Articles on Medical Diseases and Conditions

Tag: Thyroid

  • Thyroid

    Thyroid carcinoma seems to have generated a considerable number of misconceptions. About 20% of these tumors are “pure” papillary, about 10% pure follicular, about 50% mixed papillary and follicular, and about 5% (range, 2%–10%) are called medullary. However, the pure papillary carcinoma usually has a few follicular elements if enough histologic sections are made, and the reverse is sometimes true in follicular tumors. In addition, some pathologists classify the tumors according to the predominant element unless the proportions of each element are very similar. If this were done, about 65% would be called papillary and about 20% follicular. There is enough diversity in classification methods to create difficulty in relating pathology reports to statistics in the literature. Papillary and most mixed papillary-follicular carcinomas metastasize primarily to regional lymph nodes. Prognosis is excellent in young adults but less so in older persons. Follicular carcinoma tends to produce hematogenous metastases, most often to lungs and bone. About 15% (range, 4%–30%) of single palpable nodules not selected by thyroid scan or fine-needle aspiration are malignant when excised.

    Thyroid radionuclide scan. A major screening test is the thyroid scan. The characteristic appearance of thyroid carcinoma is a single nonfunctioning nodule. A gland that is multinodular on scan has less chance of containing carcinoma than one with a solitary nodule. On occasion, a palpable nodule may represent metastatic carcinoma from another primary site in a lymph node close to the thyroid.

    Radionuclide scanning of thyroid nodules can be done with radioactive iodine (RAI) or technetium 99m pertechnetate. Results from comparison studies usually agree, but occasionally carcinomas that appear to have some function on technetium scan but not on iodine scan have been found. About 20% of single thyroid nodules without demonstrable function on scan are malignant (literature range, 3%–58%). About 6% of nodules with some function (reduced, but present) and about 6%–8% of nodules with apparent normal function (literature range, 0%–38%) are reported to be malignant. In some of these cases, normal thyroid tissue above or below the nodule creates a false impression of nodule function. Hyperactive nodules are very rarely malignant, although occasionally a malignancy is found unexpectedly in the same gland.

    A minority of investigators believe that radioiodine or technetium scanning is not helpful in evaluation of thyroid nodules for possible malignancy. As noted previously, a single nodule without demonstrable function on scan has roughly a 20% chance of malignancy, which means that 80% of such nodules will be falsely positive for malignancy. On the other hand, some reports indicate that 6%–8% of nodules with apparently normal function may actually be malignant and thus represent false negative results. Therefore, some investigators rely on criteria other than thyroid scan to determine which patients with thyroid nodules should receive operative therapy. The criteria that have been used include patient history, characteristics of the nodule on physical examination, fine needle aspiration, or response of the nodule to thyroid hormone suppression. In the suppression test, failure of the nodule to diminish at least 50% in size during 3 months of suppression would increase the chance of malignancy.

    A significant number of patients are referred for thyroid scan while thyroid uptake of radionuclide is being suppressed by administration of thyroid hormone or by x-ray contrast media. This frequently produces unsatisfactory or even misleading results.

    Thyroid scan to detect thyroid carcinoma metastases. A different problem may arise when thyroid cancer is discovered and patients are referred for scanning to detect metastases, either before or after initial therapy. Unless all of the normal thyroid tissue is removed or is ablated by radioiodine therapy, enough of the scanning dose will be taken up by normal tissue to make such attempts useless in most cases. In addition, replacement thyroid hormone administration must cease for 2-4 weeks before scanning, so that the pituitary will once again produce thyroid-stimulating hormone (TSH), which, in turn, will help stimulate the tumor to take up the radioiodine. The dose of (RAI (1–5 mCi; SI, 0.037–0.185 MBq) for a metastatic tumor scan is more than 10 times the usual thyroid scan dose, and the optimal time to scan is 72 hours after administration of the dose. Some prefer a technetium phosphate bone scan to an iodine 131 (131 I) tumor scan. Most bone metastases detected by iodine are also detected by technetium phosphate, and the remaining thyroid tissue does not have to be ablated. However, a few bone metastases are detected by radioiodine and not by technetium. Lung metastases or recurrent neck tumor would be missed using technetium bone scan agents.

