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Lancet. Author manuscript; available in PMC 2019 July 10.
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Published in final edited form as:

Lancet. 2017 September 23; 390(10101): 1550–1562. doi:10.1016/S0140-6736(17)30703-1.

Hypothyroidism
Layal Chaker,
Academic Centre for Thyroid Disease, Erasmus University Medical Centre, Rotterdam,
Netherlands

Antonio C Bianco,
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA
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Jacqueline Jonklaas, and

Division of Endocrinology, Georgetown University, Washington, DC, USA

Robin P Peeters
Academic Centre for Thyroid Disease, Erasmus University Medical Centre, Rotterdam,
Netherlands

Abstract
Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed
and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is
based on statistical reference ranges of the relevant biochemical parameters and is increasingly a
matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs
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or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight
gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and
sex, among other factors. The standard treatment is thyroid hormone replacement therapy with
levothyroxine. However, a substantial proportion of patients who reach biochemical treatment
targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and
symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and
management; and highlight future directions for research.

Introduction
Hypothyroidism refers to the common pathological condition of thyroid hormone deficiency.
If untreated, it can lead to serious adverse health effects and ultimately death. Because of the
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large variation in clinical presentation and general absence of symptom specificity, the
definition of hypothyroidism is pre-dominantly biochemical. Overt or clinical primary
hypothyroidism is defined as thyroid-stimulating hormone (TSH) concentrations above the
reference range and free thyroxine concentrations below the reference range. Mild or

Correspondence to: Prof Robin P Peeters, Academic Centre for Thyroid Disease, Erasmus University Medical Center, Rotterdam 3000
CA, Netherlands, [email protected].
Contributors
All authors designed the Seminar, drafted and edited the manuscript, approved the final version, and contributed equally to this
Seminar.
Declaration of interests
RPP received lecture fees from GoodLife Fertility BV and Institut Biochemique SA. All other authors declare no competing interests.
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subclinical hypothyroidism, which is commonly regarded as a sign of early thyroid failure,

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is defined by TSH concentrations above the reference range and free thyroxine
concentrations within the normal range. Subclinical hypothyroidism has been reviewed in a
previous Lancet Seminar1 and is therefore not the focus here.

Whether the existing reference ranges of TSH and free thyroxine should be used to define
thyroid dysfunction is a matter of debate. This issue is of clinical importance because the
reference ranges are generally used as a threshold for treatment. Thyroid hormone
replacement with levothyroxine is the standard treatment for patients with hypothyroidism.
However, a substantial proportion of patients treated with levothyroxine have persistent
complaints despite reaching the biochemical therapy targets, which has prompted the
question of whether levothyroxine treatment is sufficient for all patients or whether
alternative therapies (eg, combination with liothyronine preparations) could be adopted.
Hypothyroidism in children and pregnant women are considered separate topics and have
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been discussed elsewhere.2,3

Epidemiology
Prevalence and risk factors
The prevalence of overt hypothyroidism in the general population varies between 0–3% and
3–7% in the USA and between 0–2% and 5–3% in Europe,4–8 depending on the definition
used. A meta-analysis7 of studies across nine European countries estimated the prevalence
of undiagnosed hypothyroidism, including both overt and mild cases, at around 5%.
Differences in iodine status affect the prevalence of hypothyroidism, which occurs more
frequently both in populations with a relatively high iodine intake and in severely iodine-
deficient populations.9,10 Hypothyroidism occurs more frequently in women, in older people
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(>65 years), and in white individuals, although data on ethnic differences are scarce.5,11,12
Hypothyroidism is more common in patients with autoimmune diseases, such as type 1
diabetes, autoimmune gastric atrophy, and coeliac disease, and can occur as part of multiple
autoimmune endocrinopathies. Individuals with Downs’ syndrome or Turners’ syndrome
have an increased risk of hypothyroidism. By contrast, tobacco smoking and moderate
alcohol intake are associated with a reduced risk of hypothyroidism.13,14

Genetic epidemiology
The heritability of TSH and free thyroxine concentrations in serum is estimated to be 65%
and 23–65%, respectively.15,16 Results from genome-wide association studies have so far
explained only a small proportion of thyroid function variability,17 and only three
studies18–20 have focused on hypothyroidism specifically. The loci most consistently
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implicated in hypothyroidism include autoimmunity-related genes and thyroid-specific

regulatory genes (panel). Most of these loci are also associated with serum TSH
concentrations within the reference range.17 Monogenetic disorders leading to congenital
hypothyroidism are rare and include TSH resistance (due to an inactivating mutation in the
TSH receptor), thyroid dysgenesis, and thyroid dyshormonogenesis.21

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Causes
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Hypothyroidism can be classified as primary (due to thyroid hormone deficiency), secondary

(due to TSH deficiency), tertiary (due to thyrotropin-releasing hormone deficiency), and
peripheral (extra-thyroidal; panel). Central hypothyroidism (including both secondary and
tertiary) and peripheral hypothyroidism are rare and account for less than 1% of cases.22

