SEMINAR

Seminar

Hypothyroidism

Caroline G P Roberts, Paul W Ladenson

Hypothyroidism is common, potentially serious, often clinically overlooked, readily diagnosed by laboratory testing,
and eminently treatable. The condition is particularly prevalent in older women, in whom autoimmune thyroiditis is
common. Other important causes include congenital thyroid disorders, previous thyroid surgery and irradiation, drugs
such as lithium carbonate and amiodarone, and pituitary and hypothalamic disorders. Worldwide, dietary iodine
deficiency remains an important cause. Hypothyroidism can present with nonspecific constitutional and neuro-
psychiatric complaints, or with hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or hyperhomo-
cysteinaemia. Severe untreated hypothyroidism can lead to heart failure, psychosis, and coma. Although these
manifestations are neither specific nor sensitive, the diagnosis is confirmed or excluded by measurements of serum
thyrotropin and free thyroxine. Thyroxine replacement therapy is highly effective and safe, but suboptimal dosing is
common in clinical practice. Patient noncompliance, drug interactions, and pregnancy can lead to inadequate
treatment. Iatrogenic thyrotoxicosis can cause symptoms, and, even when mild, provoke atrial fibrillation and
osteoporosis. We summarise present understanding of the history, epidemiology, pathophysiology, and clinical
diagnosis and management of hypothyroidism.

Hypothyroidism is the most common pathological reported by Murray in 1891. Thyroid hormone was
hormone deficiency. The variety of end-organ effects and crystallised in 1914 by Kendall. Reports of thyroxine’s
wide range of disease severity—from entirely synthesis by Harington and Barger, and of its initial
asymptomatic individuals to patients in coma with physiological testing both appeared in 1927. Tri-
multisystem failure—can make hypothyroidism an elusive iodothyronine was discovered by Pitt-Rivers and Gross in
clinical entity. Once suspected, the diagnosis can usually 1952; and its endogenous generation from thyroxine was
be quickly confirmed or excluded, treatment is described by Ingbar, Sterling, and Braverman in 1970. In
straightforward, and the patient’s prognosis is excellent. 1963, Condliffe purified thyrotropin (thyroid stimulating
This review summarises current understanding of the hormone), and soon thereafter Odell and Utiger both
history, epidemiology, pathophysiology, and clinical reported the first immunoassays for human thyrotropin.
diagnosis and management of hypothyroidism. In 1971, Mayberry and Hershman simultaneously
described use of thyrotropin immunoassays for diagnosis
History of hypothyroidism.
In 1874, Gull described several previously healthy women
who acquired clinical features similar to those in Definitions
cretinism. 4 years later, Ord coined the term myxoedema Hypothyroidism can be classified on the basis of its time
to describe a syndrome in five women with coarse of onset (congenital or acquired), the level of endocrine
features, mental dullness, dry skin, hypothermia, and dysfunction responsible (primary or secondary, also
oedema. At much the same time, two Swiss thyroid termed central, hypothyroidism), and its severity (overt
surgeons, Kocher and Reverdin, independently described [clinical] or mild [subclinical]). In patients with primary
cachexia strumipriva, a cretin-like state developing after hypothyroidism, in whom serum thyrotropin is elevated,
thyroidectomy. In 1883, the Clinical Society of London the distinction between overt and mild hypothyroidism
formed a committee to investigate the connection can be defined biochemically by whether the serum free
between myxoedema, cretinism, and cachexia thyroxine concentration is below or within the reference
strumipriva; and 5 years later, the committee issued its range, respectively. The term myxoedema is now usually
landmark report linking the three conditions. In 1912,
Hashimoto described autoimmune thyroiditis in four
women with goitres that seemed to have turned into Search strategy
lymphoid tissue (struma lymphomatosa); and in 1956, PubMed and Cochrane Library databases were searched for
Roitt and colleagues reported the presence of circulating the terms hypothyroid, hypothyroidism, myxoedema, central
thyroid autoantibodies in this disorder. Treatment for hypothyroidism, subclinical hypothyroidism, mild
hypothyroidism with sheep thyroid extract was first hypothyroidism, and congenital hypothyroidism. These
searches were cross-referenced with keywords relevant to the
Lancet 2004; 363: 793–803 subsections. Additional references were identified from
textbooks, reviews, and original research articles. We also
Division of Endocrinology and Metabolism, Department of relied on our own knowledge of current issues in the specialty
Medicine, Johns Hopkins University School of Medicine, Baltimore, and recent relevant work—referencing articles that, in our
Maryland, USA (C G P Roberts MD, P W Ladenson MD) opinion, represent important contributions. We gave priority,
Correspondence to: Dr Paul Ladenson, 1830 E Monument St, wherever possible, to randomised controlled trials, and to
Suite 333, Baltimore, MD 21287–0003, USA high-quality cross-sectional and case-control studies.
(e-mail: [email protected])

