Review Article

Thyroid hormone resistance

Tolulope O Olateju1 and Mark P J Vanderpump2

Addresses
1
Department of Endocrinology,
Buckinghamshire Hospitals NHS Trust,
Stoke Mandeville Hospital, Aylesbury,
Bucks HP21 8AL, UK;
2
Department of Endocrinology, Royal Free
Hampstead NHS Trust, Pond Street,
London NW3 2QG, UK
Correspondence
Dr Mark P J Vanderpump
E-mail: mark.vanderpump@royalfree.
nhs.uk
This article was prepared at the invitation of
the Clinical Sciences Reviews Committee of
the Association for Clinical Biochemistry.
Abstract
Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited
syndrome of reduced end-organ responsiveness to thyroid hormone. Patients with
RTH have elevated serum free thyroxine (FT4) and free triiodothyronine (FT3)
concentrations and normal or slightly elevated serum thyroid stimulating hormone
(TSH) level. Despite a variable clinical presentation, the common characteristic
clinical features are goitre but an absence of the usual symptoms and metabolic
consequences of thyroid hormone excess. Patients with RTH can be classified
on clinical grounds alone into either generalized resistance (GRTH), pituitary
resistance (PRTH) or combined. Mutations in the thyroid hormone receptor (TR)
b gene are responsible for RTH and 122 different mutations have now been
identified belonging to 300 families. With the exception of one family found to have
complete deletion of the TRb gene, all others have been demonstrated to have
minor alterations at the DNA level. The differential diagnosis includes a TSH-
secreting pituitary adenoma and the presence of endogenous antibodies directed
against thyroxine (T4) and triiodothyronine (T3). Failure to differentiate RTH from
primary thyrotoxicosis has resulted in the inappropriate treatment of nearly one-third
of patients. Although occasionally desirable, no specific treatment is available for
RTH; however, the diagnosis allows appropriate genetic counselling.
Ann Clin Biochem 2006; 43: 431–440

Introduction resistance can occur at the pre-receptor, receptor or

Resistance to thyroid hormone (RTH) is one example of
hormone resistance syndromes.1 The ¢rst and best
characterized was pseudohypoparathyroidism type Ia,
an inherited disease with parathyroid hormone resis-
tance and osteodystrophy. In 1942 Fuller Albright
hypothesized that pseudohypoparathyroidism was the
result of target organ unresponsiveness to hormone,
even though cell-surface receptors and e¡ector systems
had not yet been identi¢ed for any hormone.2 Pseudo-
hypoparathyroidism type Ia is now known to result
from several hereditary defects, the most common of
which resides on the G protein in cell membrane that
activates the catalytic subunit of adenylate cyclase
after the binding of parathyroid hormone to its recep-
tor.3 Since then other examples of hormone resistance,
such as insulin, growth hormone, androgens, vitamin
D and glucocorticoids, have been described, which are
most commonly due to abnormalities in cell-surface
and intracellular receptors. Occasionally they occur as
a result of defects in hormone metabolism within cells
or other abnormalities in hormone action. Hormone
post-receptor level but the common feature of such
resistance is the presence of a normal or an elevated le-
vel of the hormone in the circulation.3
In 1967 Refeto¡ described the ¢rst cases of resistance
to thyroid hormone in two siblings born to consangui-
neous parents who had signs suggestive of hypo-
thyroidism, including deaf-mutism, goitres and delayed
bone age.4 Surprisingly, they had high serum thyroid
hormone concentrations when investigated. RTH was
therefore described as a syndrome of reduced target tis-
sue responsiveness to thyroid hormone. Resistance was
con¢rmed when the administration of supraphysiologi-
cal doses of T4 or T3 were required to produce the
expected suppressive e¡ect on pituitary TSH secretion
and on the metabolic responses in peripheral tissues.
Patients with RTH have elevated serum thyroid hor-
mone (both FT4 and FT3) concentrations and a normal
or slightly elevated serum TSH in the absence of any ill-
ness, medication usage or defect in hormone transport
or metabolism or any circulating antagonist in plasma.
Since that ¢rst report,1000 cases belonging to approxi-
mately 300 families that ¢t this de¢nition have been

