R. Hall

PREDICTION OF RELAPSE IN HYPERTHYROID GRAVES' DISEASE

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.

EVIDENCE FOR AN EFFECT OF ANTITHYROID DRUGS ON THE NATURAL HISTORY OF GRAVES' DISEASE

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.

Hyperprolactinemia: Long-term effects of bromocriptine

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.

Methimazole inhibits thyroid autoantibody production by an action on accessory cells

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 drugs is mediated by an action on antigen handling by accessory cells.

The enhancement of immunoglobulin synthesis by human lymphocytes with lithium

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.

Enzyme-linked immunoassay of monoclonal and serum microsomal autoantibodies

An automated enzyme-linked immunoassay for the detection of antibodies to human thyroid microsomes has been assessed. This assay correlated 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.

Bromocriptine therapy for “nonfunctioning” pituitary tumors

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 days 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.

Dopaminergic control of TSH secretion in isolated rat pituitary cells.

There is now considerable evidence to indicate that dopamine has an inhibitory role in the control of TSH secretion in man [ 11. Studies with the dopamine antagonist domperidone [2-41, which does not cross the blood brain barrier [5] suggest that this dopaminergic control is exerted at the level of the anterior pituitary or median eminence [6,7]. This report describes an investigation of the effects of dopamine on the secretion of TSH by isolated rat pituitary cells. Our studies demonstrate that dopamine can inhibit TSH secretion directly and suggest that this type of interaction could be involved in the control of TSH secretion in vivo.

The influence of cyclosporin A on experimental autoimmune thyroid disease in the rat

Female PVG/c rats, thymectomized 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.

The interaction of graves' IgG with the thyrotrophin receptor

Sera from patients with Graves’ disease contain antibodies which inhibit the binding of thyrotrophin (TSH) to thyroid membranes [l-4]. The effect could be due to a direct interaction between the antibody and the TSH receptor or the antibody might inactivate the receptor indirectly by interacting with a different membrane component. Here, we describe attempts to distinguish between these two possibilities. Our investigations demonstrate that Graves’ IgG has similar inhibiting effects on labelled TSH binding to membrane bound receptors, crude detergent solubilised receptors and detergent solubilised receptors purified by Sepharose-TSH affinity chromatography. Furthermore, the effects of antibody are independent of detergent concentration and no evidence could be obtained for the formation of significant amounts of a complex consisting of antibody, solubilised receptors and TSH. These observations suggest that Graves’ IgG contain antibodies which interact directly with the TSH receptor.