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SEMINAR

reserved for cases of overt hypothyroidism that are severe multiple sclerosis), primary pulmonary hypertension, and
or complicated, or both. Cretinism refers to the syndrome Down’s and Turner’s syndromes (panel 1).
of mental retardation, deafness, short stature, and
characteristic facial deformities occurring with untreated Aetiology
congenital hypothyroidism. Congenital hypothyroidism
Worldwide, the most common cause of congenital
Epidemiology hypothyroidism remains endemic iodine deficiency.8 In
Hypothyroidism is a common disorder, arising more often regions with sufficient dietary iodine, congenital
in women than men and increasing in incidence with age, hypothyroidism occurs in 1 of 4000 livebirths in regions of
especially after the onset of middle life. Because primary sufficient dietary iodine; the condition is twice as common
hypothyroidism is much more frequent than secondary in female infants and is a sporadic disorder in 85% of
hypothyroidism (about 1000 to 1) in both sexes at all cases.9 In these children, congenital hypothyroidism is due
ages, serum thyrotropin measurement can be used to to thyroid gland agenesis or dysgenesis10 and defective
estimate the prevalence of hypothyroidism in populations. thyroid hormone biosynthesis.11 Thyroid dysgenesis has
In a community survey in the UK, the Whickham1 study been associated with mutations in the genes for PAX8 and
recorded an abnormally high serum thyrotropin the thyroid transcription factors 1 (TITF1) and 2
concentration in 7·5% of women and 2·8% of men. In the (FOXE1). Defects in thyroid hormone biosynthesis have
recent NHANES III survey2 of 17 353 Americans been related to mutant genes encoding thyroid
representing US demographics, 4·6% had raised peroxidase, sodium-iodide symporter, pendrin, thyroid
thyrotropin: 0·3% with overt hypothyroidism and 4·3% oxidase 2, and thyroglobulin. Numerous inherited defects
with mild hypothyroidism (figure). In individuals aged causing absent or ineffective thyrotropin stimulation have
65 years and older, 1·7% had overt hypothyroidism and also been described, including mutant genes for
13·7% had mild hypothyroidism. Similarly, in women transcription factors needed for pituitary thyrotrope
older than 60 years of age in a Birmingham general differentiation (POU1F1, PROP1, LHX3, HESX1), the
medical practice, overt and mild hypothyroidism was thyroid releasing hormone receptor, thyrotropin -chain,
present in 2·0% and 9·6%, respectively.3 In women and and thyrotropin-receptor. In pseudohypoparathyroidism,
men aged older than 74 years screened at a Colorado hypothyroidism can result from a mutation in the gene for
health fair, the prevalence of hypothyroidism (defined as a Gsx which transduces thyrotropin receptor binding to
serum thyrotropin greater than 10 mU/L) was even adenylate cyclase activation. Transplacental transmission
higher: 21% and 16%, respectively.4 In the NHANES III of anti-thyrotropin receptor inhibitory antibodies from a
survey, the prevalence of hypothyroidism was higher in mother with autoimmune thyroid disease to her fetus can
whites than in Hispanics and African-Americans (5·1%, also cause transient neonatal hypothyroidism. The
4·1%, and 1·7%, respectively). syndrome of inherited resistance to thyroid hormone,
Special populations with higher risk of developing which is attributable to a mutant tri-iodothyronine
hypothyroidism include postpartum women; 5 individuals receptor  gene in most kindreds, can interfere with
with a family history of autoimmune thyroid disorders; 6,7 thyroid hormone action in target tissues.12 A final rare
and patients with previous head and neck or thyroid cause of hypothyroidism in neonates and young children
irradiation or surgery, other autoimmune endocrine is haemangiomas, which have such high type III
conditions (eg, type 1 diabetes mellitus, adrenal deiodinase activity that thyroxine catabolism exceeds the
insufficiency, and ovarian failure), some other non- thyroid gland’s secretory capacity.13
endocrine autoimmune disorders (eg, coeliac disease,
vitiligo, pernicious anaemia, and Sjögren’s syndrome, Autoimmune thyroiditis
The most common cause of acquired hypothyroidism is
All autoimmune thyroiditis (also called Hashimoto’s disease),
White, non-Hispanic which is seven-fold more common in women with
Black, non-Hispanic increasing incidence during middle life.14 The role of
Mexican American autoimmunity in its pathogenesis is lent support by the
Other histological finding of diffuse lymphocytic infiltration of the
5 thyroid gland, presence of circulating thyroid
autoantibodies in almost all patients,15 animal models
4 created by immunisation with thyroid antigens,16 the
finding that affected thyrocytes express the MHC class II
proteins needed for antigen presentation to CD4 (helper) T
3 lymphocytes,17 and evidence of activated CD4 T cells
specific for thyroid antigens.18 There is a clear genetic
2 predisposition to autoimmune thyroiditis, with apparent
autosomal dominant inheritance of thyroid autoantibodies
in the relatives of affected patients.19 A polygenic basis for
1 autoimmune thyroiditis is suggested by linkage of the
disorder to several genetic loci in affected
0 kindreds.20 Autoimmune thyroiditis is more common in
Clinical Subclinical* Clinical Subclinical* geographic regions of higher dietary iodine,21 which has
Total population Disease-free population†
been postulated to increase thyroglobulin antigenicity; 22
but the precise environmental factors inciting the condition
Prevalence of hypothyroidism in USA by ethnic background and remain unidentified.
known thyroid status In patients with autoimmune thyroiditis, the thyroid
*Subclinical hypothyroidism is defined by elevated serum thyrotropin
concentration with normal serum free thyroxine. †Disease-free population
gland can be nonpalpable or diffusely enlarged (150–300%
is defined by the reported absence of known thyroid disease, goitre, or of normal size) with a firm consistency, irregular contour,
thyroid medication use. and palpable pyramidal lobe.12 In patients with the fibrous

