Novel frameshift mutation causes early termination of the thyroxine-binding globulin protein and complete thyroxine-binding globulin deficiency in a Chinese family: A case report.

BACKGROUND: Thyroxine-binding globulin (TBG; the gene product of SERPINA7) is the main transporter of thyroid hormones in humans. Mutations in the TBG gene may lead to inherited TBG deficiency. There have been 28 reported mutations that associate with complete TBG deficiency (TBG-CD). Here we identified a novel frameshift mutation causing early termination of the TBG protein and TBG-CD in a Chinese family. CASE SUMMARY: A 46-year-old Chinese man was referred to our hospital with normal free thyroxine, free triiodothyronine, thyrotropin, but lower total thyroxine and total triiodothyronine, and undetectable serum TBG, indicative of TBG-CD. Blood samples were obtained from the patient's family members and thyroid function and serum TBG were evaluated. Genomic DNA from peripheral blood was sequenced to detect possible TBG mutation(s). Quantitative PCR high-resolution melting curve analysis was used to screen TBG-Poly (L283F) among 117 Chinese men. A novel mutation of TBG (p.Phe135Alafs*21), a 19-nucleotide insertion in exon 1, was identified, which resulted in a truncated TBG protein product and caused TBG-CD. The other mutation, identified in the proband's father, is a known polymorphism, TBG-Poly (L283F). The frequency of the TBG-Poly allele among 117 unrelated Han Chinese men from northeast China was 21.37%. CONCLUSION: A novel mutation in the TBG gene associated with the TBG-CD phenotype was identified in a Chinese family. Additionally, it was found that 21.37% of Chinese males had TBG-Poly (L283F).

Association between iron deficiency and prevalence of thyroid autoimmunity in pregnant and non-pregnant women of childbearing age: a cross-sectional study.

BACKGROUND: Thyroid autoimmunity (TAI) is prevalent among women of reproductive age and associated with adverse pregnancy outcomes. This study aimed to investigate the association between iron nutritional status and the prevalence of TAI in women during the first trimester of pregnancy and in non-pregnant women of childbearing age. METHODS: Cross-sectional analysis of 7463 pregnant women during the first trimester of pregnancy and 2185 non-pregnant women of childbearing age nested within the sub-clinical hypothyroid in early pregnancy study, a prospective collection of pregnant and non-pregnant women's data, was conducted in Liaoning province of China between 2012 and 2015. Serum thyrotropin, free thyroxine, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), serum ferritin, and urinary iodine were measured. Iron deficiency (ID) was defined as serum ferritin <15 µg/L and iron overload (IO) was defined as ferritin >150 µg/L. TPOAb-positive was defined as >34 U/mL and TgAb-positive was defined as >115 U/mL. Multilevel logistic regression was conducted to examine the association between TAI and different iron nutritional status after adjusting for potential confounders. RESULTS: The prevalence of isolated TPOAb-positive was markedly higher in women with ID than those without ID, in both pregnant and non-pregnant women (6.28% vs. 3.23%, χ = 10.264, P = 0.002; 6.25% vs. 3.70%, χ = 3,791, P = 0.044; respectively). After adjusting for confounders and the cluster effect of hospitals, ID remained associated with TPOAb-positive in pregnant and non-pregnant women (odds ratio [OR]: 2.111, 95% confidence interval [CI]: 1.241-3.591, P = 0.006; and OR: 1.822, 95% CI: 1.011-3.282, P = 0.046, respectively). CONCLUSION: ID was associated with a higher prevalence of isolated TPOAbs-positive, but not with isolated TgAb-positive, in both pregnant women during the first trimester of pregnancy and non-pregnant women of childbearing age, while IO was not associated with either isolated TPOAb-positive or isolated TgAb-positive. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003805, http://www.chictr.org.cn/index.aspx.

[The changes of thyrotropin level in euthyroid population: a 5-year follow-up study in communities with different iodine intakes].

