(1/1222) Postoperative tetany in Graves disease: important role of vitamin D metabolites.

OBJECTIVE: To test the authors' hypothesis of the causal mechanism(s) of postoperative tetany in patients with Graves disease. SUMMARY BACKGROUND DATA: Previous studies by the authors suggested that postoperative tetany in patients with Graves disease occurs during the period of bone restoration and resulted from continuation of a calcium flux into bone concomitant with transient hypoparathyroidism induced by surgery. PATIENTS AND METHODS: A prospective study was carried out to investigate sequential changes in serum levels of intact parathyroid hormone (iPTH), calcium and other electrolytes, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)2D), and bone metabolic markers in 109 consecutive patients with Graves disease who underwent subtotal thyroidectomy. RESULTS: Preoperative serum iPTH levels negatively correlated with ionized calcium levels and positively correlated with 1,25(OH)2D or 1,25(OH)2D/25OHD. After the operation, there was a significant decline in levels of ionized calcium, magnesium, and iPTH. Serum iPTH was not detected in 15 patients after surgery. Four of these 15 patients, and 1 patient whose iPTH level was below normal, developed tetany. Preoperative serum ionized calcium levels were significantly lower, and iPTH levels were higher, in the 5 patients with tetany than in the 11 patients who did not develop tetany despite undetectable iPTH levels. The tetany group had significantly lower serum 25OHD levels and higher 1,25(OH)2D levels, and had increased 1,25(OH)2D/25OHD as an index of the renal 25OHD-1-hydroxylase activity than those in the nontetany group. These results suggest that patients with a high serum level of iPTH as a result of low serum calcium levels (secondary hyperparathyroidism) are susceptible to tetany under conditions of hypoparathyroid function after surgery. CONCLUSIONS: Postoperative tetany occurs in patients with secondary hyperparathyroidism caused by a relative deficiency in calcium and vitamin D because of their increased demand for bone restoration after preoperative medical therapy concomitant with transient hypoparathyroidism after surgery. Calcium and vitamin D supplements may be recommended before and/or after surgery for patients in whom postoperative tetany is expected to develop.  (+info)

(2/1222) HLA-DM and invariant chain are expressed by thyroid follicular cells, enabling the expression of compact DR molecules.

Thyroid follicular cells (TFC) in Graves' disease (GD) hyperexpress HLA class I and express ectopic HLA class II molecules, probably as a consequence of cytokines produced by infiltrating T cells. This finding led us to postulate that TFC could act as antigen-presenting cells, and in this way be responsible for the induction and/or maintenance of the in situ autoimmune T cell response. Invariant chain (li) and HLA-DM molecules are implicated in the antigen processing and presentation by HLA class II molecules. We have investigated the expression of these molecules by TFC from GD glands. The results demonstrate that class II+ TFC from GD patients also express li and HLA-DM, and this expression is increased after IFN-gamma stimulation. The level of HLA-DM expression by TFC was low but sufficient to catalyze peptide loading into the HLA class II molecules and form stable HLA class II-peptide complexes expressed at the surface of TFC. These results have implications for the understanding of the possible role of HLA class II+ TFC in thyroid autoimmune disease.  (+info)

(3/1222) A single technique to correct various degrees of upper lid retraction in patients with Graves' orbitopathy.

BACKGROUND: Several lengthening techniques have been proposed for upper eyelid retraction in patients with Graves' orbitopathy and variable rates of success have been reported. Most authors recommend different procedures for different degrees of retraction, but cannot prevent residual temporal retraction in a significant number of cases. The modified levator aponeurosis recession described by Harvey and colleagues, in which the lateral horn is cut completely, seems to be an exception to this rule, but was evaluated in a limited number of cases only. METHOD: The authors further modified Harvey's technique by dissecting the aponeurosis together with Muller's muscle of the tarsus and the conjunctiva medially only to the extent necessary to achieve an acceptable position and contour of the eyelid in upright position. They also used an Ethilon 6.0 suture, instead of Vicryl, on a loop. It is placed between the tarsal plate and the detached aponeurosis to prevent spontaneous disinsertion. This modification was used in 50 Graves' patients (78 eyelids) with a upper lid margin-limbus distance ranging from 1 to 7 mm and evaluated using strict criteria. RESULTS: A perfect or acceptable result was obtained in 23 of 28 patients (82%) with bilateral retraction and in 18 of 22 patients (82%) with unilateral retraction. Seven eyelids were overcorrected (too low) and three undercorrected, necessitating reoperation. All other eyelids had an almond-like contour and a lid crease of 10 mm or less. No complications except subcutaneous haematomas were seen. Two patients showed a recurrence of lid retraction 9 months after the operation. CONCLUSION: This technique is safe and efficacious and can be used for all degrees of eyelid retraction.  (+info)

(4/1222) Significance of serum antibodies reactive with flavoprotein subunit of succinate dehydrogenase in thyroid associated orbitopathy.

