7585 Week 2, Day 2 Thyroid Disorders Handout (WALLACE-GAY)

thyroid hormones
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thyroid hormones
- thyroxine (T4)
- triiodothyronine (T3)
Describe the synthesis of thyroid hormones.
- T4 and T3 are formed within a large glycoprotein known as thyroglobulin (TG).
- Iodide is transported from the extracellular space into the thyroid follicular cell.
- Thyroid peroxidase (TPO; produced by thyroid gland) oxidizes iodide and covalently binds the organified iodide to tyrosine residues with TG (known as organification).
- The iodinated tyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) combine to form the thyroid hormones (known as coupling).

**organification: the incorporation of iodine into TG for the production of thyroid hormone
**DIT + DIT = T4
**MIT + DIT = T3
When iodine is low/deficient, this causes...
- an increase in the MIT:DIT ratio in TG
- leads to a relative increase in the production of T3
Medications used to treat hyperthyroidism do what? What about medications used to treat hypothyroidism?
- hyperthyroidism: inhibit TPO, thus blocking thyroid hormone synthesis
- hypothyroidism: replace low endogenous hormone with natural or synthetic exogenous hormone
About 99.9% of circulating T4 and 99.5% of T3 is bound to and transported in the bloodstream by...
- thyroxine-binding globulin (TBG)
- thransthyretin (TTR)
- albumin

**only free hormone is able to diffuse into the cell and regulate thyroid-stimulating hormone (TSH or thyrotropin) secretion from the pituitary gland
Describe the pathophysiology of thyroid hormone stimulation and inhibition.
Stimulation:
- the hypothalamus stimulates the anterior pituitary by producing TRH
- the anterior pituitary stimulates the thyroid gland by producing TSH
- the thyroid gland produces thyroid hormones that stimulate target cells

Inhibition:
- thyroid hormones inhibit both the hypothalamus and the anterior pituitary
- TSH inhibits the hypothalamus
Describe thyroid function tests.
- the primary recommended laboratory tests are TSH and free T4 (FT₄)

additional tests include:
- total T3 (TT3)
- free T3 (FT₃)
- radioactive iodine uptake (RAIU) and scan
- thyrotropin receptor antibodies (TRAb)
- thyrotropin-stimulating antibodies (TSAb)
- ultrasound
Describe the lab values that accompany diagnoses of hyper- and hypothyroidism.
Hyperthyroidism:
- increased FT₄
- decreased TSH

Hypothyroidism:
- decreased FT₄
- increased TSH

Reference Ranges:
- FT₄ = 0.8 to 1.9
- TSH = 0.5 to 4.5
Thyrotoxicosis results when...
- tissues are exposed to excessive levels of thyroid hormone

**hyperthyroidism is one cause
**hyperthyroidism = overproduction of thyroid hormone by the thyroid gland
**abnormal TSH levels are more common in women than men
If a patient exhibits symptoms of hyperthyroidism and the clinical history and physical exam do not provide clues to the etiology of it, _____ may be used for evaluation.
- RAIU