OBJECTIVE: To determine the factors that influence the development of abnormal thyrotropin (TSH) level in an euthyroid population. METHODS: We conducted a follow-up study in 3 communities with different iodine status. Of the 3403 euthyroid subjects at baseline screened in 1999, 80.1% (n = 2727) was visited and sampled in 2004 for measuring TSH, thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). RESULTS: Iodine status in the 3 communities were stable. Decreased TSH level (< 0.3 mU/L) developed in 2.5% (n = 68) of sampled subjects, while raised TSH level (> 4.8 mU/L) in 2.4% (n = 64). A logistic analysis showed that risk factors for developing decreased TSH level included positive conversion of TPOAb (OR = 5.5), positive TPOAb both in 1999 and in 2004 (OR = 4.0), positive TgAb in 2004 (OR = 3.7) and TSH < 1.0 mU/L in 1999 (OR = 2.6). Risk factors involved in developing raised TSH level included iodine status of Zhangwu community (OR = 4.1), iodine status of Huanghua community (OR = 3.9), positive TgAb in 2004 (OR = 3.7), positive TPOAb both in 1999 and 2004 (OR = 3.6), positive conversion of TPOAb (OR = 2.7) and TSH > 1.9 mU/L in 1999 (OR = 2.6). CONCLUSIONS: Exposure to long-term iodine excess imposes danger of developing hypothyroidism. The risk will be even higher when exposing to iodine adequacy after correction of iodine deficiency. An interval between 1.0 and 1.9 mU/L of TSH level was optimal with the least probability of developing abnormal TSH level.

[A study on the mechanism of iodine-induced thyroid epithelial cell injury in the induction of autoimmune thyroiditis].

OBJECTIVE: To investigate the effect of iodine excess on thyroid follicle epithelial ultrastructure and the relationship between thyroid injury and autoimmune thyroiditis. METHODS: NOD. H-2(h4) mice and Kunming mice were randomly divided into four groups receiving plain water, 5 fold, 10 fold, and 100 fold excessive iodine water. 4, 8 and 24 weeks after receiving iodine water, the mice were killed. After fixation with osmic acid and dual staining with uranyl chloride and citrate lead, thyroid gland ultrastructure was examined with electron microscopy. RESULTS: Iodine treated NOD. H-2(h4) mice exhibited marked accumulation of peroxisome and secondary lysosomes, apoptosis and necrosis of thyroid epithelial cell, damage of thyroid follicles and lymphocytic infiltration. The observed changes induced by iodine were in a dose dependent way. CONCLUSION: The oxidative injury on the thyroid epithelial cells induced by iodine excess might be the prerequisite for the creation of autoimmune thyroiditis.

Effect of NHE1 antisense gene transfection on the biological behavior of SGC-7901 human gastric carcinoma cells.

AIM: To study the effect of type 1 Na(+)/H(+) exchanger (NHE1) antisense human gene transfection on the biological behavior of gastric carcinoma cell line SGC-7901. METHODS: Antisense NHE1 eukaryotic expression on vector pcDNA3.1 was constructed by recombinant DNA technique and transfected into gastric carcinoma cell line SGC-7901 with DOTAP liposome transfection method. Morphological changes of cells were observed with optic and electron microscopes. Changes in cell proliferative capacity, apoptosis, intracellular pH (pH(i)), cell cycle, clone formation in two-layer soft agar, and tumorigenicity in nude mice were examined. RESULTS: Antisense eukaryotic expressing vectors were successfully constructed and transfected into SGC-7901. The transfectant obtained named 7901-antisense (7901-AS) stablely produced antisense NHE1. There was a significant difference between the pH(i) of 7901-AS cells (6.77 +/- 0.05) and that of 7901-zeo cells and SGC-7901 cells (7.24 +/- 0.03 and 7.26 +/- 0.03, P < 0.01). Compared with SGC-7901 and 7901-zeo cells, 7901-AS cells mostly showed cell proliferation inhibition, G1/G0 phase arrest, increased cell apoptotic rate, recovery of contact inhibition, and density contact. The tumorigenicity in nude mice and cloning efficiency in the two-layer soft agar were clearly inhibited. CONCLUSION: NHE1 antisense gene significantly restrains the malignant behavior of human gastric carcinoma cells, suppresses cell growth and induces cell apoptosis, and partially reverses the malignant phenotypes of SGC-7901. These results suggest a potential role for human tumor gene therapy.

