Thyroid Plasma Membranes Research Articles

Hypothyroidism

Thyroid DevelopmentTHYROID HORMONE SYNTHESIS AND CONTROLThyroid hormones (TH) are critical for normal growth, development, and metabolism during infancy and childhood. They are synthesized by the thyroid gland follicular cells, the function of which is to concentrate iodide from the blood and return it to peripheral tissues in a hormonally active form. The thyroid cell iodide-concentrating mechanism, often referred to as the iodide pump, confers on the gland its ability to concentrate iodide to many times its level in plasma. The steps involved in synthesis and release of TH include: 1) iodide trapping by the thyroid gland; 2) synthesis of thyroglobulin; 3) organification of trapped iodide as iodotyrosines (monoiodotyrosine, MIT, and diiodotyrosine, DIT); 4) coupling of the iodotyrosines to form the iodothyronines thyroxine (T4) and triiodothyronine (T3) and storage in follicular colloid; 5) endocytosis of colloid droplets and hydrolysis of thyroglobulin to release MIT, DIT, T4, and T3; and 6) deiodination of MIT and DIT with intrathyroidal recycling of the iodine.The concentration of iodide in plasma under normal circumstances is less than 0.2 µg/dL. The iodide is removed from plasma almost entirely by the kidney and the thyroid gland. Transport of iodide across the thyroid cell membrane is the first and ratelimiting step in TH biosynthesis.

Inhibition of thyroid NADPH-oxidase by 2-iodohexadecanal in a cell-free system

The major nonpolar iodolipid formed in horse thyroid cells has recently been identified as 2-iodohexadecanal (2-IHDA). We have investigated in vitro the effect of 2-IHDA on the NADPH-oxidase, NADPH-cytochrome c reductase, and thyroid peroxidase (TPO) activities of a porcine thyroid plasma membrane preparation. 2-IHDA inhibited NADPH-oxidase activity, with half-inhibition at 3–5 μM, but it had no effect on NADPH-cytochrome c reductase. It inhibited the TPO-catalyzed iodination of protein, but not iodide oxidation. Hexadecanal also inhibited NADPH-oxidase. Inhibition by the non-iodinated lipid aldehydes depended on the length of their aliphatic chain: dodecanal and tridecanal gave maximal inhibition. Free iodide, 2-iodohexadecanol and palmitic acid all had no inhibitory effect. Washing treated membranes showed that the inhibition of NADPH-oxidase by hexadecanal was fully reversible, whereas that of 2-IHDA and other iodinated or brominated alkanals was irreversible. Thus the interaction between some residues of the thyroid NADPH-oxidase and the lipid aldehyde groups was favored or stabilized by the iodine atom. Modification of primary amine and thiol groups of NADPH-oxidase inhibited its activity. These groups could also be the target of lipid aldehydes. We suggest that 2-IHDA, because it inhibits TPO and more profoundly the H 2O 2-generating system in thyroid plasma membrane, modulates iodide metabolism in the thyrocyte and may mediate the Wolff-Chaikoff effect.

Studies on the Action of Thyroid Stimulation Blocking Antibody (TSBAb) on Thyroid Cell Membrane

The effect of thyroid stimulation blocking antibody (TSBAb) on stimulated cyclic AMP (cAMP) production induced by adenylate cyclase stimulators in porcine thyroid membrane (PTM) and porcine thyroid cells (PTC) has been studied. Ten TSBAbs with high TSH binding inhibitory immunoglobulin (TBII) activities significantly blocked TSH-stimulated cAMP production in PTC. The blocking effect of TSBAb on the cAMP increase induced by forskolin or GTP-gamma S stimulation in PTC was found in a few cases. However, there was no blocking action of TSBAb on the cAMP increase stimulated by forskolin, GTP gamma S, or NaF in isolated PTM. When TSBAb-globulin was absorbed with PTM or guinea pig epididymal fat membrane (GPFM), the TBII activity in TSBAb-globulin was significantly absorbed by these membranes. A decrease of TSBAb activity (blocking activity for TSH-stimulated cAMP production in PTC) by PTM absorption, but no decrease by GPFM absorption, was found in six cases. This suggests that the potent TSBAb-neutralizing component may be associated with a non-TSH receptor site in the thyroid membrane. The other four cases showed a decrease of TSBAb activity by absorption with both PTM and GPFM. This suggests that the TSBAb-neutralizing activity may be associated with the TSH receptor site of both PTM and GPFM. The results of the present study suggest that TSBAb may block TSH action either via the TSH receptor itself or via a non-TSH receptor component of the thyroid membrane and not at a postreceptor level.

