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clinical review

Hypothyroidism and Subclinical Hypothyroidism in the Older Patient

Samuel L. Gurevitz, Jennifer A. Snyder, Katie L. Peterson, Kristin L. Kelly

obJecTive: To review the etiology, precipitating factors,

clinical findings, screening recommendations, and treatment

for primary hypothyroidism and subclinical hypothyroidism in

the older patient.

daTa sources: A PubMed search of English language

articles using a combination of words: elderly, thyroid,

hypothyroid,* subclinical hypothyroid,* etiology, screening,

diagnosis, and treatment to identify original studies,

guidelines, and reviews on primary hypothyroidism and

subclinical hypothyroidism published between 1979

and present.

sTudy selecTion and daTa exTracTion: Overall, 51

clinical reviews, original studies, references, and guidelines

were obtained and evaluated on their clinical relevance to

the older patient population.

daTa synThesis: The literature included guidelines and

considerations for the diagnosis, screening, and management

of subclinical and overt primary hypothyroidism in the

older patient.

conclusion: Females and individuals 60 years of age or

older have a higher prevalence of primary hypothyroidism

and subclinical hypothyroidism. While screening

recommendations exist, the need or suggested age to initiate

screening varies among organizations. TSH and free T4

values are used for diagnosing and monitoring. Levothyroxine

remains the drug of choice for replacing endogenous thyroid

hormone. Despite evidence to suggest its need, the treatment

of subclinical hypothyroidism remains controversial.

Key words: Elderly, Geriatrics, Hypothyroidism, Screening,

Subclinical hypothyroidism, Treatment.

abbreviaTions: AACE = American Association of Clinical

Endocrinologists, ATA = American Thyroid Association,

NTI = Narrow therapeutic index, T3 = Triiodothyronine,

T4 = Thyroxine, TBG = Thyroxine-binding globulin, TPO =

Thyroid peroxidase, TRH = Thyrotropin-releasing hormone,

TSH = Thyroid-stimulating hormone.

Consult Pharm 2011;26:000-00.

IntroductionPrimary hypothyroidism, or insufficiency of the thyroid leading to a reduction in thyroid hormones thyroxine (T4) and triiodothyronine (T3), is a common disorder affecting 1% to 10% of the U. S. population.1-4 It is more often found in females and has a higher prevalence in those 60 years of age or older. Subclinical hypothyroid-ism is defined as an elevated serum thyroid-stimulating hormone (TSH) level associated with normal total or free T4 and T3 levels.5 Subclinical hypothyroidism is also more common in white females and is on the rise in the United States with a variable reported prevalence rate of 4% to 20%.1,2,4-6 According to the American Association of Clinical Endocrinologists’ (AACE) guidelines regarding thyroid dysfunction, subclinical hypothyroidism affects up to 20% of persons older than 60 years of age.7 In long-term care facilities, undiagnosed hypothyroidism can be found as frequently as one in every four residents.8,9 As a large portion of the U. S. population continues to age, clinicians are likely to see an increased incidence of hypothyroid and subclinical hypothyroid disorders. This review will summarize the etiology, precipitating factors, clinical findings, screening recommendations, and treatment for hypothyroidism and subclinical hypothyroidism in the older patient.

Etiology The thyroid gland is located immediately below the larynx and anterior to the trachea and is responsible for secreting the thyroid hormones T4 and T3. The secretion of thyroid hormones is initiated by thyrotropin-releasing hormone (TRH), released from the hypothalamus.10 TRH stimulates the anterior pituitary to secrete TSH.11 Available data conclude no change occurs in the TSH response to TRH with aging.12 TSH then causes thyro-peroxidase to liberate iodine and allow the coupling of iodine and tyrosine in specific regions of thyroglobulin molecules.13,14 This leads to the synthesis of T4 and T3. These hormones are then secreted from the thyroid. In elderly patients, thyroid secretion and degradation is reduced, leading to unchanged serum T4.15 The secretion of TRH and TSH is regulated by feedback inhibition of T4 and T3.11 The most biologically active thyroid

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hormone is T3; however, it is secreted by the thyroid in a lesser amount than T4. The majority of T3 is produced by peripheral conversion of T4 by the enzymes T4-5’-deiodinases, which selectively remove iodine from T4.16,17

Hypothyroidism can be divided into three major categories: primary, secondary, and tertiary.18 Primary hypothyroidism is an insufficiency of thyroid hormone specifically as a result of dysfunction of the thyroid. Secondary and tertiary hypothyroidism are caused by pathologies associated with pituitary gland and hypo-thalamus dysfunction, respectively. This review will focus specifically on primary hypothyroidism.

