Thyroid & Parathyroid Hormones

Hashimoto's Thyroiditis Most patients first exhibit autoimmune

"thyroiditis," thyroid inflammation

~99% of T3 and T4 bind with PLASMA proteins for transport:

* Thyroxine-Binding Globulin (TBG) * Transthyretin (TTR) * Albumin

Absorption

- via intestines

Effects of Thyroid Hormone on METABOLISM (3)

-Stimulates carbohydrate metabolism -Stimulates protein synthesis & protein catabolism -Stimulates fat metabolism

Plasma Calcium and Phosphate Changes in the phosphate level of the EC fluid to

2-3X normal does not cause major immediate effects.

The biologic half-life of human TSH is about TSH Secretion is ____ Rise at ? Peak at? Decline?

60 min. TSH secretion is pulsatile (note the stars below that show pulses). Output starts to rise at about 9:00 PM, peaks at midnight, and then declines during the day.

Thyroid Gland: Structural Characteristics

About 93 % of the metabolically active hormones secreted by the thyroid gland is Thyroxine (T4), and 7 % Triiodothyronine (T3) Triiodothyronine is about four times as potent as thyroxine, but it is present in the blood in much smaller quantities and persists for a much shorter time than does thyroxine.

Control points for calcium and phosphate

Absorption Excretion Temporary Storage

Thyroid Follicular Cells ___ transport ___

Actively Transports I-

parafollicular cells aka

Also called C Cells

Thyroid Hormones are ____Hormones

Amine made from thyrosine AA

Hashimoto's Thyroiditis

Autoimmune reaction against thyroid gland destroys gland rather than stimulating it.

Calcitonin Stimulates ______ and inhibits ____ ____ plasma calcium

Bone Matrix Deposition & Inhibits Osteoclasts LOWERING plasma calcium

Vitamin D3 & Parathyroid Hormone Stimulate _____ _____ plasma calcium and Phosphate

Bone Matrix Resorption (releasing minerals by osteoclasts) RAISING plasma calcium & phosphate

PTH Targets and Functions Increases Plasma Calcium

Bone Resorption Reabsorption of Calcium by Renal Tubules which reduces excretion Converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (Vitamin D/Calcitriol), which causes intestinal calcium absorption.

Hyperthyroidism Oral Symptoms BEG CW

Burning Mouth Syndrome Excessive salivation Gum disease Increased caries risk Weakening of mandible

Thyroid Glands

Butterfly shaped; inferior to larynx They have follicles (circle shaped structure) Colloid contains protein called thyroglobulin where thyroid hormones are produced. There are also parafollicular cells (C CELLS) outside- next to follicles which secrete calcitonin

parafollicular cells Secrete

Calcitonin ( decreased Ca2+)

Stimulates carbohydrate metabolism (3)

Causes rapid uptake of glucose by cells Enhances glycolysis, enhances gluconeogenesis Increases rate of CHO absorption from G.I. tract

T3 and T4 action in target tissues

Changes transcription and translation. T4-->T3; synthesis of new proteins and affects a lot of thing such as growth, development of NS, cardiovascular, metabolism.

Parathyroid Hormone (PTH) secreted by

Chief Cells

T3 and T4 are produced in the

Colloid and Complexed with Thyroglobulin (TG) Through pinocytosis, they get engulfed back by follicular cells. Then the secretion is stimulated ty TSH (thyroid stimulated hormone) from anterior pituitary glad-causes secretion of T3 and T4 in blood. Also enzyme called peroxidase and proteases will cleave of T3 and T4 to allow for secretion Building block for all of this is: tyrosine and the thyroglobulin molecule has a lot of tyrosine

Cretinism Results from:

Congenital absence of thyroid gland (congenital cretinism) Iodine deficient diet (endemic cretinism): most common cause worldwide

Three different deiodinases act on thyroid hormones: All are unique in that they contain the rare amino acid _____ essential for enzymatic activity of conversion of ? Why would a patietn appear to have hypothyroidism based on these deiodinases?

D1, D2, and D3. All are unique in that they contain the rare amino acid selenocysteine, with selenium (Se) in place of sulfur, which is essential for their enzymatic activity for conversion of T4--> T3. So a patient can appear to be hypothyroidism because deiodonases are not functioning as they should. They need to convert T4-->T3 to have target cell action.

PTH Targets and Functions Decrease Plasma Phosphate

Decreased reabsorption by renal tubules leading to increased urinary excretion

Thyroid Storm (Thyrotoxicosis) Cause? Symptoms? In patients with hyperthyroidism or those that exhibit signs/symptoms of it, administration of____ is contraindicated and elective dental care should be deferred.

