Hypothyroidism in Adults

Hypothyroidism in Adults
Overview and Recommendations

Background
● Hypothyroidism is a de!ciency of thyroid hormone usually caused by primary thyroid
failure, and less often due to pituitary failure, hypothalamic failure, or congenital
thyroid hormone resistance.
⚬ Overt primary hypothyroidism is de!ned as elevated thyroid stimulating hormone
(TSH) with low free thyroxine (FT4), and can be autoimmune-related, congenital, or
caused by thyroid surgery, previous radioablation or radiation therapy to the neck,
or endemic iodine de!ciency.
⚬ Subclinical hypothyroidism is de!ned as elevated TSH with normal free T4.
⚬ Central hypothyroidism usually presents with low to normal TSH with low FT4, and
can be caused by hypopituitarism (secondary hypothyroidism), a hypothalamic
process (tertiary hypothyroidism), or severe illness (nonthyroidal illness
syndrome).
⚬ Drugs that may cause hypothyroidism include lithium and amiodarone.
● The most common cause of hypothyroidism is autoimmune disease (Hashimoto
thyroiditis).
● There is a higher incidence of primary thyroid failure in older adults and among
women.
● Complications of hypothyroidism include cardiovascular, neuropsychiatric,
musculoskeletal, and other important sequelae.
● There is insu"cient evidence to recommend routine screening for hypothyroidism in
asymptomatic, nonpregnant adults with low risk for hypothyroidism, but screening
may be considered for older adults (> 60 years old) and adults at increased risk for
hypothyroidism (such as those with autoimmune disease or a !rst-degree relative
with hypothyroidism).
Evaluation
● Hypothyroidism may present with:
⚬ no symptoms (condition detected on screening)
⚬ mild-to-moderate symptoms, such as slow mental and physical activity, cold
intolerance, constipation, and weight gain
⚬ changes in mental status (myxedema coma) in advanced disease
● Examine symptomatic patients for bradycardia, hypothermia, dry skin, facial and
periorbital edema, thyroid gland for size and irregularities, heart failure and other
cardiopulmonary !ndings, and increased relaxation phase of deep tendon re#exes.
● In symptomatic patients or in those with signs of hypothyroidism, measure thyroid-
stimulating hormone (TSH). Measure free thyroxine (FT4) if the TSH is elevated or if a
disorder other than primary hypothyroidism is suspected.
● Serum TSH may be physiologically higher in older adults.
⚬ The most commonly used reference range in nonpregnant adults is 0.5-4
milliunits/L, but can be as high as 4.5 milliunits/L.
⚬ In older adults (> 70 years old), the reference range may extend to 4-6 milliunits/L.
● Diagnosing hypothyroidism in nonpregnant adults
⚬ The diagnosis of overt primary hypothyroidism may be suspected in patients with
classic signs and symptoms of hypothyroidism, and is diagnosed when blood tests
show:
– elevated TSH, often > 10 milliunits/L
– low serum FT4
⚬ The diagnosis of subclinical primary hypothyroidism (which is typically
asymptomatic or mildly symptomatic) is con!rmed by blood tests showing:
– elevated TSH
– normal serum FT4
⚬ The diagnosis of central (secondary and tertiary) hypothyroidism is usually made
in patients with signs and symptoms consistent with primary hypothyroidism plus
!ndings associated with hypothalamic or pituitary de!ciency (such as menstrual
disturbances, galactorrhea, diminished libido, and/or infertility) and con!rmed by
blood tests showing low to normal TSH and low serum FT4.
● In pregnancy, diagnose hypothyroidism if TSH is elevated above the normal limit of
the trimester-speci!c reference range (Strong recommendation).
● The di$erential diagnosis includes nonthyroidal illness. Other conditions that cause
similar symptoms are anemia, pregnancy, and liver failure, and falsely elevated TSH
levels as a result of medications or other illnesses.
Management
● Thyroid hormone replacement therapy
⚬ Levothyroxine (LT4) monotherapy is the recommended treatment for patients
with hypothyroidism (Strong recommendation).
⚬ Indications for levothyroxine
– Treat all patients with overt hypothyroidism with levothyroxine (Strong
recommendation).
– The decision to treat subclinical hypothyroidism is controversial.
● For nonpregnant patients with subclinical hypothyroidism, consider
treatment with levothyroxine if serum TSH levels are > 10 milliunits/L due to
increased risk for heart failure and cardiovascular mortality (Weak
recommendation).
● If the decision is made to treat subclinical hypothyroidism, consider a lower
dose (25-75 mcg/day orally), depending on the degree of TSH elevation
(Weak recommendation).
● Levothyroxine oral dosing
⚬ For young, healthy adults with overt hypothyroidism, consider starting with a full
replacement dose (1.6 mcg/kg/day or 100-125 mcg/day in typical adults) (Weak
recommendation).
⚬ For older patients with coronary artery disease, consider starting with 12.5-25
mcg/day.
● Monitor TSH levels 4-6 weeks after any dose change (Strong recommendation).
● After an adequate replacement dose has been determined, consider measuring TSH
levels after 6 months and then at 12-month intervals, or more frequently based on
clinical situation (Weak recommendation).
● Management in pregnant adults and postpartum
⚬ For pregnant adults with overt hypothyroidism, treat with levothyroxine (Strong
recommendation).
⚬ A full starting dose of levothyroxine (2-2.4 mcg/kg/day orally) is suggested for
overt hypothyroidism discovered during pregnancy.
⚬ For pregnant adults with subclinical hypothyroidism
– Treat with levothyroxine if:
● thyroid peroxidase antibody (TPOAb) titers are positive and TSH is greater
than the trimester-speci!c reference range (Strong recommendation)
● TPOAb titers are negative and TSH is > 10 milliunits/L (Strong
recommendation)
– Consider treating with levothyroxine if:
● TPOAb titers are positive and TSH is > 2.5 milliunits/L and below the upper
limit of the trimester-speci!c reference range (Weak recommendation)
● TPOAb titers are negative and TSH is greater than the trimester-speci!c
reference range but < 10 milliunits/L (Weak recommendation)
⚬ Monitoring during pregnancy and postpartum
– In pregnant adults with overt and subclinical hypothyroidism (treated or
untreated) or those at risk for hypothyroidism, monitor TSH level every 4 weeks
until midgestation and at least once near 30 weeks (Strong recommendation).
– For adults being treated for hypothyroidism during pregnancy, consider a
target TSH goal in the lower half of a trimester-speci!c reference range (or < 2.5
milliunits/L if a speci!c range is not available) (Weak recommendation).
– Follow-up after delivery
● Readjust the levothyroxine dose to the preconception dose at delivery and
monitor thyroid function at about 6 weeks postpartum (Strong
recommendation).
● Consider discontinuing levothyroxine in certain adults who initiated
levothyroxine during pregnancy, especially those with a dose ≤ 50 mcg/day
(Weak recommendation).
⚬ The patient should be involved in the decision.
⚬ Measure serum TSH at about 6 weeks postpartum if levothyroxine is
discontinued.
● Management in patients with myxedema coma
⚬ Myxedema coma is a medical emergency and requires urgent recognition and
treatment.
⚬ In patients with suspected myxedema coma, treatment should be initiated based
on clinical suspicion alone and not delayed until results of blood tests are
available.
⚬ Admit the patient to the intensive care unit for continuous pulmonary and
cardiovascular monitoring and support.
⚬ Provide stress doses of IV glucocorticoid prior to levothyroxine administration
(Strong recommendation) (for example, hydrocortisone 100 mg IV every 8 hours).
⚬ Administer a levothyroxine loading dose of 200-400 mcg IV (give lower doses for
smaller or older patients and those with a history of coronary artery disease or
arrhythmia) followed by a replacement oral dose of 1.6 mcg/kg/day (if given IV, use
75% of oral dose) (Strong recommendation).
⚬ In addition to levothyroxine, consider administering a liothyronine loading dose of
5-20 mcg IV followed by a maintenance dose of 2.5-10 mcg IV every 8 hours until
the patient is clearly improving (Weak recommendation).
– Use lower doses for smaller or older patients and those with coronary artery
disease or arrhythmia.
– High doses should be avoided because of the reported association of high
serum triiodothyronine with mortality.
● Most patients with uncomplicated hypothyroidism will not require perioperative
dose adjustments.
General Information
Description
● hypothyroidism is a common condition characterized by thyroid hormone
de!ciency 1
● manifestations are many and varied, but treatment is relatively straightforward with
special considerations in select circumstances, such as pregnancy 1
Definitions
● normally functioning thyroid is de!ned as thyroid-stimulating hormone (TSH) within
reference range (0.4-4 milliunits/L is most commonly used) and free thyroxine (FT4)
within reference range (range depends on assay and population studied) 1
⚬ reference ranges can di$er with age, sex, and ethnicity (for example, TSH
reference range can increase in older adults)
⚬ reference ranges do not account for risk of adverse events or disease
● overt (clinical) primary hypothyroidism - elevated TSH with low FT4 1
● subclinical primary hypothyroidism - elevated TSH with normal FT4 1
● central hypothyroidism - usually low to normal TSH with low FT4 (occasionally, TSH
levels are mildly elevated possibly due to decreased bioactivity) 1
● myxedema coma - severe, long-standing hypothyroidism with mental status
deterioration, which can result in hypothermia, lethargy, bradycardia, multiple organ
dysfunction, and death 1
Types
● classi!cation of hypothyroidism 1
⚬ primary hypothyroidism (most common)
– caused by thyroid hormone de!ciency
– overt hypothyroidism is clinically de!ned by high thyroid-stimulating hormone
(TSH) and low free thyroxine (T4) levels
– subclinical hypothyroidism is clinically de!ned by elevated TSH and normal FT4
⚬ central hypothyroidism (rare)
– more likely to be caused by pituitary or hypothalamus disorders than thyroid
disorders, but thyroid disorders may also be present
– overt central hypothyroidism clinically de!ned by low to normal TSH and low
free T4 levels (although, occasionally TSH levels are mildly elevated)
– subtypes includes
● secondary - due to TSH de!ciency
● tertiary - due to thyrotropin-releasing hormone de!ciency
⚬ peripheral (extrathyroidal) hypothyroidism (rare)
– can be caused by consumptive hypothyroidism due to aberrant expression of
the deiodinase 3 enzyme (which inactivates thyroid hormone)
– can also be caused by rare genetic syndromes that lead to a congenital reduced
sensitivity to thyroid hormone (for example, mutations in MCT8, SECISBP2, THRA,
or THRB)
Image 1 of 4
Primary and secondary hypothyroidism

comparison
Left: Primary hypothyroidism, in which the thyroid

cannot produce enough thyroid hormones (thick green
arrow). Right: Secondary hypothyroidism, in which the
thyroid is not stimulated by the pituitary gland to
produce necessary hormone levels (thin green arrow).
Image courtesy of Gwen Shockey/Science Source/Science Photo

Library.
Epidemiology
Who Is Most A!ected
● primary hypothyroidism more frequently occurs in
⚬ older adults (especially > 65 years old) 1
⚬ women 1
● central hypothyroidism is rare and appears equally common in men and women 1
● can occur both in populations with excessively high iodine intake and in populations
with severe iodine de!ciency 1
Incidence/Prevalence
● hypothyroidism is common worldwide (Nat Rev Endocrinol 2018 May;14(5):301 )
● reported prevalence of overt hypothyroidism in iodine-su"cient
countries/continents
⚬ about 1%-2% overall
⚬ 0.3%-3.7% in the United States
⚬ 0.2%-5.3% in Europe
⚬ up to 7% in older adults aged 85-89 years
⚬ Reference - Nat Rev Endocrinol 2018 May;14(5):301
STUDY
● SUMMARY
about 3% prevalence of hypothyroidism in children and adults in Europe between
1975 and 2012
SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2014 Mar;99(3):923

Details
⚬ based on systematic review of population-based cohort studies
⚬ systematic review of 17 population-based cohort studies evaluating incidence or
prevalence of thyroid dysfunction in children and adults in Europe between 1975
and 2012
⚬ mean population prevalence of hypothyroidism
– 3.05% overall (previously diagnosed and undiagnosed) in analysis of 9 studies
with 752,773 children and adults
– 4.94% undiagnosed in analysis of 7 studies with 50,364 children and adults
⚬ mean annual incidence in analysis of 7 studies with 24,444,106 children and adults
– 226 per 100,000 overall
– 370 per 100,000/year in females
– 73 per 100,000/year in males
⚬ undiagnosed thyroid dysfunction in analysis of 7 studies with 50,364 persons
– 6.71% overall
– 4.94% with undiagnosed hypothyroidism and 1.72% with undiagnosed
hyperthyroidism
⚬ Reference - J Clin Endocrinol Metab 2014 Mar;99(3):923
● reported prevalence of elevated thyroid-stimulating hormone (TSH) in pregnant

women in United States
⚬ 0.3%-0.5% of pregnant women with decreased free thyroxine (T4) levels (overt
hypothyroidism)
⚬ 2.5%-3% of pregnant women with normal free T4 levels (subclinical
hypothyroidism)
⚬ see Thyroid Disease in Pregnancy for additional information, including trimester-
speci!c upper reference limits from various organizations
Risk Factors
● female gender 1
● older age, especially > 65 years 1
● family history of thyroid disease or other autoimmune diseases 1 , 2
● postpartum thyroiditis (10%-20% of postpartum thyroiditis cases reported to result in
permanent hypothyroidism) 4
● radiation therapy or surgery involving the head and neck area 1
● certain genetic conditions, including Down syndrome or Turner syndrome 1
STUDY
● SUMMARY
iodinated contrast media exposure associated with increased risk of overt
hypothyroidism
CASE-CONTROL STUDY: Arch Intern Med 2012 Jan 23;172(2):153

Details
⚬ based on nested case-control study in adults
⚬ 213 incident cases of hypothyroidism matched with 779 euthyroid controls
⚬ iodinated contrast media exposure associated with increased risk of incident overt
hypothyroidism (follow-up thyroid-stimulating hormone [TSH] level > 10
milliunits/L) in prespeci!ed secondary analysis (odds ratio [OR] 3.05, 95% CI 1.07-
8.72)
⚬ iodinated contrast media exposure not associated with increased risk of incident
hypothyroidism (thyrotropin level above assay reference range) (OR 1.58, 95% CI
0.95-2.62)
⚬ Reference - Arch Intern Med 2012 Jan 23;172(2):153 , editorial can be found in
Arch Intern Med 2012 Jan 23;172(2):159 , Arch Intern Med 2012 Jan 23;172(2):161
Associated Conditions
● other autoimmune disorders can occur in patients with autoimmune thyroiditis, such
as
⚬ pernicious anemia 2
⚬ diabetes mellitus type 1 1
⚬ autoimmune gastric atrophy 1
⚬ vitiligo 2
⚬ alopecia 2
⚬ celiac disease 2
⚬ adrenocortical insu"ciency (Addison disease) 2
⚬ systemic lupus erythematosus (SLE) 2
⚬ autoimmune hypophysitis 2
⚬ primary biliary cirrhosis (PBC) 2
⚬ multiple autoimmune endocrinopathies (MAEs); also called autoimmune
polyendocrine syndromes 2
– MAE type 1 is ≥ 2 of hypoparathyroidism, Addison disease, and mucocutaneous
candidiasis
● autoimmune thyroiditis present in 10%-15%
● caused by autoimmune regulator (AIRE) gene mutation
– MAE type 2 (also called Schmidt syndrome) is ≥ 2 of autoimmune thyroiditis,
Addison disease, and diabetes mellitus type 1
● hyperprolactinemia - occasional reports of pseudo-adenomas of pituitary gland
⚬ long-standing primary hypothyroidism may be associated with hyperprolactinemia
and sellar mass due to hyperplasia of pituitary thyrotrophs
⚬ hyperprolactinemia and mass resolves with thyroxine therapy
● hyperlipidemias
STUDY
⚬ SUMMARY
elevated thyroid-stimulating hormone level associated with elevated
cholesterol levels
CROSS-SECTIONAL STUDY: Arch Intern Med 2002 Apr 8;162(7):773

Details
– based on cross-sectional study
– 2,799 persons aged 70-79 years (51% female) were evaluated for thyroid-
stimulating hormone (TSH), free thyroxine, and total cholesterol levels
● 94% were euthyroid and 10% took thyroid hormone
● 3.1% of persons not taking thyroid hormone had subclinical hypothyroidism
– in multivariate analysis
● TSH level > 5.5 milliunits/mL associated with 9 mg/dL (0.23 mmol/L) increase
in cholesterol level
● TSH level < 0.35 milliunits/mL associated with 19 mg/dL (0.49 mmol/L)
decrease in cholesterol level
– Reference - Arch Intern Med 2002 Apr 8;162(7):773
STUDY
⚬ SUMMARY
hypertriglyceridemia associated with subclinical hypothyroidism in women
CASE-CONTROL STUDY: J Clin Endocrinol Metab 2015 May;100(5):1887

Details
– based on case-control study
– 24,100 adults aged ≥ 40 years with similar and stable iodine nutrition status in
China were evaluated by an overnight fasting blood sample and a self-reported
questionnaire
– 5,033 patients with a diagnosis of subclinical hypothyroidism and 5,033
matched controls (matched by age, gender, and region) had triglyceride levels
compared
– in multivariate analysis, hypertriglyceridemia associated with increased risk for
subclinical hypothyroidism
● in women (p < 0.001)
● in men (p = 0.047)
– Reference - J Clin Endocrinol Metab 2015 May;100(5):1887
STUDY
● SUMMARY
autoimmune/iodine deficiency hypothyroidism associated with diabetes and other
autoimmune conditions in adults
POPULATION-BASED SURVEILLANCE: Eur J Endocrinol 2017 May;176(5):533

Details
⚬ based on population-based cohort study
⚬ 136,036 people with hypothyroidism (125,972 with autoimmune/iodine de!ciency
hypothyroidism; 10,064 with iatrogenic hypothyroidism) in 2012 in Piedmont, Italy
were evaluated
⚬ compared to nonhypothyroid individuals, patients with autoimmune/iodine
de!ciency hypothyroidism had increased prevalence of
– in men
● type 1 diabetes (age-adjusted odds ratio [OR] 4.14, 95% CI 3.56–4.8)
● type 2 diabetes (age-adjusted OR 1.52, 95% CI 1.46-1.59)
● celiac disease (age-adjusted OR 5.8, 95% CI 4.52-7.44)
● lupus erythematosus (age-adjusted OR 4.99, 95% CI 3.06-8.15)
● rheumatoid arthritis (age-adjusted OR 1.74, 95% CI 1.39-2.19)
● ankylosing spondylitis (age-adjusted OR 1.99, 95% CI 1.17-3.38)
● psoriatic arthritis (age-adjusted OR 1.43, 95% CI 1.02-1.99)
● multiple sclerosis (age-adjusted OR 2.07, 95% CI 1.39-3.08)
– in women
● type 1 diabetes (age-adjusted OR 3.29, 95% CI 3.02–3.59)
● type 2 diabetes (age-adjusted OR 1.49, 95% CI 1.46-1.52)
● gestational diabetes (age-adjusted OR 1.69, 95% CI 1.71-2.02)
● celiac disease (age-adjusted OR 3.1, 95% CI 2.84-3.39)
● lupus erythematosus (age-adjusted OR 2.23, 95% CI 1.96-2.53)
● rheumatoid arthritis (age-adjusted OR 2.08, 95% CI 1.96-2.2)
● ankylosing spondylitis (age-adjusted OR 1.94, 95% CI 1.47-2.56)
● psoriatic arthritis (age-adjusted OR 1.56, 95% CI 1.35-1.8)
● multiple sclerosis (age-adjusted OR 1.71, 95% CI 1.52-1.93)
⚬ Reference - Eur J Endocrinol 2017 May;176(5):533
Etiology and Pathogenesis

