Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overproduction of thyroid hormones promotes bone resorption in vivo and in vitro, and we have evaluated whether mediators of such effects could include the osteotropic cytokines. Previous studies have demonstrated raised serum interleukin (IL)-6 in thyrotoxic patients, but differentiating the contribution of the elevated thyroid hormones from that of the autoimmune inflammation present in Graves' disease (GD) has been difficult. We undertook a longitudinal study of 34 patients (19-45 yr old) with GD, toxic nodular goiter (TNG), or a history of thyroid carcinoma but no evidence of disease recurrence, receiving sufficient T4 to suppress TSH. Controls were 12 euthyroid females. The following measurements were made basally and for 6 months after carbimazole treatment: serum free T4, T3, bone-specific alkaline phosphatase (b-ALP), IL-6, IL-8, IL-1beta, tumor necrosis factor-alpha, IL-11, and urinary deoxypyridinoline (Udpd). Compared with controls (IL-6, 1.1 +/- 0.3 ng/L; IL-8, 3.2 +/- 0.8 ng/L), untreated patients with GD and TNG had elevated IL-6 (GD, 7.11 +/- 0.88 ng/L; TNG, 7.30 +/- 0.77 ng/L; P < 0.001) and IL-8 (GD, 10.3 +/- 1.23 ng/L; TNG, 9.81 +/- 1.27 ng/L; P < 0.001). These levels fell after treatment and were then indistinguishable from those in control subjects. Thyroid carcinoma patients on TSH suppressive therapy also had significantly raised levels of IL-6 (2.5 +/- 0.42 ng/L) and IL-8 (4.4 +/- 0.63 ng/L). When data from all the patients were pooled, the levels of IL-6 and IL-8 correlated with serum T3 and free T4 but not with Udpd or b-ALP. IL-1beta, IL-11, and tumor necrosis factor-alpha were not raised in any patient. The elevations in serum IL-6 and -8 that occur in hyperthyroidism seem to result from the chronic effects of thyroid hormone excess rather than the accompanying autoimmune inflammatory condition produced by Graves' thyroid or eye disease. The site of the presumed increased production of IL-6 and -8 is most likely from bone osteoblasts, despite the inability of bone markers (such as Udpd and b-ALP) to correlate with acute changes in thyroid hormone status produced by antithyroid therapy.
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PMID:Serum cytokines in thyrotoxicosis. 1002 97

Hyperthyroid patients have high bone turnover and negative calcium and phosphorus balance often associated with mild osteopenia. Early during antithyroid treatment bone turnover decreases, the mineral balance is converted to positive, and sometimes hypocalcemia occurs. The aim of this investigation was to study the mechanisms of the changes in some parameters of bone and mineral metabolism after treatment of thyrotoxicosis. Thirteen newly diagnosed patients with Graves' disease (seven postmenopausal women, four premenopausal women, and two men) were studied longitudinally, every 6 weeks, for 1 yr after commencing antithyroid treatment with methimazole. Mean serum calcium and phosphorus were both slightly above the normal mean at week 0 and decreased significantly (by 10% and 24%, respectively) during treatment. Fasting urinary calcium was 236 +/- 4 (mean +/- SEM) mg/g creatinine, and the fractional excretion of Ca was 2.0 +/- 0.33% before treatment; both fell significantly to minimums of 61 +/- 20 mg/g and 0.6 +/- 0.16%, respectively. Urinary phosphorus was 282 +/- 60 mg/g creatinine, and the fractional excretion of phosphorus was 3.3 +/- 0.6% before treatment; both increased significantly to 452 +/- 40 mg/g and 8.4 +/- 1.0%, respectively, during treatment. The z-scores were calculated from the mean and SD ofthe respective control groups. The z-score of urinary N-telopeptides of type I collagen (U.NTx) was 9.3 +/- 1.3 at week 0 and declined exponentially, but failed to normalize after 1 yr of antithyroid treatment. The serum alkaline phosphatase (ALP) z-score was initially 2.2 +/- 0.2, increased to 6.0 +/- 1.0 at week 6, and declined slowly there after to 1.0 +/- 1.1 at week 54. The serum osteocalcin (OC) z-score showed a temporal pattern similar to that of ALP. It was initially 2.2 +/- 0.2, increased to 4.0 +/- 0.6 at week 6, and later declined slowly to 0.7 +/- 0.5 at week 54. The failure of the markers of bone turnover to normalize after 1 yr of therapy indicates an on-going high rate of bone turnover despite the attained euthyroidism. The uncoupling index (UI = z-score of U.NTx minus z-score of OC) was 7.1 +/- 1.2 before treatment, indicating unbalanced bone turnover in favor of bone resorption, and fell close to zero at week 30 of treatment. Pretreatment plasma PTH was suppressed slightly to 2.17 +/- 0.47 pmol/L and rose significantly during treatment, reaching a plateau of 5.27 +/- 0.78 at week 12. In all postmenopausal women PTH increased above the upper limit of normal (6.84 pmol/L). Pretreatment serum 25-hydroxyvitamin D was normal and remained unchanged during treatment, whereas 1,25-dihydroxyvitamin D was initially subnormal and rose to normal level after treatment. There was a significant positive linear correlation between PTH and U.NTx after week 12. PTH was also significantly correlated with ALP, but not with OC. ALP and OC were significantly correlated. A significant positive correlation was found between T3 and U.NTx, and a negative correlation was found between T3 and each of the formation markers (ALP and OC) over the 0- to 12-week interval. The latter correlations and the very high pretreatment UI indicate some inhibitory effect of the high thyroid hormone levels on the osteoblasts. The marked and sustained elevation of PTH, more pronounced in the postmenopausal women, during the first year of treatment of hyperthyroidism seems to play a pivotal role in maintaining a relatively high rate of bone turnover despite euthyroidism, and in the conservation of calcium by reducing renal calcium excretion and increasing calcium absorption (via 1,25-dihydroxyvitamin D). It may also account in part for the additional rise of the bone formation markers by an anabolic effect on the osteoblasts. Endogenous PTH may be important in the restoration of bone mineral density of treated hyperthyroid patients.
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PMID:Changes in parameters of bone and mineral metabolism during therapy for hyperthyroidism. 1072 46

