Download Thyroid Disease

Thyroid Disease
J.B. Handler, M.D.
Physician Assistant Program
University of New England
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Abbreviations
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TSH- Thyroid stimulating
hormone
TBG- thyroid binding globulin
TBPA- thyroid binding prealbumin
IT- iodothyroxine
Tg- thyroglobulin
TPO- thyroperoxidase
TSI- thyroid stimulating
immunoglobulin
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PTU- propylthiouracil
FNA- fine needle aspirate
Ca- cancer
RAI- radioactive iodine
D/C- discontinue
CHD- coronary heart disease
HF- heart failure
ST- sinus tachycardia
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Thyroid Physiology
Hypothalamic-Pituitary-Thyroid axis
 TSH- turns thyroid on and off- binds to
receptors of follicular cells.
 Iodine essential for manufacture of thyroid
hormones- need 0.2 mg daily dietary intake,
60 ug into thyroid.
 Iodine deficiency – significant source of
hypothyroidism world wide; rare in U.S.A
because of iodized salt.
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Thyroid Hormone Synthesis
Iodine trapping followed by thyroid
peridoxidase linking of I to tyrosine.
 MIT+DIT+TG = T3- Triiodothyronine
 DIT+DIT+TG = T4 - Thyroxine
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– Thyroid makes 15x more T4 than T3
MIT- monoiodotyrosine
DIT- diiodotyrosine
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Thyroid Hormone Synthesis
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T4 99.98% protein bound, .025% free
T3 99.7% protein bound, 0.3% free (3-4x more
biologically active than T4)
– Only free hormone (T4 or T3) enters cells and
exhibits biologic activity.
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T4 conversion to T3 in periphery (liver, brain,
heart) by deiodinase enzymes after release from
gland. Clinical application: see Rx of
hyperthyroidism.
– Conversion represents 80-90% of circulating T3
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Thyroid Hormone Transport
Thyroxine Binding Globulin (TBG) made in
liver binds 80% thyroid hormone;
remainder bound to TBPA and albumin.
 Alterations of TBG will lead to changes in
total T4 and T3 in absence of clinical
disease. Example: TBG levels increased
with estrogen (pregnancy, OCP)- total T4
will be elevated but free T4 and TSH will
be normal. (see below).
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Thyroid Hormone Actions
Bind to nuclear receptors in most tissues,
especially brain, heart, kidneys, muscle,
pituitary and liver.
 Crucial role in cell differentiation during
development- cell growth, maturation, and
gene expression. If absent at birthsevere
mental retardation “cretinism”; TSH
screening in all newborns in USA.
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Thyroid Hormone Actions
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Help maintain thermogenic and metabolic
homeostasis in the adult. Essential for normal
metabolism, protein synthesis and organ
function.
The most common disorders of the thyroid gland
are the result of autoimmune processes that
either cause glandular destruction and
underproduction of thyroid hormone or stimulate
overproduction of thyroid hormone.
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History and Physical
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History: Wt. changes, energy level, heat/cold
intolerance, skin/hair changes, fluid retention,
mood changes (anxiety, depression), visual
disturbance, diarrhea/constipation, neck swelling,
palpitations, SOB, and more (see below).
PE: VS, weight, scalp, hair, eyes, neck, skin,
heart, abdomen, extremities, neuro/reflexes.
– Detailed thyroid exam: size, tenderness, enlargement,
texture, nodularity, firmness, bruits.
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Goiter
Google.images.com
Evaluation of Thyroid Function
Numerous tests available; interpretation can
be confusing.
 Thyroid Stimulating Hormone (TSH) and
free T4 are the most informative tests of
thyroid function and have replaced the need
in most situations to order additional
testing.
 T3 levels (total or free) may be useful in
special circumstances (below).
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Thyroid Stimulating Hormone
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Secretion controlled via negative feedback from
thyroid hormones.
Extremely sensitive indicator of thyroid
function.