Causes
Primary Hypothyroidism
● primary hypothyroidism is caused by thyroid hormone de!ciency, which can develop
secondary to a medical condition, iodine de!ciency or excess, use of certain
medications, or iatrogenic injury to the thyroid 1 , 2
● autoimmune thyroiditis (Hashimoto thyroiditis) is the most common cause of
hypothyroidism in iodine-su"cient populations 1 , 3 , 4
● less common causes of primary hypothyroidism
⚬ severe iodine de!ciency or excessive iodine consumption 1
⚬ iatrogenic injury to the thyroid, including 1
– radioiodine therapy for management of hyperthyroidism (Graves disease or
toxic nodular disease)
– radiation therapy for management of head or neck cancer
– thyroid surgery, including hemithyroidectomy
STUDY
● SUMMARY
21% risk of hypothyroidism after hemithyroidectomy
SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2012 Jul;97(7):2243

Details
⚬ based on systematic review of observational studies
⚬ systematic review of 32 cohort studies reporting incidence or prevalence
of hypothyroidism in 4,899 patients after hemithyroidectomy
⚬ risk of hypothyroidism after hemithyroidectomy 21% (95% CI 17%-25%) in
analysis of 22 studies
⚬ Reference - J Clin Endocrinol Metab 2012 Jul;97(7):2243
⚬ transient thyroiditis, including 1

– postpartum thyroiditis
– silent thyroiditis
– destructive thyroiditis
– viral infection (subacute thyroiditis or De Quervain syndrome)
⚬ use of certain medications, including 1
– iodine
– amiodarone
– lithium
– tyrosine kinase inhibitors (such as sunitinib)
– interferon-alfa
– thalidomide
– monoclonal antibodies (such as ipilimumab and nivolumab)
– antiseizure medications (such as valproate)
– second-line drugs for multidrug-resistant tuberculosis (such as ethionamide
and prothionamide)
● rare causes of primary hypothyroidism
⚬ thyroid in!ltration 1
– infectious
– malignant (primary thyroid lymphoma)
– autoimmune (sarcoidosis)
– !brosis (Riedel thyroiditis)
⚬ genetic predisposition, which may be related to 1
– autoimmunity-related genes (HLA class 1 region, PTPN22, SH2B3, and VAV3)
– general and thyroid speci!c genes (FOXE1), ATXN2, and PDE8B)
Central Hypothyroidism
● central hypothyroidism includes 1
⚬ secondary hypothyroidism (hypopituitarism) - due to thyroid-stimulating hormone
(TSH) de!ciency
⚬ tertiary hypothyroidism (hypothalamic process) - due to thyrotropin-releasing
hormone de!ciency
● most cases of central hypothyroidism are caused by compressive and/or invasive
lesions a$ecting the pituitary sella region, including
⚬ pituitary macroadenomas
⚬ craniopharyngiomas
⚬ meningiomas or gliomas
⚬ Rathke cleft cysts
⚬ metastatic seeding
⚬ carotid aneurysm
⚬ Reference - Eur Thyroid J 2018 Oct;7(5):225 full-text
● medications that can cause central hypothyroidism include
⚬ dopamine 1
⚬ somatostatins 1
⚬ glucocorticosteroids 1
⚬ retinoid X 1
⚬ oral bexarotene 2
⚬ immune checkpoint inhibitors (Crit Rev Oncol Hematol 2019 Sep;141:23 )
● less common causes include
⚬ cranial surgery or radiation therapy
⚬ traumatic head injuries
⚬ vascular accidents
– pituitary infarction
– Sheehan syndrome
– subarachnoid hemorrhage
⚬ autoimmune diseases (postpartum or lymphocytic hypophysitis)
⚬ in!ltrative lesions
⚬ inheritable defects (multiple pituitary hormone de!ciency or isolated central
hypothyroidism)
⚬ infective diseases
– tuberculosis
– mycoses
– syphilis
⚬ Reference - Eur Thyroid J 2018 Oct;7(5):225 full-text
Peripheral Hypothyroidism
● peripheral (extrathyroidal) hypothyroidism can be caused by 1
⚬ consumptive hypothyroidism due to inappropriate expression of the deiodinase 3
enzyme (which inactivates thyroid hormone) in tumor tissues
⚬ rare genetic syndromes that lead to a reduced sensitivity to thyroid hormone (for
example, mutations in MCT8, SECISBP2, THRA, or THRB)
Pathogenesis
● regulation of thyroid hormones
⚬ systemic regulation of thyroid hormone levels in circulation is achieved via a
negative feedback loop involving the hypothalamus, pituitary, and thyroid glands
– when thyroid hormone levels are low, the hypothalamus produces thyrotropin-
releasing hormone (TRH)
● TRH stimulates the pituitary gland to produce thyroid-stimulating hormone
(TSH)
● TSH stimulates follicular cells in the thyroid gland to produce more thyroid
hormones
– as thyroid hormone levels increase, production of TRH by the hypothalamus
decreases, ensuring thyroid hormone homeostasis
⚬ intracellular regulation of thyroid hormone levels involves
– control of thyroid hormone entry into cell by speci!c transmembrane transport
proteins, including monocarboxylate transporter 8 (MCT8)
– control of thyroid hormone metabolism by iodothyronine deiodinase enzymes
required for activation (converting T4 to T3) or inactivation (converting T4 to
reverse T3 or converting T3 to T2)
⚬ Reference - Biochim Biophys Acta 2013 Jul;1830(7):3987 full-text
● physiologic e$ects of thyroid hormones
⚬ thyroid hormones thyroxine (T4) and triiodothyronine (T3) circulate in blood and
induce physiologic actions including growth, metabolism, cardiac e$ects, and
central nervous system development
⚬ although T4 is the main hormone produced by the thyroid gland, T3 is the more
active hormone
⚬ binds thyroid hormone receptors to modulate target gene expression
– thyroid receptors are ligand-inducible transcription factors that bind speci!c
sequences in regulatory regions of target genes as a heterodimer with retinoid
X receptor, as a homodimer, or as a monomer
– in the absence of thyroid hormone, the heterodimer/homodimer recruits a
corepressor complex that represses basal transcription of the gene
– when T3 binds the thyroid receptor, the corepressor complex is displaced, and
transcriptional activators are recruited, which ultimately promotes transcription
of target genes
⚬ tissue-speci!c e$ects of thyroid hormone are mediated by di$erential expression
of 2 types of thyroid receptor alpha (TR-alpha, encoded by THRA gene) and thyroid
receptor beta (TR-beta, encoded by THRB gene); alternative splicing of each gene
produces 2 distinct proteins with di$erential expression in target tissues
– TR-alpha 1 is ubiquitously expressed and present at high levels in the central
nervous system, bone, skeletal muscle, gastrointestinal tract, and myocardium
– TR-alpha 2 is unable to bind thyroid hormones and its physiologic e$ects are
poorly understood; however, it is expressed in various tissues (for example,
brain and testis)
– TR-beta 1 is ubiquitously expressed and is the predominant isoform in liver and
kidney
– TR-beta 2 expression is limited to hypothalamus, pituitary, inner ear, and retina
⚬ References - Best Pract Res Clin Endocrinol Metab 2015 Aug;29(4):647 full-text
● pathogenesis of Hashimoto thyroiditis
⚬ environmental factors in genetically susceptible individuals injure thyrocytes (cells
lining thyroid follicles)
– when thyrocytes are damaged, they acquire new antigens or hidden epitopes
are exposed, activating major histocompatability complex (MHC) class II-
positive antigen presenting cells (APCs) including macrophages and dendritic
cells
– APCs present thyroid-speci!c antigens to lymphocytes in the lymph nodes,
resulting in clonal expansion of autoreactive B cells, CD4+ T cells, and CD8+
cytotoxic T cells
– autoreactive B and T cells accumulate in the thyroid, damaging thyroid
epithelial cells
– apoptosis of thyroid epithelial cells leads to Hashimoto thyroiditis
– Reference - Eur Rev Med Pharmacol Sci 2014;18(23):3611 full-text
⚬ see also Hashimoto Thyroiditis
●
Image 2 of 4
Hormone changes occurring during

development of primary hypothyroidism
In mild thyroid failure, the only detectable

abnormality is a mildly elevated serum TSH level.
Moderate hypothyroidism is characterized by further
elevation of serum TSH and a reduction in serum T4,
but the T3 level is relatively preserved by enhanced
T4 to T3 conversion. In severe hypothyroidism, the
TSH level is very high, the T4 level is further reduced,
and the serum T3 level becomes low. Abbreviation:
TSH, thyroid-stimulating hormone.
Used with permission from the American College of

Physicians.
Image 3 of 4
Hormone changes occurring during

development of central hypothyroidism
Because this disorder is due to impaired pituitary

TSH secretion, the serum TSH level does not rise and
thus there is no signal of mild thyroid failure. When
central hypothyroidism is moderate, the serum T4
level becomes low, the serum T3 level remains
normal and the serum TSH is low or low-normal.
Severe central hypothyroidism is characterized by
very low serum T4 level, low serum T3 level, and a
low or low-normal serum TSH level. Abbreviation:
TSH, thyroid-stimulating hormone.
Used with permission from the American College of

Physicians.
● in patients with hypothyroidism who are de!cient in endogenously produced thyroid

hormone 3
⚬ exogenous introduction of T4 as levothyroxine leads to T4 conversion into its
active metabolic T3
⚬ because thyroid hormone action a$ects many biological pathways, response is
measurable in almost all organ systems after administration of levothyroxine
History and Physical

Clinical Presentation
● may be asymptomatic, especially subclinical hypothyroidism 1
● symptoms are nonspeci!c, especially in older adults who present with fewer and less
classic signs and symptoms compared to younger patients 1
● typical symptoms of primary hypothyroidism 1 , 2
⚬ dry skin
⚬ cold sensitivity
⚬ fatigue
⚬ muscle cramps
⚬ voice changes
⚬ constipation
⚬ menstrual irregularities (menorrhagia, dysfunctional uterine bleeding, infertility)
⚬ lethargy
⚬ weight gain
⚬ slow mental activity with poor memory
⚬ apathy
⚬ hearing loss (middle ear myxedema)
⚬ decreased libido
● clinical presentation in patients with severe hypothyroidism
⚬ signs and symptoms may include 2
– carpal tunnel syndrome
– obstructive sleep apnea
– hyponatremia
⚬ rare presentations may include 1
– myxedema coma, which may present with altered mental status, hypothermia,
progressive lethargy, bradycardia, and multiple organ dysfunction
– pituitary hyperplasia with pituitary pathology (such as secondary adrenal
insu"ciency) and related symptoms (such as amenorrhea)
● clinical presentation in patients with central hypothyroidism
⚬ typical hypothyroid symptoms
⚬ comorbid or preexisting hypothalamic or pituitary disease
⚬ symptoms that suggest intracranial lesion (recurrent headache, visual defects)
⚬ abnormal !ndings on hypothalamus/pituitary imaging
⚬ exclusion of nonthyroid illness, Allan-Herndon-Dudley syndrome, and TRalpha1
mutations
⚬ Reference - J Clin Endocrinol Metab 2012 Sep;97(9):3068
● clinical manifestations of hypothyroidism may be observed in multiple organ
systems 1
Table 1. Clinical Presentation of Hypothyroidism According to Organ Systems
Organ System Symptoms Physical

Exam/Laboratory
Testing Results
General metabolism ⚬ Weight gain ⚬ Increase in body

⚬ Cold intolerance mass index
⚬ Fatigue ⚬ Low metabolic rate
⚬ Myxedema*
⚬ Hypothermia*
Cardiovascular ⚬ Exertional fatigue ⚬ Bradycardia

⚬ Shortness of breath ⚬ Hypertension
⚬ Diastolic
dysfunction*
⚬ Pericardial e$usion*
⚬ Electrocardiogram
changes*
⚬ Hyperlipidemia (total
cholesterol, low-
density lipoprotein)
⚬ Elevated
homocysteine*
Neurosensory ⚬ Hoarseness ⚬ Neuropathy

⚬ Impaired taste, ⚬ Cochlear dysfunction
vision, or hearing ⚬ Reduced olfactory
and gustatory
sensitivity
Neurological and ⚬ Memory loss ⚬ Impaired cognitive

psychiatric ⚬ Paresthesia function
⚬ Impaired mood ⚬ Delayed relaxation of
tendon re#exes
⚬ Depression*
⚬ Dementia*
⚬ Ataxia*
⚬ Carpal tunnel
syndrome and other
nerve entrapment
syndromes*
⚬ Myxedema coma*
Gastrointestinal Constipation ⚬ Reduced esophageal

motility
⚬ Nonalcoholic fatty
liver disease*
⚬ Ascites (very rare)
Reproductive - female ⚬ Infertility ⚬ Goiter

⚬ Menstrual ⚬ Abnormal glucose
disturbance metabolism
⚬ Galactorrhea ⚬ Increased prolactin
⚬ Pituitary
hyperplasia*
Reproductive - male ⚬ Decreased libido ⚬ Reduced

⚬ Erectile dysfunction testosterone level
⚬ Delayed ejaculation ⚬ Impaired
⚬ Poor semen quality spermatogenesis
Respiratory ⚬ Shortness of breath ⚬ Depressed hypoxic

⚬ Upper airway respiratory drive
obstruction ⚬ Depressed
⚬ Hypoventilation ventilatory response
⚬ Sleep apnea to hypercapnia
⚬ Pleural e$usion
⚬ Pulmonary
hypertension
⚬ Respiratory failure
Musculoskeletal ⚬ Muscle weakness ⚬ Elevated creatine

⚬ Muscle cramps phosphokinase
⚬ Arthralgia ⚬ Ho$man syndrome*
Hemostasis and ⚬ Bleeding ⚬ Mild anemia

hematological ⚬ Fatigue ⚬ Acquired von
Willebrand disease*
Skin and hair ⚬ Dry skin ⚬ Coarse skin

⚬ Hair loss ⚬ Loss of lateral
eyebrows*
⚬ Yellow palms*
⚬ Alopecia areata*
Electrolytes and kidney Reduced kidney ⚬ Decreased estimated

function function glomerular !ltration
rate
⚬ Hyponatremia* (due
to reduced free
water clearance)
* Uncommon presentation.
Reference - Lancet 2017 Sep 23;390(10101):1550 full-text , Thyroid 2016

Nov;26(11):1519 , J Assoc Physicians India 2017 Aug;65(8):68 , Endocr Pract 2012
Nov;18(6):988 , Asian Pac J Reprod 2019 May;8:203 .
History
History of Present Illness (HPI)
● increase in severity of (change of 7 or more) symptoms in past year reported to
increase likelihood of hypothyroidism 1
Medication History
● ask about use of medications associated with thyroid dysfunction, including 1
⚬ iodine
⚬ amiodarone (contains iodine)
⚬ lithium
⚬ tyrosine kinase inhibitors (such as sunitinib)
⚬ interferon-alfa
⚬ thalidomide
⚬ monoclonal antibodies (such as ipilimumab and nivolumab)
⚬ antiseizure medications (such as valproate)
⚬ second-line drugs for multidrug-resistant tuberculosis (such as ethionamide and
prothionamide)
Past Medical History (PMH)

● ask about 1 , 2
⚬ radiation therapy for head/neck cancers, including lymphoma
⚬ thyroid surgery
⚬ other autoimmune disorders that can occur in patients with autoimmune
thyroiditis and hypothyroidism
– pernicious anemia
– diabetes mellitus type 1
– autoimmune gastric atrophy
– vitiligo
– alopecia
– celiac disease
– adrenocortical insu"ciency (Addison disease)
– systemic lupus erythematosus (SLE)
– autoimmune hypophysitis
– primary biliary cirrhosis (PBC)
– multiple autoimmune endocrinopathies (MAEs); also called autoimmune
polyendocrine syndromes
⚬ history of head trauma
⚬ genetic conditions, such as
– Down syndrome
– Turner syndrome
Physical
General Physical
● general metabolic signs may include 1
⚬ increase in body mass index
⚬ low metabolic rate
⚬ hypothermia
Skin
● look for 1
⚬ coarse or dry skin
⚬ yellow palms (uncommon)
⚬ alopecia areata (uncommon)
HEENT
● assess for
⚬ hair loss, including loss of lateral eyebrows 1
⚬ periorbital edema (Am Fam Physician 2012 Aug 1;86(3):244 )
Image 4 of 4
Brittle nails and hair loss in hypothyroidism
(A) Dry skin, thickened and brittle nails with

horizontal ridges. (B) Marked hair loss with coarse
hair. Five years following treatment, nail changes (C)
and hair loss (D) resolve.
© 2018 Massachusetts Medical Society. All rights reserved.

