eMedicine Specialties > Endocrinology > Thyroid

Graves Disease: Differential Diagnoses & Workup

Author: Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Coauthor(s): Mouhammed Amir Habra, MD, Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center; Alice Cua Chiu, MD, Consulting Staff, Department of Internal Medicine, Division of Endocrinology, Columbia Bayshore Medical Center
Contributor Information and Disclosures

Updated: Jun 4, 2009

Differential Diagnoses

Anxiety Disorders
Thyroid, Papillary Carcinoma
Hashimoto Thyroiditis
Thyroiditis, Subacute
Hyperemesis Gravidarum
Toxicity, Cocaine
Pheochromocytoma
Wolff-Parkinson-White Syndrome
Pituitary Macroadenomas
Pituitary Microadenomas
Struma Ovarii

Other Problems to Be Considered

Drug-induced hyperthyroidism (eg, iodinated contrast, amiodarone, iodine supplements)
Drug-induced thyroiditis (eg, amiodarone, interferon-alfa)
Exogenous thyroid hormone (intentional or unintentional)
Radiation-induced thyroiditis
Toxic multinodular goiter
Trophoblastic tumors
Silent thyroiditis
Postpartum thyroiditis
Pituitary resistance to thyroid hormone
Abnormal thyroid-binding protein (eg, thyroxine autoantibodies, abnormal concentration or binding of thyroxine-binding globulin or transthyretin)

A summary of the differential diagnoses for thyrotoxicosis is as follows:

  • Graves disease: Special features include a diffusely enlarged thyroid gland, thyroid bruits, ophthalmopathy, pretibial myxedema, and the presence of TSIs.
  • Subacute thyroiditis: Special features include a history of antecedent respiratory tract infection, neck tenderness, elevated sedimentation rate, low or absent radioactive iodine uptake, and a self-limited course.
  • Silent thyroiditis: Special features include painless thyroiditis, which may be seen in postpartum women (postpartum thyroiditis); a self-limited course; and low radioiodine uptake.
  • Multinodular toxic goiter: Special features include a propensity to occur in elderly individuals and multiple nodules palpated or observed after thyroid scanning.
  • Toxic adenoma: Special features include a solitary palpable nodule and a hot nodule observed after thyroid scanning.
  • Factitious thyrotoxicosis: Special features include no goiter, a low thyroglobulin level, and low radioiodine uptake.
  • Iatrogenic thyrotoxicosis: The special feature is a history of thyroid hormone intake.
  • Iodide-induced thyrotoxicosis: The special feature is a propensity to occur in patients with a history of nodular thyroid disease who have been exposed to iodine-containing contrast agents or drugs such as amiodarone.
  • Thyrotropin-secreting pituitary adenoma: Special features include inappropriately elevated or normal thyrotropin levels in the setting of elevated free levothyroxine (T4) and free triiodothyronine (T3) levels, evidence of other pituitary hormone deficiencies, elevated alpha subunit level, and compressive symptoms.
  • Beta-human choriogonadotropin–induced thyrotoxicosis: Special features include a positive pregnancy test result, a history of hydatidiform mole, choriocarcinoma, and embryonal carcinoma of the testis. Also, rarely, it may be observed in normal gestation.

Workup

Laboratory Studies

  • Ultrasensitive (third-generation) thyrotropin assays remain the best screening test for thyroid disorders.
    • With the exception of thyrotropin-induced hyperthyroidism, subnormal or suppressed thyrotropin levels are seen in most patients with thyrotoxicosis.
    • Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index. Subclinical hyperthyroidism, defined as a free T4 or free T3 level within the reference range with suppressed thyrotropin, also can be seen.
    • On occasion, only the free T3 level is elevated, a syndrome known as T3 toxicosis. This may be associated with toxic nodular goiter or the ingestion of T3.
    • Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive.
    • Detection of TSIs is diagnostic for Graves disease.
    • The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated.
    • Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present.
    • Other autoantibodies that may be present include thyrotropin receptor–blocking antibodies and anti–sodium-iodide symporter antibody.
    • The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.
  • Liver function test results should be obtained to monitor for liver toxicity caused by thioamides (antithyroid medications).
  • A CBC count with differential should be obtained at baseline and with the development of fever or symptoms of infection. Graves disease may be associated with normocytic anemia, low-normal to slightly depressed total WBC count with relative lymphocytosis and monocytosis, low-normal to slightly depressed platelet count.  Thionamides may rarely cause severe hematologic side effects, but routine screening for these rare events is not cost-effective. 
  • Investigation of gynecomastia associated with Graves disease may reveal increased sex hormone–binding globulin levels and decreased free testosterone levels.
  • Graves disease may worsen diabetes control and may be reflected by an increase in hemoglobin A1C in diabetic patients.
  • A fasting lipid profile may show decreased total cholesterol levels and decreased triglyceride levels.
  • Thyrotropin-releasing hormone testing has largely been replaced by third-generation thyrotropin assays.
  • A high titer of serum antibodies to collagen XIII is associated with active Graves ophthalmopathy.

