Thyroid Disorders

Overview of Thyroid Hormones

  • Thyrotropin releasing hormone (TRH) causes the production of thyroid stimulating hormone (TSH) which causes the release of thyroid hormone from the thyroid gland
    • Feedback inhibition occurs via the hypothalamus-pituitary axis system (the presence of T4/T3 inhibits the production of TRH & TSH)
    • T4 = thyroxine  (what is secreted by the thyroid gland)
      • 40% of T4 gets converted to T3 in the body.
      • Not as completely absorbed as T3
      • Slower onset of action & longer half life than T3
      • Levothyroxine should be dosed daily in order to reduce fluctuations in concentration but in comparison to T3 there are less consequences to missing a dose
      • ~100% protein bound primarily to thyroid binding globulin (TBG)
  • T3 = triiodothyronine  (converted from T4 in the liver & kidneys)
  • Most of it (~80%) is derived from the conversion from T4 in the liver & kidneys
  • T3 has a more rapid onset of action than T4
  • ~100% protein bound primarily to thyroid binding globulin (TBG)
  • 3-5 times as active as T4
    • More pharmacologically active free drug than T4
  • Shorter half-life (1.5 days) than T4
    • Greater fluctuations in serum concentrations than T4;  needs to be doses 2-3 times a day
  • Free T4:  normal level = 0.8-1.5 ng/dL
    • Increased significantly in hyperthyroidism and decreased significantly in hypothyroidism
  • TSH (thyroid stimulating hormone):  normal level = 0.25-6.7 mIU/L
    • Decreased significantly in hyperthyroidism & increased significantly in hypothyroidism
    • Increased Thyroid Binding Globulin (TBG) is normal
    • TSH & T4 work opposite of one another
    • Radioactive iodine uptake (RAIU) is used to evaluate the etiology of thyrotoxicosis  aka hyperthyroidism (indicates iodine use by the thyroid)
      • Elevated RAIU indicates hyperthyroidism
      • LOW RAIU indicates thyroid gland hyperfunction isn’t present
  • Therapeutic options for various Thyroid disorders
    • Hyperthyroidism (Thyrotoxicosis):  excessive levels of T3, T4, or both & low TSH levels
      • Many causes (more common in women):  Graves’ disease (autoimmune disorder; most common reason), toxic adenoma, toxic multinodular goiter, painful or silent thyroiditis, iodine induced, excessive pituitary TSH or trophoblastic disease, excessive ingestion of thyroid hormone
      • Lab findings associated with hyperthyroidism:  increased T4, T3 & RAI uptake, decreased TSH
      • S/S of hyperthyroidism:
General

Heat intolerance, weight loss with increased appetite, increased sweating, hyperkinetic speech and behavior

Skin

Warm, velvety skin; onycholysis and softening of the nails, infiltrative dermopathy (only in Graves’)

Head

Thinning of hair, fine texture

Eyes

Exophthalmos, lid lag, lid retraction, stare

Neck

Goiter with or without bruits/thrills

Cardiac

Tachycardia, palpitations, high-output failure, increased systolic pressure, murmurs, angina

Gastrointestinal

Loose stools, hyperdefecation

Genitourinary

Polyuria, amenorrhea or decreased duration of menses, decreased fertility, impotence and gynecomastia in men

Neuromuscular

Fatigue, weakness, tremor, quick deep tendon reflexes

Emotional

Nervousness, irritability, lability, insomnia

  • Hypothyroidism
    • Primary is caused by thyroid gland failure  (chronic autoimmune thyroiditis–Hashimoto’s disease is the most common cause)
    • Secondary is caused by a reduction of thyroid function from non-thyroid source
      • Drugs that may cause this:  amiodarone, Li, PTU/MMI, iodine, K-perchlorate, IFN-alpha
      • May also caused by pituitary or hypothalamic disease
    • Lab findings associated with hypothyroidism:  increased TSH, decreased FT4, TT4 & T3 levels
    • s/s of hypothyroidism:
General

Cold intolerance, weight gain with anorexia, hoarseness, fatigue, decreased sweating, mental slowing

Head

Puffy facies, large tongue, dry/brittle hair, thinning eyebrows

Eyes

Ptosis, edematous lids

Neck

Goiter in primary hypothyroidism (due to TSH)

