20.  Screening for Thyroid Disease

RECOMMENDATION

Routine screening for thyroid disease with thyroid function tests is not

recommended for asymptomatic children or adults. There is insufficient

evidence to recommend for or against screening for thyroid disease with

thyroid function tests in high-risk patients, but recommendations may be

made on other grounds (see Clinical Intervention). Clinicians should

remain alert to subtle symptoms and signs of thyroid dysfunction when

examining such patients. Screening for congenital hypothyroidism is

discussed in Chapter 45.

Burden of Suffering

Hyperthyroidism and hypothyroidism together account for considerable

morbidity in the U.S. The total prevalence of these two disorders in

adolescents and adults is estimated to be 1-4%; prevalence is higher in

women and persons with Down syndrome, and increases with increasing

age.1-10 The annual incidence in adults has been estimated to be 0.05-

0.1% for hyperthyroidism and 0.08-0.2% for hypothyroidism, with the

higher incidences cited occurring in elderly women.2,11 In adolescents, an

incidence of 0.06%/year for these two disorders has been reported.5

Symptoms of thyroid dysfunction, involving the nervous, cardiovascular,

and gastrointestinal systems, may have an important impact on health and

behavior.12 Rarely, fatalities may occur due to thyroid storm in

hyperthyroidism and myxedema coma in hypothyroidism.13 Thyroid

dysfunction during pregnancy is associated with an increased risk of

adverse maternal and fetal outcomes.14-18 Most patients with thyroid

dysfunction will present with typical clinical symptoms and signs within

a few months of disease onset, although overt disease may occasionally be

overlooked. Studies in which asymptomatic adults of all ages were

screened in the clinical setting, often using older, less sensitive tests,

detected previously unsuspected thyroid disease in 0.6-0.9% of persons

screened.2,3,19,20 

The clinical diagnosis of thyroid dysfunction can be more difficult in

certain high-prevalence populations, including the elderly, those with

Down syndrome, and postpartum women, possibly delaying treatment and

risking complications.13 Older persons may experience apathetic

hyperthyroidism, without the goiter, ophthalmopathy, and signs of

sympathetic nervous system hyperactivity typically seen in younger

persons.21 Typical symptoms and signs of hypothyroidism, like fatigue,

constipation, dry skin, and poor concentration, may be confused with

symptoms of aging,22 and may also occur less frequently in elderly

hypothyroid patients.23 Screening persons 60 years or older in the clinical

setting detects previously unsuspected hyperthyroidism in 0.1-0.9% and

hypothyroidism in 0.7-2.1%.2,19,24-27 The clinical diagnosis of

hypothyroidism may also be overlooked in patients with Down syndrome

because some symptoms and signs, such as slow speech, thick tongue, and

slow mentation, are typical findings of both conditions.6,7 Screening

persons with Down syndrome has detected previously unrecognized thyroid

disease, primarily hypothyroidism, in 2.9% (range 0-6.5%).6,7,28

Screening reveals thyroid dysfunction, primarily thyroiditis, in 4-6% of

postpartum women.29-32 This dysfunction is sometimes accompanied by

nonspecific symptoms, such as fatigue, palpitations, impaired

concentration, or depression,31,33,34 that may be mistakenly attributed

to the postpartum condition. Women with a personal or family history of

thyroid or autoimmune disease, or with thyroid antibodies, are at

increased risk for postpartum thyroid dysfunction.16,30,35-37

Postpartum thyroid dysfunction is usually transient, but it may require

short-term treatment to control symptoms.

Subclinical thyroid dysfunction as typically defined in the literature is a

biochemical abnormality,38 characterized by an abnormal level of

thyroid-stimulating hormone (TSH) with otherwise normal thyroid tests

and no clinical symptoms. Subclinical hypothyroidism, recognized by an

elevated TSH level, is seen in 6-8% of adult women and 3% of adult men.1

As with overt disease, the prevalence is higher in the elderly and in

persons with Down syndrome.6,7,24,25,27,28,39-41 Progression to overt

hypothyroidism occurred in  2% of patients who had subclinical

hypothyroidism without evidence of thyroid autoimmunity or prior

thyroid-related disorders and who were followed for 2-15 years; in those

with thyroid antibodies, however, progression occurs in about 5-7%/year,

and in as many as 20-24%/year in elderly patients with

antibodies.25,28,39,42-45 Other than the risk of developing overt

hypothyroidism, the importance of subclinical hypothyroidism is unknown.

Case series have suggested adverse effects of an isolated elevated TSH

level on blood lipid profile, myocardial function, and neuropsychiatric

function,22,46-48 but controlled observational studies have reported

conflicting evidence regarding an association between subclinical

hypothyroidism and any of these adverse effects.49-54

Subclinical hyperthyroidism, recognized by a subnormal TSH level, is seen

in 0.2-5% of the elderly population;  1%/year progress to overt

disease.11,40,55,56 Subnormal levels of TSH are often transient,

returning to normal without intervention.3,25,57 There is limited

evidence of risk from subclinical hyperthyroidism except when it is due to

excessive thyroxine replacement. Case series have reported subclinical

hyperthyroidism in a number of patients with atrial fibrillation.58-61

Older controlled observational studies found no association between

subclinical hyperthyroidism and atrial fibrillation,62,63 but a significant

association was reported in one carefully controlled cohort study that

used a sensitive TSH assay.57 One controlled study reported a

significantly lower total cholesterol level in patients with a subnormal

TSH level,51 suggesting a possible benefit of this condition.

