Treatment of Graves' hyperthyroidism with radioiodine: results of a prospective randomized study.

In this paper, we report the results of a randomized prospective study on radioiodine treatment in patients with Graves' hyperthyroidism. Complete data were obtained in group 1 from 98 patients 6 months after application of a standard activity of 15 mCi (555 MBq) of 131I and in group 2 from 107 patients who received a target dose of 100 Gy. In group 1, the overall success rate was 71%, but the results in the subgroups clearly were related inversely to the thyroid volume, ranging from 100% in patients with a thyroid volume < 15 mL to about 20% in those with a thyroid size of > 60 mL. In contrast, patients who received a target of 100 Gy showed very similar results, with success rates of about 40-50% in all but one subgroup. Only patients with a thyroid volume < 15 mL had a success rate of about 80%. But due to an incidental increase of uptake and/or effective half-time from the test to the therapy activity, this subgroup received a target dose of about 160 Gy. Additional calculation of the actual target dose in group 1 (standard activity) showed that, with a dose of 200 Gy, a success rate of 80% was obtained. Also, the thyroid volume reduction was related inversely to the target dose. Because the literature is abundant, only a restricted number of references are discussed that are either in agreement with our results or in sharp contrast to them. The reason for these discrepant results might be the difference in the scheme of pretreatment or the different alimentary iodine supply between, for example, Great Britain and the United States on the one hand and Germany on the the other hand.

Earliest prevention of endemic goiter by iodine supplementation during pregnancy.

During pregnancy complex changes of maternal thyroid function occur and they are influenced by the maternal iodine supply. It has been demonstrated that with decreasing iodine supply maternal goiter and hypothyroxinemia as well as fetal and neonatal hypothyroidism become more prevalent. Therefore iodine supplementation during pregnancy is now strongly recommended also in areas of moderate iodine deficiency. To monitor the success of iodine supplementation and its theoretical risk of increasing the frequency of thyroid autoantibodies, we have investigated the thyroid volume, thyroid function, urinary iodine excretion and antibodies to thyroid peroxidase at 10-12 weeks of gestation and postpartum in 38 mothers receiving 300 micrograms potassium iodide/day and in 70 mothers without iodine supplementation. In all of their newborns thyroid volume was determined by ultrasound. The thyrotropin (TSH) levels and antibodies to thyroid peroxidase (TPO-ab) in the neonates were measured in dried blood spots on filter paper from their newborn screening. Urinary iodine excretion was increased significantly after iodine supplementation in mothers (p < 0.001) and their newborns (< 0.05). No hypo- or hyperthyroidism was observed in the mothers or newborns. Interestingly, no difference of maternal thyroid volumes was observed between the two groups after pregnancy, but the volumes of the thyroid glands in newborns of mothers who received iodine were significantly (p < 0.004) lower (0.7 +/- 0.4 ml) than in the control group (1.5 +/- 1.1 ml). There was no change in the frequency of TPO-ab in either group after pregnancy. In four mothers transplacental passage of these antibodies was documented by positive measurement in the blood sample of the newborn. This study documents that iodine supplementation during pregnancy in an area of moderate iodine deficiency results in a lower size of neonatal thyroid volume and that this supplementation was not accompanied by an increase in the frequency of TPO-ab.

Reduction in thyroid volume after radioiodine therapy of Graves' hyperthyroidism: results of a prospective, randomized, multicentre study.

