At a Glance

Patients with central hypothyroidism have either a failure of the anterior pituitary to secrete TSH (also known as secondary hypothyroidism), failure of the hypothalamus to secrete thyroid releasing hormone (TRH) known as tertiary hypothyroidism, or, in some rare cases, a TSH deficiency with no other findings of pituitary or hypothalamus abnormality. The most common cause of central hypothyroidism is pituitary mass lesions. Treatment, such as surgery or radiation therapy for these lesions, can also lead to central hypothyroidism.

TSH Deficiency

Although rare, mutations in gene coding for the TSH-beta subunit can cause an isolated congenital TSH deficiency. These patients have a single base substitution in the amino acid sequence regulating the TSH-beta subunit.

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Patients with congenital isolated TSH deficiency shows signs of cretinism, such as mental and growth retardation (see chapter on congenital hypothyroidism).

Another very rare cause of isolated TSH deficiency is drug-induced TSH deficiency and is seen in patients treated with a retinoid X receptor ligand (bexarotene), which selectively inhibits TSH secretion.

Although cases of isolated TSH deficiency, congenital isolated TSH deficiency, and drug-induced isolated TSH deficiency have occurred, by far the majority of patients with TSH deficiency hypothyroidism have coexisting deficiencies in other pituitary hormones.

Patients with thyroid stimulating hormone (TSH) deficiency often present with symptoms similar to the more common primary hypothyroidism, including fatigue, lethargy, cold intolerance, and weight gain.

Other symptoms of hypothyroidism seen in TSH deficiency include the usual myriad of symptoms seen in hypothyroidism in general: brittle fingernails; coarsening and thinning hair; puffy eyes; pale, dry skin; weakness; and constipation. Hoarseness; menstrual disorders; puffy hands, face and feet; thickening of the skin; thinning of eyebrows; increased cholesterol levels; muscle and/or joint aches and stiffness; slowed speech; and decreased hearing are symptoms usually expressed later in the course of the disease. There are no symptoms that differentiate TSH deficiency from other types of hypothyroidism. TSH deficiency is, however, more difficult to diagnose than primary hypothyroidism because in the case of TSH deficiency TSH levels cannot be used as a guide (Table I).

Table I.n

Test Results Indicative of TSH deficiency

Transient TSH deficiency

Transient forms of central hypothyroidism also exist. This condition can occur in three clinical situations:

  • Serum TSH levels can remain low for a period of time after treatment of hyperthyroidism with an antithyroid drug, radioiodine, or surgery. Serum free T4 (FT4) can also be affected and fall below normal during this time.

  • Serum TSH concentrations may also be low after the discontinuation of T4 therapy.

  • Lastly, patients with severe nonthyroidal illness can have transient central hypothyroidism.

Hypopituitary Hypothyroidism

When low thyroid hormone levels are the result of a failure of the anterior pituitary to secret TSH, the resulting hypothyroidism is pituitary hypothyroidism, also known as secondary hypothyroidism. Causes of pituitary hypothyroidism include head trauma; infiltrates into the pituitary; brain tumors, Sheehan’s syndrome (post-partum pituitary necrosis); and post radiation of the pituitary, nasopharyngeal, or para nasal sinus tumors. Symptoms of hypopituitary hypothyroidism are the same as all causes of hypothyroidism.

Treatment involves replacement of thyroid hormones with levothyroxine (L-T4).

Hypothalamic Hypothyroidism.

When low thyroid hormone levels trace back to a failure of the hypothalamus to secrete Thyroid Releasing Hormone (TRH), which in turn stimulates the anterior pituitary to produce TSH, the resulting hypothyroidism is hypothalamic hypothyroidism, also known as tertiary hypothyroidism. Hypothalamic hypothyroidism can be idiopathic or result from demonstrable hypothalamic disease.

Again signs and symptoms are the same as those for other types of hypothyroidism.

Treatment involves replacement of thyroid hormones and, in some cases, surgical removal of a precipitating tumor.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The use of thyrotropin releasing hormone (TRH) stimulation in the diagnosis of central hypothyroidism has decreased substantially, due to the greater sensitivity of the TSH analysis. The use of TRH stimulations is still recommended in the diagnosis of congenital central hypothyroidism in neonates, so that appropriate therapeutic intervention can be undertaken quickly. When TRH stimulation is used, normal patients respond with a doubling of their TSH in about 30 minutes after injection of synthetic TRH. A patient with hypothalamic hypothyroidism will show a normal response, but the peak is delayed to 45- 60 minutes after injection. Patients with pituitary hypothyroidism will not respond with an increase in TSH. Patients with primary hypothyroidism will show an exaggerated TSH response.