Used with permission.
Neck
● goiter may or may not be present 2
Cardiac
● signs may include 1
⚬ bradycardia
⚬ hypertension
Lungs
● respiratory manifestations can develop in patients with severe hypothyroidism and
myxedema coma, including
⚬ hypoventilation resulting from depression of respiratory drive
⚬ respiratory failure resulting from reduced sensitivity of central nervous system to
hypoxia and hypercapnia
⚬ pleural e$usion and swelling resulting from impacted vascular permeability
⚬ Reference - J Assoc Physicians India 2017 Aug;65(8):68
Extremities
● pseudo hypertrophy of muscles (Ho$mann syndrome) is a rare presentation 1
● nonpitting edema has been reported (BMJ 2008 Jul 28;337:a801 )
Neuro
● assess for neurologic and psychiatric manifestations, including 1
⚬ impaired cognitive function
⚬ rare signs
– depression
– dementia
– ataxia
● in severe cases, may present with signs of carpal tunnel syndrome (pain, burning,
tingling, and/or paresthesias in the distribution of the median nerve distal to the
wrist) and other nerve entrapment syndromes 1 , 3
Diagnosis
Making the Diagnosis
● diagnosing primary hypothyroidism
⚬ suspect primary hypothyroidism in patients (especially older adults and women)
who present with typical symptoms of hypothyroidism, which may include 1 , 2
– dry skin
– cold sensitivity
– fatigue
– muscle cramps
– voice changes
– constipation
– menstrual irregularities (menorrhagia, dysfunctional uterine bleeding, infertility)
– lethargy
– weight gain
– decreased libido
⚬ the diagnosis of overt primary hypothyroidism is con!rmed by blood tests
showing
– elevated thyroid-stimulating hormone (TSH), often > 10 milliunits/L 4
– low serum free thyroxine (FT4) 1
⚬ the diagnosis of subclinical primary hypothyroidism (which is typically
asymptomatic or mildly symptomatic) is con!rmed by blood tests showing 1
– elevated TSH
– normal serum FT4
⚬ primary hypothyroidism in pregnancy is de!ned as TSH elevated above normal
limit of trimester-speci!c reference range (ATA Strong recommendation, High-
quality evidence) 4
● diagnosing central hypothyroidism
⚬ suspect central hypothyroidism in patients with signs and symptoms consistent
with primary hypothyroidism plus !ndings associated with hypothalamic or
pituitary de!ciency, such as menstrual disturbances, galactorrhea, or infertility 1
⚬ the diagnosis of central (secondary and tertiary) hypothyroidism is usually
con!rmed by blood tests showing low to normal TSH and low serum FT4 1 , 2
– in some cases of central hypothyroidism with nonfunctioning pituitary
adenomas, TSH may be mildly elevated 2
– diagnosis of mild central hypothyroidism (borderline low FT4 and low TSH) may
require additional blood tests and imaging studies 1
Di!erential Diagnosis
● nonthyroidal illness syndrome (also known as euthyroid sick syndrome) 1 , 2
⚬ abnormalities in thyroid-stimulating hormone (TSH) or thyroid hormone levels in
ill patients in the absence of known underlying thyroid disease
⚬ associated with acute, severe systemic illness
⚬ common pattern is low total and free triiodothyronine (T3)
⚬ TSH level may be low (rarely undetectable) in the acute setting, and is often
increased transiently during illness recovery
● euthyroid hypothyroxinemia (reduced total serum thyroxine [T4] with normal serum
TSH and no clinical features of thyroid dysfunction)
⚬ free T4 levels are usually normal
⚬ can be caused by
– thyroid hormone replacement using only exogenous T3 (Biomed Pharmacother
2016 Dec;84:655 )
– T4 displacement from binding proteins due to the use of certain medications,
including
● salicylates (Clin Chim Acta 1993 Dec 31;223(1-2):159 )
● high-dose furosemide in patients with chronic kidney disease (J Clin
Endocrinol Metab 1985 May;60(5):1025 )
– hereditary de!ciency in thyroxine-binding globulin (TBG) (J Clin Endocrinol
Metab 2002 Mar;87(3):1045 )
– hormonal excess resulting in a fall in serum TBG levels, which can result from
● use of glucocorticoids (J Clin Endocrinol Metab 1966 Jul;26(7):715 )
● use of high-dose androgens (Ann Intern Med 1994 Aug 15;121(4):247 )
● acromegaly (Med Clin North Am 1985 Sep;69(5):863 )
● Cushing syndrome (Med Clin North Am 1985 Sep;69(5):863 )
– nephrotic syndrome (Am J Nephrol 1982;2(2):70 )
– medications which lower serum TBG levels, such as
● L-asparaginase (N Engl J Med 1979 Aug 2;301(5):252 )
● danazol (Obstet Gynecol 1980 Mar;55(3):395 )
● nicotinic acid (Mayo Clin Proc 1995 Jun;70(6):556 )
● other causes of similar symptoms 1 , 2
⚬ anemia
⚬ pregnancy (low TSH levels during !rst trimester)
● other causes of increased TSH level 1
⚬ human antianimal antibodies
⚬ thyroid in!ltration
⚬ assay interference
⚬ nonadherence to levothyroxine therapy
⚬ thyroid hormone resistance
⚬ nonfunctioning pituitary adenomas 2
⚬ adrenal insu"ciency 2
⚬ thyrotropinomas
⚬ use of certain medications
– heparin
– metoclopramide
– chlorpromazine
– haloperidol
– amiodarone
– lithium
Testing Overview
● routine testing of thyroid function in critically ill patients is not recommended, and
testing should be reserved for patients with clinically suspected thyroid disorder
(AACE/ATA Grade A, Level 2) 1 , 2
● perform blood tests to assess thyroid function in all patients (including pregnant
women) with clinically suspected thyroid disorder
⚬ measure thyroid-stimulating hormone (TSH) as the initial test in most patients
⚬ measure free thyroxine (FT4) if central hypothyroidism is suspected or if TSH
results are abnormal
⚬ assessment of total or free triiodothyronine (T3) is not recommended to diagnose
hypothyroidism as levels are often normal, even in severe hypothyroidism
(AACE/ATA Grade A, Level 2)
● assessment of anti-thyroid peroxidase antibodies (TPOAb) may be performed in
select cases
⚬ evaluate thyroid peroxidase antibody (TPOAb) status in all pregnant women with
elevated TSH (if not already known)
⚬ consider in nonpregnant patients with
– suspected subclinical hypothyroidism (AACE/ATA Grade B, Level 1)
– suspected autoimmune thyroid disease (AACE/ATA Grade D, Level 4)
– recurrent miscarriage, with or without infertility (AACE/ATA Grade A, Level 2)
Blood Tests
Thyroid-Stimulating Hormone (TSH)
● TSH is the primary diagnostic test for suspected thyroid dysfunction, including in
pregnant women 1
● TSH level does not necessarily correlate with severity of clinical symptoms (BMJ 2003
Feb 8;326(7384):311 full-text )
● reference ranges in nonpregnant populations
⚬ reference ranges for normal TSH vary widely and are dependent on the
population studied and the assay used 3
– most commonly used reference range in nonpregnant adults is 0.5-4
milliunits/L, but can be as high as 4.5 milliunits/L
– in older adults (aged > 70 years), reference range may extend to 4-6 milliunits/L
⚬ reference range of a given laboratory should determine upper limit of normal for
third-generation TSH assay (AACE/ATA Grade A, Level 1) 2
● hypothyroidism with normal TSH can occur with 2
⚬ central hypothyroidism
⚬ use of certain medications, including dopamine or steroids
⚬ nonthyroidal illness in critically ill patients
● American Society for Clinical Pathology recommends against ordering multiple tests
in the initial evaluation of a patient with suspected thyroid disease, and instead
recommends ordering TSH and, if abnormal, following up with additional evaluation
or treatment depending on !ndings (Choosing Wisely 2015 Feb 3)
Thyroid Hormones
Thyroxine (T4)
● measure free T4 if central hypothyroidism is suspected, or if TSH levels are
abnormal 1
● reference range varies according to assay and population but are usually between
0.7 and 1.94 ng/dL (9-25 pmol/L) (Circulation 2017 Nov 28;136(22):2100 full-text )
● American Association of Clinical Endocrinologists/American Thyroid Association
(AACE/ATA) recommendations for assessment of serum free T4 in patients with
suspected thyroid disorder 2
⚬ measurement of serum free T4 (active, nonprotein-bound form) recommended
instead of total T4 in evaluation of hypothyroidism (AACE/ATA Grade A, Level 1) 2
⚬ in nonpregnant patients, assessment of serum free T4 includes free T4 index or
free T4 estimate and direct immunoassay of free T4 without physical separation
using anti-T4 antibody (AACE/ATA Grade A, Level 1)
⚬ in patients with suspected central hypothyroidism, use free T4 or free T4 index,
and not TSH, to con!rm the diagnosis and guide treatment of hypothyroidism
(AACE/ATA Grade A, Level 1)
● total T4 is less reliable than free T4 as it may be a$ected by changes in thyroxine
binding globulin (TBG) concentration 3
⚬ drugs or conditions that may increase TBG concentration include
– pregnancy
– estrogens (including oral contraceptives with estrogen) and selective estrogen
receptor modulators (SERMs)
– hepatitis
– methadone
– #uorouracil
– mitotane
– perphenazine
– porphyria
– congenital elevated TBG
⚬ drugs or conditions that may decrease TBG concentration include
– androgens
– high-dose steroids
– severe illness
– nephrotic syndrome
– cirrhosis
– asparaginase
– niacin
– congenital TBG de!ciency
⚬ inhibitors of binding of TBG to T4 include
– salicylates
– furosemide
– phenytoin
– free fatty acids
– heparin
– carbamazepine
– nonsteroidal anti-in#ammatory drugs (NSAIDs)
Triiodothyronine (T3)
● assessment of total or free T3 is not recommended to diagnose hypothyroidism
(AACE/ATA Grade A, Level 2) 2
● serum T3 levels are often normal, even in severe hypothyroidism, due to 2
⚬ high levels of TSH resulting in hyperstimulation of remaining functioning thyroid
tissue
⚬ upregulation of type 2 iodothyronine deiodinase
● T3 levels can be low in absence of thyroid disease in patients with severe illness 2
Thyroid Antibodies
● autoimmune thyroid disease may occur with elevated antithyroid antibody titers
including 2
⚬ anti-thyroid peroxidase antibodies (TPOAb)
⚬ TSH receptor antibodies (TSHRAbs, also called thyrotropin receptor antibodies
[TRAb]), which may act as
– TSH agonist - thyroid-stimulating immunoglobulin (TSI)
– TSH antagonist - thyrotropin binding inhibitory immunoglobulin (TBII)
⚬ anti-thyroglobulin antibody (TgAb)
● guideline organization recommendations di$er regarding testing for anti-thyroid
peroxidase antibodies (TPOAb)
⚬ AACE/ATA recommends considering TPOAb testing for 2
– evaluating patients with subclinical hypothyroidism as presence of TPOAb titers
are associated with progression to overt hypothyroidism (AACE/ATA Grade B,
Level 1)
– identifying autoimmune thyroiditis when nodular thyroid disease is suspected
to be due to autoimmune thyroid disease (AACE/ATA Grade D, Level 4)
⚬ Canadian Society of Endocrinology and Metabolism recommends against routinely
testing for TPOAb
– positive TPOAb titers are not unusual in a healthy population
– presence of positive TPOAb titers, in the context of thyroid disease, only assists
in indicating that the pathogenesis is probably autoimmune
– as thyroid autoimmunity is a chronic condition, once diagnosed there is rarely a
need to remeasure TPOAb titers
– it is uncommon that measurement of TPOAb in#uences patient management
– Reference - Choosing Wisely Canada 2014 Oct 29
Other Blood Tests

● for assessment of central hypothyroidism, consider assessment of the following
⚬ prolactin
⚬ adrenocorticotropic hormone (ACTH) and/or ACTH stimulation
⚬ gonadotropin levels in postmenopausal women and men (normal menstruation
indicates normal gonadotropin secretion)
⚬ response to TSH-releasing hormone (TRH) (not available in the United States)
⚬ Reference - BMJ 2008 Jul 28;337:a801
⚬ see also Hypopituitarism
● creatine phosphokinase (a cardiac biomarker) may be elevated in patients with
hypothyroidism but is not used for diagnosis 1
● cholesterol levels and muscles enzymes should not be used to diagnose
hypothyroidism (AACE/ATA Grade B, Level 2) 2
● tissue biomarkers of thyroid hormone action 3
⚬ tissue biomarkers of thyroid hormone action under investigation include sex
hormone-binding globulin (SHBG), osteocalcin, urinary N-telopeptides (NTX), total
cholesterol, low-density lipoprotein (LDL) cholesterol, lipoprotein(a), creatine
kinase, ferritin, myoglobin, tissue plasminogen enzyme level, angiotensin-
converting enzyme (ACE) level, and glucose 6-phosphate dehydrogenase enzyme
level
⚬ tissue biomarkers of thyroid hormone action are not recommended for clinical
use outside of research setting (ATA Weak recommendation, Low-quality evidence)
⚬ in patients with secondary hypothyroidism in whom the only available biochemical
thyroid parameters are thyroid hormone levels, tissue markers of thyroid
hormone action may be used as an adjunctive means of judging adequacy of
levothyroxine replacement (ATA Weak recommendation, Low-quality evidence)
● genetic testing (for type 2 deiodinase gene polymorphisms) not recommended for
selecting patients for combination treatment with levothyroxine and liothyronine
(ATA Strong recommendation, Moderate-quality evidence) 3
Imaging Studies
● imaging studies are rarely needed in patients with suspected hypothyroidism, but
thyroid ultrasound may be used to assess for nodules in patients with abnormal
thyroid palpation 1
● for central hypothyroidism, consider imaging of pituitary to rule out tumor or other
lesion (see also Hypopituitarism)
● professional associations recommending against routinely ordering a thyroid
ultrasound in patients with abnormal thyroid function tests (unless there is a
palpable abnormality of the thyroid gland) include
⚬ Endocrine Society (Choosing Wisely 2013 Oct 16)
⚬ Canadian Society of Endocrinology and Metabolism (Choosing Wisely Canada 2014
Oct 29)
⚬ Endocrine Society of Australia (Choosing Wisely Australia 2016 Mar 1)
Other Diagnostic Testing

● in patients with levothyroxine dose requirements that are much higher than
expected, consider evaluation for gastrointestinal disorders, such as (ATA Strong
recommendation, Moderate-quality evidence) 3
⚬ Helicobacter pylori-related gastritis
⚬ atrophic gastritis
⚬ celiac disease
Management
Management Overview
● thyroid hormone replacement therapy is the recommended treatment for patients
with hypothyroidism
⚬ levothyroxine (LT4) monotherapy is recommended treatment for patients with
hypothyroidism (ATA Strong recommendation, Moderate-quality evidence) in
preference over liothyronine, combination of synthetic levothyroxine and
liothyronine, or animal thyroid extracts
⚬ indications for levothyroxine
– treat all patients with overt hypothyroidism (including pregnant women) with
levothyroxine treatment (ATA Strong recommendation, Moderate-quality
evidence)
– for nonpregnant patients with subclinical hypothyroidism, consider treatment
with levothyroxine if serum thyroid-stimulating hormone (TSH) levels > 10
milliunits/L due to increased risk for heart failure and cardiovascular mortality
(AACE/ATA Grade B, Level 1)
– for pregnant women with subclinical hypothyroidism
● American Thyroid Association (ATA) recommends thyroid hormone
replacement for women with
⚬ positive thyroid peroxidase antibodies (TPOAb) titers and TSH greater
than trimester-speci!c reference range (ATA Strong recommendation,
Moderate-quality evidence)
⚬ negative TPOAb titers and TSH > 10 milliunits/L (ATA Strong
recommendation, Low-quality evidence)
● consider thyroid hormone replacement for women with
⚬ positive TPOAb titers and TSH > 2.5 milliunits/L and below upper limit of
trimester-speci!c reference range (ATA Weak recommendation,
⚬ negative TPOAb titers and TSH greater than the trimester-speci!c
reference range but < 10 milliunits/L (ATA Weak recommendation, Low-
quality evidence)
● levothyroxine formulations
⚬ consistent use of a single, identi!able formulation of levothyroxine (brand-name
or generic) is recommended in patients who are frail, pregnant, or have high-risk
thyroid cancer (ATA Strong recommendation, Low-quality evidence)
⚬ consider consistent use of a single, identi!able formulation of levothyroxine
(brand-name or generic) in all other patients (ATA Weak recommendation, Low-
quality evidence)
⚬ measure TSH levels at steady state after any change in formulation (ATA Weak
● levothyroxine dosing
⚬ in young, healthy adults with overt hypothyroidism, consider starting with full
replacement dose (1.6 mcg/kg/day, or 100-125 mcg/day orally in typical adults)
⚬ in patients with subclinical hypothyroidism, consider lower starting doses (25-75
mcg/day orally) (AACE/ATA Grade B, Level 2)
⚬ levothyroxine should be consistently taken 60 minutes before breakfast, or ≥ 3
hours after evening meal to maximize absorption (ATA Weak recommendation,
⚬ careful titration of levothyroxine is required to avoid iatrogenic thyrotoxicosis
(subnormal TSH levels, especially < 0.1 milliunits/L) and reduce risk for atrial
!brillation and osteoporosis, especially in older patients and postmenopausal
women (ATA Strong recommendation, Moderate-quality evidence)
● follow-up
⚬ assess serum TSH 4-6 weeks after any dose change (ATA Strong recommendation,
⚬ after adequate replacement dose has been determined, measure TSH levels after
6 months and then at 12-month intervals, or more frequently based on clinical
situation (AACE/ATA Grade B, Level 2)
⚬ target TSH range should be normal range of third-generation TSH assay, generally
0.45-4.12 milliunits/L (AACE/ATA Grade B, Level 2)
⚬ for women being treated for hypothyroidism during pregnancy, consider a target
TSH goal in lower half of trimester-speci!c reference range (or < 2.5 milliunits/L if
not available) (ATA Weak recommendation, Moderate-quality evidence)
Medications
Indications for Thyroid Hormone Replacement Therapy
● indications for thyroid hormone replacement
⚬ treat all patients with overt hypothyroidism (including pregnant women) with
levothyroxine treatment (ATA Strong recommendation, Moderate-quality
evidence) 3
⚬ for nonpregnant patients with subclinical hypothyroidism, consider treatment with
levothyroxine if serum thyroid-stimulating hormone [TSH] levels > 10 milliunits/L
due to increased risk for heart failure and cardiovascular mortality (AACE/ATA
Grade B, Level 1) 2
⚬ in hospitalized but not critically ill patients who are about to be treated with
levothyroxine, consider possibility of adrenal insu"ciency (ATA Strong
recommendation, Low-quality evidence) 3
⚬ patients with untreated adrenal insu"ciency may have elevated TSH, but defer
diagnosis of hypothyroidism until after starting treatment because TSH may
normalize with glucocorticoid replacement therapy 2
● American Thyroid Association (ATA) recommends against levothyroxine for
management of symptoms of hypothyroidism in patients with normal thyroid
function, including 3
⚬ routine use of levothyroxine treatment in patients who have nonspeci!c
symptoms and normal biochemical indices of thyroid function (ATA Strong
recommendation, High-quality evidence)
⚬ routine use of levothyroxine for treatment of euthyroid patients with depression,
due to a paucity of controlled e"cacy data (ATA Weak recommendation, Low-
quality evidence)
⚬ treatment of obesity with levothyroxine in euthyroid patients, due to lack of
treatment e"cacy (ATA Strong recommendation, Moderate-quality evidence)
⚬ treatment of urticaria with levothyroxine in euthyroid patients, due to lack of
treatment e"cacy (ATA Strong recommendation, Moderate-quality evidence)
⚬ use of levothyroxine for hospitalized patients experiencing critical illness
exhibiting “nonthyroidal illness syndrome,” due to safety concerns and limited
evidence not showing signi!cant clinical bene!t (ATA Strong recommendation,
● see Thyroid Replacement Therapy for additional information
Preparations Recommended for Routine Management of Hypothyroidism

● ATA recommendations for preparations for routine management of hypothyroidism 3
⚬ levothyroxine (LT4) monotherapy is recommended treatment for patients with
hypothyroidism (ATA Strong recommendation, Moderate-quality evidence) in
preference over liothyronine, combination of synthetic levothyroxine and
liothyronine, or animal thyroid extracts
⚬ consistent use of a single, identi!able formulation of levothyroxine is
recommended in patients who are frail, pregnant, or have high-risk thyroid cancer
(ATA Strong recommendation, Low-quality evidence)
⚬ consider consistent use of a single, identi!able formulation of levothyroxine in all
other patients (ATA Weak recommendation, Low-quality evidence)
● oral tablets are the preferred formulation of levothyroxine 1
Agents and Preparations Not Recommended for Routine Management of

