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## Complete Summary

#### GUIDELINE TITLE

Subclinical thyroid disease: scientific review and guidelines for
diagnosis and management.

#### BIBLIOGRAPHIC SOURCE(S)

Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA,
Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ.
Subclinical thyroid disease: scientific review and guidelines for
diagnosis and management. JAMA 2004 Jan 14;291(2):228-38. \[96
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14722150)

#### GUIDELINE STATUS

This is the current release of the guideline.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Subclinical (mild) thyroid disease (subclinical hypothyroidism and
subclinical hyperthyroidism)

#### GUIDELINE CATEGORY

Diagnosis\
Evaluation\
Management\
Screening\
Treatment

#### CLINICAL SPECIALTY

Endocrinology\
Family Practice\
Internal Medicine\
Obstetrics and Gynecology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To define subclinical thyroid disease, review its epidemiology,
recommend an appropriate evaluation, explore the risks and benefits of
treatment and consequences of nontreatment, and determine whether
population-based screening is warranted

#### TARGET POPULATION

-   Individuals with subclinical hyperthyroidism or subclinical
    hypothyroidism (evaluation and treatment)

-   Pregnant women or women who wish to become pregnant who have
    subclinical hypothyroidism (evaluation and treatment)

-   Individuals at high risk for thyroid dysfunction, including women
    older than 60 years, those with a family history of thyroid
    dysfunction, individuals with type I diabetes mellitus, and
    individuals with autoimmune disorders or atrial fibrillation
    (screening)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis/Evaluation/Screening**

1.  Serum thyroid stimulating hormone (TSH) levels

2.  Serum free thyroxine (FT~4~) concentration

3.  Serum total triiodothyronine (T~3~) or free T~3~ concentration

4.  Anti-thyroid peroxidase (TPO) antibody levels (not recommended
    routinely)

5.  Evaluation for signs and symptoms of thyroid disease, previous
    treatment for thyroid disease, or family history of thyroid disease

6.  Evaluation for atrial fibrillation or other cardiac disease

7.  Lipid profiles

8.  Population-based screening for thyroid disease (not routinely
    recommended; case ascertainment in high-risk groups is encouraged)

**Treatment**

1.  Levothyroxine therapy

2.  Thyroid hormone therapy

3.  Antithyroid drug therapy

4.  Use of beta-blockers

5.  Radioiodine therapy

6.  Partial thyroidectomy

#### MAJOR OUTCOMES CONSIDERED

-   Prevalence of subclinical hypothyroidism and hyperthyroidism in the
    US adult population

-   Morbidity and mortality related to thyroid dysfunction

-   Symptomatic benefit of therapy for hypothyroidism or hyperthyroidism

-   Progression to overt symptomatic hyperthyroidism or hypothyroidism

-   Cardiac dysfunction or adverse cardiac end points

-   Adverse outcomes of pregnancy for either the fetus or the mother

-   Changes in bone mineral density (BMD)

-   Risk of fractures

-   Systemic hyperthyroid and neuropsychiatric symptoms

-   Total and low-density lipoprotein (LDL) cholesterol levels

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

The Lewin Group, an independent consulting organization, was contracted
to review the literature and summarize the evidence relating to the
clinical questions. Relevant articles were identified by searching
MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality
(AHRQ) National Guideline Clearinghouse, the Cochrane Database of
Systematic Reviews, the Cochrane Controlled Trials Register, and several
National Health Services (UK) databases, including the Database of
Abstracts of Reviews of Effectiveness, the Economic Evaluation Database,
and the database of the International Network of Agencies for Health
Technology Assessment. Key search terms were *subclinical* (text word)
or *subclinic\** and *hypothyroidism* or *thyroid deficien\** or
*thyroid insufficien\**; *subclinical* (text word) or *subclinic\** and
*hyperthyroidism* or *thyrotoxicosis* or *overactive thyroid*. The
following areas were evaluated (key words in parentheses): epidemiology
(*etiology* or *ethnology* or *epidemiology* or *mortality*), screening
(*screening* or *thyroid function tests*), treatment (*therapy* or
*treatment* or *radiotherapy* or *surgery* or  *complication* or
*hormon\**), consequences of no treatment (*complications* or
*mortality*), and economics (*cost* or *costs* or *cost analysis* or
*cost-benefit* or *cost effective\**).

All English-language research articles or translations published on the
topic from 1995 to July 2002 were reviewed, as well as 21 relevant
articles and 4 abstracts published before 1995 that were identified by
the planning committee. Excluded were editorials, individual case
studies, studies enrolling fewer than 10 patients, and many
nonsystematic reviews. The final count was 195 articles, including the
earlier relevant publications identified by the planning committee.

#### NUMBER OF SOURCE DOCUMENTS

195

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Strength of the Overall Evidence**

**Good**\
Evidence includes consistent results from well-designed, well-conducted
studies in representative populations that directly assess effects on
health outcomes.