A normal increase in prolactin is seen after TRH stimulation in isolated TSH deficiency and can be used to differentiate TSH deficiency hypothyroidism from hypopituitary or hypothalamic hypothyroidism (Table I).

MRI of the pituitary and/or hypothalamus regions should be performed in patients with evidence of central hypothyroidism, not known to be TSH deficiency.

To diagnose central hypothyroidism, FT4 and TSH tests are performed. Normally TSH is the more sensitive test due to the relationship between TSH and fT4 being log/linear. Intraindividual variation in free T4 is quite small. But any small deficiency in fT4 would be sensed by the pituitary relative to the individual’s set point and cause an amplified inverse response in TSH. In patients with a failure of the pituitary or hypothalamus, this negative feedback is not seen. Since TSH cannot demonstrate the normal negative feedback, used alone, TSH is not diagnostic of central hypothyroidism. A combined TSH and fT4 are a better approach.

Serum fT4 levels will be low, and serum TSH levels may be low, normal, or possibly even slightly elevated (up to 10 mU/L). Patients with central hypothyroidism often lack a nocturnal TSH surge.

Since TSH is often normal in pituitary hypothyroidism, TSH cannot be used for confirmation of a pituitary problem. It is believed that bio-inactive TSH accounts for this phenomenon. The anterior pituitary produces several hormones that, in turn stimulate other glands (i.e., growth hormone, the gonadotropins, TSH, prolactin, and adrenocorticotropin hormone (ACTH)). It was previously thought that the anterior pituitary hormones drop off in a predictable manner, growth hormone being the first to decline, followed by luteinizing hormone and follicle stimulating hormone. Those decreases would be followed by TSH. ACTH would be the last pituitary hormone to be lost. However, there is no one analyte to test for pituitary function, and selective deficiencies of pituitary hormone are possible. Prolactin is often used as an indicator of pituitary function, since some pituitary tumors secret prolactin. When pituitary failure is suspected, each of the functions of the anterior pituitary should be evaluated. (Table II).

Table II.n

Test Results Indicative of the Central Secondary or Tertiary Hypothyroidism

It has been suggested that the best confirmation of hypothyroidism from any cause is an evaluation of response to a trial dose of thyroxine supplement. For a change in analytical value to have clinical significance, the difference should take into account analytical and biological variations. The magnitude of difference in thyroid test values reflecting a clinical significance when monitoring a patient’s response to therapy is:

  • T4 28 nmol/L (2.2 µg/dL)

  • Free T 6 pmol/L (0.5 ng/dL)

  • T3 0.55 nmol/L (35 ng.dL)

  • Free T3 1.5 pmol/L (0.1 ng/dL)

  • TSH 0.75 mIU/L

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

TSH or free T4 levels may be diagnostically misleading in cases of abnormalities in hypothalamus or pituitary function, in which the usual negative feedback is not seen and TSH may remain within normal limits.

Misinterpretation due to the inclusion of biologically inactive TSH isoforms in TSH assays can lead to a missed diagnosis of central hypothyroidism. TSH assays include biologically inactive TSH isoforms, which are secreted when the pituitary is damaged or when hypothalamic TRH stimulation is deficient.

Most thyroid testing is performed by either immunoassay, in which labeled and unlabeled ligands compete for a limited number of antibody sites, or immunometric assays, in which an antibody is bound to a solid surface rather than an antibody. Cross reactivity of auto-antibodies or heterophilic antibodies can affect diagnostic accuracy of competitive binding-based tests.

The term heterophilic antibodies is often loosely applied to relatively weak antibodies with multiple activity sites, known as auto-antibodies, seen in auto immune disorders; broadly reactive antibodies induced by infections or exposure to therapy containing monoclonal mouse antibodies (HAMA); or human anti-animal immunoglobulins produced against well defined, specific antigens following exposure to therapeutic agents containing animal antigen or by coincidental immunization through exposure to animal antigens.

The latter, Human Anti-Animal Antibodies (HAAA), are strong reactors. HAMA and HAAA affect immunometric assays more than they affect simple competitive immunoassays. In immunometric assays HAMA and HAAA can form a bridge between the capture and signal antibodies. Auto-antibodies and heterophilic antibody interferences can sometimes be detected by simply using a different manufacturer’s method that employs a slightly different antibody. Tests in which dilutions are acceptable, such as total T4, total T3, or TSH, but not free T4 or free T3, may be checked for linearity of response to help identify heterophilic antibody interference.

Most circulating thyroid hormones are bound to protein. Only that hormone that is free is biologically active. Variations in binding protein will cause variations in concentrations of total hormones. In general, serum TSH is less affected by binding issues than T3 and T4, and T4 is bound more tightly than T3. T3 and T4 circulate in the body bound to thyroid binding globulin (TBG); transthyretin, formally known as thyroxine binding prealbumin; and serum albumin. Physiological shifts toward greater total hormone binding will decrease available free hormone. Theoretically, free T3 and free T4 are not affected analytically by binding, but in reality, all of the free methods are binding dependent to varying degrees.

