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Thyroid echogenicity in manic-depressive patients receiving lithium therapy
Journal of Affective Disorders 70 (2002) 85–90 www.elsevier.com / locate / jad
Brief report
Thyroid echogenicity in manic-depressive patients receiving lithium therapy a, b Uwe Schiemann *, Karin Hengst a
¨ Munchen ¨ ¨ , Pettenkoferstr. 8 a, 80336 Munchen , Medizinische Poliklinik, Klinikum Innenstadt der Ludwig-Maximilians-Universitat Germany b ¨ ¨ Munster ¨ ¨ , 48129 Munster , Germany Medizinische Klinik B der Westf alischen Wilhelms-Universitat Received 22 May 2000; received in revised form 4 October 2000; accepted 10 October 2000
Abstract Background: Lithium is known to induce subclinical or overt hypothyroidism and changes of thyroid volume in manic-depressive patients. Little is known about alterations of thyroid echogenicity due to drug-induced dysfunction. Methods: Twenty manic-depressive patients receiving lithium therapy for at least 6 months and 20 euthyroid volunteers without any antidepressive medication as control group, matched in age and gender, were investigated by laboratory measurements and thyroid ultrasonography including standardized grey scale analyses in representative regions of interest (ROI). Results: Thyroid function was normal in all patients (mean FT4 1.160.2 ng / dl, mean TSH 1.660.9 m U / ml) and controls (mean FT4 1.560.4 ng / dl, TSH 1.160.3 m U / ml). Except for two patients, no thyroid autoantibody levels could been detected. Thyroid volumetry revealed significant higher mean values for the lithium treated patients (16.9611.9 ml) compared with the controls (11.464.5 ml, P , 0.05) with a considerable number of goiters (six patients vs. one control). Thyroid echogenicities in both groups were similar (patients 23.963.7 grey scales, Grauwerteinheiten 5 GWE, controls 24.261.3 GWE) and did not depend on the size of the organs. Conclusion: Lithium treatment contributes to increased thyroid volumes, probably due to inhibition of thyroid function and TSH upregulation, but not to changes of thyroid echo levels in patients with still euthyroid function. Further echogenicity studies on patients with lithium-induced overt hypothyroidism and autoimmune activity will be of special interest. 2002 Elsevier Science B.V. All rights reserved. Keywords: Lithium; Hypothyroidism; Thyroid volume; Manic-depression; Drug-induced dysfunction
1. Introduction Lithium is an effective drug in the treatment of *Corresponding author. Tel.: 1 49-89-5160-3549; fax: 1 4989-5160-4485. E-mail address: [email protected] (U. Schiemann).
manic-depressive disorders (Schou and Thomsen, 1975). One of its side effects is the inhibition of thyroid function with prevalence of overt hypothyroidism in 3–5% (Berens et al., 1970; Albrecht and Hopf, 1982) and subclinical hypothyroidism in up to 21% of patients (Perrild et al., 1990). Lithium reduces the release of thyroid hormones (Rogers and Whybrow, 1971; Spaulding et al., 1972; Lindstedt et
0165-0327 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00374-8
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U. Schiemann, K. Hengst / Journal of Affective Disorders 70 (2002) 85 – 90
al., 1977; Bagchi et al., 1978) and upregulates basal and TRH stimulated TSH (McLarty et al., 1975; Emerson et al., 1973; Wasilewski et al., 1978; Lee et al., 1992; Lombardi et al., 1993). Additionally several authors detected thyroglobulin (Tab)- and peroxidase (TPO) antibodies in patients treated with lithium (Lindstedt et al., 1977; Wasilewski et al., 1978; Lazarus et al., 1981, 1986; Smigan et al., 1984; Calabrese et al., 1985; Leroy et al., 1988; Bocchetta et al., 1991). The prevalence of thyroid antibodies differed between 7.8% (Smigan et al., 1984) and 48.7% (Lazarus et al., 1986). It is supposed that lithium induces exacerbation of predisposed autoimmune Hashimoto’s thyroiditis (Bonnyns et al., 1979; Calabrese et al., 1985) by immunomodulation (Shenkman et al., 1981; Myers et al., 1985). This theory implies changes of thyroid morphology with development of hypoechogenic tissue patterns (Espinasse et al., 1980; Hayashi et al., 1986; Gutenknust et al., 1989; Marcocci et al., 1991). Ultrasonographical investigations of patients receiving lithium therapy revealed tendency to develop goiter (Schou et al., 1968; Wasilewski et al., 1978; Perrild et al., 1990; Bocchetta et al., 1996; Loviselli et al., 1997), but till now no changes of thyroid echogenicity have been described in the literature. Recently we established standardized conditions for thyroid grey scale ultrasonography and characterized echogenicity levels in Graves’ disease with association to autoimmune activity (Schiemann et al., 1999). At present, no evaluated data exist about lithiuminduced thyroid dysfunction in correlation to the appearance of hypoechogenic tissue patterns. We have, therefore, examined 20 manic-depressive patients receiving lithium therapy for at least 6 months and 20 euthyroid volunteers as control group in a retrospective study to determine thyroid echo levels by standardized grey scale ultrasonography.
