eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Graves Disease: Differential Diagnoses & Workup

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Coauthor(s): Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Contributor Information and Disclosures

Updated: Jun 4, 2009

Differential Diagnoses

Anxiety Disorder: Generalized Anxiety
Attention Deficit Hyperactivity Disorder
McCune-Albright Syndrome
Thyroiditis

Other Problems to Be Considered

TSH-secreting pituitary tumor
Autonomously functioning thyroid nodule
Toxic multinodular goiter
Ingestion of exogenous thyroid hormone
Hydatidiform mole/choriocarcinoma
Struma ovarii associated with a teratoma
Pituitary resistance to thyroid hormone
Subacute thyroiditis
Metastatic follicular carcinoma
Bipolar disorder

Workup

Laboratory Studies

  • Thyroid-stimulating hormone
    • TSH levels are suppressed in Graves disease and in all forms of thyrotoxicosis except thyrotoxicosis due to a TSH-secreting tumor of pituitary or other origin.
    • Children with pituitary thyroid hormone resistance also have elevated TSH levels.
  • Thyroxine
    • Total serum thyroxine (TT4) levels are elevated in almost all patients with thyrotoxicosis except those with pure elevations in T3 (T3 toxicosis) and individuals with decreased thyroxine (T4) binding.
    • Acutely ill individuals with sick syndrome may appear euthyroid when they are thyrotoxic.
    • FT4 may also be measured and is elevated except in patients with pure T3 toxicosis or the sick syndrome. T4 and FT4 are elevated in patients with pituitary insensitivity to thyroid hormone.
  • Thyroid hormone binding index
    • Thyroid hormone binding index (THBI), sometimes referred to as the T3 resin uptake (T3RU), measures binding of thyroid hormone to serum proteins. In combination with the TT4, THBI estimates FT4.
    • THBI is elevated in almost all patients with thyrotoxicosis except for those with pure T3 toxicosis. THBI is also elevated in patients with decreased serum thyroid binding proteins (TBG deficiency).
    • THBI may not be elevated in acutely ill individuals with sick syndrome.
    • Like T4, THBI is elevated in patients with pituitary insensitivity to thyroid hormone.
  • Triiodothyronine
    • T3 is elevated in all patients with thyrotoxicosis unless they are acutely or chronically ill, malnourished, or taking medication (eg, propylthiouracil) that interferes with the conversion of T4 to T3 peripherally.
    • T3 is slightly elevated in obesity and in overfeeding.
    • T3 levels are higher in children in the first several years of life than in older children.
    • Children with pituitary resistance to thyroid hormone also have elevated serum T3.
  • Antithyroid antibodies
    • Graves disease is almost always associated with measurable markers of autoimmunity in the form of suppressive or destructive antibodies.
    • Elevated levels of anti-TPO, antimicrosomal, or antithyroglobulin antibodies (in order of sensitivity) usually confirm the autoimmune nature of the thyrotoxicosis without recourse to the more difficult in vitro bioassays for TBI or TSI.
  • Thyroid-stimulating or thyroid-binding immunoglobulins
    • Measures of these antibodies by in vitro bioassay confirm Graves disease but are rarely necessary for diagnosis. Occasionally, these are not measurable even in patients with clinically proven Graves disease.
    • Maternal titers of these antibodies may be predictive of the severity of neonatal thyrotoxicosis.
  • CBC count: Graves disease may be associated with a leukopenia and relative increase in lymphocytes as well as a mild anemia. In a child who is treated with an antithyroid drug, a baseline CBC count may be reassuring if later CBC counts reveal a slight leukopenia because propylthiouracil (PTU) and methimazole may induce neutropenia.
  • Liver function tests
    • Severe thyrotoxicosis may be associated with elevations in liver enzymes and in bilirubin (thyroid storm).
    • If antithyroid drugs are to be used to treat thyrotoxicosis, initial liver enzyme levels (aspartate aminotransferase [AST] or SGPT is usually sufficient) that are within the reference range are reassuring because these drugs can induce hepatitis.
  • Other measures of autoimmune function, including antinuclear antibody
    • Thyrotoxicosis may be associated with lupus.
    • In patients with nonspecific symptoms of joint and muscle pain, a negative antinuclear antibody (ANA) can be reassuring. The ANA may become positive during treatment with antithyroid drugs if an immune response to the medication occurs, and this is associated with arthritis or arthralgia.
  • Serum calcium, urine calcium-to-creatinine ratio
    • Rare individuals have symptoms of polyuria, nocturia, and thirst as a result of hypercalcuria.
    • Documentation of hypercalcuria and reference range serum calcium levels may be useful.

