Sequential psychological testing during the course of autoimmune hyperthyroidism

Summary Although the psychological disturbances accompanying Graves' disease are well known, the time required for normalisation of these disturbances during antithyroid drug treatment is not known. Therefore sequential psychological testing during the course of Graves' disease was done. There are also contradictory results concerning the possible correlation of neurophysiological and psychological test results during the course of Graves' disease with thyroid hormone values. Finally, psychological disturbances have been proposed as possible etiologic factors in Graves' disease.In our study, a significant decrease in anxiety and irritability could be observed at the time euthyroidism was achieved. Self-evaluations of depressivity, activity, exhaustion, well-being, extraversion, introversion, and the ability to concentrate changed 1 or 2 months after euthyroidism was induced. Similar test results could be observed after induction of euthyroidism by antithyroid drugs and subtotal thyroid resection. Therefore the mode of therapy does not seem to influence the course of normalisation of psychological parameters.In contrast to other investigations there was hardly any correlation between thyroid hormone values and psychological test results or the ability to concentrate. Nontheless, patients with Graves' disease showing high scores for depression and anxiety exhibit abnormal peripheral helper/suppressor T-lymphocyte relations. Furthermore, patients suffering from Graves' disease tend to be more anxious than controls. It remains to be determined whether an increased susceptibility to psychological disturbances has led to these alterations of lymphocyte subsets in Graves' disease patients with severe depression and anxiety.Supported by SFB 258     

Does infection initiate Graves disease? A population based 10 year study

In order to detect whether micro-organisms could initiate the autoimmune process in Graves' disease we have studied the temporal and spatial distribution of 857 cases of hyperthyroidism occurring in a community over ten years. Cases were identified through biochemistry laboratory records and following the exclusion of patients with toxic nodular goitre or with insufficient clinical data there were 599 with Graves' disease--an average annual incidence of 15.9 per 100,000. There was a tendency for cases to present in the summer months. The reported onset of symptoms, however, peaked in December and June. There was no evidence of clustering of cases in space and time using two different statistical methods. Incidence rates doubled between 1976 and 1980 and then declined--a trend that could neither be explained by changes in laboratory or clinical diagnosis nor did it correlate with any pattern of microbial disease in the area. We conclude that it is unlikely that infections that behave in an epidemic manner have a causative role in triggering Graves' disease.     

Review of thyroid disease and recent progress in thyroid research

Major thyroid diseases and recent progress in thyroid research are reviewed, including our clinical experiences and data on genetic analysis. Of the 19,944 patients receiving care in our endocrinology and metabolism department over the past 26 years(from 1974 to 2000), there were 4,471(22.4%) patients with thyroid diseases. Of these patients with thyroid disease, 37.3% had Graves' disease, 24.1% had Hashimoto's thyroiditis, and 22.2% had a benign thyroid tumor. Male-to-female ratio for Graves' disease was 1:3.2. The precise mechanism and genetic or environmental factors underlying the onset and progression of autoimmune thyroid disease need further investigation, although recent thyroid research, especially molecular level studies, has resulted in many new insights. Our genetic analysis of patients and experimental animals with thyroglobulin(Tg) abnormalities indicated the amino acids involved in the surface electric charge were important in maintaining the solid structure of Tg and thyroid hormone synthesis in addition to tyrosine and cysteine. In three patients with hyperthyroid Graves' disease, Hashimoto's thyroiditis or idiopathic hypothyroidism, followed by the author for 8 to 20 years, it was indicated that continued comprehensive care was needed for various episodes, even those arising from non-endocrine conditions, throughout the clinical course, although clinical and laboratory findings showed improvement of the thyroid disease itself.     

