methimazole and Autoimmune-Diseases

Thyroid autoimmunity is characterized by a large number of identified factors, and determining the relative importance of genetics and environment, for instance, can be difficult. In addition, the definition and progression of the individual diseases can also be challenging, and questions such as "when to begin treatment" or even "should treatment be begun" can be problematic. One approach to handling situations in which there are many factors is utilizing mathematical modeling. In a model, quantities that are clinically measurable are related through equations, based on known and inferred relationships between the systems involved.

Topics: Antithyroid Agents; Autoimmune Diseases; Autoimmunity; Computer Simulation; Humans; Methimazole; Models, Immunological; Thyroid Diseases; Thyroid Gland

Insulin autoimmune syndrome (IAS) is an uncommon disorder characterized by hyperinsulinemic hypoglycemia related to insulin-binding autoantibodies. To the best of our knowledge, we report the first case of a pregnant female with IAS.. The 26-year-old patient with Graves disease and 10 weeks pregnant developed IAS after approximately 6 months treatment with methimazole. The patient exhibited recurrent spontaneous hypoglycemia.. On evaluation, laboratory findings detected both high fasting insulin (>1000 mIU/L) and insulin autoantibodies. An oral glucose tolerance test showed elevated insulin concentrations with disproportionately elevated C-peptide levels. The imaging study showed nomasslesionsinthepancreas,and the patient was clinically diagnosed with IAS.. The patient had an abortion, discontinued methimazole and switched to oral prednisone (30 mg once daily) and propylth- iouracil (100 mg 3 times daily) for 3 months.. At the 3-month follow-up visit, hypoglycemic episodes had disappeared and insulin antibody levels were no longer detectable.. We have described this case and reviewed the relevant literature concerning diagnosis and treatment of IAS. Importantly, this case indicates that clinicians should view pregnancy as another factor of hypoglycemia in IAS.

Topics: Abortion, Spontaneous; Adult; Autoimmune Diseases; Female; Follow-Up Studies; Gestational Age; Graves Disease; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Methimazole; Prednisone; Pregnancy; Pregnancy Complications; Rare Diseases; Risk Assessment; Syndrome

Topics: Adrenal Cortex Hormones; Antithyroid Agents; Autoimmune Diseases; Diet, Carbohydrate-Restricted; Genotype; Histocompatibility Testing; HLA Antigens; Humans; Hypoglycemia; Immunosuppressive Agents; Insulin; Insulin Antibodies; Methimazole; Sulfhydryl Compounds; Syndrome

Topics: Autoantibodies; Autoimmune Diseases; Diagnosis, Differential; HLA Antigens; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Insulin Antibodies; Methimazole; Syndrome; Tiopronin

Topics: Autoantibodies; Autoimmune Diseases; History, 20th Century; HLA Antigens; Humans; Hypoglycemia; Insulin Antibodies; Japan; Methimazole; Syndrome; Tiopronin

A case of Basedow's disease, that developed after successful treatment of ulcerative colitis with a total colectomy, is presented, along with a review of the Japanese literature on the coexistence of hyperthyroidism and ulcerative colitis. A 26-year-old man was referred to our department, complaining of general fatigue, appetite loss, and palpitation. At age 14, blood was discovered in his stool and a diagnosis of ulcerative colitis was made. Since then, he has been treated with salazosulfapyridine and prednisolone. On examination, mild exophthalmos and thyroid swelling were observed. Both serum free T3 and T4 levels were increased along with a positive TSH receptor antibody, while TSH was decreased. Scintigraphic and ultrasonographic examinations of the thyroid gland showed diffuse enlargement. Treatment with thiamazole relieved the symptoms and normalized the thyroid function. Although a high incidence of autoimmune thyroid diseases in association with ulcerative colitis has been suggested, only 6 cases of hyperthyroidism coexisting with ulcerative colitis have been reported in Japan. A common immunological process has been suggested to be implicated in the pathogenesis of this association, however, the exact mechanism remains unclear.

Topics: Adult; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antithyroid Agents; Autoimmune Diseases; Chronic Disease; Colectomy; Colitis, Ulcerative; Combined Modality Therapy; Comorbidity; Diarrhea; Female; Graves Disease; Humans; Hyperthyroidism; Japan; Male; Methimazole; Middle Aged; Postoperative Complications; Prednisolone; Sulfasalazine; Thyroid Function Tests

Topics: Autoantibodies; Autoimmune Diseases; HLA-DR Antigens; Humans; Hypoglycemia; Insulin; Japan; Methimazole

Drug-induced autoimmune diseases have two immunological peculiarities. Firstly, some autoantibodies are present, which are virtually never seen in spontaneous human diseases and may be regarded as specific. This applies to antimitochondria antibody type 3 (anti M3) in the lupus-like syndrome caused by Venocuran, to antimitochondria antibody type 6 (anti M6) in iproniazide-induced hepatitis, to anti-insulin antibody found after treatment with methimazole, and to anti liver/kidney microsome antibody type 2 (anti LKM2) associated with hepatitis induced by tielinic acid. Secondly, a search for other autoantibodies shows that the immune disorder is much more limited than in spontaneous autoimmune diseases. Thus, contrary to myasthenia and idiopathic autoimmune haemolytic anaemia, we never found autoantibodies specifically directed against the thyroid, the stomach or the adrenal gland during treatment with D-penicillamine and alpha-methyldopa. Only some hypotheses may account for these peculiarities. Cross-reaction between drug and autoantigen may occur, but the fact that the antigen-antibody reaction is not inhibited by the drug or its metabolites does not support this explanation. Much more attractive is the "T-cell bypass" theory, according to which autoreacting suppressor T-cells are circumvented by helper T-cells stimulated by the drug-modified autoantigen. In this case, the autoimmune reaction would indicate to which body substance the drug is bound, thus making it immunostimulant, and not a structural similarity between the drug and the autoantigen.

Topics: Animals; Autoimmune Diseases; Cardiac Glycosides; Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Iproniazid; Lymphocytes; Methimazole; Methyldopa; Penicillamine; Plant Extracts; Pyrazoles; T-Lymphocytes; Ticrynafen

Over the past four decades, a great deal has been learned about the pharmacology and mechanisms of action of antithyroid drugs. Their ability to inhibit hormone biosynthesis involves complex interactions with thyroid peroxidase and thyroglobulin, many of which are still poorly understood. Their spectrum of activity is much wider than previously thought, and a number of clinically important extrathyroidal actions have been identified. Despite a greater appreciation for the intricacies of antithyroid-drug pharmacology, controversies still surround the use of these agents in the treatment of thyrotoxicosis. These controversies are apt to continue until the pathophysiology of Graves' disease is fully elucidated.

