Whose thyroid hormone replacement is it anyway?
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Attitude of Health Personnel↗
Biomedical subjects
A P Weetman
Publications and source records attributed to A P Weetman.
Is there a need to redefine the upper normal limit of TSH?
Mild forms of hypothyroidism--subclinical hypothyroidism--have recently been discussed as being a risk factor for the development of overt thyroid dysfunction and for a number of clinical disorders. The diagnosis critically depends on the definition of the upper normal limit of serum TSH as, by definition, free thyroxine serum concentrations are normal. Cut-off levels of 4-5 mU TSH/l have been conventionally used to diagnose an elevated TSH serum concentration. Recent data from large population studies have suggested a much lower TSH cut-off with an upper limit of 2-2.5 mU/l but application of strict criteria for inclusion of subjects from the general population studies aiming at assessing TSH reference intervals (no personal or family history of thyroid disease, no thyroid antibodies and a normal thyroid on ultrasonography) did not result in an unequivocal upper limit of normal TSH at 2.0-2.5 mU/l. When summarizing the available evidence for lowered upper TSH cut-off values and their potential therapeutic implications there is presently insufficient justification to lower the upper normal limit of TSH and, for practical purposes, it is still recommended to maintain the TSH reference interval of 0.4-4.0 mU/l. Classifying subjects with a TSH value between 2 and 4 mU/l as abnormal, as well as intervening with thyroxine treatment in such subjects, is probably doing more harm than good.
Chemistry, Clinical↗
A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.
CONTEXT: Autoimmune thyroid diseases (AITD), comprising Graves' disease and autoimmune hypothyroidism, are characterized by loss of immunological self-tolerance to thyroid antigens. These are complex diseases arising from a combination of genetic and environmental factors. An understanding of the genetic susceptibility factors for AITD could help to target treatments more effectively and identify people at risk for these conditions. OBJECTIVE: The objective of this study was to identify regions of genetic linkage to AITD that could potentially harbor genetic susceptibility factors for these conditions. DESIGN: The study design was a genome-wide screen performed on affected relative pairs with AITD. SETTING: Patients were recruited through hospital endocrinology clinics. PARTICIPANTS: Some 1119 Caucasian relative pairs affected with AITD (Graves' disease or autoimmune hypothyroidism) were recruited into the study. INTERVENTION: Blood samples were obtained from each participant for DNA analysis, and clinical questionnaires were completed. MAIN OUTCOME MEASURE: The study aimed to identify regions of genetic linkage to AITD. RESULTS: Three regions of suggestive linkage were obtained on chromosomes 18p11 (maximum LOD score, 2.5), 2q36 (maximum LOD score, 2.2), and 11p15 (maximum LOD score, 2.0). No linkage to human leukocyte antigen was found. CONCLUSIONS: The absence of significant evidence of linkage at any one locus in such a large dataset argues that genetic susceptibility to AITD reflects a number of loci, each with a modest effect. Linkage analysis may be limited in defining such loci, and large-scale association studies may prove to be more useful in identifying genetic susceptibility factors for AITD.
Chromosome Mapping↗
A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo.
Vitiligo is an acquired hypomelanotic skin disorder resulting from the loss of functional melanocytes from the cutaneous epidermis and autoimmunity has been suggested to play a part in its pathogenesis. Recently, the missense R620W polymorphism in the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (LYP), has been associated with susceptibility to autoimmune disorders. The objective of this study was to ascertain if the disease-associated 1858T allele was also associated with generalised (nonsegmental) vitiligo and so the frequencies of the PTPN22 1858C/T alleles were investigated in 165 English patients with generalised vitiligo and 304 ethnically matched control subjects. The results indicated that the 1858T allele was significantly over-represented in the vitiligo patient group compared with the control cohort. Of 330 vitiligo alleles, 48 (14.5%) encoded the Trp620 variant compared to 52 of 608 (8.6%) control alleles (P=0.006; odds ratio=1.82, 95% confidence interval=1.17-2.82). The results indicate that the LYP missense R620W polymorphism may have an influence on the development of generalised vitiligo and provide further evidence for autoimmunity as an aetiological factor with respect to this disease.
Adult↗
New understanding of the role of cytokines in the pathogenesis of Graves' ophthalmopathy.
Cytokines play a key role in the development of Graves' ophthalmopathy (GO). These molecules are produced in the orbit of GO patients by infiltrating inflammatory cells as well as orbital fibroblasts. Locally produced cytokines stimulate fibroblast proliferation and their production of glycosaminoglycans, which result in accumulation of extracellular matrix and oedema with consequent proptosis. In addition to these direct effects, cytokines can modulate the immune reaction in GO by increasing major histocompatibility complex (MHC) class II, adhesion molecules, CD40, prostaglandin and heat shock protein expression in the orbit, thereby having a role in localising and augmenting the inflammatory response.