Antibodies targeting the calcium binding skeletal muscle protein calsequestrin are specific markers of ophthalmopathy and sensitive indicators of ocular myopathy in patients with Graves' disease

We have identified several eye muscle antigens and studied the significance of the corresponding serum autoantibodies in patients with Graves' disease. Of these antigens, only calsequestrin is expressed more in eye muscle than other skeletal muscles, which could explain at least partly the specific involvement of eye muscle in patients with Graves' disease. Earlier, we found a modest relationship between anti-calsequestrin antibodies and ophthalmopathy, but in that study we used calsequestrin prepared from rabbit heart muscle and measured antibodies by immunoblotting. We have reinvestigated the prevalences of anti-calsequestrin antibodies in larger groups of well-characterized patients with thyroid autoimmunity with and without ophthalmopathy and control patients and healthy subjects, using standard enzyme-linked immunosorbent assay incorporating highly purified rabbit skeletal muscle calsequestrin, which has a 97% homology with human calsequestrin, as antigen. Anti-calsequestrin antibodies were detected in 78% of patients with active congestive ophthalmopathy, in 92% of those with active inflammation and eye muscle involvement, but in only 22% of patients with chronic, 'burnt out' disease. Tests were also positive in 5% of patients with Graves' hyperthyroidism without evident ophthalmopathy (two patients) and one patient with 'watery eyes' but no other clear signs of congestive ophthalmopathy and IgA nephropathy and no known thyroid disease, but in no patient with Hashimoto's thyroiditis, toxic nodular goitre, non-toxic multi-nodular goitre or diabetes, or age- and sex-matched healthy subjects. In serial studies of all 11 patients with Graves' hyperthyroidism who had active ophthalmopathy at the time of the first clinic visit, or developed eye signs during the first 6 months, and positive anti-calsequestrin antibodies in at least one sample, anti-calsequestrin antibodies correlated with the onset of ocular myopathy in six patients. Antibodies targeting calsequestrin appear to be specific markers for ophthalmopathy and sensitive indicators of the ocular myopathy subtype of ophthalmopathy in patients with thyroid autoimmunity. However, these results must be considered preliminary until a large prospective study of patients with newly diagnosed Graves' hyperthyroidism, in which serum levels of calsequestrin antibodies are correlated with clinical changes and orbital eye muscle and connective tissue/fat volumes, has been carried out.     

Life events and depression. Part 2. Results in diagnostic subgroups, and in relation to the recurrence of depression

Although there is evidence that the occurrence of stressful life events might be important for the onset and development of depression, it is still unclear whether differences occur in diagnostic subgroups of depressed patients, or in relation to type of episode, i.e., whether the first event or a relapse in a depression with a recurrent course. The present study has been carried out to investigate these issues more closely. Two hundred and six depressed patients have been classified into bipolar, unipolar, neurotic-reactive, and unspecified subgroups according to given definitions. The patients have also been classified into those suffering from a first episode and those suffering from recurrent depression. Each patient, when sufficiently improved, was given a semistructured interview, based on a specially constructed 56-item life events inventory. Unipolar and bipolar patients proved to have experienced significantly fewer events, even of the 'fateful' type (i.e., independent of depression) than the neurotic-reactive patients. However, this difference appeared to be due to difference in age among the groups and not to diagnosis. No difference occurred between uni- and bipolar patients. Patients with recurrent depression showed only small differences compared with patients in their first episode. These differences were consistently in the direction of fewer events in patients with recurrent depression. The implications of these results are discussed in relation to findings published by other authors.     

The balance shift in Th1/Th2 related IL-12/IL-5 cytokines in Graves' disease during methimazole therapy