[Epidemiological study of the effects of smoking cigarette on thyroid gland].

OBJECTIVE: To investigate the effect of cigarette smoking on thyroid gland volume, thyroid function and thyroid autoantibodies in the areas with different iodine intakes. METHODS: A cross-sectional epidemiological study in Panshan (mild iodine-deficient area), Zhangwu (more than adequate iodine intake area) and Huanghua (iodine-excessive area) was conducted in 3761 subjects in 1999.80.2 % of them were followed up in 2004. Questionnaires, thyroid function, thyroid autoantibodies, urinary iodine concentration,and thyroid B ultrasound were performed. RESULTS: The prevalence of goiter was higher in smokers than in non-smokers (15.1% vs. 11.5%, P< 0.05). The average thyroid volume was higher in smokers with phenomenon more obvious in Panshan and Huanghua areas. Data from logistic analysis showed that smoking cigarette was an independent risk factor of goiter. There was no difference in serum TSH and Tg level between smokers and non-smokers. The positive rate of TPOAb (>100 IU/ml) was higher in smokers than in non-smokers(10.8% vs. 9.0 % , P <0.05) and was especially obvious in Huanghua area. Smoking was a independent risk factor of increasing positive rate of TPOAb. During the prospective observation,it was found that the incidence of positive TPOAb(>,100 IU/ml) was 7.4% in the subjects that were from non-smokers turning to smokers and 2.9% in those whose smoking behavior did not change. Logistic analysis indicated that the shifting from non-smoking to smoking was independent risk factor for the increase on high incidence of positive TPOAb. CONCLUSION: Smoking cigarette was a independent risk factor of goiter. Smoking was also a risk factor of increasing TPOAb positive rate. Shifting from not smoking to smoking was an independent risk factor of increasing high incidence of positive TPOAb.

Effect of Helicobacter pylori infection on Bax protein expression in patients with gastric precancerous lesions.

AIM: To investigate the effect of Helicobacter pylori (H pylori) infection on Bax protein expression, and explore the role of H pylori in gastric carcinogenesis. METHODS: H pylori was assessed by rapid urease test and Warthin-Starry method, and expression of Bax protein was examined immunohistochemically in 72 patients with pre-malignant lesions. RESULTS: Bax protein was differently expressed in intestinal metaplasia and gastric dysplasia, and showed 63.99% positivity. The positivity of Bax protein expression in H pylori-positive gastric precancerous lesions (72.3%) was significantly higher than that in H pylori-negative gastric precancerous lesions (48.0%, chi2 = 4.191, P<0.05). H pylori infection was well correlated with the expression of Bax protein in gastric precancerous lesions (r = 0.978, P<0.01). After eradication of H pylori, the positivity of Bax protein expression significantly decreased in H pylori-positive gastric precancerous lesions (chi2 = 5.506, P<0.05). In the persisting H pylori-infected patients, the positivity of Bax protein expression was not changed. CONCLUSION: H pylori infection may be involved in the upregulation of Bax gene, which might be one of the mechanisms of H pylori infection-induced gastric epithelial cell apoptosis. H pylori might act as a tumor promoter in the genesis of gastric carcinoma and eradication of H pylori could inhibit gastric carcinogenesis.

Effect of different iodine intake on schoolchildren's thyroid diseases and intelligence in rural areas.