The reduction in thyroid size in 92 patients treated with radioiodine for Graves' thyrotoxicosis was monitored by ultrasound volumetry. The patients were randomly treated with either a standard 131I activity of 555 MBq or an activity calculated to deliver a thyroid dose of 100 Gy. Within 1 year after radioiodine treatment, a remarkable volume reduction of about 71% (median) (quantile 25% (Q 25) = 49%, Q 75 = 82%, n = 67) was observed. The bulk of this reduction (median 57%, Q 25 = 21%, Q 75 = 74%, n = 92) was found within the first 6 months. Statistical analysis reveals that the effect was clearly related to the thyroid dose actually achieved during therapy. The median reduction obtained 6 months after radioiodine application was 45% for < 100 Gy, 56% for 100-200 Gy and 67% for > 200 Gy (n = 28, 39, 25 respectively). Twelve months after radioiodine application, the effect became less evident: 53%, 68% and 75% respectively (n = 17, 29, 21). The higher median thyroid dose actually achieved by standard than by calculated activity (215 Gy vs. 116 Gy) explains the more pronounced volume reduction in the standard group than in the calculated group; 60% vs. 47% 6 months (n = 47, 45) after radioiodine treatments and 74% vs. 66% 12 months (n = 31,36) after radioiodine application. The relative reduction in thyroid size was just as marked in patients with large thyroids as in those with small glands. The goitre prevalence (thyroid volume > 20 mL in women and > 25 mL in men) was reduced from 73% to only 16% 1 year after radioiodine treatment. In patients with a thyroid volume of more than 60 mL, the median pretherapeutic thyroid volume of 102 mL was reduced to 29 mL. In conclusion, radioiodine treatment in Graves' hyperthyroidism sufficiently reduces thyroid volume in a dose-dependent manner. The findings of this study demonstrate that radioiodine is also an attractive mode of therapy for Graves' patients with substantial thyroid enlargement.

Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease.

Because particular human leukocyte antigen (HLA) DQ alleles are the major predisposing factors for type 1 diabetes mellitus (IDDM), we investigated whether they are shared by other endocrine autoimmune diseases. We, therefore, analyzed the HLA DQ genotypes of 171 patients with IDDM, 271 with Graves' disease (GD), 65 with Hashimoto's thyroiditis, 51 with postpartum thyroiditis, 53 with Addison's disease (AD), and 271 healthy controls. HLA DQA1 and DQB1 alleles were defined by polymerase chain reaction and sequence-specific oligonucleotide hybridization as well as by single strand conformational polymorphism analysis. HLA DQA1*0501 was significantly more frequent in IDDM (60%), GD (65%), and AD (70%) than in controls (43%); DQA1*0301 was significantly more frequent only in IDDM (67% vs. 30% controls). The heterozygous state DQA1*0301/*0501 was found in 9% of controls and 35% of IDDM (relative risk, 5.6). An arginine at position 52 on either DQA1 allele was significantly more frequent in patients with IDDM (94%), GD (80%), and AD (89%) compared with controls (66%). HLA DQB1*0201 and DQB1*0302 were more frequent in IDDM patients (*0201, 62% vs. 36% in controls, *0302, 59% vs. 19% controls), whereas DQB1*0602 was less frequent in IDDM (4%) and GD (18% vs. 31% of controls). In conclusion, endocrine autoimmunity has a common immunogenetic background; susceptibility is conferred by DQA1*0501 as well as an arginine at position 52 of DQA1 alleles, and protection against IDDM and GD is conferred by DQB1*0602.

Radioiodine therapy of Graves' hyperthyroidism: standard vs. calculated 131iodine activity. Results from a prospective, randomized, multicentre study.

The present prospective, randomized, multicentre study was performed to directly compare for the first time the effectiveness of a standard activity of 555 MBq 131iodine vs. an activity calculated to deliver 100 Gy for treatment of Graves' thyrotoxicosis. Therapeutic success was defined as the elimination of hyperthyroidism 6 months after radioiodine application (range 4.5-8 months). A success rate of more than 90% in eliminating hyperthyroidism was reported for both approaches, but only in retrospective investigations. Investigated prospectively, hyperthyroidism was eliminated in only 71% of the patients receiving standard activity (70/98) and 58% of those randomized for calculated activity (62/107). In the patients with standard activity, therapeutic success was inversely related to thyroid size. The rate was 100% for thyroid volumes < or = 15 mL, 95% for 16-30 mL, 68% for 31-45 mL, 44% for 46-50 mL, 20% for 61-75 mL and 25% for > or = 75 mL. In those patients with an activity calculated to deliver 100 Gy (except in those with a volume < or = 15 mL) this size/outcome dependency was almost compensated. The rates were 86%, 65%, 45%, 61%, 41% and 45%, respectively. Furthermore, detailed statistical analysis revealed a strong correlation between the success of therapy and the radiation dose actually absorbed by the thyroid. The rate was 11% for a target dose of 50 Gy, 50% for 100 Gy, 67% for 150 Gy, 80% for 200 Gy, 84% for 250 Gy, 88% for 300 Gy, 90% for 350 Gy and 93% for 400 Gy.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid cytotoxic antibodies in atrophic and goitrous autoimmune thyroiditis.

