Hypothyroidism affects up to 0.5% of the US population and is most commonly caused by Hashimoto's thyroiditis. Treatment focuses on thyroid hormone replacement therapy using levothyroxine. Replacement should begin at a low dose, especially in the elderly and those with cardiac risks, and the dose should be gradually increased while monitoring laboratory values. Annual monitoring of thyroid-stimulating hormone levels is usually unnecessary once a stable replacement dose is found, except possibly in older patients. Some patients may benefit from adding a low dose of triiodothyronine to levothyroxine therapy.

1. COVER ARTICLE
PRACTICAL THERAPEUTICS
Treatment of Hypothyroidism
WILLIAM J. HUESTON, M.D., Medical University of South Carolina, Charleston, South Carolina
Thyroid disease affects up to 0.5 percent of the population of the United States. Its
prevalence is higher in women and the elderly. The management of hypothy-
roidism focuses on ensuring that patients receive appropriate thyroid hormone
replacement therapy and monitoring their response. Hormone replacement should
be initiated in a low dosage, especially in the elderly and in patients prone to car-
diac problems. The dosage should be increased gradually, and laboratory values
should be monitored six to eight weeks after any dosage change. Once a stable
dosage is achieved, annual monitoring of the thyroid-stimulating hormone (TSH)
level is probably unnecessary, except in older patients. After full replacement of
thyroxine (T4) using levothyroxine, the addition of triiodothyronine (T3) in a low
dosage may be beneficial in some patients who continue to have mood or memory
problems. The management of patients with subclinical hypothyroidism (a high
TSH in the presence of normal free T4 and T3 levels) remains controversial. In these
patients, physicians should weigh the benefits of replacement (e.g., improved car-
diac function) against problems that can accompany the excessive use of levothy-
roxine (e.g., osteoporosis). (Am Fam Physician 2001;64:1717-24.)
H
ypothyroidism is second ation of the thyroid subsequent to
only to diabetes mellitus Graves’ disease and surgical removal of
as the most common the thyroid gland.
endocrine disorder in Long-term thyroid dysfunction after
the United States, and its subacute granulomatous thyroiditis
prevalence may be as high as 18 cases per (de Quervain’s thyroiditis) or subacute
1,000 persons in the general population.1 lymphocytic thyroiditis (silent or pain-
The disorder becomes increasingly com- less thyroiditis) is fairly rare. Full thyroid
mon with advancing age, affecting about function is regained in 90 percent of
2 to 3 percent of older women.2 Because patients with these conditions.6
hypothyroidism is so common, family Hypothyroidism can also develop sec-
physicians need to know how to diag- ondary to hypothalamic and pituitary
nose the disorder and select appropriate disorders. These endocrine conditions
thyroid hormone replacement therapy. occur primarily in patients who have
undergone intracranial irradiation or
Etiology surgical removal of a pituitary adenoma.
A number of conditions can lead to
hypothyroidism (Table 1).3 Of noniatro- Signs and Symptoms
Members of various fam- genic causes, Hashimoto’s thyroiditis, or The signs and symptoms of hypothy-
ily practice departments chronic lymphocytic thyroiditis, is the roidism are nonspecific and may be con-
develop articles for
“Practical Therapeutics.”
most common inflammatory thyroid fused with those of other clinical condi-
This article is one in a disorder and the most frequent cause of tions, especially in postpartum women
series coordinated by the goiter in the United States.4 For an and the elderly. Because of the variety of
Department of Family unknown reason, the prevalence of possible manifestations, family physi-
Medicine at the Medical Hashimoto’s thyroiditis has been in- cians must maintain a high index of sus-
University of South Car-
olina, Charleston. Guest
creasing dramatically in this country picion for the disorder, especially in
editor of the series is over the past 50 years.5 Other common high-risk groups.
