Resistance to thyroid hormone (RTH)

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.