It is unknown whether in chronic lymphocytic thyroiditis the goitrous (Hashimoto's thyroiditis) and atrophic forms (primary myxedema) are variants of the same disease or different pathogenic entities. Conventional thyroid-related autoimmune parameters are unable to separate both diseases serologically. It is assumed that cellular and humoral cytotoxic events induce gland atrophy and thus should be detectable more often in non-goitrous than goitrous autoimmune thyroiditis. We determined antibody-dependent cell-mediated cytotoxicity in 67 patients with autoimmune thyroiditis, using a 51chromium-release assay against human thyroid cells. Thyroid volume had been measured by ultrasonography. Other thyroid-specific antibodies, like TSH binding-inhibiting antibodies, TSH function-blocking antibodies, thyroglobulin antibodies and thyroid peroxidase antibodies, were determined. Cytotoxic antibody activity was 20.5% (median, range 0-54.5%) in patients with autoimmune thyroiditis and 8.3% (median, range 0-18.4%) in controls (p < 0.0001). Analysis of cytotoxicity regarding thyroid size showed a high incidence of cytotoxic antibodies in atrophic disease (median thyroid volume 6 ml), where cytotoxic antibodies were detectable in 80% versus 39% (x2 = 9.6; p < 0.0001) in goitrous disease (median thyroid volume 36 ml). The specific lysis of 30% (median; 95% confidence limit 23.9-32.9) in non-goitrous thyroiditis patients was significantly higher than in goitrous patients (16.9%; 95% confidence limit 13.2-20.4) (p = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS)

Subclinical hypothyroidism and hyperlipoproteinaemia: indiscriminate L-thyroxine treatment not justified.

It is still under discussion whether subclinical hypothyroidism is a biochemical syndrome or a disease associated with an increased risk for development of vascular diseases due to lipid elevation. Therefore, we investigated lipid values in 40 patients with subclinical hypothyroidism, which is defined in terms of normal (N = 26) or slightly increased (N = 14) basal TSH values and/or an exaggerated TSH response (N = 34) to TRH (> 25 mU/l). Patients with increased lipid values were treated with L-thyroxine and reanalysed three months later. Mean levels of total cholesterol. LDL- and HDL-cholesterol and triglycerides in patients with subclinical hypothyroidism were comparable with those in normal subjects. Individual analysis, however, revealed hyperlipoproteinaemia (HL) in 22.5% of the patients investigated (HL type IIa in seven, type IV in two patients). Thyroid function was the same in affected patients as in those with normal lipid values, whereas higher age was significantly more often associated with this syndrome (p < 0.01). Treatment with L-thyroxine resulted in a significant decrease in total and LDL-cholesterol (p < 0.05), although a normalization of their lipid values could be obtained only in half of the patients. None of the subjects with hyperlipoproteinaemia had a history or clinical signs of actual vascular disease. Although the incidence of hyperlipoproteinaemia in our study group of patients with mild subclinical hypothyroidism (22.5%) is comparable to that of the normal population (21.5%), it is more severe in the former group (LDL-cholesterol in patients 5.26 +/- 0.58 vs 4.8 +/- 0.56 mmol/l in controls; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of bone mineral density by quantitative computed tomography and single photon absorptiometry in subclinical hyperthyroidism: a risk of early osteopaenia in post-menopausal women.

