Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism

Assays for the thyroid-stimulating antibody (TSAb) of Graves' disease were performed with serum obtained from 17 women with 20 pregnancies who either had or had had Graves' disease, or who had delivered a child with neonatal hyperthyroidism. Ten of the children, of eight women, were diagnosed as being hyperthyroid; all eight mothers had high concentrations of TSAb, as measured by adenylate cyclase stimulation. In the infants with neonatal hyperthyroidism, a minimum 500% increase in cAMP was found on assay of maternal immunoglobulin G, and no such high values were associated with a euthyroid infant. Blood samples for TSAb assay were available from 11 mothers on both the day of delivery and at least 1 other time in the pre- or postpartum period. In 7 mothers, the lowest value (negative in 4) was obtained coincident with delivery, and in the remaining 4, there was no pregnancy-associated change. Thus, a pattern, related to pregnancy, of a decline in TSAb concentration or a subsequent postpartum increase was observed in the majority of subjects. Apparently, neonatal hyperthyroidism due to transplacental passage of TSAb occurred only when this decline did not reduce the concentration to a low value.     

Biological activity of FGF-23 and pathophysiologic role in chronic kidney disease

Recent studies indicate that FGF-23, which was originally identified as an endogenous causative factor for hypophosphatemic diseases, is a physiologic factor for the regulation of phosphate homeostasis and vitamin D metabolism. In patients with renal failure, serum concentrations of FGF-23 positively correlate with serum levels of phosphate, Ca-P product, and prathyroid hormone. It is plausible that increased FGF-23 levels are responsible for the reduction of 1,25(OH)2D levels in the early stage of renal insufficiency and also involved in the development of secondary hyperparathyroidism in chronic and end-stage kidney disease.     

Temporal relationship between onset of Graves' ophthalmopathy and onset of thyroidal Graves' disease

The temporal relationship between the onset of Graves' ophthalmopathy and the onset of thyroidal Graves' disease was evaluated in 125 consecutive patients with Graves' ophthalmopathy. Thyroidal Graves' disease--past or present--was clinically evident in 99 patients (79%): hyperthyroidism in 3 cases. Thyroid disease preceded the eye disease in 37 patients, it occurred simultaneously with the eye disease in 39 patients, and it developed after the eye disease in 23 patients (in 16 cases within one yr after the onset of eye disease). The age at the onset of thyroid disease (38.7 +/- 12.9 yr) was lower than the age at the onset of ophthalmopathy (41.8 +/- 12.5 yr; p less than 0.001). Among the 26 clinically euthyroid patients (21%) laboratory evidence of thyroidal Graves' disease was found in 14 cases (11%): abnormal TRH test, n = 9; normal TRH test but abnormal T3-suppression test, n = 4; normal TRH and T3-suppression tests but positive thyroid stimulating antibodies, n = 1). We conclude that Graves' ophthalmopathy as a rule develops at a time when thyroid autoimmunity also exists. This strongly suggests a common factor in the pathogenesis of thyroidal and ocular expressions of Graves' disease.     

Autologous mixed lymphocyte reaction in Graves' disease: relationship to clinical status

The autologous mixed lymphocyte reaction (AMLR), i.e. the ability of T lymphocytes to proliferate when cultured with autologous non-T cell fractions, is an 'in vitro' phenomenon showing immunological memory and specificity, probably related to the cooperation ability of immunocompetent cells. We have evaluated AMLR in 27 patients with Graves' disease of varying clinical status (untreated and treated with antithyroid drugs, surgery or 131I). The results obtained show: Impaired AMLR in untreated patients (as in other autoimmune diseases). Significantly higher AMLR in cured patients, and that AMLR in cured patients varies with the treatment (higher after surgery or radioiodine than after medical treatment). These results are consistent with the hypothesis of a functional defect of T cells in Graves' disease, which improves when clinical remission is achieved.     

