- Email: [email protected]
Effect of lithium carbonate therapy on thyroid immune status in manic depressive patients: A prospective study
Journal of Affective Elsevier
155
Disorders, 11 (1986) 155-160
JAD 00403
Effect of Lithium Carbonate Therapy on Thyroid Immune Status in Manic Depressive Patients: A Prospective Study John H. Lazarus, Alan M. McGregor, Marion Ludgate, Chris Darke I, Fionula M. Creagh and Chris J. Kingswood Department
of Medicine,
University of Wales College of Medicine, University Hospital of Wales, CardifA and ’ Welsh Regional Transfusion Centre, Rhydlafar, Cardi& Wales (U.K.) (Received 2 May, 1986) (Revised, received 21 July, 1986) (Accepted 6 August, 1986)
Summary Serum thyroid autoantibodies to thyroglobulin (TG) and thyroid microsomes (M) were measured by ELISA prospectively in 37 manic depressive patients prior to receiving lithium carbonate and during therapy with this drug for a mean of 16.2 months. They were also measured once in 27 normal subjects and several times in five psychiatric patients not receiving lithium. Sixteen patients (43%) had either thyroglobulin, microsomal antibodies or both before receiving lithium therapy. During therapy significant fluctuations in antibody titre, both upwards and downwards were observed in ten out of 12 patients with M antibodies and in nine out of 11 with TG antibodies. The fluctuations in antibody titre are consistent with an immunomodulatory effect of lithium as has been shown in animal studies. It is suggested that psychiatric patients should have thyroid antibodies measured routinely before and during lithium therapy.
Key words: Lithium
carbonate - Thyroid immune status - Manic depressive patients
Introduction Lithium therapy is highly effective in the prophylaxis of manic depressive disorder (Schou and Thomsen 1975). In the United Kingdom approximately one adult per 2000 population is receiving the drug. The duration of administration is often many years as there are few data reporting Correspondence to: Dr. J.H. Lazarus, Senior Lecturer in Medicine, University of Wales College of Medicine, University Hospital of Wales, Heath Park, Cardiff, U.K. 0165-0327/86/$03.50
0 1986 Elsevier Science Publishers
- Prospective
study
the effects of stopping the drug on the psychiatric illness. Since the first description of the goitrogenic effect of lithium it has been appreciated that patients receiving the drug can develop thyroid enlargement which may persist or disappear (Lazarus 1982). The goitre is associated with the presence or absence of circulating antibodies to thyroglobulin (TG) and thyroid microsomes (M) and some patients may develop hypothyroidism. Cross-sectional studies have reported a higher prevalence of thyroid antibodies in lithium-treated
B.V. (Biomedical
Division)
156 patients than in control psychiatric subjects or the normal population (Lazarus 1986). In addition, recent data suggest that lithium can modulate the expression of antibodies in an animal model of thyroiditis (Hassman et al. 1985). We have, therefore, examined the effect of lithium on thyroid antibody titres in psychiatric patients in a prospective longitudinal study. In view of the known HLA haplotype restriction of autoimmune thyroiditis (Walfish and Farid 1985) the HLA status of the patients was studied where possible. Patients and Methods Thirty-seven consecutive psychiatric out-patients (17 males, 20 females), mean age 49.3 years (range 28-71), diagnosed as having bipolar manic depressive disorder (by DSM-III criteria) and who agreed to attend regularly for blood samples to be taken were studied. Patients wjth significant concomitant medical illness were excluded from the study and no patient had been previously treated with lithium. The patients were given lithium carbonate for treatment and prophylaxis of manic depressive disorder (Baastrup 1980). One-third of the patients were on other drugs during the period they took lithium; these included benzodiazepines, tricyclic antidepressants and phenothiazines. Patients were reviewed at regular intervals by a psychiatrist and physician at a routine lithium clinic. A blood sample was obtained before lithium treatment was started and further samples collected for a mean of 16.2 + 6.9 SD months (range 5-33). An average of 5.8 blood samples (3-12) per patient was obtained. Five schizophrenic patients (1 male, 4 females, mean age 47.4, range 40-62) receiving long-term fluphenazine (Modecate) were also studied for 18.4 months (range 9-23). Serum was stored at - 20 o C prior to assay. Antibodies to TG and M were measured by an ELISA assay previously described (Weetman et al. 1984). This assay is more sensitive than haemagglutination but has a good correlation with haemagglutination assays (Weetman and McGregor 1984). Sera from 27 normal controls (laboratory staff) with no family history of thyroid disease were used to define the control values of optical density (OD) for this assay. A titre was considered to be elevated if it was greater than 2 SD from the
mean of this group. All samples from any one patient were assayed in the same assay and the assay was performed blind with respect to the treatment. The within-assay variation of the ELISA was 5.5% and variations in OD units of more than 50 for TG and M were regarded as significant fluctuations. Serum free T4 and free T3 levels were measured by radioimmunoassay at each follow-up visit - Amerlex Kit (Amersham International plc). TRH tests using a 200 pg i.v. injection of TRH were performed before starting lithium and twice more during follow-up in 21 of the patients and all the control subjects. Serum lithium was measured by atomic absorption spectrophotometry. HLA-A, B and DR phenotypes were established using standard techniques. Results Twenty-one patients (12 males, 9 females) had antibody titres within the control reference range before lithium treatment but two of these (both female) developed positive but low titres to TG antibody, 11 and 15 months after starting lithium respectively. The remaining 16 patients (8 males and 8 females) had elevated circulating thyroid antibodies before lithium treatment commenced. Seven of these (2 males, 5 females) had both TG and M antibodies, 12 had M antibodies and 11 had TG antibodies. Two male patients with M antibodies before lithium therapy developed positive titres to TG antibodies after 3 months of treatment. No patient in the negative antibody
Fig. 1. Antimicrosomal antibodies during the course of lithium therapy. All patients had antibodies before lithium therapy and no other patient developed antibodies.
