Pediatric Graves Disease Workup

The following laboratory studies may be indicated:

• Thyroid-stimulating hormone

• Thyroxine

• Free thyroxine (free T4)

• Triiodothyronine

• Antithyroid antibodies (thyrotropin receptor antibody, thyroid stimulating immunoglobulin)

• Thyroid hormone binding index 

• Complete blood count (CBC)

• Liver function tests (LFTs, such as circulating levels of SGPT, SGOT, GGT, and bilirubin)

• Antinuclear antibody

• Serum calcium, urine calcium-to-creatinine ratio ^[13]

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 (TT ₄ ) levels are elevated in almost all patients with thyrotoxicosis except those with pure elevations in T ₃ (T ₃ toxicosis) and individuals with decreased T ₄ binding. Acutely ill individuals with sick syndrome may appear euthyroid when they are thyrotoxic.

FT ₄ may also be measured and is elevated except in patients with pure T ₃ toxicosis or the sick syndrome. T ₄ and FT ₄ are elevated in patients with pituitary insensitivity to thyroid hormone.

Triiodothyronine

T ₃ is elevated in all patients with thyrotoxicosis unless they are acutely or chronically ill, malnourished, or taking medication (eg, PTU) that interferes with the conversion of T ₄ to T ₃ peripherally.

T ₃ is slightly elevated in obesity and in overfeeding. Also, T ₃ 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 T ₃ .

Thyroid hormone binding index

The thyroid hormone binding index (THBI), sometimes referred to as the T ₃ resin uptake (T ₃ RU), measures binding of thyroid hormone to serum proteins. In combination with the TT ₄ , THBI estimates FT ₄ . 

THBI is elevated in almost all patients with thyrotoxicosis except for those with pure T ₃ 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 T ₄ , THBI is elevated in patients with pituitary insensitivity to thyroid hormone. Recent free T4 assays overcome most of the limitations of THBI. 

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

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 may be reassuring if later CBC counts reveal a slight leukopenia, because PTU or 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.

Additional tests

Ultrasonography of the thyroid may help to define anatomy in puzzling cases but is almost never indicated in classic Graves disease.

If cardiovascular complications are a concern, an electrocardiogram can be beneficial but is not routinely done in practice. 

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.

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 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 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, 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.

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. The formation of many small, new 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 seen. T cells and B cells may be identified. ^[14] 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.

Fluid accumulates in periorbital tissues. Extraocular muscles may be infiltrated with lymphocytes.

Thickening of the subcutaneous tissues because of deposition of glycosaminoglycans (pretibial myxedema) may rarely be found in children.