酪氨酸在小鼠甲状腺肿发病中作用的实验研究
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摘要
目的：地方性甲状腺肿（以下简称地甲病）是碘缺乏病（以下简称IDD）中最易发现、最易诊断的一种疾病。但是人们在防治地甲病的过程中只注意到碘因素的作用，而忽略了甲状腺激素的另外一种合成原料—-酪氨酸的作用，致使某些地区出现了一些与用碘防治地甲病的理论不完全相符的问题。为此，我们对酪氨酸对小鼠甲状腺肿的影响进行了研究，研究了酪氨酸的致甲状腺肿作用及其与碘的交互作用，为完善IDD的病原学理论，进而改善IDD防治措施和彻底消除IDD提供依据。
方法：选用健康昆明种小鼠（体重为12~15克）96只，按2×2析因实验设计方法将小鼠随机分为四组，每组24只，雌雄各半：（1）适碘适酪氨酸组、（2）适碘低酪氨酸组、（3）低碘适酪氨酸组、（4）低碘低酪氨酸组。喂养120天后，内眦取血离心，用放射免疫法测定小鼠血清中T3、T4、TSH含量；将小鼠颈脊髓离断处死摘取甲状腺，称量其重量并计算相对重量；经HE染色和重金属双重染色后，在光镜和电镜下观察甲状腺组织结构的病理变化；应用HPIAS-1000高清晰度彩色病理图文报告分析系统（9.0版）测量甲状腺体视学指标，指标包括：平均面积（S）、面积体积（V）、形状因子（Sf）、平均灰度（G）、面数密度（NA）。对实验数据用SAS8.0进行统计分析。
结果：1.在适酪氨酸的情况下，低碘组与适碘组相比：
低碘组小鼠甲状腺体积增大，其重量和相对重量明显增加（P<0.01，P<0.01），其中相对重量增加了64.72％；颜色由粉红色变为鲜红色；光镜和电镜下为典型的增生性甲状腺肿的表现。光镜：滤泡和滤泡腔变小，滤泡上皮细胞增生，胶质减少呈絮状分布，毛细血管增生。电镜：线粒体增生，粗面内质网扩张，可见溶酶体，滤泡上皮细胞游离面微绒毛增多，胶质的电子密度下降。体视学指标中，滤泡及滤泡腔S、VA和Sf均减小，滤泡NA和胶质G增大，以上变化均有统计学意义（P<0.01）；血清T4含量降低（P<0.01），T3、TSH含量升高(P<0.01, P<0.01)。在低酪氨酸的情况下，低碘组与适碘组相比：低碘组小鼠甲状腺体积明显增大，颜色由淡红色变为深红色；光镜下滤泡腔内胶质量极少甚至缺如；电镜下滤泡上皮细胞游离面在微绒毛增加的基础上又出现了纤毛；血清T3含量减少但无显著性差异（P>0.05）；其他变化同上。2.在适碘的情况下，低酪氨酸组与适酪氨酸组相比：低酪氨酸组小鼠甲状腺体积轻微增大，其重量、相对重量均增加但无统计学意义（P>0.05），其中相对重量增加了15.24％；颜色由粉红色变成淡红色；光镜：滤泡上皮细胞变为高柱状或为双层，胶质量减少呈筛眼状分布。电镜：线粒体轻度增生，粗面内质网轻度扩张；体视学指标中，滤泡及滤泡腔S、VA和Sf减小，滤泡NA和胶质G增大，以上变化除胶质G外均无统计学意义（P>0.05）；血清T4含量轻度降低（P>0.05），T3、TSH含量轻度升高(P>0.05, P>0.05)。在低碘的情况下，低酪氨酸组与适酪氨酸组相比：低酪氨酸组甲状腺体积继续增大，其重量和相对重量均明显增加（P<0.01）；颜色由鲜红色变为深红色；光镜：滤泡上皮细胞增生更加明显，滤泡腔
形状极度不规则，胶质缺如，毛细血管等细胞间质明显增生；电镜：线粒体极度增生，粗面内质网扩张呈池状，上皮细胞游离面有大量微绒毛，并出现纤毛，胶质的电子密度继续下降；体视学指标中，滤泡及滤泡腔S、VA和Sf均减小，滤泡NA和胶质G增大，以上变化均有显著性差异（P<0.01）；血清T4含量降低（P<0.05），T3含量降低（P<0.01）、TSH含量升高(P<0.05)。3. 碘和酪氨酸在甲状腺重量、甲状腺相对重量、T3、体视学指标等指标中有交互作用；在T4、TSH指标中无交互作用。4. 小鼠从适碘适酪氨酸组到低碘低酪氨酸组，甲状腺肿大率（以下简称甲肿率）依次增加，组间差异显著（P<0.01）。在适酪氨酸的情况下，低碘组与适碘组相比，前者为60％，后者为5.3％，甲肿率明显升高（P<0.01）；在低酪氨酸的情况下，低碘组与适碘组相比，前者为90％，后者为16.7％，甲肿率升高更为明显（P<0.01）；在适碘的情况下，低酪氨酸组的甲肿率高于适酪氨酸组，但无统计学意义（P>0.05）；而在低碘的情况下，低酪氨酸组的甲肿率明显高于适酪氨酸组（P<0.05）。碘和酪氨酸对小鼠甲肿率的变化有交互作用。