The chemiluminescence assays for detection of autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg) implemented on the IMMULITE 2000 system (Diagnostic Products Corporation) were evaluated. These were immunometric assays with antigen-coated beads and monoclonal murine anti-IgG antibodies conjugated with alkaline phosphatase. Precision was satisfactory with an intraassay precision of 5.3-5.5% for anti-Tg and 4.8-5.3% for anti-TPO and an interassay precision of 5.7-7.3% for anti-TPO and 5.2-7.5% for anti-Tg. The lower detection limit was determined as 5 IU/ml for anti-TPO and 2.2 IU/ml for anti-Tg. The average dilution linearities of 102% for anti-TPO and 100% for anti-Tg and the average recovery of 80-127% for anti-TPO and 93-112% for anti-Tg were acceptable. The findings of the tests were compared with the systems from Pharmacia & Upjohn, ORGenTec, Roche Diagnostics, Byk Sangtec Diagnostica and BRAHMS Diagnostica. Taking the respective cutoff value into account, concordance was 87-96% for anti-Tg and 87-97% for anti-TPO. Summarizing all results from the different methods revealed a clinical agreement of 95% for anti-TPO and 93% for anti-Tg. A good agreement was found with the IMMULITE anti-TPO and anti-Tg assays, which are closely related as regards method and biochemistry. Regression analysis gave the following results: anti-TPO IMMULITE 2000 vs anti-TPO IMMULITE: anti-TPO IMMULITE 2000 = 0.99 x IMMULITE anti-TPO - 1.43 IU/ml (r = 0.99, n = 144). anti-Tg IMMULITE 2000 vs anti-Tg IMMULITE: anti-Tg IMMULITE 2000 = 0.98 x IMMULITE anti-Tg + 1.63 IU/ml (r = 0.99, n = 86). Further age-dependent normal ranges were evaluated. A higher prevalence of elevated autoantibody titers was found for patients older than 50 years. The rate of elevated antibody titer can be reduced by using an age-dependent reference range: < or = 50 years anti-TPO < 35 IU/ml, anti-Tg < 40 IU/ml and > 50 years anti-TPO < 100 IU/ml, anti-Tg < 80 IU/ml. Further samples from clinically diagnosed Hashimoto's thyroiditis and Graves' disease were investigated. The levels of positive anti-Tg values and anti-TPO values accorded with those stated in the literature and were comparable to those measured with a reference assay. In the tested INSTAND e. V. interlaboratory samples there was high-level accordance with the expected clinical results.
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PMID:Evaluation of chemiluminescence immunoassays for detecting thyroglobulin (Tg) and thyroid peroxidase (TPO) autoantibodies using the IMMULITE 2000 system. 1074 78

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally no significant association was seen between age-adjusted BMD and genotype, patients in remission for >5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (Z = 1.14 ff vs. Z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.
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PMID:Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease. 1088 83

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally, no significant association was seen between age-adjusted BMD and genotype, patients in remission for fewer than 5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (z = 1.14 ff vs. z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.
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PMID:Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease. 1090 90

