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FIRST CONSULT
Hyperthyroidism
Key points
Hyperthyroidism, the presence of excessive thyroid hormone produced by the thyroid gland, is
usually caused by Graves disease, toxic multinodular goiter, toxic uninodular goiter, and
thyroiditis
Diagnosis involves testing to assess levels of thyroid-stimulating hormone (TSH) and thyroid
function
Treatment is aimed at relieving symptoms and restoring metabolic function
Take immediate action in patients with thyroid storm, a life-threatening condition
Background
Description
Epidemiology
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Men: 33/100,000
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Demographics
Age:
Graves disease peaks in third to fourth decade of life, rare before 10 years of age
Toxic multinodular goiter is more common in patients older than 50 years and with history
of nontoxic goiter
Toxic solitary nodules are most common in patients in third and fourth decades of life
Gender:
Graves disease affects more women than men in a ratio of 7:1
Toxic multinodular goiter is more common in women
Genetics:
Graves disease has a familial predisposition and can overlap clinically and immunologically
with Hashimoto disease
Common causes:
Toxic diffuse goiter or Graves disease (most common cause): an autoimmune disease in
which thyroid gland is being stimulated by thyrotropin receptor antibodies, also known as
thyroid-stimulating immunoglobulin
Toxic multinodular goiter: multiple areas in thyroid gland overproduce thyroid hormone
independently of TSH
Toxic uninodular goiter (adenoma): solitary nodule in thyroid gland overproducing thyroid
hormone independently of TSH
Subacute thyroiditis : usually idiopathic but sometimes can be result of virally mediated
inflammation and destruction of thyroid gland. Consequently, stored thyroid hormones are
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released into circulation, causing transient thyrotoxic state and thyroid pain
Associated disorders
Myasthenia gravis
Pernicious anemia
Type I diabetes mellitus
Vitiligo
Rheumatoid arthritis
Systemic lupus erythematosus
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Addison disease
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Screening
Not applicable.
Primary prevention
Preventive measures
Tobacco:
Diagnosis
Summary approach
Normal or high uptake is seen in Graves disease and toxic uninodular or toxic multinodular
goiter. Falsely elevated uptake may also be seen in patients recently treated with diuretics,
which may deplete endogenous iodine. Thyroid scan helps discriminate between these
entities
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Hashimoto thyroiditis and Graves disease) and as risk factor for postpartum and
drug-related thyroiditis
Clinical presentation
Symptoms
Nervousness
Sweating
Sensitivity to heat
Fatigue
Eye irritation
Palpitations
Dyspnea
Increase in appetite
Increased frequency of bowel movement, or diarrhea
Oligomenorrhea or amenorrhea
Swelling in legs
Signs
Tachycardia
Fever
Weight loss (although weight gain can occur in up to one third of patients due to increased
appetite)
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In elderly patients:
Unexplained weight loss
Congestive heart failure
Atrial fibrillation
Proximal muscle weakness
In children:
Accelerated linear growth
Eye signs are more common
Examination
Note appearance of toxicity or confusion. Consider thyroid storm
Assess vital signs, including weight. Patients will usually be tachycardic at rest, and there
may be orthostasis secondary to decreased intravascular volume
Examine hands for warmth and fine tremor
Check eyes for erythema, stare, lid lag, and proptosis. Comparison of a photograph from the
past with patient's current appearance can bring out subtle changes in proptosis
Inspect neck for goiter, thyroid nodules, lymphadenopathy, asymmetry, and thyroid bruit
Perform cardiac exam to check for arrhythmia and for cardiac bruit, which may have
resulted from long-standing hyperthyroidism and high-output failure
Inspect muscle strength and reflexes, especially proximal muscle weakness. Have patient
squat; usually he/she has difficulty standing back up
Patients will have brisk reflexes with rapid relaxation phase and may even exhibit clonus
Questions to ask
Presenting condition:
What symptoms are you experiencing? For how long? Have you ever experienced them
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Has anyone commented that your appearance is changed? Patients frequently report that
others have commented that they look flushed or bright-eyed
Do you have any difficulty swallowing or pain in your throat? Suggests significant goiter
size, recent change in goiter size, or possibly subacute thyroiditis
Do you have any history of head or neck irradiation? Patients with nodular thyroid disease
and history of irradiation are at increased risk of thyroid cancer
Do you have difficulty climbing steps, arising from a chair, or lifting objects over your
head? Suggests weakness of proximal muscles
Have you taken any over-the-counter or illicit drugs? Ephedrine, pseudoephedrine, and