结论：1. 在适酪氨酸或低酪氨酸的情况下，碘缺乏均可导致小鼠增生性甲状腺肿，低酪氨酸的情况下病情更为严重。2. 在适碘时, 酪氨酸缺乏可使小鼠有发生甲状腺肿的趋势；在低碘时，酪氨酸缺乏可加重其对甲状腺的损害。3. 碘和酪氨酸对小鼠地甲病的发生、发展有明显的交互作用――协同作用。4. 根据本次研究结果，在小鼠地甲病的致病因素中，碘的致甲肿作用占60％左右，酪氨酸作用占15％左右。
Objective: Endemic goiter is one of the diseases that were found and diagnosed easiest of iodine deficiency disorders (IDD). But people pay more attention to the prevention and cure effects of iodine while neglect the effects of tyrosine, which is one of the essential materials to synthesis thyroid hormone. Consequently many experts are puzzled by some problems that not accord with the theory to prevent IDD only with iodine in some areas. This experiment was undertaken to clarify if tyrosine has effects on thyroid, and then to study the combined effects of iodine and tyrosine, and to provide evidence for the improvement of etiology and complete eradication of IDD.
Methods: 96 healthy mice (weight 12~15g) were divided into 4 groups randomly according to 2×2 factorial experiment design, and every group has 12 male and 12 female mice: (1) Adequate iodine and adequate tyrosine (AIAT), (2) adequate iodine and low tyrosine (AILT), (3) low iodine and adequate tyrosine (LIAT) and (4) low iodine and low tyrosine (LILT). 120 days later, a blood sample was taken from medial canthus vein of each mouse, and the content of serum T3, T4, TSH was measured using radio-immunity method after the blood having been centrifuged. Then all animals were decapitated by breaking
spinal cord at nuchae. Thyroids were weighted immediately and their relative weights were counted. The pathological changes of the tissue were observed with light microscope and electronic microscope. And the stereological indexes of thyroid such as S, V, Sf, G and NA were measured using correlated soft. All data was analyzed by SAS8.0.
