Endocrinology exam 2

thyroid gland

located in front of trachea from C5-T1, lobes wrap around cricoid cartilage and superior rings of trachea like a shield, requires a good supply of iodine from diet to function correctly

arterial supply to thyroid gland

superior/inferior thyroid arteries

venous drainage of thyroid gland

superior/middle/inferior thyroid veins

innervation of thyroid gland

sympathetic- fibers from superior and middle cervical sympathetic ganglia; parasympathetic- fibers from vagus that reach gland via branches of laryngeal nerves

cell types of thyroid gland

follicular epithelial cells, parafollicular cells, chief cells (on posterior parathyroid glands)

function of thyroid gland

produce thyroid hormones T4- thyroxine and T3- triiodothyronine

what type of hormones are thyroid hormones?

they are amines that choose to act lipophilic, the only hormones using the steroid mechanism that aren’t derived from cholesterol, controls most of intracellular chemical reactions in body

functions of thyroid hormones

regulate body metabolism, regulate growth and development of tissues, act on virtually every organ system, act synergistically with growth hormone and somatomedins to promote bone formation

major effects of thyroid gland on body systems

metabolic → cardiovascular system → nervous system → integumentary system; muscular system → skeletal system → gastrointestinal system → reproductive system

pathway to secrete T3/T4

hypothalamus produces TRH → TRH stimulates thyrotrophs of anterior pituitary to secrete TSH → TSH stimulates production of T3 and T4

T3

triiodothyronine, 20% of thyroid production, 3x more active than T4, short half-life (days), converted from T4 by target tissues (heart, kidney, liver)

T4

thyroxine, 80% of thyroid production, less active, long half-life, converted to T3 by target tissues (heart, kidney, liver)

follicular epithelial cells

also called thyroid epithelial cells or thyrocytes, synthesize thyroid hormones

parafollicular (C) cells

secrete calcitonin, affect cells close to them (paracrine)

thyroid releasing hormone (TRH)

peptide hormone (phospholipase C mechanism- DAG/IP3), secreted in paraventricular nuclei of hypothalamus, stimulates thyrotrophs in anterior pituitary to transcript and secrete TSH/thyrotropin, also stimulates some secretion of prolactin from lactotrophs

thyroid stimulating hormone (TSH)

glycoprotein (adenylyl cyclase mechanism- cAMP), secreted by thyrotrophs of anterior pituitary, stimulates thyroid gland to secrete T3/T4, regulates growth of thyroid gland via thyroidal blood flow, first secreted gestational week 13

T3/T4 effects on TSH

T3 has feedback to hypothalamus and anterior pituitary (AP), T4 also has some influence on AP

thyroid-stimulating immunoglobulins (TSI)

antibodies to TSH receptor, mimic TSH and binds to receptors to increase production of TH, leads to oversecretion and hypertrophy/hyperplasia of thyroid gland, components of IgG plasma proteins, also called TSHR-ab, TBI-ab, TR-Ab

thyroid hormone synthesis (ATE ICE)

active transport → thyroglobulin formed → exocytosis → iodide oxidation/iodination → coupling → endocytosis

step 1 of thyroid hormone synthesis (A)

active transport of iodide into follicular cells via sodium-iodide symporter NIS- iodide is low in blood and high in follicular cell while sodium is high in blood and low in follicular cell, sodium flows from high to low and iodide follows making it secondary active transport

step 2 of thyroid hormone synthesis (T)

thyroglobulin (Tg) formed in follicular ribosomes and placed into secretory vesicles

step 3 of thyroid hormone synthesis (E)

exocytosis of thyroglobulin into follicle lumen where it’s stored as colloid

step 4 of thyroid hormone synthesis (I)

iodide oxidation and iodination of thyroglobulin (organification)- iodine is made reactive by enzyme thyroid peroxidase (oxidation), iodine binds to benzene ring on tyrosine residues of Tg and form monoiodotyrosine (MIT) then diiodotyrosine (DIT)

step 5 of thyroid hormone synthesis (C)

coupling/conjugation- MIT and DIT combine to get T3, DIT and DIT combine to get T4 (10x faster), iodinated Tg stored in follicular lumen as colloid until thyroid gland is stimulated to secrete its hormones by TSH

step 6 of thyroid hormone synthesis (E)

endocytosis of iodinated thyroglobulin back into follicular epithelial cell- Tg undergoes proteolysis by lysosomes to cleave iodinated tyrosine residues from larger protein, free T3/T4 released, Tg backbone recycled

