Graves' dermopathy and acropachy are markers of severe Graves' ophthalmopathy.

It is generally considered that thyroid dermopathy and acropachy almost always occur with Graves' ophthalmopathy and that these two extrathyroidal manifestations are indicators of severe autoimmune disease and hence of more severe ophthalmopathy. However, documentation of these anecdotal impressions is needed. We assessed the presence of optic neuropathy and frequency of orbital decompression in 2 referral cohorts: 40 patients with acropachy and dermopathy (acropachy group) and 138 patients with Graves' dermopathy and no acropachy (dermopathy group). We compared those cohorts with a cohort of 114 patients who had ophthalmopathy without dermopathy and acropachy (control group). We considered optic neuropathy and the need for orbital decompression to be indicators of severe Graves' ophthalmopathy. The frequency of orbital decompression was significantly higher in the dermopathy group than in the control group (odds ratio, 3.55) and even higher in the acropachy group (odds ratios: 20.68 for acropachy group compared with control group; 5.83 for acropachy group compared with dermopathy group). The same trend occurred with optic neuropathy but was not statistically significant (alpha = 0.05; p = 0.07). Five patients were exceptions: they had definite Graves' dermopathy without clinically obvious ophthalmopathy. In conclusion, dermopathy and acropachy appear to be markers of severe ophthalmopathy. Occasionally, however, Graves' dermopathy occurs without clinical ophthalmopathy.     

Elephantiasis-like appearance of upper and lower extremities in Graves' dermopathy

Graves' dermopathy, affecting upper as well as lower extremities, is reported in a 50-year-old male patient addicted to multiple narcotic drugs. The narcotic drug administration routes include subcutaneous and intravenous injection in all limbs over a period of 29 years. The combination of drug injection trauma and Graves' dermopathy produced elephantiasis-like appearance of upper and lower limbs with impairment of their function; the left hand required amputation. Other features of Graves' disease, ie, hyperthyroidism and ophthalmopathy were severe and required multiple modes of therapy. Although the pathogenesis of Graves' dermopathy is unclear, it is surmised that trauma to skin might exacerbate it and preventive measures for trauma might be helpful in the management of dermopathy.     

Thyrotropin receptor autoantibodies are associated with continued thyrotropin suppression in treated euthyroid Graves' disease patients

Antithyroid treatment effectively restores euthyroidism in patients with Graves' hyperthyroidism. After a few months of treatment, patients are clinically euthyroid with normal levels of thyroid hormones, but in many patients TSH levels remain suppressed. We postulated that TSH receptor autoantibodies could directly suppress TSH secretion, independently from thyroid hormone levels, via binding to the pituitary TSH receptor. To test this hypothesis, we prospectively followed 45 patients with Graves' hyperthyroidism who were treated with antithyroid drugs. Three months after reaching euthyroidism, blood was drawn for the analysis of thyroid hormones, TSH, and TSH binding inhibitory Ig (TBII) levels. After 6.7 +/- 1.5 months since start of antithyroid treatment, 20 patients still had detectable TBII levels, and 25 had become TBII negative. The two groups had similar levels of free T(4) and T(3), but TBII-positive patients had lower TSH values than TBII-negative patients: median 0.09 (range < 0.01-4.30) mU/liter vs. 0.84 (0.01-4.20; P = 0.015). In addition, TSH levels correlated only with TBII titers (r = -0.424; P = 0.004), and not with free T(4) or T(3) values. Our findings suggest that TBII suppress TSH secretion independently of thyroid hormone levels, most likely by binding to the pituitary TSH receptor.     

Biological activity of lymphocytotoxic antibodies in Graves' disease and Hashimoto's thyroiditis