r 2006 The Association for Clinical Biochemistry 431

432 Olateju and Vanderpump
recognized.5,6 Despite a variable clinical presentation,
the common clinical features characteristic of the
RTH syndrome are the presence of a goitre but the
absence of the usual symptoms and metabolic conse-
quences of thyroid hormone excess.
RTH, although varying in severity of clinical presen-
tation, is always partial. The magnitude of the hormo-
nal resistance is dependent on the nature of the
underlying defect. Invariably this is a mutation in one
allele of the TRb gene which interferes with the capa-
city of that TRb receptor to respond normally to T3,
usually by reducing its binding a⁄nity to T3. The
mutant receptor also inhibits the function of the
remaining normal receptors, both TRa and TRb, which
are products of the three normal alleles. This phenom-
enon is termed dominant negative inhibition and
accounts for the autosomal dominant pattern of
inheritance in all but one case.6 The study of the func-
tion of mutant receptors in this disorder has provided
major insight into the mechanism of thyroid hormone
action and the pathogenesis of disease. This review
describes the classi¢cation, molecular pathogenesis,
clinical features, diagnosis and treatment of thyroid
hormone resistance from a clinician’s perspective.
Classification
Before gene defects in the TR were recognized, patients
with RTH were classi¢ed on clinical grounds alone into
either generalized resistance (GRTH), pituitary resis-
tance (PRTH) or combined. Other than assessment of
pituitary TSH feedback, the available measurements of
thyroid hormone responses were insensitive and non-
speci¢c, so all tissues other than the pituitary were
grouped together under the term peripheral tissues. In
GRTH, all thyroid responsive tissues are a¡ected to var-
ious degrees.5,6 These patients tend to have high circu-
lating concentrations of thyroid hormones with near
normal TSH, but they do not exhibit signs of hyperthyr-
oidism as the relatively high concentrations of thyroid
hormones are needed to overcome peripheral tissue
hyposensitivity and patients tend to be euthyroid or
sometimes hypothyroid. In PRTH, there is predomi-
nantly pituitary resistance to circulating thyroid
hormone and patients tend to exhibit features of
hyperthyroidism such as agitation or sinus tachycar-
dia. This is because while peripheral tissues retain their
normal sensitivity to thyroid hormones, higher con-
centrations of thyroid hormones are needed to evoke a
response at the level of the pituitary.
However, it is now generally thought that the two
groups might actually be a single genetic entity with
individual patients having di¡erent responses with
similar biochemical features. An identical mutation in
di¡erent patients has been found to be responsible for
Ann Clin Biochem 2006; 43: 431–440
the two di¡erent types and other peripheral markers
of thyroid hormone action such as sex-hormone bind-
ing globulin (SHBG) were not found to be elevated in
PRTH.7 A third category called isolated peripheral
tissue RTH (PTRTH) has only been seen in a single
patient.8 Although serum TSH was suppressed
with physiological doses of T3, supraphysiological
doses of this hormone failed to produce symptoms and
signs of thyrotoxicosis in this individual with a partial
thyroid ablation.
Despite the signi¢cant overlap between the two main
entities, the absence or presence of overt thyrotoxic
symptoms, signifying either generalized or pituitary
resistance to thyroid hormone, is a clinical distinction
and remains a useful guide to the most appropriate
form of treatment.
Incidence
The precise incidence of RTH is unknown. Because
routine neonatal screening programs are based on
the determination of TSH, RTH is rarely identi¢ed by
this means. A limited neonatal survey measuring
blood T4 concentration suggested the occurrence of
one case per 40,000 live births.9 Currently published
cases exceed 1000, of which 349 have been previously
reviewed in detail.4 RTH has been found with equal
frequency in both genders and appears to have wide
geographic and ethnic distribution, although the
prevalence may vary among di¡erent ethnic groups.
Familial occurrence of RTH has been documented in
approximately 75% of cases. Taking into account only
those families in whom both parents of the a¡ected
subjects have been studied, the true incidence of spora-
dic cases is 21.3%, which is in agreement with current
estimates of the frequency of de novo mutations of
22.5%.5 There do not appear to be any credible reports
of acquired RTH. Inheritance is almost invariably auto-
somal dominant and has only been shown to be clearly
recessive in one family.4,10
Molecular pathogenesis
Thyroid hormone receptors (TR) belong to a super-
family of nuclear hormone receptors, which include
vitamin D, retinoic acid, peroxisomal proliferators and
steroid receptors.11--13 The cloning of theTR in 198614,15
allowed greater understanding of the action of thyroid
hormones. Both T4 and T3 regulate many cellular pro-
cesses in virtually every type of tissue. The synthesis of
thyroid hormones is controlled by hypothalamic thyro-
trophin-releasing hormone (TRH) and pituitary TSH
and, in turn,T4 and T3 regulate TRH and TSH produc-
tion as part of a negative feedback loop. Thyroid
hormone (mainly T3) acts by upregulating or