Topics: Adult; Agranulocytosis; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Child; Female; Fetus; Graves Disease; Humans; Hyperthyroidism; Immunity; Immunoglobulins; Infant, Newborn; Insulin Antibodies; Leukopenia; Lupus Vulgaris; Methimazole; Milk, Human; Pregnancy; Pregnancy Complications; Propylthiouracil; Vascular Diseases

We studied 26 patients with Graves' disease, from a population with sufficient iodine supply, treated with high doses of methyl mercaptoimidazole (MMI) during eight moths. We evaluated: a) their evolution after treatment withdrawal; b) the correlation between evolution and TSH-receptor antibodies (TRAb), thyroid hormone levels, microsomal antibodies (MAb), T3/T4 index and clinical data; c) their prognosis. The patients were followed during 12-60 months, and blood samples were collected before treatment withdrawal. Out of 26 patients, 20 relapsed, with T3/T4 index and TRAb significantly higher than those under remission. The T3/T4 index correlated with TRAb. All the TRAb-positive patients, and only 57.1% of the negatives, relapsed. The relapses were significantly more frequent prior to the 6th month in the TRAb-positive patients than afterwards. The TRAb-negatives who relapsed during that period, showed TRAb and age means significantly higher than those under remission. The TRAb test, as a prognostic marker of evolution, showed a sensitivity of 60% and a specificity of 100%. No significant differences were found between evolution to relapse or to remission and the other parameters. It can be concluded that TRAb and T3/T4 index were different in the group that relapsed from that which remitted, and that a TRAb positive value, at the moment of treatment withdrawal, is a useful marker of relapse.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Biomarkers; Female; Graves Disease; Humans; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Microsomes; Middle Aged; Prognosis; Receptors, Thyrotropin; Recurrence; Remission Induction; Thyroid Hormones; Treatment Outcome

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies and fasting or late postprandial hypoglycemia. The number of reports on the association of long-term follow-up of IAS in China is limited. We herein report a case of drug-induced IAS in a 44-year-old Chinese woman. She had been taking methimazole for Graves' disease and had subsequently presented with recurrent hypoglycemic episodes. Laboratory assessments on admission revealed that her serum insulin level was significantly elevated (>1000 µIU/mL) and that she was positive for serum insulin autoantibody, leading to a diagnosis of IAS. Human leukocyte antigen DNA typing identified *04:06/*09:01:02, an immunogenetic determinant associated with IAS. After treatment with prednisone for 2 months, the hypoglycemic episodes disappeared, her serum insulin level gradually declined, and her insulin antibody levels became negative. Clinicians should be aware of the potential for methimazole to trigger autoimmune hypoglycemia in people with a genetic predisposition.

Topics: Adult; Autoimmune Diseases; Female; Follow-Up Studies; Graves Disease; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulin; Methimazole

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by high levels of blood insulin autoantibodies. It has been documented that drugs containing sulfhydryl groups may result in IAS. In this study, we present two cases of IAS induced by methimazole, along with their corresponding treatments and a long-term follow-up after hospitalization.. We report two patients with Grave's disease (GD), carrying the HLA-DRB1 04:06 genotype, who experienced hypoglycemic episodes after taking methimazole. Inpatient treatments helped return their blood glucose levels to normal. Although no recurrences of hypoglycemia were present in the two cases studied, insulin autoantibodies remained positive for the previous follow-up sessions, which turned negative only three years after discharge.. GD patients who carry the HLA-DRB1 04:06 genotype are prone to IAS if they take drugs containing sulfhydryl groups. It may take time for the elimination of insulin autoantibodies after the recovery from the hypoglycemic episode in IAS patients.

Topics: Autoantibodies; Autoimmune Diseases; Follow-Up Studies; Graves Disease; HLA-DRB1 Chains; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulins; Methimazole; Patient Discharge; Sulfhydryl Compounds

Hypoglycemia is an emergent condition with many causes, including underlying diabetes mellitus either with the use of insulin or oral anti-diabetic medications for glucose control, and organ (heart, hepatic, or renal) failure. Insulin autoimmune syndrome (IAS) can also cause hypoglycemia, however it is relatively difficult to diagnose as it is rare clinically. Although uncommon, IAS can be life threatening in patients with persistent hypoglycemia.. We report the case of a 27-year-old female with underlying Graves' disease who was treated with methimazole (MTZ). After 6 weeks of treatment, she developed hypoglycemia symptoms accompanied by dizziness and cold sweating. We excluded underlying diabetes mellitus, the use of insulin or oral anti-diabetic medications, and organ failure.. Laboratory data showed elevated insulin and C-peptide levels. Therefore, insulinoma and IAS were suspected. Abdominal computed tomography and magnetic resonance imaging ruled out insulinoma, and MTZ-induced IAS was finally diagnosed.. The hypoglycemia symptoms resolved after MTZ was switched to propylthiouracil, confirming the diagnosis of IAS.. This case emphasizes the significance of life-threatening MTZ-induced IAS. IAS should be suspected in patients who develop spontaneous hypoglycemia, especially in those with underlying Graves' disease receiving MTZ who present with hyperinsulinism.

Topics: Adult; Autoimmune Diseases; Diabetes Mellitus; Female; Graves Disease; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Methimazole; Pancreatic Neoplasms

The number of case reports of insulin autoimmune syndrome (IAS) induced by methimazole (MMI) is increasing. The purpose of this study is to explore the clinical characteristics and provide a scientific reference for clinical diagnosis, treatment and prevention.. The literature on IAS cases and case series induced by MMI in Chinese and English was collected for retrospective analysis.. A total of 106 patients (males 33, females 73) were described in the Chinese and English literature. The median age of patients with IAS induced by MMI was 37 years (range 15-76) occurring during both regular and irregular MMI therapy or after resumption of medication. The onset of symptoms occurred at night or early morning, within days in some and up to 6 months in others; the symptoms were neuropathic in 65.31% and related to the autonomic nervous system in 33.67%. Blood glucose concentration in samples presumably taken during the hypoglycaemic phase was 1.7 mmol/L (median; range 0.03-4.7); insulin concentrations were elevated ≥100 mU/L (ref range) and associated with low C-peptide levels (<10 μg/L; ref range). Tests for IgG insulin autoantibodies (IAA) were positive in 104 patients (98.02%) and negative in two patients (1.98%). The 75-g oral glucose tolerance test (OGTT) showed impaired glucose tolerance and diabetic curves. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Withdrawal of MMI alone or with corticosteroid treatment reduced hypoglycaemic episodes within days to 3 months. IAA decreased and became negative in 3 months (median; range 1-12). Follow-up showed no recurrent hypoglycaemic episodes at 5 months (median; range 1-60).. Methimazole-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment that should be treated promptly.

