A 2013 European survey of clinical practice patterns in the management of Graves' disease.

OBJECTIVE: Management of Graves' disease (GD) in Europe was published in 1987. Aim of this survey was to provide an update on clinical practice in Europe, and to compare it with a 2011 American survey. DESIGN: Members of the European Thyroid Association (ETA) were asked to participate in a survey on management of GD, using the same questionnaire of a recent American survey. RESULTS: A total of 147 ETA members participated. In addition to serum TSH and free T4 assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (85·6%) and thyroid ultrasound (70·6%) to confirm aetiology, while isotopic studies were selected by 37·7%. Antithyroid drug (ATD) therapy was the preferred first-line treatment (83·8%). Compared to the previous European survey, Europeans currently more frequently use TRAb measurement and thyroid ultrasound for diagnosis and evaluation, but first-line treatment remains ATDs in a similar percentage of respondents. Current clinical practice patterns differ from those in North America, where isotopic studies are more frequently used, and radioiodine (RAI) still is first-line treatment. When RAI treatment is selected in the presence of mild Graves' orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis is frequently used. The preferred ATD in pregnancy is propylthiouracil in the first trimester and methimazole in the second and third trimesters, similar to North America. CONCLUSIONS: Significant changes in clinical practice patterns in Europe were noted compared to the previous European survey, as well as persisting differences in diagnosis and therapy between Europe and North America.

Addition of chlorine during water purification reduces iodine content of drinking water and contributes to iodine deficiency.

Drinking water is the major natural source of iodine in many European countries. In the present study, we examined possible sites of iodine loss during the usual water purification process.Water samples from 6 sites during the technological process were taken and analyzed for iodine content. Under laboratory circumstances, prepared iodine in water solution has been used as a model to test the effect of the presence of chlorine. Samples from the purification sites revealed that in the presence of chlorine there is a progressive loss of iodine from the water. In the chlorine concentrations employed in the purification process, 24-h chlorine exposure eliminated more than 50% of iodine when the initial iodine concentration was 250 µg/l or less. Iodine was completely eliminated if the starting concentration was 16 µg/l.We conclude that chlorine used during water purification may be a major contributor to iodine deficiency in European communities.

Novel biomarker SYT12 may contribute to predicting papillary thyroid cancer outcomes.

AIM: To investigate biomarkers for predicting papillary thyroid cancer outcomes. MATERIALS & METHODS: The expression of biomarkers (ITGA2, SYT12 and CDH3) was studied in a prospective cohort of patients with papillary thyroid cancer. Three outcomes of initial metastases, baseline status and longitudinal status were analyzed and correlated with the biomarkers. RESULTS: SYT12 provided the best prediction of initial metastasis (sensitivity: 72%; specificity: 54%). SYT12 had the highest accuracy for predicting longitudinal status (sensitivity: 100%; specificity: 47%). The best performance for longitudinal status resulted from combining SYT12 with American Thyroid Association risk stratification, with sensitivity and specificity of 88 and 73%, respectively. CONCLUSION: SYT12 has some prognostic significance in papillary thyroid cancer. Further validation studies in larger populations are warranted.

Production, isolation, and characterization of rabbit anti-idiotypic antibodies directed against human antithyrotrophin receptor antibodies.

