Clinical Endocrinology (1992) 36, 291-294
Graves’ ophthalmopathy in relation to cigarette smoking and ethnic origin Marlsol Tellez, Jackie Cooper and Charles Edmonds Endocrinology and Epidemiofogy, Medical Research Council and Northwick Park Hospital, Harrow, UK (Received 15 August 1991; returned for revision 23 September 1991; finally revised 22 October 7991; accepted 30 October 1991)
Summary OBJECTIVE We aimed to study the effect of cigarette smoking on the prevalence and severity of Graves’ ophthalmopathy (GO). PATIENTS One hundred and fifty-five newly diagnosed patients with Graves’ disease (GD) were dlagnosed cllnlcally and by routine biochemical methods. Twenty-five per cent (39)were of Asian origin. METHODS Eye signs were classified according to the American Thyroid Assoclation Classification. A detailed smoking questionnaire and data from hospital notes were used to calculate an index of cigarette consumption. RESULTS Thirty-four per cent of all patients had Graves’ ophthalmopathy, and the prevalence In males (26%) and females (36%) did not differ significantly. There was a prevalence of 42% among Europeans compared to 7.7% in Asians (P= 0.0002). The overall risk for Europeans for developing Graves’ ophthalmopathy was 6.4 (1.78-22.7 confidence interval) times higher than for Asians. Corrected for the ethnic factor the increased risk from smoking for Europeans was 2.4 (1.12-5.18, 95% confidence interval) times higher. There was a significant dose effect (P = 0.008). CONCLUSIONS The present findings confirm an effect of cigarette smoking on Graves’ ophthalmopathy and in addltion show that Europeanshave a substantially greater risk of developing Graves’ ophthalmopathy than have Asians.
Among the factors that predispose to Graves’ ophthalmopathy (GO), cigarette smoking appears to be one of significance (Hagg & Asplund 1987; Bartalena et ai., 1989; Shine et al., 1990; Balaz et al., 1990). Moreover, we have been impressed by the low prevalence of this form of eye disease in Asian patients who presented with Graves’ disease (GD) Correspondence: Dr M. Tellez, Northwick Park Hospital, Wdtford Road, Harrow, Middlesex HA1 3UJ, UK.
suggesting that an ethnic factor was also important. Previous studies on the effect of cigarette smoking have, for the most part, been on selected populations. In contrast, the present study was on patients referred by their general medical practitioners to an endocrine clinic in a district general hospital for assessment and management of hyperthyroidism. The object of the study was to determine the prevalence and severity of GO in these patients, particularly in relationship to smoking habit and ethnic origin. Patients and methods
The patients comprised 155 subjects (Table I), who attended the endocrine clinic during the period June 1985 until May 1990, and were newly diagnosed as having GD. A substantial proportion of the patients were Asian immigrants (15% of the total population, Department of Public Health survey for Harrow), from families coming originally from the Indian subcontinent. The diagnosis of Graves’ disease was based on the measurement of plasma T 3 and TSH and the demonstration of a diffusely increased thyroid uptake on scanning 20 minutes after injection of 9 9 m T ~ 0GO 4 . was present in 47 at presentation; five developed eye signs during the treatment with antithyroid drugs. Ophthalmopathy was classified independently by one of us (CE) in all patients using the abridged Classification of Eye Changes in G D of the American Thyroid Association (Werner, 1969). Classes were as follows: Class I , upper lid retraction, usually with lid lag; Class 2, soft tissue changes: periorbital and conjunctival; Class 3, proptosis ( > 20 mm o n exophthalmometry); Class 4, extraocular muscle involvement, usually with diplopia. There were no patients showing changes of Classes 5 or 6 in our group. Details on smoking habits were recorded in all the patients at their first attendance. In addition, from 1987 onwards, the patients completed a detailed questionnaire based on the one used by the Smoking Research Group, Epidemiology Division, Medical Research Council. Those patients, about onethird of the total, who had attended initially before the study commenced and were still attending the clinic, also completed the questionnaire. Fourteen patients did not complete it satisfactorily and for them the information was derived from that recorded in the hospital notes. Ex-smokers were those who had stopped smoking for 6 months or more. An index for cigarette consumption using cigarette years (daily consumption x years of smoking) was constructed in 291
292
M . Tellez et a / .