Normal range: 0.27-4.2mU/L (varies by lab)
– 95% of euthythyroid patients have TSH < 2.5mU/L
(goal Rx in pts with hypothyroidism)
– Asymptomatic patients with TSH levels 3-6 mU/L
should be followed for development of hypothyroidism.
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Thyroid Stimulating Hormone
Decreased in primary hyperthyroidism
(Graves, toxic nodular goiter, etc.).
 Increased in primary hypothyroidism.
 New generation assays are sensitive to
.01mU.
 With rare exceptions, normal TSH
excludes hypo/hyperthyroidism.
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TSH and Screening
Part of prenatal, mood disorder, atrial
fibrillation, wt change, dementia/delerium
and certain dyslipidemia work-ups.
 Almost always abnormal with
hypo/hyperthyroid states
 Neonatal screening
 Inexpensive
 Highly sensitive/specific marker of primary
thyroid disease.
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Free T4
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Occasionally needed to confirm presence of
hypo/hyperthyroidism.
Direct measure of unbound T4
Useful in management of thyrotoxicosis
(severity and response to Rx). Goal is FT4 in the
normal range.
May be normal in patients with T3 thyrotoxicosis;
if TSH low, FT4 normal and patient clinically
hyperthyroid – essential to check total or free T3.
Normal 9-24 pmol/L or 0.7-2.0 ng/dl (varies with
method)
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Anti-thyroid Antibodies
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Autoimmune thyroid disease is common.
Antibodies elevated in Hashimoto’s thyroiditis
(vs TPO and Tg) and Graves disease (see below)
– the most common thyroid diseases.
TSH-R AB (TSAb) - Thyroid stimulating
hormone receptor antibodies (IgG) that stimulate
gland activity.
– Also referred to as TSI: Thyroid Stimulating
Immunoglobulin
– Elevated in 80% patients with Graves disease.
– stimulate hormone production
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Other Tests
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Total T4: normal 5-11 ug/dL- screening as adjunct
to TSH; usually not needed
Total and free T3: normal total is 95-190 ng/dL
RAI131 uptake/scan: Oral I131 taken up by thyroid;
% uptake indicates activity. Scan provides picture
of the gland; useful for differentiating types of
thyrotoxicosis and in f/u of thyroid cancer:
– Thyrotoxicosis: Diffuse (Grave’s) vs toxic nodule
– Follow-up of patients treated for thyroid
cancerrecurrent local disease or metastases
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Fine Needle Aspiration
Definitive test for evaluating thyroid
nodules; more information than scans.
 Essential for diagnosis of thyroid cancer
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Hypothyroidism
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Autoimmune – Hashimoto’s Thyroiditis
– Idiopathic- absence of anti-thyroid antibodies
Iatrogenic: post Rx with RAI for
hyperthyroidism
 Congenital: 1/4000 newbornsscreening
 Drug induced: amiodarone (hypo and
hyper)
 Secondary forms- hypothalamic or pituitary
disease (uncommon)
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Autoimmune Hypothyroidism
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Symptoms may vary from mild to florid
Goiter often present
4/1000 woman, 1/1000 men (annual incidence)
Lymphocytic infiltration of gland – early phase
may be hyperthyroidism (release of stored
hormone) but end result is hypothyroidism.
TPO and Tg antibodies- often high titers
Insidious onset
Diffusely enlarged, firm, finely nodular thyroid.
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Symptoms (Hypothyroidism)
Early
 Fatigue, Lethargy
 Weakness, arthralgias
 Cold intolerance
 Constipation
 Dry skin, hair loss
 Headaches
 Menorrhagia
Late
 Slow speech
 Altered mentation
 Muscle cramps
 Hoarse voice
 Weight gain
 Amenorrhea
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Signs
Early
 Thin, brittle nails
 Thin, dry hair
 Delayed DTR
relaxation
Late
 Goiter
 Facial/eyelid puffiness
 Alopecia
 Bradycardia
 *Edema- non-pitting
 Pleural/Pericardial
effusions
*Myxedema: abnormal interstitial fluid accumulation
(mucopolysacchrides) in skin giving it a waxy/coarsened (nonpitting) appearance; pleural/pericardial effusions in severe cases.