2. Methods
2.1. Patients Twenty manic-depressive patients (12 females, eight males), age range 23–72 years, mean age
44.5614.2 years were investigated and compared to 20 euthyroid volunteers (12 females, eight males), age range 24–69 years, mean age 44.1613.8 years. The patients underwent medical treatment with lithium carbonate for at least 6 months in therapeutical dosages to reach serum levels between 0.3 and 1.3 mmol / l. Other drugs like benzodiazepines or tricyclic antidepressives were not given. Euthyroid control persons did not receive any antidepressive medication.
2.2. Laboratory measurements Thyroid function was evaluated by measurement of FT4 (normal range 0.7–1.65 ng / dl) and TSH (normal range 0.35–4 m U / ml) values, determined radioimmunologically using commercially available kits (Chiron Chemiluminescence ACS 180). Thyroglobulin- (normal range , 100 U / ml), TSH receptor- (normal range , 10 U / l) and peroxidase (normal range , 100 U / ml) antibodies were quantified to detect autoimmune phenomena.
2.3. Ultrasound examination Thyroid ultrasonography was carried out using an ultrasound scanner (Picker CS 192, Espelkamp, Germany) with a 7.5-MHz linear real-time transducer. Patients were examined in supine position, with the neck in hyperextension. The transducer was placed on the skin, longitudinal and transverse scans of the thyroid lobes were made. Volumetry was performed according to Brunn et al. (1981). Patients with focal thyroid lesions like cysts or nodules were excluded from the study. Measurement of thyroid echogenicity was carried out by grey scale histogram analysis under standardized conditions as we described previously (Schiemann et al., 1999). After adjustment of ultrasound power level, brightness gain, depth range, frame rate, dynamic range, enhancement level and scan correlation a histogram of up to 63 grey scales (Grau-Wert-Einheiten 5 GWE) within a specified region of interest (ROI) on a B-mode image was displayed. Photographs were recorded on Polaroid demonstrating the circumference (C), area (A), total number of grey scales (N), mean density (MD), standard deviation (S.D.), density with highest fre-
U. Schiemann, K. Hengst / Journal of Affective Disorders 70 (2002) 85 – 90
quency of occurrence (%Mode) and its frequency (%). The mean tissue density (MD) was taken as relevant parameter for echogenicity determination.
2.4. Statistics Statistical evaluation was carried out employing Student’s t-test. The level of significance was taken as P , 0.05.
87
and controls were in normal ranges (females , 18 ml, males , 25 ml), but the values in the patient group (16.9611.9 ml) were significantly higher as in the control group (11.464.5 ml, P , 0.05). Among the patients, six individuals had developed goiter, one patient with an extremely high volume of 55 ml, compared to only one goiter in the control group (Table 1).
3.3. Grey scale ultrasonography 3. Results
3.1. Laboratory findings Thyroid function was normal in all manic depressive patients with a mean FT4 value of 1.160.2 ng / dl and a mean TSH level of 1.660.9 m U / ml as well as in all controls with a mean FT4 value of 1.560.4 ng / dl and a mean TSH level of 1.160.3 m U / ml (Table 1). Except for one lithium-treated patient with a slightly elevated thyroglobulin antibody level of 120 U / l and another patient with slightly elevated peroxidase antibody level of 154 U / l, no considerable autoantibody levels could been detected. Mean values are given in Table 1.