Topics: Adolescent; Adult; Aged; Antithyroid Agents; Autoimmune Diseases; Blood Glucose; C-Peptide; Female; Humans; Immunoglobulin G; Insulin; Male; Methimazole; Middle Aged; Syndrome; Young Adult

Insulin autoimmune syndrome (IAS) is a rare endocrine disease characterized by repeated fasting hypoglycemia or episodes of hypoglycemia late after meals, elevated serum insulin, and positivity for insulin autoantibody (IAA) or insulin receptor antibody (IRA). We summarize the clinical manifestations and treatment experiences of 3 patients with IAS.. One patient with >20-year history of type 2 diabetes mellitus had irregular episodes of hypoglycemia 2 years of after treatment with insulin. Another patient with a 6-year history of type 2 diabetes mellitus presented irregular episodes of hypoglycemia after 6 months of treatment with insulin. One patient with a history of Graves' disease showed hypoglycemia after administration of thiamazole.. Serum islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA) were negative, while antibody insulin autoantibodies were positive in all the 3 patients. Two patients demonstrated diabetes mellitus after an oral glucose tolerance test, while one had normal glucose tolerance. Furthermore, serum insulin levels significantly elevated and did not matched C peptide levels. No abnormalities were found on enhanced MRI of the pancreas, and all 3 patients were clinically diagnosed with IAS.. In case one, insulin aspart 30 injection was withdrawn after admission. In addition, the patient was prescribed sublingual acarbose 3 times daily. Two weeks after admission, prednisone acetate was administered orally once daily at night. In case 2, insulin aspart 30 injection was withdrawn after admission, the patient was prescribed sublingual acarbose 3 times daily with a meal. Five days after admission, oral prednisone acetate was administered once daily at night. In case 3, oral propylthiouracil was prescribed and thiamazole withdrawn after admission, and the patient consumed an extra meal before sleeping.. At the 3-month follow-up visit, the hypoglycemic episodes had disappeared, serum insulin levels were significantly decreased, and insulin antibody (IA) levels were no longer detectable in all 3 patients.. For those patients with high-insulin hypoglycemia, IAA should be evaluated if serum insulin concentrations are inconsistent with C peptide levels. Therapeutically, a lower dose of glucocorticoids with more appropriate medication timing can be used to achieve good results.

Topics: Adult; Aged; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Diabetes Mellitus, Type 2; Female; Graves Disease; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Methimazole; Middle Aged; Syndrome

The older of a pair of sisters experienced hypoglycemia after the start of thiamazole (MMI) treatment. Based on a high insulin antibody level, she was diagnosed with insulin autoimmune syndrome (IAS). HLA-DNA typing identified DRB1*04:06. Although a 75-g oral glucose tolerance test (OGTT) showed biphasic insulin secretion, the secretion pattern became monophasic after discontinuation of the MMI. The younger sister was diagnosed with IAS after the start of MMI treatment. HLA-DNA typing identified DRB1*04:06. The 75-g OGTT showed biphasic insulin secretion, but it became monophasic after discontinuation of the MMI. According to the similar insulin secretion kinetics in the two sisters with IAS, we suspect that a genetic predisposition may be associated with the features of anti-insulin antibodies.

Topics: Adult; Antithyroid Agents; Autoimmune Diseases; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Graves Disease; HLA-DRB1 Chains; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Insulin Secretion; Methimazole; Siblings

Topics: Adult; Antithyroid Agents; Asian People; Autoimmune Diseases; Female; Graves Disease; Humans; Insulin; Methimazole

Topics: Aged, 80 and over; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Diabetes Mellitus, Type 2; Female; Graves Disease; Graves Ophthalmopathy; Humans; Hypoglycemia; Hypoglycemic Agents; Immunosuppressive Agents; Insulin, Regular, Human; Methimazole; Prednisone; Recombinant Proteins; Treatment Outcome

A 12-year-old girl presented signs and symptoms of hyperthyroidism. She had a firm goiter (II°) and she stated that she felt constant warmth, nervousness and experienced palpitations. Autoimmune hyperthyroidism was diagnosed (TSH 0.022 mIU/L↓; fT4 21.0 pmol/L; fT3 7.5 pmol/L↑; antithyroperoxidase antibodies 1148.0 U/mL↑; antithyroglobulin antibodies 41.4 U/mL; thyroid-stimulating hormone receptor antibodies 2.3 U/L↑). Thyroid ultrasound showed multiple hypoechogenic areas with increased vascular flow. During treatment with methimazole, a small hyperpigmented and moderately irritated region was found on the right side of the umbilicus. It was not an allergic skin reaction to methimazole but the classic contact allergic dermatitis, probably a result of nickel in her belt. Two years after stopping the treatment she returned to clinics. She was euthyroid but manifested a firm goiter and ultrasonographic features of autoimmune thyroid disease. The diagnostic work-up concerning antithyroid antibodies is mandatory to confirm the ongoing autoimmune process with a long-term significance.

Topics: Autoimmune Diseases; Child; Dermatitis, Allergic Contact; Female; Humans; Hyperthyroidism; Methimazole

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African-American adolescent. A 16-yr-old healthy African-American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio-ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia.

