SCIENTIFIC REVIEW
AND CLINICAL APPLICATIONS
Subclinical Thyroid Disease
Clinical Applications
Nananda F. Col, MD, MPP, MPH
Martin I. Surks, MD
Gilbert H. Daniels, MD
S
UBCLINICAL HYPOTHYROIDISM
and hyperthyroidism repre-
sent the earliest stages of thy-
roid dysfunction. Subclinical
hypothyroidism is defined as an eleva-
tion in serum thyroid-stimulating hor-
mone (TSH) above the upper limit of
the reference range (0.45-4.5 mIU/L)
with a normal serum free T4 (FT4) con-
centration; subclinical hyperthyroid-
ism is defined as a decrease in serum
TSH concentration below the refer-
ence range, with normal serum FT4 and
T3 concentrations. Most patients have
few if any signs or symptoms of thy-
roid dysfunction; therefore, it is a di-
agnosis based on laboratory evalua-
tion. Because the risk for subclinical
thyroid dysfunction, particularly sub-
clinical hypothyroidism, increases with
age,1 the number of cases should in-
crease as the US population ages.
Management of patients with thy-
roid dysfunction remains controversial
because the body of scientific evidence
available to guide clinical decisions is
limited. Fundamental questions such as
whom to screen and when to initiate
treatment remain largely unanswered.
Based on the available data, withhold-
ing treatment for individuals with se-
rum TSH values that are slightly above
or below the reference range (4.5-10 or
0.1-0.45 mIU/L) likely poses no harm,
and initiating treatment likely poses no
clear gains. Individuals with serum TSH
concentrations lower than 0.1 or higher
See also p 228.
2004 American Medical Association. All rights reserved.
Downloaded from www.jama.com on December 13, 2006
CLINICIANS CORNER
Subclinical hypothyroidism and hyperthyroidism are diagnoses based on labo-
ratory evaluation with few if any clinical signs or symptoms. Subclinical hy-
pothyroidism is defined as an elevation in serum thyroid-stimulating hor-
mone (TSH) above the upper limit of the reference range (0.45-4.5 mIU/L)
with normal serum FT4 concentration; subclinical hyperthyroidism is de-
fined as a decrease in serum TSH below the reference range with normal se-
rum FT4 and T3 concentrations. Though these conditions represent the ear-
liest stages of thyroid dysfunction, the benefits of detecting and treating
subclinical thyroid disease are not well established. Most persons found to
have subclinical thyroid disease will have TSH values between 0.1 and 0.45
mIU/L or between 4.5 and 10 mIU/L, for which the benefits of treatment
are not clearly established; treatment may be beneficial in individuals with
serum TSH lower than 0.1 mIU/L or higher than 10 mIU/L. This article il-
lustrates approaches to managing patients with subclinical hypothyroidism
and hyperthyroidism through 5 case scenarios that apply the principles of
evidence-based medicine. Because of the substantial uncertainty concern-
ing the consequences of untreated subclinical hypothyroidism and hyper-
thyroidism, as well as the benefit of initiating treatment, patient prefer-
ences are important in deciding on management of subclinical disease.
JAMA. 2004;291:239-243 www.jama.com
than 10 mIU/L are more likely to ben- well as the expense and inconvenience
efit from treatment, though some un- of treatment vs monitoring. FIGURES 1
certainty remains. Subclinical thyroid and 2 depict simplified clinical algo-
dysfunction predicts future progres- rithms for approaching subclinical hy-
sion to overt disease; however, TSH lev- pothyroidism and hyperthyroidism.
els in some individuals with subclini-
cal hypothyroidism or hyperthyroidism Clinical Context
return to the reference range. Initiating Patient 1. A 28-year-old aerobics in-
treatment for subclinical hypothyroid- structor in excellent health had labo-
ism does not alter the natural history of
the disease but may prevent symptoms Author Affiliations: Division of Womens Health and
Department of Medicine, Harvard Medical School,
and signs of overt disease. Brigham and Womens Hospital, Boston, Mass (Dr Col);
In disorders for which the definition Department of Medicine and Pathology, Montefiore
of the condition is imprecise and the ben- Medical Center and the Albert Einstein College of Medi-
cine, Bronx, NY (Dr Surks); and Thyroid Unit and De-
efits and risks of treatment are not clearly partment of Medicine, Massachusetts General Hos-
established, patient preferences play a pital, Harvard Medical School, Boston (Dr Daniels).
