HYPERTHYROIDISM
 Apathetic thyrotoxicosis – fatigue and weight loss
Thyrotoxicosis – state of thyroid hormone excess
Hyperthyroidism – result of excessive thyroid function
THYROTOXICOSIS
Grave’s Disease
EPIDEMIOLOGY
 60-80% of thyrotoxicosis
 Genetic factors and iodine intake
 Women (2%) > Men (1/10)
 Age 20-50
o Rare in adolescent
o Occurs in elderly
PATHOGENESIS
Autoimmune hypothyroidism
 Combination of environmental and genetic factors like
polymorphisms of:
o HLA-DR
o Immunoregulatory genes – CTLA-4, CD25, PTPN22,
FCRL3, CD226
o Gene encoding TSH-R
 Monozygotic twins (20-30%) and dizygotic twins (<5%)
 Stress – operates the neuroendocrine effects on immune system
 Smoking – minor for Grave’s disease and major for
ophthalmopathy
 Precipitates GD:
o Sudden increase in iodine intake
o Postpartum
o Immune reconstitution phase after HAART or
alemtuzumab treatment
 TSI (thyroid-stimulating immunoglobulin) from thyroid gland,
bone marrow, and lymph nodes causes hyperthyroidism in GD.
o Detected by bioassays or TBII assays (thyrotropin-
binding inhibitory immunoglobulin)
o TBII – useful for monitoring pregnant GD patients in
whom high levels of TSI can cross placenta  neonatal
thyrotoxicosis
 TPO (thyroid peroxidase) and Tg (thyroglobulin) antibodies –
occur in 80% of cases
 Cytokines – major role in thyroid-associated ophthalmopathy
o Release of cytokines (IFN-y, TNF, IL-1)  Fibroblast
activation and increase synthesis of
glycosaminoglycans that trap water  Muscle swelling
 Irreversible fibrosis of muscles (late)
 TSH-R – shared autoantigen expressed in the orbit.
o Association with autoimmune thyroid disease
 Increased fat – cause of retrobulbar tissue expansion. Increase in
intraorbital pressure  Proptosis, diplopia, and optic neuropathy
CLINICAL MANIFESTATION
 Clinical presentation depends on:
o S – severity of thyrotoxicosis
o D – duration of disease
o S – susceptibility to excess TH
o A – age
o Mistaken for depression in elderly
 Unexplained weight loss despite enhanced appetite – due to
increased metabolic rate
 Weight gain (5%) – due to increased food intake
 Hyperactivity, nervousness, and irritability  Easy fatigability
 Insomnia and impaired concentration
 Fine tremor – frequent finding
 Hyperreflexia, muscle wasting, and proximal myopathy without
fasciculation
 Chorea – rare
 Hypokalemic periodic paralysis – common in Asian males
Cardiovascular
 Sinus tachycardia with palpitations – due to supraventricular
tachycardia
 High cardiac output  Bounding pulse, widened pulse pressure,
and aortic systolic murmur  Worsened angina or HF
 Atrial fibrillation – age >50
Skin
 Warm and moist
 Sweating and heat intolerance
 Palmar erythema, onycholysis, pruritus, urticaria, and diffuse
hyperpigmentation
 Fine hair texture and diffuse alopecia (40%) – persist for months
after euthyroidism
 Thyroid dermopathy (<5%) – always with moderate or severe
ophthalmopathy
o Appears 1-2 years after the development of Grave’s
hyperthyroidism
 Pretibial myxedema – skin changes over anterior and lateral
aspects of lower leg
 Typical lesion – indurated plaque with deep pink or purple color,
non-inflamed, and orange-skin appearance
 Nodular involvement – in lower leg; mimic elephantiasis
 Thyroid acropachy – form of clubbing found in <1%
GI, GU, etc.
