Suppression of Thyroid Function during Ingestion of Seaweed Kombu (Laminaria japonoca) in Normal Japanese Adults

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1 Endocrine Journal 2008, 55 (6), NOTE Suppression of Thyroid Function during Ingestion of Seaweed Kombu (Laminaria japonoca) in Normal Japanese Adults KIYOSHI MIYAI*, **, TOMOYASU TOKUSHIGE*, MASAHIKO KONDO*** AND IODINE RESEARCH GROUP* *The College of Nutrition, Koshien University **Present position: Professor Emeritus, Osaka University ***Osaka Kessei Research Laboratories Abstract. The effect of ingesting seaweed Kombu (Laminaria japonica) on thyroid function was studied in normal Japanese adults. Ingesting 15 and 30 g of Kombu (iodine contents: 35 and 70 mg) daily for a short term (7 10 days) significantly increased serum thyrotropin (TSH) concentrations, exceeding the normal limits in some subjects. The serum free thyroxine (FT 4 ) and/or free 3,5,3'-triiodothyronine (FT 3 ) concentrations were slightly decreased within the normal limits. During long term daily ingestion of 15 g of Kombu (55 87 days), the TSH levels were elevated and sustained while the FT 4 and FT 3 levels were almost unchanged. Urinary excretion of iodine significantly increased during ingestion of Kombu. These abnormal values returned to the initial levels 7 to 40 days after discontinuing the ingestion of Kombu. Based on these findings that thyroid function was suppressed during ingestion of Kombu, though the effect was reversible, we recommend Japanese people avoid ingesting excessive amounts of seaweed. Key words: Excess iodine, Seaweed ingestion, Hypothyroidism, Kombu (Laminaria japonica), Urinary iodine excretion (Endocrine Journal 55: , 2008) SINCE iodine is an essential element of thyroid hormones, changes in iodine intake may cause various thyroid disorders. It is well known that iodine deficiency induces hypothyroidism, whereas excess iodine may induce not only hyperthyroidism but also hypothyroidism. A number of studies have shown that excess intake of iodide or iodine- containing drugs resulted in hypothyroidism, particularly in subjects living in iodine-sufficient area, neonatal or elderly persons, patients with underlying thyroid disorders such as autoimmune thyroid diseases, subacute thyroiditis, thyroidectomy and so on [1 3]. Since most Japanese people eat iodine-rich foods such as seaweed, Japan is considered as an iodine-sufficient area. Thus, cases of hypothyroidism or goiter due to excess iodine Received: April 21, 2008 Accepted: June 25, 2008 Correspondence to: Kiyoshi MIYAI, M.D., Ph.D., , Mino, Mino-shi, Osaka , Japan Iodine Research Group members (Present family name): Kiyoshi MIYAI, Masako KONDO (OTSUKA), Tomoyasu TOKUSHIGE, Masatoshi TAKAHASHI, Risa WATANABE intake have been reported. Namba et al. [4] demonstrated that administration of iodine-containing tablets to normal Japanese people resulted in a rise in serum thyrotropin (TSH) with a slight decline in serum free thyroxine (FT 4 ) levels and enlarged thyroid volume. However, Takamura et al. [5] reported that iodinecontaining tablet or solution was effective for rapid blockage of thyroid function but iodine-rich food was not effective. Therefore, we designed this study to determine whether ingestion of seaweed affects thyroid function in normal Japanese adults. Subjects and Methods A total of 23 experiments were performed in 13 normal adults (8 male and 5 female healthy volunteers, 27 ± 12 years old) whose serum TSH, FT 4 and free 3,5,3'-triiodothyronine (FT 3 ) concentrations were within normal limits and anti-thyroid antibodies were negative.