**Fair**\
Evidence is sufficient to determine effects on health outcomes, but the
strength of the evidence is limited by the number, quality, or
consistency of the individual studies; generalizability to routine
practice; or indirect nature of the evidence on health outcomes.

**Insufficient**\
Evidence is insufficient to assess the effects on health outcomes
because of limited number or power of studies, important flaws in their
design or conduct, gaps in the chain of evidence, or lack of information
on important health outcomes.

Source: Adapted from the US Preventive Services Task Force, Agency for
Healthcare Research and Quality.

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

The evidence report consisted of tables and summaries of each subject
area indicating the authors, year of publication, numbers of subjects,
nature of study (e.g., cohort, blinded, randomized), and principal
findings. The complete report is available at
<http://www.endo-society.org/educationevents/print/evidence-report.cfm>.

On the first 1 1/2 days of the consensus conference, 12 experts
identified by the planning committee presented reviews of selected areas
including epidemiology, laboratory testing, symptoms, effects on bone,
lipids, and cardiovascular systems, screening, and effects of treatment
to the panel and audience. These expert presenters left the conference
at the end of the information gathering session. Over the remaining 1
days, the panel discussed the information presented and the data
abstracted from the literature review to address the questions posed by
the planning committee.

The expert panel assessed the data for quality, scope, and relevance.
Using criteria adopted from the US Preventive Services Task Force
(USPSTF), the panel rated the strength of the available evidence as
either good, fair, or insufficient as it related to the association of
thyroid status or benefits of treatment to specified outcome.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Consensus Development Conference)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Representatives of the American Thyroid Association (ATA), the American
Association of Clinical Endocrinologists (AACE), and the Endocrine
Society formed a planning committee for a consensus development
conference to review the literature and attempt to formulate some
recommendations to guide clinical practice. The committee adopted an
approach patterned on the National Institutes of Health (NIH) consensus
development process. The planning committee drafted a series of
clinically relevant questions related to the diagnosis and management of
subclinical hypothyroidism and hyperthyroidism. These questions were

-   What is the definition of subclinical thyroid disease?

-   What is the epidemiology of subclinical thyroid disease?

-   What are the consequences of untreated subclinical thyroid disease?
    How should it be evaluated?

-   What are the risks and benefits of treatment for subclinical thyroid
    disease?

-   Is screening for subclinical thyroid disease warranted?

The questions were presented to a panel of 13 experts selected by the
planning committee who were either senior endocrinologists not known to
publish or be advocates in this area or experts in other relevant
fields. Members of the planning committee were not members of the panel.
Eight of the panelists were experts in thyroid disease and the remaining
5 had expertise in cardiology, epidemiology, biostatistics,
evidence-based medicine, health services research, general internal
medicine, and clinical nutrition.

The conference was held September 21-23, 2002. The meeting was open to
the public and attended by members of the 3 sponsoring societies (i.e.,
the American Thyroid Association, the American Association of Clinical
Endocrinologists, and the Endocrine Society).

Given the paucity of randomized controlled trials (RCTs), the panel
relied on the available published evidence as well as that presented
during the expert presentations, particularly for data related to
clinical outcomes. When evidence was not available, was contradictory,
or was judged to be insufficient, the panelists relied on their
experience, judgment, and interpretation of the available literature in
formulating recommendations for clinical practice. Differences of
opinion were settled by a majority vote after extensive discussion. The
recommendations for clinical practice were developed on the basis of the
evidence evaluations during the conference deliberations.

Each clinical practice recommendation was rated by individual members of
the panel for strength of supporting evidence (good, fair, insufficient,
or based on expert opinion). Panel members were asked to indicate their
level of agreement (none, minimal, moderate, or strong) with each
recommendation. Panel members submitted their assessments of the
strength of evidence and their support for the recommendations during
their review of the draft manuscript. A summary of the panelist\'s
assessment of the strength of evidence and his/her degree of support for
each recommendation is available at
<http://www.endo-society.org/educationevents/print/evidence-report.cfm>.
All but 2 of the recommendations were supported unanimously.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Strength of Panelists\' Recommendations Based on Available Evidence**

**Rating**

A: Strongly recommends. The recommendation is based on good evidence
that the service or intervention can improve important health outcomes.

B: Recommends. The recommendation is based on fair evidence that the
service or intervention can improve important health outcomes.

C: Recommends. The recommendation is based on expert opinion.

D: Recommends against. The recommendation is based on expert opinion.

E: Recommends against. The recommendation is based on fair evidence that
the service or intervention does not improve important health outcomes
or that harms outweigh benefits.

F: Strongly recommends against. The recommendation is based on good
evidence that the service or intervention does not improve important
health outcomes or that harms outweigh benefits.

