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Background: In the UK, the delivery of health care in cardiovascular disease is guided by 'national service frameworks', which are a source of standards of practice and evidence that help to define and aid the implementation of service models capable of responding to public health goals. The revised British Hypertension Society guidelines reflect a lower target blood pressure consistent with those recommended in the US and by the WHO. The lowering of the target for the control of blood pressure has increased the estimated proportion of treated patients with inadequate control in the UK from 37% to 72%. Objective: To identify the requirements for the provision of a pharmacy service that supports hypertension monitoring, and to gain insights into how such a service might be delivered as part of a wider provision of pharmaceutical care in the UK. Method: Two pharmacists followed a structured programme of observation involving three centres in the United States (Minnesota, Colorado and Iowa). Twelve clinical settings were observed, and the pharmacists who provided the services were also the subjects of documented interviews. The settings offered different models of pharmaceutical care from which issues relevant to the international development of such services were identified. Findings: Differences noted between the service models observed included; physical environment of the community pharmacy, the use and type of documentation, methods of blood pressure measurement, extent of monitoring and follow‐up, inter‐professional communication and service orientation in terms of the provision of comprehensive pharmaceutical care to patients or specific disease management. Conclusion: If clearly defined operational models of pharmaceutical care practice in the primary care setting are to form part of a national public health strategy in the UK, they must also be capable of responding to local opportunities and patients' needs. Future development of models and services must be patient‐centred and more widely informed by the range of practice experience gained elsewhere.

Anti-microsomal antibody (AMA) activity was inhibited in 14 of 16 sera and in all 12 IgG preparations from patients with postpartum thyroiditis following incubation with F(ab′)2 fragments from normal polyspecific immunoglobulin for therapeutic use (ivIg). Similar results were observed with sera from seven of seven patients with Graves' disease and five of six patients with autoimmune hypothyroidism. Results of these competitive binding assays and affinity chromatography of AMA IgG on Sepharose-bound F(ab′)2 fragments from ivIg indicated that AMA antibodies reacted with ivIg through idiotypic-anti-idiotypic interactions. Eight out of 10 IgG preparations from patients with autoimmune thyroid disease also showed inhibition of AMA activity when coincubated with autologous IgM at various IgG:IgM molar ratios. These observations suggest that ivIg can inhibit anti-microsomal antibodies through idiotype-anti-idiotype interactions and that such interactions occur with IgM anti-idiotype antibodies in vivo, providing evidence of a role for idiotypic network regulation in the control of thyroid autoimmunity.

Cordocentesis has permitted the study of fetal thyroid function in utero. In normal fetuses, fetal TSH, TBG, and thyroid hormone concentrations increase progressively throughout intrauterine life. Fetal TSH concentrations are always high compared to nonpregnant adult values. TBG concentrations reach adult levels at term. TT4 and FT4 concentrations reach adult levels at approximately 36 weeks gestation, but TT3 and FT3 are always below adult concentrations. There are no significant associations between fetal and maternal concentrations of TSH, TBG, or thyroid hormones. The maternal administration of TRH from at least 25 weeks gestation stimulates the fetal pituitary gland to produce TSH. The response is rapid, unrelated to gestational age, and much greater than that of the mother. These findings suggest that in intrauterine life there is independent and autonomous maturation of the pituitary, thyroid, and liver. The fetal pituitary is able to respond to the maternal administration of TRH and appears to be more sensitive than in the adult. In small-for-gestational-age fetuses, the concentrations of TSH are higher and the concentrations of TT4 and FT4 are lower than in appropriately grown fetuses. The degrees of elevation of TSH and fall in thyroid hormones are significantly related to the degree of fetal hypoxemia and acidemia, respectively. Although the low concentrations of thyroid hormones may have some beneficial effects by reducing oxygen requirements, they may adversely affect brain development.

