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IPHY 4440: HPT AXIS
Thyroid Gland location and function
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Single unpaired gland located ventral to the trachea although it is paired in most non-mammals
produces thyroid hormones under control of TSH from pituitary
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What is the source of thyroid hormones?
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Follicles of the thyroid
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How many people (men/women) have thyroid deficiencies
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13 million Americans (11 million are women)
half of the cases are probably undiagnosed
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How many people have thyroid hyperactivity
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3.8 million Americans
3.6 million are women
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what disease causes most of Thyroid hyperactivity?
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Graves Disease (70-80%)
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what are some symptoms of hypothyroidism?
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metal retardation, physically sluggish, somnolent, sensitive to cold, hypophagic, low BMR and Goiter
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what are some symptoms of hyperthyroidism?
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mentally quick, restless, irritable, hyperkinetick, wakeful, sensitive to heat, hyperphagic, high BMR and Goiter
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Quick overview of HPT axis
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PVN in hypothalamus secretes TRH. TRH travels to pituitary and stimulates thyrotropes to secrete TSH. this stimulates the thyroid to make Thyroid Hormone which feeds back negatively on PVN
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Where is the site of origin for the thyroid?
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Develops from they pharynx as a ventral evagination and later detaches
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Development of Parathyroid and Ultimobranchial glands
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Parathyroid: 3rd and 4th pharyngeal pouches. secretes PTH
Ultramobranchial: 5th pharyngeal pouch. secretes CT (calcitonin)
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What is within the lumen of the follicles of the thyroid?
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colloid
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Describe the thyroid gland structre
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Made up of follicles. Follicular epithelium consists of a single layer of follicle cells which surrounds a lumen, filled with colloid. C-cells which secrete calcitonin surround the follicular cells. Nucleus is typically on the basal side of the follicular cell
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What is important about the height of the thyroid cell?
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height of the follicular epithelium functions as a diagnostic feature because height is directly proportional to TSH levels
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Different cell shapes and the activity they indicate:
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squamous: low to normal activity
cuboidal: intermediate activity
columnar: high activity
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Describe the vascularization of the thyroid gland
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thyroid gland is highly vascularized organ. the entire blood volume passes by three times per hour
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Origin of Parafollicular (C) cells
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Origin: ultimobranchial body (UBB)
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function of Parafollicular Cells;
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They secrete CT (calcitonin) which is sometimes called thyrocalcitonin. hypocalcemic. parathyroid hormone hypercalcemic. deals with calcium homeostatsis
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are we considering CT or Paraythyroid hormones as thyroid hormones?
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NO |
Describe the synthesis of Thyroid Hormones
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Tyrosine to 3 Monoiodotyrosine to 3,5 Diiodityrosine to T4 to T3 or rT3
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How do you get T4 from DIT
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add two DIT's together and link them with an ether
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what raw materials do you need to synthesize THs?
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Iodine in the form of iodide and thyroglobulin
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what is thyroglobulin
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a protein containing tyrosines
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when does iodination occur?
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it first occurs at carbon 3 but is does to tyrosines already in thyroglobulin (TgB)
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which enzyme is used to add two DITs together to form a T4 and describe the action
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Thyroide Peroxidase (TPO) cleaves off one phenolic group and attaches it to the hydroxyl end of the other DIT
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what does TPO control
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Iodination and coupling
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when does a majority of conversion from T4-T3 occur
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after secretion from the thyroid typically in the liver but can occur in the thyroid or target tissue
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How is T4 converted to T3
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the outer ring loses the iodide at the 5' position
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How can T4 be converted to T3
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instead of losing the 5' I the inner ring loses its 5 I. this also primarily occurs in the liver but can happen in the thyroid gland
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what is the biological activity of rT3?
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it has no biological activity
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how does TSH stimulate T4 synthesis?
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TSH increases TPO levels, Tgb synthesis and iodided uptake via the NIS (sodium iodide symporter)
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how does thyroglobulin get into the lumen of the follicular cell?
