Thyroid hormone resistance and its management

Ana Marcella Rivas, MD, and Joaquin Lado-Abeal, MD, PhD

The syndrome of impaired sensitivity to thyroid hor- Table 1. Thyroid function panel from 2009 to 2014
mone, also known as syndrome of thyroid hormone Reference
resistance, is an inherited condition that occurs in value 12/2009 10/2010 08/2011 04/2012 02/2013 07/2014
1 of 40,000 live births characterized by a reduced TSH (mcIntUnit/mL) 0.27–4.20 10.37 42.41 46.62 37.70 26.39 39.00
responsiveness of target tissues to thyroid hor-
FT4 (ng/dL) 0.93–1.70 3.00 1.81 2.07 1.91 1.82 1.05
mone due to mutations on the thyroid hormone
receptor. Patients can present with symptoms of FT3 (pg/mL) 2.3–4.2 N/A N/A N/A N/A 8.86 3.64
hyperthyroidism or hypothyroidism. They usually FT3 indicates free triiodothyronine; FT4, free thyroxine; NA, not available; TSH, thyroid-stimulating hormone.
have elevated thyroid hormones and a normal or
elevated thyroid-stimulating hormone level. Due to
their nonspecific symptomatic presentation, these patients can be misdi- for the patient. Her family history was relevant for a son with
agnosed if the primary care physician is not familiar with the condition. “hypothyroidism.”
This can result in frustration for the patient and sometimes unnecessary The patient’s thyroid function panels from 2009 to 2014
invasive treatment such as radioactive iodine ablation, as in the case were reviewed and are presented in Table 1. During this pe-
presented herein. riod of time she was on different doses of thyroid replacement
therapy, her TSH remained elevated despite normal or elevated
free T4 levels. She also had magnetic resonance imaging of the

T
he syndrome of impaired sensitivity to thyroid
hormone (ISTH) is a condition of decreased tissue
sensitivity to thyroid hormone action usually caused
by germline mutations of the thyroid hormone recep-
tor beta (THRB) gene. The mutant receptor has lower binding
affinity for thyroid hormone and, as a consequence, serum
thyroid-stimulating hormone (TSH) levels remain nonsup-
pressed despite elevated thyroid hormones (1–3). We present
the case of a 66-year-old woman who was referred for evalu-
ation of an abnormal thyroid function panel that suggested
ISTH.
CASE REPORT
A 66-year-old woman was referred for evaluation of thyroid
dysfunction. Her complaints were memory loss and intermit-
tent gastrointestinal symptoms with alternating diarrhea and
constipation attributed to irritable bowel syndrome. In 1998,
she had been diagnosed with “a thyroid condition that no one
was able to fix.” At that time, she had a goiter and was treated
with radioactive iodine (I-131) and was subsequently started
on thyroid replacement therapy. For nearly 30 years, she was
seen by multiple physicians who continuously modified her
thyroid hormone replacement but had been unable to “normal-
ize” her thyroid hormone levels, and this resulted in frustration
head, which showed a possible right-sided pituitary microad-
enoma. A thyroid ultrasound showed a normal thyroid gland
with some nonspecific nodules.
PCR amplification of THRB gene exons 10, 9, and 8 fol-
lowed by gene sequencing showed a heterozygous missense mu-
tation C>A located at exon 10. The mutation caused a change in
thyroid hormone receptor beta protein amino acid 453 proline
to threonine, P453T (Figure 1).
We recommended that the patient resume thyroid hormone
replacement with liothyronine 10 mg twice a day and levothy-
roxine 75 mcg daily; unfortunately, she was lost to follow up
thereafter.
DISCUSSION
We describe a case of ISTH caused by a common germline
mutation located at THRB exon 10 hot spot (4). The patient
went undiagnosed for many years. When reviewing her thyroid
From the Department of Medicine, Division of Endocrinology and Metabolism,
Mayo Clinic, Jacksonville, Florida (Rivas); and the Department of Medicine,
Division of Endocrinology, Texas Tech University Health Science Center, Lubbock,
Texas (Lado-Abeal).
Corresponding author: Ana Marcella Rivas, MD, 4500 San Pablo Road,
Jacksonville, FL 32224 (e-mail: rivasmejia.ana@mayo.edu).