phenylpropanolamine all mimic and exacerbate the symptoms of hyperthyroidism, as do
several illicit drugs
Do you have any medication allergies? Allergy to thioamides will affect choice of therapy
Are you pregnant or breastfeeding? Affects choice of therapy
Contributory or predisposing factors:
What other medical conditions do you have? Other autoimmune diseases may suggest
predisposition to Graves disease
Do you use tobacco? Tobacco usage may aggravate Graves ophthalmopathy and may
influence therapy
Have you recently taken intravenous radiographic contrast, expectorants, amiodarone, or
health foods containing kelp or seaweed? These agents have high iodine contents and may
exacerbate hyperthyroidism and confound thyroid uptake testing
Family history:
Any family history of thyroid problems? Autoimmune thyroid disease can present as
hyperthyroidism or hypothyroidism in a family
Diagnostic testing
High-sensitivity thyroid-stimulating hormone (TSH) (178807)is the best single screen for
hyperthyroidism. Normal test rules out all sources of thyrotoxicosis except those from
excess TSH
Peripheral thyroid function tests (281595): Free T4is preferred as lead thyroid function test after
TSH. Regular T4and T3resin uptake are alternatives to assess level of circulating T4levels.
Useful to assess severity and follow therapy
gland will produce excess of T3rather than T4. Useful if T4is normal but patient is clinically
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Radioiodine uptake (178815)measures avidity with which thyroid gland is absorbing iodine.
High or normal in cases of hyperthyroidism from Graves disease or toxic nodular goiter but
low or absent in thyroiditis
Thyroid scan (178831)can be done with either 123-iodine or 99-technetium and identifies
areas in thyroid gland that are taking up iodine. Useful in evaluating palpable nodules in
thyroid gland to tell if they are functioning and in differentiating Graves disease from toxic
nodular goiter
Testing for thyrotropin receptor autoantibodies (1214353)is useful in the pregnant Graves patient
to assess likelihood that newborn will have hyperthyroidism
Description
Description
Thyroxine (T4), triiodothyronine (T3) resin uptake, and free thyroid index or free T4,
T3radioimmunoassay, or free T3
Cuffed venous blood sample
Normal ranges
Serum T4: 5.5 to 12.5 g/dL
Serum T3resin uptake: 25% to 35%
Serum T3: 60 to 180 ng/dL
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T3 radioimmunoassay or free T3
Description
Radioiodine uptake
Description
Thyroid scan
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Description
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Nuclear medicine test using a radioactive iodine tracer to measure thyroid functionality
Normal result
Lobes of thyroid appear as pear-shaped homogenous structures connected by thin
isthmus on scintiscan
Dimensions of normal thyroid are up to 5 cm x 3 cm
Comments
Useful in delineating structural abnormalities of thyroid; helps distinguish Graves
disease from multinodular goiter and toxic adenoma from cold nodule
Patient must return for scanning at 24 hours
Contraindicated in pregnancy and breastfeeding because of risk of radiation to
developing thyroid in fetus or infant
Similar to uptake function test. Imaging can be performed in combination with thyroid
uptake but requires larger dose of isotope
Overall, of limited use in evaluation of hyperthyroidism
Description
Description
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Several types of autoantibodies to thyrotropin receptors occur, and several are capable of
activating thyroid hormone production
Description
Differential diagnosis
Anxiety
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Thyroid malignancy
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Acquired immune deficiency syndrome (AIDS) leaves individual vulnerable to illnesses that a
Thyroiditis
In Hashimoto thyroiditis, thyroid gland is firmer and more lobulated than in Graves
disease
Antithyroid antibodies may be elevated in both conditions
In subacute thyroiditis, antibodies are negative, gland is usually tender to touch, there is
often a viral prodrome, and ESR is elevated
In post-partum or sporadic thyroiditis, antibody levels may also be elevated, but course
more closely resembles that of subacute thyroiditis. Patient may subsequently develop
permanent hypothyroidism
Pheochromocytoma
Pheochromocytoma most commonly arises from chromaffin cells of adrenal medulla but
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Consultation
Infiltrative orbitopathy of Graves disease may follow a course independent from thyroid
Treatment
Summary approach
Immediate action
except in children and pregnant women. Achieves permanent cure of hyperthyroidism and
has lower costs and complications when compared to surgery. However, there is risk of
permanent hypothyroidism and thyroiditis, as well as usual risks associated with radiation
They offer patients a chance of permanent remission; advantages include low cost and no
risk of permanent hypothyroidism. May be used as monotherapy in patients with mild
disease or to treat symptoms before patients are treated with radioactive iodine or surgery.
