A quantitative cytochemical assay for the measurement of total NADPH formation in guinea pig thyroid tissue following incubation with thyroid stimulators was validated and applied to the measurement of such stimulators in IgG concentrates prepared from human plasma. Pentose shunt enzyme activity was not uniformly distributed in thyroid tissue but this could be overcome and NADPH generation in such tissue used to assess accurately thyroid stimulators if a sufficient number of thyroid cells were measured. Specificity studies showed that antiserum to human IgG significantly diminished the NADPH generating capacity of IgG concentrates prepared in plasma from goitrous patients while antiserum to h-TSH had no such effect. The measurement of thyroid growth stimulating immunoglobulins (TGI) depended not only on the amount of NADPH generated but also on the IgG concentration at which maximum responses occurred. TGI present in goitrous Graves' disease were 10 times more potent than those present in euthyroid goitre, while such stimulators when present in toxic nodular goitre appeared to possess an intermediate potency. This finding, when taken together with the demonstration that TSH stimulation decreased intercellular differences in pentose shunt activity, provides experimental evidence for the hypothesis that an acute intense growth stimulus affecting all thyroid cells produces the diffuse hyperplasia characteristic of Graves' disease. In contrast, the weaker stimulus observed in nodular goitre may, over a period of time, result in the asymmetric hyperplasia commonly observed in this condition.

Abstract. The rare occurrence of hyperthyroidism with an autonomously functioning nodule which following 131I therapy presented as toxic diffuse goitre (Graves' disease) is described in a 60 year old male. This progression was characterised by the presence of varying concentrations of IgG thyroid stimulators, thyroid stimulating immunoglobulins and thyroid growth stimulating immunoglobulins, as measured by cytochemical bioassay. It is postulated that the presence of the nodule and its associated hypersecretion of thyroid hormones may have protected the gland from the effects of IgG stimulators by bringing about inhibitory short-loop feedback on normal thyroid cells. It is further suggested that following therapeutic ablation of the nodule, normal thyroid cells became sensitive to the thyroid stimulators with the evolution of typical features of toxic diffuse goitre.

Thyroid growth stimulating immunoglobulins (TGI) were assayed in IgG concentrates prepared from human plasma using a cytochemical bioassay (CBA) based on the measurement of changes in glucose-6-phosphate dehydrogenase (G6PD) activity in guinea pig thyroid follicular cells. TGI was present in all 8 patients studied who had goitrous Graves' disease, in 9 who had toxic diffuse goitres with asymmetric uptake on scintigram and/or symptomatic ophthalmopathy and in 4:8 who had toxic uninodular goitre with autonomously functioning nodules. TGI were also present in 34:54 (64%) of patients who had non-toxic goitres. In contrast, TGI were undetectable in 4 patients who had Graves' disease without palpable goitre and in all 18 euthyroid non-goitrous volunteers. Maximum increases in G6PD activity occurred at an IgG concentration of 50 \g=m\g/ml in all patients who had goitrous Graves' disease and in 5:7 who had diffuse non-toxic goitres. In contrast, IgG concentrates from 20:27 patients with nodular goitres caused maximum increases in G6PD activity at an IgG concentration of 500 \g=m\g/ml . A comparison of the prevalence of TGI with that of thyroid stimulating immunoglobulins (TSI), also measured by CBA, in 63 patients showed that although both stimulators were present in 8 patients who had goitrous Graves' disease they were only simultaneously present in 18:43 (42%) who had non-toxic goitres of various aetiologies. Thyrotrophin receptor antibodies (TRAb) were present in 11/44 (25%) of non-toxic goitrous patients but there was no significant correlation with IgG stimulators in such patients. It is concluded that the finding of IgG stimulators in a variety of thyroid disorders suggests common immunological features in their pathogenesis. The presence or absence of such stimulators and their relative potencies may play a part in determining functional or structural variations between common forms of goitre.

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