Corresponding Author: Martin I. Surks, MD, Mon-
critical role in treatment decisions. To tefiore Medical Center, 111 E 210th St, Bronx, NY
make informed decisions, patients 10467 (e-mail: msurks@westnet.com).
Reprints: Society Services, The Endocrine Society, 8401
should understand the benefits and risks Connecticut Ave, Suite 900, Chevy Chase, MD 20815
of initiating vs withholding treatment, as (e-mail: societyservices@endo-society.org).
(Reprinted) JAMA, January 14, 2004Vol 291, No. 2 239
SUBCLINICAL THYROID DISEASE

ratory tests performed by her primary amined carefully. The patient should be
care physician as part of a routine of- asked about previous radioactive io-
fice visit. All results were normal, in- dine treatment, thyroid surgery, levo-
cluding complete blood cell count and thyroxine treatment, a family history of
lipid profile, except for the serum TSH thyroid disease, and her lipid profile
concentration of 7.9 mIU/L. should be determined.
Before making a treatment deci- Three months later, the patients se-
sion, guidelines recommend repeat- rum TSH was 6.8 mIU/L and FT 4 ,
ing the serum TSH and measuring FT4 1.4 ng/dL (18 pmol/L); antithyroid per-
within 2 to 12 weeks, depending on the oxidase (TPO) antibodies were ab-
clinical setting, to exclude transient sent. She was referred to an endocri-
forms of hypothyroidism. Transient hy- nologist for evaluation and treatment
pothyroidism is most commonly caused of subclinical hypothyroidism. The pa-
by destructive thyroiditis (including tient reported no symptoms of hypo-
painful subacute thyroiditis, silent sub- thyroidism. She was taking no medi-
acute thyroiditis, or postpartum thy- cations other than oral contraceptives,
roiditis) or recovery from severe non- her menses occurred regularly, and she
thyroidal illness. The clinician should was not intending to become preg-
assess the patient for symptoms and nant. Her family history included one
signs of hypothyroidism, including fa- maternal aunt with hypothyroidism and
tigue, lethargy, slow cerebration, di- a maternal grandmother with diabetes
minished sweating, dry skin, cold in- mellitus. Her examination findings were
tolerance, dry hair, weight gain, unremarkable and her thyroid gland
constipation, hoarseness, paresthe- was palpable but not enlarged.
sias, menstrual alterations, and muscle Routine measurement of anti-TPO
pain. The thyroid gland should be ex- levels is controversial. Although anti-
Figure 1. Suggested Approach to Diagnosis and Management of Subclinical Hypothyroidism
Serum TSH >4.5 mIU/L
Repeat Serum TSH Measurement With FT4
Measurement 2 to 12 Weeks Later
No Serum TSH Level Within Yes Monitor Every
Reference Range 6 to 12 mo for
(0.45 to 4.5 mIU/L)? Several Years
Serum TSH Level Serum TSH Level
4.5 to 10 mIU/L >10 mIU/L
Yes FT4 No Yes FT4 No
Level Decreased Level Decreased
(<0.8 ng/dL)? (<0.8 ng/dL)?
Pregnant or Pregnant or
Treat With Yes
Contemplating
No Treat With Yes
Contemplating
Levothyroxine Levothyroxine
Pregnancy? Pregnancy?
Consider Levothyroxine
Treatment With
Yes Signs or Symptoms
Consistent With
No
Periodic Monitoring Hypothyroidism?