**normal 24-hour RAIU: 10%-30%
**elevated RAIU indicates endogenous hyperthyroidism (gland is overproducing T4, T3, or both; the treatment strategy is to decrease the rate of synthesis, secretion, or both)
**low RAIU in the absence of iodine excess indicates that high levels of thyroid hormone are not due to thyroid gland hyperfuncton, but is likely due to thyroiditis or hormone ingestion
clinical presentation of hyperthyroidism- s/sx of thyrotoxicosis affect multiple organ systems - symptoms are typically present for an extended period of time prior to diagnosis - Graves' Disease: an autoimmune syndrome that typically includes hyperthyroidism, thyroid enlargement, exophthalmos, thyroid acropachy and pretibial myxedema - Graves' Disease is the most common cause of hyperthyroidismsigns of hyperthyroidism- warm, moist skin - exophthalmos (Graves') - pretibial myxedema (Graves') - unusually fine hair/thinning of the hair - onycholysis - lid lad - tachycardia at rest - fine tremo - hyperactive reflexes - thyromegaly - Plummer's nailssymptoms of hyperthyroidism- nervousness, irritability, insomnia - anxiety - palpitations - emotional lability - fatigue - menstrual disturbances (amenorrhea) - heat intolerance - weight loss (possible weight gain due to increased appetite) - diarrhea/frequent bowel movementsthree features of Graves' disease- periorbital edema - dermopathy over the lateral aspects of the shins - thyroid acropachytreatment of hyperthyroidism- three common treatment modes: surgery, anti-thyroid medications/drugs (ATDs), and radioactive iodine (RAI) - Clinical Goal: eliminate excess thyroid hormone and minimize the symptoms and long-term consequences on hyperthyroidism - treatment must be patient-specific (based on age, gender, comorbid conditions, and response to prior treatments)considerations for surgical removal of the thyroid for patients with hyperthyroidism- large gland size (>80 g) - severe opthalmopathy - lack of remission on ATD treatment - patient should be rended euthyroid prior to surgery in order to prevent thyroid storm - most patients with GD should be on potassium iodide prior to surgery - thyroid hormone supplementation should be started immediately following surgery (L-thyroxine T4 1.7 mcg/kg/day)drug of choice for making a patient euthyroid prior to surgery- methimazole (6-8 weeks) followed by the addition of iodides 500 mg/day (10-14 days before surgery) to reduce vascularity of the gland - propranolol may be given for several weeks before and 7-10 days after surgery to maintain pulse <90 bpm (may combine propranolol and potassium iodide for pre-treatment)potassium iodide regimens/timing to be given before surgery for patients with hyperthyroidism- potassium iodide TID for 10-14 days prior to surgery - saturated solution of potassium iodide (SSKI): 1-2 drops (50 mg iodide/drop) OR - Lugol's solution: 5-7 drops (8 mg iodide/drop)What should be started immediately after surgery for hyperthyroidism?- thyroid supplementation with L-thyroxine (T4) 1.7 mcg/kg/dayWhat is the role of adrenergic blockers in the management of hyperthyroidism?- many manifestations of hyperthyroidism are mediated by beta-adrenergic receptors - beta-blockers may be used (especially propranolol) to reduce symptoms such as palpitations, anxiety, tremor, and heat intolerance - propranolol and nadolol partially block conversion of T4 to T3 but the overall therapeutic effect is small - beta-blockers are typically used as adjunct therapy with antithyroid drugs, RAI, or iodides when treating Graves' disease/toxic nodules, preparing for surgery, or when the patient is experiencing a thyroid storm **work well for symptom control but do not affect peripheral thyrotoxicosisWhat is the initial and thyroid storm dosing for propranolol for patients with hyperthyroidism?- Initial: 10-40 mg PO TID or QID - Thyroid Storm: 60-80 mg PO q4hWhat are contraindications for propranolol use?- reactive airway disease - sinus bradycardia - concurrent TCAsWhat are the role(s) of iodides in the treatment of hyperthyroidism?- first form of drug therapy for Graves' disease - blocks thyroid hormone release - inhibits hormone biosynthesis by interfering with intrathyroidal iodide utilization (Wolff-Chaikoff effect) - decreases the size and vascularity of the gland - provides symptom improvement in 2-7 days (serum T3/T4 may be reduced for weeks) - the normal and hyperfunctioning thyroid soon escapes from this inhibitory effect within 1-2 weeks by decreasing the active transfer of iodide into the gland - often used as adjunct therapy for surgical preparation for patients with Graves' disease, acute inhibition of the thyroid in severely thyrotoxic patients with cardiac decompensation, and the inhibition of the thyroid following RAI surgeryHow are iodides supplied?- saturated solution (SSKI; 38 mg per gtt): 3-10 gtts daily in water or juice x10 days prior to surgery - Lugol's solution (6.3 mg per gtt): 3-5 gtts in juice TID x10 days prior to surgeryWhat are the ADRs for iodides?- allergic reactions - dose-related toxicity - metallic taste - "escape" phenomenonWhat is/are the role(s) of RAI in the treatment of hyperthyroidism?- goal of RAI is to ablate the thyroid tissue - disrupts hormone synthesis by incorporating into thyroid hormones and gland tissue - after the first few weeks, small vessels in the thyroid will be destroyed, leading to edema/fibrosis of interstitial tissue - administered as a colorless/tasteless liquid (well-absorbed; concentrates in the thyroid) - after RAI, destruction of the gland diminishes the hyperthyroid state and hypothyroidism commonly occurs months to years after (patients will need thyroxine tablets to replace hormone needs)What is the dosing for RAI?