When thyroid hormone levels are insufficient

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The key to managing hypothyroidism is establishing the primary cause and determining whether the disorder is persistent or transient.

This statistic may surprise you: Hypothyroidism is the second most common endocrine disorder (after diabetes) encountered in primary care. Failure to produce sufficient amounts of thyroid hormone occurs in children and adults and increases in frequency with age. In the Third National Health and Nutrition Examination Survey (NHANES III), the prevalence of an elevated thyroid-stimulating hormone (TSH) in 17,353 people older than age 11 years in the United States was 4.6%. The prevalence was higher in whites (5.1%) than Hispanics (4.1%) or African Americans (1.7%).

In those older than 50, hypothyroidism is more common in females than males. In the Framingham study of adults older than age 60, a TSH >10 mU/L was found in 5.9% of females and 2.4% of males, or approximately a 2:1 ratio of women to men. Worldwide, hypothyroidism is even more common than in the United States because of widespread iodine deficiency.

Clinical presentation

In a cross-sectional study, the symptoms that correlated best with hypothyroidism were (in descending order) hoarse and/or deep voice, muscle cramps, slow thinking, puffy eyes, fatigue, constipation, depression, math difficulty, cold sensitivity, dry skin, and heavy menstrual flow.1 Only 30% of newly diagnosed patients had symptoms, while 17% of normal control patients had the same complaints. The severity of symptoms generally correlates with the severity of the disease.

Physical findings of hypothyroidism are also nonspecific — slow heart rate, low core body temperature, and increased BP and weight. The hair may be coarse, and the skin may be pale, cool, and dry. In some patients, a goiter is present. Myxedema (nonpitting generalized edema) may be seen in severely affected patients. Deep tendon reflexes are sometimes decreased, with delay in the relaxation phase. Associated biochemical abnormalities include hyponatremia, hypercholesterolemia (with a rise in both the LDL and triglyceride concentrations), and elevations in homocystine, creatinine, and creatine kinase.

Screening

Because benefit from early diagnosis and treatment in adults with hypothyroidism is unclear, recommendations for routine screening of asymptomatic adults vary among experts and organizations. In its most recent review, the U.S. Preventive Services Task Force (USPSTF) found no significant clinical benefit in screening asymptomatic individuals. However, the USPSTF does recommend testing in patients with symptoms of thyroid disorders, especially in high-risk individuals with even vague symptoms. Such individuals include those with a history of surgery or iodine-131 therapy for hyperthyroidism, the elderly, postpartum women, and patients with Down syndrome.

Diagnosis

Hypothyroidism is usually diagnosed with biochemical testing. The recent development of highly sensitive assays for TSH has led to their emergence as the preferred screening tests. Since hypothyroidism is almost always the result of disorders of the thyroid gland (primary hypothyroidism), the TSH is elevated in nearly all patients. The exception is hypothyroidism caused by disorders of the hypothalamus or pituitary (central or secondary hypothyroidism), in which the TSH level may be low, normal, or elevated.

If you suspect hypothyroidism, order a TSH. If the TSH is high (normal range 0.45-4.5 mIU/L), obtain a second TSH along with a measurement of a free thyroxine (FT4) level. A low FT4 (normal range 0.8-2.0 ng/dL) establishes the diagnosis of overt hypothyroidism.

If the TSH is elevated (between 4.5 and 10.0 mIU/L) and theFT4 is normal, the patient may be classified as having subclinical or mild hypothyroidism. Over time, many with subclinical hypothyroidism will develop overt hypothyroidism, depending on the underlying cause. One longitudinal study recently reported that in a cohort of 82 women with subclinical hypothyroidism, 28% developed overt hypothyroidism over a mean study period of 9.8 years.2

Other than hypothyroidism, there are few conditions that cause TSH elevation. In these circumstances, even when the TSH is elevated, the FT4 will not be decreased. Sometimes, an acute, severe illness may cause TSH elevation, but on postrecovery repeat testing, the TSH is normal and the patient is euthyroid. Rarely, an elevated TSH could indicate peripheral resistance to thyroid hormone or a TSH-secreting pituitary tumor. In these situations, the FT4 is elevated, not decreased.

Metoclopramide, a dopamine receptor blocker, is the only drug recognized to cause elevation of TSH, but, as noted, the FT4 in this situation will be normal or elevated. Additionally, there is physiologic diurnal variation in TSH levels. Levels measured in the evening or at night may be 75% higher when compared with daytime levels. This can be significant enough to suggest hypothyroidism, but again FT4 levels will be normal.

Persistent hypothyroidism

Hypothyroidism may be chronic or temporary. In the United States, the most common cause of persistent hypothyroidism is autoimmune (Hashimoto’s) thyroiditis, which is generally associated with a painless goiter. This form of hypothyroidism is more common in females than males, at an 8:1 ratio, and more common in older age groups. Elevations of serum thyroid peroxidase (TPO) antibody (also referred to as “microsomal antibody”) are present in 90% of patients; a TPO antibody titer >200 IU/mL is highly suspicious for autoimmune disease. In addition, up to 50% of patients have an elevated serum thyroxine-binding globulin (TBG), or thyroglobulin antibody, level. Patients with thyroiditis often develop other autoimmune disorders. Conversely, autoimmune thyroiditis occurs more often in individuals with other pre-existing autoimmune disorders, such as type 1 diabetes.

A second common cause of persistent hypothyroidism in the United States is damage to the thyroid gland from surgery or irradiation — usually for the treatment of hyperthyroidism or another thyroid disorder. With surgery, the onset of hypothyroidism is abrupt, but over time, there may be some improvement in function. Following irradiation, thyroid function declines gradually.