Th1 and Th2-like cytokines are involved in the pathogenesis of Graves' disease. The shift in balance in IL-12/IL-5 cytokines was applied in judging the immunological events in 74 patients with Graves' disease (50 had ophthalmopathy) during methimazole therapy and in 15 controls. The serum levels of IL-12 and IL-5 were measured with enzyme-linked immunosorbent assay in all Graves' patients. Twelve cases for IL-5 and 20 cases for IL-12 were positive. In Graves' patients only those without ophthalmopathy had higher levels of IL-12 when compared to controls (192.66 +/- 29.19 vs. 85.09 +/- 8.95 pg/ml, P < 0.04). After 2 months of methimazole therapy in Graves' patients without ophthalmopathy an increase in the ratio of IL-12 to IL-5 was also observed as compared to those with eye symptoms (91.78 +/- 34.14 vs. 20.72 +/- 6.36, P < 0.015). Age-related difference in the serum level of IL-5 could be demonstrated between Graves' patients without and those with ophthalmopathy aged < or = 35 years (4.89 +/- 0.57 vs. 50.14 +/- 20.2 pg/ml, P < 0.002). No association was found among the serum levels of IL-5 or IL-12, thyroid hormones and TSH receptor antibodies. The results demonstrated a difference in the balance shift of IL-12/IL-5 between Graves' patients with and without ophthalmopathy. The increased ratio of IL-12 to IL-5 after methimazole therapy could be explained by the elevation of serum IL-12 due to methimazole therapy and the age-related decrease of serum IL-5.     

Intrathyroidal accumulation of T cell phenotypes in autoimmune thyroid disease.

In this study we have correlated peripheral T cell subset phenotypes with intrathyroidal lymphocyte accumulation in patients with autoimmune thyroid disease (Graves' and Hashimoto's disease). Our study utilized euthyroid family members for one of our control groups (n = 48) thus significantly limiting familial, but not disease-specific, influences on these T cell phenotypes. Our principal new observations were found only in patients with Graves' disease. As previously reported, there was a decrease in CD8+ (suppressor/cytotoxic) T cells in the peripheral blood of patients with untreated hyperthyroid Graves' disease (n = 27) (mean +/- SEM, 19 +/- 1.1% in patients compared with 25 +/- 1.2% in controls, p = 0.03), a finding not observed in treated, euthyroid Graves' disease patients or their relatives. However, the relative number of CD8+ T cells, assessed by CD4:CD8 ratios, was increased in the intrathyroidal T cell populations (n = 10), when compared to normal and patient peripheral blood. There were no consistent changes in total CD4+ (helper) T cells in the peripheral blood of patients with treated and untreated Graves' disease but a reduction in CD4+2H4+ (suppressor-inducer) T cells was seen in patients undergoing surgery for Graves' disease (13 +/- 6.9% compared with 39 +/- 3.4%). Again, however, this T cell subset was increased within the target organ of the same patients (41 +/- 5.9%). These data point to either a selective accumulation, or a specific "homing", of certain T cell subsets within the thyroid gland of patients with Graves' disease where T cell differentiation may be strongly influenced by antithyroid drug treatment and the local immune environment.     

Heterogeneity of immunoregulatory T cells in human thyroid autoimmunity: influence of thyroid status.

Monoclonal antibodies of the OKT series were used to identify circulating T lymphocytes (OKT3+), their helper-inducer (OKT4+) and suppressor-cytotoxic (OKT8+) subsets and cells bearing Ia antigen (OKIa+) in 75 patients with thyroid autoimmune disorders, including 14 Graves' disease, 21 myxoedema, 20 asymptomatic thyroiditis, 12 Hashimoto's thyroiditis and eight simple goitre with superimposed thyroiditis. In the whole population of patients, a negative correlation was observed between the percentage of OKT8+ cells and serum free thyroxine levels whatever the type of thyroiditis. The percentage of OKT8+ cells was decreased in Graves' disease and increased in myxoedema while it reversed after adequate treatment of the two diseases. However, a trend to a decrease in the proportion of OKT8+ cells was still observed in treated Graves' disease and in all the other groups of thyroiditis with euthyroidism. The minor modifications observed for OKT3+ and OKT4+ cells were in relation with those of OKT8+ cells. There was an increased percentage of Ia+ cells in Graves' disease and in Hashimoto's thyroiditis partly reflecting the presence of activated lymphocytes. In conclusion, these data suggest first of all a direct influence of serum T4 on the distribution of circulating OKT8+ cells in addition to documenting the heterogeneity of T cell immunoregulatory factors.     