Hyperthyroid patients exhibit accelerated bone loss by increased bone turnover, and normalization of thyroid function is associated with a significant attenuation of increased bone turnover, followed by an increase in bone mineral density. However, of patients with Graves' disease (GD) maintained on antithyroid drug (ATD) treatment, some exhibit persistent suppression of TSH long after normalization of their serum free T3 (FT3) and free T4 (FT4) levels. The aim of this study was to examine whether bone metabolism is still enhanced in TSH-suppressed premenopausal GD patients with normal FT3 and FT4 levels after ATD therapy (n = 19) compared with that in TSH-normal premenopausal GD patients (n = 30), and to evaluate the relationship between serum TSH receptor antibody (TRAb), an indicator of disease activity of GD, and various biochemical markers of bone metabolism. No difference was found between the two groups in serum Ca, phosphorus, or intact PTH, or in urinary Ca excretion. Serum bone alkaline phosphatase (B-ALP), bone formation markers, and urinary excretions of pyridinoline (U-PYD) and deoxypyridinoline (U-DPD), which are bone resorption markers, were significantly higher in the TSH-suppression group than in the TSH-normal group (B-ALP, P < 0.05; U-PYD, P < 0.001; U-DPD, P < 0.001). For the group of all GD patients enrolled in this study, TSH, but neither FT3 nor FT4, exhibited a significant negative correlation with B-ALP (r = -0.300; P < 0.05), U-PYD (r = -0.389; P < 0.05), and U-DPD (r = -0.446; P < 0.05), whereas TRAb exhibited a highly positive and significant correlation with B-ALP (r = 0.566; P < 0.0001), U-PYD (r = 0.491; P < 0.001), and U-DPD (r = 0.549; P < 0.0001). Even in GD patients with normal TSH, serum TRAb was positively correlated with B-ALP (r = 0.638; P < 0.001), U-PYD (r = 0.638; P < 0.001), and U-DPD (r = 0.641; P < 0.001). In conclusion, it is important to achieve normal TSH levels during ATD therapy to normalize bone turnover. TRAb was not only a useful marker for GD activity, but was also a very sensitive marker for bone metabolism in GD patients during ATD treatment.
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PMID:Persistent increase in bone turnover in Graves' patients with subclinical hyperthyroidism. 1109 47

Abnormal liver function in thyroid disorders may be secondary to thyrotoxicosis or to autoimmune injury to the liver. We report the case of a 36-year-old female who developed jaundice and pruritus with mild cholestasis and moderately elevated transaminase levels. The diagnosis of Graves' disease was made shortly thereafter. Laboratory findings were: alanine and aspartate aminotransferase 219 (IU/I (N: 9-50) and 102 IU/I (N: 10-15) respectively, alkaline phosphatase 336 IU/I (N: 40-135), bilirubin 24 micromol/I (N: 2-23), and gamma-glutamyl transpeptidase 232 IU/I (N: 9-43). Abdominal ultrasonography showed normal bile ducts; echocardiography ruled out heart failure; viral and autoimmune markers for hepatitis and cirrhosis were negative. Percutaneous liver biopsy showed moderate intrahepatic steatosis, anisokaryosis, lymphocyte infiltration in the portal areas, and Kupffer cell hyperplasia. Outcome was favorable after seven months of iodine therapy, confirming the diagnosis of thyrotoxicosis hepatitis.
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PMID:[Thyrotoxicosis hepatitis: a case report]. 1145 76

Little is known about the effects of thyroid hormone excess in male patients. Our aim was to evaluate bone mineral density (BMD), bone turnover markers, and thyroid function in male patients with treated thyroid cancer on long-term suppressive L-T4 therapy (TC) and in male patients with Graves' disease (GD). We studied 49 male patients (aged 45+/-12 years), 17 with TC (29-288 months on L-T4 suppressive therapy; free T4: 1.9+/-0.6 ng/dl [normal< or =2.0]; TSH: 0.2+/-0.3 microU/ml [Normal 0.5-5.0]) and 32 with recent onset GD (<12 weeks, free T4: 2.0+/-1.4 ng/dl; TSH: 1.07+/-1.8 microU/ml; TSHRAb 53+/-45% [normal < 15]). BMD was measured by dual X-ray absorptiometry (DXA, Hologic QDR1000w) at the lumbar spine (L2-L4, LS), femoral neck (FN), and Ward's triangle (WT). Results were expressed as Z-score (SD compared to national controls). Total alkaline phosphatase (ALP), osteocalcin (BGP), iPTH, serum phosphorus, serum, and 24 h urine calcium were measured as bone markers. Age, weight, and body mass index were comparable in both groups. Patients with TC and with GD showed reduced axial BMD (95% confidence interval: LS: TC (-1.27-0.01)(P = 0.046), GD (-1.06 to-0.38)(P < 0.001); FN: TC (-0.82 to-0.16)(P = 0.007), GD (-0.95 to-0.15)(P = 0.008); WT: TC (-0.82 to -0.18)(P = 0.004), GD (-0.97 to -0.08)(P = 0.024). No significant differences in BMD were found between the groups. Among bone markers, total ALP and osteocalcin levels showed higher levels in Graves' disease (ALP: 139+/-76 vs. 88+/-34, P < 0.01; BGP: 7.5+/-3.7 vs. 4.6+/-1.6; P < 0.001). Our data suggest a mild deleterious effect of thyroid hormone excess in the axial bone mass from male subjects. A skeletal status assessed by BMD in male patients with chronic TSH suppression by L-T4 or history of hyperthyroidism is recommended.
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PMID:Bone mineral density in male patients with L-thyroxine suppressive therapy and Graves disease. 1168 28