Other causes of persistent hypothyroidism include infiltrative diseases of the thyroid, such as lymphoma, and central, or secondary, hypothyroidism (one of every 2,000 cases of hypothyroidism).

Transient hypothyroidism

An estimated 4.9% of new mothers will develop postpartum thyroiditis; approximately 90% of them will return to a euthyroid state3 within several months. Drugs may also be associated with transient hypothyroidism. Those most often implicated include lithium, amiodarone, aminoglutethimide, stavudine, interferon-a, interleukin-2, and thalidomide. Diagnosis can usually be suspected on the basis of history. Discontinuation of the drug, when possible, may result in recovery of thyroid function.

While iodine deficiency is not a common cause of hypothyroidism in the United States, it does occur and can be easily corrected. Malnutrition or a diet low in natural sources of iodine and without iodinated salt may cause iodine deficiency. Addition of iodine to the diet will correct the problem. Maternal iodine deficiency can lead to congenital hypothyroidism.

Treatment

Identifying the cause of each patient’s hypothyroidism is helpful in determining prognosis as well as necessity and duration of treatment. As indicated earlier, some causes will result in persistent, progressive hypothyroidism, while other causes may produce transient disease that requires no treatment or only temporary treatment. Failure to recognize this may commit the patient to a lifetime of unnecessary therapy with thyroid hormone. This was recently demonstrated in a study of nursing-home patients who had normal TSH values on thyroid replacement therapy and consented to hormone withdrawal. Of 22 patients completing the study, eight had normal TSH levels <4.5 mIU/L three months after withdrawal.4

Treatment of hypothyroidism with l-thyroxine is relatively straightforward and generally well tolerated. Surprisingly, the NHANES III study found that only 15% of patients who reported thyroid disease had laboratory evidence of hypothyroidism and 18% demonstrated some degree of hyperthyroidism. Only 67% of those reporting thyroid disease were adequately treated.

Treatment with excessive amounts of thyroid hormone may accelerate loss of calcium from bones, increasing patients’ risk for developing osteoporosis. Inadequate amounts of hormone might result in incomplete resolution of the condition. Pregnancy (or other conditions that increase estrogen, such as use of oral contraceptives or postmenopausal HRT) can raise the level of circulating TBG, necessitating higher doses of l-thyroxine (as much as 50% higher in pregnancy). Untreated pregnant hypothyroid patients have an increased risk of developing pre-eclampsia and associated complications during pregnancy. The American College of Obstetricians and Gynecologists recommends that TSH be monitored every four weeks early in pregnancy until the TSH level stabilizes. It should be checked again at least once during the second and third trimesters.

Adequacy of thyroid hormone dose in patients with primary hypothyroidism can be determined by measuring TSH levels. For adequate treatment, the TSH should be normalized. Many experts use a target TSH level of 0.45-2.0 mIU/L, but there are no data to support improved clinical outcomes with this lower goal. However, if a patient continues to be symptomatic after treatment, the clinician may wish to increase the dose of l-thyroxine until this lower goal is achieved in hopes of improving the symptomatic response.

Because l-thyroxine has a relatively long serum half-life of seven days, it is generally recommended that one wait at least six weeks after dosage change to measure the TSH response. Interest in combination therapy with l-thyroxine and liothyronine, the metabolically active form of the hormone triiodothyronine, has been stimulated by a 1999 study showing that combination therapy improved mood.5 Since then, several larger follow-up studies have been published using more heterogeneous populations. Some of these studies have reported that patients prefer the combination medication, but objective measures of mood or feelings of well-being have not demonstrated statistically significant superiority of combination therapy to l-thyroxine monotherapy.6-9

There are concerns that because triiodothyronine has such a short half-life, the patient will be transiently hyperthyroid shortly after taking a dose of combined thyroid hormone. This may be solved when manufacturers develop extended-release combination preparations. Also, the optimal ratio of thyroxine to triiodothyronine in such preparations has not been determined. Until these issues are resolved, l-thyroxine monotherapy remains the preferred treatment. Controversy exists about the value of treating subclinical hypothyroidism because there is little evidence of benefit.

This mild form of hypothyroidism is usually associated with few symptoms and does not appear to be associated with significant adverse outcomes.10 If the individual is symptomatic, treatment with l-thyroxine would be appropriate, especially if there is a primary cause that is likely to persist or worsen with time. Some patients who are treated experience subjective improvement in symptoms of well-being. A fasting lipid profile should also be checked; if LDL is elevated, the individual should be treated with l-thyroxine to observe the degree of LDL improvement before instituting other lipid-lowering therapy, such as a statin drug. If treatment is not necessary, watchful waiting with repeat TSH testing and evaluation for symptoms of hypothyroidism should be done at least annually.

Dr. Flinders is assistant clinical professor of family medicine at the University of Utah in Salt Lake City and assistant director of Utah Valley Family Medicine in Provo.

References

1. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med. 1997;12:544-550.

2. Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87:3221-3226.

3. Lucas A, Pizarro E, Granada ML, et al. Postpartum thyroiditis: epidemiology and clinical evolution in a nonselected population. Thyroid. 2000;10:71-77.

4. Coll PP, Abourizk NN. Successful withdrawal of thyroid hormone therapy in nursing home patients. J Am Board Fam Pract. 2000;13:403-407.

5. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340:424-429.

6. Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab. 2003;88:4543-4550.

7. Sawka AM, Gerstein HC, Marriott MJ, et al. Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88:4551-4555.

8. Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism, a randomized controlled trial. JAMA. 2003;290:2952-2958.

9. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, et al. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing l-thyroxine plus liothyronine with l-thyroxine alone. Ann Intern Med. 2005;142:412-424.

10. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228-238.

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