Primary hypothyroidism
In iodine-sufficient areas, the most common cause of hypothyroidism is chronic autoimmune
thyroiditis (also known as Hashimoto’s disease). High concentrations of anti-thyroid
antibodies (predominantly thyroid peroxidase antibodies and anti-thyroglobulin antibodies)
are present in most patients with autoimmune thyroiditis. Raised concentrations of thyroid
peroxidase antibodies are also detected in about 11% of the general population.8 In patients
with subclinical hypothyroidism, thyroid peroxidase antibody measurements help to predict
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progression to overt disease.23,24 The exact mechanisms underlying autoimmune thyroiditis

are not known, but both genetic and environmental factors are involved. A higher genetic
risk score—calculated using five genetic variants for thyroid peroxidase antibodies identified
by genome-wide association studies—showed a graded association with higher TSH
concentrations and clinical hypothyroidism.25,26 Smokers have lower thyroid peroxidase
antibody concentrations than non-smokers, and incidence of autoimmune thyroiditis
increases after smoking cessation.27,28 Other environmental factors implicated in
autoimmune thyroiditis are vitamin D and selenium deficiency, and moderate alcohol intake.
29

Iodine is an essential component of thyroid hormone. Iodine deficiency can result in goitre,
thyroid nodules, and hypothyroidism. The most severe consequence of iodine deficiency is
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cretinism (ie, restricted mental and physical development in utero and during childhood).
Iodine fortification programmes are one of the safest and cheapest public health
interventions for the prevention of cognitive and physical impairment.30,31 Despite such
efforts, suboptimal iodine status still affects large parts of Africa and Asia, as well as
specific subpopulations in several high-income countries—most notably, pregnant women in
some areas of Italy, USA, and the UK.31–33 In populations that shift from severe to mild
iodine deficiency, the prevalence of hypothyroidism decreases; in populations shifting from
mild deficiency to optimum or excessive intake of iodine, the prevalence of autoimmune
hypothyroidism increases.34,35

Iodine-containing drugs (eg, amiodarone) can restrict thyroid hormone production through
iodine overload, immediately blocking thyroid hormone synthesis (ie, Wolff-Chaikoff
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effect). About 14% of patients treated with amiodarone develop hypothyroidism.36 Lithium
also causes hypothyroidism via effects on thyroid hormone synthesis and release.37 In a
large population-based cohort study,38 6% of patients needed levothyroxine therapy within
18 months of starting lithium treatment. Tyrosine kinase inhibitors are used as targeted
therapy for several cancers. An analysis of clinical reports from the US Food and Drug
Administration Adverse Event Reporting System,39 found that patients who received
sunitinib developed hypothyroidism more frequently than patients treated with sorafenib.
Several other drugs—including interferon-alfa, thalidomide, some monoclonal antibodies,

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antiepileptic drugs, and drugs for second-line treatment of multidrug-resistant tuberculosis—

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can also cause primary hypothyroidism (panel).

Hypothyroidism is common after radioiodine treatment, after hemithyroidectomy, and after

neck radiation or surgery for cancer therapy.40–44 In the long term, about 80% of patients
with Grave’s disease who are treated with radioiodine will develop hypothyroidism, even
when low doses are used. Hypothyroidism is reported to occur in 55% of patients treated for
toxic nodular goitre40 and about 8% of patients treated for solitary toxic nodules.45 In a
meta-analysis43 of 32 studies, 20% of patients developed hypothyroidism after
hemithyroidectomy. Other causes of primary hypothyroidism include transient thyroiditis
and infiltrative disease (panel).

Central hypothyroidism
Central hypothyroidism is rare and affects both sexes equally. It is more often associated
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with pituitary than hypothalamic disorders but frequently involves both.22 Biochemically,
central hypothyroidism is defined by low or low-to-normal TSH concentrations and a
disproportionately low concentration of free thyroxine. Occasionally, TSH concentration is
mildly elevated, probably because of decreased bioactivity.46 Over half of central
hypothyroidism cases are caused by pituitary adenomas.22 Other causes of central
hypothyroidism include pituitary or hypothalamic dysfunction due to head trauma, pituitary
apoplexy, Sheehan’s syndrome, surgery, radiotherapy, genetic, and infiltrative disease.
Several drugs are known to affect the hypothalamic–pituitary–thyroid axis (panel).47,48

Peripheral hypothyroidism
Consumptive hypothyroidism is caused by aberrant expression of the deiodinase 3 enzyme
(which inactivates thyroid hormone) in tumour tissues. Although very rare, such
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overexpression can induce severe hypothyroidism. Elevated concentration of deiodinase 3

was first described in a newborn baby with infantile hepatic haemangiomatosis, but can also
occur in patients with vascular and fibrotic tumours and gastrointestinal stromal tumours.49
Patients with rare genetic syndromes that lead to a reduced sensitivity to thyroid hormone
(panel) usually have normal TSH concentrations, but can also present with tissue-specific
hypothyroidism.50

Clinical presentation and implications

Myxedema coma and severe hypothyroidism
The clinical manifestations of hypothyroidism range from life threatening—in the case of
myxedema coma—to no signs or symptoms. Myxedema coma, which was first described in
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the late 1900s as an outcome of long-standing untreated and severe hypothyroidism, has
become a rare condition. Nevertheless, because the disease course is striking, with mortality
of 40% despite treatment, early recognition is vital.51 Myxedema coma leads to an altered
mental status, hypothermia, progressive lethargy, and bradycardia and can eventually result
in multiple organ dysfunction syndrome and death. Therefore, early initiation of thyroid
hormone therapy and other supportive measures is crucial.52