We have considered how an endocrine disease may impair an individual's ability to both conceive and be delivered of a healthy full-term infant. There are few endocrine conditions that result in an irreversible loss of fertility that is usually restored with correction of the primary disorder. Pregnancy may mimic or alter the clinical presentation of several endocrine diseases and its effect on the biochemical parameters routinely used to assess endocrine function can make the diagnosis of an endocrine disorder extremely difficult

Clinical studies in thyrotoxicosis reveal a state of high bone turnover leading, eventually, to osteoporosis. Recently there has been concern that thyroxine (T4) treatment may have a similar effect on bone. Rat models have been used to study the effects of T4 on bone, but the majority of studies have looked at the effects of T4 after only 3 weeks of treatment. The aim of this study was to evaluate histomorphometric changes in rats after 12 weeks of thyroxine overtreatment or 12 weeks of hypothyroidism compared with untreated control animals. Animals received either T4 200 μg/kg per day, 0.1% propylthiouracil, or vehicle for 12 weeks. Tetracycline was administered 1 week and 3 weeks prior to killing. Iliac crest bone was used for histomorphometry. Serum T4 measurements (taken at killing) confirmed hyper- and hypothyroidism in the appropriate animal groups (between group difference p < 0.001 by ANOVA). In hyperthyroid animals there was an increase in mineral apposition rate (MAR; 0.94 vs. 0.59 μm/day, p < 0.001) and mineral formation rate (MFR/BS; 0.24 vs. 0.12 × 10−2 μm3/μm2 per day, p < 0.001) and a slight increase in eroded surfaces (ES/BS%; 1.54 vs. 1.36, p < 0.05) compared with controls, consistent with previous in vitro and in vivo observations. In hypothyroid rats there was a marked reduction in osteoid surfaces (OS/BS%; 1.7 vs. 24.8, p < 0.001) and MAR (0.3 vs. 0.59 μg/day, p < 0.001), a reduction in ES/BS% (0.51 vs. 1.36, p < 0.05), and an increase in cancellous bone volume (BV/ TV%; 30.29 vs. 19.6, p < 0.05), suggesting that thyroid hormones are a requirement for normal bone turnover. This study characterizes the histomorphometric changes following 12 weeks of T4 overtreatment in rats and demonstrates profound changes due to hypothyroidism in a rat model. To the best of our knowledge, it is the first study to show such effects in an animal model.

The revolution in molecular techniques has allowed dissection of the autoimmune response in a way impossible to imagine 10 yr ago. There have been spectacular advances in our understanding of self-tolerance mechanisms and how these may fail, combined with a detailed comprehension of antigen presentation, functional T cell subsets, and TCR utilization in autoimmunity, albeit usually in animal models that resemble, but do not exactly duplicate, human diseases. More gradually, these findings are being translated to thyroid autoimmunity, where the major achievement of the last decade has been the molecular characterization of the three main thyroid autoantigens. This in turn has allowed epitope identification, although again the only clear data so far have come from animal models of EAT. Another advance has been the recognition that the thyrocyte is not a helpless target of autoaggression, being capable of expressing a wide array of immunologically active molecules, which may exacerbate or diminish the autoimmune response. In 1983, there was considerable excitement at the discovery of the first of these phenomena, namely MHC class II expression, but its possible role in autoantigen presentation remains to be defined. By analogy with pancreatic beta-cells, and based on our own data, we believe that class II-expressing thyrocytes have little, if any, such role and suspect that instead this may be a mechanism for inducing peripheral tolerance. Defining the contribution of thyrocytes to the intrathyroidal autoimmune response, whether from released cytokines or surface-bound molecules, will be crucial to our future understanding, as well as holding the promise that these thyroid-derived products might be therapeutic targets. Despite molecular developments in HLA analysis, there have been no really major improvements in our understanding of the immunogenetics of thyroid autoimmunity, equivalent to those made in type 1 diabetes mellitus. The available data suggest strongly that non-MHC genes play an important role in susceptibility, and novel approaches will be required to identify these. On the other hand, we know more about the importance of environmental and endogenous (most probably hormonal) factors in thyroid autoimmunity. Understanding the basic immunological changes in the postpartum period is still poor, however, as most studies to date have concentrated on epidemiology and clinical delineation. As PPTD undergoes spontaneous remission, elucidation of these mechanisms has clear implications for treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Publisher Summary This chapter discusses the medical aspects of thyroid disease. The thyroid gland is situated in the anterior aspect of the neck and consists of two lobes connected by a central isthmus approximately at the level of the cricoid cartilage. The adult thyroid weighs 15–20 g. It is derived embryologically as an epithelial proliferation from the floor of the pharynx, which migrates downwards anterior to the foregut before reaching its final position in front of the trachea by the seventh week. During migration, the gland remains connected to the floor of the pharynx by the thyroglossal duct, which subsequently disappears. The failure of resolution of the thyroglossal duct or persistence of thyroid remnants along its course may result in a thyroglossal cyst, fistula, or aberrant thyroid tissue. Thyroid hormones are not produced in the fetal thyroid until the twelfth week of gestation. Graves' disease is the most common cause of thyrotoxicosis, being about five times more frequent in females than in males; although it may develop at any age, it has a peak incidence at 20–40 years. The natural history of the untreated disease is one of remissions and exacerbations over many years.