Accuracy of Screening Tests

Thyroid function tests to detect thyroid disease, including total thyroxine

(TT4), free thyroxine (FT4), and TSH, are influenced by a variety of

diagnostic and biologic factors that may affect their accuracy. For

example, while TT4 is usually elevated in hyperthyroidism, it misses 5%

of cases that are due to triiodothyronine (T3) toxicosis.64 TT4

concentration is strongly influenced by the concentrations and binding

affinities of thyroxine-binding globulin and other thyroid-binding

proteins.38 Falsely abnormal TT4 results often occur with conditions that

affect these proteins, such as pregnancy, use of certain drugs, and

nonthyroidal illness.38,64 FT4 has the advantage over TT4 of being

independent of thyroid-binding protein concentrations. Equilibrium

dialysis (ED), regarded as the reference method for FT4, is not suitable for

routine screening due to its high cost.38,65 Immunoassay or index (FTI)

methods to estimate FT4 are simpler, less expensive than ED, and have

specificities of 93-99% compared to ED;20,66-68 these methods are not

always independent of thyroid-binding protein concentrations,

however,38,69 and they may show substantial interlaboratory variation.65

TT4 and FT4 cannot be reliably measured in ill patients, because a

substantial proportion will have abnormal thyroid function in the absence

of true thyroid disease, due to "sick euthyroid syndrome."69-71 Screening

with TT4 or FT4 will generate many false-positive results in healthy

populations.2,19,20,71 With test specificities in the mid-90% range or

lower, the low prevalence of previously unsuspected thyroid disease

means that the likelihood of disease given an abnormal test will be quite

low. In one study, thyroid disease requiring treatment was found in only

13% of those with abnormal FTI results.20 Because TT4 and FT4 are

normal by definition in subclinical thyroid dysfunction, they are not useful

as screening tests for this condition.

The immunometric ("sensitive") TSH (sTSH) assays detect low as well as

high serum TSH levels, and have become the standard for detecting

hyperthyroidism and hypothyroidism. They therefore offer promise as

first-line thyroid screening tests. In unselected populations, sTSH has a

sensitivity of 89-95% and specificity of 90-96% for overt thyroid

dysfunction, as compared to reference standards incorporating clinical

history, examination, repeat measurement, and/or additional testing

including thyrotropin-releasing hormone tests.3,40,68 In an asymptomatic

older population, the likelihood of thyroid disease given an abnormal sTSH

was only 7%, however, reflecting the low prevalence of disease in healthy

people.40 Acutely ill patients, pregnant women, and persons using certain

drugs such as glucocorticoids may have false-positive sTSH

results,38,72,73 although specificity is better than for TT4 and FT4 when

the three tests have been directly compared.38,74 Newer sTSH assays

reduce but do not eliminate false-positive diagnoses in such patients.75-

77 sTSH may respond slowly to abrupt changes in thyroid function,38 such

as those that occur after treatment for hyperthyroidism, but such changes

are not generally relevant to the screening of asymptomatic patients.

Effectiveness of Early Detection

Screening for occult thyroid dysfunction in adults would be valuable if

there were clinical benefits of early treatment, including relief of

previously unrecognized symptoms. We found no studies evaluating the

treatment of hyperthyroidism detected by screening in asymptomatic

persons, or of subclinical hyperthyroidism in persons with atrial

fibrillation. Uncertainties about the benefits of treating hyperthyroidism

detected by screening are particularly important because of the costs and

potential adverse effects (e.g., agranulocytosis, induced hypothyroidism,

surgical complications) of treatment with antithyroid medications,

radioactive iodine ablation, or subtotal thyroidectomy.78,79

Several studies have evaluated the effectiveness of treating patients with

subclinical hypothyroidism. Most of the subjects had previously identified

thyroid disease, however, and the results may not apply to asymptomatic

patients identified only by screening. In a randomized placebo-controlled

trial of 33 women with subclinical hypothyroidism, all with a past history

of treated hyperthyroidism, there were significant improvements in

myocardial contractility and in previously unrecognized symptoms, but no

significant changes in basal metabolic rate, pulse, body weight, skin

texture, or serum lipid levels.80 The long-term clinical importance of

subtle changes in myocardial contractility is unknown. An uncontrolled

experiment in 17 women identified by screening found a significantly

improved mean clinical symptom score after treatment, mixed effects on

myocardial function, and no effect on cholesterol, resting heart rate, body

mass, or blood pressure.81 Methodologic flaws make it difficult to

interpret the results of this study. Uncontrolled experiments in adult

patients, mostly women, with subclinical hypothyroidism due to

previously identified thyroid disease have reported variable improvement

in myocardial function but little effect on lipoproteins with thyroxine

treatment.82-89 A randomized controlled trial measuring the effects of

thyroid replacement on quality of life, lipids, neuropsychological function,

bone mineral density, and myocardial function in elderly patients with

subclinical hypothyroidism is ongoing (personal communication, Dr. R.