The causes of both overt and subclinical primary hypothyroidism include processes such as autoimmune destruction, substrate deficiency or excess, enzymatic dysfunction, and iatrogenic etiologies. According to AACE, the most common cause of primary hypo-thyroidism in the United States, including the elderly population, is Hashimoto’s thyroiditis.7 It is a chronic autoimmune destruction of the thyroid gland resulting in the inhibition of the action of TSH through thyroper-oxidase and thyrogobulin antibodies or TSH receptor antibodies.7,19 This blockade results in damage and eventually atrophy of the thyroid gland.20 Hashimoto’s thyroiditis expresses a genetic component, showing familial clustering and a higher incidence in monozy-gotic twins than in dizygotic twins, as well as in some cases expressing the human leukocyte antigen types.21 The disease also has a predilection for Caucasians with a lower incidence in Japanese- and African-Americans.19

Table 1. daily recommended iodine levels

Infant (under 1 year)

Children, 2-6 years of age

Children, 7-12 years of age

Beyond 12 years of age–adults,

including elderly

Pregnant and lactating women

mcg/day

50

90

120

150

200

source: Reference 24.

Table 2. medications That may induce hypothyroidism or alter the effects of levothyroxine

induce hypothyroidism by inhibiting thyroid hormone

production and/or release

Aminogluthimide

Amiodarone

Interferon-α

Iodine

Lithium

Perchlorate

Thionamides

interfere with levothyroxine absorption

Antacids containing aluminum hydroxide

Calcium carbonate

Cholestyramine

Colesevalam

Ferrous sulfate

Lanthanum

Proton pump inhibitors

Raloxifene

Sevelamer

Sucralfate

alter levothyroxine metabolism leading to increasing

dosage requirements

Amiodarone

Carbamazepine

Estrogen

Phenytoin

Rifampin

source: References 19, 25, 26, 41, 48.

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Other etiologies of hypothyroidism include both excessive iodine intake and severe iodine deficiency.14 Excessive amounts of iodine, from 500 to 1,000 µ/ day, cause suppression of thyroid function. This results in decreased thyroid hormone production. Severe iodine deficiency directly suppresses the production of T4 hormone by limiting the “building blocks” for T4 production.19 Furthermore, a drastic fluctuation in the amount of iodine consumed can greatly impact the formation of thyroid hormones.22,23 The World Health Organization establishes the recommended daily

requirements for iodine, and the level is age dependent (Table 1).24

Additional causes of hypothyroidism include thyroid atrophy and fibrosis associated with the normal aging process, thyroid surgery that is often associated with thyroid cancer or Graves’ disease, and high doses of radioiodine therapy that result in thyroid gland destruction.25 Several medications are known to cause drug-induced hypothyroidism (Table 2); therefore, with their use, periodic monitoring of TSH is suggested.25,26

Clinical FindingsWhile subclinical hypothyroidism may be asymptomatic, there are a range of symptoms and signs associated with both overt and subclinical hypothyroidism (Table 3).6,15,19 Signs and symptoms of hypothyroidism and subclinical hypothyroidism may go unrecognized in the elderly population as a result of subtle clinical manifestations that may be misinterpreted as normal characteristics of aging (e.g., cognitive impairment, constipation).27 Additionally, chronic disease states and other comorbid conditions may mask findings of hypothyroidism and make the diagnosis difficult.15,25

Hypothyroidism, if left untreated, may increase the risk of hyperlipidemia, cardiac dysfunction, or cognitive impairment. Hypothyroidism is a risk factor for statin-induced myopathy.28 Subclinical hypothyroidism may progress to overt hypothyroidism.6,7 New evidence sug-gests that subclinical hypothyroidism leads to increased levels of homocysteine, which is an independent risk factor for atherosclerotic heart disease.29 A recent cohort study of elderly adults determined that men with subclinical hypothyroidism have an increased risk of developing a hip fracture.30

