Paolo Beck - Enfoques terapéuticos en enfermedades raras tiroideas
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Los días 22 y 23 de octubre de 2015, organizamos en la Fundación Ramón Areces un Simposio Internacional sobre un área prioritaria para esta institución: la investigación de las enfermedades raras. En este caso, las doctoras Susan Webb y Eugenia Resmini, del Hospital de la Santa Creu i Sant Pau de Barcelona, coordinaron un encuentro científico sobre 'Enfermedades raras endocrinas, de la investigación al manejo clínico'.
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Paolo Beck - Enfoques terapéuticos en enfermedades raras tiroideas
- 1. Therapy in rare thyroid diseases Paolo Beck-Peccoz, MD Professor Emeritus University of Milan, Italy paolo.beckpeccoz@unimi.it
- 3. The treatment of most rare thyroid disorders accompained by hypothyroidism, rests on administation of L-T4. • Pendred syndrome • Congenital Hypothyroidism (TSH-R, NIS, Tg, TPO, DUOX2 and its maturation factor DUOXA2, or DEHAL) • Multiple pituitary hormone deficiency (PIT1, PROP1, HEXS1, LHX3 and others) • Mutations of TRH receptor gene • Drug-induced hypothyroidism
- 4. The treatment of most rare thyroid disorders accompained by hyperthyroidism, rests on administation of antithyroid drugs (MMI, PTU), radioiodine or thyroidectomy. • Familial non-autoimmune hyperthyroidism due to activating mutations of TSH receptor • Familial hypersensitivity to hCG • hCG-induced gestational hyperthyroidism • Hydatiform mole, choriocarcinoma • Struma ovarii
- 5. Now, I will focus my presentation on 4 rare thyroid disorders 1. TSH-secreting pituitary adenomas (TSHomas) 2. Resistance to thyroid hormone (RTHb) 3. Central hypothyroidism 4. Graves orbitopathy
- 7. Inappropriate secretion of TSH High levels of FT3/FT4 in the presence of measurable TSH Avoid “analog” tecnique, since analogs binds anti-T4/T3 Ab, abnormal binding proteins forms, and even transthyretin. Avoid also «one step» techniques. Measure FT3/FT4 with “two-step” methods Measure TSH with ultrasensitive, non competitive methods. Anti-T4/T3antibodies Familialdysalbuminemic hyperthyroxinemia Heterophilicantibodies againstmouseg-globulins Anti-TSHantibodies FACTORS THAT MAY INTERFERE IN MEASUREMENT METHODS
- 8. When should TSHoma be suspected? 1. High concentrations of circulating total or free thyroid hormones in the presence of non-suppressed TSH levels characterize TSHomas. 2. Signs and symptoms of hyperthyroidism are usually mild and frequently masked by those of concomitant hypersecretion of other pituitary hormones (mixed adenomas), in particular GH (acromegaly in 16% of patients with TSHoma).
- 9. Therapeutic approaches to TSHomas • Neurosurgery • Radiotherapy • SRIH analogs Octreotide Lanreotide SOM 230
- 11. 0 5 10 15 20 25 30 35 40 45 50 All patients Previous thyroid ablation No thyroid ablation Intrasellar Extrasellar Invasive
- 12. Which are the criteria of cure of a TSHoma? 0.1 1 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Baseline Patients with intact thyroid Patients with thyroid ablation Case # Before neurosurgery After neurosurgerySerumTSHmU/L T3 suppression test Baseline T3 suppression test
- 13. Results of chronic somatostatin analog treatment of TSH-secreting pituitary adenomas TSH/a-GSU reduction 92% Thyroid hormone normalization 95% Vision improvement 75% Tumor mass shrinkage 52% True resistance 4% Discontinuation due to side effects 10%
- 14. 0 5 10 15 20 25 30 35 40 0 2 4 6 12 24 TSH a-GSU FT4 FT3 GH Months HormonelevelsHormone levels after somatostatin analogs in a patient with mixed GH/TSH adenoma Serum IGF-I levels normalized after 4 months
- 15. The classical form of RTH: 1. rare autosomal dominant disorder, mainly due to heterozygous TRb mutations, 2. characterized by high circulating FT4 and FT3 levels concentrations in the presence of measurable TSH, 3. and displaying a highly variable clinical phenotype.
- 16. Dominant Negative Effects Negatively regulated genes Positively regulated genes (Courtesy of Krishna Chatterjee, Cambridge University, UK)
- 17. Cain & Abel Marc Chagall
- 18. Therapeutical approaches to RTH • None • TH analogs:TRIAC, DT4, GC1 (binds wtTRb>TRa), HY1 (acts on TRb mut R320C) • Cardiac selective b-blockers • Inhibition of mutant gene expression • T3 receptor selective antagonists
- 21. Serum TSH and free T4 in central hypothyroidism In summary: Forget the TSH reflex Consider that you can loose congenital hypo Use FT4 measurement methods based on «two-step» to prevent interference
- 22. Start treatment with low doses of L-T4 (25 µg/day or less taking into consideration patient body weight) and increase the dose every 3-6 weeks pondering the severity and the duration of the disease. Remind to take the pills at least half an hour before breakfast. Treatment of central hypothyroidism Rule out the possible presence of central hypoadrenalism. Start cortisol or cortisone treatment BEFORE that of LT4 therapy.
- 23. Monitoring LT4 substitutive therapy • Withdraw blood before LT4 administration. • Maintain serum FT4 levels between 13-15 pmol/L, if the normal range is 9-20 pmol/L. • If doubts, measure some parameters evaluating peripheral thyroid hormone action (see Ferretti et al, JCEM 1999). Tailor the dose for each individual patient!!
- 24. Koulouri et al., Clin Endocrinol (Oxf) 2011: 74, 744
- 25. In conclusion, L-T4 substitutive therapy might be optimal if the following conditions are fulfilled: a) start therapy only after exclusion of adrenal insufficiency, b) establish the final dose based on age and sex (1.4-1.7 mg/kg bw), c) maintain the levels of circulating FT4 in the middle of the laboratory reference values, d) reassess the dose of L-T4 whenever additional replacement with other pituitary hormones is necessary, e) be sure during the follow-up that blood for FT4 measurement is withdrawn before ingestion of daily L-T4 tablets, f) suspect undertreatment when TSH levels are >0.2 mU/L, g) in iodine-deficient countries, consider the possible presence of a nodular goiter with autonomous thyroid hormone secretion in order to prevent possible L-T4 overtreatment.
- 27. Rituximab (RTX) is a humanized chimeric anti-CD20 monoclonal antibody whose variable (antigen-binding) region is derived from a mouse antibody. The binding of RTX to the CD20 antigen blocks the activation and differentiation of B-cells. Since Graves’ disease is typically a B-cell-mediated autoimmune disease, this fact represents the rationale for patients’ therapy with RTX.
- 28. Salvi et al. JCEM 2015;100:422-31
- 29. The results of this trial confirm preliminary reports on a better therapeutic outcome of RTX in active moderate to severe GO, when compared with ivMP, even after a lower RTX dose. The better eye motility outcome, visual functioning of the quality of life assessment, and the reduced number of surgical procedures in patients after RTX seem to suggest a disease-modifying effect of the drug.