Production of thyroid stimulation blocking antibody without TSH receptor binding activity in rabbits with experimental autoimmune thyroiditis.

When rabbits were immunized with porcine thyroid plasma membrane, some cases of produced antibodies showed the blocking activity for TSH stimulated cAMP production in cultured porcine thyroid cells in spite of negative TSH binding inhibitory immunoglobulin (TBII) activity. The inhibitory effect of these thyroid stimulation blocking antibodies (TSBAbs) on cAMP increase by forskolin and GTP gamma S in porcine thyroid cells was observed in 1 and 3 rabbits, respectively. When the blocking activity of these antibodies for stimulated cAMP production by forskolin, GTP gamma S and NaF was examined in the isolated porcine thyroid membrane, no blocking activity for these 3 stimulators except in 1 case was found. The blocking activity of these antibodies could be absorbed significantly by incubation with porcine thyroid plasma membrane as antigen. The blocking activity was not observed in rabbits immunized with porcine thyroglobulin. The present experiment demonstrated that the produced antibody in rabbits against porcine thyroid membrane had the blocking activity for TSH stimulation to thyroid cells without affecting TSH binding to its receptor. These facts suggest that this type of blocking antibody may be produced against any antigen of thyroid membrane origin except the TSH receptor.

Purification and Properties of an Indian Major Carp (Cirrhinus mrigala, Ham.) Pituitary Thyrotropin

Thyroid stimulating hormone (TSH) was isolated and purified from the pituitaries of Indian major carp, Cirrhinus mrigala, with the help of a sensitive in vitro bioassay system, based on incubating isolated thyroid follicles from murrel, Channa gachua. In this assay, addition of test material containing TSH increased thyroxine (T4) release into the medium which was then measured by radioimmunoassay (RIA). TSH activity was eluted as one major peak on Sephadex G-100 gel filtration (peak 1), which also contained gonadotropin (GtH) and extraneous proteins as contaminants. GtH was monitored by RIA. Chromatography of peak I of gel filtration on concanavalin A-Sepharose was useful in harvesting glycoprotein hormones; adsorbed (Con A-II) material showed strong TSH activity and low GtH content. To separate TSH from GtH completely, immunoaffinity chromatography was used; more than a 200-fold purification was achieved. Polyacrylamide gel electrophoresis of carp TSH (cTSH) showed a single band, indicating it to be a homogenous protein. The molecular weight (MW) of cTSH was estimated by Sephadex G-100 gel filtration to be 42.000 Da. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cTSH revealed two dissimilar subunits, α and β, and MW of α was 21,000 Da while that of β was 24,000 Da. When tested in similar doses, cTSH released more T4 from murrel thyroid follicle than bovine TSH (bTSH), cTSH stimulated the T4 release from rat and goat thyroid but its activity was less than that of bTSH. Radiolabeled cTSH (125]-cTSH) bound specifically to a murrel thyroid follicular plasma membrane preparation, and Scatchard analysis showed the Kd to be 0.17 × 10-10M and the maximum binding (Bmax) to be 15.2 fmol/mg protein. 125 I-cTSH also binds to the goat thyroid plasma membrane preparation with a Kd = 0.23 × 10-10M and a Bmax 9.8 fmol/mg protein. Findings indicate that carp pituitary thyrotropin is approximately similar in size to that of vertebrates, its biological activity is not restricted only to fish but is also observed in rat and goat, and it has a receptor in teleost and goat thyroid.