Previous studies have shown that anti-idiotypic antibodies can be developed in vivo through animal immunization with idiotype, and that these antibodies can be isolated from other anti-immunoglobulin antibodies by affinity purification. These techniques have relied on large amounts of idiotype, which were produced either by hyperimmunization or by monoclonal antibodies, to serve as the affinity adsorbent. In the present study, we produced anti-idiotypic antibodies to human anti-thyroid-stimulating hormone (TSH) receptor antibodies by first injecting rabbits with (TSH receptor purified) IgG from Graves' patients. The resulting antiserum was then adsorbed with Sepharose-coupled TSH in an attempt to specifically bind and isolate the anti-idiotype. The antibody obtained from this process was shown to bind specifically to TSH receptor-binding antibodies from Graves' patients, and this binding could be inhibited by 56% with the addition of 10(-4) M TSH but not by HCG (10(-2) M). The anti-idiotype also bound to TSH, and this binding could be specifically inhibited by receptor-purified Graves' IgG (60% inhibition at 10 micrograms/ml IgG), but not by IgG from normal subjects (no inhibition at 50 micrograms/ml IgG). In a TSH receptor binding assay, the anti-idiotype could inhibit TSH receptor binding in Graves' sera at a 1,000-fold lower concentration than could anti-kappa/lambda antiserum; the anti-idiotypic antiserum also inhibited in vitro TSH-mediated adenylate cyclase stimulation at an IgG concentration of 5 micrograms/ml, while heterologous anti-TSH antisera and normal IgG at similar concentrations had no effect. Finally, despite being generated against a single patient's TSH receptor binding antibody, the anti-idiotype was able to block TSH receptor binding in the serum of six other Graves' patients, thus suggesting that there may be conformational conservation in the antigen that is recognized by different individuals' TSH receptor-binding immunoglobulins.

Partial characterization and clinical correlation of circulating human immunoglobulins directed against thyrotrophin binding sites in guinea pig fat cell membranes. Development of a direct enzyme immunoassay.

To obviate several problems inherent in indirect thyroid-stimulating hormone (TSH) receptor antibody assays, we developed an enzyme-linked immunosorbent assay (ELISA) that measures antibodies binding to guinea pig fat cell membrane, which contain high concentrations of TSH receptors. Solubilized guinea pig fat cell membranes were adsorbed to plastic microtiter plates and served as the solid-phase antigen. Test sera and affinity-purified alkaline phosphatase-conjugated anti-human IgG were co-incubated with membranes, after which p-nitrophenyl phosphate was added. Results were read when a positive control reached a standard color change (OD405nm). Specificity of this assay was demonstrated by the inability of albumin, insulin, TSH subunits, propranolol, or dexamethasone to block binding 30. normal subjects had a mean OD value of 0.080 +/- 0.050 (SD). 23 of 25 untreated Graves' patients had OD values at least 2 SD above the normal mean (Grave's mean +/- SD; 0.46 +/- 0.33, P less than 0.001) and in each case 10(-6) M TSH inhibited the binding by at least 60%, suggesting that the immunoglobulins were directed at the TSH receptor. Seven of 25 serum samples from patients with Hashimoto's disease, seven of 23 serum samples from patients with transient hyperthyroidism (subacute thyroiditis or painless thyrotoxic thyroiditis), and two of 10 samples from patients with thyroid carcinoma had significant elevations in the titers of membrane-directed immunoglobulins. Graves' patients who were treated with ablative therapy at least 6 mo earlier and who were euthyroid when restudied continued to have abnormally elevated membrane-directed immunoglobulins in six of eight samples studied. Further studies involved the substitution of affinity-purified alkaline phosphatase anti-IgM antisera for the anti-IgG antisera routinely used. Seven of 12 serum samples from patients with Graves' disease had significant elevations in binding which in every instance was inhibited by greater than 60% by 10(-6) M TSH. In sum, the present results indicate that (a) we have developed a sensitive, specific, reproducible, convenient ELISA for the measurement both of the total amount of circulating membrane-directed antibodies and of TSH-displaceable membrane-directed immunoglobulins. (b) This ELISA detected significant elevations in TSH-displaceable guinea pig membrane binding in 23 of 25 untreated Graves' patients as well as in approximately 30% of patients with Hashimoto's thyroiditis and subacute thyroiditis. (c) Elevated membrane directed antibodies may continue to be present many months or years after restoration of the euthyroid state. (d) Circulating membrane binding IgM immunoglobulins have been detected in patients with Graves' disease. Further studies using this ELISA should prove useful in a variety of investigative and clinical studies.

Overexpression and overactivation of Akt in thyroid carcinoma.

