Thyroid Diseases: Salvi M

Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas G, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. · Department of Clinical Medicine, University of Insubria, Varese, Italy. · Thyroid. · Pubmed #18341379 No free full text.

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Mizokami T, Salvi M, Wall JR. · Department of Clinical and Biomedical Sciences: Barwon Health, University of Melbourne, The Geelong Hospital, Victoria, Australia. · J Endocrinol Invest. · Pubmed #15164997 No free full text.

Abstract: The extra ocular (eye) muscles are one of the principal tissues involved in the autoimmune-mediated inflammation of Graves' ophthalmopathy (GO). Several eye muscle proteins are targeted by autoantibodies or sensitized T lymphocytes, or both, and include: G2s, which is now identified as the terminal 141 amino acids of the winged-helix transcription factor FOXP1, the flavoprotein (Fp) subunit of the mitochondrial enzyme succinate dehydrogenase, the so-called "64kDa protein", a non-tissue specific membrane protein called 1D and the calcium binding protein calsequestrin. Of these, antibodies against G2s and Fp are the most sensitive markers of eye muscle damage in patients with thyroid autoimmunity even though neither antigen is specific to eye muscle and neither antibody is specific to GO. However, the recent finding that the calsequestrin gene is 4.7 times more expressed in eye muscles than other skeletal muscles suggests that we should reconsider the possible role of anti-calsequestrin autoantibodies in ophthalmopathy. GO may comprise two main subtypes with different pathogenetic mechanisms, namely ocular myopathy in which eye muscle inflammation predominates and congestive ophthalmopathy where inflammatory changes occur in the periorbital connective tissues in the absence of eye muscle dysfunction. Anti-G2s and anti-Fp antibodies are closely associated with the ocular myopathy subtype of GO while antibodies targeting type XIII collagen, the only member of the collagen family to have a transmembrane domain, are closely linked to congestive ophthalmopathy. Since both G2s and Fp are intracellular antigens it is unlikely that either antibody causes eye muscle fiber damage in GO, although a role in the later stages of the disease when the fiber has released its cellular contents has not been excluded. Eye muscle antibodies that are cytotoxic to eye muscle cells in antibody-dependent cell-mediated cytotoxicity (ADCC) are more likely to play a role in eye muscle fiber damage since they target a putative eye muscle cell membrane antigen, the identity of which is currently being investigated. While anti-G2s and anti-Fp antibodies are probably secondary to an underlying reaction, such as cytotoxic T lymphocyte targeting of an eye muscle membrane antigen that has yet to be identified, they are reliable markers of immunologically mediated eye muscle fiber damage in patients with Graves' hyperthyroidism. In conclusion, while a pathogenic role for eye muscle antibodies has not been excluded, they are most likely secondary to cytotoxic T cell reactions in GO and, as such, good markers of this autoimmune disease.

Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. · Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore IRCCS, Milan, Italy. · Eur J Endocrinol. · Pubmed #17218723 links to  free full text

Abstract: INTRODUCTION: Hyperthyroid Graves' disease (GD) is a B-cell-mediated condition caused by TSH receptor antibodies (TRAb), which decline when GD remits. Anti-CD20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophthalmopathy (TAO). METHODS: Nine patients with GD, (seven with active TAO, two with mild lid signs) were studied. The trial was only approved as an open pilot study; thus we compared the effect of RTX therapy to that of i.v. glucocorticoids (IVGC) in 20 consecutive patients. Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with IVGC (500 mg i.v. for 16 weeks). TAO was assessed by the clinical activity score (CAS) and severity was classified using NOSPECS (No signs or symptoms; Only signs (lid); Soft tissue involvement; Proptosis, Extraocular muscle involvement; Corneal involvement; Sight loss). Thyroid function and lymphocyte count were measured by standardized methods. RESULTS: All patients attained peripheral B-cell depletion with the first RTX infusion. Minor side effects were reported in three patients. Thyroid function was not affected by RTX therapy and hyperthyroid patients required therapy with methimazole. After RTX, the changes in the levels of thyroglobulin antibodies, thyroperoxidase antibodies and TRAb were neither significant nor correlated with CD20+ depletion (P = NS). CAS values before RTX were 4.7 +/- 0.5 and decreased to 1.8 +/- 0.8 at the end of follow-up (P < 0.0001) and more significantly compared with IVGC (P < 0.05). Proptosis decreased significantly after RTX both in patients with active TAO (ANOVA; P < 0.0001) and those with lid signs (ANOVA; P < 0.003). The degree of inflammation (class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). Relapse of active TAO was not observed in patients treated with RTX, but occurred in 10% of those treated with IVGC, who also experienced adverse effects more frequently (45 vs 33% of patients). CONCLUSIONS: RTX positively affects the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TRAb. If our findings are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

Minelli R, Braverman LE, Valli MA, Schianchi C, Pedrazzoni M, Fiaccadori F, Salvi M, Magotti MG, Roti E. · Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, Università degli Studi di Parma, Italy. · Clin Endocrinol (Oxf). · Pubmed #10341861 No free full text.