- 4000-8000 rad (may repeat dose in 6 months if euthyroid state is not achieved) - 60% become euthyroid at 6 months or lessDescribe adjunct agents and RAI.- RAI can be given with beta-blockers without compromising RAI (they are a mainstay of therapy to RAI) - iodides should be given 3-7 days after RAI to prevent interference - thionamides are often given prior to RAI ablation (especially the elderly and those with cardiac disease) because thyroid hormone levels will transiently increase following RAI (due to the release of pre-formed thyroid hormone) - corticosteroids may be administered to blunt/delay the rise in antibodies to the TSH receptor, TG, and thyroid peroxidase while reducing T3/T4 concentrations following RAI - lithium is used to prevent post-therapy increase in thyroid hormone, increase cure rate, and shorten time to cureHow does pregnancy affect the management of hyperthyroidism?- hyperthyroidism in pregnancy is almost always caused by Graves' Disease - symptoms include failure to gain weight despite good appetite and persistent tachycardia - RAI is contraindicated in pregnancy - surgery is not usually recommended (especially first trimester) - PTU is the drug of choice in the first trimester - MMI readily crosses the placenta and appears in breast milk - MMI considered the drug of choice in the second and third trimesters **MMI-associated embryopathy outweighs the risk of PTU-associated hepatotoxicityWhat are the characteristics of a thyroid storm?decompensated thyrotoxicosis - high fever - tachycardia/tachypnea - dehydration - delirium - coma - n/v - diarrheaWhat are some precipitating factors for the development of a thyroid storm?- infection - trauma - surgery - RAI treatment - withdrawal from antithyroid drugsClinical decompensation of a thyroid storm typically lasts for about _____.72 hours **general symptoms may persist for up to 8 daysDescribe the management of thyroid storm.- suppression of thyroid hormone formation/secretion: large dose of PTU may be preferred due to interference with hormone production and peripheral conversion of T4 to T3 - antiadrenergic therapy: short-acting agents preferred - administration of corticosteroids: may assist with antipyretic effects and BP stabilization; do not administer ASA/NSAIDs due to possible displacement of bound thyroid hormone - treat associated complications/co-existing factors that may have precipitated the stormWhat is the initial dosing for PTU/MMI?- MMI: 30-60 mg/day in 2-3 divided doses - PTU: 300-600 mg/day in 3-4 divided dosesWhat is the dosing for PTU and MMI?- PTU: 500-1000 mg LD, then 250 mg MD q4h - MMI: 60-80 mg/dayWhat is the dosing for hydrocortisone (preferred corticosteroid)?- 300 mg IV LD, then 100 mg q8h **alternative drug is dexamethasoneHow should outcomes be evaluated for patients treated for hyperthyroidism?- follow-up should take place monthly until the patient reaches euthyroidism - watch for clinical signs of continuing thyrotoxicosis or development of hypothyroidism - beta-blockers may be used to control symptoms of thyrotoxicosis until euthyroid state is reachedDescribe the epidemiology and etiology of hypothyroidism.- occurs in 1.5%-2% of women and 0.2% of men - two categories for etiology: thyroid gland dysfunction (primary hypothyroidism) and pituitary or hypothalamus dysfunction (secondary hypothyroidism) - primary: most cases are due to thyroid gland failure secondary to chronic autoimmune thyroiditis - secondary: pituitary failure is uncommon; will usually have decreased T4 and normal/low TSHWhat are the clinical signs of secondary hypothyroidism?- abnormal menses - decreased libido - signs of pituitary adenoma (visual field defects, galactorrhea, etc.)What are the major causes of primary hypothyroidism?**dysfunction of the thyroid gland** Hashimoto's Disease: - chronic autoimmune thyroiditis - most common cause of spontaneous hypothyroidism in the adult - antithyroid peroxidase antibodies are present in virtually all patients with Hashimoto's thyroiditis and appear to be directed against the enzyme thyroid peroxidase Iatrogenic Hypothyroidism: - follows exposure to destructive amounts of radiation or surgery - hypothyroidism occurs within 3-12 months after RAI therapy in most patients treated for Graves' Disease - excessive levels of thionamide therapy may also cause iatrogenic hypothyroidismWhat are the major causes of secondary hypothyroidism?**central hypothyroidism** Pituitary Disease: - TSH is required for normal thyroid secretion - pituitary failure leads to thyroid atrophy and decreased thyroid secretion - may be caused by tumors, surgery, trauma, post-partum pituitary necrosis, external pituitary radiation, tuberculosis, and autoimmune mechanisms - TSH deficiency most often occurs along with other pituitary hormone deficiencies Hypothalamic Hypothyroidism: - thyrotropin-releasing hormone deficiency causes a rare form of central hypothyroidism - may be caused by cranial radiation, trauma, infiltrative disease, or neoplastic diseaseWhat are some potential issues that may accompany hypothyroidism?- can lead to a variety of end organ effects with a wide range of disease severity, from entirely asymptomatic to coma with multisystem failure - thyroid hormone is essential for normal growth and development during embryonic life - uncorrected hormone deficiency may lead to fetal/neonatal mental retardation and/or cretinism - hormone deficiency may lead to slowing physical/mental activity as well as impair CV, GI, and neuromuscular function in both adults and childrenWhat is the clinical presentation of hypothyroidism?