For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Professional phagocytes generate high levels of reactive oxygen species (ROS) using a superoxide-generating NADPH oxidase as part of their armoury of microbicidal mechanisms. The multicomponent phagocyte oxidase (Phox), which has been well characterized over the past three decades, includes the catalytic subunit gp91phox. Lower levels of ROS are seen in non-phagocytic cells, but are usually thought to be 'accidental' byproducts of aerobic metabolism. The discovery of a family of superoxide-generating homologues of gp91phox has led to the concept that ROS are 'intentionally' generated in these cells with distinctive cellular functions related to innate immunity, signal transduction and modification of the extracellular matrix.

NOX enzymes and the biology of reactive oxygen

Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...

https://www.thyca.org/download/document/486/PregnancyandPostpartum.pdf

2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum

Neutrophilic polymorphonuclear leukocytes (neutrophils) are highly specialized for their primary function, the phagocytosis and destruction of microorganisms. When coated with opsonins (generally complement and/or antibody), microorganisms bind to specific receptors on the surface of the phagocyte and invagination of the cell membrane occurs with the incorporation of the microorganism into an intracellular phagosome. There follows a burst of oxygen consumption, and much, if not all, of the extra oxygen consumed is converted to highly reactive oxygen species. In addition, the cytoplasmic granules discharge their contents into the phagosome, and death of the ingested microorganism soon follows. Among the antimicrobial systems formed in the phagosome is one consisting of myeloperoxidase (MPO), released into the phagosome during the degranulation process, hydrogen peroxide (H2O2), formed by the respiratory burst and a halide, particularly chloride. The initial product of the MPO-H2O2-chloride system is hypochlorous acid, and subsequent formation of chlorine, chloramines, hydroxyl radicals, singlet oxygen, and ozone has been proposed. These same toxic agents can be released to the outside of the cell, where they may attack normal tissue and thus contribute to the pathogenesis of disease. This review will consider the potential sources of H2O2 for the MPO-H2O2-halide system; the toxic products of the MPO system; the evidence for MPO involvement in the microbicidal activity of neutrophils; the involvement of MPO-independent antimicrobial systems; and the role of the MPO system in tissue injury. It is concluded that the MPO system plays an important role in the microbicidal activity of phagocytes.

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Myeloperoxidase: friend and foe

Objective: The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). Evidence: This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocri...

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Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline

Summary OBJECTIVE To evaluate the impact of maternal hypothyroxinaemia during early gestation (fT4 below the lowest tenth percentile and TSH within the reference range: 0·15‐2·0 mIU/l) on infant development, together with any subsequent changes in fT4 during gestation. DESIGN A prospective 3-year follow-up study of pregnant women and their children up to the age of 2 years. MEASUREMENTS Child development was assessed by means of the Bayley Scales of Infant Development in children of women with hypothyroxinaemia (fT4 below the tenth percentile at 12 weeks’ gestation) at 12 weeks’ gestation (cases), and in children of women with fT4 between the 50th and 90th percentiles at 12 weeks’ gestation, matched for parity and gravidity (controls). Maternal thyroid function (fT4 and TSH) was assessed at 12, 24 and 32 weeks’ gestation. The mental and motor function of 63 cases and 62 controls was compared at the age of 1 year, and of 57 cases and 58 controls at the age of 2 years. RESULTS Children of women with hypothyroxinaemia at 12 weeks’ gestation had delayed mental and motor function compared to controls: 10 index points on the mental scale (95% CI: 4·5‐15 points, P = 0·003) and eight on the motor scale at the age of 1 year (95% CI: 2·3‐12·8 points, P = 0·02), as well as eight index points on the mental (95% CI: 4‐12 points, P = 0·02), and 10 on the motor scale (95%CI: 6‐16 points, P = 0·005) at the age of 2 years. Children of hypothyroxinaemic women in whom the fT4 concentration was increased at 24 and 32 weeks’ gestation had similar scores to controls, while in the controls, the developmental scores were not influenced by further declines in maternal fT4 at 24 and 32 weeks’ gestation. CONCLUSIONS Maternal hypothyroxinaemia during early gestation is an independent determinant of a delay in infant neurodevelopment. However, when fT4 concentrations increase during pregnancy in women who are hypothyroxinaemic during early gestation, infant development appears not to be adversely affected. In the past decade, interest has been rekindled in the relationship between maternal plasma thyroid hormone concentration during pregnancy and subsequent infant neurodevelopment (Pop et al ., 1995, 1999a; Haddow et al ., 1999; Lazarus, 1999; Smit et al ., 2000). It is well known that both maternal thyroid dysfunction during pregnancy (especially hypothyroidism) and severe iodine deficiency adversely affect the outcome of neurodevelopment in children (Delange, 1994; Glinoer, 1997; Mestman, 1999). Even in areas in which there is sufficient iodine intake in the general population, pregnant women often have fT4 plasma levels in the lower ranges, without elevated TSH. This is defined as hypothyroxinaemia, and is generally regarded as a normal condition. However, there is growing concern that hypothyroxinaemia during early gestation could be harmful to the offspring (Pop et al ., 1999b; Utiger, 1999; Morreale de Escobar et al ., 2000). In fact, little is known about maternal fT4 levels during normal pregnancy, or their relationship to the development of the child. This paper describes the results of a longitudinal prospective study that investigates whether maternal thyroid hormone levels, assessed in women without (sub)clinical thyroid function at three different trimesters during pregnancy, are adversely related to child development at 1 and 2 years of age.

Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study

Background Several genetic defects are associated with permanent congenital hypothyroidism. Immunologic, environmental, and iatrogenic (but not genetic) factors are known to induce transient congenital hypothyroidism, which spontaneously resolves within the first months of life. We hypothesized that molecular defects in the thyroid oxidase system, which is composed of at least two proteins, might be involved in the pathogenesis of permanent or transient congenital hypothyroidism in babies with defects in iodide organification, for which the oxidase system is required. Methods Nine patients were recruited who had idiopathic congenital hypothyroidism (one with permanent and eight with transient hypothyroidism) and an iodide-organification defect and who had been identified by the screening program for congenital hypothyroidism. The DNA of the patients and their relatives was analyzed for mutations in the genes for thyroid oxidase 1 (THOX1 ) and 2 (THOX2 ). Results The one patient with permanent and severe t...

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Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism.

The fact that neonates who subsequently have severe hypothyroidism have no evidence of the condition at birth suggests the possibility of the placental transfer of thyroid hormones. Recent studies have demonstrated the existence of such transfer in hypothyroid rats. To determine whether there is a transfer of thyroxine (T4) from mother to fetus, we studied 25 neonates born with a complete inability to iodinate thyroid proteins and therefore to synthesize T4. This total organification defect is an autosomal recessive disorder with an incidence of approximately 1 in 60,000 neonates in the Netherlands. In the cord serum of affected neonates, T4 levels ranged from 35 to 70 nmol per liter. Since these patients were unable to produce any T4, the T4 must have originated in their mothers. The estimated biologic half-life of serum T4 was 3.6 days (95 percent confidence interval, 2.7 to 5.3). In 15 neonates with thyroid agenesis, the serum levels and the disappearance kinetics of T4 were the same as those in the neonates with a total organification defect, suggesting that in these infants, the T4 also had a maternal origin. We conclude that in infants with severe congenital hypothyroidism, substantial amounts of T4 are transferred from mother to fetus during late gestation.

Maternal-Fetal Transfer of Thyroxine in Congenital Hypothyroidism due to a Total Organification Defect or Thvroid Aaenesis

Presented is a cohort study to assess the nature and frequency of thyroid peroxidase (TPO) mutations in 45 patients (35 families) with congenital hypothyroidism due to a total iodide organification defect; incidence is 1:66,000 in The Netherlands. The presentation is consistently similar with a severe form of congenital hypothyroidism and also characterized by a complete and immediate release of accumulated radioiodide from the thyroid after sodium perchlorate administration. Sixteen different mutations were found, including eight novel mutations; the majority occurs in exons 8, 9, or 10. The GGCC insertion in exon 8 at nucleotide 1277, leading to an early termination signal in exon 9, is the most frequently occurring mutation. These mutations were detected in 29 families in both TPO alleles (13 homozygous and 16 compound heterozygous). In one family, partial maternal isodisomy of 2p was detected, in four families only one mutated TPO allele could be detected, and in one family no inactivating TPO mutation could be found. Because all patients clearly had the clinicopathologic features of a total iodide organification defect, we conclude that in these five families the mutations in the (other) alleles could be either located in the intronic sequences or in the promoter region. Mutations in the TPO gene result in total iodide organification defects.

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Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update).

Much worldwide attention is given to the adverse effects of maternal Graves’ disease on the fetal and neonatal thyroid and its function. However, reports concerning the adverse effects of maternal Graves’ disease on the pituitary function, illustrated by the development of central congenital hypothyroidism (CCH) in the offspring of these mothers, are scarce. We studied thyroid hormone determinants of 18 children with CCH born to mothers with Graves’ disease. Nine mothers were diagnosed after pregnancy, the majority after their children were detected with CCH by neonatal screening. Four mothers were diagnosed during pregnancy and treated with antithyroid drugs since diagnosis. Another four mothers were diagnosed before pregnancy, but they used antithyroid drugs irregularly; free T4 concentrations less than 1.7 ng/dl (<22 pmol/liter) were not encountered during pregnancy. All neonates had decreased plasma free T4 concentrations (range 0.3–0.9 ng/dl, 3.9–11.5 pmol/liter); plasma TSH ranged between 0.1 and 6....

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Jan J. M. de Vijlder

Papers

Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study

Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism.

Maternal-Fetal Transfer of Thyroxine in Congenital Hypothyroidism due to a Total Organification Defect or Thvroid Aaenesis

Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update).

Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed.