyroidism, considering treatment of subclinical hypothyroidism, and not treating euthyroid patients with recurrent pregnancy loss who test positive for thyroid antibodies” (Hong Li & Marren, 2018).

Joint Task Force on Practice Parameters (JTFPP) of the Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology 
The JTFPP within their guidelines concerning the diagnosis and management of acute and chronic urticaria state, “Targeted laboratory testing based on history or physical examination findings is appropriate, and limited laboratory testing can be obtained. Limited laboratory testing includes a CBC with differential, sedimentation rate, and/or C-reactive protein, liver enzyme, and thyroid-stimulating hormone (TSH) measurement… Targeted laboratory testing based on history and/or physical examination (eg, obtaining TSH in a patient with weight gain, heat/cold intolerance, and thyromegaly) is recommended” (Bernstein et al., 2014).

American Society for Clinical Pathology (ASCP)
The American Society for Clinical Pathology recommends against ordering multiple tests for an initial evaluation for a patient with a suspected thyroid condition. The ASCP recommends starting with TSH and proceeding from that result. Any diagnosis made by the physician should be confirmed with free thyroxine (T4) testing. (ASCP, 2015). 
On September 1, 2020, ASCP released a recommendation to avoid TSH screening in annual well-visits for asymptomatic adults, regardless of age, as there is no evidence to support that routine screening improves patient care. ASCP advises TSH screening when patients are considered at-risk or demonstrate subtle or direct signs of thyroid dysfunction upon physical evaluation (ASCP, 2020). 

American Family Physician
The American Family Physician recommends “the term failure to thrive should be used as a clinical finding and not as a diagnosis. Recognition depends on reliable and valid measurements over time; therefore, serial measurements of weight and height must be accurately obtained and charted on an appropriate reference scale. No standard set of laboratory tests is recommended for failure to thrive. A thorough history and physical examination may be all that is indicated to initiate treatment. If used, reasonable initial laboratory testing includes complete blood count, urinalysis, electrolyte measurement, thyroid tests, and testing for celiac disease. Specific testing for cystic fibrosis, food allergies, human immunodeficiency virus infection, or tuberculosis may be indicated depending on the presentation. Additional testing should be specific for a suspected diagnosis based on history and physical examination findings” (Homan, 2016). 

Endocrine Society 
The Endocrine Society recommends against testing for total or free T3 when evaluating LT4 dose in hypothyroid patients. They also recommend against ordering routine ultrasounds for patients without palpable abnormalities of the thyroid. While routine thyroid ultrasounds should not be ordered without palpable abnormalities, thyroid vascularity assessments may be performed by color flow Doppler in patients who show overt hyperthyroidism evidenced by elevated free T4 and T3 and lower TSH values; color flow Doppler (a noninvasive ultrasound test) may help diagnose Graves’ hyperthyroidism and toxic nodular goiter from destructive thyroiditis  (Endocrine Society, 2022).

European Thyroid Association (ETA) 
Management of Thyroid Dysfunction following Immune Reconstitution Therapy (IRT) (Kahaly et al., 2018; Muller et al., 2019)

This guideline discusses IRT in the context of three clinical situations; “alemtuzumab (Lemtrada) treatment for active relapsing remitting multiple sclerosis (MS); (2) after treatment of human immunodeficiency virus (HIV) infected patients with highly active antiretroviral therapy (HAART); (3) following allogeneic bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT)”.

The ETA recommends measuring TSH in all subjects before IRT. If TSH is abnormal, fT4 and fT3 are recommended to be measured.
Routine measurement of TPOAb or TRAb is not recommended before IRT.

TSH measurement is recommended post-IRT, and fT4 may also be routinely measured. If TSH is low (0.10–0.39 mU/L), another test is recommended within 1 month. If TSH is elevated, a repeat TSH test is recommended, along with fT4. If TSH is “suppressed” (<0.10 mU/L), TSH, fT4, and fT3 are recommended to be tested.

Following alemtuzumab, the ETA recommends “biochemical follow-up” with TSH testing every 3 months. Routine TSH monitoring is not recommended following HAART treatment in HIV patients, although TSH measurement should be performed if thyroid dysfunction is suspected.

Routine measurement of thyroid autoantibodies is not recommended in euthyroid patients during surveillance. 
The ETA recommends “routine 3 monthly measuring of thyroid function to be continued for 4 years following the last alemtuzumab treatment” (Muller et al., 2019).

Thyroid Disorders Prior to and during Assisted Reproduction
The ETA recommends women of subfertile couples (“subfertile” is defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse) should be screened routinely for the presence of thyroid disorders. The ETA notes that severe thyroid dysfunction is linked to menstrual disorders as well as subfertility. In a meta-analyses that included mostly women with TSH levels above 4.0 mIU/L, treatment with levothyroxine was effective at increasing live birth rates (Poppe et al., 2021).