downregulating the expression of target genes. T3
binds to nuclear receptors present as dimers bound to
speci¢c DNA sequences located usually in the promoter
region of thyroid hormone responsive genes. Dimers of
unliganded (no T3) TR bind to thyroid hormone
response elements, resulting in inhibition of expression
of genes that are positively regulated by T3 through
association with co-repressor proteins. T3 binding to
the receptors results in release of the co-repressor pro-
tein, dissociation of the dimers, and formation of het-
erodimers of TR and retinoid X receptors that then
bind coactivator proteins. These changes promote gene
expression and increase the synthesis of speci¢c pro-
teins (Figure 1).
There are two TRs, a and b, which are encoded by
separate genes, located on chromosomes 17 and 3,
respectively. Alternate splicing generates three main
receptor isoforms (TRa1,TRb1,TRb2), which are widely
expressed but have di¡erent tissue distributions. TRa1
is most abundant in the central nervous system, myo-
cardium and skeletal muscle. This explains why overt
cretinism is uncommon, as TRa1 are una¡ected. TRb1
is predominant in liver and kidney whilst theTRb2 iso-
form is most highly expressed in the pituitary and
hypothalamus.16--19
RTH is due to a mutation in one allele of the TRb
gene. A total of about122 di¡erent mutations have been
identi¢ed belonging to 300 families; approximately 45
of these mutations are shared by more than one family.
In most instances, identical mutations have developed
independently in di¡erent families.20 In addition, dif-
α
α
β
α
Figure 1 Schematic depiction of thyroid hormone action. rT2, reverse diiodothyronine; rT3, reverse triiodothyronine; RXR, retinoid
X receptor; T3, triiodothyronine; T4, thyroxine; TRa, thyroid hormone receptor a gene; TRb, thyroid hormone receptor b gene; TRE,
thyroid hormone response element.
(Figure kindly provided by Professor Graham Williams, Imperial College London School of Medicine, Hammersmith Hospital)
Thyroid hormone resistance 433
ferent mutations producing more than one amino acid
substitution at the same codon have been found at 37
di¡erent sites. All TRb gene mutations are localized in
the functionally relevant domain of T3-binding and its
adjacent hinge region.With the exception of the family
with TRb gene deletion, in all others inheritance is
autosomal dominant. No mutations have so far been
detected in the TRa gene. Recent ¢ndings in mice with
targeted mutations in the TRa gene (knock in mice)
indicate that such mutations do not produce the RTH
phenotype.21--23
Various mechanisms can be postulated to explain
the tissue di¡erences in RTH within the same subject
and among individuals. Some variations of the RTH
phenotype have been shown to have a clear molecular
basis. Subjects heterozygous for a TRb gene deletion
have a normal clinical phenotype presumably because
the expression of a singleTRb allele is su⁄cient for nor-
mal function. RTH manifests in homozygotes comple-
tely lacking the TRb gene and in heterozygotes that
express a mutant TRb with dominant negative e¡ect.
The most severe form of RTH, with extremely high
FT4 and FT3 concentrations and signs of both
hypothyroidism and thyrotoxicosis, occurred in a homo-
zygous individual expressing only mutant TRs.24,25
The severe hypothyroidism manifesting in bone and
brain of the patient who was homozygous for the
receptor defect can be explained by the severe domi-
nant negative e¡ect of the mutant receptor on the func-
tion of normal TRa;26 a situation which does not
occur in homozygous subjects with TRb deletion. The
D
Ann Clin Biochem 2006; 43: 431–440
434 Olateju and Vanderpump
variation in distribution of receptor isoforms in tissues
accounts for greater hormonal resistance of the liver
as compared with the heart. In contrast, the manifesta-
tion of thyrotoxicosis in other tissues, such as the
heart, may be explained by the e¡ect high thyroid
hormone concentrations have on tissues that normally
express predominantly TRa1.27,28 It is for the same
reason that tachycardia is a relatively common ¢nding
in RTH.29 The relative concentrations of mutant and
wild-type gene expression may explain di¡erences in
the degree of resistance among individuals harbouring
the same mutation. Such di¡erences have been found
in one study30 but not in another.31 In a growing num-
ber of individuals, RTH occurs in the absence of muta-
tions in the TRa or b genes (nonTR-RTH).32 They
represent 15% of families and 7% of cases with RTH.
Such individuals may have a defect in one of the cofac-
tors involved in the mediation of thyroid hormone
action.
Clinical features
The clinical presentation in general is thought to be
dependent on the severity or type of the hormone
resistance (e.g. whether GRTH or PRTH), the e¡ective-
ness of compensatory mechanisms, the presence of
modulating genetic factors and the e¡ect of previous
treatment.33--35 Characteristic biochemical ¢ndings on
presentation most frequently lead to further investiga-
tion and ultimately the diagnosis of RTH, which has
few clinical manifestations and a high index of suspi-
cion is required to ensure diagnosis is made. The most
common clinical presentation in adult patients is a goi-
tre or recurrence of a goitre following inappropriate
treatment and, in children, growth retardation with
delayed bone age. Reasons prompting further investi-
gation of the key family member in published studies
include goitre (38%), hyperactive/learning disability
(10%), developmental delay (8%) and sinus tachycardia
(7%).4 Suspected thyrotoxicosis was the reason in
only 3%.
The majority of untreated subjects maintain a nor-
mal metabolic state, although circulating thyroid hor-
mone concentrations remain high. The degree of this
compensation of tissue hyposensitivity to the hormone
is highly variable among individuals as well as in di¡er-
ent tissues. As a consequence, clinical and laboratory
evidence of thyroid hormone de¢ciency and excess
often coexist. The common clinical features and their
frequency are given in Table 1. Symptoms of hypothyr-
oidism are more common in those subjects who,
because of a mistaken diagnosis, have received
ablative treatment with radioiodine or thyroidectomy
to normalize their circulating thyroid hormone
concentrations.
Ann Clin Biochem 2006; 43: 431–440
Table 1 The overall frequency of signs and symptoms of RTH
at presentation
Clinical presentation Frequency (%)
Nervous system
Attention deficit hyperactivity disorder 40–60
Emotional disturbances 60
Hyperkinetic behaviour 33–68
Learning disability 30
Mental retardation 4–16
Sensorineural hearing loss 10–22
Thyroid gland
Goitre 66–95
Cardiovascular system
Tachycardia 33–75
Musculoskeletal system
Delayed bone age 29–47
Low body mass index (in children) 33
Short stature 18–25
Immune system
Recurrent ear and throat infections 55
Goitre is the most common presenting sign reported
in almost all cases. This can be detected on ultrasound
if not clinically obvious and is normally di¡use in char-
acter and is due to the e¡ect of serum TSH stimulating
thyroid gland hyperplasia. Sinus tachycardia is also
very common, with some studies reporting frequency
as high as 75%.36 The presence of palpitations or the
¢nding of tachycardia is the most common reason for
the erroneous diagnosis of autoimmune thyrotoxicosis
or the suspicion of PRTH. The tachycardia can be
explained by the fact that thyroid hormone e¡ect in
the heart is primarily dependent on TRa, which has
not been implicated in RTH.6
Careful evaluation of subjects with RTH has shown
that about one-half have some degree of learning dis-
ability with or without attention de¢cit hyperactivity
disorder (ADHD).37 One-quarter have intellectual quo-
tients (IQ) less than 85% but frank mental retardation
(IQo60) has been found only in 3% of cases. Impaired
mental function was found to be associated with
impaired or delayed growth (o5th percentile) in 20%
of subjects, though growth retardation alone is rare
(4%).5,6 Despite the high prevalence of ADHD in
patients with RTH, the occurrence of RTH in children
with ADHD must be very rare as no cases of RTH have
been detected in 330 carefully evaluated children with
ADHD.38,39 Current data do not support a genetic link-
age of RTH with ADHD. The higher prevalence of low