William J. Hueston, M.D. causes of hypothyroidism include irradi- Patients with severe hypothyroidism
NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1717

2. TABLE 1 TABLE 2
Causes of Hypothyroidism Common Signs and Symptoms
of Hypothyroidism*
Primary hypothyroidism (95% of cases)
Idiopathic hypothyroidism* Sign or symptom Affected patients (%)
Hashimoto’s thyroiditis
Weakness 99
Irradiation of the thyroid subsequent to Graves’
disease Skin changes 97
(dry or coarse skin)
Surgical removal of the thyroid
Late-stage invasive fibrous thyroiditis Lethargy 91
Iodine deficiency Slow speech 91
Drug therapy (e.g., lithium, interferon) Eyelid edema 90
Infiltrative diseases (e.g., sarcoidosis, amyloidosis, Cold sensation 89
scleroderma, hemochromatosis) Decreased sweating 89
Secondary hypothyroidism (5% of cases) Cold skin 83
Pituitary or hypothalamic neoplasms
Thick tongue 82
Congenital hypopituitarism
Facial edema 79
Pituitary necrosis (Sheehan’s syndrome)
Coarse hair 76
*—Probably old Hashimoto’s thyroiditis (i.e., a Skin pallor 67
“burned out” thyroid from Hashimoto’s thyroiditis). Forgetfulness 66
Adapted with permission from Hueston WJ. Thyroid Constipation 61
disease. In: Rosenfeld JA, Alley N, Acheson LS,
Admire JB, eds. Women’s health in primary care. Bal- *—Only signs and symptoms that occur in 60 per-
timore: Williams & Wilkins, 1997:617-31. cent or more of patients with hypothyroidism are
listed in this table.
Adapted with permission from Larsen PR, Davies TF,
Hay ID. The thyroid gland. In: Wilson JD, Foster DW,
generally present with a constellation of signs Kronenberg HM, Larsen PR, eds. Williams Textbook
of endocrinology. 9th ed. Philadelphia: Saunders,
and symptoms that may include lethargy,
1998:461.
weight gain, hair loss, dry skin, forgetfulness,
constipation and depression. Not all of these
signs and symptoms occur in every patient,
and many may be blunted in patients with tum thyroiditis, which has many of the same
mild hypothyroidism. The most common symptoms as postpartum depression.
manifestations of hypothyroidism are listed Physical findings in patients with hypothy-
in Table 2.7 roidism are also nonspecific. These findings
In older patients, hypothyroidism can be can include lowered blood pressure with
confused with Alzheimer’s disease and other bradycardia, nonpitting edema, generalized
conditions that cause cognitive impairment. hair loss (especially along the outer third of
Because depression can be a manifestation the eyebrows), dry skin and a diminished
of hypothyroidism, patients with this endo- relaxation phase of reflexes.
crine condition may be treated as depressed, A primary challenge is to differentiate the
and other signs and symptoms of the disor- generalized symptoms of early hypothy-
der may be overlooked. This is particularly roidism from the similar symptoms of
true with hypothyroidism that develops or fatigue and depression that occur in many
worsens during pregnancy, or with postpar- other conditions.
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3. Hypothyroidism
Diagnosis In primary hypothyroidism, the thyroid-stimulating hormone
The evaluation of patients with new-onset (TSH) level is elevated, and free thyroid hormone levels are
hypothyroidism is quite limited. In patients depressed. In secondary hypothyroidism, the TSH level is low
with primary hypothyroidism, the thyroid-
or undetectable. A follow-up assessment of the free thyrox-
stimulating hormone (TSH) level is elevated,
indicating that thyroid hormone production ine level can help distinguish between primary and secondary
is insufficient to meet metabolic demands, hypothyroidism.
and free thyroid hormone levels are depressed.
In contrast, patients with secondary hypothy-
roidism have a low or undetectable TSH level. with secondary hypothyroidism, further
TSH results have to be interpreted in light investigation with provocative testing of the
of the patient’s clinical condition. A low TSH pituitary gland can be performed to deter-
level should not be misinterpreted as hyper- mine if the underlying cause is a hypothala-
thyroidism in the patient with clinical mani- mic or pituitary disorder. In patients with
festations of hypothyroidism. When symp- pituitary dysfunction, imaging is indicated to
toms are nonspecific, a follow-up assessment detect microadenomas, and levels of other
of the free thyroxine (T4) level can help distin- hormones that depend on pituitary stimula-
guish between primary and secondary hypo- tion should also be measured. In general, evi-
thyroidism. A guide to the laboratory diagno- dence of decreased production of more than
sis of hypothyroidism and the interpretation one pituitary hormone is indicative of panhy-
of TSH, T4 and triiodothyronine (T3) levels is popituitary problems.
provided in Table 3.