Management of Graves’ Hyperthyroidism 
The ETA notes measurement of TSH-R-stimulating antibody (TSH-R-Ab) as a “sensitive and specific” tool for rapid and accurate differential diagnosis for Graves’ hypothyroidism. Differentiation of TSH-R-Ab is also “helpful and predictive” in Graves’ patients during pregnancy/postpartum, as well as extrathyroidal manifestations. 

The ETA also remarks that measurement of TSH-R-Ab levels prior to stopping antithyroid drug treatment (ATD). 

For pregnant patients, maternal fT4 and TSH should be measured every 2 weeks after initiation of therapy, every 4 weeks after achieving the target value. All patients with history of autoimmune thyroid disease should have their TSH-R-Ab levels tested at first presentation with pregnancy, and if maternal TSH-R-Ab remains high (>3 times normal cutoff), monitoring the fetus for thyroid dysfunction throughout pregnancy is recommended (Kahaly et al., 2018).

In 2022, the ETA published guidelines for the management of GD in pediatric patients. Hyperthyroidism caused by GD is relatively rare in children and treatment options for pediatric patients are the same as those available to adults (ATD, radioactive iodine (RAI), or thyroid surgery). However, the risks and benefits of each modality are different in pediatric patients than they are in adult patients. The ETA recommends that “clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases” (Mooij et al., 2022).

Diagnosis and Management of Central Hypothyroidism
The ETA also published a guideline regarding central hypothyroidism (CeH). Below are the relevant recommendations:

• “We recommend that the diagnosis of CeH should be considered in every subject with low serum concentrations of FT4 and low or normal TSH on a screening examination.
• We recommend that the diagnosis of CeH should be considered in neonates and children with clinical manifestations of congenital hypothyroidism but low or normal neonatal TSH screening.
• We suggest that the diagnosis of CeH should be considered in patients with a low serum concentration of FT4 and slight TSH elevations (< 10 mU/L, or inappropriately lower than expected on the basis of the hypothyroid state).
• We recommend screening for CeH all children with a familial history of CeH and/or failure to thrive, developmental delay, GH deficiency, delayed or precocious puberty, or other hypothalamic-pituitary defects or lesions.
• We recommend that CeH due to immunoglobulin superfamily member 1 (IGSF1) defect should be ruled out in adolescents or adult patients with macroorchidism.
• We recommend screening for CeH all patients with a personal or familial history of hypothalamic-pituitary lesions or diseases, moderate to severe head trauma, stroke, previous cranial irradiation, hemochromatosis or iron overload, in particular when hypothyroid manifestations are present.
• We recommend screening for CeH all patients with hypothyroid manifestations associated with clinical findings pointing to a hypothalamic-pituitary disease (e.g., hyperprolactinemia, acromegalic features, diabetes insipidus, recurrent headaches, visual field defects), newborns with hypotonia and/or prolonged jaundice, and/or signs of congenital hypopituitarism (e.g., micropenis with undescended testes), as well as children with developmental delay.
• We recommend that the onset of CeH should be evaluated in patients with hypothalamic/pituitary disease after the start of treatment with recombinant human growth hormone (rhGH) or estrogen.
• We recommend that the onset of CeH should be evaluated in patients on treatments with ligands of the retinoid X receptor (RXR), ipilimumab (or other checkpoint inhibitors), or mitotane.”

Regarding diagnosis of CeH, the guideline recommends the following:

• “We recommend the combined determination of serum FT4 and TSH in order to evaluate the presence of CeH.
• We recommend that CeH diagnosis should be confirmed by the combined findings of serum FT4 concentrations below the lower limit of the normal range and inappropriately low/normal TSH concentrations on at least two separate determinations, and after exclusion of the conditions reported in Table 3.
• The isolated finding of low FT3 or total T3 concentrations is not indicative of CeH, but rather of nonthyroidal illness or deiodination defects (e.g., selenocysteine (Sec) insertion sequence-binding protein 2 (SBP2) gene defect).
• In patients under follow-up for hypothalamic-pituitary disease, FT4 and TSH should be monitored during childhood at least biannually and later on a yearly basis, and we suggest that CeH diagnosis should be considered when serum FT4 falls in the lower quartile of the normal range, in particular when a FT4 decrease > 20% of previous values is seen (provided that the variables are measured by the same assay) despite a low or normal TSH.
• We suggest that the diagnosis of mild CeH (borderline low FT4, with inappropriately low TSH) should be supported by a combination of several other findings summarized in Table 4 (the relative application and importance of these tests and findings may vary in different settings).

National Institute for Health and Care Excellence 
Thyroid Disease: Assessment and Management
NICE states to “consider” thyroid dysfunction tests for adults, children, and “young people” for the following indications:

• “a clinical suspicion of thyroid disease”
• New-onset atrial fibrillation
• Type 1 diabetes or other autoimmune disease
• Depression or unexplained anxiety
• For children and young people, consider tests for abnormal growths or unexplained change in behavior or school performance

NICE states not to test for thyroid dysfunction if a patient only has type 2 diabetes or if the patient has an unrelated acute illness.