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Although very rare, severe primary hypothyroidism can lead to pituitary hyperplasia with
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concomitant pituitary pathology (eg, secondary adrenal insufficiency) and symptoms (eg,
amenorrhoea).53

Signs and symptoms

The most common symptoms of hypothyroidism in adults are fatigue, lethargy, cold
intolerance, weight gain, constipation, change in voice, and dry skin, but the clinical
presentation can include a wide variety of symptoms that differ with age, sex, and time
between onset and diagnosis (table 1).54,55 The symptoms for the diagnosis of
hypothyroidism are non-specific, especially in elderly patients who present with fewer and
less classic signs and symptoms than younger individuals.55 An increase in the severity of
symptoms might predict hypothyroidism, since a change in seven or more symptoms in the
past year increases the likelihood of hypothyroidism (likelihood ratio 8–7).56 However, in a
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case-control study,57 none of 34 hypothyroidism-related symptoms could be used to identify

patients with hypothyroidism. Furthermore, 15% of patients with autoimmune
hypothyroidism are asymptomatic or report only one hypothyroidism-associated symptom,
whereas 70% of euthyroid controls have one or more thyroid- associated complaints.57

Hypothyroidism has clinical implications related to nearly all major organs (table 1), but the
cardiovascular system is the most robustly studied. Hypothyroidism results in increased
vascular resistance, decreased cardiac output, decreased left ventricular function, and
changes in several other markers of cardiovascular contractility. Myocardial injuries and
pericardial effusions are more common in patients with hypothyroidism than in matched
euthyroid controls.58 Furthermore, patients with hypothyroidism have a higher prevalence of
cardiovascular risk factors and often have features of metabolic syndrome, including
hypertension, increased waist circumference, and dyslipidaemia.59 Hypothyroidism also
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increases total cholesterol, low-density lipoprotein, and homocysteine concentrations.

Patients with acute hypothyroidism, in the context of thyroid cancer treatment, show a
decline in mood and quality of life.60 Hypothyroidism is considered a cause of reversible
dementia; however, how often this occurs and in what proportion of patients dementia is
truly reversible is unclear.61 Other manifestations include neurosensory, musculoskeletal,
and gastrointestinal signs and symptoms (table 1). Because of the pleiotropic effects of
thyroid hormone, hypothyroidism can also affect the course of other disorders. For example,
statin intolerance is more prevalent in individuals with hypothyroidism than in controls
without hypothyroidism.62

Long-term outcomes
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Most long-term consequences of hypothyroidism have been studied in the context of

subclinical hypothyroidism, because overt hypothyroidism is generally treated. Few
studies63–65 have investigated the association of hypothyroidism with all-cause mortality and
results are mainly available for subclinical hypothyroidism. Results from a population-based
follow-up study65 of 599 participants aged 85 years suggested that, in elderly populations,
subclinical hypothyroidism might be associated with better survival than euthyroidism or
suppressed TSH. However, this finding was not confirmed in a large individual participant-

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based meta-analysis63 that included more than 2500 participants (aged >80 years). This
meta-analysis63 showed an increased risk of coronary heart disease events and mortality in
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those with higher TSH concentrations, particularly those with TSH concentrations above 10
mIU/L. However, the association between hypothyroidism and coronary artery disease has
been recognised for a long time.66 Subclinical hypothyroidism with TSH concentrations
above 10 mIU/L has also been associated with an increased risk of heart failure.63,67 Patients
with hypothyroidism undergoing percutaneous coronary intervention have more major
adverse cardiovascular and cerebral events than those with normal thyroid function and
those with adequately treated hypothyroidism.68 By contrast, the association with stroke is
less evident and might be apparent only in younger individuals (<65 years).69 Patients with
hypothyroidism have fewer neurological deficits post-stroke than controls without elevated
TSH concentrations;70 normally after a stroke localised hypothyroidism is observed as a
result of deiodinase 3 induction in the ischaemic brain area.71,72 The risk of coronary heart
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disease in patients with subclinical hypothyroidism does not differ by thyroid peroxidase
antibody concentrations, suggesting that autoimmunity per se is not a contributing factor to
the association.73 Hypothyroidism can present with cognitive impairments and dementia but
the association is controversial, because results from several population-based cohort
studies74–77 showed a protective effect of elevated TSH concentrations on the risk of
dementia.

Hypothyroidism has also been associated with nonalcoholic fatty liver disease, cancer
mortality, arthritis, kidney dysfunction, and diabetes; however, in most cases causality is
suggested but not proven.78–82

Diagnosis
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Primary hypothyroidism is defined by TSH concentrations above the reference range (most
commonly used 0–4-4–0 mIU/L) and free thyroxine concentrations below the reference
range, which is dependent on the type of assay used and the population studied (figure 1).
The US Preventive Service Task Force83 has suggested reserving the term overt
hypothyroidism for cases in which patients present with symptoms. However, such a
definition is challenging in practice because of the large variability in presentation of even
severe hypothyroidism. Additionally, patients might recognise previous symptoms only after
the initiation of levothyroxine treatment.