3.2. Thyroid volumetry Mean thyroid volumes of lithium-treated patients Table 1 Gender, age, mean values of laboratory parameters and ultrasonographical measurements in manic-depressive patients and euthyroid controls Manic depressive patients (n 5 20) Female / male Age (years) FT4 (ng / dl) TSH (U / ml) Thyroglobulin Ab (m U / ml) TSH receptor Ab (U / l) Peroxidase Ab (U / ml) Thyroid volume (ml) Goiter (n) Focal lesions Thyroid echogenicity (grey scales 5 GWE)
Controls (n 5 20)
12 / 8 44.5614.2 1.160.2 1.660.9 , 100 , 10 , 100 16.9611.9 6 No
12 / 8 44.1613.8 1.560.4 1.160.3 , 100 , 10 , 100 11.464.5 1 No
23.963.7
24.261.3
Manic-depressive patients receiving lithium therapy revealed similar thyroid echo levels (23.963.7 GWE) as compared to the controls (24.261.3 GWE) without significant difference (Table 1, Figs. 1 and 2). Echogenicity did not depend on the size of thyroid glands. Goiters showed similar thyroid echo levels (23.862.6 GWE, n 5 6) as thyroid glands with normal size (24.062.2 GWE, n 5 14).
4. Discussion Beside its therapeutic effects in the treatment of manic depression lithium may lead to overt or subclinical hypothyroidism, probably due to induction of autoimmune thyroiditis with increased levels of thyroid autoantibodies (Lindstedt et al., 1977; Deniker et al., 1978; Wasilewski et al., 1978; Lazarus et al., 1981, 1986; Albrecht and Hopf, 1982; Smigan et al., 1984; Calabrese et al., 1985; Leroy et al., 1988; Bocchetta et al., 1991; Lee et al., 1992). It is controversially discussed if dosage and duration of lithium therapy influences levels of autoantibodies. Bocchetta et al. (1991) described a positive correlation, whereas others did not (Albrecht and Hopf, 1982; Lazarus et al., 1986; Valle et al., 1999). Lazarus et al. (1986) and Loviselli et al. (1997) showed that increased levels of thyroid antibodies can be detected in patients who already revealed positive autoimmune phenomena before medical treatment, whereas de novo synthesis due to lithium is rare. Additionally, the prevalence of thyroid autoantibody in the normal population and in patients with non-affective psychiatric disorders is as high as in lithium-treated manic-depressive patients with ranges from 5 to 15% (Tunbridge et al., 1977;
88
U. Schiemann, K. Hengst / Journal of Affective Disorders 70 (2002) 85 – 90
Fig. 1. Transverse scan of the thyroid gland of a lithium-treated manic-depressive patient. Grey scales (GWE) were measured in the region of interest (ROI) in both thyroid lobes. The considerable thyroid echo levels are indicated as mean densities (MD) with 22.4 grey scales (Grauwerteinheiten 5 GWE) in the right and 22.7 GWE in the left thyroid lobe.
Haggerty et al., 1990). These data suggest a modulative effect of lithium on autoimmune predispostion with exacerbation of Hashimoto’s thyroiditis which was already proved in an animal model (Hassman et al., 1985). Recent evidence indicates that lithium is able to inhibit the function of the T suppressor cells, whose role it is to prevent uncontrolled formation of antibodies against self-antigens (Shenkman et al., 1981). This influence on cellular activity may contribute to autoimmune mechanisms in the thyroid gland with lymphocytic cell infiltration. Under this conditions the microfollicular texture of the organ could change to diffuse hypoechogenic tissue patterns as described for patients with Graves’ disease (Becker et al., 1989; Schiemann et al., 1999) and Hashimoto’s thyroiditis (Espinasse et al., 1980;
Hayashi et al., 1985, 1986; Gutenknust et al., 1989; Marcocci et al., 1991). Our data indicate in agreement with others (Schou et al., 1968; Wasilewski et al., 1978; Perrild et al., 1990; Bocchetta et al., 1996; Loviselli et al., 1997) that patients receiving lithium therapy show higher thyroid volumes as the normal population. This could be due to inhibition of hormone release with compensatory TSH upregulation. Of course, TSH levels in our patients were not significantly higher as compared to the levels in the control group, but their slight elevation seems to be effective enough to explain the difference of thyroid volumes in both groups. In longitudinal investigations it has been shown that thyroid echography is a sensitive tool in the identification of patients at risk of developing hypo-
U. Schiemann, K. Hengst / Journal of Affective Disorders 70 (2002) 85 – 90
89
Fig. 2. Transverse scan of the thyroid gland of an euthyroid control person. Grey scales (24.8 and 24.7 GWE) are only slightly higher than in the lithium-treated patient shown in Fig. 1.
thyroidism during lithium therapy (Loviselli et al., 1997). If drug-induced subclinical or overt hypothyroidism in these patients is associated with significantly hypoechogenic thyroid tissue patterns has to be investigated in further studies, including standardized grey scale analyses before and after lithium therapy.