Thyroid-stimulating antibodies in patients with long-term remission of Graves' hyperthyroidism

Summary The persistence of TSH receptor antibodies in Graves' disease despite the remission of hyperthyroidism has been described. Our study was designed to evaluate whether this extends to functionally active stimulators of the thyroid, since the occurrence of thyroid-stimulating antibodies (TSAb) in a euthyroid patient could well have important implications on our understanding of the pathogenetic role of such autoantibodies. Forty-four patients with a previous history of Graves' hyperthyroidism were reexamined after having been in long-lasting remission for 3 to 35 years (mean 8 years). Of the patients 16 had been treated by radioiodine, 17 by surgery, and 11 exclusively by antithyroid drugs. The determination of TSAb was based on T3 release from thyroid tissue in vitro to document the final response to these immunoglobulins. TSH-binding inhibiting immunoglobulins (TBII) were evaluated by a radioreceptor assay.TSAb were highly elevated in three of the 44 patients. These three patients showed a normal TSH response to i.v. TRH, suffered from endocrine ophthalmopathy, and had been treated by radioiodine for hyperthyroidism. TBII were found positive in seven patients including the three patients mentioned. The majority of patients positive for TSAb or TBII had been treated by radioiodine and none exclusively by antithyroid drugs.In conclusion, not only TBII but also T3 release-stimulating antibodies may occur in a minority of patients with long-term remission of Graves' hyperthyroidism. However, an absence of hyperthyroidism in these patients despite the presence of such thyroid stimulators seems to be only possible in association with a lack of functional responsiveness of the target organ due to previous administration of destructive therapies. Moreover, a major role of TBII in the absence of TSAb representing stimulatory inactive autoantibodies to the maintenance of remission was not apparent.Abbreviations cAMP cyclic adenosine monophosphate - T3 triiodothyronine - T4 tetraiodothyronine - TBII TSH-binding inhibiting immunoglobulins - TRH TSH-releasing hormone - TSAb thyroid-stimulating antibodies - TSH thyroidstimulating hormone     

生活应激事件与希望感对农村留守儿童抑郁的影响

目的:探讨生活应激事件与希望感对农村留守儿童抑郁的影响。方法:采用流调中心抑郁自评量表(CES-D)、青少年自评生活事件量表(ASLEC)、儿童希望感量表(CHS)对1313名留守儿童进行调查。结果:1农村留守儿童在抑郁、希望感的动力因子、生活事件的受惩罚因子和其它因子得分上存在显著性别差异(t=1.99,4.82,6.11;P0.05);2生活应激事件、抑郁和希望感之间两两显著相关(P0.01);3希望感对抑郁水平的变化有显著的负向预测作用(β=-0.097,P0.01);生活应激事件中各因子对抑郁水平的变化具有显著的正向预测作用(P0.05);生活应激事件中的学习压力因子与希望感的交互作用对抑郁水平的变化具有显著的负向预测作用(β=-0.828,P0.001)。结论:希望感能够缓解学习压力给农村留守儿童抑郁带来的不良影响。     

Antibodies to Yersinia enterocolitica in immunogenic thyroid diseases

In 1976 Shenkman et al. revealed that in patients with thyroid disorders antibodies against Yersinia enterocolitica could be demonstrated in increased frequency. In 1983 Ingbar et al. first established that the gram-negative bacterium Yersinia enterocolitica shows on its surface saturable binding sites for thyrotropin (TSH). If such binding sites resemble immunologically human TSH receptors this would indicate that TSH receptor antibodies could be produced in selected individuals having been infected with bacteria showing TSH receptors. The aim of our study was to compare the incidence of antibodies against Yersinia enterocolitica in two groups of thyroid disorders which are either immunogenic (Graves' disease and Hashimoto thyroiditis) or non-immunogenic (toxic adenomas, endemic goitre). In our series of 111 patients antibodies against Yersinia enterocolitica were demonstrated in a significantly higher percentage (36.3%) in patients suffering from immunogenic than in patients with non-immunogenic thyroid disorders (19.6%). The antibody titres were mainly directed towards Yersinia subtypes 8 and 3. It may, therefore, be assumed that the gram-negative bacterium Yersinia enterocolitica may have an active part in triggering immunogenic thyroid diseases such as Graves' disease or Hashimoto thyroiditis.     