Jaeshke, St. Joseph's Hospital, Hamilton, Ontario, August 4, 1995).

In children and adults with Down syndrome and subclinical

hypothyroidism, a double-blind crossover placebo-controlled trial failed

to document any cognitive, social, or physical changes attributable to 8-

14 weeks of thyroxine treatment,41 although treatment duration may have

been inadequate to effect change. There is otherwise little evidence

regarding the benefits of early intervention in these individuals.

Thyroxine replacement therapy can have adverse effects with even

moderate degrees of overtreatment (as detected by low TSH or high TT4

levels), including decreased bone density compared to matched

controls.90-93 Reduced bone density could increase the risk of fractures

in the elderly, but one large series found no significant difference in risk

for fractures (or for ischemic heart disease) in treated patients with

normal TSH levels compared to those with suppressed TSH due to

overtreatment.94 The fracture rate in the two groups was the same as in

the general population, while the risk of ischemic heart disease was

higher in treated patients irrespective of TSH levels. The study was not

designed to determine whether the latter finding was due to treatment or

to the underlying disease, however. A small randomized controlled trial in

postmenopausal women with subclinical hypothyroidism found no bone

density reduction after 14 months of appropriate thyroxine treatment.95

Evidence therefore suggests against an adverse impact of appropriate

thyroxine treatment.

Recommendations of Other Groups

No organizations recommend routine screening for thyroid disease in the

general population, except screening newborns for congenital

hypothyroidism (see Chapter 45). The American Academy of Family

Physicians (AAFP)96 and the American Association of Clinical

Endocrinologists97 recommend measuring thyroid function periodically in

all older women. The policy of the AAFP is currently under review. The

Canadian Task Force on the Periodic Health Examination recommends

maintaining a high index of clinical suspicion for nonspecific symptoms

consistent with hypothyroidism when examining perimenopausal and

postmenopausal women.98 The American College of Physicians

recommends screening women over age 50 with one or more general

symptoms that could be caused by thyroid disease.99 The American

College of Obstetricians and Gynecologists recommends that physicians

and patients be aware of the symptoms and risk factors for postpartum

thyroid dysfunction, and evaluate patients when indicated.100 The

American Academy of Pediatrics recommends that children with Down

syndrome have thyroid screening tests at 4-6 and 12 months of age, and

annually thereafter.101 The American Thyroid Association recommends

screening thyroid function in elderly patients, postpartum women, and all

patients with autoimmune disease or with a strong family history of

thyroid disease, using serum TSH measurement.64,102

Discussion

The prevalence of unsuspected thyroid disease in healthy people in the

general population is very low. Despite the high specificity of thyroid

function tests such as the newer TSH assays, their routine use in the

asymptomatic general population results in many false-positive results.

Because of the low prevalence of unsuspected disease, only 1 in 5-10

persons with abnormal screening tests will prove to have thyroid disease.

Given the low risk, the lack of evidence that treatment of subclinical

thyroid disease identified by screening results in important health

benefits, and the potential adverse effects of treatment, screening the

asymptomatic general population is not recommended.

The prevalence of thyroid disease is higher in certain populations,

including elderly persons (particularly women), persons with Down

syndrome, and postpartum women, and these patients might be candidates

for thyroid function testing if the results could provide an explanation for

nonspecific and insidious symptoms, such as fatigue, memory impairment,

or depression, that might be attributed mistakenly to other medical or

psychiatric causes. Clinicians should therefore maintain a high index of

suspicion for such nonspecific symptoms, and for thyroid disease when

these types of symptoms are found, when examining high-risk patients.

There is, however, little evidence that routinely screening high-risk

patients results in important clinical benefits.

CLINICAL INTERVENTION

Routine screening for thyroid disease with thyroid function tests is not

recommended for asymptomatic children or adults ("D" recommendation).

This recommendation does not mean that clinicians should not monitor

thyroid function in patients with a previous history of thyroid disease.

There is insufficient evidence to recommend for or against screening for

thyroid disease with thyroid function tests in high-risk patients,

including elderly persons, postpartum women, and persons with Down

syndrome, but recommendations may be made on other grounds, such as the

higher prevalence of disease and the increased likelihood that symptoms

of thyroid disease will be overlooked in these patients ("C"

recommendation). Clinicians should remain alert for subtle or nonspecific

symptoms of thyroid dysfunction when examining such patients, and

maintain a low threshold for diagnostic evaluation of thyroid function.

Examples of such symptoms include easy fatiguability, weight gain, dry

skin or hair, cold intolerance, difficulty concentrating, depression,

nervousness, and palpitations. If screening is performed, the preferred

test is measurement of thyroid-stimulating hormone (TSH) using a

sensitive immunometric or similar assay, because of its superior

sensitivity and specificity. Screening for congenital hypothyroidism is

discussed in Chapter 45.

The draft update of this chapter was prepared for the U.S. Preventive

Services Task Force by Carolyn DiGuiseppi, MD, MPH.

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