Topics: Adolescent; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Black or African American; Diazoxide; Graves Disease; Humans; Hypoglycemia; Insulin; Male; Methimazole; Prednisone; Propranolol

The present study investigated risk factors and subjective symptoms associated with drug-induced leucopenia. We selected 248 patients with drug-induced leucopenia from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database of over 47000 case reports of adverse drug reactions and assigned them to a case group. We also randomly selected 743 cases of adverse drug reactions not associated with leucopenia as a control group. A comparison of patient characteristic data between the two groups using logistic-regression analysis revealed that female sex, autoimmune disease and renal damage were background risk factors for drug-induced leucopenia. In addition, thiamazole, ritodrine, propylthiouracil, ticlopidine, allopurinol, minocycline and captopril administration significantly increased the risk of drug-induced leucopenia. A significant association was also found for fever, chills and pharyngeal abnormalities. Based on these findings, we developed two estimated regression equations to help prevent drug-induced leucopenia in the community pharmacy setting.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Autoimmune Diseases; Case-Control Studies; Child; Databases, Factual; Female; Humans; Kidney Diseases; Leukopenia; Logistic Models; Male; Methimazole; Methotrexate; Middle Aged; Risk Factors; Ritodrine; Sex Factors; Ticlopidine; Young Adult

Although insulin autoimmune syndrome (IAS) was found to be strongly related with methimazole, rapidly increasing numbers of cases with alpha lipoic acid-induced IAS have been confirmed to be reported since 2003. As alpha lipoic acid has gained popularity as a supplement for dieting and anti-aging, a warning should be issued.

Topics: Autoimmune Diseases; Dietary Supplements; Humans; Hypoglycemia; Insulin; Methimazole; Thioctic Acid

Myasthenia gravis (MG) is an acquired autoimmune disorder causing skeletal muscle fatigue and weakness. This is a report of one woman and her daughter presenting with myasthenia and gravis and Grave's disease. It highlights possible hereditary component of this condition which has not been commonly reported in our setting.

Topics: Adult; Antithyroid Agents; Autoimmune Diseases; Cholinesterase Inhibitors; Female; Graves Disease; Humans; Methimazole; Middle Aged; Myasthenia Gravis; Pyridostigmine Bromide; Thyroid Diseases

Many possible causes of resistance to human recombinant erythropoietin (rh-EPO) have been reported in patients with renal failure. This case presents an unusual cause of erythropoietin-resistant anemia in a patient with chronic renal failure. A 61-year-old male patient who was on chronic hemodialysis program due to diabetic nephropathy for seven months developed erythropoietin resistant anemia. No iron deficiency was revealed by laboratory data, no megaloblastic anemia were found by biochemical investigation, and no inflammatory states including infection or neoplastic diseases were disclosed by abdominal ultrasonography, chest X-ray, bone marrow aspiration and biopsy, or other methods (normal C-reactive protein levels). This hemodialysis patient had epoetin-resistant anemia with primary autoimmune hyperthyroidism. The anti-thyroid therapy was effective not only against the hyperthyroidism but also against his epoetin resistant anemia.

Topics: Anemia; Antithyroid Agents; Autoimmune Diseases; Drug Resistance; Erythropoietin; Humans; Hyperthyroidism; Kidney Failure, Chronic; Male; Methimazole; Middle Aged; Recombinant Proteins; Renal Dialysis

Clinical and serological profiles of idiopathic and drug-induced autoimmune diseases can be very similar. We compared data from idiopathic and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA)-positive patients. From 1993 to 2003, 2474 patients were tested for ANCA in the Laboratory for Allergy and Clinical Immunology in Belgrade. Out of 2474 patients, 72 (2.9%) were anti-proteinase 3 (PR3)- or anti-myeloperoxidase (MPO)-positive and their clinical and serological data were analyzed. The first group consisted of ANCA-associated idiopathic systemic vasculitis (ISV) diagnosed in 56/72 patients: 29 Wegener's granulomatosis (WG), 23 microscopic polyangiitis (MPA) and four Churg-Strauss syndrome. The second group consisted of 16/72 patients who became ANCA-positive during ATD therapy (12 receiving propylthiouracil and four receiving methimazole). We determined ANCA and antinuclear (ANA) antibodies by indirect immunofluorescence; PR3-ANCA, MPO-ANCA, anticardiolipin (aCL) and antihistone antibodies (AHA) by ELISA; and cryoglobulins by precipitation. Complement components C3 and C4, alpha-1 antitrypsin (alpha1 AT) and C reactive protein (CR-P) were measured by nephelometry. Renal lesions were present in 3/16 (18.8%) ATD-treated patients and in 42/56 (75%) ISV patients (p <0.001). Skin lesions occurred in 10/16 (62.5%) ATD-treated patients and 14/56 (25%) ISV patients (p <0.01). ATD-treated patients more frequently had MPO-ANCA, ANA, AHA, aCL, cryoglobulins and low C4 (p <0.01). ISV patients more frequently had low alpha1 AT (p = 0.059) and high CR-P (p <0.001). Of 16 ATD-treated patients, four had drug-induced ANCA vasculitis (three MPA and one WG), while 12 had lupus-like disease (LLD). Of 56 ISV patients, 13 died and eight developed terminal renal failure (TRF). There was no lethality in the ATD-treated group, but 1/16 with methimazole-induced MPA developed pulmonary-renal syndrome with progression to TRF. ANCA-positive ISV had a more severe course in comparison with ATD-induced ANCA-positive diseases. Clinically and serologically ANCA-positive ATD-treated patients can be divided into two groups: the first consisting of patients with drug-induced WG or MPA which resemble ISV and the second consisting of patients with LLD. Different serological profiles could help in the differential diagnosis and adequate therapeutic approach to ANCA-positive ATD-treated patients with symptoms of systemic disease.

Topics: Adolescent; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Antithyroid Agents; Autoantigens; Autoimmune Diseases; Churg-Strauss Syndrome; Cyclophosphamide; Female; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Granulomatosis with Polyangiitis; Graves Disease; Hashimoto Disease; Humans; Hyperthyroidism; Immunoprecipitation; Kidney; Lung; Male; Methimazole; Middle Aged; Myeloblastin; Nephelometry and Turbidimetry; Peroxidase; Polyarteritis Nodosa; Prednisone; Pregnancy; Pregnancy Complications; Propylthiouracil; Retrospective Studies; Serine Endopeptidases; Skin; Vasculitis; Vasculitis, Leukocytoclastic, Cutaneous

Clinical recognition of drug-induced vasculitic and lupus-like syndromes is very important because continued use of the offending drug can lead to irreversible and life-threatening vasculitic organ damage (e.g. end-stage renal disease or pulmonary haemorrhage). Withdrawal of the drug often leads to spontaneous recovery, meaning that immunosuppressive therapy can be avoided. The presence of myeloperoxidase-antineutrophil cytoplasmic antibodies, IgM anticardiolipin antibody, and antihistone antibodies in combination was found to be characteristic of drug-induced vasculitic syndromes caused by the antithyroid drugs propylthiouracil and methimazol. Clinically, skin vasculitis and arthralgias predominated and renal vasculitis was rare.