A method for measuring H 2O 2 based on the potentiation of peroxidative NADPH oxidation by superoxide dismutase and scopoletin

NADPH oxidation catalyzed by horseradish peroxidase is considerably increased by scopoletin and superoxide dismutase. These effects were used to develop a method for measuring H 2O 2 in a horseradish peroxidase, superoxide dismutase, and scopoletin system by measuring the NADPH oxidation rate. The optimal concentration of each reactant was determined. H 2O 2 could be detected and measured when it was present free in the medium or when it was produced by an H 2O 2-generating system, such as glucose-glucose oxidase or NADPH oxidase from thyroid plasma membranes. H 2O 2 was measured either by taking aliquots of the incubation medium or by placing NADPH directly in the medium and following the kinetics of NADPH oxidation. This latter approach required smaller amounts of biological material. In contrast to other methods, the H 2O 2 which is measured is regenerated. This method is 10 times more sensitive than the standard scopoletin method for H 2O 2 measurement and will detect a H 2O 2 production rate as low as 0.2 nmol per hour. The method is particularly suitable for biological systems in which small quantities of biological material are available.

Chloride conductance of apical membrane in cultured porcine thyroid cells activated by cyclic AMP

The thyroid epithelium transports fluid bidirectionally using active transport of Na + ions from apical to basal poles and active transport of Cl - in the reverse direction. In these studies we sought evidence for cyclic AMP activated Cl - channels on the apical membranes of thyroid cells in monolayer culture. A Cl --dependent basal-positive short-circuit current (I sc) was demonstrated in bicameral chambers after blocking Na + transport with phenamil, and responded to prostaglandin (PG) E 2 with a spike of 5–10 min duration followed by a plateau. The onset of the spike coincided with an increase in the conductance of the epithelium. Application of an external Cl - concentration gradient, by replacing the medium in the apical compartment with Cl --free medium, resulted in an increase in I sc after, but not before, addition of PGE 2. Forskolin and thyroid-stimulating hormone (TSH), but not A23187, also stimulated Cl - transport. In conjunction with previous observations that Cl - transport was mediated by a bumetanidesensitive NaKCl 2 symporter on the basal membrane, these observations indicated the presence of a cyclic AMP activated Cl - conductance in the apical membrane of thyroid cells.

Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue.

Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.

T-lymphocyte activation in adult-onset idiopathic hypoparathyroidism

purpose: Patients with adult-onset idiopathic hypoparathyroidism (AOIH) often have antibodies against the parathyroid glands and other tissues, suggestive of immune activation. The purpose of this study was to determine whether T-cell activation is also a component of the endocrine disease. patients and methods: We identified eight patients with idiopathic hypoparathyroidism diagnosed after the age of 30 years at two tertiary care centers and evaluated peripheral blood lymphocyte subset phenotype frequencies using monoclonal antibodies and flow cytometry. Control subjects were 13 patients with Graves' disease (five thyrotoxic and eight euthyroid) and 110 healthy volunteers. In two of the patients with AOIH, we also determined the mitogenic response to parathyroid cell membranes in peripheral lymphocytes. results: Patients with AOIH had higher than normal frequencies of the following phenotypes (p <0.05 versus controls, one-way analysis of variance): CD4, helper T cells; CD29/CD4, inducer of helper T cells; CD16 and CD56, natural killer cells; and CD3/DR, activated T cells coexpressing DR. Patients with Graves' disease had significantly higher than control frequencies of CD25 (T cells bearing the interleukin-2 receptor), CD3/DR, and CD26 (also a marker of Tcell activation); whereas the frequency of CD29/CD4 was significantly less than the control frequency. Neither of the two AOIH patients tested showed lymphocyte proliferation in response to parathyroid or thyroid cell membrane fractions. conclusions: Generalized T-cell activation represents a novel feature associated with AOIH. Although we could not demonstrate parathyroid-specific lymphocyte clonal expansion, these data are suggestive of a generalized immune disturbance possibly related to autoimmunity, in which one of the manifestations is hypoparathyroidism.

Characterization of thyroidal membrane-bound Mg-adenosinetriphosphatase activated by trypsin or poly-L-lysine.

The Mg-adenosinetriphosphatase (ATPase) in the thyroidal NaI-treated microsome fraction was activated by treatment with basic polyamino acids or trypsin, but not with acidic polyamino acids and basic proteins such as lysozyme and ribonuclease. The enzyme kinetics showed that the activation of trypsin or poly-L-lysine was due to an increase in the maximal velocity of the hydrolyzing reaction without a change in the affinity of the enzyme for its substrate. A break at about 25 degrees C was observed in the Arrhenius plots of Mg-ATPase in the trypsin- or poly-L-lysine treated preparations, but there was no break in the control preparation. These results suggest that the activating effect of trypsin or poly-L-lysine on Mg-ATPase activity in the thyroidal NaI-treated microsome fraction is related to the lipid environment surrounding the enzyme molecule in the thyroid cell membrane.

