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Thyroid Dysfunction Advanced Clinical Focus: Hormones and Endocrinology Thyroid Pathologies • Hypothyroidism • Hyperthyroidism • Autoimmune thyroid (Hashimoto’s and Grave’s) • Thyroid cancer Advanced Clinical Focus: Hormones and Endocrinology Thyroid Definitions • Thyrotropin releasing hormone (TRH): hormone made by hypothalamus • Thyroid Stimulating Hormone (TSH): hormone made by pituitary • Thyroxine (T4): hormone made by thyroid • Triiodothyronine (T3): active thyroid hormone • Thyroid peroxidase (TPO): enzyme that makes thyroid hormone • Thyroglobulin: protein that joins iodine to make T4 Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism T3 Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH Pituitary releases TSH Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH 93% is T4 Pituitary releases TSH TSH stims TPO 7% is T3 ✓ Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH 93% is T4 Pituitary releases TSH 60% converted to T3 in liver TSH stims TPO 7% is T3 ✓ Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH 93% is T4 Pituitary releases TSH 60% converted to T3 in liver TSH stims TPO 20% goes to reverse T3 (inactive) 7% is T3 ✓ Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH 93% is T4 Pituitary releases TSH 60% converted to T3 in liver TSH stims TPO 20% goes to reverse T3 (inactive) 7% is T3 ✓ 20% converted to active T3 in GI ✓ Advanced Clinical Focus: Hormones and Endocrinology Thyroid Metabolism Hypothalamus sends TRH 93% is T4 Pituitary releases TSH 60% converted to T3 in liver TSH stims TPO 20% goes to reverse T3 (inactive) 7% is T3 ✓ 20% converted to active T3 in GI ✓ Remaining T4 to T3 in tissues ✓ Advanced Clinical Focus: Hormones and Endocrinology Thyroid Statistics (US) • 27 million with thyroid disease • 13 million undiagnosed • 14 million Hashimotos • 80% are women American Association of Clinical Endocrinologists (AACE) Advanced Clinical Focus: Hormones and Endocrinology The thyroid is the ‘sentinel’ gland for the environment. Dr. Jeffrey Bland Advanced Clinical Focus: Hormones and Endocrinology Loss of Thyroid Function • No thyroid gland • Nutritional deficiencies or excesses • Autoimmune • Thyroid hormone • Postpartum thyroiditis resistance • Medications • Toxins • Stress Advanced Clinical Focus: Hormones and Endocrinology Thyroid Symptoms (Most Common) • Fatigue • Excessive sleep • Weight gain • Hypochlorhydria • Depression • Itchy, dry skin • Constipation • Dry, brittle hair • Hypersensitivity to cold water • Hair loss • Poor circulation • ↓ Body temp • Muscle cramps • Edema (esp. face) • ↓ Immunity • Lost of outer 1/3 of eye brow • Slow wound healing Advanced Clinical Focus: Hormones and Endocrinology Others Signs Indicating Thyroid Issues • Heart palpitations • Difficulty gaining weight • Inward trembling • Increased pulse rate • Feeling nervous • Insomnia • Night sweats Advanced Clinical Focus: Hormones and Endocrinology Top 10 Symptoms: Hypothyroidism 1. Fatigue 7. Edema 2. Weight gain 8. Muscle aches and joint pain 3. Feeling cold 9. Constipation 4. Dry hair and skin 10. Depression 5. Hair loss 6. Menstrual irregularities Advanced Clinical Focus: Hormones and Endocrinology Hypothyroid Hypothyroidism can affect all organ systems. These manifestations are largely independent of the underlying disorder but are a function of the degree of hormone deficiency. Shilomo, Melmed, Kenneth S. Polonsky, et .al. Williams Textbook of Endocrinology, 12th Ed. Elsevier Saunders: Philadelphia, PA. 2011. Advanced Clinical Focus: Hormones and Endocrinology Assessing Thyroid Function • Symptomatology (questionnaire) • Basal temperature test • Blood work • Ultrasound • Biopsy Advanced Clinical Focus: Hormones and Endocrinology Thyroid Questionnaire Advanced Clinical Focus: Hormones and Endocrinology Simple Test • Basal Temperature Test • Easy, non-invasive • Monitor progress • Not well validated • Not diagnostic Advanced Clinical Focus: Hormones and Endocrinology Hypothyroidism • Primary: ↑TSH, ↓FT4 • Secondary: ↓TSH, ↓ FT4 • Subclinical: ↑TSH, normal FT4 • Hashimoto’s thyroiditis: antibodies Dx present Advanced Clinical Focus: Hormones and Endocrinology Hyperthyroidism • ↓TSH, ↑FT4 • Subclinical: ↓TSH, normal FT4, high FT3 • Grave’s disease: antibodies present Dx Advanced Clinical Focus: Hormones and Endocrinology Thyroid: Lab Testing • Standard of care = TSH • Is this enough? Advanced Clinical Focus: Hormones and