I: Recommends neither for nor against. The panel concludes that the
evidence is insufficient to recommend for or against providing the
service or intervention because evidence is lacking that the service or
intervention improves important health outcomes, the evidence is of poor
quality, or the evidence is conflicting. As a result, the balance of
benefits and harms cannot be determined.

Source: Adapted from the US Preventive Services Task Force, Agency for
Healthcare Research and Quality.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

[**Subclinical Thyroid Disease: Questions and
Recommendations**]{.underline}

Subclinical thyroid disease is, by its very nature, a laboratory
diagnosis. Patients with subclinical disease have few or no definitive
clinical signs or symptoms of thyroid dysfunction. Thus, it is
critically important that the normal reference range for thyroid
stimulating hormone (TSH) be standardized and that laboratories engage
in appropriate quality control procedures to ensure that the results
they report are accurate and reproducible. The TSH method used should
have a functional sensitivity of at least 0.02 mIU/L, and the functional
sensitivity should be independently established by each laboratory.

**What Is the Definition of Subclinical Hypothyroidism?**\
Subclinical hypothyroidism is defined as a serum TSH concentration above
the statistically defined upper limit of the reference range when serum
free T~4~ (FT~4~) concentration is within its reference range. Other
causes of an elevated serum TSH must be excluded, for example: recent
adjustments in levothyroxine dosage with failure to reach a steady
state, particularly in poorly compliant patients; transient increase in
serum TSH in hospitalized patients during recovery from severe illness
or during recovery from destructive thyroiditis, including post-viral
subacute thyroiditis and postpartum thyroiditis; untreated primary
adrenal insufficiency; patients receiving recombinant human TSH
injections; and the presence of heterophilic antibodies against mouse
proteins, which cause falsely high TSH concentrations in some assays.
Although central hypothyroidism (usually hypothalamic) may cause a
mildly elevated serum TSH concentration (due to a circulating
bioinactive TSH molecule), the serum FT~4~ concentration is generally
clearly low in these patients.

Some investigators suggest that the upper limit of normal for serum TSH
concentration should be 2.5 mIU/L in a population rigorously screened to
exclude thyroid disease or drugs that influence thyroid function. In
support of this position are a higher rate of progression to overt
hypothyroidism and a higher prevalence of antithyroid antibodies in
individuals with serum TSH higher than 2.5 mIU/L compared with those
with serum TSH between 0.5 and 2.5 mIU/L. Although a serum TSH
concentration higher than 2.5 but less than 4.5 mIU/L may identify some
individuals with the earliest stage of hypothyroidism and those suspect
for Hashimoto thyroiditis, there is no evidence for associated adverse
consequences. Furthermore, serum TSH concentrations between 2.5 and 4.5
mIU/L may be due to minor technical problems in the TSH assay,
circulating abnormal TSH isoforms, or heterophilic antibodies; normal
individuals with serum TSH concentrations in this range would be
misidentified as having hypothyroidism. Given these concerns as well as
the pulsatile nature and continuous distribution of serum TSH
concentrations, the panel defined the reference range of normal serum
TSH concentration as 0.45 to 4.5 mIU/L.

**What Is the Definition of Subclinical Hyperthyroidism?**\
Subclinical hyperthyroidism is defined as a serum TSH concentration
below the statistically defined lower limit of the reference range when
serum FT~4~ and T~3~ concentrations are within their reference ranges.
Other causes of a low serum TSH must be excluded. Subclinical
hyperthyroidism may result from endogenous overproduction of thyroid
hormone or intended or inadvertent overadministration of thyroid
hormone. Among other causes of a low serum TSH concentration with normal
concentrations of FT~4~ are delayed recovery of the pituitary
TSH-producing cells during or after therapy for hyperthyroidism, normal
pregnancy, various nonthyroidal illnesses (euthyroid sick syndrome), or
the administration of dopamine, glucocorticoids, and possibly
dobutamine. Although subnormal serum TSH concentrations are common in a
variety of severe nonthyroidal illnesses, undetectable serum TSH
concentrations (\<0.01 mIU/L) are rare unless patients are receiving
concomitant glucocorticoids (usually in high doses) or dopamine.
Although patients with pituitary or hypothalamic failure (including
anorexia nervosa) frequently have subnormal serum TSH concentrations,
the FT~4~ is also usually subnormal. When serum FT~4~ is in the normal
range, it is almost invariably in the lower part of the range in those
with nonthyroidal illness in contrast to the high normal FT~4~
concentration of typical subclinical hyperthyroidism.