    Serum thyroglobulin (TG) assay. Serum thyroglobulin (TG) assay has been advocated to follow patients after treatment of thyroid carcinoma. TG is synthesized by thyroid epithelial cells. It is present in measurable amounts in the serum of normal persons on immunoassay (using antibodies against TG) and is increased following TSH stimulation. Elevated values are found in active thyrotoxicosis (diffuse or nodular), thyroiditis, iodine deficiency, benign thyroid adenomas, and differentiated thyroid carcinomas. Therefore, TG elevation is too nonspecific to use for diagnosis of thyroid carcinoma. In thyroid carcinoma, the TG level is usually elevated in papillary, follicular, and mixed papillary-follicular neoplasms. Some anaplastic thyroid carcinomas produce elevated values and some do not. Medullary carcinomas do not produce measurable serum levels of TG. The TG assay can be used to monitor the progress of differentiated thyroid carcinomas after treatment. The half-life of circulating TG is said to be 8-22 hours, so circulating levels should be absent in 7-14 days after total destruction of all normal thyroid tissue and tumor tissue by surgery. Ablation by radioactive iodine is much more gradual and variable. TG values that are nondetectable or nearly so following therapy signify that no residual thyroid or tumor remains, and future elevations mean tumor recurrence or metastasis. Thyroglobulin values that are within the reference range following therapy could either be tumor or could be remnants of normal thyroid, and a thyroid tumor scan with 131 I is required to differentiate these possibilities.

    One advantage of TG monitoring is less need for 131 I scanning. This avoids both additional radiation and the need to temporarily stop thyroxine replacement therapy to perform the scan. Also, occasionally patients with metastases associated with elevated TG levels but not detected on 131 I tumor scan have been reported. Disadvantages include a small number of patients with metastases detected on 131 I tumor scan but TG values within the reference range. This occurs in about 4% of cases (literature range, 0%–63%). TG levels are more likely to be normal with pure papillary tumors or those with only lung metastases. Also, the presence of patient anti-TG autoantibodies may interfere with the TG assay.

    Fine-needle aspiration cytology. Fine-needle aspiration of thyroid nodules with cytologic smear examination of the aspirate has been advocated to aid diagnosis and, when possible, to replace surgical biopsy. Results in the literature vary rather widely, partially depending on experience with the technique, patient selection, and method of reporting positive results (for example, “definitely malignant” would detect fewer cases of carcinoma than the combination of “malignant” and “suspicious for malignancy”). Some centers report a false negative rate of less than 5% and a false positive rate of less than 2%. Most hospitals could not expect to achieve such good results. The average false negative rate for malignancy with experienced cytologists is about 5%–10%, and the average reported rate overall is about 10%–15% (literature range, 0%–50%). Follicular carcinoma is more difficult to diagnose than papillary carcinoma. The average false positive rate for experienced cytologists is about 2%–4%, and the average reported rate overall is about 5% (range, 0%–14%). Most pathologists without special interest or extensive experience in fine-needle aspiration cytology are better able to interpret needle tissue biopsy material than thyroid aspiration cytology, because thyroid cytology takes special training and experience. However, well-differentiated follicular carcinoma is difficult to diagnose on needle biopsy as well as on aspiration. Needle biopsy is also useful to diagnose thyroiditis.

    Thermography and B-mode ultrasound have been used to help evaluate thyroid nodules for malignancy. Results of thermography to date have been rather disappointing. Ultrasound has been used to differentiate cystic thyroid lesions from solid ones. About 15%–20% of thyroid nodules that fail to concentrate radioactive iodine are cystic. Typical completely cystic lesions are rarely malignant (about 2%; literature range, 0%–14%). Ultrasound accuracy in differentiating pure cystic lesions from solid or mixed cystic-solid lesions is usually quoted as about 95% (80%–100%). The procedure in many clinics is to perform aspiration with cytology on ultrasonically pure cysts.

    Medullary carcinoma of the thyroid. Medullary carcinoma constitutes 5% (range, 2%–10%) of thyroid carcinomas. It is derived from certain stromal cells known as “C-cells.” The tumor has an intermediate degree of malignancy. It may occur sporadically or in a hereditary form. The sporadic form comprises 80%–90% of cases and is usually unilateral. The familial variety is transmitted as an autosomal dominant trait, is usually present in both thyroid lobes, and is frequently associated with other neoplasms (phenochromocytoma, mucosal neuromas) as part of MEN II (Sipple Syndrome,Table 33-13) or MEN III. This also includes some degree of association with other endocrine abnormalities, such as parathyroid adenoma and Cushing’s syndrome. The tumor may have a variety of histologic patterns, but the classic form is solid nests of cells that are separated by a stroma containing amyloid. These tumors have aroused great interest, since most secrete abnormal amounts of the hormone calcitonin (thyrocalcitonin). Calcitonin has a calcium-lowering action derived from inhibition of bone resorption; therefore, calcitonin acts as an antagonist to parathyroid hormone. Thyroid C cells produce calcitonin as a normal reaction to the stimulus of hypercalcemia. About 70%–75% of medullary carcinomas produce elevated levels of serum calcitonin; this includes most sporadic (nonfamilial) cases. About 25%–30% of familial medullary carcinoma (MEN type III or IIB) have normal basal calcitonin levels. In patients with normal basal calcitonin levels, elevated calcitonin values can be induced by stimulation with calcium infusion or pentagastrin. Glucagon also stimulates calcitonin secretion but not as effectively. A few medullary carcinomas are reported to secrete serotonin or prostaglandins. About 30% of patients experience diarrhea. Besides medullary thyroid carcinoma, calcitonin secretion has been reported in as many as 60% of patients with bronchogenic carcinoma (small cell and adenocarcinoma tumor types).