Monitor Serum TSH
Every 6 to 12 mo
The normal range of free T4 (FT4) is 0.8 to 2.0 ng/dL (10-25 pmol/L); the normal range of thyroid-stimulating
hormone (TSH) is 0.45-4.5 mIU/L.
*In rare instances a slightly elevated serum TSH represents hypothalamic/pituitary disease. In these situations
the FT4 is extremely low when the TSH is only slightly elevated, in contrast to primary hypothyroidism in which
the TSH increases exponentially with small decreases in serum FT4 concentration.
240 JAMA, January 14, 2004Vol 291, No. 2 (Reprinted)
body positivity predicts an increased
risk of progressing to overt hypothy-
roidism (2.6% per year if negative, 4.3%
if positive),2 it does not affect the ef-
fectiveness of treatment. Nonetheless,
the increased rate of progression may
tip the balance toward treatment in
some cases. The presence of anti-TPO
antibodies does predict an increased
risk of miscarriage as well as postpar-
tum thyroiditis.3
Having confirmed the diagnosis of
subclinical hypothyroidism, deciding
whether to initiate levothyroxine would
depend on her serum TSH concentra-
tion, the presence of any signs or symp-
toms suggestive of hypothyroidism, her
risk of progression to overt disease, and
her preferences. There is no evidence
that levothyroxine treatment in healthy,
asymptomatic patients with TSH be-
tween 4.5 and 10 mIU/L results in sig-
nificant improvements in either qual-
ity of life or clinical outcomes. Initiating
treatment would prevent symptoms and
signs of hypothyroidism should this pa-
tient eventually progress to overt hy-
pothyroidism. The risk of progression
to overt hypothyroidism is 2% to 5% per
year. However, serum TSH decreases to
the reference range in a similar per-
centage during the 2 to 4 years after el-
evated serum TSH is discovered.2 No
risks of delaying detection of overt hy-
pothyroidism have been demon-
strated as long as individuals are care-
fully monitored.
In the absence of symptoms, the only
other benefit of levothyroxine treat-
ment in this patient would be possible
improvement in cardiac function. Sev-
eral small, unblinded studies suggest that
subclinical hypothyroidism might be as-
No sociated with subtle declines in cardiac
contractility.4 However, evidence con-
cerning the impact of subclinical hypo-
thyroidism, treated or untreated, on clini-
Consider
Levothyroxine cal cardiac end points is limited. Because
Treatment in
Appropriate
of the lack of clear clinical benefits, rou-
Clinical Settings tine treatment with levothyroxine is not
recommended in such patients. There is
no compelling evidence that low-
density lipoprotein (LDL) cholesterol is
higher in individuals with serum TSH in
the range of 4.5 to 10 mIU/L.
2004 American Medical Association. All rights reserved.

Downloaded from www.jama.com on December 13, 2006


After discussing the risks and ben-
efits of treatment, this patient elected
not to be treated but to be followed with
annual determination of serum TSH and
to be alert for signs and symptoms of
overt hypothyroidism.
If she were contemplating preg-
nancy, treatment with levothyroxine
should be started, and serum TSH
should be restored to the reference
range. Although some data suggest that
withholding treatment may result in an
increased risk of fetal loss and neuro-
psychological complications in the off-
spring,5,6 there is no compelling evi-
dence that levothyroxine decreases the
risk of miscarriage or improves the neu-
ropsychiatric complications. The re-
quirement for levothyroxine in treated
hypothyroid patients often increases
during pregnancy and serum TSH
should be monitored each trimester.