Screening and DiagnosisGiven the many comorbidities and complications associated with overt and subclinical hypothyroidism, screening the elderly population for thyroid disease may be worthwhile in decreasing morbidity and mortality; however, large-scale studies are needed.31 While the U. S. Preventive Services Task Force concludes there is insuf-ficient evidence to screen the general patient population

Table 3. symptoms and signs of hypothyroidism

Arthralgias and/or myalgias

Ataxia

Bradycardia

Coarseness or loss of hair

Cold intolerance

Constipation

Decreased concentration

Delayed deep tendon reflexes

Depression

Dry and/or yellow skin

Dyspnea

Fatigue

Goiter

Hoarseness

Hyperlipidemia

Hypothermia

Infertility

Irregular or heavy menses

Memory and mental impairment

Myxedema fluid infiltration of tissues

Weakness

Weight gain

source: References 6,9,16.

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for thyroid disease, there are other national organizations that do recommend screening (Table 4).32-35

If a patient has nonspecific symptoms or signs that can be attributable to thyroid dysfunction, thyroid function tests should be ordered. The single most useful test to screen for thyroid dysfunction is the sensitive TSH assay.7 An elevated TSH assay helps to establish the diagnosis of hypothyroidism in primary thyroid disease (Table 5).36 If TSH is elevated, a total T4 should be ordered to determine the functioning status of the thyroid. In primary hypothyroidism, T4 levels are decreased. T4 levels are highly bound to proteins (thyroxine-binding globulin [TBG], albumin, and trans-thyretin) and may be abnormal as a result of medication usage.19 The most common cause of hypothyroidism in a euthyroid elderly subject is lithium, estrogen, cytokine, or amiodarone therapy, whereas low T4 is seen during therapy with carbamazepine and similar drugs.19 Total T4 may be adjusted to obtain a ‘free T4 estimate’ using the T3 test or by measuring TBG and adjusting for TBG abnormalities. Hypothalamic and pituitary dysfunc-tion can lead to normal TSH levels and yet abnormal

thyroid hormone levels; therefore, a T4 level should be included if overt hypothyroidism symptoms and signs are present.19

TSH levels have a narrow normal range. According to a 20-year longitudinal study performed by Vanderpump utilizing the Whickham Survey, 1,700 sub-jects demonstrated a higher prevalence of progression to overt thyroid disease when their TSH level was greater than 2 mIU/L.37 The risk was much higher in individu-als also positive for antithyroid antibodies at baseline testing. If patients have an upper level normal reference range TSH, they should be retested in 3 to 6 months to determine if there is a change in their status, especially if they have positive antithyroid peroxidase antibodies.38

Serum T3 is not a sensitive marker of thyroid hypo-function. Serum T3 tends to remain normal until severe hypothyroidism develops. This is probably caused by a combination of enhanced T3 synthesis in the stimulated thyroid and enhanced T4 deiodination to T3 catalyzed by deiodinase type 2.19 On the other hand, severe disease, starvation, and many drugs lead to a low serum T3 not caused by hypothyroidism. In a study by Iglesias et al., the reduction of free T3 values, found in about two thirds of the patients, was a powerful predictor for mortality during hospitalization in elderly patients.2

The most common supplementary test to evaluate involvement of autoimmunity is thyroid peroxidase (TPO) antibodies in serum. In patients with subclinical hypothyroidism, the presence of TPO

Table 4. screening Guidelines for Thyroid disease

american Thyroid

association

united states Preventive

services Task force

american college of

Physicians

american academy of

family Physicians

Adults should be screened

beginning at age 35 years

and at intervals every 5 years

thereafter.

There is insufficient evidence

to screen the general patient

population for thyroid

disease.

Screening women older than

50 years may be indicated.

Recommends against routine

screening for thyroid disease

in patients younger than 60.

source: References 32-35.

Table 5. normal adult Thyroid function Panel values

Thyroid-stimulating hormone

Total T4

Free T4

Thyroperoxidase antibodies

0.4-4.2 mIU/L

5.4-11.5 mcg/dL

0.7-2.0 ng/dL

Negative

source: Reference 36.

lab normal range

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antibodies indicates enhanced risk of progression of thyroid insufficiency.