 Decrease transit time  Increase stool frequency often with
diarrhea and mild steatorrhea
 Oligomenorrhea or amenorrhea
 Impaired sexual function and gynecomastia
 Osteopenia – in long-standing thyrotoxicosis
 Mild hypercalcemia (20%)
 Hypercalciuria
Neck
 Diffusely enlarged thyroid gland (2-3x)
 Firm but nodular
 Thrill or bruit – best detected at inferolateral margins of thyroid
lobes due to increased vascularity of the gland and hyperdynamic
circulation
Eyes
 Lid retraction causing a staring appearance – due to sympathetic
overactivity
 Grave’s ophthalmopathy or Thyroid-associated ophthalmopathy
o Occurs in the absence of hyperthyroidism (10%)
o Autoimmune hypothyroidism or thyroid antibodies
o UTZ or CT imaging of orbits
 Unilateral signs (10%)
o Sensation of grittiness, eye discomfort, and excess
tearing – early manifestations
o Proptosis – best detected by visualization of sclera
between the lower border of iris and lower eyelid
 measured using exopthalmometer
 Corneal exposure and damage, especially if
there is failure of lids to close during sleep
o Periorbital edema, scleral injection, and chemosis
 o Severe muscle swelling  Diplopia (5-10%) – late TREATMENT
appearance due to fibrosis of extraocular muscles Antithyroid drugs
o Compression of optic nerve at the apex of the orbit   Thionamides – inhibit function of TPO  reducing oxidation and
Papilledema, peripheral field defects, and permanent organification of iodide
loss of vision (serious) o PTU 100-200mg q6-6h, and divided doses
 NO SPECS – to evaluate ophthalmopathy  50-100 mg (maintenance)
o 0 No signs or symptoms  Inhibits deiodination of T4 to T3
o 1 Only signs of lid retraction or lag  Shorter half-life = 90 min
o 2 Soft tissue involvement (periorbital edema)  Hepatotoxic
o 3 Proptosis (>22 mm)  Limit indication to 1st trimester of
o 4 Extraocular muscle involvement (diplopia) pregnancy, treatment of thyroid storm, and
o 5 Corneal involvement patients with minor adverse reactions to
o 6 Sight loss methimazole
o Carbimazole/Methimazole 10-20 mg q8-12h, OD after
LABORATORY EVALUATION euthyroidism
 Suppressed TSH  2.5-10 mg (maintenance)
 Increased TH (total and unbound)  Methimazole (active metabolite of
 Increased T3 (T3 toxicosis) – 2-5% carbimazole)
 TPO and TBII – used when diagnosis is unclear  Half-life = 6 h
 Elevated bilirubin, liver enzymes, and ferritin  The starting dose can be gradually reduced as thyrotoxicosis
 Microcytic anemia and thrombocytopenia improves (based on unbound T4 because TSH often remain
suppressed for months and do not provided sensitive index for
DIFFERENTIAL DIAGNOSIS treatment response)
 GD – biochemically confirmed thyrotoxicosis, diffuse goiter,  High doses may be combined with Levothyroxine to avoid
ophthalmopathy, and family history of immune disorders hypothyroidism.
 Radionuclide scan and uptake of thyroid – for those with lack of  Review thyroid function test 4-6 weeks after initiation of
features treatment.
o GD vs. Destructive thyroiditis, Ectopic thyroid tissue,  Maximum remission rates – 12-18 months
and Factitious thyrotoxicosis o Higher in those with no TRAb detection or with TRAb
o Toxic adenoma or toxic MNG persistence
 TRAb measurement – diagnose GD  Relapse when treatment stops
 Color-flow Doppler UTZ – distinguish between hyperthyroidism o Younger patients
and destructive thyroiditis o Males
 CT or MRI – tumor o Smokers
o History of allergy
Differentials o Severe hyperthyroidism
 Mimic panic attacks, mania, pheochromocytoma, and weight loss o Large goiters
associated with malignancy  Side effects:
 Exclude thyrotoxicosis if TSH and unbound T3 and T4 are normal o Minor
 Rash – use antihistamine
CLINICAL COURSE  Urticaria
 Mortality before therapy is 10-30%  Fever
 Spontaneous relapses and remissions  Arthralgia (1-5%)
 Resolve spontaneously or after using
 Fluctuation of hypo- and hyperthyroidism due to changes in TSH-R
alternative drug
antibodies activity
o Major – stop meds immediately
 Patients who enter remission after treatment (15%) 
 Hepatitis (PTU) – avoid in children
Hypothyroidism 10-15 years as a result of destructive
 Cholestasis (M&C)
autoimmune process
 Agranulocytosis (<1%)
 Ophthalmopathy – worsens over the initial 3-6 months followed
 Sore throat
by plateau phase over the next 12-18 months.
 Fever
 Radioiodine treatment – worsens eye disease especially smokers
 Mouth ulcers
 Urgent CBC to confirm
BB
 Propanolol 20-40 mg q6h
 Atenolol – longer-acting selective B1 receptor blockers
o Control adrenergic symptoms
o Thyrotoxic periodic paralysis
o Pending correction of thyrotoxicosis

Anticoagulants
 Warfarin – for atrial fibrillation
o Spontaneous reversion to sinus rhythm with control of
hyperthyroidism
o If digoxin is used, increase dose.

Radioiodine – causes progressive destruction of thyroid cells and used as

initial treatment for relapses after antithyroid drugs.
 Small risk of thyrotoxic crisis after RI – minimized by pretreatment
with antithyroid drugs for at least a month befor RI
 Antithyroid drugs + BB – for elderly patients and those with
cardiac problems.
  Carbimazole or methimazole must be stopped 2-3 days before RI
administration to achieve optimum iodine uptake and restarted 3-
7 days after RI in those with worsening thyrotoxicosis.
