Diagnosis of and Screening For Hypothyroidism in Nonpregnant Adults

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Diagnosis of and screening for hypothyroidism in nonpregnant adults
Author: Douglas S Ross, MD

Section Editor: David S Cooper, MD
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2018. | This topic last updated: Nov 07, 2017.
INTRODUCTION — The diagnosis of hypothyroidism relies heavily upon laboratory tests because of the lack
of specificity of the typical clinical manifestations. Primary hypothyroidism is characterized by a high serum
thyroid-stimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration, whereas
subclinical hypothyroidism is defined biochemically as a normal free T4 concentration in the presence of an
elevated TSH concentration. Secondary (central) hypothyroidism is characterized by a low serum T4
concentration and a serum TSH concentration that is not appropriately elevated.
This topic will review diagnosis of and screening for hypothyroidism in nonpregnant adults. Screening for
hypothyroidism during pregnancy and in neonates is reviewed separately. (See "Hypothyroidism during
pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Screening' and "Clinical features
and detection of congenital hypothyroidism", section on 'Newborn screening'.)
The major clinical manifestations, causes, and treatment of hypothyroidism and the diagnosis and
management of subclinical hypothyroidism are discussed separately. (See "Clinical manifestations of
hypothyroidism" and "Disorders that cause hypothyroidism" and "Treatment of primary hypothyroidism in
adults" and "Subclinical hypothyroidism in nonpregnant adults".)
EPIDEMIOLOGY — In community surveys, the prevalence of overt hypothyroidism varies from 0.1 to 2
percent [1-5]. The prevalence of subclinical hypothyroidism is higher, ranging from 4 to 10 percent of adults,
with possibly a higher frequency in older women [1,2,6,7]. However, there is an age-related shift towards
higher TSH concentrations in older patients, and therefore, if age-adjusted normal ranges are used, the
prevalence may not increase with old age. (See "Laboratory assessment of thyroid function", section on
'Serum TSH concentration'.)
Hypothyroidism is five to eight times more common in women than men, and more common in women with
small body size at birth and during childhood [5,8].
In the United States National Health and Nutrition Examination Survey (NHANES) III, 13,344 people without
known thyroid disease or a family history of thyroid disease had measurements of serum TSH, T4,
thyroglobulin antibodies, and thyroid peroxidase (TPO) antibodies with the following results [6]:
● Hypothyroidism was found in 4.6 percent (0.3 percent overt and 4.3 percent subclinical).
● Hyperthyroidism was found in 1.3 percent (0.5 percent overt and 0.7 percent subclinical).
● Serum TPO antibody concentrations were high in 11 percent.
● Mean serum TSH concentrations were significantly lower in blacks than in whites or Mexican-Americans.
Thus, a significant proportion of the United States population has laboratory evidence of thyroid disease,
suggesting that routine screening could be useful. (See 'Screening' below.)
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CLINICAL FEATURES — The clinical manifestations of hypothyroidism are highly variable, depending upon
the age at onset and the duration and severity of thyroid hormone deficiency. Common symptoms of thyroid
hormone deficiency include fatigue, cold intolerance, weight gain, constipation, dry skin, myalgia, and
menstrual irregularities (table 1). Physical examination findings may include goiter (particularly in patients
with iodine deficiency or goitrous chronic autoimmune thyroiditis [Hashimoto's thyroiditis]), bradycardia,
diastolic hypertension, and a delayed relaxation phase of the deep tendon reflexes. In the majority of patients
with chronic autoimmune thyroiditis, thyroid peroxidase (TPO) antibodies are elevated. A variety of metabolic
abnormalities may be present including hypercholesterolemia, macrocytic anemia, elevated creatine kinase,
and hyponatremia [9]. The symptoms, signs, and metabolic abnormalities of hypothyroidism are discussed in
more detail elsewhere. (See "Clinical manifestations of hypothyroidism".)
DIAGNOSIS — Because of the lack of specificity of the typical clinical manifestations, the diagnosis of
hypothyroidism is based primarily upon laboratory testing.
● Primary hypothyroidism is characterized by a high serum TSH concentration and a low serum free T4
concentration. Patients with a high serum TSH concentration and a normal serum free T4 concentration
may have subclinical hypothyroidism. (See "Subclinical hypothyroidism in nonpregnant adults", section
on 'Diagnosis' and "Subclinical hypothyroidism in nonpregnant adults", section on 'Differential
diagnosis'.)
● Central hypothyroidism is characterized by a low serum T4 concentration and a serum TSH

