Thyroid peroxidase antibodies in early pregnancy: utility for prediction of postpartum thyroid dysfunction and implications for screening.

Thyroid peroxidase antibodies (TPOAb) in pregnancy are a marker for postpartum (PPTD) and long-term thyroid dysfunction, with variable sensitivity and specificity in PPTD prediction. To test its utility in prediction, we recruited 308 TPOAb-positive (147 developed PPTD (PPTD group) and 161 remained euthyroid [PPTE group]) and 102 TPOAb-negative women (none developed PPTD), in early pregnancy (median, 18; range, 9-19 weeks' gestation). TPOAb levels were higher in the PPTD group (median) (125.2 kIU/L; p < 0.001), and in its hypothyroid (162.4 kIU.; p < 0.0001), hyperthyroid (114.2 kIU/L; p < 0.007), and biphasic (105.1 kIU/L; p < 0.02) variants, compared to the PPTE group (66.7 kIU/L) The incidence of PPTD was significantly higher with TPOAb levels above 58.2 kIU/L (early pregnancy versus postpartum; relative risk, 1.37 [95% confidence interval [CI] 1.17-1.61] versus 0.78 [95% CI 0.5-1.2]) compared to levels below. The integrated postpartum TPOAb response was higher in the PPTD group (median) (159 kIU/L per week) and its variants (hypothyroid; 199 kIU/L per week; biphasic, 180 kIU/L per week; hyperthyroid, 120 kIU/L per week), compared to the PPTE group (86 kIU/L per week p < 0.004). Median early pregnancy TPOAb levels in the PPTD and PPTE groups correlated well with the postpartum antibody response (r = 0.58, p < 0.001). The sensitivity of TPOAb in PPTD prediction was 100% (early pregnancy and postpartum), specificity 62% (early pregnancy) versus 41% (postpartum) and positive predictive value 48% (early pregnancy and postpartum). The timing of TPOAb testing, the sensitive assay used and the absence of PPTD in TPOAb-negative subjects contributed to this high sensitivity. We recommend TPOAb in early pregnancy as a useful predictor of PPTD, particularly in populations where PPTD does not occur in TPOAb-negative women.     

Thyroid peroxidase/microsomal antibodies are not identical with thyroid cytotoxic antibodies in autoimmune thyroiditis

Cytotoxic activity in sera of patients with Hashimoto's thyroiditis was measured with an antibody-dependent cell-mediated cytotoxicity assay. Cytotoxicity was determined in a 51chromium release assay using human thyroid cell targets incubated with heat-inactivated serum or IgG from patients with Hashimoto's thyroiditis. Effector cells were obtained from peripheral mononuclear cells of normal subjects. Cytotoxicity was significantly increased in patients with Hashimoto's thyroiditis (median specific lysis 20.2%, range 2.1-58.8) compared with normals (median specific lysis 8.1%, range 0-19.5; p less than 0.00001). The amount of percent specific lysis did not correlate with the titres of microsomal antibodies determined by different methods: passive hemagglutination technique (r = 0.2), enzyme immunoassay with microsomal antigen (r = 0.16), and radioimmunoassay for thyroid peroxidase antibody (r = 0.02). The cytotoxic activity was located in the IgG fraction, both in microsomal antibody positive and negative sera. After pre-incubation of microsomal antibody/thyroid peroxidase antibody positive or negative sera with purified thyroid peroxidase followed by analysis in the antibody-dependent cell-mediated cytotoxicity assay, cytotoxicity decreased in only 2 cases but was unchanged in the remaining sera. Western blot experiments with solubilized thyroid membranes and immunoblotting with cytotoxic-positive/microsomal antibody negative sera showed no binding to thyroid peroxidase. Our data suggest that cytotoxicity in sera from patients with Hashimoto's thyroiditis is not mediated by antibodies against thyroid peroxidase, but by antibodies not yet identified.     

Thyroid peroxidase antibodies in dried blood specimens of newborns.

Previous studies have disclosed that a substantial percentage of infants from mothers with thyroid autoimmunity have antibodies to thyroid peroxidase (TPOAb) at birth. Furthermore, these antibodies have been shown to be of maternal origin. In view of this we thought it would be of interest to determine the prevalence of TPOAb in newborns from an unselected population of women. This was done by retrieving stored dried blood specimens from 240 full-term healthy infants, which had been obtained during 1999 for routine newborn screening. Ten percent of the randomly selected specimens tested TPOAb positive. Thyroid function in the mothers could not be evaluated because all specimens had been tested anonymously. In summary, our results indicate that a significant percentage of newborns were TPOAb positive. It is unclear at this time whether such antibodies reflected maternal thyroid autoimmunity and/or other autoimmune disorders. However, the close association between autoimmune thyroid disease and TPOAb positivity raises the possibility of abnormal thyroid function in some of the mothers.     

