Transcript L1_Thyroid Disorders..

PHCL 424
Thyroid Disorders
Ahmed Shaman
Clinical Pharmacy Department
KSU
[email protected]
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Introduction
• There are two main hormones produced by the
thyroid gland:
– Thyroxin (T4) and
– Triiodothyronine (T3).
• Both hormones are derived from the amino acid
Tyrosine and contain Iodine that is extracted from
the blood.
• Thyroid hormone synthesis and release are under
negative feedback regulation by the
hypothalamic-pituitary-thyroid axis
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T3 Vs. T4
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T3 ~5X as active as T4
T4 secreted solely form thyroid gland
<20% T3 secreted from the thyroid gland
Majority of T3 from breakdown of T4
(de-iodination) in peripheral tissue
Mostly liver and kidneys
Thyroid Physiology
Thyrotropin-releasing hormone (TRH)
Thyroid-stimulating hormone (TSH)
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Laboratory Tests to Evaluate Thyroid
Function
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Serum total thyroxine (total)
Unbound or serum free thyroxine
Serum total triiodothyronine (T3)
Serum TSH
Serum Thyroglobulin
Iodide-123 uptake/24 hrs
Antibodies
Interpretations of Lab Tests
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Interpretations of Lab Tests
Total T4
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Free T4
Total T3
TSH
Normal
4.5–10.9
mcg/dL
0.8–2.7 ng/dL 60–181 ng/dL 0.5–4.7 milli–
international
units/L
Hyperthyroid
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Hypothyroid
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Signs and Symptoms
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Hypothyroidism
Hyperthyroidism
Bodyweight gain
Bodyweight loss
Cold intolerance, dry skin
Heat intolerance, sweating
Facial swelling
Eye signs (lid retraction, exophthalmia)
Lethargy, depression
Tremor, insomnia, anxiety
Bradycardia
Tachycardia, palpitations, atrial
fibrillation, cardiac failure
Menstrual disturbances ( heavy menses)
Menstrual disturbances (decreased flow)
Hypothyroidism
• Clinical syndrome from deficiency of thyroid
hormone
• Results in generalized slowing of metabolism
• Affects 8% of women, 2% of men
– High prevalence in women
• Incidence increases with age
– Peaks during seventh decade
– May occur at any age
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Diagnosis of Hypothyroidism
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SLUGGISH
Sleepiness, Fatigue, Lethargy
Loss of memory, Trouble concentrating
Unusually dry skin, Coarse skin
Goiter (Enlarged Thyroid)
Gradual Personality Changes, Depression
Increase in weight, Bloating or Puffiness (Edema)
Sensitivity to Cold
Hair Loss, Sparseness of Hair
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Treatment of Hypothyroidism
• There are three major goals
– replace the missing hormones,
– relieve symptoms,
– achieve a stable biochemical euthyroid state
• While these goals should not be difficult to
achieve, 20% to 40% of treated patients are
not receiving optimal pharmacotherapy
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Treatment Endpoints
• Monitor clinical symptoms and thyroid function test results.
• In primary hypothyroidism
– Monitor TSH and T4 levels every 6–8 weeks and adjust thyroxine
dosage to achieve required TSH
– The target TSH for most patients being treated for thyroid disorders
should be the mean normal value of 1.4 μU/mL
• (target range 0.5–2.5 milliunits/L or 0.5–2.5 microunits/mL)
– Then monitor annually (more frequently in children)
• In hypothyroidism due to hypothalamic or pituitary disease
– TSH cannot be used as an indication of adequate replacement.
– Adjust thyroxine dosage to achieve T4 in mid-to-upper normal range.
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Hypothyroidism Management
• Thyroid hormones replacement
– Thyroxine (T4)
• Is the drug of choice for replacement therapy in primary and
secondary hypothyroidism.
• Peripheral tissues convert T4 to T3 as needed, based on metabolic
demands.
• Its long half-life (7 days) gives stable serum concentrations and a
long duration of effect.
– Liothyronine (T3)
• Has a more rapid onset of action and a shorter half-life (2–3 days)
than thyroxine
• May be used for severe hypothyroidism, e.g. myxedema coma
• Not recommended in pregnancy because of preferential use of T4
by the developing brain.