Imaging Studies

  • Radioactive iodine scanning and measurements of iodine uptake are useful in differentiating the causes of hyperthyroidism. In Graves disease, the radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland.
  • Ultrasounds with color-Doppler evaluation have been found to be cost-effective and should be performed as a first step in all hyperthyroid patients, and that scintigraphic examination should be limited only to the uncommon cases in which physician's observation, laboratory assays, and/or ultrasounds are not diagnostic.22 A prospective trial showed that thyroid ultrasound findings are predictive of radioiodine treatment outcome and that in patients with Graves disease, normoechogenic and large glands are associated with increased radioresistance.23
  • Computed tomography scanning or magnetic resonance imaging (of the orbits) may be necessary in the evaluation of proptosis. If routinely performed, most patients have evidence of orbitopathy, such as an increased volume of extraocular muscles and/or retrobulbar connective tissue. These techniques are useful to monitor changes over time or to ascertain the effects of treatment.

Histologic Findings

In select cases in which thyroidectomy was performed for the treatment of severe hyperthyroidism, the thyroid glands from patients with Graves disease show lymphocytic infiltrates and follicular hypertrophy, with little colloid present.

More on Graves Disease

Overview: Graves Disease
Differential Diagnoses & Workup: Graves Disease
Treatment & Medication: Graves Disease
Follow-up: Graves Disease
Multimedia: Graves Disease
References
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Further Reading

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Keywords

Graves’ disease, diffuse toxic goiter, thyrotoxicosis, hyperthyroidism, Basedow's disease, Basedow disease, autoimmune thyroid disorder, autoimmune polyglandular syndrome, pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic lupus erythematosus, thyroid antigens, thyroglobulin, thyroperoxidase, sodium-iodide symporter, TSH receptor, life-threatening thyrotoxic crisis, thyroid storm, Graves ophthalmopathy, thyroid acropachy, severe weight loss

osteoporosis, apathetic hyperthyroidism, cardiac hypertrophy, CTLA-4, pretibial myxedema, palpitation, nervousness, tremor, heat intolerance, hyperdefecation, inability to concentrate, proximal muscle weakness, easy fatigability with physical activity, proptosis, lid retraction, lacrimation, gritty sensation in the eye, photophobia, eye pain, diplopia, hyperhidrosis, increased sweating

restlessness, anxiety, irritability, insomnia, thyrotoxic periodic paralysis, onycholysis, alopecia, hyperactive deep-tendon reflexes, brisk deep-tendon reflexes, hypokalemic periodic paralysis, atrial fibrillation, cardiomyopathy, elevated transaminases, lid lag, irregular menstrual periods, gynecomastia, impotence, increased sex hormone–binding globulin levels,decreased free testosterone levels, decreased parathyroid hormone levels, decreased total cholesterol, decreased triglycerides, hand tremor, thyroid bruits

conjunctival injection, conjunctival chemosis, Yersinia enterocolitica, postpartum thyroid syndrome, use of interferons, use of interleukins, injection of percutaneous ethanol

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Contributor Information and Disclosures

Author

Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Mouhammed Amir Habra, MD, Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center
Mouhammed Amir Habra, MD is a member of the following medical societies: American College of Physicians, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Alice Cua Chiu, MD, Consulting Staff, Department of Internal Medicine, Division of Endocrinology, Columbia Bayshore Medical Center
Alice Cua Chiu, MD is a member of the following medical societies: American Medical Association and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Steven R Gambert, MD, MACP, Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine
Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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