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Hypothyroid
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Labs
Increased TSH
 Decreased FT4 (not needed for eval or Rx)
 Dyslipidemia – TC & tryglycerides,
HDL
 Anti-thyroid antibodies
 Anemia, elevated LFT’s, late
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Complications
CV – pericardial effusions,
cardiomyopathy, accelerated CHD, HF
 Encephalopathy- rare, can progress to
confusioncoma
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Treatment
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Levothyroxine (Synthroid, Levoxyl, others)
Full replacement dose 1.6 ug/kg/d
Initiate 50-100 ug/day and titrate towards
full dose over time, following TSH levels.
Caution: age >60; patients with CHDlower
starting dose, slower titration.
Check TSH levels every 2-3 mos. until normal
(0.5-2.5 mU/L for most patients)
Goal: clinically euthyroid state: symptoms
improve slowly (months or more).
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Congenital Hypothyroidism
Early detection essential to prevent
cretinism
 Neonatal screening of TSH should eliminate
this disease
 Replacement therapy 10-15 ug/kg/d
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Cretinism
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Hyperthyroidism
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Thyrotoxicosis- clinical syndrome associated with
with excessive levels of thyroid hormone.
Graves disease
Toxic/“hot” adenomas/nodule(s)
Early phase of Hashimoto’s or sub-acute (viral)
thyroiditis- self limited; release of stored hormone
Factitious- excessive thyroid hormone intake
TSH secreting adenoma (rare)
Amiodarone (both hypo and hyperthyroidism)
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Graves’ Disease
Most common cause of hyperthyroidism
 Autoimmune- TSH-R Ab (TSAb) - IgG
antibodies (aka: TSI) directed to TSH
receptor: over-activate gland
hypersecretion, hypertrophy and
hyperplasia- goiter common.
 8x more common in women
 Onset 20-40 year old
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Symptoms
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Hyperactivity, irritability, restlessness, anxiety
Heat Intolerance
Sweating
Palpitations
Fatigue, weakness
Increased appetite, weight loss
Diarrhea
Decreased libido, oligomenorrhea
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Signs
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Tachycardia
Arrhythmias (ST, Afib)
Fine Tremor
Goiter/bruit
Warm, moist skin
Oily, fine hair
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Proximal muscle
weakness
Opthalmopathy
Dermopathy
Hyperreflexia
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Goiter
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Hyperthyroid Labs
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Very low TSH – often <0.1 mU – requires
sensitive TSH assay.
Total and FT4 elevated (exception is T3
thyrotoxicosis- below); need to follow FT4 during
treatment phase to document euthyroid state; TSH
may remain suppressed).
Do not need TSH-R Ab (TSI) for diagnosis
T3 thyrotoxicosis in 2-5% of patients with Graves
– requires total or free T3 for diagnosis.
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Opthalmopathy/Dermopathy
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Unique to “Graves” disease; 20-40% of cases
Proptosis/exophthalmos,“lid-lag”, conjunctival
inflammation/edema, corneal drying
Pathology- lymphocytic infiltration of orbit,
muscles, eyelids; may cause diplopia and
compression of optic nerve.
Skin: Non-inflammatory induration and plaque
formation of pre-tibial areas leading to edema,
thickened skin with “orange skinned” appearance.
– “Pre-tibial myxedema”
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Graves Opthalmopathy
Proptosis/exopthamos
“lid lag”
Google.images.com
Graves Opthalmopathy
Severe exopthalmos
Elsevier Inc.
Graves Dermopathy
“Pre-tibial
myxedema”
Images.google.com
Complications
Cardiac arrhythmias – ST, new onset atrial
fibrillation
 High-output cardiac failure – toxic, dilated
cardiomyopathy.
 Thyroid storm and crises – extreme
thyrotoxicosis with delerium, high fever,
dehydration and death. Uncommon with
current approaches to thyrotoxicosis.
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Treatment of Graves
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Endocrinology consult essential if available.