Hypothyroidism
● ATA recommends against alternative treatments for routine clinical use in
management of hypothyroidism, including 3
⚬ liothyronine (synthetic, active form of thyroid hormone T3) monotherapy (ATA
Strong recommendation, Moderate-quality evidence)
⚬ levothyroxine and liothyronine combination therapy (ATA Weak recommendation,
⚬ thyroid extracts (ATA Strong recommendation, Moderate-quality evidence)
⚬ thyroid analogs (ATA Strong recommendation, Low-quality evidence)
● no randomized trials found evaluating Chinese herbal medicine (alone or in
combination with thyroid hormone therapy) in patients with hypothyroidism based
on Cochrane review (Cochrane Database Syst Rev 2015 Feb 12;(2):CD008779 )
Management of Overt Primary Hypothyroidism

● levothyroxine (LT4) monotherapy is the recommended treatment for overt primary
hypothyroidism (ATA Strong recommendation, Moderate-quality evidence) 3
⚬ goals for levothyroxine replacement include (ATA Strong recommendation,
– resolve patient's symptoms, including biological and physiological markers
– normalize serum concentrations of thyroid-stimulating hormone (TSH) and
thyroid hormone
– avoid overtreatment, especially in older adults
⚬ timing and frequency of administration
– it is recommended that levothyroxine be consistently taken 60 minutes before
breakfast, or ≥ 3 hours after evening meal to maximize absorption (ATA Weak
recommendation, Moderate-quality evidence)
– if adherence cannot be maintained with daily levothyroxine dosing, consider
weekly oral administration of full week’s dose of levothyroxine (ATA Weak
⚬ levothyroxine absorption can be a$ected by certain drugs, foods (such as co$ee),
and coexisting gastrointestinal disorders
– levothyroxine dosing should be separated from other potentially interfering
medications and supplements (such as calcium carbonate and ferrous sulfate)
(ATA Weak recommendation, Low-quality evidence); 4-hour separation is
traditional, but untested
– if levothyroxine dose required is much higher than expected, evaluate for
gastrointestinal disorders such as Helicobacter pylori-related gastritis, atrophic
gastritis, or celiac disease; if such disorders are detected and e$ectively treated,
reevaluate thyroid function and levothyroxine dose (ATA Strong
– see Levothyroxine and Thyroid Replacement Therapy for additional information
on factors that may a$ect levothyroxine absorption and requirements
● initiating and monitoring levothyroxine therapy
⚬ factors to consider when determining levothyroxine starting dose include (ATA
Strong recommendation, Moderate-quality evidence) 3
– patient's weight and lean body mass (dose requirement increases with
increasing weight, particularly lean body mass)
– age (dose requirement typically decreases with increasing age)
– pregnancy status (dose requirement typically increases in !rst trimester of
pregnancy)
– etiology of hypothyroidism (patients with Hashimoto [autoimmune] thyroiditis
may require lower levothyroxine dose than patients who are athyreotic as a
consequence of thyroidectomy)
– degree of elevation in serum TSH
– general clinical context such as presence of cardiac disease
– serum TSH goal appropriate for clinical situation
⚬ start with full replacement dose or partial replacement dose, with gradual upward
adjustments using appropriate serum TSH target as therapeutic goal (ATA Strong
recommendation, Moderate-quality evidence) 3
– adjust doses when there are large changes in body weight, with aging, or during
pregnancy, or when starting or stopping medications which alter thyroxine-
binding globulin (TBG) levels
– assess serum TSH 4-6 weeks after any dose change (ATA Strong
– generally, dose adjustments of 12.5-25 mcg/day (either up or down) are made
depending on serum TSH after initial dose
⚬ after adequate replacement dose has been determined, measure TSH levels after
6 months and then at 12-month intervals, or more frequently based on clinical
situation (AACE/ATA Grade B, Level 2) 2
⚬ initial dosing of levothyroxine for management of hypothyroidism in adults
Table 2. Starting Oral Levothyroxine Doses Based on Age, Physiological, and

Pathological Conditions
Age/Condition Starting Levothyroxine Dose
Young, otherwise-healthy adults with – 1.6-1.8 mcg/kg/day

primary hypothyroidism
Adults with mild hypothyroidism (TSH – 25-75 mcg/day, depending on

≤ 10 milliunits/L) degree of TSH elevation
– Further adjustments should be
guided by clinical response and
follow-up laboratory
determinations including TSH
values
Older adults (> 65 years old) – 25-50 mcg/day with 12.5-25

mcg/day incremental dose every
4-6 weeks
– Many experts recommend
starting older adults with low
dose, but may not be necessary
in older adults without
cardiovascular disease
Very old patients (> 80 years old) – 12.5-25 mcg/day with 12.5-25
4-6 weeks based on follow-up
TSH level
Patients with coronary heart disease – 12.5-25 mcg/day with 12.5

4-6 weeks based on symptoms
and serum TSH levels
Pregnancy – For women with preexisting

hypothyroidism, dose increase of
20%-30% (achieved by taking 2
additional tablets weekly)
recommended upon
con!rmation of pregnancy (ATA
Strong recommendation, High-
quality evidence)
– For overt hypothyroidism
discovered during pregnancy, full
dose suggested (2-2.4
mcg/kg/day orally)
Central hypothyroidism – Estimated starting dose 1.3

mcg/kg/day for adults and
children
Patients with cirrhosis or renal failure – No dose adjustment necessary
Abbreviation: TSH, thyroid-stimulating hormone.
Reference - Thyroid 2012 Dec;22(12):1200 , Thyroid 2014 Dec;24(12):1670 , Endocr

Rev 2014 Jun;35(3):433 .
● dose adjustment and other management

⚬ avoid excess or inadequate levothyroxine 3
– avoid excessive levothyroxine to prevent iatrogenic thyrotoxicosis (subnormal
TSH levels, especially < 0.1 milliunits/L), especially in older patients and
postmenopausal women, to reduce risk of atrial !brillation and osteoporosis
(ATA Strong recommendation, Moderate-quality evidence)
– use levothyroxine doses adequate to normalize serum TSH levels to avoid
adverse e$ects of thyroid hormone de!ciency including progression of
cardiovascular disease and detrimental e$ects on serum lipid pro!le(ATA
⚬ for unresolved symptoms despite normal TSH levels, consider evaluation of
alternative causes (ATA Weak recommendation, Low-quality evidence) 3
● in rare case of putative allergies to excipients, consider switching from usual tablet
formulation to oral gel capsule (ATA Weak recommendation, Low-quality evidence) 3
⚬ oral gel preparations consist of gelatin capsules (for example, Tirosint) containing
levothyroxine dissolved in glycerin; they do not contain excipients and dyes found
in standard levothyroxine preparations 3
⚬ small preliminary studies suggest possible better absorption in selected
circumstances such as concomitant use of proton pump inhibitors or concomitant
co$ee consumption, but insu"cient data to support a recommendation for such
use 3
STUDY
⚬ SUMMARY
liquid levothyroxine may be more e!ective than tablet levothyroxine for
reducing thyroid-stimulating hormone levels in patients with malabsorption
DynaMed Level 3
META-ANALYSIS: Endocrine 2018 Jul;61(1):28

Details
– based on nonclinical outcomes in systematic review of observational studies
– systematic review of 8 cohort studies comparing liquid vs. tablet (LT4) in 295
patients on thyroid hormone suppressive or replacement therapy in Italy
– compared to LT4 tablet formulation, liquid LT4 was associated with greater
reduction in TSH levels in patients with malabsorption taking
● LT4 suppressive therapy (mean di$erence [MD]) -2.26, 95% CI -3.59 to -0.93)
in analysis of 2 studies with 16 patients
● LT4 replacement therapy (MD -3.2, 95% CI -5.08 to -1.32) in analysis of 7
studies with 79 patients, results limited by signi!cant heterogeneity
– no signi!cant di$erence in reduction of TSH levels comparing liquid and tablet
LT4 in patients without malabsorption having either suppressive or
replacement therapy
– Reference - Endocrine 2018 Jul;61(1):28
● therapeutic endpoint
⚬ serum TSH level is the most reliable therapeutic endpoint for the treatment of
primary hypothyroidism 2
⚬ manage patients with overt hypothyroidism with adequate doses of levothyroxine
to normalize TSH levels, in order to reduce or eliminate adverse e$ects of thyroid
de!ciency (such as detrimental e$ects on serum lipids and progression of
cardiovascular disease) (ATA Strong recommendation, Moderate-quality
evidence) 3
⚬ de!ning normal TSH levels 2
– use TSH reference range of a given laboratory to determine upper limit of
normal for third-generation TSH assay (AACE/ATA Grade A, Level 1)
– normal TSH reference range changes with age
– if age-based upper limit of normal for third-generation TSH assay is not
available in iodine-su"cient area, consider upper limit of normal of 4.12
milliunits/L and lower limit of normal of 0.45 milliunits/L (AACE/ATA Grade B,
Level 2)
– if lower limit of normal is not available, consider using lower limit of normal of
0.45 milliunits/L (AACE/ATA Grade B, Level 2)
⚬ in nonpregnant patients, evidence does not support targeting a speci!c TSH level
within normal reference range (AACE/ATA Grade B, Level 2) 2
⚬ in patients with hypothyroidism and overweight or have depression or
dyslipidemia, insu"cient evidence of bene!t to recommend treatment targets of
low-normal TSH or high-normal T3 values (ATA Strong recommendation,
Moderate-quality evidence) 3
⚬ insu"cient evidence of bene!t to recommend that levothyroxine treatment be
targeted to achieve low-normal TSH levels or high-normal T3 values in patients
who are athyreotic (ATA Strong recommendation, Moderate-quality evidence) 3
STUDY
⚬ SUMMARY
targeting low-normal, high-normal, or mildly elevated TSH levels associated
with similar health, mood, and cognitive outcomes DynaMed Level 2
RANDOMIZED TRIAL: J Clin Endocrinol Metab 2018 May 1;103(5):1997 | Full Text
Details
– based on randomized trial with unclear method of randomization
– 151 adult patients with hypothyroidism, stable levothyroxine dose for ≥ 3
months, and normal TSH levels were randomized to 1 of 3 TSH ranges
● low-normal TSH (0.34-2.5 milliunits/L)
● high-normal TSH (2.51-5.6 milliunits/L)
● mildly elevated TSH (5.61-12 milliunits/L)
– levothyroxine doses were adjusted every 6 weeks based on TSH levels until TSH
was in target range and were followed for 6 months
– no signi!cant di$erences in health status, mood, or cognitive outcomes among
the 3 groups
– Reference - J Clin Endocrinol Metab 2018 May 1;103(5):1997 full-text
● in some patients, thyroid hormone replacement therapy (levothyroxine

monotherapy) may not relieve all symptoms, even if serum thyroid stimulating
hormone levels are normalized (Hormones (Athens) 2018 Dec;17(4):491 full-text )
● certain patients with overt hypothyroidism require additional considerations,
including
⚬ pregnant women
⚬ older adults
⚬ patients on enteral nutrition
⚬ surgical patients
Management of Subclinical Primary Hypothyroidism

● decision to treat patients with subclinical hypothyroidism (SCH) is controversial as
treatment is reported to improve surrogate markers of disease but not clinical
outcomes 3
(AACE/ATA) recommendations for treating subclinical hypothyroidism 2
⚬ decision to treat subclinical hypothyroidism may vary by thyroid-stimulating
hormone (TSH) level
– TSH > 10 milliunits/L - general agreement that patients should be treated
– TSH 4.5-10 milliunits/L - uncertain which patients will bene!t from treatment
– TSH 2.4-4.5 milliunits/L - there is very little evidence to support treatment
except possibly for thyroid peroxidase antibody (TPOAb)-positive women during
pregnancy
⚬ if decision is made to treat subclinical hypothyroidism (AACE/ATA Grade B, Level 2)
– initial levothyroxine (LT4) dosing generally lower than what is required in
treatment of overt hypothyroidism
– consider levothyroxine 25-75 mcg/day, depending on degree of TSH elevation
– make further dose adjustments based on clinical response and follow-up labs,
including TSH level
EVIDENCE SYNOPSIS
Levothyroxine therapy does not appear to improve thyroid-related symptoms or

quality of life in nonpregnant adults with subclinical hypothyroidism.
STUDY
⚬ SUMMARY
thyroid hormone replacement therapy may not improve overall quality of life
or thyroid-related symptoms in adults with subclinical hypothyroidism
DynaMed Level 2
SYSTEMATIC REVIEW: JAMA 2018 Oct 2;320(13):1349

Details
– based on systematic review of trials with methodologic or procedural
limitations
– systematic review of 21 randomized trials comparing thyroid hormone therapy
(triiodothyronine, thyroxine, or combination of both) vs. placebo or no therapy
in 2,192 nonpregnant adults with subclinical hypothyroidism
● subclinical hypothyroidism de!ned as TSH above reference range plus free
thyroxine within reference range
● burden of symptoms at baseline was mild-to-moderate in 7 trials that
provided information on symptoms at baseline
– levothyroxine was given in 17 trials and thyroxine in 4 trials
– treatment duration ranged from 3 to 18 months and mean TSH at end of
follow-up in intervention group ranged between 0.5 and 3.7 milliunits/L
– trials included in meta-analysis for overall quality of life and thyroid-related
symptom outcomes had ≥ 1 limitation including
● small sample size
● lack of intention-to-treat analysis
● unclear blinding of patients and caregivers
● unclear allocation concealment
– no signi!cant di$erences in
● general quality of life in analysis of 4 trials with 796 adults, results limited by
signi!cant heterogeneity
● thyroid-related symptoms in analysis of 4 trials with 958 adults
● depressive symptoms in analysis of 4 trials with 278 adults
● cognitive function in analysis of 4 trials with 859 adults
– e$ect on lipids was not evaluated in review
– Reference - JAMA 2018 Oct 2;320(13):1349
STUDY
⚬ SUMMARY
levothyroxine replacement therapy does not appear to improve mood or
quality of life in patients with subclinical hypothyroidism DynaMed Level 2
SYSTEMATIC REVIEW: Cochrane Database Syst Rev 2007 Jul 18;(3):CD003419

Details
– based on Cochrane review with limited data (small sample sizes for clinical
outcomes)
– systematic review of 12 randomized trials evaluating thyroid hormone
replacement in 350 adults with subclinical hypothyroidism
– follow-up 6-14 months
– no trials evaluated cardiovascular morbidity or mortality
– levothyroxine associated with improved cognitive function in 1 trial with 66
patients (p = 0.03)
– no signi!cant di$erences in mood or quality of life in 7 trials, but largest meta-
analysis for clinical outcomes (change in symptom score) was limited to 3 trials
with 164 patients
– no signi!cant di$erences in adverse events in 4 trials, but speci!c adverse
events only reported in 1-2 trials with maximum 71 patients
– Reference - Cochrane Database Syst Rev 2007 Jul 18;(3):CD003419 ,
commentary can be found in ACP J Club 2008 Jan-Feb;148(1):6 , Cochrane for
Clinicians summary can be found in Am Fam Physician 2008 Apr 1;77(7):953
full-text
STUDY
⚬ SUMMARY
levothyroxine does not appear to improve thyroid-related symptoms in older
adults with persistent subclinical hypothyroidism DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2017 Jun 29;376(26):2534
Details
– based on randomized trial without intention-to-treat analysis
– 737 adults ≥ 65 years old (mean age 74 years, 54% female) with persistent
subclinical hypothyroidism (TSH level 4.6-19.99 milliunits/L and free thyroxine
(FT4) within reference range) were randomized to levothyroxine vs. placebo
and followed for 1 year
● levothyroxine dose was 50 mcg/day orally (25 mcg/day if body weight < 50
kg [110 lbs] or patient had coronary heart disease) with dose adjustments
according to serum TSH level (target range 0.4-4.59 milliunits/L)
● mock dose adjustments were performed in placebo group
– thyroid-related quality of life was assessed using Hypothyroid Symptoms score
and Tiredness score of Thyroid-Related Quality of Life Patient-Reported
Outcome measure (ThyPRO) (range 0-100, higher scores indicate more severe
symptoms or tiredness); minimum clinically important di$erence de!ned as 9
points
– both groups had approximate baseline scores of 17 points on Symptoms scale
and 26 points on Tiredness scale
– 86.6% had primary outcome data available and were included in analysis at 1
year
– comparing levothyroxine vs. placebo at 1 year
● mean Hypothyroid Symptoms score 16.6 points vs. 16.7 points (not
signi!cant)
● mean Tiredness score 28.7 points vs. 28.6 points (not signi!cant)
● mean TSH level 3.63 milliunits/L vs. 5.48 milliunits/L (p < 0.001)
– no signi!cant di$erences in fatal or nonfatal cardiovascular events,
cardiovascular death, all-cause mortality, new-onset atrial !brillation, heart
failure, fracture, or newly diagnosed osteoporosis
– Reference - TRUST trial (N Engl J Med 2017 Jun 29;376(26):2534 )
– consistent results in older adults with high symptom burden at baseline
DynaMed Level 2
● based on post hoc secondary analysis of TRUST trial

● 638 adults who completed 1-year follow-up were analyzed
⚬ 20.7% had Hypothyroid Symptoms score > 30 points at baseline
⚬ 20.8% had Tiredness score > 40 points at baseline
● comparing levothyroxine vs. placebo at 1 year, no signi!cant di$erences in
⚬ mean change in Hypothyroid Symptoms score
– -12.3 points vs. -10.4 points in adults with baseline score > 30 points
– +3.5 points vs. +2.9 points in adults with baseline score ≤ 30 points
⚬ mean change in Tiredness score
– -8.9 points vs. -10.9 points in adults with baseline score > 40 points
– +7.1 points vs. +7 points in adults with baseline score ≤ 40 points
● Reference - Ann Intern Med 2020 Jun 2;172(11):709
EVIDENCE SYNOPSIS
Levothyroxine may improve blood pressure and lipid levels in nonpregnant adults
with subclinical hypothyroidism.
STUDY
⚬ SUMMARY
levothyroxine may reduce systolic blood pressure in nonpregnant adults with
subclinical hypothyroidism DynaMed Level 3
SYSTEMATIC REVIEW: Front Endocrinol (Lausanne) 2018;9:454

Details
– based on nonclinical outcome in systematic review limited by clinical
heterogeneity
– systematic review of 29 studies (10 randomized trials and 19 cohort studies)
evaluating e$ects of levothyroxine (LT4) therapy on blood pressure in 2,208
nonpregnant adults (mean age range 29.2-74.8) with (SCH)
– clinical heterogeneity included di$erences across studies in extent of elevated
TSH, baseline blood pressure, and patient characteristics (race and age)
– TSH cuto$ for SCH diagnosis was 3.6 milliunit/L to 6 milliunit/L
– comparing LT4 therapy to placebo, LT4 associated with
● reduced systolic blood pressure (SBP) (mean di$erence [MD] -2.48 mm Hg,
95% CI -4.63 to -0.33 mm Hg) in analysis of 10 trials with 1,637 patients
● no signi!cant di$erence in diastolic blood pressure (DBP) in analysis of 10
trials with 1,637 patients
– Reference - Front Endocrinol (Lausanne) 2018;9:454
STUDY
⚬ SUMMARY
levothyroxine may reduce lipid levels in patients with subclinical
hypothyroidism DynaMed Level 2
SYSTEMATIC REVIEW: Clin Endocrinol (Oxf) 2017 Jul;87(1):1