References Albrecht, J., Hopf, U., 1982. Humoral autoimmune phenomena under long-term treatment with lithium with special regard to thyroidal autoantibodies. Klin. Wochenschr. 60, 1501–1504. Bagchi, N., Brown, T.R., Mach, R.E., 1978. Studies on the mechanism of inhibition of thyroid function by lithium. Biochim. Biophys. Acta 542, 163–169. ¨ Becker, W., Frank, R., Borner, W., 1989. Bedeutung einer quan-
titativen Grauwertanalyse des Sonogramms bei ‘diffusen’Er¨ Fortschr. Rontgenstr. ¨ krankungen der Schilddruse. 150, 66–71. Berens, S.C., Bernstein, R.S., Robbins, J. et al., 1970. Antithyroid effects of lithium. J. Clin. Invest. 49, 1357–1367. Bocchetta, A., Bernardi, F., Pedditzi, M., Loviseti, A., Velluzzi, F., Martino, E., del Zompo, M., 1991. Thyroid abnormalities during lithium treatment. Acta Psychiatr. Scand. 83, 193–198. Bocchetta, A., Cherchi, A., Loviselli, A., Mossa, P., Velluzzi, F., Derai, R., Del Zompo, M., 1996. Six-year follow-up of thyroid function during lithium treatment. Acta Psychiatr. Scand. 94 (1), 45–48. Bonnyns, M., Glineor, D., Ermans, A.M., 1979. Secondary effects of lithium on thyroid function, mechanisms, diagnostic and treatment. Acta Psychiatr. Belg. 79 (5), 570–577. Brunn, I., Block, U., Ruf, G., Bos, I., Kunze, W.P., Scriba, P.C., ¨ 1981. Volumetrie der Schilddrusenlappen mittels Real-TimeSonographie. Dtsch. Med. Wschrft. 106, 1338–1340. Calabrese, J.R., Gulledge, A.D., Hahn, K., Skwerer, R., Kotz, M., Schuhmacher, O.P., Gupta, M.K., Krupp, N., Gold, P.W., 1985. Autoimmune thyroiditis in manic-depressive patients treated with lithium. Am. J. Psychiatry 142, 1318–1321. Deniker, P., Eyquem, A., Bernheim, R., Loo, H., Delarue, P.,
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1978. Thyroid autoantibody levels during lithium therapy. Neuropsychology 4, 270–275. Emerson, C.H., Dyson, W.L., Utiger, R.D., 1973. Serum thyrotropin and thyroxin concentrations in patients receiving lithium carbonate. J. Clin. Endocrinol. Metab. 36, 338–346. Espinasse, P., Espinasse, D., Estour, B., Navarro, D., 1980. Echography in thyroiditis. Ultrasonics 1, 345–352. Gutenknust, R., Hafermann, W., Mansky, T., Scriba, P.C., 1989. Ultrasonography related to clinical and laboratory findings in lymphocytic thyroiditis. Acta Endocrinol. 121, 129–135. Haggerty, J.J., Evans, D.L., Golden, R.N., Pedersen, C.A., Simon, J.S., Nemeroff, C.B., 1990. The presence of antithyroid antibodies in patients with affective and nonaffective psychiatric disorders. Biol. Psychiatry 27, 51–60. Hassman, R.A., Lazarus, J.H., Dieguez, C., Weetman, A.P., Hall, R., McGregor, A.M., 1985. The influence of lithium chloride on experimental autoimmune thyroid disease. Clin. Exp. Immunol. 61, 49–57. Hayashi, Y., Tamai, H., Fukata, S., Hirota, Y., Katayama, S., Kuma, K., Kumagai, F., Nagataki, S., 1985. A long term clinical, immunological, and histological follow-up study of patients with goitrous chronic lymphocytic thyroiditis. J. Clin. Endocrinol. Metab. 61, 1172–1178. Hayashi, N., Tamaki, N., Konishi, J., Yonekura, Y., Senda, M., Kasagi, K., Yamamoto, K., Iida, Y., Misaki, T., Endo, K., Torizuka, K., Mori, T., 1986. Sonography of Hashimoto’s thyroiditis. J. Clin. Ultrasound 14, 123–126. Lazarus, J.H., John, R., Bennie, E.H., 1981. Lithium therapy and thyroid function: a long-term study. Psychol. Med. 11, 85–92. Lazarus, J.H., McGregor, A.M., Ludgate, M., Darke, C., Creagh, F.M., Kingswood, C.J., 1986. Effect of lithium carbonate therapy on thyroid immune status in manic depressive patients: A prospective study. J. Affect. Disord. 