J. Crooks

POST-THYROIDECTOMY HYPOCALCÆMIA: A FEATURE OF THE OPERATION OR THE THYROID DISORDER?

It has been suggested that post-thyroidectomy hypocalcaemia is related to the presence of a thyrotoxic osteodystrophy for which a high serum concentration of bone alkaline phosphatase is a marker. Changes in serum-calcium (corrected to a standard albumin concentration of 40 g/l), alkaline phosphatase (A.P.), inorganic phosphate, and albumin were studied prospectively in 54 euthyroid patients with drug-treated Graves disease, and in 17 controls with simple non-toxic goitre, before and serially after partial thyroidectomy. All data were paired and results indicate that the pattern of biochemical change was the same in both types of patient and that the degree of change was not related to the serum-A.P. concentration in the Graves-disease patients. Of the patients studied within the first 24 h of operation, 5 out of 12 with Graves disease and raised serum-A.P. (group I), 9 of 20 with Graves disease and normal serum-A.P. (group II), and 7 of 15 controls (group III) showed a fall in serum-calcium below the lower limit of the reference range. In all three groups there was a highly significant fall in serum-calcium 24 h after operation but there was no significant difference in serum-calcium between the groups either immediately before or 24 h after operation. Serum-calcium returned to pre-surgical concentrations within 7 days of thyroidectomy and serum-A.P. concentrations by 4 to 6 weeks in all groups. There was no evidence that post-thyroidectomy hypocalcaemia is related to thyrotoxic osteodystrophy and the pattern of the biochemical changes was thought to be consistent with release of thyrocalcitonin at operation.

Changes in Human Drug Metabolism after Long-term Exposure to Hypnotics

The influence of the newer, non-barbiturate hypnotics Mandrax (diphenhydramine-methaqualone) and nitrazepam on drug-metabolizing capacity was assessed and compared with the effect of amylobarbitone, a known inducer of drug-metabolizing enzymes. Plasma antipyrine and phenylbutazone half-lives and urinary output of 6β-hydroxycortisol were used as indices. Volunteer subjects were exposed to therapeutic amounts of these agents and, in the case of Mandrax and barbiturates, further studies were carried out in dependent patients. Mandrax but not nitrazepam increased the rate of drug metabolism, presumably by enzyme induction. The degree of induction was comparable with that produced by hypnotic doses of amylobarbitone. The Mandrax-dependent and barbiturate-dependent patients were the fastest metabolizers studied. It is concluded that drug interactions resulting from interference with drug metabolism are as likely to occur with Mandrax as with barbiturates. On the other hand, it is unlikely that such drug interactions would occur with nitrazepam.

High TSH concentrations in "euthyroidism": explanation based on control-loop theory.

High concentrations of thyroid-stimulating hormone (TSH) in the serum have often been reported in apparently euthyroid patients with damaged thyroids. We have confirmed this finding in 14 patients 18 months after subtotal thyroidectomy for Gravess disease (group 1) and in 14 patients with manic-depressive psychosis (group 2) receiving lithium carbonate, which reduces thyroid reserve. One factor common to groups 1 and 2 but not to the controls was reduced thyroid reserve or functioning capacity, and, using established physical principles of servo-control, we have tried to define the mechanism. A series of curves were projected to indicate how TSH might be expected to vary with functioning thyroid capacity.

Autoantibodies in thyrotoxicosis: a quantitative study of their behavior in relation to the course and outcome of treatment