Proc (Bayl Univ Med Cent) 2016;29(2):209–211 209

Figure 1. Sequence analysis of the thyroid hormone receptor beta (THRB) gene showing a heterozygous mutation C>A located in exon 10. The mutation results in
a change of proline for threonine at amino acid position 453, P453T.
function tests, we noted a nonsuppressed serum TSH despite
a normal or elevated free T4 level. These abnormal values led
us to suspect THRB mutation and proceed with genetic stud-
ies, which confirmed the diagnosis. The diagnosis of ISTH re-
quires a high degree of suspicion, and we therefore believe it is
important for the general practitioner to be able to recognize
the syndrome to avoid delay in diagnosis and unnecessary in-
vasive treatments, such as thyroid surgery or radioactive iodine
ablation.
Thyroid hormone genomic actions are exerted by thyroid
hormone binding mostly to nuclear receptors located in the
nuclei and interaction with DNA to regulate the transcription of
target genes. Most of the cases of ISTH are caused by mutations
in the THRB gene located in chromosome 3, and these muta-
tions most often clustered in three hot spots located in exons 8,
9, and 10. The mutant thyroid hormone receptor beta protein
has either reduced affinity for T3 or abnormal interaction with
cofactors involved in thyroid hormone action, making the target
tissues refractory to thyroid hormones (5–7).
In 15% of cases of ISTH, a gene mutation is not identi-
fied (6). Mutations affecting thyroid hormone cell membrane
transporters and thyroid hormone metabolism have now been
described, and the concept of syndrome of reduced sensitivity
to thyroid hormone is used to encompass any defect causing
reduced effectiveness of the thyroid hormone (3).
The clinical presentation of patients with THRB mutations
is variable. Patients may present with symptoms of hyperthy-
roidism, hypothyroidism, or a combination of symptoms of
thyroid hormone deficiency and excess depending on the level of
THRB and THRA gene expression in the target tissues (5, 6, 8).
210 Baylor University Medical Center Proceedings
Symptoms tend to decrease with age, and patients eventually
become clinically euthyroid. Goiter is one of the most common
findings for which patients seek medical attention. It’s usually
refractory and recurs after surgery or treatment with radioactive
iodine. Other common complaints include tachycardia, learning
disabilities, and hyperactivity (8).
The classic pattern of thyroid function test that these patients
present with is elevated thyroid hormones with nonsuppressed
TSH in serum. The response of TSH to thyrotropin-releasing
hormone is normal or exaggerated, and thyroidal radioiodine
uptake may be elevated (5).
ISTH can be difficult to differentiate from TSH-producing
pituitary tumors, which present with a similar thyroid func-
tion profile. A case of coexistence of both conditions has been
reported (9). TSH-producing pituitary tumors present elevated
serum levels of T4, T3, and nonsuppressed TSH. In contrast to
patients with ISTH who may be clinically euthyroid, patients
with TSHomas usually present with symptoms of mild to severe
hyperthyroidism and compression symptoms resulting from
tumor growth (7).
When treating these patients, one should concentrate on the
patient’s symptoms and clinical picture instead of aiming to nor-
malize thyroid hormone levels (5, 8). Most patients, if left alone,
adequately overcome the resistance by increased thyroid hor-
mone secretion and therefore do not require treatment (8, 10).
Treating patients who present with normal TSH is more chal-
lenging; in these patients, administration of supraphysiological
doses of thyroid hormone might be required and, if so, should
be closely monitored. Patients who present with symptoms
of hyperthyroidism should be treated symptomatically with
Volume 29, Number 2
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