Patient 2. During an annual evalu-
ation, a healthy 70-year-old woman
complained of mild fatigue, dry skin,
and constipation. Physical examina-
tion results were normal, including a
nonpalpable thyroid gland and nor-
mal relaxation phase of deep tendon re-
flexes. The serum TSH was 8.1 mIU/L;
serum total cholesterol, 215 mg/dL
(5.57 mmol/L); high-density lipopro-
tein (HDL) cholesterol, 47 mg/dL (1.22
mmol/L); LDL cholesterol, 148 mg/dL
(3.83 mmol/L); and triglycerides, 78
mg/dL (0.88 mmol/L). Repeat testing
2 months later revealed a serum TSH
of 8.3 mIU/L and an FT4 of 1.4 ng/dL
(18 pmol/L).
Up to 20% of women older than 60
years have subclinical hypothyroid-
ism; 75% of those have serum TSH be-
tween 4.5 and 10 mIU/L.1,7,8 Routine
treatment with levothyroxine is not rec-
ommended because data are insuffi-
cient to link this degree of hypothy-
roidism with any adverse health
outcomes, and no clear benefits of treat-
ment have been demonstrated. How-
ever, because this patient has symp-
toms that may be associated with
hypothyroidism, levothyroxine treat-
ment may be considered. Although one
study found patients with subclinical
hypothyroidism to have more symp-
2004 American Medical Association. All rights reserved.
Downloaded from www.jama.com on December 13, 2006
SUBCLINICAL THYROID DISEASE
toms than euthyroid patients,1 other tension, type 2 diabetes mellitus, and
studies found no differences between hypercholesterolemia who presents for
patients and euthyroid controls.9-11 medical clearance before embarking on
There are no data clearly demonstrat- an exercise program is found to have a
ing that treatment will improve symp- serum TSH of 12 mIU/L. Repeat test-
toms in patients with elevated serum ing 2 months later reveals a serum TSH
TSH concentrations higher than 4.5 but of 14 mIU/L, FT 4 of 1.3 ng/dL (17
lower than 10 mIU/L. While there ap- pmol/L), and total serum cholesterol of
pear to be no adverse effects of initiat- 235 mg/dL (6.09 mmol/L). Current
ing levothyroxine treatment in this set- medications included metformin, 850
ting, inadvertent overtreatment occurs mg twice each day, hydrochlorothia-
in about 20% (range, 14%-21%)12,13 of zide, 25 mg/d, and pravastatin, 20 mg/d.
levothyroxine-treated patients, carry- He reports occasional constipation and
ing the potential risks of osteoporosis fatigue. His physical examination find-
and atrial fibrillation when serum TSH ings are unremarkable other than obe-
falls below 0.1 mIU/L. Treatment also sity (body mass index of 35).
involves the costs and inconvenience Among patients with a serum TSH
of taking a daily medicine for the rest higher than 10 mIU/L and normal se-
of ones life. Although follow-up diag- rum FT4 who have signs and symp-
nostic testing to adjust dosage is also toms possibly consistent with hypo-
necessary, periodic thyroid function thyroidism, there is suggestive evidence
tests are also necessary in individuals supporting treatment with levothyrox-
who are not treated. ine. Potential benefits include a lower-
Patient 3. A 58-year-old sedentary, ing of serum total and LDL choles-
obese man with well-controlled hyper- terol concentrations, an improvement
Figure 2. Suggested Approach to Diagnosis and Management of Subclinical Hyperthyroidism
Serum TSH <0.45 mIU/L
Yes Signs or Symptoms of Heart Disease (Congestive No
Heart Failure, Atrial Fibrillation, or Arrhythmias)?
Repeat Serum TSH Measurement With Repeat Serum TSH Measurement With
FT4 and T3 or FT3 FT4 and T3 or FT3
Measurements Within 2 Weeks Measurements 3 to 12 Weeks Later
Yes No
FT4 or
T3 Elevated?
