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Departments of Immunology (A.M., H.D.) and Internal Medicine (A.M.), Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands; and Department of Internal Medicine (A.B.), Medical Center Rijnmond Zuid, 3075 EA Rotterdam, The Netherlands
Correspondence: Address all correspondence and requests for reprints to: A. F. Muller M.D., Department of Internal Medicine, Diakonessenhuis Utrecht, Bosboomstraat 1, 3508 TG, Utrecht, The Netherlands. E-mail: amuller{at}diakhuis.nl
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Abstract |
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 Top Abstract I. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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I. Introduction
II. Epidemiology of Postpartum Thyroiditis
III. Thyroid Antibodies, Autoimmune Thyroiditis, and Postpartum Thyroiditis
A. Thyroid peroxidase and thyroglobulin (Tg) antibodies
B. TSH-receptor antibodies (TSH-R Abs)
IV. Cell-Mediated Immunity, Autoimmune Thyroiditis, and Postpartum Thyroiditis
A. Histology of postpartum thyroiditis
B. T lymphocytes
C. Natural killer (NK) cells
V. The Pathogenesis of Autoimmune Thyroiditis: A Polygenic, Multifactorial Disease. Are Multiple Factors Also Involved in the Outbreak of Postpartum Thyroiditis?
A. Genetic influences
B. Female gender, pregnancy, and thyroid autoimmune predisposition
C. Environmental factors, iodine intake
D. Environmental factors, toxins, and cigarette smoking
VI. Postpartum Thyroiditis Viewed as a Transient Exacerbation of a Preexisting and Ongoing Process of Autoimmune Thyroiditis
VII. The Clinical Course of a Postpartum Exacerbation of Autoimmune Thyroiditis
VIII. The Diagnosis, Follow-Up, and Treatment of a Postpartum Exacerbation of Autoimmune Thyroiditis
IX. Adverse Consequences of Autoimmune Thyroiditis During Pregnancy and Postpartum
A. Effects of autoimmune thyroiditis on conception and pregnancy
B. Consequences of autoimmune thyroiditis for the offspring
C. Consequences of autoimmune thyroiditis for older women
X. Screening, What and When?
XI. Conclusion
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I. Introduction |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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The syndrome of hypothyroidism after pregnancy was first described in 1948 by Roberton (10). Ginsberg and Walfish (11) recognized the classical thyrotoxic phase preceding this syndrome of puerperal hypothyroidism, and Amino et al. (12) highlighted its clinical importance in the 1980s. Subsequently, the clinical awareness of this condition has become widespread.
Postpartum thyroid syndromes distinct from postpartum thyroiditis have also been identified and include postpartum disturbances in thyroid function in patients with previous or current thyroid disease (2, 3, 13) and postpartum secondary hypothyroidism (14, 15). Combinations of these postpartum thyroid syndromes, as well as combinations of preexisting Graves’ disease and Hashimoto’s disease with postpartum thyroiditis, have also been described (16, 17, 18, 19).
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II. Epidemiology of Postpartum Thyroiditis |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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). This wide variation is largely due to
differences in the definition of postpartum thyroiditis
(39); on the other hand, variable and sometimes inadequate
ascertainment and follow-up play a role. Furthermore, in some studies
thyroid scintigraphy has been omitted in some of the thyrotoxic
patients, thus leading to a possible underestimation of postpartum
Graves’ disease. Apart from these methodological considerations,
environmental and genetic factors in the population are thought to play
a role in the variability of prevalence data.
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In patients with type I diabetes mellitus, higher frequencies of postpartum thyroiditis have been described. Gerstein (40) performed a prospective cohort study of 51 pregnant subjects with type I diabetes who were not taking thyroid medication. Forty patients completed follow-up. Thyroid dysfunction occurred in 10 patients: thyroiditis developed in 9 and Graves’ disease in 1 patient during the first 6 months after delivery (40). Alvarez-Marfany et al. (41) followed 41 women with type I diabetes mellitus, 28 of whom completed follow-up at 31 months postpartum: seven subjects developed thyroiditis. Thus, the incidence of postpartum thyroiditis in type I diabetes mellitus is at least 15%.
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III. Thyroid Antibodies, Autoimmune Thyroiditis, and Postpartum Thyroiditis |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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). Indeed,
if a pregnant women is positive for TPO antibodies early in pregnancy,
her chances of developing postpartum thyroiditis are 30–52% (4, 42, 43, 44).
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Evidence for a pathogenetic role of TPO complement-fixing antibodies is circumstantial. Activation of the complement cascade—an important mechanism for lysis of target cells in immune processes—is associated with the IgG subclasses 1, 2, and 3 (57). With regard to postpartum thyroiditis Parkes et al. (58) used both the complement fixation and complement C3 activation index to quantify the interaction of the complement system with thyroid antigen/antibody-complexes. They studied 152 TPO antibody-positive women and an equal number of TPO antibody-negative women. Seventy-five of the TPO antibody positive women remained euthyroid during the postpartum year, and 73 showed biochemical signs of postpartum thyroiditis. The authors provided evidence that the onset and progression of thyroid dysfunction in women with TPO antibodies was not only a function of the titer of the TPO antibodies present, but also of their ability to activate the complement system (58). Also, in another study, the same authors showed that the severity of postpartum thyroiditis, as indicated by the duration of thyroid dysfunction, is related to the ability of TPO antibodies to interact with and activate the complement system (59).
Regarding the IgG subclasses of TPO antibodies Jansson et al. (60) found that the relative concentration of IgG1 TPO antibodies was significantly increased in women who became hypothyroid. Hall et al. (61) showed significant relative elevations in IgG2- and IgG3-associated TPO antibody activity in women who developed a biphasic thyroid dysfunction. The relative IgG3 elevation coincided with the onset of thyrotoxicosis. Briones-Urbina et al. (62) found raised IgG1- and IgG2-associated TPO activity and low IgG3-associated TPO antibody activity in women with postpartum thyroiditis. However, Weetman et al. (63) found no differences in IgG subclass-associated TPO antibody distribution between women with postpartum thyroiditis and controls. Therefore, at present, there is no agreement on the significance of the subclass of TPO antibodies in postpartum thyroiditis. What seems clear, however, is that the IgG4-associated TPO antibody activity—which is non-complement-activating—remains unchanged in the postpartum period (60, 62, 63).
Although the association of TPO antibodies with postpartum thyroiditis
is strong, a causative role of these antibodies in the pathogenesis of
this syndrome remains unclear. In Hashimoto’s thyroiditis, antibodies
to TPO are thought to play only a secondary aggravating role in
addition to other immune destructive mechanisms (6, 55)
(Fig. 2). TPO antibodies are indeed able
to bind to thyroid follicular cells and to activate the complement
system and to set in motion antibody-dependent cell mediated
cytotoxicity (ADCC) (see below). However, it is relevant to recall
that: 1) TPO is only expressed at the apical border of thyroid
follicular cells in a position where it is hardly accessible to
circulating antibodies if the follicles are intact (64);
2) there is only a weak association between complement-fixing thyroid
cytotoxic antibodies and hypothyroidism in chronic autoimmune
thyroiditis, these antibodies being found even in sera of euthyroid
patients (56); 3) babies born to mothers with chronic
autoimmune thyroiditis and circulating TPO antibodies have normal
thyroid function (65); 4) circulating TPO antibodies are
found in sera of a consistent percentage of euthyroid elderly women
(66).
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In conclusion, there is a strong association between the presence of TPO antibodies and the risk of developing postpartum thyroiditis. However, there are several good arguments against a role of TPO antibodies as the primary disruptive event in the pathogenesis of postpartum thyroiditis.
B. TSH-receptor antibodies (TSH-R Abs)
The number of studies on the role of TSH-R Abs in postpartum
thyroiditis is limited. In a study from the United Kingdom TSH-R Abs
were found in none of 37 women who experienced a thyrotoxic phase of
postpartum thyroiditis (59). In North America and Japan,
however, TSH-R Abs have been reported to occur in postpartum
thyroiditis, particularly in the thyrotoxic phase. In a study of 25
Japanese postpartum women, TSH binding inhibitory Igs (TBII) were
present in six, and in five of these thyroid-stimulating antibody
(TSAb) activity was high. This study showed, additionally, that the
hypothyroid phase was associated with an increased activity of TBII
and/or a disappearance of TSAb activity (69). In another
Japanese study of 71 TPO antibody-positive subjects in early pregnancy,
7 were also positive for TSH-R Abs, and all 7 developed thyroid
dysfunction in the postpartum period. Five developed Graves’ disease,
and the remaining 2 developed transient hypothyroidism
(70).