Abstract: OBJECTIVE: To determine whether the administration of pharmacological quantities of iodine during interferon-alpha (rIFN-alpha) treatment of chronic viral hepatitis B and C (HCV) would exacerbate the potential adverse effects of rIFN alpha on thyroid function. DESIGN: Thyroid function tests were carried out in 48 euthyroid patients before and during rIFN-alpha therapy of HCV. Twenty-one of these patients were also treated with 10 drops saturated solution of potassium iodine (SSKI, approximately 350 mg iodine daily). Eight patients with HCV but not treated with rIFN-alpha received 10 drops SSKI. PATIENTS: All patients were enthyroid prior to rIFN-alpha therapy for HCV or iodine and thyroid function tests were similar in the three groups. MEASUREMENTS: Serum free T4, free T3, and TSH concentrations were measured prior to and at 30 and 60 days of rIFN-alpha therapy in the three groups of patients. The serum TSH response to TRH was assessed before rIFN-alpha therapy and on day 60. Thyroid peroxidase antibodies were measured before and during therapy. RESULTS: During the 2-month study period, similar small but significant decreases in serum FT4 and FT3 and compensatory small significant increases in TSH concentrations were observed in the patients treated with rIFN-alpha + iodine and iodine alone but not in the patients receiving rIFN-alpha alone. Abnormal thyroid function tests were observed more frequently in patients receiving rIFN-alpha + iodine and iodine alone compared to those receiving rIFN-alpha alone. CONCLUSIONS: Excess iodine administered to patients treated with rIFN-alpha induced small changes in thyroid function similar to those observed in patients treated with iodine alone. Thus, rIFN-alpha and iodine do not appear to be synergistic in the development of abnormal thyroid function tests over a 2-month treatment period.

Salvi M, Vannucchi G, Campi I, Currò N, Simonetta S, Covelli D, Pignataro L, Guastella C, Rossi S, Bonara P, Dazzi D, Ratiglia R, Beck-Peccoz P. · Department of Medical Sciences (Padiglione Granelli), University of Milan, Fondazione Ospedale Maggiore, IRCCS Via Sforza, Milan, Italy. · Clin Immunol. · Pubmed #19195932 No free full text.

Abstract: Rituximab (RTX) has been shown in previous work to improve thyroid-associated ophthalmopathy (TAO), but very little data is available on the effects of RTX in the target tissues. We studied the effects of RTX on peripheral lymphocytes and on the intra-orbital infiltrates in one patient with severe TAO who was treated with two cycles of therapy. Intra-orbital tissues derived at decompression from 3 patients with moderate-severe and 1 with severe TAO, treated with standard immunosuppression, were studied as controls. Peripheral blood lymphocytes were analyzed throughout the study period, while intra-orbital tissue lymphocytes at decompression. In the patient treated with RTX visual field and acuity improved in response to peripheral CD 20+ cell depletion, although there was a proportion of persisting CD 19+ cells. After RTX re-treatment the patient's optic nerve function improved only transiently. The number of CD 20+ cells was lower in orbital tissues (0-1%) than in the peripheral blood (3%). A greater percentage of CD 19+ was observed in the orbits compared to the periphery, most of which were CD 19+5+ (80%). By immunohistochemistry, orbital tissues from all control patients showed CD 20+ and CD 3+ cells, independently of the duration of TAO and of the treatment with either steroids or radiotherapy. This is the first report on the therapeutic effect of RTX in active, severe TAO associated to the depletion of intra-orbital CD 20+ lymphocytes. After RTX, CD 19+5+ lymphocytes were shown to be 2-3 times more prevalent in the orbital infiltrates, compared to CD 20+ cells. Persistence of autoreactive cells is believed to be related to TAO relapse.

Salvi M, Vannucchi G, Campi I, Currò N, Beck-Peccoz P. · Department of Medical Sciences, Endocrinology Unit, University of Milan, 20100 Milan, Italy. · Ann Endocrinol (Paris). · Pubmed #18417090 No free full text.