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 SEMINAR

Panel 1: Indications to test for hypothyroidism

Clinical symptoms and signs ● Personal or family history of associated autoimmune
● Fatigue disorders (eg, vitiligo, pernicious anaemia, adrenal
● Cold intolerance insufficiency, diabetes mellitus type 1, ovarian failure,
● Constipation coeliac disease, Sjögren’s syndrome)
● Impaired memory ● Primary pulmonary hypertension
● Slowed mental processing ● Multiple sclerosis
● Depression
Previous thyroid injury
● Nerve entrapment syndromes ● Thyroidectomy or other neck surgery
● Ataxia ● Radioactive iodine therapy
● Muscle weakness ● External radiotherapy
● Muscle cramps ● Exposure to polybrominated and polychlorinated biphenyls,
● Menstrual disturbance
and resorcinol
● Infertility
● Bradycardia Postpartum status
● Diastolic hypertension Drugs impairing thyroid function
● Hoarseness ● Lithium carbonate
● Goitre ● Amiodarone
● Periorbital oedema ● Aminoglutethimide
● Weight gain ● Interferon 
● Galactorrhoea ● Thalidomide
Laboratory test abnormalities ● Betaroxine
● Hypercholesterolaemia ● Stavudine
● Hyponatraemia Hypothalamic disorders
● Hyperprolactinaemia ● Hypothalamic or suprasellar mass
● Hyperhomocysteinaemia ● History of hypothalamic radiotherapy or surgery
● Anaemia ● Disorders causing hypothalamic dysfunction—eg,
● Creatine phosphokinase elevation
sarcoidosis, haemochromatosis, Langerhans’ cell
Radiological abnormalities histiocytosis
● Pericardial and pleural effusions
Pituitary disorders
● Pituitary gland enlargement ● Known pituitary tumour
Risk factors for hypothyroidism ● Other elements of hypopituitarism
Autoimmune thyroiditis ● Manifestations of a sellar mass (eg, headache, bitemporal
● Established serological or tissue diagnosis haemianopsia, or diplopia)
● Diffuse goitre ● History of pituitary surgery or radiotherapy
● Previous Graves’ disease, de Quervain’s thyroiditis, or ● History of head trauma
painless (postpartum) thyroiditis ● History of pituitary apoplexy, including Sheehan’s
● Family history of autoimmune thyroid disease syndrome
● Down’s syndrome ● History of other disorders causing hypopituitarism—eg,
● Turner’s syndrome metastatic cancer and lymphocytic hypophysitis

variant, the thyroid gland is hard and markedly the risk of progression to overt hypothyroidism was
enlarged.23 Rarely, the gland can be painful and 38 times higher (22–65), with a 4% annual risk of
tender.24 Patients with autoimmune thyroiditis might be developing overt hypothyroidism.
hypothyroid or euthyroid; transient thyrotoxicosis followed Autoimmune thyroiditis can arise in conjunction with
by hypothyroidism (“Hashitoxicosis”) takes place other endocrine deficiency states in polyendocrine failure
infrequently.25,26 Euthyroid individuals with autoimmune syndromes: type 1 most commonly including
thyroiditis are at increased risk of subsequently developing hypoparathyroidism, adrenal insufficiency, and chronic
hypothyroidism. Detection of circulating thyroid auto- mucocutaneous candidiasis; and type 2 most frequently
antibodies confirms the diagnosis of autoimmune thyroidi- including adrenal insufficiency, type 1 diabetes mellitus,
tis in patients with typical clinical presentations—eg, diffuse and primary ovarian failure.29 Patients with autoimmune
goitre with or without primary hypothyroidism. thyroiditis are also at increased risk of other autoimmune
Antimicrosomal or anti-thyroid peroxidase antibodies are disorders, including vitiligo, atrophic gastritis, pernicious
present in 95% of affected individuals, whereas anaemia, systemic sclerosis, and Sjögren’s syndrome. Some
antithyroglobulin antibodies are present in only 60%.13 researchers have shown that affected women are more likely
Immunoassay for anti-thyroid-peroxidase antibodies is the to have spontaneous abortion, but results of other surveys
most sensitive thyroid autoantibody test;27 and presence of have not confirmed these findings.30
these antibodies has been more strongly associated with an
elevated serum thyrotropin concentration than have anti- Acquired primary hypothyroidism
thyroglobulin antibodies.2 In the Whickham follow-up Acquired primary hypothyroidism can also result from
study, women with thyroid autoantibodies (11% of the previous thyroid injury by surgery or irradiation (after
population) had an eight-fold higher likelihood (95% CI external beam radiotherapy for head and neck malignant
5–15) of developing overt hypothyroidism over 20 years disease),31 radioactive iodine therapy for thyrotoxicosis,32
than did antibody-negative women.28 In women with both accidental environmental exposure to radioiodine,33 and
thyroid autoantibodies and isolated thyrotropin elevation, experimental use of radioiodinated immunoglobulins for