Clinical Endocrinology (1992) 36
Table 1 Ophthalmopathy in 155 patients with Graves’ disease according to sex, ethnic group and smoking
Age average (range) (years)
Sex
Ethnic group
Smoking
Male
Female
European
Asian
Non
EX-S
Current-S
Eye signs absent (n= 103)
41.5 ( I 1-86)
25
78
67
36
60
14
29
Eye signs present (n = 52)
45.0 (15-73)
9
43
49
3
15
14
23
34
121
I16
39
15
28
52
Total
60
3
2o
50
r
*
6 40
0 21
g 3c P
$
20
.-0
2
lo Class I Non-smoker
A B C (1-199) (200-300)(>400) Cigarette-years
Fig. 1 Percentage of patients with GO in relation to ‘cigarette consumption index’. Non-smoker (n= 74); A(n = 20); B(n = 19); C(n= 24).
order to investigate the effect of dose. The four groups were as follows, 0, non-smokers; A, 1-199, light smokers; B, 200399, moderate; C, > 400, heavy smokers. For the statistical analysis, two-tailed Chi-squared tests were used to assess differencesin type of complication by sex, age, ethnic group and smoking status. Differences in the proportion of patients developing eye signs were assessed, using a logistic regression model of the form lO&{P/(l -p)}=a+bx wherep is the probability of developingeye signs. This model allowed the examination of smoking effect after adjustment for age and ethnic differences. Relative risks of developing GO and 95% confidence intervals were obtained. Results
Ophthalmopathy was observed in 52 (34%) of all patients (Table 1) and the prevalences in males (26%) and females (36%) did not differ significantly. There was a significant ethnic factor, the prevalence among Europeans being 42% compared with 7.7% in Asians (P=0.0002). Only three
Class 2 Class 3 Class of eye sign
Class 4
Flg. 2 Number of patients, in relation to the presence of each class of eye sign. 0,Non-smokers; E, ex-smokers; W, current smokers.
Asians had eye signs and of these, two were smokers. After adjustment for smoking the risk of Europeans developing ophthalmopathy relative to Asians was 6.36 (1.78-22.7,95% confidence interval). Among all current smokers and ex-smokers the prevalence of ophthalmopathy was greater than in those who had never smoked (Table 1; P=0.0005). Fifty per cent of the 28 patients who had stopped smoking developed GO. They were all Europeans. No significant relationship was present between the development of GO in these patients and the length of time since stopping (mean=7*3 years, range 6 months to 25 years), or the amount smoked. Some of this effect was due to the difference in smoking habits between Asian and European patients as only nine (23%) of the Asians smoked, compared with 61.2% of the Europeans. However, only three Asian patients had eye signs and the effect of smoking remained statistically significant after adjustment for the ethnic group. Smokers had a risk of 2.41 (1-12-5.18,95% confidence interval) of developing eye signs relative to non-smokers (P=0.02). Moreover, the proportion of patients with GO increased as cigarette consumption increased (Fig. 1; P= 0.008).
Graves’ ophthalmopathy, smoking and ethnic origin
Clinical Endocrinology (1992) 36
293
Table 2 Type and distribution of eye signs
according to sex, ethnic origin and cigarette smoking habit in the 52 patients with Graves‘ disease who had ophthalmopathy
Sex
Ethnic group
Smoking habit
Male (9)
Female (43)
European (49)
Asian (3)
Non
Eye signs* Lids Oedema Proptosis Extraocular muscles
8 4 3 2
33 25 17 13
38 26 19
3 3 1 0
13
I5
(15)
5 5
4
Ex-S (14)
Curr-S (23)
II 7
17 17 10 8
5
3
* Eye signs were scored independently by one of us (CE), using the American Thyroid Association Classification (Werner, 1969). We had no patients with Class 5 (corneal involvement) or Class 6 (sight loss).