    33-13

    Table 33-13 Multiple endocrine neoplasias

  • Thyroiditis

    The usual classification of thyroiditis includes acute thyroiditis, subacute thyroiditis, chronic thyroiditis, and Riedel’s struma.

    Acute thyroiditis is generally defined as acute bacterial infection of the thyroid. Signs, symptoms, and laboratory data are those of acute localized infection.

    Riedel’s struma consists of thyroid parenchymal replacement by dense connective tissue. In some cases at least this presumably represents scar tissue from previous thyroiditis. Thyroid function tests are either normal (if sufficient normal thyroid remains) or indicate primary hypothyroidism.

    Subacute thyroiditis (granulomatous thyroiditis or de Quervain’s disease) features destruction of thyroid acini with a granulomatous reaction consisting of multinucleated giant cells of the foreign body reaction type and large histiocytes. The etiology is unknown but possibly is viral or autoimmune. The classic syndrome of subacute thyroiditis includes thyroid enlargement (usually less than twice normal size) with pain and tenderness, symptoms of thyrotoxicosis, substantially increased ESR, increased T4, T3-RIA, and THBR (T3U) values, and decreased RAIU values. Thyroid scans demonstrate patchy isotope concentration throughout the thyroid gland (occasionally, only in focal areas) or else very little uptake. Classic cases have been reported to progress through four sequential stages: hyperthyroidism, followed by transient euthyroidism, then hypothyroidism, and then full recovery. Recovery in most cases takes place in 3-5 months. The classic syndrome is estimated to occur in approximately 50%-60% of patients with subacute thyroiditis. Milder or nonclassic cases lack the symptoms and laboratory findings of thyrotoxicosis. However, the ESR is usually elevated, and the RAIU value is usually decreased.

    Painless thyroiditis (also called “silent thyroiditis”) describes a group of patients with a syndrome combining some elements of subacute thyroiditis with some aspects of chronic thyroiditis (Hashimoto’s disease). These patients have nonpainful thyroid swelling with or without clinical symptoms of thyrotoxicosis. Laboratory data include increased T4, T3-RIA, and THBR values, decreased RAIU value, patchy thyroid scan, and normal or minimally elevated ESR. Painless thyroiditis thus differs from subacute thyroiditis by lack of pain in the thyroid area and by normal ESR. Although some consider this syndrome to be a painless variant of subacute thyroiditis, biopsies of most cases have disclosed histologic findings of chronic lymphocytic thyroiditis rather than subacute thyroiditis. The reported incidence of this condition has varied from 5%-30% of all cases of hyperthyroidism. However, one report suggests that the incidence varies with geographic location, with the highest rates being in the Great Lakes region of the United States and in Japan.

    Postpartum transient toxicosis is a syndrome that is said to occur in as many as 5%-6% (literature range, 5%-11%) of previously euthyroid postpartum women. There is transient symptomatic or asymptomatic thyrotoxicosis with elevated T4 and low RAIU values, similar to the findings in thyrotoxic silent thyroiditis. This episode in some cases is followed by transient hypothyroidism. Thyroid autoantibody titers are elevated, suggesting lymphocytic thyroiditis.

    Chronic thyroiditis is characterized histologically by dense lymphocytic infiltration of the thyroid with destruction of varying amounts of thyroid parenchyma. Chronic thyroiditis is frequently divided into two subdivisions: lymphocytic thyroiditis, most frequent in children and young adults, and Hashimoto’s disease, found most often in adults aged 30-50 years. In both cases females are affected much more often than males. In approximately one half of chronic thyroiditis patients, serum T4 levels are normal and the patients are clinically euthyroid. In 20%-40% the T4level is decreased, and there may be variable degrees of hypothyroidism. In some patients with decreased T4 levels the T3-RIA may be normal and presumably is responsible for maintaining clinical euthyroidism. The RAIU value is normal in 30%-50% of cases. In 10%-30% the RAIU value is increased, especially in the early stages of the disease. In fact, an elevated RAIU value with a normal T4 value definitely raises the possibility of active (early) chronic thyroiditis. The ESR is usually normal. Thyroid scan discloses generalized patchy isotope distribution in approximately 50% of cases and focal patchy or reduced uptake in 5%-10% more. In approximately one third of cases various precursors of T4 or abnormal thyroglobulin derivatives are released from damaged thyroid acini. In about 5% of patients with chronic thyroiditis, release of thyroid hormone derivatives produces hyperthyroidism with increased serum T4 levels. The RAIU value may be elevated or decreased. If the RAIU value is decreased, these patients might be considered part of the “thyrotoxic silent thyroiditis” group. On the other hand, some patients with chronic thyroiditis eventually develop sufficient damage to the thyroid to produce permanent hypothyroidism.

