Hypothalamic Disease

At a Glance

The thyroid gland produces two related hormones, thyroxine (T4) and triiodothyronine (T3), which play a critical role in thermogenic and metabolic homeostasis. T4 and T3 are normally synthesized and released in response to a combined hypothalamic pituitary signal mediated by thyroid stimulating hormone (TSH) from the anterior pituitary and thyrotropin releasing hormone (TRH) from the hypothalamus. There is a negative feedback from thyroid hormone concentration, primarily T3, to TSH production, causing total T4, total T3, free T4, and free T3 concentrations to move in opposition to TSH concentration.

Hypothyroidism is a condition in which the thyroid gland is functionally inadequate. Causes of hypothyroidism include autoimmune disorders, such as Hashimoto’s thyroiditis, atrophic thyroiditis, and postpartum thyroiditis; iodine deficiency, the most common cause of hypothyroidism in underdeveloped areas; congenital defects; medications or treatments that can result in hypothyroidism; central hypothyroidism in which the thyroid is not stimulated by the pituitary or hypothalamus; and infiltrative processes that may damage thyroid, pituitary, or hypothalamus. These different causes of hypothyroidism are often interrelated. Usually, the exact cause of the hypothyroidism cannot be definitively differentiated.

When low thyroid hormone levels are the result of a failure of the hypothalamus to secrete TRH, which, in turn, stimulates the anterior pituitary to produce TSH, the resulting hypothyroidism is hypothalamic hypothyroidism, also known as tertiary hypothyroidism. Hypothalamic hypothyroidism belongs to the group of hypothyroidisms collectively known as central hypothyroidism. Hypothyroidism cause by diminished TSH from the anterior pituitary is another central hypothyroidism. Hypothalamic hypothyroidism can be idiopathic or result from demonstrable hypothalamic disease.

The lack of thyroid hormone produced by the thyroid gland as a consequence of failure of the hypothalamus to initiate TSH production in the anterior pituitary presents with the same signs and symptoms as are seen with other hypothyroid conditions (i.e., fatigue, cold intolerance, weight gain, depression, and dry skin).

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?

TSH and free T4 are the usual laboratory diagnostic tools in the diagnosis of hypothyroidism. In hypothyroidism due to a hypothalamic disorder, free T4 is decreased. T3 is not generally reliable in the diagnosis of hypothyroidism. Measuring free T4 or other analytes will not identify the cause of the hypothyroidism as hypothalamic.

Normally, TSH is the more sensitive test in the diagnosis of hypothyroidism, since the relationship between TSH and free T4 is log/linear. Intraindividual variation for free T4 is quite small. Therefore, any small deficiency of free T4 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 hypothalamus, this negative feedback is not seen. Since TSH cannot demonstrate the normal negative feedback, used alone, TSH is not diagnostic for central hypothyroidisms. A combined TSH and free T4 are thought to be a better approach.

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?

Interferences may obscure the diagnosis of hypothalamic hypothyroidism or complicate the monitoring of the effectiveness of thyroid replacement therapy.

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 autoantibodies 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 autoantibodies, 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. Autoantibodies and heterophilic antibody interferences can sometimes be detected simply by 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 cause variations in concentrations of total thyroid 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 decrease available free hormone. Theoretically, free T3 and free T4 are not affected analytically by binding. 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 hormone 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.

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.

Propranolol 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.

What Lab Results Are Absolutely Confirmatory?

TRH stimulation test is no longer thought of as a confirmatory test for hypothalamic hypothyroidism, as a sufficiently sensitive TSH can detect a low basal TSH, providing the same information.

Otherwise, it has been suggested that the best confirmation of hypothyroidism is an evaluation of response to a trial administration of thyroxine supplement in patients with symptoms of hypothyroidism.

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

TRH level analysis is not generally available but may be viewed indirectly through a TRH stimulation test. In the past, TRH stimulation testing was used to diagnose hypothalamic hypothyroid disease. If TSH is low or normal in the presence of symptoms of hypothyroidism, a TRH test can be performed. In the TRH test, synthetic TRH is given. Normal patients respond with a doubling of their TSH about 30 minutes after injection. A patient with hypothalamic hypothyroidism shows a normal response, but the peak is delayed to 45-60 minutes after injection. Patients with pituitary hypothyroidism or hyperthyroidism will not respond with an increase in TSH. Patients with primary hypothyroidism will show an exaggerated TSH response.