IQ scores may result in a greater likelihood of subjects
with RTH exhibiting ADHD symptoms.40
Avariety of physical defects that cannot be explained
on the basis of thyroid hormone de¢ciency or excess
have been recorded. These include major or minor
somatic defects, such as winged scapulae, vertebral
anomalies, pigeon breast, prominent pectoralis, bird-
like facies, scaphocephaly, craniosynostosis, short
fourth metacarpals, as well as Besnier’s prurigo, conge-
nital ichthyosis, and bull’s eye type macular atrophy.5,6
No defect appears to be particularly prevalent in RTH.
A distinct body habitus and deaf-mutism occurred in
all three a¡ected members of a single family with TRb
gene deletion.4 The outcome of those subjects diag-
nosed with RTH is variable. Some patients have normal
growth and development despite high thyroid hormone
concentrations and a goitre. Others have variable
degrees of mental and growth retardation. Goitres re-
cur in every patient who has had ablative therapy with
radioiodine or a thyroidectomy. Only one death has
ever been attributed to RTH.5
Investigational findings
Serum FT4 and FT3 are required to be elevated for the
diagnosis of RTH. Serum thyroxine binding globulin
(TBG) is normal. Serum T4 and T3 values vary from
just above to several times the upper limit of the refer-
ence range and although the concentrations may vary
in the course of time in the same patient,41 the degree of
T4 and T3 elevation is usually equal, resulting in a nor-
mal T3:T4 ratio. Reverse T3 concentration is also high
as are serum thyroglobulin (TG) concentrations re£ect-
ing the level of TSH-induced thyroid gland hyperactiv-
ity. Serum TSH is detectable despite elevated thyroid
hormone concentrations and the TSH response to TRH
is either normal or exaggerated.42 In most cases, the
basal serum TSH concentration is normal and the cir-
cadian rhythm is preserved.43,44 Serum TSH values
above 10mU/L usually only occur in subjects that have
received inappropriate treatment aimed at reducing
their high level of thyroid hormones. Serum TSH,
though within normal range in RTH, is thought to have
an increased biological activity and its stimulatory
e¡ect would explain the presence of a goitre and the
increased production and secretion of thyroid hor-
mones commonly seen in this condition.45,46 There is
usually no evidence of thyroid autoimmunity except
for the rare occurrence of coincidental autoimmune
thyroiditis.47
As reduced responsiveness to thyroid hormone is
central to the pathogenesis of the syndrome, patients
have been given T4 and T3 in order to observe their
responses and thereby establish the presence of hypo-
sensitivity to the hormone even in PRTH. Thyroid
Thyroid hormone resistance 435
hormone administration will suppress serum TSH but
the dose necessary to produce such an e¡ect has been
variable, as has been the relative e¡ectiveness of T3
compared to T4. The impact of thyroid hormone on
peripheral tissues has been assessed in vivo by a variety
of tests. Such tests involve the administration of supra-
physiological doses of T3, with tissue hyposensitivity
being demonstrated by biochemical markers such as
SHBG and osteocalcin (Bone-Gla-Protein) still being
within normal range following even these large
doses.5,36 No signi¢cant di¡erences are seen in these
indices between GRTH and PRTH, further emphasizing
the point that in PRTH, resistance is not only in the
pituitary but also in the liver. These biochemical mar-
kers have low sensitivity and speci¢city but, although
of limited use, they may be helpful when RTH is not as-
sociated with TR gene mutations.31,32 Metabolic status
has been evaluated by measurements of the basal
metabolic rate (BMR), serum cholesterol, carotene,
triglycerides, creatine kinase, alkaline phosphatase,
angiotensin-converting enzyme, SHBG, ferritin and
osteocalcin, all of which usually have been within the
normal range. Urinary excretion of magnesium, hydro-
xyproline, creatine, creatinine, carnitine, and cyclic
adenosine monophosphate (cAMP), all found to be
elevated in thyrotoxicosis, have been normal or low,
also suggesting normal or slightly reduced thyroid
hormone e¡ect.
With the exception of increased resting pulse rate in
about 50% of patients with RTH, cardiac function is
only minimally altered on echocardiography with mild
hyperthyroid e¡ect on myocardial systolic and diastolic
function.29 Evaluation of other endocrine function has
shown no abnormalities other than those related to the
thyroid. Pituitary imaging has shown no abnormal-
ities. Evidence of delayed bone maturation has been
observed in approximately 50% of patients with RTH
diagnosed during infancy or childhood5 but most
achieve normal adult stature. It is unclear whether
the presence, in some cases, of stippled epiphyses is also
the consequence of reduced thyroid hormone action.
Differential diagnosis
The diagnosis of RTH is based on clinical ¢ndings and
standard laboratory tests and is, when possible, con-
¢rmed by genetic studies and requires awareness of
the possible presence of RTH. A variety of other condi-
tions are associated with hyperthyroxinaemia with
detectable TSH concentrations (Table 2). Failure to
di¡erentiate RTH from ordinary thyrotoxicosis has
resulted in the inappropriate treatment of nearly
one-third of the patients.6
Initially it is helpful to establish whether the free
hormones (FT4 and FT3) are also raised, excluding an
Ann Clin Biochem 2006; 43: 431–440
436 Olateju and Vanderpump
Table 2 Differential diagnosis of conditions associated with an
elevated TT4 with non-suppressed TSH and associated free
thyroid hormone levels (analogue immunoassay)
FT3 FT4
Resistance to thyroid hormone m m
TSH-secreting pituitary tumour m m
Interfering antibodies to thyroid hormones k or N m resonance imaging but the occurrence of pituitary
Non-thyroidal illness k or N m incidentalomas and pituitary hyperplasia following
(including acute psychiatric disorders)
Neonatal period m m
Thyroxine replacement therapy m m or N
Drugs such as amiodarone, k or N m or N
oral cholecystographic agents, heparin
Amphetamine abuse k or N m relatives are virtually diagnostic of RTH, as the disorder
Familial dysalbuminaemic k or N m is familial in 90% of cases. In addition to symptoms and
hyperthyroxinaemia
N, normal
elevated total T4 due to increased serum TBG.
(Changes in TBG concentration or its binding ability
are paralleled by changes in total T4 and T3 even when
T4 and T3 production are unchanged.) Familial dysal-
buminaemic hyperthyroxinaemia is an autosomal
dominant inherited condition due to the presence
of an abnormal albumin-like protein, which has
increased a⁄nity for T4. The use of an equilibrium dia-
lysis or direct ‘two-step’ method to assay FT4 excludes
artifactual elevation due to dysalbuminaemia or the
presence of anti-iodothyronine (anti-T4, anti-T3) anti-
bodies. If the measured TSH falls linearly with serial
dilution of serum, a spurious result due to anti-TSH
antibodies may be less likely, but is not necessarily
excluded. Use of blocking reagents to detect interfer-
ence from heterophilic antibodies may also be helpful.
Other possible causes such as acute systemic illnesses,
acute psychiatric disorders, the neonatal period and
certain drugs can be excluded by recognition of the
clinical context and return to normal thyroid function
following recovery or drug withdrawal. Thyroxine
replacement therapy can be another cause of
hyperthyroxinaemia with normal serum TSH, if taken
intermittently or in overdose.48
The main di¡erential diagnosis to be excluded is
inappropriate TSH secretion from a pituitary tumour
(TSHoma) and this distinction may be di⁄cult as there
are no signi¢cant di¡erences in age, gender, FT4, FT3
and TSH concentrations in both conditions. Lack of
clinical symptoms and signs of hyperthyroidism are
not su⁄cient to establish the diagnosis of RTH and,
because resistance to the hormone is variable in di¡er-
ent tissues, no single test measuring a particular re-
sponse to thyroid hormone is diagnostic. Furthermore,
results of most tests that measure the e¡ect of thyroid
hormone on peripheral tissues show considerable over-
Ann Clin Biochem 2006; 43: 431–440
lap among thyrotoxic, euthyroid and hypothyroid sub-
jects.48 One investigation of particular value is serum
SHBG, which is often elevated into the thyrotoxic range
in TSH secreting tumours but is invariably normal
in RTH. Measurement of the free a-subunit of TSH
may also be diagnostic. A tumour, particularly a
macroadenoma, may be demonstrated on magnetic
inappropriate thyroid ablation may cause diagnostic
di⁄culties. A TSHoma should be suspected when other
members of the family, and particularly the parents of
the patient, fail to exhibit thyroid test abnormalities.
Similar thyroid function abnormalities in ¢rst-degree
signs of thyrotoxicosis, some patients with TSHomas
may present with clinical evidence of growth hormone
excess due to the concomitant hypersecretion of
growth hormone by the tumour. Galactorrhoea and
amenorrhoea in association with hyperprolactinemia
have also been reported in TSHomas. A typical ¢nding
in patients with TSHomas is a disproportionate abun-
dance of serum glycoprotein hormone free a subunit
but this level is normal in RTH.49
Dynamic tests of the pituitary--thyroid axis can be
helpful (Table 3). Circulating TSH shows a normal or ex-
aggerated response to TRH and is suppressed following
T3 administration (Werner test: 80--100 mg orally for
8--10 days)48 in patients with RTH, whereas TSH secre-
tion from autonomous tumours is unresponsive. T3
rather than T4 is used because of its direct e¡ect on tis-
sues, bypassing potential defects of T4 transport and
metabolism, which may also produce attenuated
responses. In addition, the more rapid onset and short-
er duration of T3 action reduces the period required to
complete the evaluation and shortens the duration of
symptoms that may arise in individuals with normal
responses to the hormone (Figure 2).
Genetic testing
Genetic testing is available and is indicated in patients
with clinical features and abnormal thyroid function
tests consistent with those found in RTH supported by
a family history. Genetic testing involves extraction,
direct sequencing and restriction analysis of the
patient’s DNA to demonstrate a TRb gene defect. Pre-
natal diagnosis by chorionic villus sampling may be
indicated in pregnant women with a history of PRTH
with maternal hyperthyroidism to avoid fetal thyro-
troph hyperplasia, reduce fetal goitre and maintain
maternal euthyroidism during pregnancy.50 The risks
versus bene¢ts, however, needs to be weighed because
of the potentially serious complications including fetal
 Thyroid hormone resistance 437