Imaging Studies

  • Thyroid scanning and radioactive iodine uptake
    • Thyroid scanning is rarely indicated for the diagnosis of classic Graves disease.
    • If a thyroid nodule is identified and autonomously functioning nodular disease is suspected, perform an iodine I-123 (123 I) scanning.
    • Technetium scans reveal the thyroid, but quantitation of uptake is not usually possible. Technetium is taken up by the thyroid but not organified; thus, discrepancies between iodine and technetium scanning results may be observed. Administration of123 I also facilitates calculation of a radioactive iodine uptake (RAIU), which is not necessary for the diagnosis of Graves disease.
    • Because iodine sufficiency in the North American diet widely varies, standards for RAIU are quite wide and may be confusing in the diagnosis of thyrotoxicosis; however, radioactive iodine (RAI) scanning and uptake can be useful when a goiter is not noted in a hyperthyroid patient or other disorders are suspected. For instance, the hyperthyroidism of subacute thyroiditis is associated with the release of thyroid hormone from a damaged thyroid gland. Therefore, despite thyrotoxicosis, the RAIU is very low. Similarly, in factitious hyperthyroidism because of thyroid hormone ingestion or the rare hyperthyroidism associated with struma ovarii, the RAIU is suppressed.
    • Because of higher radiation exposure, RAIUs using iodine I-131 (131 I) are now limited to patients who undergo RAI therapy for treatment of thyrotoxicosis or for visualization of residual thyroid malignancy.
  • Ultrasonography: Ultrasonography of the thyroid may help to define anatomy in puzzling cases but is almost never indicated in classic Graves disease.

Procedures

  • Fine-needle aspiration biopsy of the thyroid is rarely indicated in the diagnosis of Graves disease, but biopsy of a suspicious nodular lesion can usually be conducted without incident, even in the presence of the vascular gland of Graves disease.

Histologic Findings

  • Thyroid: The TSH receptor antibodies that are etiologic in Graves disease stimulate the thyroid gland and produce diffuse hyperplasia. Loss of normal thyroid colloid and a hyperemic gland is observed. Formation of many new small follicles is noted, and the thyroid cells form tall columnar structures. The blood vessels are larger than normal. Patchy lymphocytic infiltrates are found between follicles, and lymphoid hyperplasia may be found. Both T cells and B cells may be identified. The outflow from the thyroid gland is enriched with anti-TSH receptor antibodies, suggesting that these mononuclear cells are a major source of the autoantibodies that maintain the disorder.
  • Eyes: Fluid accumulates in periorbital tissues. Extraocular muscles may be infiltrated with lymphocytes.
  • Skin: Thickening of the subcutaneous tissues because of deposition of glycosaminoglycans (pretibial myxedema) may rarely be found in children.

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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References

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Further Reading

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Keywords

Graves disease, Graves's disease, hyperthyroidism, thyrotoxicosis, von Basedow disease, thyroid-stimulating immunoglobulin, TSI, thyroxine, T4, triiodothyronine, T3, transient neonatal Graves thyrotoxicosis, insomnia, attention deficit hyperactivity disorder, ADHD, heat intolerance, muscle wasting, decreased bone density, hypercalcuria, hyposthenuria, nocturnal enuresis, thyroid storm, exophthalmos, enlarged thyroid, attention deficit disorder, ADD, mitral valve prolapse, atrial fibrillation, hypokalemia, acanthosis nigricans, café au lait spots, McCune-Albright syndrome

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers Bureau Honoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Independent contractor; MacroGenics, Inc. Grant/research funds Independent contractor; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Independent contractor

Coauthor(s)

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds PI, also occasional consultant

Medical Editor

Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece
George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

 
 
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