Hypothyroidism

Primary hypothyroidism

1) disease state processes that compromise thyroid gland function=immune attack; 2) congenital defects=genetic abnormalities, not common but when occur need to be resolved quickly, and two types=abnormal gland development and another functional abnormality=congenital or genetic defect (or surgery) in enzymes, receptors, and transporters that regulate function; 3) drugs that turn things off/system off=dopamine, glucocorticoids (most likely to see drug induced), number one is lithium, amiodarone, interferon, carbamazebine=normal unless hypothyroid even if treated because increase hepatic metabolism of T4 many many drugs; goitrogens=cruciferous vegetables including cauliflower, cabbage, boo chou, broccoli, brussel sprouts, etc=problem if hypothyroid because produce glucosinulates and get lots of anions when inhest=bind to transporter for iodine and block and can diffuse inside and inhibit TPO

Primary common causes

1) overwhelming majority of hypothyroidism in USA and most in europe; attack and destroy constituents of thyroid gland and becomes irreversible over time because will not replenish after killed; 2) reversible immune=second most common in UA; temporary attack on thyroid gland; exclusively in females and is post partum from regeneration of immune system after suppression to avoid attacking fetus and over time=stops; 3) other immune disorders of infections that invade thyroid and temporarily decrease thyroid function; first three=90% of cases and two of them are self resolving; 4) thyroid gland removed (cancer or radiation) 5) congenital defects=gland or biochemical; 6) functionality=congential defects, iodine deficiency and excess, drugs=lithium, amiodarone=causes hyper and then hypo

Medication errors

5 errors per 100 medication orders in inpatient settings; 1.3 errors per 100 prescriptions dispensed in community settings; not all of these errors result in patient harm; more errors in inpatient because system complexicity and more meds=lot new meds in short time; orbs that promote sea med practices: institute for safe medication practices=ISMP, institute of medicine=IOM, joint commission, National coordinating council for medication error reporting and prevention=NCC MERP, FDA safe use initiative

Hypothyroidism major signs and symptoms

CV: bradycardia, hypertension; dermatologic: cool and dry skin, coarse hair, brittle nails, yellowish discoloration to skin; neurologic: slow mentation, hyperthyroid speech (slow, low pitched, occasionally slurred), hyporeflexia, associated with a prolonged relaxation phase of the ankle reflex; other: hypothermia, non-pitting, generalized edema

Liothyronine

Cytomel; synthetic T3; 3 doses 5-50MCG; rapid onset; half life of 36 hours; rapid peaks and troughs; dosing: initial at 25 MCG once daily and increase by 12.5 to 25 MCG/day every 1 to 2 weeks because active form and half life shorter; maintenance 25 to 75 MCG/day; Pros: active form so quicker onset because of shorter half life, well absorbed, active form included, short half life so quicker reverser of ADRs/toxicity, good for acute situations/medical emergency; Cons: less dosing options so less individualized, caution with CV and DM, expensive, peaks and troughs, monitor more frequently, increase ADRs because giving active form=start low ad go slow

Thyroid hormone physiological functions (developmental and functional)

Development: required for neurological/neuron development=brain and peripheral nerve development and function, skeletal development=bone, muscle development and function; Function: CV=increase HR, cardiac contractility and cardiac output, promote vasodilation=enhanced blood flow; central nervous system=alterations in mental state, to little=sluggish and induces anxiety and nervousness; reproductive system=normal behavior and physiology is dependent on having essentially normal level of thyroid hormone and hypo commonly with infertility; others: muscle (contractility), skin/hair (structure, sensation), GI tract (motility)

Effect of Non thyroidal conditions on TFTs

ESS=euthyroid sick syndrome; TFTs can be affected by non thyroidal conditions for a variety of reasons, all is shifting in metabolism and have a net consequence of some combination of decreased TSH, decreased or increased free T4, decreased free T3 and increased rT3; common causes: pregnancy, any critical illness, liver disease, renal disease, malnutrition, and various medications; TRANSIENT; labs in absence of symptoms=no disease

