Strategies for Thyroid Funtion Testing

Volume 4 Issue 2 Fall 2004

STRATEGIES FOR THYROID FUNCTION TESTING

The lifetime prevalence of thyroid dysfunction, hypothyroidism and hyperthyroidism is about 10% in North America. Thyroid disease occurs in women 2-3 times more commonly than men. Thyroid dysfunction may have a variable clinical presentation, depending on the age of the patient, degree of dysfunction, and the duration of the disease. The clinical picture, together with the judicious use of a limited number of biochemical tests and imaging modalities can be used to diagnose most of the thyroid illnesses encountered in primary care and family practice.

Thyroid Physiology
Thyroid hormones, L-Thyroxine (T₄) and the more active form, Triiodothyronine (T₃), travel in the circulation bound 99.97% and 99.5%, respectively, to a group of serum thyroid hormone binding proteins synthesized in the liver. Thyroid hormones bound to a carrier protein are biologically inactive. The Free T₄ and T₃ are the biologically active components. Thus, a small quantity of free thyroid hormone can enter a cell and bind to its intranuclear receptor to alter gene expression, which in turn, alters cellular function and determines the thyroid status of the patient. T₃ binds with higher affinity to the thyroid hormone receptor and is approximately 15-20 times more biologically active than T₄. L-Thyroxine is made exclusively by the thyroid gland, while T₃ is made primarily in peripheral tissues by deiodination of T₄ by a group of enzymes. The activity of these enzymes and the resulting T₃ level can be reduced by hypothyroidism, drugs (beta blockers, Ipodate, and Amiodarone), malnutrition and severe illness.

Measurement of Thyroid Hormone Levels
"A thyroid panel" is a term commonly used and often misused. The thyroid tests that comprise the thyroid panel are different at each laboratory and often do not include the most important diagnostic test, a TSH (thyroid stimulating hormone). The measurement of TSH should replace any thyroid panel as the initial step in the assessment of thyroid function in the healthy ambulatory patient. However, when the TSH is not believed to be sufficient by itself for diagnosis (first trimester pregnancy, pituitary-hypothalamic dysfunction, critical illness, etc.), or to accurately assess the degree of hyperthyroidism when the TSH is low, the measurement of thyroid hormone levels should also be obtained.

Evaluation of Hypothyroidism
Excluding surgical thyroidectomy and radioactive iodine (131-I ablation of the thyroid), the most common causes of hypothyroidism in the adult are Hashimoto's thyroiditis and the hypothyroid phase of subacute thyroiditis, including postpartum thyroiditis. Signs and symptoms of hypothyroidism are nonspecific and not all patients will have all of the symptoms. The symptoms depend on the degree and duration of thyroid dysfunction and most frequently include weight gain, fatigue, constipation, and menstrual irregularities or infertility.

Recommended Tests for Hypothyroidism
The recommended initial test for hypothyroidism is serum TSH. It is the most sensitive and specific method to diagnose hypothyroidism. It is almost always elevated in primary hypothyroidism and the TSH rise occurs prior to the fall in the T₄ or T₃ levels. TSH is not however a good initial test for secondary hypothyroidism and should not be used to assess the thyroid status of the patient with known or suspected hypothalamic or pituitary disease, or severe non-thyroidal illness. These diseases however are uncommon and often clinically apparent. If the TSH is within normal limits, the patient does not have hypothyroidism and can be followed periodically. If the TSH is elevated, the recommendation is to commence treatment with Synthetic T₄, L-Thyroxine, for hypothyroidism as most of these patients will be symptomatic or will have subnormal Free T₄ levels if checked. If the TSH level is borderline, it is recommended repeating the TSH and adding a Free T₄ level, most commonly done about one month later. Measurement of total or Free T₃ level is not indicated as the T₃ level is maintained within the normal range for a long period of time in mild hypothyroidism because of the increased conversion of T₄ to T₃ in the periphery. If the Free T₄ level is subnormal, it is recommended that treatment for hypothyroidism be commenced.

Subcliniuthe Free T₄ level is normal, the patient has subclinical hypothyroidism. This is defined as an elevated TSH with a normal free thyroid hormone level. The appropriable management of these patients is a matter of controversy. In general, the decision to treat patients with subclinical hypothyroidism depends of the presence of signs and/or symptoms of hypothyroidism or increased risk of progression to overt hypothyroidism as indicated by a positive risk factor, presence of goiter, and/or significant titers of anti-thyroid antibodies.