Details
– based on systematic review of randomized trials limited by heterogeneity
– systematic review of 12 randomized trials evaluating lipid-lowering e$ect of
LT4 therapy in 940 adults with SCH
– comparing LT4 to control (placebo or observation) in analysis of 12 trials with
940 patients, LT4 associated with
● reduced total cholesterol (TC) (weighted mean di$erence [WMD] -0.29
mmol/L, 95% CI -0.42 to -0.16 mmol/L), results limited by signi!cant
heterogeneity
● reduced low-density lipoprotein (LDL-C) (WMD -0.22 mmol/L, 95% CI -0.36 to
-0.09 mmol/L), results limited by signi!cant heterogeneity
● no signi!cant di$erences in high-density lipoprotein (HDL) cholesterol or
triglycerides
– comparing long-term LT4 treatment (> 6 months) to short-term LT4 treatment
(≤ 6 months), long-term treatment associated with weaker but still signi!cant
lipid-lowering e$ects in analysis of 12 trials with 940 patients
– similar results for patients with mild SCH (thyroid-stimulating hormone < 10
milliunits/L)
– Reference - Clin Endocrinol (Oxf) 2017 Jul;87(1):1
Management of Central Hypothyroidism
● in patients with central hypothyroidism, thyroid-stimulating hormone (TSH)
concentration cannot be used as a reliable measure of thyroid status, therefore,
patients treated for secondary hypothyroidism may potentially be exposed to
adverse e$ects of inadequate or excessive thyroid hormone without the usual signal
from an abnormal TSH 3
● patients with central hypothyroidism should be treated with levothyroxine with the
goal of maintaining serum free thyroxine (T4) levels in upper half of reference range
(ATA Strong recommendation, Moderate-quality evidence) 3
● recommendations for monitoring thyroid hormone replacement therapy in patients
with central hypothyroidism
⚬ in patients with central hypothyroidism, assessment of free T4 or free T4 index,
not TSH, should be performed to diagnose and guide treatment of hypothyroidism
(AACE/ATA Grade A, Level 1) 2
⚬ tissue markers of thyroid hormone action (such as soluble interleukin-2 receptor
or creatinine kinase) may be used in addition to thyroid hormone parameters to
judge adequacy of levothyroxine replacement (ATA Weak recommendation, Low-
quality evidence) 3
⚬ monitoring changes in clinical parameters alone has insu"cient sensitivity and
speci!city for judging adequacy of thyroid replacement therapy; however, limited
evidence suggests that clinical parameters may be helpful for determining
adequacy of thyroid replacement therapy in patients in whom biochemical
assessment is limited to serum free thyroxine levels (ATA Weak recommendation,
● recommended biochemical targets in patients with central hypothyroidism (ATA
Strong recommendation, Moderate-quality evidence) 3
⚬ maintain serum free T4 levels in upper half of reference range
⚬ lower serum free thyroxine target level may be appropriate in older patients or
patients with comorbidities who may be at higher risk of complications of thyroid
hormone excess
STUDY
● SUMMARY
targeting serum free T4 within normal range associated with improved body
composition and lipid markers in patients with hypopituitarism and central
hypothyroidism DynaMed Level 3
COHORT STUDY: J Clin Endocrinol Metab 2013 Sep;98(9):3802

Details
⚬ based on retrospective cohort study without clinical outcomes
⚬ 208 patients with hypopituitarism who were treated with growth hormone therapy
at Danish tertiary center had medical record reviewed at median follow-up of 4.1
years
– 163 patients (78%) had central hypothyroidism (TSH-de!cient), of whom 147
received levothyroxine therapy
– TSH-de!cient patients (baseline serum free T4 ≤ 12 pmol/L or treated with
levothyroxine) were divided into tertiles based on free T4, with free T4 < 13.1
pmol/L (!rst tertile), free T4 13.1-16.7 pmol/L (second tertile), or free T4 ≥ 16.8
pmol/L (third tertile)
– 46 patients were considered TSH-su"cient at baseline and did not receive
levothyroxine treatment
⚬ lower serum free T4 was associated with increased body mass index (p = 0.03),
increased waist circumference (p = 0.03), and decreased high-density lipoprotein
cholesterol (p < 0.001)
⚬ among 192 (92%) patients with data at median follow-up of 4.1 years, 31 (16%)
were considered TSH-su"cient
– 89 patients had either started levothyroxine or required a dose increase
including 12 patients considered TSH-su"cient at baseline; 14 patients in third
tertile either stopped levothyroxine or had dose reduction
– patients in !rst and second tertiles had signi!cant increase in serum free T4
(mean free T4 now within normal range) whereas patients in third tertile had
signi!cant decrease in serum free T4 (mean free T4 for each tertile was within
normal range at follow-up)
⚬ in analysis adjusting for change in insulin growth factor and change in growth
hormone and hydrocortisone dose, increase in free T4 associated with signi!cant
decrease in body mass index, lean body mass, total cholesterol, and low-density
lipoprotein cholesterol
⚬ Reference - J Clin Endocrinol Metab 2013 Sep;98(9):3802
Management of Older Adults

● levothyroxine dose is generally lower in older adults (aged ≥ 65-70 years) due to age-
related decrease in T4 turnover; however, dose may be closer to that predicted for a
younger patient due to decreased absorption of thyroid hormone, concomitant drug
use, and other comorbidities, all common in this population 3
● American Thyroid Association (ATA) recommendations for initiating and adjusting
dose in older adults 3
⚬ initiate levothyroxine with low dose and titrate slowly based on serum thyroid-
stimulating hormone (TSH) using age-appropriate TSH reference range (higher
serum TSH targets may be appropriate in patients > 65 years old) (ATA Strong
– suggested initial oral dose levothyroxine 25-50 mcg/day, with 12.5-25 mcg/day
incremental change in dose every 4-6 weeks as necessary
– for older adults with cardiovascular disease initiate therapy with low
levothyroxine dose 12.5-25 mcg/day orally, with gradual increases based on
serum TSH and symptoms
– target serum TSH between 4 and 6 milliunits/L in patients aged 70-80 years
⚬ careful titration of levothyroxine is required to avoid iatrogenic thyrotoxicosis
(subnormal TSH levels, especially < 0.1 milliunits/L), especially in older patients
and postmenopausal women, to reduce risk for atrial !brillation and osteoporosis
● if maintenance of regular daily dosing schedule is problematic, consider
administering all levothyroxine pills once weekly (or half the pills twice weekly) by a
guardian or visiting nurse if appropriate 3
Alternative Routes of Levothyroxine

● although alternative routes of levothyroxine (including oral gel capsules and oral
solutions) have been reported to be better absorbed than standard levothyroxine
tablets in certain situations (such as concomitant co$ee consumption or concomitant
use of proton pump inhibitors), there is currently no recommendation supporting
the use of alternative routes of levothyroxine in these situations due to lack of data
from long-term outcome studies (ATA Weak recommendation, Low-quality
evidence) 3
● alternative routes of levothyroxine may be considered in certain situations
⚬ consider switching from usual tablet formulation to oral gel capsule in rare case of
putative allergies to excipients (ATA Weak recommendation, Low-quality
evidence) 3
⚬ oral levothyroxine solutions may be considered an alternative to tablet
levothyroxine formulations in
– patients who are unable to swallow
– patients with suspected poor levothyroxine absorption
– patients intolerant to excipients found in levothyroxine tablets
– Reference - Endocrine 2016 Oct;54(1):3
● ATA generally recommends against compounded thyroid hormones (either
levothyroxine or liothyronine) (ATA Strong recommendation, Low-quality evidence);
in patients with suspected allergy to an excipient in standard thyroid hormone
preparations that cannot be avoided with change in brand or dose formulation,
including trial of levothyroxine gel capsules, use of compounded thyroid hormones
may be reasonable 3
Management of Specific Populations

Management of Hospitalized Noncritically Ill Patients
● in hospitalized noncritically ill patients, give oral levothyroxine ATA Weak
recommendation, Low-quality evidence 3
● if oral levothyroxine is not feasible, other enteral routes can be used ATA Weak
recommendation, Low-quality evidence 3
● using IV levothyroxine as an alternative route of levothyroxine
⚬ consider IV levothyroxine formulation in
– patients unable to take oral levothyroxine or if there are concerns about
signi!cant malabsorption ATA Weak recommendation, Low-quality evidence 3
– patients receiving enteral feeding and feeding may not be interrupted 2
⚬ equivalent IV dose is about 75% of oral dose, assuming patient achieved
euthyroidism with oral levothyroxine dose (ATA Weak recommendation, Low-
quality evidence) 3
Management of Patients on Enteral Nutrition

● crushed levothyroxine tablets suspended in water can be administered through
nasogastric tube to patients on enteral nutrition (Endocr Rev 2014 Jun;35(3):433 )
● to ensure optimal absorption, feeding should be stopped before administration of
levothyroxine; restarting feeding should be delayed for as long as possible (at least 1
hour) after levothyroxine dose (Endocr Rev 2014 Jun;35(3):433 )
Management of Surgical Patients

● perioperative considerations
⚬ if possible, delay surgery until patient is euthyroid and on stable dose of
levothyroxine
⚬ for patients on stable levothyroxine dose, oral levothyroxine may be held on
morning of surgery, since half-life of levothyroxine is about 1 week
⚬ for patients needing urgent cardiac surgery
– rapid levothyroxine titration associated with increased risk of ischemia
– delaying thyroid replacement may increase risk of postsurgical myxedema
coma
– management based on expert opinion suggests starting thyroid replacement
after surgery
– consider consult with endocrinologist
⚬ for patients with severe hypothyroidism or for patients who may need thyroid
replacement prior to emergent surgery
– consider levothyroxine 200-500 mcg IV over 30 minutes prior to emergent
surgery; follow with 50-100 mcg/day IV
– if adrenal status unknown, consider need for glucocorticoid replacement
(glucocorticoids should be started prior to initiating thyroid hormone)
– monitor for airway patency and postoperative signs of myxedema coma
⚬ Reference - Anesthesiol Clin 2010 Mar;28(1):139
● patients restarting levothyroxine therapy after interruption (< 6 weeks) and without
intercurrent cardiac event or signi!cant weight loss may resume their previously
used full replacement doses (AACE/ATA Grade D, Level 4) 2
● see also Anesthesia for the Patient With Thyroid Disease
Consultation and Referral

● endocrinologist consultation recommended in diagnosis and treatment of
hypothyroidism for (AACE/ATA Grade C, Level 3) 2
⚬ patients with di"culty maintaining euthyroid state
⚬ pregnant patients
⚬ women planning conception
⚬ patients with cardiac disease
⚬ patients with goiter, nodule, or other structural changes in thyroid gland
⚬ patients with other endocrine disease such as adrenal or pituitary disorders
⚬ patients who have unusual constellation of thyroid function test results
⚬ patients with unusual causes of hypothyroidism such as those induced by agents
that
– interfere with absorption of levothyroxine
– impact thyroid gland hormone production or secretion
– a$ect the hypothalamic-pituitary-thyroid axis (directly or indirectly)
– increase clearance
– peripherally impact metabolism
Follow-up
Monitoring in Nonpregnant Adults
● monitoring serum thyroid-stimulating hormone (TSH) levels
⚬ monitor serum TSH levels in patients being treated for established
hypothyroidism
– check TSH 4-6 weeks after any dose change (ATA Strong recommendation,
– after adequate replacement dose has been determined, measure TSH levels
after 6 months and then at 12-month intervals, or more frequently based on
clinical situation (AACE/ATA Grade B, Level 2) 2
– remeasure TSH within 4-6 weeks of starting treatment with drugs that decrease
bioavailability or alter metabolism of levothyroxine (LT4) (AACE/ATA Grade A,
Level 1) 2
⚬ change in levothyroxine formulation should be followed by evaluation of TSH at
steady state (ATA Weak recommendation, Low-quality evidence) 3
● monitoring thyroid hormone levels
⚬ assess serum free thyroxine (FT4) when monitoring levothyroxine therapy in
patients with central hypothyroidism (AACE/ATA Grade B, Level 1) 2
⚬ signi!cance of alterations in serum triiodothyronine (T3) levels within reference
range, or of mildly low serum triiodothyronine levels, is unknown 3
⚬ Endocrine Society recommends against ordering total or free T3 level when
assessing (LT4) dose in hypothyroid patients (Choosing Wisely 2013 Oct 16)
● monitoring symptoms and tissue biomarkers of thyroid hormone action
⚬ symptoms alone have insu"cient sensitivity and speci!city for judging adequacy
of thyroid replacement therapy; symptoms should be followed and considered in
the context of serum TSH levels, relevant comorbidities, and other potential
causes (ATA Weak recommendation, Low-quality evidence) 3
⚬ tissue biomarkers of thyroid hormone action are not recommended in clinical
setting for determining adequacy of levothyroxine replacement due to lack of
sensitivity, speci!city, availability, and standardization (ATA Weak
recommendation, Low-quality evidence) 3
Targets in Nonpregnant Adults

● American Thyroid Association (ATA) recommended targets for nonpregnant adults 3
⚬ patients with overt hypothyroidism should be treated with levothyroxine doses
adequate to normalize serum TSH levels, to reduce detrimental e$ects of
hypothyroidism on serum lipid pro!le and progression of cardiovascular disease
⚬ avoid iatrogenic thyrotoxicosis (subnormal TSH levels, especially < 0.1 milliunits/L),
especially in older patients (aged ≥ 65 years) and postmenopausal women, to
reduce risk for atrial !brillation and osteoporosis (ATA Strong recommendation,
⚬ insu"cient evidence of bene!t to recommend treatment targets of low-normal
TSH or high-normal T3 values in patients with hypothyroidism with overweight or
athyreotic or have depression or dyslipidemia (ATA Strong recommendation,
⚬ biochemical targets in patients with central (secondary) hypothyroidism (ATA
– recommended primary biochemical treatment goal is serum free thyroxine
levels in upper half of reference range
– lower serum free thyroxine target level may be appropriate in older patients or
patients with comorbidities who may be at higher risk of complications of
thyroid hormone excess
(AACE/ATA) recommended targets for nonpregnant adults 2
⚬ target TSH range should be normal range of third-generation TSH assay
– consider 4.12 milliunits/L upper limit of normal if age-based upper limit of
normal for third-generation TSH assay not available in iodine-su"cient area
– consider 0.45 milliunits/L lower limit of normal if laboratory-speci!c reference
range not available
– in nonpregnant patients, evidence does not support speci!c TSH levels within
normal reference range (AACE/ATA Grade B, Level 2)
⚬ TSH reference range of a given laboratory should determine upper limit of normal
for third-generation TSH assay (AACE/ATA Grade A, Level 1)
– normal TSH reference range changes with age
– consider 4.12 milliunits/L upper limit of normal if age-based upper limit of
normal for third-generation TSH assay is not available in iodine-su"cient area
⚬ in patients with central hypothyroidism, target serum free T4 level should exceed
midnormal range for assay being used (AACE/ATA Grade B, Level 3)
Complications and Prognosis

Complications
Myxedema Coma
● myxedema coma is a rare condition representing a decompensated state of long-
standing or severe untreated hypothyroidism that can eventually lead to multiple
organ failure and death
● despite being called myxedema coma, most patients will present with altered
consciousness (obtunded) with decompensated hypothyroidism rather than in a
comatose state
● in patients who are not in a comatose state, typical clinical presentation includes
⚬ profound hypothermia
⚬ hypoxemia
⚬ decreased mentation (often presents as confusion with lethargy and obtundation)
⚬ generalized edema
⚬ other clinical !ndings consistent with severe hypothyroidism
● diagnosis of myxedema coma is based on clinical presentation and exclusion of
other causes of coma, as no set of laboratory test results de!nitively establishes
diagnosis
● see Myxedema Coma for details
Neurocognitive Complications
EVIDENCE SYNOPSIS
Subclinical hypothyroidism may increase risk for dementia and cognitive

impairment in adults < 75 years old, but does not appear to further increase risk in
older adults.
STUDY
⚬ SUMMARY
subclinical hypothyroidism associated with cognitive impairment and
dementia in adults < 75 years old
SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2015 Nov;100(11):4240
Details
– based on systematic review of observational studies
– systematic review of 13 observational studies (8 cohort, 4 cross-sectional, and
1 case-control study) evaluating association between cognitive function and
subclinical hypothyroidism in 18,674 adults
● mean age ranged from 50.3 to 85 years, with mean age < 75 years in 7
studies and > 75 years in 6 studies
● 1,747 adults (9.3%) had subclinical hypothyroidism, with only 3 studies
including patients on thyroid hormone replacement therapy
– cognitive function impairment was composite endpoint derived from
incidence or prevalence of dementia, or reduced Mini-Mental State Exam,
Wechsler Memory Scale-Revised, total memory quotient, or Wechsler Adult
Intelligence Scale scores
– among studies including adults with mean age < 75 years, subclinical
hypothyroidism associated with increased risk of
● cognitive function impairment composite (odds ratio 1.56, 95% CI 1.07-2.27)
in analysis of 7 studies, results limited by signi!cant heterogeneity
● dementia (odds ratio 1.81, 95% CI 1.43-2.28) in analysis of 4 studies
– no signi!cant di$erence in cognitive function impairment composite or
dementia in analysis of studies including adults with mean age > 75 years
– Reference - J Clin Endocrinol Metab 2015 Nov;100(11):4240
STUDY
⚬ SUMMARY
subclinical hypothyroidism does not appear to increase risk of dementia or
cognitive impairment in older adults
SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2016 Dec;101(12):4945 | Full Text
Details
– based on systematic review of observational studies
– systematic review of 11 prospective cohort studies evaluating association
between subclinical thyroid dysfunction and risk of dementia and cognitive
impairment in 16,805 older adults (mean age range 68-85)
– median follow-up 44.4 months
– compared to euthyroidism, subclinical hypothyroidism not associated with
increased risk of
● dementia in analysis of 6 studies with 7,401 patients
● cognitive impairment in analysis of 7 studies with 8,960 patients
– Reference - J Clin Endocrinol Metab 2016 Dec;101(12):4945 full-text
STUDY
● SUMMARY
subclinical hypothyroidism (SCH) may increase risk of depression
SYSTEMATIC REVIEW: Front Endocrinol (Lausanne) 2019;10:340