157 group or the TG antibody-only group developed M antibodies. During the study period significant fluctuations (both up and down) in M antibody
titres were seen in four, a significant rise in five, a decrease in one, and two others had stable titres (Fig. 1). The TG titres rose in five, fell in four and
I
I
700,
. Anti To . Anti Mic
600,
ab I
ob I
I
OD
* /
’ /’
‘/
- -________
- ________-
_______y;
0
2
0
4
6
6
IO
12
2
4
6
6
IO
Months
12
I4 16
16 20 22 24
Monlhs
Fig. 2.
Fig. 3.
500 w400 300 OD 200
__&_----
_______
0
2
_
4 6 Months
Fe=
-----__
0
100
\
----__---_-
10
0. 2
--
4
6
8
----___----_-___-__-_____
IO
12
14
&___-a
MC
+---‘----Tg
16 18 20
22 24
26
28
30
32 34
36
5.8 40
Month
Fig. 4. Figs. 2-5. Antithyroglobulin limits of normal for anti-TG
Fig. 5 antibody titres and antimicrosomal antibody titres in four patients during lithium therapy. (- - - - - -) and anti-M (- -) antibodies in a normal population are shown by the horizontal
The upper lines.
158 showed no change in two. Examples of the variation in progression of the titres in four individuals are shown in Figs. 2-5. There was no correlation between thyroid antibody status and serum lithium (range 0.34-0.87 mmol/l) or between thyroid antibody status and degree of depression or mania as judged clinically. No patient or control developed clinical hypothyroidism. None of the manic depressive group had abnormal free T4 or free T3 levels before starting lithium therapy and these values remained within normal limits during the study except for a 42-year-old female with TG and M antibodies who was found to be hypothyroid with low free T4 after 6 months’ lithium therapy. The TRH tests were exaggerated (i.e. 20 min TSH value more than 15.6 pU/ml in males and more than 20.5 @J/ml in females and/or 60 n-tin TSH value more than 11.5 &j/ml in males and more than 15.6 $-J/ml in females) in six out of ten of those patients with no thyroid antibodies, three out of 11 with antibodies and in none of the controls (&i-squared not significant between any two groups). Thyroid hormone concentrations were normal at all times in the psychiatric control group although one of these did develop positive M antibodies. Only two patients (females) in the lithium group had a family history of thyroid disease. One had no antibodies and the other developed TG antibodies. HLA typing was performed on 27 patients (26 for DR), 12 of whom had developed thyroid antibodies. No significant disturbance in HLA frequencies was found between the total patient group and a random control population of 600 residing in the same geographical area. However, the frequency of DR3 in the patients was 42.3% compared with only 27.5% in the random population (P > 0.05). There was no increase in HLA B8 and/or DR3 in the patients with antibodies compared with the group without antibodies or the random population. However, the frequency of DR4 showed a high level in the antibody group (41.7%) compared with patients without antibodies (14.3%) which was not significant (P > 0.05). Discussion The prevalence of thyroid antibodies has been found to be higher in lithium-treated patients than
that in a normal population in several large crosssectional studies of psychiatric patients (Emerson et al. 1973; Lindstedt et al. 1977; Deniker et al. 1978; Wasilewski et al. 1978; Lazarus 1981; Albrecht 1982) although one recent study has not confirmed this (Ellyin et al. 1985). Calabrese et al. (1985) in an open uncontrolled study reported that in three manic depressive patients who had thyroid antibodies before lithium treatment marked increases in antibody titre occurred during therapy. None of the other 13 patients studied by these authors had thyroid antibodies before or during therapy with lithium. The present prospective study is similar to that of Calabrese et al. but has included more patients and more extensive thyroid function testing. It was considered important to study a prospective control group of psychiatric patients at the same time. Although 30 schizophrenic patients were initially studied as the control group, only five were available for longterm study because of poor compliance or non-attendance at the clinic. A surprising finding in this study was