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exocytosis
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what happens to excess iodide?
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it ends up in the colloid. accomplished via Pendrin (transporter on the apical side)
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where is T4 synthesized and where is TPO located
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T4 is synthesized in the colloid and TPO is found in the apical membrane
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describe what happens in teh colloid
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Iodide needs TPO to become Active Iodide. Active I then binds with tyrosine in Tgb to form MIT. MIT is iodinated to make DIT then two DITs are combined to make T4
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what enzyme is responseible for converting T4 to T3?
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deiodinase
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how does TSH stimulate the release of teh T4?
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endocytosis of Tgb back into the cell. endosome fuses with lysosome to form and endolysosome. the Tgb is digest by enzymes into AA. T4 is then released from teh endolysosome and leaves the cell on the basal surface
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Explain the accumulation of iodide.
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most of our iodide comes from our diet. Enters the cell through the basal side on the NIS (Na/I) co transporter. it is a symporter. The thyroid concentrates iodide to 20-50x that of plasma levels. the mammary also accumulates iodide during lactation
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Radioisotopes that can be taken up the same way as iodide
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131 I: Strong gamma emitter. half life = 8 days
125 I: Weaker gamma emitter
123 I: Weakest gamma emitter therefore safest to use
dangerous b/c they can be used in iodinated tyrosine
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What is pertechnetate?
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TcO4
gets taken up in the thyroid same as iodide but is not incorporated into the tyrosine molecules. much less radiation therefor safer
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Isotope Safety
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131 I: 1000 rads/ microCi
125 I: 650 rads/microCi
123 I: 2
99 Tc: .2
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what is the advantage of using weaker isotopes
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can use higher levels which gives better resolution. and it is safer for patients. these higher concentrations are easier to detect and allow for better images of whats going on in the thyroid gland
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list the best uses for the isotopes listed above
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131: radiothyrox
125: radioimmunoassay and synthesis studies
123: imaging
99: uptake and imaging
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what happens with iodide deficiency
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Reduced T4 plasma levels
increased TSH secretion
hypertrophy and hyperplasia (in extreme cases)
enlarged thyroid (goiter)
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what is a goitrogen?
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these cause goiters and block iodide uptake. they are all anions
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what are some examples of goitrogens
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thiocyanate (SCN)
perchlorate (HClO4)
excessive pertechnetate (TcO4)
Excessive iodide (I)
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explain progoitrin
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this is found in many flowering plants and is converted to goitrin. cooking will destroy myrosinase (the enzyme that converts progoitrin to goitrin) however gut bacteria convert progoitrin to goitrin anyways
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where is progoitrin found?
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common in cabbage, kale, broccoli, rutabagas and turnips
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where can cyanogenic glycosides found?
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these can be found in lima beans, linseeds, sorghum and sweet potatotes
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these can be found in lima beans, linseeds, sorghum and sweet potatotes
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can be metabolized into thiocyanates
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where is genistein found?
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soy products
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what does genistein do?
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it can impair the activity of TPO
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what pharmaceuticals can block the formation of active iodide?
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thiourea
propylthioracil (PTU)
methimazole
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Thyronine (T4) metabolism
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Deiodinase Type 1: outer and inner ring deiodinase: T3 and rT3
Type 2: only outer ring T3
Type 3: only inner ring rT3
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where is D1 located?
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liver, kidney and thyroid
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where is D2 located
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brain, pituitary and placenta
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where is D3 located
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brain, skin, placenta and gut
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how doe T3 and T4 reach target cells
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TBGs: Thyroid-binding Globulins
rT3 will not bind to TBGs
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how do T3 and T4 enter target cells?
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Organic anion transporter polypeptides (oatps)
MCT8: monocarboxylate transporter gene 8
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mechanisms of action in target cell
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thyroid receptors (TR) located in the nucleus and cytoplasm. they have a higher affinity for T3 than T4 and form a heterodimer with RXR. then activate TRE
there are also plasma membrane receptors
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TRs...
