Subclinical Hypothyroidism

US Pharm. 2010;35(6):20-22.

Thyroid disorders are common in the elderly. These conditions are diagnostically challenging and are often overlooked in seniors since signs and symptoms are frequently nonspecific and are attributed to comorbidities or the normal aging process.¹ Pharmacists who interact with patients and/or monitor patients’ response to pharmacotherapy have an opportunity to recognize the signs and symptoms of hypothyroidism (TABLE 1) and identify medications that may affect thyroid function (TABLE 2). This column will focus on the relatively common condition known as subclinical hypothyroidism, also referred to as mild thyroid failure.

Role of the Thyroid Gland

With regard to metabolism, the thyroid gland and thyroid hormones influence practically all cellular function.² The largest endocrine organ in the body, the two-lobed thyroid gland, is located in the anterior neck and produces the two main thyroid hormones: triiodothyronine (T₃), the most active form, and tetraiodothyronine (thyroxine, T₄), which has minimal hormonal activity.^1,3,4 Approximately 80% of the production of T₃ is derived from T₄-to-T₃ conversion in extrathyroidal tissues (liver, muscles, kidneys); the thyroid gland secretes the remaining 20% of T₃.¹  

The hypothalamus, the anterior pituitary, and the thyroid gland regulate thyroid hormones through a negative feedback loop.¹ Thyrotropin-releasing hormone (TRH) within the hypothalamus stimulates the release of thyroid-stimulating hormone (TSH) from the anterior pituitary gland; TSH is responsible for increasing thyroid hormone synthesis and secretion.¹ From the serum, T₃ and T₄ feed back to inhibit TSH and TRH production and secretion.¹

Of note, the thyroid gland also secretes the hormone calcitonin, which is classified as a serum calcium–lowering hormone.⁴ Preparations of calcitonin (e.g., calcitonin-salmon) help regulate calcium via bone, renal, and gastrointestinal effects, and are used in the treatment of osteitis deformans, postmenopausal osteoporosis, and hypercalcemia.^5,6

While the thyroid gland is not essential for life, in a newborn, thyroid hormone is required for normal brain function and somatic tissue development; in individuals of all ages, thyroid hormone regulates protein, carbohydrate, and fat metabolism.^3,4 By maintaining a level of metabolism in the tissues that is optimal for normal function, the thyroid gland facilitates normal growth and maturation.⁴

Age-Related Changes in Thyroid Function

The notion that biological aging is a multifactorial process, is commonly accepted.⁷ In general, changes associated with aging occur morphologically (e.g., sclerosis of heart valves, decreased elasticity of lung) and/or functionally (e.g., decreased T-cell activity, increased motor response time, slowed intestinal motility).⁷ With regard to the thyroid, age-related changes manifest as alterations in anatomy (e.g., increase in fibrosis) and function (e.g., decrease in T₃ concentration); the vast majority of seniors, however, maintain normal thyroid function.¹

Thyroid Failure

The insidious process of thyroid failure and a state of decreased thyroid hormone available to peripheral tissues constitutes the clinical situation known as hypothyroidism.¹ In the general population, in patients over the age of 60 years the incidence of overt hypothyroidism is approximately 2% to 10%.¹ Medications such as amiodarone and lithium often induce hypothyroidism.⁸ Other risk factors for failure of the thyroid gland can be found in TABLE 3. 