iodine

essential for synthesis of thyroid hormones, too much or too little is detrimental- only need 1 teaspoon in lifetime but because it can’t be stored the body continually needs tiny amounts, high in seafood/seaweed, dairy products, iodized salt

wolff-chaikoff effect

ingestion of a large amount of iodine causes a reduction of thyroid hormone levels

iodine deficiency

significant problem worldwide other than where its freely available in milk, fish, etc, can cause thyroid-related growth and development disorders, can occur in pregnant women as they need 50% more than normal

high iodine levels

induce hypothyroidism or hyperthyroidism in susceptible patients

goitrogens, halogens, gluten

goitrens interfere with body’s use of iodine; halogens block iodine receptors; gluten can mimic TSH and inhibit/block receptors

conversion of T4 to T3

occurs in target tissues (liver, gut, heart, muscle), done via enzyme 5’ deiodinase (D1, D2), target tissues convert portion of T4 to reverse T3 (RT3) that is inactive via D3

5’ deiodinase

D1 (extracellular) and D2 (intracellular) convert T4 to T3 by removing an atom of iodine

reverse T3 (RT3) production

done by D3 in target tissues, T4 is made inactive by removing an iodine, an evolutionary adaptation to protect thyroid, occurs in times of stress, physical trauma, injury, and illness to lower T3 levels

reverse T3 (RT3)

inactive version of T3 that blocks T3 effects, occupies but doesn’t activate T3 receptors

thyroxine-binding globulin (TBG)

very specific transport protein that transports T3/T4 in blood to target tissue, because it’s so specific it can travel further, provides large reservoir of circulating thyroid hormones that can be released and added to pools of free hormones when needed

bound vs unbound thyroid hormones

hormones are only active when they are unbound (free), when hormones are being transported to target tissues they are bound to TBG and inactive

steroid hormone mechanism

steroid hormone diffuses across cell membrane and enters target cell in cytosol or nucleus → binds to E domain → hormone receptor dimerizes and binds to C domain → hormone-receptor complex becomes transcription factor regulating transcription of gene → new mRNA transcribed → leaves nucleus → translated to new proteins specific to hormone

increase in basal metabolic rate (BMR)

increases oxygen consumption and body temperature, thyroid hormones increase oxygen consumption in all tissues except brain, gonads, and spleen by inducing synthesis and increasing activity of sodium-potassium ATPase

Na-K ATPase

responsible for primary active transport of Na and K in all cells, highly correlated with/accounts for a large percent of total oxygen consumption and heat production of body, increased by thyroid hormones

thyroid effects on metabolism

increase both protein synthesis and degradation, overall effect is catabolic resulting in decreased muscle mass; increase glucose absorption from GI tract and potentiate effects of other hormones on gluconeogenesis, lipolysis and proteolysis; increased O2 consumption depends on increased availability of substrates for oxidative metabolism

bone age in kids with hypothyroidism

is less than chronologic age

thyroid on CNS

effects are age-dependent, prenatal- essential for normal maturation of system, deficiency causes intellectual disabilities; adults- deficiency causes lack of energy, weight/hair loss, imparied memory, etc while overproduction causes hyperexcitability, irritability, hyperreflexia, and nervous/anxious energy

thyroid on autonomic nervous system

hormones interact with sympathetic nervous system, many effects are similar to catecholamines via beta-adrenergic receptors, synergism with catecholamines shows in effectiveness of beta-adrenergic blocking agents in treating hyperthyroidism

thyrotoxicosis

clinical manifestation of excessive thyroid hormone action at tissue level due to inappropriately high-circulating TH, TSH is low because AP senses high level of TH via its negative feedback loop, ranges from asymptomatic to thyroid storm

hyperthyroidism

type of thyrotoxicosis, over activity of thyroid gland results in excessive secretion of thyroid hormones and accelerated metabolic effects

graves’ disease

most common cause of hyperthyroidism (70-80% with a diffuse goiter), immune system releases antibodies that attack/bind to thyroid cells (autoimmune), TSIs increase secretion of TH causing hypertrophy of gland, stimulates thyroid gland to grow and produce TH, familial, increases risk for type 1 diabetes and addison’s disease

causes of hyperthyroididm

graves disease MC, thyroiditis, too much thyroid medication, toxic nodular goiter, hyper-functioning thyroid adenoma, neonatal hyperthyroidism, jod-basedow syndrome

jod-basedow syndrome

iodine-induced thyrotoxicosis, taking iodine → body thinks it needs to use it → hyperthyroidism

