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The clinical and biochemical characteristics of 15 elderly patients with low levels of thyrotrophin (TSH) (< 0.1 mU/L) but normal free tri-iodothyronine (T3) and free thyroxine (T4) (group S) were compared with 10 euthyroid subjects (group E) and 10 hyperthyroid patients (group T). Free T3 and free T4 were significantly higher (p < 0.05) in group S (6.3 +/- 0.5 and 18.6 +/- 1.0 pmol/l, respectively) than in group E (4.6 +/- 0.3, 12.6 +/- 0.6). In common with elderly hyperthyroid patients (group T), patients in group S had few signs or symptoms of thyrotoxicosis, but the Wayne score (clinical index of hyperthyroidism) was higher in group S than in euthyroid subjects (p < 0.05). Thyroid microsomal, thyroglobulin or thyrotrophin receptor antibodies were common in group T (n = 9) but not in groups S (n = 2) or E (n = 1). This suggests a low prevalence of Graves' disease in group S compared to group T. Combined thyrotrophin releasing hormone (TRH; 200 micrograms i.v.) and gonadotrophin releasing hormone (GnRH; 100 micrograms i.v.) tests were performed; no cases of low TSH due to hypopituitarism were identified in group S. During a mean of 7.9 (4-12) months of observation TSH reverted to the normal range (> 0.2 mU/L) in 7 of 15 patients in group S; thyroid hormone concentrations rose above the normal range in four, however, only two patients required treatment for hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

We have used a method based on a perchlorate discharge test to estimate the duration of antithyroid effect of two doses of methimazole (MMI). Six patients with diffuse toxic goitre took 5 mg MMI twice daily and six took 20 mg twice daily over the study period of 12 weeks. Biochemical control of hyperthyroidism was achieved in all patients and thyroid hormone supplementation was required by all of the patients in the higher dose group to avoid hypothyroidism. Discharge of radioiodine from the thyroid by perchlorate diminished in both groups with time after MMI. After 5 mg MMI, perchlorate discharge as a percentage of the 30-min uptake (mean +/- SD), was 81.7 +/- 3.3% at 2.2 h, 69.3 +/- 18.9% at 5.9 h, 22.6-23.4% at 13.4 h and 2.7-6.7% at 25.1 h. After 20 mg MMI, the discharge was 92.5 +/- 1.9% at 2.2 h, 84.3 +/- 8.8% at 6.3 h, 64.8 +/- 24.1% at 13.3 h and 26.9-29.4% at 25.1 h. Only four patients (one in the lower dose group) showed a detectable discharge at 25 h and one of the patients treated with the lower dose showed no discharge at 13 h. These estimates of the effect of MMI on thyroidal iodide organification are not in keeping with published thyroidal MMI concentrations which do not show a fall between 3-6 h and 17-20 h after carbimazole. The explanation for this disparity is not clear but may be based on a redistribution of thioureylenes within the thyroid with time after dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective study of thyroid function including serial tracer radioisotope uptake measurements in 55 patients treated with 131I therapy is described. Five patients had an episode of transient hypothyroidism within eight months of treatment: in three of these patients this was due to impaired organification of iodide, with normal iodide trapping by the thyroid (as measured by a twenty minute 123I uptake) being preserved. In contrast, in all patients who developed permanent hypothyroidism, iodide trapping was markedly diminished and did not recover. It is suggested that hypothyroidism due to organification failure following 131I therapy is potentially short-lived; where hypothyroidism is associated with gross impairment of iodide trapping, recovery is unlikely. Early iodine uptake measurements may be of value in selecting those patients whose hypothyroidism is transient and who do not require permanent thyroid hormone replacement.

1 A high performance liquid chromatographic (HPLC) method was used to study the pharmacokinetics of methimazole after oral administration of carbimazole to women in various stages of pregnancy. 2 In one patient it was possible to conduct the study in the first and third timesters: there was an appreciable increase in the apparent clearance of methimazole. 3 Based on the assumption of complete absorption and hydrolysis of carbimazole to methimazole the mean apparent clearance was found to be significantly higher in pregnant patients receiving 10 mg carbimazole than in non-pregnant patients receiving the same dose.

Two patients remained clinically euthyroid following treatment for thyrotoxicosis with antithyroid drugs in spite of persistently elevated thyroid radioiodine uptakes not suppressable by exogenous triiodothyronine. Perchlorate discharge tests showed a defect in the intrathyroidal organification of iodine. Circulating levels of thyroxine were normal. From our study of 105 patients treated for thyrotoxicosis with antithyroid drugs, apparent remission of thyrotoxicosis by this mechanism might occur in up to 2 percent of patients.