Once the diagnosis of primary hypothy- Thyroid Hormone Replacement
roidism is made, additional imaging or sero- SELECTING THE APPROPRIATE AGENT
logic testing is unnecessary if the thyroid Thyroid medications were once prepared
gland is normal on examination. In patients from desiccated samples of ground thyroid
TABLE 3
Laboratory Values in Hypothyroidism
TSH level Free T4 level Free T3 level Likely diagnosis
High Low Low Primary hypothyroidism
High (> 10 µU per mL Normal Normal Subclinical hypothyroidism with high risk for future
[10 mU per L]) development of overt hypothyroidism
High (6 to 10 µU per mL Normal Normal Subclinical hypothyroidism with low risk for future
[6 to 10 mU per L]) development of overt hypothyroidism
High High Low Congenital absence of T4-T3–converting enzyme;
amiodarone (Cordarone) effect on T4-T3 conversion
High High High Peripheral thyroid hormone resistance
Low Low Low Pituitary thyroid deficiency or recent withdrawal of
thyroxine after excessive replacement therapy
TSH = thyroid-stimulating hormone; T4 = thyroxine; T3 = triiodothyronine.
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4. In most healthy young adults, replacement is
Because levothyroxine can cause increases in the resting heart initiated using levothyroxine in a dosage of
rate and blood pressure, replacement should begin at a low 0.075 mg per day, with the dosage increased
slowly as indicated by continued elevation of
dosage in older patients and patients at risk for cardiovascular
the TSH level.
compromise. Levothyroxine should be initiated in a low
dosage in older patients and those at risk for
the cardiovascular compromise that could
glands from cows, and standardization was occur with a rapid increase in resting heart
based on the iodine content of the extract rate and blood pressure.9 In these patients,
rather than its T3 or T4 content. The actual the usual starting dosage is 0.025 mg per day.
thyroid hormone content of the products This dosage can be increased in increments of
varied considerably from manufacturer to 0.025 to 0.050 mg every four to six weeks
manufacturer, and even within products from until the TSH level returns to normal.
the same manufacturer, depending on the Thyroid hormone is usually given once
thyroid status of the cows. Fortunately, this daily, but some evidence suggests that weekly
method of preparing thyroid hormone has dosing may also be effective. In a small study10
been abandoned, and replacement is now of 12 patients with hypothyroidism, a bolus
accomplished primarily with synthetic thy- dose of thyroid hormone equal to seven times
roid hormones. the usual daily dose was well tolerated. Before
A recent analysis8 of four levothyroxine weekly replacement can be recommended,
preparations, including two brand-name however, more investigation is required,
products (Synthroid and Levoxyl) and two including definitions of the populations in
generic preparations, demonstrated relative which this approach is indicated.
bioequivalence. Patients switched from any In a study11 of 33 middle-aged patients
one of the four preparations to another (mostly women) with stable hypothyroidism
showed insignificant variations in their thy- who were already receiving levothyroxine,
roid function tests. Among the four products, small improvements in mood, memory and
the only difference noted was that Synthroid cold tolerance occurred after triiodothyro-
produced a more rapid and higher rise in the nine was added, in a dosage of 0.0125 mg per
T3 level after administration. However, the day, with a concomitant 0.05-mg decrease in
difference was not statistically significant and the usual levothyroxine dosage. Although this
is of questionable clinical importance. study was small, it suggests that some patients
who are chemically euthyroid but have linger-
INITIATING TREATMENT ing neuropsychiatric problems might benefit
Most otherwise healthy adult patients with from triiodothyronine. Further investigation
hypothyroidism require thyroid hormone is required to determine the role of tri-
replacement in a dosage of 1.7 µg per kg per iodothyronine in these patients, as well as the
day, with requirements falling to 1 µg per kg long-term consequences of its use.