Propranolol – IV/PO will reduce symptoms and
stabilize heart. Dose 20-40 mg 4x/d, then
conversion to long acting forms.
Thiourea drugs- Propylthiouricil (PTU) or
Methimazole- inhibit thyroid peroxidase and
block organification of iodine;  hormone
production. Useful in mild to moderate
thyrotoxicosis, presence of small goiter.
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Thiourea Drugs
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Agranulocytosis (PTU>Methimazole) can occuressential to follow WBC.
Pruritus (common) and allergic dermatitis occur
Methimazole 30- 60 mg/daily
PTU 75-150 mg q.i.d. – also stops peripheral
conversion of T4T3
Essential to monitor FT4
Treat for 12-18 months
Recurrent thyrotoxicosis in 50% after drug
D/C’d
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Other Meds (Severe Sx - IO)
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Saturated Iodine solution: Block Thyroid release
of hormone- severe thyrotoxicosis
Iodinated Contrast agents: Used for temporary
relief of severe thyrotoxic symptoms or thyroid
storm.
– Inhibit peripheral conversion of T4T3
– T3 levels drop by up top 60% within 24 hours.
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Glucocorticoids: severe thyrotoxicosis
– Inhibit peripheral conversion of T4T3
– need for cortisol during thyroid storm
IO- interest only
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Radioactive Iodine
Definitive therapy: 131I used to destroy
overactive thyroid tissue.
 Preferentially concentrated by thyroid
because of iodine component of 131I.
 No associated risks of radiation. This has
become definitive treatment of choice in
USA.
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– Must avoid during pregnancy
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Radioactive Iodine (RAI)
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Essential to follow FT4 and clinical status
Permanent hypothyroidism often occurs within
one year – thyroid replacement therapy then
necessary for life.
Ophthalmopathy may appear or worsen
following treatment, especially in smokers; does
not improve with RAI alone. Unclear as to why.
– Rx with prednisone post RAI decreases
progression/improves opthalmopathy in up to 2/3rd of
patients.
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Thyroid Surgery
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No longer first line therapy
– Treatment of choice for Graves in children or
hyperthyroidism during pregnancy when sx
can’t be controlled with thiourea drugs.
Indicated in patients with recurrent Graves
following failed Rx with 131I.
 Subtotal thyroidectomy performed with
preservation of parathyroid glands to
prevent hypoparathyroidism.
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Graves’ Prognosis
Recurrences common if only treatment is
thiourea, and sometimes occur post 131I or
subtotal thyroidectomy.
 Cardiac, ocular and psychological
complications may persist following
treatment.
 Post treatment hypothyroidism is common
but easily treated with replacement Rx.
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Thyroid Nodules
Evaluation essential; may be single or
multiple likely to be found on PE.
 When single, usually a benign adenoma or
colloid cyst, but cancer is a possibility.
 Nodules may hypersecrete thyroid hormone
leading to thyrotoxicosis “hot nodule”.
 Fine needle aspirate essential to exclude
thyroid cancer.
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Toxic Thyroid Nodules
Present with thyrotoxicosis (no eye/skin
findings).
 Nodules may be single (young) or multiple
(elderly).
 Treatment of solitary nodule:
RAI is preferred over surgery for patients >
40 y/o; surgery or RAI if younger
 Treatment of multinodular goiter- RAI
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Thyroid Cancer
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30,000 cases/yr/USA; 3x incidence in women.
Most are well differentiated, slow growing and
treatable, often with cure. Do not effect thyroid
function.
76% are papillary Ca, 16% follicular Ca.
Risk factor: prior head and neck radiation or
radiation exposure.
PE: firm, non-tender nodule
Dx via FNA, ultrasound of neck
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Treatment
Surgery- near total thyroidectomy with
preservation of parathyroid gland(s).
 Post-op suppression therapy with
levothyroxine to suppress TSH stimulation
of any remaining thyroid tissue.
 Follow up total body RAI scan to detect any
remaining thyroid tissue/metastasis with
further treatment (131I) if indicated.
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