Abstract: Steroids have been used in the therapy of the moderate to severe forms of Graves' ophthalmopathy (GO) and other autoimmune diseases as they act only as general immunosuppressants. Previous work has shown that blocking the CD-20 receptor on B lymphocytes has significantly affected the clinical course of GO, by rapidly reducing inflammation and the degree of proptosis. We have studied nine patients with Graves' disease, of whom seven had active GO and two, with newly diagnosed hyperthyroidism, only mild lid signs. We also studied a group of 20 consecutive patients, treated with intravenous glucocorticoids (IVGC) according to a standard protocol. Patients treated with RTX (1000mg i.v. twice at two-week interval) and those treated with IVGC (500mg i.v. for 16 weeks) were studied monthly up to 12 months after the first drug infusion. By ophthalmological examination, GO was assessed by the clinical activity score (CAS) and by the NOSPECS score. Thyroid function and lymphocyte count were measured by standardized methods. RTX was well-tolerated and only minor side-effects were reported in 30% of patients during the first infusion. All patients attained peripheral B-cell depletion with the first RTX infusion. All but one patients showed both CD20+ cells and CD19+ cells depletion, while one had persistent 3-5% CD19+ cells in the periphery, mostly CD19+5+. Thyroid function was not affected by RTX therapy. Titers of antithyroglobulin (TgAb), antithyroperoxidase and anti-TSH receptor antibodies (TRAb) did not change significantly (P=NS) and did not correlate to CD20+ depletion (P=NS). CAS values decreased significantly (P<0.0001). Proptosis decreased significantly after RTX in both patients with active GO (ANOVA; P<0.0001) and in those with Graves' hyperthyroidism and lid signs (ANOVA; P<0.003). The degree of inflammation (NOSPECS class 2) decreased significantly in response to RTX (ANOVA; P<0.001). In patients treated with IVGC, mean CAS value decreased significantly less than in those treated with RTX (P<0.05). Adverse effects were more frequent after IVGC (45% of patients). Seventy-five percent of patients responded to IVGC and 10% showed relapse of active GO six to eight weeks after withdrawal. The results of this study on RTX in GO suggest that the drug is effective in modifying the disease course and that the improvement of the clinical activity of GO after RTX was more significant than after IVGC. We did not observe relapse of active GO, even after B-cell return in peripheral blood. This might be related to the persistence of a significant degree of B-cell depletion after RTX observed in the peripheral blood as late as two years of follow-up. RTX therapy was also effective in improving proptosis and soft tissue inflammation. The mechanism by which RTX affects GO is unknown. It may act as a true immunosuppressor by switching off reactions inducing the active phase of TAO, perhaps by influencing the cytokine production in the orbit or by inducing depletion of antigen presenting B-cells.

Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM, Anonymous00022. · Department of Clinical Medicine, University of Insubria, 21100 Varese, Italy. · Eur J Endocrinol. · Pubmed #18299459 links to  free full text

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Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, Guastella C, Avignone S, Pirola G, Ratiglia R, Beck-Peccoz P. · Institutes of Endocrine Sciences, University of Milan, Fondazione Ospedale Policlinico IRCCS, Italy. · Eur J Endocrinol. · Pubmed #16556712 links to  free full text

Abstract: One patient with Graves' hyperthyroidism and ophthalmopathy in its active phase and unresponsive to steroid, was treated with the anti-CD20 monoclonal antibody, rituximab (RTX), as part of an open study. The effect of RTX in the thyroid and the orbital tissues was studied. The ophthalmopathy responded to RTX therapy by ameliorating the eye signs with a decrease in the clinical activity score from 5 to 2 in 3 months, while the patient had peripheral B-cell depletion. Hyperthyroidism did not improve during the 6 months of B-cell depletion and serum TSH-receptor antibodies (TRAb) levels did not significantly change after RTX therapy. Therefore, the patient underwent total thyroidectomy and few B-cells were found in the thyroid tissue specimens. While the patient eye disease remained stable (clinical activity score = 2), we performed corrective orbital decompression and we found absence of lymphocytes in the orbital tissue specimens. We believe that RTX treatment in Graves' disease may cause amelioration of ophthalmopathy by depleting total lymphocytes population in the orbit. The persistence of Graves' hyperthyroidism suggests that a single cycle of RTX does not result in complete lymphocyte depletion in thyroid tissue and thus no decline in serum TRAb was observed.

Salvi M, Vannucchi G, Sbrozzi F, Del Castello AB, Carnevali A, Fargion S, Beck-Peccoz P. · Institute of Endocrine Sciences, Ospedale IRCCS, University of Milan, Milan, Italy. · Thyroid. · Pubmed #15320978 No free full text.