per day in the elderly. Thus, levothyroxine in
a dosage of 0.10 to 0.15 mg per day is needed MONITORING THYROID FUNCTION
to achieve euthyroid status. For full replace- In patients with an intact hypothalamic-
ment, children may require up to 4 µg per kg pituitary axis, the adequacy of thyroid hor-
per day.9 mone replacement can be followed with ser-
In young patients without risk factors for ial TSH assessments. However, changes in the
cardiovascular disease, thyroid hormone TSH level lag behind serum thyroid hormone
replacement can start close to the target goal. levels. Thus, the TSH level should be evalu-
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5. Hypothyroidism
ated no earlier than four weeks after an
adjustment in the levothyroxine dosage. The SUBCLINICAL HYPOTHYROIDISM
full effects of thyroid hormone replacement The TSH level can be mildly elevated when
on the TSH level may not become apparent the free T4 and T3 levels are normal, a situation
until after eight weeks of therapy.12 that occurs most often in women and becomes
In patients with pituitary insufficiency, increasingly common with advancing age.
measurements of free T4 and T3 levels can be This condition has been termed “subclinical
performed to determine whether patients hypothyroidism,” based on the supposition
remain euthyroid. In these patients, the goal is that it reflects early failure of the thyroid hor-
to maintain free thyroid hormone levels in mone and eventual development of hypothy-
the middle to upper ranges of normal to roidism.17 However, it appears that patients
ensure adequate replacement. with a TSH level between 6 and 10 µU per mL
TSH or free T4 levels are monitored annu-
ally in most patients with hypothyroidism, al-
though no data support this practice. Gener- Treatment of Hypothyroidism
ally, once a stable maintenance dosage of
levothyroxine is achieved, that dosage will re- Is there a documented need for
main adequate until patients are 60 to 70 years thyroid hormone replacement?
of age. With age, thyroid binding may
decrease, and the serum albumin level may
decline. In this setting, the levothyroxine Is the patient > 50 years of age
and/or at risk for cardiac disease?
dosage may need to be reduced by up to
20 percent.13,14 Although less frequent than
annual monitoring could be justified in
Yes No
younger adult patients whose weight is stable,
annual monitoring in older patients is neces- Start levothyroxine,
Start levothyroxine,
sary to avoid overreplacement.15 0.025 to 0.05 mg per day. 0.075 mg per day.
A guideline for initiating and monitoring
thyroid hormone replacement therapy is pro-
vided in Figure 1.
Monitor TSH level (if primary hypothyroidism)
INTRAVENOUS REPLACEMENT or free T4 level (if secondary hypothyroidism)
every 6 to 8 weeks; adjust levothyroxine
Because thyroid hormone has a large vol- dosage until laboratory tests are normal.
ume of distribution and long half-life, par-
enteral replacement is unnecessary in
patients who are unable to take medication Does the patient still have
lethargy or memory problems?
orally for a few days to a week. However,
some patients may be unable to take oral
medications for much longer periods. Intra-
venous administration is advised in these Yes No
patients and in those who need to begin thy-
Consider adding triiodothyronine, Continue to monitor TSH
roid hormone replacement but cannot take 0.0125 mg per day (although or T4 levels annually.
oral medications. Only about 70 to 80 per- long-term effects are not known).
cent of an oral dose of replacement medica-
tion is absorbed. Therefore, parenteral
replacement should be initiated at 70 to 80 FIGURE 1. Initiation and monitoring of treatment for hypothyroidism.
percent of the usual oral dose.16 (TSH = thyroid-stimulating hormone; T4 = thyroxine)
NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1721

6. (6 to 10 mU per L) are not at risk for subse- subclinical hypothyroidism. More research is
quent hypothyroidism.1 In contrast, patients needed to sort out the most appropriate
with a higher TSH level (above 10 µU per mL) management.
progress to overt hypothyroidism at a rate of
1 to 20 percent per year.1 Conditions Affecting Thyroid Hormone
Thyroid hormone replacement may have Replacement Requirements
some benefits in patients with subclinical Because thyroid hormone is highly protein
hypothyroidism, but there is also a potential bound, medical conditions that alter the
for adverse effects, particularly in older amount of binding hormones and drugs that
patients. Some studies have shown that sup- compete for binding may change the amount
plementation of thyroid hormone accelerates of available free thyroid hormone. The thy-
bone mineral loss in older women with sub- roid replacement dosage must be changed in
clinical hypothyroidism, and that estrogen response to alterations in binding status.