Anti-Thyroid Antibodies and Hypothyroidism
Thyroid dysfunction is often the result of autoimmune disease where immunogobulins (IgG antibodies) are formed against thyroid proteins such as the TSH receptor (TSHRAb), the thyroid peroxidase (TPOAb, previously known as antimicrosomal antibodies), and thyroglobulin (TgAb).

Almost all patients with autoimmune thyroid disease (Graves' disease and Hashimoto's thyroiditis) will have elevated titers of the thyroid peroxidase antibody and the thyroglobulin antibody. It is important to remember that the peroxidase antibody is not always diagnostic of autoimmune thyroid disease. The higher the titer of an anti-thyroid antibody, the most likely the patient has autoimmune thyroid disease. Even with autoimmune thyroiditis, it is not necessary to routinely measure thyroid antibodies since it will not alter the therapy for the hypothyroidism. However, in acute thyroiditis, the release of thyroid antigens into the circulation often leads to the development of low levels of antibodies to the peroxidase or thyroglobulin. Very high levels of antibodies are most likely to be secondary to autoimmune thyroiditis. Postpartum thyroiditis, a transient autoimmune thyroid disorder, is also associated with the presence of antibodies.

Monitoring Patients with Hypothyroidism
Hypothyroidism is treated with supplementation with a synthetic form of L-Thyroxine. In patients with primary hypothyroidism, the majority of patients, adjustments in their dose should be made based on serum TSH levels measured every 6-8 weeks. The goal of treatment is to normalize the serum TSH level. Once the TSH is normalized, the patient is followed with TSH determinations every 6-12 months.

Evaluation of Hyperthyroidism
The most common cause of adult hyperthyroidism in North America is Graves' disease and autoimmune thyroid hyperfunction. Other common causes of hyperthyroidism include toxic multi-nodular goiter (MNG), toxic adenoma, and the thyrotoxic phase of subacute thyroiditis, including postpartum thyroiditis. The diagnosis and management of hyperthyroidism is more involved and time consuming than that of hypothyroidism. The evaluation and treatment of a patient with hyperthyroidism is often best managed by the endocrinologist.

Symptoms and Signs of Hyperthyroidism
Hyperthyroidism is approximately ten times less common than hypothyroidism at any age and its presentation is not as ambiguous as hypothyroidism, except in the elderly. Elderly patients often have more cardiac symptoms but less systemic manifestations of thyrotoxicosis. Patients should be evaluated for signs and/or symptoms of weight loss, heat intolerance, tremor, palpitations, anxiety, menstrual abnormalities, and new onset of atrial fibrillation. Routine screening for asymptomatic patients for hyperthyroidism is not recommended.

Thyroid Function Tests in the Evaluation of Hyperthyroidism
Measurement of serum TSH is the most sensitive way to diagnose hyperthyroidism as it is almost always suppressed in the most common forms. Secondary hyperthyroidism from a TSH secreting pituitary adenoma is extremely rare. When interpreting low TSH values, remember that not all suppressed TSH values are associated with hyperthyroidism. Certain medical conditions, such as severe non-thyroidal illness, acute psychiatric illness, weight loss, aging and pregnancy, as well as certain medications such as glucocorticoids, in addition to hypothalamic or pituitary disease, can result in low TSH.

If the TSH is within normal limits, the patient does not have hyperthyroidism and no further workup is indicated. If the TSH is low, Free T₄ levels should be determined in addition to repeat measurement of TSH. Since the relationship between TSH and thyroid hormone is inverse log-linear, then small increases of the thyroid hormone level will cause a disproportionate suppression of TSH. The degree of hyperthyroidism therefore cannot be assessed by looking at the TSH alone. If the TSH is suppressed, then measurements of Free T₄, a thyroid hormone pavlidoline globulin and Free T₃ can assess the degree of hyperthyroidism. The measuring of Free T₃ is needed in the evaluation of hyperthyroidism at some primary thyroid hyperfunction states, such as Graves' disease, secrete predominantly T₃ and excessive T₄.