Enhanced activation of Akt occurs in Cowden's disease, an inherited syndrome of follicular thyroid, breast, colon, and skin tumors, via inactivation of its regulatory protein, PTEN. Whereas PTEN inactivation is uncommon in sporadic thyroid cancer, activation of growth factor pathways that signal through Akt is frequently identified. We hypothesized that Akt overactivation could be a common finding in sporadic thyroid cancer and might be important in thyroid cancer biology. We examined thyroid cancer cells lines and benign and malignant thyroid tissue for total Akt activation and isoform-specific Akt expression. In thyroid cancer cells, Akt 1, 2, and 3 proteins were expressed, total Akt was activated by insulin phosphatidylinositol 3'-kinase, and inhibition of phosphatidylinositol 3'-kinase reduced cell viability. In human thyroid tissue, increased levels of phosphorylated total Akt were identified in follicular but not papillary cancers compared with normal tissue. Levels of Akt 1 and 2 proteins and Akt 2 RNA were elevated only in the follicular cancers. In paired samples, Akt 1, 2, 3, and phospho-Akt levels were higher in five of six cancers, including three of three follicular cancers. These data suggest that Akt activation may play a role in the pathogenesis or progression of sporadic thyroid cancer.

Autoantibodies to insulin are present in sera of patients with autoimmune thyroid disease.

It has been clinically suspected that patients with autoimmune thyroid disease are at an increased risk of developing other autoimmune diseases later in life. To determine the presence and potential importance of a more generalized deregulation of immune response in patients with Grave's disease and Hashimoto's disease, sera from 33 patients with Graves' disease and 16 patients with Hashimoto's disease were screened for the presence of anti-insulin antibodies and anti-insulin-receptor antibodies. An enzyme-linked immunosorbent assay was used to identify the presence of IgG against human insulin. The optical density indicating the presence of IgG against insulin in sera from patients with Graves' disease averaged .172 +/- .024 (mean +/- SE; range .010-.802), compared to the mean normal value of .098 +/- .0009 (range .012-.238) in 33 control subjects. Ten of 33 patients with Graves' disease had values greater than .200, whereas control sera values were less than .200 in all but one case (P less than .005, Graves' sera vs. controls). The sera from patients with Hashimoto's disease had a mean optical density of .110 +/- .016, with 15 of 16 values between .010 and .200. These values were not significantly different from controls with an insulin-binding inhibition assay. Anti-insulin-receptor antibodies were not detected in any of 33 patients with Graves' disease, and cytoplasmic islet cell antibodies were not detected in sera from seven patients with Graves' disease who had insulin-binding antibodies. These data support the hypothesis that the immunologic response in autoimmune thyroid disease may be more heterogeneous and polyclonal than previously believed.

Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer.

INTRODUCTION: Akt activation is involved in the pathogenesis of inherited thyroid cancer in Cowden's syndrome and in sporadic thyroid cancers. In cell culture, Akt regulates thyroid cell growth and survival; but recent data suggest that Akt also regulates cell motility in non-thyroid cell lines. We therefore sought to evaluate the role of Akt in thyroid cancer progression. METHODS: We evaluated 46 thyroid cancer, 20 thyroid follicular adenoma, and adjacent normal tissues samples by immunohistochemistry for activated Akt (pAkt), Akt 1, 2, and 3, and p27 expression. Immunoblots were performed in 14 samples. RESULTS: Akt activation was identified in 10/10 follicular cancers, 26/26 papillary cancers, and 2/10 follicular variant of papillary cancers, but in only 4/66 normal tissue samples and 2/10 typical benign follicular adenomas. Immunoactive pAkt was greatest in regions of capsular invasion; and was localised to the nucleus in follicular cancers and the cytoplasm in papillary cancers, except for invasive regions of papillary cancers where it localised to both compartments. Immunoactive Akt 1, but not Akt 2 or Akt 3, correlated with pAkt localisation, and nuclear pAkt was associated with cytoplasmic expression of p27. In vitro studies using human thyroid cancer cells demonstrated that nuclear translocation of Akt 1 and pAkt were associated with cytoplasmic p27 and cell invasion and migration. Cell migration and the localisation of Akt 1, pAkt, and p27 were inhibited by PI3 kinase, but not MEK inhibition. DISCUSSION: These data suggest an important role for nuclear activation of Akt 1 in thyroid cancer progression.

Angiotensin-converting enzyme activity. A potential marker of tissue hypothyroidism in critical illness.