Thyroid diseases after treatment of Hodgkin's disease

BACKGROUND AND METHODS. Thyroid disease, especially hypothyroidism, is common in patients with Hodgkin's disease who have been treated with irradiation. We reviewed the records of 1787 patients (740 women and 1047 men) with Hodgkin's disease who were treated with radiation therapy alone (810 patients), radiation and chemotherapy (920 patients), or chemotherapy alone (57 patients) at Stanford University between 1961 and 1989. Among these patients, 1533 were alive at the last follow-up, and 254 had died of causes other than Hodgkin's disease. (Four other patients were excluded from the analysis because they had undergone thyroidectomy before treatment for Hodgkin's disease. The thyroid was irradiated in 1677 patients. Follow-up averaged 9.9 years. RESULTS. A total of 573 patients had clinical or biochemical evidence of thyroid disease. Among the 1677 patients whose thyroid was irradiated, the actuarial risk of thyroid disease 20 years after treatment was 52 percent, and it was 67 percent at 26 years. Hypothyroidism was found in 513 patients. A total of 486 patients received thyroxine therapy for elevated serum thyrotropin concentrations and either low free thyroxine (208 patients) or normal free thyroxine values (278 patients); 27 had transient elevations of the serum thyrotropin level that were not treated. Graves' hyperthyroidism developed in 30 patients (2 of whom had not undergone thyroid irradiation), and ophthalmopathy developed in 17 of these patients. Ophthalmopathy developed in four other patients with Graves' disease during a period of hypothyroidism (n = 3) or euthyroidism (n = 1). The risk of Graves' disease was 7.2 to 20.4 times that for normal subjects. Silent thyroiditis with thyrotoxicosis developed in six patients. Forty-four patients were found to have single or multiple thyroid nodules, 26 of whom underwent thyroidectomy. Six of the 44 had papillary or follicular cancers. Among the patients who did not undergo operation, 12 had small functioning nodules, 4 had cysts, and 2 had multinodular goiters. The actuarial risk of thyroid cancer was 1.7 percent. The risk of thyroid cancer was 15.6 times the expected risk. CONCLUSIONS. High risks of thyroid disease persist more than 25 years after patients have received radiation therapy for Hodgkin's disease, reinforcing the need for continued clinical and biochemical evaluation. Prolonged follow-up confirms an elevated risk of thyroid cancer and Graves' disease as well as hypothyroidism in these patients.     

Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations

The aim of this work was to study the mutations within ATP7B in Egyptian children with Wilson disease and to evaluate any potential correlation between genotype and phenotype in this cohort. The study consisted of 48 children with Wilson disease from 32 independent families. The 21 exons of the ATP7B gene were amplified in a thermal cycler. Direct sequencing of the amplified polymerase chain reaction (PCR) products was performed by cycle sequencing using fluorescent dye terminators in an automatic ABI sequencer. Thirty-one different mutations in 96 chromosomes were detected (19 missense, three nonsense, seven frameshift deletions, and two splice-site mutations). Of these, 12 mutations have not been previously reported. The p.N1270S, p.C703Y, IVS18-2A > G, p.R1319X, c.2304-2305insC, and p.H1069Q were present in 7.8%, 6.2%, 6.2%, 6.2%, 4.7%, and 4.7%, respectively, of studied chromosomes in independent families. One patient was homozygous for both p.N1270S and p.T1434M mutations. Frameshift and nonsense mutations were found in 50% of patients with disease onset < or =8 years compared with only 26% in patients with onset >8 years. Despite mutation heterogeneity in Egyptian children, genotype-phenotype correlation analysis seems to be promising in this population, as many patients carry homozygous mutations, a situation that mandates a larger-scale population screening to identify the carrier rate in this community.     

Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness

The incidence and the significance of TSH-receptor antibodies in Graves' disease and in various thyroid disorders have been evaluated. TSH-binding inhibiting antibodies (TBIAb) and thyroid stimulating antibodies (TSAb) were detected in a large proportion of Graves' disease patients (TBIAb in 68.8% and TSAb in 77.8%), in a small number of patients with idiopathic myxoedema or Hashimoto's thyroiditis, and were not detected in patients with endemic euthyroid goitre, differentiated thyroid carcinoma and toxic adenoma. Furthermore, TSH-receptor antibodies were present in some patients with toxic multinodular goitre (TBIAb in 12.7% and TSAb in 15.9%). When TSH-receptor and other thyroid autoantibodies were compared, it was found that 13 of the 15 Graves' patients with negative tests for thyroglobulin and thyroid microsomal antibodies were positive for TSH-receptor antibodies. On the other hand, 9 of the 11 patients with toxic multinodular goitre who had positive TSH-receptor antibody tests, also had serum thyroglobulin and/or thyroid microsomal antibodies. No significant differences in the prevalence of TSH-receptor antibodies were found in Graves' patients irrespective of the presence of ophthalmopathy or pretibial myxoedema. Elevated TBIAb activity at the end of anti-thyroid drug treatment was found in 52.9% of Graves' patients who subsequently relapsed, while in Graves' patients in remission TBIAb was always negative. TSH-receptor antibody results were not predictive of the outcome of radioiodine treatment in Graves' disease. Finally no correlation could be found between TBIAb and TSAb in Graves' disease and Hashimoto's thyroiditis. In conclusion: the high incidence of TSH-receptor antibodies in Graves' disease confirms their pathogenetic role in the development of hyperthyroidism; TSH-receptor antibodies in Graves' disease are not significantly associated with the presence of ophthalmopathy or pretibial myxoedema; TSH-receptor antibody assays may be useful for the diagnosis of Graves' disease in the absence of other signs of autoimmunity. TBIAb seems to be a good predictor of relapse in Graves' patients treated with anti-thyroid drugs; a fraction of toxic multinodular goitre could be a nodular variant of Graves' disease.     

Progression to end stage renal disease in post-streptococcal glomerulonephritis (PSGN)---Chandigarh Study

193 patients (142 adults and 51 children) with acute PSGN were followed long term. Sixty percent had elevated serum creatinine and 14% had nephrotic range proteinuria at the onset. By two years 28 patients (14%) had died from uremia, and 19 were lost to follow up. Amongst the remainder, 8 patients (4%) had developed mild to moderate renal insufficiency, 12% were hypertensive, and 22% had urinary abnormalities. Of the 146 patients alive at 2 years, 107 were followed up to 10 years (mean 4.8 years). In addition to the 8 patients with renal insufficiency at 2 years, another 7 developed renal failure subsequently. Four out of these 15 patients progressed to uremia within 4 to 10 years after the onset of disease. Hypertension and persistent urinary abnormalities were present in 15% and 24% respectively. Progression to uremia occurred in 6% of children and 20% of adults. Nephrotic range proteinuria, renal insufficiency at the onset, and crescents in more than one third of glomeruli indicated a poor prognosis.     

Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of Myasthenia-Myositis association from a large cohort of patients

Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported.We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10–14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24–73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31–237 months). IM was suspected by CK elevation in all patients (ranging 800–3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.     

The Operation of Immunological Networks in Graves'' Disease

Association between Graves' disease and HLA--B8 has been previously documented, as have been associations between 1 gG heavy chain allotype markers (Gm). We found a significant increase in the phenotype fnb/fb (ie. positivity for fb) in patients with Graves' disease compared to controls, raising the possibility of allotypic restriction of thyroid stimulating antibodies thought to be causally related to the disease. The influence of fb on the susceptibility to Graves' disease was found to be independent of HLA--B8 status suggesting that the immunological network operated by the Histocompatibility-linked genes is independent of that centered around IgG allotypes. It is postulated that, whereas the former genes determine the level of helper T lymphocyte function in the production of thyroid stimulating antibodies in Graves' disease, a person who also happens to carry the Gm marker fb would be assured of the production of IgG antibodies with thyroid stimulatory activity.     

Head-up tilt test in complicated neurocardiogenic syncope in children.

