Thyroid Diseases: Weetman AP

Weetman AP. · The Medical School, Beech Hill Road, Sheffield, UK. · Clin Endocrinol (Oxf). · Pubmed #17466000 No free full text.

Abstract: Radioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have occurred with the realization that accurate dosimetry is incapable of avoiding the risks of hypothyroidism, while more accurate assessment of the risks of other adverse effects of radioiodine such as ophthalmopathy and carcinogenesis have become available. More is also known of the potential for pretreatment with an antithyroid drug to affect the outcome of radioiodine treatment. However, we are still uncertain of the benefits of radioiodine treatment in subclinical hyperthyroidism. During the last two decades there has been wider acceptance of radioiodine as a safe and effective therapy for benign, nontoxic goitre, coupled with waning enthusiasm for the use of levothyroxine, as the risks and benefits of this option have become more apparent. The use of recombinant TSH offers the prospect that radioiodine treatment of nontoxic goitre can be simplified and improved, although more studies of this strategy are urgently required.

Weetman AP. · No affiliation provided · Thyroid. · Pubmed #11201851 No free full text.

This publication has no abstract.

Ajjan RA, Weetman AP. · Division of Diabetes and Cardiovascular Research, LIGHT Laboratories, University of Leeds, UK. · Nat Clin Pract Endocrinol Metab. · Pubmed #18574503 No free full text.

Abstract: The presence of antibodies to TSH receptor (TSHR) is the hallmark of Graves disease (GD). These antibodies mimic the action of TSH, resulting in TSHR stimulation and hyperthyroidism, and have been associated with GD-associated extrathyroidal manifestations. TSH binding inhibition assays and bioassays for measurement of TSHR antibody levels have been used for clinical and research purposes. In the former, inhibition of TSH binding to purified or recombinant TSHR by a patient's immunoglobulins is measured by radioactive or chemiluminescent techniques. In the latter, cyclic AMP production is measured by use of radioimmunoassays or chemiluminescent methods in cells natively or artificially expressing TSHR. In this Review, the different techniques used for the detection of antibodies to TSHR are discussed, together with the clinical applications of antibody measurement, including diagnosis of GD and Graves ophthalmopathy. Prediction of relapse after medical treatment and the clinical course of Graves ophthalmopathy are also addressed.

Brabant G, Beck-Peccoz P, Jarzab B, Laurberg P, Orgiazzi J, Szabolcs I, Weetman AP, Wiersinga WM. · Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule, Hannover, Germany. · Eur J Endocrinol. · Pubmed #16645008 links to  free full text

Abstract: 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.

Weetman AP. · Clinical Sciences Centre, University of Sheffield, Northern General Hospital, Sheffield S5 7AU, UK. · Best Pract Res Clin Endocrinol Metab. · Pubmed #15826920 No free full text.

Abstract: Autoimmune thyroid disease is frequently accompanied by other organ-specific and non-organ-specific diseases, most likely because there is sharing of genetic and possibly environmental susceptibility factors. These associations are well recognized in the autoimmune polyglandular syndromes; autoimmune thyroid disease is one of the three major endocrinopathies in the type 2 syndrome and occurs in around 4% of type 1 patients. This review considers the frequency of disease-specific autoantibodies in patients with thyroid autoimmunity and briefly examines the role of such antibodies in performing screening for the associated conditions. Recommendations are made for using such autoantibody tests in the setting of patients with autoimmune thyroid disorders, and also for the utility of screening for thyroid autoimmunity in patients with pernicious anaemia, Addison's disease, coeliac disease, primary biliary cirrhosis, myasthenia gravis, lymphocytic hypophysitis, systemic lupus erythematosus and rheumatoid arthritis. At present, however, there are no large-scale trials that have shown the cost-benefit ratio of autoantibody screening for autoimmunity screening, and clinicians must use individual judgement combined with heightened awareness to identify who to test.

Weetman AP. · Clinical Sciences Centre, University of Sheffield, Northern General Hospital, Sheffield, S5 7AU, UK. · Autoimmunity. · Pubmed #15518055 No free full text.

This publication has no abstract.

