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Mild Hypothyroidism
by J. Larry Jameson
Lecture related to:
Chapter 320: Disorders of the Thyroid Gland
Slide 1: Mild Hypothyroidism
Today's lecture will focus on mild hypothyroidism, an increasingly recognized clinical problem.
Slide 2: Case Presentation
It is useful to begin with a typical clinical presentation. This 51-year old woman presents for routine health exam. She is perimenopausal and relates some fatigue and hair loss but generally feels well. She has no significant previous or current health care problems. Her family history is significant for a sister with a thyroid problem that was most likely Graves' Disease followed by hypothyroidism. Her physical examination is unremarkable aside from a slightly enlarged thyroid gland that has a firm texture. Laboratory studies reveal that the TSH is increased at 12 mU/L and the free T4 is in the low normal range at 0.9 ng/dL. This patient's presentation raises a number of questions including:
- Since the free T4 level is still in the normal range, is she biochemically hypothyroid?
- Does she have clinical manifestations of hypothyroidism, some of which may be difficult to ascertain?
- Should she receive thyroid hormone replacement? If so, how should this be administered?
Slide 3: Clinical Progression of Hypothyroidism
The clinical progression of hypothyroidism has been recognized for more than a century. As clearly illustrated by these lithographs from the 1800s, hypothyroidism and its extreme manifestation myxedema, are readily recognized when one has the luxury to examine a patient sequentially over several years or compare current clinical features with old photographs. Unfortunately, these circumstances are uncommon.
Slide 4: Clinical Features of Hypothyroidism
The clinical symptoms and signs of hypothyroidism are listed on this slide. Note that many of the symptoms of hypothyroidism are relatively nonspecific and include features that are common in the population at large. Complaints of tiredness, dry skin, hair loss, constipation, and weight gain are too frequent to be useful for deciding when to test for hypothyroidism. Similarly, physical signs of hypothyroidism such as dry, coarse skin, puffiness around the eyes or in the extremities, bradycardia, and delayed reflexes are consistent with hypothyroidism but are not particularly sensitive for identifying this disorder. Nonetheless, when a patient presents with a constellation of symptoms and signs that include many of these features, hypothyroidism should be suspected and laboratory tests should be performed.
Slide 5: Mechanism of Thyroid Hormone Action
There have been a number of important advances in our understanding of how thyroid hormone acts in various organs to regulate gene expression and cellular function. The major thyroid hormones, T4 and T3, act via nuclear thyroid hormone receptors, termed TRα and TRβ, to stimulate or repress target genes through thyroid hormone response elements or TREs. In the absence of hormone binding, co-repressor proteins bind the receptor to silence gene expression. Upon T3 binding to the TR, the co-repressor proteins dissociate, relieving gene repression, and co-activator proteins are recruited to the TR to stimulate gene expression. Two important points emerge from this information. First, the discovery of co-repressor and co-activator proteins helps to explain the dynamic range of thyroid hormone action that can vary from the silencing of gene expression in the absence of hormone to strong activation of gene expression in the presence of hormone. It follows from this information that the amounts and types of co-repressor and co-activator proteins in various tissues can influence thyroid hormone responsiveness. Second, the fact that there are two different types of thyroid hormone receptor, TRα and TRβ, provides an additional variable for tissue responsiveness to thyroid hormones by defining the amounts and types of receptors present in the cells. Taken together, these findings imply that different organs or cell types can vary in response to the same amount of circulating thyroid hormone.
Slide 6: Deiodinases
It is also important to note that two different thyroid hormones, T4 and T3, are produced by the thyroid gland. T3 is approximately 10 times as potent as T4 in terms of binding and activating thyroid hormone receptors. Enzymes, referred to as deiodinases, convert T4 to T3.
Slide 7: Deiodinases Result in Tissue-selective Exposure to T3
The deiodinase enzymes can also contribute to tissue-selective responses to thyroid hormone. For example, the hypothalamus and the brain contain relatively large amounts of the type 2 deiodinase. In contrast, the thyroid gland and many peripheral organs contain relatively larger amounts of the type 1 deiodinase. These enzymes are regulated differently by thyroid hormone levels. For example, the type 2 enzyme is suppressed by thyroid hormone. Consequently, as thyroid hormone levels fall, the type 2 enzyme is stimulated, leading to more efficient conversion of T4 to the more biologically active T3. This may provide the central nervous system with a protective mechanism because residual amounts of T4 are efficiently converted into T3. These findings have potentially important implications for thyroid testing, which is largely based on TSH levels, as well as strategies for thyroid hormone replacement.
