Subclinical Hypothyroidism
Risk Factors in Subclinical Thyroid Disorders
Subclinical hypothyroidism (SH) has causes and symptoms similar to those of overt hypothyroidism. This article describes SH and explains why it should be treated.
In the early 1970s, when clinical laboratories developed blood tests to measure thyrotropin, which is also called thyroid stimulating hormone or TSH, the term subclinical hypothyroidism (SH) first emerged. SH refers to elevated TSH levels in patients with normal levels of thyroid hormone, both FT4 and FT3, associated with few or no symptoms of hypothyroidism. Prior to this time, doctors recognized that some patients with normal thyroid hormone levels had symptoms of hypothyroidism. These patients were said to have conditions of preclinical myxedema, compensated euthyroidism, preclinical hypothyroidism or decreased thyroid reserve. Today, it's accepted that most SH, like most overt hypothyroidism, is caused by autoimmune thyroid disease. Autoimmune hypothyroid disorders include: 1) a chronic condition of lymphocytic thyroiditis called Hashimoto's thyroiditis, which usually is accompanied by goiter; and 2) an atrophic form of thyroiditis called primary myxedema, which usually causes progressive thyroid destruction.
Subclinical hypothyroidism also occurs in patients with infectious, silent, or postpartum thyroiditis, patients on excessive doses of anti-thyroid medications, patients on lithium and other medications, patients with hypothyroidism who are on inadequate doses of replacement hormone, and patients with diminished thyroid function related to permanent treatment for hyperthyroidism.
THE TSH LAG
Normally, thyroid hormone production is regulated by a system known as the hypothalamic-pituitary-thyroid axis in which the hypothalamus situated at the base of the brain regulates thyroid hormone levels via the pituitary gland. When the hypothalamus senses that our thyroid hormone levels are too low for our body's needs, it orders the pituitary gland to release TSH. TSH, in turn, raises thyroid hormone levels by ordering thyroid cells to grow and produce more hormone. Likewise, when thyroid hormone levels rise, the pituitary stops secreting TSH and TSH levels fall. Through this mechanism, thyroid hormone levels are under pituitary control. However, the hypothalamus is savvy enough to know that our needs for hormone vary from day to day and sudden changes happen. So it proceeds slowly and orders the pituitary to take it slow.
Although TSH may start rising and become abnormally elevated before thyroid hormone levels fall below the range, it takes at least 6 weeks for serum TSH levels to accurately reflect thyroid status. Even with this lag, TSH levels are considered the best test to screen for thyroid disease. Under normal circumstances, an elevated TSH level is the best indicator of thyroid hormone deficiency.
Normally, the pituitary gland secretes TSH in pulses throughout the day, with peak levels produced at night. The rate of TSH production varies, depending on our general health, diet, exposure to stress, temperature, circadian rhythm, altitude and other needs. However, if thyroid function begins to decline due to autoimmune, surgical, or ablative destruction of the thyroid gland the, TSH level can reach 1,000 and still fail to induce production of sufficient thyroid hormone. Then, thyroid hormone levels are no longer maintained by pituitary control. The body requires exogenous (from outside of the body) thyroid replacement hormone. Eventually, after thyroid replacement hormone restores the body's levels, pituitary control is reinstated. Again, the pituitary pitches in to help when the hypothalamus notices thyroid hormone levels starting to rise and fall. In treated patients, unless interferences from autoimmunity or medications affect the results, TSH levels can again be used to reflect thyroid status.
TSH INFLUENCES
However, TSH levels can be influenced by other factors. For instance, when the immune system produces blocking TSH receptor antibodies that contribute to hypothyroidism, the TSH receptors (the cellular signaling system) on thyroid cells recognize these antibodies as if they were TSH. Consequently, thinking that we have adequate TSH levels in our blood, TSH production slows down and the serum TSH level is falsely decreased. TSH can also be falsely decreased by medications including dexamethasone and corticosteroids. TSH levels also rise for a week and then fall in conditions of non-thyroidal illness, including surgery, trauma or infection. TSH levels may be falsely elevated by test interferences caused by TSH antibodies, heterophile antibodies and anti-human antibodies. These interferences will be described further in an upcoming article on laboratory test interferences. It's important to recognize that a low or normal TSH doesn't mean that one can't be hypothyroid and a high TSH doesn't always indicate subclinical hypothyroidism. An evaluation of signs, symptoms and thyroid hormone levels is also needed.
Furthermore, a normal TSH level may not be normal or adequate for the individual. Normally, we all have optimal levels of FT4, and our TSH will vary as it works to keep FT4 stable. Since the TSH test was implemented its reference or normal range has changed several times with early tests using a range of 10-20 mu/L based on the TSH levels of hospital workers, many with undiagnosed thyroid disorders. The newer ranges use a better representation of the normal population. The current recommended reference range for TSH is 0.3-3.0 mu/L.
TO TREAT OR NOT
Over the last three decades, physicians and researchers have debated the significance of SH and questioned the need for treatment. This is partially because few long-terms studies of SH exist, and considering the early TSH range, there's no way to estimate its true prevalence. Has the incidence of subclinical hypothyroidism increased since the 70s or have newer, more sensitive TSH tests and changes to the reference range made this appear to be the case? Furthermore, because symptoms wax and wane in autoimmune disorders, TSH levels might be elevated one month and normal the next. Patients with roller coaster results may have been told their suspected thyroid condition had resolved and sent home. Thus, a wait and see approach prevails among some practitioners.
Recent studies have confirmed this notion that patients with both subclinical hypothyroidism and hyperthyroidism can spontaneously recover. One recent study confirmed that SH can improve or resolve months or years after the initial diagnosis. According to this study, remission is not related to age, sex, or levels of thyroid peroxidase (TPO) antibodies. However, levels of blocking TSH receptor antibodies were not measured and they are often the cause of subclinical hypothyroidism.
Unfortunately, treatment is often withheld in SH despite a well-documented list of associated symptoms. These include: elevated lipid levels, cardiac abnormalities, depression, congestive heart failure, latency of motor nerve conduction, increased intraocular pressure, arthralgia, and cognitive changes. For years laboratory workers have noted a high incidence of cardiac events in ER patients with subclinical hypothyroidism but not subclinical hyperthyroidism. A recent study by Walsh, et al. confirmed that subclinical hypothyroidism, but not subclinical hyperthyroidism, is associated with an increase in fatal and nonfatal coronary heart disease.
A more provocative study would be a determination of how many cardiac events occur among patients waiting for their doctors to decide if treatment for SH is needed.
References:
Diez JJ, Iglesias P, Burman KD, Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2005; 90:4124-4127.
Walsh JP, Bremner AP, Bulsara, MK, O'Leary P, Leedman PJ, Feddema P, Michelangeli V, Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005; 165:2467-2472.
Douglas S. Ross, Subclinical Hypothyroidism, chapter 84 in Werner & Ingbar's The Thyroid, A Fundamental and Clinical Text, 8th Edition, Philadelphia: Lippincott Williams & Wilkins, 2000.