concentration that is not appropriately elevated. In this setting, differentiation must be made between
pituitary (secondary hypothyroidism) and hypothalamic (tertiary hypothyroidism) disorders. (See "Central
hypothyroidism", section on 'Diagnosis'.)
Primary hypothyroidism — Primary thyroid disease accounts for over 95 percent of cases of
hypothyroidism.
In most patients with symptoms or signs suggestive of hypothyroidism (table 2), the serum TSH should be
the initial test. If the serum TSH concentration is elevated, the TSH measurement should be repeated along
with a serum free T4 to make the diagnosis of hypothyroidism (table 3).
● If the repeat serum TSH value is still high and the serum free T4 is low, consistent with primary
hypothyroidism, replacement therapy with T4 should be initiated. (See "Treatment of primary
hypothyroidism in adults".)
● If the repeat serum TSH value is still high but the serum free T4 value is within the normal range,
indicating subclinical hypothyroidism, the decision about T4 replacement is made on a case-by-case
basis and depends partly upon the degree of TSH elevation. (See "Subclinical hypothyroidism in
nonpregnant adults".)
● If the TSH is normal but the patient has convincing symptoms of hypothyroidism, we measure a repeat
serum TSH and a free T4 to assess for central hypothyroidism. (See 'Secondary and tertiary (central)
hypothyroidism' below.)
We define an elevated serum TSH as a TSH concentration above the upper limit of the normal TSH
reference range, which is typically 4 to 5 mU/L in most laboratories. Presently there is considerable
controversy over the appropriate upper limit of normal for serum TSH. Some experts have suggested that the
true upper limit is only 2.5 or 3 mU/L in healthy individuals without thyroid disease, while others argue that the
serum TSH distribution shifts towards higher values with age, independent of the presence of antithyroid
antibodies [10], or in obesity [11]. In these cases, the upper limit of normal could be as high as 6 to 8 mU/L in
healthy octogenarians, or as high as 7.5 mU/L in morbid obesity. This topic is reviewed in detail separately.
(See "Laboratory assessment of thyroid function", section on 'Serum TSH concentration'.)
Secondary and tertiary (central) hypothyroidism — Thyrotropin-releasing hormone (TRH) and TSH are
required for normal thyroid hormone secretion. Central hypothyroidism is due to insufficient stimulation of the
thyroid gland by TSH, and it is caused by either hypothalamic (tertiary hypothyroidism) or pituitary (secondary
hypothyroidism) disease [12,13]. Central hypothyroidism is much less common than primary hypothyroidism.
Secondary and tertiary hypothyroidism should be suspected in the following circumstances:
● There is known hypothalamic or pituitary disease
● A mass lesion is present in the pituitary
● When symptoms and signs of hypothyroidism are associated with other hormonal deficiencies
In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase
appropriately as T4 secretion falls. As a result, the symptoms and the serum free T4 value must be used to
make the diagnosis. Thus, we measure both serum TSH and free T4 if pituitary or hypothalamic disease is
suspected (eg, a young woman with amenorrhea and fatigue). We also measure free T4 if the patient has
convincing symptoms of hypothyroidism despite a normal TSH result. In patients with central hypothyroidism,
the serum free T4 value is low-normal to low and serum TSH may be frankly low, inappropriately normal (for
the low T4), or slightly high (7 to 15 mU/L) due to secretion of biologically inactive TSH (table 3) [14].
The clinical manifestations, diagnosis, differential diagnosis, and treatment of central hypothyroidism are
reviewed in detail separately. (See "Central hypothyroidism".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of an elevated serum TSH level includes
resistance to TSH or thyroid hormone, recovery from nonthyroidal illness, and TSH-secreting pituitary
adenomas (table 4). High serum TSH concentrations may also occur in primary adrenal insufficiency [15] and
factitiously in rare patients who have antibodies to the murine immunoglobulins used in the assay [16], or
complexes of TSH bound to immunoglobulin G (IgG) [17].
Resistance to TSH or thyroid hormone — An elevated TSH concentration may rarely be due to resistance
to TSH secondary to alterations in the TSH receptor [18], failure of the cell to express the receptor at the cell
surface, or to receptor-independent mechanisms. Many of these patients are euthyroid, while others are
hypothyroid. Serum free T4 and triiodothyronine (T3) concentrations are typically normal or low. The thyroid
gland is not enlarged. It may be difficult to distinguish subclinical hypothyroidism (common) from resistance to
TSH (rare). The presence of other family members expressing the same phenotype and ultimately a defect in
the TSH receptor confirms the diagnosis of resistance to TSH. (See "Resistance to thyrotropin and
thyrotropin-releasing hormone".)
Patients with mutations in the T3 receptor (generalized thyroid hormone resistance) have a normal or
elevated TSH, but serum free T4 and T3 are also elevated. Some patients have manifestations of
hypothyroidism; however, most such patients are euthyroid. (See "Impaired sensitivity to thyroid hormone"
and "Disorders that cause hypothyroidism".)
Nonthyroidal illness — Euthyroid patients with nonthyroidal illness may have transient elevations in serum
TSH concentrations (up to 20 mU/L) during recovery from nonthyroidal illness. In patients with a recent
illness, TSH and free T4 should be repeated four to six weeks after recovery. Few of these patients prove to
have hypothyroidism when reevaluated after recovery from their illness. (See "Thyroid function in
nonthyroidal illness".)
Thyrotropin-secreting pituitary adenomas — TSH-secreting pituitary adenomas are a rare cause of