Animals↗
Evaluation of conformational epitopes on thyroid peroxidase by antipeptide antibody binding and mutagenesis.
Autoantibodies to thyroid peroxidase (TPO) recognize predominantly conformational epitopes, which are restricted to two distinct determinants, termed immunodominant domain region (IDR) A and B. These dominant determinants reside in the region with structural homology to myeloperoxidase (MPO)-like domain and may extend into the adjacent complement control protein (CCP) domain. We have explored the location of these determinants on the MPO-like domain of the structural model of TPO, by identifying exposed hydrophilic loops that are potential candidates for the autoantigenic sites, generating rabbit antipeptide antisera, and competing with well characterized murine monoclonal antibodies (mabs) specific for these two IDRs. We recently defined the location of IDR-B, and here report our findings on the location of IDR-A and its relationship to IDR-B, defined with a new panel of 15 antipeptide antisera. Moreover, in combination with single amino acid replacements by in vitro mutagenesis, we have defined the limits of the IDR-B region on the TPO model. The combination of antisera to peptides P12 (aa 549-563), P14 (aa 599-617) and P18 (aa 210-225) inhibited the binding of the mab specific for IDR-A (mab 2) by 75%. The same combination inhibited the binding of autoantibodies to native TPO from 67 to 94% (mean 81.5%) at autoantibody levels of 5 IU. Fabs prepared from the antipeptide IgG and pooled in this combination were also effective in competition assays, thus defining the epitopes more precisely. IDR-A was found to lie immediately adjacent to IDR-B and thus the two immunodominant epitopes form an extended patch on the surface of TPO. Finally, by single amino acid mutagenesis, we show that IDR-B extends to residue N642, thus further localizing the boundary of this autoantigenic region on the structural model.
Amino Acids↗
Induction of hyperthyroidism in mice by intradermal immunization with DNA encoding the thyrotropin receptor.
Intramuscular injection with plasmid DNA encoding the human thyrotropin receptor (TSHR) has been known to elicit symptoms of Graves' disease (GD) in outbred but not inbred mice. In this study, we have examined, firstly, whether intradermal (i.d.) injection of TSHR DNA can induce hyperthyroidism in BALB/c mice and, secondly, whether coinjection of TSHR- and cytokine-producing plasmids can influence the outcome of disease. Animals were i.d. challenged at 0, 3 and 6 weeks with TSHR DNA and the immune response was assessed at the end of the 8th or 10th week. In two experiments, a total of 10 (67%) of 15 mice developed TSHR-specific antibodies as assessed by flow cytometry. Of these, 4 (27%) mice had elevated thyroxine (TT4) levels and goitrous thyroids with activated follicular epithelial cells but no evidence of lymphocytic infiltration. At 10 weeks, thyroid-stimulating antibodies (TSAb) were detected in two out of the four hyperthyroid animals. Interestingly, in mice that received a coinjection of TSHR- and IL-2- or IL-4-producing plasmids, there was no production of TSAbs and no evidence of hyperthyroidism. On the other hand, coinjection of DNA plasmids encoding TSHR and IL-12 did not significantly enhance GD development since two out of seven animals became thyrotoxic, but had no goitre. These results demonstrate that i.d. delivery of human TSHR DNA can break tolerance and elicit GD in inbred mice. The data do not support the notion that TSAb production is Th2-dependent in murine GD but they also suggest that codelivery of TSHR and Th1-promoting IL-12 genes may not be sufficient to enhance disease incidence and/or severity in this model.
Animals↗
Cellular immune responses in autoimmune thyroid disease.
Recent research in autoimmune thyroid disease (AITD) has largely focused on delineation of the autoantigens and their epitopes, but there is now renewed interest in the immunoregulatory properties of T cells, an understanding of which may explain the emergence of AITD in experimental settings. T cell recognition of autoantigens has shown considerable intra- and interindividual heterogeneity, and a mixed pattern of cytokine production indicates that both the Th1 and Th2 limbs of the helper T cell response are involved in all types of AITD. It is now clear that secretion of chemokines and cytokines within the thyroid accounts for the accumulation and expansion of the intrathyroidal lymphocyte pool, and that the thyroid cells themselves contribute to this secretion. The thyroid cells also produce a number of proinflammatory molecules which will tend to exacerbate the autoimmune process. Thyroid cell destruction in autoimmune hypothyroidism is dependent on T cell-mediated cytotoxicity with the likely additional effect of death receptor-mediated apoptosis.
Autoantigens↗
Endocrine emergencies.