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there more multiple kinds of TRs. they bind more strongly to T3 than T4
T4 is often converted to T3 in target cells
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what are some metabolic action of thyroid hormone?
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1. control of Basal Metabolic Rate (BMR)
2. Thermogenic Action
3. synthesis of other mitochondrial proteins
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what else does thyroid hormone affect?
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growth and differentiation
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Explain BMR
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measurement of O2 consumption
THs increase causes a BMR increase
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Explain thermogenic action
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Heat production. acclimation to chronic cold. may also play a role in arousal from hibernation. uncoupling oxidative phosphorylation
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explain uncoupling oxidative phosphorylation
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T3 stimulates synthesis of Uncoupling protein 1 (UCP1).
use glucose to produce heat instead of ATP
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thyroid hormones stimulate production of what mitochondrial proteins?
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succinoxidase
cytochrome C
cytochrome oxidase
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how do thyroid hormones affect growth and differentiation
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it acts as a synergist to GH on body growth. also affects nervous system development. (might be most important action of THs). THs are essential to attain genetic mental capacity
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what can happen if there is low thyroid activity during pregnancy?
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can cause permanent impaired neural development
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how do THs affect nervous system function
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essential for normal functioning in children and adults. people with hypothyroid exhibit slow mental activity
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explain the effects of TH on hair
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Low TH + high F results in hair lass
High TH + low F results in hair growth
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THs and reproduction
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hypothyroid individuals have delayed sexual maturation, decreased androgens (males) and irregular ovarian cycles (females)
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What are some permissive roles of THs?
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Enhance other regulators:
a. increases adenylyl cyclase levels
b. affects responsiveness of CNS
c. Hypothyroidism depresses all body function
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Enhance other regulators:
a. increases adenylyl cyclase levels
b. affects responsiveness of CNS
c. Hypothyroidism depresses all body function
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thyrotoxicosis |
what is primary hyperthyroidism
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it is caused by toxic mutlinodular goiters. multiple aggregates of hyperactive follicles. or several large hyperactive follicles.
may or may not be TSH dependent
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Secondary Hyperthyroidism
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Graves accounts for most cases of hyperthyroidism. it is 20x more common in females then males. this is do to LATS, an abnormal gamma globulin. this is an autoimmune disease
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what are other causes of secondary hyperthyroidism other than graves?
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choriocarcinomas: placenta secretes TSH
pituitary adenomas: secrete TSH, but are VERY rare
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explain thyroid storm:
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also called thyroid crisis. it is rarely seen today, but is associated with hyperthyroidism. usually follows withdrawal of antithyroid drugs, 131I therapy or thyroid surgery. body temp exceeds 40 degrees C
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List some exams of hypothyroidism
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Myxedema, juvenile myxedema and iodide deficiency disease (IDD)
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Myxedema |
No thyroid hormones in adults. this is reversible with treatment
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Juvenine Myxedema
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Cretinism: 1 in 8500 births: severe mental retardation. this mental retardation is permanent.
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IDD |
iodide deficiency disease is the most common cause of mental retardation in the world, especially during pregnancy. can be prevented by iodide and thyroid hormones during pregnancy. best eliminated by iodized salt
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what are other causes of hypothyroidism?
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thyroid hormone resistance. linked to ADHD.
EDCs: polychlorinated biphenyls, perchlorate ion, antibacterial agents
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What does HClO4 do to thyroid action?
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it inhibits thyroid secretion. currently contaminating drinking water and poses special concerns during pregnancy and childhood b/c of its affects on mental development
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what did they study in the great lake region show?
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children of women who at PCB contaminated fish while pregnant exhibited learning difficulties by middle school age
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what is the concern with anti-bacterials?>
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they are a newly recognized category of endocrine disruptor. and are thyroid mimics known as triclosan
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triclosan...
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mimics thyroid hormones. also converted to dioxins and furans. estrogenic. related chemically to PCBs
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what is euthyroid sick syndrome?
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thyroid gland is responsive to whats going on in other body systems and will compensate for problems in other systems.
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