- T4 (thyroxine) and T3 (triiodothyronine) are formed on thyroglobulin, a large glycoprotein synthesized within the thyroid cell

- Inorganic iodide enters the thyroid follicular cell and is oxidized by thyroid peroxidase and covalently bound to tyrosine residues of thyroglobulin

- The iodinated tyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) combine (couple) to form iodothyronines in reactions catalyzed by thyroid peroxidase.

- Two molecules of DIT combine to form T4, and MIT and DIT join to form T3.

- Thyroid hormone is liberated into the bloodstream by the process of proteolysis within thyroid cells. T4 and T3 are transported in the bloodstream by three proteins: thyroid-binding globulin, thyroid-binding prealbumin, and albumin. Only the unbound (free) thyroid hormone is able to diffuse into the cell, elicit a biologic effect, and regulate thyroid-stimulating

hormone (TSH) secretion from the pituitary.

- T4 is secreted solely from the thyroid gland, but less than 20% of T3 is produced there; the majority of T3 is formed from the breakdown of T4 catalyzed by the enzyme 5'-monodeiodinase found in peripheral tissues. T3 is about five times more active than T4.

- Results when tissues are exposed to high levels of T3, T4, or both

- TSH secreting pituitary tumors may release active hormone that is unresponsive to normal feedback, it may also release prolactin or growth hormone, so patients may present with acromegaly, amenorrhea, or galactorrhea

- Graves disease -->thyroid stimulating antibodies (TSAb) --> bind thyrotropin receptor on surface of thyroid cells --> activate adenylate cyclase just like TSH would

- Autonomous thyroid nodule is a discrete thyroid mass whose function is independent of pituitary control (usually occurs in masses 3cm or larger)

- Plummer's disease --> multinodular goiters with follicles that have high autonomous function, coexisting with normal thyroid function --> hyperthyroidism

- Painful subacute thyroiditis (granulomatous or de Quervain's) cause by viral invasion of thyroid parenchyma

- Thyrotoxicosis factitia is hyperthyroidism caused by ingestion of exogenous thyroid hormone (innappropriate therapy)

- Amiodarone can cause hypo OR hyperthyroidism, reduces conversion of T4 -> T3, iodide release from drug may cause iodide excess

- Nervousness, anxiety, palpatations, heat intolerance, loss of weight, increased bowel movements, proximal muscle weakness (noted on climbing stairs or standing from seated position), scanty or irregular menses in women

- Warm smooth skin, fine hairs, separation of ends of fingernails from nail beds (onycholysis), retraction of eyelids and lagging of upper lid behind globe in a downward gaze (lid lag), tachycardia at rest, systolic ejection murmur

- In Graves; hyperthyroidism, diffuse thyroid enlargement, exophthalmosis (bulging of eyes), pretibial myxedema (strange skin irritation on the shin area)

- In subacute thyroiditis; patients complain of severe pain in thyroid region which often extends to ear

- Painless thyroiditis - has a triphasic course that mimics that of painful subacute thyroiditis. Most patients present with mild thyrotoxic symptoms;

lid retraction and lid lag are present but exophthalmos is absent. The thyroid gland may be diffusely enlarged, but thyroid tenderness is absent.

- Thyroid Storm - life-threatening medical emergency characterized by severe thyrotoxicosis, high fever (often greater than 39.4°C [103°F]), tachycardia,

tachypnea, dehydration, delirium, coma, nausea, vomiting, and diarrhea. Precipitating factors include infection, trauma, surgery, radioactive iodine (RAI) treatment, and withdrawal from antithyroid drugs.

- Elevated 24h radioactive iodine uptake shows true hyperthyroidism (normal value 10-30%)

- Low RIU indicated excess thyroid is not a consequence of thyroid gland hyperfunction but is more likely thyroiditis or hormone ingestion

- TSH induced hyperthyroidism is diagnosed by: evidence of peripheral metabolism, diffuse thyroid gland enlargement, elevated free thyroid hormone levels, and elevated serum immunoreactive TSH concentrations

- TSH-secreting pituitary adenomas are diagnosed by lack of TSH response to thyrotropin releaseing hormone stimulation.  

- Surgical removal if gland > 80g, severe opthalmopathy, or a lack of remission on antithyroid treatment

- If thyroidectomy planned, propylthiouracil (PTU) or methimazole (MMI) is given until the patient is euthyroid (about 6-8 weeks),followed by iodides (500mg/day) for 10-14 days to decrease the vascularity of the gland.  Levothyroxine may be added to maintain euthyroid state

- Propranolol has been used preoperatively and for 7-10 days after surgery to maintain a pulse rate of 90 beats/min

- PTU and MMI block thyroid hormone synthesis by inhibiting peroxidase enzyme system of the thyroid gland, preventing oxidation of trapped iodide and hence incorporation into iodotyrosines and ultimately iodothyronine ("organification"), and by inhibiting coupling of MIT and DIT to form T4 and T3

