Are you sure the patient has TSH resistance?

Diagnosis of patients with classic signs and symptoms of hypothyroidism in whom there is elevated thyroid stimulating hormone (TSH) and low thyroid hormone (TH) levels is relatively straightforward.

When serum TSH is mildly elevated and TH levels are normal the diagnosis of resistance to TSH (RTSH) is considered. RTSH is defined as decreased activity of TSH in the presence of a TSH molecule with normal bioactivity. As in other syndromes of hormone resistance, defects can be in the cognate receptor or the post-receptor cascade of events. Patients with RTSH have biologically active TSH but usually harbor a defect in the TSH receptor (TSHR) such that TSH signaling does not occur in the normal fashion.

There are 3 types of RTSH:

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  • TSHR gene mutations

  • PAX 8 gene mutations – PAX8 being an important gene regulating thyroid gland development and expression of the TSHR

  • RTSH linked to a locus on the long arm of chromosome 15 for which there is no specific gene yet identified.

Among the patients with TSHR mutations, there is a spectrum of clinical severity, such that some subjects can be:

  • Fully compensated and are euthyroid with elevated TSH (euthyroid hyperthyrotropinemia);

  • Partially compensated where the TSH elevation cannot completely compensate for the defect and there is mild hypothyroidism;

  • Uncompensated with elevated serum TSH levels and low TH levels, similar to severe classic primary hypothyroidism.

RTSH is inherited in an autosomal recessive pattern, where affected individuals are usually compound heterozygous for a different mutation in each of the TSHR alleles. There are also examples of a dominant mode of inheritance.

The hallmark of RTSH is lack of goiter, elevated serum TSH and free T4 and free T3 that range from low, low normal, to normal. All patients have suppressible TSH with exogenous TH as the TH receptor is intact and normal.

What else could the patient have?

Conditions which result in impaired thyroid hormone secretion in the presence of normal pituitary function could mimic RTSH. These include other congenital causes of hypothyroidism such as dyshormonogenesis or ectopic thyroid. Unlike RTSH, some causes of dyshormonogenesis result in a goiter or ectopic thyroid tissue which is absent in RTSH.

Subjects with partially compensated RTSH have mild hypothyroidism. Such subjects may be diagnosed as subclinical hypothyroidism in which the TSH is mildly elevated while the TH levels are normal or at the low range of normal. Subclinical hypothyroidism is usually associated with antithyroid antibodies (antimicrosomal antibodies or antithyroglobulin antibodies).

Additionally, subclinical hypothyroidism is usually isolated, whereas RTSH may have more than one family affected with a clear mode of inheritance. Whether patients with subclinical hypothyroidism may also have RTSH based on mild abnormalities in the TSH receptor has not been fully answered.

Key laboratory and imaging tests

Measurement of FT4 and TSH are the major tests in the diagnosis of RTSH. In subjects with uncompensated RTSH, serum TSH concentrations are usually greater than 100 mU/L and FT4 are reduced more than 50% of the lower limit of normal. Partially compensated or compensated RTSH due to mutations in the TSHR have TSH values between 10 and 100 mU/L and normal FT4 values.

Sequencing of the TSHR (9 exons) can be helpful in confirming the diagnosis of RTSH. Most loss of function mutations are located in the extracellular domain of the TSHR, in contrast to gain of function mutations which are located in the transmembrane domain.

Sequencing of the PAX8 gene confirms the etiology of this form of RTSH.

Patients with the RTSH phenotype with an autosomal dominant pattern of inheritance and have neither TSHR nor PAX8 mutations nor inactivating mutations in G-proteins should be evaluated for linkage for a region on the long arm of chromosome 15. Although the exact gene involved in unknown at this time, further evaluation and narrowing of the area of interest on chromosome 15 will result in identification of the gene.

Other tests that may prove helpful diagnostically

Measurement of thyroid hormone levels in other family members can be very helpful in distinguishing RTSH from subclinical hypothyroidism.

Management and treatment of the Disease

1. TSHR Mutations

  • Fully compensated: This requires no treatment. Recognition of the abnormality is sufficient to confirm to the physician and patient that their defect is compensated and no further treatment is required.

  • Partially compensated: Since TH sensing via the thyroid hormone receptor is normal, titration of LT4 treatment to normalization of the TSH is sufficient for treatment.

  • Uncompensated: Treatment is as in any patient with primary hypothyroidism, which is to normalize the TSH.

2. PAX8 Mutations

  • Treatment with L-T4 to normalize the TSH.

3. Chromosome 15 associated RTSH

  • Treatment with L-T4 to normalize the TSH.

What’s the Evidence?/References

Sunthornthepvarakui, T, Gottschalk, ME, Hayashi, Y, Refetoff, S. “Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene”. N Engl J Med. vol. 332. 1995. pp. 155-60. (The first documented family with RTSH due to a compound heterozygous mutation in the TSHR.)

Bereket, A, Liao, XH, Turoglu, T, Aribal, E, Refetoff, S. “Analysis of the PAX8 gene in congenital hypothyroidism caused by different forms of thyroid dysgenesis in a father and daughter”. J Pediatr Endocrinol Metab. vol. 17. 2004. pp. 1021-1029.

Hermanns, P, Grasberger, H, Refetoff, S, Pohlenz, J. “Mutations in the NKX2.5 gene and the PAX8 promoter in a girl with thyroid dysgenesis”. J Clin Endocrinol Metab. vol. 96. 2011. pp. E977-81. (The above two references demonstrate RTSH in patients with PAX8 mutations.)

Grasberger, H, Mimouni-Bloch, A, Vantyghem, MC. “Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci”. J Clin Endocrinol Metab. vol. 90. 2005. pp. 4025-34.

Grasberger, H, Vaxillaire, M, Pannain, S. “Identification of a locus for non-goitrous congenital hypothyroidism on chromosome 15q25.3-26.1”. Hum Genet. vol. 118. 2005. pp. 348-55. (These two articles discuss the linkage of the long arm of Chromosome 15 with kindreds having RTSH without known mutations in the TSHR. The exact gene causing this disorder has not yet been found, however the interval in which it is located has been identified.)

Bonomi, M, Busnelli, M, Beck-Peccoz, P. “A family with complete resistance to thyrotropin-releasing hormone”. N Engl J Med. vol. 360. 2009. pp. 731-4. (Description of uncompensated RTSH.)

Wartofsky, L. “Levothyroxine therapy for hypothyroidism: should we abandon conservative dosage titration?”. Arch Intern Med. vol. 165. 2005. pp. 1683-4.

Wartofsky, L, Dickey, RA. “The evidence for a narrower thyrotropin reference range is compelling”. J Clin Endocrinol Metab. vol. 90. 2005. pp. 5483-8. (These three articles put forward a case for subclinical hypothyroidism. It is still unknown whether the individuals have RTSH or more likely represent a spectrum of autoimmune thyroid disease.)

Persani, L, Calebiro, D, Cordella, D. “Genetics and phenomics of hypothyroidism due to TSH resistance”. Mol Cell Endocrinol. vol. 322. 2010. pp. 72-82. (A detailed review of RTSH and the molecular pathogenesis.)