Details
⚬ systematic review of 21 studies evaluating association between SCH and
depression in > 100,000 patients
⚬ serum cuto$ range for SCH diagnosis was 3.5 milliunits/L to 6 milliunits/L
⚬ compared to euthyroidism, SCH associated with increased risk of depression (odds
ratio 1.78, 95% CI 1.11-2.86) in analysis of 7 studies with 103,375 patients
⚬ Reference - Front Endocrinol (Lausanne) 2019;10:340
Cardiac Complications
● cardiac complications may include 1
⚬ increased vascular resistance
⚬ decreased cardiac output
⚬ decreased left ventricular function
⚬ changes in other cardiovascular contractility
⚬ myocardial injuries
⚬ pericardial e$usion
⚬ increased total cholesterol
⚬ increased low-density lipoprotein
⚬ increased homocysteine concentrations
⚬ coronary heart disease (with thyroid-stimulating hormone levels > 10 milliunits/L)
Respiratory Complications
● obstructive sleep apnea 2
● respiratory complications can develop in patients with severe hypothyroidism and
myxedema coma, including
⚬ hypoventilation resulting from depression of respiratory drive
⚬ respiratory failure resulting from reduced sensitivity of central nervous system to
hypoxia and hypercapnia
⚬ pleural e$usion and swelling resulting from impacted vascular permeability
⚬ Reference - J Assoc Physicians India 2017 Aug;65(8):68
Gastrointestinal Complications
● gastrointestinal complications may include
⚬ esophageal motility disorder presenting as dysphagia or heartburn
⚬ dyspepsia, nausea, or vomiting (may be due to delayed gastric emptying)
⚬ abdominal discomfort, #atulence, and bloating due to bacterial overgrowth
⚬ constipation due to peristalsis, which can result in ileus, megacolon, or rarely
pseudo-obstruction
⚬ Reference - J Clin Gastroenterol 2010 Jul;44(6):402
● less common gastrointestinal complications may include 1
⚬ nonalcoholic fatty liver disease
⚬ ascites (rare)
Renal Complications
● severe cases of hypothyroidism are associated with increased risk of renal failure,
potentially requiring renal replacement therapy
⚬ mechanism is likely multifactorial and may include abnormalities in systemic and
intrarenal hemodynamics in addition to direct e$ects on renal tubular function
⚬ hypothyroidism can also be associated with rhabdomyolysis, which can contribute
to impaired renal function
⚬ Reference - Intern Med J 2019 Feb;49(2):276
Musculoskeletal Complications
● musculoskeletal complications of overt hypothyroidism may include 1
⚬ muscle weakness
⚬ muscle cramps
⚬ arthralgias
⚬ Ho$man syndrome (proximal weakness and pseudohypertrophy of muscle)
⚬ increased risk for osteoporotic fracture
● carpal tunnel syndrome (CTS)
⚬ CTS is attributed to pseudomucinous material deposited on median nerve
⚬ in untreated hypothyroidism, swelling and thickening of synovial membranes
around carpal tunnel tendons can occur
⚬ some evidence suggests CTS can be reversed with at least 3 months of thyroid
hormone replacement therapy, however, longer disease duration with increased
accumulation of mucinous substance can result in irreversible CTS
⚬ Reference - J Clin Diagn Res 2016 Feb;10(2):OC36 full-text
⚬ see also Carpal Tunnel Syndrome
STUDY
● SUMMARY
subclinical hypothyroidism may not be associated with increased risk of hip or
nonspine fracture in adults
SYSTEMATIC REVIEW: Ann Intern Med 2014 Aug 5;161(3):189

Details
⚬ systematic review of 7 population-based cohort studies evaluating association of
subclinical thyroid dysfunction and risk for hip and nonspine fractures in 50,245
adults
⚬ subclinical hypothyroidism not associated with increased risk of
– hip fracture in analysis of 5 studies with 39,233 patients
– nonspine fracture in analysis of 5 studies with 36,713 patients
⚬ similar results noted when thyroxine recipients excluded
⚬ Reference - Ann Intern Med 2014 Aug 5;161(3):189
Hematological Complications
● anemia is common in patients with hypothyroidism and may result from
⚬ depressed marrow due to a lack of thyroid hormone
⚬ blood loss from menorrhagia
⚬ decreased intestinal absorption of iron, folic acid, and vitamin B12
⚬ reduced erythroprotein levels
⚬ Reference - Endocr J 2012;59(3):213
● bleeding complications have been reported in patients with hypothyroidism,
including
⚬ easy bruising
⚬ menorrhagia
⚬ prolonged bleeding after procedures
⚬ acquired von Willebrand disease
⚬ Reference - J Thromb Haemost 2018 Apr;16(4):634 full-text
Prognosis
Prognosis of Overt (Clinical) Hypothyroidism
● most cases of overt hypothyroidism will require life-long thyroid hormone
replacement therapy 3
● in some patients, thyroid hormone replacement therapy (T4 monotherapy) may not
relieve all symptoms, even if serum thyroid stimulating hormone levels are
normalized (Hormones (Athens) 2018 Dec;17(4):491 full-text )
STUDY
● SUMMARY
overt hypothyroidism may be associated with slightly increased all-cause
mortality, but does not appear to be associated with cardiovascular mortality in
older adults ( 60 years old)
SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2020 Jun

1;105(6):doi:10.1210/clinem/dgz186
Details
⚬ based on systematic review of observational studies limited by heterogeneity
⚬ systematic review of 27 cohort studies (15 prospective and 12 retrospective)
evaluating association between hypothyroidism and mortality in 1,114,638 older
adults (aged ≥ 60 years)
⚬ hypothyroidism associated with increased all-cause mortality overall (risk ratio
[RR] 1.26, 95% CI 1.15-1.37) in analysis of 26 studies with 560,819 patients
⚬ in subgroup analyses, results were only signi!cant for patients with overt (clinical)
hypothyroidism (RR 1.1, 95% CI 1.01-1.2) in analysis of 5 studies with 561,231
patients
⚬ no signi!cant association between
– subclinical hypothyroidism and all-cause mortality in analysis of 26 studies with
560,819 patients, results limited by signi!cant heterogeneity
– hypothyroidism (over or subclinical) and cardiovascular mortality in analysis of
12 studies with 604,461 patients, results limited by signi!cant heterogeneity
⚬ Reference - J Clin Endocrinol Metab 2020 Jun 1;105(6):doi:10.1210/clinem/dgz186
Prognosis of Subclinical Hypothyroidism

● subclinical hypothyroidism can progress to overt hypothyroidism or normalize over
time
⚬ 2%-6% reported risk of progression to overt hypothyroidism per year
– risk factors for progression include
● female gender
● higher thyroid-stimulating hormone levels (TSH), especially ≥ 10 milliunits/L
● higher thyroid peroxidase antibodies levels (risk doubles in patients with
positive test of antibodies compared with negative test results)
– Reference - N Engl J Med 2017 Jun 29;376(26):2556
STUDY
⚬ SUMMARY
higher thyroid-stimulating hormone levels may be associated with increased
risk of progression to overt hypothyroidism in patients with subclinical
hypothyroidism
COHORT STUDY: J Clin Endocrinol Metab 2004 Oct;89(10):4890

Details
– based on prospective cohort study
– 107 patients > 55 years old (87% female) with mildly elevated TSH levels (5-20
milliunits/L) and normal free thyroxine (T4) level were followed for mean 32
months
Table 3. Thyroid Disease Progression Based on TSH Level
Baseline TSH Number of Developed Developed

in milliunits/L Patients Hypothyroidis Normal TSH
m (%) Levels (%)
5-9.9 71 6 52
10-14.9 15 40 13
15-19.9 21 86 5
Abbreviation: TSH, thyroid-stimulating hormone.
– Reference - J Clin Endocrinol Metab 2004 Oct;89(10):4890
STUDY
⚬ SUMMARY
spontaneous resolution of subclinical hypothyroidism may occur over 1-5 years
COHORT STUDY: J Clin Endocrinol Metab 2005 Jul;90(7):4124

Details
– 40 patients with spontaneous subclinical hypothyroidism (TSH > 5 milliunits/L
and normal free T4) with no intervention were followed for 12-72 months
– TSH values normalized without T4 therapy for all patients throughout follow-up
– normalization occurred in median 18 months (6-60 months)
– Reference - J Clin Endocrinol Metab 2005 Jul;90(7):4124
STUDY
● SUMMARY
subclinical hypothyroidism associated with increased all-cause mortality and risk
of fatal or nonfatal cardiovascular disease in persons < 65 years old and increased
all-cause mortality in persons 65 years old at high risk for cardiovascular disease
SYSTEMATIC REVIEW: Thyroid 2018 Sep;28(9):1101

Details
⚬ systematic review of 35 prospective cohort studies evaluating association between
subclinical hypothyroidism and all-cause mortality and risk of cardiovascular
disease in 555,530 persons
– mean age ≥ 65 years in 18 studies and < 65 years in 14 studies
– 21,176 persons (3.8%) had subclinical hypothyroidism
⚬ all-cause mortality 12.8% in pooled analysis of 29 studies and fatal or nonfatal
cardiovascular event in 4.7% in pooled analysis of 27 studies
⚬ high risk for cardiovascular disease de!ned as having history of dilated
cardiomyopathy, heart failure, atrial !brillation, venous thromboembolism,
diabetes, chronic kidney disease, cardiovascular disease risk factors, or coronary,
cerebral, or peripheral artery disease based on World Health Organization criteria
⚬ subclinical hypothyroidism associated with
– increased all-cause mortality (all results limited by signi!cant heterogeneity)
● overall (adjusted relative risk [RR] 1.2, 95% CI 1.08-1.34) in analysis of 30
studies with 532,332 persons
● in persons at high risk for cardiovascular disease (adjusted RR 1.62, 95% CI
1.28-2.04) in analysis of 10 studies
● in analysis of 13 studies with mean age < 65 years (adjusted RR 1.28, 95% CI
1.1-1.48)
● in analysis of 6 studies with mean age ≥ 65 years and persons at high risk for
cardiovascular disease (adjusted RR 1.41, 95% CI 1.08-1.85)
– increased risk of fatal and nonfatal cardiovascular disease (all results limited by
signi!cant heterogeneity)
● overall (adjusted RR 1.33, 95% CI 1.14-1.54) in analysis of 27 studies with
283,578 persons
● in persons at high risk for cardiovascular disease (adjusted RR 2.2, 95% CI
● in persons at low risk for cardiovascular disease (adjusted RR 1.15, 95% CI
● in analysis of 12 studies with mean age < 65 years (adjusted RR 1.54, 95% CI
1.21-1.96)
⚬ no signi!cant di$erences in
– all-cause mortality in
● persons at low risk for cardiovascular disease (adjusted RR 1.1, 95% CI 0.98-
1.24) in analysis of 20 studies
● analysis of 13 studies with mean age ≥ 65 years and persons at low risk for
– risk of fatal and nonfatal cardiovascular disease in analysis of
● 11 studies with mean age ≥ 65 years and persons at low risk for
● 6 studies with mean age ≥ 65 years and persons at high risk for
⚬ Reference - Thyroid 2018 Sep;28(9):1101
EVIDENCE SYNOPSIS
Patients with subclinical hypothyroidism and high TSH levels (for example, ≥ 10
milliunits/L) may have increased risk for cardiovascular events. However, subclinical
hypothyroidism with TSH levels within the normal population reference range does
not appear to be associated with increased cardiovascular risk.
STUDY
⚬ SUMMARY
subclinical hypothyroidism with thyroid stimulating hormone 10
milliunits/L may be associated with increased risk of heart failure events
SYSTEMATIC REVIEW: Circulation 2012 Aug 28;126(9):1040

Details
– based on systematic review of prospective cohort studies
– systematic review of 6 prospective cohort studies evaluating subclinical thyroid
dysfunction and heart failure events (de!ned as hospitalization or death due
to heart failure, or documented physician diagnosis) in 25,390 adults aged 21-
100 years (median 70 years)
– median follow-up 10.4 years
– baseline thyroid status
● 89% of patients were euthyroid (de!ned as TSH 0.45-4.49 milliunits/L)
● 8% of patients had subclinical hypothyroidism (TSH 4.5-19.9 milliunits/L),
including
⚬ 1,422 (69%) with TSH 4.5-6.9 milliunits/L
⚬ 422 (20%) with TSH 7-9.9 milliunits/L
⚬ 224 (11%) with TSH 10-19.9 milliunits/L
● 3% of patients had subclinical hyperthyroidism (TSH < 0.45 milliunits/L),
including 154 (24%) with TSH < 0.1 milliunits/L
– 2,069 adults had ≥ 1 heart failure event during 216,248 person-years of follow-
up
– compared with euthyroidism, adults with subclinical hypothyroidism had
● increased risk of heart failure events with TSH 10-19.9 milliunits/L (adjusted
hazard ratio [HR] 1.59, 95% CI 1.15-2.19)
● no signi!cant di$erences in risk of heart failure events with TSH < 10
milliunits/L
– Reference - Circulation 2012 Aug 28;126(9):1040
STUDY
⚬ SUMMARY
higher thyroid-stimulating hormone levels in patients with subclinical
hypothyroidism associated with increased risk of coronary heart disease (CHD)
and coronary heart disease mortality
SYSTEMATIC REVIEW: JAMA 2010 Sep 22;304(12):1365

Details
– based on systematic review of prospective cohort studies
– systematic review of 11 prospective cohort studies reporting baseline thyroid
function and subsequent coronary heart disease events, coronary heart
disease mortality, and total mortality with 55,287 persons
– subclinical hypothyroidism de!ned as TSH 4.5-19.9 milliunits/L with normal
thyroxine concentrations
– higher TSH levels associated with increased risk of adverse cardiovascular
outcomes
● compared to TSH 0.5-4.49 milliunits/L, higher TSH associated with increased
risk of coronary heart disease in analysis of all studies
⚬ TSH 4.5-6.9 milliunits/L (adjusted hazard ratio [HR] 1, 95% CI 0.86-1.18)
⚬ TSH 7-9.9 milliunits/L (adjusted HR 1.17, 95% CI 0.96-1.43)
● compared to TSH 0.5-4.49 milliunits/L, higher TSH associated with increased
coronary heart disease mortality in analysis of 7 studies with 25,977
persons
⚬ TSH 4.5-6.9 milliunits/L (adjusted HR 1.09, 95% CI 0.91-1.3)
– no signi!cant association between TSH levels and total mortality
– Reference - JAMA 2010 Sep 22;304(12):1365
STUDY
⚬ SUMMARY
high thyroid-stimulating hormone levels within population reference range
(0.45-4.49 milliunits/L) do not appear to be associated with increased risk of
coronary heart disease
META-ANALYSIS: JAMA Intern Med 2015 Jun;175(6):1037

Details
– based on individual patient data meta-analysis of observational studies
– individual patient data meta-analysis of 14 cohort studies evaluating TSH levels
and risk of CHD in 55,412 patients with no previous thyroid or cardiovascular
disease
– follow-up ranged from 3.3 to 20 years
– patients had baseline TSH levels ranging from 0.45 milliunits/L to 4.49
milliunits/L
– 3.3% (1,813) of all patients died of CHD in 643,183 person-years of follow up
– 9.5% (4,666) of patients had !rst-time CHD event in 533,408 person-years of
follow up in analysis of 10 studies with 48,875 patients
– for each 1 milliunit/L increase of TSH level within reference range, no
signi!cant di$erences in
● CHD mortality (hazard ratio [HR] 0.97, 95% CI 0.9-1.04)
● CHD event (HR 0.97, 95% CI 0.83-1.13)
– similar HRs in group with highest TSH levels (3.5-4.49 milliunit/L) and lowest
levels (0.45-1.49 milliunits/L)
● CHD mortality (HR 0.94, 95% CI 0.74-1.2)
● CHD event (HR 0.97, 95% CI 0.83-1.13)
– Reference - JAMA Intern Med 2015 Jun;175(6):1037
STUDY
⚬ SUMMARY
subclinical hypothyroidism might be associated with worse prognosis in
patients with heart failure
COHORT STUDY: Can J Cardiol 2018 Jan;34(1):80

Details
– 1,100 patients with decompensated heart failure were divided into groups
based on serum levels of TSH and FT4 and followed for mean 3 years
● 132 patients (12%) in subclinical hypothyroid group (serum TSH > 4
milliunits/L and serum FT4 0.7-1.9 ng/dL)
● 911 patients (82.8%) in euthyroid group (serum TSH 0.4-4 milliunits/L and
serum FT4 0.7-1.9 ng/dL)
– of 1,043 patients in these 2 groups, 232 had worsening heart failure and 236
died (108 cardiac deaths and 128 noncardiac deaths)
– compared to euthyroid group, subclinical hypothyroidism group had
● increased risk of cardiac event (adjusted hazard ratio [HR] 1.43, 95% CI 1.03-
1.97)
● increased all-cause mortality (adjusted HR 1.42, 95% CI 1.01-2.01)
● increased mean pulmonary artery pressure (p = 0.02)
● increased pulmonary vascular resistance (p = 0.001)
● reduced oxygen consumption in cardiopulmonary exercise test (p = 0.01)
– Reference - Can J Cardiol 2018 Jan;34(1):80
Prevention and Screening