Cardiac

Cardiomegaly, low-output failure, dyspnea

Gastrointestinal

Constipation

Genitourinary

Dysmenorrhea, menorrhagia

Neuromuscular

Delayed deep tendon reflexes, muscle weakness

Extremities

Cool, dry skin, brittle nails

Emotional

Depression, apathy, lethargy

  • Subclinical thyroid disease
  • 3-20% progress to overt hypothyroidism
  • Risks:  progression to overt hypothyroidism, CV effects, hyperlipidemia, neuropsychiatric effects
  • Treatment is controversial
  • Normal T3 & T4 concentrations, elevated TSH, few or no s/s
  • Myxedema coma
    • Results from long-standing, uncorrected hypothyroidism, can be life threatening
    • Presentation:  symptoms develop slowly, hypothermia, hyponatremia, hypoglycemia, hypoventilation, delayed deep tendon reflexes, altered senses, shock, coma, death

Treatment options for various thyroid disorders

  • Treatment of hyperthyroidism
    • Goal is to decrease excess production & availability of thyroid hormones & to decrease or control the symptoms of thyrotoxicosis
    • Thionamides (PTU, methimazole)
      • Preferred treatment in kids, adolescents & prego
        • PTU is the only drug that can be used in the first trimester
      • Uses:  oral therapy for Graves’ disease, prep treatment prior to radioactive iodine therapy or surgery, thyrotoxic crisis/thyroid storm
      • MOA:  inhibits thyroid peroxidase resulting in iodine being diverted away from receptor sites of the thyroid gland thus blocking iodination such that thyroid hormone isn’t synthesized
      • Well absorbed in GI tract & peak concentrations are seen within an hour although it takes 4-8 weeks to see clinical improvement
        • Start to taper dose once you see clinical improvement
        • Usually need to treat for 6 months to 2 years (if relapse occurs it will happen w/in 6 months of d/c)
      • Elderly & cardiac patients may require pretreatment with thionamide prior to RAI (radioactive iodine) b/c of hyperthyroidism
      • Most common SE:  rash (trxt w/ antihistamines & topical steroids), benign transient leukopenia (very common), arthralgias, myalgias, lupus-like syndrome, GI disturbances
        • Agranulocytosis (s/s:  fever, malaise, gingivitis, sore throat, oropharyngeal infections) is a severe SE that is treated by d/c the drug
        • Liver toxicity most commonly occurs within the first 3 months of therapy  (monitor LFTs routinely)
          • w/ both liver toxicity & agranulocytosis you can’t switch to other thionamides
      • Propylthiouracil (PTU) is highly protein bound, has a short half life (1-2.5 hours), quick onset & inhibits the conversion of T4 to T3 in the periphery at high doses
        • Initial dose:  300-600 mg/day divided in 3-4 doses
        • Maintenance dose:  50-300 mg/day                     (max:  1200 mg/day)
        • Black box warning of hepatotoxicity
      • Methimazole (MMI) is the preferred oral agent if the patient isn’t in their first trimester
        • 10x more potent that PTY & it’s not protein bound
        • Longer half life & onset of action isn’t as quick so you don’t see the symptoms decrease as quickly
        • Initial dose:  30-60 mg/day divided in 3 doses
        • Maintenance dose:  5-30 mg/day                     (max:   120 mg/day)
        • Crosses the placenta & appears in breast milk
    • Beta Blockers (especially propranolol) are used as adjunctive treatment
      • Help decrease palpitations, anxiety, tremor, heat intolerance
      • Don’t have a large effect on the management of thyroid disease itself but they do help prevent the conversion of T4 to T3 at high doses
      • Initial dose = 20-40 mg QID    (up to 240-480 mg/day)
      • May use diltiazem 120 mg q8h or clonidine 0.1 mg BID when BB are contraindicated
    • Iodides are used as adjunctive therapy
      • Uses:  prep prior to surgery for Graves’, thyrotoxic crisis/thyroid storm, inhibit thyroid hormone release following RAI
      • MOA:  acutely blocks thyroid hormone synthesis & release, reduces size & vascularity   (symptoms usually are relieved in 2-7 days)
        • Normalizes thyroid hormone levels in a few weeks (rapid)
      • Potassium iodide
        • Saturated solution (SSKI) is 38 mg iodide per drop (typically 120-400 mg/day)
        • Lugol’s solution is 6.3 mg iodide per drop (typically 160-320 mg/day)
        • Monitor for hypersensitivity reactions (most common SE–skin rash, fever, rhinitis, conjuctivitis), iodisim (S/S:  metallic taste, burning of mouth & throat, sore gums & teeth, upset stomach, diarrhea, symptoms of a head cold), salivary gland swelling, GI upset, gynecomastia