Causes of hypothyroidism

Secondary/central=hypothalamic and pituitary disease, much less common than primary, some disease that impairs function of hypothalamus and pituitary (vasculature=impairs to communicate with pituitary); primary=disease with thyroid gland/third organ: hashimoto's disease, iatrogenic hypothyroidism, less common=iodine deficiency, enzyme defects, thyroid hypoplasia, goitrogens; peripheral hypothyroidism=tissues not responding-receptors,

Iodination and Coupling

after I- taken in by pump, has to be taken to colloid cell as well as TG so SLC26A/pendrin transports I- to apical membrane and another one pumps TG to colloid cell; 1) TPO binds I- to aromatic rings of TG to create diiodotyrosine with 2I- or monoiodotyrosine 1I- and TPO activity is positively modulated by TSH=iodination step; 2) coupling by TPO of the rings to create T4=two diiodotyrosines or T3=one diiodotyrosine and one monoiodotyrosine; 3) TG with attached thyroid hormones transported by LRP2 transporter in to follicle cell; 4) once in follicle cells, T4 and T2 digested off of protein by lysosomes; 5) released from protein by being exported by MCT pump to blood; inhibit TPO=propylthiouracil, methimazole, and too high or too low levels of I-; l; inhibition of T4/T3 secretion: lithium, iodide, amiodarone, aminoglutethimide

Goiter

another major sign and symptom for hypothyroidism; most common etiology with Hashimoto's; most commonly see goiter; no T3/T4 then no feedback so increase TRH and TSH and as gland under attack=swelling and constant stimulation by TSH so growing and a lot of times under attack; second most common=graves disease=hyperhtyroidism so goiter with TSH receptor Ab stimulates; goiter with iodine deficiency=increase TSH with no T3/T4; goiter different depending on cause=nodule, tenderness, thyroid bruit=turbulent flow of blood and vessels compressed when enlarged; graves=diffuse and big and swollen; hashimoto=swollen but tougher and firmer and can get nodules; subacute thyroiditis=temporary, tenderness=subacute and postpartum; no goiter if abuse; if large=swallowing problems and sometimes breathing

Medication error definition

any preventable event that may cause or lead to inappropriate med use or patient harm while med is in control of professional; Prescribing or dispensing error; prescribing errors: missing info, illegibility, incorrect drug name, incorrect dose, incorrect frequency, incorrect abbreviation, incorrect instructions for use; dosing: expired meds (he missed) wrong drug, wrong strength, incorrect labeling, not correctly identifying allergies, wrong name (jr., sr)

Thyroid USP

armour thyroid; synthetic T4:T3 at 4:1 ratio but in body it is 14:1; 15 to 300 MG with 8 doses; bioavailability: 48% to 79%; desiccated pork thyroid gland; dosing: initial 30mg per day, increase by 15 mg every 2 to 3 weeks and maintenance 60 to 120 mg per day; Pros: numerous dosing options so increase individualization, combo of T3 and T4=some active form if need both, natural product, generic available so inexpensive, been around along time=clinical history (not evidence); cons: cultural issues (pig), different dosing unit so more med error, not recommended for elderly with CV, less reliable and variable bioavailability, exacerbate DM, possible food allergies=immunogenicity because animal product and not human derived

negative feedback thyroid function and regulation

as T3/T4 levels increase (more so T3 but some T4)=bind to hypothalamus (and some pituitary=similar feedback inhibition) and binds to beta 2 receptors and disrupt CREB to turn off TRH production and also allows binding of transcription factors to shut off TRH synthesis; other off mechanism=metabolism; balance of levels is dependent on both negative feedback and metabolism

Thyroid meds

bad news=very complicated, tricky with medication units and therapeutic substitutions; good news=treatable and simple to treat; levothyroxine (synthroid), thyrolar (liotrix), liothyronine (cytomel), thyroid USP (armor thyroid); all can increase mood and decrease symptoms of depression; all cannot use with CV; all cause weight loss; exacerbate DM=any time give thyroid hormones because they are involved in glucose metabolism