- Only PTU inhibits the peripheral conversion of T4 to T3

- Improvement in 4-8 weeks, but must make monthly changes to dose

- Antithyroid therapy should continue for 12-24 months to induce long term remission

- Monitor patients every 6-12 months after remission, if relapse occurs do RAI therapy

- Adverse rxns include pruritic macropapular rashes, arthralgia, fever, and benign transient leukopenia.  Cross sensitivity is 50% likely

- Major adverse events are agranulocytosis (fever, malaise, gingivitis, oropharyngeal infection, granulocyte count less than 250/mmcubed) aplastic anemia, lupus like syndrome, polymyositis, GI intolerance, hepatotoxicity, and hypoprothrombinemia. Agranulocytosis would occur in the first three months.  If patient experiences major adverse event do NOT try them on an alterate thiourea

Iodide - Acutely blocks thyroid hormone release, inhibits thyroid hormone biosynthesis by interfering with intrathyroidal iodide use, and decreases the size and vascularity of the gland.  Sx improves in 2-7 days, T4/T3 concentrations reduced in a few weeks.  Used as adjunctive to prepare those with Graves' for surgery, acutely inhibit thyroid hormone release, quickly attain euthyroid state in severey thyrotoxic patients with cardiac decompensation, or inhibit thyroid release following RAI therapy

- Potassium iodide (SSKI 38mg per drop, Lugols 6.3mg/drop).  Starting dose is 120-400mg qd in water or juice.  If preparing patient for surgery, do 7-14 days preoperatively.  

- If adjunct to RAI, used 3-7 days AFTER RAI treatment so that the RAI can concentrate in the thyroid

- Adverse events: Hypersensitivity rxns, salivary gland swelling, "iodism" (metallic tase, burning mouth and throat, sore teeth and gums, sx of head cold, upset stomach)and gynecomastia

- B-blockers used to ameliorate thyrotoxic sx such as: palpitations, anxiety, tremor, heat intolerance

- Do NOT effect peripheral thyrotoxicosis and protein metabolism, reduce TSAb or prevent thyroid storm

- Propranolol and nadolol partially block conversion of T4 to T3, but contributation to therapy is small

- Usually adjunct to antithyroid drugs, RAI, or iodides when treating Graves' disese, tosxic nodules, presurgery, or in thyroid storm

- Are primary therapy ONLY for thyroiditis or iodine-induced hyperthyroidism

- Propranolol doses vary, initial of 20-40mg qid, younger or more thyrotoxic patients 240mg/480mg/day

- Contraindicated in those with decompensated heart failure, UNLESS it is caused soley by tachycardia.  Other CI include: sinus bradycardia, therapy with MAOI's or TCA's, patient with spontaneous hypoglycemia

- Adverse rxns include nausea, vomiting, anxiety, insomnia, lightheadedness, bradycardia, hematologic disturbances

- Centrally acting sympatholytics (clonidine) and CCB's (diltiazem) may be useful for symptom control when CI to B-blockade exist

- Oral liquid that concentrates in thyroid

- Disrupts hormone synthesis by incorporating into thyroid hormone and thyroglobulin --> over a few weeks, follicles that have taken up RAI and surrounding follicles develop celluar necrosis and fibrosis

- Treatment of choice for Graves' disease, toxic autonomous nodules, and toxic multinodular goiters, ABSOLUTE CONTRAINDICATION IS PREGNANCY!

- Beta-blockers are primary adjunctive therapy since they may be given at any time

- If elderly or cardiac disease, pretreat with thionamides prior to RAI because thyroid levels will transiently increase after RAI (due to release of preformed thyroid hormone)

- Antithyroid drugs are typically NOT used after RAI (higher incidence of posttreatment hyperthyroidism)

- If iodides are administered, give 3-7 days AFTER RAI to prevent interference with updtake of RAI in thyroid gland

- Goal of therapy is to destroy overactive thyroid cells

- Dose of 4k - 8k rad results in euthryoid state in 60% of patients at 6 months or less, second dose given 6 months after first treatment if still hyperthyroid

- Adverse rxns include hypothyroidism months/years later, short term affects are mild thyroidal tenderness and dysphagia --> no long term effects yet

Therapeutic measures: Suppression of thyroid hormone formation and secretion, antiadrenergic therapy, administration of corticosteroids, treatment of associated complications/coexisting factors

Drug Dosages in thyroid storm:

PTU 900-1200mg divided qid or 6x daily

Methimazole 90-120mg/day qid or 6x daily

Sodium iodide Up to 2g/day IV in single or divided doses

Lugol's 5-10 drops tid in water or juice

Kiodide 1-2 drops tid in water or juice

Propranolol - 40-80mg q6h

Dexamethasone 5-20mg/day po or IV in divided doses

Prednisone 25-100mg/day po in divided doses

Methylpred 20-80mg/day IV in divided doses

Hydrocortisone 100-400mg/day IV in divided doses

Significant information:

- PTU in large doses is preferred thionamide because it interferes with production of thyroid hormones and blocks peripheral conversion of T4 to T3