the high prevalence (43%) of significant titres of thyroid antibodies in the psychiatric patients before starting lithium therapy. In the normal population thyroid antibody prevalence ranges from 5 to approximately 15% (Tunbridge et al. 1977) and in psychiatric patients not on lithium a figure of 7.5% has been found in one study (Deniker et al. 1978). The significance of the high antibody titres in relation to the pathogenesis or treatment of manic depressive disorder is not clear although one study cites a high prevalence of thyroid disease in so-called ‘rapid cyclers’ (Cowdry et al. 1983). It should be noted that the frequency of HLA B8, DR3 and DR4 antigens (i.e. those predisposing to thyroid disease) was not significantly increased. While we have not shown any significant ability of lithium to induce antibody formation, we believe we have demonstrated an immunomodulatory effect of the drug on circulating thyroid antibodies in patients possessing these antibodies at the start of treatment. At the same time we admit we are unable to exclude the possibility that fluctuation in antibody titre might be due to the manic depressive disorder itself as we were not able to study a control group of such patients receiving other drugs. However, we suggest that
159 the changes in antibody titres in the lithium group are much greater than those seen in patients with Hashimoto’s thyroiditis studied over many years (Papapetrou et al. 1972; Hayashi et al. 1985) and cannot be explained as merely the natural progression of thyroiditis. It is conceivable that the patients with antibodies were at different stages of the progression of autoimmune thyroiditis when lithium was started. This may explain why the antibody titres increased in some (Figs. 2 and 3) and declined in others (Fig. 5) in a similar way to that observed in a rat model of thyroiditis treated with lithium (Hassman et al. 1985). The mechanisms of the immunomodulatory effects of lithium have been examined in vivo and in vitro and there is evidence of increased immunoglobulin production by lymphocytes of lithium-treated patients (Weetman et al. 1982). Lithium also alters the ionic milieu of the lymphocyte and, at least in vitro, can thus affect its function (Hart 1981). The question arises as to whether the increases in thyroid antibody titres in some of these patients predict that worsening thyroiditis and hypothyroidism will ensue. The low incidence of hypothyroidism in this and other studies suggests that the appropriate immune background is necessary, a view supported by experiments in chickens (Sundick et al. 1974, 1979). We attempted to partially characterise the immune background of our patients by HLA typing but there was no evidence of a predisposition to the effect of lithium on thyroid antibodies. The small numbers available for HLA analysis make interpretation of these data only tentative. The abnormal TRH tests in lithium-treated patients have been noted previously both in those with thyroid antibodies and those without; the pathophysiology of the thyroid hormone and TSH changes has been discussed previously (Lazarus et al. 1981). This study has shown changes in man consistent with an immunomodulatory effect of lithium that has been previously shown in animals. Patients receiving lithium therapy should have thyroid antibody measurements performed before and during treatment in addition to routine thyroid function tests.
Acknowledgements We are grateful to Dr. W. Waheed, St. Cadoc’s Hospital, Caerleon for permission to study her patients and to the nursing staff at the Lithium Clinic for their help. We thank Dr. E.P. Worrall, Glasgow, Dr. A.M. Langley, Chichester, Dr. D.G. Goodhead, Doncaster and Dr. D.M. Shaw, Cardiff for referring patients. We are grateful to Dr. J.A.F. Napier of the Welsh Regional Transfusion Centre for the tissue typing and to the Department of Medical Biochemistry, University Hospital of Wales for the thyroid hormone measurements. The study was supported by Delandale U.K. Ltd. References Albrecht, J. and Hopf, U., Humoral autoimmune phenomena under long-term treatment with lithium with special regard to thyroidal autoantibodies, Klin. Wochenschr., 60 (1982) 