We measured serum angiotensin-converting enzyme (ACE) activity radiometrically as a possible indicator of reduced thyroid function in 57 euthyroid controls, 27 patients in a noncardiac intensive care unit (13 with medical and 14 with surgical disorders), and 29 patients having coronary artery bypass grafting. In the last group, blood was obtained preoperatively and one day and one month after surgery (group 1; n = 18) or preoperatively and six hours and one day after surgery (group 2; n = 11). Patients in group 1 had significant reductions in levels of serum thyroxine (T4), triiodothyronine (T3), and thyrotropin response to protirelin one day postoperatively. The ACE activity fell significantly. Patients in group 2 had low levels of T4, T3, thyrotropin, and ACE six hours postoperatively. All these levels remained low the next day, and free T4 and free T3 levels were also reduced; the reverse T3 level became elevated. Changes in ACE significantly paralleled changes in T3. The 27 patients without coronary artery bypass grafting also had significant reductions in serum T4, T3, and ACE levels. Dilution studies and dialysis of serum with low ACE activity failed to demonstrate an inhibitor to explain the reduced enzyme function.

Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea.

Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. There are presently no markers that can reliably distinguish benign and malignant neuroendocrine tumors. Here we describe a 63-year-old woman who developed sudden chest pain and hypertension combined with increased stool frequency. An incidental adrenal mass 5 cm in size with a bright signal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and (131)I-metaiodobenzylguanidine (MIBG) scintigraphy were negative. Histopathological examination revealed a mature adrenal GN. Neuroblastoma, the immature form of a GN, is known for deletions on chromosomal locus 1p36, and adrenal tumors frequently show allele loss on 17p. To further elucidate the histo- and pathogenesis of adrenal GN, we performed loss of heterozygosity studies on chromosomal loci 1p34-36 and 17p13 (the p53 gene locus) after careful microdissection of tumor and normal tissue. We did not detect allelic losses at these loci with the informative polymorphic markers used, suggesting that these loci are not involved in tumorigenesis. In addition, immunohistochemical investigation of the GN was positive for vasoactive intestinal peptide, a hormone commonly expressed in ganglion cells. We suggest that in our patient with an adrenal GN, the combination of biochemical, scintigraphic, molecular, immunohistochemical, and histopathological findings are all consistent with the benign morphology of this tumor.

The effect of experimental hyperthyroidism and hypothyroidism on 5'-monodeiodination of 3,3',5'-triiodothyronine and 3',5'-diiodothyronine by rat liver and kidney.

To study the effect of alterations in thyroid status on 5'-monodeiodinase activity, conversions of rT3 to 3,3'-diiodothyronine and 3',5'-diiodothyronine (3',5'-T2) to 3'-monoiodothyronine were examined in vitro. Rats were injected either with T4 (10 micrograms/100 g BW, ip, daily for 12 days) to make them thyrotoxic or thyroidectomized to render them hypothyroid, and liver and kidney homogenates were prepared. Liver homogenates from hyperthyroid animals demonstrated a 2-fold increase in 5'-monodeiodination of both rT3 and 3',5'-T2; both reactions were also significantly increased in the kidneys of hyperthyroid rats. Hypothyroidism produced a significant decrease in 5'-deiodination of both rT3 and 3',5'-T2 in liver and kidney homogenates. These data indicate that the in vitro 5'-deiodination of both rT3 and 3',5'-T2 is increased in hyperthyroidism and decreased in hypothyroidism and suggest that these two iodothyronines are metabolized in a similar fashion in rat liver and kidney homogenates in states of altered thyroid function.

Reduction in hepatic triiodothyronine binding capacity induced by fasting.

Triiodothyronine (T3) receptor kinetics were determined in liver nuclei isolated from fasting and fed rats. The results indicate that although affinity equilibrium constants (Ka) did not differ in the two groups, mean (+/- SE) maximal binding capacity (MBC) was reduced significantly to .30 +/- .05 nM/mg DNA in fasting compared to .46 +/- .07 nM/mg DNA (p less than .01) in the fed state. This observed decrease in MBC during fasting apparently could not be accounted for by a differential rates of loss of either DNA or of the receptor during the period of incubation.