Graves病甲状腺内树突细胞与体液免疫紊乱的关系

目的　探讨Graves病(GD)甲状腺内树突细胞 (DC)与其体液免疫紊乱的关系。方法用抗S 100蛋白抗体SP免疫组化法对 34例GD和 5例正常对照甲状腺内的DC进行定位和半定量研究。用表达重组促甲状腺激素 (TSH)受体的人胚肾细胞检测术前血清中的甲状腺刺激性抗体(TSAb)。对甲状腺内DC的浸润密度与血清TSAb值进行相关分析。结果　正常甲状腺内未见DC,在所有被检GD患者的甲状腺内均可见到DC异常增多,且大多数DC与其周围甲状腺上皮细胞或间质浸润淋巴细胞密切接触。GD患者甲状腺内DC的浸润密度与血清TSAb值密切正相关 (r=0 4461,P<0 01)。结论　GD患者甲状腺内异常增多的DC与其体液免疫紊乱有密切关系,在其自身免疫反应的发生发展中起着重要作用。     

血清CXC趋化因子配体10水平与Graves病的关系

检测不同临床阶段Graves病(GD)患者和正常对照者血清CXC趋化因子配体10(CXCL10),发现GD未治疗组及复发组高于GD缓解组及正常对照组(P＜0.01),且前2组间差异也有统计学意义(P＜0.01),后2组间差异无统计学意义(P＞0.05).血清CXCL10与FT3、FT4水平呈正相关,与TSH水平呈负相关(均P＜0.01).多元线性回归分析显示:CXCL10是影响FT3、FT4、TSH水平的危险因素(P＜0.01).     

Purine metabolism in leukocytes and erythrocytes in Graves' or Hashimoto's disease

INTRODUCTION: Adenosine deaminase (ADA), purine nucleoside phosphorylase (PNPase), S-adenosylhomocysteine hydrolase (SAHH), 5'-nucleotidase (5N), and deoxycytidine kinase (dCK) are involved in purine salvage metabolism. Changes of the activities of the above enzymes have been observed in blood cells in patients with immunological disorders. MATERIALS AND METHODS: The activities of ADA, PNPase, SAHH, 5'N, and dCK in lysates of leukocytes and erythrocytes, obtained from patients with Graves' or Hashimoto's disease, were measured, using chromatographic analysis. Serum concentrations of antithyroglobulin (Tg Ab) and antithyroperoxidase (TPO Ab) antibodies were measured by an immunoenzymatic method. RESULTS: (1) ADA activity in leukocytes, obtained from patients with Hashimoto's disease, was significantly higher than in control leukocytes, as well as in leukocytes from patients with Graves' disease; (2) dCK activities in leukocytes from patients with both Graves' and Hashimoto's diseases were approximately four and five times higher, respectively, than in leukocytes of control subjects; (3) a positive correlation was observed between dCK activity in leukocytes and serum Tg Ab concentration in patients with Graves' disease. In conclusion, the increased ADA and dCK activities in leukocytes from patients with Graves' and Hashimoto's diseases may be regarded as indicators of autoimmunological thyroid diseases.     

Bone mineral density and disorders of mineral metabolism in chronic liver disease