1501-1504. Baastmp, P.C., Lithium in the prophylactic treatment of recurrent affective disorders. In: F.N. Johnson (Ed.), Handbook of Lithium Therapy, MTP Press, Lancaster, 1980, pp. 26-38. Calabrese, J.R., Gulledge, D.A., Hahn, K., Skwerer, R., Katz, M., Schumacher, O.P., Gupta, M.K., Krupp, N. and Gold, P.W., Autoimmune thyroiditis in manic-depressive patients treated with lithium, Am. J. Psychiatry, 142(11) (1985) 1318-1321. Cowdry, R.W., Wehr, T.A., Zis, A.P. and Goodwin, F.K., Thyroid abnormalities associated with rapid-cycling bipolar illness, Arch. Gen. Psychiatry, 40 (1983) 414-420. Deniker, P., Eyquem, A., Bemheim, R., Loo, H. and Delarue, P., Thyroid autoantibody levels during lithium therapy, Neuropsychobiology, 4 (1978) 270-275. Ellyin, F.M., Kumar, Y., Shamsabad, F., Singh, S.P., Gilden, J.L. and Snyder, A.K., Lithium therapy and thyroid autoantibodies. In: The Endocrine Society 67th Annual Meeting, Baltimore, MD, 1985, Abstract 1368. Emersen, C.H., Dyson, W.L. and Utiger, R., Serum thyrotropin and thyroxine concentrations in patients receiving lithium carbonate, J. Clin. Endocrinol. Metab., 36 (1973) 338-346. Hart, D.A., Ability of monovalent cations to replace potassium during stimulation of lymphoid cells, Cell. Immunol., 57 (1981) 209-218. Hassman, R.A., Lazarus, J.H., Dieguez, C., Weetman, A.P., Hall, R. and McGregor, A.M., The influence of lithium chloride on experimental autoimmune thyroid disease, Clin. Exp. Immunol., 61 (1985) 49-57. Hayashi, Y., Tamai, H., Fukata, S., Hirota. Y., Katayama, S., Kuma, K., Kumagai, F. and Nagataki, S., A long term clinical, immunological, and histological follow-up study of patients with goitrous chronic lymphocytic thyroiditis, J. Clin. Endocrinol. Metab., 61 (1985) 1172-1178.
160 Lazarus, J.H., Endocrine and metabolic effects of lithium, Adv. Drug React. AC. Pois. Rev., 1 (1982) 181-200. Lazarus, J.H., Effect of lithium on the thyroid gland. In: Endocrine and Metabolic Effects of Lithium, Plenum Press, New York, 1986, pp. 99-117. Lazarus, J.H., John, R., Benme, E.H., Chalmers, R.J. and Crockett, G., Lithium therapy and thyroid function; a long-term study, Psychol. Med. (London), 11 (1981) 85-92. Lindstedt, G., Nilsson, L.-A., Walinder, J., Skott, A. and Ohman, R., On the prevalence, diagnosis and management of lithium-induced hypothyroidism in psychiatric patients, Br. J. Psychiatry, 130 (1977) 452-458. Papapetrou, P.D., Lazarus, J.H., MacSween, R.N.M. and Harden, R.McG., Long-term treatment of Hashimoto’s thyroiditis with thyroxine, Lancet, ii (1972) 1045-1048. Schou, M. and Thomsen, K., Lithium prophylaxis of recurrent endogenous affective disorders. In: F.N. Johnson (Ed.), Lithium Research and Therapy, Academic Press, New York, 1975, pp. 63-69. Sundick, R.S. and Wick, G., Increased 13iI uptake by the thyroid glands of obese strain (OS) chickens derived from non-protamone-supplemented hens, Clin. Exp. Immunol., 18 (1974) 127-139. Sundick, R.S., Bag&i, N., Livezey, M.D., Brown, T.R. and Mack, R.E., Abnormal thyroid regulation in chickens with
autoimmune thyroiditis, Endocrinology, 105 (1979) 493499. Tunbridge, W.M.G., Evered, D.C., Hall, R., Appleton, D., Brewis, M., Clark, F., Grimley Evans, J., Young, E.. Bird, T. and Smith, P.A., The spectrum of thyroid disease in a community: the Wickham survey, Clin. Endocrinol., 7 (1977) 481-493. Von Wasilewski, B., Steinbock, R., Kohl, R., Greil, W. and Bottermann, P., Schilddrtisenfunktion bei der Lithiumprophylaxe, Arzneim.-Forsch., 28(2) (1978) 1297-1298. Walfish, P.G. and Farid, N.R., The immunogenetic basis of autoimmune thyroid disease. In: P.G. Walfish, J.R. Wall and R. Volpe (Eds.), Autoimmunity and the Thyroid, Academic Press, New York, 1985, pp. 9-36. Weetman, A.P. and McGregor, A.M., Autoimmune thyroid disease: developments in our understanding, Endocr. Rev., 5 (1984) 309-355. Weetman, A.P., McGregor, A.M., Lazarus, J.H., Rees-Smith, B. and Hall, R., The enhancement of immunoglobulin synthesis by human lymphocytes with lithium, Clin. Immunol. Immunopathol., 22 (1982) 400-407. Weetman, A.P., Rennie, D.P., Hassman, R., Hall, R. and McGregor, A.M., Enzyme-linked immunoassay of monoclonal and serum microsomal antibodies, Clin. Chim. Acta, 138 (1984) 237-244.