11, 155–160. Lee, S., Chow, C.C., Wing, Y.K., Shek, C.C., 1992. Thyroid abnormalities during chronic lithium treatment in Hong Kong Chinese: a controlled study. J. Affect. Disord. 26 (3), 173–178. Leroy, M.C., Villeneuve, A., Lajeunesse, C., 1988. Lithium, thyroid function and antithyroid antibodies. Prog. Neuropsychopharmacol. Biol. Psychiatry 12 (4), 483–490. ¨ Lindstedt, G., Milsson, L.A., Walinder, J., Skott, A., Ohman, R., 1977. On the prevalence, diagnosis and management of lithium-induced hypothyroidism in psychiatric patients. Br. J. Psychiatry 130, 452–458. Lombardi, G., Panza, N., Biondi, B., Di Lorenzo, L., Lupoli, G., Muscettola, G., Carella, C., Bellastella, A., 1993. Effects of lithium treatment on hypothalamic–pituitary–thyroid axis: a longitudinal study. J. Endocrinol. Invest. 16 (4), 259–263. Loviselli, A., Bocchetta, A., Mossa, P., Velluzzi, F., Bernardi, F., del Zompo, M., Mariotti, S., 1997. Value of thyroid echography in the long-term follow-up of lithium-treated patients. Neuropsychobiology 36 (1), 37–41.
Marcocci, C., Vitti, P., Cetani, F., Catalano, F., Concetti, R., Pinchera, A., 1991. Thyroid ultrasonography helps to identify patients with diffuse lymphocytic thyroiditis who are prone to develop hypothyroidism. J. Clin. Endocrinol. Metab. 72, 209– 213. McLarty, D.G., O’Boyle, J.H., Spencer, C.A., Ratcliffe, J.G., 1975. Effect of lithium on hypothalamic–pituitary–thyroid function in patients with affective disorders. Br. Med. J. 13 (3), 623–626. Myers, D.H., Carter, R.A., Burns, B.H., Armond, A., Hussain, S.B., Chengapa, V.K., 1985. A prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies. Psychol. Med. 15, 55–61. Perrild, H., Hegedus, L., Baastrup, P.C., Kayser, L., Kastberg, S., 1990. Thyroid function and ultrasonically determined thyroid size in patients receiving long-term lithium treatment. Am. J. Psychiatry 147 (11), 1518–1521. Rogers, M.P., Whybrow, P.C., 1971. Clinical hypothyroidism occurring during lithium treatment: two case histories and a review of thyroid function in 19 patients. Am. J. Psychiatry 128, 158–163. Schou, M., Amdisen, A., Jensen, S.E. et al., 1968. Occurrence of goitre during lithium treatment. Br. Med. J. 3, 710–713. Schou, M., Thomsen, K., 1975. Lithium prophylaxis of recurrent endogenous affective disorders. In: Johnson, F.N. (Ed.), Lithium Research and Therapy. Academic Press, New York, pp. 63–69. Schiemann, U., Gellner, R., Riemann, B., Schierbaum, G., Menzel, J., Domschke, W., Hengst, K., 1999. Standardized grey scale ultrasonography in Graves’ disease: correlation to autoimmune activity. Eur. J. Endocrinol. 141, 332–336. Shenkman, L., Wadler, S., Borkowsky, W. et al., 1981. Adjuvant effects of lithium chloride on human mononuclear cells in suppressor enriched and suppressor depleted systems. Immunopharmacology 3, 1–3. Smigan, L., Wahlin, A., Jacobsson, L., von Knorring, L., 1984. Lithium therapy and thyroid function test. A prospective study. Neuropsychobiology 11, 39–43. Spaulding, S.W., Burrow, G.N., Bermudez, F., Himmelhoch, J.M., 1972. The inhibitory effect of lithium on thyroid hormone release in both euthyroid and thyrotoxic patients. J. Clin. Endocrinol. Metab. 35, 905–911. Tunbridge, W.M.G., Evered, D.C., Hall, R., 1977. The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. 7, 481–492. Valle, J., Ayuso-Gutierrez, J.L., Abril, A., Ayuso-Mateos, J.L., 1999. Evaluation of thyroid function in lithium-naive bipolar patients. Eur. Psychiatry 14 (6), 341–345. Wasilewski, B., Steinbock, R., Kohl, R., Greil, W., Bottermann, P., ¨ 1978. Schilddrusenfunktion bei der Lithiumprophylaxe. Arzneim.-Forsch. 28 (2), 1297–1298.