Monitor Serum
No Serum TSH Within Reference Yes TSH Every 12 mo
Evaluate and Treat or Sooner
Range (0.45 to 4.5 mIU/L)?
if Symptoms
Develop
Serum TSH <0.1 mIU/L Serum TSH 0.1 to 0.45 mIU/L
Determine Etiology (Radioactive Iodine Uptake and Scan)
Monitor; No
Graves
Yes
No Treatment;
No
Heart Disease,
Yes
Disease or Monitor 3 to 12 mo Osteoporosis, or
Treatment
Optional
Nodular Later or Sooner if Symptoms of
Goiter? Symptoms Develop Hyperthyroidism?
Monitor;
Heart Disease, Determine Etiology (Radioactive
No Osteoporosis, Yes
Treatment
Age >60 y, or Estrogen
Iodine Uptake and Scan);
Consider Treatment
Optional
Depleted?
Consider Treatment
TSH indicates thyroid-stimulating hormone; FT4, free T4; FT3, free T3.
(Reprinted) JAMA, January 14, 2004Vol 291, No. 2 241
SUBCLINICAL THYROID DISEASE
in cardiac function, and a possible im-
provement in symptoms. However, the
study suggesting that levothyroxine
treatment reduced cholesterol levels
among individuals with subclinical hy-
pothyroidism did not compare treated
with untreated groups,14 and the small,
unblinded trials suggesting that treat-
ment improved cardiac function exam-
ined intermediate end points of uncer-
tain clinical significance.4 No blinded,
randomized controlled studies have as-
sessed the impact of levothyroxine on
important clinical cardiac end points.
Because the risk of progression to overt
hypothyroidism may be higher in these
patients than in patients with serum
TSH between 4.5 and 10 mIU/L, treat-
ment may prevent the manifestations
and consequences of hypothyroidism
in those who would have progressed.
After discussing the potential ben-
efits of treatment on his serum choles-
terol concentration, exercise toler-
ance, and constipation, the patient
decided to begin treatment with levo-
thyroxine.
Patient 4. A 36-year-old healthy
woman was found to have a serum TSH
concentration of 0.26 mIU/L, which is
in the low (0.45 mIU/L) but detect-
able (0.1 mIU/L) range. She has no
personal or family history of thyroid dis-
ease. She has one child and has monthly
menstrual periods. Her examination re-
sults were unremarkable, and her thy-
roid gland was not palpable.
When the serum TSH concentra-
tion is found to be low but detectable,
the assay should be repeated along with
a serum FT4 and total or free T3 con-
centration within several months,
sooner if any cardiac signs or symp-
toms are present such as atrial fibrilla-
tion or palpitations. If free thyroid hor-
mone concentrations are within their
reference ranges and serum TSH re-
mains low, the following causes of low
serum TSH should be excluded: treat-
ment with levothyroxine, high-dose
glucocorticoid or dopamine therapy, se-
vere nonthyroidal illness, or preg-
nancy. Although a low serum TSH may
also be due to hypothalamic or pitu-
itary disease or anorexia nervosa, FT4
242 JAMA, January 14, 2004Vol 291, No. 2 (Reprinted)
Downloaded from www.jama.com on December 13, 2006
is usually low in these situations.
Patients with serum TSH levels be-
tween 0.1 and 0.45 mIU/L infre-
quently progress to overt hyperthyroid-
ism, defined as serum TSH lower than
0.1 mIU/L and elevated concentra-
tions of FT4 and/or FT3. However, the
rate of progression varies according to
the underlying etiology. Patients with
large autonomously functioning ad-
enomas (3.0 cm diameter) or toxic
multinodular thyroids are at greater risk
for progression to overt hyperthyroid-
ism, especially when exposed to high
concentrations of iodine, most com-
monly after treatment with amioda-
rone or radiocontrast agents.
Routine treatment is likely not ben-
eficial in young asymptomatic per-
sons because there are no data that this
condition is associated with adverse
health outcomes. Additional studies
such as a 24-hour radioiodine uptake
and radionuclide thyroid scan to de-
termine the etiology of the subclinical
hyperthyroidism are usually not nec-
essary in asymptomatic individuals with
serum TSH concentrations in this range,
if therapy is not being considered. In
older patients, however, treatment
should be based on clinical judgment
because of a possible association of sub-
clinical hyperthyroidism with in-
creased cardiovascular mortality and os-
teoporosis and the higher risk of
progression to hyperthyroidism.