hyper-functioning adenoma

benign tumor of thyroid gland formed by uncontrollably growing follicular cells, produces excessive amounts of exogenous thyroid hormones

neonatal hyperthyroidism

newborns of mom’s that have Graves’ disease, start to generate too much TH in response to thyroid-stimulating immunoglobulins crossing placenta

toxic nodular goiter

mutated TSH receptor that triggers production of TH, keeps follicular cells active

symptoms of hyperthyroidism

severity depends on duration/extent of excess TH and age, bulging eyes, grave’s dermopathy, breathlessness on exertion, sore throat/goiter, weight loss accompanied by increased food intake from increased metabolism, excessive heat production from increased oxygen consumption, rapid HR from up-regulated beta-1 cardiac receptors, losing hair, abnormal cycle, diarrhea, palpitation, tremors/nervousness/irritability from CNS affects

goiter

increased activity of the thyroid causes it to enlarge, may compress esophagus and cause difficulty swallowing

Grave’s dermopathy

redness and swelling of the skin, especially in shins and feet

thyroid storm/thyrotoxic crisis

a rare and life-threatening condition that happens when thyroid suddenly produces and releases large amounts of thyroid hormone, hyperthyroid symptoms become exaggerated, death results if not treated within 48 hours; treatment is inhibition of thyroid (not immediate) via anti-thyroid medication

symptoms of thyroid storm

fever, irritable, high systolic/low diastolic BP, nausea/vomiting, diarrhea, shock/delirium, confusion, sleepiness, yellowing skin, difficulty breathing, coma, heart failure/death

tests to diagnose hyperthyroidism

blood- high T4 and low TSH = primary, problem is in gland; high T4 and high TSH = secondary, problem is in hypothalamus/AP; ophthalmic exam, EKG/ECG, radioactive iodine uptake (RAIU), thyroid scan and ultrasound

biotin interference

high levels can interfere with hyperthyroidism exams, can give a falsely decreased TSH value and elevated fT$ or TRab, patients told to stop intake 12 hours prior to blood tests to prevent this

radioactive iodine uptake test (RAIU)

small oral dose of radioactive iodine given then checked after 4, 6, 24 hours to see how much collects in the thyroid gland

high intake indicated by RAIU

thyroid is producing too much thyroxine, indicates graves’ disease or hyper-functioning thyroid nodules

low intake indicated by RAIU

T4 stored in thyroid leaking into bloodstream, indicates thyroiditis

thyroid scan

radioactive isotope ejected to show how iodine collects in thyroid

thyroid ultrasound

used to detect nodules, no exposure to radiation

3 types of treatments for hyperthyroidism

ablation with radioactive iodine (I-131), anti-thyroid toxin medications (PTU or methimazole), surgery

radioactive treatment for hyperthyroidism

radioactive iodine taken orally and absorbed by thyroid causes it to shrink and reduce symptoms within 3-6 months, may slow thyroid enough to induce hypothyroidism- patient must then take daily meds

anti-thyroid medications for hyperthyroidism

beta-blockers, reduce symptoms by preventing thyroid from producing TH; Propylthiouracil (PTU) MC in US, methimazole

beta-blockers (HP meds)

HP meds, can help reduce tachycardia and palpitations

thyroidectomy

removal of thyroid gland, 2 main factors to consider- type/extend of thyroid disease present, anatomy of thyroid gland; requires lifetime treatment with levothyroxine

subclinical hyperthyroidism

when pituitary gland signal thyroid to make less hormone, TSH is low but TH is normal, ruled out over administration of TH, asymptomatic to mild symptoms

hypothyroidism

abnormally low activity of thyroid, MC in women 60+ but can be anyone, autoimmune, treated with radioactive iodine or anti-thyroid meds, potential causes- Hashimoto’s thyroiditis (MC), radiation exposure to neck/upper chest, thyroid surgery, pregnant or delivered within 6 months, hyperthyroidism treatment, congenital, iodine deficiency, damage to pituitary