TSH has circadian fluctuations, with higher concentrations towards the evening. Patients
with severe hypothyroidism show irregularity of TSH secretion.84 Seasonal variations have
also been described, with higher TSH concentrations in winter and spring than in autumn
and summer.85 No indications exist for routine measurement of total tri-iodothyronine, total
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thyroxine, or free tri-iodothyronine. Measurement of thyroid peroxidase antibody is not

strictly necessary to diagnose hypothyroidism but is useful to affirm the diagnosis of
autoimmune primary hypothyroidism. Hypothyroidism is often characterised by a
hypoechogenic pattern on thyroid sonography, even in the absence of raised thyroid
peroxidase antibody concentrations. However, in the absence of additional clinical
indications, such as abnormal thyroid palpation, an ultrasound is not required.

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Reference ranges of thyroid function tests

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Most commercially available TSH and free thyroxine assays are immunoassays, and their
reference ranges are statistically defined as between the 2 · 5th and 97 · 5th percentile in an
apparently healthy population. Therefore, the reference ranges do not consider symptoms or
the risk of adverse events or disease, which is demonstrated by studies showing an increased
risk of adverse events with variations in thyroid function even within these reference ranges.
76,86–89 Furthermore, the reference ranges differ with age, sex, and ethnic origin.90 The

applied reference ranges for thyroid function have been a matter of debate in recent years.
91,92 The upper limit of TSH reference ranges typically increases with age in adults, and

age-specific reference ranges gave conflicting results in younger individuals in studies from
the UK and Australia.93,94 Nevertheless, in both studies,93,94 the use of age-specific
reference ranges led to a reclassification from abnormal to normal thyroid function
predominantly in older individuals. Little information exists about the consequences of
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treatment and thus no convincing arguments have been put forward to change the applied
reference ranges.

Conditions that interfere with diagnosis

Several conditions can interfere with the laboratory measurements of thyroid analytes.
Interference should be suspected when thyroid function tests do not match the clinical
presentation (figure 2). Human anti-animal antibodies in patient’s serum can cause falsely
high TSH concentrations and can interfere with free thyroxine equilibrium dialysis platform
assays. Heparin, including low-molecular-weight heparin, can lead to falsely elevated
concentrations of free thyroxine.95 High intake of biotin, a popular over-the-counter
supplement, can interfere with biotin-based hormone assays, leading to false results of
thyroid function tests.
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Free thyroxine measurement is important to the diagnosis of hypothyroidism (eg, central

hypothyroidism) and during follow-up and treatment. The accuracy of free thyroxine
immunoassays has been questioned in conditions that affect binding protein concentrations
(ie, albumin or thyroxine-binding globulin), such as pregnancy or acute illness. However,
free thyroxine assays generally perform well in daily clinical practice. Free thyroxine
measured by liquid chromatography-tandem mass spectrometry seems to perform better than
immunoassays in certain clinical conditions, such as acute illness and pregnancy,96 but is not
available in most health-care facilities.

Independent of measurement artifacts, severe illness is characterised by low thyroid

hormone status, but TSH concentration is generally within the normal range, although it can
be transiently increased during recovery from a non-thyroidal illness.97 Changes in thyroid
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hormone metabolism, thyroid hormone transporters, and thyroid hormone receptors all have
a role in the pathophysiology of non-thyroidal illness. Non-thyroidal illness occurs in
different disease states, but is present in almost all critically ill patients.97 Thyroid function
testing should therefore not be done in these patients, unless thyroid disease or central
hypothyroidism is suspected. No evidence exists that thyroid hormone replacement therapy
is beneficial in critically ill patients.

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Screening
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Despite the high prevalence of hypothyroidism, easy diagnostics, and cheap treatment, no
consensus has been reached about TSH screening in specific subgroups of the general
population. Several organisations—including the American Thyroid Association, American
Association of Clinical Endocrinologists, and the Latin American Thyroid Society—
recommend screening above a particular age (ranging from every 5 years for individuals
aged >35 years to periodically for those aged ≥60 years), especially in women.98,99 The US
Preventive Services Task Force83 found no evidence for or against screening, whereas the
UK Royal College of Physicians100 suggests that screening of the general population is
unjustified. However, evidence98 does support case finding in patients with dementia,
infertility, autoimmune diseases, hypercholesterolaemia, dysmenorrhoea, or a family history
of autoimmune hypothyroidism, in patients taking amiodarone or lithium, or in those at risk
of iatrogenic hypothyroidism (eg, after neck radiation).
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Treatment
Levothyroxine monotherapy in solid formulation, taken on an empty stomach, is the
treatment of choice. The presence of clinical features of hypothyroidism, with biochemical
confirmation of overt hypothyroidism, is the indication for treatment initiation. No rationale
exists for avoiding the prescription of generic preparations, but switches between
levothyroxine products in patients who are stable are not recommended.101 The optimal
daily dose in overt hypothyroidism is 1·5—1·8 μg per kg of bodyweight.101–103 In patients
with coronary artery disease, the starting dose is generally 12·5—25·0 μg per day and should
be gradually increased on the basis of symptoms and TSH concentrations.101 This regimen
is often preferred in the elderly, especially in patients with many co-morbidities.101,102 In
younger patients without comorbidities, the full dose can usually be given from the start
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with adequate monitoring to avoid overtreatment. After the initiation of therapy, TSH
measurement is repeated after 4–12 weeks and then every 6 months and, once stabilised,
annually. Adjustments should be made according to laboratory findings, keeping in mind
that in some patients (ie, those with low bodyweight or older patients) small changes in dose
can have substantial effects on serum TSH concentrations. The clinical significance of low
tri-iodothyronine concentrations in some patients despite reaching normal TSH
concentrations is unknown. Routine measurement of tri-iodothyronine should not be used to
assess treatment effectiveness.104