Effects of thyroid hormone on the insulin receptor in rat liver membranes.

Although many studies have investigated the complex interrelationships between thyroid hormone levels and insulin-glucose secretion and action, there is at present a lack of information concerning the effects of various thyroid hormone levels on insulin receptors. In the present study, rat liver membranes were prepared from control, hyperthyroid [10 micrograms L-T4 (T4)/100 g BW for 14 days], and hypothyroid rats and the binding characteristics of [125I]iodoinsulin to these membranes were studied. In addition, serum T3, T4, glucose, and insulin levels were measured. The mean (+/- SD) serum T4 and T3 levels were higher (P less than 0.05) in the T4-injected rats than in the hypothyroid rats (T4, 9.1 +/- 0.6 vs. 1.7 +/- 0.4 microgram/dl; T3, 144 +/- 18 vs. 30 +/- 16 ng/dl). When compared to controls, glucose levels were higher in the hypothyroid rats (116 +/- 11 vs. 141 +/- 14 mg/dl; P less than 0.05) and were statistically unaltered in thyrotoxicosis. Plasma insulin levels were increased in hypothyroidism (6.5 +/- 0.8 vs. 10.8 +/- 2.9 microU/ml; P less than 0.05) and decreased in thyrotoxicosis (7.5 +/- 0.5 vs. 28.3 +/- 15 microU/ml; P less than 0.05). Despite these alterations, membrane binding and the derived Scatchard plots were not significantly different in the hyperthyroid or hypothyroid groups. In summary, the present studies indicate that plasma membrane insulin receptor number and affinity are unaltered regardless of the thyroid state of the rat.

Serum triiodothyronine in undernourished rats: dependence on dietary composition rather than total calorie or protein intake.

Serum triiodothyronine (T3) in rats did not change if food intake was restricted without altering the composition of the diet. Feeding a hypocaloric low-protein high-carbohydrate diet caused increases in serum T3, while feeding a hypocaloric high-protein low-carbohydrate diet caused decreases in serum T3. These changes were not related to reductions in intake of either calories or protein, and concomitant changes in serum thyroxine (T4) were not observed. Reduction in the dietary content of valine, without changes in the percentage of carbohydrate in the diet, caused increases in serum T3 when compared to growth-matched controls on a diet with normal valine concentration. Serum T3 in undernourished rats depends on the composition of the diet and not on total intake of calories or protein.

Uremia decreases nuclear 3,5,3'-triiodothyronine receptors in rats.

The maximal binding capacity (MBC) of hepatic T3 nuclear receptors was decreased in uremic rats (132 +/- 37 fmol/mg DNA) compared to sham-operated controls (212 +/- 44 fmol/mg DNA; P < 0.025), while the equilibrium affinity constants (Ka) remained unaltered (1.8 +/- 0.4 and 1.5 +/- 0.3 X 10(9) M-1 in the uremic and control rats, respectively, P = NS). There was also a reduction in the MBC of the kidney T3 receptors, from 73 +/- 14 fmol/mg DNA in the control animals to 32 +/- 7 fmol/mg DNA in the uremic rats (P < 0.10), while the Ka values were identical in both groups (1.9 +/- 0.5 X 10(9) M-1). In addition, there were significant reductions in serum T4 (1.5 +/- 0.7 microgram/dl) and T3 (92 +/- 10 ng/dl) in the uremic rats compared to control rats, whose T4 levels averaged 4.4 +/- 0.1 microgram/dl (P < 0.005) and whose T3 levels averaged 140 +/- 13 ng/dl (P < 0.005). Further, insulin levels averaged 83 +/- 21 microU/ml in uremic rats and 38 +/- 7 microU/ml in control rats (P < 0.025), while glucagon levels averaged 457 +/- 114 pg/ml in the uremic rats and 101 +/- 30 pg/ml in the control animals (P < 0.0125). These data suggest that 1) in addition to starvation and hepatectomy, uremia is another pathological condition associated with the modification of the number of T3 receptors, 2) the reduction in MBC observed may be generalized rather than organ specific for hepatic nuclear receptors, and 3) elevated glucagon levels are associated with reduced MBC in uremia, but it is indeterminate whether hyperglucagonemia is the etiology of the decrease.