155
Disorders, 11 (1986) 155-160
JAD 00403
Effect of Lithium Carbonate Therapy on Thyroid Immune Status in Manic Depressive Patients: A Prospective Study John H. Lazarus, Alan M. McGregor, Marion Ludgate, Chris Darke I, Fionula M. Creagh and Chris J. Kingswood Department
of Medicine,
University of Wales College of Medicine, University Hospital of Wales, CardifA and ’ Welsh Regional Transfusion Centre, Rhydlafar, Cardi& Wales (U.K.) (Received 2 May, 1986) (Revised, received 21 July, 1986) (Accepted 6 August, 1986)
Summary Serum thyroid autoantibodies to thyroglobulin (TG) and thyroid microsomes (M) were measured by ELISA prospectively in 37 manic depressive patients prior to receiving lithium carbonate and during therapy with this drug for a mean of 16.2 months. They were also measured once in 27 normal subjects and several times in five psychiatric patients not receiving lithium. Sixteen patients (43%) had either thyroglobulin, microsomal antibodies or both before receiving lithium therapy. During therapy significant fluctuations in antibody titre, both upwards and downwards were observed in ten out of 12 patients with M antibodies and in nine out of 11 with TG antibodies. The fluctuations in antibody titre are consistent with an immunomodulatory effect of lithium as has been shown in animal studies. It is suggested that psychiatric patients should have thyroid antibodies measured routinely before and during lithium therapy.
Key words: Lithium
carbonate - Thyroid immune status - Manic depressive patients
Introduction Lithium therapy is highly effective in the prophylaxis of manic depressive disorder (Schou and Thomsen 1975). In the United Kingdom approximately one adult per 2000 population is receiving the drug. The duration of administration is often many years as there are few data reporting Correspondence to: Dr. J.H. Lazarus, Senior Lecturer in Medicine, University of Wales College of Medicine, University Hospital of Wales, Heath Park, Cardiff, U.K. 0165-0327/86/$03.50
0 1986 Elsevier Science Publishers
- Prospective
study
the effects of stopping the drug on the psychiatric illness. Since the first description of the goitrogenic effect of lithium it has been appreciated that patients receiving the drug can develop thyroid enlargement which may persist or disappear (Lazarus 1982). The goitre is associated with the presence or absence of circulating antibodies to thyroglobulin (TG) and thyroid microsomes (M) and some patients may develop hypothyroidism. Cross-sectional studies have reported a higher prevalence of thyroid antibodies in lithium-treated
B.V. (Biomedical
Division)
156 patients than in control psychiatric subjects or the normal population (Lazarus 1986). In addition, recent data suggest that lithium can modulate the expression of antibodies in an animal model of thyroiditis (Hassman et al. 1985). We have, therefore, examined the effect of lithium on thyroid antibody titres in psychiatric patients in a prospective longitudinal study. In view of the known HLA haplotype restriction of autoimmune thyroiditis (Walfish and Farid 1985) the HLA status of the patients was studied where possible. Patients and Methods Thirty-seven consecutive psychiatric out-patients (17 males, 20 females), mean age 49.3 years (range 28-71), diagnosed as having bipolar manic depressive disorder (by DSM-III criteria) and who agreed to attend regularly for blood samples to be taken were studied. Patients wjth significant concomitant medical illness were excluded from the study and no patient had been previously treated with lithium. The patients were given lithium carbonate for treatment and prophylaxis of manic depressive disorder (Baastrup 1980). One-third of the patients were on other drugs during the period they took lithium; these included benzodiazepines, tricyclic antidepressants and phenothiazines. Patients were reviewed at regular intervals by a psychiatrist and physician at a routine lithium clinic. A blood sample was obtained before lithium treatment was started and further samples collected for a mean of 16.2 + 6.9 SD months (range 5-33). An average of 5.8 blood samples (3-12) per patient was obtained. Five schizophrenic patients (1 male, 4 females, mean age 47.4, range 40-62) receiving long-term fluphenazine (Modecate) were also studied for 18.4 months (range 9-23). Serum was stored at - 20 o C prior to assay. Antibodies to TG and M were measured by an ELISA assay previously described (Weetman et al. 1984). This assay is more sensitive than haemagglutination but has a good correlation with haemagglutination assays (Weetman and McGregor 1984). Sera from 27 normal controls (laboratory staff) with no family history of thyroid disease were used to define the control values of optical density (OD) for this assay. A titre was considered to be elevated if it was greater than 2 SD from the
mean of this group. All samples from any one patient were assayed in the same assay and the assay was performed blind with respect to the treatment. The within-assay variation of the ELISA was 5.5% and variations in OD units of more than 50 for TG and M were regarded as significant fluctuations. Serum free T4 and free T3 levels were measured by radioimmunoassay at each follow-up visit - Amerlex Kit (Amersham International plc). TRH tests using a 200 pg i.v. injection of TRH were performed before starting lithium and twice more during follow-up in 21 of the patients and all the control subjects. Serum lithium was measured by atomic absorption spectrophotometry. HLA-A, B and DR phenotypes were established using standard techniques. Results Twenty-one patients (12 males, 9 females) had antibody titres within the control reference range before lithium treatment but two of these (both female) developed positive but low titres to TG antibody, 11 and 15 months after starting lithium respectively. The remaining 16 patients (8 males and 8 females) had elevated circulating thyroid antibodies before lithium treatment commenced. Seven of these (2 males, 5 females) had both TG and M antibodies, 12 had M antibodies and 11 had TG antibodies. Two male patients with M antibodies before lithium therapy developed positive titres to TG antibodies after 3 months of treatment. No patient in the negative antibody
Fig. 1. Antimicrosomal antibodies during the course of lithium therapy. All patients had antibodies before lithium therapy and no other patient developed antibodies.