The α-galactosyl epitope on mammalian thyroid cells

Studies on the distribution of alpha-galactosyl epitopes with the structure Gal alpha 1----3Gal beta 1----4GlcNac-R on mammalian thyroid cell membranes are of interest, since a natural antibody interacting with this carbohydrate antigen (i.e. the natural anti alpha-galactosyl IgG antibody) was found to increase in its titre in patients with autoimmune thyroid disorders. By using a radioimmunoassay for quantification of the alpha-galactosyl epitope, we found variable concentrations of the alpha-galactosyl epitope, we found variable concentrations of this epitope on thyroid cell membranes of all nonprimate mammals and New World monkeys studied, but not in Old World monkeys and human thyroid. The absence of the identifiable alpha-galactosyl epitopes on human and Old World monkey thyroid cells correlates with diminished activity of the enzyme, alpha 1-3 galactosyltransferase, which, in other species, synthesizes the alpha-galactosyl epitopes within the Golgi apparatus. It is argued that a proportion of anti-thyroid reactivity in human normal and pathologic sera, when assayed with mammalian thyroid cells, may be attributed to natural anti alpha-galactosyl IgG antibody, which interacts with alpha-galactosyl epitopes on thyroid tissues used for the bioassay.

Mechanism of hydrogen peroxide formation catalyzed by NADPH oxidase in thyroid plasma membrane

The thyroid plasma membrane contains a Ca2(+)-regulated NADPH-dependent H2O2 generating system which provides H2O2 for the thyroid peroxidase-catalyzed biosynthesis of thyroid hormones. The plasma membrane fraction contains a Ca2(+)-independent cytochrome c reductase activity which is not inhibited by superoxide dismutase. But it is not known whether H2O2 is produced directly from molecular oxygen (O2) or formed via dismutation of super-oxide anion (O2-). Indirect evidence from electron scavenger studies indicate that the H2O2 generating system does not liberate O2-, but studies using the modified peroxidase, diacetyldeuteroheme horseradish peroxidase, to detect O2- indicate that H2O2 is provided via the dismutation of O2-. The present results provide indirect evidence that the cytochrome c reductase activity is not a component of the NADPH-dependent H2O2 generator, since it was removed by washing the plasma membranes with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid without affecting H2O2 generation. Spectral studies with diacetyldeuteroheme-substituted horseradish peroxidase showed that the thyroid NADPH-dependent H2O2 generator does not catalyze superoxide anion formation. The O2- adduct compound (compound III) was formed but was completely inhibited by catalase, indicating that the initial product was H2O2. The rate of NADPH oxidation also increased in the presence of diacetylheme peroxidase. This increase was blocked by catalase and was greatly enhanced by superoxide dismutase. The O2- adduct compound (compound III) was produced in the presence of NADPH when glucose-glucose oxidase (which does not produce O2-) was used as the H2O2 generator. NADPH oxidation occurred simultaneously and was enhanced by superoxide dismutase. We conclude that O2- formation occurs in the presence of an H2O2 generator, diacetylheme peroxidase and NADPH, but that it is not the primary product of the H2O2 generator. We suggest that O2- formation results from oxidation of NADPH, catalyzed by the diacetylheme peroxidase compound I, producing NADP degree, which in turn reacts with O2 to give O2-.

Stimulation of calcitonin secretion in the pig by calcitonin gene-related peptide

Pig thyroid glands were surgically isolated in situ and perfused with autologous blood to which was added known concentrations of calcitonin gene-related peptide (αCGRP). When thyroids were perfused with measured concentrations of CGRP within the range of 0.6–600 nM, the secretion rate of calcitonin (CT) was stimulated while the release of T 3, T 4, and somatostatin remained unchanged. Specific binding of 125I-CGRP to pig thyroid plasma membranes was demonstrated, and binding was inhibited by unlabelled CGRP but not by CT or by other peptides unrelated structurally to CGRP. The findings indicate that the pig thyroid gland contains plasma membrane binding sites for CGRP and that CGRP is capable of stimulating the secretion of CT.