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SEMINAR

cancer treatment.34 Iron infiltration of the thyroid gland in Central (secondary) hypothyroidism
haemochromatosis can cause hypothyroidism.35 Toxic Central hypothyroidism can be acquired when diseases
injury to the thyroid gland has been reported after exposure interfere with thyrotropin-releasing hormone (TRH)
to polybrominated biphenyls and polychlorinated production by the hypothalamus or its delivery via the
biphenyls. Resorcinol has been reported to cause pituitary stalk, or with pituitary thyrotropin production.
hypothyroidism in exposed textile workers and in a patient The most common causes of central hypothyroidism are
on haemodialysis. Despite concern that environmental pituitary adenomas and the surgery and/or radiotherapy42
perchlorate exposure might cause congenital or acquired used to treat them. Central hypothyroidism can also result
hypothyroidism, this has not been shown to happen at from tumours impinging on the hypothalamus (eg,
concentrations found in contaminated drinking water. germinoma, glioma, and meningioma) or the pituitary
Thalidomide causes hypothyroidism by an unknown stalk in suprasellar region (eg, craniopharyngioma and
mechanism in some thalidomide-treated patients. The chordoma). Sarcoidosis,43 haemochromatosis,44 and
antiretroviral agent stavudine has also been associated with Langerhans’ cell histiocytosis can impair hypothalamic
overt and subclinical hypothyroidism. TRH production. Head trauma transecting the pituitary
Several drugs can cause hypothyroidism by interfering stalk can interrupt TRH delivery.45 Pituitary thyrotrope
with thyroid hormone production or provoking thyroid function can also be affected by lymphocytic hypophysitis,
autoimmunity. Pharmacological quantities of iodine, such infection, metastatic disease, apoplectic infarction (eg,
as those to which patients treated with amiodarone or other Sheehan’s syndrome) and the retinoid X receptor-
iodine-containing compounds are exposed, can inhibit selective ligand betaroxine.46
thyroid hormone production, especially when combined
with underlying autoimmune thyroiditis, and cause Molecular and biochemical pathophysiology
hypothyroidism. In one prospective study, 22% of Clinical hypothyroidism indicates a pervasive deficit in
amiodarone-treated patients developed overt or mild thyroid hormone actions, including modulation of
hypothyroidism. Similarly, lithium interferes with glandular calorigenesis and oxygen consumption in most tissues and
hormone release, causing transient thyrotropin elevation in additional organ-specific effects. The following
more than a third of lithium carbonate-treated patients and description of the basis for thyroid hormone action
persistent hypothyroidism in approximately 10%, especially summarises how deficient tri-iodothyronine actions at the
those with underlying autoimmune thyroiditis. The genomic level cause biochemical, hormonal, ion transport,
chemotherapeutic agent aminoglutethimide inhibits thyroid and mechanical changes in target tissues. Thyroxine, the
hormone synthesis and can cause goitrous hypothyroidism. principal product of the thyroid gland and circulating
Treatment with interferon  can instigate thyroid auto- thyroid hormone, is converted by outer-ring
immunity, causing either hypothyroidism or hyperthy- monodeiodination to tri-iodothyronine in the cytoplasm
roidism, which is often reversed by discontinuation of the and nucleus of target tissues by three distinct tissue
drug. specific deiodinases.47 Most classic thyroid hormone
Transient primary hypothyroidism can also take place actions are believed to be mediated genomically by tri-
with two inflammatory conditions, subacute thyroiditis iodothyronine binding to one of the tri-iodothyronine
(also called de Quervain’s thyroiditis) and lymphocytic receptor isoforms (TR1, TR1, and TR2), which are
thyroiditis (also called painless, silent, and postpartum members of the nuclear receptor superfamily.48 Tri-
thyroiditis). In both disorders, hypothyroidism lasting iodothyronine receptors possess domains for tri-
2–8 weeks typically follows transient thyrotoxicosis, which iodothyronine binding, DNA binding, and coupling with
is due to unregulated leakage of stored thyroxine; residual another tri-iodothyronine receptor or other nuclear
impairment of hormonogenesis is responsible for the receptor (eg, retinoic acid X receptor) to form dimers.
subsequent hypothyroid phase. Subacute thyroiditis, which The receptors bind to DNA at sites with certain specific
is believed, but not yet proven, to be a viral illness, also orientations of paired thyroid response elements with
usually causes a painful, tender, woody hard goitre and specific hexameric oligonucleotide sequences (eg,
constitutional symptoms, such as fever and malaise. AGGTCA) that are typically located in the 5 regulatory
Lymphocytic thyroiditis is an idiopathic disorder affecting regions of thyroid hormone-responsive genes. In most
6% of women 2–12 months postpartum; 36 it rarely occurs cases, interaction of tri-iodothyronine with its receptor
in women without preceding pregnancy and in men. prompts the binding of accessory protein cofactors that
Lymphocytic thyroiditis causes modest thyroid either activate or repress a specific gene’s transcription49
enlargement, which is not painful or tender. Since most (as tri-iodothyronine does to the hypothalamic thyroid
patients with both conditions recover to euthyroidism— releasing hormone and thyrotrophe thyrotropin  subunit
about 85% with subacute thyroiditis37 and 75% with genes).
lymphocytic thyroiditis—only temporary thyroxine Based on this model, some clinical manifestations of
treatment for symptomatic patients or no thyroid hormone hypothyroidism are understood at the molecular level. For
therapy at all is generally needed. example, failure to stimulate the growth hormone gene in
However, women with a previous episode of postpartum pituitary somatotrophs causes short stature in prepubertal
thyroiditis remain at increased risk of developing children; a deficit in expression of the hepatic LDL
hypothyroidism and should be monitored for its receptor gene mediated by thyroid hormone regulated
appearance. Reassessment of thyroid status is particularly SREBP2 (sterol regulatory element binding transcription
important for women who are planning subsequent factor 2) decreases the rate of LDL-cholesterol clearance,
pregnancy or who are newly pregnant, since acceleration of causing hypercholesterolaemia; and decreased expression
thyroxine catabolism during gestation can lead to of myocardial sarcoplasmic reticulum ATPase and
hypothyroidism in women with limited thyroid reserve. -myosin heavy chain impairs diastolic and systolic
This is particularly important because, if untreated, even ventricular performance, respectively. Many other clinical
mild hypothyroidism can lead to subtle impairment of manifestations of hypothyroidism are not yet linked to
subsequent childhood neuropsychological development.38 specific genomic actions. In addition to the nuclear
Diagnosis and management of these disorders have been actions of thyroid hormone, tri-iodothyronine stimulates
discussed in several reviews.39–41 cellular uptake of aminoacids and glucose, augments