Thyroid-stimulating hormone was measured in fetal blood samples obtained by cordocentesis before and after blood transfusion in Rh-affected pregnancies at 25 to 37 weeks' gestation. In eight of 26 study subjects thyrotropin-releasing hormone was given to the mothers immediately after the pretransfusion samples were obtained. In this group the fetal thyroid-stimulating hormone concentrations in the posttransfusion samples were significantly higher than those before the transfusion.

The effect of excessive tri-iodothyronine (T3) in vivo was assessed using normal human lymphocytes. Cells from normal subjects were frozen in liquid nitrogen before and after oral administration of T3 for 1 week to permit a direct comparison under identical culture conditions. Within the group of individuals studied, some subjects did show changes in B or T cell function but hypertri-iodothyroninaemia produced no consistent effect for the whole group on circulating T cell subsets or T and B cell activation measured by short-term culture or stimulation of lymphocyte cultures with phytohaemagglutinin or pokeweed mitogen. Tri-iodothyronine supplementation of cultures in vitro did not affect pokeweed mitogen stimulation. These findings suggest that the immunological abnormalities in Graves' disease are not the result of increased circulating thyroid hormone levels and that remission following medical treatment is due to an immuno-suppressive effect of the drug rather than the restoration of euthyroidism. J. Endocr. (1984) 101,81–86

An automated enzyme-linked immunoassay for the detection of antibodies to human thyroid microsomes has been assessed. This assay correlates closely with the established commercial passive haemagglutination method. Variations in the purity of crude microsome preparations and the degree of thyroglobulin contamination make careful comparison of different preparations essential for meaningful interpretation of results, and attempts to circumvent these problems by further purification of microsome preparations using gel filtration are discussed. The application of this method for routine screening of serum samples is demonstrated using populations of normal subjects and patients with rheumatoid arthritis and anti-glomerular basement membrane disease. This assay has also permitted the establishment of murine hybrid myelomas secreting monoclonal antibodies to human thyroid microsomes.

Female PVG/c rats, thymectomised on weaning and given 4 courses of whole body irradiation to a total dose of 1000 rads, developed experimental autoimmune thyroid disease (EAITD) as assessed by histological evidence of thyroiditis and circulating levels of antithyroglobulin antibodies. Hypothyroidism resulted. Induction of the disease was associated with a highly significant fall in T lymphocyte numbers. Eight weeks after their last dose of irradiation the animals commenced treatment with Cyclosporin A (10 mg/kg rat/day, intragastrically) and were treated for varying time intervals thereafter. The reversal of the T lymphocyte helper: suppressor ratio on Cyclosporin A therapy was associated with a significant improvement in the disease process. The alterations in the T cell subsets and in the disease lasted only as long as the drug was administered and thereafter reverted towards that seen in the control groups of animals receiving no treatment.

Cyclosporin given to two patients with Graves' ophthalmopathy produced a rapid objective improvement in both, including restoration of ocular-muscle function and visual acuity, improvement in exophthalmos, and reduction in orbital muscle swelling judged by computed tomographic scan. Thyroid autoantibody levels fell with treatment, and T-cell subset abnormalities returned towards normal. In one patient an absent thyrotropin response to thyrotropin-releasing hormone became normal after treatment. These results suggest that cyclospirin treatment should be considered in patients with the congestive ophthalmopathy of Graves' disease.

It is now possible to demonstrate production of thyroglobulin antibodies by Hashimoto lymphocytes when they are cultured with autologous thyroglobulin-primed accessory cells. When accessory cells are primed with antigen in the presence of the antithyroid drug methimazole, antibody production is blocked. This finding suggests that the immunosuppressive action of this group of antithyroid drug is mediated by an action on antigen handling by accessory cells.

Conflicting data on subpopulations of peripheral blood lymphocytes in patients with autoimmune disease largely reflect variations in methods of study. An investigation was therefore conducted aimed at avoiding this difficulty. Serial samples of peripheral blood mononuclear cells from 42 patients with hyperthyroid Graves' disease were collected at monthly intervals before, during, and for 12 months after a six month course of carbimazole. Samples were stored in liquid nitrogen until completion of the study, when they were thawed and all samples from each patient analysed within the same assay using mouse monoclonal antibodies to human cell subsets and a fluorescence activated cell sorter. Proportions of cytotoxic/suppressor (OKT8) positive cells before treatment (mean 17.4 (SEM 0.8)%) were significantly lower (p less than 0.001) than those in normal controls (29.8 (1.9)%; n = 10) and returned to normal by the end of treatment. In contrast, the proportions of activated T cells (OKIa-OKM1) were significantly raised before treatment as compared with normal (14.4 (0.6)% versus 4.6 (0.8)%; p less than 0.001) and fell to normal by the end of treatment. Proportions of OKT3 and OKT4 positive T cells remained unchanged throughout treatment and in the succeeding 12 months. In patients who relapsed after treatment there was a rise in the proportion of activated T cells and a fall in OKT8 positive T cells, which returned towards normal with retreatment. The explanation for the alterations in numbers of circulating T cells remains to be determined but they may provide a means for predicting more accurately the outcome of Graves' disease after treatment with carbimazole.

The clinical utility of ELISA assays for antibodies reactive with a variety of porcine orbital tissue antigen preparations is described using sera from large numbers of patients. Use of such assays does not allow reliable identification of patients with Graves' ophthalmopathy (GO) due to the overlap between patients with and without eye involvement and normal individuals. In 5 6 patients showing high levels of reactivity with porcine eye muscle membrane antigen, a considerable but variable proportion of the binding was found to be species, rather than tissue, specific. No consistent pattern of change in ELISA reactivity with time was seen in studies of serum samples from patients treated medically for hyperthyroidism and patients who received immunosuppressive therapy with cyclosporin A for active, severe ophthalmopathy. Use of previously published ELISA methods using the crude antigen preparations described is therefore not likely to be of use in the routine clinical management of GO patients.

Patients with hyperprolactinemia may be managed by pituitary surgery or irradiation, bromocriptine treatment, or a combination of these methods, and some patients remain untreated. Little is known of the long-term consequences of some of these therapeutic regimens. Forty-six hyperprolactinemic patients (40 female and six male) managed solely with bromocriptine or no treatment over a period of 12 months to six years were therefore evaluated in this study. Nine patients with radiologically normal pituitary fossae were untreated and 10 received bromocriptine, 7.5 to 10 mg daily, while 20 patients with radiologic evidence of a pituitary tumor were treated with bromocriptine, generally 10 to 20 mg daily. Patients were assessed clinically, biochemically, and radiologically before treatment and at least six weeks after discontinuation of therapy. A further seven patients were similarly assessed before and after eight bromocriptine-induced pregnancies. Symptoms persisted in the untreated group of nine patients, although menstruation returned in four of the females with previous amenorrhea; serum prolactin levels remained elevated, other pituitary function did not change, and pituitary fossae remained normal radiologically. In all patients treated with bromocriptine, symptoms improved irrespective of radiologic findings on the pituitary, and were abolished in 67 percent during treatment associated with a decrease in serum prolactin levels in all, and a return of levels to within normal limits in 80 percent of patients. Persistent side effects were usually dose-related, but remained troublesome in 13 percent. Bromocriptine-induced tumor regression was evident radiologically in all patients with suprasellar tumor tissue and in some with purely intrasellar adenomas. This effect occurred rapidly and persisted or increased throughout follow-up. On discontinuation of treatment, prolactin levels remained significantly lower than before therapy (mean 2,934 versus 5,052 mU/liter, p less than 0.05) but were within the normal range in only two patients. Other pituitary function was unaltered, or improved in some patients with definite tumors. Bromocriptine-induced pregnancy produced no permanent change in clinical, biochemical, or radiologic status. Long-term bromocriptine treatment for hyperprolactinemia is thus highly effective in alleviating symptoms and suppressing prolactin secretion, and induces persistent tumor regression on treatment without deterioration of other pituitary function in patients with macroadenomas. On discontinuation of therapy, however, hyperprolactinemia usually recurs, and treatment may therefore need to be continued for years.