Topics: Acute Kidney Injury; Antibodies, Anticardiolipin; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Churg-Strauss Syndrome; Diagnosis, Differential; Granulomatosis with Polyangiitis; Humans; Immunoglobulin M; Kidney; Lupus Erythematosus, Systemic; Methimazole; Propylthiouracil; Skin; Thrombophilia; Vasculitis, Leukocytoclastic, Cutaneous

Methimazole (methyl-mercapto-imidazole, MMI), a compound used clinically in therapy of Graves' thyroiditis, was found to inhibit development of several autoimmune diseases in animal models. It was suggested on the basis of in vitro data that inhibition is through down-regulation of interferon-gamma (IFN-gamma)-induced expression of major histocompatibility complex class I and class II molecules. Here, we investigate the effect of MMI on experimental autoimmune uveoretinitis (EAU) and study its mechanism(s). Treatment of EAU with MMI administered in drinking water inhibited induction of the disease and associated antigen (Ag)-specific proliferation and cytokine production by draining lymph node cells (LNCs). The treatment was protective only if administered during the first but not during the second week after immunization, suggesting an effect on the induction phase of EAU. It is interesting that MMI inhibited disease in IFN-gamma knockout mice, indicating that the in vivo protective effect is IFN-gamma-independent. Flow cytometric analysis of draining LNCs extracted 5 days after immunization showed that MMI partly to completely reversed the increase in Mac-1(+)/class I(+)/class II(+) cells induced by immunization and reduced the proportion of B7-1 and CD40-positive cells, suggesting a deficit in the Ag-presenting cell (APC) population. APC from untreated mice largely restored antigen-specific proliferation of MMI-treated LNCs. We suggest that MMI inhibits EAU at least in part by preventing the recruitment and/or maturation of APC, resulting in reduced generation of Ag-specific T cells.

Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Antithyroid Agents; Autoimmune Diseases; Cytokines; Disease Models, Animal; Eye Proteins; Female; Flow Cytometry; Interferon-gamma; Lymph Nodes; Macrophage-1 Antigen; Methimazole; Mice; Mice, Inbred C57BL; Mice, Knockout; Retinitis; Retinol-Binding Proteins; Uveitis

Acquired hemophilia due to autoantibody to Factor VIII coagulant (Factor VIIIc) is a rare event which may be observed in patients with different autoimmune diseases. To our knowledge, this association has been reported only once in patients with autoimmune thyroid disease. Here we describe a patient presenting with a severe hemorrhagic disorder due to Factor VIIIc antibody in whom biochemical screening for thyroid diseases led to a diagnosis of hyperthyroid Graves' disease not associated to overt clinical features. This case underlines the importance of carrying out a complete screening for autoimmunity, including thyroid autoimmune disease, in all patients with apparently isolated serum Factor VIIIc inhibitors.

Topics: Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Factor VIII; Female; Graves Disease; Hematuria; Hemoperitoneum; Hemophilia A; Humans; Hysterectomy; Leiomyoma; Methimazole; Middle Aged; Ovariectomy; Postoperative Hemorrhage; Thyroid Hormones; Thyrotropin; Uterine Neoplasms

Topics: Antithyroid Agents; Autoimmune Diseases; Baclofen; Cyclophosphamide; Heart; Humans; Hyperthyroidism; Immunosuppressive Agents; Male; Methimazole; Middle Aged; Multiple Sclerosis, Chronic Progressive; Stroke Volume; Tachycardia, Sinus

Topics: Antibody Specificity; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Biotransformation; Blood Platelets; Carbimazole; Cross Reactions; Humans; Methimazole; Platelet Endothelial Cell Adhesion Molecule-1; Prodrugs; Purpura, Thrombocytopenic, Idiopathic

In order to ascertain whether methimazole, a drug commonly used for the treatment of hyperthyroidism, interferes with the progression of autoimmune-mediated myocardial injury, we investigated the effect of methimazole on experimental autoimmune myocarditis (EAM) in rats. EAM was induced by immunization with porcine cardiac myosin. Methimazole administration markedly slowed the body weight growth in both normal and EAM rats, but did not induce morphologic change of cardiac tissue in normal rats. In EAM rats, macroscopic examination revealed discoloration of the cardiac surface, and histopathological examination by light microscopy showed extensive myocardial necrosis, infiltration by inflammatory cells and myocardial fibrosis. In the EAM rats treated with methimazole, the discolored areas on the cardiac surface were markedly diminished in size, and the myocardial necrosis, cellular infiltration and fibrosis were significantly less severe. To identify the mechanism responsible of this effect, we investigated the change of regulatory lymphocyte subsets in peripheral blood using an immunofluorescence technique with a flow cytometer. A decrease in the helper/suppressor T cell ratio as a result of the increased proportion of suppressor T cells and a decrease in the proportion of B cells were observed in normal rats after methimazole administration, and similar findings were made in the EAM rats treated with methimazole. These results indicate that methimazole interferes with the progression of EAM, and immunosuppression may, at least in part, be involved in the inhibitory effect of methimazole on EAM in rats.

Topics: Animals; Autoimmune Diseases; Body Weight; CD4-CD8 Ratio; Immunosuppressive Agents; Male; Methimazole; Myocarditis; Myocardium; Organ Size; Rats; Rats, Inbred F344

The patient, a 24-year-old man, had suffered from hunger, sweating, tachycardia and palpitation for three years. He was diagnosed as having Graves' disease (GD) and treated with methimazole (MMI) for 3 months. He noted that palpitation and perspiration seemed to particularly occur when he was hungry, and thus he was examined to determine whether these symptoms were caused by hypoglycemia. As a markedly elevated immunoreactive insulin level and the presence of insulin antibody in serum were found, he was diagnosed as having insulin autoimmune syndrome (IAS). HLA typing revealed the patient to be positive for group Bw62/Cw4/DR4, which is reportedly a specific HLA type in MMI-treated euthyoroid GD patients with IAS. In spite of the continuation of MMI treatment, the % binding of IRI decreased and the hypoglycemic episode disappeared. In contrast to the previously reported MMI induced IAS in GD cases, MMI is unlikely to have exacerbated IAS in the present case, although his HLA combination is identical to that of the previous cases.