Weetman AP. · Clinical Sciences Centre, University of Sheffield, Northern General Hospital, UK. · Clin Endocrinol (Oxf). · Pubmed #15473869 No free full text.

Abstract: 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.

Ajjan RA, Weetman AP. · Academic Unit of Molecular and Vascular Medicine, University of Leeds, The General Infirmary at Leeds, Leeds, United Kingdom. · J Endocrinol Invest. · Pubmed #15164999 No free full text.

Abstract: 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.

Ajjan RA, Weetman AP. · Academic Unit of Molecular Vascular Medicine, University of Leeds, The General Infirmary at Leeds, Leeds LS1 3EX, UK. · Autoimmunity. · Pubmed #14669942 No free full text.

Abstract: The role of cytokines in the pathogenesis of autoimmune thyroid disease (ATD) has been extensively investigated over the past years. In patients with ATD, these molecules can be found in both the thyroid and sites of extrathyroidal complications of the disease. Cytokines can affect the autoimmune process through a number of mechanisms including recruitment of inflammatory cells and upregulation of molecules essential for perpetuation of the inflammatory response in the affected site. In addition, cytokines can interfere with thyroid hormone synthesis, implicating them directly in thyroid dysfunction found in ATD patients. Also, these molecules can modulate the function of cells in orbital tissue, which results in localised oedema, indicating a central role for cytokines in the development of proptosis, the cardinal feature of thyroid associated ophthalmopathy.

Allahabadia A, Weetman AP. · Department of Endocrinology and Clinical Sciences Centre, Northern General Hospital, Sheffield, UK. · J Endocrinol Invest. · Pubmed #14604064 No free full text.

Abstract: 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.

Weetman AP. · University of Sheffield Clinical Sciences Centre, Northern General Hospital, Sheffield, S57AU, United Kingdom. · Ann Endocrinol (Paris). · Pubmed #12707629 No free full text.

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Weetman AP. · University of Sheffield Clinical Sciences Centre, Northern General Hospital, Sheffield, UK. · Horm Res. · Pubmed #12638522 No free full text.

Abstract: 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.

Weetman AP. · University of Sheffield Clinical Sciences Centre, Northern General Hospital, Sheffield, S5 7AU, UK. · Eur J Endocrinol. · Pubmed #12534350 links to  free full text

Abstract: Autoimmune thyroid disease is the archetype for organ-specific autoimmune disorders. Progress in treating these disorders lies in improvements of our understanding of the predisposing factors responsible, the mechanisms responsible for progression of disease, and the interaction between thyroid antigens and the immune system at the level of the T cell and antibody. In common with other autoimmune diseases, genetic, environmental and endogenous factors are required in an appropriate combination to initiate thyroid autoimmunity. At present the only genetic factors which have been confirmed lie in the HLA complex and CTLA-4 or a closely linked gene. Identifying other predisposing genes will require large-scale family studies, or further insights into likely candidate genes. A number of environmental factors are known to predispose to autoimmune thyroid disease, including smoking, stress and iodine intake, while immunomodulatory treatments are revealing new pathways for disease emergence.The thyroid cell itself appears to play a major role in disease progression, interacting with the immune system through expression of a number of immunologically active molecules including HLA class I and II, adhesion molecules, cytokines, CD40 and complement regulatory proteins. New techniques, in particular phage display libraries, are providing the methods with which to identify autoantibody diversity in autoimmune thyroid disease and to provide tools for mapping autoantigenic epitopes. Application of these techniques is likely to lead to an understanding of how TSH receptor antibodies interact with the receptor to cause Graves' disease and also to the identification of novel orbital autoantigens in thyroid-associated ophthalmopathy.

Jenkins RC, Weetman AP. · University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, United Kingdom. · Thyroid. · Pubmed #12490075 No free full text.

Abstract: Autoimmune thyroid disease (AITD) is common and occurs frequently in conjunction with other diseases. Many putative disease associations have been suggested for AITD but the validity of these associations is not clear in all cases. It is important to define disease associations correctly because this may offer a means to rationally screen for true associations, may shed light on shared pathophysiologic mechanisms and may be important if the associated disease impacts on patient management. This review has examined the evidence base for a large number of the suggested associations.