Uterine peroxidase as a marker for estrogen action.

Administration of a single dose of estradiol to immature rats gives rise to the appearance of substantial amounts of peroxidase (donor:hydrogen-peroxide oxidoreductase, EC 1.11.1.7) enzyme activity in the uterus. This enzyme induction, which is inhibited by administration of actinomycin D and cycloheximide, can be detected at 4 hr after administration of estradiol, reaches a maximum level by 20 hr, and thereafter declines. The amount of uterine peroxidase seen at 20 hr after a single dose increases with dose from 0.1 to 100 microgram of estradiol. Estrone and estriol also show dose-dependent induction of peroxidase, and the quantitative peroxidase responses to these steroids follow their uterotropic capacities. The antiestrogen CI628, capable of low levels of enzyme induction by itself, can inhibit the induction due to estrogen. Solubilization of the uterine enzyme with divalent cations, especially calcium, results in a substantially increased yield of peroxidase. This extraction method provides an enzyme of about 50,000 molecular weight in distinction to the large aggregated form obtained by the usual extraction with sodium chloride.     

People with tuberculosis are associated with a subsequent risk of depression

BackgroundThere is some evidence that the prevalence of depression in patients with tuberculosis (TB) is higher than those in the general population. However, the incidence of depression after Mycobacterium tuberculosis infection remains unknown. Our aim was to assess the association between TB and the subsequent risk of depression.MethodsWe conducted a retrospective cohort study using data from the National Health Insurance (NHI) system of Taiwan. The TB cohort included 9020 patients who were newly diagnosed and recruited between 2000 and 2010. Each patient was randomly frequency-matched for age, sex and the year of index date with four people without TB from the general population. The newly diagnosed depression was followed up until the end of 2011. The relative risks of depression were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities.ResultsThe overall incidence rate of depression was 1.54-fold higher in the TB cohort as compared with the controlled cohort (8.15 vs. 5.29 per 1000 person-years, 95% confidence interval [CI] = 1.45–1.64). Stratified analyses by gender, age group, monthly income and comorbidities revealed that the adjusted hazard ratio (HR) of depression was higher in males as well as individuals older than 65 years with a low monthly income and comorbidities.ConclusionPeople who have been diagnosed with TB have a significantly higher risk of developing depression compared with those in the general population. We should pay more attention to this group of individuals and ensure that they are offered appropriate support.     

甲状腺过氧化物酶抗体球蛋白抗体微粒体抗体在甲状腺自身免疫性疾病中的改变

目的 观察甲状腺过氧化物酶抗体(TPO Ab)、甲状腺球蛋白抗体(TG Ab)和甲状腺微粒体抗体(TM Ab)在自身免疫性甲状腺疾病(AITD)中的改变,探讨TPO Ab在临床诊断和治疗上的作用和意义.方法 收集AITD患者,根据甲状腺功能不同分为甲状腺功能亢进(简称甲亢)组(Graves病、GD,57例)、甲低组(桥本氏甲状腺炎、HT,48例)、亚甲低组(41例)和AITD复诊组(甲状腺功能恢复正常1～6个月,41例).另取一级亲属无GD或HT的健康人群53例为对照组.采用放射免疫分析法检测血清中甲状腺自身抗体(TPO Ab、TG Ab和TM Ab)及甲状腺激素和促甲状腺激素(FT3、FT4,sTSH)水平.结果 甲亢组、甲低组和亚甲低组中TPO Ab阳性率(87.70%、97.20%、100.00%)均明显高于同组内TG Ab阳性率(43.90%、60.42%、48.78%)和TM Ab阳性率(43.90%、79.10%、60.98%);3种甲状腺自身抗体的阳性率和阳性患者的抗体水平均高于相应的对照组.AITD复诊组的TPO Ab阳性患者的抗体水平[(683.04±606.55)kU/L]明显低于甲亢组、甲低组和亚甲低组[(1049.31±941.00)、(106 440.79±272.38)、(5133.01±4449.67)kU/L].结论 TPO Ab在AITD的诊断更具有代表意义,抗体水平为AITD治疗及预后评估提供了重要的依据.     