hyperthyroidism. TSH-secreting adenomas secrete biologically active TSH in a more or less autonomous
fashion. The characteristic biochemical abnormalities in patients with hyperthyroidism caused by a TSH-
secreting adenoma are normal or high serum TSH concentrations and high serum total and free T4 and T3
concentrations. (See "TSH-secreting pituitary adenomas".)
IDENTIFYING THE CAUSE — The clinical evaluation of a patient with biochemical evidence of primary
hypothyroidism should be directed toward confirming the presence and identifying the cause of the hormone
deficiency (table 5). The history, for example, may uncover past treatment of hyperthyroidism with radioiodine
or thyroidectomy, the use of drugs that affect thyroid hormone synthesis, or history of iodine deficiency or
excess. Physical examination may, in some cases, reveal thyroid enlargement (goiter) or an old
thyroidectomy scar. (See "Disorders that cause hypothyroidism".)
Thyroid peroxidase antibodies — Chronic autoimmune hypothyroidism (Hashimoto's thyroiditis) is the most
common cause of primary hypothyroidism in iodine sufficient areas of the world. The two major forms of the
disorder are goitrous autoimmune thyroiditis and atrophic autoimmune thyroiditis, with the common
pathologic feature being lymphocytic infiltration and the common serological feature being the presence of
high serum concentrations of antibodies to thyroid peroxidase (TPO) and thyroglobulin. Serum
concentrations of TPO autoantibodies are elevated in more than 90 percent of patients [19].
We do not routinely measure TPO antibodies in patients with primary overt hypothyroidism, because almost
all have chronic autoimmune thyroiditis. However, many thyroid experts measure serum TPO antibodies in
patients with (see "Clinical presentation and evaluation of goiter in adults", section on 'Initial testing' and
"Subclinical hypothyroidism in nonpregnant adults", section on 'Identifying the cause'):
● Goiter, especially in the absence of hypothyroidism, to identify immunologically mediated goiter
● Subclinical hypothyroidism, painless (silent) thyroiditis, or postpartum thyroiditis, to predict the likelihood
of progression to permanent overt hypothyroidism
Sometimes TPO antibodies are measured concomitantly with TSH in patients who have symptoms of
hypothyroidism and/or a goiter on physical examination, and TPO antibodies are found to be elevated in
patients with normal thyroid function tests. These patients have chronic autoimmune thyroiditis but do not
have hypothyroidism. They are more likely to develop hypothyroidism than antibody negative individuals [7].
Such patients should have serum TSH measured annually.
SCREENING — "Screening" refers to the measurement of thyroid function tests in asymptomatic patients at
risk of having thyroid disease who are presently not known to have thyroid disease. The primary benefit of
screening for hypothyroidism is the detection of hypothyroidism before the occurrence of symptoms.
Subclinical thyroid dysfunction is common in the adult population [6]. However, there is no evidence that early
detection and treatment with T4 improves clinically important outcomes in individuals with hypothyroidism
detected by screening. Although T4 replacement therapy has few side effects when properly dosed,
overtreatment with thyroid hormone is common and may be associated with adverse skeletal and
cardiovascular effects, particularly in older patients. (See "Subclinical hyperthyroidism in nonpregnant adults",
section on 'Exogenous subclinical hyperthyroidism'.)
There are two strategies for screening asymptomatic individuals: screening all individuals over a certain age
(when risk of hypothyroidism increases), or screening only those individuals with clinical risk factors for
hypothyroidism. In the absence of data supporting any screening strategy, we suggest screening patients at
increased risk for hypothyroidism, including but not limited to patients with goiter, history of autoimmune
disease, previous radioactive iodine therapy, and/or head and neck irradiation, family history of thyroid
disease, and use of medications that may impair thyroid function (table 2).
We recommend measurement of serum TSH as a screening test for hypothyroidism.
Effectiveness — There are no clinical trials evaluating the effectiveness of screening for hypothyroidism. A
computer decision model that evaluated a hypothetical cohort of women and men screened every five years
beginning at age 35 years showed that screening for hypothyroidism was similarly cost effective as other
accepted preventive practices (eg, breast cancer or hypertension screening) [20]. Benefit accrued mainly
from the avoidance of symptoms of hypothyroidism when diagnosed and treated early and from the decrease
in adverse cardiovascular outcomes associated with the lower serum cholesterol concentrations in treated
hypothyroid patients. The cost effectiveness of screening was most favorable in older women.
Although hypothyroidism is common in older adults (eg, 5 to 15 percent in women over the age of 65 years),
there is no evidence that it is associated with adverse outcomes in the oldest individuals when detected by
screening alone. This was illustrated in a population-based, prospective study of 558 individuals in the
Netherlands who were screened for hypothyroidism during the month of their 85th birthday and again three
years later [21]. Annual follow-up (for four years) was also performed to assess activities of daily living
(ADLs), cognitive performance, and depressive mood with the following results:
● Twelve percent had hypothyroidism at baseline (7 percent overt and 5 percent subclinical). Those with
overt hypothyroidism were referred to their primary care clinician for further evaluation (although none
were started on levothyroxine, as clinicians in the area do not routinely start treatment for disorders
identified by screening only). None of the patients with subclinical hypothyroidism had progressed to
overt hypothyroidism when retested at age 88 years.
● At baseline, there was no association between baseline serum TSH concentration and cognitive
function, depressive symptoms, or disability in ADLs.
● All of the above measures of performance declined over time, but the decline was not accelerated in
those with either subclinical or overt hypothyroidism. In fact, increasing serum TSH at baseline was
associated with a slower decline in ability to perform "instrumental" ADLs (such as preparing one's own
meals, shopping for groceries and personal items, managing one's money, using the telephone, and
doing housework).
● Higher baseline TSH was also associated with lower all-cause and cardiovascular mortality, in spite of
higher baseline serum cholesterol concentrations.
Candidates for screening — All patients with symptoms of hypothyroidism (table 1) should be evaluated for
hypothyroidism. Screening of asymptomatic individuals is controversial [22,23]. In the absence of data
showing any benefit of population-based screening, we suggest not routinely measuring thyroid function in
asymptomatic, nonpregnant individuals.
As an alternative, we suggest screening for hypothyroidism in patients with laboratory or radiologic