Mechanism of thyroid stimulation by human chorionic gonadotropin in sera of normal pregnant women

To elucidate the mechanism of thyrotropic activity of human chorionic gonadotropin in sera of normal pregnant women, we examined the effect of blockade of the TSH receptor on the serum-induced cAMP accumulation and the effect of hCG on the TSH binding to FRTL-5 cells. In the presence of crude immunoglobulin fractions in sera from patients with primary hypothyroidism, cAMP accumulation induced by both crude and purified hCG, and normal pregnant women serum were significantly inhibited compared with that in the presence of normal IgGs. The mode of inhibition of these IgGs on the cAMP accumulation was similar for TSH and hCG when analysed by Lineweaver-Burk plots. Moreover, binding of [125I]bTSH to the TSH receptor in porcine thyroid cell membrane was apparently inhibited by adding 4 x 10(6) IU/l of purified hCG. Binding studies of TSH in FRTL-5 cells also indicated the dose-dependent displacements of [125I]TSH by hCG. Although half-maximal inhibitory concentration of hCG was about 20 times as high as that of TSH on a molar basis, displacement of [125I]TSH was observed at a concentration of hCG of 10(5)IU/l or more, which could be a physiological concentration of hCG in sera of normal pregnant women. These results suggest that thyrotropic activity of hCG in sera of normal pregnant women is, at least in a part, mediated by TSH receptors.

Glycosyl phosphatidylinositol in thyroid: cell signalling or protein anchor?

During the last 10 years, attention has been focused on the stimulation by various agonists of the hydrolysis of phosphatidylinositol bis-phosphate into the second messengers inositol tris phosphate and diacylglycerol. Two other aspects of the metabolism of phosphoinositides were therefore not paid sufficient attention. The first one was the release by insulin of a glycosyl inositolphosphate from a glycosyl phosphatidylinositol, the hydrosoluble product being able to reproduce some of the hormone effects; the second was the discovery that several membrane proteins were anchored via a glycosyl phosphatidylinositol. For over 20 years, we have been interested in the effect of thyreostimulin (TSH) on the turnover of phosphatidylinositol in pig thyrocyte. As this effect did not seem to result from the hydrolysis of phosphatidylinositol bis-phosphate we explored another possibility, the synthesis of glycosyl inositol-phosphate. We have shown that, in cultured pig thyrocytes, TSH stimulates the release of the polar head of a glycosyl phosphatidylinositol. This soluble glycosyl inositol-phosphate which acts as insulin on adipocyte, modulates the cAMP accumulation and iodine metabolism in thyrocytes and could be held responsible for the cAMP independent effects of TSH. However, we do not yet know if there is a link between the glycosyl phosphatidylinositol sensitive to TSH and the anchor membrane protein. To date, the amount of 2 of these proteins: NAD glyco-hydrolase in thyroid cell membranes and heparan sulfate proteoglycan have been shown to be increased by TSH treatment of thyroid cells.

The α-Galactosyl Epitope on Human Normal and Autoimmune Thyroid Cells

As much as 1% of circulating IgG in man (the natural anti-Gal antibody) is directed against the alpha-galactosyl epitope, with the structure Gal alpha 1----3Gal beta 1----4GlcNAc-R. The alpha-galactosyl epitope is abundantly expressed on cells of nonprimate mammals, prosimians, and New World monkeys. Its expression is diminished in Old World monkeys, apes, and humans. It has been previously suggested that interaction between anti-Gal and aberrantly expressed alpha-galactosyl epitopes on thyroid cells may contribute to the initiation of autoimmune thyroid disorders. To study this possibility, alpha-galactosyl epitope expression on thyroid cell membranes of normal individuals and patients with Graves' disease was assessed by a sensitive radioimmunoassay. alpha-Gal-actosyl epitopes were found both on normal and diseased thyroid cells. Whereas the concentration of these epitopes on Graves' disease thyroid membranes was somewhat higher than that observed in normal glands, the difference was not significant. The activity of the enzyme, alpha 1-3-galactosyltransferase, which synthesizes the alpha-galactosyl epitope, was higher in microsomal fractions obtained from some patients as compared with healthy controls, but not significantly different. In view of the abundance of anti-Gal antibody in the circulation, it is argued that, under physiologic conditions, the interaction of this antibody with alpha-galactosyl epitopes does not elicit pathologic effects. However, aberrant expression of the alpha-galactosyl epitope may result in effective anti-Gal binding to thyroid cells (e.g., rearrangement of this structure on the cell membrane or its increased expression).(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleotide regulation of vasoactive intestinal peptide binding to bovine thyroid plasma membranes