OBJECTIVE: There is evidence that treatment with L-thyroxine increases the risk of early osteopaenia. The aim of our study was to investigate the effect of subclinical hyperthyroidism in patients on TSH-suppressive L-thyroxine in view of the increased risk of decalcification. DESIGN: Measurements of bone mineral density were performed in patients with subclinical hyperthyroidism at different scanning sites of varying trabecular portion. Bone mineral values as well as biochemical data were compared to those of normal controls. PATIENTS: Fifty patients (nine men, 25 premenopausal and 16 post-menopausal women) on TSH-suppressive doses of L-thyroxine were investigated after removal of thyroid cancer. MEASUREMENTS: Dual energy quantitative computed tomography was used for osteodensitometry in the lumbar spine. Single photon absorptiometry from a 125I source was applied to the calcaneus, midshaft radius and distal as well as proximal scanning sites of the distal radius. Normal bone mineral values for each measurement site were taken from healthy reference populations. RESULTS: A significant decrease of bone mineral density in the calcaneus was found in 26 of 50 patients. Bone mass assessment yielded a 9.1% decrease of mean bone mineral content in all patients compared to controls (P less than 0.01). The decrease in post-menopausal women was 22% (P less than 0.001). In premenopausal women bone mineral density changes in the calcaneus were not statistically significant. Cortical measurement sites like the midshaft radius and the proximal scanning site of the distal forearm showed a 14.8% (P less than 0.05) and 10.8% (P = NS) decalcification in post-menopausal women but normal values at the distal scanning site. The lumbar spine was not affected by subclinical hyperthyroidism in either pre or post-menopausal women. In hypoparathyroid patients, bone density did not essentially differ from normals. There was no significant correlation between bone mineral values and duration of treatment or osteocalcin values. CONCLUSIONS: Our data suggest that TSH suppressive L-thyroxine treatment has a detrimental effect on the appendicular skeleton in post-menopausal women. Additional effects of oestrogen deficiency and subclinical hyperthyroidism might lead to accelerated bone loss requiring close supervision to determine the smallest dose needed for suppression of the pituitary-thyroid axis.

HLA-DR/DQ gene variation in nongoitrous autoimmune thyroiditis at the serological and molecular level.

The etiology of autoimmune diseases is multifactorial with genetic factors being an important prerequisite. There are two clinical manifestations of autoimmune thyroiditis: the goitrous form (Hashimoto's thyroiditis) and the atrophic variant, which is characterized by hypothyroidism (primary myxoedema). Different genetic markers were assumed to be predisposing factors for the distinct clinical presentation. In the present study, we determined HLA A,B,C,DR,DQ alloantigens serologically and HLA-DQ by gene analysis in patients with nongoitrous autoimmune thyroiditis and randomly chosen controls. To verify the exact classifications, thyroid volume (median 5.85 ml) was measured by ultrasonography. HLA-DR5 was found in 16 of 36 (44%) patients with nongoitrous autoimmune thyroiditis and in only 26 of 175 controls (15%) (Pc = 0.0018). There was a tendency towards a lower frequency of HLA-DR7 with 6% positivity in patients vs. 29% in controls (Pc = 0.052). Regarding HLA-DQ, DQ7 was found in 17 of 35 patients (48%) vs. 21 of 98 controls (21%) (Pc = 0.028) (relative risk 3.5). No other association was found with HLA-A,B,C and HLA-DR and -DQ. Our data indicate that the genetic susceptibility to autoimmune nongoitrous thyroiditis is closely associated to HLA-DR5 and DQ7 and not distinct from goitrous disease. We conclude that factors other than genetic ones explain the different immunological and clinical manifestation of chronic lymphocytic thyroiditis.

The relevance of genetic susceptibility in Graves' disease and immune thyroiditis.

It has been known for a long time that there is an increased incidence of Graves' disease and immune thyroiditis in certain families. Genetic research of this disease has shown that it is most probably transmitted in a multifactorial way, i.e. that environmental as well as genetic factors play a role in the genesis of the diseases. This hypothesis is supported by the fact that the rate of concordance is maximally 50% in identical twins. The following model of threshold values is conceivable for the formal genetics of Graves' disease and immune thyroiditis: the diseases break out whenever the sum of environmental (viruses, bacteria, iodine excess, hormones, stress) and genetic (MHC and non MHC-restricted) factors is higher than a given threshold. One of the major genes influencing the genesis of the diseases seems to be HLA-DR3 (or a closely linked gene in strong linkage disequilibrium). If this gene is present, fewer environmental factors are possibly needed.

