PREDICTION OF RELAPSE IN HYPERTHYROID GRAVES' DISEASE

1101

with age, the difference women aged 25 and over.

becoming highly significant

in

Requests for reprints should be addressed to L.E.B., Department of Medicine, Karolinska Hospital, S-104 01 Stockholm, Sweden.

REFERENCES

Böttiger LE, Westerholm B. Oral contraceptives and thromboembolic disease. Acta Med Scand 1971; 190: 455-63. 2. Inman WHW, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; ii: 203-09. 3. Kristoferson K, Wessling A. Tre ars receptundersökningar (A three-year prescription study). Svensk Farmaceutisk Tidskrift 1977; 61: 309-16. 4. Miettinen OS. Simple interval estimation of risk ratio. Am J Epidemiol 1974; 1

100:515-16. 5. Böttiger LE, Westerholm B. Hjärtinfarkt hos yngre kvinnor—finns samband med p-piller? (Myocardial infarction in young women—is there any connection with the use of oral contraceptives?) Läkartidningen 1972; 69: 3649-52. 6. Böttiger LE, Westerholm B. Drug-induced blood dyscrasias in Sweden. Br J Med 1973; iii: 339-43. 7. Westerholm B. Unpublished observations, reported at the international symposium on epidemiological evaluation of drugs, Milan, 1977.

PREDICTION OF RELAPSE IN HYPERTHYROID GRAVES’ DISEASE B. REES SMITH

A. M. MCGREGOR

R. HALL

Department of Medicine,

Welsh National School of

M. MILLER

Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne P.

J. DEWAR

Regional Transfusion Centre, Newcastle upon Tyne Within

65 unselected patients with hyperthyroid Graves’ disease women, 14 men; mean age 42 years) were studied. Diagnosis was made on the basis of clinical assessment, elevated serum thyroxine (T4),6 failure of the serum TSH to respond to thyrotrophin-releasing hormone,’ and diffuse thyroidal uptake on a technetium-99m scan. Patients were treated with carbimazole (45 mg daily) supplemented with thyroxine (0-15 mg daily) after 6 weeks, and the combined therapy was continued for a further 18 weeks. The patients were then followed at regular intervals for at least 12 months. Antibodies interacting with the TSH receptor were measured by the method of Smith and Hall. Results were expressed as % inhibition of labelled TSH binding to human thyroid membranes. Studies on 67 healthy control subjects indicated that inhibition values of greater than 20% represented the presence of detectable

(51

TSH-receptor-antibody activity. All patients were typed for HLA

A and B locus antigens. The presence of the HLA-DRw 2,3,4, and 7 antigens was assessed with the standard N.I.H. lymphocytotoxic test,9 using sera which were used in the 8th Histocompatibility Workshop or standardised against workshop specificities. The frequencies of HLA A and B loci in the local white population were established in 325 healthy unrelated subjects and DRw antigens in 135 subjects. The statistical significance of the HLA-DRw3 associations with Graves’ disease and its recurrence after a course of treatment were determined by the X2 test and were not corrected for the number of antigens tested. Student’s t test was used for all other statistical analyses. Relative risk was calculated as described by Svejgaard et al. 10

Medicine,

Cardiff M. M. PETERSEN

Methods

year of stopping a 6-month Summary 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. a

Introduction A MAJOR problem in the management of patients with Graves’ disease is to predict which patients will relapse after treatment with antithyroid drugs. Relapse is more common in patients who at the end of drug therapy still show loss of thyrotrophin (thyroid-stimulating hormone, TSH) control of thyroid function’ or the presence of antibodies which interact with the TSH receptor.2.3 Furthermore, relapse tends to occur in patients with certain HLA specificities (HLA-B8 and Dw3).4,5 However, these analyses have proved to be only modest predictors of disease course, and in this paper we examine the combination of HLA assessment and TSH-receptor-antibody measurements as a means of predicting relapse. Our study suggests that this may well be a useful means of assessing the course of Graves’ disease.