Brief report
Thyroid echogenicity in manic-depressive patients receiving lithium therapy a, b Uwe Schiemann *, Karin Hengst a
¨ Munchen ¨ ¨ , Pettenkoferstr. 8 a, 80336 Munchen , Medizinische Poliklinik, Klinikum Innenstadt der Ludwig-Maximilians-Universitat Germany b ¨ ¨ Munster ¨ ¨ , 48129 Munster , Germany Medizinische Klinik B der Westf alischen Wilhelms-Universitat Received 22 May 2000; received in revised form 4 October 2000; accepted 10 October 2000
Abstract Background: Lithium is known to induce subclinical or overt hypothyroidism and changes of thyroid volume in manic-depressive patients. Little is known about alterations of thyroid echogenicity due to drug-induced dysfunction. Methods: Twenty manic-depressive patients receiving lithium therapy for at least 6 months and 20 euthyroid volunteers without any antidepressive medication as control group, matched in age and gender, were investigated by laboratory measurements and thyroid ultrasonography including standardized grey scale analyses in representative regions of interest (ROI). Results: Thyroid function was normal in all patients (mean FT4 1.160.2 ng / dl, mean TSH 1.660.9 m U / ml) and controls (mean FT4 1.560.4 ng / dl, TSH 1.160.3 m U / ml). Except for two patients, no thyroid autoantibody levels could been detected. Thyroid volumetry revealed significant higher mean values for the lithium treated patients (16.9611.9 ml) compared with the controls (11.464.5 ml, P , 0.05) with a considerable number of goiters (six patients vs. one control). Thyroid echogenicities in both groups were similar (patients 23.963.7 grey scales, Grauwerteinheiten 5 GWE, controls 24.261.3 GWE) and did not depend on the size of the organs. Conclusion: Lithium treatment contributes to increased thyroid volumes, probably due to inhibition of thyroid function and TSH upregulation, but not to changes of thyroid echo levels in patients with still euthyroid function. Further echogenicity studies on patients with lithium-induced overt hypothyroidism and autoimmune activity will be of special interest. 2002 Elsevier Science B.V. All rights reserved. Keywords: Lithium; Hypothyroidism; Thyroid volume; Manic-depression; Drug-induced dysfunction
1. Introduction Lithium is an effective drug in the treatment of *Corresponding author. Tel.: 1 49-89-5160-3549; fax: 1 4989-5160-4485. E-mail address: [email protected] (U. Schiemann).
manic-depressive disorders (Schou and Thomsen, 1975). One of its side effects is the inhibition of thyroid function with prevalence of overt hypothyroidism in 3–5% (Berens et al., 1970; Albrecht and Hopf, 1982) and subclinical hypothyroidism in up to 21% of patients (Perrild et al., 1990). Lithium reduces the release of thyroid hormones (Rogers and Whybrow, 1971; Spaulding et al., 1972; Lindstedt et
0165-0327 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00374-8
86
U. Schiemann, K. Hengst / Journal of Affective Disorders 70 (2002) 85 – 90
al., 1977; Bagchi et al., 1978) and upregulates basal and TRH stimulated TSH (McLarty et al., 1975; Emerson et al., 1973; Wasilewski et al., 1978; Lee et al., 1992; Lombardi et al., 1993). Additionally several authors detected thyroglobulin (Tab)- and peroxidase (TPO) antibodies in patients treated with lithium (Lindstedt et al., 1977; Wasilewski et al., 1978; Lazarus et al., 1981, 1986; Smigan et al., 1984; Calabrese et al., 1985; Leroy et al., 1988; Bocchetta et al., 1991). The prevalence of thyroid antibodies differed between 7.8% (Smigan et al., 1984) and 48.7% (Lazarus et al., 1986). It is supposed that lithium induces exacerbation of predisposed autoimmune Hashimoto’s thyroiditis (Bonnyns et al., 1979; Calabrese et al., 1985) by immunomodulation (Shenkman et al., 1981; Myers et al., 1985). This theory implies changes of thyroid morphology with development of hypoechogenic tissue patterns (Espinasse et al., 1980; Hayashi et al., 1986; Gutenknust et al., 1989; Marcocci et al., 1991). Ultrasonographical investigations of patients receiving lithium therapy revealed tendency to develop goiter (Schou et al., 1968; Wasilewski et al., 1978; Perrild et al., 1990; Bocchetta et al., 1996; Loviselli et al., 1997), but till now no changes of thyroid echogenicity have been described in the literature. Recently we established standardized conditions for thyroid grey scale ultrasonography and characterized echogenicity levels in Graves’ disease with association to autoimmune activity (Schiemann et al., 1999). At present, no evaluated data exist about lithiuminduced thyroid dysfunction in correlation to the appearance of hypoechogenic tissue patterns. We have, therefore, examined 20 manic-depressive patients receiving lithium therapy for at least 6 months and 20 euthyroid volunteers as control group in a retrospective study to determine thyroid echo levels by standardized grey scale ultrasonography.