To confirm the usefulness of head-up tilt test (HUT) in neurocardiogenic syncope (NCS) with complicating clinical features, retrospective analysis were done on 12 selected children. The age at onset was 12.7 +/- 1.9 (mean +/- SD) years. Associated clinical features were postoperative congenital heart disease (PO CHD) in 3, coexistent arrhythmia in 8 (persistent ventricular arrhythmia during exercise in 3, premature ventricular contractions in 2, ventricular couplets in 1, sinoatrial exit block in 1 and resting sinus bradycardia in 1) and ST segment depression during exercise in 1. Four of them had a history of exercise-related syncope. All 3 patients with PO CHD had arrhythmia (ventricular tachycardia in 1, sinus bradycardia in 1 and atrioventricular block in 1). HUT provoked NCS in 8 (2 during baseline tilt, 6 during isoproterenol infusion). In one each, ventricular tachycardia and loss of consciousness without hypotension and bradycardia were induced. Atenolol was tried in 5 with improvement of NCS in 4 and aggravation of dizziness in 1. During follow-up, 7 became asymptomatic (2 with atenolol) and 5 were stationary. In conclusion, HUT was valuable in diagnosing NCS even in children with complicating clinical features such as arrhythmias or PO CHD. HUT could be done as apart of initial diagnostic tests if the past history suggests NCS, regardless of associated clinical features. In some cases, the unexpected results of the test turned out useful in managing children with syncope or dizziness.     

Heterogeneity of thyroid autoantigens identified by immunoblotting

Autoimmune thyroid disease in man is commonly associated with autoantibodies against thyroglobulin, microsomes, and the TSH receptor, and the character and specificity of these antithyroid antibodies have been extensively utilized in investigating these conditions. In the present study we have asked whether other thyroid-related antigens exist, against which autoantibodies may be directed. A crude thyroid extract was separated by polyacrylamide gel electrophoresis followed by immunoblotting with serum obtained from patients with Graves' disease or Hashimoto's thyroiditis. Antibodies in sera from patients with Graves' disease and Hashimoto's thyroiditis reacted with many antigenic determinants in immunoblots of the thyroid membrane preparation (2000g supernatant). These determinants were disease specific in that sera from normals and patients with Addison's disease and rheumatoid arthritis did not react, but there was no difference between the patterns of reactivity with Graves' disease or Hashimoto's thyroiditis sera. Thyroglobulin produced two predominant bands of reactivity at 320 and 200 kDa, whereas purified microsomal antigen produced a triplet of bands around 105 kDa, when these preparations were reacted with appropriate autoimmune sera. Nonetheless, some sera produced additional bands with the microsomal antigen blots, indicating that some of the antigens which were detected using crude thyroid membrane remained in the microsome preparation to produce multiple antibody binding reactivities. We were unable to inhibit any of the antibody binding with TSH. Purification of individual thyroid antigens on the basis of their molecular weights should standardize current antibody assays and permit more detailed evaluation of the cellular immune responses in Graves' disease and Hashimoto's thyroiditis.     

Current topics on immunological laboratory tests-thyroid diseases

Current topics in the field of thyroid disease are the development of the second generation assay for TSH receptor antibody (TRAb) using recombinant human TSH receptor and the appearance of antineutrophil cytoplasmic antibodies(ANCA) in Graves' disease patients treated with propylthiouracil(PTU). This new TRAb assay is very useful, since the sensitivity and the specificity were almost 100%, respectively, in the diagnosis of Graves' disease. Furthermore, a new coated tube assay for the detection of blocking TRAb has been developed by using TSH/LH receptor chimera. The prevalence of ANCA is high in Graves' disease patients treated with PTU, but the clinical significance of ANCA is under controversy, since only a part of them develop vasculitis, and recently it has been reported that ANCA is frequently positive in Graves' disease patients before the onset of methimazole treatment. The 7th version of guidelines for the diagnosis of thyroid disease have been prepared by the Japan Thyroid Association, and opens to public inspection. They show the importance of immunological laboratory tests in this field.