2 1104 MIYAI et al. Table 1. Serum TSH, FT 4, FT 3 concentrations and urinary iodide excretion before, during and after discontinuation of Kombu ingestion (A) 15 g Kombu, short term (n = 6) before during (7 10 days) after (7 14 days) TSH (µu/ml) [ ] FT 4 (ng/dl) [ ] FT 3 (pg/ml) [ ] Urinary iodide (iodine mg/day) 2.15 ± ± 0.57 [[4/6]] 2.33 ± 0.47 p<0.05 t,w p<0.05 t,w 1.21 ± ± ± 0.13 ns f 3.17 ± ± ± 0.12 p<0.05 w p<0.05 w p<0.01 f ns w 0.56 ± ± ± 0.33 p<0.001 t p<0.005 t ns t (B) 30 g Kombu, short term (n = 14) TSH (µu/ml) 1.54 ± ± 0.41 [[4/14]] 1.88 ± 0.22 p<0.005 t, 0.01 w p<0.01 w, 0.05 t FT 4 (ng/dl) 1.36 ± ± ± 0.04 p<0.01 t,w p<0.01 w, 0.05 t FT 3 (pg/ml) 3.20 ± ± ± 0.08 p<0.01 w, 0.05 t p<0.01 t,w ns w,t Urinary iodide (iodine mg/day) 1.11± ± ±0.15 p<0.001 t, 0.01 w p<0.001 t, 0.01 w The subjects ingested ordinary Japanese foods without seaweed throughout the experimental period. Then Kombu (Laminaria japonica) was added to the ordinary diet as follows: the daily amounts of 15 g (experiments A and C) or 30 g (experiment B) of Kombu which contain 35 mg or 70 mg of iodine, for 7 10 days for the short-term experiment (A, B) and days for the long-term experiment (C). Kombu as Tororo Kombu (iodine content was 2.3 mg ( mol)/g (dry weight)) was purchased from Oguraya Co. Ltd. Japan. Serum TSH, FT 4 and FT 3 concentrations were measured by chemiluminescence immunoassay [6] using commercial kits of Chemilumi ACS-TSHII R, -T 4 R and T 3 II R (Beyer Co. Ltd.). Anti-thyroid antibodies, anti-thyroglobulin and -microsome antibodies, were determined by the agglutination method (thyroid and microsome tests) [7, 8] using commercial kits of Serodia-ATG R and -AMC R (Fuji Rebio Co. Ltd.). On each urination, part of urine was collected at a constant ratio (1/50 5/50) using Urine-mate R (Sumitomo Bakelite Co. Ltd.). Iodine concentration in urine was determined by the ion electrode method [9] with correction of chloride interference using iodide- and chloride-ion selective electrodes [10]. The differences in data between groups were ana-

3 SEAWEED SUPPRESSED THYROID FUNCTION 1105 Table 1. (continued) (C) 15 g Kombu, long term (n = 3) before during (55 87 days) after (7 40 days) TSH (µu/ml) n 1 : 3.44 ± ± ± 0.38 n 2 : 1.34 ± ± ± 0.20 n 3 : 0.98 ± ± ± 0.21 p<0.001 t (n 1 ), 0.01 t (n 2 ), 0.02 t (n 3 ) p<0.001 t (n 1 ), 0.01 t (n 2 ), 0.05 t (n 3 ) FT 4 (ng/dl) n 1 : 1.10± ± ± 0.75 n 2 : 1.36 ± ± ± 0.16 n 3 : 1.53 ± ± ± 0.04 ns t (n 1, n 3 ), t (n 2 ) FT 3 (pg/ml) n 1 : 2.83± ± ± 0.71 n 2 : 3.14 ± ± ± 0.05 n 3 : 3.47 ± ± ± 0.04 Urinary iodide (iodine mg/day) n 1 : 0.60± ± ± 0.26 n 2 : 0.54 ± ± ± 0.22 n 3 : 0.56 ± ± ± 0.99 p<0.001 t (n 1, n 3 ), t (n 2 ) p<0.001 t (n 1, n 3 ), t (n 2 ) Values are mean ± standard error of mean (SEM). The significance of differences between groups was analyzed by t (t), Wilcoxon (w) and Friedman (f) tests. ns: not significant, n: number of experiments, n 1, n 2, n 3 : subject numbers, [ ]: normal limits, [[ ]]: number of subjects with abnormal values/total number of subjects. lyzed parametrically by the t test and non-parametrically by Wilcoxon and Friedman tests. Results Table 1 summarized changes in serum TSH, FT 4 and FT 3 concentrations and urinary excretion of iodide, before, during and discontinuation of Kombu ingestion (15 g (A, C) or 30 g (B) of Kombu for the short-term (A, B) and long-term (C) experiments). During ingestion of Kombu, serum TSH concentrations increased significantly with peak values over the normal limits in some subjects (4/6 (A), 4/14 (B) and 1/3 (C) subjects) in all experiments. Serum FT 4 (B) and FT 3 (A, B) levels were lowered slightly within normal limits in the short-term experiments and these values were almost unchanged in long-term experiments. Urinary excretion of iodide were elevated to about 