Using a protein A plaque assay to detect immunoglobulin synthesis we have shown that culture of pokeweed mitogen (PWM)-stimulated lymphocytes in the presence of lithium significantly increased IgG production at concentrations of 10−3 to 10−2 mM. Enhanced IgG and IgM synthesis was found in cultures with lithium alone at concentrations of 1–10 mM, levels within the therapeutic range. Significantly higher numbers of spontaneous IgM plaque-forming cells were found in the peripheral blood of patients receiving lithium carbonate therapy than in normal controls suggesting that these findings may have clinical relevance.

Within a year of stopping a 6-month course of carbimazole treatment 41 of 65 patients (63%) with hyperthyroid Graves' disease had a recurrence of their hyperthyroidism. By combined analysis of the HLA-DRw3 status and the level of thyrotrophin-receptor antibody at the time of drug withdrawal relapse or remission could be predicted in 62 of the 65 patients.

Bromocriptine therapy may cause regression of prolactinomas, but its effect on nonsecretory pituitary tumors is uncertain. Conventional treatment for such "functionless" tumors is surgery and/or radiotherapy, but recurrences pose a therapeutic dilemma. We describe a patient with such a tumor treated by surgery and radiotherapy who presented with recurrent disease 14 years later. On treatment with bromocriptine, 20 mg daily for 25 months, the intrasellar tumor recurrence had diminished in size and a suprasellar extension had almost disappeared. Bromocriptine therapy may therefore benefit some patients with nonsecretory pituitary tumors considered unsuitable for surgery or radiotherapy.

Microsomal and thyroglobulin autoantibody activity has been detected in synovial fluid from 34 of 50 patients with various arthritides (rheumatoid arthritis, ankylosing spondylitis, osteoarthrosis, and gout). Serum from only 4 of these patients showed thyroid-autoantibody activity, and the serum titres were considerably lower than the synovial-fluid titres. This suggests that thyroid autoantibody is produced locally in the joints of these patients.

A study was conducted investigating the possibility that the immunosuppressive action of methimazole (the active metabolite of the antithyroid drug carbimazole) might be due to an effect on the production of oxygen radicals by monocytes. Techniques comprised measurement of luminol dependent chemoluminescence in monocytes and a spectrophotometric assay for production of hydrogen peroxide. The results showed definite inhibition of formation of oxygen radicals by resting and stimulated monocytes, which may explain the immunosuppressive action of the drug in Graves9 disease. The findings also suggest that the formation of oxygen radicals and the initiation of the immune response may be closely related.

A simple combined culture and assay system for small numbers of human lymphocytes is described which permits rapid detection of immunoglobulin adherent to 96-well plates after 18 h culture, by means of an enzyme-linked immunosorbent assay (ELISA). The method is capable of detecting thyroglobulin antibody secreted by cells obtained from fine needle aspiration of the thyroid and therefore allows investigation of B cells activated in vivo from different sites by quantitation of the amount of immunoglobulin or antibody secreted.