Thyroidal binding of iodide was studied by kinetic analysis of [123I]iodide uptake and its discharge by perchlorate in 80 hyperthyroid subjects receiving antithyroid drug therapy. Five dosage regimens ranging from 5 mg carbimazole twice daily to 15 mg methimazole twice daily were studied. Binding inhibition was estimated at 5-7 h after drug as an index of the mean effect of the 12 hourly regimen. In all cases, except one in the lowest dose group, binding was found to be markedly reduced with mean binding rates ranging from 0.002 to 0.020 min-1 (normal greater than 0.15 min-1). The net clearance of iodide in the lowest dose group was reduced to a mean value near the upper limit of the euthyroid range, whereas in the highest dose group it lay at the lower limit of the euthyroid range. These results were reflected in the serum thyroid hormone response. There was a reducing incidence of inadequate control of hyperthyroidism and an increasing incidence of hypothyroidism with increasing thiourylene dose. The exit rate constant of free iodide for the various doses showed values from 0.048 to 0.055 min-1. Corresponding mean values for the discharge rate constant after perchlorate were 0.087 to 0.105 min-1. This suggests that perchlorate increases the rate of iodide release from the thyroid gland. Studies at a later interval after drug (12-14 h) showed no change in discharge rate constant. This leads to the conclusion that perchlorate may further inhibit iodide binding in subjects receiving antithyroid drug therapy.

1 Methimazole plasma concentrations were measured in two groups of hyperthyroid subjects after the oral administration of either carbimazole or methimazole. 2 With the HPLC method it was also possible to measure the concentration of a methimazole metabolite, 3-methyl-2-thiohydantoin in one patient. 3 Large interindividual differences were observed, especially within the carbimazole group. 4 Incomplete absorption of carbimazole could explain particular high apparent volumes of distribution and apparent clearances.

A study of antithyroid drug (ATD) therapy with a mean follow-up period of 10 years (range 2-25) in 434 patients with Graves' disease has been made by linking hospital records with those of a central follow-up register. The majority (89%) were treated with carbimazole and 87% received combined therapy with triiodothyronine (T3) (73%) or thyroxine (T4) (14%). Sixty-one per cent were assessed for T3 suppression tests on completion of treatment, of whom 61% (95% CL, 55-67%) suppressed. The overall 5-year cumulative proportion developing recurrent hyperthyroidism was 54-62% with rates of 26-44% in suppressed patients and 65-79% in those not suppressed. In unsuppressed patients, most (72%) of the recurrences occurred within 1 year with only an additional 10% predicted up to 10 years. In suppressed patients 30% of recurrences occurred in the first year, 60% between 1 and 5 years and a further 10% between 5 and 10 years. Suppression with T3 is probably the best and cheapest predictor of outcome but has an accuracy of only 70% for both positive and negative tests which limits its usefulness in planning long-term follow-up and surveillance. A standard format should be adopted for the analysis and reporting of follow-up studies, based on actuarial methods of estimating the cumulative proportion with recurrences or other events, to facilitate comparisons between different centres.

1 The effect of small doses of carbimazole on the binding rate constant of intrathyroidal iodide, plasma methimazole concentrations and circulating thyroid hormone concentrations in five hyperthyroid patients is presented. 2 In all patients there was a marked reduction in iodide binding with carbimazole doses as low as 5 to 10 mg daily. 3 In three patients little further reduction in the observed binding rate occurred with daily doses in excess of 10 mg despite progressive increases in plasma methimazole concentrations. 4 At the end of 4 weeks' treatment with 10 mg carbimazole daily, the reduction in thyroid hormone concentrations and clinical improvement were such as to suggest that this dose may be an effective starting dose in many patients.

