W. D. Alexander

Concentration of 35S-propylthiouracil by the thyroid gland and its relationship to anion trapping mechanism

Abstract Propylthiouracil is concentrated by the thyroid gland in rats and man. Four 35 S compounds were demonstrated in the rat and human thyroid by thin-layer chromatography: sulphate, intact propylthiouracil, an unknown metabolite X and origin 35 S activity which is protein bound. Unbound 35 S compounds in plasma include propylthiouracil, the glucuronide conjugate of PTU, sulphate, and X. The thyroid concentration rather than the plasma level of propylthiouracil determines the duration of inhibition of organic binding of iodine in the thyroid. The effect of perchlorate and iodide on the thyroid concentrating mechanism for 35 S-propylthiouracil and 125 I-iodide was studied. The level of perchlorate and iodide which almost completely blocked the concentration of 125 I-iodide also partially reduced the concentration of 35 S-propylthiouracil. Iodide but not perchlorate decreased the rate of metabolism of 35 S-propylthiouracil in the thyroid gland.

Remission of Thyrotoxicosis during Treatment with Propranolol

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 132I 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.

ISOTOPE UPTAKE AND SCANNING OF STOMACH IN MAN WITH 99mTc-PERTECHNETATE

Abstract The stomach can be displayed in man by means of the isotope, 99m Tc-pertechnetate. This isotope is concentrated by the stomach and the uptake can be quantitated by a radioisotope scanning procedure. The gastric uptake is significantly higher than that of the thyroid or the salivary glands. The isotope was completely discharged from the stomach 40 minutes after potassium-perchlorate administration. Wider experience is needed in order to establish the precise role of isotope scanning of the stomach in the investigation of gastric function and disease.

Association of Thyrotoxicosis and Auto-immune Thyroiditis

Roitt and Doniach (1958) have demonstrated that circulating thyroid auto-antibodies are present in a large proportion of patients with auto-immune thyroiditis (Hashimotos disease). In this paper we show that the application of these immunological tests in patients with symptoms suggestive of thyrotoxicosis is of considerable practical importance, since we have been able to identify two groups in which the correct diagnosis could not otherwise have been made and where mismanagement might have occurred. In the first group evidence of auto-immune thyroiditis was found in patients with undoubted thyrotoxicosis. Only one fully documented case of this association has been previously described (Doniach and Hudson, 1959; Doniach et al., 1960). We were also able to define a second group of patients who had been referred to the clinic because of suspected thyrotoxicosis and in whom radioiodine tests had appeared to confirm this diagnosis. Further investigations, however, showed that these patients were in fact euthyroid and that the presence of auto-immune thyroiditis explained the abnormal laboratory findings.

35S‐ANTITHYROID DRUG CONCENTRATION AND ORGANIC BINDING OF IODINE IN THE HUMAN THYROID

35S‐methimazole (MMI), 35S‐carbimazole or 35S‐propylthiouracil (PTU) were given orally to fifty‐five patients at various times up to 12 h before surgical thyroidectomy. The amount of 35S radioactivity and labelled drug in thyroid and plasma samples was measured. Intrathyroidal inhibition of organic binding of iodine by MMI, carbimazole and PTU was measured after intravenous administration of 131I, 132I or 125I‐iodide. After administration of 35S‐carbimazole or 35S‐MMI the thyroid to serum (T/S) ratio of 35S radioactivity was greater in thyrotoxic glands than in non‐toxic adenoma tissue. 35S‐MMI was found in thyroid and plasma samples after administration of 35S‐carbimazole. The T/S 35S‐MMI was greater than 1 in most but not all patients. 35S radioactivity was also concentrated in the thyroid after administration of 35S‐PTU. In thyrotoxic glands there was an 80% inhibition of iodine organification in patients receiving MMI and 60% for those receiving PTU. It is suggested that carbimazole and MMI can be given once or twice daily in some patients but PTU would be less suitable for this dose schedule.

Effect of pretreatment with carbimazole on early outcome following radio-iodine (131I) therapy

Of a group of 55 thyrotoxic patients given therapeutic radio-iodine (131I), 24 were made euthyroid with carbimazole before131I: the remainder were given131I alone. Carbimazole was discontinued 5 days before131I was administered. By 3 months after131I treatment there was a greater incidence of hypothyroidism in the group given131I alone (42% vs 25%), but a lower incidence of persistent thyrotoxicosis (16% vs 46%), (P>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.

Some aspects of the absorption and concentration of iodide by the alimentary tract in man.

SYMPOSIUM PROCEEDINGS I967 disease is furthermore often associated with chronic pancreatic damage. It is therefore interesting to find that patients with cirrhosis often have markedly increased iron absorption and that this can be reduced towards normal on giving the test dose with pancreatin (Callender, 1965). In an attempt to elucidate further the part played by the pancreas in iron absorption, Helen Brown (unpublished), in our laboratory, produced pancreatic damage with ethionine in rats on a restricted protein intake. She investigated the absorption in two groups of rats, one given an iron supplement and one iron-deficient. These groups were further subdivided into those with and those without pancreatic damage. Iron absorption in the rats with the iron supplement was increased in those with pancreatic damage and addition of pancreatin restored absorption to normal, but in the iron-deficient rats the findings were reversed, i.e., pancreatic damage was accompanied by diminished iron absorption which was restored to control values by the addition of pancreatin. These contradictory findings emphasize the complexity of the problems of iron absorption. In these few remarks I have only touched on some of the factors which affect iron absorption. Iron deficiency remains one of the world’s greatest nutritional problems and until we learn a great deal more about the complex mechanisms and interactions of the many factors concerned in the control of iron absorption, it is likely to remain with us.

TOTAL THYROIDAL CONTENT OF IODINE IN THYROTOXIC PATIENTS MEASURED BY IN VIVO NEUTRON ACTIVATION ANALYSIS

This paper describes an in vivo method for measurign 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 untreted 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 relaible in vivo measurement obtained at a single visit and should enable the definition of the relationship of thyroidal iodine stores to pathophysiology and prognosis.

DURATION OF ANTITHYROID ACTION OF METHIMAZOLE ESTIMATED WITH AN INTRAVENOUS PERCHLORATE DISCHARGE TEST

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. The present data suggest that once daily is not the optimum dosage interval for MMI with respect to its effect on the organification of iodide.

Radioprotective Action of Carbimazole in Radioiodine Therapy for Thyrotoxicosis - Influence of the Drug on Iodine Kinetics

Pretreatment with carbimazole of patients given radioiodine (131I) therapy for thyrotoxicosis reduces the incidence of early hypothyroidism. The possibility that this radioprotective effect might be a consequence of drug induced alteration in thyroidal iodide turnover, leading to a reduction in thyroid irradiation, was investigated in a prospective study of 24 thyrotoxic patients. Subjects were randomly assigned to receive 131I alone or to be treated with carbimazole for a minimum of three months before 131I. Thyroxine supplements were given in the latter group to prevent iatrogenic hypothyroidism. The effective half-life of therapeutic 131I in the thyroid was measured using a gamma camera/computer system after oral administration of the dose, allowing the biological half life of the anion and estimated radiation dose to the thyroid to be derived. Effective half life of 131I, biological half life of 131I and estimated radiation dose to the thyroid were similar in the two groups of subjects. It is concluded that the radioprotective action of carbimazole is not a consequence of altered thyroidal iodide kinetics.