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T4 and T3 combinations
• Use of LT4 and T3 combinations in ratios that
mimic human physiology
• A meta-analysis of 11 RCTs comparing LT4 and
T3 combinations with LT4 monotherapy
– No outcome benefit with combination therapy
• There is no rationale for using combinations of
LT4 and T3 to treat hypothyroidism
– Except in rare circumstances (such as patients
with impaired T4-to-T3 conversion)
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Thyroid Hormone Dosage
• Thyroxine (T4)
– Adult (1.6 mcg/kg/day based on IBW if obese)
• Initially, 50–100 micrograms once daily
• If no history of cardiac disease, start full replacement dose
• Increase by 25–50 micrograms daily every 6–8 weeks if
necessary, according to TSH
• Maintenance, 100–200 micrograms once daily
– Elderly, IHD
• Initially, 25–50 micrograms once daily
• Increase daily dose by 25 micrograms every 6–8 weeks
• Usual maintenance, 50–200 micrograms once daily.
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Thyroid Hormone Dosage
• Liothyronine (T3)
– 20–25 micrograms liothyronine is approximately
equivalent in activity to 100 micrograms thyroxine
– Usual range, oral 20–60 micrograms daily in 2 or 3
divided doses
– IV liothyronine may be used for severe
hypothyroidism such as myxedema coma, or when
oral replacement therapy cannot be given
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Thyroid Hormones Replacement
• Pregnancy
– Thyroxine is safe to use
– Increased dose (by about 25–50%) likely to be
required
– Check TSH monthly
– Try to avoid using liothyronine because of preferential
use of thyroxine by the developing brain
• Breastfeeding
– Safe to use.
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Risks of Over- and Under-treatment
• Overtreatment is more common
• Patients with long-term overtreatment are at
higher risk for
– AF and other cardiovascular morbidities
– Mental status changes
– Postmenopausal osteoporosis
• Patients who are undertreated are at higher risk
for
– Hypercholesterolemia and other cardiovascular
problems, depression or mental status changes, and
obstetric complications
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Thyroid Hormone Interaction
• Drugs reduce GI absorption
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Calcium carbonate
Cholestyramine
Ciprofloxacin
Ferrous sulfate
Lanthanum
Orlistat
• Advise the patient to take the LT4 dose at least 2 hours
before or 6 hours after these medications.
• Drugs that increase nondeiodinative T4 clearance
include rifampin, carbamazepine, and possibly
phenytoin.
• Selenium deficiency and amiodarone may block
the conversion of T4 to T3
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Monitoring LT4 Therapy
• Serum TSH:
– Every 6–12 months or if change in clinical status
– 6–8 weeks after any dose or product change
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In first trimester pregnancy, then monthly
Same product prescribed/dispensed with every refill
Watch for mg/mcg dosing errors
Assess patient’s understanding of disease, therapy, and
need for adherence and tight control
• Assess for signs/symptoms of over- and
undertreatment
• Identify potential interactions between LT4, and foods
and/or drugs
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Practice Points in Hypothyroidism
• Thyroxine replacement is lifelong except in
– Subacute or postpartum thyroiditis, radioactive iodine
treatment or partial thyroidectomy
• Allow at least 6 weeks after changing thyroxine dosage
before checking TSH as thyroxine has a long half-life
• Failure to respond to thyroxine may be due to:
– Lack of compliance (most common reason)
– Possible impaired absorption by food, binding to other drugs in
the gut (eg calcium, iron) or disease of the small intestine
– Increased thyroxine clearance by interacting drugs
– Possible loss of tablet potency due to inappropriate storage
conditions
• Metabolism of many drugs is reduced in hypothyroidism
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– to avoid toxicity, use lower doses of hypnotics, digoxin,
warfarin, anaesthetic agents and analgesics until the person is
euthyroid
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Subclinical Hypothyroidism
• Characterized by mild elevation in TSH (often
asymptomatic) with normal T4
• Risk of progression to overt hypothyroidism is
higher in people with thyroid peroxidase
antibodies and rising TSH
• Possible association with increased
cardiovascular morbidity and mortality
• Monitor thyroid function every 6–12 months
• Decision to begin T4 replacement should be
individualized
• TSH >10 mIU/L is generally accepted as an
indication to start replacement therapy.