Results

TSH-receptorAntibodies Receptor-antibody activity was detected in 49 (75%) of the patients before therapy and in 25 (38%) immediately after drug withdrawal (see figure). The mean ±SEM level was 46±4% inhibition of TSH binding before treatment and 24 ±3% after 6 months. The difference between these two values was highly significant

(p
than the

level of 10±1% in the remission group Of the 25 patients who were receptor-anti(p<0.001). body positive immediately after drug withdrawal only 1 did not relapse (see table), and the relative risk of relapselo in patients who were receptor-antibody positive at this stage was 32. mean

DRw3-positive Patients 29 (45%) of the 65 patients were DRw3 positive, compared with 27 (20%) of the 135 control subjects. This difference was statistically significant (y=13-2; P<0-001). There was no significant difference between the pre-treatment serum T4 levels in the DRw3 positive and negative patients (p>0-5). The relative risk of DRw3-positive patients developing Graves’ disease was 3-2. All but 2 DRw3-positive patients relapsed within 12 months of withdrawal of antithyroid-drug therapy (see figure). Of the 36 DRw3-negative patients, 14 relapsed. The association between the presence of DRw3 and

relapse (see table) p<0-0001) and the

was

highly significant (=20-3; a DRw3-positive pa-

relative risk of

1102 USE OF VARIOUS MARKERS TO PREDICT DISEASE COURSE AFTER

WITHDRAWAL OF ANTITHYROID-DRUG TREATMENT IN PATIENTS WITH HYPERTHYROID

*TSH-receptor-antibody measurements stopping antithyroid drug treatment.

GRAVES’

were

made

65

DISEASE

immediately

after

Discussion

levels and HLA-DRw3 status in 65 patients with Graves’ disease.

TSH-receptor-antibody

Antibody

tient

made immediately before start of a antithyroid-drug therapy and immediately after

measurements were

6-month course of drug withdrawal.

relapsing within

ment was

12 months of stopping

drug treat-

21.

DRw3 and TSH-receptor

Antibodies

levels of receptor antibody before treatsimilar in DRw3-positiye and DRw3-negative patients (44±6% and 48±3% inhibition of TSH binding, respectively; p>0.5), but immediately after drug withdrawal the mean receptor-antibody level was significantly higher in the DRw3-negative group (30±5% versus 17±3%; p<005). Furthermore, there was a striking difference between the TSH-receptor-antibody levels within the DRw3-negative group. In particular, all 14 DRw3-negative patients who relapsed showed readily detectable levels of receptor antibody immediately after drug withdrawal, whereas DRw3-negative patients who remained in remission showed low or undetectable antibody activity at this time (see figure). Analysis of both the DRw3 and TSH-receptor-antibody status in all 65 patients greatly increased the ability to predict the disease course (see table). The mean levels of receptor antibody for the DRw3-negative relapse and remission groups were 62±3% and 10+2% inhibition, respectively. This difference was highly significant The

mean

ment were

(p<0.001).

Our studies indicated that over 90% of patients with hyperthyroid Graves’ disease who were DRw3 positive relapsed within 12 months of withdrawal of antithyroiddrug treatment. HLA-DRw3, when detectable, was clearly a valuable predictor of disease course. 55% of the patients with Graves’ disease were DRw3 negative, and in this group disease course could not be predicted from HLA-DR status alone. However, DRw3-negative patients who relapsed were characterised by readily detectable TSH-receptor-antibody levels at the time of drug withdrawal, whereas only 1 DRw3-negative patient in remission showed detectable receptor antibody and this very low level. Consequently, in the DRw3negative group receptor-antibody measurements were a valuable predictor of disease course. Overall, therefore, a combination of HLA-DR typing and TSH-receptorantibody measurements enabled the disease course to be predicted in 62 (95%) of the 65 patients. Our observations on the increased incidence of HLA DRw3 in patients with Graves’ disease agrees with an earlier report." Previous studies have also shown that patients with HLA Dw35 and HLA B84 tend to relapse