[Study of antibody-dependent cell mediated cytotoxicity and thyroid growth blocking antibodies in congenital hypothyroidism]. / Etude de la cytotoxicité cellulaire dépendante des anticorps et des anticorps bloquant la croissance thyroïdienne dans l'hypothyroïdie congénitale.

Antibody-dependent cell mediated cytotoxicity (ADCC) and thyroid growth immunoglobulin blocking (TGI block) which have been found in autoimmune thyroiditis in adults, as well as TSH receptors binding inhibitory antibodies (TBI ab) and antimicrosomal (Mc ab) and antithyroglobulin (Tg ab) antibodies were search in 42 mothers-infants pairs called at hospital after a positive screening for congenital hypothyroidism. The etiologic diagnoses were: 12 athyreosis, 12 ectopies, 7 anatomically normal glands and 11 transients. Tg ab and Mc ab were measured by commercial hemagglutination tests, TBI ab were determined using a radio ligand assay. ADCC in a 51Cr release assay by human thyroid cells in culture and TGI block by incorporation of 3H-thymidine using the same cells. Results were 38% for TBI ab in infants mainly in patients with dysgenesis without any concordance between mothers and infants. ADCC were found in 24% and TGI block in 24% with respectively mothers-infants concordance of 90% and 84%. Five mothers had autoimmune diseases (2 thyroiditis, 2 Graves' diseases and 1 insulin-dependent diabetes). Beside these rare cases of maternal diseases, the significantly high number of antibodies without any expression in the mothers suggests that autoimmunity plays a role in the etiology of congenital hypothyroidism.

Plasma exchange and hemoperfusion in iodine-induced thyrotoxicosis.

Iodine-induced thyrotoxicosis is a life-threatening disease. Plasma exchange and hemoperfusion are the available means of detoxication. Both methods were applied repeatedly to 4 patients with iodine-induced thyrotoxicosis, and the efficacy of these treatment methods was compared. Thyroxine plasma levels were decreased by 33%, while the calculated body stores were reduced by 18% during plasma exchange. Hemoperfusion was less effective. With both methods, a rebound of plasma levels was seen. Improvement of the clinical condition was delayed for 1 week after discontinuation of treatment. One patient died, probably because detoxication was discontinued too soon after the thyroid hormone levels had normalized. Plasma exchange by using albumin (120 g/4,000 ml = 30 g/l) as replacement fluid is superior to that by using fresh-frozen plasma (2,000 ml/4,000 ml), since less thyroxine is administered (19 vs. 160 nmol).

Increase in antimicrosomal antibody-related IgG1 and IgG4, and titers of antithyroid peroxidase antibodies, but not antibody dependent cell-mediated cytotoxicity in post-partum thyroiditis with transient hyperthyroidism.

To evaluate possible immunological mechanisms involved in the development of postpartum thyroiditis with transient hyperthyroidism followed by transient hypothyroidism (PPT), antithyroid peroxidase antibodies (anti-TPO), antimicrosomal antibody (AMA) related immunoglobin G subclass and antibody-dependent cell-mediated cytotoxicity (ADCC) were studied in 43 post-partum (PP) women who were euthyroid at delivery and completed a subsequent 1 year follow up. Among the 25 mothers who developed PPT, 14 had positive AMA (PPT:AMA+) and 11 negative AMA (PPT:AMA-) at delivery. Among the 18 mothers who remained euthyroid (E) up to one year post-partum and were used as controls, 8 were AMA positive (E:AMA+) and 10 AMA negative (E:AMA-) at delivery. AMA measured by a hemagglutination method correlated well with anti-TPO antibodies measured by RIA in the PP mothers studied. When AMA-related IgG subclass activity was analysed comparing PPT women with appropriate euthyroid controls at the different time intervals studied, it was seen that PPT:AMA+ when compared to E:AMA+ women have significantly increased activity of AMA related IgG1 at all PP time intervals studied (p less than 0.001), but IgG4 was only increased at 5-7 months PP (p less than 0.05). PPT:AMA-when compared to E:AMA- have significantly increased IgG4 at 2-4 (p less than 0.001), 5-7 and 10-12 (p less than 0.05) months PP, but IgG1 is only increased at 5-7 months PP (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid peroxidase/microsomal antibodies are not identical with thyroid cytotoxic antibodies in autoimmune thyroiditis.