Women of childbearing age

Because of physiological changes during pregnancy, an increase in levothyroxine dose is
required to maintain euthyroidism.105 Therefore, women of childbearing age with
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levothyroxine-treated hypothyroidism should be informed to increase their dose by 30%

once pregnant and directly contact their physician for further guidance.106 Screening, the
definition of subclinical hypothyroidism, and potential treatment during pregnancy are
beyond the scope of this Seminar.107,108

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Treatment targets
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Treatment targets include normalisation of TSH concentrations and resolution of physical

and mental complaints, while avoiding undertreatment or overtreatment.101 Nevertheless, an
estimated 35—60% of patients treated with levothyroxine do not reach the target range of
TSH (either overtreated or undertreated).109,110 Results from a retrospective cohort study in
the UK109 showed that, after 5 years of levothyroxine therapy, almost 6% of patients have
TSH concentrations below 0–1 mIU/L and more than 10% have TSH concentrations above
10–0 mIU/L. Overtreatment (ie, iatrogenic subclinical or overt hyperthyroidism) can have
deleterious health effects, such as atrial fibrillation and osteoporosis, and should always be
avoided, especially in the elderly and postmenopausal women. Undertreatment (ie, persistent
thyroid hormone deficiency) can result in an increased risk of cardiovascular disease and
persistent signs and symptoms. Treatment targets for central hypothyroidism are different
from primary hypothyroidism because clinicians cannot rely on the so- called reflex TSH
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strategy. Further information on the treatment of central hypothyroidism can be found

elsewhere.22

Failure to reach treatment targets

Factors that prevent patients from reaching therapy targets include prescription or intake of
inadequate doses, interaction with supplements or medication, concurrent medical
conditions, and non-adherence to therapy (table 2). Lower levothyroxine doses are needed to
suppress TSH secretion in the elderly and higher doses are needed after thyroidectomy.
Levothyroxine treatment and therapy targets in the context of thyroid malignancy are beyond
the scope of this Seminar.

Levothyroxine is absorbed in the small intestine and intake is advised in the morning 30–60
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min before breakfast. Intake before bedtime (2–3 h after last meal) might improve
absorption and can be considered to increase compliance.111 Several drugs can interfere with
the absorption, availability, or metabolism of levothyroxine, although evidence for some of
these preparations comes from n-of-1 trials. Gastrointestinal conditions that reduce
levothyroxine absorption include Helicobacter pylori gastritis, coeliac disease, and
autoimmune atrophic gastritis. Results from some studies112,113 suggest that liquid and soft
gel formulations of levothyroxine do not depend on gastric pH for absorption, and could
provide a solution for patients with difficulties ingesting levothyroxine 30–60 min before
breakfast. In a double-blind randomised crossover trial114of liquid thyroxine in 77
treatment-naive patients with hypothyroidism, no significant differences in thyroid function
tests were seen when the liquid preparation was ingested at breakfast or 30 min before
breakfast. However, no studies have compared liquid gel formulations of levothyroxine with
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solid formulations in relation to clinical outcomes.

For individuals in whom high TSH concentrations persist and other causes have been
excluded, the possibility of non-adherence, a common cause of therapy failure, should be
considered and discussed with the patient. High TSH concentrations with normal or
highnormal free thyroxine concentrations can be a result of levothyroxine tablets taken
shortly before blood sampling. A supervised thyroxine absorption test to distinguish non-

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adherence from other reasons for undertreatment should be considered. Figure 3 shows a
suggested protocol that combines both acute and long-term supervised administration.115,116
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Persistent complaints despite biochemical normalisation of TSH

About 5–10% of biochemically well controlled patients with levothyroxine-treated
hypothyroidism have persistent symptoms, such as depression and impaired mental
wellbeing.117 Concurrent diseases or perimenopausal status might cause these complaints
and should be excluded. Patients with hypothyroidism have a higher prevalence of
autoimmune diseases than the general population, which could give rise to similar
symptoms. Autoimmunity per se has been suggested to lead to persistent symptoms.118

Circulating thyroid hormone concentrations are regulated by the hypothalamic–pituitary–

thyroid axis with an individually determined set-point, reflected by a smaller intraindividual
variability than interindividual variability.119 Therefore, the TSH concentration needed to
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achieve similar concentrations of circulating thyroid hormones differs between individuals.

Differences in individual set-point could explain why patients with similar TSH
concentrations under treatment respond differently. However, the individual set-point before
hypothyroidism is rarely known. Also, studies120,121 that target different TSH goals
generally do not show alterations in wellbeing or other clinical parameters.