Thyroid peroxidase as an autoantigen.

Thyroid peroxidase (TPO) evokes high-affinity, IgG-class autoantibodies [TPO autoantibodies (TPOAbs)] and TPO-specific T cells that are markers of thyroid infiltration or implicated in thyroid destruction, respectively. A diverse repertoire of human monoclonal TPOAbs, unparalleled in other autoimmune diseases, provides invaluable probes for investigating antibody epitopes. Human TPOAbs recognize an immunodominant region comprising overlapping A and B domains on conformationally intact TPO. Amino acids recognized by TPOAbs are located in the regions with homology to myeloperoxidase (MPO) and the complement control protein (CCP) but not in the epidermal growth factor (EGF)-like region. T cells recognize epitopes in the MPO-like region but not in the CCP- or EGF-like regions in humans. Monoclonal human TPOAbs modulate processing of TPO protein to provide peptides for some T cells. A human T cell clone expressed transgenically in mice induces lymphocytic infiltration and hypothyroidism. This T cell's epitope is only generated by thyrocyte processing of endogenous TPO. Further, intact TPO expressed in vivo is also required for induction of TPOAbs in mice that resemble human autoantibodies. Overall, some TPO-specific T cells and the majority of autoantibodies in humans develop in response to TPO presented by thyroid cells, rather than to TPO released by damaged thyrocytes.     

Thyroid-stimulating antibodies and thyroid stimulation-blocking antibodies during the pregnancy and postpartum period: a case report.

This report describes a unique pattern of changes in thyroid function and thyroid antibodies in a woman during the course of two pregnancies and two postpartum periods. A 25-year-old woman developed hypothyroidism in the postpartum period after the delivery of her first child. She was found to have potent thyroid stimulation-blocking antibodies (TSBAb) in the serum. One year later, she became pregnant again, and during the pregnancy, TSBAb had decreased to an undetectable level. She gave birth to the second healthy child and developed postpartum thyrotoxicosis, probably due to destruction of the thyroid gland, which gradually resolved. In this postpartum period, serum TSBAb levels increased. Eight months postpartum, she developed what appeared to be Graves' disease with an elevated 123I-thyroid uptake. Serum thyroid-stimulating antibodies (TSAb) were found at that time, and the TSBAb had disappeared from her serum.     

Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum

We have recently uncovered the presence of an oxytocin system in the heart and found that oxytocin is a physiological regulator of atrial natriuretic peptide (ANP), a diuretic, natriuretic and vasodilator cardiac hormone. However, dynamic changes in these systems during gestation, when mechanisms of volume and pressure homeostasis are altered, are not clear. Accordingly, ANP, oxytocin and oxytocin receptors were evaluated in rat hearts and plasma at three stages of gestation (7, 14 and 21 days) and at 2 and 5 days postpartum. Compared with non-pregnant controls, plasma ANP was elevated in mid-gestation, but significantly decreased at term (21 days), to increase again postpartum. Right and left atrial ANP mRNA levels were not altered throughout gestation but increased by 1.5- to 2-fold postpartum (P<0.01). At term, ANP content in right (8.7+/-1.2 vs 12.7+/-1.1 micro g/mg protein, P<0.04) and left (3.5+/-0.6 vs 8.5+/-2.0 micro g/mg protein, P<0.01) atria increased. These findings imply that decreased plasma ANP at term results from inhibition of release rather than decreased synthesis. In parallel, oxytocin, a stimulator of ANP release, decreased in left atria at day 7 to 50% of non-pregnant levels and remained low throughout gestation. Oxytocin receptor mRNA increased in left atria at 7 and 14 days of gestation by 2- and 5-fold respectively, but decreased at 21 days to lower than non-pregnant levels to increase again (3-fold) postpartum. The changes in oxytocin receptor expression at term and postpartum paralleled oxytocin receptor protein determined by Western blot. These results imply that pregnancy is associated with dynamic changes in the cardiac oxytocin system (peptide and/or receptors), which may influence natriuretic peptide release. Together, these peptides would act on their receptors in the heart, vasculature and kidneys to maintain vascular tone and renal function throughout gestation and postpartum.     

