Resistance to thyroid hormone (RTH)
Dr. A.Narendra , MBBS.
Dominantly
inherited
characterized
by
1.
elevated free thyroid hormones in the serum
2.
failure to suppress pituitary thyroid stimulating hormone (TSH)
secretion
3.
with variable refractoriness to hormone action in peripheral tissues.
Two
major forms:
asymptomatic
individuals with generalized resistance (GRTH) and patients with thyrotoxic features,
suggesting predominant pituitary resistance (PRTH).
Molecular genetic analyses indicate that both GRTH and
PRTH are associated with diverse mutations in the thyroid hormone
receptor beta
gene, which localize to three regions in the hormone binding domain of
the receptor.
In
addition to being functionally impaired, the mutant receptors are also able to inhibit their wild-type
counterparts in a dominant
negative manner.
The thyroid
hormone receptor (TR) and retinoid X receptor (RXR) form heterodimers that bind specifically to
thyroid hormone response elements (TRE) in the promoter regions of target genes.
In the absence
of hormone, TR binds co-repressor (CoR) proteins that silence gene expression.
The numbers
refer to a series of ordered reactions that occur in response to thyroid
hormone:
(1) T4 or T3
enters the nucleus;
(2) T3
binding dissociates CoR from TR;
(3)
Coactivators (CoA) are recruited to the T3-bound receptor;
(4) gene
expression is altered.
·
Recognized features of RTH include
o failure to thrive, growth
retardation and attention-deficit hyperactivity disorder in childhood,
o goitre and thyrotoxic cardiac
symptoms in adults.
The
pathogenesis
of variable tissue resistance is not fully understood but may be
1.
related to the differing tissue distributions of a and b thyroid
hormone receptors
a.
TRa is particularly abundant in brain, kidneys, gonads, muscle, and
heart,
b.
whereas TRb expression is relatively high in the pituitary and liver.
c.
Both receptors are variably spliced to form unique isoforms.
d.
The TRb2 isoform,
which has a unique amino terminus, is selectively expressed in the hypothalamus
and pituitary, where it plays a role in feedback control of the thyroid axis
e.
The TRa 2 isoform contains a unique carboxy terminus that precludes
thyroid hormone binding; it may function to block the action of other TR
isoforms.
2.
variable dominant negative activity of mutant receptors on different
target genes.
RTH must be distinguished from other
causes of euthyroid hyperthyroxinemia (e.g., FDH) and inappropriate
secretion of TSH by TSH-secreting pituitary adenomas
In most patients, no treatment is indicated;
the importance of making the diagnosis is to
1. avoid
inappropriate treatment of mistaken hyperthyroidism
2. to
provide genetic counseling.