If secondary thyroid disease (pituitary disease) is not suspected, NICE states to “consider” measuring TSH. If TSH is “above reference range”, measure fT4 in same sample; if TSH is “below reference range”, measure fT4 and fT3 in same sample.

Measurement of both TSH and fT4 is to be considered for children or young people or if secondary thyroid dysfunction is suspected in adults. If TSH is below the reference range, fT3 should be measured. If symptoms in the above situations worsen, repeat the algorithms.

For adults with TSH levels above the reference range, TPOAb measurement may be considered. However, this testing should not be repeated. This applies to primary and subclinical hypothyroidism.

For children and young people, this measurement should be repeated when they become adults. 

“For adults who are taking levothyroxine for primary hypothyroidism, consider measuring TSH every 3 months until the level has stabilised (2 similar measurements within the reference range 3 months apart), and then once a year.” For adults with hypothyroidism symptoms after starting levothyroxine, consider measuring fT4 along with TSH.

For children ages 2 and over and young people taking levothyroxine for primary hypothyroidism, consider measuring fT4 and TSH at the following intervals:
“every 6 to 12 weeks until the TSH level has stabilised (2 similar measurements within the reference range 3 months apart), then every 4 to 6 months until after puberty, then once a year.”

For children under 2, consider measuring fT4 and TSH at the following intervals:

“every 4 to 8 weeks until the TSH level has stabilised (2 similar measurements within the reference range 2 months apart), then every 2 to 3 months during the first year of life, and every 3 to 4 months during the second year of life.”

For adults with untreated subclinical hypothyroidism or adults that have stopped treatment, consider measuring TSH and fT4 once a year if they are symptomatic, or once every 2-3 years if they are asymptomatic. 

NICE states to consider measuring fT4 and TSH for children 2 and over with untreated subclinical hypothyroidism and TSH <10 mlU/liter at the following intervals: “every 3 to 6 months if they have features suggesting underlying thyroid disease, such as thyroid dysgenesis (an underdeveloped thyroid gland) or raised levels of thyroid autoantibodies, or every 6 to 12 months if they have no features suggesting underlying thyroid disease.”

“Every 1-3 months for children ages 28 days-2 years with untreated subclinical hypothyroidism”. TSH measurements may be stopped in children and young people if TSH has stabilized (defined as “2 similar measurements within the reference range 3 to 6 months apart”) and there are no underlying features suggesting thyroid disease. 

Differentiating between thyrotoxicosis with hyperthyroidism and thyrotoxicosis without hyperthyroidism may be performed by measuring TSH receptor antibodies (TRAbs). In children and young people, measuring TPOAbs and TRAbs may be done to differentiate. 

After radioactive iodine treatment, consider measuring fT3, fT4, and TSH every 6 weeks for the first 6 months, until TSH is within reference range. '

“For adults, children and young people with TSH in the reference range 6 months after radioactive iodine treatment, consider measuring TSH (with cascading) at 9 months and 12 months after treatment.”

“For adults, children and young people with TSH in the reference range 12 months after radioactive iodine treatment, consider measuring TSH (with cascading) every 6 months unless they develop hypothyroidism”

For patients taking antithyroid drugs for hyperthyroidism, consider measuring TSH, FT4, and FT3 every 6 weeks until TSH is within reference range, then TSH (with cascading) every 3 months until antithyroid drugs are stopped. 

“For adults who have stopped antithyroid drugs, consider measuring: TSH (with cascading) within 8 weeks of stopping the drug, then TSH (with cascading) every 3 months for a year, then TSH (with cascading) once a year.”

“For children and young people who have stopped antithyroid drugs, consider measuring: TSH, FT4 and FT3 within 8 weeks of stopping the drug, then TSH, FT4 and FT3 every 3 months for the first year, then TSH (with cascading) every 6 months for the second year, then TSH (with cascading) once a year.”

“Consider measuring TSH every 6 months for adults with untreated subclinical hyperthyroidism. If the TSH level is outside the reference range, consider measuring FT4 and FT3 in the same sample.”

“Consider measuring TSH, FT4 and FT3 every 3 months for children and young people with untreated subclinical hyperthyroidism.”

“Consider stopping TSH measurement for adults, children and young people with untreated subclinical hyperthyroidism if the TSH level stabilizes (2 similar measurements within the reference range 3 to 6 months apart)” (NICE, 2019).

Society for Maternal-Fetal Medicine (SMFM)
The SMFM recommends against screening asymptomatic pregnant women for subclinical hypothyroidism (SMFM, 2019). The SMFM states that “thyroid testing in pregnancy should be conducted for women “at risk,” including known thyroid disease, symptoms of overt thyroid disease, suspected goiter, autoimmune medical disorders such as Type 1 diabetes mellitus”, but also asserts that “routine treatment of subclinical hypothyroidism is not recommended” and “routine thyroid testing of women with hyperemesis gravidarum is not recommended” (Society for Maternal-Fetal Medicine, 2014). 