    • Surgery (removal of the gland) is the most definitive treatment
      • Thionamide agents are used until the patient becomes euthyroid
      • Iodides may be added to decrease vascularity prior to surgery
      • Levothyroxine is used to maintain the euthyroid state post surgery & propranolol is used to maintain heart rate
    • Lithium is the last option that’s used in patients were surgery & antithyroid meds aren’t optios
  • Amiodarone-induced hyperthyroidism
    • Baseline TSH should be done prior to the initiation of amiodarone & every 6 months
    • 200 mg of amiodarone = 6 mg iodide
      • Avg iodine content in American diet is 0.3 mg/day
    • Amiodarone’s effect on thyroid:  transient suppression of thyroid function, hypothyroidism in those susceptible to the inhibitory effects of a high iodine load, thyrotoxicosis from the iodine load
  • Subclinical hyperthyroidism
    • TSH level < 0.1 uIU/mL & normal free T4 & T3 levels
    • Likely to progress to overt hyperthyroidism (loss of bone mass, cardiac hypertrophy, a. fib, etc)
  • Thyroid storm
    • Life-threatening medical emergency
    • Symptoms:  high fever, dehydration, psychosis, agitation, n/v/d, tachycardia, delirium, weight loss, coma, jaundice
    • Precipitating factors:  infection, surgery, stress, withdrawal from thionamides
    • Usually lasts 72 hours to 8 days
    • Treatment:  suppression or thyroid hormone formation & secretion, anti-andrenergic therapy, admin of high dose corticosteroids, treat complications & coexisting factors that caused the storm
      • Use high doses of meds used to treat normal thyrotoxicosis
  • Hypothyroidism
    • Goal is restore normal thyroid hormone levels in tissues, relieve symptoms, prevent neurological deficits, reverse biochem abnormalities
    • Levothyroxine (T4) is the drug of choice
      • Need to monitor TSH every 4-6 weeks
      • Absorption can be affected by malabsorptive states & patient age
      • Take on an empty stomach.  Increased absorption with acidic environment.
      • Don’t change between brands of thyroid meds  (IV dose is about 50% of oral dose)
      • Weight base dosing:  1.6 mcg/kg/day            empiric dosing:  50 mcg/day
        • May need to lower dose in elderly or patients w/ CV disease
    • Adjust the dose no sooner than 4 weeks
    • Dose increases are typically 10-15% of weekly dose
    • Some people are allergic to dyes
    • Liothyronine (T3, aka cytomel) isn’t as good as levothyroxine
      • Need to admin twice to three times daily
      • Half life is 1.5 days
      • Used in situations when quicker symptom relief is needed
    • Liotrix (T4/T3)
      • Fixed 4:1 ratio of levothyroxine to liothyronine
      • No clinical advantage over levothyroxine
      • may used in treatment of myxedema coma when peripheral conversion of T4 to T3 may be reduced
    • Desiccated thyroid is derived from natural resources & has variable potency (T4 to T3 ratio) & an unstable shelf life
      • 1 grain (60 mg) = 100 mcg T4
    • Causes of persistent TSH elevation:  non-compliance, drug interactions, inadequate dose, decreased absorption, prego, thyroid hormone resistance, fiber supplements, med exposure to light, moisture, air, increased metabolism
  • Treatment of hypothyroidism:  TSH > 10, elevated TPO antibody, prior treatment with RAI
    • Goal TSH = ~1 mIU/L
  • Treatment of myxedema coma
    • Supportive treatment, HCT 100 mg q8h to rule out coexisting adrenal suppression
    • IV Thyroid replacement 300-500 mcg bolus followed by 75-100 mcg of maintenance therapy

Effects of decreased Thyroid levels on different organs

  • Liver:  increased levels of LDLs & Triglycerides
  • Intestines:  constipation & decreased GI motility
  • Kidneys:  decreased function, increased fluid retention/edema
  • Heart:  Decreased heart rate & cardiac output, may increase or decrease blood pressure
  • Brain:  increased risk of depression, decreased ability to concentrate
  • Reproductive system:  decreased fertility, menstrual abnormalities

Drugs that may have an adverse affect on thyroid function

  • Oral contraceptives (& other estrogen containing drugs) may increase TBG binding capacity
  • Androgens, glucocorticoids, salicylates may decrease TBG binding capacity
  • Glucocorticoids, PTU, amiodarone & propranolol may decrease the peripheral conversion of T4 to T3
  • CYP3A4 inducers can decrease Thyroid levels
  • Divalent Cations will decrease the bioavailability of thyroid dedications

Levothyroxine can increase the anticoagulant effects of Warfarin

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