**[Subclinical Hypothyroidism: Questions and
Recommendations]{.underline}**

**What Are the Consequences of Untreated Subclinical Hypothyroidism?**\
Possible consequences of subclinical hypothyroidism include cardiac
dysfunction or adverse cardiac end points (including atherosclerotic
disease and cardiovascular mortality), elevation in total and
low-density lipoprotein (LDL) cholesterol, systemic hypothyroid symptoms
or neuropsychiatric symptoms, and progression to overt, symptomatic
hypothyroidism (See Table 1 in the original document entitled \"Quality
of Evidence on the Strength of Association and Risks/Benefits of
Treatment of Subclinical Hypothyroidism\").

**[How Should Subclinical Hypothyroidism Be Evaluated?]{.underline}**

If the serum TSH concentration is high and serum FT~4~ concentration has
not been measured, the TSH measurement should be repeated along with an
FT~4~ measurement at a minimum of 2 weeks, but no longer than 3 months,
after the initial assessment. The panel recommends thyroid hormone
therapy in individuals with elevated serum TSH concentrations whose
FT~4~ concentration is below the reference range (0.8-2.0 ng/dL
\[10.3-25.7 pmol/L\]).

If a high serum TSH concentration is confirmed on repeat testing and
serum FT~4~ is within the reference range, the patient should be
evaluated for signs and symptoms of hypothyroidism, previous treatment
for hyperthyroidism (radioiodine, partial thyroidectomy), thyroid gland
enlargement, or family history of thyroid disease. Lipid profiles should
be reviewed. Women who are pregnant or hope to become pregnant in the
near future deserve special consideration.

The evidence was insufficient to recommend either for or against routine
measurement of anti-thyroid peroxidase (TPO) antibodies in patients with
subclinical hypothyroidism. The presence of anti-TPO antibodies
identifies an autoimmune etiology for thyroid dysfunction and predicts a
higher risk of developing overt hypothyroidism (4.3% per year vs. 2.6%
per year in antibody-negative individuals). Still, antibody presence or
absence does not change the diagnosis of subclinical hypothyroidism
(which is based on serum TSH measurements) or the expected efficacy of
treatment.

**What Are the Risks and Benefits of Treating Subclinical
Hypothyroidism?**\
Among patients with untreated subclinical hypothyroidism, there is no
single level of serum TSH at which clinical action is always either
indicated or contraindicated. As the serum TSH concentration increases
above 10 mIU/L, however, the basis for initiating treatment is more
compelling. Clinical context is particularly important. This opinion
reflects clinical experience and judgment as well as the literature that
suggests improvement in symptoms and possible lowering of LDL
cholesterol. There are no studies that demonstrate decreased morbidity
or mortality with treatment. The potential risks of therapy are limited
to the development of subclinical hyperthyroidism, which may occur in 14
to 21% of individuals treated with levothyroxine.

*Subclinical Hypothyroidism With Serum TSH of 4.5 to 10 mIU/L*. Although
some studies suggest an association between subclinical hypothyroidism
and systemic hypothyroid symptoms or cardiac dysfunction, others do not.
No population-based studies examined symptoms in patients with serum TSH
concentrations between 4.5 and 10 mIU/L. The likelihood of progression
to overt hypothyroidism appears to be higher than for those with TSH
levels lower than 4.5 mIU/L (see Table 1 in the original guideline
document). Although early levothyroxine therapy does not alter the
natural history of the disease, it may prevent symptoms and signs of
overt disease in those who do progress. The available data do not
confirm clear-cut benefits for early therapy compared with treatment
when symptoms or overt hypothyroidism develop (see Table 1 of original
document). Therefore, the panel does not recommend routine levothyroxine
treatment for patients with TSH levels between 4.5 and 10 mIU/L, but
thyroid function tests should be repeated at 6- to 12-month intervals to
monitor for improvement or worsening in TSH level.

The panel realizes that some individuals with TSH levels between 4.5 and
10 mIU/L have symptoms compatible with hypothyroidism. Clinicians and
patients may decide on a several-month trial of levothyroxine, while
monitoring for improvement in hypothyroid-type symptoms. Continuation of
therapy should be predicated on clear symptomatic benefit. Still, the
panel considers the likelihood of improvement small, and it must be
balanced against the inconvenience, expense, and potential risks of
therapy. Physicians and patients must understand that there is
insufficient evidence to expect therapeutic benefit in patients in this
group and that distinguishing a true therapeutic effect from a placebo
effect in an individual patient is difficult. Still, the possibility
that some patients may benefit cannot be ruled out. Physicians and
patients should understand the natural history of subclinical
hypothyroidism and the small but definite risk of progression to overt
hypothyroidism. The special case of pregnancy or the planned pregnancy
in women with subclinical hypothyroidism is discussed below.

*Subclinical Hypothyroidism With Serum TSH Higher Than 10 mIU/L*.
Levothyroxine therapy is reasonable for patients with subclinical
hypothyroidism and serum TSH higher than 10 mIU/L. The rate of
progression is 5% in comparison with patients with lower levels of TSH,
and treatment may potentially prevent the manifestations and
consequences of hypothyroidism in those patients who do progress. Still,
the evidence that therapy will reduce total and LDL cholesterol levels
and improve symptoms in these patients is inconclusive (See Table 2 of
original guideline document).

