1. The Thyroid Gland

2. Learning Objectives Be able to answer “What is the thyroid gland?” Understand the form and function of Thyroid hormone  Understand the importance of Iodine Become familiar with thyroid regulatory mechanisms Understand the role of the thyroid in maintaining metabolic balance Get a feeling for how thyroid dysfunction could affect a patient.

3. Hormones Regulate Energy Useage Where does energy go in the body?  Digestion & Absorption Pancreas: Insulin & Glucagon  Physical activity Adrenal Glands: Adrenaline, Cortisol  Basal Metabolism Thyroid: Thyroxine

4. Basal Metabolism Energy required just to stay alive  Maintain cellular respiration  Allow vital organs to function Influences on basal metabolism  Lean Body Mass  Age  Growth requirements  Thyroid Hormone

5. Meet the Thyroid The Thyroid is a large, bi-lobed gland, positioned in the neck. 20-60 grams in an adult You can feel your thyroid: place a finger to either side of the neck, below the thyroid cartilage (the “Adam’s Apple”), and swallow. The spongy, soft tissue you can feel move beneath the skin is your thyroid gland

6. Where does it come from? In the human embryo, tissue that becomes the thyroid starts in the same place as the tongue. It then migrates distally as fetal development continues, ultimately reaching its adult position. Rare but interesting result: misplaced thyroid tissue may occur along the path that the thyroid travels, called the Thyroglossal Duct. Important in ruling out thyroid cancer.

7. Quick Histo Review

9. What does it do? Produces and releases Thyroxine (T4), the thyroid hormone. Allows for maintenance of basal metabolic rate Thyroid Metabolically active cells

10. Who needs a thyroid? Everyone! In infants, a lack of thyroid hormone will quickly lead to permanent developmental impairments. In adults, lack of thyroid hormone is not as devastating, but still causes significant problems if untreated.

11. Thyroid Hormone Thyroid hormone is the main product of the thyroid gland It is produced by action of the follicular cells It is synthesized extracellularly from protein, called colloid, stored in the follicles.

12. So, what IS thyroid Hormone? Thyroxine, or T4, Starts its life as Tyrosine residues in a protein called Thyroglobulin, the main component of Colloid.

13. So, what IS thyroid Hormone? Enzymes in the thyroid add Iodine to the Tyrosine residues, forming Diiodotyrosine

14. So, what IS thyroid Hormone? Two of these residues are then joined together to form Thyroxine, or T4.

15. What’s the only part of that you need to care about? Iodine! The thyroid needs a lot of it! Or at least 80  g per day.  Despite the gland being ~0.05% of the body weight, 30% of the body’s iodine is in the thyroid Why might this be significant?  A lack of iodine will affect the thyroid first  Too much iodine will affect the thyroid first  Radioactive iodine will concentrate in the thyroid, which is exploited in medicine. Low doses: imaging High doses: destroy the thyroid

16. So we’ve made T4, what now? T4 is actually not very potent In order to be maximally effective, one Iodine has to be removed to form Triiodothyronine, or T3 This conversion occurs systemically, by the action of deiodonase I and II A third deiodonase produces reverse T3, which is inactive

17. What? Why?! It’s all about regulation  T4 has low activity, is present in high concentration, is cleared slowly,and is heavily protein bound. It provides a reservoir for the rapid production of T3.  T3 has high activity, is present in low concentration, is cleared quickly, and is slightly less protein bound. This allows the body to quickly eliminate T3 if it’s had enough.

18. Thyroid function is under two regulatory systems The Hypothalamus-Pituitary-Thyroid Axis: good for long-term maintenance TRHTSHT4,T3 ++ --

19. Thyroid function is under two regulatory systems Systemic Deiodonase Balance: good for maintaining fine control - Cortisol

20. Other regulating factors Release of TRH and activity of Deiodonase II are also under thermogenic control. TSH, DI II T4,T3 -+

21. How do T4&T3 work? Unbound T4 and T3 enter cells by an uncertain mechanism – evidence of both diffusion and transporter-mediated cell entry. Once inside, the hormones bind to Thyroid Response elements  TREs associate with DNA and other proteins to form regulatory complexes.  If the TRE is binding hormone, then it forms a gene promotor complex  If the TRE is not binding hormone, it forms a gene supressor complex

22. How do T4&T3 work? Therefore, thyroid hormone both:  Promotes the transcription of some genes  Prevents the suppression of other genes

