Kenneth A. Woeber

Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association

OBJECTIVE Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. METHODS The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. RESULTS Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. CONCLUSIONS Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

Thyrotoxicosis and the Heart

Many patients with thyrotoxicosis have clinical features that reflect the effects of excess thyroid hormone on the cardiovascular system. Thyrotoxicosis can aggravate preexisting cardiac disease and can also lead to atrial fibrillation, congestive heart failure, or worsening of angina pectoris. In elderly patients, these cardiac manifestations may dominate the clinical picture and warrant the measurement of the serum thyrotropin concentration. In the absence of preexisting cardiac disease, treatment of thyrotoxicosis usually results in a return of normal cardiac function.

Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors.

Anaplastic thyroid carcinoma (ATC) is rare but is one of the most aggressive human malignancies. Several prognostic factors have been observed in patients with ATC, and some experts advocate aggressive multimodal therapy in selected patients. However, it is unclear whether such an approach significantly improves survival. The authors analyzed prognostic factors and treatment outcomes in patients with ATC reported in the National Cancer Institutes Surveillance, Epidemiology, and End Results data base.

The contribution of thyroxine-binding prealbumin to the binding of thyroxine in human serum, as assessed by immunoadsorption

An immunoadsorption technique employing a rabbit antiserum specific for human serum prealbumin has been devised to remove thyroxine (T(4))-binding prealbumin (TBPA) from serum completely without affecting the T(4)-binding activity of thyroxine-binding globulin (TBG) or the concentration of the other major proteins in serum. As judged from the proportion of T(4) associated with the antigen-antibody precipitate, only about 15% of the endogenous T(4) is bound by TBPA, a value considerably less than that indicated by electrophoretic methods. As judged from the increase in the proportion of free T(4) that followed immunoadsorption of TBPA, TBPA does act as one determinant of the proportion of free T(4) but is far less important than TBG in this respect. A decrease in the T(4)-binding capacity of TBPA cannot solely account for the increase in the proportion of free T(4) in the sera of ill patients, since a comparable increase does not occur in normal sera after complete removal of TBPA. From data obtained in normal and abnormal sera before and after immunoadsorption of TBPA, estimates of the equilibrium constants for the interactions between T(4) and its binding proteins, as they exist in serum, have been derived. The values obtained were: K(ALB), 6.2 x 10(5); K(TBPA), 2.3 x 10(8); and K(TBG), 1.7 x 10(10).

Induction of Myxedema by Iodide in Patients Euthyroid after Radioiodine or Surgical Treatment of Diffuse Toxic Goiter

Abstract In all 10 patients with diffuse toxic goiter of Graves disease rendered euthyroid by radioiodine six months to six years earlier, myxedema (as evidenced by typical signs and symptoms, rise...

Results of Rosiglitazone Therapy in Patients with Thyroglobulin-Positive and Radioiodine-Negative Advanced Differentiated Thyroid Cancer

BACKGROUND Rosiglitazone is a peroxisome proliferator-activated receptor (PPAR) gamma agonist that has shown promise as both an antiproliferative and redifferentiating agent for the treatment of thyroid cancer in preclinical studies. We investigated the efficacy and side effects of rosiglitazone therapy in patients with differentiated thyroid cancer of follicular cell origin that fails to take up radioiodine or is unresectable. METHODS Twenty patients with differentiated thyroid cancer were enrolled in an open-label, phase II trial of oral rosiglitazone treatment (4 mg daily for 1 week, then 8 mg daily for 7 weeks). RESULTS Five of 20 patients had a positive radioiodine scan after rosiglitazone treatment. Four patients had radioiodine uptake in the neck and one patient had uptake in the pelvis. Unstimulated thyroglobulin levels after rosiglitazone treatment increased in five patients, remained stable in 12 patients, and decreased in three patients. Seven patients had progressive disease on follow-up cross-sectional imaging; six patients in the size and number of lung metastasis and two patients in the size of the neck tumors. Overall, five patients had a partial response (decreased thyroglobulin or positive radioiodine uptake), three patients had stable disease (no change in thyroglobulin and radioiodine uptake status), and 12 patients had disease progression (increased thyroglobulin). By RECIST criteria, no patient had a complete or partial response to rosiglitazone treatment at 3 months follow-up. The mean follow-up time after protocol treatment was 12 months (median 12 months). CONCLUSIONS Our findings suggest that rosiglitazone therapy may induce radioiodine uptake and reduce serum thyroglobulin levels in some patients with differentiated thyroid cancer but this did not result in clinically significant response on long-term follow-up. Moreover, no patients had response to rosiglitazone therapy by anatomic imaging studies.

Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations

Although the normal thyroid gland secretes both levothyroxine (L-T4) and levotriiodothyronine (L-T3), normalization of serum TSH with LT4-replacement therapy alone in hypothyroidism is generally believed to result in a normal serum L-T3 and to reflect a euthyroid state. However several recent studies suggest that this may not be the case,. Accordingly, the relationship between serum free L-T4 and free L-T3 was examined in 20 normal individuals (group A) and in 53 patients with chronic autoimmune thyroiditis, 18 with normal TSH on no L-T4-replacement (group B), and 35 with normal TSH on L-T4-replacement therapy for hypothyroidism (group C). Data were analyzed by applying a one-way analysis of variance with correction for multiple comparisons. Serum TSH values were very similar among the 3 groups. In groups A and B, mean serum free T4 and free T3 were very similar. In group C, the mean free T4 (16±2 pmol/l) was significantly higher than the values in groups A (14±1) and B (14±2) (p<0.001) and the mean free T3 lower (4.0±0.5 pmol/l vs 4.2±0.5, NS and 4.4±0.5, p<0.02). Consequently, the mean molar ratio of free T4 to free T3 was significantly higher in group C than the ratios in groups A and B (p<0.0001), despite very similar TSH values. These findings indicate that in hypothyroid patients L-T4-replacement, that is sufficient to maintain a normal serum TSH, is accompanied by a serum free T4 that is higher than that in untreated euthyroid patients or normal individuals and may not result in an appropriately normal serum free T3 concentration.

Metabolism of L-Thyroxine by Phagocytosing Human Leukocytes

Intact normal human leukocytes deiodinated L-thyroxine (T(4)) with the generation of inorganic iodide, chromatographically immobile origin material, and small quantities of L-triiodothyronine (T(3)). When phagocytosis was induced in the leukocytes through the addition of zymosan particles that had been opsonized by coating with plasma, T(4)-deiodination was greatly stimulated. In addition to the stimulation of T(4)-deiodination, the accumulation by the leukocytes of undegraded T(4) was increased. Anoxia, which has previously been shown not to interfere with phagocytosis, did not prevent the increased cellular accumulation of T(4) that phagocytosis induced, but virtually abolished T(4)-deiodination. On the other hand, calcium, which has previously been shown to be required for optimal phagocytosis, was required for the increase in both the cellular accumulation and deiodination of T(4) that phagocytosis induced. Phospholipase-C, which has previously been shown to induce a metabolic burst that mimics that induced by phagocytosis, did not increase the cellular accumulation or deiodination of T(4). On the other hand, colchicine, which has previously been shown to depress the metabolic burst that accompanies phagocytosis, did not prevent the increase in either the cellular accumulation or deiodination of T(4) that phagocytosis induced. Thus, increased accumulation of T(4) by the leukocytes during phagocytosis appears to be the primary factor responsible for the stimulation of deiodination that phagocytosis induces. The increased accumulation of T(4) did not appear to be owing to engulfment of suspending medium surrounding the particles or to binding of T(4) to the particles themselves. In addition to the enhanced cellular accumulation, other factors related to the metabolic burst that accompanies phagocytosis might also be involved in the stimulation of T(4)-deiodination. In leukocytes from two patients with chronic granulomatous disease, a disorder in which phagocytosis appears to occur normally but in which the metabolic burst and attendant increase in hydrogen peroxide generation do not occur, stimulation of T(4)-deiodination was either greatly diminished or totally lacking. In myeloperoxidase-deficient leukocytes, on the other hand, stimulation of T(4)-deiodination was at least as great as that in normal cells. Thus, we conclude that the primary factor responsible for the increased deiodination of T(4) that phagocytosis induces is the enhanced cellular uptake of hormone. The increased generation of hydrogen peroxide that accompanies phagocytosis may be necessary for the enhanced deiodination of the accumulated T(4), but the latter reaction does not require the mediation of myeloperoxidase.