 PTU has prolonged radioprotective effect.
 Give fixed-dose based on clinical features such as severity of
thyrotoxicosis, size of goiter, and level of RI uptake.
o Dosage = 370-55 MBq (10-15 mCi)
 Safety precautions:
o Avoid close, prolonged contact with children and
pregnant women for 5-7 days because of possible
transmission of residual isotope and exposure to
radiation emanating from the gland.
o Mild pain due to radiation thyroiditis 1-2 weeks after
treatment
o Hyperthyroidism can persist for 2-3 months before RI
takes full effect.
o Persistent hyperthyroidism – treat with 2nd dose of RI 6
months after first dose.
 Pregnancy and BF are absolute contraindications.
o Can conceive 6 months after treatment.
 Caution to ophthalmopathy especially in smokers.
o Prednisone 30 mg/d at the time of RI treatment, and
tapered over 6-8 weeks – prevent exacerbation
Total or near-total thyroidectomy
 Indications
o For those who relapse after antithyroid drugs
o Prefer this over RI
o Young individuals with a very large goiter
 Antithyroid drugs followed by SSKI 1-2 drops orally TID x 10 days
o Given prior to surgery to avoid thyrotoxic crisis and
reduce vascularity of the gland
 Complications:
o Bleeding
o Laryngeal edema
o Hypoparathyroidism
o Damage to recurrent laryngeal nerve
 For pregnant:
o Dose titration based on free or total T4 or above
pregnancy reference range
o PTU – until 14-16 weeks of gestation (1st trimester)
 Methimazole/Carbimazole embryopathy –
Aplasia cutis, choanal atresia,
trachaeoesophageal fistulae
o After 1st trimester:
 PTU  Methimazole or carbimazole
 15-20 mg of PT is to 1 mg methimazole
o Possible to stop in last trimester because TSIs decline
in pregnancy
 Fetal or neonatal thyrotoxicosis:
o FHR > 160
o Advanced bone age
o Fetal goiter
o High levels of maternal TSI after 26 weeks of gestation
 GD in children:
o Methimazole or carbimazole
 Thyrotoxic crisis or thyroid storm – exacerbation of
hyperthyroidism accompanied by fever, delirium, seizures, coma,
vomiting, diarrhea, and jaundice
o Precipitated by acute illness, surgery, or RI
o PTU 500-1000 mg loading dose and 350 mg q4h orally
or via NGT or per rectum
o Methimazole 20 mg q6h
o On hour of first dose: SSKI 5 drops q6h is given – to
block thyroid hormone synthesis via Wolff-Chaikoff
effect
o Propanolol 60-80 mg PO q4h or 2 mg IV q4h – to
reduce adrenergic manifestations
 Caution to avoid acute negative inotropy
o Short-acting IV esmolol – decrease HR while
monitoring signs of HF
o Glucocorticoids like hydrocortisone 300 mg IV bolus
then 100 mg q8h
o Antibiotics if infection is present
o Cholestyramine to sequester thyroid hormones
o Cooling, oxygen and IV fluids
 Ophthalmopathy
o Smoking cessation
o Discomfort
 Hypromellose 0.3%
 Carbomer 0.2%
 Paraffin-based eye ointment
 Dark glasses with side frames
o Periorbital edema – upright sleeping position or
diuretic
o Corneal exposure – use of patches or taping eyelids
shut
o Diplopia – prisms fitted to spectacles
 Selenium 100 ug bd
o Optic nerve involvement or chemosis
 IV methylprednisolone 500 mg/wk x 6
weeks then 350 mg/wk x 6 weeks
 Preferable to oral
glucocorticoids (moderate)
 Orbital decompression – remove bone from
wall of the orbit, allowing displacement of
fat and swollen extraocular muscles
 Transantral route – no external
incision
o Proptosis – recedes an average of 5 mm  Diplopia
 Surgery
 External beam radiotherapy of orbits – for
those moderately active who failed with
glucocorticoid treatment
 Rituximab
o Thyroid dermopathy
 Topical high-potency glucocorticoid
ointment under an occlusive dressing
 Ocreotide
OTHER CAUSES OF THROTOXICOSIS
Destructive thyroiditis
 Subacute or silent thyroiditis
 Short thyrotoxic phase due to release of preformed hormones
and catabolism of Tg
 True hyperthyroidism is absent as demonstrated by low RI uptake
 Increase Tg
Thyyrotoxicosis factitial, iodine excess, and ectopic thyroid tissue (teratomas
of ovary or struma ovarii and metastatic follicular carcinoma)
 Low or absent RU uptake
 Low levels of Tg (ectopic thyroid tissue and thyrotoxicosis factitia)
Amiodarone (10%) – in areas of low iodine intake