*Subclinical Hypothyroidism During Pregnancy*. The panel gave a rating
of \"fair\" to the evidence of an association between subclinical
hypothyroidism and adverse outcomes of pregnancy for either the fetus or
the mother. However, the panel made the following recommendation: a TSH
level might be obtained in pregnant women and women who wish to become
pregnant if they have a family or personal history of thyroid disease,
physical findings or symptoms suggestive of goiter or hypothyroidism,
type 1 diabetes mellitus, or a personal history of autoimmune disorders.
For women who already take levothyroxine but whose TSH level is in the
subclinical hypothyroidism range, compliance and appropriateness of dose
should be assessed.

Pregnant women or women of childbearing potential planning to become
pregnant who are found to have elevated serum TSH should be treated with
levothyroxine to restore the serum TSH concentration to the reference
range. This recommendation is based on the possible association between
high TSH and either increased fetal wastage or subsequent
neuropsychological complications occurring in the offspring due to
thyroid insufficiency. Although there are no published intervention
trials assessing the benefits of thyroid hormone replacement in this
special population, the potential benefit-risk ratio of levothyroxine
therapy justifies its use. It is important to note that the requirement
for levothyroxine in treated hypothyroid women frequently increases
during pregnancy. Therefore, serum TSH concentration should be monitored
every 6 to 8 weeks during pregnancy and the levothyroxine dose modified
as needed. The risks of appropriately managed levothyroxine therapy in
pregnancy are minimal. Continuation of levothyroxine treatment post
partum is beyond the scope of this discussion.

*Subclinical Hypothyroidism in Treated Overt Hypothyroid Individuals*.
When subclinical hypothyroidism is noted in levothyroxine-treated
patients with overt hypothyroidism, the dosage of levothyroxine should
be adjusted to bring the serum TSH into the reference range. Whether the
target TSH level should be in the lower half of the reference range is
controversial because there are no data demonstrating improved clinical
outcomes with this strategy. Nevertheless, when the serum TSH is in the
upper half of the reference range and levothyroxine-treated patients
continue to note symptoms suggestive of hypothyroidism, it is reasonable
to increase the levothyroxine dosage to bring the serum TSH into the
lower portion of the reference range. The rapidity of the dosage
adjustment depends on the patient\'s age and medical comorbidities.
Minimal TSH elevations may not require dosage adjustment in patients who
feel well, particularly those with arrhythmias or other cardiac
disorders.

**[Subclinical Hyperthyroidism: Questions and
Recommendations]{.underline}**

**What Are the Consequences of Untreated Subclinical Hyperthyroidism?**\
*Assessment of Evidence*. The panel evaluated the strength of the
evidence for the association of untreated subclinical hyperthyroidism
and the following clinical outcomes: progression to overt
hyperthyroidism, adverse cardiac end points, atrial fibrillation,
cardiac dysfunction, systemic and neuropsychiatric symptoms, reduced
bone mineral density and fractures (See Table 2 in the original
guideline document). The panel also assessed the strength of the
association between the TSH level and the risks and benefits of
treatment (See Table 2 in the original guideline document). Similar to
the approach taken in many reported studies, the panel classified
patients with subclinical hyperthyroidism into 2 categories: those with
mildly low but detectable serum TSH (0.1-0.45 mIU/L) and those with a
clearly low serum TSH (\<0.1 mIU/L). In all clinical settings, causes of
subnormal serum TSH concentration other than subclinical hyperthyroidism
must be excluded.

**How Should Subclinical Hyperthyroidism Be Evaluated?**\
*Individuals With Serum TSH 0.1 to 0.45 mIU/L Not Treated With
Levothyroxine*. If serum TSH is reported to be between 0.1 and 0.45
mIU/L, the measurement should be repeated for confirmation. The panel
recommends measuring FT~4~ and either total T~3~ or FT~3~ levels to
exclude central hypothyroidism or nonthyroidal illness. Clinical
circumstances dictate when the retesting should occur. For patients with
atrial fibrillation, cardiac disease, or other serious medical
conditions, repeat testing within 2 weeks is prudent. When these factors
are absent, repeat testing is recommended within 3 months.

If the repeat serum TSH concentration remains higher than 0.1 but lower
than 0.45 mIU/L, with normal FT~4~ and T~3~ concentrations, and the
patient has no signs or symptoms of cardiac disease, atrial
fibrillation, or other arrhythmias, retesting should occur at 3- to
12-month intervals, until either serum TSH normalizes or the clinician
and patient are confident that the condition is stable. Patients with
known nodular thyroid disease may develop overt hyperthyroidism when
exposed to excess iodine (e.g., radiographic contrast agents) and
require special consideration.