Interestingly, some case reports from North America have described postpartum thyroiditis preceding the onset of Graves’ disease (71, 72). On the basis of an extensive immunological evaluation of two of these cases, Sarlis et al. (71) have proposed a possible pathogenic association in which TSH-R Abs play a role in the transient phases of thyrotoxicosis and hypothyroidism in the postpartum period. The authors demonstrated heterogeneity in TBII and showed the presence of stimulating TSH-R Abs activating either the cAMP or the phosphatidylinositol 4,5-bisphosphate signal cascades at the time of diagnosis of postpartum Graves’ disease. It was therefore suggested that susceptible individuals might develop an immunological response that can trigger the appearance of a mixture of species of TSH-R Abs, which may lead to the sequential occurrence of painless thyroiditis and Graves’ disease after pregnancy. The multiple phases of thyrotoxicosis and hypothyroidism that can occur in these patients may then reflect the existence and changing spectrum of the various TSH-R Abs in their sera (71). In our area—The Netherlands—however, the prevalence of TSH-R Abs is very low (0.3%), and until now—as in the United Kingdom—cases of TBII-positive postpartum thyroiditis have not been reported. We are thus of the opinion that in Western Europe TSH-R Abs in the postpartum period should be taken as reflecting de novo or relapsing Graves’ disease (and not of postpartum destructive thyroiditis in the sense we discuss it here).
Interestingly, several studies have found that the first postpartum year not only constitutes an important risk factor for the development of autoimmune destructive thyroiditis, but also of Graves’ disease (73, 74, 75, 76). With regard to persistent thyrotoxicosis after pregnancy, Hayslip et al. (77) tested serum for the presence of TSH-R Abs in three such cases, all of which were positive for both TBII and TSAb. The authors also tested 21 women with classical postpartum thyroiditis for TSH-R Abs. Only one woman with hypothyroidism had high levels of TSH-R Abs when she was hypothyroid and 1 month after initiation of T4 therapy.
In conclusion, exacerbation of existing Graves’ disease or de novo Graves’ disease does occur after pregnancy. However, studies differ in prevalence between North America and Japan vs. Europe. It would be of interest to study the onset of Graves’ disease in relation to the puerperal period in larger prospective studies.
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IV. Cell-Mediated Immunity, Autoimmune Thyroiditis, and Postpartum Thyroiditis |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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First, autoreactive T lymphocytes must be involved in the autoimmune process because the autoreactive B lymphocytes need the help of T-helper 2 (TH2) lymphocytes to produce the TPO and Tg antibodies of the IgG isotype (90). TH2 lymphocytes bear the marker CD4 and produce the B cell-stimulatory cytokines IL-4 and IL-5 (91). Another TH2 type cytokine is IL-10, which has immunosuppressive capabilities, particularly for cell-mediated immune destructive mechanisms (92, 93). Hence TH2 lymphocytes are presently considered as relatively harmless for target cells in endocrine autoimmune diseases, also because the antibodies play only a secondary role.
Apart from TH2 lymphocytes, there is a subset of T cells that is also
CD4+, the so-called T-helper 1 (TH1) lymphocytes. These cells
are—unlike TH2 cells—well equipped to stimulate the cytotoxic and
cytolytic arm of the cell-mediated immune system, e.g., to
activate macrophages and natural killer (NK) cells via cytokines such
as 
-interferon (IFN) to kill target cells (94) (Fig. 2
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In addition to CD4+ TH1 cells, T lymphocytes of CD8+ phenotype are also
generally involved in the destruction of target cells (Fig. 2)
(6). These cytotoxic cells recognize autoantigens directly
on target cells when in the context of major histocompatibility complex
(MHC) class I molecules. Target cells are killed by CD8+ T lymphocytes
via perforin and other cytotoxic molecules.
The balance between life and death of target cells is also regulated by proapoptotic and antiapoptotic factors operative in the target cells when under immune attack. Proapoptotic signal generation by the death receptor CD95—also known as Fas— requires recruitment and activation of downstream initiator and effector caspases (a family of cysteine proteases that catalyze the enzymatic and catabolic reactions that lead to cell death), which can be antagonized by antiapoptotic molecules such as members of the bcl-2 family and cFLIP (95, 96).
The interaction between CD95 and its ligand CD95L has recently been
proposed as a major mechanism for autoimmune thyrocyte destruction in
Hashimoto’s thyroiditis (97, 98). CD95L is constitutively
expressed on thyrocytes (99). After autoimmune T and B
cell inflammation, thyrocytes also start to express CD95 in
Hashimoto’s thyroiditis. The thyrocytes are therefore likely to die
through "suicide" or "fratricide" (100). Although
CD8+ T cells do occur in high numbers in Hashimoto’s thyroiditis, a
direct cytotoxic effect of CD8+ infiltrating T lymphocytes is, however,
less likely as a major contributor to thyrocyte destruction: CD8+ T
cells that approach thyrocytes are CD95 positive and are thereby
themselves vulnerable to apoptosis via the CD95L expression by
thyrocytes (99). It is probably the secretion of TH1
cytokines by CD4+ and CD8+ T cells in Hashimoto’s thyroiditis that is
important: IFN activates infiltrating macrophages to become
cytolytic/cytotoxic, while the cytokine also promotes the caspase
up-regulation and CD95-induced apoptosis in thyrocytes of Hashimoto’s
glands (6, 101). There are indications that in Graves’
disease T cell infiltrates work differently—although up-regulating
CD95 on thyrocytes, the T cells now also up-regulate
antiapoptotic mechanisms (cFLIP and Bcl-xl) in the thyrocytes due to
their TH2 type character. The final outcome is then nondestructive
(102).
There are many studies on immune cell abnormalities in postpartum thyroiditis. These will be reviewed below. Collectively, these studies support the notion that such mechanisms play a role and that indeed the syndrome should—at least in part—be regarded as belonging to the spectrum of autoimmune thyroid diseases.
A. Histology of postpartum thyroiditis
The histological features of postpartum thyroiditis are entirely
consistent with an autoimmune etiology. Two types of thyroidal lymphoid
cell infiltrates are normally observed in classical Hashimoto’s
thyroiditis:
1. Destructive infiltrates (103). These infiltrates do not show a recognizable pattern of topological organization and consist of mixtures of CD4+ and CD8+ T lymphocytes, macrophages, NK cells, and some B lymphocytes. The infiltrating cells are found in areas of destroyed thyrocytes, which are CD95 and CD95L positive. The milieu of the infiltrates is presumably of TH1 character, promoting its cytolytic potential (91).
2. Focal accumulations of lymphoid cells with a high degree of histological organization (104). These infiltrates are not destructive and may be found side-by-side intact thyrocytes in mild forms of Hashimoto’s autoimmune thyroiditis (focal thyroiditis). They can also be seen in Graves’ disease (105, 106, 107). The infiltrates represent intrathyroidally developed lymphoid tissue of an architecture similar to that of mucosa-associated lymphoid tissue. Such thyroid-associated lymphoid tissue is composed of T cell zones, B cell follicles, and plasma cells in the periphery of the focal infiltrate. Sometimes the plasma cells extend in cord-like structures radiating from the lymphoid tissue between the thyroid follicles. We presume that this lymphoid tissue is involved in the generation of the actual thyroid autoimmune reaction, including the production of autoantibodies (108). The T cell zones of the intrathyroidal lymphoid tissue consist of CD4+ and CD8+ lymphocytes in a ratio of about 2–3:1. The function of the T lymphocytes in these focal accumulations is thought to be the regulation of the autoimmune response. In Graves’ disease, such infiltrates presumably have a TH2 pattern of cytokine production that might confer a defense against apoptotic destruction.
With regard to postpartum thyroiditis, Mizukami et al.
(109) described histological and immunohistochemical
findings of thyroid tissue in a series of 15 patients with this
disease. Histology revealed both the focal organized and the diffuse
destructive type of lymphocytic thyroiditis with folliculolysis and
disruption. Intact follicles showed mild epithelial hyperplasia. There
was no difference between the hypothyroid and early recovery phase.
Three specimens from the late recovery phase showed only histological
features of focal thyroiditis without follicular destruction.
Unfortunately, there are no histological data on patients with
permanent hypothyroidism after an episode of postpartum thyroiditis.
The immunohistochemical examination by Mizukami et al. (Ref.
109 , but see Ref. 110) as well also
showed a significantly increased expression of MHC class II antigen on
thyroid follicular cells. Since inflammatory T cell cytokines, such as
IFN, up-regulate MHC class II expression on thyrocytes, such
expression probably indicates a local production of such cytokines by
infiltrating T cells (111, 112). The importance of MHC
class II expression on thyroid epithelial cells is no longer viewed as
a sign of the thyrocytes’ capability to present antigen to T cells.
Although capable of stimulating T cells, other professional
antigen-presenting cells in their vicinity, such as the dendritic
cells, are better in such function. The MHC class II expression
of the thyrocytes is therefore just a sign of the TH1 pattern of
cytokine production in their vicinity, which will actually contribute
to their destruction.
B. T lymphocytes
Chan and Walfish (113) studied the expression of MHC
class II as a marker of T lymphocyte activation. Of 28 postpartum
patients, 4 were studied in the thyrotoxic phase and 11 in the
hypothyroid phase, and the remaining 13 were euthyroid after a
previously documented hypothyroid or thyrotoxic phase. Patients in the
thyrotoxic phase had a significantly increased proportion of
circulating activated T lymphocytes. Similar data were not provided for
patients in the hypo- and euthyroid phases. When CD4 and CD8 subsets
were quantified, patients in the hypo- and euthyroid states had
significantly higher percentages of the CD4+ subset and significantly
lower percentages of the CD8+ subset, leading to higher CD4/CD8 ratios
compared with thyrotoxic patients.