Results: 1. Compared with the AIAT group, in the LIAT group, the thyroid volume increased; the weight and the relative weight increased (P<0.01, P<0.01), and the value of the latter index was increased by 64.72%; the color of thyroid changed into ponceau from pink; light microscope: follicle and follicle cavity diminished. Follicle epithelial cells hyperplasied. Colloid reduced and distributed flocky. Blood capillary hyperplasied; electronic microscope: mitochondrion hyperplasied. Rough endoplasmic reticulum dilated. Some lysosomes emerged. The number of the microvilli increased and the colloid’s electronic density lowered; the stereological indexes such as S, VA and Sf of the follicle and follicle cavity declined while G and NA went up; the content of serum T4 decreased while T3 and TSH ascended. The changes of the indexes above were significant (P<0.01). Compared with the AILT group, the thyroid of the LILT group enlarged markedly; the color changed into carmine from rosiness; the colloid quantity diminished evidently and there was no colloid in some follicle cavity when the specimen was observed with light microscope; some cilias appeared at the free side of the epithelial cell when with electronic microscope;
the content of serum T3 changed with no significance (P>.05); other changes were id. 2. Compared with the AIAT group, thyroid of the AILT group enlarged appreciably; its weight and relative weight increased with no significance (P>0.05, P>0.05), and the value of the latter index was increased by 15.24%; the color changed into rosiness from pink; light microscope: epithelial cells expanded and arrayed multilayerly. Colloid reduced and distributed sieve-porely; electronic microscope: mitochondrion hyperplasied slightly and rough endoplasmic reticulum dilated ratherish; the stereological indexes such as S, VA and Sf of the follicle and follicle cavity declined while G and NA went up; the content of serum T4 reduced and T3, TSH increased. But the changes of the indexes above were not significant (P>0.05) except G (P<0.05). Compared with the LIAT group, thyroid of the LILT group enlarged continually and its weight and relative weight increased (P<0.01, P<0.01); color changed into carmine from ponceau; light microscope: follicle epithelial cells hyperplasied overly and the shape of the follicle was very irregular. Colloid disappeared. Blood capillary hyperplasied, dilated and was obviously hyperemic; electronic
方法：选用健康昆明种小鼠（体重为12~15克）96只，按2×2析因实验设计方法将小鼠随机分为四组，每组24只，雌雄各半：（1）适碘适酪氨酸组、（2）适碘低酪氨酸组、（3）低碘适酪氨酸组、（4）低碘低酪氨酸组。喂养120天后，内眦取血离心，用放射免疫法测定小鼠血清中T3、T4、TSH含量；将小鼠颈脊髓离断处死摘取甲状腺，称量其重量并计算相对重量；经HE染色和重金属双重染色后，在光镜和电镜下观察甲状腺组织结构的病理变化；应用HPIAS-1000高清晰度彩色病理图文报告分析系统（9.0版）测量甲状腺体视学指标，指标包括：平均面积（S）、面积体积（V）、形状因子（Sf）、平均灰度（G）、面数密度（NA）。对实验数据用SAS8.0进行统计分析。
结果：1.在适酪氨酸的情况下，低碘组与适碘组相比：