Inadequate secretion of thyroid hormone (hypothyroidism) results in a variety of signs and symptoms (TABLE 1), including bradycardia, cold intolerance, and mental and physical slowing. There may be a delay in clinical suspicion of hypothyroidism in elderly patients because early manifestations, such as fatigue and constipation, may be attributed to aging itself.⁹ In fact, elderly patients have fewer symptoms of hypothyroidism than their younger counterparts and present with more subtle and vague complaints.¹⁰

Pharmacists should note that this is in contrast to excess secretion of thyroid hormones (hyperthyroidism) resulting in signs and symptoms including tachycardia, cardiac arrhythmias, body wasting, nervousness, tremor, and excess heat production.⁴

Serum TSH (adult reference range approximately 0.3-4 mIU/L) is generally considered the best screening test for thyroid disease due to its sensitivity and specificity; elevated values usually are indicative of hypothyroidism, and decreased values usually are indicative of hyperthyroidism.^6,9 Laurberg et al recommend that TSH levels be part of biochemical testing for undiagnosed medical conditions in elderly patients.⁸

The sensitivity of serum TSH measurement may reveal patients with elevated serum TSH levels, however, implying hypothyroidism but with an accompanying normal free T₄ levels (adult reference range approximately 0.8-1.8 ng/dL); see Subclinical Hypothyroidism, below.^6,9

Subclinical Hypothyroidism

During a routine screening for thyroid disease, a patient may be found to have subclinical hypothyroidism—an elevated TSH level in conjunction with a free T₄ level that is not below normal and is also referred to as mild thyroid failure.^1,9 The patient may be asymptomatic or present with minimal symptoms of hypothyroidism.⁷ Subclinical hypothyroidism is frequently an early stage of hypothyroidism.⁹ When a patient presents with a serum TSH > 10.0 mIU/L, there is a high likelihood of progression to overt hypothyroidism presenting with low serum free T4 in the upcoming 10 years.³

The prevalence of subclinical hypothyroidism is approximately 3% to 8.5% of the general population; it is more common in women than in men, and its prevalence increases with age—rising to as high as 20% in women over the age of 60 years.^11,12 Subclinical hypothyroidism progresses to overt hypothyroidism at a rate of 5% to 20% per year in patients who have both mildly elevated TSH levels and antithyroid (peroxidase) antibodies.^1,9 Patients with this condition are more likely to have hypercholesterolemia.³ According to Hak et al, the Rotterdam study indicated that subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women.¹³ Furthermore, Biondi et al have noted subclinical hypothyroidism to be associated with left ventricular diastolic dysfunction that is improved with T₄ therapy.¹⁴

Subclinical hypothyroidism is far more common than subclinical hyperthyroidism.³ It occurs especially in geriatric women with an underlying autoimmune thyroiditis (Hashimoto’s thyroiditis).³ While Surks et al indicate that there is insufficient evidence to support population-based screening, they indicate that aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.¹⁵

Treatment

Although it has been controversial as to whether or not to treat patients with subclinical hypothyroidism, patients with this condition sometimes have subtle hypothyroid symptoms and may have mild abnormalities of serum lipoproteins and cardiac function.¹² Furthermore, there is the risk of progression to overt hypothyroidism in these individuals; therefore, patients with definite and persistent TSH elevation should be considered for thyroid treatment.^9,16

While various preparations of thyroid hormone are available, levothyroxine is preferred; therapy is initiated at low doses (12.5-25 mcg) in the elderly.³ Fatourechi notes that large-scale randomized studies are required for evidence-based recommendations regarding screening for subclinical hypothyroidism and levothyroxine therapy for this condition.¹² However, these researchers note that currently the practical approach is routine levothyroxine therapy, which normalizes serum TSH levels for persons with a persistent serum TSH of greater than 10.0 mIU/L, and individually tailored therapy for those with a TSH of less than 10.0 mIU/L.¹² Other experts specify that for those patients with TSH levels between 4.5 and 10 mIU/L, it is reasonable to introduce a trial of levothyroxine if early hypothyroid symptoms (e.g., fatigue, depression) are present.³ Treatment is also recommended in patients with subclinical hypothyroidism if there are clinical features of hyperlipidemia or goiter.¹

Pharmacists may also refer to an algorithm for the management of subclinical hypothyroidism that has been proposed by Cooper (see Reference 17).   