The influence of smoking habit on the different classes of eye complication (lids, soft tissue oedema, proptosis, muscle) is shown in Fig. 2. All were more frequent among current smokers, but only for Class 2 was the difference statistically significant ( P = 0.04). There were no significant differences due to ethnic group ( P = 0 . 6 0 ) or sex ( P = 0 . 8 6 , Table 2). Discusslon
It is likely that GO like GD is of autoimmune origin (Weetman, 1991). Antibodies interacting with orbital muscle membranes have been described (Kendall-Taylor e f a/., 1984). Not all patients with G D develop clinically apparent GO and in those that do, the clinical presentation is variable from patient to patient. Probably therefore other factors are involved in the expression of this disorder. The present results support the previous findings (Hagg & Asplund, 1987; Bartalenaeral., 1989; Shineefal., 1989, 1990; Balaz et al., 1990) in showing that cigarette smoking is one such factor, as the effect of smoking remained significant even after correcting for the difference in ethnic factor. Cigarette smoking in Europeans produced a 2-4 times higher risk for developing eye signs than in those who had never smoked. The effect was dose related, with a higher proportion of patients developing eye changes as cigarette consumption increased. Our results indicated that it was especially the Class 2 changes which were more common in the patients who smoked. The way in which smoking effects are mediated remains speculative at present but there are several possible connections. Smoking is known to affect the immune system (Miller e i a/., 1982) and also to have a variety of biochemical effects. These include elevation of the blood thiocyanate level, which can influence thyroid function (Wollman, 1962), and the production of biochemical changes in various tissues (Kusick et al., 1990). It is possible too that a local effect of cigarette smoke is important, and this is perhaps suggested by the
predominant effect on the inflammatory component (conjunctival injection and oedema, and periorbital oedema) of the ophthalmopathy. In the Asian population living in our area, GD is not less common than in Europeans; of our patient with GD 25% were Asians, compared with 15% of Asians in the local population. The prevalence of ophthalmopathy was however markedly lower, a difference only partly attributable to the lower frequency of smoking. The Asian patients living in our area, for the most part, were living in similar circumstances. It is possible that exogenous factors, such as diet, may be involved in the differing prevalence of GO but it seems more likely that genetic factors are responsible. Several studies have looked at the possibility that genetic variations may be linked to the occurrence of GO in some patients but the results so far have not been conclusive (Weetman et a[., 1988).
References Balaz, C., Stensky, V., Farid, N. (1990) Association between Graves’ ophthalmopathy and smoking. Lancet, 336, 754. Bartalena, L., Martino, E., Marcocci, C., Bogazzi, F., Panicucci, M., Velluzzi, F., Loviselli, A. & Pinchera, A. (1989) More on smoking habits and Graves’ Ophthalmopathy. Journal of Endocrinological Ini~estigution.t2, 133-731. Hagg, E. & Asplund, K. (1987) Is endocrine ophthalmopathy related to smoking? British Medical Journal, 295, 634-635. Kendall-Taylor, P.. Atkinson, S. & Holcombe, M. (1984) A specific IgG in Graves’ ophthalmopathy and its relation to retro-orbital and thyroid autoimmunity. Briiish Medical Journal, 288, 11831186. Kusick, J., Routledge, M., Jenkins, D. &Garner, R.C. (1990) DNA adducts in different tissues of smokers and non smokers. International Journal of Cancer, 45,673-678. Miller, L.C., Goldstein, M., Murphy, M. & Gins, L.C. (1982) Reversible alterations in immunoregulatory T cells in smoking. Analysis by monoclonal antibodies and flow cytometry. Chest, 82, 526-529.
294
M. Tellez et a / .
Shine, B., Edwards, O.M. & Weetman, A.P. (1989) Graves ophthalmopathy and smoking. Acta Endocrinologica (Copenhagen), 121 (SUPPI. 2). 182-1 84. Shine, B., Fells, P., Edwards, O.M. & Weetman, A.P. (1990) Association between Graves’ ophthalmopathy and smoking. Lancet, 335, 1261-1263. Weetman. A.P. (1 991) Thyroid associated eye disease: pathophysiology. Lancet. 338,25-28. Weetman. A.P., So, A.K., Warner, C.A., Foroni, L., Fells, P. &
Clinical Endocrinology (1992) 36
Shine, B. (1988) Immunogenetics of Graves’ ophthalmopathy. Clinical Endocrinology, 28,619-628. Werner, S . (1969) Classification of the eye changes of Graves’ disease. Journal of Clinical Endocrinology and Metabolism, 29, 982-984.
Wollman, S.N. (1962) Inhibition by thiocyanate of accumulation of radioiodine by thyroid gland. American Journal of Physiology, 203,5 17-524.