Remember that both thioureylenes and 131-iodine are effective only in patients producing
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excess thyroid hormone ( eg , Graves disease) but not in those with thyroiditis
Subtotal or total thyroidectomy (178904)is rarely treatment of first choice. May be recommended
in young children, pregnant women who have had adverse reaction to pharmacotherapy,
patients with compressive symptoms, those in whom there is concern about possibility of
thyroid cancer, and when rapid control of hyperthyroidism is needed or avoidance of
with surgery. Surgery may be more effective in treating Graves ophthalmopathy than other
treatment modalities
Treatment with alternative agents, such as lithium, potassium perchlorate, iodine ipodate
Calcium-channel blockers are rarely used (unless -blockers are contraindicated) as they do
not have any antiadrenergic properties. Diltiazem may be useful for rate control in patients
intolerant to propranolol
There is no evidence that moderating amount of iodine in diet will have any clinical effect in
hyperthyroid patients
Graves disease
Graves disease may remit in up to 40% of cases and can be treated with thioureylenes for 6
to 18 months
If no remission is achieved, patient can receive radioactive 131-iodine or thyroidectomy
There is some evidence to suggest that Graves ophthalmopathy improves after thyroid
surgery but not after radioactive iodine ablation. Rituximab has been used to treat Graves
ophthalmopathy
Active Graves ophthalmopathy may benefit from various means of eye protection, such as
sunglasses, artificial tears, elevation of head of bed, and eye protection at night
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Patients with toxic uninodular and multinodular goiter do not go into remission and require
surgery or radioactive 131-iodine. Thioureylenes and/or -blockers may be given prior to
definitive therapies
Medications
Thioureylenes
Indication
Treatment of hyperthyroidism
Dose information
Methimazole :
Adult: 300 to 450 mg/d initially by mouth given in divided doses every 8 hours; usual
maintenance dose is 100 to 150 mg/d, given in divided doses every 8 hours to a
maximum of 1200 mg/d
Pediatric: 5 to 7 mg/kg/d by mouth given in divided doses every 8 hours
Major contraindications
Breastfeeding (methimazole)
Comments
Safety and efficacy of propylthiouracil in patients younger than 6 years of age have not
been established
Evidence
A small randomized trial that compared a single daily dose of methimazole versus a
single daily dose of propylthiouracil for 12 weeks in 71 patients with newly diagnosed
Graves disease found that methimazole (15 mg/d) was more effective than
propylthiouracil in promoting euthyroidism. [1] Level of evidence: 2
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treatment with methimazole. However, this effect was often transient and could be
prevented by administration of prednisone. [2] Level of evidence: 2
References
Propranolol
Indication
Use caution in patients with diabetes (may mask signs of hypoglycemia), severe
peripheral vascular disease, hyperthyroidism, pheochromocytoma, vasospastic angina,
coronary artery disease, bronchospastic disease, myocardial infarction, cardiac failure,
and those patients preparing for surgery
Evidence
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References
Non-drug treatments
Radioactive 131-iodine
Description
Thyroidectomy
Description
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Indication
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Often recommended in young children (in whom safety of radioactive iodide therapy is
not established)
Pregnant women who have had a major adverse reaction to antithyroid agents. If
thyroidectomy is necessary in pregnancy it is safest in second trimester
Patients in whom a large goiter is causing tracheal compression
Patients in whom there is concern about possibility of thyroid cancer
Potentially patients with Graves ophthalmopathy
When rapid control of hyperthyroidism is necessary or when avoidance of worsening of
symptoms is required ( ie , cardiac patients)
Complications
Bleeding:
Postoperative bleeding in neck is a particular problem because it occurs in confined
space with airway. Even small amounts of hematoma can cause airway compromise
Typical signs and symptoms of postoperative bleeding include expanding mass,
impending sense of doom, squeaky voice, patient sitting up and leaning forward, and
airway compromise
If bleeding is suspected, it is critical that incision and underlying tissue layers are opened
to trachea immediately. This should not be delayed by intubation or by returning patient
back to operating room