AIMS: Thyroid associated orbitopathy (TAO) is an autoimmune disorder of extraocular muscles and orbital connective tissue. Identification of the principal target antigens would help the understanding of the pathogenesis of the disease and possibly lead to the development of specific therapies in the future. The purpose of this study was to measure serum antibodies against the flavoprotein subunit of succinate dehydrogenase in patients with TAO and correlate their presence with factors of TAO. METHODS: Sera of patients with active TAO of 6 months' duration or less were tested for antibodies against the flavoprotein subunit of succinate dehydrogenase. Clinical data were obtained by retrospective review of patients' charts. Enzyme linked immunosorbent assay was used to test sera for serum antibodies against purified succinate dehydrogenase. RESULTS: 38 patients with TAO and 32 healthy age and sex matched controls were included in the study. Anti-flavoprotein antibodies were detected in 24 out of 38 patients with TAO (63.16%) and in five out of 32 healthy controls (15.63%) (p<0.01). Neither age, sex, duration of thyroid disease, thyroid status, treatment of thyroid disease, smoking history, duration of orbitopathy, activity of orbitopathy, nor the presence of lid retraction were significantly associated with the presence of serum anti-flavoprotein antibodies (p>0.05). However, the total number of rectus muscles affected in both eyes of the patients was significantly correlated with the finding of a positive antibody test (p<0.05). CONCLUSIONS: Serum antibodies reactive with the flavoprotein subunit of succinate dehydrogenase are associated with extraocular muscle involvement in active TAO of recent onset.  (+info)

(5/1222) The role of octreoscan in thyroid eye disease.

Until recently there was no imaging technique available which could demonstrate pathological changes in orbital tissues and could be regarded as a reliable measure of inflammation in thyroid eye disease (TED). Pentetreotide (a synthetic derivative of somatostatin) labelled with 111In has been used to localize tumours which possess surface or membrane receptors for somatostatin in vivo using a gamma camera (1). This technique visualizes somatostatin receptors in endocrine-related tumours in vivo and predicts the inhibitory effect of the somatostatin analogue octreotide on hormone secretion by the tumours (1). By applying 111In-DTPA-d-Phe octreotide scintigraphy (octreoscan), accumulation of the radionuclide was also detected in both the thyroid and orbit of patients with Graves' disease (2-4). If peak activity in the orbit 5h after injection of radiolabelled octreotide is set at 100%, a decrease to 40+/-4% is found at 24h, significantly different from the decrease in blood pool radioactivity, which is 15+/-4% at 24h. Accumulation of the radionuclide is most probably due to the presence in the orbital tissue of activated lymphocytes bearing somatostatin receptors (5). Alternative explanations are binding to receptors on other cell types (e.g. myoblasts, fibroblasts or endothelial cells) or local blood pooling due to venous stasis by the autoimmune orbital inflammation.  (+info)

(6/1222) The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus.

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.  (+info)

(7/1222) Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves' disease.

Autoimmune diseases which follow allogeneic BMT from a donor who is a patient or a carrier of an autoimmune condition are considered to be a paradigm of adoptive autoimmunity. Seven cases of autoimmune thyroiditis associated with clinical hyperthyroidism have been published to date. In the case reported here a 35-year-old female patient with AML of the M2 subtype received unmanipulated PBSC from her HLA-identical sister who had therapeutically controlled Graves' disease. Antithyroid antibodies, including thyrotropin receptor (TSHR) antibodies, appeared 1 year after transplant. Clinical hyperthyroidism requiring thyrostatic medication appeared after 2 years. The biological and clinical implications of adoptive, post-transplant autoimmunity are briefly discussed.  (+info)

(8/1222) The effect of thyrotropin receptor antibodies on the proliferation of FRTL-5 cells and the expression of protooncogene c-fos mRNA.

OBJECTIVE: Hyperthyroidism and a diffuse goiter are the main symptoms of Graves' disease (GD) associated with autoantibodies to thyroid-stimulating hormone (TSH) receptor (TRAb). The present study was conducted to evaluate effects of autoantibodies in patients with GD (TRAb-IgG) on induction of the proliferation and c-fos mRNA expression in FRTL-5 cells (Fisher rat thyroid cell line). METHODS: Highly purified IgG fractions were isolated from 11 patients with GD, TRAb-IgG and 15 normal individuals (normal controls) with Protein A Sepharose CL-4B affinity column chromatograph. FRTL-5 cells, which had been grown to subconfluency and deprived of TSH for a few days. Then, these cells were used for measuring cAMP content, 3H-thymidine incorporation in cells and the expression of c-fos mRNA respectively. RESULTS: After stimulation of TRAb-IgG, the cAMP production and 3H-thymidine incorporation in FRTL-5 cells were much higher than those from normal controls (P < 0.05 respectively). Using 32P labelled v-fos probe by the Northern Blot method, the expression of c-fos mRNA could be induced by IgGs from patients with GD. CONCLUSIONS: These data suggest that the stimulation of TRAb-IgG followed by cAMP production and 3H-thymidine incorporation is related to the induction of c-fos mRNA and, thus, to the growth of FRTL-5 cells.  (+info)