Graves’ ophthalmopathy in relation to cigarette smoking and ethnic origin Marlsol Tellez, Jackie Cooper and Charles Edmonds Endocrinology and Epidemiofogy, Medical Research Council and Northwick Park Hospital, Harrow, UK (Received 15 August 1991; returned for revision 23 September 1991; finally revised 22 October 7991; accepted 30 October 1991)
Summary OBJECTIVE We aimed to study the effect of cigarette smoking on the prevalence and severity of Graves’ ophthalmopathy (GO). PATIENTS One hundred and fifty-five newly diagnosed patients with Graves’ disease (GD) were dlagnosed cllnlcally and by routine biochemical methods. Twenty-five per cent (39)were of Asian origin. METHODS Eye signs were classified according to the American Thyroid Assoclation Classification. A detailed smoking questionnaire and data from hospital notes were used to calculate an index of cigarette consumption. RESULTS Thirty-four per cent of all patients had Graves’ ophthalmopathy, and the prevalence In males (26%) and females (36%) did not differ significantly. There was a prevalence of 42% among Europeans compared to 7.7% in Asians (P= 0.0002). The overall risk for Europeans for developing Graves’ ophthalmopathy was 6.4 (1.78-22.7 confidence interval) times higher than for Asians. Corrected for the ethnic factor the increased risk from smoking for Europeans was 2.4 (1.12-5.18, 95% confidence interval) times higher. There was a significant dose effect (P = 0.008). CONCLUSIONS The present findings confirm an effect of cigarette smoking on Graves’ ophthalmopathy and in addltion show that Europeanshave a substantially greater risk of developing Graves’ ophthalmopathy than have Asians.
Among the factors that predispose to Graves’ ophthalmopathy (GO), cigarette smoking appears to be one of significance (Hagg & Asplund 1987; Bartalena et ai., 1989; Shine et al., 1990; Balaz et al., 1990). Moreover, we have been impressed by the low prevalence of this form of eye disease in Asian patients who presented with Graves’ disease (GD) Correspondence: Dr M. Tellez, Northwick Park Hospital, Wdtford Road, Harrow, Middlesex HA1 3UJ, UK.
suggesting that an ethnic factor was also important. Previous studies on the effect of cigarette smoking have, for the most part, been on selected populations. In contrast, the present study was on patients referred by their general medical practitioners to an endocrine clinic in a district general hospital for assessment and management of hyperthyroidism. The object of the study was to determine the prevalence and severity of GO in these patients, particularly in relationship to smoking habit and ethnic origin. Patients and methods
The patients comprised 155 subjects (Table I), who attended the endocrine clinic during the period June 1985 until May 1990, and were newly diagnosed as having GD. A substantial proportion of the patients were Asian immigrants (15% of the total population, Department of Public Health survey for Harrow), from families coming originally from the Indian subcontinent. The diagnosis of Graves’ disease was based on the measurement of plasma T 3 and TSH and the demonstration of a diffusely increased thyroid uptake on scanning 20 minutes after injection of 9 9 m T ~ 0GO 4 . was present in 47 at presentation; five developed eye signs during the treatment with antithyroid drugs. Ophthalmopathy was classified independently by one of us (CE) in all patients using the abridged Classification of Eye Changes in G D of the American Thyroid Association (Werner, 1969). Classes were as follows: Class I , upper lid retraction, usually with lid lag; Class 2, soft tissue changes: periorbital and conjunctival; Class 3, proptosis ( > 20 mm o n exophthalmometry); Class 4, extraocular muscle involvement, usually with diplopia. There were no patients showing changes of Classes 5 or 6 in our group. Details on smoking habits were recorded in all the patients at their first attendance. In addition, from 1987 onwards, the patients completed a detailed questionnaire based on the one used by the Smoking Research Group, Epidemiology Division, Medical Research Council. Those patients, about onethird of the total, who had attended initially before the study commenced and were still attending the clinic, also completed the questionnaire. Fourteen patients did not complete it satisfactorily and for them the information was derived from that recorded in the hospital notes. Ex-smokers were those who had stopped smoking for 6 months or more. An index for cigarette consumption using cigarette years (daily consumption x years of smoking) was constructed in 291
292
M . Tellez et a / .