Stagnaro-Green et al. prospectively followed 33 thyroid autoantibody-positive and 28 antibody-negative women during pregnancy and 6 months postpartum. Evidence of T cell activation (i.e., raised numbers of MHC-class II+ cells) was found in the postpartum period, and a higher CD4/CD8 ratio occurred in women developing postpartum thyroiditis compared with normal postpartum TPO antibody-negative controls (34).
In a prospective study of 291 women, 15 of whom developed postpartum
thyroiditis, Kuijpens et al. studied various cell-mediated
immune parameters including the number of circulating MHC-II+ T
lymphocytes in pregnant women from 12 wk of gestation until 9 months
postpartum. They too detected T cell activation in TPO-positive women
subsequently developing postpartum thyroiditis: percentages of MHC-II+
T cells were significantly higher at all time points studied (12 and 32
wk of gestation and 4 wk postpartum) in TPO-positive women developing
postpartum thyroiditis compared with TPO-positive women not developing
the disease (26) (Fig. 3).
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Jansson et al. (114) investigated circulating, as well as intrathyroidal, lymphocyte subsets in different stages of postpartum thyroiditis. The authors were unable to find differences in circulating lymphocyte subsets between 9 thyrotoxic and 18 hypothyroid patients vs. normal controls. Intrathyroidal lymphocyte subsets obtained by fine-needle aspiration were comparable in the 10 hypothyroid and the 3 thyrotoxic patients with adequate aspirates (in normal subjects, intrathyroidal lymphocytes are absent). The authors found differences between subset distribution in the thyroid and the circulation. There was a relative accumulation of B cells within the thyroid of hypothyroid patients compared with peripheral blood. Also, a relative decrease in intrathyroidal CD8+ T cells resulted in higher CD4+/CD8+ ratios in the thyroid aspirates than in the blood of hypothyroid patients with postpartum thyroiditis. According to the authors, these data are compatible with the local synthesis of thyroid-directed autoantibodies in postpartum thyroiditis (114). However, in our opinion these data just highlight the different migration and homing patterns of the various subsets of immune cells to sites of chronic inflammation.
C. Natural killer (NK) cells
Apart from the CD3+ T cells and the CD19+ CD20+ B cells, there is
yet another subset of lymphocytes important in cell-mediated immunity.
These are the NK cells or large granular lymphocytes. NK cells are
lymphocytes with distinct morphological and functional properties.
Their cell surface classically expresses CD16 and CD56 antigens. NK
cells are able to kill tumor cells without the need for prior
sensitization. NK cells are activated by IL-2, IFN
, and -ß and
particularly by IL-12. The cells have two main mechanisms of target
cell killing.
The first mechanism is ADCC. Fc receptor-bearing cells, such as the NK cells and macrophages, are capable of binding to the thyrocyte via a linking of their Fc receptors with antibodies bound to the surface of thyrocytes. Once activated, the NK cells lyse target cells via the release of perforin and lymphotoxin (6, 115, 116).
The second mechanism makes use of cell-cell contact in which special,
yet ill defined, lectin-like NK-receptors, known as NKR-P1 receptors,
recognize glycosylated surface molecules on target cells. Once
activated, the NK cells lyse target cells again via the release of
perphorin and lymphotoxin. NK cells are also able to secrete cytokines
such as IFN, which further promotes the cellular immune response and
recruits T cells. Interestingly, NK cells (but also the CD8+ cytotoxic
T lymphocytes) possess, in addition to the above described receptors
that activate the killing machinery in the cell, special inhibitory
receptors. These so-called killer cell inhibitory receptors (KIRs) are
able to recognize MHC class I molecules. Hence, when target cells
abundantly express MHC-class I molecules, NK cells will not be able to
kill these cells (116).
Neither Hayslip et al. (77) nor Hidaka et al. (117) observed a difference in functional NK activity of peripheral blood lymphocytes in patients with postpartum thyroiditis compared with normal postpartum women. However, when Hidaka et al. (117) analyzed serial changes of NK cell activity in individual patients they found a significant increase in NK activity during the postpartum phase of thyrotoxicosis caused by either destructive thyroiditis or Graves thyrotoxicosis (around 2–4 months postpartum). This might suggest that thyrotoxicosis per se stimulates NK cell activity. Indeed, IL-12—a NK activating cytokine—is raised in the thyrotoxic state (118).
We, ourselves, should also realize that NK cells are not only involved in target cell lysis, but also act in the regulation of the B and T cell growth and activation (119). Changes in NK cell numbers and activities may therefore not only serve defense mechanisms directly, but may also reflect altered setpoints in the immune system. This latter notion may explain observations by Kuijpens et al. (26). These investigators found that NK cell levels were not associated with postpartum thyroiditis itself, but with TPO antibody positivity: TPO antibody-positive pregnant women had low percentages of circulating NK cells. There was no difference between those developing postpartum thyroiditis and those who did not. Interestingly, NK cell numbers are also low in states of psychological depression and may therefore reflect altered setpoints in the hypothalamo-pituitary-adrenal axis, which occurs in severely depressed patients.
In conclusion, changes in NK cell numbers and activities have been found in postpartum thyroiditis, but the role of NK cells in the development of postpartum thyroiditis remains uncertain. Clearly, further research is needed.
When the above described data on TPO antibodies, complement, activated T cells, apoptosis, and the histology of postpartum thyroiditis are combined, a picture is emerging that at least part of the postpartum thyroiditis cases must be regarded as aggravations of an ongoing process of thyroid autosensitization, leading to an enhanced violation of thyrocyte integrity. When their cases of postpartum thyroiditis are studied in detail, it is relevant to note that Kuijpens et al. (26) came to the conclusion that two forms of postpartum thyroiditis might exist, an autoimmune and a nonautoimmune form. The autoimmune form, 10 of their relatively low number of 15 cases, was immunologically characterized by the presence of TPO antibodies and various cell-mediated immune disturbances. The nonautoimmune form, 5 cases, lacked any sign of immune involvement. These latter cases were also different in their symptomatology in that they experienced only a mild transient phase of thyrotoxicosis. Further research on larger series of postpartum thyroiditis cases is necessary to confirm or refute the existence of two such forms and their associated clinical implications.
In postpartum thyroiditis the rapid destruction of thyroid follicles is most frequently followed by a recovery of thyroid function. At present, it is largely unclear how the immune system generally regains equilibrium after activation; and this is also the case for the recovery phase after postpartum thyroiditis. A few mechanisms have been discussed in this respect (74). First, apoptosis of T cells can be induced by exposure to large amounts of antigen. The transience in postpartum thyroiditis might thus be due to the induction of clonal apoptosis of thyroid-specific T cells that may follow the release of thyroid antigens in the circulation when many thyrocytes lose their integrity. Second, it is now known that cells traffic between fetus and mother during normal human pregnancy (120), and particularly the delivery is a time for major entry of fetal cells into the mother’s circulation (121). It has therefore been hypothesized that if tolerance to these microchimeric cells develops, immuno-tolerogenic mechanisms similar to those observed during pregnancy are involved, and that this may lead to an attenuation of the thyroid autosensitization (74, 122). Indeed, in a mouse model it has recently been shown that in 60% of pregnant animals with experimentally induced thyroiditis fetal cells were present within the maternal thyroid, as compared with no fetal cells in the thyroids of the control mice (123, 124). Also the induction of PRL secretion as a result of breast-feeding is a factor that could play a role in the transient character of postpartum thyroiditis. PRL is able to influence immune function (125). Human T and B lymphocytes contain PRL receptors, the immuno-incompetent state in hypophysectomized mice is restored by PRL administration, and antibodies to PRL can inhibit lymphocyte proliferation (126, 127, 128). The effects of hyperprolactinemia on human immune function have, however, not been clearly elucidated. With respect to breast-feeding and the occurrence of postpartum thyroiditis, it should be noted that in a prospective study no relation between breast-feeding and postpartum thyroiditis was noted (21).
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V. The Pathogenesis of Autoimmune Thyroiditis: A Polygenic, Multifactorial Disease. Are Multiple Factors Also Involved in the Outbreak of Postpartum Thyroiditis? |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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)
(6, 87). The interaction of various permissive
environmental factors with an immune system that fails to distinguish
adequately between self and nonself leads to the activation of a
plethora of pathogenic immune mechanisms. In the animal models an
afferent stage of enhanced autoantigen presentation, a central stage
with excessive expansion and maturation of autoreactive T and B
lymphocytes, and an efferent stage of the pathogenic effects of
autoreactive T lymphocytes and B lymphocytes on their targets can be
discerned (Fig. 4). In each stage, endogenous and/or exogenous factors
are able to elicit the abnormalities characteristic of that stage (Fig. 4). Only combinations of genetic susceptibilities, gender, and
environmental factors, such as infectious agents, dietary factors, and
toxins, lead to clinically overt autoimmune disease.