30-fold (A, C) and 44-fold (B) the initial levels. These abnormal values returned to the initial levels 7 to 40 days after discontinuation of Kombu ingestion. An example is shown in Fig. 1. Discussion Previous reports demonstrated that thyroid functions were suppressed in normal subjects following administration of drugs containing various amounts of iodine as follows: mg as Na I [11], mg as NaI [12], 12.5 mg as Lugol s solution [13], 27 mg as licorice lecithin-bound iodine [4], mg as KI [14] per day. In the present study, 35 or 70 mg of iodine as 15 or 30 g of seaweed Kombu were administered daily, and the daily excretion of urinary iodine as iodide which is known to be the most valid index of absorbed iodine was estimated to be about 20 or 50 mg (57 71% of the iodine administered as Kombu). The present study demonstrated that daily ingestion

4 1106 MIYAI et al. Fig. 1. The effect of ingesting 15 g of Kombu containing 35 mg of iodine per day over a prolonged period on serum levels of TSH, FT 4 and FT 3 and urinary excretion of iodine in a normal Japanese adult. abnormal values: solid circles, normal limits: vertical shaded column. of Kombu over the short term resulted in a significant increase in serum TSH with a slight decrease in serum FT 4 and/or FT 3 concentrations. During ingestion of Kombu for long term, serum TSH levels were elevated and sustained but FT 4 and FT 3 concentrations were almost within normal limits. FT 4 and FT 3 concentrations were influenced by various factors such as the degrees of inhibitory effect of iodine on thyroid function, increase of TSH by the negative feedback mechanism, responsiveness and compensatory enlargement of thyroid gland to TSH. The inhibitory action of excess iodine (acute Wolff-Chaikoff effect) [15] is known to be temporary (escape from the Wolff- Chaikoff effect [16]). However, the inhibitory effect of Kombu ingestion in the present study persisted for at least 3 months. These findings indicate that thyroid function in normal Japanese adults was suppressed during ingestion of Kombu, although the suppression was slight and reversible. It is well known that Japan is an iodine-rich areas probably because of seaweed ingestion. Urinary iodine excretion by normal Japanese has been reported to be as high as 0.06 to 9.3 mg per day [9, 10, 17 19] compared to 0.03 to 0.7 mg by people from other countries [9]. Furthermore, various cases of hypothyroidism caused by excess iodine ingestion have been reported, such as endemic goiter in Hokkaido where Kombu is routinely eaten with meals [20], and newborn babies with transient hypothyroidism or persistent hyperthyrotropinemia born to mothers who consume excessive iodine [21], a woman with hypothyroidism and anorexia nervosa who took iodine-rich diet [22], a woman with hypothyroidism caused by drinking Ne-Kombu water in which roots of Kombu have been dipped, as a folk remedy for hypertention [23], a boy with growth retardation due to hypothyroidism caused by eating Kombu everyday as a snack [24] etc. Recently, Kasagi et al. [25] reported that one third of cases of consecutive hypothyroidism in Japan became euthyroid after iodine restriction. Thus the Ministry of Health, Labour, and Welfare, Japan recommended an upper intake level of iodine as