Clinical Endocrinology (1992) 36
Table 1 Ophthalmopathy in 155 patients with Graves’ disease according to sex, ethnic group and smoking
Age average (range) (years)
Sex
Ethnic group
Smoking
Male
Female
European
Asian
Non
EX-S
Current-S
Eye signs absent (n= 103)
41.5 ( I 1-86)
25
78
67
36
60
14
29
Eye signs present (n = 52)
45.0 (15-73)
9
43
49
3
15
14
23
34
121
I16
39
15
28
52
Total
60
3
2o
50
r
*
6 40
0 21
g 3c P
$
20
.-0
2
lo Class I Non-smoker
A B C (1-199) (200-300)(>400) Cigarette-years
Fig. 1 Percentage of patients with GO in relation to ‘cigarette consumption index’. Non-smoker (n= 74); A(n = 20); B(n = 19); C(n= 24).
order to investigate the effect of dose. The four groups were as follows, 0, non-smokers; A, 1-199, light smokers; B, 200399, moderate; C, > 400, heavy smokers. For the statistical analysis, two-tailed Chi-squared tests were used to assess differencesin type of complication by sex, age, ethnic group and smoking status. Differences in the proportion of patients developing eye signs were assessed, using a logistic regression model of the form lO&{P/(l -p)}=a+bx wherep is the probability of developingeye signs. This model allowed the examination of smoking effect after adjustment for age and ethnic differences. Relative risks of developing GO and 95% confidence intervals were obtained. Results
Ophthalmopathy was observed in 52 (34%) of all patients (Table 1) and the prevalences in males (26%) and females (36%) did not differ significantly. There was a significant ethnic factor, the prevalence among Europeans being 42% compared with 7.7% in Asians (P=0.0002). Only three
Class 2 Class 3 Class of eye sign
Class 4
Flg. 2 Number of patients, in relation to the presence of each class of eye sign. 0,Non-smokers; E, ex-smokers; W, current smokers.
Asians had eye signs and of these, two were smokers. After adjustment for smoking the risk of Europeans developing ophthalmopathy relative to Asians was 6.36 (1.78-22.7,95% confidence interval). Among all current smokers and ex-smokers the prevalence of ophthalmopathy was greater than in those who had never smoked (Table 1; P=0.0005). Fifty per cent of the 28 patients who had stopped smoking developed GO. They were all Europeans. No significant relationship was present between the development of GO in these patients and the length of time since stopping (mean=7*3 years, range 6 months to 25 years), or the amount smoked. Some of this effect was due to the difference in smoking habits between Asian and European patients as only nine (23%) of the Asians smoked, compared with 61.2% of the Europeans. However, only three Asian patients had eye signs and the effect of smoking remained statistically significant after adjustment for the ethnic group. Smokers had a risk of 2.41 (1-12-5.18,95% confidence interval) of developing eye signs relative to non-smokers (P=0.02). Moreover, the proportion of patients with GO increased as cigarette consumption increased (Fig. 1; P= 0.008).
Graves’ ophthalmopathy, smoking and ethnic origin
Clinical Endocrinology (1992) 36
293
Table 2 Type and distribution of eye signs
according to sex, ethnic origin and cigarette smoking habit in the 52 patients with Graves‘ disease who had ophthalmopathy
Sex
Ethnic group
Smoking habit
Male (9)
Female (43)
European (49)
Asian (3)
Non
Eye signs* Lids Oedema Proptosis Extraocular muscles
8 4 3 2
33 25 17 13
38 26 19
3 3 1 0
13
I5
(15)
5 5
4
Ex-S (14)
Curr-S (23)
II 7
17 17 10 8
5
3
* Eye signs were scored independently by one of us (CE), using the American Thyroid Association Classification (Werner, 1969). We had no patients with Class 5 (corneal involvement) or Class 6 (sight loss).