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). Genetic factors are not the only
determinants in the development and progression of the disease. This is
elegantly illustrated by studies of chronic autoimmune hypothyroidism
in twins (129). Genetic susceptibility is implicated in
autoimmune thyroid disorders by concordance rates that are higher in
monozygotic pairs than in dizygotic pairs. However, the fact that the
concordance rate among monozygotic twins is always below 1 strongly
suggests that environmental factors also are of etiological
importance.
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)
(87). There is a strong association between the genetic
inheritance of the MHC molecules HLA-DR3, -DR-4, and -DR-5 and the
occurrence of thyroid-specific autoimmune diseases (131).
It is thought that these MHC molecules and the associated DQ molecules
represent structures with an enhanced capability to present the major
thyroid antigens TPO and Tg to T cells (57).
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) (133). The CTLA-4 locus has recently been linked to and
associated with the occurrence of Graves’ disease and
thyroid-associated orbitopathy as well as with the occurrence of type I
diabetes (134, 135, 136, 137).
With regard to postpartum thyroiditis, several authors have reported an
association between the syndrome and HLA-DR3 (34, 138, 139, 140), HLA-DR 4 (5, 141, 142), and HLA-DR5
(35, 61, 139, 143) (Table 2). Jansson et al.
(5) found that all three women who developed permanent
hypothyroidism were HLA-DR5 positive, suggesting that this phenotype
might be related to the development of permanent hypothyroidism. In a
population-based case-control study in the United Kingdom including 122
women (of whom 58 had TPO and/or Tg antibodies and 64 had postpartum
thyroiditis) and 161 thyroid autoantibody-negative controls, no
significant association was found between the CTLA-4 polymorphism and
postpartum thyroiditis (144).
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B. Female gender, pregnancy, and thyroid autoimmune
predisposition
Thyroid autoimmune diseases have a predilection for the female
gender (145, 146). The female-male ratio for most thyroid
diseases is 4:1 (147, 148). Likewise, in the NOD mouse
model, females are more prone to autoimmune diseases. Castration of
young males increases the prevalence rates of type I diabetes mellitus
at a later age, indicating a protective role of T. Indeed, when the
male castrated NOD mice are treated with T, autoantibody levels and
autoimmune inflammation decrease again (149, 150).
However, castration of young female NOD mice does not lead to a
significant lowering of autoimmune insulitis; neither does treatment
with supraphysiological doses of E of NOD mice lead to an acceleration
of autoimmunity (150). In other animal models of
autoimmune disease (systemic lupus erythematosus models) E
administration does have some accelerating effects (151).
This might indicate that the role of female hormones is limited in
endocrine autoimmune diseases. In human male-to-female transsexuals
castration followed by treatment with female hormones did not induce
higher levels of TPO antibodies compared with the normal female
population (152). This illustrates the complexity of the
phenomenon of T-induced immunosuppression and highlights the danger of
extrapolating from animal data to the human situation.
During pregnancy many patients with autoimmune disorders experience a remission (148, 153, 154, 155, 156). The explanation for this phenomenon is based on a heightened state of immune tolerance induced by the pregnant state (157, 158). Adaptation of the maternal immune system is essential for immune tolerance of the fetus, since the fetus expresses paternal MHC molecules (157, 158).
The placental immune system plays a central role in the acceptance of
the fetus (159, 160, 161). In early and successful pregnancies
nonclassical NK cells (with a distinctive phenotype: CD56+ CD16-
CD3-) and macrophages accumulate in the decidua at the feto-maternal
interface. These cells exert only a low cytolytic activity on the fetal
trophoblastic cells and play a primary role in placental morphogenic
processes and down-regulate the local immune response
(162). The functions of these local immune cells are
governed by various mechanisms, such as the expression on the
trophoblastic cells of a special paternally imprinted MHC-class I
molecule, i.e., HLA-G, and also by the local production of
various pregnancy-associated proteins and hormones (93, 121, 163). These proteins and hormones include the enzyme indolamine
2,3 dioxygenase involved in tryptophan metabolism (164, 165), a pregnancy-specific glycoprotein encoded by the gene
PSG11 and the hormones progesterone, E2, and human CG (hCG). These
later hormones have, in addition to their local placental effects,
systemic effects (163, 166). Particularly progesterone is
an important contributor to pregnancy-associated immunomodulation
(167). Immunological effects of progesterone are partly
mediated by a protein fraction of 34 kDa: the so-called
progesterone-induced blocking factor (PIBF) (168, 169).
This factor is produced by progesterone-exposed activated T cells and
affects both placental NK cells and macrophages, but also the
circulating cells (168, 169, 170). PIBF is endowed with
immunomodulatory properties such as a strong regulating activity on
perforin expression by NK cells (158, 169, 171). It also
affects the TH1/TH2 balance via an increased production of IL-3, IL-4,
and IL-10 and a decreased production of IL-12 from lymphocytes and
macrophages (158). Treatment with anti-PIBF induces a
shift toward a TH1 response (decreased IL-10 and increased IFN
production) and leads to increased rates of pregnancy resorption
(172).
E2 has a similar effect on the TH1/TH2 balance (163). In
neuroantigen-specific T cell clones, E2 showed a dose-dependent
enhancement of antigen-stimulated IL-10 secretion. The secretion of
IFN was also enhanced but the maximum enhancement occurred at
lower E2 concentrations and at lower magnitudes than observed for IL-10
(173).
Interestingly, progesterone induces hCG release from the trophoblast through its stimulation of TH2-type cytokines (158, 166, 170). hCG subsequently stimulates progesterone production from the corpus luteum (166), thus creating a positive feedback loop.
In conclusion, various factors, but particularly hormonal factors, down-regulate TH1-mediated effector arms of the immune system during pregnancy.
A rebound reaction to the above described pregnancy-associated immunomodulations is thought to induce the aggravation of thyroid autoimmune syndromes in the puerperal period. If, indeed, autoimmune thyroid failure is induced by TH1 mechanisms while TPO antibodies are secondary to thyroid destruction, a TH2 to TH1 "return shift" in the puerperium might explain the outbreak of postpartum thyroiditis. However, considering the shift from TH1 to TH2 immune response during pregnancy, the amelioration of Graves’ disease frequently observed during pregnancy remains puzzling, since this disease is considered to be a typical TH2-type disease. Apparently, immunomodulating mechanisms other than TH1/TH2 shifts also play a role in pregnancy.
Interestingly, and from a clinical point of view, important, the fall in TPO antibodies during pregnancy is not associated with an improvement of thyroid function. In a prospective study of 87 thyroid antibody-positive women with normal thyroid function at the time of initial screening, Glinoer et al. (174) found that despite the expected decrease in the titers of thyroid antibodies during gestation, thyroid function showed a gradual deterioration toward subclinical hypothyroidism. This is due to the fact that pregnancy in itself, in addition to the above described immunological phenomena, affects thyroid function directly since there is an increased demand for thyroid hormones. Three independent factors concur to exert stimulatory effects on the thyroid machinery to fulfill this increased demand. The first factor is the thyroidal response in the first trimester to adjust to the marked increase in the circulating levels of T4 binding globulin, the latter due to increased E production from the placenta. The second factor is related to the thyrotropic action of hCG, also occurring in the first trimester. The third factor, operative later in gestation, is related to modifications in the peripheral metabolism of thyroid hormones, particularly at the placental level (175, 176).
C. Environmental factors, iodine intake
Both iodine excess and iodine deficiency are capable of disturbing
an existing tolerance for thyroid autoantigens. Most important in this
respect is an iodine excess in autoimmune-prone individuals
(177, 178, 179). After the introduction of iodine
supplementation to a population, a rise in thyroid autoantibodies and a
higher incidence of lymphocytic thyroiditis has been observed
(180, 181, 182, 183, 184). In goitrous NOD mice, OS-chickens, or BB-DP
rats, a high iodine intake induces a rise in the titer of thyroid
autoantibodies and an outburst or acceleration of lymphocytic
thyroiditis in these animals (185, 186, 187).
Proposed pathogenic mechanisms of this iodine-induced thyroid autoimmunity are: 1) an iodine-induced thyrocyte necrosis with an increased release of autoantigens resulting in an enhanced attraction of antigen-presenting cells (188, 189); 2) a higher antigenicity of Tg due to a higher iodination grade (190, 191, 192); and 3) a direct stimulation of B lymphocytes, T lymphocytes, dendritic cells and macrophages by iodine or iodinated substances.
The prevalence of postpartum thyroiditis does not seem to be related to
the iodine intake status of a population (Table 1). Interestingly, in
this respect, in a case-control study, Othman et al.