was at a

after antithyroid-drug treatment. However, our observations suggest that the DRw3 antigen reflects far"more closely the processes which lead to relapse. The relation between DRw3 status and TSH-receptor-antibody activity was complex. Mean antibody levels in untreated patients were similar in the DRw3-positive and DRw3-negative groups. However, receptor-antibody levels fell during therapy, as observed previously,3.12,13 and this fall appeared to be related to the presence of HLA-DRw3, the mean antibody level being significantly

higher immediately after drug withdrawal in the DRw3negative group. It would therefore seem that Graves’ disease is weakly but significantly associated with the presence of HLA-DRw3. However, disease severity measured in terms of serum-thyroid-hormone levels orTSHreceptor-antibody activity showed no relation to DRw3 status, though the processes involved in relapse were closely related to the presence of the antigen. These processes are likely to be complex-for example, factors such as those controlling TSH-receptor-antibody syn-

1103

thesis, thyroid responsiveness, and autoimmune destruction might all be expected to be involved. All but 1 patient with detectable TSH-receptor antibodies immediately after drug withdrawal relapsed, and the relative risk of relapse in patients who were antibody positive at this stage was 32. These observations agreed with those of Davies et al .2 and Teng and Yeung.3 However, when receptor antibodies were undetectable the disease course could not be predicted from receptor-antibody measurements alone. This situation was similar to attempts at assessment with HLA-DRw3 alone, when prediction was possible only in antigenpositive patients. However, assessment with both TSHreceptor-antibody activity and DRw3 as markers allowed prediction of disease course in all but 3 of the 65 patients. We thank Miss Ann Stratton for technical assistance and Margaret Clayton for typing the manuscript. This work was supported by grants from the Medical Research Council, the North of England Cancer Campaign, the Wellcome Trust, the League of Friends of the Royal Victoria Infirmary, the Ernest and Minnie Dawson Cancer Trust, and the Research Committee, Newcastle Area Health Authority (Teaching).

Requests for reprints should be addressed to A.M.McG., Departof Medicine, Welsh National School of Medicine, Heath Park,

ment

Cardiff CF4 4XN. REFERENCES et al. Prediction of the long-term antithyroid drug therapy for thyrotoxicosis. J Clin Endocrinol ffiMetab 1970; 30: 540-43. 2. Davies TF, Yeo PPB, Evered DC, Clark F, Rees Smith B, Hall R. Value of ffithyroid-stimulating-antibody determinations in predicting short-term thyrotoxic relapse in Graves’ disease. Lancet 1977, i: 1181-82. 3 Teng CS, Yeung RTT. Changes in thyroid-stimulating antibody activity in Graves’ disease treated with antithyroid drugs and its relationship to ffirelapse: a prospective study. J Clin Endocrinol Metab 1980; 50: 144-47. 4 Irvine WJ, Gray RS, Morris PJ, Ting A. Correlation of HLA and thyroid antibodies with clinical course of thyrotoxicosis treated with antithyroid drugs. Lancet 1977; ii: 898-900. 5 Bech K, Lumholtz B, Nerup J, et al. HLA antigens in Graves’ disease. Acta Endocrinol (Copenhagen) 1977; 86: 510-16. 6. Evered DC, Vice P, Green EC, Appleton DJ. Assessment of thyroid hormone assays. J Clin Pathol 1976; 29: E 1054-59. 7. Ormston BJ, Gary R, Cryer RJ, Besser GM, Hall R. Thyrotrophin-releasing

1 Alexander

WD, McLarty DG, Robertson J,

results of

hormone as a thyroid-function test. Lancet 1971; ii: 10-14. 8. Smith BR, Hall R. Thyroid-stimulating immunoglobulins in Graves’ disease. Lancet 1974; ii: 427-31. 9. Bodmer WF, Batchelor JR, Bodmer JG, Festenstein H, Morris DJ, eds. Histocompatibility testing 1977. Copenhagen- Munksgaard, 1978. 10. Svejgaard A, Hauge M, Jersil DC, et al. The HLA system: an introductory survey. Monogr Hum Genet 1975; 7: 55. 11. Farid NR, Sampson L, Noel EP, et al. A study of human leukocyte D locus-

related antigens in Graves’ disease. J Clin Invest 1979; 63: 108-13. G, Hashizume K, Roudbush CD, De Groot LJ. Changes in thyroid-stimulating immunoglobulins during antithyroid therapy. J Clin Endocrinol