Hashimotos

caused by thyroid infiltrating lymphocytes=B cell s and T cells that infiltrate thyroid gland; under auto immune disregulation and auto Antibodies attack TG, TPO, and TSH-receptors and infiltrate to get to TPO and TG on colloid side; when attack decrease TPO concentration so can't make T3 and T4; B cells release Abs to attack enzymes in gland; T cells are largely invasive and can induce apoptosis; over slow period time=attack and kill follicle cells and as enough die=lose capacity to make T3 and T4; lot of reserve=so a lot destroyed before have symptoms because takes years to show up; not uncommon to see different Abs; mostly see TPO and TG; wax and wane with Abs=time factor to whether see; other autoimmune diseases much less likely to see antibodies

Endocrine system (thyroid specifically)

central: hypothalamic pituitary axis; hypothalamus regulate pituitary with hormones and releases hormones that travels through blood to various tissues and organs; hormones from anterior or posterior pituitary; anterior=TSH and many others and posterior=ADH and oxytocin; in thyroid hormone system thyroid gland is third hormone down; TRH from hypothalamus to pituitary that secretes TSH to thyroid gland that causes secretion of T3 and T4; stage I=hypothalamus, II=pituitary, III=thyroid gland, IV=liver muscle (convert T4 to T3) and five=target tissues, specifically heart, nerves, bone, liver, muscle glands

Special population

change patient from levothyroxine to liotrix=direct administration of T3 is unreliable because extensively metabolized and T4 converted to T3 so T3 is unnecessary; patient childbearing age=levothyroxine; pregnant=levothyroxine but 60% of women will need dose adjustment usually by 8 weeks=increase dose because blood volume increase in pregnant women so a lot more protein bound so need more and adjust again after delivery and monitor TSH, thyroid hormone needed for fetal growth; what if depressive symptoms: no depression should improve with treatment but still monitor for progress; what if after one week of levi patient high TSH and low T4=change?=mp mpg seen full effect need 4-6 weeks

Thyroid hormone uptake and conversion

diffuses to organs/ higher exposure rates to drug with high perfusion because more access to blood=kidney, liver, brain (lung 100%) (heart low % of blood); drugs carried in by MCT; once inside cell=deiodinases can convert T4 to T3 by chopping off internal I- or can convert T4 to rT3, an inactive form but chopping of I- from external ring; T3 active form=I- on outer ring and two on inner form (why more T4 released); Type 1=appear third, thyroid gland, liver, and kidney and Type 2=appear second, pituitary, brain, thyroid, CNS, brown adipose tissue (to burn fat), muscle convert to active hormone and Type 3=appear first, placenta (protect fetus from mother's thyroid hormone so that baby can develop own) iodide is found in thyroid tissue and pituitary TS appear at 11 weeks and D3 destroys so very little reaches fetal circulation and after 15-18 weeks fetus control own thyroidal secretion, developing brain, and skin convert to inactive hormone

THBP alterations

displacement from TBG: furosemide, phenytoin, probenecid, heparin, NSAID; decreased TBG levels: androgens, glucocorticoids, nicotinic acid; increased TBG levels: estrogen (on average, females have more in body), raloxifene, tamoxifen, methadone, mitotane, fluorouracil; and levels vary with liver function and disease

Selecting an agent

drug of choice=levothyroxine, why? chemically stable profuct=reliable bioavailability and response, inexpensive, no antigenicity=synthetic not animal product, reliable potency; Dose: weight: 1.6-1.7 MCG/Kg/day so 125 MCG day typical, severity/duration of disease: 50 MCG for longstanding or very severe disease (dormant and can overshoot), age over 65: 50 MCG initial dose (lexicomp says 50 and dipiro 45=menopause cuz slows metabolism); Disease (CV)=25 MCG initial dose