低碘组小鼠甲状腺体积增大，其重量和相对重量明显增加（P<0.01，P<0.01），其中相对重量增加了64.72％；颜色由粉红色变为鲜红色；光镜和电镜下为典型的增生性甲状腺肿的表现。光镜：滤泡和滤泡腔变小，滤泡上皮细胞增生，胶质减少呈絮状分布，毛细血管增生。电镜：线粒体增生，粗面内质网扩张，可见溶酶体，滤泡上皮细胞游离面微绒毛增多，胶质的电子密度下降。体视学指标中，滤泡及滤泡腔S、VA和Sf均减小，滤泡NA和胶质G增大，以上变化均有统计学意义（P<0.01）；血清T4含量降低（P<0.01），T3、TSH含量升高(P<0.01, P<0.01)。在低酪氨酸的情况下，低碘组与适碘组相比：低碘组小鼠甲状腺体积明显增大，颜色由淡红色变为深红色；光镜下滤泡腔内胶质量极少甚至缺如；电镜下滤泡上皮细胞游离面在微绒毛增加的基础上又出现了纤毛；血清T3含量减少但无显著性差异（P>0.05）；其他变化同上。2.在适碘的情况下，低酪氨酸组与适酪氨酸组相比：低酪氨酸组小鼠甲状腺体积轻微增大，其重量、相对重量均增加但无统计学意义（P>0.05），其中相对重量增加了15.24％；颜色由粉红色变成淡红色；光镜：滤泡上皮细胞变为高柱状或为双层，胶质量减少呈筛眼状分布。电镜：线粒体轻度增生，粗面内质网轻度扩张；体视学指标中，滤泡及滤泡腔S、VA和Sf减小，滤泡NA和胶质G增大，以上变化除胶质G外均无统计学意义（P>0.05）；血清T4含量轻度降低（P>0.05），T3、TSH含量轻度升高(P>0.05, P>0.05)。在低碘的情况下，低酪氨酸组与适酪氨酸组相比：低酪氨酸组甲状腺体积继续增大，其重量和相对重量均明显增加（P<0.01）；颜色由鲜红色变为深红色；光镜：滤泡上皮细胞增生更加明显，滤泡腔
形状极度不规则，胶质缺如，毛细血管等细胞间质明显增生；电镜：线粒体极度增生，粗面内质网扩张呈池状，上皮细胞游离面有大量微绒毛，并出现纤毛，胶质的电子密度继续下降；体视学指标中，滤泡及滤泡腔S、VA和Sf均减小，滤泡NA和胶质G增大，以上变化均有显著性差异（P<0.01）；血清T4含量降低（P<0.05），T3含量降低（P<0.01）、TSH含量升高(P<0.05)。3. 碘和酪氨酸在甲状腺重量、甲状腺相对重量、T3、体视学指标等指标中有交互作用；在T4、TSH指标中无交互作用。4. 小鼠从适碘适酪氨酸组到低碘低酪氨酸组，甲状腺肿大率（以下简称甲肿率）依次增加，组间差异显著（P<0.01）。在适酪氨酸的情况下，低碘组与适碘组相比，前者为60％，后者为5.3％，甲肿率明显升高（P<0.01）；在低酪氨酸的情况下，低碘组与适碘组相比，前者为90％，后者为16.7％，甲肿率升高更为明显（P<0.01）；在适碘的情况下，低酪氨酸组的甲肿率高于适酪氨酸组，但无统计学意义（P>0.05）；而在低碘的情况下，低酪氨酸组的甲肿率明显高于适酪氨酸组（P<0.05）。碘和酪氨酸对小鼠甲肿率的变化有交互作用。
结论：1. 在适酪氨酸或低酪氨酸的情况下，碘缺乏均可导致小鼠增生性甲状腺肿，低酪氨酸的情况下病情更为严重。2. 在适碘时, 酪氨酸缺乏可使小鼠有发生甲状腺肿的趋势；在低碘时，酪氨酸缺乏可加重其对甲状腺的损害。3. 碘和酪氨酸对小鼠地甲病的发生、发展有明显的交互作用――协同作用。4. 根据本次研究结果，在小鼠地甲病的致病因素中，碘的致甲肿作用占60％左右，酪氨酸作用占15％左右。
Objective: Endemic goiter is one of the diseases that were found and diagnosed easiest of iodine deficiency disorders (IDD). But people pay more attention to the prevention and cure effects of iodine while neglect the effects of tyrosine, which is one of the essential materials to synthesis thyroid hormone. Consequently many experts are puzzled by some problems that not accord with the theory to prevent IDD only with iodine in some areas. This experiment was undertaken to clarify if tyrosine has effects on thyroid, and then to study the combined effects of iodine and tyrosine, and to provide evidence for the improvement of etiology and complete eradication of IDD.
Methods: 96 healthy mice (weight 12~15g) were divided into 4 groups randomly according to 2×2 factorial experiment design, and every group has 12 male and 12 female mice: (1) Adequate iodine and adequate tyrosine (AIAT), (2) adequate iodine and low tyrosine (AILT), (3) low iodine and adequate tyrosine (LIAT) and (4) low iodine and low tyrosine (LILT). 120 days later, a blood sample was taken from medial canthus vein of each mouse, and the content of serum T3, T4, TSH was measured using radio-immunity method after the blood having been centrifuged. Then all animals were decapitated by breaking
spinal cord at nuchae. Thyroids were weighted immediately and their relative weights were counted. The pathological changes of the tissue were observed with light microscope and electronic microscope. And the stereological indexes of thyroid such as S, V, Sf, G and NA were measured using correlated soft. All data was analyzed by SAS8.0.
