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Thyroid Diseases
Q1: The most common thyroid
function disorder is?
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1)
2)
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4)
Graves’ disease
Hypothyroidism
Sub-acute thyroiditis
Thyroid cancer
Q2: The most sensitive test for thyroid
function is?
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1)
2)
3)
4)
Free T4
Free T3
TSH
Thyroid ultra sound
Q3: The best assay to confirm that a
patient’s hypothyroidism is autoimmune in
nature?
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1) Thyroid stimulating
immunoglobulins
2) Anti-nuclear antibody
3) TSH
4) Thyroid peroxidase antibodies
Q4: The best assay to confirm that a
patient’s hyperthyroidism is autoimmune
in nature?
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1) Thyroid stimulating
immunoglobulins
2) Anti-nuclear antibody
3) TSH
4) Thyroid peroxidase antibodies
Q5: Which is the best study to confirm
the etiology of a patient’s thyrotoxicosis?
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1)
2)
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4)
I123 thyroid scan/uptake
Neck CT or MRI
Thyroid ultrasound
Fine needle aspiration of the thyroid
Q6: Which is the best study to make the
initial evaluation for thyroid nodules
discovered on routine physical exam?
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1)
2)
3)
4)
I123 thyroid scan/uptake
Neck CT or MRI
Thyroid ultrasound
Fine needle aspiration of the thyroid
Q7: Patient has a thyroid U/S showing a solid
dominant (>10mm) nodule and normal thyroid
function, what is your next step?
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1)
2)
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4)
Re-check thyroid U/S in 1 year
Fine needle aspiration of the thyroid
Neck CT or MRI
I123 thyroid scan/uptake
Q8: Thyroid U/S shows homogeneous
increased radiotracer uptake, the
diagnosis is?
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1)
2)
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4)
Metastatic thyroid cancer
Graves’ disease
Toxic multi-nodular goiter
Toxic thyroid nodule
Q9: Methimazole or propylthiouracil and
used to treat hypothyroidism?
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1) True
2) False
Q10: Which is not an appropriate
treatment for Graves’ disease?
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1) Thyroidectomy
2) Anti-thyroid medications such as
propylthiouracil or methimazole
3) Levothyroxine sodium
4) I131 radioactive iodine
Synthesis and Secretion
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Follicular cells arranged in clumps.
Clumps of cells contain colloid.
Colloid an iodine containing protein
called thryoglobulin. This is the
precursor and storage form of thyroid
hormone.
Thyroxine (T4), Triiodothyronone (T3)
Thyroid hormone action
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T4 and T3 circulate in the blood bound to
plasma proteins.
TBG(70%), TBPA(20%) and albumin(10%).
T3 is the active form, 5 times more active
than T4.
T4 is converted to T3 outside the thyroid,
mostly in liver and kidney.
T3 binds to a nuclear receptor
Thyroid hormone action
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T4 and T3 circulate in the blood bound to
plasma proteins.
TBG(70%), TBPA(20%) and albumin(10%).
T3 is the active form, 5 times more active
than T4.
T4 is converted to T3 outside the thyroid,
mostly in liver and kidney.
T3 binds to a nuclear receptor
Regulation of the H-P-T axis
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TRH secreted from hypothalmus controls TSH
production.
TSH from anterior pituitary stimulates
secretion of T4 and T3 from thyroid.
Regulated by a negative feedback loop.
Major Thyroid Abnormalities
Functional / Biochemical
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Hypothyroidism
Hyperthyroidism
Structural / Anatomy
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Thyroid
– Goiter
– Nodules
• Cold
• Warm or Hot
– Cysts
– Malignancies
At Risk Population for Thyroid Dysfunction
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Women, elderly, postpartum 4-8 months.
FamHx of Hashimoto’s or Graves’ dz.
PMHx or FamHX autoimmune diseases – SLE,
RA, DM1, Addison’s, vitiligo, pernicious
anemia.
Type 1 DM: ~20% increase risk for thyroid
dysfunction, mainly hypothyroid.