Hashimoto’s thyroiditis

thyroid is generating energy while adrenals are weak and struggling to keep up; symptoms present but labs are normal- '“it’s in your head, lets give you antidepressants/sleeping meds”, treatment is steroids that could do more harm than good, not all people with this have hypothyroidism but it’s very likely; weak adrenals → hypothyroidism symptoms, adrenal stress → interferes with HPA axis and T4→T3 conversion (makes RT3 instead)

stress and cortisol on thyroid hormones

elevated levels of cortisol in circulation can slow TH production, cortisol affects 5’ Deiodinase converting T4→T3, stress causes increased release of cytokines, prolonged elevated levels of cortisol cause excess estrogen to accumulate, prolonged stress suppresses immune system

when the cause of hypothyroidism is a defect in the thyroid

a goiter develops from the unrelenting stimulation of thyroid gland by high circulating levels of TSH

myxedema

happens in severe hypothyroidism, caused by hypothyroidism + a stressor that triggers an increase in metabolism so TH is depleted, leads to life-threatening myxedema coma, treated with hormone replacement, correcting fluid/electrolyte imbalance, supportive care, and treating cause (hypothyroidism)

cretinism

irreversible form of growth and intellectual disabilities, results from hypothyroidism in perinatal period that was left untreated

diagnosis of hypothyroidism

history + exam, blood tests + symptoms, TSH and TH levels- primary caused by high TSH/low TH, secondary caused by low TSH/low TH

treatment of hypothyroidism

thyroid hormone replacement therapy (usually T4 assuming there is no conversion issue) using Levothyroxine- measured monthly until TSH is stable; if TSH increases dose is too low, if TSH decreases dose is too high; Cytomel (T3)- rarely used due to being hard to tolerate and rapid onset; compounded control (T3)- better tolerated, higher dose taken in morning; combo of T3/T4- controversial, fixed amount, not much control

subclinical hypothyroidism

mild thyroid failure, thyroid losing the ability to produce TH, early and mild form of hypothyroidism, grades I and II, usually asymptomatic, more common in older women with higher iodine intake, treatment is debatable

thyroid-stimulating immunoglobulin (TBI) antibodies

mimic TSH and bind to receptors → increased production of TH → hyperthyroidism , commonly associated with graves’

thyroid-binding-inhibiting immunoglobulin (TBII) antibodies

block the action of TSH → decrease production of TH → hypothyroidism

thyroglobulin antibody (TGAb) test

marker for autoimmunity and cancer

thyroid peroxidase antibody (TPOAb) test

autoimmunity present and tissue damage occurs, associated with hashimoto’s thyroiditis

TSH level indications

high= hypothyroidism/Hashimoto’s; low= hyperthyroidism/Graves’

free thyroxine (T4) level indications

high= hyperthyroidism; low= hypothyroidism

free triiodothyronine (T3) levels indications

low= hypothyroidism

primary hyperthyroidism

high T4, low TSH; the issue is with the thyroid gland, it is oversecreting TH even though the TSH levels are low to try and fix the issue

secondary hyperthyroidism

high T4, high TSH; issue is with the hypothalamus or anterior pituitary oversecreting TSH- thyroid gland is just responding accordingly

primary hypothyroidism

low T4, high TSH; problem is with thyroid gland- even though TSH levels are high to try and fix the issue it is undersecreting TH

secondary hypothyroidism

low T4, low TSH; problem is with hypothalamus or anterior pituitary undersecreting TSH- thyroid gland is just responding accordingly

poor gut health

suppresses thyroid function, triggers Hashimoto’s, decreases HCl, causes constipation which impairs hormone clearance, increases inflammation, infection, and malabsorption

short chain fatty acids (SCFAs)

can serve as an energy source for enterocytes, with thyroid hormones enhances enterocyte differentiation and strengthens intercellular tight junctions

probiotics

non-pathogenic microorganisms that reach the colon alive and contribute beneficial health effects

synbiotic supplementation

pro and pre-biotics together are showed to reduce TSH, levothyroxine dose, and fatigue, increases fT3 in hypothyroid patients

24 hour urine iodine test

take iodine supplement → collect urine over 24 hours → if level normal no supplement needed, if number goes down supplement has been absorbed and a supplement may be beneficial to patient- starts with selenium

selenium

very mild iodine supplement- can reduce antithyroid antibodies, improve thyroid structure, metabolism, and improve symptoms, found in plants, animal products, brazil nuts

zinc

essential for thyroid function and homeostasis, required for 5’ deiodinase, deficiency impairs TRH synthesis, found in oysters, red meat, seafood

iron

needed to convert T4 → T3, deficiency common with hypothyroidism

thyroid nodules

lumps/bumps in thyroid gland, most benign, sometimes make TH in hyperthyroidism, cyst filled are stored for of TH and result in degenerating thyroid adenomas, solid are more likely cancerous

papillary thyroid cancer (PTC)

most common (80%) thyroid cancer, 30-50 y/o women, slow-growing, follicular epithelial cells are differentiated

follicular thyroid cancer (FTC)

second most common (1/10), due to not enough iodine, in women 50+, slow-growing, more aggressive than PTC, worse prognosis