Abstract: A 43-year-old woman with Hashimoto's thyroiditis (HT), euthyroid on levothyroxine since 1999, developed thyroid-associated ophthalmopathy (TAO) in February 2002. She had involvement of the eye muscles, as shown by computed tomography (CT) scan. She was started on methylprednisolone pulse therapy 7.5 mg/kg of body weight, (one cycle every 2 weeks, each cycle comprising two infusions on alternate days), with rapid improvement of soft tissue inflammation and of eye motility, as confirmed by the reduction of clinical activity score (CAS) and eye muscles size on CT scan. At the end of treatment the patient showed a marked and rapid increase of serum aminotransferases (up to 1200 U/L). She had negative hepatitis A, B, and C viruses serology, but circulating antinuclear antibodies. A liver biopsy, performed at 4 weeks after the discontinuation of intravenous steroids, led to the diagnosis of autoimmune hepatitis (AIH). The patient was treated with oral steroids with a rapid reduction of serum aminotransferases concentrations. To our knowledge, there have been only two reports of liver dysfunction after intravenous steroids for TAO, but the etiology of such hepatitis had not been established. AIH may develop in patients with multiple autoimmunity and may not become overt until immune rebound occurs (i.e. after cessation of or between immunosuppressive treatment cycles). Steroids are the first line of treatment for AIH, hence their use would not be contraindicated when patients with TAO have chronic hepatitis, provided that the modalities of treatment are appropriate.

Salvi M, Dazzi D, Pellistri I, Neri F, Wall JR. · Cattedra di Endocrinologia, Università degli Studi di Parma, Parma, Italy. · Ophthalmology. · Pubmed #12208720 No free full text.

Abstract: OBJECTIVE: We have used an artificial neural network in an attempt to classify and predict the progression of thyroid-associated ophthalmopathy (TAO) at the first clinical examination. DESIGN: This retrospective comparative case series included a group of patients examined by the ophthalmologist only once because of the absence of signs of progressive disease (GR1), as subsequently monitored by an endocrinologist, and a group of patients on follow-up because of progressive disease (GR2). PARTICIPANTS AND METHODS: We examined 242 patients, of whom 207 were women and 35 were men. GR1 included 129 patients (257 eyes) who, on ophthalmologic assessment, were further classified as having no TAO (n = 53; GR1a) and only lid signs or inactive, stable TAO (n = 76; GR1b). GR2 included 113 patients (219 eyes). One hundred three normal subjects (205 eyes), 50 women and 53 men, were tested to provide normal ranges for proptosis values. We applied a model of back propagation neural network with 17 input variables, a training matrix of 414 observations, a randomly selected test group of 115 observations, and, as output, the progression of disease. The ophthalmologic assessment included (1) lid fissure measurement, (2) Hertel, (3) color vision, (4) cover test and Hess screen, (5) visual acuity, (6) tonometry, (7) fundus examination, (8) visual field, and (9) orbital computed tomography scan or ultrasonography. Other parameters included in the neural analysis were gender and age of the patients, their cigarette smoking, and the interval between follow-up visits. RESULTS: The prevalence of smokers among patients without TAO was significantly lower than that among those with TAO (P < 0.03). Mean proptosis values (Hertel) were significantly different in GR1, in GR2, and in a group of normal eyes (P < 0.0001), and the changes of values in consecutive measurements were associated with progression of the disease (P < 0.01). Differences of the proptosis values in the two groups of patients were not related to smoking. The neural network correctly classified 78.3% of 115 eyes (87 patients) and predicted TAO progression in 69.2% of 39 eyes (28 patients). CONCLUSIONS: In our opinion, neural network analysis can be successfully applied for classifying TAO and predicting progression at the first clinical examination.

Salvi M, Dazzi D, Pellistri I, Neri F. · Thyroid Center and Department of Ophthalmology, University of Parma, Italy. · Thyroid. · Pubmed #11952045 No free full text.