(193) did not observe a difference in iodine excretion in
the immediate postpartum period between 73 women who developed
postpartum thyroiditis and those 135 women who did not. With regard to
the effect of changes in iodine intake on the occurrence of postpartum
thyroiditis, the data are conflicting. On the one hand, there are data
indicating that increased iodine intake can influence the severity of
thyroid dysfunction in postpartum thyroiditis. In Sweden, an
iodine-sufficient area, Kämpe et al. treated 20 women
who were TPO positive in early pregnancy with iodine (0.15 mg/d) for 40
wk postpartum. In those women who developed thyroid dysfunction, TSH
levels were higher and T4 levels were lower
compared with the group who received no medication (194). On the other
hand, Nøhr et al. (195) in Denmark, in an area
with mild to moderate iodine insufficiency, performed a
placebo-controlled, randomized, double-blind trial on the impact of
iodine supplementation (0.15 mg/d) during pregnancy and the postpartum
period in 72 TPO antibody-positive women. In this study, iodine
supplementation did not induce or worsen postpartum thyroiditis
(184).
D. Environmental factors, toxins, and cigarette smoking
Chemical toxins constitute another source of potential pathogenic
factors in the development of thyroid autoimmunity (196). Exposure to
methylcholanthrene enhances the thyroid autoimmune response in Buffalo
rats (177).
In humans, thiocyanate from tobacco smoke is probably the most important environmental toxic factor in the development of Graves’ disease. Thiocyanate is actively metabolized by the thyroid and is able to inhibit iodine transport. It is also a competitive substrate for TPO (197, 198, 199, 200, 201, 202). It is therefore not surprising that it has been hypothesized that the toxic effects of thiocyanate explain why smoking leads to thyrocyte necrosis and/or thyroid metabolic abnormalities, processes that are driving forces behind a thyroid-specific autoimmunization (203).
Alternatively, smoking might have direct effects on the immune system. Smoking leads to clear alterations in the function of pulmonary monocyte-derived cells and to an altered production of proinflammatory cytokines in the lung. Whether this is reflected in functional aberrations of systemic or intrathyroidal monocytes and other antigen-presenting cells needs to be investigated.
In the United Kingdom, almost two-thirds of patients with Graves’ ophthalmopathy smoke cigarettes in contrast to 10–20% of the normal healthy population (204, 205). In a recent population-based twin case-control study, clinically overt autoimmune thyroid disease was significantly associated with smoking. Most importantly, this association remained significant in disease-discordant monozygotic twin pairs, eliminating the effect of genetic factors in the development of thyroid disease (206).
With regard to postpartum thyroiditis, a case-control study in the United Kingdom showed that smoking more than 20 cigarettes/d was significantly related to the development of the syndrome (21) but not with the development of permanent autoimmune hypothyroidism (207). In a prospective study of 291 women, of whom 15 developed postpartum thyroiditis, Kuijpens et al. (208) found by multivariate analysis that "ever smoked" was an independent risk factor for postpartum thyroiditis with a relative risk of 3.1, compared with "never smoked."
In conclusion, evidence is growing that smoking is a clear precipitating factor for autoimmune thyroid disease, including the outbreak of postpartum thyroiditis.
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VI. Postpartum Thyroiditis Viewed as a Transient Exacerbation of a Preexisting and Ongoing Process of Autoimmune Thyroiditis |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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). From this perspective, postpartum thyroiditis is "just" an
aggravation of an existing autoimmune thyroiditis after an amelioration
of the inflammation during pregnancy (see above). The fluctuations in
intensity are driven by the hormonal changes associated with pregnancy
and the subsequent puerperal period, and eliciting environmental
factors. This is clearly illustrated by the pattern of the TPO antibody
titer during pregnancy and the postpartum period (Fig. 5).
Figure 1 summarizes the reports on the TPO antibody status in women
with postpartum thyroiditis. Collectively, these reports show that
30–60% of women positive for TPO antibodies in pregnancy develop
postpartum thyroiditis. After a first episode of postpartum
thyroiditis, the chance of recurrence after a subsequent pregnancy is
70% in women who are TPO antibody positive. The chance of postpartum
thyroiditis is 25% in TPO antibody-positive women without a history of
previous thyroid dysfunction in the puerperal period
(209).
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VII. The Clinical Course of a Postpartum Exacerbation of Autoimmune Thyroiditis |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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) (12, 23, 25, 36, 211).
During the thyrotoxic phase the physical symptoms are usually mild
compared with Graves’ thyrotoxicosis, and fatigue, palpitations,
weight loss, heat intolerance, and irritability were more prevalent in
women with postpartum thyroiditis than in euthyroid postpartum women.
Other reported symptoms are psychological disturbances (12, 22, 23, 24, 27, 30, 209, 212), tremor, and nervousness (12, 20, 24, 27, 29, 209, 213). The thyrotoxic phase of postpartum
thyroiditis is due to leakage of thyroid hormones from destroyed
thyrocytes and is therefore self-limiting.
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). It is generally believed that mental depression is the most prominent discriminatory symptom of the hypothyroid phase of postpartum thyroiditis, often ascribed to the changes consequent upon delivery and the lack of night rest (12, 21, 23, 24, 27, 29, 32, 33, 36). Several studies have specifically, and solely, investigated the association between postpartum thyroiditis and postpartum depression. A critical appraisal of the literature revealed that postpartum depression is significantly associated with postpartum thyroid dysfunction regardless of the thyrotoxic or hypothyroid phase (22, 212). Consequently, in terms of clinical management and appropriate treatment, it is pivotal to recognize the origin of the depressive symptoms.
Harris et al. (214) examined the rates at which
depression occurred at 6–8 wk postpartum in 65 thyroid antibody (Tg
and TPO)-positive and 82 antibody-negative women. Women with postpartum
thyroiditis had a small but significant excess of DSM III defined major
depression (Table 4). Pop et
al. (212) studied 293 women from 32 wk of gestation
until 34 wk postpartum and also found an association of major and minor
depression (according to Research Diagnostic Criteria) with postpartum
thyroiditis. Kent et al. (25) also found that
postpartum thyroiditis carries a slightly increased risk for the
occurrence of depression. However, in a recent study from Spain in
which 605 women were followed Lucas et al. (28)
found no association of depression with postpartum thyroiditis. A
different sociological background in Spain compared with the countries
in which the other studies were performed might explain this negative
result. The presence of TPO antibodies per se is not
associated with postpartum depression (22, 25, 30).
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Whether goiter is a symptom of postpartum thyroiditis is still questionable. In most clinical studies of postpartum thyroiditis, a high prevalence of goiter was observed (12, 23, 27, 29, 31, 33). However, this was not a universal finding (20, 21), and iodine intake probably plays a role here. In iodine-replete areas the thyroid as measured by ultrasonography does not increase in size during pregnancy (217), while it does in iodine-deficient areas. This increase is most likely due to an adaptation to the low environmental iodine, leading to a more vigorous response of the thyroid to growth stimuli (218) and exacerbated by the pregnant state (see above). Apart from this adaptation mechanism, the development of a goiter in postpartum thyroiditis could be a symptom of the autoimmune thyroiditis process itself, representing a glandular enlargement due to the lymphocellular infiltration. A palpable goiter at term was found to be predictive for postpartum thyroiditis in areas of mild iodine deficiency (33, 219). This was not the case in iodine-sufficient areas (21). A palpable goiter, however, can be interpreted as a symptom of preexisting autoimmune thyroiditis. In women with type I diabetes, Gerstein (40) found that the presence of a goiter at term was a risk factor for the development of postpartum thyroiditis. In conclusion, the presence of a goiter most likely is a symptom of postpartum thyroiditis especially in iodine-sufficient areas.
Adams et al. (220) studied the ultrasonographic appearance of women at risk of postpartum thyroiditis. Between 4 and 8 wk postpartum, hypoechogenicity was present only in 45% of thyroid antibody-positive women who subsequently developed postpartum thyroiditis, compared with 17% in thyroid antibody- positive women in whom thyroid function remained normal (P < 0.05). Hypoechogenicity was present in only 1.5% of thyroid antibody-negative women (P < 0.001). These observations have recently been extended by the investigators who found that persistent hypoechogenicity on thyroid ultrasound after the puerperal period indicated an ongoing process of destructive thyroiditis that was related to the development of permanent hypothyroidism (221). However, at present, the use of thyroid ultrasound in the follow up of postpartum thyroiditis is not well documented. From these studies we conclude that the ultrasound appearance of postpartum thyroiditis is hypoechogenicity. It should be noted, however, that 14% of women with TPO antibodies and postpartum thyroiditis had no ultrasound hypoechogenicity. Conversely, only 3% of TPO antibody-negative women without postpartum thyroiditis had ultrasound hypoechogenicity, but 39% of women with TPO antibodies but not postpartum thyroiditis did have ultrasound hypoechogenicity (220). The clinical value of thyroid ultrasound in the diagnosis and follow-up of postpartum thyroiditis seems therefore limited.
