Thyroid resistance v.s. TSH secreting pituitary tumor A clinical picture

1. Thyroid resistance v.s. TSH secreting pituitary tumorA clinical picture

2. Introduction Aim - to reach a diagnosis in measurements of elevated TSH and raised free T4

3. Thyroid axis

4. Hyperthyroidism: • Primary - Grave’s disease • Secondary (central) - inappropriate TSH secretion. Raised TSH + raised T4 - reaching a diagnosis: Differential diagnosis • TSH secreting tumour • Resistance to Thyroid Hormone • Non-compliance with thyroid replacement therapy Investigations to reach a diagnosis • Primary or secondary hyperthyroidism? Establish that TSH is inappropriate • Differentiate between TSH-secreting tumour and resistance to thyroid hormone

5. TSH-oma v.s. RTH • Neurological signs and symptoms? Suggestive of a TSH-oma • MRI – look at pituitary area – suggestive of a TSHoma • Free thyroid hormone are the same in patients with TSH-oma and RTH • Familial condition? Suggestive of RTH • Baseline TSH – normal or mildly elevated TSH-secreting tumour/ always normal in TRH • Elevated -subunit and high -subunit/TSH molar ratio – suggestive of TSH oma • TRH stimulation test – unresponsive in TSH-oma/ always exaggerated response in PRTH • T3 suppression test – unresponsive in TSH-oma - useful in TSH-oma pts that are thyroidectomized to distinguish TSH-oma from non-compliance with thyroid therapy

6. Peripheral action of thyroid hormones at tissue level – SHBG (liver) and ICTP (bones) – hyperthyroid range in TSHoma and normal/ low range in RTH • An octreotide test – suppressed TSH in TSHoma/ RTH showed none or little decrease in TSH (different response due to somatostatin receptors on TSH-secreting tumours, usually respond immediately to somatostatin with a marked decrease in TSH secretion) For diagnostic purposes, the dynamic tests (T3 suppression and octreotide) should be reserved for patients in whom the classical tests are atypical

7. TSHomas • TSH-secreting pituitary tumors - 1% of all pituitary adenomas • Cause secondary (central) hyperthyroidism • First cases were reported in 1960 – now 336 cases have been reported • Most secrete TSH alone, normally accompanied by hypersecretion of  subunit. They may also co-secrete PRL or GH • The recent development of ultrasensitive TSH assays facilitates earlier diagnosis by detecting TSH in the presence of elevated free thyroid hormones, thus ruling out primary hyperthyroidism, meaning that TSHomas are often diagnosed before they reach the macroadenoma stage, thus complete cure more likely. Macroadenoma are highly invasive – particularly high incidence amongst patients with previous thyroid ablation – i.e. effects of incorrect diagnosis!

8. Clinical manifestation • Hyperthyroid features, goitre, visual field defects and headache are the most common features. • Degree of thyrotoxic symptoms revealed that thyroid hormone levels correlated with the intensity of signs and symptoms. • Clinical manifestations vary at the time of diagnosis depending on whether the patient has previously been treated with thyroid surgery. • No preferential for women, unlike most thyroid problems.

9. Diagnosis Most patients are often diagnosed after having been mistaken for having Graves’ disease, resulting in unwarranted thyroidectomy which altered the hormonal profile. 1. Serum tests: In untreated patients, the classical diagnostic criteria • unresponsive TRH test • high -subunit, • high -subunit/TSH ratio • elevated baseline TSH 2. Imaging  MRI of the pituitary gland (if pit tumour seen, although strongly suggestive, is not diagnostic of TSH-secreting tumour, as pituitary incidentalomas have been found on MRI in up to 10% of normal subjects.) BUT In difficult cases, more recent dynamic tests, including octreotide and T3 suppression tests may be useful.

10. Treatment Surgery • Transsphenoidal surgery – first line therapy , but complications are related to the size of the tumour • Use of antithyroid or octreotide + propanolol pre surgery to make pt euthyroid In the absence of surgical cure,  external radiation of the pituitary (but long term complications) For the patients who were still hyperthyroid despite surgery and external radiation, medical treatment is necessary. a. Initially bromocriptine or cabergoline was used, but with limited success b. Long acting somatostatin analogs – octreotide or lanreotide – Leads to a reduction in TSH and  subunit secretion, with restoration of euthyroid state in most. c. Thyroid hormone therapy necessary in patients with prior thyroidectomy or ablation.

11. Prognosis The size and invasiveness of the tumour, duration of symptoms, and intensity of hyperthyroidism were the main prognostic factors. Thus, early diagnosis and treatment are the keys to a good outcome.