The specific binding of vasoactive intestinal peptide (VIP) to bovine thyroid plasma membranes is inhibited by guanine nucleotides. Guanosine 5'-triphosphate (GTP) and the non-hydrolyzable GTP analogs guanosine 5'-beta,gamma-imidotriphosphate (Gpp(NH)p) and guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) inhibited markedly the binding of VIP to its receptors. This inhibition was higher with GTP than with Gpp(NH)p and GTP-gamma-S and was due to an increase of the rate of dissociation of peptide bound to membranes. Other nucleotides did not show any effect.

Molecular heterogeneity of the subclasses of islet-activating protein (pertussis toxin)-sensitive GTP-binding proteins in porcine thyroid tissue

From porcine thyroid cell membranes, we purified five GTP-binding proteins (G-proteins); Nos. 1 to 3 have 41-kDa α-subunits, and Nos. 4 and 5 have 40-kDa α-subunits. They were chromatographically (Mono Q) separable and served as specific substrates for islet-activating protein (pertussis toxin). G-proteins 1 and 2 were indistinguishable from porcine brain G i 1 with respect to three criteria, i.e., mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), p I of the ADP-ribosylated α-subunit, and immunoreactivity. G-protein 3 was identified as G i 3 by immunoreactivity. The SDS-PAGE and isoelectric focusing (IEF) analyses identified G-proteins 4 and 5 as being chromatographically heterogeneous subtypes of G i 2 in comparison with a pure porcine brain preparation. The IEF analysis also disclosed that each of the g i 1, G i 2, and G i 3 subspecies isolated in the present study has a minor component characterized by a slightly lower p I of its α-subunit. We conclude that porcine thyroid tissue contains at least G i 1, G i 2, and G i 3, and that each is made up of heterogeneous populations.

Graves' ophthalmopathy. Is it really thyroid disease?

The triad of hyperthyroidism, diffuse goiter, and ophthalmopathy was identified as a disease entity by Parry, 1 Graves, 2 and von Basedow 3 in the first part of the 19th century. Although there is a strong temporal relationship between the onset of hyperthyroidism and eye symptoms, 4 many patients with hyperthyroidism do not experience clinical eye findings, and some patients with ophthalmopathy fail to manifest overt or subclinical signs of thyroid dysfunction. 5-9 The absence of a consistent linkage between the thyroid disease and the eye disease has been an impediment to the identification of a common causal agent and to agreement on the optimal clinical management of the ophthalmopathy. See also p 1098. Graves' disease is considered to be autoimmune in origin. Thyroid-stimulating immunoglobulins stimulate the thyroid-stimulating—hormone receptor on the thyroid cell membrane. 10 Some thyroid-stimulating immunoglobulins were once thought to cause ophthalmopathy, but that belief is no longer

Graves' Ophthalmopathy

The triad of hyperthyroidism, diffuse goiter, and ophthalmopathy was identified as a disease entity by Parry,¹Graves,²and von Basedow³in the first part of the 19th century. Although there is a strong temporal relationship between the onset of hyperthyroidism and eye symptoms,⁴many patients with hyperthyroidism do not experience clinical eye findings, and some patients with ophthalmopathy fail to manifest overt or subclinical signs of thyroid dysfunction.^5-9The absence of a consistent linkage between the thyroid disease and the eye disease has been an impediment to the identification of a common causal agent and to agreement on the optimal clinical management of the ophthalmopathy. See also p 1098. Graves' disease is considered to be autoimmune in origin. Thyroid-stimulating immunoglobulins stimulate the thyroid-stimulating—hormone receptor on the thyroid cell membrane.¹⁰Some thyroid-stimulating immunoglobulins were once thought to cause ophthalmopathy, but that belief is no longer