In the United Kingdom, about half the patients with Graves' disease who are given antithyroid drugs are still in remission one year after treatment is stopped. The most widely held view is that such remission rates are due only to the biochemical effects of the drugs, the disease either spontaneously remitting or abating when the immune system is no longer subject to the stimulatory effects of excessive thyroid hormone. We review here the accumulating evidence against both of these alternatives. In contrast, there is now a large body of work which shows that thyrotrophin receptor antibody levels, central to the aetiology of Graves' hyperthyroidism, fall during antithyroid treatment and that remission may be related to this fall in a fashion which is dependent on the dose and duration of treatment. This immunosuppressive effect is supported by experimental data and on the basis of these results we propose that antithyroid drugs may modify the natural history of Graves' disease and contribute to the remission which occurs in a proportion of treated patients.

We have investigated the prevalence of proteinuria in patients with Graves' disease and chronic autoimmune thyroiditis attending a routine thyroid clinic. Using the urine protein creatinine index, proteinuria was found in 29.8% of patients with autoimmune thyroid disease and in 9.5% of patients attending the same clinic but without these conditions. When patients with Graves' disease were treated with 131I, proteinuria measured by 24 h collections developed in 9 of 14 patients without pre-existing proteinuria and appeared to diminish in 4 patients in whom proteinuria had been present before treatment. The prevalence and fluctuation of proteinuria was independent of thyroglobulin and microsomal antibody levels. We were unable to confirm previous reports of a high prevalence of circulating immune complexes in autoimmune thyroid disease; complexes were detected in only 7.9% of patients and did not correlate with proteinuria. The causes of mild proteinuria in autoimmune thyroid disease are not apparent, but previous case reports suggesting that membranous glomerulonephritis is associated with Graves' disease, albeit rarely, indicate that immunological mechanisms may be implicated.

The use of in vitro assays of cell-mediated immunity has provided evidence of a defect in thyroid antigen-specific T suppressor cells in the peripheral blood of patients with autoimmune diseases. We employed a direct assay of T lymphocyte migration inhibition in an attempt to demonstrate cell-mediated immune responses to thyroid antigens in untreated patients with hyperthyroid Graves' disease and examined the influence of (1) a variety of antigen preparations, (2) different assay conditions, and (3) the HLA-DR3 status of normal subjects on this system. There was no significant difference in the migration of lymphocytes from 13 untreated patients with hyperthyroid Graves' disease to a crude 800 X g supernatant antigen preparation of normal human thyroid when incubated at either 20 or 37 C compared with the response of 13 normal subjects. The mean migration index was 57 +/- 22 (+/- SD) in the Graves' patients compared with 65.2 +/- 19.9 in the normal subjects at 20 C and 83 +/- 16.9 in the Graves' patients compared with 86.6 +/- 15.1 in the normal subjects at 37 C. Similarly, there was no significant difference in the migration indices obtained with T cells from Graves' patients and normal subjects using an 800 X g supernatant prepared from the thyroid glands of 2 patients with Graves' disease, incubated at 20 or 37 C (44.0 +/- 22.5 in the Graves' patients compared with 45.7 +/- 12.8 in the normal subjects at 20 C and 67.9 +/- 20.8 in the patients compared with 72 +/- 12.6 in the controls at 37 C). In contrast, the migration indices calculated for 20 C incubation were significantly lower than the corresponding value at 37 C using 800 X g normal thyroid antigen (P less than 0.05) and 800 X g Graves' thyroid antigen (P less than 0.01) in both patient and control groups. An identically prepared uterine antigen produced a similar reduction in the migration indices at 20 C compared with those at 37 C in 6 normal donors (P less than 0.05), but no temperature effect was found when 8 normal subjects were tested with purified protein derivative of tuberculin. The responses of 12 normal individuals to 800 X g supernatants of the normal and Graves' thyroid antigens were not influenced by the HLA-DR3 antigen.(ABSTRACT TRUNCATED AT 400 WORDS)

Men with hyperprolactinaemia present with large tumours. Conventional therapy with surgery and/or irradiation is unsatisfactory, with up to 100% of patients remaining hyperprolactinaemic (or subsequently developing pituitary insufficiency). In view of reports of bromocriptine-induced regression of prolactinomas, eight consecutive male hyperprolactinaemic patients with impotence and/or symptoms related to local tumour effects were treated with bromocriptine 20 mg daily as sole therapy for 3-11 months. Symptoms were relieved partly or completely in seven patients and serum prolactin was restored to normal or near normal in all men. Serum thyroxine and plasma cortisol response to hypoglycaemia became normal in two men who had subnormal values before therapy. Mean serum growth hormone response to hypoglycaemia rose significantly as did plasma testosterone concentrations. Evidence of tumour regression, sometimes massive, was seen in the six patients who underwent repeat radiology. The symptomatic relief and biochemical and radiological improvement in these patients indicate that bromocriptine therapy may now be the treatment of choice for hyperprolactinaemic men with large tumours.