The influence of smoking habit on the different classes of eye complication (lids, soft tissue oedema, proptosis, muscle) is shown in Fig. 2. All were more frequent among current smokers, but only for Class 2 was the difference statistically significant ( P = 0.04). There were no significant differences due to ethnic group ( P = 0 . 6 0 ) or sex ( P = 0 . 8 6 , Table 2). Discusslon
It is likely that GO like GD is of autoimmune origin (Weetman, 1991). Antibodies interacting with orbital muscle membranes have been described (Kendall-Taylor e f a/., 1984). Not all patients with G D develop clinically apparent GO and in those that do, the clinical presentation is variable from patient to patient. Probably therefore other factors are involved in the expression of this disorder. The present results support the previous findings (Hagg & Asplund, 1987; Bartalenaeral., 1989; Shineefal., 1989, 1990; Balaz et al., 1990) in showing that cigarette smoking is one such factor, as the effect of smoking remained significant even after correcting for the difference in ethnic factor. Cigarette smoking in Europeans produced a 2-4 times higher risk for developing eye signs than in those who had never smoked. The effect was dose related, with a higher proportion of patients developing eye changes as cigarette consumption increased. Our results indicated that it was especially the Class 2 changes which were more common in the patients who smoked. The way in which smoking effects are mediated remains speculative at present but there are several possible connections. Smoking is known to affect the immune system (Miller e i a/., 1982) and also to have a variety of biochemical effects. These include elevation of the blood thiocyanate level, which can influence thyroid function (Wollman, 1962), and the production of biochemical changes in various tissues (Kusick et al., 1990). It is possible too that a local effect of cigarette smoke is important, and this is perhaps suggested by the
predominant effect on the inflammatory component (conjunctival injection and oedema, and periorbital oedema) of the ophthalmopathy. In the Asian population living in our area, GD is not less common than in Europeans; of our patient with GD 25% were Asians, compared with 15% of Asians in the local population. The prevalence of ophthalmopathy was however markedly lower, a difference only partly attributable to the lower frequency of smoking. The Asian patients living in our area, for the most part, were living in similar circumstances. It is possible that exogenous factors, such as diet, may be involved in the differing prevalence of GO but it seems more likely that genetic factors are responsible. Several studies have looked at the possibility that genetic variations may be linked to the occurrence of GO in some patients but the results so far have not been conclusive (Weetman et a[., 1988).
References Balaz, C., Stensky, V., Farid, N. (1990) Association between Graves’ ophthalmopathy and smoking. Lancet, 336, 754. Bartalena, L., Martino, E., Marcocci, C., Bogazzi, F., Panicucci, M., Velluzzi, F., Loviselli, A. & Pinchera, A. (1989) More on smoking habits and Graves’ Ophthalmopathy. Journal of Endocrinological Ini~estigution.t2, 133-731. Hagg, E. & Asplund, K. (1987) Is endocrine ophthalmopathy related to smoking? British Medical Journal, 295, 634-635. Kendall-Taylor, P.. Atkinson, S. & Holcombe, M. (1984) A specific IgG in Graves’ ophthalmopathy and its relation to retro-orbital and thyroid autoimmunity. Briiish Medical Journal, 288, 11831186. Kusick, J., Routledge, M., Jenkins, D. &Garner, R.C. (1990) DNA adducts in different tissues of smokers and non smokers. International Journal of Cancer, 45,673-678. Miller, L.C., Goldstein, M., Murphy, M. & Gins, L.C. (1982) Reversible alterations in immunoregulatory T cells in smoking. Analysis by monoclonal antibodies and flow cytometry. Chest, 82, 526-529.
294
M. Tellez et a / .
Shine, B., Edwards, O.M. & Weetman, A.P. (1989) Graves ophthalmopathy and smoking. Acta Endocrinologica (Copenhagen), 121 (SUPPI. 2). 182-1 84. Shine, B., Fells, P., Edwards, O.M. & Weetman, A.P. (1990) Association between Graves’ ophthalmopathy and smoking. Lancet, 335, 1261-1263. Weetman. A.P. (1 991) Thyroid associated eye disease: pathophysiology. Lancet. 338,25-28. Weetman. A.P., So, A.K., Warner, C.A., Foroni, L., Fells, P. &
Clinical Endocrinology (1992) 36
Shine, B. (1988) Immunogenetics of Graves’ ophthalmopathy. Clinical Endocrinology, 28,619-628. Werner, S . (1969) Classification of the eye changes of Graves’ disease. Journal of Clinical Endocrinology and Metabolism, 29, 982-984.
Wollman, S.N. (1962) Inhibition by thiocyanate of accumulation of radioiodine by thyroid gland. American Journal of Physiology, 203,5 17-524.