Monitoring

efficacy: labs TSH, T4, Cholesterol=resolves earlier, vitals=HR and BP, signs and symptoms=start feeling and operating normally: constipation, hair, skin, fatigue; safety: Labs: TSH, T4 in 4-6 weeks and signs and symptoms=variable; if undertreated=look same with constipation, fatigue, hair fragility, lab abnormalities; over treatment: hyper thyroidism, CV: palpitations, heart failure, angina, myocardial infarction; bone: hyper-remodeling of cortical and trabecular bone=osteoporosis and more common in post menopausal women and look at drug allergy=highest with natural products and lowest with levothyroxine

Thyroid dysfunction

either hypo or hyper; hypothyroidism: bradycardia, hypotension, slow mentation, slow and low pitched speech, hyporeflexia, coarse hair, high cholesterol (appears earliest because primarily responsible for burning), constipation, muscle weakness, puffy eyes, goiter, sore throat, trouble swallowing, menstrual irregularities etc, have some of symptoms but not all of them and dependent on onset of disease=metabolic ones first and structural (hair and skin) last and if have had long standing=bunch of CNS effects and Skin and skin relating phenomenon=loss of hair, dry skin, cold intolerance weight gain; hyperthyroidism: tachycardia, hypertension, psychomotor hyperactivity, pressured speech, hyperreflexia, warm and moist skin, fine and abundant hair, heat intolerance, weight loss; thyroiditis can be caused by: interferon, interleukin-2, amiodarone, subunit inhib

Solutions to Medication Errors

five rights: right patient, right drug, right dose, right time, right route; communication=learn patient name, written and verbal, active listening; periodic audits=JC come to make sure adhering to safe practices with fewest opportunity for errors; Medication Reconciliation=long term care and hospitals, when come in and discharged take appropriate and complete med list so no error on way in or out; positive culture (fat fridays); follow legal requirements

Other regulators of thyroid hormone production

four key points: TRH=increases; Cortisol=decreases; cytokines=decreases; dopamine=decreases; if cortisol levels high=important to fix those first

on levothyroxine, call HCP if experiencing

headache; sleep problems; feeling nervous or irritable; fever, hot flashes, sweating; pounding heartbeats or fluttering in your chest; changes in your menstrual periods; appetite changes, weight changes

causes of med errors

human error: at risk behaviors, reckless conduct (shortcuts); abbreviations: inconsistent, illegible; look alike/sound alike: lamisil and lamictal, plavix and paxil, premarin and prevacid; improper/complex systems; high alert meds (dangerous with errors): insulins, opiods, antibiotics, immunosuppressants, anticoagulants, chemotherapy agents

stage I

hypothalamic control; has off switch in hypothalamus for T3 and T4 production as well; stimulus inputs such as cold or stress from sensory receptors; G protein membrane receptors activate Gs, which increases the level of cyclic AMP in cell, which phosphorylates PKA, which phosphorylates CREB that is translocated in to nucleus and binds to specific regulatory sites on DNA that causes an increase synthesis of TRH that is released into blood (axis between hypothalamus and pituitary); TRH also increases release of prolactin and travels from hypothalamus and travels to anterior pituitary via hypothalamic-hypophysial portal system

Thyroid hormones metabolic

increased basal metabolic rate=increased oxygen and ATP consumption and heat production: lipids=fat mobilization increased fatty acids in plasma, enhanced oxidation of fatty acids and metabolism of cholesterol and triglycerides; sugars: stimulating all aspects of carbohydrate metabolism, including insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose=comlex; protein=stimulating expression of some proteins (receptors) and metabolism of others; these all affect weight and appetite (decrease weight and appetite)

Thyrolar

liotrix; synthetic T4:T3 at 4:1 ratio but in body it is 14:1; 5 doses 12.5 to 100 MCG; half life T4=7 days and T3=2 days; relatively high T3:T4 ratio; dosing is in grains: 1/2=typical starting dose (1/4, 1/2, 1, 2, 3); one grain=60mg; pros: shorter onset=earlier resolution of signs and symptoms, active T3 so if conversion messed up get some active form, inexpensive, individualization with numbers dosing, combo=hitting two therapeutic targets; Cons: dosing in grains=more challenges, empty stomach=patient counseling, must be refrigerated, not physiological ratio=increase ADRs (too much T3), limited use in patients with CV, additional monitoring for diabetics