abnormalities that could be caused by hypothyroidism, patients with risk factors for hypothyroidism (eg,
patients with goiter, history of autoimmune disease, previous radioactive iodine therapy and/or head and neck
irradiation, family history of thyroid disease), and patients taking drugs that may impair thyroid function (table
2). As examples, thyroid function should be measured in patients with the following:
● Substantial hyperlipidemia or a change in lipid pattern, which occurs with increased frequency in
hypothyroidism (see "Lipid abnormalities in thyroid disease")
● Hyponatremia, often resulting from inappropriate production of antidiuretic hormone, which is another
laboratory manifestation of hypothyroidism (see "Causes of hypotonic hyponatremia in adults", section
on 'Hypothyroidism')
● High serum muscle enzyme concentrations
● Macrocytic anemia (see "Approach to the adult with anemia", section on 'Macrocytic anemia')
● Pericardial or pleural effusions (see "Diagnostic evaluation of pleural effusion in adults: Additional tests
for undetermined etiology", section on 'History')
● Previous thyroid injury (eg, radioiodine therapy, thyroid or neck surgery, external radiation therapy)
● Pituitary or hypothalamic disorders (see "Central hypothyroidism")
● History of autoimmune diseases
The universal screening of asymptomatic pregnant women for hypothyroidism during the first trimester of
pregnancy is controversial. This topic is reviewed in detail elsewhere. In brief, we suggest a targeted
approach to screening pregnant women. We favor screening pregnant women if they are from an area of
moderate to severe iodine insufficiency, have symptoms of hypothyroidism, a family or personal history of
thyroid disease, or a personal history of thyroid peroxidase (TPO) antibodies, type 1 diabetes, head and neck
radiation, recurrent miscarriage, morbid obesity, or infertility. (See "Hypothyroidism during pregnancy: Clinical
manifestations, diagnosis, and treatment", section on 'Screening'.)
Screening tests — Third-generation serum TSH assays are both more sensitive and specific than serum
free T4 measurements for detecting primary hypothyroidism in ambulatory patients (see "Laboratory
assessment of thyroid function"). Although the normal range for serum free T4 concentrations is wide
(approximately 0.8 to 1.8 ng/dL [10 to 36 pmol/L]), each person has an endogenous setpoint dictating the
optimum concentration for that individual. TSH secretion increases when the serum free T4 concentration
falls below that level. (See "Thyroid hormone synthesis and physiology", section on 'Regulation of thyroid
hormone production'.)
Primary thyroid disease accounts for over 95 percent of cases of hypothyroidism. As a result, measurement
of serum TSH (rather than free T4 or total T4) is an excellent screening test for hypothyroidism in ambulatory
patients [24]. There are, however, three settings in which measurement of serum TSH may not be a useful
tool for the diagnosis of hypothyroidism:
● If pituitary or hypothalamic disease is known or suspected.
● In hospitalized patients, since there are many other factors in acutely or chronically ill euthyroid patients
that influence TSH secretion. (See "Thyroid function in nonthyroidal illness".)
● In patients receiving drugs or with underlying diseases that affect TSH secretion (table 4). Drugs that can
decrease TSH secretion include dopamine, high doses of glucocorticoids, and somatostatin analogues
(such as octreotide). Drugs that increase TSH secretion include dopamine antagonists (metoclopramide
or domperidone), amiodarone, and oral cholecystographic dyes (eg, sodium ipodate).
Because errors may be made when only TSH is measured in patients with secondary or central
hypothyroidism or TSH-mediated hyperthyroidism, some experts recommend that both serum TSH and free
T4 be measured in all patients for screening purposes.
This approach adds considerable cost to screening and is likely to pick up few cases of unsuspected pituitary
disease. As a result, many laboratories are using strategies such as the following to limit unnecessary
laboratory testing:
● Serum TSH normal – No further testing performed
● Serum TSH high – Free T4 added to determine the degree of hypothyroidism
Screening inpatients is a more difficult problem and is not recommended unless thyroid disease is strongly
suspected since changes in thyroid hormones, binding proteins, and TSH concentrations occur in severe
nonthyroidal illness. (See "Thyroid function in nonthyroidal illness".)
Recommendations by expert groups — Screening recommendations from major groups have been
conflicting.
● The American Academy of Family Physicians (AAFP) recommends periodic assessment of thyroid
function in older women [25].
● The American College of Physicians (ACP) suggests that office screening of women older than 50 years
may be indicated [26].
● The American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists
(AACE) recommend measurement of TSH in any individual at risk for hypothyroidism (eg, personal
history of type 1 diabetes or other autoimmune disease, family history of thyroid disease, history of neck
radiation to the thyroid, history of thyroid surgery) and consideration of measurement of TSH in patients
over the age of 60 years [27].
● The United States Preventive Services Task Force found insufficient evidence to assess the benefits and
harms of screening [28,29].
Recommendations for screening pregnant women are discussed separately. (See "Hypothyroidism during
pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Screening'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links:
Hypothyroidism".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (The Basics)")
● Beyond the Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● The clinical manifestations of hypothyroidism are highly variable, depending upon the age at onset and
the duration and severity of thyroid hormone deficiency. Common symptoms of thyroid hormone
deficiency include fatigue, cold intolerance, weight gain, constipation, dry skin, myalgia, and menstrual
irregularities (table 1). Physical examination findings may include goiter (particularly in patients with
iodine deficiency or goitrous chronic autoimmune thyroiditis [Hashimoto's thyroiditis]), bradycardia,
diastolic hypertension, and a delayed relaxation phase of the deep tendon reflexes. Serum
concentrations of thyroid peroxidase (TPO) autoantibodies are elevated in more than 90 percent of
patients with hypothyroidism due to chronic autoimmune hypothyroidism (Hashimoto's thyroiditis). (See
'Clinical features' above and "Clinical manifestations of hypothyroidism".)
● The diagnosis of hypothyroidism is based primarily upon laboratory testing. In most patients with
symptoms suggestive of hypothyroidism, the serum thyroid-stimulating hormone (TSH) should be the
initial test. If the serum TSH concentration is elevated, the TSH measurement should be repeated along
with a serum free thyroxine (T4) to make the diagnosis of hypothyroidism (table 3). If the repeat serum
TSH value is still high and the serum free T4 is low, suggesting primary hypothyroidism, replacement
therapy with T4 should be initiated. (See 'Diagnosis' above and "Treatment of primary hypothyroidism in
adults".)
Patients with a high serum TSH concentration and a normal serum free T4 concentration may have
subclinical hypothyroidism. (See 'Diagnosis' above and 'Primary hypothyroidism' above.)
● If central hypothyroidism is suspected (eg, presence of pituitary or hypothalamic disease), or if the