Cytotoxic activity in sera of patients with Hashimoto's thyroiditis was measured with an antibody-dependent cell-mediated cytotoxicity assay. Cytotoxicity was determined in a 51chromium release assay using human thyroid cell targets incubated with heat-inactivated serum or IgG from patients with Hashimoto's thyroiditis. Effector cells were obtained from peripheral mononuclear cells of normal subjects. Cytotoxicity was significantly increased in patients with Hashimoto's thyroiditis (median specific lysis 20.2%, range 2.1-58.8) compared with normals (median specific lysis 8.1%, range 0-19.5; p less than 0.00001). The amount of percent specific lysis did not correlate with the titres of microsomal antibodies determined by different methods: passive hemagglutination technique (r = 0.2), enzyme immunoassay with microsomal antigen (r = 0.16), and radioimmunoassay for thyroid peroxidase antibody (r = 0.02). The cytotoxic activity was located in the IgG fraction, both in microsomal antibody positive and negative sera. After pre-incubation of microsomal antibody/thyroid peroxidase antibody positive or negative sera with purified thyroid peroxidase followed by analysis in the antibody-dependent cell-mediated cytotoxicity assay, cytotoxicity decreased in only 2 cases but was unchanged in the remaining sera. Western blot experiments with solubilized thyroid membranes and immunoblotting with cytotoxic-positive/microsomal antibody negative sera showed no binding to thyroid peroxidase. Our data suggest that cytotoxicity in sera from patients with Hashimoto's thyroiditis is not mediated by antibodies against thyroid peroxidase, but by antibodies not yet identified.

[What is the recurrence rate for Basedow's disease treated with thyrostatic agents. Answers from a prospective study]. / Wie häufig rezidiviert ein thyreostatisch behandelter M. Basedow? Antworten aus einer prospektiven Studie.

Graves' disease is an autoimmune disease whose development involves immunogenetic and exogenous factors such as viruses, bacteria and iodine excess. In a number of patients the disease follows a chronic recurrent course. A recurrence rate of 50% can be expected one year after the end of therapy. Based on the preliminary results of the prospective study presented here, this recurrence rate does not differ in groups where patients underwent long-term treatment with 10 or 40 mg thiamazole. Retrospectively obtained data suggest that the time at which euthyroidism occurs under low-dose treatment is dependent on the alimentary iodine supply. A number of groups have attempted to develop clinically applicable methods to identify patients at risk for recurrence at the end of treatment. All the studies yielded controversial results. A prospective multicenter study was undertaken to reinvestigate the importance of measuring TSH receptor antibodies and performing the TRH test and the suppression test at the end of therapy in connection with this problem. In 451 patients the recurrence rate was 50.3% one year after the end of treatment. The patients in the recurrence group had a significantly higher rate of persistent antibody activity, no increase in TSH after TRH (negative TRH test), no normal suppressibility of thyroid 123 iodine uptake (negative suppression test) and larger goiter. The calculation of sensitivities and specificities shows, however, that these differences are not large enough to be of clinical importance for the individual patient.

[Diagnosis and therapy of hyperthyroidism in pregnancy]. / Diagnostik und Therapie der Hyperthyreose in der Schwangerschaft.

In pregnancy hyperthyroidism occurs with a prevalence of 0.04-0.2%. It occurs even less frequently de novo in previously undiagnosed patients. Within a short period of time we treated 3 patients, who also developed signs of pre-eclampsia. Specific principles of the management during pregnancy are explained.