- Iodides, which rapidbly block release of preformed thyroid hormone, should be given AFTER PTU to inhibit iodide use by overactive gland

- Esmolol is BB of choice because it can be used in patients with pulmonary disease or at risk for cardiac failure because its effects can be rapidly reversed

- Corticosteroids are generally recommended, but there is no real evidence of adrenocortical insufficiency in thyroid storm.  Benefits could be related to antypyretic action and BP stabilization

- General support includes APAP (aspiron or NSAIDS may displace bound thyroid), fluid and electrolyte replacement, sedatives, digoxin, antiarrhythmics, insulin, and abx as indicated.  Plasmapheris and peritoneal dialysis have been used to remove excess hormone in patients not responding to conservative measures

- Majority have thyroid gland failure (primary); main causes are chronic autoimmune thyroiditis (Hashimoto's), atregenic hypothyroidism, iodine deficiency, enzyme defects, thyroid hypoplasia, and goitrogens

- Pituitary failure (secondary hypothyroidism) is an uncommon cause resulting from pituitary tumors, surgical therapy, external pituitary radiation, postpartum pituitary necrosis, and metastatic tumors, TB, histiocytosis, and autoimmune mechanisms

- Dry skin

- Cold intolerance

- Weight gain

- Constipation

- Weakness

- Lethargy

- Fatigue

- Muscle cramps

- Myalgia/stiffness

- Lack of ambition or energy

- In children, growth retardation

Physical signs: coarse skin/hair, cold/dry skin, periorbital puffiness, bradycardia, slowed or hoarse speech, objective weakness, neurologic syndromes, cerebral dysfunction.

- Most patients with secondary hypothyroidism have clinical signs of pituitarty insufficiency such as abnormal menses and decreased libido, evidence of pituitary adenoma such as visual field defects, galactorrhea, or acromegaloid features

- Myxedema coma is rare consequence of decompensated hypothyroidism manifested by hypothermia, advanced stages of hypothyroid sx, and altered sensorium ranging from delirium to coma.  Untreated disease has high mortality rate.  

- Rise in TSH is first evidence

- Most patients have normal T4 with few sx, but T4 will continue to drop.  T3 can remain normal

- Antithyroid peroxidase antibodies and antithyroglobulin antibodies are probably elevated.

-RAIU is not a useful test b/c it can be normal or even elevated

- Pituitary failure should be suspected in patients with decreased T4 and normal/low TSH

- T4 is drug of choice: chemically stable, inexpensive, free of antigenicity, uniform potency, any commercial product can be used

- Because T3 is the biologically active form, T4 acts as a pool of thyroid hormone that is readily and consistently converted to T3

- Young patients and those >45 with no cardiac disease should be started at 50mcg and increased to 100mcg after 1 month

Thyroglobulin - Proloid (partially purified pork thyroglobulin)

Liotrix - Thyrolar (synthetic T4:T3 in 4:1 ratio) (like armour thyroid only synthetic)

- In older individuals with cardiac disease, start at 25mcg and titrate up by 25mcg at monthly intervals

- Avg maintenance  dose is 125mcg/day, but there is a wide range of replacement doses

- Levothyroxine is DOC for pregnant women, objective is to decrease TSH to 1mIU/L and to maintain free T4 concentrations in normal range

- Cholestyramine, calcium carbonate, sucralfate, aluminum hydroxide, ferrous sulfate, soybean formula, and dietary supplements impaire absorption of levothyroxine from GI tract

- Drugs that increase nondeiodinative T4 clearance: rifampin, carbamazepine, possibly phenytoin.  Amiodarone may block conversion of T4 to T3

- Thyroid (dessicated thyroid) is derived from hog, beef, or sheep thyroid; it may be antigenic in allergic or sensitive patients; generic brands may not be bioequivalent

- Thyroglobulin is purified hog-gland extract that is stnadardized biologically to give T4/T3 ratio of 2.5:1, has no clinical advantages and is not widely used

- Liothyronine (T3) has uniform potency but has a higher incidence of cardiac adverse effects, higher cost, and difficulty in monitoring with convential laboratory tests

- Liotrix is chiemically stable, pure, and has a predictable potency but is expensive.  It lacks therapeutic rationale because about 35% of T4 is converted to T3 peripherally

- Excessive doses of thyroid could cause: HF, angina pectoris, and MI.  Allergic rxns can occur with natural animal-derived products, but are extremely rare with synthetic products used today.  Excess exogenous thyroid hormone may reduce bone desnity and increase risk of fracture

- Immediate and aggerssive therapy with IV bolus levothyroxine, 300-500mcg.  Initial treatment with liothyronine or combo has been advocated because of impaired conversion in some patients

- Hydrocortisone 100mg q8h should be given until xoexisting adrenal suppression is ruled out

- Consciousness, lowered TSH concentrations and normal vital signs are expected within 24h

- Maintenance levothyroxine doses are typically 75 to 100mcg IV until patient stabilizes or oral therapy starts

- Supporitve  therapy (ventilation, euglycemia, BP, body temperture, check for sepsis and MI) must be instituted