Prevention
● selenium not recommended to prevent or treat hypothyroidism (AACE/ATA Grade B,
Level 2) 2
Screening
Screening in Nonpregnant Adults
● thyroid screening guidelines
⚬ American Association of Clinical Endocrinologists/American Thyroid Association
(AACE/ATA) recommendations on screening in nonpregnant adults 2
– consider screening for hypothyroidism in patients > 60 years old (AACE/ATA
Grade B, Level 1)
● strong evidence that hypothyroidism is common in patients > 60 years old
● insu"cient evidence of bene!t or cost-e$ectiveness for screening
– consider aggressive case !nding in patients at increased risk for
hypothyroidism (AACE/ATA Grade B, Level 2), including those with
● autoimmune disease, such as diabetes mellitus type 1
● pernicious anemia
● !rst-degree relative with autoimmune thyroid disease
● history of neck radiation to thyroid gland, including radioactive iodine
therapy for hyperthyroidism and external beam radiation therapy for head
and neck malignancies
● prior history of thyroid surgery or dysfunction
● an abnormal thyroid exam
● psychiatric disorders
● current use of amiodarone or lithium
● any of the following
⚬ adrenal insu"ciency
⚬ anemia (unspeci!ed)
⚬ alopecia, changes in skin texture, vitiligo
⚬ congestive heart failure, cardiac dysrhythmia, prolonged QT interval,
hypercholesterolemia, mixed hyperlipidemia, or hypertension
⚬ constipation, weight gain, dementia, dysmenorrhea, myopathy, or malaise
and fatigue
⚬ United States Preventive Services Task Force (USPSTF) recommendations for
screening nonpregnant, asymptomatic adults
– insu"cient evidence to recommend for or against routine screening for thyroid
dysfunction (USPSTF Grade I recommendation)
● screening can identify abnormal serum thyroid-stimulating hormone (TSH)
levels in asymptomatic adults and may be bene!cial, but de!nition of
abnormal TSH levels is unclear
● widespread screening and treatment of subclinical thyroid dysfunction may
be harmful due to psychological e$ects of labeling, false-positive results,
overdiagnosis, and overtreatment
● screening for and treatment of thyroid dysfunction in asymptomatic adults
does not appear to improve quality of life or provide clinically meaningful
improvements in clinical and nonclinical outcomes
– if screening for thyroid dysfunction is o$ered to asymptomatic adults, clinicians
should make sure patients clearly understand uncertainties of potential clinical
bene!t and possibility of harm
– Reference - Ann Intern Med 2015 May 5;162(9):641 full-text , editorial can
be found in Ann Intern Med 2015 May 5;162(9):664 , summary for patients
can be found in Ann Intern Med 2015 May 5;162(9):I
⚬ Nurse Practitioner Association of Canada recommends against ordering thyroid
function tests as screening for asymptomatic, low-risk patients (Choosing Wisely
Canada 2017 Sep 15)
⚬ Royal Australian College of General Practitioners recommends against testing
thyroid function as population screening for asymptomatic patients (Choosing
Wisely Australia 2016 Mar 1)
⚬ Canadian Medical Association’s (CMA) Forum on General and Family Practice
Issues, and College of Family Physicians of Canada recommend against ordering
thyroid function tests in asymptomatic patients (Choosing Wisely Canada 2014 Oct
29)
STUDY
● SUMMARY
insu"cient evidence to determine benefits and harms of screening for thyroid
dysfunction in nonpregnant asymptomatic adults
SYSTEMATIC REVIEW: Ann Intern Med 2015 Jan 6;162(1):35 | Full Text
Details
⚬ based on systematic review for United States Preventive Services Task Force
⚬ systematic review of 14 studies (13 randomized trials, 1 cohort study) evaluating
screening and treatment of subclinical and screening-detected overt
hypothyroidism and hyperthyroidism in adults without goiter or thyroid nodules
⚬ each identi!ed randomized trial included 14-120 adults, all studies excluded
pregnant women
⚬ no study directly compared
– clinical bene!ts and harms of screening for thyroid dysfunction to no screening
– treatment of screen-detected overt thyroid dysfunction to no treatment or
waiting for symptomatic presentation to initiate treatment
⚬ for treatment of subclinical hypothyroidism, comparing treatment to control (no
treatment or placebo)
– treatment associated with decreased risk for coronary heart disease events in 1
fair-quality cohort study with 4,735 adults
– no clear bene!t associated with treatment for quality of life, cognitive function,
blood pressure, or body mass index in identi!ed randomized trials
⚬ for treatment of subclinical hyperthyroidism, no study evaluated clinical outcomes
with treatment vs. no treatment
⚬ Reference - Ann Intern Med 2015 Jan 6;162(1):35 full-text
● no randomized or controlled trials found evaluating screening for subclinical thyroid

dysfunction based on systematic review (AHRQ Comparative E$ectiveness Review
2011 Nov:24 PDF )
STUDY
● SUMMARY
normal thyroid-stimulating hormone levels likely to remain normal for at least 5
years, while abnormal thyroid-stimulating hormone levels may normalize with
repeat testing
COHORT STUDY: Arch Intern Med 2007 Jul 23;167(14):1533

Details
⚬ based on retrospective cohort study
⚬ 422,242 outpatients without thyroid disease or pregnancy had TSH levels
measured and were followed for 5 years
⚬ 95% initial serum TSH levels were normal (0.35-5.5 milliunits/L) of which 98%
remained normal
⚬ 1.2% initial TSH levels were decreased (< 0.35 milliunits/L) of which 62% of patients
not taking thyroid-speci!c medications had subsequent normal TSH levels
⚬ 3% initial TSH levels were increased (5.5-10 milliunits/L) of which 51% of patients
not taking thyroid-speci!c medications had subsequent normal TSH levels
⚬ 0.7% initial TSH levels were highly increased (> 10 milliunits/L) of which 27% of
patients not taking thyroid-speci!c medications had subsequent normal TSH levels
⚬ Reference - Arch Intern Med 2007 Jul 23;167(14):1533 , commentary can be
found in Arch Intern Med 2008 Feb 11;168(3):330
Screening in Pregnancy
● ATA recommendations on screening for thyroid dysfunction preconception and
during pregnancy 4
⚬ universal screening
– no recommendation for or against universal screening for abnormal thyroid-
stimulating hormone (TSH) levels in early pregnancy or during preconception
with the exception of women planning assisted reproduction or those known to
have thyroid peroxidase antibodies (TPOAb) (ATA No recommendation,
Insu"cient evidence)
– universal screening for detection of low free T4 levels in pregnant women is not
recommended (ATA Weak recommendation, Moderate-quality evidence)
⚬ screen euthyroid women at risk for hypothyroidism (including those who have
tested positive for thyroid antibodies, undergone hemithyroidectomy, or had
radioiodine treatment) with serum TSH every 4 weeks until mid-gestation, and at
least once near 30 weeks (ATA Strong recommendation, High-quality evidence)
⚬ case-!nding approach
– ask all pregnant women at initial prenatal visit about any history of thyroid
dysfunction and prior or current use of levothyroxine or antithyroid
medications (ATA Strong recommendation, High-quality evidence)
– clinically evaluate all newly pregnant women or those seeking pregnancy and
measure serum TSH in those with following risk factors (ATA Strong
● history of
⚬ hypothyroidism or hyperthyroidism
⚬ head or neck radiation
⚬ thyroid surgery
⚬ type 1 diabetes or other autoimmune disorders
⚬ pregnancy loss, preterm delivery, or infertility
⚬ ≥ 2 prior pregnancies
⚬ use of amiodarone or lithium
⚬ recent administration of iodinated radiologic contrast
● family history of autoimmune thyroid disease or thyroid dysfunction
● current signs and symptoms of thyroid dysfunction including presence of a
goiter
● known thyroid antibody positivity
● > 30 years old
● morbid obesity (body mass index ≥ 40 kg/m2)
● living in area with known moderate-to-severe iodine insu"ciency
● evidence for screening for thyroid dysfunction during pregnancy
STUDY
⚬ SUMMARY
levothyroxine treatment for maternal hypothyroidism based on antenatal
screening not associated with improved cognition in children at age 3 years
DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2012 Feb 9;366(6):493 | Full Text

Details
– based on randomized trial with high dropout rate
– 21,846 pregnant persons at ≤ 15 6/7 weeks gestation providing blood samples
for measurement of thyrotropin and free thyroxine were randomized to
screening group vs. control group
● screening group had serum sample measurements obtained immediately
and received levothyroxine 150 mcg/day (with dosing adjusted as indicated
to achieve target thyrotropin level of 0.1-1 milliunits/L) if positive screening
results
● control group had serum stored and measurements obtained after delivery
– screening result considered positive if thyrotropin levels > 97.5th percentile
and/or free thyroxine (T4) levels < 2.5th percentile
– 499 pregnant persons (4.6%) in screening group and 551 pregnant persons (5%)
in control group tested positive
– median gestational age at start of levothyroxine was 13 3/7 weeks
– psychological testing completed at age 3 years in
● 390 children (78.2%) in screening group
● 404 (73.3%) in control group
– comparing children born to pregnant person with positive results from
screening group vs. control group
● mean IQ scores 99.2 points vs. 100 points (not signi!cant)
● IQ scores < 85 in 12.1% vs. 14.1% (not signi!cant)
– Reference - CATS trial N Engl J Med 2012 Feb 9;366(6):493 full-text , editorial
can be found in N Engl J Med 2012 Feb 9;366(6):562
DynaMed Commentary
Maternal thyroid hormone appears to be most critical for fetal brain

development in the !rst trimester. Levothyroxine therapy started at 13
weeks may have been too late to demonstrate signi!cant bene!t.
STUDY
⚬ SUMMARY
treatment of suboptimal gestational thyroid function (SGTF) with levothyroxine
starting at median gestational age 13 3/7 weeks associated with increased
hyperactivity, and social interaction and behavioral di"culties in children aged
7-10 years compared to no gestational thyroid dysfunction, consistent results
comparing over treatment (free thyroxine [FT4] > 17.7 pmol/L) to untreated
SGTF DynaMed Level 2
COHORT STUDY: J Clin Endocrinol Metab 2020 Mar 1;105(3):dgz098

Details
– based on secondary cohort analysis of randomized trial
– 4,609 patients (21%) from treated and untreated groups in CATS trial above
living in UK with children aged 7-10 years were invited to complete 3
questionnaires about their children (higher scores indicate more severe
symptoms)
● Strengths and Di"culties Questionnaire (SDQ) assessing 5 subscales for
hyperactivity, emotional symptoms, conduct problems, peer problems, and
prosocial behavior (total range 0-50 points)
● Child Attention-De!cit/Hyperactivity Disorder Questionnaire (ADHDq)
assessing 3 subscales for inattention, hyperactivity and impulsivity (total
range 0-54 points)
● Social Communication Questionnaire (SCQ) with score of ≥ 15 points
indicating possible autism spectrum disorder
– 475 persons were eligible and successfully completed questionnaires
● 246 had gestational thyroid function within normal limits
● 125 had SGTF and received treatment with levothyroxine (including 41
patients who received over treatment de!ned as FT4 > 97.5th percentile of
UK cohort [> 17.7 pmol/L at 20 or 30 weeks gestation])
● 104 had suboptimal gestational thyroid function and did not receive
treatment with levothyroxine
– 95.6% were included in analysis
– at baseline, higher median TSH in treated SGTF group (4.1 milliunits/L)
compared to untreated-SGTF group (3.6 milliunits/L)
– rates of scores above clinical thresholds for likely disorder (de!ned as ≥ 90th
percentile for SDQ, > 2 standard deviations higher for ADHDq, and > 15 points
for ASD)
● conduct problem subscale of SDQ
⚬ 15.4% for treated SGTF (p < 0.05 vs. euthyroid, NNH 14)
– 11.7% for optimally treated SGTF
– 22.5% for over treated SGTF (p < 0.01 vs. untreated SGTF, NNH 7)
⚬ 7% for untreated SGTF
⚬ 8.5% for euthyroid
● hyperactivity subscale of ADHDq
⚬ 10.2% for treated SGTF (p < 0.05 vs. euthyroid, NNH 15)
– 17.5% for over treated SGTF (p < 0.05 vs. untreated SGTF, NNH 7)
● SCQ
⚬ 6% for treated SGTF (p < 0.05 vs. euthyroid, NNH 23)
– 7.5% for over treated SGTF (p < 0.05 vs. untreated SGTF)
– total questionnaire scores comparing euthyroid vs. treated SGTF vs. untreated
SGTF
● SCQ 4.3 points vs. 5.2 points vs. 4.1 points (p = 0.08 across groups)
● SDQ 8.2 points vs. 8.9 points vs. 8.2 points (not signi!cant across groups)
● ADHDq 11.2 points vs. 13.2 points vs. 11.7 points (not signi!cant across
groups)
– Reference - J Clin Endocrinol Metab 2020 Mar 1;105(3):dgz098
STUDY
⚬ SUMMARY
levothyroxine treatment for maternal subclinical hypothyroidism based on
antenatal screening not associated with improved cognition in children at age 5
years DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2017 Mar 2;376(9):815 | Full Text
Details
– based on randomized trial without intention-to-treat analysis
– 97,228 pregnant women underwent thyroid screening between 8-20 weeks
gestation, and 3,057 women (3%) were diagnosed with subclinical
hypothyroidism
– 677 pregnant women < 20 weeks gestation with a screening diagnosis of
subclinical hypothyroidism were randomized to levothyroxine 100 mcg/day vs.
placebo
● mean gestational age at start of levothyroxine was 16.7 weeks
● levothyroxine dose was adjusted to attain a normal thyrotropin or free T4
level (maximum dose 200 mcg/day)
– children underwent annual developmental and behavioral testing for 5 years
– 649 children had IQ scores available and were included in primary analysis
– comparing children of birthing parent treated with levothyroxine vs. placebo
● median IQ score at age 5 years 97 points vs. 94 points (not signi!cant)
● no signi!cant di$erences between groups in any other neurocognitive or
pregnancy outcomes or in the incidence of adverse event
– Reference - N Engl J Med 2017 Mar 2;376(9):815 full-text
DynaMed Commentary
Maternal thyroid hormone appears to be most critical for fetal brain

development in the !rst trimester. Levothyroxine therapy started at 16.7
weeks may have been too late to demonstrate signi!cant bene!t.
STUDY
⚬ SUMMARY
universal screening may be more e!ective than targeted case finding for
reducing adverse maternal and neonatal outcomes in pregnant women at low
risk for thyroid dysfunction DynaMed Level 2
RANDOMIZED TRIAL: J Clin Endocrinol Metab 2010 Apr;95(4):1699

Details
– based on subgroup analysis of randomized trial
– 4,562 women in !rst 11 weeks of gestation with no history of thyroid disease
were randomized to universal screening vs. targeted case !nding
– universal screening associated with reduced adverse maternal and neonatal
outcomes in subgroup of 3,590 women classi!ed as at low risk for thyroid
dysfunction
● complications per patient 0.74 for universal screening (95% CI 0.52-1.02)
● complications per patient 1.67 for targeted case !nding (95% CI 1.2-2.13)
– no signi!cant di$erences in adverse maternal and neonatal outcomes overall
– Reference - J Clin Endocrinol Metab 2010 Apr;95(4):1699 , editorial can be
found in J Clin Endocrinol Metab 2010 Apr;95(4):1575
⚬ no additional trials found in Cochrane review evaluating thyroid dysfunction

screening before or during pregnancy (Cochrane Database Syst Rev 2015 Sep 21;
(9):CD011263 )
STUDY
● SUMMARY
prevalence of trimester-specific elevated thyroid-stimulating hormone and overt
hypothyroidism appear similar in women with and without targeted thyroid
testing during pregnancy
COHORT STUDY: Obstet Gynecol 2014 Jul;124(1):10

Details
⚬ based on population-based retrospective cohort study
⚬ 5,254 pregnant women with blood samples collected in conjunction with routine
ultrasound screening at 17-19 weeks gestation were evaluated
⚬ 1,054 women meeting ≥ 1 of the following 5 criteria had targeted thyroid testing:
personal or family history of thyroid dysfunction, goiter, insulin-dependent
diabetes, or presence of other autoimmune diseases
⚬ of the 4,200 pregnant women not tested for thyroid dysfunction, 1,006 were
randomly selected for retrospective thyroid testing conducted on stored blood
samples (untested group)
⚬ comparing targeted testing vs. nontesting (retrospective testing)
– trimester-speci!c TSH elevation in 12.6% vs. 12.1% (not signi!cant)
– overt hypothyroidism in 1.1% vs. 0.7% (not signi!cant)
⚬ Reference - Obstet Gynecol 2014 Jul;124(1):10 , editorial can be found in Obstet
Gynecol 2014 Jul;124(1):8
Hypothyroidism in Pregnancy
Background
● hypothyroidism in pregnancy is de!ned as thyroid-stimulating hormone (TSH)
elevated above normal limit of trimester-speci!c reference range (ATA Strong
recommendation, High-quality evidence) 4
● pooled prevalence of thyroid disease in pregnancy in systematic review of 63 studies
(results calculated from studies using the 97.5th percentile as an upper limit for TSH)
⚬ 0.5% overt primary hypothyroidism
⚬ 3.47% subclinical hypothyroidism
⚬ 2.05% isolated hypothyroxinemia
⚬ Reference - Thyroid 2019 Feb;29(2):278
● prevalence of elevated TSH is higher in areas of iodine de!ciency 4
● Hashimoto thyroiditis is most common cause of hypothyroidism in pregnant women
after iodine de!ciency 4
● 30%-60% of pregnant women with elevated TSH reported to also have positive titer
for thyroid autoantibodies 4
● euthyroid women at risk of developing hypothyroidism during pregnancy includes
patients with 4
⚬ thyroid autoimmunity
⚬ history of hemithyroidectomy or treatment with radioactive iodine
⚬ family history of hypothyroidism or other autoimmune disease
● see Screening in Pregnancy section above for additional information
Diagnosis
Thyroid-stimulating Hormone (TSH)
● trimester-speci!c TSH reference ranges 4
⚬ when available, use population-based, trimester-speci!c reference ranges for
serum TSH de!ned by assessment of local population representative of provider's
practice; reference population should include pregnant women without known
thyroid disease, adequate iodine intake, and negative thyroid peroxidase antibody
(TPOAb) status (ATA Strong recommendation, High-quality evidence)
– across populations, TSH levels in early pregnancy are decreased compared to
nonpregnant populations, but the extent of the decrease can vary signi!cantly
– di$erences in normal TSH levels may be attributed to variability between
populations in iodine status, body mass index, geography, and ethnicity
⚬ if assessment of local population not possible or available, use reference ranges
obtained from similar patient populations performed using similar TSH assays
(ATA Strong recommendation, High-quality evidence)
⚬ if internal or transferable pregnancy-speci!c reference ranges are not available,
an upper reference limit of approximately 4 milliunits/L may be used, which
corresponds to a reduction of approximately 0.5 milliunits/L from the upper
reference limit of TSH in nonpregnant women (ATA Strong recommendation,
Thyroxine (T4)
● American Thyroid Association (ATA) recommendations for measuring T4 levels in
pregnant women 4
⚬ if measuring free thyroxine (FT4) by indirect analog immunoassay, use method-
speci!c and trimester-speci!c pregnancy reference ranges where available (ATA
⚬ in absence of method-speci!c and trimester-speci!c pregnancy reference ranges
for free T4
– measure total T4 (TT4) in lieu of FT4 using pregnancy-adjusted reference range
(1.5 times nonpregnancy range in second and third trimesters), as it is highly
reliable for estimating thyroid hormone concentrations during last part of
pregnancy(ATA Strong recommendation, Moderate-quality evidence)
– calculate FT4 index, which can accurately estimate FT4 concentrations (ATA
Strong recommendation, Moderate-quality evidence), using serum thyroid
uptake test such as thyroid hormone binding ratio
Thyroid Antibodies
● ATA recommends evaluating anti-thyroid peroxidase antibodies (TPOAb) status in
pregnant women with TSH levels > 2.5 milliunits/L due to risk of pregnancy
complications 4
(AACE/ATA) recommends considering TPOAb testing for evaluating patients with
recurrent miscarriage, with or without infertility (AACE/ATA Grade A, Level 2) 2
● Canadian Society of Endocrinology and Metabolism recommends against routinely
testing for TPOAb
⚬ in euthyroid pregnant patients deemed at high risk of developing thyroid disease,
TPOAb may in#uence frequency of surveillance for hypothyroidism during
pregnancy
⚬ Reference - Choosing Wisely Canada 2014 Oct 29
Management
Management of Known Hypothyroidism Prior to or Immediately After
Conception
● ATA recommendations for preconception planning in women with preexisting
hypothyroidism 4
⚬ explain to women of reproductive age treated with levothyroxine (LT4) the
likelihood of increased demand for LT4 during pregnancy and counsel them to
promptly contact healthcare provider upon con!rmed or suspected pregnancy
(ATA Strong recommendation, High-quality evidence)
⚬ in woman treated with LT4 planning pregnancy, evaluate serum thyroid-
stimulating hormone (TSH) preconception and adjust LT4 dose to a target TSH
between lower reference limit and 2.5 milliunits/L (ATA Strong recommendation,
● for pregnant women with existing hypothyroidism, increase levothyroxine dose by
20%-30% (can be achieved by taking 2 additional tablets weekly) as soon as
pregnancy con!rmed (ATA Strong recommendation, High-quality evidence)
Management of Overt Primary Hypothyroidism During Pregnancy