Mitochondrial Medicine Society (MMS)
In 2017, the MMS created a working group to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. From the guidelines, “initial triage stratification of critically ill mitochondrial patients should include a systemic assessment of all body systems since the disease is multisystemic and patients may develop new organ system involvement during an acute decompensation” and thyroid dysfunction can occur in patients with mitochondrial disease, as “both hypothyroidism and, to a far lesser extent, hyperthyroidism have been reported in patients with primary mitochondrial diseases.” In addition to routine intensive-care management that might be undertaken for a critically ill patient, they recommend that “thyroid and adrenal function should be assessed in patients at times of critical illness and reassessed during a prolonged intensive care unit stay. Hypo- and hyperglycemia can occur and regular blood glucose monitoring is needed.” They also state that “an annual hemoglobin A1c (HgbA1c), thyroid-stimulating hormone, free thyroxine level (FT4), vitamin D, and screening for hypoparathyroidism (serum calcium, magnesium, phosphate, parathyroid hormone, vitamin D (25-OHD and 1,25-OHD); urine: creatinine, calcium, and phosphate) can be considered in individuals with mitochondrial diseases. In those with mtDNA deletions, which are more strongly associated with secondary endocrinopathies, annual screening is recommended” (Parikh et al., 2017).
 

References 

1. AACE. (2023). All About the Thyroid. https://www.aace.com/disease-and-conditions/thyroid/all-about-thyroid
2. AAFP. (2012). Hypothyroidism: An Update. https://www.aafp.org/afp/2012/0801/p244.html
3. AAFP. (2018). Thyroid Dysfunction Screening. https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/thyroid-dysfunction.html 
4. AAP. (2017).  http://www.choosingwisely.org/clinician-lists/aap-soen-avoid-measuring-thyroid-function-and-insulin-levels-in-obese-children/
5. ACOG. (2020). Thyroid Disease in Pregnancy: ACOG Practice Bulletin, Number 223. Obstet Gynecol, 135(6), e261-e274. https://doi.org/10.1097/aog.0000000000003893 
6. Alexander, E. K., Pearce, E. N., Brent, G. A., Brown, R. S., Chen, H., Dosiou, C., Grobman, W. A., Laurberg, P., Lazarus, J. H., Mandel, S. J., Peeters, R. P., & Sullivan, S. (2017). 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid, 27(3), 315-389. https://doi.org/10.1089/thy.2016.0457 
7. ASCP. (2015). http://www.choosingwisely.org/clinician-lists/american-society-clinical-pathology-suspected-thyroid-disease-evaluation/ 
8. ASCP. (2020). American Society for Clinical Pathology. https://www.choosingwisely.org/clinician-lists/ascp32-avoid-thyroid-stimulating-hormone-tsh-screening-in-annual-well-visits-for-asymptomatic-adults-regardless-of-age/ 
9. Bernstein, J. A., Lang, D. M., Khan, D. A., Craig, T., Dreyfus, D., Hsieh, F., Sheikh, J., Weldon, D., Zuraw, B., Bernstein, D. I., Blessing-Moore, J., Cox, L., Nicklas, R. A., Oppenheimer, J., Portnoy, J. M., Randolph, C. R., Schuller, D. E., Spector, S. L., Tilles, S. A., & Wallace, D. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5), 1270-1277. https://doi.org/10.1016/j.jaci.2014.02.036 
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16. Endocrine Society. (2022). Don’t routinely order a thyroid ultrasound in patients with abnormal thyroid function tests if there is no palpable abnormality of the thyroid gland. http://www.choosingwisely.org/clinician-lists/endocrine-society-thyroid-ultrasounds-in-patients-with-abnormal-thyroid-function-tests/
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19. Gholve, C., Kumarasamy, J., Kulkarni, S., & Rajan, M. G. R. (2017). In-House Solid-Phase Radioassay for the Detection of Anti-thyroglobulin Autoantibodies in Patients with Differentiated Thyroid Cancer. Indian J Clin Biochem, 32(1), 39-44. https://doi.org/10.1007/s12291-016-0568-7 
20. Gomes-Lima, C., & Burman, K. D. (2018). Reverse T3 or perverse T3? Still puzzling after 40 years. Cleve Clin J Med, 85(6), 450-455. https://doi.org/10.3949/ccjm.85a.17079 