Microsomal antibodies and antibodies directed toward the receptor for thyroid-stimulating hormone (TSH) decreased in parallel while patients with Graves' disease were taking carbimazole, whereas no significant changes were observed during treatment with placebo or propranolol. The changes in autoantibody levels during carbimazole treatment were independent of changes in serum thyroxine and could have been due to a direct effect of the drug on autoantibody synthesis. Evidence for this suggestion was provided when low doses of methimazole (the active metabolite of carbimazole) were found to inhibit thyroid-autoantibody production in cultured lymphocytes. Since thyroid lymphocytes are probably a major site of thyroid-antibody synthesis in Graves' disease and methimazole is concentrated in the thyroid during treatment, a local action of the drug on antibody production seems likely. This possibility could be important in the use of carbimazole to control hyperthyroidism.

INTRODUCTION THIS REVIEW of autoimmune thyroid disease will highlight the recent advances made in understanding the control of the autoimmune process particularly at pathogenetic and therapeutic levels. Many novel techniques have recently been applied to the investigation of thyroid autoimmunity although the results obtained have not always clarified the overall picture. These new methodologies are discussed and attention is also focused upon experimental thyroiditis produced in a variety of animals. We believe that these models have been neglected somewhat by clinically oriented investigators. Yet their use originally led to the foundation of autoimmune concepts, and experimental thyroiditis continues to provide major insights into the possible etiology and pathogenesis of the human counterpart. Before discussing thyroid disease in detail however, it is worth considering the current themes in autoimmunity in general.

Phorbol myristate acetate (PMA), a known lymphocyte mitogen, has been shown to inhibit immunoglobulin synthesis by human peripheral blood lymphocytes. This effect occurs with low concentrations of the agent and following only 12 h contact with the lymphocytes. PMA was also capable of preventing pokeweed mitogen stimulation of lymphocytes. These experiments suggest that PMA prevents the complete differentiation of B-cells into plasma cells capable of secreting immunoglobulin.

A robust, rapid, sensitive and specific enzyme-linked immunosorbent assay (ELISA), using an in-house immunoglobulin-A-sub-class mouse monoclonal human-thyroglobulin antibody (WNSM2), with a sensitivity of 1·51 pmol/l has been established for the measurement of thyroglobulin in serum. Standard curves in varying dilutions of human serum were similar to standard curves obtained in serum-free medium, thus demonstrating no significant cross-reactivity with any serum proteins other than thyroglobulin. Levels of serum thyroglobulin detected by ELISA correlated significantly (r = 0·93, P < 0·001) with those from a standardized and well-characterized radioimmunoassay. The coefficients of variation within and between ELISA assays were 3·9 and 7·1% respectively. Thyroglobulin was detectable in 87% of 54 normal subjects who had no history of thyroid or autoimmune disease, the mean (±s.d.) for this group being 15 ± 6·6 pmol/l with a range of 1·51–53 pmol/l. Using this assay, levels of thyroglobulin were shown to be significantly (P < 0·002) increased in patients with untreated hyperthyroid Graves' disease compared with normal subjects. J. Endocr. (1985) 107, 383–387

A criticism of current techniques for monitoring changes in T-cell subset numbers over extended periods in individuals with disease states in which such changes might provide insight in the fact that serial samples taken are usually analysed fresh and therefore not in the same assay. To try to overcome this problem we have stored peripheral blood mononuclear cells frozen in liquid nitrogen and thence examined their ability to form sheep red blood cell (E) rosettes and to label with OK monoclonal antibodies. Results obtained show that cell viabilities following freezing and T-cell subset analysis of E-rosette positive cells are no different when fresh or frozen and subsequently thawed peripheral blood mononuclear cells are used.