Sera of 48 patients with Graves' disease (GD) and 23 with Hashimoto's thyroiditis (HT) were tested for lymphocytotoxic (LCT), granulocytotoxic (GCT) and monocytotoxic (MCT) activity. In GD, 12 patients (25%) had cold-reacting LCT and 13 patients (27%) had warm-reacting LCT. LCT were cytotoxic to both B and T cells but the majority of sera with cold-reacting LCT and eluates from lymphocytes were more cytotoxic to B lymphocytes. Warm-reacting LCT were directed exclusively against B cells. LCT did not correlate with peripheral lymphocyte counts, antithyroglobulin or antimicrosomal antibodies, sex, age, pregnancies, thyroid status or medication. However the mean duration of the disease was 15 months in LCT positive group and 55 months in LCT negative group (p less than 0.01). Weak GCT were found in 8 of 35 sera (23%). Six of 33 sera (18%) contained cold-reacting MCT and 9 (27%) had warm-reacting MCT. Some cytotoxins were directed against several types of cells as evidenced by cytotoxicity of eluates from lymphocytes against PMN and/or monocytes. Of 23 patients with HT, 11 (48%) had cold-reacting LCT. None had warm-reacting LCT. Sera and eluates from lymphocytes showed predominant cytotoxicity toward B cells. No correlation to the presence of antibodies, sex, age, pregnancies, thyroid status or medication was detected. Four of 23 sera had weak cold-reacting GCT, 5 had cold-reacting MCT which killed on average 31% of monocytes and 4 had weak warm-reacting MCT. Twelve of 22 sera from GD and HT had cytotoxic activity against thyroid cells (TCT). TCT correlated with LCT at p less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thyrotropin receptor autoantibodies in Graves' disease.

Clinical thyrotoxicosis in Graves' disease patients is caused by thyrotropin receptor (TSHR)-stimulating autoantibodies. The molecular mechanisms of TSHR post-translational modification, TSHR signaling and TSHR-autoantibody interaction are still debatable, and the precise interaction of stimulating and blocking autoantibodies with TSHR is unclear. Recent TSHR epitope studies indicate that binding sites for stimulating and blocking autoantibodies are close together, not on distinct or distant parts of the molecule. Furthermore, new methods to detect TSHR autoantibodies and their clinical use are addressed. Highly sensitive TSHR autoantibody assays are widely available and cost efficient, and their routine clinical use might help in the differential diagnosis of hyperthyroidism and disease outcome prediction in patients with high levels of TSHR autoantibodies.     

Spontaneous hypoglycemia and insulin autoantibodies in a patient with Graves' disease

A 31-year-old woman with Graves' disease developed fasting hypoglycemia after treatment for 3 weeks with methimazole. Although the patient had not received exogenous insulin, high titers of insulin autoantibodies were found in serum and large amounts of total and free insulin (1550 and 82 microU/ml, respectively) and C-peptide reactivity (CPR, 22 ng/ml) were detected in serum. After glucose loading, blood glucose and total insulin levels increased abnormally. The immunoglobulin class of the autoantibodies was IgG and the light chains were of the kappa type. The titers of insulin autoantibodies, elevated serum total and free insulin, and CPR levels decreased gradually, but insulin autoantibodies and elevated insulin levels were still present in the serum 8 months after the episode of hypoglycemia. These findings suggest that the patient's fasting hypoglycemia was due to excess free insulin released from antibody-bound insulin, and that methimazole might play a role in the initiation of production of insulin autoantibodies.     

Autoimmune hepatitis associated with Graves' disease

A 31-year-old woman with Graves' disease with a 12-month-history of propylthiouracil intake and autoantibodies in the sera was admitted to our hospital. The differential diagnosis between autoimmune hepatitis and propylthiouracil-induced hepatitis was intractable. Steroid therapy was started and she showed a complete response to the treatment. Liver biopsy demonstrated acute hepatitis and plasma cell infiltration. A second liver biopsy, which was performed 10 months after starting steroid therapy, showed some inflammatory cells in the portal tracts. These findings suggest that she had been suffering from autoimmune hepatitis.     

Anaplastic thyroid carcinoma associated with Graves' disease

This report concerns a 79-year-old woman with coexisting anaplastic thyroid carcinoma (ATC) and Graves' disease (GD). The patient was referred to our clinic because of palpitation and a palpable mass on the left side of her neck. Thyroid function tests showed hyperthyroidism with elevated thyroid-stimulating antibodies. Ultrasonography of the thyroid demonstrated an adenomatous nodule-like marcated nodule (27.6 x 26.5 x 36.4 mm) with cystic degeneration inside the left lobe. (123)I thyroid scintigraphic imaging showed a cold area corresponding to the nodule with continuous uptake in the remaining thyroid tissue despite suppressed TSH levels. These findings led to a diagnosis of GD. On the other hand, the thyroid nodule could not be definitely diagnosed even after fine needle aspiration biopsy (FNAB) which produced findings suggestive of both papillary thyroid carcinoma and ATC. Open biopsy of the nodule showed an ATC. Regional lymph node metastases as well as multiple lung metastases, which could not be found at the initial visit, had been already developed by that time. Our case is pathophysiologically interesting because it suggests that GD or thyroid-stimulating antibodies (TSAb) may stimulate malignant transformation of differentiated carcinoma. It is also clinically important because it indicates that all thyroid nodules, particularly palpable cold nodules, associated with GD require careful management to detect malignancy because they are at higher risk of harboring malignancy.     