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 SEMINAR

calcium-ATPase activity in cardiomyocytes, and alters hypothyroidism.78 4–14% of hypercholesterolaemic

mitochondrial ATP-generation by non-genomic patients have been reported to have hypothyroidism,79 a
mechanisms.50 Thyroid hormone also interacts with relation that is often unsuspected by primary care
G protein-coupled membrane receptors and activates the physicians.80 Hyponatraemia, hyperprolactinaemia,81
82
mitogen-activated protein kinase (MAPK) pathway; hyperhomocysteinaemia, hypoglycaemia, and elevated
deficits in these non-genomic actions could account for creatine phosphokinase83 (predominantly MM band) can
some of the additional consequences of hypothyroidism. all be caused by hypothyroidism.

Clinical manifestations Laboratory diagnosis

Symptoms and signs Serum thyrotropin measurement
Overt hypothyroidism has been associated with a familiar Serum thyrotropin measurement is the first-line
set of symptoms and signs, including cold intolerance, diagnostic test for hypothyroidism in most clinical
weight gain, constipation, dry skin, bradycardia, settings, including case-finding prompted by clinical or
hoarseness, and slowed mental processing. In one study of routine laboratory findings, and patient or population
patients with short-term hypothyroidism, 38% to 58% of screening (panel 1).84,85 Raised serum thyrotropin
patients had one or more of these clinical findings.51 In concentrations identify patients with primary hypo-
screened populations, however, the diagnostic accuracy of thyroidism irrespective of its cause or severity, even those
clinical findings is lower. In newly diagnosed hypothyroid with thyroid hormone deficiency so mild that the serum
patients in a case-control study, only 30% had any thyroxine concentration remains within the reference
symptoms, whereas 17% of euthyroid controls had at least range for a population. Normal serum thyrotropin levels
one of the same nonspecific complaints.52 Consequently, in disease-free individuals, typically cited as about
the positive predictive value of individual hypothyroid 0·4 mU/L to 4·0 mU/L, are distributed logarithmically,
symptoms was only 8% to 12%. Inaccuracy in clinical with the geometric mean thyrotropin concentration in the
diagnosis of hypothyroidism is attributable to the many lower half of the reference range, 1·5 mU/L.2
medical and lifestyle causes of similar symptoms, their Consequently, even a serum thyrotropin level at the upper
gradual onset, and occasionally the impaired insight that end of the normal range (ie, greater than 3·0 mU/L) might
hypothyroidism itself can produce in affected patients. indicate very mild thyroid dysfunction with greater risk of
Symptoms that are new or arise in combination are more progression to hypothyroidism, especially if thyroid
likely to indicate hypothyroidism. In the same case- autoantibodies are detected.
control study, hypothyroid patients reported symptoms Furthermore, investigators in one study found that
that had changed from the previous year more often than individuals with serum thyrotropin concentrations in the
did euthyroid individuals; and those with seven or more upper half of the reference range had higher mean serum
new symptoms were almost nine-fold more likely to be cholesterol level than those with low-to-normal serum
hypothyroid than those with fewer changed symptoms thyrotropin values.86 As a result, some authorities have
(95% CI 4–20). recommended lowering the thyrotropin assay’s upper limit
of normal even further to 2·5 mU/L.87 When elevated serum
Atypical clinical presentations thyrotropin is detected in a potentially hypothyroid patient
Atypical clinical presentations of hypothyroidism53 can or an individual in a screened population, the thyrotropin
include hypothermia,54 congestive heart failure,55,56 assay should usually be repeated along with measurement
pericardial57,58 and pleural effusions,59 ileus and intestinal of serum free thyroxine. This method confirms the
pseudo-obstruction,60 and coagulopathy.61 Neurological diagnosis for patients who will generally be committed to
manifestations can include depression,62 psychosis,63,64 lifelong thyroid hormone replacement therapy, and more
ataxia,65 seizures,66 and coma.67 Hypothyroidism has been fully defines the severity of hypothyroidism.69
associated with several neurocognitive deficits,
particularly in memory.68 The condition has traditionally Limitations of serum thyrotropin testing
been included in the differential diagnosis of reversible The thyrotropin assay can be insensitive in diagnosing
dementias and is occasionally seen in elderly patients with hypothyroidism in a few circumstances. In patients with
dementia, but thyroid hormone treatment rarely reverses central hypothyroidism due to hypothalamic or pituitary
dementia in these individuals.69,70 disorders, the amount of serum thyrotropin can be low
because of decreased production, or inappropriately
Congenital hypothyroidism normal or only modestly elevated88 as a result of synthesis
Congenital hypothyroidism usually presents in severely of a thyrotropin molecule with reduced bioactivity.89
affected infants with hypothermia, poor feeding, Central hypothyroidism should be suspected in several
bradycardia, jaundice, and an enlarged posterior circumstances: when there are persuasive clinical features
fontanelle and umbilical hernia; but most affected infants of hypothyroidism despite absence of raised serum
have no apparent clinical manifestations in the early thyrotropin; when there are clinical findings suggesting
neonatal state, justifying the practice of routine thyroid other anterior pituitary hormone deficiencies or a sellar
function screening.71 Additional presentations of mass lesion; or when a patient has a condition known to
hypothyroidism in children and adolescents can include cause hypopituitarism—eg, sarcoidosis, previous cranial
growth failure with markedly delayed bone maturation,72 injury or radiotherapy, or cancers with potential pituitary
slipped capital femoral epiphysis,73 delayed eruption of metastasis. In these settings, the serum free thyroxine
permanent teeth, muscle pseudohypertrophy,74 concentration should be measured along with thyrotropin.
unexplained anaemia, pituitary enlargement due to The finding of a low serum free thyroxine concentration,
thyrotroph hyperplasia,75 galactorrhoea,76 and delayed or regardless of the thyrotropin concentration, should then
precocious puberty.77 prompt further testing, which could include pituitary
imaging, a thyroid releasing hormone stimulation test to
Routine laboratory abnormalities assess thyrotropin responsiveness,90 and other pituitary
Abnormalities in routine laboratory indices can sometimes function testing. In a highly suggestive clinical setting,
be the first diagnostic clue to, or might be explained by, even serum free thyroxine levels in the lower third of the