● ATA recommendations for management of hypothyroidism during pregnancy and
following delivery 4
⚬ treat overt hypothyroidism during pregnancy (ATA Strong recommendation,
⚬ oral levothyroxine is recommended treatment; other preparations such as
triiodothyronine (T3) or desiccated thyroid are not recommended due to limited
evidence for their use (ATA Strong recommendation, Low-quality evidence)
⚬ reasonable to target TSH goal in lower half of trimester-speci!c reference range
(or < 2.5 milliunits/L if not available) (ATA Weak recommendation, Moderate-
quality evidence)
● full starting dose of levothyroxine (2-2.4 mcg/kg/day orally) suggested for overt
hypothyroidism discovered during pregnancy (Endocr Rev 2014 Jun;35(3):433 )
Management of Subclinical Primary Hypothyroidism During Pregnancy

● guidance for management of subclinical hypothyroidism in pregnancy di$ers among
professional organizations
Table 4. Recommendations on Use of Thyroid Replacement Therapy in Women

With Subclinical Hypothyroidism in Pregnancy
ATA ACOG ETA
⚬ Recommended for No speci!c Recommended, starting

women with positive recommendation made dose 1.2 mcg/kg/day
TPOAb titers and regarding use of (ETA Strong
TSH greater than thyroid replacement recommendation,
trimester-speci!c therapy in women with Moderate-quality
reference range (ATA subclinical evidence)
Strong hypothyroidism
recommendation,
Moderate-quality of
evidence)
⚬ Recommended for
women with
negative TPOAb
titers and TSH > 10
milliunits/L (ATA
Strong
recommendation,
Low-quality of
evidence)
Abbreviations: ACOG, American College of Obstetrics and Gynecology; ATA, American

Thyroid Association; ETA, European Thyroid Association; TPOAb, thyroid peroxidase
antibody; TSH, thyroid-stimulating hormone.
Reference - Thyroid 2017 Mar;27(3):315 , Obstet Gynecol 2020 Jun;135(6):e261 , Eur

Thyroid J 2014 Jun;3(2):76 full-text .
Table 5. American Thyroid Association (ATA) Recommendations for Levothy-

roxine Therapy in Pregnant Women With Subclinical Hypothyroidism
TSH Level TPOAb Recommendation
Greater than trimester- Positive Give LT4 therapy (ATA

speci!c range Strong
recommendation,
Moderate-quality
evidence)
> 10 milliunits/L Negative Give LT4 therapy (ATA

Strong
recommendation, Low-
quality evidence)
Between 2.5 milliunits/L Positive Consider LT4 therapy

and upper limit of (ATA Weak
trimester-speci!c range recommendation,
Moderate-quality
evidence)
Between upper limit of Negative Consider LT4 therapy

trimester-speci!c range (ATA Weak
and 10 milliunits/L recommendation, Low-
quality evidence)
Normal (or < 4 Negative Do not give LT4 therapy

milliunits/L of (ATA Strong
trimester-speci!c recommendation, High-
reference not available) quality evidence)
Abbreviations: LT4, levothyroxine; TPOAb, thyroid peroxidase antibody; TSH, thyroid-

stimulating hormone.
Reference - Thyroid 2017 Mar;27(3):315 .
STUDY
● SUMMARY
levothyroxine may reduce risk of pregnancy loss and preterm birth in women with
subclinical hypothyroidism DynaMed Level 2
SYSTEMATIC REVIEW: Hum Reprod Update 2019 May 1;25(3):344

Details
⚬ based on systematic review limited by clinical heterogeneity
⚬ systematic review of 13 studies (8 randomized trials and 5 retrospective cohort
studies) comparing LT4 supplementation vs. no treatment or placebo in 7,970
patients with subclinical hypothyroidism and/or thyroid autoimmunity
⚬ results limited by heterogeneity in
– de!nitions of pregnancy loss and preterm birth
– normal ranges of thyroid function test results
– LT4 supplementation start time
– LT4 dose
⚬ in patients with subclinical hypothyroidism and/or thyroid autoimmunity, LT4
supplementation associated with decreased risk of
– pregnancy loss in analysis of 12 studies with 1,958 patients
● risk ratio 0.56 (95% CI 0.42-0.75)
● NNT 15-34 with pregnancy loss in 12% of controls
– preterm birth in analysis of 8 studies with 1,852 patients
● risk ratio 0.68 (95% CI 0.51-0.91)
● NNT 19-102 with preterm birth in 11% of controls
⚬ in patients with only subclinical hypothyroidism, LT4 supplementation associated
with decreased risk of
– pregnancy loss in analysis of 5 studies with 1,005 patients
● risk ratio 0.43 (95% CI 0.26-0.72)
– pregnancy loss in pregnancies achieved with assisted reproduction in subgroup
analysis of 2 trials with 77 patients
● risk ratio 0.27 (95% CI 0.14-0.52)
⚬ Reference - Hum Reprod Update 2019 May 1;25(3):344
STUDY
● SUMMARY
in women having assisted reproductive technologies (ART), thyroxine may
improve live birth rate in women with subclinical hypothyroidism, but may not
improve live birth rate in women with euthyroid autoimmune thyroid disease
DynaMed Level 2
COCHRANE REVIEW: Cochrane Database Syst Rev 2019 Jun 25;6:CD011009

Details
⚬ based on Cochrane review with limited evidence
⚬ systematic review of 4 trials comparing thyroxine vs. placebo or no treatment in
820 women with subclinical hypothyroidism or euthyroid autoimmune thyroid
disease having ART
⚬ in 1 trial with 64 women with subclinical hypothyroidism with and without
autoimmune disease
– thyroxine associated with increased live birth rate (53% with thyroxine vs. 25%
with control) (p = 0.03, NNT 4)
– no signi!cant di$erence in miscarriage rates (0% with thyroxine vs. 12% with
control)
⚬ in 2 trials with 686 women with euthyroid autoimmune thyroid disease, no
signi!cant di$erences in
– live birth rate (risk ratio 1.04, 95% CI 0.83-1.29)
– miscarriage (risk ratio 0.83, 95% CI 0.47-1.46), but CI includes possibility of
bene!t or harm
⚬ adverse events rarely reported
⚬ Reference - Cochrane Database Syst Rev 2019 Jun 25;6:CD011009
Monitoring and Follow-up During Pregnancy and After Delivery

● American Thyroid Association (ATA) recommendations for monitoring and follow-up
in pregnant women with hypothyroidism 4
⚬ in women with overt and subclinical hypothyroidism (treated or untreated) or
those at risk for hypothyroidism, monitor thyroid-stimulating hormone (TSH) level
every 4 weeks until midgestation and at least once near 30 weeks (ATA Strong
recommendation, High-quality evidence)
⚬ for women being treated for hypothyroidism during pregnancy, consider a target
TSH goal in lower half of trimester-speci!c reference range (or < 2.5 milliunits/L if
not available) (ATA Weak recommendation, Moderate-quality evidence)
⚬ follow-up after delivery
– readjust levothyroxine dose to preconception dose following delivery and
monitor thyroid function at about 6 weeks postpartum (ATA Strong
– consider discontinuing levothyroxine in certain women who initiated
levothyroxine during pregnancy, especially those with dose ≤ 50 mcg/day (ATA
Weak recommendation, Moderate-quality evidence)
● patient should be involved in decision
● measure serum TSH at about 6 weeks postpartum if levothyroxine is
discontinued
● see Thyroid Disease in Pregnancy for additional information
Complications During Pregnancy
● hypothyroidism associated with increased maternal and fetal complications during
pregnancy, such as 4
⚬ miscarriage or stillbirth (including recurrent pregnancy loss)
⚬ preterm birth
⚬ hypertension
⚬ postpartum hemorrhage
● fetus does not begin to produce enough thyroid hormone to support development
until weeks 18-20, and is dependent on thyroid hormone from mother (Clin Obstet
Gynecol 1997 Mar;40(1):16 )
● associated risk of complications a$ecting pregnancy and fetus (and treatment
recommendations) varies depending on whether the hypothyroidism is overt or
subclinical
Table 6. Types of Hypothyroidism
Type De!nition Associated Treatment

Adverse With
Outcomes Levothyroxine
Overt ⚬ Elevated TSH ⚬ Gestational Recommended

hypothyroidism ⚬ Decreased hypertension
free T4 ⚬ Anemia
⚬ Preeclampsia
⚬ Pregnancy
loss
⚬ Spontaneous
abortion
⚬ Placental
abruption
⚬ Postpartum
hemorrhage
⚬ Premature
birth
⚬ Low birth
weight
⚬ Lower
o$spring IQ
Subclinical ⚬ Elevated TSH Adverse Guidance varies

hypothyroidism ⚬ Normal free pregnancy
T4 outcomes
reported in most
but not all
studies
Abbreviation: T4, thyroxine; TSH, thyroid-stimulating hormone.
Reference - Thyroid 2017 Mar;27(3):315 , Curr Opin Obstet Gynecol 2015 Dec;27(6):406
.
STUDY
● SUMMARY
hypothyroidism in first trimester of pregnancy may not be associated with poor
educational performance of child
COHORT STUDY: BMJ 2018 Feb 20;360:k452 | Full Text

Details
⚬ based on prospective cohort study
⚬ 4,615 pregnant women in !rst trimester (median gestation 10 weeks) were
assessed for thyroid dysfunction
– 0.7% had hypothyroidism
– 3.6% had subclinical hypothyroidism
⚬ 4,461 o$spring were evaluated for educational performance from age 54 months
to 15 years
⚬ no consistent signi!cant associations between maternal hypothyroidism or
subclinical hypothyroidism in !rst trimester and performance of child in national
educational assessments up to age 15 years
⚬ Reference - BMJ 2018 Feb 20;360:k452 full-text
STUDY
● SUMMARY
first trimester maternal thyroid-stimulating hormone level 4.5 milliunits/L
associated with increased risk of miscarriage in levothyroxine-treated pregnant
women
COHORT STUDY: J Clin Endocrinol Metab 2014 Oct;99(10):3895

Details
⚬ based on retrospective cohort study
⚬ 769 pregnant women aged 18-45 years with hypothyroidism treated with
levothyroxine initiated ≥ 6 months before conception had TSH level measured in
!rst trimester
⚬ 62.8% had TSH level > 2.5 milliunits/L, and 7.4% had TSH level > 10 milliunits/L
⚬ 118 miscarriages occurred
⚬ compared to TSH level 0.2-2.5 milliunits/L
– nonsigni!cant increase in risk of miscarriage for TSH level > 2.5 milliunits/L
(adjusted odds ratio [OR] 1.09, 95% CI 0.61-1.93)
– increased risk of miscarriage for TSH level
● 4.5-10 milliunits/L (adjusted OR 1.8, 95% CI 1.03-3.14)
● > 10 milliunits/L (adjusted OR 3.95, 95% CI 1.87-8.37)
⚬ Reference - J Clin Endocrinol Metab 2014 Oct;99(10):3895
● see Thyroid Disease in Pregnancy for additional information
Quality Improvement
Choosing Wisely
● American Society for Clinical Pathology recommends against ordering multiple tests
in the initial evaluation of a patient with suspected thyroid disease, and instead
recommends ordering thyroid-stimulating hormone (TSH) and if abnormal following-
up with additional evaluation or treatment depending on the !ndings (Choosing
Wisely 2015 Feb 3)
● Endocrine Society recommends against ordering total or free T3 level when assessing
levothyroxine (T4) dose in hypothyroid patients (Choosing Wisely 2013 Oct 16)
● Endocrine Society recommends against routine use of thyroid ultrasound in patients

with abnormal thyroid function tests if there is no palpable abnormality of thyroid
gland (Choosing Wisely 2013 Oct 16)
Choosing Wisely Australia

● Royal Australian College of General Practitioners recommends against testing thyroid
function as population screening for asymptomatic patients (Choosing Wisely
Australia 2016 Mar 1)
● Endocrine Society of Australia recommends against ordering a total or free T3 level

when assessing thyroxine dose in hypothyroid patients (Choosing Wisely Australia
2016 Mar 1)
● Endocrine Society of Australia recommends against routinely ordering a thyroid

ultrasound in patients with abnormal thyroid function tests if there is no palpable
abnormality of the thyroid gland (Choosing Wisely Australia 2016 Mar 1)
Choosing Wisely Canada

● Canadian Medical Association’s (CMA) Forum on General and Family Practice Issues,
and College of Family Physicians of Canada recommend against ordering thyroid
function tests in asymptomatic patients (Choosing Wisely Canada 2014 Oct 29)

ordering a thyroid ultrasound in patients with abnormal thyroid function tests unless
there is a palpable abnormality of the thyroid gland
⚬ thyroid ultrasound is used to identify and characterize thyroid nodules, and is not
part of the routine evaluation of abnormal thyroid function tests (over- or under-
active thyroid function) unless the patient also has a large goiter or a lumpy
thyroid
⚬ incidentally discovered thyroid nodules are common
⚬ overzealous use of ultrasound will frequently identify nodules, which are
unrelated to the abnormal thyroid function, and may divert the clinical evaluation
to assess the nodules, rather than the thyroid dysfunction
⚬ imaging may be needed in thyrotoxic patients; when needed, a thyroid scan, not
an ultrasound, is used to assess the etiology of the thyrotoxicosis and the
possibility of focal autonomy in a thyroid nodule
● Canadian Society of Endocrinology and Metabolism recommends against using free

T4 or T3 to screen for hypothyroidism or to monitor and adjust levothyroxine (T4)
dose in patients with known primary hypothyroidism
⚬ T4 is converted into T3 at the cellular level in virtually all organs
⚬ intracellular T3 levels regulate pituitary secretion and blood levels of thyroid-
stimulating hormone (TSH), as well as the e$ects of thyroid hormone in multiple
organs
⚬ therefore, in most people a normal TSH indicates either normal endogenous
thyroid function or an adequate T4 replacement dose
⚬ TSH only becomes unreliable in patients with suspected or known pituitary or
hypothalamic disease when TSH cannot respond physiologically to altered levels
of T4 or T3

testing for antithyroid peroxidase (anti-TPO) antibodies
⚬ positive anti-TPO titers are not unusual in the "normal" population
⚬ presence of positive anti-TPO titers, in the context of thyroid disease, only assists
in indicating that the pathogenesis is probably autoimmune
⚬ as thyroid autoimmunity is a chronic condition, once diagnosed there is rarely a
need to remeasure anti-TPO titers
⚬ in euthyroid pregnant patients deemed at high risk of developing thyroid disease,
anti-TPO antibodies may in#uence the frequency of surveillance for
hypothyroidism during the pregnancy
⚬ it is uncommon that measurement of anti-TPO antibodies in#uences patient
management
● Nurse Practitioner Association of Canada recommends against ordering thyroid

function tests as screening for asymptomatic, low risk patients (Choosing Wisely
Canada 2017 Sep 15)
Choosing Wisely Italy
● Italian Association of Medical Endocrinologists (AME) recommends against
⚬ routinely requesting or performing thyroid ultrasound in persons without signs or
symptoms of thyroid disease and not belonging to risk groups for thyroid cancer;
limit the indication and execution of !ne needle aspirations on low-risk nodules
⚬ prescribing the dosage of FT3 (free triiodothyronine) for initial evaluation of the
functional state of the thyroid and in the periodic control of hypothyroidism in
therapy
⚬ Reference - Choosing Wisely Italy 2021 Nov PDF , Choosing Wisely Italy 2021 Nov
PDF [Italian]
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Hypothyroidism in Adults

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Hypothyroidism in Adults

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Hypothyroidism in Adults

Overview and Recommendations

Primary and secondary hypothyroidism

Left: Primary hypothyroidism, in which the thyroid

Image courtesy of Gwen Shockey/Science Source/Science Photo

SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2014 Mar;99(3):923

● reported prevalence of elevated thyroid-stimulating hormone (TSH) in pregnant

CASE-CONTROL STUDY: Arch Intern Med 2012 Jan 23;172(2):153

CROSS-SECTIONAL STUDY: Arch Intern Med 2002 Apr 8;162(7):773

CASE-CONTROL STUDY: J Clin Endocrinol Metab 2015 May;100(5):1887

POPULATION-BASED SURVEILLANCE: Eur J Endocrinol 2017 May;176(5):533

Etiology and Pathogenesis

SYSTEMATIC REVIEW: J Clin Endocrinol Metab 2012 Jul;97(7):2243

⚬ transient thyroiditis, including 1

Hormone changes occurring during

In mild thyroid failure, the only detectable

Used with permission from the American College of

Hormone changes occurring during

Because this disorder is due to impaired pituitary

Used with permission from the American College of

● in patients with hypothyroidism who are de!cient in endogenously produced thyroid

History and Physical

Table 1. Clinical Presentation of Hypothyroidism According to Organ Systems

Organ System Symptoms Physical

General metabolism ⚬ Weight gain ⚬ Increase in body

Cardiovascular ⚬ Exertional fatigue ⚬ Bradycardia

Neurosensory ⚬ Hoarseness ⚬ Neuropathy

Neurological and ⚬ Memory loss ⚬ Impaired cognitive

Gastrointestinal Constipation ⚬ Reduced esophageal

Reproductive - female ⚬ Infertility ⚬ Goiter

Reproductive - male ⚬ Decreased libido ⚬ Reduced

Respiratory ⚬ Shortness of breath ⚬ Depressed hypoxic

Musculoskeletal ⚬ Muscle weakness ⚬ Elevated creatine

Hemostasis and ⚬ Bleeding ⚬ Mild anemia

Skin and hair ⚬ Dry skin ⚬ Coarse skin

Electrolytes and kidney Reduced kidney ⚬ Decreased estimated

Reference - Lancet 2017 Sep 23;390(10101):1550 full-text , Thyroid 2016

Past Medical History (PMH)

Brittle nails and hair loss in hypothyroidism

(A) Dry skin, thickened and brittle nails with

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Other Blood Tests

Other Diagnostic Testing

Preparations Recommended for Routine Management of Hypothyroidism

Agents and Preparations Not Recommended for Routine Management of

Management of Overt Primary Hypothyroidism

Table 2. Starting Oral Levothyroxine Doses Based on Age, Physiological, and

Age/Condition Starting Levothyroxine Dose

Young, otherwise-healthy adults with – 1.6-1.8 mcg/kg/day

Adults with mild hypothyroidism (TSH – 25-75 mcg/day, depending on

Older adults (> 65 years old) – 25-50 mcg/day with 12.5-25

Patients with coronary heart disease – 12.5-25 mcg/day with 12.5

Pregnancy – For women with preexisting

Central hypothyroidism – Estimated starting dose 1.3

Patients with cirrhosis or renal failure – No dose adjustment necessary

Abbreviation: TSH, thyroid-stimulating hormone.

Reference - Thyroid 2012 Dec;22(12):1200 , Thyroid 2014 Dec;24(12):1670 , Endocr

● dose adjustment and other management

META-ANALYSIS: Endocrine 2018 Jul;61(1):28

● in some patients, thyroid hormone replacement therapy (levothyroxine

Management of Subclinical Primary Hypothyroidism

Levothyroxine therapy does not appear to improve thyroid-related symptoms or

SYSTEMATIC REVIEW: JAMA 2018 Oct 2;320(13):1349