2. Methods
2.1. Patients Twenty manic-depressive patients (12 females, eight males), age range 23–72 years, mean age
44.5614.2 years were investigated and compared to 20 euthyroid volunteers (12 females, eight males), age range 24–69 years, mean age 44.1613.8 years. The patients underwent medical treatment with lithium carbonate for at least 6 months in therapeutical dosages to reach serum levels between 0.3 and 1.3 mmol / l. Other drugs like benzodiazepines or tricyclic antidepressives were not given. Euthyroid control persons did not receive any antidepressive medication.
2.2. Laboratory measurements Thyroid function was evaluated by measurement of FT4 (normal range 0.7–1.65 ng / dl) and TSH (normal range 0.35–4 m U / ml) values, determined radioimmunologically using commercially available kits (Chiron Chemiluminescence ACS 180). Thyroglobulin- (normal range , 100 U / ml), TSH receptor- (normal range , 10 U / l) and peroxidase (normal range , 100 U / ml) antibodies were quantified to detect autoimmune phenomena.
2.3. Ultrasound examination Thyroid ultrasonography was carried out using an ultrasound scanner (Picker CS 192, Espelkamp, Germany) with a 7.5-MHz linear real-time transducer. Patients were examined in supine position, with the neck in hyperextension. The transducer was placed on the skin, longitudinal and transverse scans of the thyroid lobes were made. Volumetry was performed according to Brunn et al. (1981). Patients with focal thyroid lesions like cysts or nodules were excluded from the study. Measurement of thyroid echogenicity was carried out by grey scale histogram analysis under standardized conditions as we described previously (Schiemann et al., 1999). After adjustment of ultrasound power level, brightness gain, depth range, frame rate, dynamic range, enhancement level and scan correlation a histogram of up to 63 grey scales (Grau-Wert-Einheiten 5 GWE) within a specified region of interest (ROI) on a B-mode image was displayed. Photographs were recorded on Polaroid demonstrating the circumference (C), area (A), total number of grey scales (N), mean density (MD), standard deviation (S.D.), density with highest fre-
U. Schiemann, K. Hengst / Journal of Affective Disorders 70 (2002) 85 – 90
quency of occurrence (%Mode) and its frequency (%). The mean tissue density (MD) was taken as relevant parameter for echogenicity determination.
2.4. Statistics Statistical evaluation was carried out employing Student’s t-test. The level of significance was taken as P , 0.05.
87
and controls were in normal ranges (females , 18 ml, males , 25 ml), but the values in the patient group (16.9611.9 ml) were significantly higher as in the control group (11.464.5 ml, P , 0.05). Among the patients, six individuals had developed goiter, one patient with an extremely high volume of 55 ml, compared to only one goiter in the control group (Table 1).
3.3. Grey scale ultrasonography 3. Results
3.1. Laboratory findings Thyroid function was normal in all manic depressive patients with a mean FT4 value of 1.160.2 ng / dl and a mean TSH level of 1.660.9 m U / ml as well as in all controls with a mean FT4 value of 1.560.4 ng / dl and a mean TSH level of 1.160.3 m U / ml (Table 1). Except for one lithium-treated patient with a slightly elevated thyroglobulin antibody level of 120 U / l and another patient with slightly elevated peroxidase antibody level of 154 U / l, no considerable autoantibody levels could been detected. Mean values are given in Table 1.