Low serum thyroxine and high serum triiodothyronine in nephrotic rats: etiology and implications for bioavailability of protein-bound hormone.

Traditionally, it has been thought that the bioavailable fraction of circulating serum hormones, i.e. that which is available for cellular uptake and is physiologically active, is limited to the free (nonprotein bound) hormone. However, recent evidence, based on acute organ uptake of labeled hormone, suggests that the amount of hormone which is bioavailable in vivo may exceed that which is calculated to be free in vitro. To explore the bioavailability of circulating protein-bound thyroid hormones under steady state conditions in vivo, we altered serum thyroid hormone-binding proteins in rats by inducing nephrotic syndrome with puromycin aminonucleoside. Nephrotic rats (serum albumin, 1.1 g/dl) were found to have a marked reduction in serum T4 [2.1 +/- 0.2 (SEM) vs. 6.5 +/- 0.3 microgram/dl; P less than 0.01] and an elevation of serum T3 [141 +/- 8 vs. 51 +/- 2 ng/dl; P less than 0.01]. Estimated T4 production rate was normal in nephrotic rats, and the 3- to 4-fold increase in T4 MCR appeared to account for the marked reduction in serum T4. By contrast, increased serum T3 levels in nephrotic rats reflected both a reduction (55%) in T3 MCR and an increased rate of peripheral conversion of T4 to T3. A circulating inhibitor of T4 binding to serum proteins appeared to be present in nephrotic rats. The changes in the various serum components of thyroid hormone [T4-binding prealbumin (TBPA)-bound, albumin-bound, free] produced by nephrotic syndrome were compared with the corresponding changes in indices of thyroid hormone bioavailability (MCR, urinary excretion, hepatic content, TSH suppression, single pass extraction by liver). These comparisons suggested that nephrotic syndrome results in increased bioavailability of circulating T4 and decreased bioavailability of circulating T3. The bioavailable fraction of circulating T3 in vivo seemed to include both free T3 and that which is albumin bound in vitro. The bioavailable fraction of circulating T4 resembled free T4 more than non-TBPA-bound T4 (= albumin bound + free), although a nephrosis-induced increase in bioavailability of TBPA-bound T4 was also possible. We conclude that nephrotic rats have low serum T4, which is related to accelerated T4 clearance, and high serum T3, which is related both to decreased T3 clearance and increased peripheral conversion of T4 to T3. Under steady state conditions in vivo, bioavailable circulating T3 appears to include both free T3 and the T3 that is bound to albumin in vitro.

Current trends in the management of well differentiated papillary thyroid carcinoma.

Clinical members of the American Thyroid Association were surveyed in regard to their diagnostic assessment, treatment, and long term assessment of differentiated papillary thyroid carcinoma. For a 39-yr-old female with a 2-cm solitary nodule and no history of radiation (index patient), respondents were asked to provide their preferences for diagnostic evaluation, treatment assuming a papillary carcinoma was focal, and follow-up. Of 408 surveys mailed, 233 (57.1%) were analyzed. Diagnostic studies included thyroid scan (56%), fine needle aspiration (96%), total serum T4 (49%), and third generation TSH (56%). Treatment included surgery (99%), with 86% preferring near-total/total thyroidectomy. After surgery, 61% recommended 131I ablation; long term therapy using L-T4 alone was recommended by 97%, with most preferring suppression to a target TSH level of less than 0.01 microIU/mL (22%), 0.01-0.05 (38%), or 0.06-0.50 (32%). For variations from the index patient, respondents' treatment were not different for a history of radiation, age of either 16 or 60 yr, nodule size of 1.5 cm, male sex, the presence of less than 1-cm multiple foci in the contralateral lobe, or capsular invasion of the nodule. Treatment and follow-up did change if there was blood vessel invasion or distant metastasis. In summary, our survey indicated consensus on diagnostic assessment of the index patient by fine needle aspiration and management by surgery and 131I therapy. However, management varied widely for the ablative dose of 131I, the target TSH level after ablation, and the frequency and type of follow up.

Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects.

To further elucidate the peripheral metabolism of rT3 and to determine if rT3 production rates vary directly with thyroid function, we measured the disappearance of [125I]rT3 in thyrotoxic and hypothyroid subjects as well as in athyreotic patients maintained eumetabolic on exogenous T4. Kinetic parameters were determined by noncompartmental analysis, and serum concentrations of rT3 and T4 were determined by specific RIAs. In six hyperthyroid, seven euthyroid, and six hypothyroid subjects, the MCRs were 190.7 +/- 15.7, 111.7 +/- 13.2, and 71.8 +/- 7.0 liters/day kg, respectively (mean +/- SE). Production rates (PR) for these same groups were 271.3 +/- 40.5, 51.7 +/- 9.1, and 4.3 +/- 0.6 micrograms/day/70 kg. The observed differences in MCR and PR among the three study groups were highly significant (P less than 0.002). These data indicate that in comparison to euthyroid subjects, rT3 PR and MCR are increased in thyrotoxic and decreased in hypothyroid individuals.

Resin hemoperfusion: a method of removing circulating thyroid hormones.

The ability of an extracorporeal hemoperfusion system employing neutral Amberlite resin to bind thyroid hormone and to decrease circulating levels of triiodothyronine (T3), thyroxine (T4), and free thyroxine (FT4) was evaluated in dogs made thyrotoxic by the intramuscular administration of thyroid hormone. Since the resin column and tubing were charged with saline, the effects of hemodilution from this source on serum T3 and T4 was assessed by control perfusion through a column which did not contain any resin. After correction for hemodilution, the mean serum T3, T4 and FT4 decreased during 2 hours of resin hemoperfusion by 39%, 35%, and 46%, respectively. Hormonal clearance rates were calculated in two experiments and the estimated net hormone removed averaged 60.4 mug of T3 and 1990 mug of T4. Hematologic indices and routine chemistries did not change significantly in these dogs during the procedure except for a decrease in mean serum albumin concentration and an increase in mean serum glucose concentration. Hemoperfusion through this resin system seems to be a safe, effective means of decreasing serum T3, T4, and FT4 in thyrotoxic dogs and warrants evaluation for the treatment of thyroid storm in man.

Killer cell activity and antibody-dependent cell-mediated cytotoxicity are normal in Hashimoto's disease.

Antibody-dependent cell-mediated cytotoxicity (ADCC) is the process by which antibodies interact with killer cells to effect cell lysis, whereas natural killing (NK) refers to the ability of peripheral blood killer cells to lyse target cells in the absence of specific antibody. The purpose of the present study was to determine if either NK cells or ADCC might play a role in the development of Hashimoto's thyroiditis (HD) by testing the ability of killer cells to cause lysis of K562 erythroleukemia tumor cells and human thyrocytes in the presence and absence of serum from normal and HD patients. Using K562 target cells, NK activity was 70 +/- 4% (mean +/- SEM) for HD effector cells and 66 +/- 5% for normal effector cells at an effector to target ratio of 100:1. Similarly, with thyrocytes as targets, effector cells from HD patients (38 +/- 3%) and normal subjects (34 +/- 5%) caused comparable lysis (at an effector to target ratio of 100:1). Using K562 target cells, ADCC was 35% when effector cells from HD or normal subjects were coincubated with either normal or HD sera. Using thyrocyte target cells, lysis was about 25-30%, but, again, no differences were found between HD and normal effector cells or serum. There was a significant correlation between lysis for K562 and thyrocyte target cells, but there was no significant correlation between the titer of serum antithyroid microsomal antibodies and specific lysis. Intrathyroidal lymphocytes and peripheral lymphocytes from one patient with HD caused comparable lysis of labeled thyrocyte targets, as did normal peripheral lymphocytes. We conclude that ADCC and NK activities in peripheral lymphocytes were normal in HD patients and, therefore, may not have a primary role in mediating thyrocyte destruction in Hashimoto's thyroiditis.