Endocrinology Example of TSH Unreliability • Patient with Hashimoto's getting no treatment TSH January 4.5 February 0.08 March 2.3 April 3.8 May 8.7 June 7.4 July 1.6 Advanced Clinical Focus: Hormones and Endocrinology TSH Considerations… • Can TSH reflect variations in target cell sensitivity? • Can TSH reflect peripheral T4 to T3 conversion? • Can TSH reflect cellular transport problems where there is faulty transport into the mitochondria? • Can TSH reflect displacement of thyroid hormones from cellular receptors by RT3? Advanced Clinical Focus: Hormones and Endocrinology What Does TSH Test? • TSH indicates pituitary production • Genetic and environmental factors can effect TSH secretion • Pituitary hormone levels alone are not sufficient to measure the function of the gland they regulate Advanced Clinical Focus: Hormones and Endocrinology European Thyroid Association • “…pituitary TSH secretion may not reflect what happens in other target tissues, and therefore serum TSH alone may not be a good marker for the adequacy of thyroid hormone replacement.” Wiersinga W.M., L. Duntas. V. Fadeyev. et al. ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism.. European Thyroid Journal 2012 . Vol 1 No. 12 2012 Advanced Clinical Focus: Hormones and Endocrinology TSH Range • Standard of care for thyroid monitoring 1-2 mU/L Symptoms Symptoms 0.0-0.39 mU/L 0.4-5.5 mU/L 5.5+ mU/L Hyperthyroid/ Normal Hypothyroid/ Grave’s Hashimotos Advanced Clinical Focus: Hormones and Endocrinology National Academy of Clinical Biochemistry (NACB) • New guideline suggested in 2002 • TSH may be too wide • People in this range = borderline thyroid disease 1-2 mU/L Symptoms Symptoms 0.0-0.39 mU/L 0.4-5.5 mU/L 5.5+ mU/L Hyperthyroid/ Normal Hypothyroid/ Grave’s Hashimotos Advanced Clinical Focus: Hormones and Endocrinology American College of Clinical Endocrinologists • Clinicians should consider treatment for patients who “test outside the boundaries of a narrower margin based on a target TSH level of 0.3-3.04 mU/L.” • “ The AACE believes the new range will result in proper diagnosis for millions of Americans who suffer from a mild thyroid disorder, but have gone untreated until now.” TSH is normal but my patient is not well. ACCE Press release January 2003 Advanced Clinical Focus: Hormones and Endocrinology TSH Conclusion • “Normal” is too wide • Optimal should be 0.4-2.0 mU/L Following an optimal range, is probably a much better approach. Vanderpump M.P.J., W.M.G. Tunbridge, J.M. French, et al. The incidence of thyroid disorders in the community; a twenty year follow up of the Whickham survey. Clinical Endocrinology 1995; 43(1):55-68 Advanced Clinical Focus: Hormones and Endocrinology What to Measure • TSH • Free-T4 • Free-T3 • Thyroid antibodies Advanced Clinical Focus: Hormones and Endocrinology “Bound” is Unavailable Thyroid Hormone 99% Bound 1% Free Free T3 Free T4 Advanced Clinical Focus: Hormones and Endocrinology Why Test for T3? All had normal TSH Medication No Meds 15.2% below normal 29.6% below normal for Free-T3 FT3/FT4 Gullo D, et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011; 6(8):e22552. Advanced Clinical Focus: Hormones and Endocrinology Why Test for T3? “…a subset of patients…do not reach a serum FT3/FT4 ratio within the reference range…These patients, therefore, live in chronic condition of abnormal thyroid hormone availability for the peripheral tissues, even if the administered levothyroxine dose is able to maintain the serum TSH within the normal range.” Gullo D, et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011; 6(8):e22552. Advanced Clinical Focus: Hormones and Endocrinology Why Test for T3? The insufficient T3 peripheral production cannot be appropriately corrected by increasing levothyroxine because T4 inhibits the conversion, and furthers the problem. Gullo D, et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011; 6(8):e22552. Advanced Clinical Focus: Hormones and Endocrinology European Thyroid Association • “Theoretically, thyroid hormone replacement therapy should aim not only at normalization of serum TSH but also at normalization of serum free T4, free T3 and FT4:FT3.” Wiersinga W.M., L. Duntas, V. Fadeyev , et. al. ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. European Thyroid Journal 2012. Vol 1 No. 12 2012 Advanced Clinical Focus: Hormones and Endocrinology Reverse T3 Hypothalamus send TRH 93% is T4 Pituitary releases TSH 60% converted to T3 in liver TSH stims