12 Fenzi

Metab 1979; 48: 572-76. Petersen MM, Capiferri R, Evered DC, Rees Smith B, Hall R. Effect of radioiodine on thyrotrophin binding inhibiting immunoglobulins in Graves’ disease. Clin Endocrinol 1979, 11: 437-44.

13. McGregor AM,

"Red Cross

youth work offers what formal education alone give by imparting critical social and problem-solving skills in the real world and encouraging career development through jobs that put young people in a variety of settings, offering a taste of... various careers ... the Red Cross teaches youth empathy. Many psychologists believe that altruism will not develop without empathy-a quality that young people cannot

their Red Cross service teaches them to ’tune in’ to other people’s needs. Some psychologists think children are able to learn the rudiments of sharing, and therefore of empathy, as early as age one. The implication is clear: it is essential to begin teaching youth to care for others early. If we should fail in our mission to develop empathy and altruism early in a person’s life, the Red Cross’s future as a humanitarian endeavour may be dim."-MICHAEL FRISCH. Panorama 1979/7. League of Red Cross Societies, Geneva.

learn

as

PREDISPOSITION TO OBESITY

J. S. GARROW PENELOPE M. WARWICK Nutrition Research

SANDRA E. BLAZA MARGARET A. ASHWELL

Group, Clinical Research Centre, Harrow, Middlesex

65 women whose build ranged from normal to grossly obese were investigated to the hypothesis that obese people, especially those

Summary test

with

genetic predisposition to obesity (manifest by and family history of obesity), have a low enearly For the group as a whole, resting expenditure. ergy metabolic rate was related to obesity index, but the age of onset and family history of obesity had no effect on this relationship. The findings suggest that a familial predisposition to obesity is more likely to relate to energy intake than to energy expenditure. a

onset

Introduction OBESITY tends to run in families. Since obesity can develop only if energy intake exceeds energy expenditure a familial tendency towards obesity might be the result of a hyperphagic trait, or of a lower metabolic rate. In genetically obese rodent strains hyperphagia is common,2 but it is not the sole cause of obesity, since genetically obese mice become obese even when they are pairfed with their lean littermates,3 because they have a lower resting energy expenditure and a smaller thermogenic response to stimuli such as cold.4 Dietary surveys have repeatedly failed to show that obese people eat significantly more than lean people, but within each type of body build there is a huge variation in intake, and it is very difficult to measure habitual dietary intake with sufficient accuracy to throw light on this problem.5 It is iechnically easier to test the alternative hypothesis that obese people, and in particular those with a genetic predisposition to obesity, have a low energy expenditure. Among those who are not engaged in heavy manual work the resting metabolic rate (RMR) is the main factor determining daily energy expenditure, since the energy cost of minor activity is proportional to resting metabolic rate.6 However RMR is itself related to the degree of obesity, conveniently measured by the obesity index W 1112, where W is body weight in kg and H is height in m. We have investigated the possibility that, for a given degree of obesity, those with early onset and/or a family history have a lower RMR than those without these features. We assumed that obese patients with early onset of obesity, or with a family history of obesity, are likely to show the metabolic defect predisposing to obesity,7.8 and that those with onset in adult life and without a family history are unlikely to show this defect.

Subjects

and Methods

65 women with W/H2 ranging from 22 to 52-i.e., of normal build to grossly obese-were studied: the age of onset of obesity was classified as "childhood", "adolescent", or "adult" by interview with the patients, and verified by photographs. On this basis onset was childhood in 18, adolescent in 11, and adult in 36. Family history of obesity was calculated from the number of parents and siblings, but not children, who were reported to be obese: if obese relatives made up more than 30%