An alternative explanation for persistent complaints in specific patients might be the

imperfections oflevothyroxine monotherapy itself. Generally, levothyroxine can ensure
adequate concentrations of circulating thyroxine that can then be converted into tri-
iodothyronine by deiodination via deiodinase 1 and deiodinase 2. However, in euthyroid
patients, about 20% of circulating tri-iodothyronine is derived from direct thyroidal
secretion, whereas in patients on levothyroxine monotherapy all tri-iodothyronine is derived
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from the conversion of peripheral thyroxine to triiodothyronine. Consequently, patients on

levothyroxine monotherapy have higher free thyroxine to triiodothyronine ratios than
euthyroid individuals. Some patients with normalised TSH have serum tri-iodothyronine
concentrations below the reference range, while free thyroxine serum concentrations are
high.122–124 The clinical significance of this occurrence is unknown. However,
levothyroxine monotherapy cannot restore physiological tri-iodothyronine concentrations or
thyroid hormone-dependent biological effects in all tissues of hypothyroid rats.125,126
Although a normal TSH concentration reflects euthyroidism at the level of the pituitary, this
might not necessarily reflect euthyroidism in all tissues. Tissue-specific differences in the
inactivation of deiodinase 2 could play a part, resulting in the normalisation of
triiodothyronine concentrations in the hypothalamus before tri-iodothyronine concentrations
have fully normalised in the rest of the body.125
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Levothyroxine–liothyronine combination therapy

Several trials using combined levothyroxine–liothyronine therapy have been done in the past
15 years.127 Although some studies128–131 show a beneficial effect, such as patient
preference for combination therapy or an improved metabolic profile, patients on
combination therapy generally do not have improved outcomes compared with those on
levothyroxine monotherapy.132 Possible explanations include inadequate levothyroxine and

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liothyronine doses or frequency of administration.133 Liothyronine has a short half-life and

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no previous studies used a slow-release tri-iodothyronine. Additionally, most trials were of

short duration (<4 months) and used questionnaires to record patients’ symptoms, which
might not have been targeted or sensitive enough.

Alternatively, trials might have failed to identify the appropriate subgroups that would
benefit from combination therapy. Most trials did not specifically recruit patients who feel
unwell on levothyroxine or those with particularly low serum tri-iodothyronine
concentrations. Individuals with genetic variations in thyroid hormone metabolism have not
been specifically targeted.133 A subgroup that could be targeted is individuals with common
genetic variations in DIO2, which encodes the deiodinase 2 enzyme that converts thyroxine
to tri-iodothyronine locally in several tissues, including the brain.134 The Thr92Ala
polymorphism in DIO2 gives rise to deiodinase 2 with a longer half-life than the wild-type
enzyme and ectopic localisation in the Golgi apparatus. It was shown to alter expression
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profiles in the cerebral cortex in a similar pattern as seen in neurodegenerative disease,

without evidence of altered thyroid hormone signalling.135 In a study136 of 552 people, the
Thr92Ala polymorphism in DIO2 was associated with lower baseline psychological
wellbeing in patients on levothyroxine replacement therapy and with better response to
combination therapy, compared with patients without the polymorphism on levothyroxine
replacement therapy. However, after appropriate multiple testing correction, the results were
not significant. Results from a population-based cohort study137 showed no effect of the
Thr92Ala polymorphism on quality of life or cognitive function measures. Sufficiently
powered prospective randomised controlled trials are therefore needed before conclusions
can be drawn.

Although the American Thyroid Association101 and European Thyroid Association138

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guidelines generally recommend against the routine use of combination therapy in patients
with hypothyroidism, the recommendations concerning trials in patients with persistent
symptoms differ slightly. The European Thyroid Association states that a 3 month trial of
levothyroxine–liothyronine combination might be considered experimentally in adherent,
biochemically well controlled patients who have persistent complaints despite levothyroxine
treatment138 and provides methods for calculating levothyroxine and liothyronine doses.138
However, treatment should be initiated only by accredited doctors of internal medicine or
endocrinologists, closely monitored, and discontinued if no improvement is seen. By
contrast, the American Thyroid Association recommends against any routine use of such
trials outside of formal research and clinical trials, mainly because of uncertainty regarding
benefit and long-term safety.101 Both the European Thyroid Association and American
Thyroid Association agree on the need for long-term randomised controlled trials to assess
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risk-benefit ratios. Such trials would need to incorporate investigation of the ideal thyroid
parameters to monitor during combination therapy, and whether tri-iodothyronine
concentrations would be an important parameter. The timing of phlebotomy is also
important, particularly if liothyronine is being administered more than once daily.

Little evidence exists to support other therapies for hypothyroidism. The use of thyroid
extracts or liothyronine monotherapy is generally not recommended because of potential
safety concerns associated with the presence of supraphysiological serum tri-iodothyronine

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 Chaker et al. Page 12

concentrations and a paucity of long-term safety outcome data. The use of compounded
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thyroid hormones, dietary supplements, and any over-the-counter drug for the treatment of
hypothyroidism is discouraged.

Directions for future research

Although great advances have been made in the identification of causes, knowledge of
clinical implications, diagnosis, and treatment of hypothyroidism, several unanswered
questions remain, especially regarding diagnosis and treatment.