If the serum TSH is low, and the Free T₄ and the Free T₃ are low, hypothalamic or pituitary disease needs to be considered.

If the serum TSH is low, and the Free T₄ and the Free T₃ are within normal limits, the patient has subclinical hyperthyroidism. These patients have few or no symptoms. If the patient is taking thyroid hormone, the dose should be adjusted to normalize the TSH. The only clinical situation in which L-Thyroxine suppression of TSH below the normal range is acceptable is in patients with thyroid cancer where the goal of treatment is subclinically hyperthyroidism to suppress thyroid growth.

Anti-Thyroid Antibodies in Hyperthyroidism
Measurement of anti-thyroid antibodies is not essential if a thyroid scan is performed. The presence of antibodies is not diagnostic of any specific etiology. The measurement of the antibodies or a thyroid scan however, can be useful in the diagnosis of patients suspected of having Graves' disease. Treatment modalities for primary hyperthyroidism include radioactive ablation, anti-thyroid medications, and thyroidectomy. Monitoring of thyroid status is done by measurement of TSH, Free T₄ and T₃ with adjustment of anti-thyroid medication every 1-2 months until euthyroid.

Pregnancy and Thyroid Dysfunction
Hyperthyroidism is associated with menstrual irregularities and infertility. Therefore, a new diagnosis of hypothyroidism during pregnancy is uncommon. When diagnosed, hypothyroidism is almost always mild and almost always due to Hashimoto's thyroiditis.

Many signs and symptoms of hyperthyroidism occur in normal pregnancy. Therefore, a high degree of clinical suspicion is needed to diagnose hyperthyroidism during pregnancy. The most common cause is Graves' disease. Measurement of TSH alone cannot be used to diagnose thyroid dysfunction in early pregnancy because of the crossover stimulation of the thyroid by high hCG levels. Measurements of TPOAb can confirm the autoimmune nature of the thyroid dysfunction.

Thyroid dysfunction occurs more commonly during the postpartum period than during pregnancy. It represents an exacerbation of autoimmune thyroid disorders. The most common cause of postpartum thyroid dysfunction is subacute thyroiditis followed by exacerbation of, or new onset Graves' thyrotoxicosis, or Hashimoto's hypothyroidism. Postpartum thyroiditis is a form of transient autoimmune lymphocytic thyroiditis. It is painless and affects approximately 8% of the North American postpartum women, and may occur up to one year postpartum. The peak prevalence is six months postpartum. Similar to other forms of subacute thyroiditis, it is associated with transient thyrotoxicosis, followed by transient hypothyroidism with an eventual return to the euthyroid state in 90% of the women.

Non-Thyroidal Illness/Euthyroid Sick Syndrome
This is not considered a primary thyroid disorder. Evaluation of chronically ill or hospitalized patients with abnormal thyroid function can often be confusing. It is recommended that thyroid function tests during acute illnesses not be conducted unless thyroid dysfunction is thought to contribute to the illness. Measurement of serum TSH, thyroid binding globulin, Free T₄ and T₃ should be done for full evaluations. The Free T₃ is decreased secondary to enzymatic dysfunction in the conversion of T₄ to T₃. T₄ is converted to reverse T₃ (rT₃) which is inactive.

REFERENCES

Pittas AG, Lee SL. Evaluation of Thyroid Function. Contemporary Endocrinology: Handbook of Diagnostic Endocrinology. Edited by: J.E. Hall and L.K. Nieman. Humana Press Inc., Totowa, NJ 2003.
Larsen PR, Davies TF, Schlumberger MJ, Hay ID. Thyroid Physiology and Diagnostic Evaluation of Patients with Thyroid disorders. Williams Textbook of Endocrinology. 10^th Ed. Edited by: PR Lasen, HM Kronenberg, S. Melmed, K. Polousky. Sanders, Phila PA 2003.
Bower BF, Moore RE. Endocrine Function and Carbohydrates. Clinical Laboratory Medicine. 2^nd Ed. Edited by: KD McClatchey. Lippincott Williams & Wilkins, Phila PA 2002.

FOR MORE INFORMATION CONTACT DR. SUSAN SHAPIRO AT 419-534-3505

Prepared by F. Michael Walsh, M.D., Consultants in Laboratory Medicine