Slide 8: Thyroid Feedback Axis
The thyroid feedback axis underscores how we use TSH as our primary indicator of thyroid function. The thyrotrope cells in the pituitary secrete TSH that stimulates the thyroid gland to synthesize and release T4 and T3. Because the hypothalamus and pituitary are under negative feedback regulation by thyroid hormone, increasing levels of thyroid hormone inhibit TSH production and release. In this steady state, TSH levels and thyroid hormone levels are within the normal range. In early thyroid failure, thyroid hormone levels begin to decline. Because feedback inhibition is reduced, TSH levels rise and stimulate the thyroid to produce more hormone, partially compensating for thyroid hormone deficiency. However, normal thyroid hormone levels are achieved only at the expense of a raised TSH. Thus, TSH serves as a sensitive indicator of slightly reduced thyroid hormone levels. This pattern of hormone regulation is typical in mild thyroid failure.
Slide 9: Log-Linear Relationship Between Serum TSH and FT4I
There is a log-linear relationship between serum TSH and free thyroid hormone levels. Thus, for any change in free T4, there is a striking increase in TSH. This relationship helps explain why TSH is such a sensitive indicator of thyroid hormone deficiency or excess. In addition, ultra-sensitive TSH assays have been developed, making measurements of TSH particularly sensitive, even below the normal range.
Source: Spencer CA et al: J Clin Endocrinol Metab 70: 453, 1990
Slide 10: "Subclinical" or Mild Hypothyroidism: Definition
With this background of clinical features of hypothyroidism and new insights into thyroid hormone action, I will turn to the disorder of subclinical or mild hypothyroidism. Like the patient described previously, this disorder is characterized by few symptoms of hypothyroidism. The free T4 and T3 remain within the normal or low-normal range, but TSH is increased as a mechanism to compensate for the falling thyroid hormone levels.
Slide 11: Progression of Mild Thyroid Failure
It is useful to review the biochemical changes associated with the progression of mild thyroid failure. As a patient begins to develop thyroid failure, T4 levels (shown in yellow) begin to fall to the lower end of the normal range. Concomitant with these changes, TSH levels rise and become elevated, even before T4 levels have fallen outside the normal range. Please note that T3 levels decline more slowly than T4. This feature likely reflects the role of the deiodinase enzymes to convert T4 to T3. Overt hypothyroidism is defined by frankly low free T4 levels in association with increased TSH.
Slide 12: Causes of Mild Thyroid Failure
The causes of mild thyroid failure are the same as those that cause overt hypothyroidism. By far the most common cause is autoimmune thyroiditis or Hashimoto's thyroiditis. Another common cause of hypothyroidism is the treatment of Graves' disease using radioactive iodine treatment, antithyroid drugs, or surgery. Certain medications such as lithium or amiodarone predispose to hypothyroidism as do iodide or iodide-containing medications. External radiation to the chest or neck for diseases such as lymphoma can also cause thyroid failure.
Slide 13: Hypothyroidism: Greater Prevalence in Women
Several studies have assessed the prevalence of hypothyroidism in different parts of the world. It is striking that hypothyroidism is more common in women than in men in each of these studies, reflecting the increased incidence of autoimmune thyroid disease in women. Most of these studies reveal a prevalence of hypothyroidism between 5-15% in middle-aged women. The recognition that hypothyroidism is this common has raised questions about whether population-based screening should be performed.
References
- Tunbridge WMG et al: The spectrum of thyroid disease in a community: the Whickham Survey. Clin Endocrinol 7: 481-493, 1977
- Sawin CT et al: The aging thyroid: thyroid deficiency in the Framingham Study. Arch Intern Med 45: 1386-1388, 1986
- Canris GJ et al: The Colorado thyroid disease prevalence study. Arch Intern Med 160: 523-534, 2000
- Hak AE et al: Sublinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infraction in elderly women: the Rotterdam Study. Ann Intern Med 132: 270-278, 2000
Slide 14: Screening for Hypothyroidism in the Adult
Hypothyroidism meets most of the criteria that are generally applicable to cost-effective screening. TSH testing is highly sensitive, specific, and relatively inexpensive in most assay formats. After age 35 to 40 years, the prevalence of hypothyroidism is great enough to justify screening. Most debate has centered on whether symptoms associated with mild hypothyroidism are significant enough to justify the cost of testing and treatment. This is a challenging issue because most of the symptoms of mild hypothyroidism are relatively nonspecific and do not pose substantial additional health risks aside from mild elevations of LDL. Studies focused on quality of life issues suggest that some patients feel better when mild hypothyroidism is treated.