Results: 1. Compared with the AIAT group, in the LIAT group, the thyroid volume increased; the weight and the relative weight increased (P<0.01, P<0.01), and the value of the latter index was increased by 64.72%; the color of thyroid changed into ponceau from pink; light microscope: follicle and follicle cavity diminished. Follicle epithelial cells hyperplasied. Colloid reduced and distributed flocky. Blood capillary hyperplasied; electronic microscope: mitochondrion hyperplasied. Rough endoplasmic reticulum dilated. Some lysosomes emerged. The number of the microvilli increased and the colloid’s electronic density lowered; the stereological indexes such as S, VA and Sf of the follicle and follicle cavity declined while G and NA went up; the content of serum T4 decreased while T3 and TSH ascended. The changes of the indexes above were significant (P<0.01). Compared with the AILT group, the thyroid of the LILT group enlarged markedly; the color changed into carmine from rosiness; the colloid quantity diminished evidently and there was no colloid in some follicle cavity when the specimen was observed with light microscope; some cilias appeared at the free side of the epithelial cell when with electronic microscope;
the content of serum T3 changed with no significance (P>.05); other changes were id. 2. Compared with the AIAT group, thyroid of the AILT group enlarged appreciably; its weight and relative weight increased with no significance (P>0.05, P>0.05), and the value of the latter index was increased by 15.24%; the color changed into rosiness from pink; light microscope: epithelial cells expanded and arrayed multilayerly. Colloid reduced and distributed sieve-porely; electronic microscope: mitochondrion hyperplasied slightly and rough endoplasmic reticulum dilated ratherish; the stereological indexes such as S, VA and Sf of the follicle and follicle cavity declined while G and NA went up; the content of serum T4 reduced and T3, TSH increased. But the changes of the indexes above were not significant (P>0.05) except G (P<0.05). Compared with the LIAT group, thyroid of the LILT group enlarged continually and its weight and relative weight increased (P<0.01, P<0.01); color changed into carmine from ponceau; light microscope: follicle epithelial cells hyperplasied overly and the shape of the follicle was very irregular. Colloid disappeared. Blood capillary hyperplasied, dilated and was obviously hyperemic; electronic