Thyroid hormone binding in nonthyroid illness

Abstract The binding of the thyroid hormones, L-thyroxine (T 4 ) and L-triiodothyronine (T 3 ), was examined in eight sera obtained from patients with severe illness and the results compared to those obtained in a concurrently studied normal serum pool. In these eight sera, the values for percent free T 4 (%FT 4 ) and free T 3 (%FT 3 ) measured by dialysis were distinctly increased. The calculated values for the absolute concentration of FT 4 in six of the eight sera were increased relative to the value in the normal pool and in all eitht sera were greatly underestimated by a free T 4 index based on an in vitro T 3 -uptake test. By contrast, the absolute concentration of free T 3 was distinctly increased in only one of the eight sera and this increase was reflected in the free T 3 index. Mixing of the normal serum pool with seven of the eight sera produced values for %FT 4 that significantly exceeded those in normal pool diluted with buffer so that the resulting values for thyroxine-binding globulin (TBG) binding capacity were equivalent to those in the serum mixtures. By contrast, values for %FT 3 in these sera did not differ in a consistent manner from those in the normal pool diluted with buffer to equivalent values for TBG binding capacity. Ultrafiltrates prepared from each of the eight sera, when employed in place of buffer as diluent for serum in the dialysis method for measuring %FT 4 , did not affect the %FT 4 in the normal serum pool. Likewise, immunoglobulin concentrates prepared from three sera were also without effect on the %FT 4 in the normal pool. We conclude that there is present in the serum of some patients with severe nonthyroid illness either a nonultrafilterable binding inhibitor or a protein-protein interaction that interferes with T 4 -binding to a greater extent than T 3 -binding, thereby resulting in a value for %FT 4 that is greater than can be accounted for by a decrease in TBG. Such a phenomenon might contribute to the underestimation by the in vitro T 3 -uptake test of the %FT 4 .

The Effects of Noncalorigenic Congeners of Salicylate on the Peripheral Metabolism of Thyroxine

Various experiments have indicated the presence in whole human serum of three major thyroxine (T4)-binding 1 proteins: T4-binding globulin (TBG), T4-binding prealbumin (TBPA), and albumin (1, 2). It is well established that, in vitro, TBGand TBPA are the major T4-binding proteins, whereas albumin is a relatively weak secondary carrier (3-5). These proteins interact with the hormone in a reversible binding equilibrium in which the majority of the hormone is bound but a measurable proportion is unbound or free. Free T4 has been suggested as the metabolically active component available to the cells in vivo for degradation, excretion, and initiation of hormonal action, with the bound hormone acting as a metabolically inert reservoir (3-5). The role of TBGin the transport and peripheral metabolism of T4 in man is well accepted. This acceptance is based on studies demonstrating a consistent relationship between changes in the T4-binding activity of TBG, as assessed by electrophoresis in vitro and changes in the concentration and fractional turnover of T4 in vivo (6-8). From these observations, the conclusion has been drawn that TBGregulates the peripheral metabolism of T4 by limiting the concentration of unbound hormone. The existence of TBPA as a normal constituent of human serum has been satisfactorily demonstrated by several techniques, and earlier doubts concerning its function in binding T4 at physiological pH have been dispelled (5, 9, 10). The role, if any, of -TBPA in regulating the peripheral metabolism of T4 in vivo has remained uncertain.