*Individuals With a Serum TSH Lower Than 0.1 mIU/L*. If serum TSH
concentration is lower than 0.1 mIU/L, the panel recommends repeating
the measurement, along with an FT~4~ and a total T~3~ or FT~3~, within 4
weeks of the initial measurement. If the patient has signs or symptoms
of cardiac disease, atrial fibrillation, or other arrhythmia, or medical
issues requiring urgent diagnosis and treatment, these tests should be
performed within a shorter interval particularly if there are signs or
symptoms of hyperthyroidism.

*Endogenous Subclinical Hyperthyroidism (TSH Lower Than 0.45 mIU/L)*.
The panel recommends further evaluation to establish the etiology of the
low serum TSH. A radioactive iodine uptake measurement and scan can
distinguish between destructive thyroiditis and hyperthyroidism due to
Graves\' disease or nodular goiter.

**What Are the Risks and Benefits of Treatment of Subclinical
Hyperthyroidism?**\
The risks of treatment of subclinical hyperthyroidism with antithyroid
drugs are potential allergic reactions including agranulocytosis.
Radioactive iodine therapy commonly causes hypothyroidism and may cause
exacerbation of hyperthyroidism or Graves eye disease.

*Exogenous Subclinical Hyperthyroidism With TSH 0.1 to 0.45 mIU/L*. When
the serum TSH concentration is between 0.1 and 0.45 mIU/L in a
levothyroxine-treated individual, the indication for thyroid hormone
therapy should be reviewed. Many patients with thyroid cancer and some
patients with thyroid nodules require TSH suppression, and the target
TSH level should be reviewed by the treating endocrinologist or other
physician. When levothyroxine is prescribed for hypothyroidism in the
absence of thyroid nodules or thyroid cancer, the panel recommends
decreasing the dosage of levothyroxine to allow serum TSH to increase
toward the reference range. This dosage adjustment may be particularly
important when the serum TSH is in the lower part of the range (See
Table 2 in the original guideline document).

*Exogenous Subclinical Hyperthyroidism With TSH Lower Than 0.1 mIU/L*.
When the serum TSH concentration is lower than 0.1 mIU/L in a
levothyroxine-treated individual, the indication for thyroid hormone
therapy should be reviewed. For patients with thyroid cancer and thyroid
nodules, the target serum TSH value should be reviewed by the patient\'s
endocrinologist or treating physician. When levothyroxine is prescribed
for hypothyroidism in the absence of thyroid nodules or thyroid cancer,
the panel recommends decreasing the dosage of levothyroxine to allow
serum TSH to increase toward the reference range.

*Endogenous Subclinical Hyperthyroidism (Serum TSH 0.1-0.45 mIU/L)*. The
panel recommends against routine treatment for all patients whose TSH is
mildly decreased (0.1-0.45 mIU/L). The panel found insufficient evidence
to establish a clear association between this mild degree of
hyperthyroidism and adverse clinical outcomes, including atrial
fibrillation. However, because of a possible association with increased
cardiovascular mortality, clinicians might consider treatment of elderly
individuals, despite the absence of supportive data from intervention
trials.

*Endogenous Subclinical Hyperthyroidism (Serum TSH Lower Than 0.1
mIU/L)*. Subclinical hyperthyroidism due to destructive thyroiditis
(including post-viral subacute thyroiditis and postpartum thyroiditis)
resolves spontaneously. Treatment, apart from symptomatic therapy (e.g.,
beta-blockers), is usually not required.

The panel recommends that treatment be considered for subclinical
hyperthyroidism (TSH \<0.1 mIU/L) due to Graves\' or nodular thyroid
disease. The panel recognizes the paucity of intervention trials, apart
from those demonstrating stabilization of bone density. However, the
panel was concerned about the risk of atrial fibrillation and/or bone
loss, particularly in the elderly. Specifically, treatment should be
considered for patients who are older than 60 years and for those with
or at increased risk for heart disease, osteopenia, or osteoporosis
(including estrogen-deficient women), or for those with symptoms
suggestive of hyperthyroidism. Younger individuals with subclinical
hyperthyroidism and serum TSH persistently (months) lower than 0.1 mIU/L
may be offered therapy or follow-up depending on individual
considerations.

**Is Screening for Subclinical Thyroid Disease Warranted?**\
The rationale for population screening hinges on the high prevalence of
subclinical thyroid dysfunction in the adult population and on the
potential health benefits and risks of detecting and treating these
diseases. The panel used the US Preventive Services Task Force criteria
for recommending a screening test, which requires evidence of
effectiveness of early detection. One of the most important criteria for
recommending a screening test is that screening asymptomatic persons and
treating them for the condition should result in improved measurable and
important health outcomes when compared with persons who are not
screened and who present with signs or symptoms of the disease. An
alternative to population screening is aggressive case finding, defined
as the application of a test to a person presenting to a clinician for a
reason usually unrelated to the test being applied to determine the
person\'s likelihood of having a particular disease or condition.