AIM： To estimate the prevalence and identify the risk factors for metabolic bone disease in patients with cirrhosis. METHODS： The study was performed on 72 Indian patients with cirrhosis （63 male, 9 female; aged 〈 50 years）. Etiology of cirrhosis was alcoholism （n = 37）, hepatitis B （n = 25） and hepatitis C （n = 10）. Twenty-three patients belonged to Child class A, while 39 were in class B and 10 in class C. Secondary causes for metabolic bone disease and osteoporosis were ruled out. Sunlight exposure, physical activity and dietary constituents were calculated. Complete metabolic profiles were derived, and bone mineral density （BMD） was measured using dual energy X ray absorptiometry. Low BMD was defined as a Z score below -2. RESULTS： Low BMD was found in 68% of patients. Lumbar spine was the most frequently and severely affected site. Risk factors for low BMD included low physical activity, decreased sunlight exposure, and low lean body mass. Calcium intake was adequate, with unfavorable calcium： protein ratio and calcium： phosphorus ratio. Vitamin D deficiency was highly prevalent （92%）. There was a high incidence of hypogonadism （41%）. Serum estradiol level was elevated significantly in patients with normal BMD. Insulin-like growth factor （IGF） 1 and IGF binding protein 3 levels were below the age-related normal range in both groups. IGF-1 was significantly lower in patients with low BMD. Serum osteocalcin level was low （68%） and urinary deoxypyridinoline to creatinine ratio was high （79%）, which demonstrated low bone formation with high resorption. CONCLUSION： Patients with cirrhosis have low BMD. Contributory factors are reduced physical activity, low lean body mass, vitamin D deficiency and hypogonadism and low IGF-1 level.     

The relationship of psychological factors to the prognosis of hyperthyroidism in antithyroid drug-treated patients with Graves' disease

OBJECTIVE: The relationship between emotional stress and the onset of hyperthyroidism has been well investigated, but the relationship between psychological factors and prognosis of antithyroid drug-treated hyperthyroidism is not well known. This study has examined not only emotional stresses but also patients' personality traits using specific tests. DESIGN: A prospective cohort study. SUBJECTS: Sixty-nine patients with hyperthyroid Graves' disease in the euthyroid state after 2-5 years of antithyroid drug therapy and 32 healthy subjects as the control group. MEASUREMENTS: Patients responded to three types of questionnaires, including the Minnesota Multiphasic Personality Inventory for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses. RESULTS: In the Graves' disease patients, stress scores of life events correlated significantly with serum TSH receptor antibody activity (r = 0.424, P < 0.001) and thyroid volume (r = 0.480, P < 0.001). When the patients were divided according to prognosis (41 with relapse and 28 with remission), four personality traits including hypochondriasis, depression, paranoia and psychasthenia (mental fatigue) were significantly (P = 0.0146, 0.0052, 0.0125, and 0.0186, respectively) more common in the relapsed Graves' disease group than those of the remitted group. Six personality traits of conversion hysteria, psychopathic deviation, masculinity and feminity, schizophrenia, hypomania, and social introversion were not significantly different between the two groups. The scores of daily hassles (problems of daily life) were also significantly (P = 0.0124) greater in the relapsed Graves' disease group than in the remitted group. The scale scores of depression and psychasthenia showed a positive correlation with scores of daily hassles (r = 0.535, P < 0.0001; r = 0.580, P < 0.0001, respectively), while an inverse correlation with scores of daily uplifts (r = -0.373, P = 0.0332; r = -0.322, P = -0.0120, respectively). CONCLUSIONS: The results suggest that major life events, personality traits of hypochondriasis and depression, paranoia, mental fatigue, and daily problems aggravate the prognosis of antithyroid drug-treated hyperthyroidism. Escape from life events is virtually impossible; thus coping strategies suggested by the physician may be useful in improving prognosis in Graves' disease.     

Triiodothyronine autoantibodies in Graves' disease: their changes after antithyroid therapy and relationship with the thyroglobulin antibodies.