Many risk factors have been identified for abnormal TSH concentrations, free thyroxine
concentrations, and thyroid disease, but only a small proportion of the variability is
explained.139 Therefore, identification of risk factors is important. Increasing evidence
shows that endocrine-disrupting chemicals might be casual factors for endocrine diseases.
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Thyroid-disrupting chemical exposure can come from sources ranging from environmental
(eg, flame retardants) to dietary (eg, food packaging material).140 A transatlantic call for
action has been made to answer these questions in a collaborative effort.141

The association of hypothyroidism with cardiovascular disease has been established and
replicated in several studies.63,67 However, the mechanisms behind this association remain
unclear. The link between hypothyroidism and several cardiovascular diseases seems
independent of traditional cardiovascular risk factors.63,67,69 Further research focused on
novel cardiovascular risk factors or other pathways could shed light on the exact
mechanisms, which would be crucial to support treatment decisions and monitor strategies
in patients with asymptomatic hypothyroidism.

The diagnosis of hypothyroidism is currently based on statistically defined reference ranges

Author Manuscript

for TSH and free thyroxine, which do not consider whether patients are at risk to develop
disease. Because of the arbitrary nature of the cutoffs that define mild and overt
hypothyroidism, an alternative grading system based on thyroid function tests has been
proposed. The arbitrary nature of these cutoffs was also highlighted by the US Preventive
Service Task Force83 as one of the important factors hampering decision making for
screening of thyroid dysfunction in asymptomatic patients. These cutoffs also affect
treatment decisions in asymptomatic patients with hypothyroidism. More research is needed
to identify which adverse health events occur after long-term thyroid dysfunction.
Furthermore, which concentrations of TSH and free thyroxine are accompanied by an
increased risk of disease needs to be established. This information can be obtained from
collaborative observational cohort studies with sufficiently long follow-up. Once this
information is available, randomised controlled trials can assess whether treatment of
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thyroid function beyond these cutoffs for thyroid function test concentrations reduces excess
risk and also the risk–benefit ratio of treatment.

Levothyroxine monotherapy is the standard treatment for hypothyroidism. However, several

unresolved issues exist concerning patients who are biochemically well controlled but
unsatisfied with their treatment outcome. Future studies should address whether alternative
regimens could provide a solution for at least a proportion of patients with residual

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 Chaker et al. Page 13

symptoms. Research areas most urgently in need of progress include: identification of the
Author Manuscript

causes of persistent symptoms in biochemically well controlled patients, assessment of

whether a more adequate dose (eg, tailored to patient serum triiodothyronine or to a patient’s
own particular TSH set-point) produces more satisfactory outcomes, investigation of
whether new formulations (eg, slow-release liothyronine) or increased administration
frequency of levothyroxine–liothyronine combination therapy (eg, liothyronine three times
daily) can ameliorate patient symptoms, and identification of patient subgroups that could
benefit from therapies other than levothyroxine monotherapy (eg, by identifying additional
genetic polymorphisms that could provide information on the individual thyroid set-point).
Genome-wide association studies that include a large number of individuals with detailed
genotyping could provide such information.

Supplementary Material
Author Manuscript

Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
We thank Wichor Bramer (Erasmus Medical Center, Rotterdam, Netherlands) for the important contribution to the
literature search.

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Search strategy and selection criteria

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We searched Embase, MEDLINE, and the Cochrane database between Jan 1, 2000 and
Sept 22, 2016, for articles published in or translated into English. The full search and
search terms are provided in the appendix. We mainly selected publications from the past
3 years, but did not exclude commonly referenced and highly regarded older publications.
We also searched the reference lists of articles identified by this search and selected those
we judged relevant. We supplemented the search with mainly older records from personal
files. Review articles are cited to provide additional details and references.
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Panel: Causes of hypothyroidism

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Primary hypothyroidism

• Chronic autoimmune thyroiditis (also known as Hashimoto’s thyroiditis)

• Iodine—severe iodine deficiency, mild and severe iodine excess

• Drugs—eg, amiodarone, lithium, tyrosine kinase inhibitors, interferon-alfa,

thalidomide, monoclonal antibodies (eg, ipilimumab and nivolumab),
antiepileptic drugs (eg, valproate), drugs for second-line treatment of
multidrug-resistant tuberculosis

• Iatrogenic—radioiodine treatment (eg, for Graves’ disease or toxic nodular

disease), hemithyroidectomy, radiotherapy or surgery in the neck or head
region
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• Transient thyroiditis—viral (De Quervain’s syndrome), post-partum, silent

thyroiditis, destructive thyroiditis

• Thyroid gland infiltration*—infectious (eg, mycoplasma), malignant (eg,

thyroid malignancy, lymphoma, metastasis of malignancy elsewhere),
autoimmune (eg, sarcoidosis), inflammatory (eg, Riedels’s thyroiditis)

• Genetic*—autoimmunity-related genes (eg, HLA class I region, PTPN22,

SH2B3, and VAV3), general and thyroid-specific genes (eg, FOXE1, ATXN2,
and PDE8B)

Central hypothyroidism

• Pituitary tumours (secreting or non-secreting)

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• Pituitary dysfunction (eg, Sheehan’s syndrome)

• Hypothalamic dysfunction (eg, post-traumatic)

• Resistance to thyroid-stimulating hormone (TSH) or thyrotropin-releasing

hormone

• Drugs (eg, dopamine, somatostatins, glucocorticosteroids, and retinoid X

receptor selective ligands)

• Increased TSH concentration due to leptin stimulation†

Peripheral (extra-thyroidal) hypothyroidism

• Consumptive hypothyroidism
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• Tissue-specific hypothyroidism due to decreased sensitivity to thyroid

hormone (eg, mutations in MCT8 [also known as SLC16A2], SECISBP2,
THRA, THRB)
*Rare causes of primary hypothyroidism. †Evidence mainly from animal models.

