Hypothyroidism Workup

Updated: May 25, 2022
  • Author: Philip R Orlander, MD, FACP; Chief Editor: George T Griffing, MD  more...
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Laboratory Studies

Third-generation thyroid-stimulating hormone (TSH) assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism. [3] The generally accepted reference range for normal serum TSH is 0.40-4.2 mIU/L.

In the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), of 17,353 people evaluated, 80.8% had a serum TSH below 2.5 mIU/L; TSH concentrations rose with advancing age. [75] Certain physiologic conditions, such as illness, psychiatric disorders, and significant physical stress (eg, running a marathon), exposure to extremes in temperature, negative energy balance), can produce marked variations in TSH levels.

If TSH levels are above the reference range, the next step is measure free thyroxine (T4). Another option is to measure total T4 and binding proteins. T4 is highly protein-bound (99.97%), with approximately 85% bound to thyroid-binding globulin (TBG), approximately 10% bound to transthyretin or thyroid-binding prealbumin, and the remainder bound loosely to albumin.

The levels of these binding proteins can vary by hormonal status, inheritance, and in various disease states. Hence, free T4 assays, which measure unbound (ie, free) hormone, are the accepted standard. However, free T4 assays can be unreliable in the setting of severe illness or pregnancy.

Free T4 can be directly measured via equilibrium dialysis. Results are independent of binding protein concentrations. However, this test is more costly and labor intensive. Free thyroid hormone levels can be estimated by calculating the percentage of available thyroid hormone-binding sites (triiodothyronine [T3] resin uptake, or thyroid hormone binding ratio [THBR]) or by measuring the TBG concentration. A free T4 index (FTI) serves as a surrogate of the free hormone level. The FTI is the product of T3 resin uptake and total T4 levels.

In pregnancy, the variation in the results of commercially available free T4 assays has led the American Thyroid Association to recommend using method-specific and trimester-specific reference ranges for serum free T4. If these specific ranges are not available, TSH, total T4, and FTI can be used to monitor the pregnant patient.

Patients with primary hypothyroidism have elevated TSH levels and decreased free hormone levels. Patients with elevated TSH levels (usually 4.5-10.0 mIU/L) but normal free hormone levels or estimates are considered to have mild or subclinical hypothyroidism.

Primary hypothyroidism is virtually the only disease that is characterized by sustained rises in TSH levels. As the TSH level increases early in the disease, conversion of T4 to T3 increases, maintaining T3 levels. In early hypothyroidism, TSH levels are elevated, T4 levels are normal to low, and T3 levels are normal. Given this early protection of the T3 level, routine checking of T3 is not recommended if one suspects that a patient is hypothyroid. Drawing a reverse T3 is also not recommended as a routine part of the hypothyroidism workup.

Assays for anti–thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies may be helpful in determining the etiology of hypothyroidism or in predicting future hypothyroidism. However, once a patient has been found to be antibody positive, repeated antibody testing adds little to the clinical picture and thus is not recommended. Anti-TPO antibodies have been associated with increased risk of infertility and miscarriage; whether levothyroxine (LT4) treatment can lower this risk is controversial. [76, 77]

In patients with nonthyroidal disease, TSH secretion is normal or decreased, total T4 levels are normal or decreased, and total T3 levels are decreased to markedly decreased. This scenario can be confused with secondary hypothyroidism. In these patients, the primary abnormality is decreased peripheral production of T3 from T4. They have an increased reverse T3, which can be measured. (See Euthyroid Sick Syndrome.)

Other abnormalities seen in patients who are critically ill include decreased TBG levels and abnormalities in the hypothalamic-pituitary axis. During recovery, some patients have transient elevations in serum TSH concentrations (up to 20 mIU/L). Hence, thyroid function should not be evaluated in a critically ill person unless thyroid dysfunction is strongly suspected, and if evaluation is warranted, screening with TSH alone is insufficient. When needed, however, multiple thyroid hormone measurements over time may assist with interpretation.

In patients with hypothalamic or pituitary dysfunction, TSH levels do not increase in appropriate relation to the low free T4 levels. The absolute levels may be in the reference range or even slightly elevated while still being inappropriately low for the severity of the hypothyroid state. Hence, when secondary or tertiary hypothyroidism is suspected, measurement of serum TSH alone is inadequate; free T4 should also be measured.

The TRH stimulation test is an older and rarely needed test for helping to assess pituitary and hypothalamic dysfunction. With the improvements in TSH and free T4 assays, TRH stimulation has become outmoded. In the United States, this medication is available only at the National Institutes of Health (NIH).