Sera of 63 patients with Graves' disease, and 49 control subjects were assayed for T3 autoantibodies by a sensitive radioimmunoassay after being stripped of the endogenous thyroid hormone. T3 autoantibodies were demonstrated in 27% of patients with Graves' disease. After antithyroid treatment, T3 autoantibodies in 75% of the patients with positive antibody before therapy changed to negative titre during a follow-up period of 1 to 12 months. Also, a significant decrease of T3 autoantibodies was observed at 1 month after therapy in all patients who received antithyroid treatment. A further study of T3 autoantibodies and anti-thyroglobulin antibodies showed that the latter were demonstrated in 100% of patients with positive T3 autoantibodies and that T3 autoantibodies existed in about one third of patients with positive anti-thyroglobulin antibodies. The results suggested that T3 autoantibodies could be a subpopulation of the heterogenous anti-thyroglobulin antibodies. Although the fall of T3 autoantibodies in some patients was correlated to that of anti-thyroglobulin antibodies, the overall correlation between T3 autoantibodies and anti-thyroglobulin antibodies was poor. In conclusion: 1. T3 autoantibodies may be suppressed by antithyroid drugs. 2. Being a subpopulation of anti-thyroglobulin antibodies, T3 autoantibodies may be caused by an antigenic site within the big thyroglobulin molecule, whereas their titre was not correlated with that of the overall heterogenous anti-thyroglobulin antibodies.     

成纤维细胞生长因子23与慢性肾脏病矿物质代谢

目的:观察慢性肾脏病(CKD)不同阶段血成纤维细胞生长因子23(FGF23)水平变化及其与甲状旁腺素(PTH)等生化指标的相关性,初步探讨FGF23在CKD进展中与矿物质代谢相互关系及对机体的影响。方法:选择78例估算的肾小球滤过率(eGFR)波动在4～96ml/(min·1.73m2)CKD住院患者及20例健康志愿者,测定外周血FGF23及其他生化指标,分析它们之间的相关性。结果:(1)各组CKD患者血FGF23水平均高于健康对照组,LogPTH各组间差异性显著(P<0.05),LogFGF23及血磷在CKD4,5期组中存在显著性差异(P<0.01),而CKD1～2期组与CKD3期组之间无明显差异(P>0.05);(2)四组间血磷(r=0.54,P<0.01)、LogPTH(r=0.61,P<0.01)及1,25羟维生素D3[1,25(OH)2D3](r=0.32,P<0.01)与LogFGF23均呈显著正相关,而eGFR(r=-0.64,P<0.01)与LogFGF23呈显著负相关;(3)FGF23甲旁亢组值(4372.25±1996.66pg/ml)较非甲旁亢组值(2943.99±1981.21pg/ml)明显升高(P<0.01),LogFGF23与LogPTH仅在甲旁亢组中显著正相关(r=0.569,P<0.01),而LogFGF23与1,25(OH)2D3仅在非甲旁亢组中显示正相关(r=0.437,P<0.05);两组中LogFGF23与eGFR均显著负相关,但与血磷间均有正相关性;(4)多元线性回归分析显示多因素(年龄、血清白蛋白、活性维生素D3、eGFR及"有甲旁亢")与LogFGF23有相关性(P<0.05)。结论:(1)血FGF23水平在CKD早期已高出正常,并随着肾功能减退不断升高,在终末期异常升高。(2)慢性肾脏病终末期血磷水平显著升高并刺激FGF23生成增加,高FGF23水平与继发性甲旁亢发生相关。(3)年龄、活性维生素D3、肾功能状态、营养状况及有无"甲旁亢"均能影响血FGF23水平。     

The relationship between circulating osteoprotegerin levels and bone mineral metabolism in healthy women

OBJECTIVE: Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the RANK ligand. Moreover, OPG has been shown to be an important inhibitor of osteoclastogenesis in animal models. However, the relationship between circulating OPG levels and female bone status in human populations is unclear. In this study we undertook to investigate the relationship between circulating OPG levels and bone mineral metabolism in healthy women. PATIENTS AND MEASUREMENTS: Our subjects were 287 women aged 37-73 years (mean age 51.5 years). The serum concentrations of OPG were determined by enzyme-linked immunosorbent assay (ELISA). The biochemical markers of bone turnover and FSH were measured using standard methods. Bone mineral densities at the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry. RESULTS: Postmenopausal women had a significantly higher mean value of serum OPG than premenopausal women (1358.5 +/- 32.5 pg/ml vs. 1228.8 +/- 33.3 pg/ml, P < 0.01). Serum OPG levels were positively correlated with age (r = 0.169, P < 0.01), as were urine deoxypyridinoline levels (r = 0.133, P < 0.05) and serum FSH levels (r = 0.187, P < 0.01) in a bivariate correlation analyses. In a multiple regression analysis, only urine calcium excretion was identified as a significant predictor for serum OPG levels. CONCLUSIONS: Circulating OPG levels were found to be associated with urine calcium excretion and menopause in healthy women. Our observations suggest that circulating OPG levels reflect an antiresorptive activity in bone, and they are related to endogenous oestrogen levels.     