Patient 5. An active 77-year-old
woman with a history of myocardial in-
farction and osteoporosis feels well
other than experiencing rare exer-
tional angina. She takes atenolol and
atorvastatin daily, alendronate weekly.
Her pulse is 75/min and she is normo-
tensive. Her thyroid gland is difficult
to examine due to kyphosis but feels
somewhat prominent. Thyroid func-
tion tests reveal serum TSH concentra-
tion lower than 0.01 mIU/L and FT4 and
FT3 within the reference ranges. A thy-
roid ultrasound reveals a multinodu-
lar goiter. She has not received iodin-
ated contrast material in the past year.
Although other causes of low se-
rum TSH should be sought, subclini-
cal hyperthyroidism due to a toxic mul-
2004 American Medical Association. All rights reserved.
tinodular goiter is the likely etiology.
A 24-hour radioiodine uptake and ra-
dionuclide thyroid scan is the most ef-
ficient method to distinguish the vari-
ous etiologies of hyperthyroidism.
Hyperthyroidism due to the various
forms of destructive thyroiditis is tran-
sient and self-limited; the 24-hour ra-
dioioidine uptake is close to zero when
these conditions are present. In con-
trast, individuals with Graves hyper-
thyroidism have normal or elevated 24-
hour radioiodine uptakes and a
homogeneous pattern on radionu-
clide scan. Autonomous adenomas ap-
pear as hot nodules on scans. Indi-
viduals with toxic nodular goiters may
have single or multiple hot areas but
commonly have a heterogeneous pat-
tern of uptake.
Thyroid autonomy in a single-
nodule or multinodular goiter in-
creases the likelihood of progression to
subclinical or overt hyperthyroidism,
especially if patients receive excess io-
dine such as radiocontrast dyes or amio-
darone. However, nodules that do not
concentrate radioactive iodine (cold
nodules) also occur in this setting and
in some individuals with Graves dis-
ease. These nodules may require a fine-
needle aspiration biopsy.
Untreated subclinical hyperthyroid-
ism with suppressed serum TSH (0.1
mIU/L) carries the potential risks of atrial
fibrillation,15 cardiovascular mortal-
ity,16 and osteoporosis.17,18 Because these
risks are higher among patients older
than 60 years, the balance is shifted to-
ward treatment among older patients.
There are no studies that compare the
risk of atrial fibrillation in treated vs un-
treated patients, but bone density is
higher in treated compared with un-
treated postmenopausal women with
subclinical hyperthyroidism and de-
creased serum TSH.19,20 The risks of treat-
ment include allergic reactions (rash, fe-
ver, arthralgias, agranulocytosis,
hepatotoxicity, vasculitis) after antithy-
roid drug administration, and transient
worsening hyperthyroidism, perma-
nent hypothyroidism, or worsening
Graves ophthalmopathy after therapy
with iodohippurate sodium I 131.21

Conclusion
The definition of subclinical thyroid dys-
function is based on serum TSH deter-
mination and is of necessity somewhat
arbitrary. There is substantial uncer-
tainty concerning the consequences of
untreated subclinical hypothyroidism
and hyperthyroidism, as well as the ben-
efit of initiating treatment. Although
treatment may be beneficial in individu-
als with serum TSH lower than 0.1 mIU/L
or higher than 10 mIU/L, most persons
found to have subclinical thyroid dys-
function will have values between 0.1
and 0.45 mIU/L or between 4.5 and 10
mIU/L, for which the benefits of treat-
ment are not clearly established.
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(Reprinted) JAMA, January 14, 2004Vol 291, No. 2
SUBCLINICAL THYROID DISEASE
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