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Brahmbhatt SR, Brahmbhatt RM, Mboyages SC. Impact of protein energy malnutrition on thyroid size in an iodine deficient population of Gujarat (India): Is it an aetiological
factor for goiter. Enr J Endocrinol, 2001,145(1): 11~17
姜新民, 苏茂义, 蒋继勇, 等. 新疆柯尔克孜族居民地方性甲状腺肿调查报告. 全国第四届碘缺乏病学术会议论文专辑, 1991:248~249
王顺吉, 李云峰. 西藏阿里地区7~14岁中小学生地方性甲状腺肿调查. 全国第四届碘缺乏病学术会议论文专辑, 1991:264
任永, 丁士辉, 黄耆, 等. 凉城县地方性甲状腺肿克汀病病区营养状况调查. 中华预防医学杂志, 1989,23(6):371
于志恒, 朱惠民, 陈祖培, 等. 新疆南疆地区碘缺乏病流行情况调查. 1995中国碘缺乏病监测, 北京:人民卫生出版社, 1999:146~152
Gaitan EH. Epidemiology of endemic goiter in Colobia. Bull Wld Helth Org, 1980,59:957~965
刘守军, 高本, 孙树秋. 中国8、9、10岁儿童甲状腺容积分布及其正常界限.中国地方病学杂志,2001,20(6):440~442
于志恒，朱惠民，尹桂山.实验性高碘对机体的影响及其与高碘地甲病发病机理的联系.中国地方病学杂志《专辑》，1991，全国第四届IDD学术会议论文汇编：1~5
欧阳安, 庞宣平, 程云超, 等. 酪蛋白预防大鼠缺碘性甲状腺肿的实验研究.中华内分泌代谢杂志, 1992,8(3):159~160
高秋菊，张世勇，许崇亮，等. 碘与小鼠甲状腺形态体视学的剂量－反应关系. 中华预防医学杂志，2002,36(1):38~40
房辉，陈贯一，王素莉，等. 碘缺乏与碘过多大鼠甲状腺定量形态学研究. 中国地方病学杂志，2000,19(3):161~163
Garrel DR, Todd KS, Pugeat MM, et al. Hormonal Changes In Normal Man Under Marginally Negative Energy Balance. Am J Clin Nutr, 1984,39:930~936
Chopa IJ. An Assessment Of Daily Production And Significance Of Thyroidal Secretion 3,3’, 5-Triiodothyronine In Man. J Clin Invest, 1976,58:32~40
Osman A, Khalid BA, Tan TT, et al. Serum thyroid stimulating hormone (TSH) in malnutrition: preliminary results. Singapore Med J, 1993,34(3): 225~228
Turkay S, Kus S, Gokalp A, et al. Effects Of Protein Malnutrition On Circulating Thyroid Hormones. Indian Pediatr, 1995,32(2): 193~197
房辉，阎玉芹，陈祖培. 碘缺乏与碘过多对大鼠甲肿形成及功能的影响.中国地方病防治杂志，1999,14(3):136~138
Ingenbleek Y, De Nayer PH, De Visscher M. Thyroixine-Binding Globulin In Infant Protein-Calorie Malnutrition. J Clin Endocrinol Metab, 1974,39:178
Ingenbleek Y, Beckers C. Triiodothyronine And Thyroid Stimulating Homone In Protein-Calorie Malnutrition In Infants.Lancet, 1975,2:845
Ingenbleek Y, De Nayer PH, De Visscher M. Total And Free Throxine In Protein-Calorie Malnutrition. Acta Paediatr Belg, 1976,29:145
朱惠民，王凤荣，尹桂山.实验性高碘和低碘甲状腺肿的
对比研究.中国地方病学杂志,1988,7(4):199
卢惆章. 甲状腺功能的控制与调节. 马泰,等主编. 碘缺乏病. 北京: 人民卫生出版社, 1993:35~46
尹桂山,王桂香,杜秀全,等.高碘和低碘甲状腺肿小鼠血清T3、T4和TSH的变化比较.河北医学院学报,1989,8(4):14
刘守军，苏晓辉，于钧，等. 2002年中国碘缺乏病监测资料汇总分析报告. 中国地方病学杂志，2003,22:142~144
Gaitan E, Merino H. Antigoitrogenic effect of casein. Acta Endocrinol (Copenh), 1976,83(4): 763~771
闫玉芹.碘缺乏病的发病机理与病理.马泰,等主编.碘缺乏病.北京:人民卫生出版社,1993:145~180