Transient ST-segment depression as a marker of myocardial ischemia during daily life

Patients with angina and coronary artery disease (CAD) have many episodes of transient ST-segment depression during ordinary daily life, and these are often asymptomatic. To investigate this signal as a marker of myocardial ischemia, 30 patients with chronic stable angina and CAD underwent positron tomography, recording the regional myocardial uptake of rubidium-82, pain and ST-segment changes before, during and after 59 technically satisfactory exercise tests, 35 cold pressor tests and 22 episodes of unprovoked ST depression. Exercise resulted in 53 episodes of ST depression with angina and in 5 episodes without pain. After cold pressor tests, there were 3 episodes of ST depression and pain and 12 of painless ST depression. Only 9 episodes of unprovoked ST depression were accompanied by pain. Tomography showed independent evidence of ischemia in 63 (97%) of the total 65 episodes of ST depression with angina and in all 30 episodes of painless ST depression. In each patient perfusion defects occurred in the same myocardial segment during painful and painless ST depression and responses were significantly different from those in 16 normal subjects studied in the same way. These findings support the use of transient ST depression in continuous monitoring to assess the activity of CAD, but only in patients with typical angina pectoris, ST depression during exercise and proved CAD. They strengthen the evidence derived from ambulatory monitoring for a wider picture of the disease than is generally appreciated, with more frequent episodes of silent myocardial ischemia than of angina pectoris.     

Usefulness of exercise-induced ST-segment depression in the inferior leads during exercise testing as a marker for coronary artery disease.

Multiple lead systems are shown to have a higher sensitivity than that of single leads for detecting coronary artery disease (CAD) during exercise testing, but the value of ST-segment depression isolated to the inferior leads is questionable. To ascertain the diagnostic accuracy of inferior limb lead II compared with that of precordial lead V5, a retrospective analysis of 173 men was performed (108 in a training population and 65 in a validation cohort). All patients had a standard exercise test and underwent diagnostic coronary angiography within 15 days of the exercise test (range 1 to 65). Sixty-three patients had greater than or equal to 1 coronary stenoses greater than or equal to 70%, or left main lesion greater than or equal to 50%, whereas 45 patients in the training population did not. Exclusion criteria were female sex, left ventricular hypertrophy, left bundle branch block or resting ST-segment depression on the baseline electrocardiogram, previous myocardial infarction or revascularization procedures, and any significant valvular or congenital heart disease. Lead V5 had a better combination of sensitivity (65%) and specificity (84%) (chi-square = 24.11; p less than 0.001) than that of lead II (sensitivity 71%, specificity 44%) (chi-square = 2.25; p = 0.13) at a single cut point, and this improved specificity was substantial (95% confidence interval for observed difference 22 to 58%). Receiver-operating characteristic curve analysis also revealed that lead V5 (area = 0.759) was markedly superior to lead II (area = 0.582) over multiple cut points (z = 3.032; 2p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)     

Thyroid peroxidase antibodies, levels of thyroid stimulating hormone and development of hypothyroidism in euthyroid subjects

ObjectiveThyroid peroxidase antibodies (TPOAbs) have been found to be related to the levels of thyroid stimulating hormone (TSH) and to predict future development of thyroid failure in selected populations. We investigated these relations in a euthyroid general population.DesignCross-sectional investigation of the relationship of TPOAbs and levels of TSH in euthyroid subjects. Prospective investigation of the association of TPOAbs and TSH with development of hypothyroidism. Incident hypothyroidism was defined as initiation of l-thyroxine in the absence of thyreostatic medication.SubjectsThe study was performed in a random sample of 2703 participants of the PREVEND study. A total of 309 subjects were excluded from analyses, mainly because of TSH outside the reference range (0.35–4.94 mIU/l; n = 115).ResultsMean (SD) baseline age was 47.7 (12.5) years, with 50.8% females. Prevalence of positive TPOAbs (≥ 12 kU/l) was 8.4%. TSH concentrations were increased in subjects with TPOAbs (P < 0.001). During a median follow-up of 9.1 years, 15 (0.6%) subjects developed hypothyroidism (3.5% in TPOAbs positive vs. 0.4% in TPOAbs negative subjects; P < 0.001). Female sex (P = 0.02), and TSH (P < 0.001) were also significantly associated with incident hypothyroidism. In multivariate analysis, TSH and TPOAbs remained independent predictors (both P < 0.001).ConclusionsWe confirmed the positive relationship of the presence of TPOAbs with levels of TSH and showed that TPOAbs and TSH predict future development of hypothyroidism. These results are consistent with the presence of TPOAbs necessitating a compensatory increase in levels of TSH for maintenance of euthyroidism, even in the euthyroid range.     

Neurocirculatory asthenia revisited: elevated arterial pressure at presentation is a marker for subsequent hypertension.