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Myxedema Coma
• Rare complication of untreated hypothyroidism
• Usually occurs in
– Elderly women
– During the winter as a result of stress
• Mortality rate may be 60% to 70%
• Characterized by
– Progressive weakness, stupor, hypothermia,
hypoventilation, hypoglycemia, and hyponatremia,
and it may ultimately result in shock and death
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Treatment of Myxedema Coma
• T4 IV due to poor drug absorption
– Initial loading dose of 300 to 500 g of IV T4
– Followed by 80% of the calculated full replacement dose
(75 to 100 mcg) IV daily until the patient stabilizes and oral
therapy is begun
– deiodinase activity is markedly reduced, impairingT4 to
T3 conversion
• IV T3, or a combination
– Risk of precipitating angina, heart failure, or arrhythmias in
older patients with underlying coronary artery disease
• Start treatment slowly
• Glucocorticoids, such as IV hydrocortisone 50 to 100
mg every 6 hours, are administered owing to concern
about simultaneous adrenal insufficiency
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Hyperthyroidism
• Hyperthyroidism may be
– A primary condition that results from an
overactive thyroid gland.
– Secondary to excessive stimulation of the thyroid
by TSH from the pituitary.
– Grave’s disease: the most common causes of
hyperthyroidism
– A tumor of the thyroid. In rare cases carcinomas
arising outside of the thyroid may produce thyroid
hormone or TSH.
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Hyperthyroidism
• Increased synthesis and release of T3 and T4
• Hyperthyroidism is also referred to as
Thyrotoxicosis
• Generally 2 types of hyperthyroidism
– High-uptake (thyroid gland is actively
overproducing)
– Low-uptake (not thyroid gland hyperfunction)
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Differential Diagnosis of Thyrotoxicosis
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Increased RAIU
Decreased RAIU
TSH-induced hyperthyroidism
Inflammatory thyroid disease
TSH-secreting tumors
Subacute thyroiditis
Selective pituitary resistance to T4
Painless thyroiditis
Thyroid stimulators other than TSH
Ectopic thyroid tissue
TSAb (Graves’ disease)
Struma ovarii
hCG (trophoblastic diseases)
Metastatic follicular carcinoma
Thyroid autonomy
Exogenous sources of thyroid hormone
Toxic adenoma
Medications containing thyroid hormone
or iodine
Multinodular goiter
Food sources containing thyroid gland
Hyperthyroidism – Graves’
• Etiology:
– Patients produces (Thyroid Stimulating
Immunoglobulin) TSI antibodies which are
agonists to the TSH receptors
• Classic Triad (15-20%):
– Diffuse goiter, Hyperthyroidism, and
Ophthalmopathy (exophthalmos)
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Screening & Diagnosis of
Hyperthyroidism
• Low TSH level (less than 0.5) will signify
thyrotoxicosis
• Free T4 is elevated in overt hyperthyroidism
• Increased radioiodine uptake in the thyroid
indicates increased hormone production by
the thyroid gland
• Almost all patients with Graves’ disease will
have positive
– TSHR-Abs
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Treatment of Hyperthyroidism
• Treatment of thyrotoxicosis due to
hyperthyroidism is similar, regardless of the
underlying cause
• Three common treatment modalities are used in
the management of hyperthyroidism:
– surgery, antithyroid medications, and RAI
• The goals of treating hyperthyroidism are
– to relieve symptoms,
– to achieve biochemical euthyroidism,
– to prevent long-term adverse consequences
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Treatment of Hyperthyroidism
• β-Blocking drugs
• Methods to Reduce Thyroid Hormone
Synthesis
– Iodides
– Thioamides (antithyroid drugs)
– Radioactive iodide (ablative therapy)
– Surgery (ablative therapy)
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β-Blocking drugs
• To rapidly relieve palpitations, tremor, anxiety,
and heat intolerance
• They do not reduce the synthesis of thyroid
hormones
– used only until more specific antithyroid therapy is
effective
• Nonselective agents can impair the conversion
of T4 to T3
– propranolol and nadolol are used
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β-Blocking drugs
• Initial propranolol dose of 20 to 40 mg four
times daily should be titrated to relieve signs
and symptoms
• Not be used in patients with
– Decompensated heart failure or asthma
• When a contraindication to β-blockers exists
– clonidine or diltiazem may be used
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Iodide
• Large doses of iodide inhibit the synthesis and
release of thyroid hormones
• Serum T4 levels may be reduced within 24 hours,
and the effects may last for 2 to 3 weeks
• Iodides are used most commonly in Graves’
disease patients
– prior to surgery
– to quickly reduce hormone release in patients with
thyroid storm
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Iodide
• Potassium iodide is administered
– Saturated solution (SSKI): 38 mg iodide per drop
– Lugol’s solution: 6.3 mg iodide per drop
• The typical starting dose is 120 to 400 mg/day
• Iodide therapy should start 7 to 14 days prior to
surgery
• Iodide should not be given prior to radioactive iodine
treatment because the iodide will inhibit concentration
of the radioactivity in the thyroid.