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SEMINAR

normal range should be regarded as suggestive of mild populations2,4 and patients cared for in general3 and
central hypothyroidism, and might justify additional specialist practices107—have noted that about a fifth of
evaluation. hypothyroid patients are receiving an inadequate
Conversely, there are several situations in which raised thyroxine dose, and a fifth are given an excessive amount
serum thyrotropin might not be indicative of of medication (panel 2). Thyroxine is well absorbed by
hypothyroidism, including euthyroid patients with adrenal the proximal small bowel, circulates with a long 7-day
glucocorticoid insufficiency,91 renal failure,92 and exposure half-life because of plasma protein binding, and is
to cold temperatures.93 Circulating antibodies against metabolised in target tissues, in part by deiodination to
thyrotropin94 or mouse immunoglobulins,95 when used as tri-iodothyronine.
assay reagents, can also yield falsely raised thyrotropin
immunoassay readings. Two rare forms of thyrotropin- Dose considerations and drug interactions
mediated hyperthyroidism, thyrotropin-secreting pituitary The optimum dose of thyroxine for hypothyroid patients
tumours96 and isolated pituitary resistance to thyroid is related to bodyweight (about 1·8 g per kg in adults)108
hormone,97 can present as clinical and biochemical and age, with a dose requirement that is higher in infants
hyperthyroidism with an inappropriately elevated serum and young children and is lower in older adults (0·5 g
thyrotropin, but raised serum free thyroxine or tri- per kg per day).109 The thyroxine dose is generally higher
iodothyronine, or both, in these patients suggest these in patients with previous thyroidectomy than in those with
diagnoses. autoimmune thyroiditis, in which there may be some
residual functioning thyroid tissue. The dose needed for
Effects of non-thyroidal illnesses and drugs individuals with mild hypothyroidism is usually lower as
In clinical practice, the greatest challenge in diagnosis of well (0·5 g per kg per day).110 Thyroxine absorption can
the condition is in patients with changes in thyroid be decreased in patients with malabsorption from
hormone and thyroid function test results that are usually gastrointestinal disorders111 or previous small bowel bypass
seen in severe non-thyroidal illnesses. In those with surgery.112 Several drugs (panel 2), iron113 and calcium
systemic illness, accompanying thyrotropin suppression carbonate114 mineral supplements, cholestyramine,
can mask mild,98 but not severe, primary hypothyroidism. aluminum hydroxide gel, sucralfate, dietary soy,115 and
Three drugs used in severely ill patients, glucocorticoids,99 perhaps fibre116,117 have all been reported to interfere with
dopamine,100 and dobutamine,101 can suppress serum thyroxine absorption.
thyrotropin even in patients with overt primary Thyroxine disposal is accelerated by nephrotic
hypothyroidism. Conversely, patients recovering from syndrome,118 other severe systemic illnesses,119 and several
severe illness may have a transiently raised thyrotropin anti-seizure medications (phenobarbital, phenytoin, and
concentration.102 Thus, thyroid function testing is best carbamazepine) and rifampin.120 Pregnancy increases the
reserved for severely ill patients in whom there is a thyroxine dose requirement in 75% of women,121 probably
substantial clinical suspicion of hypothyroidism; because of increased degradation by the placental
otherwise, abnormal results are much more likely to deiodinase. Initiating postmenopausal hormone replace-
represent false-positive than true-positive findings. A ment therapy increases the dose needed in 35% of
diagnostic challenge similar to nonthyroidal illnesses can women, perhaps due to an increased circulating
arise in patients taking the anti-seizure medications thyroxine-binding globulin level.122 Patient non-
phenytoin and carbamazepine, which can cause low compliance with prescribed thyroxine, the most common
serum total thyroxine and thyrotropin levels and be cause of inadequate treatment, might be suspected in
confused with central hypothyroidism.103 patients with a dose that is higher than expected, variable
thyroid function test results that do not correlate well with
Antithyroid antibodies prescribed doses, and an elevated serum thyrotropin
Laboratory tests are seldom necessary to define the concentration with serum free thyroxine at the upper end
underlying cause of primary hypothyroidism; the history is of the normal range, which can suggest improved
usually sufficient, identifying factors such as previous neck compliance immediately before testing due to a lag in the
irradiation, radioiodine therapy, thyroid surgery, thyrotropin response.
postpartum state, or medications inducing thyroid The metabolism of other pharmacological agents can be
dysfunction. In patients with none of these findings and altered in patients with hypothyroidism. The mechanism
sustained primary hypothyroidism, the cause can usually might be decreased expression of hepatic enzymes involved
be assumed to be autoimmune thyroiditis. Although not in drug metabolism, as seen in hypothyroid rats.123,124 As a
essential, it is sometimes helpful for the patient to have result, increased sensitivity to anaesthetic125 and sedative
this diagnosis confirmed by detection of thyroid agents,126 and higher serum levels of phenytoin have been
autoantibodies. Other uses of thyroid autoantibody reported.127 Hypothyroidism can also cause higher serum
screening include prediction of subsequent hypo- digoxin values,128 an effect attributed to a decreased
thyroidism in patients with mild hypothyroidism26 and in volume of drug distribution.129,130 Conversely, hypo-
pregnant104 and postpartum women,105 and for the thyroidism might decrease sensitivity to warfarin due to
differential diagnosis of diffuse goitre. slowed metabolism of the vitamin K-dependent clotting
factors;131 and restoration of euthyroidism can then
Management of hypothyroidism increase the warfarin dose requirement.
Thyroxine pharmacokinetics
The treatment of choice for hypothyroidism is Initiating thyroxine therapy
levothyroxine sodium (thyroxine), which has convenient Physicians should usually initiate treatment with a dose at
pharmacokinetic properties, and when given in the proper the lower end of the anticipated dose requirement—eg,
dose, a high degree of effectiveness and small risk of 125 g per day in a 70 kg adult. In most patients who are
adverse reactions.106 However, thyroid hormone has a otherwise healthy, titration of the dose upward from a low
narrow toxic-to-therapeutic ratio; and despite the starting dose of 25–50 g per day is unnecessary and
assumption that treatment should be straightforward, prolongs recovery. Laboratory monitoring of treated
researchers in several studies—undertaken in large hypothyroid patients is appropriate 4–6 weeks after