Patients treated with amiodarone, lithium,
others
HYPOTHALAMIC / PITUITARY THYROID
AXIS
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TRH: stimulate anterior pituitary to release
TSH.
TSH: stimulate thyroid for synthesis and
release of T4 and T3.
Low T4, Low T3: stimulate TSH and TRH.
High T4, High T3: inhibit TSH and TRH.
THYROID HORMONES
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T4 to T3 secretion ratio of 10:1.
T3 is 4X more biologically active than T4.
T1/2: T4 = 7days, T3 = 1 day.
T4,T3: 99% bound to protein, i.e.
metabolically inactive.
From thyroid: 100% - T4, 20% - T3
remainder of T3 is from T4 to T3 conversion
in peripheral tissues.
THYROID TESTING
Biochemical
TSH - highly sensitive, best test for thyroid
function.
1)
Free T4 (FT4)- biologically active.
2)
Free T3 (FT3) - biologically active.
- rarely need to check unless, TSH is low
or undetectable with a normal FT4.
THYROID TESTING
(more specific)
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Thyroid Peroxidase Antibodies (TPO-Ab’s)
- Hashimotos Thyroiditis
Thyroid Stimulating Immunoglobulins (TSI’s)
or TSH receptor antibodies (TRAb).
- Unique to Graves’ disease
I-123 RAIU (Radio Active Iodine Uptake)
evaluation for thyrotoxicosis, shape, size.
Don’t use to confirm hypothyroidism.
DON’T FORGET THE BASICS
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History of present illness and ROS.
PMHx – postpartum
– Past Hx of thyroid pain/tenderness/nodule/
enlargement or goiter
– H/O autoimmune diseases
FamHX – thyroid dysfunction, thyroid
cancer, Autoimmune diseases.
Medications
Systematic physical exam
Hypothyroidism
HYPOTHYROIDISM
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Prevalence: 4 - 8% general population.
Mean age of Dx: 5th decade of life
Female to male ratio: 10:1
Secondary hypothyroidism-causes
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Hypothalamic disease
Pituitary disease
PRIMARY HYPOTHYROIDISM
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Identification on clinical basis can be
challenging.
Symptoms generally vague.
Frequently goes unnoticed, confused as other
health problems.
Insidious onset + poor index of suspicion =
misdiagnosis
ETIOLOGY
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Autoimmune:
- Chronic lymphocytic thyroiditis = Hashimoto’s
- positive TPO-Ab’s
- remember postpartum thyroiditis
Iatrogenic: I-131 RAI, total/subtotal thyroidectomy,
neck irradiation.
Congenital: agenesis, dysgenesis.
Drug induced: lithium, amiodarone, chemotherapy,
others.
Clinical Symptoms of Hypothyroidism
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Fatigue
Lethargy
Cold intolerance
Constipation
Decreased memory
Depression
Mental Impairment
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Arthralgias
Hoarseness
Heavy menstrual
flow
Paresthesias
Sleepiness
Weight gain ,edema
Muscle cramps
Clinical Signs of Hypothyroidism
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Bradycardia
Coarse hair, hair loss
Delayed relaxation phase of deep tendon reflexes
Dry, cool, pale skin
Goiter
Hoarseness
Non-pitting edema (myxedema)
Puffy eyes and face
Slow movements
Slow speech
Thinning lateral third of eyebrows
Example of Clinical Manifestations
of Hypothyroidism
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Patient example
– Fatigue (“no energy”), cold intolerance,
constipation, weight gain, fatigue,
problems with concentration (“mental
clouding”), dry skin
CLINICAL MANIFESTATONS
EXAM
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NECK: thyroid may be normal, enlarged,
symmetric/asymm., smooth or lumpy.
HEART: bradycardia.
EXTREMS: pretibial/ankle edema, dry cool
skin, brittle nails.
NEURO: DTR’s with delayed relaxation
phases
HEENT: periorbital puffiness, loss of lateral
eyebrows, coarse/thinning hair.