Thyroid dysfunction is more prevalent in certain population groups,
including women older than 60 years, persons with previous radiation
treatment of the thyroid gland (radioactive iodine or therapeutic
external beam radiation), those who have had previous thyroid surgery or
thyroid dysfunction, and those who have type 1 diabetes mellitus, a
personal history of autoimmune disease, a family history of thyroid
disease, or atrial fibrillation. The panel recommends aggressive case
finding in these high-risk groups. The panel also endorses thyroid
function testing (serum TSH measurement) for patients seeking medical
care who have signs or symptoms suggestive of thyroid dysfunction or
those being evaluated for palpable thyroid abnormalities.

The panel recommends against population-based screening for thyroid
disease. Case ascertainment in certain high-risk groups is encouraged.
The panel finds the evidence insufficient to recommend for or against
routine determination of TSH levels (screening) in pregnant women or
women planning to become pregnant. It is reasonable to consider serum
TSH measurement for women with a family history of thyroid disease,
prior thyroid dysfunction, symptoms or physical findings suggestive of
hypothyroidism or hyperthyroidism, an abnormal thyroid gland on
examination, type 1 diabetes mellitus, or a personal history of an
autoimmune disorder.

**Conclusion**\
The review of the literature revealed a striking paucity of evidence
bearing on the major clinical questions examined. These recommendations
are based on the existing evidence and the panel members\' clinical
experience, but they are limited by the paucity of definitive data.
Well-conceived and executed intervention trials are needed to bring
definitive data to light on these questions. Until such data are
available, clinical judgment and patients\' preferences remain
paramount. Although the panel recommended against population screening
for subclinical thyroid disease, clinicians are encouraged to make
individual patient assessments when determining the need for testing and
treatment.

**[Definitions]{.underline}**:

**Strength of the Overall Evidence**

**Good**\
Evidence includes consistent results from well-designed, well-conducted
studies in representative populations that directly assess effects on
health outcomes.

**Fair**\
Evidence is sufficient to determine effects on health outcomes, but the
strength of the evidence is limited by the number, quality, or
consistency of the individual studies; generalizability to routine
practice; or indirect nature of the evidence on health outcomes.

**Insufficient**\
Evidence is insufficient to assess the effects on health outcomes
because of limited number or power of studies, important flaws in their
design or conduct, gaps in the chain of evidence, or lack of information
on important health outcomes.

Source: Adapted from the US Preventive Services Task Force, Agency for
Healthcare Research and Quality.

**Strength of Panelists\' Recommendations Based on Available Evidence**

**Rating**

A: Strongly recommends. The recommendation is based on good evidence
that the service or intervention can improve important health outcomes.

B: Recommends. The recommendation is based on fair evidence that the
service or intervention can improve important health outcomes.

C: Recommends. The recommendation is based on expert opinion.

D: Recommends against. The recommendation is based on expert opinion.

E: Recommends against. The recommendation is based on fair evidence that
the service or intervention does not improve important health outcomes
or that harms outweigh benefits.

F: Strongly recommends against. The recommendation is based on good
evidence that the service or intervention does not improve important
health outcomes or that harms outweigh benefits.

I: Recommends neither for nor against. The panel concludes that the
evidence is insufficient to recommend for or against providing the
service or intervention because evidence is lacking that the service or
intervention improves important health outcomes, the evidence is of poor
quality, or the evidence is conflicting. As a result, the balance of
benefits and harms cannot be determined.

Source: Adapted from the US Preventive Services Task Force, Agency for
Healthcare Research and Quality.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are based on the existing evidence and the panels\'
clinical experience, but they are limited by the paucity of definitive
data.

The panel examined the quality of the evidence for the strength of an
association with certain adverse consequences of subclinical hypothyroid
disease and the quality of the evidence addressing the risks and
benefits of treatment (See Table 1 of the original guideline document.)

The panel evaluated the strength of the evidence for the association of
untreated subclinical hyperthyroidism and the following clinical
outcomes: progression to overt hyperthyroidism, adverse cardiac end
points, atrial fibrillation, cardiac dysfunction, systemic and
neuropsychiatric symptoms, reduced bone mineral density, and fractures).
The panel also assessed the strength of the association between the
thyroid-stimulating hormone (TSH) level and the risks and benefits of
treatment (See Table 2 of the original guideline document.)

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Appropriate evaluation and treatment of subclinical hypothyroidism
    and hyperthyroidism

-   Avoidance of the risks of adverse events associated with the
    treatment of patients with subclinical thyroid disease

-   Positive outcomes of treatment are associated in individuals at high
    risk of thyroid dysfunction, including pregnant women and women over
    60 years of age.