Abstract: In the present work we analyzed patients with thyroid-associated ophthalmopathy (TAO) at various clinical stages of disease progression and implemented a model of neural analysis for disease classification and prediction of progression. We studied 246 patients (group 1), seen only once because they had absent, minimal, or inactive TAO and 152 patients (group 2), seen two or more times because of active and/or progressive TAO. The ophthalmologic assessment included: (1) lid fissure measurement; (2) Hertel; (3) color vision; (4) cover test and Hess screen; (5) visual acuity; (6) tonometry; (7) fundus examination; (8) visual field; (9) orbital computed tomography (CT) scan or ultrasound. A back propagation model of neural network was based on the relative variations of 13 clinical eye signs (input variables) for classification and prediction of disease progression (output variable). Approximately 300 eyes (20%) were randomly selected as a test group. Correlation between expected and calculated patients' classification was highly significant (p < 0.00001). Concordance between clinical assessment and the neural network prediction was obtained in 78 of 117 eyes (67%). We have developed a neural model that allows classification of TAO and preliminary prediction of disease progression at the first clinical examination. The results are validating the classification into the two groups on which our initial assumption was based.

Salvi M, Pedrazzoni M, Girasole G, Giuliani N, Minelli R, Wall JR, Roti E. · Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, Istituto di Clinica Medica Generale, UniversitA degli Studi di Parma, Parma, Italy. · Eur J Endocrinol. · Pubmed #10913938 links to  free full text

Abstract: OBJECTIVE: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb). SUBJECTS: We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers. RESULTS: Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking. CONCLUSIONS: Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.

Roti E, Gardini E, Magotti MG, Pilla S, Minelli R, Salvi M, Monica C, Maestri D, Cencetti S, Braverman LE. · Centro per lo Studio, Diagnosi e Cura delle Tireopatie, Università degli Studi di Parma, Italy. · J Endocrinol Invest. · Pubmed #10219885 No free full text.

Abstract: In spite of data supporting the use of the serum thyrotropin (TSH) concentration as the best test to detect abnormal thyroid function, measurement of circulating thyroid hormones with or without a serum TSH continues to be frequently requested to evaluate thyroid function. We have analyzed how combinations of thyroid function tests were ordered by referring physicians and the results of the tests in order to offer some suggestions as to how to use thyroid function tests in a cost effective manner. During 1995, 19,181 inpatient and outpatient requests (45,865 different tests) for thyroid function tests were received by the laboratory of a 1600 bed University Hospital in Parma, Italy. The following tests were carried out: T4, free T4, T3, free T3 and TSH. Serum TSH values below and above the normal range were considered to reflect abnormal thyroid function i.e. hyperthyroidism, or hypothyroidism including subclinical disease independent of the results of the other tests. Combinations of ordered tests and the percent of the total for each combination were: TSH+T4+T3 (56%), TSH+FT4+FT3 (14%), TSH (12%), TSH+FT4 (9%), TSH+T4 (1%), TSH+T4+T3+FT4+FT3 (5%), others (3%). The T4+T3+TSH panel (10,780 requests) had normal serum TSH values in 80.6% and the FT4+ FT3+TSH panel (2,590 requests) had normal TSH values in 73.2%. Elevated serum TSH concentrations were observed more frequently in hospitalized than in ambulatory patients (9.7% vs 7.4% p<0.001). T3 (elevated serum T3, normal T4 and low TSH concentrations) and T4 (elevated serum T4, normal T3 and low TSH concentrations) toxicosis were observed in 8.1% and 9.4%, respectively, of the requested test (NS). FT3 and FT4 toxicosis, defined as for T3 and T4 toxicosis, were observed in 7.5% and 4.9%, respectively (NS). The low T3 and low FT3 syndrome in hospitalized patients was present in 1.6% and 2.3% of the requests, respectively (NS). The low T4+low T3 and low FT4+low FT3 syndrome was present in only 0.3% and 0.2%, respectively, of the requests. Our study shows that a) in hospitalized patients thyroid function tests were requested in 20% of the patients and only one in 14 of these patients at the highest could have abnormal thyroid function, as indicated by abnormal TSH value b) FT4 (or T4) is as useful as FT3 (or T3) in the diagnosis of hyperthyroidism, c) in hospitalized patients the low T3 syndrome was far less common than that reported in the literature, probably due to the lower severity of illness, d) panels which include T3 and FT3 are not justified, and e) serum TSH alone is the most appropriate initial thyroid function test.

Gunji K, De Bellis A, Kubota S, Swanson J, Wengrowicz S, Cochran B, Ackrell BA, Salvi M, Bellastella A, Bizzarro A, Sinisi AA, Wall JR. · Department of Medicine, Allegheny University Hospitals, Allegheny General, Pittsburgh, Pennsylvania 15212-4772, USA. · J Clin Endocrinol Metab. · Pubmed #10199764 links to  free full text

Abstract: Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.

Salvi M, Spaggiari E, Neri F, Minelli R, Roti E. · No affiliation provided · Am J Med. · Pubmed #10460062 No free full text.

This publication has no abstract.