Clinical Features
Skin and Reproduction
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Dry skin
Erythema ab igne
Vitiligo
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Infertility
Menorrhagia
Galactorrhoea
Clinical Features
Neurological and Haematological
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Aches and Pains
Carpal Tunnel
Deafness
Hoarseness
Ataxia
Depression
Psychosis
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Iron deficiency A
Pernicious Anemia
LABORATORY EVALUATION
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TSH - high
Free T4 - low
Check both if new diagnosis to make sure
PITUITARY-THYROID AXIS intact.
Consider TPO-Ab
Additional abnormal tests.
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Fasting cholesterol and triglycerides may be
raised
Ck AST and LDH (SMAC 20) may be raised
FBC Anemia
ECG Slow rate. Small complexes.
Levothyroxine Sodium (LT4 )
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Exogenously administered LT4 hormone
Indistinguishable from endogenous T4, both
in its physiologic effects and its quantification
as measured in blood
LT4 is the treatment of choice as replacement
or supplemental hormone therapy
Branded preparations are preferred
TREATMENT
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Levothyroxine (LT4), narrow
therapeutic range
– 0.3 – 3.0 IU/mL, caution in
lower range TSH.
Brand vs. generic vs. T4 + T3
combination.
Lifelong treatment, most cases
Dosing: 1.6 mcg/kg/day = ~100 125 mcg/day.
Compliance, empty stomach,
competing agents for absorption
(Iron, Calcium )
Check TSH no sooner than 6
weeks after initial start of LT4 or
any adjustment.
Therapy Monitoring
• Clinical and laboratory monitoring enable
– Evaluation of the clinical response
– Assessment of patient compliance
– Assessment of drug interactions, if applicable
– Adjustment of dosage, as needed
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Clinical and laboratory evaluations should be
performed
– At 6- to 8-week intervals while titrating
– Annually once a euthyroid state is established
Factors That May Reduce
Levothyroxine Effectiveness
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Malabsorption Syndromes
– Post jejunoileal bypass
surgery
– Short bowel syndrome
– Celiac disease
Reduced Absorption
– Colestipol hydrochloride
– Sucralfate
– Ferrous sulfate
– Food (eg, soybean
formula)
– Aluminum hydroxide
– Cholestyramine
– Sodium polystyrene
sulfonate
Drugs That Increase
Clearance
– Rifampin
– Carbamazepine
– Phenytoin
• Factors That Reduced T4 to
T3 Clearance
– Amiodarone
– Selenium deficiency
• Other Mechanisms
– Lovastatin
– Sertraline
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Thyroid Hormone Therapy
Special Treatment Populations
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Patients 50 years of age or with underlying
cardiac disease
– Initial dose of LT4 - 25 to 50 mcg/d
Elderly patients with cardiac disease
– Initial dose of LT4 - 12.5 to 25 mcg/d
Patients with heart failure
– Both hypo- and hyperthyroidism can
worsen heart failure
Treating Hypothyroidism Before and
During Pregnancy
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Encourage adherence with LT4 replacement therapy
before conception
Monitor TSH levels before conception and during first
trimester
Consider increase of LT4 dosage in athyreotic
patients by 25% - 50% when pregnancy is confirmed
Monitor TSH levels every 6 to 8 weeks throughout
pregnancy
Reinstate pre-pregnancy LT4 dosage immediately
following delivery
Over-Replacement Risks
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Switching a narrow therapeutic index drug, such as LT4, without
retesting and re-titrating can cause inconsistent TSH control,
resulting in over-replacement
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Over-replacement risks (TSH <0.5 IU/mL)
– Iatrogenic thyrotoxic state
– Increased heart rate and myocardial contractility
– For cardiac patients, increased risk of angina and MI
– Reduced bone density/osteoporosis
– Psychiatric symptoms, such as anxiety, sleep disturbance,
irritability, and fatigue
Case 1
46 y.o. female presents with a 3 - 4 month
history of heavier than usual menstrual
cycles, fatigue, “feeling sleepy all of the
time”, depressed, constipation, problems
concentrating, cold intolerance.