157 group or the TG antibody-only group developed M antibodies. During the study period significant fluctuations (both up and down) in M antibody
titres were seen in four, a significant rise in five, a decrease in one, and two others had stable titres (Fig. 1). The TG titres rose in five, fell in four and
I
I
700,
. Anti To . Anti Mic
600,
ab I
ob I
I
OD
* /
’ /’
‘/
- -________
- ________-
_______y;
0
2
0
4
6
6
IO
12
2
4
6
6
IO
Months
12
I4 16
16 20 22 24
Monlhs
Fig. 2.
Fig. 3.
500 w400 300 OD 200
__&_----
_______
0
2
_
4 6 Months
Fe=
-----__
0
100
\
----__---_-
10
0. 2
--
4
6
8
----___----_-___-__-_____
IO
12
14
&___-a
MC
+---‘----Tg
16 18 20
22 24
26
28
30
32 34
36
5.8 40
Month
Fig. 4. Figs. 2-5. Antithyroglobulin limits of normal for anti-TG
Fig. 5 antibody titres and antimicrosomal antibody titres in four patients during lithium therapy. (- - - - - -) and anti-M (- -) antibodies in a normal population are shown by the horizontal
The upper lines.
158 showed no change in two. Examples of the variation in progression of the titres in four individuals are shown in Figs. 2-5. There was no correlation between thyroid antibody status and serum lithium (range 0.34-0.87 mmol/l) or between thyroid antibody status and degree of depression or mania as judged clinically. No patient or control developed clinical hypothyroidism. None of the manic depressive group had abnormal free T4 or free T3 levels before starting lithium therapy and these values remained within normal limits during the study except for a 42-year-old female with TG and M antibodies who was found to be hypothyroid with low free T4 after 6 months’ lithium therapy. The TRH tests were exaggerated (i.e. 20 min TSH value more than 15.6 pU/ml in males and more than 20.5 @J/ml in females and/or 60 n-tin TSH value more than 11.5 &j/ml in males and more than 15.6 $-J/ml in females) in six out of ten of those patients with no thyroid antibodies, three out of 11 with antibodies and in none of the controls (&i-squared not significant between any two groups). Thyroid hormone concentrations were normal at all times in the psychiatric control group although one of these did develop positive M antibodies. Only two patients (females) in the lithium group had a family history of thyroid disease. One had no antibodies and the other developed TG antibodies. HLA typing was performed on 27 patients (26 for DR), 12 of whom had developed thyroid antibodies. No significant disturbance in HLA frequencies was found between the total patient group and a random control population of 600 residing in the same geographical area. However, the frequency of DR3 in the patients was 42.3% compared with only 27.5% in the random population (P > 0.05). There was no increase in HLA B8 and/or DR3 in the patients with antibodies compared with the group without antibodies or the random population. However, the frequency of DR4 showed a high level in the antibody group (41.7%) compared with patients without antibodies (14.3%) which was not significant (P > 0.05). Discussion The prevalence of thyroid antibodies has been found to be higher in lithium-treated patients than
that in a normal population in several large crosssectional studies of psychiatric patients (Emerson et al. 1973; Lindstedt et al. 1977; Deniker et al. 1978; Wasilewski et al. 1978; Lazarus 1981; Albrecht 1982) although one recent study has not confirmed this (Ellyin et al. 1985). Calabrese et al. (1985) in an open uncontrolled study reported that in three manic depressive patients who had thyroid antibodies before lithium treatment marked increases in antibody titre occurred during therapy. None of the other 13 patients studied by these authors had thyroid antibodies before or during therapy with lithium. The present prospective study is similar to that of Calabrese et al. but has included more patients and more extensive thyroid function testing. It was considered important to study a prospective control group of psychiatric patients at the same time. Although 30 schizophrenic patients were initially studied as the control group, only five were available for longterm study because of poor compliance or non-attendance at the clinic. A surprising finding in this study