Elevated Thyroid Hormone with stressful events (trauma, surgery, severe emotional distress) or serious illness (DKA, MI, etc.). Symptoms: fever, tachycardia, elevated BP, nausea, vomiting, diarrhea, breathing problems, etc. In patients with hyperthyroidism or those that exhibit signs/symptoms of it, administration of epinephrine is contraindicated and elective dental care should be deferred.

However, these individuals are generally still euthyroid (not hyper- or hypo-thyroid). How is this possible?

Euthryoid: normal of free thyroid hormone. Normal levels of active thyroid hormone because if they have high and low binding proteins levels but normal levels of free, their system has adjusted and plasma levels have reached a new kind of equilibrium to allow for the free level of hormone. Its all about the free level of the hormone. So, total level: bound or unbound and symptoms: about free levels of active hormone

Primary Hyperparathyroidism

Excess PTH secretion due to a parathyroid gland tumor

Treatments for Osteoporosis

Exercise (walking and weight-bearing 3X per week) Physical Therapy (postural exercises, muscle strengthening) Estrogen (replacement or receptor agonists) Calcium (carbonate or citrate) Vitamin D Bisphosphonates

Hyperthyroidism Symptoms

Exophthalmos (adipocyte and proliferation of eye- bilateral!) Increased appetite Goiter Weight loss b/c of High BMR Tachycardia Irritable Muscle wasting Hot Pretibial myxedema (deposition of connective tissue- increase synthesis of CT)

Chvostek's Sign

Flick facial nerve - Response is contraction of facial muscles ranging from twitching of the angle of the mouth to hemifacial contractions. Low specificity; 25% normal individuals will have Chvostek's Sign

Parathyroid Gland

Four pea-sized glands on the posterior surface of the thyroid gland.

Study Guide - Thyroid Hormones

General anatomy of the thyroid gland as it relates to thyroid hormone synthesis (Thyroxine (T4) and Triiodothyronine (T3)) and secretion. Pathway for synthesis of T3 and T4; role of colloid, iodide/iodine, Na+/I- symporter, pendrin, thyroglobulin and perioxidase. Control of thyroid hormone secretion; including negative feedback pathway Transport of T3 and T4 in circulation and role of plasma proteins Compare and contrast T3 and T4 in regards to the amount secreted, half-life and action Effects of T3 and T4 on metabolism and organ systems function (nervous, cardiovascular, endocrine and gastrointestinal) Definition of goiter and causes for it Hyperthyroidism: Graves' Disease (causes of, signs/symptoms including oral manifestations and treatment); Thyrotoxicosis and its dental implications Hypothyroidism: Hashimoto's Thyroiditis (causes of, signs/symptoms including oral manifestations and treatment), Cretinism

In hypothyroid states: Goiter: ? No goiter: ?

Goiter: iodine deficiency No goiter: TSH deficiency

Hypothyroidism

Hashimoto's Thyroiditis most common Low levels of iodine (T3 and T4 levels low)

These increase Binding Hormone levels H(e) CAME

Heroin Clofibrate Antipsychotic drugs Methodone Estrogen STILL EUTHYROID

Secondary Hyperparathyroidism

High PTH levels occur as compensation for hypocalcemia not due to primary abnormality of parathyroid glands

Control of Parathyroid Secretion by Ca2+ ↓ ECF Ca2+ concentration -->

INCREASE rate of PTH secretion hypertrophy of parathyroid gland *Pregnancy *Rickets *Lactation

Some other Physiological Effects of Thyroid Hormones GASTROINTESTINAL System (2)

Increased appetite and food intake Increased rate of secretion and motility of the GI tract (i.e. hypothyroidism can produce constipation)

Some other Physiological Effects of Thyroid Hormones Endocrine System (3)

Increased glucose consumption results in increased insulin secretion Activation of bone formation causes a need for increased PTH secretion Causes increased inactivation of glucocorticoids which lead to more ACTH release.

Some other Physiological Effects of Thyroid Hormones Cardiovascular System (2)

Increased β-adrenergic receptors- B1 on heart. -----With hyperthyroidism: tachycardia- increase heart rate and force contraction. DONT GIVE EPINEPHRINE!!!! b/c it binds to B1 receptors Increased blood flow, heart rate, and heart contractility.