Fragu P, et al. Human Thyroid Peroxidase Activity In Benign Malign Thyroid Disorders. J Clin Indocrinol And Metab, 1977,45:1089
Nagasaga A, et al. Effect Of Antithyroid Agents 6-Propyl-2-Thiuracil And 1-Methyul-2-Mercaptoimidazole On Human Thyroid Iodide Peroxidase. J Clin Endocrinol Metab, 1976,43:152
Imoddi AR. Effects of dietary protein level on growth and proteolytic activity of the avidin pancreas. J Nutrition, 1967,91:421
苏天水,欧阳安,秦贵军,等. 实验性甲状腺肿甲状腺过氧化物酶活性的改变. 中国地方病学杂志, 1994,13(2):86~88
Carvalho DP, Feweira AC, Coelho SM, et al. Thyroid Peroxidase Activity Is Inhibited By Amino Acids. Braz J
Med Boil Res, 2000,33(3): 355~361
Ingenbleek Y, Beckers C. Evidence For Intestinal Malabsorption Of Iodine In Protein-Calorie Malnutrition. Am J Clin Nutr, 1973,26:1323~1333
蒋继勇, 杨成忠, 曹学义. 碘缺乏地区的亚临床克汀病. 国外医学医学地理分册, 1992,13(4):150~152
Vir SC. Current status of iodine deficiency disorders (IDD) and strategy for its control in India. Indian J Pediatr, 2002,69(7): 589~596
De Benoist B, Clugston G. Eliminating iodine deficiency disorders. Bull Wld Helth Org, 2002,80(5): 341
Darnton-Hill I. The challenge to eliminate micronutrient
malnutrition. Australian and New Zealand Journal of Public Health, 1999,23(3): 309~314
全国碘缺乏病监测组. 1999年全国碘缺乏病监测资料汇总分析. 中国地方病学杂志, 2000,19(4):269~271
陈祖培. 全民加碘的意义及当前人群碘营养状况的基本评价. 中国地方病防治杂志, 2002,17(4):251~254
全国碘缺乏病监测组. 中国学龄儿童尿碘含量(1999). 中国地方病学杂志, 2000,19(6):448~450
马泰. 甲状腺的生理与病理生理. 马泰,等主编. 碘缺乏病. 北京: 人民卫生出版社, 1993:18~34
于志恒, 刘守军. 对碘缺乏病病原学问题的探讨于思考. 中华医学杂志, 2002,82(19):1359~1361
朱惠民,胡宣扬,姚玉霞,等.实验性高碘甲状腺肿.中国地方病学杂志,1986,5(1):1~4
闫玉芹. 碘缺乏病的发病机理与病理. 马泰,等主编. 碘缺乏病. 北京: 人民卫生出版社, 1993:145~182
于志恒，朱惠民，尹桂山.对高碘地甲病发生学的新认识及其对机体影响的估价.中国地方病防治杂志,1991,6(6):364
朱惠民，王凤荣，尹桂山，等.高碘地方性甲状腺肿发病机理的实验研究. 中国地方病防治杂志,1989,8(4):220
周爱儒. 氨基酸代谢. 顾天爵,等主编. 生物化学. 北京: 人民卫生出版社,2000:191~221
Brahmbhatt SR, Brahmbhatt RM, Mboyages SC. Impact of protein energy malnutrition on thyroid size in an iodine deficient population of Gujarat (India): Is it an aetiological
factor for goiter. Enr J Endocrinol, 2001,145(1): 11~17
姜新民, 苏茂义, 蒋继勇, 等. 新疆柯尔克孜族居民地方性甲状腺肿调查报告. 全国第四届碘缺乏病学术会议论文专辑, 1991:248~249
王顺吉, 李云峰. 西藏阿里地区7~14岁中小学生地方性甲状腺肿调查. 全国第四届碘缺乏病学术会议论文专辑, 1991:264
任永, 丁士辉, 黄耆, 等. 凉城县地方性甲状腺肿克汀病病区营养状况调查. 中华预防医学杂志, 1989,23(6):371
于志恒, 朱惠民, 陈祖培, 等. 新疆南疆地区碘缺乏病流行情况调查. 1995中国碘缺乏病监测, 北京:人民卫生出版社, 1999:146~152
Gaitan EH. Epidemiology of endemic goiter in Colobia. Bull Wld Helth Org, 1980,59:957~965
刘守军, 高本, 孙树秋. 中国8、9、10岁儿童甲状腺容积分布及其正常界限.中国地方病学杂志,2001,20(6):440~442
于志恒，朱惠民，尹桂山.实验性高碘对机体的影响及其与高碘地甲病发病机理的联系.中国地方病学杂志《专辑》，1991，全国第四届IDD学术会议论文汇编：1~5