Topics: Adult; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Follow-Up Studies; Graves Disease; Histocompatibility Testing; Humans; Hyperthyroidism; Hypoglycemia; Insulin; Male; Methimazole; Syndrome; Thyroid Hormones

(NZB x NZW)F1 mice spontaneously develop with age an autoimmune disease that resembles the human disease, systemic lupus erythematosus (SLE). The present study demonstrates that methimazole (MMI), an agent used in the treatment of autoimmune thyroid disease, is effective in mitigating the development of this SLE-like autoimmune disease in (NZB x NZW)F1 mice. MMI significantly reduces the incidence and severity of proteinuria and deposition of immune complexes in the kidney. Previous studies have demonstrated that development of an experimentally induced SLE, which was prevented by MMI treatment, depended on the expression of MHC class I molecules. We now report that class I levels on both T cells and B cells from old (NZB x NZW)F1 MHC class I are markedly elevated relative to those from young F1 mice. Furthermore, treatment of (NZB x NZW)F1 mice with MMI reduced MHC class I expression on their PBL concomitant with amelioration of disease, raising the possibility that class I molecules may play a role in the generation of spontaneous autoimmune disease in these mice.

Topics: Aging; Animals; Autoantibodies; Autoimmune Diseases; Disease Models, Animal; DNA; Female; Histocompatibility Antigens Class I; Lupus Erythematosus, Systemic; Methimazole; Mice; Mice, Inbred BALB C; Mice, Inbred NZB

This study investigated T-cell activation markers HLA-DR and CD69 in both naive (CD45RA+) and memory (CD45RA-) CD4+ as well as CD8+ T cells in peripheral blood of patients with autoimmune thyroiditis (AT, N = 28) or hyperthyroid untreated Graves' disease (GDH, N = 34) using three-color flow cytometry. It was demonstrated that patients with AT, but not those with GDH, expressed increased amounts of HLA-DR antigen compared to healthy subjects (HS, N = 26) on total CD4+ (AT: 14.1%; GDH: 11.3%; HS: 10.9%) and CD8+ cells (AT: 31.9%; GDH: 23.5%; HS: 19.4%) as well as on CD45RA- CD4+ cells (AT: 11.2%; GDH: 7.7%; HS: 7.9%). In GDH (+71%) and AT (+91%) only the proportion of HLA-DR+ CD45RA+ CD8+ cells was increased vs HS. Furthermore, euthyroid GD patients on methimazole (GDE, N = 22) displayed greater HLA-DR+ expression on total and CD45RA- cells within both CD4+ (+37 and 40%, respectively) and CD8+ cells (+47 and 93%, respectively) than GDH. In addition, total and CD45RA+ CD4+ and CD8+ cells were increased vs HS. In contrast, proportions of CD69 positive T cells were increased in AT and GDH on total CD4+ (+97 and 74%, respectively) and CD8+ (+95 and 68%, respectively) cells and all subsets thereof (except for CD45RA- cells in GDH), but normalized upon thyrostatic treatment. We conclude that patients with autoimmune thyroid disease harbor an almost twofold greater proportion vs HS of (a) HLA-DR+ CD45RA+ CD8+ T cells, and of (b) CD69 on total CD4+ and CD8+ cells, and an even more marked elevation on their CD45RA+ subset in AT and untreated GD. In addition, (c) thyrostatic treatment by methimazole in GD is accompanied by a further increase in circulating HLA-DR+ CD4+ and CD8+ cells and their CD45RA- subsets, but decreased CD69 expression. These data suggest association of HLA-DR expression with ongoing autoimmunity, while increased CD69 expression relates in part also to elevated thyroid hormone concentration in GDH.

Topics: Adult; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antithyroid Agents; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Graves Disease; HLA-DR Antigens; Humans; Lectins, C-Type; Leukocyte Common Antigens; Lymphocyte Activation; Male; Methimazole; Middle Aged; Thyroid Diseases

Two cases are reported in which a rare hyperthyroidism appeared: in a female after radioiodine therapy for toxic multinodular goiter and in a male after spontaneous regression of a toxic adenoma. Both subjects showed a relapse of hyperthyroidism after a period of well-being lasting almost eight months in the first and three years in the second. Thyroid scans were consistent with an immunogenic hyper-thyroidism because there was a diffuse trapping of 131I in the thyroids while the previous autonomously functioning nodules became "cold". Serum TSH was undetectable, free thyroid hormones were increased, TgAb and TRAb were always normal in both patients, TPO became moderately positive only in the female. TRAb were evaluated only by radioimmunoassay. In these patients a diagnosis of Graves'-like disease was made because of the clinical and scintigraphic pattern. Moreover US did not reveal nodular areas different from those highlighted by scans. None of the subjects developed ophthalmopathy and/or dermopathy. Our remarks show that in particular subjects, genetically susceptible to autoimmunity, the release of antigenic materials secondary to destruction of thyroid nodules can trigger an autoimmune thyroid response resembling Graves' disease. Therefore all patients carrying autonomous nodules should be carefully evaluated for a possible autoimmune disposition before treatment and after admission. Radionuclide imaging is a simple, reliable, non invasive technique which can be applied in the evaluation of the etiology of the relapses.

Topics: Adenoma; Aged; Antithyroid Agents; Autoimmune Diseases; Female; Goiter, Nodular; Graves Disease; Humans; Male; Methimazole; Middle Aged; Radionuclide Imaging; Thyroid Neoplasms

A 58-year-old woman was admitted because of jaundice, ascites and marked oedema. For three years she had suffered from nervousness, decreasing fitness and weight loss, which had been assumed as due to chronic alcoholism. Liver biopsy revealed extensive fibrosis, in part with early cirrhotic transformation. This was followed by cardiac failure with atrial fibrillation (ventricular rate 140/min) and marked pleural effusions. The thyroid was diffusely enlarged and there were signs of exophthalmos.. Bilirubin concentration was 3 mg/dl, lactate dehydrogenase activity was 310 U/l, cholesterase 1.3 kU/l and the prothrombin test was 21%. The TSH level was 0.01 microU/ml while the free thyroxine level was 4.7 ng/dl and that of free triiodothyronine 13.5 pg/ml. Chest radiograph revealed cardiomegaly, bilateral peripheral pulmonary congestion and pleural effusions to midfield. Right heart catheterization excluded pulmonary hypertension; cardiac output was 10l/min. The thyroid was enlarged on ultrasound and diffusely echopoor, as in immune thyroid disease.. Cardiac failure regressed and thyroid function normalized within ten days on propranolol, 4 x 40 mg and thiamazole 3 x 40 mg daily intravenously. Subtotal thyroidectomy was performed three weeks later with subsequent thyroid hormone substitution. Liver functions were normal six months later and ultrasound showed no signs of cirrhotic change and the ascites had resolved.. Hyperthyroidism is frequently associated with changes in liver functions. In extreme cases, high-output cardiac failure may occur, with liver congestion and clinical as well as histological changes like those in liver cirrhosis.

