Biomedical subjects
Publications and source records attributed to C Spitzweg.
Five patients with active Graves disease had moderate to severe autoimmune thrombocytopenic purpura at the time of diagnosis. Correction of hyperthyroidism and restitution of a euthyroid state by carbimazole therapy resulted in complete normalization of platelet counts.
Several lines of experimental and clinical evidence favor a close etiologic link between Graves' disease and its associated extrathyroidal manifestations, ophthalmopathy and pretibial dermopathy. The human TSHR represents a candidate antigen shared between the thyroid gland and the involved extrathyroidal sites in Graves' disease. Here, we demonstrate that ribonucleic acid encoding exons 1-10 of human TSHR can be detected in fibroblasts derived from the affected orbital and pretibial space in patients with Graves' ophthalmopathy and pretibial dermopathy. RNA prepared from cultured fibroblasts was reverse transcribed and the resulting cDNA amplified by the polymerase chain reaction using primers spanning exons 1 through 10 of TSHR. The predicted transcripts (1890 and 2092 bp, respectively) were obtained with cDNA derived from orbital and pretibial fibroblasts of all patients with GO and PTM, and orbital fibroblasts of one healthy individual, and confirmed by southern hybridization. Sequencing of TSHR transcripts confirmed their identity with the reported nucleotide sequence of the human TSHR. Immunostaining using both monoclonal and polyclonal antibodies directed against the recombinant human TSHR revealed specific TSHR-like immunoreactivity in fibroblasts and adipose/connective tissue derived from the orbital and pretibial space of patients with GO and PTD, but not in normal individuals or control tissues. Detection, within the orbital and pretibial tissues, of RNA encoding nonvariant hTSHR and of immunoreactivity for this important autoantigen in Graves' disease suggests that the pathogenic role of the TSHR may extend beyond the thyroid gland, and may include the associated extrathyroidal manifestations.
Because the thyrotropin receptor (TSHR) has long been considered a thyroid-specific protein, its presence in extrathyroidal tissues has been controversial. In this study, we sought to detect and quantify this potentially low abundance mRNA in various extrathyroidal tissues using liquid hybridization analysis (LHA) and to detect protein with immunohistochemical studies. Strongly positive protected bands, indicating the presence of both intact (2.4 kb) and variant (1.3 kb) TSHr mRNA, were apparent in LHA gel lanes corresponding to normal thyroid, Graves' thyroid, and thymus. Less abundant protected bands of the same sizes were present in lanes corresponding to normal adrenal, and samples from normal kidney were faintly positive. The full-length transcript:variant transcript ratio was approximately 1:1 in all positive tissues. Immunohistochemical analysis of TSHR-like reactivity in paraffin-embedded thymus, adrenal, and kidney revealed specific staining in each of these tissues. No TSHR mRNA or TSHR-like immunoreactivity was detected in samples from several other normal human tissues. We conclude that measurable TSHR mRNA and protein expression is not restricted to the thyroid gland. Further study is warranted to determine whether these extrathyroidal receptors play a role in normal physiology or in disease.
Administration of the anti-oxidative trace element selenium is currently being evaluated for its benefits in patients with inflammatory diseases. However, little is known about the risks of selenium. We report on a patient in whom, along with standard therapy, administration of large intravenous doses of selenite for sepsis secondary to pneumonia resulted in development of marked hypothyroidism. In addition, severe iodine deficiency was noted, and supplementation with iodine led to normalisation of thyroid function.
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To further explore a potential role for the human TSH receptor (hTSHR) in the propagation of thyroid autoimmune disease, we examined immunomodulatory effects in response to its stimulation by Graves' Igs both in human thyroid tissue transplanted to the nude mouse and in primary cultures of human thyrocytes. We injected nude mice bearing transplants derived from normal human thyroid with protein A-Sepharose-purified Graves' IgGs (0.05-1 mg) on 2 days and assessed, in addition to functional stimulation, the expression of intercellular adhesion molecule-1 (ICAM-1) by transplant thyrocytes. In parallel to functional stimulation, as demonstrated by thyroid follicular cell hypertrophy in the transplants and increased T4 production, Graves' IgGs induced a marked dose-dependent expression of ICAM-1 by transplanted thyrocytes, which exceeded that of a continuous interferon-gamma infusion (200 IU/24 h) for 2 days. Normal IgGs were ineffective. Bovine TSH (bTSH) had little effect by itself, but did enhance interferon-gamma-induced ICAM-1 expression. To assess the specificity of their effects, experiments with Graves' IgGs were conducted in the presence and absence of a selective hTSHR antagonist (asialoagalacto-hCG). Asialoagalacto-hCG nearly completely abolished the stimulatory effect of Graves' IgGs on ICAM-1 expression and significantly reduced the combined bTSH/interferon-gamma effect. It failed, however, to affect interferon-gamma action. In vitro studies using human thyroid cells in primary culture confirmed the in vivo observations, treatment with saline resulted in 14% of cells expressing ICAM-1, with pooled normal IgGs (500 mg/L) in 18% and with Graves' IgGs (patient A, 448 mg/L; patient B, 260 mg/L) in 78% and 51%, respectively. Upon exposure to Graves' IgGs (90 mg/L) plus asialo-hCG(350 mg/L), 25% of the cells stained positively for ICAM-1, 29% to bTSH (10 IU/L), 31% to recombinant human TSH (10 IU/L), and 84% to interferon-gamma (10 IU/mL). In conclusion, stimulation of human thyroid cells, either transplanted to the nude mouse in vivo or studied under in vitro conditions, with Igs derived from patients with Graves' disease increased the expression of ICAM-1 on the surface of the cells. The action appears to be specific and mediated by the hTSHR. This particular property of TSHR autoantibodies may be of pathophysiological relevance in Graves' disease, as it may assist in targeting the autoimmune attack and in promoting lymphocyte recruitment to the thyroid gland.