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 SEMINAR

Panel 2: Potential causes of thyrotropin elevation In addition to anticipating changing dose requirements,
in thyroxine-treated patients with primary avoiding drug interactions, and optimising patient
hypothyroidism compliance, physicians should be aware of specific
problems in management of hypothyroidism in patients
Suboptimal dosing
with coexisting ischaemic heart disease, persistent
Inadequate prescribed dosage
symptoms despite normal laboratory test results, mild
Noncompliance
hypothyroidism, and complicated myxoedema.
Dispensing error (incorrect dose or formulation change)
Patients with ischaemic heart disease
Progressive decrease in endogenous thyroxine production Thyroxine treatment of hypothyroid patients might
Autoimmune thyroiditis exacerbate myocardial ischaemia in those with underlying
Previous thyroid irradiation coronary artery disease due to positive inotropic and
Reduced thyroxine absorption chronotropic effects of thyroid hormone. Starting
Drug interactions treatment at lower doses in these patients—eg, 25 g per
Iron day, can be justified. The traditional recommendation has
Calcium carbonate been gradual titration of the thyroxine dose upward to
Cholestyramine euthyroidism in 12·5 to 25·0 g increments at intervals of
Aluminum hydroxide gel 4–6 weeks along with vigilant clinical and electrocardio-
Sucralfate graphic monitoring. However, long-term suboptimal
Dietary soy and fibre dosing increases the risk of worsening coronary
atherosclerosis.137 Starting or supplementing -adrenergic
Comorbid conditions blockade might be helpful. Hypothyroid patients can
Disorders causing malabsorption—eg, coeliac disease undergo coronary angioplasty138 and even surgical bypass
Previous small bowel surgery grafting with only slightly, if at all, increased perioperative
Increased thyroxine clearance risk.139
Drug interactions
Phenytoin Residual symptoms and tri-iodothyronine therapy
Carbamazepine Even adequately treated hypothyroid patients more
Phenobarbital commonly have constitutional and neuropsychological
Rifampin complaints and a decreased sense of well-being than do
euthyroid individuals.140 The cause of this is unknown,
Coexisting conditions
and it might represent an ascertainment bias—ie,
Pregnancy
individuals with inclination to complain and seek medical
Nephrotic syndrome
care are more likely to be diagnosed with hypothyroidism.
Other systemic illnesses
However, another postulated cause of this problem is
Other absence of the small amount of tri-iodothyronine directly
Postmenopausal hormone replacement therapy produced by the thyroid gland, in addition to the
preponderance of endogenous tri-iodothyronine
generated from the extrathyroidal thyroxine. Results of a
instituting a new thyroxine dose, and yearly or when clinical trial in which a fraction of the thyroxine dose was
persistent symptoms suggesting thyroid hormone replaced by the addition of a small dose of tri-
deficiency or excess arise. In patients with primary iodothyronine showed significant improvement in some
hypothyroidism, serum thyrotropin concentration should symptoms.141 However, these findings were confounded
be assessed, with the aim of restoring the thyrotropin because the ratio of tri-iodothyronine to thyroxine used
value to the lower half of the normal range (about was supraphysiological; thus, some patients had
1·0 mU/L). In individuals with central hypothyroidism, depression, and some were actually overtreated with a
serum free thyroxine concentration must be monitored, suppressed serum thyrotropin concentration.
and should generally be maintained in the upper half of Furthermore, researchers in two subsequent investi-
the normal range. gations have failed to confirm these findings; Sawka and
colleagues142 did not record enhancement of mood or
Adverse reactions and problems sense of well-being with tri-iodothyronine plus thyroxine
Adverse reactions to thyroxine treatment are related to treatment compared with thyroxine alone,142 and Walsh
excessive or increased thyroid hormone action, and include and co-workers143 noted no improvements in well-being,
symptomatic thyrotoxicosis, subclinical thyrotoxicosis with cognitive function, or quality of life with combined
increased risks of bone loss,132 and atrial tachyarrhyth- treatment of tri-iodothyronine and thyroxine compared
mias.133 Complications can also arise from restoration of with thyroxine only. Also, such combined therapy has the
euthyroidism in patients who have underlying ischaemic disadvantage of a fluctuating tri-iodothyronine concen-
heart disease134 and borderline adrenal cortical insuf- tration due to its 1-day half-life, which can result in a
ficiency; this insufficiency can arise in people with supraphysiological tri-iodothyronine concentration during
hypopituitarism and those with the type 2 polyendocrine part of the day. Additionally, use of a combination of
failure syndrome (Schmidt’s syndrome), which is synthetic thyroxine and tri-iodothyronine formulations
comprised of autoimmune thyroiditis and idiopathic leads to increased complexity and expense of treatment.
(autoimmune) adrenal insufficiency. A syndrome of acute Thus, its benefit in routine management of hypothyroid
sympathomimetic symptoms soon after start of thyroxine patients remains unproven.
treatment has been described,135 and could be attributable
to anaemia in some cases.136 Transient scalp hair loss can Mild (subclinical) hypothyroidism
also take place during the first few weeks of hormone Whether patients with mild hypothyroidism should be
replacement. Allergy to commonly prescribed thyroxine treated is controversial. Some have argued that diagnosis
formulations has not been well documented. of mild and overt hypothyroidism satisfies criteria for