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Figure 1: Diagnosis and treatment of primary hypothyroidism

TSH=thryoid-stimulating hormone.
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Figure 2: Interpretation of thyroid function tests associated with hypothyroidism

TSH=thryoid-stimulating hormone. TRH=thyrotropin-releasing hormone. *TSH can also be
suppressed.
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Figure 3: Thyroxine absorption test

Protocol for supervised thyroxine absorption test, followed by weekly supervised thyroxine
administration. Adapted from reference 115, by permission of Elsevier. TSH=thryoid-
stimulating hormone. *Laboratory test values, especially an increase in free thyroxine, can
be interpreted already at this stage. †Adequate free thyroxine rise is estimated to be roughly
50% from baseline at 120 min.116
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Table 1:

Clinical presentation and implications of hypothyroidism

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Presentation Signs and implications

General metabolism Weight gain, cold intolerance, Increase in body-mass index, low metabolic rate, myxedema*,
fatigue
hypothermia*
Cardiovascular Fatigue on exertion, shortness of Dyslipidaemia, bradycardia, hypertension, endothelial dysfunction or
breath increased intima-media thickness*, diastolic dysfunction*, pericardial
effusion*, hyperhomocysteinemia*, electrocardiogram changes*
Neurosensory Hoarseness of voice, decreased Neuropathy, cochlear dysfunction, decreased olfactory and gustatory
taste, vision, or hearing sensitivity
Neurological and psychiatric Impaired memory, paresthesia, Impaired cognitive function, delayed relaxation of tendon reflexes,
mood impairment depression*, dementia*, ataxia*, Carpal tunnel syndrome and other
nerve entrapment syndromes*, myxedema coma*
Gastrointestinal Constipation Reduced oesophageal motility, non-alcoholic fatty liver disease*,
ascites (very rare)
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Endocrinological Infertility and subfertility, Goiter, glucose metabolism dysregulation, infertility, sexual
menstrual disturbance, dysfunction, increased prolactin, pituitary hyperplasia*
galactorrhoea
Musculoskeletal Muscle weakness, muscle Creatine phosphokinase elevation, Hoffman’s syndrome*, osteoporotic
cramps, arthralgia
fracture* (most probably caused by overtreatment)
Haemostasis and haematological Bleeding, fatigue Mild anaemia, acquired von Willebrand disease*, decreased protein C
and S*, increased red cell distribution width*, increased mean platelet
volume*
Skin and hair Dry skin, hair loss Coarse skin, loss of lateral eyebrows*, yellow palms of the hand*,
alopecia areata*
Electrolytes and kidney function Deterioration of kidney function Decreased estimated glomerular filtration rate, hyponatraemia*

*
Uncommon presentation.
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Table 2:

Reasons for failure to reach levothyroxine treatment goals and recommendations

Recommendations
Chaker et al.

Elevated TSH with or without (persistent) symptoms

Inadequate dose Consider higher doses, especially in patients with no remaining functional thyroid capacity (eg, after total thyroidectomy
or radioablation therapy for Graves’ disease)
Simultaneous intake of levothyroxine with food can impair absorption Intake 30–60 min before breakfast or at bedtime (2–3 h after evening meal); discuss patient preference

Some drugs can affect levothyroxine absorption—eg, calcium carbonate*, Separate intake of levothyroxine from interfering medications and supplements
(eg,4 h)
ferrous sulfate*, proton pump inhibitors, aluminium containing antacid,
sucralfate, and orlistat
Some drugs can affect levothyroxine availability and requirement— eg, Monitor TSH at initiation and adjust levothyroxine dose if required
oestrogens, androgens, sertraline, phenobartbital†, carbamazepine,
phenytoin, and rifampicin
Malabsorption due to gastrointestinal disease and conditions Helicobacter pylori gastritis, coeliac disease, autoimmune atrophic gastritis, and diabetic gastropathy should be considered
and treated if possible
Non-adherence Common cause, but should be suspected after other causes have been excluded; consider thyroxine absorption test
Normal TSH and (persistent) symptoms
Concurrent (autoimmune) disease or causes Autoimmune atrophic gastritis with pernicious anaemia, Addison’s disease, diabetes, and rheumatoid arthritis could be
considered
Inadequate thyroid hormone concentrations at the tissue level Acknowledgment of the patient’s symptoms; check if the patient feels better at a different TSH concentration in the normal
range (ie, an individual set-point); a trial of levothyroxine–liothyronine combination therapy can be considered in adherent
patients with long-lasting steady state of TSH in serum
Low TSH with or without (persistent) symptoms
Overtreatment due to high doses Consider lower doses in elderly individuals and patients with subclinical hypothyroidism; ask if the patient takes any over-
the-counter preparations that might contain thyroid hormone

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Medical conditions—certain drugs (eg, metformin) and weight loss can Consider lower doses
decrease TSH concentrations

TSH= thyroid-stimulating hormone.

*
Evidence from prospective trials.
†
Antiepileptic drugs accelerate thyroxine and tri-iodothyronine conjugation but serum concentrations of TSH do not necessarily increase.
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