Of note, pregnant women and women who plan to become pregnant are treated with levothyroxine to avoid harmful effects secondary to hypothyroidism with regard not only to the pregnancy but to fetal development as well.³ 

Monitoring for Efficacy and Toxicity

Patients under treatment for subclinical hypothyroidism should be evaluated for efficacy of thyroid hormone therapy; assessment of serum lipid concentrations, cognitive function, and psychiatric status is recommended.¹ Since therapy with levothyroxine decreases LDL-C and apolipoprotein B level and decreases the ratio of cholesterol to HDL-C in patients with subclinical hypothyroidism, there may be a reduction in the risk for the development of coronary artery disease.¹

Patients with subclinical hypothyroidism who are asymptomatic and do not receive levothyroxine therapy should be monitored to assess the progress of their condition; this is achieved by measurement of serum TSH and free T₄ every 6 months to annually.^1,3 Symptoms of hyperthyroidism (e.g., weight loss, increased sweating, palpitations) will occur with excessive thyroid hormone replacement.² Patients should be made aware of this possibility and instructed to report such occurrences to a health care professional. Due to the long half-life of levothyroxine, laboratory assessment is generally not carried out at less than 6-week intervals.² 

Conclusion

The prevalence of hypothyroidism increases dramatically in geriatric individuals. Subclinical hypothyroidism is more common in women than in men, and its prevalence increases with age. According to researchers, the most important implication of this disorder is the high likelihood of progression to overt hypothyroidism. Furthermore, patients with subclinical hypothyroidism are more likely to have hypercholesterolemia and atherosclerosis. Pharmacists can assist in the identification of subclinical hypothyroidism and provide recommendations regarding appropriate pharmacotherapy, thyroid function testing and outcome management including monitoring for efficacy and toxicity.

REFERENCES

1. Hak AE, Pols HAP, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med. 2000;132:270-278.
2. Biondi B, Fazio S, Palmieri EA, et al. Left ventricular diastolic function in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999;84:2064-2067.
3. Cooper DS. Subclinical hypothyroidism. N Eng J Med. 2001;345:260.
4. Huber G, Staub J-J, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metabl. 2002;87:3221-3226.
5. Laurberg P, Andersen S, Bülow Pedersen I, et al. Hypothyroidism in the elderly: pathophysiology, diagnosis and treatment. Drugs Aging. 2005;22:23-38.
6. Rosario PW. Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/l: a prospective study. Clin Endocrinol (Oxf). 2010;72:685-688.
7. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228-238.
8. Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24.
9. Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84:65-71.
10. Adlin V. Subclinical hypothyroidism: Deciding when to treat. American Academy of Family Physicians.org. 1998. American Family Physician. www.aafp.org/afp/980215ap/adlin.html. Accessed May 17, 2010.
11. Hassani S, Hershman JM. Thyroid Diseases. In: Hazzard WR, Blass JP, Halter JB, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York, NY: McGraw-Hill, Inc; 2003:837-853.
12. Kane RL, Ouslander JG, Abrass IB. Essentials of Clinical Geriatrics. 5th ed. New York, NY: McGraw-Hill, Inc; 2004:3-15,305-334.
13. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:937,1192,1202-1203.
14. Dorland’s Pocket Medical Dictionary. 28th ed. Philadelphia, PA: Elsevier Saunders: 2009.
15. Monaghan MS, Kissinger JF, Archer Jeanne. Endocrine disorders: thyroid and adrenal conditions. In: Youngkin EQ, Sawin KJ, Kissinger JF, et al, eds. Pharmacotherapeutics: A Primary Care Guide. Upper Saddle River, New Jersey: Pearson Prentice Hall; 2005:649-667.
16. Howland RD, Mycek MJ. Pharmacology, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:271-280.
17. My Epocrates, Version 9.0. San Mateo, CA: Epocrates, Inc. www.epocrates.com. Accessed May 15, 2010.
18. Beers MH, Jones TV, Berkwits M, et al, eds. The Merck Manual of Geriatrics. 3rd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2000:642-647.

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