21. Homan, G. J. (2016). Failure to Thrive: A Practical Guide. Am Fam Physician, 94(4), 295-299. https://www.ncbi.nlm.nih.gov/pubmed/27548594 
22. Hong Li, Y., & Marren, A. (2018). Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust J Gen Pract, 47(7), 432-436. https://doi.org/10.31128/AJGP-01-18-4459 
23. Jin, H. Y. (2018). Prevalence of subclinical hypothyroidism in obese children or adolescents and association between thyroid hormone and the components of metabolic syndrome. J Paediatr Child Health, 54(9), 975-980. https://doi.org/10.1111/jpc.13926 
24. Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., & Sawka, A. M. (2014). Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid, 24(12), 1670-1751. https://doi.org/10.1089/thy.2014.0028 
25. Kahaly, G. J., Bartalena, L., Hegedus, L., Leenhardt, L., Poppe, K., & Pearce, S. H. (2018). 2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism. Eur Thyroid J, 7(4), 167-186. https://doi.org/10.1159/000490384 
26. Kazerouni, F., & Amirrasouli, H. (2012). Performance characteristics of three automated immunoassays for thyroid hormones. Caspian J Intern Med, 3(2), 400-104. 
27. Kiel, S., Ittermann, T., Völzke, H., Chenot, J.-F., & Angelow, A. (2020). Frequency of thyroid function tests and examinations in participants of a population-based study. BMC Health Services Research, 20(1), 70. https://doi.org/10.1186/s12913-020-4910-7 
28. Kluesner, J. K., Beckman, D. J., Tate, J. M., Beauvais, A. A., Kravchenko, M. I., Wardian, J. L., Graybill, S. D., Colburn, J. A., Folaron, I., & True, M. W. (2018). Analysis of current thyroid function test ordering practices. J Eval Clin Pract, 24(2), 347-352. https://doi.org/10.1111/jep.12846 
29. Korevaar, T. I. M., Derakhshan, A., Taylor, P. N., Meima, M., Chen, L., Bliddal, S., Carty, D. M., Meems, M., Vaidya, B., Shields, B., Ghafoor, F., Popova, P. V., Mosso, L., Oken, E., Suvanto, E., Hisada, A., Yoshinaga, J., Brown, S. J., Bassols, J., . . . Peeters, R. P. (2019). Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis. Jama, 322(7), 632-641. https://doi.org/10.1001/jama.2019.10931 
30. Kravets, I. (2016). Hyperthyroidism: Diagnosis and Treatment. Am Fam Physician, 93(5), 363-370. 
31. LetsGetChecked. (2023). Home Thyroid Testing. https://www.letsgetchecked.com/home-thyroid-test/ 
32. Leung, A. M., & Brent, G. A. (2016). The Influence of Thyroid Hormone on Growth Hormone Secretion and Action. In L. E. Cohen (Ed.), Growth Hormone Deficiency: Physiology and Clinical Management (pp. 29-46). Springer International Publishing. https://doi.org/10.1007/978-3-319-28038-7_4 
33. Li, D., Radulescu, A., Shrestha, R. T., Root, M., Karger, A. B., Killeen, A. A., Hodges, J. S., Fan, S. L., Ferguson, A., Garg, U., Sokoll, L. J., & Burmeister, L. A. (2017). Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults. Jama, 318(12), 1150-1160. https://doi.org/10.1001/jama.2017.13705 
34. Livingston, M., Birch, K., Guy, M., Kane, J., & Heald, A. H. (2015). No role for tri-iodothyronine (T3) testing in the assessment of levothyroxine (T4) over-replacement in hypothyroid patients. Br J Biomed Sci, 72(4), 160-163. 
35. Luewan, S., Chakkabut, P., & Tongsong, T. (2011). Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch Gynecol Obstet, 283(2), 243-247. https://doi.org/10.1007/s00404-010-1362-z 
36. Masika, L. S., Zhao, Z., & Soldin, S. J. (2016). Is measurement of TT3 by immunoassay reliable at low concentrations? A comparison of the Roche Cobas 6000 vs. LC-MSMS. Clin Biochem, 49(12), 846-849. https://doi.org/10.1016/j.clinbiochem.2016.02.004 
37. Mooij, C. F., Cheetham, T. D., Verburg, F. A., Eckstein, A., Pearce, S. H., Leger, J., & van Trotsenburg, A. S. P. (2022). 2022 European Thyroid Association Guideline for the management of pediatric Graves' disease. Eur Thyroid J, 11(1). https://doi.org/10.1530/ETJ-21-0073 