patient has convincing symptoms of hypothyroidism despite a normal TSH result, we measure serum
TSH and free T4. In patients with central hypothyroidism, the serum free T4 value is low-normal or low
and serum TSH may be frankly low, inappropriately normal (for the low T4), or slightly high (5 to 10
mU/L) due to secretion of biologically inactive TSH (table 3). (See 'Diagnosis' above and "Central
hypothyroidism".)
● The differential diagnosis of an elevated serum TSH concentration includes resistance to TSH, recovery
from nonthyroidal illness, and a TSH-secreting pituitary adenoma. (See 'Differential diagnosis' above.)
● The clinical evaluation of a patient with primary hypothyroidism should be directed toward confirming the
presence and identifying the cause of the hormone deficiency (table 5). The history, for example, may
uncover past treatment of hyperthyroidism with radioiodine or thyroidectomy, the use of drugs that affect
thyroid hormone synthesis, or history of iodine deficiency or excess. We do not routinely measure TPO
antibodies in patients with primary overt hypothyroidism, because almost all have chronic autoimmune
thyroiditis. (See 'Identifying the cause' above.)
● We suggest not performing population-based screening for hypothyroidism (Grade 2C). As an

alternative, we prefer to screen individuals who are at increased risk for hypothyroidism (table 2). (See
'Candidates for screening' above.)
TSH is the most sensitive test for detecting primary hypothyroidism in ambulatory patients. However,
TSH alone may not be a useful tool for the diagnosis of hypothyroidism if pituitary or hypothalamic
disease is known or suspected; in hospitalized patients, since there are many other factors in acutely or
chronically ill euthyroid patients that influence TSH secretion; and in patients receiving drugs or with
underlying diseases that affect TSH secretion (table 4). (See "Thyroid function in nonthyroidal illness".)
● The universal screening of asymptomatic pregnant women for hypothyroidism during the first trimester of
pregnancy is controversial. We suggest a targeted approach rather than universal screening (Grade 2C).
We favor screening pregnant women if they are from an area of moderate to severe iodine insufficiency,
have symptoms of hypothyroidism, a family or personal history of thyroid disease, or a personal history
of TPO antibodies, type 1 diabetes, morbid obesity, head and neck radiation, recurrent miscarriage, or
infertility. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment",
section on 'Screening'.)
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REFERENCES
1. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the
Whickham survey. Clin Endocrinol (Oxf) 1977; 7:481.
2. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community:
a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43:55.
3. Vanderpump MP, Tunbridge WM. The epidemiology of thyroid diseases. In: The thyroid: A fundamental
and clinical text, 8th, Braverman LE, Utiger RD (Eds), Lippincott Williams and Wilkins, Philadelphia 200
0. p.467.
4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch
Intern Med 2000; 160:526.
5. Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the United States population and their
association with participant characteristics: National Health and Nutrition Examination Survey (NHANES
1999-2002). Thyroid 2007; 17:1211.
6. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United
States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J
Clin Endocrinol Metab 2002; 87:489.
7. Walsh JP, Bremner AP, Feddema P, et al. Thyrotropin and thyroid antibodies as predictors of
hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay
techniques. J Clin Endocrinol Metab 2010; 95:1095.