BACKGROUND: Reports are increasingly appearing on the side effects caused by excessive iodine intake. Our objective was to find out whether iodine excess would impair the thyroid function and intelligence of schoolchildren in rural areas of China. METHODS: A comparative epidemiological study was made on thyroid function and intelligence of the schoolchildren in the areas of low, moderate or excessive intake of iodine. In the area of low intake of iodine (Panshan, Liaoning province, median urinary iodine (MUI) was 99 microg/L), of moderate intake of iodine (Zhangwu, Liaoning Province, MUI was 338 microg/L) and of excessive intake of iodine (Huanghua, Hebei Province, MUI was 631 microg/L). The numbers of schoolchildren from each area selected to take part in a Chinese version of Raven's Test were 190, 236 and 313, respectively, and then 116, 110 and 112 of them were tested for thyroid function, thyroid autoantibody (TAA) and urinary iodine (UI). RESULTS: There were no significant differences in the incidences of overt hyperthyroidism, subclinical hyperthyroidism and overt hypothyroidism in Panshan, Zhangwu and Huanghua. But significant differences were found in the incidences of subclinical hypothyroidism (P = 0.001) in these three areas. The incidences of subclinical hypothyroidism in Huanghua and Zhangwu were 4.76 and 3.37 times higher than that in Panshan. TAA were negative in all the schoolchildren with subclinical hypothyroidism except for one. No significant difference was found among the rates of thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in these three areas. Mean serum thyroglobulin (TG) value of Huanghua was markedly higher than those of the other two (P = 0.02). Mean serum TG value of Zhangwu was higher than that of Panshan but the difference was not significant. Mean IQ value of the schoolchildren in Huanghua was markedly higher than that for Zhangwu (P = 0.001). Mean IQ value of the schoolchildren in Panshan was lower than that of Huanghua and higher than that of Zhangwu but, again, the differences were not significant. CONCLUSIONS: The increase of iodine intake may increase the risk for schoolchildren of subclinical hypothyroidism. In the area of iodine excess, most of the subclinical hypothyroidism cases are not of autoimmune origin. No obvious effect of excess iodine was found on mental development of schoolchildren.

[Correlation between serum thyroglobulin and thyroid stimulating hormone in populations with non-toxic goiter].

OBJECTIVE: To investigate the correlation between serum thyroglobulin (Tg) and thyroid stimulating hormone (TSH) in populations with non-toxic goiter. METHODS: Thyroid ultrasonography was conducted, and determination of serum triiodothyronine (FT3), thyroxin (FT4), Tg, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb) and TSH, and urine iodine were carried out among 609 persons with an average age of 35.4 in Panshan county, a mild iodine-deficient area in Liaoning province, and 1136 persons aged 39.1 on average in Zhangwu county, an iodine sufficient area in Liaoning province, totally 2 320 persons. RESULTS: The serum TSH levels of the populations with diffuse and nodular goiter in Panshan county were (0.11 +/- 0.08) mU/L and (0.90 +/- 0.10) mU/L, significantly higher than those of the normal population in the same areas (1.33 +/- 0.04) mU/L, both P < 0.01. The serum TSH levels of the populations with diffuse and nodular goiter in Zhangwu county were (1.29 +/- 0.13) mU/L and (0.89 +/- 0.14) mU/L, significantly higher than those of the normal population in the same areas (1.74 +/- 0.04) mU/L, both P < 0.01. The serum TSH level of normal population in iodine deficient area was significantly lower than that of normal population in iodine sufficient area (P < 0.01). The serum TSH level of the normal population in Panshan County was significantly lower than that of the normal population in Zhangwu County (P < 0.01). The serum Tg level of the populations with diffuse and nodular goiter in Panshan county were (12.0 +/- 1.21) ng/L and (50.1 +/- 12.20) ng/L, significantly higher than that of the normal population in the same area (9.1 +/- 2.44) ng/L, P < 0.05 and P < 0.01. The serum Tg level of the populations with diffuse and nodular goiter in Zhangwu county were (12.4 +/- 2.11) ng/L and (61.2 +/- 11.86) ng/L, significantly higher than that of the normal population in the same area (7.7 +/- 2.3) ng/L, P < 0.05 and P < 0.01. The Tg level of the normal population in Panshan County was significantly higher than that of the normal population in Zhangwu county (P < 0.01). The Tg level was positively correlated with the thyroid volume in the nodular goiter population. CONCLUSION: The occurrence of goiter is not directly related to TSH stimulation in mild iodine deficient area. Nontoxic goiter shows a thyroid autonomic function. The major cause of high serum Tg in nodular goiter may be the leakage of Tg into blood circulation caused by degeneration of large colloid follicles and destruction of follicular architecture, not the volume increase of thyroid and its autonomic function.