Prevalence and clinical associations of intraocular pressure changes in Graves' disease

We investigated an unselected series of 55 patients with treated or untreated hyperthyroid Graves' disease, assessing their clinical and laboratory status and ophthalmological findings, including the difference in intraocular pressure (dIOP) between upgaze and straight gaze using applanation tonometry. An increased dIOP (greater than 2 mm Hg) was detected in only 22% of Graves' patients [who had a mean dIOP of 3.5 +/- 1.6 (+/- SEM) mm Hg]. dIOP did not correlate with age, sex, age at disease onset, duration of disease, mode of antithyroid treatment, or thyroid function testing at the time of examination. Mean Hertel exophthalmometry measurements in patients with a dIOP greater than 2 mm Hg were 22.0 +/- 2.9 mm compared with 18.4 +/- 3.7 mm in those with a dIOP less than 2 mm Hg (P less than 0.027, by Wilcoxon rank sum test). Only 58% of patients with increased dIOP had clinical exophthalmos, but all had other evidence of Graves' eye disease. Computed tomographic scanning revealed significant proptosis and/or orbital muscle involvement in all of the patients with increased dIOP.     

Enhanced thyroid iodine metabolism in patients with triiodothyronine-predominant Graves' disease

Some patients with hyperthyroid Graves' disease have increased serum T3 and normal or even low serum T4 levels during treatment with antithyroid drugs. These patients with elevated serum T3 to T4 ratios rarely have a remission of their hyperthyroidism. The aim of this study was to investigate thyroid iodine metabolism in such patients, whom we termed T3-predominant Graves' disease. Mean thyroid radioactive iodine uptake was 51.0 +/- 18.1% ( +/- SD) at 3 h, and it decreased to 38.9 +/- 20.1% at 24 h in 31 patients with T3-predominant Graves' disease during treatment. It was 20.0 +/- 11.4% at 3 h and increased to 31.9 +/- 16.0% at 24 h in 17 other patients with hyperthyroid Graves' disease who had normal serum T3 and T4 levels and a normal serum T3 to T4 ratio during treatment (control Graves' disease). The activity of serum TSH receptor antibodies was significantly higher in the patients with T3-predominant Graves' disease than in control Graves' disease patients (60.5 +/- 19.2% vs. 20.4 +/- 18.2%; P less than 0.001). From in vitro studies of thyroid tissue obtained at surgery, both thyroglobulin content and iodine content in thyroglobulin were significantly lower in patients with T3-predominant Graves' disease than in the control Graves' disease patients. Thyroid peroxidase (TPO) activity determined by a guaiacol assay was 0.411 +/- 0.212 g.u./mg protein in the T3-predominant Graves' disease patients, significantly higher than that in the control Graves' disease patients (0.129 +/- 0.112 g.u./mg protein; P less than 0.01). Serum TPO autoantibody levels determined by immunoprecipitation also were greater in T3-predominant Graves' disease patients than in control Graves' disease patients (52.6 +/- 27.7% vs. 32.4 +/- 11.4%; P less than 0.05). Binding of this antibody to TPO slightly inhibited the enzyme activity of TPO, but this effect of the antibody was similar in the two groups of patients. The data suggest enhanced iodine metabolism in the thyroid gland of patients with T3-predominant Graves' disease, which may relate to the discordant T3 overproduction in patients with this type of Graves' disease.