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VIII. The Diagnosis, Follow-Up, and Treatment of a Postpartum Exacerbation of Autoimmune Thyroiditis |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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The differential diagnosis of the thyrotoxicosis comprises primarily Graves’ disease. Because management and follow-up of postpartum destructive thyrotoxicosis and Graves’ disease differ, it is important to establish a causal diagnosis. Clinical features have been discussed in the previous section; here it is important to note that symptoms and the presence of a goiter are not helpful in differentiating postpartum destructive thyrotoxicosis from Graves’ disease. The presence of ophthalmopathy, however, points to a diagnosis of Graves’ disease (222). Diagnosis is further based on the presence of TSH-R Abs and thyroid scintigraphy (222). The presence of TSH-R Abs represents Graves’ disease, which was either unrecognized before pregnancy and relapsed after delivery, or developed de novo after delivery (39, 210). It is important to be aware that thyrotoxicosis in patients with a previous history of Graves’ disease does not necessarily represent relapse: postpartum thyroiditis can be superimposed on Graves’ disease (18). Momotani et al. systematically followed 96 episodes of postpartum hyperthyroidism in the first year after delivery in women with a history of Graves’ disease: in 26 cases radioiodine uptake was low (<10%) during the thyrotoxic phase, indicating destructive postpartum thyroiditis (19). Indeed, the diagnosis of postpartum destructive thyrotoxicosis (i.e., postpartum thyroiditis) is best established by the presence of a low radioiodine uptake. Thyroid scintigraphy should therefore be part of the diagnostic workup. During breast-feeding, however, the administration of iodine-131 is contraindicated. When iodine-123 is used, breast-feeding should be stopped for 3 d (223, 224). By using technetium (99 mTc) pertechnetate, interruption of breast-feeding for only 24 h is required (223, 225).
Serum Tg has been considered as an early indicator of postpartum thyroiditis (226). But as serum Tg concentrations are also elevated in nearly all patients with Graves’ disease (227), the determination of the serum Tg concentration is not helpful in differentiating postpartum destructive thyrotoxicosis from Graves’ disease. In women with postpartum thyroiditis, thyroid ultrasound hypoechogenicity correlates well with thyroid dysfunction (228). Similar abnormalities, however, have also been described in Graves’ disease (220). Increased IL-6 levels have been found in Graves’ disease and several thyroid-destructive processes (229, 230). In postpartum thyroiditis, however, IL-6 levels are not different compared with women without postpartum thyroiditis (231). Therefore, IL-6 measurement could be potentially useful in the differential diagnosis of postpartum thyrotoxicosis. However, the routine measurement of IL-6 is currently not always available.
With regard to the follow-up, permanent hypothyroidism is the most important sequel of postpartum thyroiditis. Nicolai et al. (29) found a prevalence of hypothyroidism of 12% after 3 yr . Tachi et al. (140) followed 44 Japanese women with a history of postpartum thyroiditis for a mean interval from delivery of 8.7 yr (range 5–16 yr) and found 29% of them to be permanently hypothyroid. In the study by Jansson et al. (24), the prevalence of hypothyroidism was 30% at the end of 5 yr. Othman et al. (207) followed 43 patients with postpartum thyroiditis (90% TPO antibody positive) during a period of 2–4 yr. Twenty-three percent of the women developed permanent hypothyroidism compared with none of 171 controls. Very recently, Premawardhana et al. (221) reported a follow-up on 98 TPO-positive women, of whom 48 developed postpartum thyroiditis. During a follow-up period of 66–140 months, 24.5% developed (sub)clinical hypothyroidism, whereas only 1.4% of a group of 70 TPO antibody-negative controls developed thyroid dysfunction. Lucas et al. (28) followed 42 patients during a mean period of 40 months. Five of these 42 women became permanently hypothyroid. In this study there was no significant difference in percentage of TPO positivity between women with postpartum thyroiditis who subsequently became hypothyroid and those who did not. TPO antibody levels, however, were higher in those women who developed permanent hypothyroidism. Barca et al. (37) followed 49 women with postpartum thyroiditis during the second postpartum year and found 30 of these women to have developed hypothyroidism at 24 months.
So we can conclude from these studies that permanent hypothyroidism occurs in 12–61%, a wide variation thus far unexplained. Differences in definition and variable ascertainment of follow-up may explain this wide variability.
Considering the occurrence of permanent hypothyroidism, studies performed by Roti et al. (232) and Creagh et al. (233) are of interest. They performed iodide perchlorate discharge tests in women with previous postpartum thyroiditis and found organification defects in 41% and 64%, respectively. Follow-up in these two studies was 3 to 7 yr. Collectively, the above data show the persistent character of the underlying thyroid disorder in postpartum thyroiditis and emphasize the need for a prolonged follow-up, particularly in TPO-positive women.
Special consideration should be given to women with hypothyroidism antedating pregnancy. An increased need for T4 during pregnancy is well documented in these women (175, 232, 234) and after delivery the T4 requirement is presumed to return to its pregestational level (235). However, it should be stressed here that in analogy to what has been described for Graves’ disease, postpartum thyroiditis can occur in patients with a known previous diagnosis of primary hypothyroidism, leading to a further decline in thyroid function. In a recent study, Caixàs et al. (17) observed discordance between pregestational and postpartum T4 requirements suggestive of postpartum thyroiditis in 12 of 18 patients diagnosed with autoimmune thyroiditis before pregnancy.
Do patients with postpartum thyroiditis need treatment? With respect to thyrotoxicosis, we have already pointed out the importance of an accurate diagnosis. In symptomatic cases a short course of ß-blockade may be beneficial, e.g., 40–120 mg propranolol or 25–50 mg atenolol daily until serum fT4 concentrations are normal. Antithyroid drug therapy should obviously not be given because there is no increased thyroid hormone synthesis.
Hypothyroidism should always be treated with T4 replacement therapy. Spontaneous recovery of thyroid function should not be anticipated (236). Instead, it is reasonable to stop T4 after 2–6 months to determine whether remission has occurred (4). If so, we advise discontinuation of treatment followed by yearly assessment of thyroid function. Others suggested a pragmatic approach: to maintain the T4 replacement therapy and postpone the cessation of therapy until the family is complete (237). In discussing T4 replacement therapy with the patient, it is important to realize that T4 administration does not always improve the psychological disturbances if present.
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IX. Adverse Consequences of Autoimmune Thyroiditis During Pregnancy and Postpartum |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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A. Effects of autoimmune thyroiditis on conception and
pregnancy
The relationship between existing thyroid autoimmunity and the
probability of spontaneous abortion has been the subject of a number of
studies. Stagnaro-Green et al. (238) found that
the presence of TPO and/or Tg antibodies in the first trimester of
pregnancy is a risk factor for spontaneous fetal loss. The authors
studied 552 consecutive women in the first trimester of pregnancy and
found that the spontaneous abortion rate in thyroid antibody-positive
women was significantly higher than in antibody-negative women (17%
vs. 8.4%). These results were confirmed by Glinoer et
al. (239) who found a higher rate of spontaneous
abortion in 45 women with thyroid autoantibodies compared with 603
controls: 13.3% vs. 3.3%.
In a prospective study of 54 women who conceived after in vitro fertilization (IVF) we were unable to find a significant association between the spontaneous abortion rate and the presence of TPO antibodies before pregnancy. Although miscarriages occurred in 33% of TPO antibody-positive women and in only 19% of the TPO-negative women, the difference was not statistically significant (240). Surprisingly, we found a nearly significant (P = 0.05) higher pregnancy rate in the TPO-positive women compared with the TPO-negative women. Our results thus contradict those of the two studies mentioned above, and several biases can be proposed to explain this discrepancy (241). First, the number of women with thyroid autoimmunity was low in our study, and the severity of the thyroid autoimmune process was mild (defined by the presence and cutoff value, respectively, of TPO antibodies). Second, we determined TPO antibodies before pregnancy—as opposed to during pregnancy—in women without a history of habitual abortion. In view of the discussed immunological changes occurring during pregnancy, these differences in study design have probably led to an inclusion of women with less severe forms of thyroid autoimmunity which might, at least in part, explain the discrepancy.
It has also been postulated that thyroid autoimmunity and its consequences influence the timing of miscarriage. Singh et al. studied 487 women who conceived with assisted reproductive techniques and found that the presence of thyroid autoantibodies, measured 14 d after embryo transfer, identified women at risk of later miscarriage. Later miscarriage was defined as a miscarriage occurring after clinical recognition of the pregnancy, i.e., after visualization of the gestational sac by ultrasonography. TPO antibody positivity had no effect on early, hCG-detected, miscarriage rates (242).
In women with a history of habitual abortion the presence of non-organ-specific autoantibodies, notably of antiphospholipid and anticardiolipin antibodies, has been associated with fetal loss (243). Data on the relationship between thyroid autoantibodies and habitual abortion are conflicting. Several studies found an association between TPO antibodies and recurrent first-trimester fetal loss (244, 245, 246, 247, 248). However, others could not confirm this observation (249, 250). Interestingly, Vaquero et al. (251) have recently investigated the role of mild thyroid abnormalities in women with thyroid antibodies and recurrent first-trimester abortions. A total of 42 women with TPO and/or Tg antibodies and recurrent first-trimester abortions were studied. In this study, treatment with intravenous Igs was compared with thyroid hormone treatment. The authors showed that treatment with thyroid hormone was more effective than treatment with intravenous Igs since 55% of women with thyroid antibodies treated with intravenous Igs resulted in live births as compared with 81% live births in women with thyroid antibodies treated with thyroid hormone. The authors and editors explained these data suggesting that mild degrees of thyroid insufficiency, perhaps at the level of the female genital tract, not detectable by routine thyroid testing, and not thyroid autoimmunity per se, is causal in the earlier mentioned association between the presence of thyroid antibodies and recurrent abortion (251, 252).