Table 3 Biochemical differences observed in patients with thyroid hormone resistance (RTH) and TSH-producing adenoma
(TSHoma)
Biochemical test RTH TSHoma
Serum TSH levels Usually o10 mU/L Usually 410 mU/L
Normal TSH circadian rhythm Preserved Absent
TSH response to supraphysiologic TH doses Suppressed Not suppressed
TSH response to TRH test Normal or exaggerated Absent
Free a subunit/TSH molar ratio Normal Disproportionate increase
Serum SHBG Normal Usually increased

Raised FT3 and FT4, speci¢c mutations in the TRs provides a means for pre-
Normal or raised TSH natal diagnosis and appropriate family counselling.
This is particularly important in families in which
Repeat TFTs, if same a¡ected members show evidence of growth or mental
results, exclude thyroid retardation. The ideal treatment will be one directed
hormone transport speci¢cally at correcting the defect. Fortunately, in
defects
most cases of RTH the partial tissue resistance to thyr-
Check TFTs in
oid hormone appears to be adequately compensated for
first-degree by an increase in the endogenous supply of thyroid hor-
relatives mone and treatment is unnecessary. Clinical hypothyr-
oidism may be present in patients in whom hormone
If normal, resistance at a peripheral tissue level is not compen-
measure
-subunit sated for by increased thyroid hormone concentra-
tions. This group can be treated by the administration
of supraphysiological doses of thyroid hormone but
If elevated
-subunit, If normal
-subunit, with careful monitoring of the peripheral markers of
investigate for perform thyroid hormone actions to avoid thyrotoxic symp-
TSHoma Werner’s test
toms. It has been recently shown that treatment with
supraphysiological doses of T3, given as a single dose
If TSH suppressed,
carry out every other day, is successful in reducing goitre size
genetic studies with remarkable cosmetic bene¢ts and without caus-
ing side e¡ects.51 This appears to be the treatment of
Figure 2 Suggested diagnostic sequence in patients sus- choice considering that goitre recurrence is the rule.
pected of having RTH syndrome. Thyroid hormone binding The T3 dose must be adjusted in increments until ser-
defects can be excluded by direct measurement and by um TSH and TG are suppressed and reduction of goitre
estimation of the circulating free T4 level. Werner’s test (L-T3 size is observed.
suppression test) is performed by administration of 80–100 mg The exact criteria for treatment of RTH in infancy
orally for 8–10 days. Serum TSH shows a normal or have not been established. This is often an issue when
exaggerated response to TRH that is suppressed following the diagnosis is made at birth or in early infancy. In
T3 administration in patients with RTH, whereas TSH secretion infants with elevated serum TSH concentrations, sub-
from autonomous tumours is unresponsive clinical hypothyroidism may be more harmful than
treatment with thyroid hormone. Indications for treat-
ment may include a TSH level above the upper limit of
loss which could occur during diagnosis or even while normal, retarded bone development and failure to
monitoring the e¡ects of treatment in utero. With rou- thrive. The outcome of a¡ected older members of the
tine neonatal screening for primary hypothyroidism, family who did not receive treatment may serve as a
genetic screening may be indicated to help di¡erentiate guideline. Longer follow-up and psychological testing
it from RTH. of infants who have been given treatment will deter-
mine the e⁄cacy of early intervention.5
Patients with PRTH usually develop thyrotoxic
symptoms and often require treatment. In PRTH,
Treatment supranormal thyroid hormone does not inhibit TSH
Although no speci¢c treatment is available to correct secretion as the regulation of TSH secretion is a¡ected.
fully and speci¢cally for the defect, the ability to identify The symptoms are often subjective and non-speci¢c

Ann Clin Biochem 2006; 43: 431–440

438 Olateju and Vanderpump

Table 4 Key points: resistance to thyroid hormone

RTH is a rare autosomal dominant inherited syndrome of reduced end-organ responsiveness to thyroid hormone.

Patients with RTH have elevated serum FT4 and FT3 concentrations and normal or slightly elevated serum TSH level.

The common characteristic clinical features are goitre but an absence of the usual symptoms and metabolic consequences of
thyroid hormone excess.

RTH is classified on clinical grounds alone into either generalised resistance, pituitary resistance or combined.

Mutations in the TRb gene are responsible for RTH.

The differential diagnosis includes a TSH-secreting pituitary adenoma, the presence of endogenous antibodies directed against
T4 and T3 and primary thyrotoxicosis.

No specific treatment is available or often required for RTH but the diagnosis allows appropriate genetic counselling.

and treatment can be di⁄cult. While thyroid hormone
concentrations and hence features of hyperthyroidism
can treated with radioiodine ablation, thyroidectomy
and antithyroid medications, these do not lower TSH
concentrations. Treatment may be directed at achiev-
ing symptom relief. Atenolol is useful for treatment of
tachycardia and tremors. Propanolol is not a good
choice as it inhibits the conversion of T4 to T3 and
therefore reduces T3-mediated feedback inhibition
centrally. Other drugs of interest are those that sup-
press thyroid hormone concentrations by suppression
of TSH. Somatostatin analogues have limited use
because of their side e¡ects and their inability to main-
tain TSH suppression and may cause a paradoxical
increase in TSH concentrations in some patients with
RTH. TSH secretion can be suppressed by glucocorti-
coids but this occurs only at doses that cause suppres-
sion of the hypothalamic--pituitary--adrenal axis and
other undesirable side e¡ects. Some studies have also
shown successful suppression of TSH in patients with
PRTH with dextro-thyroxine as this does not result in
iatrogenic hyperthyroidism.52--54
Triiodothyroacetic acid (TRIAC) is a thyroid hor-
mone analogue that has been found to be useful in the
treatment of RTH.55 Co-transfection studies have
shown that TRIAC has similar a⁄nities for both wild
type TRb1 and TRb1 mutations while T3 has less a⁄-
nity for TRb1 mutations. TRIAC is able to inhibit the
secretion and biological activity of TSH with very little
thyromimetic e¡ects at the level of peripheral tis-
sues.56--58 TRIAC reduces goitre size and also alleviates
some of the symptoms due to e¡ects of thyroid hor-
mone on peripheral tissues. The proposed modes of
action of TRIAC include hyperactivation of residual
normal TRb function, restoration of mutant TRb1func-
tion towards normal or reduction of the dominant
negative e¡ect of the mutant TRb1. Di¡erent studies
have shown con£icting outcomes with regard to the
usefulness of TRIAC in the treatment of RTH.59--61
Patients who have previously been misdiagnosed
and treated with ablative therapy resulting in a
reduced thyroid reserve and thyroid dysfunction
may need very high doses of thyroid hormone replace-
ment in future. The increased TSH may potentiate the
risk of thyrotroph hyperplasia and possible adenoma
formation.62--64
Future perspective
Key points relating to current knowledge of RTH are
summarized in Table 4. For the future, gene therapy
with excision of the defective genes may be a therapeu-
tic option. In vitro fertilization (IVF) and implantation
of selected oocytes which do not harbour abnormal
alleles from individuals a¡ected with RTH may also
become possible. However, ethical issues will need to
be addressed if this becomes a treatment modality in
RTH; the potential complications associated with IVF,
which cannot guarantee a normal pregnancy, also
make this a less attractive alternative. A more promis-
ing treatment option will be the development of speci¢c
thyroid hormone agonists and antagonists that are TR
isoform speci¢c, thereby allowing the stimulation or
blockade of speci¢c tissues e¡ects identi¢ed in indivi-
dual patients with RTH.60 Development of better ani-
mal models (e.g. by targeted disruption of mouse
TRb and TRa loci) should also enable improved under-
standing of thyroid hormone action in the future.65
References
1 Verhoeven GFM, Wilson JD. The syndromes of primary hormone
resistance. Metabolism 1979; 28: 253–89
2 Albright F, Burnett CH, Smith PH, Parson W. Pseudo-
hypoparathyroidism – an example of ‘Seabright–Bantam Syn-
drome’. J Clin Endocrinol Metab 1942; 30: 922–32
3 Wilson JD, Foster DW, Kronenberg H, Larson PR. Principles of
endocrinology. In: Wilson JD, Foster DW, Kronenberg H, Larson
PR, eds. Williams Textbook of Endocrinology, 9th edn.
Philadelphia, PA: WB Saunders Company, 1998; 1–10
4 Refetoff S, De Wind LT, DeGroot LJ. Familial syndrome
combining deaf – mutism, stippled epiphyses, goitre, and
abnormally high PBI: possible target organ refractoriness to
thyroid hormone. J Clin Endocrinol Metab 1967; 27: 279–94

Ann Clin Biochem 2006; 43: 431–440


5 Refetoff S. Resistance to thyroid hormone. In: Braverman LE,
Utiger RE, eds. Werner and Ingbars’s The Thyroid: A fundamental
and clinical Text, 9th edn. Philadelphia, PA: Lippincott, Williams
and Wilkins, 2005; 1109–29
6 Chatterjee VK, Gurnell M. Thyroid hormone resistance syndrome.
In: Wass JAH, Shalet SM, eds. Oxford Textbook of Endocrinology.
London: Oxford University Press, 2002; 339–49
7 Beck–Peccoz P, Roncoroni R, Mariotti S, et al. Sex hormone-
binding globulin measurement in patients with inappropriate
secretion of thyrotropin (IST): Evidence against selective pituitary
thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol
Metab 1990; 71: 19–25
8 Kaplan MM, Swartz SL, Larsen PR. Partial peripheral resistance
to thyroid hormone. Am J Med 1981; 70: 1115–21
9 La Franchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N,
Brent GA. Follow-up of newborns with elevated screening T4
concentrations. J Pediatr 2003; 143: 296–301
10 Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive
inheritance of thyroid hormone resistance caused by complete
deletion of the protein-coding region of the thyroid hormone
receptor-b gene. J Clin Endocrinol Metab 1992; 73: 49–55
11 McKenna NJ, Lanz RB, O’Malley BW. Nuclear receptor
coregulators: cellular and molecular biology. Endocr Rev 1999;
20: 321–44
12 Jameson JL. Thyroid hormone resistance: pathophysiology at the
molecular level. J Clin Endocrinol Metab 1992; 74: 708–11
13 Yen PM. Molecular basis of resistance to thyroid hormone. Trends
Endocrinol Metab 2003; 14: 327–33
14 Sap J, Munoz A, Damm K, et al. The c-erb-A protein is
a high-affinity receptor for thyroid hormone. Nature 1986; 324:
635–40
15 Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DL, Evans
RM. The c-erb-A gene encodes a thyroid hormone receptor.
Nature 1986; 324: 641–6
16 Yen PM. Physiological and molecular basis of thyroid hormone
action. Physiol Rev 2001; 81: 1097–142
17 Zhang J, Lazar MA. The mechanism of action of thyroid hormone.
Ann Rev Physiol 2000; 62: 438–66
18 Mitsuhashi T, Tennyson GE, Nikoderm VM. Alternative splicing
generates messages encoding rat c-erb-A proteins that do not
bind thyroid hormone. Proc Natl Acad Sci 1998; 85: 5804–5
19 Macchia PE, Takeuchi Y, Kawai T, Cua K, Gauthier K, Chassande
O. Increased sensitivity to thyroid hormone in mice with complete
deficiency of thyroid hormone receptor a. Proc Natl Acad Sci
2001; 98: 349–54
20 Weiss RE, Weinberg M, Refetoff S. Identical mutations in
unrelated families with generalized resistance to thyroid hormone
occur in cytosine–guanine–rich areas of the thyroid hormone
receptor beta gene: analysis of 15 families. J Clin Invest 1993; 91:
2408–15
21 Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H,
Barlow C. A targeted dominant negative mutation of the thyroid
hormone alpha 1 receptor causes increased mortality, infertility,
and dwarfism in mice. Proc Natl Acad Sci 2001; 98: 15095–100
22 Tinnikov A, Nordstrom K, Thoren P, Kindblom JM, Malin S, Rozell
B. Retardation of post-natal development caused by a negatively
acting thyroid hormone receptor alpha1. EMBO J 2002; 21:
5079–87
23 Liu YY, Schultz JJ, Brent GA. A thyroid hormone receptor alpha
gene mutation (P398H) is associated with visceral adiposity and
Thyroid hormone resistance 439
impaired catecholamine-stimulated lipolysis in mice. J Biol Chem
2003; 278: 38913–20
24 Ono S, Schwartz ID, Mueller OT, Root AW, Usala SJ, Bercu BB.
Homozygosity for a ‘dominant negative’ thyroid hormone receptor
gene responsible for generalized resistance to thyroid hormone.
J Clin Endocrinol Metab 1991; 73: 990–4
25 Usala SJ, Menke JB, Watson TL, Wondisford FE, Weintraub BD,
Bérard JB. A homozygous deletion in the c-erb-AX thyroid
hormone receptor gene in a patient with generalized thyroid
hormone resistance: isolation and characterization of the mutant
receptor. Mol Endocrinol 1991; 5: 327–35
26 Bassett DJH, Williams GR. The molecular actions of thyroid
hormone in bone. Trends Endocrinol Metab 2003; 14: 356–64
27 Johansson C, Göthe S, Forrest D, Vennström B, Thorén P.
Cardiovascular phenotype and temperature control in mice lacking
thyroid hormone receptor b or both a1 and b. Am J Physiol 1999;
276: H2006–12
28 Gloss B, Trost SU, Bluhm WF, Swanson EA, Clark R, Winkfein R.
Cardiac ion channel expression and contractile function in mice
with deletion of thyroid hormone receptor alpha or ss.
Endocrinology 2001; 142: 544–50
29 Kahaly GJ, Matthews CH, Mohr-Kahaly S, Richards CA,
Chatterjee VK. Cardiac involvement in thyroid hormone resis-
tance. J Clin Endocrinol Metab 2002; 87: 204–12
30 Mixson AJ, Hauser P, Tennyson G, Renault JC, Bodenner DL,
Weintraub BD. Differential expression of mutant and normal beta
T3 receptor alleles in kindreds with generalized resistance to
thyroid hormone. J Clin Invest 1993; 91: 2296–300
31 Hayashi Y, Janssen OE, Weiss RE, Murata Y, Seo H, Refetoff S.
The relative expression of mutant and normal thyroid hormone
receptor genes in patients with generalized resistance to thyroid
hormone determined by estimation of their specific messenger
ribonucleic acid products. J Clin Endocrinol Metab 1993; 76:
64–69
32 Sadow P, Reutrakul S, Weiss RE, Refetoff S. Resistance to
thyroid hormone in the absence of mutations in the thyroid
hormone receptor genes. Curr Opin Endocrinol Diab 2000; 7:
253–9
33 Hao E, Menke JB, Smith AM, Jones C, Geffer ME, Hershman JM.
Divergent dimerization properties of mutant b1 thyroid hormone
receptors are associated with different dominant negative
activities. Mol Endocrinol 1994; 8: 841–51
34 Meier CA, Dickstein BM, Ashizawa K, McClaskey JH, Muchmore
P, Ransom SC. Variable transcriptional activity and ligand binding
of mutant b1 3,5,3-triiodothyronine receptors from four families
with generalized resistance to thyroid hormone. Mol Endocrinol
1992; 6: 248–58
35 Nagaya T, Eberhardt NL, Jameson JL. Thyroid hormone
resistance syndrome: correlation of dominant negative activity
and location of mutations. J Clin Endocrinol Metab 1993; 77:
982–90
36 Beck-Peccoz P, Chatterjee VKK. The variable clinical phenotype
in thyroid hormone resistance syndrome. Thyroid 1994; 4: 225–32
37 Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA,
Mixson AJ. Attention deficit-hyperactivity disorder in people with
generalized resistance to thyroid hormone. N Engl J Med 1993;
328: 997–1001
38 Weiss RE, Stein MA, Trommer B, Refetoff S. Attention-deficit
hyperactivity disorder and thyroid function. J Pediatr 1993; 123:
539–45
Ann Clin Biochem 2006; 43: 431–440
440 Olateju and Vanderpump
39 Elia J, Gulotta C, Rose SR, Marin G, Rapoport J. Thyroid function
and attention-deficit hyperactivity disorder. J Am Acad Child
Adolesc Psychiatry 1994; 33: 169–72
40 Weiss RE, Stein MA, Duck SC, Chyna B, Phillips W, O’Brien T.
Low intelligence but not attention deficit hyperactivity disorder is
associated with resistance to thyroid hormone caused by mutation
R316H in the thyroid hormone receptor b gene. J Clin Endocrinol
Metab 1994; 78: 1525–8
41 Ando S, Sarlis NJ, Krishan J, Feng X, Refetoff S, Zhang MQ.
Aberrant alternative splicing of thyroid hormone receptor in a TSH-
secreting pituitary tumor is a mechanism for hormone resistance.
Mol Endocrinol 2001; 15: 1529–38
42 Sarne DH, Sobieszczyk S, Ain KB, Refetoff S. Serum thyrotropin
and prolactin in the syndrome of generalized resistance to thyroid
hormone: Responses to thyrotropin-releasing hormone stimulation
and triiodothyronine suppression. J Clin Endocrinol Metab 1990;
70: 1305–11
43 Kasai Y, Aritaki S, Utsunomiya M, Matsuno T. Twin sisters with
Refetoff’s Syndrome. J Jpn Pediatr Assoc 1983; 87: 1203–12
44 Hughes IA, Ichikawa K, DeGroot LJ, John R, Jones MK,
Hall R. Non-adenomatous inappropriate TSH hypersecretion and
euthyroidism requires no treatment. Clin Endocrinol 1987; 27:
475–83
45 Persani L, Borgato S, Romoli R, Asteria C, Pizzocardo A, Beck-
Peccoz P. Changes in the degree of sialylation of carbohydrate
chain modify the biological properties of circulating thyrotropin
isoforms in various physiological and pathological states. J Clin
Endocrinol Metab 1998; 83: 2486–92
46 Persani L, Asteria C, Tonacchera M, Vitti P, Chatterjee VKK,
Beck-Peccoz P. Evidence for secretion of thyrotropin with
enhanced bioactivity in syndromes of thyroid hormone resistance.
J Clin Endocrinol Metab 1994; 78: 1034–9
47 Lamberg BA, Rosengård S, Liwendahl K, Säarinen P, Evered DC.
Familial partial peripheral resistance to thyroid hormones. Acta
Endocrinol 1978; 87: 303–12
48 Chatterjee VKK, Beck-Peccoz P. The variable clinical phenotype
in thyroid hormone resistance syndrome. Ballieres Clin Endocrinol
Metab 1994; 8: 267–83
49 Beck-Peccoz P, Persani L, Faglia G. Glycoprotein hormone a-
subunit in pituitary adenomas. Trends Endocrinol Metab 1992; 3:
41–5
50 Asteria C, Rajanayagam O, Collingwood TN, Persani L, Romoli R,
Mannavola D. Prenatal diagnosis of thyroid hormone receptors.
J Clin Endocrinol Metab 1999; 84: 405–10
51 Anselmo J, Refetoff S. Regression of a large goitre in a patient
with resistance to thyroid hormone by every other day treatment
with triiodothyronine. Thyroid 2004; 14: 71–4
52 Hamon P, Bevier Lapeer M, Robert M, Pentad D, Pugeat M.
Hyperthyroidism due to selective pituitary resistance to thyroid
Ann Clin Biochem 2006; 43: 431–440
hormone in a 15 month old: efficacy of D-thyroxine treatment.
J Clin Endocrinol Metab 1988; 67: 1089–93
53 Dorey F, Stauch G, Gayno JP. Thyrotoxicosis due to pituitary
resistance to thyroid hormones. Successful control with
D-thyroxine: a study in 3 patients. Clin Endocrinol 1990; 32:
221–228
54 Krawczynska H, Wojcik–Musialek K, Ilig R. 10 years of successful
treatment with dextrothyroxine in a girl with TSH-induced
hyperthyroidism. Horm Res 1991; 35: 213–6
55 Takeda T, Suzuki S, Rue–Tsuan L, DeGroot LJ. Triiodothyroacetic
acid has unique potential for therapy of resistance to thyroid
hormone. J Clin Endocrinol Metab 1995; 80: 2033–41
56 Goslings B, Schwartz HL, Dillmann W, Surks MI, Oppenheimer
JH. Comparison of the metabolism and distribution of L–T3 and
Triac in the rat: a possible explanation of differential hormone
potency. Endocrinology 1976; 98: 666–75
57 Beck–Peccoz P, Piscitelli G, Cattaneo MG, Faglia G. Successful
treatment of hyperthyroidism due to nonneoplastic pituitary
TSH hypersecretion with 30 50 ‘3–triiodothyroacetic acid (TRIAC).
J Endocrinol Invest 1983; 6: 217–23
58 Orgiazzi J, Ducottet X, Barbier Y, Jordan D, Pugeat M, Morin MH.
Inappropriate TSH hypersecretion: opposite effect of T4 and T3 on
the thyrotrophs? Ann Endocrinol (Paris) 1985; 45: 86A
59 Kunitake JM, Hartman N, Henson LC, et al. 3,5,30 -Triiodothyr-
oacetic acid therapy for hyperthyroidism due to pituitary resistance
to thyroid hormone. J Clin Endocrinol Metab 1989; 75: 1071–5
60 Weiss RE, Refetoff S. Treatment of resistance to thyroid
hormone – primum non noncere. J Clin Endocrinol Metab 1999;
84: 401–4
61 Dulgeroff AJ, Geffner ME, Koyal SN, Wong M, Hershman JM.
Bromocriptine and TRIAC therapy for hyperthyroidism due to
pituitary resistance to thyroid hormone. J Clin Endocrinol Metab
1992; 75: 1071–5
62 Salmela PI, Wide L, Juustila H, Ruokonen A. Effects of thyroid
hormones (T4, T3), bromocriptine and TRIAC on inappropriate
TSH hypersecretion. Clin Endocrinol (Oxford) 1988; 28: 497–501
63 Sriwatanakul K, Mc Cormick K, Woolf P. Thyrotropin (TSH)
induced hyperthyroidism: response of TSH to dopamine and its
agonist. J Clin Endocrinol Metab 1977; 58: 255–61
64 Samaan NA, Osborne BM, Mackay B, Leavens ME, Duello TM,
Halmi NS. Endocrine and morphologic studies of pituitary
adenomas secondary to primary hypothyroidism. J Clin Endocrinol
Metab 1977; 45: 903–11
65 Flamant F, Samarut J. Thyroid hormone receptors: lessons from
knock-out and knock-in mutant mice. Trends Endocrinol Metab
2003; 14: 85–90
Accepted for publication 5 June 2006