Slide 15: Mild Hypothyroidism: Risk factors for progression
Several risk factors predict which patients are most likely to develop hypothyroidism or progress to more severe forms of hypothyroidism. There is a striking age-dependent increase in the prevalence of hypothyroidism, with a rapid rise beginning about age 35-40. High titers of antimicrosomal antibodies that are directed against thyroid peroxidase also predict patients likely to develop biochemical hypothyroidism.
Slide 16: Thyroid Dysfunction: Guidelines for Screening
The American Thyroid Association (ATA) recommends that adults, particularly women, be screened beginning at age 35 and every 5 years thereafter. They recommend the use of TSH as the most valuable screening and diagnostic test. It should be remembered, however, that secondary forms of hypothyroidism caused by hypothalamic or pituitary disease cannot be diagnosed using a TSH level alone.
Slide 17: Mild Hypothyroidism: Should patients be treated
Once mild hypothyroidism has been diagnosed, should patients be followed-up or treated? The major arguments for treatment include the idea that some symptoms may be alleviated even though they are relatively mild. Treatment may also improve the lipid profile in selected patients who have evidence of hyperlipidemia. Treatment intervention may also prevent patients from going several years with more severe forms of hypothyroidism before it is diagnosed. A major argument against treatment includes the cost, not only of therapy, but of follow-up testing for thyroid function. Several studies document that excess thyroid treatment can be deleterious, particularly because of increased risk of atrial fibrillation in the elderly and osteopenia caused by enhanced bone turnover and calcium release. It should be noted, however, that follow-up testing is indicated in most of these patients anyway to assess whether thyroid function has changed. In addition, TSH assays are sensitive enough that over-replacement with thyroid hormone can be avoided by selecting appropriate replacement doses.
Slide 18: Mild Hypothyroidism: Treatment
Most patients with mild hypothyroidism have residual thyroid function, hence it is possible to begin with relatively low doses of hormone replacement. Typically, treatment can begin using 50 µg levothyroxine each day, unless there is known cardiac disease, in which case the dose should be reduced. The half-life of levothyroxine is long (7 days) and the dose can be adjusted after several weeks or months with a goal to normalize the TSH in a range of 1-2 mU/L. Thereafter, it is reasonable to check the TSH level yearly to ensure compliance with the medication and to make adjustments in the event that thyroid function has changed.
Slide 19: Drugs and Clinical Conditions That May Reduce L-Thyroxine Effectiveness
It is also important to recognize that a variety of medications and other clinical conditions may alter levothyroxine absorption or effectiveness. Many of these disorders and medications are listed on this slide and may require adjustments in thyroid hormone replacement.
Slide 20: Summary
In summary, hypothyroidism is common, affecting as many as 10-15% of middle aged and elderly women. The diagnosis requires a high degree of clinical suspicion or routine screening to detect abnormal thyroid function. The ATA has recommended routine TSH testing in women aged 35 or greater and in men approximately a decade later. Recent insights into thyroid hormone action reveal a degree of complexity that was not previously appreciated. Multiple thyroid hormone receptors and a variety of co-repressor and co-activator molecules modulate thyroid hormone receptor action, and the expression of different types of deiodinase enzymes results in variable tissue sensitivities to circulating thyroid hormone. These findings have several potentially important implications. For example, although TSH is a highly sensitive index of hypothalamic pituitary response to thyroid hormone, it remains possible that this axis does not fully reflect thyroid hormone responses in other tissues, particularly in states of hypo- or hyperthyroidism. These findings also raise questions about how thyroid hormones should be replaced. Currently, many preparations are composed of pure T4, which is partially converted to T3 after absorption. Combined preparations of T4 and T3 more closely mimic thyroid gland production of thyroid hormones, but the relatively rapid absorption of T3 has made it difficult to use these preparations in all patients. Finally, thyroid hormone replacement is safe and effective. Sensitive TSH assays have made it possible to replace thyroid hormone in a near physiologic manner, but this requires ongoing patient education to assure compliance and intermittent monitoring of thyroid function.
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