The kinetics of [123I]iodide uptake were studied when organification of iodine by the thyroid gland was normal and when this binding function was diminished by drugs or disease. Each study was terminated by a sodium perchlorate discharge test (300--600 mg iv) at 60 min or, in some cases, 10--30 min. The results confirmed that binding takes place rapidly in the uninhibited gland with the binding rate constant being at least 0.150 min-1. Discharge from the uninhibited gland is less than 3.5% of the gland uptake when perchlorate is given 60 min after the radioiodide. Subjects with an intrinsic binding defect manifested discharges of 11% of greater of the 60 min uptake and the estimated binding rate constants ranged from 0.003--0.057 min-1. Thyrotoxic subjects receiving 5 mg carbimazole twice daily manifested discharges ranging from 5.4--64.2%, and in those receiving 20 mg twice daily the observed discharges were 67.6--94.6% of the 60 min uptake. The study shows that a correctly performed perchlorate discharge test will detect minimal inhibition of iodine binding. An important factor is the duration of the follow-up period after perchlorate is given. In some of the cases studied discharge was not complete until 60 min after the perchlorate.

This paper describes an in vivo method for measuring total thyroidal iodine stores by activation analysis, its evaluation and measurements in thyrotoxic patients. There was good correlation between measurements of solutions of iodine and post-mortem thyroids by activation analysis and chemical analysis. Measurements in thyrotoxic patients showed low levels in untreated and treated (antithyroid drugs) patients and a marked increase in patients studied whilst in clinical remission. The practical importance of this method of measurement of thyroidal iodine stores is that it is a reliable in vivo measurement obtained at a single visit and should enable the definition of the relationship of thyroidal iodine stores to pathophysiology and prognosis.

Of a group of 55 thyrotoxic patients given therapeutic radio-iodine (131I), 24 were made euthyroid with carbimazole before 131I: the remainder were given 131I alone. Carbimazole was discontinued 5 days before 131I was administered. By 3 months after 131I treatment there was a greater incidence of hypothyroidism in the group given 131I alone (42% vs 25%), but a lower incidence of persistent thyrotoxicosis (16% vs 46%), (P less than 0.05). One year after treatment a similar proportion of each group had persistent thyrotoxicosis (21% vs 23%), but there remained a lower incidence of hypothyroidism in the group pretreated with carbimazole (25% vs 45%). It is suggested that pretreatment with carbimazole reduces the degree of radiation induced thyroid damage.

This paper described the changes in the levels of serum triiodothyronine, serum thyroxine,serum thyrotrophin and other indices of thyroid function between 2-5 y after completion of antithyroid drug therapy in 35 patients who were euthyroid on clinical criteria. There was a small but significant elevation of the mean triiodothyronine and thyroxine levels with a relative hypersecretion of Triiodothyronine. No correlation was found between the levels of either thyroid hormone measured or their ratio and the radioiodine uptakes and clearance rate, the plasma inorganic iodine level, the absolute iodine uptake or the serum TSH level. There was no case of clinical hypothyroidism but in one patient the TSH level was at the upper limit of the nrmal range and an exaggerated TSH response to TRH was found.

Ninety patients who had a recurrence of thyrotoxicosis after thyroidectomy have been reviewed. All 10 patients who had a second operation and 18 out of 20 patients treated with a full course of antithyroid drugs relapsed. These results differ greatly from the results of treatment of the first episode of thyrotoxicosis, whether by thyroidectomy or antithyroid drugs. Radioiodine is the treatment of choice in this group of patients, despite the high incidence of hypothyroidism.

Twenty-eight thyrotoxic patients were treated with propranolol. In seven patients the drug had to be discontinued after one or two months, but in the remaining 21 clinical improvement was observed. Serial clinical studies and tests of thyroid function performed at monthly intervals showed that in four patients thyrotoxicosis remitted and all indices of thyroid function returned to normal. A fifth patient shows distinct evidence of remission with the 20-minute (132)I uptake falling to normal, although the free-thyroxine index remains slightly raised. It is likely that these remissions reflect the natural tendency of the disease to remit since propranolol is not considered to have any direct in-vivo effect on thyroid function.However, because of failure to gain adequate control of symptoms in all patients treated, and the fact that circulating thyroid hormone levels were often not restored to normal, propranolol is considered an unsatisfactory alternative to conventional antithyroid drugs for routine treatment.

One hundred and thirty patients who relapsed after a full course of treatment with antithyroid drugs have been reviewed. Of 22 patients receiving a second course of antithyroid drugs, 17 (77%) relapsed. In contrast, only 2 out of 44 patients treated by surgery relapsed and seven became hypothyroid. Nevertheless, local complications, in particular parathyroid insufficiency, were especially common in this group. Eighty patients received radioiodine, 11 (14%) requiring more than three doses before finally being rendered euthyroid. Postradiation hypothyroidism developed in 39 (49%) patients.