    Lymphocytic thyroiditis and Hashimoto’s disease are very similar, and some do not differentiate between them. However, in lymphocytic thyroiditis the goiter tends to enlarge more slowly, abnormal iodoproteins tend to appear more often, and the RAIU value tends to be elevated more frequently. Hashimoto’s disease tends to have more histologic evidence of a peculiar eosinophilic change of thyroid acinar epithelial cells called “Askenazi cell transformation.” Exact diagnosis of chronic thyroiditis is important for several reasons: to differentiate the condition from thyroid carcinoma, because a diffusely enlarged thyroid raises the question of possible thyrotoxicosis, and because treatment with thyroid hormone gives excellent results, especially in childhood lymphocytic thyroiditis.

    Thyroid autoantibodies. Both subgroups of chronic thyroiditis are now considered to be either due to or associated with an autoimmune disorder directed against thyroid tissue. Autoantibodies against one or another element of thyroid tissue have been detected in most cases. In addition, there is an increased incidence of serologically detectable thyroid autoantibodies in rheumatoid-collagen disease patients, conditions themselves associated with disturbances in the body autoimmune mechanisms. There are two major subgroups of thyroid autoantibodies, those active against thyroglobulin and those directed against the microsome component of thyroid cells. There are several different techniques available to detect these antibodies, including, in order of increasing sensitivity: latex agglutination (antithyroglobulin antibodies only), immunofluorescence, hemagglutination (also known as the tanned [tannic acid-treated] red blood cell [or TRC] test), and radioassay. At present radioimmunoassay and immunofluorescence are not widely available, and most reference laboratories use some modification of the hemagglutination test.

    In general, antimicrosomal antibodies are found more often in chronic thyroiditis than antithyroglobulin antibodies. Antithyroglobulin antibodies are found less often in diseases other than chronic thyroiditis, but this increase in specificity is only moderate, and neither test has adequate selectivity for chronic thyroiditis (Table 29-1). High titers are much more likely to be associated with chronic thyroiditis than with nontoxic nodular goiter or thyroid carcinoma. High titers of antimicrosomal antibodies (or both antimicrosomal and antithyroglobulin antibodies) are not specific for chronic thyroiditis, because patients with Graves’ disease or primary hypothyroidism may have either high or low titers. Normal or only slightly elevated titers, however, constitute some evidence against the diagnosis of chronic thyroiditis.

    29-1

    Table 29-1 Thyroid autoantibody test results in thyroid diseases (hemagglutination method)*

  • Monitoring of Replacement Therapy

    Desiccated thyroid and presumably other T4 and T3 combinations result in T3-RIA values that may become elevated for several hours after administration and then decrease into the reference range. T4 values remain within the reference range if replacement is adequate. In the few instances when clinical evidence and T4 results disagree, TSH assay is helpful. Elevated TSH values suggest insufficient therapy. Unfortunately, low TSH values using standard TSH kits is not a reliable indicator of over treatment since most of these kits produce considerable overlap between normal persons and those with decreased values in the low reference range area. Ultra sensitive TSH kits should solve this problem if the kit is reliable.

    L-Thyroxine (Synthroid, Levothroid) results in T3-RIA values that, in athyrotic persons, are approximately two thirds of those expected at a comparable T4 level when thyroid function is normal. This is due to peripheral tissue conversion of T4 to T3. The T3-RIA values are more labile than T4 values and are more affected by residual thyroid function. The standard test to monitor L-thyroxine therapy is the T4 assay. There is disagreement whether T4 values must be in the upper half of the T4 reference range or whether they can be mildly elevated. In general, when the TSH value returns to its reference range, the T4 level stabilizes somewhere between 2 µg above and below the upper limit of the T4 range. T4 elevation more than 2 µg above reference range probably suggests too much dosage. A minority believe that T4 values should not be above the reference range at all. On the other hand, T4 values in the lower half of the reference range are usually associated with elevated TSH levels and probably represent insufficient replacement dose. Some investigators favor T3-RIA to monitor therapy rather than T4 or TSH. The THBR value is most often within reference range with adequate replacement dose but has not been advocated for monitoring therapeutic effect.

    One report indicates that dosage requirement decreases after age 65 years.