Stimulates fat metabolism (4)

Increases lipid mobilization from fat tissue (lipolysis) Required for conversion of beta carotene to vitamin A (Hypothyroid patients have yellowish skin- bc they have a buildup of caratone that cant be converted to Vit A- visual problems) Speeds oxidation of free fatty acids by cells. Decreases circulating cholesterol levels (Hypothyroidism associated with hyperlipidemia- high cholesterol circulation in blood)

Trousseau Sign

Inflate blood pressure cuff to ~20 mmHg about systolic pressure for 3 minutes. If a carpal spasm occurs this is a positive sign. More specific than Chvostek, but a small number of normal individuals will have a positive test.

Hypothyroid Treatment-

L-thyroxine (T4)

Primary Hypoparathyroidism

Less common-often results from accidental surgical parathyroid gland removal

Primary Hypoparathyroidism all

Less common-often results from accidental surgical parathyroid gland removal Parathyroid gland removal decreases plasma Ca++ levels from 10 mg/dL to 6-7 mg/dL Hypocalcemia increases membrane Na+ permeability leading to neuromuscular excitability & muscle spasms & tetany Spasm of laryngeal muscles obstructs respiration causing death unless appropriate treatment applied

Hypothyroidism Oral Manifestations DMD- PIPS- BCD

Macroglossia Dysgeusia (distortion of taste) Delayed tooth eruption Poor wound healing increased risk of infection (due to decreased activity of fibroblasts) Increased peridontal disease Salivary gland enlargement Sensitive to: CNS depressants and barbiturates, so these medications should be used sparingly."

Hypocalcemia increases membrane

Na+ permeability leading to neuromuscular excitability & muscle spasms & tetany Spasm of laryngeal muscles obstructs respiration causing death unless appropriate treatment applied

T3 and T4 Secretion into Blood Need presence of? 4 main steps

Need presence of TSH. 1) Colloid is internalized by endocytosis. 2) The vesicles fuse with lysosomes in the cell. 3) Proteases cleave T3 and T4 from TG. 4) T3 and T4 diffuse out of the cell and into capillaries.

Some other Physiological Effects of Thyroid Hormones NERVOUS SYSTEM (5) NIMAF

Needed for normal development of the NS Impacts reflex time (i.e. hypothyroidism can cause prolonged reflex times) Muscle tremors due to increased reactivity of neuronal synapses Anxiety, worry and paranoia Feeling of tiredness but difficulty sleeping

Regulation of Plasma Calcium and Phosphate Calcium in EC fluid? Calcium in cells and organelles? Calcium in bones? Phosphate: In bone? Cells? EC fluid?

Only 0.1% of total body calcium is in the EC fluid. 1% is in cells and organelles and the rest is stored in bones. 85% of the body's phosphate is stored in bones, 14-15% in cells and less than 1% in the EC fluid (HPO42- and H2PO4-)

Is hypothyroidism due to iodine deficiency a primary or secondary endocrine disorder?

Primary! Not ending making end hormone. So iodine deficiency goiter

Treatment of Hyperthyroidism PLS RA

Propanolol given for adrenergic symptoms while awaiting resolution. L-thyroxine administered to prevent hypothyroidism in patients who have undergone ablation or surgery Surgery rarely indicated. Radioactive I 131 thyroid ablation, or Antithyroid Drugs (propylthiouracil or methimazole).

Parathyroid Hormone (PTH)

Secreted by the Chief Cells Regulates both calcium and phosphate levels by adjusting (1) Intestinal Reabsorption, (2) Renal Excretion and (3) Exchange between the EC fluid and bone.

Goiter seen in

Seen in Hypothyroidism, Hyperthyroidism, Euthyroidism

Myxedema

Seen in severely hypothyroid patients and graves disease

Signs of Hypocalcemia

Shows signs of tetany seen in hypocalcemia with resultant hyperexcitability of nerves. Chvostek's Sign Trousseau Sign

Effects of Thyroid Hormone on Metabolism

Stimulates oxygen consumption by most metabolically active tissues. Increased Basal Metabolic Rate (BMR) Hypo: BMR Falls. Weight gain, dont undergo metabolism. Half of normal BMR Hyperthyroidism: high BMR; unexplained weight loss

Triiodothyronine

T3 active thyroid hormone; much more active and potent (4x)

___ is the main circulating form responsible for

T4 most of the (-) feedback. So now you can see T4 can go to various tissue to be converted to T3.

Thyroxine

T4 active thryoid hormone

Cells contain iodinases that convert So cells can adjust how much thyroid hormone can affect them by adjusting:?