• Toxic effects of iodide therapy are
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– Hypersensitivity reactions
– Iodism (characterized by palpitations, depression, weight
loss, and pustular skin eruptions)
– Gynecomastia
Radioactive iodide (131I)
• Provides a definitive cure
• Administered orally as the sodium salts in an
aqueous solution or capsule
• Once incorporated in the thyroid gland,
radioactive iodide slowly destroys it
– Require about 6-8 weeks to induce an euthyroid state
– Destruction continues indefinitely
• Hypothyroidism an expected outcome of the
treatment
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Radioactive iodide (131I)
• Most patients are treated initially with
– β-blockers and antithyroid drugs
• Stop Thionamide at least 4 to 6 days prior to 131I
• It is contraindicated during pregnancy and
breast-feeding
• May acutely worsen Graves’ ophthalmopathy
– Prednisone 40 mg/day for patients with
prominent eye disease
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Antithyroid Drugs
• Thionamides Agents
– Propylthiouracil
– Methimazole
– Carbimazole, a prodrug of methimazole
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Antithyroid Drugs
• Block thyroid hormone synthesis;
– Propylthiouracil (PTU) also inhibits peripheral
conversion of T4 to T3
• Use short term to achieve euthyroidism before
surgery, or before and after radioactive iodine
treatment
• Use long term to treat Graves' disease as an
alternative to surgery or radioactive iodine
– remission (which may be temporary) occurs in 40-60%
of people after about 1–2 years of treatment
• Ineffective in sub-acute thyroiditis
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• Thioamides
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Adverse Drug Reactions
• Common
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Itching
Rash (if persistent, antihistamines)
Mild leucopenia (WBC less than 4,000/mm3)
Nausea
Vomiting
Gastric discomfort
Headache
Arthralgia → may require discontinuation
• Rare
– Agranulocytosis (PTU and carbimazole)
– Hepatotoxicity
• Hepatitis (PTU)
• Cholestatic jaundice (carbimazole)
– Hypoprothrombinemia (PTU)
– Vasculitis & Lupus erythematous (PTU)
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Antithyroid Drugs
• Pregnancy
– Use the lowest effective dosage as there is a small risk of fetal
hypothyroidism
– PTU preferred in first trimester (MMI-induced embryopathy)
– Carbimazole is preferred after this time
– Check TSH and free thyroid hormone every 6 weeks
• Breastfeeding
– Use the lowest effective dosage, with appropriate monitoring of
infant
– Although detected in breast milk, both drugs appear safe at
standard doses
– Carbimazole is preferred due to the greater risk of
hepatotoxicity with PTU
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Agranulocytosis
• Most likely in first 3 months of treatment;
– it occurs suddenly and unpredictably
• Patients will present with
– fever, malaise, mouth ulcers, sore throat, rash
– absolute neutrophil count will be less than
1,000/mm3.
• Patients may develop sepsis and die rapidly
– Discontinue the antithyroid drug immediately
– Broad-spectrum antibiotics if the patient is febrile
– Consider the administration of granulocyte colonystimulating factor
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Hepatotoxicity
• Asymptomatic increases in serum AST commonly
occur during the first 2 months of PTU (30%)
– resolve with continued treatment
• Serious hepatotoxic reactions occur rarely with
PTU and may be immune-based
• Cholestatic jaundice has rarely been associated
with carbimazole and methimazole
• As the mechanisms of hepatic damage with the 2
drugs are thought to be different, the other drug
may be tried cautiously in cases of drug-induced
hepatic adverse effects
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Comparative Information
• Carbimazole and methimazole have a longer
duration of action than PTU and can be given
once daily for maintenance
• Hepatotoxicity and vasculitis occur more
frequently with PTU than with carbimazole
and methimazole
• 50 mg PTU is equivalent to about 5 mg
carbimazole (10 times more potent)
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Treatment Regimens
• In Graves' disease, antithyroid drugs are usually
given for 12–24 months
• Thyroid hormone levels drop in 2 to 3 weeks
• After 6 weeks, 90% of patients with Graves’
disease will be euthyroid.