38. Muller, I., Moran, C., Lecumberri, B., Decallonne, B., Robertson, N., Jones, J., & Dayan, C. M. (2019). 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy. European Thyroid Journal, 8(4), 173-185. https://doi.org/10.1159/000500881 
39. Muraresku, C. C., McCormick, E. M., & Falk, M. J. (2018). Mitochondrial Disease: Advances in clinical diagnosis, management, therapeutic development, and preventative strategies. Curr Genet Med Rep, 6(2), 62-72. https://doi.org/10.1007/s40142-018-0138-9 
40. myLABBOX. (2023). At Home Thyroid Health Screening Test. Retrieved January 3, 2023 from https://www.mylabbox.com/product/at-home-thyroid-health-screening-test/
41. NICE. (2019). Thyroid disease: assessment and management. https://www.nice.org.uk/guidance/ng145 
42. Paloma_Health. (2023). Complete Thyroid Blood Test Kit. https://www.palomahealth.com/home-thyroid-blood-test-kit
43. Parikh, S., Goldstein, A., Karaa, A., Koenig, M. K., Anselm, I., Brunel-Guitton, C., Christodoulou, J., Cohen, B. H., Dimmock, D., Enns, G. M., Falk, M. J., Feigenbaum, A., Frye, R. E., Ganesh, J., Griesemer, D., Haas, R., Horvath, R., Korson, M., Kruer, M. C., . . . Chinnery, P. F. (2017). Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med, 19(12). https://doi.org/10.1038/gim.2017.107 
44. Poppe, K., Bisschop, P., Fugazzola, L., Minziori, G., Unuane, D., & Weghofer, A. (2021). 2021 European Thyroid Association Guideline on Thyroid Disorders prior to and during Assisted Reproduction. European Thyroid Journal, 9(6), 281-295. https://doi.org/10.1159/000512790 
45. Richmond, E. J., & Rogol, A. D. (2022). Causes of short stature. https://www.uptodate.com/contents/causes-of-short-stature
46. Ross, D. S. (2022a). Diagnosis of and screening for hypothyroidism in nonpregnant adults. https://www.uptodate.com/contents/diagnosis-of-and-screening-for-hypothyroidism-in-nonpregnant-adults
47. Ross, D. S. (2022b). Diagnosis of hyperthyroidism https://www.uptodate.com/contents/diagnosis-of-hyperthyroidism
48. Ross, D. S. (2022c). Laboratory assessment of thyroid function. https://www.uptodate.com/contents/laboratory-assessment-of-thyroid-function
49. Ross, D. S. (2022d). Overview of thryoid disease and pregnancy. UpToDate. https://www.uptodate.com/contents/overview-of-thyroid-disease-and-pregnancy
50. Ross, D. S., Burch, H. B., Cooper, D. S., Greenlee, M. C., Laurberg, P., Maia, A. L., Rivkees, S. A., Samuels, M., Sosa, J. A., Stan, M. N., & Walter, M. A. (2016). 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid, 26(10), 1343-1421. https://doi.org/10.1089/thy.2016.0229 
51. Rugge, J. B., Bougatsos, C., & Chou, R. (2015). Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med, 162(1), 35-45. https://doi.org/10.7326/m14-1456 
52. Sarkar, D. (2012). Recurrent pregnancy loss in patients with thyroid dysfunction. Indian J Endocrinol Metab, 16(Suppl 2), S350-351. https://doi.org/10.4103/2230-8210.104088 
53. SMFM. (2019). Don’t screen asymptomatic pregnant women for subclinical hypothyroidism. http://www.choosingwisely.org/clinician-lists/smfm-screening-for-subclinical-hypothyroidism/ 
54. Society for Maternal-Fetal Medicine. (2014). Screening for thyroid disease in pregnancy. Society for Maternal-Fetal Medicine. https://www.smfm.org/publications/88-screening-for-thyroid-disease-in-pregnancy
55. Stagnaro-Green, A., Abalovich, M., Alexander, E., Azizi, F., Mestman, J., Negro, R., Nixon, A., Pearce, E. N., Soldin, O. P., Sullivan, S., & Wiersinga, W. (2011). Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid, 21(10), 1081-1125. https://doi.org/10.1089/thy.2011.0087 
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58. Toloza, F. J. K., Derakhshan, A., Männistö, T., Bliddal, S., Popova, P. V., Carty, D. M., Chen, L., Taylor, P., Mosso, L., Oken, E., Suvanto, E., Itoh, S., Kishi, R., Bassols, J., Auvinen, J., López-Bermejo, A., Brown, S. J., Boucai, L., Hisada, A., . . . Maraka, S. (2022). 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, 10(4), 243-252. https://doi.org/10.1016/s2213-8587(22)00007-9 
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Coding Section  