was the high prevalence (43%) of significant titres of thyroid antibodies in the psychiatric patients before starting lithium therapy. In the normal population thyroid antibody prevalence ranges from 5 to approximately 15% (Tunbridge et al. 1977) and in psychiatric patients not on lithium a figure of 7.5% has been found in one study (Deniker et al. 1978). The significance of the high antibody titres in relation to the pathogenesis or treatment of manic depressive disorder is not clear although one study cites a high prevalence of thyroid disease in so-called ‘rapid cyclers’ (Cowdry et al. 1983). It should be noted that the frequency of HLA B8, DR3 and DR4 antigens (i.e. those predisposing to thyroid disease) was not significantly increased. While we have not shown any significant ability of lithium to induce antibody formation, we believe we have demonstrated an immunomodulatory effect of the drug on circulating thyroid antibodies in patients possessing these antibodies at the start of treatment. At the same time we admit we are unable to exclude the possibility that fluctuation in antibody titre might be due to the manic depressive disorder itself as we were not able to study a control group of such patients receiving other drugs. However, we suggest that
159 the changes in antibody titres in the lithium group are much greater than those seen in patients with Hashimoto’s thyroiditis studied over many years (Papapetrou et al. 1972; Hayashi et al. 1985) and cannot be explained as merely the natural progression of thyroiditis. It is conceivable that the patients with antibodies were at different stages of the progression of autoimmune thyroiditis when lithium was started. This may explain why the antibody titres increased in some (Figs. 2 and 3) and declined in others (Fig. 5) in a similar way to that observed in a rat model of thyroiditis treated with lithium (Hassman et al. 1985). The mechanisms of the immunomodulatory effects of lithium have been examined in vivo and in vitro and there is evidence of increased immunoglobulin production by lymphocytes of lithium-treated patients (Weetman et al. 1982). Lithium also alters the ionic milieu of the lymphocyte and, at least in vitro, can thus affect its function (Hart 1981). The question arises as to whether the increases in thyroid antibody titres in some of these patients predict that worsening thyroiditis and hypothyroidism will ensue. The low incidence of hypothyroidism in this and other studies suggests that the appropriate immune background is necessary, a view supported by experiments in chickens (Sundick et al. 1974, 1979). We attempted to partially characterise the immune background of our patients by HLA typing but there was no evidence of a predisposition to the effect of lithium on thyroid antibodies. The small numbers available for HLA analysis make interpretation of these data only tentative. The abnormal TRH tests in lithium-treated patients have been noted previously both in those with thyroid antibodies and those without; the pathophysiology of the thyroid hormone and TSH changes has been discussed previously (Lazarus et al. 1981). This study has shown changes in man consistent with an immunomodulatory effect of lithium that has been previously shown in animals. Patients receiving lithium therapy should have thyroid antibody measurements performed before and during treatment in addition to routine thyroid function tests.
Acknowledgements We are grateful to Dr. W. Waheed, St. Cadoc’s Hospital, Caerleon for permission to study her patients and to the nursing staff at the Lithium Clinic for their help. We thank Dr. E.P. Worrall, Glasgow, Dr. A.M. Langley, Chichester, Dr. D.G. Goodhead, Doncaster and Dr. D.M. Shaw, Cardiff for referring patients. We are grateful to Dr. J.A.F. Napier of the Welsh Regional Transfusion Centre for the tissue typing and to the Department of Medical Biochemistry, University Hospital of Wales for the thyroid hormone measurements. The study was supported by Delandale U.K. Ltd. References Albrecht, J. and Hopf, U., Humoral autoimmune phenomena under long-term treatment with lithium with special regard to thyroidal autoantibodies, Klin. Wochenschr., 60 (1982) 