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large doses of oral calcium and vitamin D supplements several times per day
Infection:
Infection is exceedingly rare in neck
Comments
Patient should receive thioureylenes to render them euthyroid preoperatively to decrease
risk of thyroid storm
Iodine (eg, 3-5 drops of Lugol solution three times a day by mouth for 10-14 days before
surgery) should be given preoperatively in patients with Graves disease to decrease
vascularity of gland and possibility of thyroid storm
Evidence
A meta-analysis of studies involving a total of 7241 patients with Graves disease found
that thyroidectomy (either partial or total) is successful treatment for
hyperthyroidism. All patients who underwent total thyroidectomy were rendered
hypothyroid. Of patients who underwent subtotal thyroidectomy, nearly 60% were
rendered euthyroid, about 26% became hypothyroid, and about 8% had persistent or
recurrent hyperthyroidism. [5] Level of evidence: 2
A comprehensive study of the English clinical literature from 1980 looked at the
experience in seven randomized, controlled trials (RCTs) of nearly 10,000 patients
undergoing total thyroidectomy for Graves disease and concluded that procedure was
effective therapy for both Graves disease and Graves ophthalmopathy. [6] Level of
evidence: 2
References
Other measures
Special circumstances
Comorbidities
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Frequently, pregnancy has an ameliorative effect on Graves disease, and patients can be
maintained on low dose of antithyroid medication. Patients should be seen at 4- to
6-week intervals. Thyroid-stimulating antibodies can be checked at 22 to 26 weeks
gestation and will help predict risk for neonatal hyperthyroidism
Patients should be seen 6 weeks postpartum because Graves is likely to worsen then.
Radioactive 131-iodine is contraindicated in pregnancy and when nursing. Patients with
Radioactive 131-iodine has been used safely in patients under 20 years of age but has
limited experience in patients younger than 10 years
Consultation
Follow-up
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which time thyroid function tests are ordered to check for hypothyroidism. Thyroid function
tests should be monitored every 6 to 8 weeks until euthyroidism is achieved
Secondary prevention
Patients must be followed with TSH annually after therapy. Hyperthyroidism may recur in
patients treated with thioureylenes, and hypothyroidism can develop in patients treated with
radioiodine or surgery
Prognosis
Prognosis is good with therapy. There will be some failures with initial therapy, but therapy
can be repeated or different therapy tried
Therapeutic failure:
Patients who develop serious allergic reactions to thioureylenes will need alternative therapy,
usually radioiodine
To achieve temporary control of thyrotoxicosis while awaiting effects of radioiodine,
propranolol can be prescribed for symptomatic relief
Patients who fail to respond to radioactive iodine within 6 to 9 months should be retreated
with larger dose
Pretreatment with propylthiouracil may decrease effectiveness of 131-iodine ablation
Recurrence:
About 50% of patients may not achieve sustained remission with thioamides, in which case
therapy can be repeated. However, it is more common to give definitive therapy with
radioiodine or thyroidectomy if Graves disease recurs or fails to remit
Clinical complications
Hyperthyroidism is risk factor for development of osteoporosis later in life
Untreated hyperthyroidism, even subclinical hyperthyroidism, puts patient at risk for atrial
fibrillation
Patient education
needs of euthyroid patient compared with hyperthyroid patient. Patients should concentrate
on healthy eating habits
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Patients receiving treatment for hyperthyroidism frequently experience hair loss, a result of
fluctuating hormone levels and not an adverse effect of medication
Patients with a history of hyperthyroidism are at risk for osteoporosis and will need to be
advised and counseled
Resources
Summary of evidence
Evidence
A small randomized trial that compared a single daily dose of methimazole versus a
single daily dose of propylthiouracil for 12 weeks in 71 patients with newly diagnosed
Graves disease found that methimazole (15 mg/d) was more effective than
propylthiouracil in promoting euthyroidism. [1] Level of evidence: 2
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group showed greater improvement than placebo group. [4] Level of evidence: 2
A meta-analysis of studies involving a total of 7241 patients with Graves disease found
that thyroidectomy (either partial or total) is successful treatment for hyperthyroidism.