Treatment The treatment goals for hypothyroidism are to replace the missing hormones, relieve symptoms, and reverse the biochemical abnormalities of hypothyroidism as evidenced by normal blood levels of TSH and free T4. Thyroid hormone is administered to supplement or replace endogenous production. According to the AACE, treatment is indicated in patients with TSH levels > 10 μIU/mL or in patients with TSH levels between 4.5 and 10 μIU/mL in conjunction with goiter or positive antithyroid peroxidase antibodies (or both).5

In the United States, there are several thyroid hormone preparations currently available. They include levothyroxine sodium (thyroxine), liothyronine (triiodothyronine), and desiccated thyroid (contains thyroxine and liothyronine), as well as a synthetic combination of levothyroxine sodium and liothyronine (liotrix). Desiccated thyroid extract is derived from the porcine thyroid gland, which contains both thyroxine and liothyronine in a ratio of 1:4.22. Liotrix is a syn-thetic combination with a fixed dose of thyroxine and liothyronine (1:4 ratio). Liothyronine (T3) is a synthetic version of the thyroid hormone. It has a shorter half-life (1.5 days) compared with T4 (7 days). Liothyronine has no role in the treatment of primary hypothyroidism.39 The approximate equivalent doses for different thyroid supplements are: thyroid (porcine) 1 grain (60 mg) = 1 tablet of liotrix = 25 mcg of liothyronine = 100 mcg of levothyroxine.40 According to the AACE and the American Thyroid Association (ATA), levothyroxine is the treatment of choice for hypothyroidism.7,41 Once absorbed, levothyroxine is converted to T3.There is insufficient evidence regarding the treatment with a combination of thyroxine and liothyronine. A meta-anal-ysis comparing thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for treatment of hypothyroidism found no difference in the effectiveness of the combination versus the monotherapy.42

Hypothyroidism develops over a prolonged period of time, and correction should be made slowly. Although

the appropriate dosage may vary among patients, the average levothyroxine replacement dose to normalize TSH in most patients is 1.6 to 1.7 mcg/kg/day.19,43 In older patients the requirement falls to 1 mcg/kg/day or less.41,43 Alternatively, elderly patients and those with known cardiovascular disease, should have levothyrox-ine initiated at 12.5 mcg to 25 mcg per day. This should be titrated upward in increments of 25 mcg until TSH is normalized based on subsequent measurements obtained every 4 to 6 weeks.25,44,45 The goal TSH is between 0.3 and 3 µIU/mL.7 Once the TSH is stable on a maintenance dose, follow-up monitoring in older adults should be every 6 to 12 months.19,25

Levothyroxine is recognized as a drug with a narrow therapeutic index (NTI), and its dose is adjusted to keep TSH within the desired range. It is important to recognize factors that may interfere with the ability to maintain a desired TSH concentration. Food can dimin-ish the absorption by 40% to 64%.46 It is recommended that levothyroxine be administered while fasting, usually one hour before meals. Recently a randomized, double-blind, crossover trial concluded levothyroxine taken at bedtime significantly improved thyroid hormone levels.47

In addition, many older adults have multiple comorbidities and are more likely to be affected by the risks of polypharmacy. Polypharmacy increases the risk of interactive effects of medications. There are several medications that interfere with the absorption of levo-thyroxine (Table 2).19,25,26,41,48

To alleviate this potential, levothyroxine admin-istration should be spaced at least 4 hours apart from these medications.41 Other drugs can accelerate the metabolism of levothyroxine that may lead to an increase in levothyroxine dosage (Table 2).19,26 Additional factors that may alter levothyroxine requirements are malabsorptive diseases, like celiac disease.48 Because levothyroxine has an NTI, the potential for insufficient treatment or overtreatment (iatrogenic hyperthyroidism) must be recognized. Adverse effects related to overtreat-ment include nervousness, difficulty concentrating, palpitations, tremor, or chest pain. The patient should be evaluated, and if excess T4 is confirmed, the current dose should be withheld for a week and then restarted at

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a lower dose. Some patients remain asymptomatic even though T4 is elevated. A reduced bone mineral content has been associated with over-replacement of levothy-roxine. It is recommended that these patients have their dose reduced.19,41