Thyrotropin-producing pituitary adenoma associated with Graves' disease

OBJECTIVES: The examination of potential associations between Graves' disease and thyrotropin-producing pituitary adenoma (TSHoma) after treatment using octreotide, and of the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma). DESIGN AND METHODS: A specimen of resected TSHoma tissue from our case was immunohistochemically examined for expression of somatostatin receptor 2A (SSTR2A) and PPAR gamma. Specimens of thyroid tissue from two cases with Hashimoto's thyroiditis were immunohistochemically examined for expression of SSTR2A. RESULTS: Expression of SSTR2A and PPAR gamma was identified in TSHoma cells. SSTR2A was also expressed in lymphocytes that had infiltrated thyroid tissue in Hashimoto's thyroiditis. In previous reports, three of four patients with TSHoma displayed Graves' disease after tumor resection, and TSH is also known to play a major role in regulating immunomodulatory gene expression in thyrocytes. CONCLUSIONS: Both the immunomodulatory effects of octreotide on intrathyroidal lymphocytes and rapid reductions in TSH may contribute to the onset of Graves' disease. Patients with TSHoma-associated autoimmune thyroiditis should undergo careful follow-up for development of Graves' disease after treatment. Both octreotide and the PPAR gamma receptor-activating ligands, thiazolidinediones, may be effective for patients with TSHoma.     

Increased induction of HLA-DR by interferon-gamma in cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial dermopathy

We investigated the effects of several cytokines on HLA-DR expression in cultured fibroblasts derived from retroocular connective tissue and pretibial and abdominal skin of patients with Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD), as well as from normal individuals. We hypothesized that differences in response to cytokines between fibroblasts from various anatomical areas might play a role in the site-selective involvement of the extrathyroidal manifestations of Graves' disease. HLA-DR expression in fibroblasts was quantitated by scanning densitometry of whole cell lysates subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Direct immunofluorescence of cell monolayers was also performed. We hypothesize that unique characteristics of these fibroblasts may play a role in GO and PTD. Cultured retroocular, pretibial, and abdominal fibroblasts from patients with Graves' disease as well as from normal individuals did not express HLA-DR spontaneously. Treatment in vitro with interferon-gamma (IFN gamma; 100 U/mL) for 5 days induced HLA-DR by 50- to 80-fold (P less than 0.0001) in fibroblasts from all sites and subjects studied. However, IFN gamma-induced HLA-DR expression was significantly greater in retroocular (P less than 0.005) and pretibial (P less than 0.0005) fibroblasts from patients with GO and PTD than in fibroblasts obtained from the same anatomical sites of normal individuals. Further, retroocular and pretibial fibroblasts from patients with GO and PTD responded to IFN gamma more vigorously than did abdominal fibroblasts from these same patients (P less than 0.0001). IFN gamma-induced HLA-DR expression was enhanced by concomitant treatment with tumor necrosis factor-alpha (100 U/mL). In contrast, treatment of retroocular fibroblasts with transforming growth factor-beta (10 ng/mL), epidermal growth factor (1 ng/mL), or interleukin-6 (IL-6; 100 U/mL) significantly attenuated IFN gamma-induced HLA-DR reactivity by 40-59% (P less than 0.05). Incubation of retroocular fibroblasts with tumor necrosis factor-alpha, IL-1 alpha (10 U/mL), IL-2 (10 U/mL), IL-6, granulocyte-macrophage colony-stimulating factor (100 U/mL), epidermal growth factor, and transforming growth factor-beta alone did not affect HLA-DR expression. These results indicate that several cytokines can influence HLA-DR expression in cultured fibroblasts. The enhanced induction of HLA-DR by IFN gamma in retroocular and pretibial fibroblasts compared with that in abdominal fibroblasts may partially explain the selective involvement of the retroocular connective tissue and pretibial skin in fully expressed Graves disease.     

Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies

OBJECTIVE: Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO. RESULTS: TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS 相似文献   

Characterization of the anaemia associated with Graves' disease

Background  Graves' disease (GD) is associated with hyperthyroidism. Thyrotoxicosis adversely affects multiple organ systems including haematopoiesis. Anaemia occurring specifically in GD has not been systematically studied previously.
Objective  To define the prevalence and characteristics of the anaemia associated with GD.
Design  Eighty-seven newly diagnosed patients with GD were recruited. Haematological indices, thyroid function and inflammatory parameters were examined at presentation and following successful treatment of hyperthyroidism.
Setting  Tertiary care academic referral centre.
Results  Thirty-three per cent of subjects presented with anaemia. The prevalence of anaemia not attributable to other causes (GD anaemia) was 22%. GD anaemia affected 41·6% (10/24) of men compared to 17·5% of women (11/63). Mean erythropoietin (EPO) levels (15·5 ± 5·3 mIU/ml) were within normal reference limits but significantly higher ( P =  0·004) than those of the non-anaemic controls. Hgb correlated inversely with EPO ( P =  0·05) and CRP ( P =  0·04) levels, a relationship that persisted after multivariate adjustment for TT3 or TT4. With antithyroid therapy for 16 ± 6·3 weeks, Hgb levels normalized in 8 out of 9 subjects with GD anaemia (10·7 ± 0·8 to 13·5 ± 1·3 g/dl, P  = 0·0001). After normalization of Hgb, mean MCV and TIBC were significantly increased, and median ferritin and mean EPO were significantly decreased.
Conclusions  GD anaemia is common, resembles the anaemia of chronic disease, and is associated with markers of inflammation. It corrects promptly with return to the euthyroid state following treatment.     

Direct immunostaining of TSH receptor related autoantibodies in Graves' disease

Ten thyroid specimens from patients with Graves' disease were investigated immunohistologically with respect to the localisation of thyrotropin (TSH) receptor related autoantibodies. After conventional preparation of formalin-fixed and paraffin-embedded thyroid slices for immunostaining, 3-5 micron tissue sections were incubated with a porcine thyrotropin receptor containing membrane preparation (pTSH-R). The TSH receptor containing membrane fragments bound to the thyroid tissue were revealed with a slightly modified unlabelled PAP technique according to Sternberger, using an antiserum to pTSH-R obtained from immunized rabbits. This technique resulted in a staining of a considerable portion of plasma cells within the lymphoplasmacellular infiltrates of all the Graves thyroids. No staining occurred if for negative control either pTSH-R or its antiserum from rabbit was omitted. In addition, the staining reaction was markedly reduced by pretreatment of pTSH-R with serum from patients with Graves' disease in order to occupy its binding sites for autoantibodies prior to the staining procedure. It is concluded that the staining of the intrathyroidal plasma cells is due to their synthesis of autoantibodies directed against TSH receptor related structures of thyroid epithelia. The results are in keeping with the concept that the thyroid as the target organ itself is the site of autoantibody synthesis in Graves' disease.     

A case of Graves' disease associated with polymyositis

A patient with Graves' disease associated with severe muscle weakness who was finally diagnosed as polymyositis by pathological examination of the muscle is reported. A 28-year-old women was incidentally found to have hyperthyroidism when she consulted a hospital for the evaluation and treatment of anemia in 1979. She was treated with methimazole for approximately a month when she stopped the medication by herself. Approximately two yr later (Nov. 4, 1981) she consulted another hospital with complaints of palpitation and muscle weakness. Diagnosis of hyperthyroidism due to Graves' disease and thyrotoxic myopathy were made, followed by the treatment with radioiodine (4 mCi of 131I). She was further treated with propylthiouracil (PTU). Four yr after the treatment, serum thyroid hormone concentration declined to the lower level than normal and serum TSH concentration increased. She was subsequently treated with synthetic I-T4. Despite the fact she became euthyroid with the treatment, muscle weakness as well as elevated concentrations of muscle enzymes were not improved. Muscle biopsy was made in July 1983, and she was diagnosed as immune polymyositis and treatment with prednisolone and cyclophosphamide in addition to PTU or I-T4, was started. With the treatment, serum LDH decreased to the normal range. However she still has muscle weakness and serum concentrations of CPK and aldolase are still in higher levels than normal range.     