5 SEAWEED SUPPRESSED THYROID FUNCTION mg per day [26]. The amount of g of Kombu used in the present study seems to be a lot but it is the amount normally eaten during meal for many Japanese people who favor seaweed. The absorbed iodine (20 50 mg) estimated by urinary excretion significantly exceeded the recommended upper intake level (3 mg). Therefore, we want to warn Japanese people against consuming excessive amounts of seaweed, which are promoted as healthy foods. Acknowledgements We wish to thank Ms. Y. Ito, Ms. K. Kodera, Mr. T. Michishita, Mr. K. Sato, Ms. S. Sugimoto, Mr. I. Tachibana, Mr. F. Tange, Ms. C. Tomono, Mr. A. Yoshimi for their collaboration as healthy volunteers, and Mr. Y. Izumiguchi and Osaka Kessei Research Laboratories for their help for the study. References 1. Roti E, Vagenakis AG (1991) Effect of excess iodide: Clinical aspects. In Braverman LE, Utiger RD (ed) The Thyroid. J.P. Lipincott, Philadelphia: Nagataki S (1974) Effect of quantities of iodide. In Geiger SR, Greer MA, Solomon DH et al. (ed) Handbook of Physiology. Sect 7, Vol. 3, Endocrinology. American Physiological Society, Washington DC: Nagastaki S, Shizume K, Nakao K (1967) Thyroid function in chronic excess iodide ingestion: comparison of thyroidal absolute iodine intake and degradation of thyroxine in euthyroid Japanese subjects. J Clin Endocrinol Metab 27: Namba H, Yamashita S, Kimura H, Yokoyama N, Usa T, Otsuru A, Izumi M, Nagataki S (1993) Evidence of thyroid volume increase in normal subjects receiving excess iodide. J Clin Endocrinol Metab 76: Takamura N, Hamada A, Yamaguchi N, Matsushita N, Tarasiuk I, Ohashi T, Aoyagi K, Mine M, Yamashita S (2003) Urinary iodine kinetics after oral loading of potassium iodine. Endocr J 50: Weeks I, Beheshti I, McCapra F, Campbell AK, Woodhead JS (1983) Acridinium esters as highspecific-activity labels in immunoassay. Clin Chem 29: Fulthorpe AJ, Roitt IM, Doniach D, Couchman K (1961) A stable sheep cell preparation for detecing thyroglobulin auto-antibodies and its clinical applications. J Clin Pathol 14: Amino N, Hagen SR, Yamada N, Refetoff S (1976) Measurement of circulating thyroid microsomal antibodies by the tanned red cell haemagglutination technique: its usefulness in the diagnosis of autoimmune thyroid diseases. Clin Endocrinol (Oxf) 5: Yabu Y, Miyai K, Hayashizaki S, Endo Y, Hata N, IIJima Y, Fushimi R (1986) Measurment of iodide in urine using the iodide-selective electrode. Endocrinol Jpn 33: Miyai K, Tokushige T, Kondo M, Kondo M (2000) An improved method for measurement of urinary iodide using an ion electrode. Bulltin of Koshien University College of Nutrition No. 28(A) Paul T, Meyer B, Witorsch RJ, Pino S, Chipkin S, Ingbar SH, Braverman LE (1988) The effect of small increase in dietary iodine on thyroid function in euthyroid subjects. Metabolism 37: Gardner DF, Centor RM, Utiger RD (1988) Effects of low dose oral iodide supplementation on thyroid function in normal men. Clin Endocrinol (Oxf) 28: Tan TT, Morat P, Ng ML, Khalld BA (1989) Effects of Lugol s solution on thyroid function in normals and patients with untreated thyrotoxicosis. Clin Endocrinol (Oxf) 30: Philippou G, Koutras DA, Piperingos G, Souvatzoglou A (1992) The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement. Clin Endocrinol (Oxf) 36: Wolff J, Chaikoff IL, Goldberg RC, Meier JR (1949) The temporary nature of the inhibitory action of excess iodide on organic iodine synthesis in the normal thyroid. Endocrinology 45: Eng PH, Cardona GR, Fang SL, Previti M, Alex S, Carrasco N, Chin WW, Braverman LE (1999) Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symoporter messenger ribonucleic acid and protein. Endocrinology 140: Yabu Y, Miyai K, Endo Y, Hata N, Iijima Y, Hayashizaki S, Fushimi R, Harada T, Nose O, Kobayashi A, Matsuzuka F, Kuma K (1988) Urinary iodide excretion measured with iodide-selective ion electrode: studies on normal subjects of varying ages and patients with thyroid diseases. Endocrinol Jpn 35: Konno N, Yuri K, Miura K, Kumagai M, Murakami S (1993) Clinical evaluation of iodide/creatinine ratio of casual urine samples as index of daily iodide excretion in a population study. Endocr J 40: Nagata K, Takasu N, Akamine H, Ohshiro C, Komiya I, Murakami K, Suzawa A, Nomura T (1998) Urinary

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