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PMHx: unremarkeable
FAMHx: Adopted.
Case 1 continued
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P.E. : DTR’s show delayed relaxation phases of
biceps and brachioradialis, non tender symmetric
goiter @ 2 times normal size without nodules.
LABS : TSH
77.02 (0.45-4.50)
Free T4
0.38 (0.8 – 1.50)
TPO-Ab
267 reactive greater 40.
Case 1 continued
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Dx: Hashimoto’s Thyroiditis
Tx: 100 mcg qd, non-generic LT-4
Follow-up in 6 weeks and recheck TSH
F/U: Feeling “90% better”
TSH 7.62
Increase to 112mcg qd.
Follow-up in 2 months.
2 months later
TSH – 2.11 (0.50 - 3.00).
Plan: follow and adjust LT-4 based on TSH
SUBCLINICAL HYPOTHYROIDISM
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Very difficult to diagnose clinically
High index of suspicion, may be asymptomatic
4 -15% of general population*
20% of pts. over 60 y.o. (esp. women)**
LABS: TSH - minimally high (6 - 10 IU/mL)
Free T4 – low normal
TREATMENT: controversial, consider if symptoms,
lipid abnormality, if TPO-Ab positive
Low dose LT-4 vs. surveillance, education.
Mild Thyroid Failure and
Neurobehavioral Abnormalities
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Conditions reported to occur more frequently
in patients with mild thyroid failure
– Depression
– Anxiety
– Somatic complaints
– Cognitive abnormalities
Rationale for Treating
Mild Thyroid Failure
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Potential benefits from treatment
– Prevent progression to overt
hypothyroidism
– Improve serum lipid profile, which may
reduce the risk of death from
cardiovascular causes
– Reduce symptoms, including psychiatric
and cognitive abnormalities
Treatment
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Repeat tests after an interval.
If TSH is continuing to rise in the presence of
strongly positive antibodies, the risk of
developing hypothyroidism in the future is high.
Thus treatment with thyroxine at this early stage
may be justified if symptomatic.
Beware-Thyroxine may not cure all symptoms.
Case 2
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Hx: 32 y.o. women referred for mildly
increased TSH 8.69 (0.46-4.68)
Symtoms: mild fatigue, dry skin, “not feeling
my usual self”
PMHx: no H/O thyroid disorders, or recent of
remote thyroid pain/tender.
FAMHx: Mother, two maternal aunts with
hyperthyroidism.
Case 2 continued
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P.E. : Thyroid minimally enlarged and nontender, no nodules. remainder of exam
unremarkable.
Labs:
TSH
7.5 (.46 – 4.68)
FREE T4 0.82 (0.80-1.50).
TPO-Ab
317 reactive greater than 40
Case 2 continued
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DX: Subclinical Hypothyroidism
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Hashimotos thyroiditis
Tx: “Brand LT4” 25 mcg q.d.
Follow-up and TSH in 2 months.
Follow-up: patient feeling better without
complaints
TSH 1.89 (0.5 – 3.0)
Education, need to follow
Elderly
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Non specific symptoms
Osteoporosis
Anemia
Heart Failure
Treatment with thyroxine
Start with small doses and titrate slowly.
(25ug).
Post-partum thyroiditis.
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Incidence is about 9%.
Transitory or permanent.
Early hyperthyroidism (<4/12), later
hypothyroidism (>4/12), euthyroid 10/12
later.
Increased microsomal antibodies.
Thyroxine
Myxoedema Coma
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Requires prompt treatment. Mortality of
50%.
Suspect in cases of hypothermia.
T3 20ug bd IM
Steroids recommended
Glucose to correct hypoglycaemia
Rewarming
Assisted ventilation
Hyperthyroidism
HYPERTHYROIDISM
ETIOLOGY
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Graves’ disease ( autoimmune ).
Toxic multi-nodular goiter ( toxic MNG ).