The complete blood count and metabolic profile may show abnormalities in patients with hypothyroidism. These include anemia, dilutional hyponatremia, hyperlipidemia, and reversible increases in serum creatinine. [5] Elevations in transaminases and creatinine kinase have also been found.

Primary hypothyroidism causes an elevation of TRH, which can cause an elevation of prolactin along with TSH. Prolactin levels in patients with hypothyroidism tend to be lower than those usually seen with prolactinomas (the latter are usually 150-200 ng/mL or higher).


Imaging Studies

Ultrasonography of the neck and thyroid can be used to detect nodules and infiltrative disease. It has little use in hypothyroidism per se unless a secondary anatomic lesion in the gland is of clinical concern. Hashimoto thyroiditis is usually associated with a diffusely heterogeneous ultrasonographic image. In rare cases, it may be associated with lymphoma of the thyroid. Serial images with fine-needle aspiration (FNA) of suspicious nodules may be useful.

The use of color flow Doppler scanning allows assessment of vascularity, which can help to distinguish thyroiditis from Graves disease. Glands with the former will have decreased flow, whereas glands with the latter will have increased flow.

Any thyroid nodules noted on imaging studies should undergo standard evaluation.

Radioactive iodine uptake (RAIU) and thyroid scanning are not useful in hypothyroidism, because these tests require some level of endogenous thyroid function if they are to provide useful information. Patients with Hashimoto thyroiditis may have relatively high early uptake (after 4 hours) but do not have the usual doubling of uptake at 24 hours consistent with an organification defect.

Patients undergoing whole-body F18-fluorodeoxyglucose positron emission tomography (FDG-PET) for nonthyroid disease often show significant thyroid uptake as an incidental finding. [78]  A study by Chen et al found the risk of thyroid malignancy to be 63.6% in lesions with focal uptake, while most instances of diffuse uptake were associated with chronic thyroiditis. [79]



Governmental bodies frequently mandate screening of neonates for hypothyroidism so as to prevent delay in the recognition and treatment of cretinism. No universal screening recommendations exist for thyroid disease for adults. The American Thyroid Association recommends screening at age 35 years and every 5 years thereafter, with closer attention to patients who are at high risk, such as the following [7] :

  • Pregnant women
  • Women older than 60 years
  • Patients with type 1 diabetes or other autoimmune disease
  • Patients with a history of neck irradiation

Screening recommendations from other groups

The American College of Physicians recommends screening all women older than 50 years who have 1 or more clinical features of disease. [80, 81]

The American Academy of Family Physicians recommends screening asymptomatic patients older than 60 years. [82]

The American Association of Clinical Endocrinologists recommends TSH measurements in all women of childbearing age before pregnancy or during the first trimester. [83]

The US Preventive Task Force concludes that the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults (grade I recommendation). [84]

However, the American College of Obstetricians and Gynecologists (ACOG) does not recommend universal screening for thyroid disease in pregnant women. However, those who are at increased risk warrant screening. This includes pregnant women with a personal or family history of thyroid disease, type 1 diabetes, or symptoms suggestive of thyroid disease. There is no proven benefit in screening pregnant women with a mildly enlarged thyroid gland, whereas those with a significant goiter or distinct thyroid nodules require screening. [8]


Fine-Needle Aspiration Biopsy

Thyroid nodules are often found incidentally during physical examination or on chest radiography, computed tomography (CT), or magnetic resonance imaging (MRI). Thyroid nodules can be found in patients who are hypothyroid, euthyroid, or hyperthyroid. FNA biopsy is the procedure of choice for evaluating suspicious nodules, usually with ultrasound guidance. Risk factors for thyroid nodules include age greater than 60 years, history of head or neck irradiation, and a family history of thyroid cancer.

About 5-15% of solitary nodules are malignant. Suspicious nodules are those with sonographic features such as irregular margins, hypoechoic parenchyma, or microcalcifications.


Histologic Findings

Autoimmune thyroiditis causes a decrease in intrathyroidal iodine stores, increased iodine turnover, and defective organification. Chronic inflammation of the gland causes progressive destruction of the functional tissue with widespread infiltration by lymphocytes and plasma cells with epithelial cell abnormalities. In time, dense fibrosis and atrophic thyroid follicles replace the initial lymphocytic hyperplasia and vacuoles.

Other causes of functional tissue destruction and infiltration include the following:

·       Previous administration of radioiodine

·       Surgical removal

·       Metastasis

·       Lymphoma

·       Sarcoidosis

·       Tuberculosis

·       Amyloidosis

·       Cystinosis

·       Thalassemia

·       Riedel thyroiditis

·       Hemochromatosis