Neurocirculatory asthenia (NCA) is a fairly common functional disorder often encountered among military recruits. Symptoms in NCA tend to appear in waves, and are believed to disappear completely with the passage of time. Elevated arterial pressure is known to occur as part of the various haemodynamic manifestations of NCA. However, the exact prevalence of hypertension, as well as its long-term prognosis, is still unknown. The present case-control study was designed to address these two issues. The target population consisted of 370 patients with NCA representing two separate cohorts: patients diagnosed in 1979, 10 years prior to this study, and patients diagnosed in 1983-84, 5 years prior to the study. An overall 20% prevalence rate of mild hypertension at diagnosis was calculated for the entire study population. In total, 100 patients representing equal numbers of hypertensive and matched normotensive subjects from each cohort were re-evaluated. At follow-up, hypertension was present in 27% (1979 cohort) and 30% (1983-84 cohort) of patients originally considered to be hypertensive. Hypertension was either non-existent (1979 cohort) or limited to a single case (1983-84 cohort) among originally normotensive individuals. In parallel, resting heart rate was higher in the hypertensive subjects of the 1979 cohort both at presentation (85.5 +/- 3.2 vs. 73.7 +/- 2.4 beats min-1; P less than 0.005) and at follow-up (79.6 +/- 3.2 vs. 70.0 +/- 2.5 beats min-1; P less than 0.01). These results indicate that hypertension complicates the diagnosis of NCA in 20% of patients and that, contrary to common belief, it cannot be regarded as another transient manifestation of this condition. Thus hypertension in this context is, as in the younger members of the population in general, a major risk factor for lifelong hypertension, rather than an inconsequential phenomenon.     

Anti-Saccharomyces cerevisiae antibodies: a stable marker for Crohn's disease during steroid and 5-aminosalicylic acid treatment

OBJECTIVES: An increased prevalence of elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels in patients with Crohn's disease (CD) has been described. The aim of the present work was to investigate serum ASCA levels during the courses of prednisolone and mesalamine therapy in CD patients. METHODS: Serum samples of 25 patients with active CD were studied for ASCA levels before as well as 2 and 9 wk after initiation of a prednisolone tapering regimen. The influence of mesalamine (4 g o.d.) on serum ASCA levels compared to that of placebo was tested over 1 yr in 38 patients (20 mesalamine and 18 placebo) participating in a postoperative prophylaxis study. Serum IgG and IgA ASCA levels were measured by ELISA. Sera of 91 CD and 40 ulcerative colitis (UC) patients as well as 334 healthy donors were tested for ASCA to recalculate new cut-off values. RESULTS: For IgG ASCA cut-off values were determined to be 17.0 U and 25.0 U, and for IgA ASCA 9.3 U and 14.0 U. At baseline visit, 73.0% (46/63) of patients displayed serum ASCA positivity. During prednisolone therapy, a decrease in serum IgG and IgA ASCA levels from baseline to wk 2 (p < 0.0001 and p < 0.001, respectively) as well as to wk 9 (p < 0.001 and p = 0.01, respectively) was observed. A trend toward an association of ASCA positivity and steroid responsiveness was calculated (p = 0.07). During mesalamine treatment, no differences in changes of ASCA levels were observed compared to placebo at any time point. CONCLUSIONS: ASCA are stable markers during steroid and mesalamine treatment, highlighting their reliability for use in diagnosis of CD.     

Prevalence of antibodies to the core protein P17, a serological marker during HIV-1 infection.

Studies on monitoring the immune response to viral structural proteins during human immunodeficiency virus (HIV-1) infection have established the significance of antibodies to the core protein p24 during the progression of the disease. We have studied the prevalence of antibodies to the core protein p17 in order to study their diagnostic and prognostic significance in the pathogenesis of HIV-1. Full-length HIV-1 p17, molecularly cloned and expressed in Escherichia coli was purified by immunoaffinity chromatography using an HIV-1 p17-specific monoclonal antibody. A highly sensitive enzyme-linked immunoassay was developed using the purified recombinant p17 as the serological target to detect antibodies to p17. The results indicated that antibodies to p17 decline during progression of disease, with the decline being more dramatic as patients moved from asymptomatic to AIDS-related complex (ARC). Patient specimens deficient in p24 antibody, but having detectable levels of antibody to p17 were almost always positive for p24 antigen. Under these conditions, p17 antibody is an important serological marker because it provides a more consistent marker for core antigens during HIV-1 infection.