Thyroid hormones in blood

lipids with large and not very electronegative iodine atoms attached=nonpolar so don't freely float in blood/not soluble; bind to plasma proteins made in liver; 99/97% of plasma T4 and 99.7% of T3 are bound to proteins: THBP: thyroxine binding globulin (TBG)=major binding and affinity for T4 is 10 fold greater than that of T3 so it's half life is much larger; transthyretin=carries some T4; albumin=carries small amount of T4 and T3; T4 half life=7 days and T3 half life=1 day; T3=20% is released and T4=80% is released even though T3 active form

Disease and TSH levels

lots of cross talk between disease and TSH levels if primary=not enough T3 and T4 so feedback to increase levels of TSH; drop of T4 to increase of TSH 1:10 ratio; iodine deficiency also increases TSH levels because not enough thyroid hormone

Interpretation of TFTs

low TSH and low T4=hypothalamus or pituitary problem=most likely this problem because more common; high TSH and low T3/T4=thyroid gland problem/primary and both cases look similar cuz low thyroid hormone but different origin; T3/T4 high and TSH low=hyperthyroidism and primary problem like Graves where Ab stimulate gland; TSH high and T4 high=secondary hyper problem where hypothalamus/pituitary problem; measure in mIU; TSH:0.5-4.7 mIU, free T4: 0.8-2.7ng/dL; total T4: 4.5-10.9mcg/dL; Total T3: 60-181ng/dL (units based on how much in blood); sensitivity: T4 go down and TSH go up 10 fold so important to remember with thyroid replacement hormone and hypothalamus and pituitary very sensitive to plasma T3/T4 levels

what is required for a prescription

nothing legally required unless controlled substance but some things used in practice; prescription=order for medication which is dispensed to or for an ultimate user if for immediate administration=office use and is a med order; EVERY one: patient's name, date, drug and dosage form, dose, route, frequency, quantity, refills, physician signature; changes=upon patient verification to address and upon consultation with prescriber=dosage form, stregth, quantity, directions for use, issue date; hospital order requirement similar no refills needed and quantity smaller

Thyroid function tests (TFTs)

often times check in ER; TSH is gold standard and number one to look at; also check free T4=only 0.3% of it or something; can measure T3 but less reliable and expensive and only do when TSH and T4 don't add up; may look for antibodies: Ab to thyroglobulin=TgAb, Ab to TPO=TPOAb, Anti-TSH receptor Abs=TRAb (graves=stimulate and hasi=block receipt so less T3/T4) and Hashimoto can show all three but mostly TgAb; TgAB and TPOAb attack gland and colloid space; rarely ordered: total T4 and T3, T3 resin uptake, reverse T3, TRH, TBG, TG

populations at risk for hypothyroidism

other endocrine autoimmune disorders including diabetes, adrenal insufficiency=addison's, ovarian failure=highest incidence/co-incidence; other non endocrine autoimmune disorders including celiac disease, vitiligo, pernicious anemia, Sjogren's, MS; family history of autoimmune disease; previous head/neck surgery or irradiation; postpartum women=nonendocrine autoimmune; genetic/acquired hypothalamic or pituitary disease; genetic disease=downs and turners; abnormalities in immune function and ability to create autoantibodies=relate to primary hashimotos and other major causes

legal issues for thyroid meds

part of emergency prescription fill and when cannot get into contact with doctor can fill 72 hours worth and governor can extend; substitution of generic products=used to be more strict with law because manufacturers inconsistent but now more consistent but goal is if start on product to continue on product unless have to change and law if have to change=wihtin same TE code that is determined when submit to FDA and compare to all other manufacturer's drugs and if not same TE code and new product line drug=monitor like new drug (4-6 weeks labs); can see TE codes at FDA orange book