#### POTENTIAL HARMS

-   Possible consequences of untreated subclinical hypothyroidism
    include cardiac dysfunction or adverse cardiac end points (including
    atherosclerotic disease and cardiovascular mortality), elevation in
    total and low-density lipoprotein (LDL) cholesterol, systemic
    hypothyroid symptoms or neuropsychiatric symptoms and progression to
    overt, symptomatic hypothyroidism.

-   Possible consequences of untreated subclinical hyperthyroidism
    include progression to overt hyperthyroidism, adverse cardiac end
    points, atrial fibrillation, cardiac dysfunction and reduced bone
    mineral density.

-   The potential risks of therapy in subclinical hypothyroidism are
    limited to the development of subclinical hyperthyroidism, which may
    occur in 14 to 21% of individuals treated with levothyroxine.

-   The risks of treatment of subclinical hyperthyroidism with
    antithyroid drugs are potential allergic reactions including
    agranulocytosis. Radioactive iodine therapy commonly causes
    hypothyroidism and may cause exacerbation of hyperthyroidism or
    Graves\' eye disease.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

Statements made in this publication do not represent the official policy
or endorsement of Agency for Healthcare Research and Quality (AHRQ) or
the federal government. Neither do statements made in this article
reflect official policy of the American Thyroid Association, the
American Association of Clinical Endocrinologists, and the Endocrine
Society organizers of the consensus development conference.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA,
Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ.
Subclinical thyroid disease: scientific review and guidelines for
diagnosis and management. JAMA 2004 Jan 14;291(2):228-38. \[96
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14722150)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2004 Jan 14

#### GUIDELINE DEVELOPER(S)

Consensus Conference Panel on Subclinical Thyroid Disease - Independent
Expert Panel

#### SOURCE(S) OF FUNDING

Abbott Laboratories was the first and principal sponsor. Other
supporters were Diagnostic Products Corporation, Laboratory Corporation
of America, Tosoh Medics Inc, ARUP Laboratories, and Dade Behring Inc.
Funds were donated as unrestricted educational grants to the Endocrine
Society, which coordinated the meeting.

#### GUIDELINE COMMITTEE

Not stated

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Authors*: Martin I. Surks, MD, Departments of Medicine and Pathology,
Montefiore Medical Center and the Albert Einstein College of Medicine,
Bronx, NY; Eduardo Ortiz, MD, MPH, Center for Primary Care, Prevention,
and Clinical Partnerships, Agency for Healthcare Research and Quality,
Rockville, Md; Gilbert H. Daniels, MD, Thyroid Unit and Department of
Medicine, Massachusetts General Hospital, Harvard Medical School,
Boston; Clark T. Sawin, MD, Veterans Administration, Washington, DC;
Nananda F. Col, MD, MPP, MPH, Harvard Medical School, Brigham and
Women\'s Hospital, Division of Women\'s Health and Department of
Medicine, Boston; Rhoda H. Cobin, MD, Department of Medicine, Mount
Sinai School of Medicine, New York, NY; Jayne A. Franklyn, MD, Division
of Medical Sciences, University of Birmingham, Birmingham, England;
Jerome M. Hershman, MD, Endocrinology and Diabetes Division, West Los
Angeles VA Medical Center, University of California at Los Angeles
School of Medicine; Kenneth D. Burman, MD, Endocrine Section, Washington
Hospital Center, Washington, DC; Margo A. Denke\*, MD, Department of
Medicine, University of Texas Southwestern Medical Center at Dallas;
Colum Gorman, MD, PhD, Research Development, Mayo Foundation, Rochester,
Minn; Richard S. Cooper, MD, Epidemiology, Loyola University Medical
School, Chicago, Ill; Neil J. Weissman, MD, Cardiac Ultrasound,
Washington Hospital Center, and Department of Medicine, Georgetown
University Medical College, Washington, DC

\*Dr Denke is now with the University of Texas, San Antonio.

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Dr. Burman has served on the speaker\'s bureau for Abbott Laboratories,
as a consultant for New River Pharmaceuticals, and as an advisor to
Norovax Inc.

The sponsors had no role in planning the meeting, selection of
participants, data collection or analysis, or manuscript preparation.
None of the authors had a financial relationship with the sponsors. Some
did give lectures and received honoraria that were occasionally provided
by unrestricted educational grants from the sponsors.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available to subscribers only of [The Journal of the
American Medical
Association](http://jama.ama-assn.org/cgi/content/full/291/2/228).

Print copies: Available from the Society Services, The Endocrine
Society, 8401 Connecticut Ave, Suite 900, Chevy Chase, MD 20815 (e-mail:
<societyservices@endo-society.org>).

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on November 11, 2004.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

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Date Modified: 11/3/2008