Dermatitis herpetiformis is an autoimmune skin disorder frequently associated with gastrointestinal diseases. We report a 53-year-old male with a four-year history of refractory dermatitis herpetiformis associated with hypopituitarism. Endocrine testing, ophthalmological examination and magnetic resonance imaging revealed hypopituitarism due to a non-functioning pituitary macroadenoma. Following transsphenoidal removal of the pituitary tumor and appropriate hormone replacement, complete remission of the skin disorder was obtained. We discuss the permissive role of panhypopituitarism in the course of dermatitis herpetiformis.
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The human thyrotropin receptor (hTSHR) represents an autoantigen that plays a central role in the hyperthyroidism of Graves' disease (GD). hTSHR transcripts have recently been detected by reverse transcription (RT)-PCR in various extrathyroidal tissues, suggesting that the hTSHR may be more widely distributed than previously thought, and that it may serve as a common antigen in the thyroidal and extrathyroidal manifestations of GD. Using techniques other RT-PCR, we examined whether RNA encoding hTSHR and hTSHR-specific immunoreactivity can be detected and localized in cultured orbital fibroblasts (OF), orbital connective tissue, extraocular muscle and various extraorbital tissues derived from both patients with Graves' ophthalmopathy (GO) and normal individuals. Using in situ hybridization with a digoxigenin-labeled antisense oligonucleotide probe specific for the extracellular domain of hTSHR, specific perinuclear and cytoplasmic hTSHR gene expression was detected in OF of patients with GO and, to a lesser degree, normal individuals. Using a highly sensitive immunostaining technique and a panel of monoclonal and polyclonal antibodies directed against different epitopes of recombinant hTSHR, distinct cytoplasmic hTSHR-like immunoreactivity was detected in methanol-fixed OF and orbital connective tissue, which was absent in abdominal fibroblasts, or when using isotype-matched non-immune immunoglobulins. Mouse monoclonal and pig polyclonal hTSHR antibodies detected cytoplasmic hTSHR-like immunoreactivity in perimysial fibroblasts within extraocular muscle, but not in extraocular muscle fibers. Immunocytochemical staining with rabbit polyclonal hTSHR antibody revealed, in addition, distinct cell surface-associated immunoreactivity in paraformaldehyde-fixed OF, but not in abdominal fibroblasts. Taken together, our results suggest that RNA encoding hTSHR is present and actively processed to immunoreactive hTSHR-like protein in OF residing within orbital connective tissue and extraocular muscle. These data support the concept that OF expressing intact or variant hTSHR may act as extrathyroidal targets for sensitized T-cells and immunoglobulins in GD.
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HISTORY AND CLINICAL FINDINGS: A 47-year-old patient was admitted to hospital with fever (39.2 degrees C), weight loss and sore throat. The right thyroid area was painful on palpation. INVESTIGATIONS: The erythrocyte sedimentation rate was 56/86 mm, white blood cell count 10,600/l, with shift to the left and toxic granulations. Blood culture grew Streptococcus mitis; the echocardiogram showed vegetations on the aortic valve. Therefore aortic valve endocatidits was suspected. Ultrasound examination of the thyroid gland showed an echo poor area with an enlarged thyroid artery; thyroid cytodiagnosis was unremarkable. TREATMENT: The fever quickly subsided on administration of penicillin G (7.5 mill I.U. three times daily) and tobramycin (80 mg three times daily) for two weeks, followed by penicillin G in the same dosage for four more weeks. Vancomycin was then given for two weeks (1 g twice daily intravenously). The aortic valve vegetations were no longer seen three weeks after onset of treatment. Two months after discharge the thyroid and heart were normal on ultrasound examination. CONCLUSION: Bacterial thyroiditis was caused by embolisation to the thyroid artery from vegetations on the aortic valve in aortic valve endocarditis, probably due to carious teeth.
We describe a patient in whom highly active Graves' disease occurred in close temportal relationship with extensive, recurrent, venous thrombosis due to primary antiphospholipid syndrome. (J. Rheumatol 1996;23:1435-7).