Cultured thyroid epithelial cells can be induced to express intercellular adhesion molecule-1 (ICAM-1, or CD54). However, constitutive follicular expression of ICAM-1 has been reported only in thyroid autoimmunity. We evaluated the expression of ICAM-1 mRNA and protein on thyroid tissue from different autoimmune thyroid diseases, and its relationship with other immunologically relevant surface markers, namely costimulatory molecules of B7 family. Thyroid tissue sections were obtained by surgically removed thyroid glands from 6 patients with Hashimoto's thyroiditis (HT), 6 with Graves' disease (GD) and 3 with multinodular nontoxic goiter. We used in situ hybridization to localize ICAM-1 mRNA, and immunohistochemical analysis by alkaline phosphatase anti-alkaline phosphatase (APAAP) method. We showed a clear hybridization pattern, localized in follicular cells, in sections of glands with HT. The hybridization pattern was far less pronounced in GD: no staining was apparent on follicular cells. These results were strictly consistent with those obtained by means of immunohistochemistry. Moreover, double-staining experiments demonstrated colocalization of ICAM-1 and B7.1 molecules in HT, whereas no B7.1 expression was observed in Graves' or in non-autoimmune thyroid diseases. These data agree with the hypothesis of distinct immunoregulatory phenomena and effector mechanisms in the 2 main autoimmune thyroid diseases.
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PMID:Different intrathyroid expression of intercellular adhesion molecule-1 (ICAM-1) in Hashimoto's thyroiditis and Graves' disease: analysis at mRNA level and association with B7.1 costimulatory molecule. 1193 73

Hyperthyroidism is characterized by increased bone turnover and resorptive activity. Raised levels of serum osteoporotic cytokines, such as interleukin (IL) -1beta, IL-6 and tumor necrosis factor (TNF)-alpha have been demonstrated previously in hyperthyroidism. These elevations are controversial and it is difficult to differentiate the contribution of thyroid hormones to the elevation of cytokines from that of the autoimmune inflammation in Graves' disease (GD) and follicular cell damage in thyroiditis. Therefore, we investigated the effect of thyroid hormones on serum IL-1beta, IL-6, TNF-alpha levels and bone metabolism on L-thyroxine induced hyperthyroid rats and changes in cytokine levels and bone metabolism on the same rats after reversal to euthyroidism. Rats were treated with L-thyroxine for 5 weeks (0.4 mg/ 100 g food). Plasma T3, T4, TSH and serum IL-1beta, IL-6, TNFalpha, Calcium (Ca), phosphorous (P), parathyroid hormone (PTH), alkaline phosphatase (ALP), bone alkaline phosphatase (B-ALP) levels were measured and differential leucocyte counts were made initially, at the 5th week of the experiment (hyperthyroid state) and 5 weeks after quitting the administration of L-thyroxine (euthyroid state). Significant rises in serum IL-1beta, IL-6 and TNFalpha were noted in hyperthyroidism (P < 0.001). In euthyroid state, IL-15, IL-6 and TNFalpha decreased significantly, but IL-beta and TNFalpha were significantly higher than the baseline values (P < 0.05) while IL-6 levels turned back to the baseline values. Plasma T3 and T4 levels were significantly correlated with serum cytokines in hyperthyroid state while there was no correlation in euthyroid states. Ca and P levels did not differ significantly while PTH levels declined significantly in the hyperthyroid state (P < 0.05). After the reversal to the euthyroidism, there was no significant change in Ca, P and PTH levels. ALP and B-ALP increased significantly in hyperthyroidism (P < 0.001, P < 0.01) and they did not decrease in euthyroid state. The lymphocyte number and ratio in differentials increased significantly in the hyperthyroid state (P < 0.001). In euthyroidism they decreased significantly (P < 0.001) but it was significantly higher than the baseline value (P < 0.05). Our findings showed that the deleterious effect on bone metabolism in hyperthyroidism might be mediated by cytokines and the increased bone turnover in hyperthyroidism failed to decrease despite euthyroidism.
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PMID:Osteoporotic cytokines and bone metabolism on rats with induced hyperthyroidism; changes as a result of reversal to euthyroidism. 1507 39


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