Bioequivalence of levothyroxine preparations is a significant issue. Because differences may exist among the preparations, The Endocrine Society is concerned with interchangeability of levothyroxine preparations. Changing a patient to a new levothyroxine preparation could lead to over- or undertreatment with possible adverse effects.49,50 In a study conducted by The Endocrine Society, AACE, and the ATA, switching patients to other levothyroxine products without the knowledge of the physician resulted in 160 adverse events.50 If the brand of levothyroxine is switched, the patient and physician should be informed, and the patient’s TSH should be retested in six weeks. Open communication with the prescribing health care practi-tioner is highly recommended. The pharmacist should educate the patient that switching formulations, particu-larly multiple times, may lead to increased medical costs in terms of follow-up care and unwanted adverse effects.

Significant controversy persists regarding the treat-ment of patients with subclinical hypothyroidism. Most professional organizations and evidence-based guide-lines advocate starting replacement therapy in elderly patients who have TSH concentrations greater than 10 mIU/L and in those with antithyroid antibodies, and in symptomatic elderly patients with TSH levels between 4.5 and 10 mIU/L.38,43 When the decision is made to start treatment, the initial dose should not exceed 25 mcg per day and the dose should be increased slowly to avoid precipitating coronary symptoms. Follow-up of TSH measurement should be repeated in 6 to 8 weeks.51

The target TSH in the elderly is also controversial. The current available data suggest that, in individuals older than 70 years of age, it is reasonable to initiate levo-thyroxine with the goal of a TSH level between 4 and 6 mlU/L. Treatment of subclinical hypothyroidism should probably be avoided in patients older than 85 years of age with a TSH level between 4.5 and 10 mIU/L.38,51 Prospective therapeutic trials are necessary to clarify the

necessity of replacement therapy in the elderly.

Role of the PharmacistHow can pharmacists incorporate the guidelines for hypothyroidism into their daily practice?• Review the patient’s medications that may cause

hypothyroidism or for drug interactions. • Monitor for signs and symptoms for hypothyroidism.• Confirm and make recommendations to ensure thy-

roid hormones are administered correctly in regard to meals and other medications.

• Monitor for adverse reactions and therapeutic response (signs and symptoms and TSH goal).

• Recommend patients older than 60 years of age be screened for hypothyroidism.

• Assess older patients for hypothyroidism and, if necessary, treat to attain a euthyroid state before starting statin therapy.

• Initiate low-dose levothyroxine (12.5-25 mcg per day) in those older than 60 years of age and patients with ischemic heart disease. This should be titrated upward in increments of 25 mcg until TSH is normalized based on subsequent measurements obtained every 4 to 6 weeks.

• Retest TSH levels in six weeks if the brand of levothy-roxine is switched.

ConclusionPrimary hypothyroidism is defined as an elevated TSH and a decrease in thyroid hormones; whereas, subclinical hypothyroidism is an elevated TSH associated with normal thyroid hormones. Patient presentation and physical exam findings range from asymptomatic to severe. Screening recommendations are divisive and vary among organizations. Levothyroxine remains the treatment of choice. Treatment is indicated in patients with TSH levels > 10 μIU/mL or in patients with TSH levels between 4.5 and 10 μIU/mL in conjunction with goiter or positive anti-TPO antibodies (or both). Despite evidence to suggest its need, the treatment of subclinical hypothyroidism remains controversial. TSH levels should be monitored regularly to ensure adequate supplementation.

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Samuel L. Gurevitz, PharmD, CGP, is assistant professor, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, Indianapolis, Indiana. Jennifer A. Snyder, MPAS, PA-C, DFAAPA, is associate professor, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, Indianapolis. Katie L. Peterson, ATC, PA-S, is physician assistant student, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, Indianapolis. Kristin L. Kelly, PA-S, is physician assistant student, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, Indianapolis. For correspondence: Samuel L. Gurevitz, PharmD, CGP, Physician Assistant Program, College of Pharmacy and Health Sciences, Butler University, 4600 Sunset Avenue, Indianapolis, IN 46208. Tel: (317) 940-6542; Fax: (317) 940-6172; E-mail: sgurevit@butler.edu. Disclosures: No funding was received for this study or the development of the manuscript. The authors report no potential conflicts of interest. © 2011 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2011.000.

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