• Thyroid function testing should be performed
every 4 to 6 weeks until stable
• Once the patient is euthyroid
– reduce the dose of antithyroid drug to avoid
hypothyroidism
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Dosage of Antithyroid Drugs
• Adult dose of PTU
– Initially, 300 to 600 mg daily, usually in three or
four divided doses
– Daily maintenance doses 50 to 300 mg
– Maximal blocking dose 1,200 mg daily
• Adult dose of MMI
– Initially, 30 to 60 mg/day in 2-3 divided doses
– Daily maintenance doses 5 to 30 mg
– Maximal blocking dose 120 mg daily
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Surgery
• Subtotal thyroidectomy is indicated in patients
with
– Very large goiters
– Thyroid malignancies
– Those who do not respond or cannot tolerate other
therapies.
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Patients must be euthyroid prior to surgery
Iodide preoperatively to reduce gland vascularity
Overall surgical complication rate is 2.7%
Hypothyroidism occurs in 10%
Hyperthyroid Emergencies
Thyroid Storm
• Life-threatening hypermetabolic state due to
decompensated hyperthyroidism
• Usually result from previously unrecognized or
poorly treated hyperthyroidism
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Hyperthyroid Emergencies
Thyroid Storm
• Precipitating factors:
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Infection
Trauma/Surgery
DKA
MI
CVA
PE
Withdrawal of thyroid meds
Iodine load
• 20-25% cases no precipitant found
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Hyperthyroid Emergencies
Thyroid Storm
• Clinical Features:
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Fever >38.5
Sinus tachycardia out of proportion to fever.
SVT or dysrhythmias with or without CHF
GI symptoms (nausea, vomiting, diarrhea, rarely
jaundice)
– Volume depletion.
– CNS dysfunction (agitation, confusion, delirium,
stupor, coma, seizure)
– Coma and death may ensue in up to 20% of patients
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Hyperthyroid Emergencies
Thyroid Storm
• Patients are treated with
– Short-acting β-blocker such as IV esmolol,
– IV or oral iodide,
– large doses of propylthiouracil (900–1,200 mg/day in
three to four divided doses)
– Supportive care with acetaminophen to suppress
fever
– fluid and electrolyte management
– antiarrhythmic agents
– IV hydrocortisone 100 mg every 8 hours is used often
due to the potential presence of adrenal insufficiency
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Hyperthyroid Emergencies
Thyroid Storm
• Adrenergic Symptoms
– B-blockers are treatment of choice
– 1st line: Propranolol
• Inhibits peripheral conversion of T4 to T3
– Alternatives: esmolol, Diltiazem, guanethidine,
reserpine
• Decreasing T3/T4 Synthesis
– Thioamines: PTU, Methimazole
– Inhibits thyroid peroxidase
– PTU preferred (inhibits peripheral T4 to T3 conversion)
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Adjuvant Therapy
• Dexamethasone
• Iodinated radiological contrast agents
– Iopanoic acid
– Sodium iodate
• Cholestyramine (bind thyroid hormones)
• Rituximab – Prolongs remission of Graves'
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Hyperthyroid Emergencies
Thyroid Storm
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Subclinical hyperthyroidism
• Persistently suppressed TSH with normal T4/T3
– Increased risk of AF in older people
– Decreased bone density in postmenopausal women
• There is no consensus on whether this condition
should be treated as evidence to guide clinical
decisions is limited
• Iodine loads should be avoided (e.g. IV contrast
media, amiodarone, kelp) as iodine excess may
precipitate overt hyperthyroidism.
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Case 1
HT, a 34-year-old woman, comes to the clinic
complaining of fatigue, lethargy, and having a “fuzzy
head” for the past 6 months. She thought it was
because she was working too hard, but the
symptoms have not improved despite a better work
schedule. She has noticed a 2.3-kg (5-lb) weight
gain over the past 6 months, her menses have
become heavier, she feels cold all the time, and her
skin is drier. She takes no medications other than
occasional acetaminophen for headache and milk of
magnesia for constipation.
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Case 1
Her vital signs and physical examination, including
pelvic examination are normal.
Labs
Serum cholesterol: 220 mg/dL (5.7 mmol/L; normal
less than 200 mg/dL, or 5.2 mmol/L)
TSH: 9.7 milliunits/L (normal 0.5-2.5 milliunits/L)
Free T4: 0.6 ng/dL (7.7 pmol/L; normal 0.7-1.9
ng/dL, or 9-24.5 pmol/L)
PE: Wt: 66 kg (145 lb), ht: 5 ft, 7 in. (170 cm).
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Case 1
Why should HT receive LT4 therapy?
What initial dose of LT4 would you choose?
How would you monitor and titrate her therapy?
What would you tell HT regarding the
significance of her symptoms, elevated TSH
level, and risk versus benefits of LT4 therapy?
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