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Antithyroid Agents; Arrhythmias, Cardiac; Autoimmune Diseases; Female; Heart Failure; Humans; Hyperthyroidism; Liver Cirrhosis; Methimazole; Middle Aged; Propranolol; Thyroid Hormones; Thyroidectomy; Ultrasonography

131I treatment is an effective alternative to surgery in patients with a large, (non-)toxic, compressive goiter. Late development of hyperthyroidism after 131I therapy for nontoxic nodular goiter is considered rare. We have seen this complication in 3 of approximately 80 patients treated with radioiodine for volume reduction of a large, multinodular goiter. Three women, aged 60 to 71 years, had large, multinodular goiters causing tracheal compression. They were clinically euthyroid before 131I therapy and had normal free thyroxine (FT4) levels. Serum thyroid-stimulating hormone (TSH) levels were normal in 2 patients and undetectable in 1 patient. Patients 1 and 2 received a single dose of 86 and 48 mCi 131I, respectively. Patient 3 received 20 mCi 131I twice (interval 1 month). Clinical and biochemical thyrotoxicosis with high thyroid radioactive iodide uptake (RAIU) developed 10, 6, and 3 months after 131I therapy, respectively, although at control visits 1 to 3 months earlier, serum TSH and FT4 levels were normal. Thyrotoxicosis responded well to methimazole in all three patients. The late occurrence of thyrotoxicosis, high RAIU, and good response to methimazole argue against thyroiditis as the cause of thyrotoxicosis. Serum levels of TSH receptor antibodies, which were undetectable before therapy (patients 1 and 2), were clearly elevated in all three patients during thyrotoxicosis. This is in favor of autoimmune hyperthyroidism as the cause of thyrotoxicosis. These cases illustrate that severe autoimmune hyperthyroidism may occur several months after radioiodine treatment for nontoxic, multinodular goiter. Information about symptoms of hyperthyroidism and regular control visits in the first year after therapy are important in these patients.

Topics: Aged; Autoantibodies; Autoimmune Diseases; Female; Goiter, Nodular; Humans; Hyperthyroidism; Iodine Radioisotopes; Methimazole; Middle Aged; Receptors, Thyrotropin; Thyrotropin; Thyroxine

In 1986, a 26-year-old female had been diagnosed as having Graves' disease and had been treated with methimazole for four months. After the treatment with propylthiouracil for another four months, she had been treated with methimazole once again. She was in complete remission for two years. She again experienced symptoms of hyperthyroidism, and treatment with methimazole was started again. On the thirteenth day after treatment, she experienced hypoglycemic attacks with skin eruption. The plasma glucose was 57 mg/dl, 125I-Insulin binding 69%, free IRI 196 microU/ml. The patient had the HLA-DRB1*0406.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Female; Graves Disease; Humans; Hyperinsulinism; Hypoglycemia; Insulin Antibodies; Methimazole

Insulin autoimmune syndrome (IAS) includes fasting or reactive hypoglycemia, hyperinsulinemia and the presence of insulin-binding antibodies in patients who have never been exposed to exogenous insulin. The report concerns a 34-year-old male patient with Graves' disease who had history of having taken methimazole for two months, without any consequence, 4 years previously. However, when methimazole was again administered for three weeks followed by a week of carbimazole, the patient suffered hypoglycemia 4 times during the next 4 weeks. He denied history of diabetes mellitus (DM), of taking any oral hypoglycemic agent or of having received insulin injection. Laboratory data showed total serum insulin level > 320 microU/mL, free insulin 55 microU/mL and insulin antibody 88.3%. Oral glucose tolerance test (OGTT) revealed DM pattern. Since the patient had history of allergy to anti-thyroid drugs before this event, so he was treated with radioiodine (131I). There was no episode of hypoglycemic attack during 15 months of follow-up.

Topics: Adult; Autoimmune Diseases; Carbimazole; Graves Disease; Humans; Insulin; Male; Methimazole

Self-peptides bound to HLA-DR4 (DRA-DRB1*0405 complex) were eluted from the purified DR4 complex, fractionated on reverse-phase HPLC, and subjected to NH2-terminal sequencing. Seven independent sequences were obtained, and all putative peptides synthesized bound to DRB1*0405 as well as DRB1*0406 complex, which differ only at DR beta residues 37, 57, 74, and 86. Binding assay using analogue peptides of a DR4 binder GSTVFDNLPNPE revealed that FxxLxN is an important anchor motif necessary for binding (where x is any amino acid), which was common to DRB1*0405 and 0406. Determination of the binding affinity of 60 synthetic AAFAALANAA-based analogue peptides showed that substituting F to W or C; L to F, W, or Y; and N to Q or S on AAFAALANAA changed the affinity substantially between DRB1*0405 and DRB1*0406. It is noteworthy that all patients with methimazole-induced insulin autoimmune syndrome are positive for DRB1*0406 and negative for DRB1*0405. Interestingly, the quantitative structural motif identified in this study predicted that 8TSICSLYQLE17 of human insulin alpha chain may bind specifically to DRB1*0406 using its 10IxxLxQ15 motif. Indeed, DRB1*0406 complex bound 8TSICSLYQLE17 with a high affinity, and in striking contrast, DRB1*0405 complex did not. Furthermore, a short-term T cell line specific to human insulin established from a DRB1*0406-bearing individual did show reactivity with a peptide fragment containing the 10IxxLxQ15 motif. Although this fragment probably exists at a very low level under normal physiological conditions due to the disulfide bond between flanking cysteine residues (6Cys-11Cys), a reducing compound such as methimazole may cleave the disulfide bond in vivo and allow DR alpha-DRB1*0406 complex on antigen-presenting cells to bind much of the linear fragment of insulin alpha chain, which may lead to the activation of self-insulin-specific T-helper cells.