Newer, more sensitive TSH methods have rendered the TRH stimulation test obsolete, as the failure to rise after an intravenous TRH injection has the same implication as a suppressed basal TSH.

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 hypothalamic or pituitary function in which the usual negative feedback is not seen and TSH may remain within normal ranges.

A combination of high free T4 and high TSH may be indicative of therapeutic noncompliance. Acute ingestion of missed levothyroxine (L-T4) just prior to a clinic visit raises the free T4 but fails to normalize the TSH because of a “lag effect.” Free T4 is a 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 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 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 reequilibrate to the new hormone status. Similar periods of unstable thyroid status may occur following an episode of thyroiditis.

Free T4 and TSH have reduced specificity in hospitalized patients with nonthyroid illness. Most hospitalized patients have low serum total T3 and free T3. These abnormalities are seen with both acute and chronic nonthyroid illness and are thought to be the result of a malfunction of central inhibition of hypothalamic releasing hormone. The National Academy of Clinical Biochemistry guidelines for testing of hospitalized patients with nonthyroid illness recommendations include the following:

• Acute or chronic nonthyroid illness has complex effects on thyroid function testing. Whenever possible, diagnostic testing should be deferred until the illness has resolved, except in cases in which a suggestion of presence of thyroid dysfunction exists.
• Physicians should be aware that some thyroid tests are inherently not interpretable in severely ill patients or patients receiving multiple medications.
• TSH in the absence of dopamine or glucocorticoid therapy is the more reliable test.
• TSH testing in hospitalized patients should have a functional sensitivity less than 0.02 mIU/L; otherwise, sick, hyperthyroid patients with profoundly low TSH cannot be differentiated from patients with mild transient TSH suppression caused by nonthyroid illness.
• An abnormal free T4 in the presence of serious somatic disease is unreliable. In hospitalized patients, abnormal free T4 testing should reflex to total T4. If both free T4 and total T4 are abnormal in the same direction, a thyroid condition may exist. Discordant free T4 and total T4 abnormalities are more likely the result of illness, medication, or a testing artifact.
• Total T4 abnormalities should be considered in conjunction with the severity of the patient illness. A low T4 in patients not in intensive care is suspicious of hypothyroidism, since low total T4 levels in hospitalized patients are most often seen in sepsis. If a low total T4 is not associated with an elevated TSH and the patient is not profoundly sick, hypothyroidism secondary to pituitary or hypothalamic deficiency should be considered.
• Reverse T3 formed by the loss of an iodine group from T4 in which the position of the iodine atoms on the aromatic ring is reversed is rarely helpful in the hospital setting, because paradoxically normal or low values can result from impaired renal function and low binding protein concentrations.

Trimester specific reference ranges should be used in pregnancy.

During pregnancy, estrogens increase TBG to 2-3 times prepregnancy levels. This shifts binding such that total T3 and total T4 are approximately 1.5 times nonpregnant levels at 16 weeks gestation.

TSH is also altered during pregnancy. TSH is decreased in the first trimester because of the thyroid stimulating activity of HCG. The decline in TSH is associated with a modest increase in free T4 from the increased TBG. In approximately 2% of pregnancies, the increase in free T4 leads to a condition known as gestational transient thyrotoxicosis. This condition may be associated with hyperemesis.

In the second and third trimester, free hormone levels decrease 20-40% below reference ranges.

Pregnant patients receiving L-T4 replacement may require increased dose to maintain a normal TSH and free T4.

TSH has a very short half-life of 60 minutes and is subject to circadian and diurnal variation peaking at night and reaching a nadir between 10 AM and 4 PM. T4 has a much longer half-life of 7 days.

It should be noted that there is a continuous decrease in the TSH/free T4 ratio from midgestation through completion of puberty. In adulthood, TSH increases in the elderly. Age-related reference ranges, or at least ratio adjusted reference ranges, should be used for these analytes.

For a change in analyte value to have clinical significance, the difference should take into consideration analytical and biological variabilities. The magnitude of difference in thyroid testing values reflecting a clinical significance when monitoring a patient’s response to therapy is:

T4 28 nmol/L (2.2 μg/dL)

freeT4 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

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