T4 to T3 providing local supply of T3 that mediates the physiological effects. So cells can adjust how much thyroid hormone can affect them by adjusting expression of iodinases.

Due to the strength of its binding to the transport protein, T4 has a ____ half-life

T4: long half life (6-7 days). It means that it has higher affinity for its binding protein.

Iodine (I-) is Required for

TH Synthesis

Colloid Contains the

Thyroglobulin (TG) Glycoprotein

Follicular Cells Secrete

Thyroid Hormones (T3 and T4) stored in colloid

Cretinism

Thyroid hormones required for postnatal brain maturation.

Causes of hypocalcemia:

Vitamin D deficiency Chronic renal disease-cannot synthesize Vit D3

Hypothyroidism symptoms

Weight gain Diminished perspiration (cold) Slow pulse Enlarged heart Reduced metabolic activity Loss of lateral eyebrows Myxedema (can be in severe hypothyroidism and graves disease)

Study Guide - Hormones that Regulate Calcium and Phosphate

What are the control points for regulation of calcium and phosphate levels? For Parathyroid Hormone, Calcitriol (Vitamin D) and Calcitonin, you should know..... the Organs/cells that secrete each, their impact on calcium and/or phosphate levels, the stimuli that cause their secretion, the mechanisms of action they each use to regulate calcium and phosphate levels. Causes and manifestations of Primary Hyperparathyroidism, Secondary Hyperparathyroidism Primary Hypoparathyroidism Signs of hypercalcemia and hypocalcemia (Chvostek's and Trousseau). Risk factors for osteoporosis and treatments for it.

The incidence of hip and vertebral fractures increases with

age.

High levels of thyroid hormone secretion caused by TSI suppress

anterior pituitary TSH secretion (negative feedback)

Graves' Disease An autoimmune disease where

antibodies to TSH receptor called thyroid-stimulating immunoglobulins (TSIs) stimulate the thyroid gland to excess PRIMARY PATHOLOGY; because of high T3 and T4 levels, there is strong negative feedback. So level of those hormones go back because of those negative feedback

BMR is the amount of energy expended while

at rest in a neutrally temperate environment.

T3 and T4 Action in Target Tissues T3 and T4 enter tissues slowly due to their affinity for

binding proteins. They enter slowly because they are protein bound. T4: more slowly.

Osteoporosis affects almost 10 million individuals in the US, though only a small proportion are diagnosed and treated. An additional 48 million have bone mass levels that increase their risk for developing osteoporosis. It occurs when there is an imbalance between

bone formation and resorption.

85% of the body's phosphate is stored in

bones, 14-15% in cells and less than 1% in the EC fluid (HPO42- and H2PO4-)

PTH regulates

both calcium and phosphate levels by adjusting (1) Intestinal Reabsorption, (2) Renal Excretion and (3) Exchange between the EC fluid and bone.

Tight regulation closely controls

calcitrol levels

"Patients with hypothyroidism are sensitive to

central nervous system depressants and barbiturates, so these medications should be used sparingly."

Extreme osteoclastic activity in bones causes

cystic bone disease (osteitis fibrosa cystica)

Inflammation leads to fibrosis of thyroid resulting in

decreased secretion of thyroid hormone.

Calcitonin Lowers plasma Ca2+ by

decreasing activity of osteoclasts, thus decreasing bone resorption Not a major controller of Ca2+ in humans

Calcitonin Released in response to

elevated free plasma Ca2+

Goiter is an

enlarged thyroid that DOES NOT indicate functional status!!!

Goiter caused by

excessive amounts of TSH secretion.

Decrease Binding hormone levels GADA

glucocorticoids androgen danazol asparagine STILL EUTHYROID

Osteoblastic activity also increased leading to

high secretion of alkaline phosphatase (ALP).

Myxedema Increased quantities of

hyaluronic acid and chondroitin sulfate bound with protein plus water accumulate in skin.

Graves' Disease most common form of

hyperthyroidism -more pronounced in females.

"Tetany is not specific for hypocalcemia. It also occurs with

hypomagnesemia and metabolic alkalosis, and the most common cause of tetany is respiratory alkalosis from hyperventilation." Greenspan, Ch. 8.