8. Kajantie E, Phillips DI, Osmond C, et al. Spontaneous hypothyroidism in adult women is predicted by
small body size at birth and during childhood. J Clin Endocrinol Metab 2006; 91:4953.
9. McDermott MT. In the clinic. Hypothyroidism. Ann Intern Med 2009; 151:ITC61.
10. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the
US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab
2007; 92:4575.
11. Valdés S, Maldonado-Araque C, Lago-Sampedro A, et al. Reference values for TSH may be inadequate
to define hypothyroidism in persons with morbid obesity: Di@bet.es study. Obesity (Silver Spring) 2017;
25:788.
12. Samuels MH, Ridgway EC. Central hypothyroidism. Endocrinol Metab Clin North Am 1992; 21:903.
13. Lania A, Persani L, Beck-Peccoz P. Central hypothyroidism. Pituitary 2008; 11:181.
14. Beck-Peccoz P, Amr S, Menezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive
thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J
Med 1985; 312:1085.
15. Topliss DJ, White EL, Stockigt JR. Significance of thyrotropin excess in untreated primary adrenal
insufficiency. J Clin Endocrinol Metab 1980; 50:52.
16. Kahn BB, Weintraub BD, Csako G, Zweig MH. Factitious elevation of thyrotropin in a new ultrasensitive
assay: implications for the use of monoclonal antibodies in "sandwich" immunoassay. J Clin Endocrinol
Metab 1988; 66:526.
17. Loh TP, Kao SL, Halsall DJ, et al. Macro-thyrotropin: a case report and review of literature. J Clin
Endocrinol Metab 2012; 97:1823.
18. Tonacchera M, Di Cosmo C, De Marco G, et al. Identification of TSH receptor mutations in three
families with resistance to TSH. Clin Endocrinol (Oxf) 2007; 67:712.
19. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin
Endocrinol Metab 1990; 71:661.
20. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic
health examination: a decision and cost-effectiveness analysis. JAMA 1996; 276:285.
21. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and
survival in old age. JAMA 2004; 292:2591.
22. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for
diagnosis and management. JAMA 2004; 291:228.
23. Gharib H, Tuttle RM, Baskin HJ, et al. Subclinical thyroid dysfunction: a joint statement on management
from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the
Endocrine Society. J Clin Endocrinol Metab 2005; 90:581.
24. Spencer CA. Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and
hospitalized patients. Mayo Clin Proc 1988; 63:1214.
25. American Academy of Family Physicians. Summary of policy recommendations for periodic health exa
minations. Leawood, KS: American Academy of Family Physicians, 2002.
26. Clinical guideline, part 1. Screening for thyroid disease. American College of Physicians. Ann Intern
Med 1998; 129:141.
27. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults:
cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid
Association. Thyroid 2012; 22:1200.
28. Rugge JB, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review
for the U.S. Preventive Services Task Force. Ann Intern Med 2015; 162:35.
29. LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive
Services Task Force recommendation statement. Ann Intern Med 2015; 162:641.
Topic 7893 Version 21.0
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/diagnosis-of-and-screening-for-hypothyroidism-in-nonpregnant-adults/print?sea… 10/17
GRAPHICS
Major symptoms and signs of hypothyroidism
Mechanism Symptoms Signs
Slowing of metabolic processes Fatigue and weakness Slow movement and slow speech
Cold intolerance Delayed relaxation of tendon reflexes
Dyspnea on exertion Bradycardia
Weight gain Carotenemia
Cognitive dysfunction
Mental retardation (infantile onset)
Constipation
Growth failure
Accumulation of matrix substances Dry skin Coarse skin