3.2. Thyroid volumetry Mean thyroid volumes of lithium-treated patients Table 1 Gender, age, mean values of laboratory parameters and ultrasonographical measurements in manic-depressive patients and euthyroid controls Manic depressive patients (n 5 20) Female / male Age (years) FT4 (ng / dl) TSH (U / ml) Thyroglobulin Ab (m U / ml) TSH receptor Ab (U / l) Peroxidase Ab (U / ml) Thyroid volume (ml) Goiter (n) Focal lesions Thyroid echogenicity (grey scales 5 GWE)
Controls (n 5 20)
12 / 8 44.5614.2 1.160.2 1.660.9 , 100 , 10 , 100 16.9611.9 6 No
12 / 8 44.1613.8 1.560.4 1.160.3 , 100 , 10 , 100 11.464.5 1 No
23.963.7
24.261.3
Manic-depressive patients receiving lithium therapy revealed similar thyroid echo levels (23.963.7 GWE) as compared to the controls (24.261.3 GWE) without significant difference (Table 1, Figs. 1 and 2). Echogenicity did not depend on the size of thyroid glands. Goiters showed similar thyroid echo levels (23.862.6 GWE, n 5 6) as thyroid glands with normal size (24.062.2 GWE, n 5 14).
4. Discussion Beside its therapeutic effects in the treatment of manic depression lithium may lead to overt or subclinical hypothyroidism, probably due to induction of autoimmune thyroiditis with increased levels of thyroid autoantibodies (Lindstedt et al., 1977; Deniker et al., 1978; Wasilewski et al., 1978; Lazarus et al., 1981, 1986; Albrecht and Hopf, 1982; Smigan et al., 1984; Calabrese et al., 1985; Leroy et al., 1988; Bocchetta et al., 1991; Lee et al., 1992). It is controversially discussed if dosage and duration of lithium therapy influences levels of autoantibodies. Bocchetta et al. (1991) described a positive correlation, whereas others did not (Albrecht and Hopf, 1982; Lazarus et al., 1986; Valle et al., 1999). Lazarus et al. (1986) and Loviselli et al. (1997) showed that increased levels of thyroid antibodies can be detected in patients who already revealed positive autoimmune phenomena before medical treatment, whereas de novo synthesis due to lithium is rare. Additionally, the prevalence of thyroid autoantibody in the normal population and in patients with non-affective psychiatric disorders is as high as in lithium-treated manic-depressive patients with ranges from 5 to 15% (Tunbridge et al., 1977;
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Fig. 1. Transverse scan of the thyroid gland of a lithium-treated manic-depressive patient. Grey scales (GWE) were measured in the region of interest (ROI) in both thyroid lobes. The considerable thyroid echo levels are indicated as mean densities (MD) with 22.4 grey scales (Grauwerteinheiten 5 GWE) in the right and 22.7 GWE in the left thyroid lobe.
Haggerty et al., 1990). These data suggest a modulative effect of lithium on autoimmune predispostion with exacerbation of Hashimoto’s thyroiditis which was already proved in an animal model (Hassman et al., 1985). Recent evidence indicates that lithium is able to inhibit the function of the T suppressor cells, whose role it is to prevent uncontrolled formation of antibodies against self-antigens (Shenkman et al., 1981). This influence on cellular activity may contribute to autoimmune mechanisms in the thyroid gland with lymphocytic cell infiltration. Under this conditions the microfollicular texture of the organ could change to diffuse hypoechogenic tissue patterns as described for patients with Graves’ disease (Becker et al., 1989; Schiemann et al., 1999) and Hashimoto’s thyroiditis (Espinasse et al., 1980;
Hayashi et al., 1985, 1986; Gutenknust et al., 1989; Marcocci et al., 1991). Our data indicate in agreement with others (Schou et al., 1968; Wasilewski et al., 1978; Perrild et al., 1990; Bocchetta et al., 1996; Loviselli et al., 1997) that patients receiving lithium therapy show higher thyroid volumes as the normal population. This could be due to inhibition of hormone release with compensatory TSH upregulation. Of course, TSH levels in our patients were not significantly higher as compared to the levels in the control group, but their slight elevation seems to be effective enough to explain the difference of thyroid volumes in both groups. In longitudinal investigations it has been shown that thyroid echography is a sensitive tool in the identification of patients at risk of developing hypo-
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Fig. 2. Transverse scan of the thyroid gland of an euthyroid control person. Grey scales (24.8 and 24.7 GWE) are only slightly higher than in the lithium-treated patient shown in Fig. 1.
thyroidism during lithium therapy (Loviselli et al., 1997). If drug-induced subclinical or overt hypothyroidism in these patients is associated with significantly hypoechogenic thyroid tissue patterns has to be investigated in further studies, including standardized grey scale analyses before and after lithium therapy.
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