1501-1504. Baastmp, P.C., Lithium in the prophylactic treatment of recurrent affective disorders. In: F.N. Johnson (Ed.), Handbook of Lithium Therapy, MTP Press, Lancaster, 1980, pp. 26-38. Calabrese, J.R., Gulledge, D.A., Hahn, K., Skwerer, R., Katz, M., Schumacher, O.P., Gupta, M.K., Krupp, N. and Gold, P.W., Autoimmune thyroiditis in manic-depressive patients treated with lithium, Am. J. Psychiatry, 142(11) (1985) 1318-1321. Cowdry, R.W., Wehr, T.A., Zis, A.P. and Goodwin, F.K., Thyroid abnormalities associated with rapid-cycling bipolar illness, Arch. Gen. Psychiatry, 40 (1983) 414-420. Deniker, P., Eyquem, A., Bemheim, R., Loo, H. and Delarue, P., Thyroid autoantibody levels during lithium therapy, Neuropsychobiology, 4 (1978) 270-275. Ellyin, F.M., Kumar, Y., Shamsabad, F., Singh, S.P., Gilden, J.L. and Snyder, A.K., Lithium therapy and thyroid autoantibodies. In: The Endocrine Society 67th Annual Meeting, Baltimore, MD, 1985, Abstract 1368. Emersen, C.H., Dyson, W.L. and Utiger, R., Serum thyrotropin and thyroxine concentrations in patients receiving lithium carbonate, J. Clin. Endocrinol. Metab., 36 (1973) 338-346. Hart, D.A., Ability of monovalent cations to replace potassium during stimulation of lymphoid cells, Cell. Immunol., 57 (1981) 209-218. Hassman, R.A., Lazarus, J.H., Dieguez, C., Weetman, A.P., Hall, R. and McGregor, A.M., The influence of lithium chloride on experimental autoimmune thyroid disease, Clin. Exp. Immunol., 61 (1985) 49-57. Hayashi, Y., Tamai, H., Fukata, S., Hirota. Y., Katayama, S., Kuma, K., Kumagai, F. and Nagataki, S., A long term clinical, immunological, and histological follow-up study of patients with goitrous chronic lymphocytic thyroiditis, J. Clin. Endocrinol. Metab., 61 (1985) 1172-1178.
160 Lazarus, J.H., Endocrine and metabolic effects of lithium, Adv. Drug React. AC. Pois. Rev., 1 (1982) 181-200. Lazarus, J.H., Effect of lithium on the thyroid gland. In: Endocrine and Metabolic Effects of Lithium, Plenum Press, New York, 1986, pp. 99-117. Lazarus, J.H., John, R., Benme, E.H., Chalmers, R.J. and Crockett, G., Lithium therapy and thyroid function; a long-term study, Psychol. Med. (London), 11 (1981) 85-92. Lindstedt, G., Nilsson, L.-A., Walinder, J., Skott, A. and Ohman, R., On the prevalence, diagnosis and management of lithium-induced hypothyroidism in psychiatric patients, Br. J. Psychiatry, 130 (1977) 452-458. Papapetrou, P.D., Lazarus, J.H., MacSween, R.N.M. and Harden, R.McG., Long-term treatment of Hashimoto’s thyroiditis with thyroxine, Lancet, ii (1972) 1045-1048. Schou, M. and Thomsen, K., Lithium prophylaxis of recurrent endogenous affective disorders. In: F.N. Johnson (Ed.), Lithium Research and Therapy, Academic Press, New York, 1975, pp. 63-69. Sundick, R.S. and Wick, G., Increased 13iI uptake by the thyroid glands of obese strain (OS) chickens derived from non-protamone-supplemented hens, Clin. Exp. Immunol., 18 (1974) 127-139. Sundick, R.S., Bag&i, N., Livezey, M.D., Brown, T.R. and Mack, R.E., Abnormal thyroid regulation in chickens with
autoimmune thyroiditis, Endocrinology, 105 (1979) 493499. Tunbridge, W.M.G., Evered, D.C., Hall, R., Appleton, D., Brewis, M., Clark, F., Grimley Evans, J., Young, E.. Bird, T. and Smith, P.A., The spectrum of thyroid disease in a community: the Wickham survey, Clin. Endocrinol., 7 (1977) 481-493. Von Wasilewski, B., Steinbock, R., Kohl, R., Greil, W. and Bottermann, P., Schilddrtisenfunktion bei der Lithiumprophylaxe, Arzneim.-Forsch., 28(2) (1978) 1297-1298. Walfish, P.G. and Farid, N.R., The immunogenetic basis of autoimmune thyroid disease. In: P.G. Walfish, J.R. Wall and R. Volpe (Eds.), Autoimmunity and the Thyroid, Academic Press, New York, 1985, pp. 9-36. Weetman, A.P. and McGregor, A.M., Autoimmune thyroid disease: developments in our understanding, Endocr. Rev., 5 (1984) 309-355. Weetman, A.P., McGregor, A.M., Lazarus, J.H., Rees-Smith, B. and Hall, R., The enhancement of immunoglobulin synthesis by human lymphocytes with lithium, Clin. Immunol. Immunopathol., 22 (1982) 400-407. Weetman, A.P., Rennie, D.P., Hassman, R., Hall, R. and McGregor, A.M., Enzyme-linked immunoassay of monoclonal and serum microsomal antibodies, Clin. Chim. Acta, 138 (1984) 237-244.