Diabetic and endocrine emergencies are traditionally treated by the acute medical admitting team or accident and emergency department staff. Most will see diabetic emergencies on a regular basis, as they are common and both type 1 and type 2 disease are increasing in prevalence. Diabetic emergencies are usually easily treated and the patients discharged. However, it is vital not to become complacent as these disorders can lead to death. It is particularly important to follow local guidance and to involve the diabetes team both during and after each episode. Recently it has become clear that about 30% of patients admitted with acute coronary syndrome (including infarction) have either diabetes or "stress hyperglycaemia"; evidence suggests that these patients should be treated not only as a cardiac emergency but also as a diabetic one. Thus, every patient with acute coronary syndrome or acute myocardial infarction needs diabetes to be excluded. The other endocrine emergencies are less common, but in some ways more important simply because of their rarity. A high level of suspicion is often required to make a diagnosis, although some, such as myxoedema coma, are usually obvious. Treatment must be started before the diagnosis can be confirmed. Guidance on making the diagnosis and initiating treatment should be made available on the local NHS intranet for non-endocrinologists to access; and where possible expert advice made available by telephone. The basic management steps in the common diabetic and endocrine emergencies are outlined; this is not a complete list, but rather an insight for those involved in non-selected emergency admissions.
Emergencies↗
HLA-G does not have a pathophysiological role in Graves' disease.
AIMS: It has been suggested that the non-classic HLA class I molecule HLA-G plays a role in autoimmune disease by protecting tissues from damage by infiltrating cytotoxic T cells. Such infiltration occurs in the thyroid of patients with Graves' disease (GD) and Hashimoto's thyroiditis (HT) and can eventually result in tissue destruction. The aim of the current study was to analyse thyroid tissue and thyrocytes obtained from individuals with autoimmune thyroid disease for the expression of HLA-G. METHODS: HLA-G expression was analysed in thyroid tissue taken from six patients with GD and one with HT by reverse transcriptase polymerase chain reaction. Thyroid tissue samples isolated from six patients with multinodular goitre (MNG) were used as non-autoimmune controls. HLA-G expression was also examined in cultured thyroid follicular cells (TFCs). RESULTS: The expression of HLA-G was not detected in the thyroid gland of patients with either GD, HT, or MNG. Furthermore, HLA-G expression could not be detected in cultured patient TFCs under basal conditions or after stimulation with the proinflammatory cytokines-interleukin 1alpha, interferon gamma, and tumour necrosis factor alpha. CONCLUSIONS: HLA-G expression does not occur in the thyroid of patients with GD, indicating that HLA-G does not play a pathophysiological role in this autoimmune disorder. Although the expression of HLA-G was not detected in the thyroid sample of the patient with HT, a greater sample size would be required to conclude that HLA-G does not have a part to play in this autoimmune thyroid disease.
Actins↗
Grave's disease 1835-2002.
This brief review describes the history of Graves' disease, starting with the original descriptions by Parry, Graves and von Basedow. The true aetiology of the disorder was uncovered in the 1950s and 1960s, based on the search for a novel thyroid stimulator which turned out to be an immunoglobulin G autoantibody. Assays for these thyroid stimulatory antibodies have been continually refined and their epitopes on the thyroid stimulating hormone receptor are increasingly well characterized. We also understand far more about the genetic and environmental susceptibility factors that predispose to disease, and even thyroid-associated ophthalmopathy has now been better defined as primarily a T-cell-mediated disease resulting from cytokine stimulation of orbital fibroblasts. These advances should improve treatment options for Graves' disease in the foreseeable future.
Animals↗
Overexpression of type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels.
Thyroid function is normally undisturbed in patients with thyroid carcinoma. We have identified three patients with large or widely metastatic follicular thyroid carcinoma who had a persistently increased ratio of serum T(3) to T(4) in the absence of autonomous production of T(3) by the tumor. To investigate the possibility of tumor-mediated T(4) to T(3) conversion, we assayed types 1 and 2 iodothyronine selenodeiodinase (D1 and D2) activity in a 965-g follicular thyroid carcinoma resected from one of these patients. The V(max) for D2 was 8-fold higher than in normal human thyroid tissue. Resection of this tumor, leaving the left thyroid lobe intact, normalized the serum T(3) to T(4) ratio. In two other patients, treatment with sufficient levothyroxine to suppress TSH was associated with a high normal T(3) and a subnormal free T(4) index. In one, concomitant administration of the D1 inhibitors, propylthiouracil and propranolol, did not decrease the elevated serum T(3) to T(4) ratio. These data illustrate that increased T(4) to T(3) conversion in follicular thyroid carcinomas, probably by D2, can cause a significant perturbation in peripheral thyroid hormone concentrations.
Adenocarcinoma, Follicular↗
Thyroid over-expression of type 1 and type 2 deiodinase may account for the syndrome of low thyroxine and increasing triiodothyronine during propylthiouracil treatment.