23. Get to how this affects metabolism already!! OK! OK! Calm Down! Gene products promoted by hormone-bound TREs include:  Increased transcription of RNA Polymerase I: this leads to inceased production of ALL protein- coding mRNAs.  Protease concentrations and activities also increase: this leads to faster degredation of all cellular proteins.  In a hypertyroid state, the catabolic effect exceeds the anabolic effect

24. More Effects Synthesis and activity of  -adrenergic receptors increase  Increases sensitivity of body to Epinephrine and Norepinepherine  Especially true in heart  Leads to increased stroke volume and speed

25. More effects OF SPECIAL NOTE IN INFANTS!  Thyroid hormone is VITAL to the proper development of the nervous system  Induces myelination, axon growth, neurotransmitter production.  Infants with uncorrected hypothyroidism develop a syndrome of dwarfism and mental disability (previously termed ‘cretinism’).

26. So, knowing the effects… What would happen if there’s too LITTLE Thyroid hormone?  Less protein turnover = less need for energy, O2 Slower heart rate, slower breathing, loss of appetite combined with weight gain  Loss of Thermogenic control Low body temp, cold intolerance  Cells that turn over quickly, like skin and hair, can’t be replaced fast enough Thin, brittle skin; hair loss In women: irregular menstrual cycle  Blunting of sympathetic (fight/flight) response Fatigue, exercise intolerance Weak pulse, slow maximum heart rate  Nervous system involvement Poor memory, inability to concentrate Parasthesia, i.e. “pins and needles” Loss of hearing

27. Summarry Table 335-5 Signs and Symptoms of Hypothyroidism (Descending Order of Frequency) Symptoms Tiredness, weakness Dry skin Feeling cold Hair loss Difficulty concentrating and poor memory Constipation Weight gain with poor appetite Dyspnea Hoarse voice Menorrhagia (later oligomenorrhea or amenorrhea) Paresthesia Impaired hearing Signs Dry coarse skin; cool peripheral extremities Puffy face, hands, and feet (myxedema) Diffuse alopecia Bradycardia Peripheral edema Delayed tendon reflex relaxation Carpal tunnel syndrome Serous cavity effusions

28. Major causes? Congenital  Thyroid agenesis  Failure to produce any of the hormones necessary to ultimately make T3  Mutations in thyroid-binding proteins, thyroid response elements, or transporters. Acquired  Autoimmune: body attacks own thyroid  Infective: virus attacks thyroid  Nutritional: Iodine deficiency  Drug induced

29. How about Hyperthyroidism? Protein turnover is too rapid, high O2 and metabolic demands  Fast heart rate, fast breathing, loss of weight despite ravenous appetite  Ketotic state  Muscle weakness (remember, cata > ana) Loss of Thermogenic control  Always generating too much heat; heat intolerance, disproportionate sweating Exaggerated Sympathetic response  Hyperactivity, Irritability  Bounding pulse, tachycardia, palpitations  Tremor

30. Table 335-7 Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency) SymptomsSigns a Hyperactivity, irritability, dysphoria Heat intolerance and sweating Palpitations Fatigue and weakness Weight loss with increased appetite Diarrhea Polyuria Oligomenorrhea, loss of libido Tachycardia; atrial fibrillation in the elderly Tremor Goiter Warm, moist skin Muscle weakness, proximal myopathy Lid retraction or lag Gynecomastia

31. Causes Autoimmune: Grave’s Disease  Body produces antibodies that mimic TSH Neoplastic / Hyperplasic  Primary goiter (Multinodular Goiter)  Thyroid adenoma, other active endocrine adenoma Nutritional  Too much iodine  Consuming thyroid tissue as supplement Drug induced

32. Anyone still paying attention? Or are you all just feeling dragged along?

33. VISUAL METAPHOR TIME! With the right amount of thyroid hormone:

34. If there’s too little…

35. If there’s too much…

36. Compare to too much HGH

37. Revisiting the LOs What is the Thyroid Gland?  A large, bi-lobed gland in the neck  The endocrine gland in charge of maintaining basal metabolism

38. Revisiting the LOs Thyroid hormone  You need iodine to make it  Acts on all metabolically active tissue  Stimulates protein synthesis and turnover Iodine  Need 80  g per day (150  g oral intake)  Radioiodine can be used in thyroid medicine

39. LOs, cont. Thyroid regulation:  H-P-T axis for slow regulation Classic negative feedback setup  Systemic Deiodonase activity for fast

40. LOs, cont. Effects of thyroid abnormality  Hypothyroid: weight gain, loss of energy, cold intolerance, PERMANENT neural damage in infants.  Hyperthyroid: weight loss, hyperactivity, tachycardia, heat intolerance, muscle wasting

41. Aaaaaand…we’re done!