Hoarseness Puffy facies and loss of eyebrows
Edema Periorbital edema
Enlargement of the tongue
Other Decreased hearing Diastolic hypertension

Myalgia and paresthesia Pleural and pericardial effusions
Depression Ascites
Menorrhagia Galactorrhea
Arthralgia
Pubertal delay
Graphic 62676 Version 4.0
Indications to test for hypothyroidism
Clinical symptoms and Personal or family history of associated autoimmune disorders (eg, vitiligo,
pernicious anaemia, adrenal insufficiency, diabetes mellitus type 1, ovarian
signs
failure, coeliac disease, Sjögren's syndrome)
Fatigue
Primary pulmonary hypertension
Cold intolerance
Multiple Sclerosis
Constipation
Previous thyroid injury
Impaired memory
Thyroidectomy or other neck surgery
Slowed mental processing
Radioactive iodine therapy
Depression
External radiotherapy
Nerve entrapment syndromes
Exposure to polybrominated and polychlorinated biphenyls, and resorcinol
Ataxia
Postpartum status
Muscle weakness
Drugs impairing thyroid function
Muscle cramps
Lithium carbonate
Menstrual disturbance
Amiodarone
Infertility
Aminoglutethimide
Bradycardia
Interferon α
Diastolic hypertension
Thalidomide
Hoarseness
Betaroxine
Goitre
Stavudine
Periorbital oedema
Hypothalamic disorders
Weight gain
Hypothalamic or suprasellar mass
Galactorrhoea
History of hypothalamic radiotherapy or surgery
Laboratory test
Disorders causing hypothalamic dysfunction-- eg, sarcoidosis,
abnormalities
haemochromatosis, Langerhans' cell histiocytosis
Hypercholesterolaemia
Pituitary disorders
Hyponatraemia
Known pituitary tumour
Hyperprolactinaemia
Other elements of hypopituitarism
Hyperhomocysteinaemia
Manifestations of a sellar mass (eg, headache, bitemporal haemianopsia,
Anemia or diplopia)
Creatine phosphokinase elevation History of pituitary surgery of radiotherapy
Radiological History of head trauma

abnormalities History of pituitary apoplexy, including Sheehan's syndrome
Pericardial and pleural effusions History of other disorders causing hypopituitarism - eg, metastatic cancer
and lymphocytic hypophysitis
Pituitary gland enlargement
Risk factors for

hypothyroidism
Autoimmune thyroiditis
Established serological or
tissue diagnosis
Diffuse goitre
Previous Graves' disease, de

Quervain's thyroiditis, or
painless (postpartum)
thyroiditis
Family history of autoimmune
thyroid disease
Down's syndrome
Turner's syndrome
Reproduced with permission from: Roberts, CG, Ladenson, PW. Hypothyroidism. Lancet 2004; 363:793. Copyright ©
2004 Elsevier.
Patterns of thyroid function tests during assessment of thyroid function
Serum TSH Serum free T4 Serum T3 Assessment
Normal hypothalamic-pituitary function
Normal Normal Normal Euthyroid
Normal Normal or high Normal or high Euthyroid

hyperthyroxinemia
Normal Normal or low Normal or low Euthyroid

hypothyroxinema
Normal Low Normal or high Euthyroid: T3 therapy
Normal Low-normal or low Normal or high Euthyroid: thyroid extract

therapy
High Low Normal or low Primary hypothyroidism
High Normal Normal Subclinical hypothyroidism
Low High or normal High Hyperthyroidism
Low Normal Normal Subclinical

hyperthyroidism
Abnormal hypothalamic-pituitary function
Normal or high High High TSH-mediated

hyperthyroidism
Normal or low* Low or low-normal Low or normal Central hypothyroidism
T3: triiodothyronine; T4: thyroxine; TSH: thyroid-stimulating hormone.

* In central hypothyroidism, serum TSH may be low, normal, or slightly high.
Disorders that affect serum TSH concentrations
Low serum TSH

Primary hyperthyroidism
Incomplete recovery from hyperthyroidism
Nonthyroidal illness
High levels of chorionic gonadotropin - early pregnancy, molar pregnancy, choriocarcinoma
Drugs - dopamine agonists, glucocorticoids, somatostatin analogs
Central hypothyroidism
High serum TSH