欧阳安, 庞宣平, 程云超, 等. 酪蛋白预防大鼠缺碘性甲状腺肿的实验研究.中华内分泌代谢杂志, 1992,8(3):159~160
高秋菊，张世勇，许崇亮，等. 碘与小鼠甲状腺形态体视学的剂量－反应关系. 中华预防医学杂志，2002,36(1):38~40
房辉，陈贯一，王素莉，等. 碘缺乏与碘过多大鼠甲状腺定量形态学研究. 中国地方病学杂志，2000,19(3):161~163
Garrel DR, Todd KS, Pugeat MM, et al. Hormonal Changes In Normal Man Under Marginally Negative Energy Balance. Am J Clin Nutr, 1984,39:930~936
Chopa IJ. An Assessment Of Daily Production And Significance Of Thyroidal Secretion 3,3’, 5-Triiodothyronine In Man. J Clin Invest, 1976,58:32~40
Osman A, Khalid BA, Tan TT, et al. Serum thyroid stimulating hormone (TSH) in malnutrition: preliminary results. Singapore Med J, 1993,34(3): 225~228
Turkay S, Kus S, Gokalp A, et al. Effects Of Protein Malnutrition On Circulating Thyroid Hormones. Indian Pediatr, 1995,32(2): 193~197
房辉，阎玉芹，陈祖培. 碘缺乏与碘过多对大鼠甲肿形成及功能的影响.中国地方病防治杂志，1999,14(3):136~138
Ingenbleek Y, De Nayer PH, De Visscher M. Thyroixine-Binding Globulin In Infant Protein-Calorie Malnutrition. J Clin Endocrinol Metab, 1974,39:178
Ingenbleek Y, Beckers C. Triiodothyronine And Thyroid Stimulating Homone In Protein-Calorie Malnutrition In Infants.Lancet, 1975,2:845
Ingenbleek Y, De Nayer PH, De Visscher M. Total And Free Throxine In Protein-Calorie Malnutrition. Acta Paediatr Belg, 1976,29:145
朱惠民，王凤荣，尹桂山.实验性高碘和低碘甲状腺肿的
对比研究.中国地方病学杂志,1988,7(4):199
卢惆章. 甲状腺功能的控制与调节. 马泰,等主编. 碘缺乏病. 北京: 人民卫生出版社, 1993:35~46
尹桂山,王桂香,杜秀全,等.高碘和低碘甲状腺肿小鼠血清T3、T4和TSH的变化比较.河北医学院学报,1989,8(4):14
刘守军，苏晓辉，于钧，等. 2002年中国碘缺乏病监测资料汇总分析报告. 中国地方病学杂志，2003,22:142~144
Gaitan E, Merino H. Antigoitrogenic effect of casein. Acta Endocrinol (Copenh), 1976,83(4): 763~771
闫玉芹.碘缺乏病的发病机理与病理.马泰,等主编.碘缺乏病.北京:人民卫生出版社,1993:145~180
Fragu P, et al. Human Thyroid Peroxidase Activity In Benign Malign Thyroid Disorders. J Clin Indocrinol And Metab, 1977,45:1089
Nagasaga A, et al. Effect Of Antithyroid Agents 6-Propyl-2-Thiuracil And 1-Methyul-2-Mercaptoimidazole On Human Thyroid Iodide Peroxidase. J Clin Endocrinol Metab, 1976,43:152
Imoddi AR. Effects of dietary protein level on growth and proteolytic activity of the avidin pancreas. J Nutrition, 1967,91:421
苏天水,欧阳安,秦贵军,等. 实验性甲状腺肿甲状腺过氧化物酶活性的改变. 中国地方病学杂志, 1994,13(2):86~88
Carvalho DP, Feweira AC, Coelho SM, et al. Thyroid Peroxidase Activity Is Inhibited By Amino Acids. Braz J
Med Boil Res, 2000,33(3): 355~361
Ingenbleek Y, Beckers C. Evidence For Intestinal Malabsorption Of Iodine In Protein-Calorie Malnutrition. Am J Clin Nutr, 1973,26:1323~1333
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