In a recent study DMSO was found to produce a rapid and sustained fall in autoantibody levels in rats with experimental myasthenia gravis: this was discovered when other potential immunosuppressants dissolved in DMSO were being tested (1). These clearly demonstrated effects have therapeutic implications for a wide variety of autoimmune diseases, but were criticised since the dose of DMSO used was sufficient to induce toxic or nonspecific reactions (2). Besides wishing to confirm the effect of DMSO suggested in this isolated report, the use of DMSO in the treatment of human renal amyloidosis (3, 4) provides an additional stimulus to investigate the effects of this agent on the immune system. We have therefore examined the action of DMSO at therapeutically relevant concentrations in vitro on immunoglobulin production by human peripheral blood mononuclear cells (PBM) and also in rive on thyroglobulin autoantibody production in experimental autoimmune thyroiditis induced in rats.

Serum antibodies to the acetylcholine receptor (anti-AChR) have been reported in Japanese individuals who were elderly or had Down's syndrome at frequencies of 18% and 24%, respectively. We have measured serum anti-AChR in 3 Caucasoid groups: 53 elderly patients (aged 65-92 years) with miscellaneous (non-myasthenic) disorders, 30 individuals with Down's syndrome, and 40 elderly patients (aged 71-93 years) known to have strongly positive thyroid autoantibodies. A raised titre (greater than 0.2 nmol/l) was confined to 3 patients in the third group (7.5%). We conclude that an increased frequency of anti-AChR antibodies is not a feature of Caucasians who are elderly or have Down's syndrome, and that, even in an elderly group with a high titre of another autoantibody, the frequency of anti-AChR is lower than in elderly Japanese individuals.

SINCE the development of specific assays for prolactin1 , 2 it has been possible to demonstrate that a large proportion of pituitary tumors secrete prolactin.3 Until the advent of bromocriptine, operation and irradiation had been used as the primary treatments for such tumors.4 The introduction of bromocriptine, an ergot derivative5 and dopamine agonist,6 into therapeutic regimens for pituitary disease is recent and is still being evaluated. It is a potent inhibitor of prolactin secretion. Acting primarily at the level of the pituitary,7 but with a possible hypothalamic effect not yet excluded,8 it lowers prolactin secretion in patients with hyperprolactinemia from any cause, . . .

We have used an automatic cell harvester and micro culture techniques to examine the accumulation of [35S]methimazole by monocytes, macrophages and lymphocytes. Significant temperature-dependent accumulation of the drug was found in resting monocytes and macrophages; this was increased up to 4-fold by phagocytosis. Lymphocytes accumulated little or no drug and myeloma and leukaemic cell lines accumulated none. These results show that two interrelated cells with endogenous peroxidatic activity take up the antithyroid drug methimazole providing further support for the concept that immunosuppression by this drug in Graves' disease is mediated via an action on antigen-presenting cells.

Thyroid peroxidase (TPO), the enzyme responsible for thyroid hormone synthesis, is a key autoantigen in autoimmune thyroid disease. Based on the results of a study using both isotopic and nonisotopic in situ hybridization, we assign the gene coding for human TPO to chromosome region 2p25→p24.

By suitable immunization of mice and fusion of their spleen cells with a non-secretor mouse myeloma line, monoclonal antibodies have been produced which react with the human thyroid microsomal (M) antigen. These monoclonal antibodies showed no reactivity by enzyme-linked immunoassay with liver microsomes or thyroglobulin and their specificity was confirmed by immunolocalization studies, in which they showed the staining characteristics of human M antibodies. All four monoclonal antibodies tested were immunoglobulin M; three were cytotoxic to thyroid cell monolayers. The lack of cytotoxicity with the fourth monoclonal supports the concept that certain epitopes of the M antigen may be partially or completely absent at the thyroid cell surface. These monoclonal antibodies should permit further characterization of the thyroid M antigen in view of their absence of cross-reactivity with thyroglobulin. J. Endocr. (1985) 105, 47–52