Weetman AP. · University of Shieffield Clinical Sciences Centre, Northern General Hospital, UK. · Clin Endocrinol (Oxf). · Pubmed #12100065 No free full text.

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Weetman AP. · University of Sheffield Division of Clinical Sciences, Northern General Hospital, United Kingdom. · N Engl J Med. · Pubmed #11071676 No free full text.

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Weetman AP. · University of Sheffield Clinical Sciences Centre, Northern General Hospital. · J R Coll Physicians Lond. · Pubmed #11005077 No free full text.

Abstract: Effective management for hypothyroidism has been available for a century, thanks to the pioneering efforts of George Murray, who first tested injection of thyroid gland extracts in Newcastle. Radioiodine for the diagnosis and then treatment of Graves' hyperthyroidism was introduced by Hertz and Roberts in Boston, and by Leblond in Paris, in 1943, the same year that Astwood in the USA began to use the predecessors of modern antithyroid drugs. Despite this lengthy history, debate continues as to the most effective management of these common disorders. More use of radioiodine, including its use in euthyroid goitre, is being advocated as its safety is now well established. Recent developments in optimising these treatments will be considered in this brief review.

Weetman AP, Hunt PJ. · University of Sheffield Clinical Sciences Centre, Northern General Hospital, UK. · Exp Clin Endocrinol Diabetes. · Pubmed #10614909 No free full text.

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Weetman AP. · University of Sheffield, Clinical Sciences Centre, Northern General Hospital, UK. · Exp Clin Endocrinol Diabetes. · Pubmed #10522807 No free full text.

Abstract: The etiology and pathogenesis of autoimmune endocrinopathies are now much clearer as a result of advances in our understanding of basic immunology, and particularly the development of novel animal models. Also crucial has been the molecular characterisation of target autoantigens, although this still remains elusive for some disorders, such as hypoparathyroidism and premature ovarian failure, retarding progress. The application of new genetic techniques, the detailed structural analysis of autoantigen epitopes and the creation of new experimental animal disorders (by DNA immunisation or knockouts) will ensure still more rapid progress into the new millennium.

Kilbane MT, Ajjan RA, Weetman AP, Dwyer R, McDermott EW, O'Higgins NJ, Smyth PP. · University College Dublin, St. Vincent's University Hospital, Ireland. · J Clin Endocrinol Metab. · Pubmed #10720070 links to  free full text

Abstract: In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I- symporter (NIS), whereas in the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2 of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total tissue iodine levels of 80.9 +/- 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher than those in 19 breast cancers taken from either the tumor (18.2 +/- 4.6 ng I/mg) or morphologically normal tissue taken from within the tumor-bearing breast (31.8 +/- 4.9 ng I/mg; P < 0.05 in each case). Inhibition of 125I uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49 (16.3%) benign breast disease, and 27 of 86 (31.4%) Graves' patients, but in only 1 of 33 (3.0%) age-matched female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in those with benign breast disease, once again suggesting an association between thyroid autoimmunity and breast carcinoma.

Brand OJ, Barrett JC, Simmonds MJ, Newby PR, McCabe CJ, Bruce CK, Kysela B, Carr-Smith JD, Brix T, Hunt PJ, Wiersinga WM, Hegedüs L, Connell J, Wass JA, Franklyn JA, Weetman AP, Heward JM, Gough SC. · Institute of Biomedical Research, University of Birmingham, Edgbaston, West Midlands, UK. · Hum Mol Genet. · Pubmed #19244275 No free full text.

Abstract: Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 10(-7), OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 x 10(-4)). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.

Weetman AP. · The Medical School, University of Sheffield, Sheffield, United Kingdom. a.p.weetman@sheffield · Endocr Pract. · Pubmed #19211400 No free full text.

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Weetman AP. · The Medical School, Sheffield. · Clin Med. · Pubmed #18478874 No free full text.

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Weetman AP. · Medical School, University of Sheffield, UK. · Nat Clin Pract Endocrinol Metab. · Pubmed #16932244 No free full text.

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Weetman AP. · School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK. · Clin Endocrinol (Oxf). · Pubmed #16487429 No free full text.

This publication has no abstract.