In conclusion, at present there are sufficient data showing an association of thyroid autoimmunity in early pregnancy and subsequent miscarriage. However, when taking into account the conflicting data on the presence of thyroid antibodies and recurrent abortion, the cause of this association, e.g., a defective immune system failing to become tolerant to the fetus or mild thyroid insufficiency, remains uncertain. Taking into consideration the data of Vaquero et al. (251), we are of the opinion that in women with recurrent miscarriage and thyroid antibodies, treatment with L-T4 is an option, although further controlled studies are essential.
B. Consequences of autoimmune thyroiditis for the offspring
It has become increasingly clear that maternal hypothyroxinemia in
areas of severe iodine deficiency causes not only the birth of
neurological cretins (253) but is also responsible for
less severe mental deficits (254, 255, 256, 257). Notably,
the motor and cognitive impairments of the offspring were associated
with the maternal T4 levels and not with maternal
T3 or TSH levels (258). Moreover,
because of their relatively normal T3 levels,
these women were not clinically hypothyroid (258). The
association of maternal hypothyroxinemia and neurodevelopmental outcome
of the offspring has recently been extended to populations living in
iodine-sufficient areas.
In a recent study by Pop et al. (259), a significant association between maternal TPO antibody levels at 32 wk gestation and an IQ loss of 10 points at the age of 4.5 yr in the offspring was demonstrated. In a follow-up study the authors formulated a hypothesis for this association. The neurodevelopment of 220 children aged 10 months was assessed. Children born to women with maternal serum fT4 levels below the tenth percentile at 12 wk gestation (irrespective of elevation of TSH and/or TPO antibodies) had significantly lower neurodevelopmental scores compared with children of mothers with higher fT4 values. Women with low fT4 levels at 12 wk gestation were largely affected by autoimmune thyroiditis, which can explain the previously found association between elevated TPO antibody levels at 32 wk gestation and impaired child development at 4.5 yr of age (260). However, there was no correlation between neurodevelopmental scores of the infants and maternal fT4 at 32 wk gestation, which is a puzzling finding in view of the expected deterioration in thyroid function during pregnancy in women with autoimmune thyroiditis (176, 260). Whatever the explanation for this unexpected finding, the fact remains that after appropriate statistical analysis fT4 levels below the tenth percentile at 12 wk gestation represented a significant risk factor for impaired psychomotor development.
Findings by Pop et al. have been extended by Haddow et al. (261). These investigators provided evidence that children born to mothers with hypothyroidism during the second trimester of pregnancy, as determined by an elevated TSH, have lower IQ scores and more educational difficulties at age 7–9 yr than children born to mothers with normal TSH levels during pregnancy. In their study 25,216 serum samples were prospectively collected, and 47 women with TSH levels at or above the 99th percentile of the values for all pregnant women were identified. Additionally, 15 women with TSH values between the 98th and 99.6th percentiles, and low T4 levels were also included, as were 124 matched controls. The children of the 62 women with elevated TSH levels during pregnancy performed less well on all 15 neuropsychological tests carried out (in 2 of these the difference was significant), and children had more school difficulties and learning problems (P = 0.06). In this study 77% of the women with hypothyroidism had high titers of TPO antibodies (261). These data further underline the notion that chronic autoimmune thyroiditis is the most frequent cause of low normal fT4 levels and raised TSH levels in these women. Taken together, the studies by Pop et al. and Haddow et al. provide evidence that not only overt but also relatively mild and hitherto unrecognized states of thyroid failure are associated with persistent and significant impairment in neuropsychological performance of the offspring.
In a recent publication, Morreale de Escobar et al. (258) have summarized and discussed present epidemiological and experimental evidence and argue convincingly that conditions resulting in first-trimester hypothyroxinemia (defined as a low for gestational age circulating maternal free T4, whether or not TSH is increased) pose an increased risk for poor neuropsychological development of the fetus. Although we will discuss the issue of screening in Section X of this review, it is relevant at this point to stress that the effects of screening and treatment with T4 on the progeny, and the mothers, needs to be assessed prospectively (and from a strict scientific point of view placebo-controlled, double-blind) for efficacy and safety.
We recently observed a decrease in maternal serum fT4 after ovarian hyperstimulation for IVF (262). Considering the possible importance of fT4 levels for the neuropsychological development of the offspring, our findings could potentially have serious implications, and we urge prospective neuropsychological studies to be carried out in children born after IVF. Particularly the offspring of women whose fT4 levels are already in the low normal range before the start of ovarian hyperstimulation should be followed, especially in areas of iodine deficiency and the documented relative hypothyroxinemia during pregnancy (175, 263).
C. Consequences of autoimmune thyroiditis for older women
Maternal states of mild thyroid failure due to autoimmune
thyroiditis may lead to serious long-term consequences not only for the
offspring, but also for the women themselves. First, the risk of
permanent clinical thyroid failure is high: odds ratios as high as 38
have been found (see above) (264). Second, and probably
more importantly, subclinical hypothyroidism may predispose to
myocardial infarction and arterial atherosclerosis. Hak et
al. (265) recently showed in a population-based
cross-sectional study of 1,149 women in Rotterdam, that the population
attributable risk of subclinical hypothyroidism for atherosclerosis and
myocardial infarction is comparable to other known major cardiovascular
risk factors . An association between TPO antibody positivity per
se and atherosclerosis and myocardial infarction was not found;
however, the associations between atherosclerosis and myocardial
infarction and subclinical hypothyroidism were stronger if thyroid
failure was accompanied by the presence of TPO antibodies
(265). These data are at variance with the 20-yr follow-up
of the Whickham survey cohort, which did not find an association
between evidence of autoimmune thyroiditis (defined as treated
hypothyroidism, presence of thyroid antibodies, or raised TSH)
documented at the first survey with mortality or development of
ischemic heart disease (266). These discrepant findings
are most likely due to differences in study groups (different ages) and
definitions of autoimmune thyroiditis and hypothyroidism as well as the
initiation of T4 replacement therapy in cases of
hypothyroidism in the Whickham survey (266).
All in all, evidence is accumulating that the early phases of thyroid autoimmunity, which may not immediately lead to clinically overt thyroid failure, have adverse consequences for the well-being of affected individuals and their offspring. A mild, but nevertheless relevant, decrement of the thyroid reserve often accompanies the early phases of thyroid autoimmunity. This "hidden thyroid failure" becomes more important when the thyroid needs to perform optimally, such as during pregnancy and in states when there is an otherwise heightened risk for atherosclerosis. The occurrence of postpartum thyroiditis is a clear sign that the thyroid reserve is under serious autoimmune threat and already considerably compromised.
The above listed studies provide an incentive to consider screening for autoimmune thyroiditis to prevent the potentially harmful sequels described above.
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X. Screening, What and When? |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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1. Is the prevalence of autoimmune thyroiditis high enough to justify screening?
2. Is there enough morbidity?
3. Is there an effective way to prevent this morbidity?
4. Are there effective screening tools and when should these be applied?
5. Is screening cost effective?
Ad. 1) The first question has been dealt with extensively in Section II of this review. In comparison to other diseases for which screening is recommended, the prevalence rate of around 5–7% for thyroid autoimmunity in young women and a prevalence of elevated TSH levels in pregnant women as high as 2–3% seems high enough to justify screening in women of childbearing age (175, 268).
Ad. 2) Considering the morbidity of autoimmune thyroiditis in women of childbearing age we have discussed that there is:
a. an increased risk of miscarriage;
b. a significant risk of developing hypothyroidism during gestation;
c. a potential risk for the neuropsychological development of the offspring;
d. a clearly increased risk of developing postpartum thyroiditis; and finally
e. that there is an increased risk for developing permanent clinically overt hypothyroidism in later life.
In conclusion, the morbidity associated with autoimmune thyroiditis is considerable.
Ad. 3)
a. Miscarriage.
There are now data to suggest that recurrent
miscarriage in women with thyroid antibodies can be prevented by
T4 administration (251).
b. Hypothyroidism during gestation.
Transition from mild,
subclinical hypothyroidism to overt hypothyroidism in pregnancy can be
effectively and safely treated with T4.
c. Neuropsychological development of the offspring.
It is at
present unknown whether T4 replacement therapy
will effectively prevent detrimental effects on the offspring in these
cases. Clearly, double-blind randomized trails are needed to clarify
this issue (269).
d. Postpartum thyroiditis.
There is only one study on the
prevention of postpartum thyroiditis with
L-T4 administration. In this study
postpartum treatment of 18 women who were TPO positive in early
pregnancy with L-T4 (0.1 mg daily
from 4–38 wk and 0.05 mg from 39–42 wk postpartum) did not result in
a change in the incidence or time course of postpartum thyroiditis.