Toxic nodule (hot or warm nodule)
Common Symptoms and Signs of
Thyrotoxicosis
Symptoms
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Nervous / shaky
Signs
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Fatigue
Muscle weakness
Increased
perspiration
Heat intolerance
Tremor
Palpitations
Appetite/weight changes
Menstrual disturbances
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Goiter
Hyperactivity
Tachycardia / arrhythmia
Systolic hypertension
Warm, moist, or smooth
skin
Stare and eyelid retraction
Tremor
Hyper-reflexia
GRAVES’ Dz
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~75% of cases of hyperthyroidism.
Thyroid Stimulating Immunoglobulins (TSI’s)
and / or TSH receptor antibodies (TRAb) levels
usually increased
Incidence 2nd – 4th decade of life.
~5 times more likely in women.
Thyrotoxicosis - work-up
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Labs- demonstrate thyrotoxicosis.
– TSH - Low or undetectable
– Free T4 and/or Free T3 – Increased
I123 thyroid scan / uptake
Uptake is increased.
– 4 hour:
normal ref. (5 – 15%)
– 24 hour: normal ref. (6 - 30%)
Scan (anatomical findings via radiotracer uptake)
– Homogeneous ( Graves’ Dz)
– multiple areas (Toxic MNG)
– single area (Hot or warm nodule)
PATIENT EXAMPLE
GRAVES’
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30 y.o. female with nervousness,
shakiness, heat intolerance, “fast /
pounding heart beat”, wt loss, light
menses, and muscle weakness for 3
months.
P.E. HR=118
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Eyes—lid lag, stare,
Skin: warm/moist
Thyroid: large symmetric nontender gland
Neuro—tremors, DTR’s – brisk,
hyper-reflexic
LABS: TSH: < 0.03 (0.45 – 4.50)
FT4:
2.8 (0.8-1.8)
Graves’ Work up Cont.
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I123 thyroid S/U
4hr = 28%
(5 - 15%)
24hr = 76%
(6 - 30%)
diffuse homogeneous uptake.
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TREATMENT options
Treatment of Hyperthyroidism
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Treatment depends upon
-Cause and severity of disease
-Patients age
-Goiter size
-Comorbid condition
-Treatment desired
Treatment
The goal of therapy is to correct hyper-metabaolic state
with fewest side effects and lowest incidence of
hypothyroidism.
Options
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Anti-thyroid drugs
Radioactive iodine
Surgery
Beta-blocker and iodides are adjuncts to above
treatment
Beta Blockers
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Prompt relief of adrenergic symptoms
Propranolol widely used
Any beta blocker can be used, but non-selectives
have more direct effect on hyper-metabolism
Start with 10-20 mg q6h
Increase progressively until symptoms are controlled
Most cases 80-320 mg qd is sufficient
CCB can be used if beta blocker not tolerated or
contraindicated
Iodides
Iodide blocks peripheral conversion of T4 to T3 and
inhibits hormone release. These are used as
adjunct therapy
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Before emergency non-thyroid surgery
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Beta blockers cannot curtail symptoms
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Decrease vascularity before surgery for Grave’s
disease
Iodides
Iodides are not used for routine treatment because of
paradoxical increase of hormone release with
prolonged use
Commonly used:
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Radiograph contrast agents
-Iopanoic acid
-Ipodate sodium
 Potassium iodide
Dose 1 gram/ 12 weeks
Anti-thyroid Drugs
They interfere with organification of iodine—suppress
thyroid hormone levels
Two agents:
-Tapazole (methimazole)
-PTU (propylthiauracil)
Anti-thyroid Drugs
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Remission rate: 60% when therapy continued for two
years
Relapse in 50% of cases.
Relapse more common in
-smokers
-elevated TS antibodies at end of therapy
Anti-thyroid Drugs
Methimazole
Drug of choice for non-pregnant patients because of :
 Low cost
 Long half life
 Lower incidence of side effects
 Can be given in conjunction with beta-blocker
 Beta-blockers can be tapered off after 4-8 weeks of
therapy
Dose 15-30 mg/day
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Anti-thyroid Drugs
Methimazole
Monthly Free T4 or T3 until euthyroid
Maintenance dose 5-10 mg/day
TSH levels may remain undetectable for months after
euthyroid and not to be used to monitor the therapy
Anti-thyroid Drugs
Methimazole
 At one year if patient is clinically and biochemically
euthyroid and TS antibodies are not detectable,
therapy can be discontinued
 Monitor every three months for first year then
annually
 Relapses are more common in the first year but can
occur years later
 If relapse occurs, iodide or surgery although antithyroid drugs can be restarted
Anti-thyroid Drugs
PTU
 Prefered for pregnant patients
 Methimazole is associated with rare genetic
abnormalities
Dose 100 mg t.i.d
Maintenance 100-200 mg/day
Goal: Keep Free T4 at upper level of normal
Anti-thyroid Drugs
Complications
 Agranulocytosis up to 0.5%
 High with PTU
 Can occur suddenly
 Mostly reversible with supportive Tx
 Routine WBC monitoring controversial
 Some people monitor WBC every two weeks for first
month then monthly
 Advised to stop drug if they develop sudden fever or
sore throat
Treatment with 1131 RAI
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Treatment of choice
– Goal is complete ablation i.e. hypothyroid
131 Tx
– Hypothyroid about 3-5 months post I
Follow Free T4 q 4-6 weeks until low
– Treatment: “brand” LT4
– Follow and treat as you would for hypothyroid
– Exception: the low TSH usually lags behind, often
for months, the normalization of the Free T4.
– Check Free T4 and TSH until the TSH becomes
normal or high, then only follow the TSH.
Thyroid Nodules
How thyroid nodules or masses are
found?
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By HCP: palpation on routine exam
By patient: rarely
Incidentally
– CT scan or MRI of chest / neck
– Carotid Dopplers
Thyroid Ultrasound
I123 thyroid scan / uptake
Thyroid Nodules
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5 categories:
– Benign
– Non-diagnostic
– Follicular neoplasm/lesion
– Suspicious
– Malignant.
Size - >1cm “dominant nodule”
Thyroid Nodules
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I123 thyroid scan / uptake
– Hot or warm – hormone secreting nodules
– Cold nodules can be:
• Cysts
• Benign adenomas
• Malignant tumors
• others
Ultrasound findings that increase the
risk of malignancy
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Hypoechoic
Microcalcifications
Irregular margins
Intranodular vascularity
Rounded appearance; more tall than wide,
shape of the nodule
Suspicious for malignancy
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Growing nodule
Fixed nodule
Firm or hard consistency
Cervical adenopathy
History of head and neck irradiation
Family history of medullary thyroid carcinoma (MTC),
multiple endocrine neoplasia type 2 (MEN 2), or
papillary thyroid carcinoma (PTC)
Persistent dysphonia, dysphagia or dyspnea
Age <30 or >60 years
Male sex
Thyroid Nodule Work-up
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Assess for biochemical abnormality.
?FT3)
If normal Labs
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(TSH, FT4,
U/S to evaluate: number and echotexture.
Cytopathological Eval. Fine needle aspiration (FNA) with or
without U/S guidance.
If abnormal Labs:
and or increased FT4/FT3
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I123 thyroid scan and uptake
Nodule(s) hot or warm
Treat options: I131 RAI, ATD’s, Surgery, refer to
endocrinologist for treatment
low TSH
Cold Nodules on I123 Thyroid
scan/uptake
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TSH and Free T4 normal
– Consider thyroid cancer, benign adenoma,
or thyroid cyst
– Ultrasound to delineate solid vs. cystic
lesion
– Referral for ultrasound guided FNA biopsy
– If biopsy is suspicious for cancer or
demonstrates cancer, referral to surgeon
with ample experience in thyroid surgery.
Thyroid Malignancies
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Papillary:
Follicular:
Medullary:
Anaplastic:
~80%
~15%
~3-5%
< 2%