stage II

pituitary control; TRH binds to extracellular receptors on anterior piuitary, G protein coupled membrane receptor activated GoGq and Gq activates PLC, which cleaves PIP to IP3 and DAG; DAG activates PKC, which phosphorylates mediators to turn on DNA and make TSH so stimulates synthesis; IP3=works to release TSH from membrane units where stored by affecting Ca++; TSH suppression by glucocorticoids, dopamine agonists, somatostatin analogs, rexinoids, carbamazepine/Oxcarbemazepine, metformin; TSH=a glycoprotein made up of an alpha subunit that is common to FSH, LH, and HCG and a beta subunit=unique structural unit that can bind to thyroid gland; primary function: increased release of preformed thyroid hormone, increased formation of thyroid hormone; increased size and number of thyroid cells (thyroid hormone production and thyroid gland size/functionality)

Levothyroxine

synthroid; synthetic T4; 12 dosage forms, 25 to 300MCG; half life is 7 days; predictable potency; dosing: initial 1.6 to 1.7 MCG/kg orally once daily, adjust dose in 12.5 to 25 MCG increments every 4 to 6 weeks until patient is clinically euthyroid and TSH normal; doses greater than 200mcg/day rarely needed; Pros: multiple doses so individualized, cheap, predictable, longer half life so less frequent monitoring and dosing, oral and can be crushed, availability, effective; cons: CV ADRs, wait 4-6 weeks/long onset because long half life, take a while to get to appropriate dose, assumes that from T4 to T3 is functioning and receptors=other normal responses with physiological processes

Thyroid hormone target action receptors

t3 binds to thyroid hormone receptors=THR and is translocated across pores to nucleus, where it binds to thyroid response element=TRE and most instances stimulates transcription and protein synthesis which one depends on organ; hormone controls protein synthesis; THR types: alpha 1=heart, skeletal muscle, and brain=stimulation, beta 1=brain and liver and stimulatory, beta 2=hypothalamus and pituitary and inhibitory for negative feedback for TSH secretion

Metabolism of thyroid hormone

terminate thyroid hormone through deiodinases to rT3 or through metabolism of enzyme; phase I=deamination by CYP to remove amine and carboxyl group or phase II=by UGT to glucuronide pathway; both of these are hormone inactivating; amount of T3 through balance of conversion to rT3 and metabolism of T3 and T4 by CYP and UGT; increased hepatic metabolism: phenobarbital, phenytoin, carbamazepine, rifampin, TKI, Rexinoids

thyroid gland/ NIS

thyroid gland=butterfly gland wrapped around trachea and esophagus and can compromise swallowing and breathing; number of different cells; follicle cells wrapped around colloid cell that is mostly thyroglobulin; TSH binds to receptors on follicle cells and thyroid hormones are made in colloid cells; NIS=Na+/I- cotransporter on follicle cell basolateral membrane (blood) that transports I- and Na+ into the cell; TSH binds to the NIS receptor and turns it on to pump in iodine that is needed to make thyroid hormone; takes in sodium with iodide to maintain electron neutrality; but then too much Na+ inside and can stop Na+/I- cotransporter; Na+K+ATPase that pumps Na+ out; when mess up one pump so does the other one; block Na+/I- cotransporter: thiocynate, perchlorate, pertechnetae, Br-, F-, and goitrogens (cruciferous vegetables); iodine get naturally from salt and seafood

Imaging (RAI)

thyroid imaging with radioactive iodine; solid or liquid I 123=emits nontoxic radiation and can image to see how much iodine gland takes up of iodine to measure functionality and see structure; hypo=less than 5% and irregularity of shape; kill gland I 131; can see nodule and if normal or less function and can see hot nodule=more activity

peripheral hypothyroidism

tissues not responding; genetic mutation in receptors; can be genetic mutation of resistance to thyroid hormones and have to worry about central and peripheral tissues so if in periphery=decrease functions and called peripheral resistance and if in brain=decrease feedback and called central resistance=high levels cuz not turned off, relatively rare, mostly general resistance=GRTH so a little bit of both=insensitive so hypo but levels high because not turned off; hypo=can get any possible combination of hromones