Codes	Number	Description
CPT	80438	Thyrotropin releasing hormone (trh) stimulation panel; 1 hour This panel must include the following: Thyroid stimulating hormone (tsh) (84443 x 3)
	80439	Thyrotropin releasing hormone (trh) stimulation panel; 2 hour This panel must include the following: Thyroid stimulating hormone (tsh) (84443 x 4)
	83519	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, by radioimmunoassay (e.g., RIA)
	84432	Thyroglobulin
	84436	Thyroxine; total
	84439	Thyroxine; free
	84442	Thyroxine binding globulin (TBG)
	84443	Thyroid stimulating hormone (TSH)
	84445	Thyroid stimulating immune globulins (TSI)
	84479	Thyroid hormone (T3 or T4) uptake or thyroid hormone binding ratio (THBR)
	84480	Triiodothyronine T3; total (TT-3)
	84481	Triiodothyronine T3; free
	84482	Triiodothyronine T3; reverse
	86376	Microsomal antibodies (e.g., thyroid or liver-kidney), each
	86800	Thyroglobulin antibody
ICD-10-CM	C25.4	Malignant neoplasm of endocrine pancreas
	C73	Malignant neoplasm of thyroid gland
	C74	Malignant neoplasm of adrenal gland
	C75	Malignant neoplasm of other endocrine glands and related structures
	D35.00, D35.01, D35.02	Benign neoplasm of other and unspecified endocrine glands
	D44	Neoplasm of unspecified behavior of endocrine glands
	D49.7	Neoplasm of unspecified behavior of endocrine glands
	D84.821	Immunodeficiency due to drugs
	E00.0-E00.9	Congenital iodine-deficiency syndrome
	E01.0-E01.8	Iodine-deficiency related thyroid disorders and allied conditions
	E03.0-E03.9	Other Hypothyroidism
	E05.0-E05.9	Hyperthyroidism
	E06.0-E06.9	Thyroiditis
	E07.0-E07.9	Other disorders of thyroid
	E10.21-E10.9	Type 1 diabetes mellitus
	E20.0-E20.9	Hypoparathyroidism
	E21.0-E21.5	Hyperparathyroidism and other disorders of parathyroid gland
	E22.0-E22.9	Hyper/unction of pituitary gland
	E23.0-E23.7	Hypo/unction and other disorders of the pituitary gland
	E24.0-E24.9	Cushing's syndrome
	E25.01-E25.9	Adrenogenital disorders
	E26.01-E26.9	Hyperaldosteronism
	E27.0-E27.9	Other disorders of adrenal gland
	E28.0-E28.9	Ovarian dysfunction
	E29.0-E29.9	Testicular dysfunction
	E30.0-E30.9	Disorders of puberty, not elsewhere classified
	E31.0-E31.9	Polyglandular dysfunction
	E32.0-E32.9	Diseases of thymus
	E34.0-E34.9	Other endocrine disorders
	C73, C79.89	Malignant neoplasm, thyroid
	D09.3	Carcinoma in situ, thyroid
	E01.0 - E01.2	Iodine-deficiency goiter
	E02	Subclinical iodine-deficiency hypothyroidism
	E04.0 - E04.9	Nontoxic goiter
	E05.00 - E05.01	Thyrotoxicosis w diffuse goiter (includes Graves Disease)
	E05.00 - E05.91	Thyrotoxicosis (Hyperthyroidism)
	E10.21 - E10.9	Type 1 diabetes mellitus
	E27.0 - E27.1	Other adrenocortical overactivity/insufliciency
	E27.40 - E27.49	Other and unspecified adrenocortical insufficiency
	E66.01	Morbid obesity
	E78.0 - E.78.5	Disorders of lipoprotein metabolism and other lipidemias
	E89.0	Postprocedural hypothyroidism (Postirradiation hypothyroidism; Postsurgical hypothyroidism)
	F32.0 - F33.9	Depression
	F41.1 -F41.9	Other anxiety disorders
	F53.0	Postpartum depression
	G25.0	Essential tremor
	G47.9	Sleep disorder, unspecified
	I10	Hypertension
	H81.49	V
	I45.81	Long QT syndrome
	I47.0 - 147.9	Paroxysmal tachycardia
	I49.01- 149.02	Other cardiac arrhythmias
	I50.20 - 150.9	Congestive heart failure
	I50.810	Right heart failure, unspecified
	I50.811	Acute right heart failure
	I50.812	Chronic right heart failure
	I50.813	Acute on chronic right heart failure
	I50.814	Right heart failure due to left heart failure
	I50..82	Biventricular heart failure
	I50..83	High output heartfailure
	I50..84	End stage heartfailure
	I50..89	Other heart failure
	K59.00 - K59.09	Constipation
	K75.0	Nonspecific reactive hepatitis
	L50	Urticaria
	L63.0 - L63.9; L64.8 -L64.9; L64.8 - L64.9; L65.2, L65.9	Alopecia
	L67.0, L67.8	Hair color and hair shaft abnormalities
	L80	Vitiligo
	M25.40	Effusion, unspecified joint
	M25.60	Stiffness of unspecified joint, not elsewhere classified
	M62.81	Muscle weakness (generalized)
	M62.9	Disorder of muscle, unspecified
	N92.0 - N92.6	Excessive, frequent and irregular menstruation
	N94.4 - N94.6	Dysmenorrhea
	N96	Recurrent pregnancy loss
	N97.0 - N97.9	Female infertility
	O09.00 - O85	Maternal condition(s) of viable pregnancy
	O86.11 - O86.89	Other puerperal infections
	O90.0 - O90.4	Complications of the puerperium, not elsewhere classified
	O90.5	Postpartum thyroiditis
	O90.81 - O99.215	Complications related to the puerperium and other obstetric conditions not elsewhere classified
	O99.280 - O99.285	Endocrine, nutritional and metabolic diseases complicating pregnancy
	O99.310 - O99.89	Diseases and conditions complicating pregnancy, childbirth and the puerperium
	O9A.111 - O9A.53	Maternal traumatic injuries and abuse classifiable elsewhere but complicating pregnancy, childbirth and the puerperium
	R00.0	Tachycardia, unspecified
	R00.1	Bradycardia, unspecified
	R23.4	Changes in skin texture
	R25.1	Tremor, unspecified
	R41.0 -R41.82	Other symptoms and signs involving cognitive functions and awareness
	R45.0, R45.4	Symptoms and signs involving emotional state
	R49.0 - R49.9	Dysphonia/hoarseness
	R52	Pain, unspecified
	R53.81, R53.83	Other malaise and fatigue
	R60.0 - R60.9	Edema, not elsewhere classified
	R61	Generalized hyperhidrosis (excessive sweating)
	R62.52	Short stature (child)
	R63.4	Abnormal weight loss
	R63.5	Abnormal weight gain
	R74.8-R74.9	Abnormal level of other serum enzymens
	Z30.0 - Z39.2	Encounter for maternal postpartum care and examination
	Z31.41	Encounter for fertility testing
	Z33.1	Pregnant state, incidental
	Z34.00 - Z34.93	Encounter for supervision of normal pregnancy
	Z3A.00 - Z3A.09	Weeks of gestation (unspecified thru to 9 weeks)
	Z3A.15 - Z3A.49	Weeks of gestation (15 through to > 42 weeks)
	Z79.3	long term (current) use of hormonal contraceptives
	Z79.810-Z79.818	Long term (current) use of agents affecting estrogen receptors and estrogen levels
	Z79.899	Long term (currrent) use other meds
	Z83.49	Family history of other endocrine, nutritional and metabolic diseases
	Z85.850	Personal hx malignant neoplasm of thyroid
	Z86.39	Personal history of other endocrine, nutritional and metabolic disease