replacement therapy does not counteract this With conditions that cause an increase in
effect.17 Bone-wasting effects have not been serum binding proteins, such as high estro-
observed in patients who are clinically hypo- gen states (e.g., pregnancy), oral contracep-
thyroid and receive adequate thyroid hor- tive use or postmenopausal estrogen replace-
mone replacement therapy.18 ment, the dosage of levothyroxine must be
Thyroid hormone replacement has also increased. In contrast, androgens decrease
been reported to decrease serum homocys- levels of thyroid binding proteins, necessitat-
teine levels.19 Along with changes in lipids, ing a reduction in the dosage. Older patients
hyperhomocysteinemia may be one of the also have lower serum protein levels and may
mechanisms through which hypothyroidism require reductions in their maintenance
is associated with an increased risk for cardio- dosage over time. Nephrosis, protein-losing
vascular disease.20 enteropathies and cirrhosis are other condi-
At this time, the approach to patients with tions that require a reduced thyroid hor-
subclinical hypothyroidism must be individ- mone dosage.
ualized. In patients at higher risk for osteo- A number of medications reduce the
porosis or fractures, the deleterious effects of absorption of thyroid hormone from the
excessive thyroid hormone can be avoided by intestines, necessitating an increase in the
withholding replacement until the free T4 replacement dosage (Table 4).21 Other drugs
and T3 levels drop below normal. In patients accelerate the metabolism of thyroid hor-
with hyperhomocysteinemia, existing car- mone, and an increase in the replacement
diac disease or risk factors for heart disease, dosage is then required. When these medica-
early thyroid hormone replacement may tions are started or adjusted, the TSH value
offer more advantages. Right now, consensus should be monitored to determine whether
is lacking on how to manage patients with additional thyroid hormone replacement is
indicated.
Persistently Elevated TSH Despite
The Author Thyroid Hormone Replacement
WILLIAM J. HUESTON, M.D., is professor and chair of the Department of Family Medi- Poor compliance is the most common rea-
cine at the Medical University of South Carolina, Charleston. He received his medical son for continued elevation of the TSH level
degree from Case Western Reserve University School of Medicine, Cleveland, and com-
pleted a family practice residency at Riverside Methodist Hospital, Columbus, Ohio. in patients receiving presumably adequate
thyroid hormone replacement. Patients who
Address correspondence to William J. Hueston, M.D., Department of Family Medicine,
Medical University of South Carolina, P.O. Box 250192, Charleston, SC 29425 (e-mail: do not regularly take their replacement med-
huestowj@musc.edu). Reprints are not available from the author. ication and then try to “catch up” just before
1722 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 64, NUMBER 10 / NOVEMBER 15, 2001

7. Hypothyroidism
a physician visit may restore their free T4 lev- vated, and the patients continue to have
els to normal but continue to have an elevated symptoms of hypothyroidism. These patients
TSH level. should be referred to an endocrinologist for
Very rarely, patients have tissue-level unre- further evaluation and management.
sponsiveness to thyroid hormone. This con-
dition reflects a mutation in the gene that Screening for Hypothyroidism
controls a receptor for T3, rendering it unable The U.S. Preventive Services Task Force23
to bind with the hormone. The genetic muta- does not recommend routine screening for
tion has been identified in only 300 families.22 hypothyroidism in asymptomatic persons.
In these patients, adequate amounts of thy- Recently, some expert panels24 noted that
roid hormone are produced but are ineffec- screening may be beneficial in high-risk pop-
tive. Consequently, the TSH level remains ele- ulations such as elderly women. However,
widespread screening is not likely to be cost-
effective. Because of the nonspecific symp-
TABLE 4
toms of hypothyroidism, many patients
Drugs Potentially Altering Thyroid would be tested because of their symptoms.
Hormone Replacement Requirements This practice should not be confused with
asymptomatic screening.
Increase replacement requirements
The author indicates that he does not have any con-
Drugs that reduce thyroid hormone production
flicts of interest. Sources of funding: none reported.
Lithium
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