Many previous investigations have looked into the association between thyroid autoantibodies and the course of thyrotoxicosis. However, the interpretation of these studies is often difficult, owing to their largely retrospective nature, and comparability is limited because of differences in criteria and sampling schedules. The purpose of this study was to investigate prospectively the serial changes in autoantibodies under carefully controlled conditions during treatment of thyrotoxicosis, and to relate these changes to clinical outcome and surgical histology. Sixty-seven patients with Graves’ disease were studied for 24 months; 34 were treated medically and 33 surgically. Anti-thyroglobulin (anti-Tg) and anti-microsomal (anti-M) antibodies were measured on 16 occasions. The frequency of patients showing anti-Tg fell progressively irrespective of the type of treatment, while that showing anti-M fell initially but rose again. Weak associations were found between anti-Tg and suppressibility after 5 months of drug treatment, between the cumulative amount of anti-M and the final TSH levels in those who remained euthyroid after drugs, and between the circulating levels of anti-M just before surgery and the frequency of clinical hypothyroidism 18 months later. However, no significant correlation emerged between the cumulative amount of antibody during the two-year period and the final TSH level or clinical result after surgery, nor between the prevailing antibody level and surgical histology. Wide, rapid and apparently random fluctuations of antibody levels in individuals cast considerable doubt upon the value of single estimations in the distinction of antibody-positive from antibody-negative members of a thyrotoxic population. We conclude that the measurement of thyroid autoantibodies in Graves’ disease has little practical value for the clinician.

Time and tides in Graves's disease: their implications in predicting outcome of treatment.

All vasectomies were carried out under local anaesthesia, using the Schmidt technique of light diathermy of the endothelium of each cut end of the vas without ligation then closing the sheath over only one end. Men were asked to leave a specimen of seminal fluid within four hours of collection after at least 10 ejaculations after their vasectomy. The specimen was mixed and 30 to 50 high-power fields examined. If sperms were present a count was made and any motility noted. If no sperms were found the specimen was centrifuged and re-examined. So long as no motile sperms were found, even though non-motile ones were present, the patient was advised that he was clear and that no further contraception was necessary. After 12 to 15 months all men were asked by letter, and if necessary by telephone, if their vasectomy had been successful in preventing pregnancy and offered a further seminal assay free of charge. During the period under review 461 men submitted specimens for seminal assay. There were no motile sperms in the specimens of 200 of these 461 men but some non-motile ones remained. In most the non-motile sperms were only occasional, but in 30 the count was 0-5> 109/1 or more and in two it was 24 < 109/1. Specimens had been submitted within four weeks of vasectomy by 44 men (22 00), between four and eight weeks by 97 (48 ,), and after more than eight weeks by the remainder. Replies were obtained from 190 of the 200 (95 0) on follow-up. No man reported the occurrence of a pregnancy during the year after his vasectomy. Forty-eight men (24 00) submitted a further specimen for seminal assay. There were no motile sperms in any, but in five (10 %O) an occasional non-motile sperm could still be found.

ALTERED ENDOCRINE RESPONSE TO PARTIAL THYROIDECTOMY IN PROPRANOLOL‐PREPARED HYPERTHYROID PATIENTS

The endocrine response to partial thyroidectomy in a group of twenty hyperthyroid patients prepared with propranolol alone was compared to that of a matched control group of ten euthyroid patients. In propranolol‐prepared patients the glucose response to surgery was reduced (P< 0·05) for up to 4 h post‐operatively and biochemical hypoglycaemia was noted in one patient. Both thyroxine and triiodothyronine (T3) fell significantly, associated with a marked rise in reverse T3. Growth hormone levels were higher (P<0·05) both pre‐and post‐operatively in propranolol‐prepared patients, whereas prolactin levels, although similar pre‐operatively, were lower (P<0·05) in these patients post‐operatively. Cortisol and ACTH levels were lower (P < 0·05) both before and following thyroidectomy in propranolol‐prepared patients. These results suggest that the endocrine response to surgical stress is markedly altered in propranolol‐prepared hyperthyroid patients.

SHORT-TERM TRIIODOTHYRONINE IN PREVENTION OF TEMPORARY HYPOTHYROIDISM AFTER SUBTOTAL THYROIDECTOMY FOR GRAVES' DISEASE

To determine whether short-term thyroid hormone replacement prevents or merely delays temporary hypothyroidism after surgery for Graves disease, serum T3, thyroid-stimulating hormone, and T4 were measured every 2 months for 18 months in two groups of Graves disease patients who had had subtotal thyroidectomy. Group I (18 patients) were given T3 20 microgram four times daily from surgery through the twelfth postoperative month. Group II (18 patients) received no treatment. Hypothyroidism occurred at some time during the 18-month period in 10 group-II patients, but was temporary in 7. Temporary hypothyroidism did not occur in group-I patients, whose mean T4 level rose to that in group II within 2 months of T3 withdrawal. Short-term T3 replacement after surgery for Graves disease thus prevents (and does not simply delay) temporary postoperative hypothyroidism without increasing the frequency of permanent hypothyroidism.