- low thyroid hormone (free T4) - elevated TSH Signs: - slowed relaxation of deep tendon refexes - coarse skin/hair - periorbital puffiness - bradycardia - diastolic HTN - galactorrhea - reversible carpal tunnel and polyneuropathy Symptoms: - extreme fatigue - weight gain - depression - cold intolerance - dry skin/hair loss - constipation - irregular/heavy menses - decreased concentration - infertilityDescribe the treatment strategies for hypothyroidism.**thyroid hormone replacement is the gold standard of treatment** Drug of Choice: LEVOTHYROXINE - Synthetic: l-thyroxine, liothyronine, liotric - Natural: dessicated thyroid - combination products (dessicated thyroid and liotrix) have high proportions of T3 and may cause thyrotoxicosis - liothyronine is short-acting and requires multiple daily dosing in order to achieve stable serum concentrationsWhy is levothyroxine preferred?- stable - predictable potency - generics may be bioequivalent - lower dose by 1/2 grain if switching from natural thyroid - daily dosing is preferredWhat is the MOA of levothyroxine (T4)?- increases cellular metabolism and plays an important role in growth, development, CNS/bone functions, metabolism, and body temperature - activates gene transcription and protein synthesis by binding to thyroid receptors - actions are ~80% due to T3 which is derived from T4 by deiodination in peripheral tissuesWhat is the general dosing of levothyroxine (T4)?1.6-1.7 mcg/kg/day (may use IBW instead of ABW for better estimation) - >50 yo w/o evidence of CHD: 25-50 mcg/day - patients with heart disease: 12.5-50 mcg/dayWhat are administration notes for levothyroxine (T4)?- take on an empty stomach 0.5-1 hour before breakfast - give four hours apart from medications that interfere with absorption - IV should be reconstituted with 5 mL of NS and not added to other fluidsWhat type of monitoring should be done for patients on levothyroxine?- check TSH 6-8 weeks after each dose changeWhat is 1 grain of dessicated thyroid equivalent to for T4?74 mcg of T4What is the ratio of T4 to T3 for liotrix?4:1What are some conditions and medications that can interact with levothyroxine?- the time to max absorption of T4 is approx. 2 hours - ingestion of food with l-thyroxine may impair its absorption Conditions: - celiac sprue - diabetic diarrhea - ileal bypass surgery may reduce l-thyroxine absorption Medications that reduce absorption: - cholestyramine - calcium carbonate - sucralfate - aluminum hydroxide - ferrous sulfate - dietary fiber supplements - PPIs/H2RAs Medications that increase clearance: - rifampin - phenytoin - carbamazepineHow does myxedema coma affect the treatment approach of hypothyroidism?- rare consequence of decompensated hypothyroidism Clinical Presentation: - hypothermia - advanced stage of hypothyroidism symptoms - altered mental state Initial Treatment: - levothyroxine 300 - 500 mcg IV bolus followed by 75 - 100 mcg IV until the patient is stable and oral therapy is indicated - glucocorticoid therapy (IV hydrocortisone) may be given until coexisting adrenal suppression is ruled out - supportive therapy is necessary to maintain adequate ventilation, blood pressure and body temperatureHow does congenital hypothyroidism affect the treatment approach of hypothyroidism?- full maintenance therapy should be provided as soon as possible to improve prognosis for mental/physical development - doses vary based on age and weight of the child - current recommendation is 10-15 mcg/kg/day as soon as possible after birthHow does pregnancy affect the treatment approach of hypothyroidism?- ormone deficiency during pregnancy may lead to increased rates of stillbirths and lower neuropsychological scores in resulting infants - liothyronine crossed the placental membrane slightly better that levothyroxine but levothyroxine is the drug of choice - goal TSH is <2.5 mIU/L in the first trimester and <3 mIU/L during the remainder of the pregnancy o dose of levothyroxine needed may be higher during pregnancyWhat drugs are known to commonly cause hypothyroidism?Amiodarone: - contains approximately 39% iodine by weight - treatment leads to increased plasma iodine levels - may cause hyperthyroidism (structurally similar to thyroid hormone) - may cause hypothyrodism (failure to escape form the Wolff-Chaikoff effect) Lithium: - increases serum thyroid antibody concentrations Interferon-alpha and Interleukins: - increases thyroid peroxidase antibody concentrationsHow should patients being treated for hypothyroidism be monitored?- since the half-life of T4 is approx. 7 days, patient should be monitored no more often than 4 weeks - may take >4 weeks to see clinical improvementWhat are some key points for hyperthyrodism?- thyrotoxicosis is most commonly caused by Graves' disease - may be treated with MMI, PTU, RAI, or surgical removal - MMI and PTU reduce the synthesis of thyroid hormones and are similar in efficacy, but their dosing ranges differ by 10-fold - PTU may have a more substantial side effect profile - response seen in 4-6 weeks, so beta-blockers may be used for symptom relief - max responses in 4-6 months; treatment usually continues for 1-2 years (does not correct underlying condition) - monitoring requires s/sx and TSH/free T4 measurement - many patients choose ablative therapy with RAI vs. repeated courses of MMI/PTU (require thyroid hormone supplementation post-RAI)What are some key points for hypothyrodism?- most often due to Hashimoto's (autoimmune thyroiditis) - levothyroxine is the drug of choice - monitoring requires clinical s/sx and serum TSH