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SEMINAR

secondary prevention by early detection, either case confirmed in other small studies and no large prospective
finding based on clinical suspicion or routine screening of randomised trial has been undertaken. Two decision and
specific populations or even all adults.144,145 As noted cost-effectiveness models based on these studies have
previously, mild hypothyroidism is highly prevalent, suggested that the cost-effectiveness of screening for and
particularly in older women, and clinical diagnosis alone is treating mild hypothyroidism is similar to other widely
often inaccurate. The test for its diagnosis, serum accepted preventive medicine strategies.157,158 Nonetheless,
thyrotropin measurement, and its treatment with thyroxine there remains controversy about the actual benefit of such
are effective, safe, and relatively inexpensive. The greatest therapy for individuals with mild hypothyroidism, and by
controversy surrounds the issue of whether mild extension, of thyrotropin screening of populations to
hypothyroidism has clinically important and reversible identify affected individuals.
consequences in a significant enough proportion of
affected patients to justify widespread screening.146 Severe hypothyroidism
The first potential benefit of thyroxine therapy is Myxoedema can become complicated by multiple organ
preventing patients’ progression to overt hypothyroidism, system failure when it is profound and long term,
especially in those with a serum thyrotropin concentration especially in patients who are elderly and who could have
greater than 10 mU/L, aged 65 years or older, with or other cardiac, pulmonary, neurological, renal, and
without thyroid autoantibodies indicative of underlying infectious diseases. The syndrome of myxoedema coma
autoimmune thyroiditis.26,147 The second argument for represents the most extreme form of this complicated
intervention is reduction of future risk of cardiovascular hypothyroidism,58 and despite the best of contemporary
disease, based on findings that mildly hypothyroid intensive medical care, is associated with substantial
patients have higher mean cholesterol levels4 and that mortality. In severely hypothyroid patients, these
thyrotropin-normalising thyroxine treatment might lower complications can be prevented by early and sustained
serum total and LDL cholesterol concentrations.148 thyroxine therapy, prompt attention to other underlying
Additionally, subtle and reversible changes in myocardial medical conditions (eg, heart and renal failure,
performance have been described in mild pneumonia, and metabolic disturbances), and avoidance
hypothyroidism.149,150 However, a higher risk of clinical of sedative, anaesthetic, and analgesic medications that
heart disease has only been shown in some,151 but not suppress central nervous system function, particularly
other epidemiological studies,152 and cardiovascular ventilatory drive. Treatment entails thyroid hormone
benefit of thyroid hormone treatment has never been replacement and aggressive management of the individual
rigorously tested in a randomised controlled trial. Third, organ system complications that can be present (panel 3).
four small controlled, double-blinded trials have shown Regimens shown to be effective are either thyroxine in a
that thyroxine treatment produced greater improvements large replacement dose, with or without a preceding
in mildly hypothyroid patients’ symptoms and 500 g loading dose to replete the normal total body
neuropsychological performance indices than did thyroxine pool;163 or tri-iodothyronine in divided doses,
placebo;153–56 but these observations have not been advocated because of the anticipated impairment of
thyroxine to tri-iodothyronine conversion in critically ill
patients. Although no comparative trial has proven the
Panel 3: Pathogenesis of general complications in advantage of one approach over the other, a small
management of complicated hypothyroidism retrospective experience recorded a higher mortality in
tri-iodothyronine-treated patients.164
Congestive heart failure
Impaired ventricular systolic and diastolic functions,159 Conflict of interest statement
and increased peripheral vascular resistance None declared.
Ventilatory failure
Blunted hypercapnoeic and hypoxic ventilatory drives160 Role of the funding source
No funding was provided for this work.
Hyponatraemia
Impaired renal free water excretion and syndrome of
inappropriate antidiuretic hormone secretion (SIADH) References
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