All patients who underwent total thyroidectomy were rendered hypothyroid. Of patients
who underwent subtotal thyroidectomy, nearly 60% were rendered euthyroid, about 26%
became hypothyroid, and about 8% had persistent or recurrent hyperthyroidism. [5]
Level of evidence: 2
A comprehensive study of the English clinical literature from 1980 looked at the
experience in seven RCTs of nearly 10,000 patients undergoing total thyroidectomy for
Graves disease and concluded that procedure was effective therapy for both Graves
disease and Graves ophthalmopathy. [6] Level of evidence: 2
References
References
Evidence references
3. Abraham P, Avenell A, Park CM, Watson WA, Bevan JS. A systematic review of drug
therapy for Graves' hyperthyroidism. Eur J Endocrinol. 2005;153:489-98
View In Article (refInSitu47149) | CrossRef (http://dx.doi.org/10.1530%2Feje.1.01993)
4. Henderson JM, Portmann L, Van Melle G, et al. Propranolol as an adjunct therapy for
hyperthyroid tremor. Eur Neurol. 1997;37:182-5
View In Article (refInSitucid_05362)
5. Palit TK, Miller CC 3rd, Miltenburg DM. The efficacy of thyroidectomy for Graves' disease:
a meta-analysis. J Surg Res. 2000;90:161-5
View In Article (refInSitucid_05365) | CrossRef (http://dx.doi.org/10.1006%2Fjsre.2000.5875)
Guidelines
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clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Joint statement
on management from the AACE, ATA, and ES. Subclinical thyroid dysfunction
guidelines for patients with thyroid nodules and differentiated thyroid cancer (http://www.thyroid.org
/professionals/publications/documents/Guidelinesthy2006.pdf). Thyroid. 2006;16:109-142
/upload/Clinical-Guideline-Management-of-Thyroid-Dysfunction-during-Pregnancy-Postpartum.pdf). J
Further reading
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LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin
North Am. 2006;35:117-36
Kung AW. Clinical review: Thyrotoxic periodic paralysis: a diagnostic challenge. J Clin
Endocrinol Metab. 2006;91:2490-95
Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med. 2003;348:2646-55
Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352:905-17
Bahn RS, Burch HS, Cooper DS, et al. The role of propylthiouracil in the management of
Graves' disease in adults: report of a meeting jointly sponsored by the American Thyroid
Association and the Food and Drug Administration. Thyroid. 2009;19:673-74
Rivkees SA, Mattison DR. Propylthiouracil (PTU) hepatotoxicity in children and
recommendations for discontinuation of use. Int J Pediatr Endocrinol.
2009;2009:1320-41
Rivkees SA. The treatment of Graves' disease in children. J Pediatr Endocrinol Metab.
2006;19:1095-111
Cohen-Lehman J, Dahl P, Danzi S, Klein I. Effects of amiodarone therapy on thyroid
function. Nat Rev Endocrinol. 2010;6:34-41
Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced
thyrotoxicosis. J Clin Endocrinol Metab. 2010;95:2529-35
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Reid JR, Wheeler SF. Hyperthyroidism: diagnosis and treatment. Am Fam Physician.
2005,72:623-30,635-6
Codes
ICD-9 code
FAQ
required in patients with clear stigmata of Graves disease. However, when etiology of
hyperthyroidism is unclear, radioactive iodine uptake and scan can differentiate between
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goiter and calculate I-131 dose to be given to patients undergoing radioactive iodine therapy
In which order are treatments for Graves disease generally recommended?
There is a substantial amount of regional variation in the choice of initial therapy for Graves
disease. It is important for clinicians to be guided by patient preference. Radioactive iodine
ablation is often recommended as first-line treatment because it is generally easiest and
most efficacious therapy; however, it is contraindicated in patients with significant eye
disease as worsening of eye-findings can be seen after iodine ablation. Also, many patients
do not like idea of taking radiation internally. Antithyroid medications work well and are
generally well tolerated. They can be used as long as there are no adverse effects. Surgery
may be best option if patient has severe compressive symptoms or severe ophthalmopathy
Contributors
Elizabeth Pearce, MD
David W. Toth, MD
Kathleen M. O'Hanlon, MD
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