12. Thyroid hormone resistance syndrome (RTH) • Characterised by decreased tissue responsiveness to thyroid hormones (TH) • First described in 1973 – now over 700 individuals and 250 families • Autosomal dominant inheritance (usually) • Clinically – persistent elevation of free T3 and T4 with non-suppressed TSH secretion due to mutations of the thyroid receptor 

13. RTH is clinically divided into two forms based on phenotype pattern: • generalized resistance (GRTH) • pituitary resistance to T3 (PRTH) From a genetic analysis point of view, this is not a classification – division of GRTH and PRTH is subjective based on clinical manifestations. Clinical studies do not show that the peripheral tissues of pts with PRTH have a different sensitivity to TH than those of pts with GRTH There is no distinction between these two forms at the genetic level  The same mutation can cause either GRTH or PRTH in different individuals of the same family

14. Thyroid receptors (TR) • Members of the nuclear hormone receptor superfamily and are encoded on two distinct TR genes, TR and TR. TR is further expressed as TR 1 and TR 2 • Although TR1 is widely expressed, TR2 is mainly expressed in the anterior pituitary gland. • They function as hormone-activated transcription factors thus act by modulating gene expression. • TR bind DNA in the absence of hormone, leading to transcriptional repression. • Hormone binding is associated with a conformational change in the receptor that causes it to function as a transcriptional activator.

15. Mutations in TR • In 1989 and 1990, Sakurai et al. and Usala et al. discovered the first two mutations in the ligand binding domain of the thyroid hormone receptor  gene, G345R and P453H. • Mutations in the TRs in 3 main clusters • at the ligand binding domain • at the hinge domain Effects of these mutations: • reduced affinity for T3 • impaired interaction with one of the cofactors • Dominant negative effect - in cotransfection studies – mutant TRs have been shown to block the transcriptional regulation of -subunit and TSH reporter genes by wild-type TRs.

16. Dominant Negative Effect TRs homodimerize or form heterodimers with retinoid X receptors (RXR) and bind to specific DNA sequences – called the thyroid hormone response elements (TREs)  In the absence of T3, TR homodimers and heterodimers are associated with corepressors (NCor and SMRT) that silence the transcription of genes positively regulated by T3  Binding of T3 to TRs releases the corepressors and recruits nuclear coactivators like NCoA, which then stimulate gene transcription  Mutations of TR interfere with the functions of the wild-type TRs – a phenomenon called Dominant Negative Effect (DNE)

17. DNE is thought to be responsible for the pathogenesis of RTH – mutant TR inhibits wild-type TR function • DNE involves occupation of a TRE by a mutant TR that may have: • reduced affinity for the ligand • tighter affinity for the corepressors • reduced ability to recruit coactivators needed for gene transcription. I.e. mutant receptors retain their ability to bind to DNA and block access of normal TRs to their target genes BUT… recently, families are being found with RTH that have no known mutations of either TR or TR – with a clinically identical phenotype and investigation results i.e. reduced responsiveness of the pituitary and peripheral tissue to TH – transcriptional cofactor mutation, abnormal corepressors, coactivators or coregulators that alter interaction with TR?

18. Clinical features • Mostly asymptomatic • Signs of hypothyroidism most common – growth retardation and impaired cognitive ability • Signs of thyrotoxicosis – tachycardia, hyperactivity and ADD in childhood, Goitre in adults • Variable pathogenesis – not fully understood, thought to relate to differing tissue distributions of TR and TR and variable dominant activity of mutant receptors on different target genes.

19. Diagnosis • Family history common, dominant inheritance • Absence of pit lesion • Normal -subunit/TSH molar ratio • Normal SHBG concentration • Normal or exaggerated TSH response to TRH test • Inhibition of TSH secretion following T3 suppression • Concentration of thyroid hormone and TSH doesn’t differ from TSHoma

20. Treatment • Most, if left alone, will compensate for abnormal TR through increased TH secretion • Treatment with thyroid replacement reserved for those who due to misdiagnosis received thyroid ablation OR if compensation is not enough due to concomitant presence of autoimmune thyroid disease • Triidothyroacetic acid (TRIAC) used to decrease serum TSH and TH levels - to reduce goitre and some symptoms in peripheral tissues • L-T4 treatment in high doses for GRTH in patients with signs of hypothyroidism such as growth retardation and developmental delay • pts who have symptoms of hypermetabolism – give them symptomatic control e.g. atenolol if have tremor or tachycardia • Dopaminergic drugs and somatostatin analogs – limited use due to side effects

21. Neonatal screening • to babies of parents with diagnosed RTH – neonatal measuring of T4 and TSH • Early diagnosis means early treatment - but controversial as no long term outcome knowledge • Usually treat with L-T4 if clinical indications are positive • New evidence suggesting that neonatal treatment with TRIAC may be of benefit

22. Conclusion