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology^© American Medical Association. All Rights Reserved" 

History From 2016 Forward     

04/24/2023	Annual review, updates to testing frequencies, thyroid issues in pregnancy addressed with medical necessity criteria, TRH and TBG addressed. Adding CPT  84442, also updating description, rationale, references and notes.
01/30/2023	Interim review, no change to policy intent. Removing CPT codes 84437 and 84442.
10/25/2022	Annual review, no change to policy intent. Updating policy for clarity. Updating description, table of terminology, rationale and references.
04/18/2022	Annual review, updating policy with clarifications regarding frequency of testing, updating for clarity, changing thyrotropin releasing hormone testing to not medically necessary. Updating rationale, references and coding. Adding table of terminology.
10/19/2021	Interim review to add criteria 1J related to pediatric members with short stature and ICD 10 code R62.52. No other changes made.
04/07/2021	Annual review, adding coverage related to individuals suspect of central hypothyroidism and differentiated thyroid carcinomas. Also updating coding,rationale and references.
04/13/2020	Annual review, updating policy verbiage for clarity regarding testing during pregnancy. Adding "note 1" to add further clarification. No other changes made.
07/16/2019	Interim review to update coding and specificity related to Total T4 testing during pregnancy.
04/02/2019	Annual review, adding policy statement :Testing for thyroid dysfunction in asymptomatic nonpregnant individuals for thyroid disease DOES NOT MEET COVERAGE CRITERIA during general exam without abnormal findings. Updating coding. No other changes.
01/15/2019	Corrected ICD 10 diagnosis D99.280-D99.285 to O99.280-O99.285. No other changes made.
01/08/2019	Correct typo in Coding Section. No other changes.
10/10/2018	Updated coding section adding ICD-10-CM. No change to policy intent.
08/06/2018	Reformatting policy for clarity, also removing any medical necessity for total thyroxine testing.
04/19/2018	Annual review, removing and/or statement regarding Free T4 testing, updating T3 testing to be not medically necessary from previous investigational status. Coverage criteria 6 and 7 added. No other changes made.
09/28/2017	Updated coding section with 2018 coding. No other changes.
06/28/2017	Interim review, no change to policy intent. Updating background, description, policy (for clarity), guidelines, rationale and references.
06/19/2017	Updated coding section. No other changes made.
04/25/2017	Updated category to Laboratory. No other changes
04/17/2017	Annual review, no change to policy intent.
01/04/2017	Annual review, no change to policy intent.
07/11/2016	Interim review, updating background, rationale and coding. Adding medical necessity criteria for testing in early pregnancy for members with a history of miscarriage or other preterm delivery.
04/11/2016	Interim update, adding additional criteria related to testing in women who are pregnant or post partum.
01/12/2016	NEW POLICY