Cretinism Skeletal growth is more

inhibited than soft tissue growth (obese, stocky and short with large protruding tongue)

Na+/I- symporter (NIS) is capable of producing This type of transporter

intracellular I- concentrations that are 20-40 times as great as the concentration in plasma. Secondary active transporter (na provides energy)

Calcitriol Synthesis & Action Vitamin D3 can be stored in the

liver for several months

Other characteristics of hypothyroidism:

low BMR, mental capacity, body temp., appetite, HR, RR, BP; anemia, weakness, lethargy, wt. gain; increased cholesterol and blood lipids

Hypothyroidism due to

low iodine cant make thyroid hormone. T3 and T4 low so hypothalamus ups TRH, then ant pit ups TSH and thyroid gland enlarges (goiter) but it cant fix problem because theres not iodine to do that so T3 and T4 remain low so theres not negative feedback.

Hydroxyapatite can be resorbed (broken down) to Ca10 (PO4)6 (OH)2

mobilize calcium and phosphate when plasma levels are low.

Stimulates protein synthesis & protein catabolism =

muscle loss Opposites; protein catabolism dominates but stronger affect of catabolism so muscle loss. So a person with hyperthyroidism, they are going to have muscle loss b/c of high catabolism.

T3 doesn't bind as tightly to transport proteins so its half-life is

only 2-3 days.

High PTH is a risk factor for

osteoporosis and fractures.

Peptide hormone secreted by

parafollicular cells (C cells) of the thyroid gland

Calcitonin this type of hormone

peptide hormone

Cretinism Causes

physical and mental retardation of neonates

Parathyroid gland removal decreases

plasma Ca++ levels from 10 mg/dL to 6-7 mg/dL

Hypercalcemia leads to

polyuria and calcuria Low phosphate due to increased renal excretion Muscle weakness and easy fatigability

Vitamin D deficiency leads to

rickets in children, osteomalacia in adults [inadequate mineralization of bones] and high PTH, which causes bone resorption.

What about hypothyroidism due to TSH deficiency?

secondary problem; tsh defiency. Ant pit having issues Impaired TRH or TSH

Various conditions inhibit deiodinases:

selenium deficiency, burns, trauma, advanced cancer, cirrhosis, chronic kidney disease, MI and febrile states, fasting, stress. *Could show signs of hypothyroidism.

Triiodothyronine is present in the blood in much

smaller quantities and persists for a much shorter time than does thyroxine.

Control of Thyroid Hormone Secretion Negative feedback: mainly at

the level of anterior pituitary gland. Hypothalamus secrets TRH, which stimulates secretion of TSH, and thyroid gland secretes T4.

Iodide must also exit the

thyrocyte across the apical membrane to access the colloid, where the initial steps of thyroid hormone synthesis occur. Pendrin is a Cl-/I- exchanger. -allows from movement of iodide into colloid (right side of pic)

High TSH stimulates thyroid to secrete large amounts of

thyroglobulin colloid into follicles, resulting in gland enlargement

Hyperthyroidism can also occur due to a

thyroid adenoma.

About 93 % of the metabolically active hormones secreted by the

thyroid gland is Thyroxine (T4), and 7 % Triiodothyronine (T3)

TSI antibodies have prolonged stimulating effect on

thyroid gland, lasting as much as 12 hours, in contrast to TSH of ~1 hour

Thyroid Hormone Binding Proteins Several hormones and drugs cause a change in the concentration of

thyroid hormone binding proteins. A person with hyperthyroidism/ or hypothyroidism have normal binding protein concentration but total plasma levels of hormones affect hyper/hypo. The active form of hormone is the one that is FREE.

Colloid is a reservoir of

thyroid hormones. "Humans can ingest a diet completely devoid of iodide (I-)for up to 2 months before a decline in circulating thyroid hormone levels is seen."

Triiodothyronine is about four times as potent as

thyroxine,

On the other hand, free calcium is ____regulated. %? Too low? Too high?

tightly regulated (5%) Too low = neuronal hyper-excitability (tetany) Too high = neuronal depression

Temporary storage

via bones (hydroxyapatite of ground substance)

Excretion

via urine (calcium and phosphate) and feces (calcium only)

Osteoporosis Risk factors:

vitamin D deficiency (secondary hyperparathyroidism), inadequate calcium intake (secondary hyperPTH), glucocorticoid medications, reduced physical activity, estrogen deficiency (post-menopausal), cigarette smoking, alcohol..............

T3 actions occur sooner (than T4) with the maximum activity

~2-3 days. Thyroxine: T4; slow onset prolonged effect Slow Onset but Long Duration of Action Effect for both T3 and T4

Note that without TH secretion, BMR falls to

~50% of normal.

Increased ECF Ca2+ concentration leads to

↓ activity of parathyroid gland ↓ size of parathyroid gland *increased vitamin D intake *excess quantities of calcium in the diet *bone resorption caused by factors other than PTH