Insulin autoantibodies in Graves' disease--before and after carbimazole therapy

Insulin autoantibodies (IAA) are well documented in patients with insulin-dependent diabetes (IDDM) prior to the administration of insulin and in patients with reactive hypoglycaemia--the insulin autoimmune syndrome (IAS). It has been suggested that IAA can be induced by the administration of drugs containing sulphydryl groups, such as carbimazole, and they have been frequently described in Graves' disease. An alternative explanation is the clustering of autoantibodies in autoimmune disease. We studied 39 patients (37 females, two males, age range 14 to 61 years; mean 33.8 years) with proven Graves' disease and no previous treatment with carbimazole. Fifteen of the 39 patients had a family history of other autoimmune diseases. IAA and thyroid autoantibodies were assayed at diagnosis and monthly thereafter while on treatment with carbimazole, for up to 6 months. IAA were measured using a direct-binding solid-phase ELISA and specificity was confirmed by absorption studies using insulin covalently coupled to Sepharose beads. At diagnosis 33 of the 39 patients (85%) were positive for thyroid microsomal antibodies, 13 (33%) were positive for thyroglobulin antibodies, and 4 (10%) were positive for IAA. All IAA-positive patients had microsomal antibodies at diagnosis, and two had thyroglobulin antibodies in addition. After 4 months on carbimazole, the frequency of thyroid microsomal autoantibodies was unchanged (83%), while that of anti-thyroglobulin antibodies had fallen (8.6%). All four IAA-positive patients remained positive, and studies of binding to human, porcine and bovine insulin demonstrated that one serum, initially human insulin specific, later became cross-reactive with all three. We conclude that low titres of IAA are found in Graves' disease, and are associated with the presence of autoimmunity rather than the carbimazole. Symptomatic hypoglycaemia, however, is rare in Caucasian patients.     

Pathogenesis of Graves' ophthalmopathy: the role of autoantibodies.

The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within orbital tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage.     

Severe thyroid eye disease associated with primary hypothyroidism and thyroid-associated dermopathy.

Four unusual cases of patients are described with severe thyroid eye disease (TED) who presented with primary hypothyroidism and thyroid-associated dermopathy (TAD). All four patients had moderate or severe TED and elevated circulating thyrotropin (TSH) receptor antibodies.     

Thyroid hemiagenesis associated with Graves' disease and Graves' ophthalmopathy: case report.

Failure of embryologic development of a lobe of the thyroid gland is a rare anomaly. Usually, this condition is diagnosed when there are some other pathologic conditions in the gland and is often found when a patient presents with a thyroid nodule, which in reality is compensatory hypertrophy of the side that is present, therefore appearing as a nodule. A variety of pathological conditions occur in the remaining thyroid tissue in association with this rare anomaly such as adenoma, carcinoma, subacute thyroiditis, colloid nodule, Graves' disease, simple goiter, and Hashimoto thyroiditis. Association of Graves' disease with ophthalmopathy and thyroid hemiagenesis is quite rare and very few cases are reported in the literature. We report a 29-year-old female presented as Graves' disease and Graves' ophthalmopathy with left lobe hemiagenesis of the thyroid gland.     

Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies

A study from five hepatology units documenting 157 cases of drug-induced hepatitis and a second study from a laboratory of immunology which tested more than 100,000 sera permitted us to establish the frequency of antiorganelle antibodies and their diagnostic value in drug-induced hepatitis. In drug-induced hepatitis caused by a heterogenous group of drugs consisting of ajmaline, aminopterine, isaxonine, isoniazid, perhexiline, phenylbutazone and troleandromycine, antiorganelle antibodies were absent or rare. In drug-induced hepatitis caused by another heterogenous group of drugs, including clometacin, fenofibrate, oxyphenisatin and papaverine, antismooth muscle, antinucleus and antimitochondria antibodies were found in isolation or in different combinations in 70% of cases. From the presence of antismooth muscle antibodies in sera, we could trace 30 cases of clometacin-induced hepatitis. The third group included drug-induced hepatitis with special antibody:iproniazid-induced hepatitis with antimitochondrial antibody 6 and tienilic acid (ticrynafen)-induced hepatitis with antiliver/kidney microsome antibody 2 (anti-LKM2). These two antibodies are rare in routine sera and were absent in patients who received the drug and had no liver damage. From the presence of corresponding antibodies, we detected six cases of iproniazid-induced hepatitis and 67 cases of tienilic acid-induced hepatitis. Antiorganelle antibodies found in high titers disappeared in 2 to 24 months following withdrawal of the offending drug. The fourth group was represented by halothane-induced hepatitis; antiliver/kidney microsome antibody 1 was weak and infrequent. Similarities between drug-induced hepatitis of the second group and lupo?d hepatitis suggest that drugs may reveal this spontaneous disorder.(ABSTRACT TRUNCATED AT 250 WORDS)