However, as expected, the degree of hypothyroidism was significantly
reduced compared with 20 untreated antibody-positive women (maximum TSH
23 vs. 6.9 mU/liter, P < 0.05)
(194). With regard to other treatment options,
administration of corticosteroids has been described in a woman with
recurring episodes of postpartum thyroiditis. Both the hyper- and
hypothyroid phases were prevented (270). However, in
general, the effect is small (1), and we certainly do not
recommend this approach as there are no controlled data and steroids
can have serious adverse effects.
e. Permanent hypothyroidism.
In women at risk for overt
hypothyroidism L-T4 is an effective
and safe preventive treatment.
Thus, at present, only screening to identify subjects at risk for hypothyroidism seems indicated. Clearly, a case can be made for screening of maternal hypothyroxinemia in the first trimester of pregnancy, but we, and others, are of the opinion that controlled screening trials should be required before screening of all pregnant women can be recommended (269).
Ad. 4) What screening tools could be used if the development of a (pilot)-screening program is considered and when should these tools be applied?
a. Miscarriage.
Because relevant studies have shown an
association of thyroid autoimmunity in early pregnancy and subsequent
miscarriage, measurement of TPO antibodies could be considered as soon
as pregnancy is established.
b and c. Hypothyroidism during pregnancy and neuropsychological
development of the offspring.
After publication of the study by
Haddow et al. (261), The Endocrine Society
recommended the development of a cost-effective strategy for screening
pregnant women for hypothyroidism before or early during pregnancy
(www.endo-society.org/pubrelations/pressReleases/archives/1999/hypothyroid.cfm,
assessed 23-01-01). It should be realized that in the
studies by Pop et al. and Haddow et al.
neuropsychological development of the infants was associated with
fT4 and TSH, respectively. Therefore,
fT4 and TSH are both candidates as screening
tools when developing such a screening program. In view of the
arguments presented by Morreale de Escobar et al.
(258) fT4 seems to be the most
rational choice (267). Another point to consider is that
whatever screening tool is chosen, cut-off values need to be
established taking into account the different gestational ages
(217, 267). This is especially prudent for TSH as hCG has
clear thyrotrophic actions.
What would be the best time for screening? Assuming that the (mild) hypothyroxinemia itself is responsible for impaired neuropsychological development, one would ideally start to screen fertile women antenatally. However, it seems unrealistic to expect that we will be able to organize a prepregnancy screening program. Women cannot, and probably should not, be expected to consult their physician before becoming pregnant (176). Screening in early pregnancy is probably the best that we can accomplish, and screening algorithms for autoimmune thyroiditis and subclinical and overt hypothyroidism have already been proposed (176, 271). Interestingly, a screening program in Japan, a country where the frequency of thyroid disease among pregnant women may be lower than elsewhere, was initiated in 1986 and by 1997, 70,632 early-pregnant women had been screened. Screening consisted of TSH, fT4, and Tg antibodies. Abnormal results were obtained in 2%. The overall incidence of hyperthyroidism and hypothyroidism was 1 in 413 and 1 in 692 women, respectively. Two-thirds of women with hypothyroidism had evidence of chronic autoimmune thyroiditis (272). These data show that a screening program in early pregnancy is feasible.
d. Postpartum thyroiditis.
We have already discussed that the
presence of TPO antibodies in early pregnancy is associated with a
30–52% risk of developing subsequent postpartum thyroiditis (4, 42, 43, 44). TPO antibodies in early pregnancy could thus be an
appropriate screening tool for development of postpartum
thyroiditis.
e. Permanent hypothyroidism.
To detect subclinical
hypothyroidism it is mandatory to determine TSH and, if elevated,
fT4 (preferably from the same blood sample). TPO
antibodies are a powerful risk factor for the transition from
subclinical (elevated TSH and normal fT4) to
overt hypothyroidism; therefore, the measurement of TPO antibodies, in
our opinion, is also indicated in the case of an elevated TSH with
normal fT4 (264). When considering
screening for thyroid dysfunction, it should be noted that the American
Thyroid Association recommends screening with a sensitive serum TSH
assay in adults beginning at age 35 yr and every 5 yr thereafter
(273). The American College of Physicians is more
conservative: they advise case finding in women older than 50 yr of age
who are seen by primary care physicians for non-thyroid-related reasons
(274, 275).
We stated previously that, considering treatment options, at present, screening to detect subclinical hypothyroidism and the transition to overt hypothyroidism seems indicated. We support, therefore, the recommendations by the American Thyroid Association, but suggest that screening should be performed earlier in pregnant women.
Ad. 5)We are unaware of long-term prospective studies addressing the issue of cost-effectiveness for any of the indications discussed here.
If screening programs are set up, the results should be scientifically evaluated. Before these screening programs are instituted, case finding is justified, i.e., the identification of women at risk of autoimmune thyroid disease and its consequences during pregnancy and later in life. Thus, in our view, TSH determinations should be carried out in young women with a goiter, type I diabetes, previous postpartum "depression/blues," a "thyroid history," a family history of thyroid disease, and a personal history of smoking as well as in women with an induced low fT4 level, i.e., during ovarian hyperstimulation. If the TSH level is abnormal, the fT4 should be determined, and in the case of subclinical hypothyroidism TPO should be determined additionally.
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XI. Conclusion |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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In this review, postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. The following arguments support this view: 1) the relationship between the occurrence of postpartum thyroiditis and the presence of TPO antibodies; 2) the histology of postpartum thyroiditis (both focal organized and diffuse destructive lymphocytic thyroiditis with folliculolysis and disruption); 3) the presence of circulating activated T cells in postpartum thyroiditis patients; 4) the associations between the genetic inheritance of MHC molecules and the occurrence of postpartum thyroiditis; and 5) the fact that postpartum thyroiditis frequently leads to permanent autoimmune thyroid failure.
It is the combination of genetic susceptibility and environmental factors that lead to thyroid autoimmunity in general and also to postpartum thyroiditis. From pregnancy, an enhanced state of immune tolerance ensues, leading to an amelioration of existing thyroid autoimmunity. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis.
Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem, particularly during pregnancy and postpartum. Existing thyroid autoimmunity increases the probability of spontaneous fetal loss. Moreover, there are indications that thyroid failure due to autoimmune thyroiditis, often mild and subclinical, leads to permanent and significant impairment in neuropsychological performance of the offspring. Finally, there is now emerging evidence that, as women age, subclinical hypothyroidism, as a sequel of postpartum thyroiditis, predisposes them to cardiovascular disease. Hence, the concept of postpartum thyroiditis being a mild and transient disorder is now changing. The recognition of the true nature of postpartum thyroiditis, i.e., an acute phase in an ongoing and chronic thyroid autoimmune process, and the negative consequences such a chronic process can have for offspring of affected mothers and for the mothers themselves, in the long run, are reasons to consider screening.
Designing and performing adequate studies to delineate screening tools and cost-effectiveness will be the challenge for the future. Meanwhile, case finding is mandatory. We think that, at present, there is a good case for treating subclinical hypothyroidism especially in women of childbearing age.
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Acknowledgments |
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Footnotes |
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Thyroid autoimmune research of the Department of Immunology is supported by two grants of the Dutch Government Organization NWO (903-40-167 and 903-40-193).
Abbreviations: ADCC, Antibody-dependent cell mediated cytotoxicity; CTLA-4, cytotoxic T-lymphocyte antigen-4; hCG, human CG; IFN, interferon; IVF, in vitro fertilization; MHC, major histocompatibility complex; NK, natural killer; NOD, nonobese diabetic; PIBF, progesterone-induced blocking factor; TBII, TSH binding inhibitory Igs; TH1 and TH2, T helper 1 and 2; TPO, thyroid peroxidase; TSAb, thyroid stimulating antibody; TSH-R Abs, TSH-receptor antibodies.
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References |
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TopAbstractI. IntroductionII. Epidemiology of Postpartum...III. Thyroid Antibodies,...IV. Cell-Mediated Immunity,...V. The Pathogenesis of...VI. Postpartum Thyroiditis...VII. The Clinical Course...VIII. The Diagnosis, Follow-Up,...IX. Adverse Consequences of...X. Screening, What and...XI. ConclusionReferences |
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, Prevalence of TPO antibodies in women with
postpartum thyroiditis. 
, Prevalence of TPO antibodies in women
without postpartum thyroiditis. An asterisk denotes that
the TPO antibody prevalence is not given or cannot be calculated from
the data. See Table 1
)
e.g., TPO-antibodies, recognize their target-antigens
(
) can also be
recognized by CD8+ T cytotoxic cells or
CD4+ TH1 cells producing 
) to kill thyrocytes
or to produce IL-1 and IL-6 influencing thyrocyte growth and
metabolism. 3. Furthermore, antibodies directed to the TSH-R either
stimulate or block the receptor and coupled to the receptor various
second messenger systems. This will either lead to stimulation or
blockade of thyrocyte growth and metabolism.