Primary hypothyroidism
Recovery from nonthyroidal illness
Drugs - dopamine antagonists, amiodarone, oral cholecystogram dye (sodium ipodate)
TSH-producing pituitary adenoma
Adrenal insufficiency
Heterophilic antibody interference
Generalized thyroid hormone resistance
TSH: thyroid-stimulating hormone.
Major causes of hypothyroidism
Primary hypothyroidism
Chronic autoimmune thyroiditis
Iatrogenic
Thyroidectomy
Radioiodine therapy or external irradiation
Iodine deficiency or excess
Drugs - thionamides, lithium, amiodarone, interferon alfa, interleukin-2, tyrosine kinase inhibitors, checkpoint
inhibitor immunotherapy
Infiltrative diseases - fibrous thyroiditis, hemochromatosis, sarcoidosis
Transient hypothyroidism
Painless (silent, lymphocytic) thyroiditis
Subacute granulomatous thyroiditis
Postpartum thyroiditis
Subtotal thyroidectomy
Following radioiodine therapy for Graves' hyperthyroidism
Following withdrawal of suppressive doses of thyroid hormone in euthyroid patients
Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis
Central hypothyroidism
TSH deficiency
TRH deficiency
Generalized thyroid hormone resistance (some patients)*
TRH: thyrotropin-releasing hormone; TSH: thyroid-stimulating hormone.

* Refer to UpToDate content on clinical features of thyroid hormone resistance.
Contributor Disclosures
Douglas S Ross, MD Consultant/Advisory Board: Medullary Thyroid Cancer Registry Consortium [Thyroid
cancer]; Shire [Hypoparathyroidism (Parathyroid hormone for injection)]; Spectrix Therapeutics, LLC
[Hypothyroidism (Thyroid hormone)]. Other Financial Interests: Abbott India (honorarium) [Hyperthyroidism
(carbimazole, levothyroxine)]; Quest Diagnostics (honorarium) [Hyperthyroidism]. David S Cooper,
MD Nothing to disclose Jean E Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

Diagnosis of and Screening For Hypothyroidism in Nonpregnant Adults - UpToDate

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07/12/2018 Diagnosis of and screening for hypothyroidism in nonpregnant adults - UpToDate

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Author: Douglas S Ross, MD

● Serum TPO antibody concentrations were high in 11 percent.

● Central hypothyroidism is characterized by a low serum T4 concentration and a serum TSH

Secondary and tertiary hypothyroidism should be suspected in the following circumstances:

● There is known hypothalamic or pituitary disease

● A mass lesion is present in the pituitary

Thyrotropin-secreting pituitary adenomas — TSH-secreting pituitary adenomas are a rare cause of

● Goiter, especially in the absence of hypothyroidism, to identify immunologically mediated goiter

We recommend measurement of serum TSH as a screening test for hypothyroidism.

As an alternative, we suggest screening for hypothyroidism in patients with laboratory or radiologic

● High serum muscle enzyme concentrations

● Pituitary or hypothalamic disorders (see "Central hypothyroidism")

● History of autoimmune diseases

● If pituitary or hypothalamic disease is known or suspected.

● Serum TSH normal – No further testing performed

● Serum TSH high – Free T4 added to determine the degree of hypothyroidism

SUMMARY AND RECOMMENDATIONS

● If central hypothyroidism is suspected (eg, presence of pituitary or hypothalamic disease), or if the

● We suggest not performing population-based screening for hypothyroidism (Grade 2C). As an

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 7893 Version 21.0

Major symptoms and signs of hypothyroidism

Mechanism Symptoms Signs

Accumulation of matrix substances Dry skin Coarse skin

Other Decreased hearing Diastolic hypertension

Graphic 62676 Version 4.0

Indications to test for hypothyroidism

Radiological History of head trauma

Risk factors for

Previous Graves' disease, de

Family history of autoimmune

Graphic 53510 Version 1.0

Patterns of thyroid function tests during assessment of thyroid function

Serum TSH Serum free T4 Serum T3 Assessment

Normal hypothalamic-pituitary function

Normal Normal Normal Euthyroid

Normal Normal or high Normal or high Euthyroid

Normal Normal or low Normal or low Euthyroid

Normal Low Normal or high Euthyroid: T3 therapy

Normal Low-normal or low Normal or high Euthyroid: thyroid extract

High Low Normal or low Primary hypothyroidism

High Normal Normal Subclinical hypothyroidism

Low High or normal High Hyperthyroidism

Low Normal Normal Subclinical

Abnormal hypothalamic-pituitary function

Normal or high High High TSH-mediated

Normal or low* Low or low-normal Low or normal Central hypothyroidism

T3: triiodothyronine; T4: thyroxine; TSH: thyroid-stimulating hormone.

Graphic 67935 Version 4.0

Disorders that affect serum TSH concentrations

Low serum TSH

Incomplete recovery from hyperthyroidism

High levels of chorionic gonadotropin - early pregnancy, molar pregnancy, choriocarcinoma

Drugs - dopamine agonists, glucocorticoids, somatostatin analogs

High serum TSH

Recovery from nonthyroidal illness

Drugs - dopamine antagonists, amiodarone, oral cholecystogram dye (sodium ipodate)

TSH-producing pituitary adenoma

Heterophilic antibody interference

Generalized thyroid hormone resistance