Importance of thyroxine in suppressing secretion of thyroid stimulating hormone.

SmI,-Dr Richard Smiths New Zealand report (3 April, p 1029) paints a depressing picture of New Zealands failure to come to grips with the smoking and drinking problems in that country. The author draws comparisons between Scotland and New Zealand and observes that New Zealand is not slow in most medical and social matters. Most New Zealand general practitioners would view that statement with some scepticism. New Zealand does not have a free health service as suggested by Dr Smith. While treatment in public hospitals is free, general practitioners (and many specialists) services, attract a fee commensurate with the service provided. With the introduction of a social security scheme in 1941 a government subsidy met approximately 75% of the cost of a GP consultation. This subsidy, which has not been increased to match inflation, now meets less than 20% of the average GP service. This has resulted in pressure on GPs to reduce their fees and has also led to a drop in the number of adult consultations. The failure of successive governments to increase this subsidy to a realistic level has been of growing concern to the New Zealand Medical Association, and an increase in the subsidy is now our top priority. R P CAuDw.LL General Secretary New Zealand Medical Association, Wellington 1, New Zealand

Time, carbimazole and the outcome of Graves’ disease

A detailed comparison was made over 18 months of the serial mean 20 min132 I uptake behavior between 15 Graves’ disease patients whose hyperthyroidism ultimately remitted (Group E) and 20 in whom it persisted (Group R). All were treated with carbimazole and T3. There were no qualitative differences in uptake between the 2 groups. In both, the uptake fell with time, and the slopes were parallel. The fact that the mean uptake started lower in Group E patients was sufficient to explain why it became normal much earlier than that of Group R, which had not normalized by 18 months. In both groups, over half the overall fall in uptake occurred during the first month of treatment with carbimazole. We conclude that, while time remains the most important determinant of outcome in Graves’ disease, some possible immunosuppressive action of carbimazole can shorten the cycle length to a major degree.

THE VARIATION IN SERUM TRIIODOTHYRONINE (T3) ACHIEVED DURING SUPPRESSION TESTING IN THYROTOXICOSIS

Regular measurement of thyroidal radioiodine uptake has been widely used as a means of monitoring continued extrapituitary stimulation of the thyroid during the treatment of thyrotoxicosis with carbimazole and triiodothyronine (T3). However, it is unclear to what extent the serum T3 level may vary at the time of testing, nor what effect this might have on the uptake of radioiodine. Two studies have been undertaken. In the first, serum T3 levels in twenty‐four thyrotoxic patients were measured at intervals during an 18‐month course of carbimazole combined with T3, 20 μg qid. Considerable variations in the highest and lowest levels of serum T3 were found both between and within individuals. The second study was on twenty‐three thyrotoxic patients thought to be entering remission because the iodine uptake after 5 months of drug treatment had fallen to less than 50% of the pretreatment value (suppressors). The changes in uptake of radioiodine after 5 and then 6 months of treatment were compared in seven patients, who received carbimazole and T3 throughout, with the corresponding changes in the remaining sixteen patients, whose T3 alone was withdrawn prior to the uptake test at month 6. The mean degree of suppression remained unchanged by month 6 in the first group. In the second group, however, the mean uptake rose significantly, and nine of the sixteen patients would have been classified as non‐suppressors at the sixth month (i.e. uptake greater than 50% the pretreatment value) had their failure to maintain high serum levels of T3 gone undetected. The first study indicated this could well happen in routine circumstances, and it is suggested that the reliability of suppression tests be checked with simultaneous measurement of serum T3.