Phenytoin, carbamazepine, aspirin, and furosemide compete with thyroid hormone for protein binding sites and, thus, acutely increase free hormones and reduce total hormones. Eventually, a normal equilibrium is reestablished where free levels normalize at the expense of total levels.

Heparin stimulates lipoprotein lipase, liberating free fatty acids, which inhibit total T4 protein binding and elevate free T4.

Free fatty acids are known to affect some methods.

Estrogens increase TBG, increasing total thyroid hormones.

Liver disease, androgens, and nephrotic syndrome decrease TBG, decreasing total thyroid hormones.

Indole acetic acid, which accumulates in uremia, may interfere with thyroid binding.

Pregnancy is associated with lower albumin levels. Therefore, albumin-dependent methods are not suitable for accessing thyroid status during pregnancy.

TSH levels decline in the first trimester of pregnancy partly because of the increase in total T3 and T4 from increased TBG. Total T3 and T4 are also increased in the first trimester by increased Human Chorionic Gonadotropin (HCG), which is structurally and, to some extent, functionally similar to TSH. There is a continuous decrease in the TSH/T4 ratio from mid-gestation through completion of puberty. In adulthood, TSH increased in the elderly. Age related reference ranges, or at least ratio adjusted reference ranges should be used.

Glucocorticosteroids can lower T3 and inhibit TSH production. This interaction is of particular concern in sick, hospitalized patients in whom the elevated TSH in primary hypothyroidism may be obscured.

Propanolol has an inhibitory effect on T4 to T3 conversion. Eighty percent of T3 is produced enzymatically in nonthyroid tissue by 5 monodeiodination of T4.

Free T3 and free T4 are often method dependent.

Methods that use fluorescent tags may be affected by the presence of fluorophore-related therapeutic or diagnostic agents.

A combination of high free T4 and high TSH may be an indication of therapeutic noncompliance. Acute ingestion of missed levothyroxine (L-T4) just prior to a clinic visit will raise the free T4 but fail to normalize the TSH because of a “lag effect”. Free T4 is the short-term indicator, whereas TSH is a long-term indicator. Since TSH is the long-term indicator, it is not influenced by time of L-T4 ingestion.

When testing free T4, the daily dose of L-T4 should be withheld until after sampling, as free T4 is significantly increased above baseline for up to 9 hours after ingesting L-T4. Ideally, L-T4 should be taken prior to eating, at the same time each day, and at least 4 hours apart from other medications. Many medications and even vitamins and minerals can influence L-T4 absorption. L-T4 should not be taken with iron supplements.

Patients should not switch from brand to brand of L-T4 and prescriptions should not be written generically, as doing so will allow brand to brand switches. Although stated concentrations of L-T4 may be the same, slight variations exist between pharmaceutical manufacturers in terms of bioavailability. Also, medication storage recommendations should be scrupulously followed. Medication should be stored away from humidity, light, and increased temperatures. When ordering medication it is best to avoid the summer for shipping.

TSH or free T4 levels may be diagnostically misleading during transition periods of unstable thyroid function. Often these transition periods occur in the early phase of treating hyper- or hypothyroidism or changing the L-T4 dose. It takes 6-12 weeks for pituitary TSH secretion to re-equilibrate to the new thyroid hormone status. Similar periods of unstable thyroid status may occur following an episode of thyroiditis.

Patients with central hypothyroidism may need higher doses of T4 than those with primary hypothyroidism.

Hyperprolactinemia may be present in both central and primary hypothyroidism

Of note is the fact that pituitary-adrenal function should be evaluated before a patient with central hypothyroidism starts T4 therapy. T4 may accelerate cortisol metabolism. If a patient who also has adrenal insufficiency receives T4 before adrenal hormone replacement, an adrenal crisis could occur.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Patients with either central or primary hypothyroidism can exhibit low FT4 levels and slightly high TSH levels; therefore, it is important to differentiate between the two diagnoses. Serum antithyroid peroxidase (TPO) antibody concentration is one test that can be used to differentiate between central and primary hypothyroidism. In primary hypothyroidism, TPO levels are increased, whereas the absence of anti-TPO antibodies in conjunction with other pituitary hormone abnormalities suggests central hypothyroidism.

What's the Evidence?

Demers, LM, Spencer, CA. ” Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease”.  Clin Endocrinol (Oxf). vol. 58. 2003 Feb. pp. 138-40.

Spencer, C. “Clinical Implications of New TSH Reference Range AACC Expert Access”.