Although propylthiouracil inhibits type 1 deiodinase, leading to a more rapid fall in triiodothyronine (T(3)) than thyroxine (T(4)) levels in patients treated for hyperthyroidism, we report a patient with Graves' disease whose free T(3) paradoxically rose during such treatment, despite low free T(4) levels and increasing doses of propylthiouracil. A similar response has previously been associated with high levels of thyroid stimulating antibodies, but it has been unclear why there should be a dichotomy in the circulating thyroid hormone profile. Thyroid tIssue from our patient contained very high levels of type 1 and, especially, type 2 deiodinase, in contrast to other patients treated with Graves' disease, which were most likely secondary to high levels of thyroid stimulating antibodies. This unusual response to propylthiouracil is important to recognise therapeutically, and represents a further situation in which abnormal expression of deiodinase enzymes has clinical significance.
Adult↗
The mechanisms of autoimmunity in endocrinology: application to the thyroid gland.
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Animals↗
Dynamic thyroid stimulating hormone tests: do they still have a role?
Modern assays for TSH and for free thyroid hormones have significantly reduced the need for dynamic testing of the hypothalamo-pituitary-thyroid axis in patients with biochemical thyroid dysfunction. However, under certain conditions, such as isolated TSH deficiency, thyrotropinoma and thyroid hormone resistance, the TRH test remains an important adjunctive diagnostic tool. In recent years, the development of recombinant human TSH (rhTSH) has led to a new dynamic test of thyroglobulin (Tg) secretion as a marker of recurrent or metastatic thyroid cancer. RhTSH provides an alternative to thyroid hormone suppression treatment withdrawal in patients who cannot tolerate hypothyroidism and is the agent of choice in patients unable to mount a TSH response.
Feedback, Physiological↗
Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography.
OBJECTIVE: Current thinking is that amiodarone-induced thyrotoxicosis (AIT) might be either iodine-induced thyrotoxicosis in latent hyperthyroidism (Type 1) or destructive thyroiditis (Type 2), and also that colour-flow Doppler sonography (CFDS) of the thyroid and serum interleukin 6 (IL-6) are tools that can classify AIT and direct treatment. To assess the validity of this thinking, our objective was to determine whether CFDS and IL-6 identified AIT subgroups with distinct features. DESIGN: Retrospective case-note audit of all patients presenting with AIT to the Endocrine Department of a UK teaching hospital over a 3-year period. To assess proportions of Type 1 vs. Type 2 AIT and to compare and contrast their clinical features. PATIENTS: 37 patients were identified with AIT (mean age 65, range 20-86 years). In 30 patients in whom AIT persisted, 25 underwent CFDS. RESULTS: In 25 patients who underwent CFDS, 10 (40%) were classified as Type 1, 10 (40%) as Type 2 and 5 (20%) as indeterminate type. In the patients classified by CFDS in whom AIT persisted, 40% of Type 1 patients were male vs. 90% of Type 2 patients. Also, free T4 tended to be lower in patients presenting with Type 1 AIT (52.1 +/- 7.5 pmol/l) compared to Type 2 (74.8 +/- 8.1 pmol/l, P = 0.08), free T3 was lower (8.8 +/- 0.9 vs. 15.6 +/- 3.0 pmol/l, P = 0.03) and the cumulative amiodarone dose was lower (66 +/- 20 vs. 186 +/- 28 g, P = 0.002). We used less prednisolone to achieve euthyroidism in patients with Type 1 AIT whereas carbimazole doses were not different and the time to euthyroidism was the same in both groups (81 +/- 21 vs. 88 +/- 13 days). IL-6 was raised in two patients with Type 1 and in one patient with Type 2 AIT. CONCLUSIONS: CFDS could characterize two distinct subtypes in patients with AIT. Conversely, IL-6 seemed to be an unhelpful test in this context.
Adult↗
Autoantibodies in vitiligo patients are not directed to the melanocyte differentiation antigen MelanA/MART1.
Recent studies have demonstrated the presence of circulating MelanA (MART1)-specific cytotoxic T lymphocytes in a significant number of vitiligo patients when compared to control subjects. High levels of the skin-homing receptor cutaneous lymphocyte-associated antigen were expressed on the T cells and their frequency correlated with the extent of depigmentation and disease activity in the vitiligo patients. The present study was designed to examine vitiligo patient sera for the presence of autoantibodies to MelanA. The incidence of autoantibodies to MelanA in patients with vitiligo (n = 51) and in healthy individuals (n = 20) was examined using a radiobinding assay with 35S]-labelled MelanA and using Western blot analysis with a glutathione S-transferase (GST)-MelanA fusion protein. Autoantibodies to MelanA could not be detected in any of the vitiligo patient sera or control sera analysed using either of these detection systems. It is therefore possible that MelanA only induces cellular rather than humoral autoreactivity in vitiligo.
Adolescent↗
Thyroxine treatment in biochemically euthyroid but clinically hypothyroid individuals.
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Depressive Disorder↗