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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.
Introduction
Primary 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 hypothyroidism 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 thyroperoxidase 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
The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9 657
Clinical Review
Table 1. Daily Recommended Iodine Levels
mcg/day
Table 2. Medications That May Induce
Hypothyroidism or Alter the Effects
of Levothyroxine
Infant (under 1 year)
50
Children, 2-6 years of age
90
Induce hypothyroidism by inhibiting thyroid hormone
Children, 7-12 years of age
120
production and/or release
Beyond 12 years of age–adults,
150
Aminogluthimide
including elderly
Pregnant and lactating women
Amiodarone
200
Source: Reference 24.
Interferon-α
Iodine
Lithium
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 hypothalamus 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 hypothyroidism 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 thyroperoxidase 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 monozygotic 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
658
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.
The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9
Clinical Review
Table 3. Symptoms and Signs
of Hypothyroidism
Arthralgias and/or myalgias
Ataxia
Bradycardia
Coarseness or loss of hair
Cold intolerance
Constipation
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
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.
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
Clinical Findings
While 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 statininduced myopathy.28 Subclinical hypothyroidism may
progress to overt hypothyroidism.6,7 New evidence suggests 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 Diagnosis
Given 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 insufficient evidence to screen the general patient population
The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9 659
Clinical Review
Table 4. Screening Guidelines for
Thyroid Disease
Table 5. Normal Adult Thyroid Function
Panel Values
American Thyroid
Adults should be screened
Association
beginning at age 35 years
and at intervals every 5 years
thereafter.
LabNormal Range
Thyroid-stimulating hormone
0.4-4.2 mIU/L
Total T4
5.4-11.5 mcg/dL
United States Preventive
There is insufficient evidence
Free T4
0.7-2.0 ng/dL
Services Task Force
to screen the general patient
Thyroperoxidase antibodies
Negative
population for thyroid
Source: Reference 36.
disease.
American College of
Screening women older than
Physicians
50 years may be indicated.
American Academy of
Recommends against routine
Family Physicians
screening for thyroid disease
in patients younger than 60.
Source: References 32-35.
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 transthyretin) 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 dysfunction can lead to normal TSH levels and yet abnormal
660
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 subjects 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 individuals 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 hypofunction. 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
The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9
Clinical Review
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 synthetic 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-analysis 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 levothyroxine 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 diminish the absorption by 40% to 64%.46 It is recommended
that levothyroxine be administered while fasting, usually
one hour before meals. Recently a randomized, doubleblind, 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 levothyroxine (Table 2).19,25,26,41,48
To alleviate this potential, levothyroxine administration 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 overtreatment 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
The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9 661
Clinical Review
a lower dose. Some patients remain asymptomatic even
though T4 is elevated. A reduced bone mineral content
has been associated with over-replacement of levothyroxine. 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 practitioner is highly recommended. The pharmacist should
educate the patient that switching formulations, particularly multiple times, may lead to increased medical costs
in terms of follow-up care and unwanted adverse effects.
Significant controversy persists regarding the treatment of patients with subclinical hypothyroidism. Most
professional organizations and evidence-based guidelines 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 levothyroxine 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
662
necessity of replacement therapy in the elderly.
Role of the Pharmacist
How 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 thyroid 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 levothyroxine is switched.
Conclusion
Primary 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.
The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9
Clinical Review
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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The Consultant Pharmacist SEPTEMBER 2011 Vol. 26, No. 9