[An epidemiological study on factors affecting serum thyroglobulin levels].

OBJECTIVE: To investigate the effects of several factors affecting serum thyroglobulin (TG) levels among people aged 14 or more. METHODS: We selected Panshan with median urinary iodine (MUI) 83.45 micro g/L as a deficient iodine intake community, Zhangwu with MUI 242.85 micro g/L as a sufficient iodine intake community and Huanghua with MUI 650.87 micro g/L as an excessive iodine intake community. Serum TG and thyroid stimulating hormone (TSH) were measured in 3,335 subjects whose thyroglobulin antibody (TGAb) were negative and thyroid volume were examined using B-ultrasound. RESULTS: In the population with MUI of 80 - 650 micro g/L, serum TG levels presented a "V" curve. An elevated serum TG was found in both the communities with deficient iodine intake and excessive iodine intake. The same trend was shown in the groups with different levels of serum TSH. An elevated serum TG was found in both the groups of TSH < 0.3 mU/L and TSH > 4.8 mU/L. The serum TG levels was positively correlated with thyroid volume and was higher in female subjects than in male. An increased serum TG was found in subjects of aged 50 in the community with deficient iodine intake. CONCLUSION: Serum TG level is affected by gender, amount of iodine intake, serum TSH level and thyroid volume.

[An epidemiological study on the relationship between selenium and thyroid function in areas with different iodine intake].

OBJECTIVE: To investigate the relationship between selenium status and thyroid dysfunction in 3 areas with different iodine intake. METHODS: An epidemiological research was performed in the rural communities of Panshan County (iodine-deficient area) and Zhangwu County (iodine-sufficient area), Liaoning Province, and Huanghua County, Hebei Province (iodine-excessive area). Serum selenium, TSH, FT3 and FT4 levels were examined in 329 patients with thyroid dysfunction (including clinical hypothyroidism, subclinical hypothyroidism, clinical hyperthyroidism and subclinical hyperthyroidism) and 183 normal inhabitants. RESULTS: The median serum selenium concentrations in Panshan, Zhangwu and Huanghua were 91.4, 89.1, and 83.2 microg/L respectively. There was no difference in serum selenium levels between the patients with subclinical hypothyroidism, clinical hypothyroidism, and clinical hyperthyroidism and their normal controls. The median serum selenium concentration of the subclinical hyperthyroidism patients was 82.6 microg/L, significantly lower than that of the normal controls (87.3 microg/L). The FT3/FT4 ratio was decreased, the FT4 level was increased in the subclinical hyperthyroidism patients in comparison with the normal controls, and no significant difference in FT3 level was found between them. No significant effect of sex and age was found on serum selenium level of normal inhabitants. In normal controls serum selenium was inversely correlated with serum TSH level, and the subjects with serum selenium < or = 80 microg/L had the median TSH level of 2.10 mU/L, markedly higher than that of the subjects with the serum selenium of 80-100 microg/L (1.29 mU/L) and that of the subjects with the serum selenium of 100 approximately 120 micro g/L (1.28 mU/L). For the thyroid dysfunction patients with positive thyroid auto-antibody (TPOAb) in Zhangwu County, the serum selenium was negatively associated with TPOAb level. The serum selenium level of the TPOAb highly positive group (TPOAb > 600 IU/ml) was 83.6 IU/ml, significantly lower than those of the TPOAb lowly positive group and TPOAb moderately positive group (83.6, 92.9 and 95.6 microg/L respectively). CONCLUSION: No obvious effect of selenium status is found on the development of thyroid dysfunction in these three areas. But selenium deficiency can impair thyroid function by means of disturbing thyroid hormone metabolism and decreasing antioxidant ability of the thyroid.