Topics: Alleles; Amino Acid Sequence; Autoimmune Diseases; Binding, Competitive; Cell Line; Histocompatibility Antigens Class II; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Insulin; Lymphocyte Activation; Methimazole; Molecular Sequence Data; Peptide Fragments; Peptides; T-Lymphocytes

The insulin autoimmune syndrome (IAS) is characterized by the following diagnostic criteria: severe spontaneous hypoglycemia without evidence of exogenous insulin administration, high levels of total serum immunoreactive insulin, and the presence of a high titer of antiinsulin antibody. Just before the onset of IAS, 13 of the 35 (37%) patients with IAS examined in this study had taken methimazole for the treatment of Graves' disease. To investigate the difference between the Graves' disease patients treated with methimazole who developed IAS and other IAS patients, HLA class II genes in both groups were analyzed by serological and DNA typing methods. All 13 patients with Graves' disease who developed IAS possessed a specific allelic combination, Bw62/Cw4/DR4 carrying DRB1*0406, whereas only 1 of 50 Graves' disease patients without IAS had Bw62/Cw4/DR4 (odds ratio, 891; P < 1 x 10(-10)) and carried not DRB1*0406 (odds ratio, 2727; P < 1 x 10(-10)), but DRB1*0405. Of the 22 IAS patients without Graves' disease, 13 had the combination Bw62/Cw4/DR4 carrying DRB1*0406 (odds ratio, 19.0; P < 0.07). Thus, it is highly likely that patients with Graves' disease develop IAS via treatment with methimazole when their Bw62/Cw4/DR4 carry DRB1*0406.

Topics: Adolescent; Adult; Aged; Autoimmune Diseases; Base Sequence; DNA; Female; Graves Disease; Histocompatibility Antigens Class II; HLA-B Antigens; HLA-B15 Antigen; HLA-C Antigens; HLA-DR4 Antigen; Humans; Insulin; Insulin Antibodies; Male; Methimazole; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction

Selective immunoglobulin (Ig) A deficiency is reported to occur in 1 in 16,000 in Japan and has been reported to be complicated with various autoimmune diseases. A 49-year-old woman was diagnosed as having autoimmune thyroid disease. Her serum IgA, IgM and IgG were revealed to be 4.1, 154 and 1930 mg/dl, respectively. Severe skin eruption which occurred with 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU), was relieved by reducing MMI to 15 mg/day and administering anti-allergic drugs. Although the influence of IgA deficiency on autoimmunity and allergy still remains unclear, this is a report of IgA deficiency associated with autoimmune thyroid disease.

Topics: Autoimmune Diseases; Diagnosis, Differential; Female; Humans; IgA Deficiency; Immunoglobulins; Methimazole; Middle Aged; Propylthiouracil; Thyroid Gland; Thyroid Hormones; Thyrotoxicosis

Insulin autoimmune syndrome is a syndrome consisting of fasting hypoglycemia, hyperinsulinemia and detectable insulin-binding antibodies in patients who have never been exposed to exogenous insulin. Four cases who developed symptoms of hypoglycemic attack with self-limited duration and spontaneous remission were collected in our hospital from 1984 to 1988. The elevated serum total and free insulin and C-peptide levels, as well as the titer of insulin autoantibodies, decreased gradually; but insulin autoantibodies were still present in the serum for more than six months after the initial episodes of hypoglycemia. Three of four patients had Graves' disease and developed the syndrome after methimazole treatment. The fourth one had a history of hemorrhagic cystitis and denied history of specific drug exposure. The cause or stimulus for insulin autoantibody formation is still unknown, but drugs containing a sulfhydryl group like methimazole may play a role in the development of the syndrome. Extremely high insulin antibodies in patients with fasting hypoglycemia along with elevated serum levels of insulin and C-peptide suggest a diagnosis of insulin autoimmune syndrome and usually exclude the possibility of insulinoma or factitious hypoglycemia.

Topics: Adult; Aged; Autoimmune Diseases; C-Peptide; Female; Humans; Hypoglycemia; Insulin Antibodies; Methimazole

It is a well-known fact that a thyroid stimulation blocking antibody (TSBAb) may play an important role in primary hypothyroidism. However, it has rarely been reported that TSBAb appears in only a few cases of Graves' disease which became hypothyroidism in their clinical courses. We examined TSBAb in 120 sera from 79 cases with Graves' disease before or while under methimazole (MMI)-treatment. TSBAb value was expressed as the percentage inhibition of TSH-stimulated cAMP response of porcine thyroid cells by the patient's IgG. TSBAb was positive in 9 cases (11.4%) of 79 cases of Graves' disease. In 6 of the 9 cases, TSBAb was detected at the untreated period. In the other 2 of the 9 cases, it was detected during the exacerbation related with their pregnancy. It was difficult to control Graves' disease in all 9 cases. These results suggest that TSBAb appears not only in primary hypothyroidism but also even in the hyperthyroid state of Graves' disease, and that the combination of TSAb and TSBAb may regulate the pathogenesis of Graves' disease.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Binding, Competitive; Female; Graves Disease; Humans; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Receptors, Thyrotropin; Thyroid Diseases; Thyroiditis, Autoimmune

A 47-year-old man with Graves' disease suffered from a feeling of hunger and sweating in the night, polyarthralgia and fever one month after the start of treatment with methimazole. The above symptoms were ascribed to the side effects of methimazole; insulin autoimmune syndrome and lupus-like syndrome. The change in the antithyroid drug to propylthiouracil caused an amelioration of the symptoms. In addition to an anti-insulin antibody with a high binding capacity, hyperglucagonemia (260 pg/ml with a plasma glucose level of 61 mg/dl) was observed, which returned to normal in parallel with the decrease in the insulin binding capacity of the plasma one month after beginning the treatment with propylthiouracil. A normal decrease in the plasma glucagon level due to exogenous insulin (2 mU/kg/min) was observed with the euglycemic clamp. However, the plasma glucagon level was not suppressed by the oral glucose loading and elicited a poor response to the arginine infusion. Taking previous reports into account, this basal hyperglucagonemia seems to be a characteristic finding in the insulin autoimmune syndrome, while a sluggish response of glucagon to oral glucose or arginine infusion might be ascribed to hyperthyroidism. This is the first case report concerning a kinetical study of the glucagon secretion in insulin autoimmune syndrome with Graves' disease.

Topics: Arginine; Autoimmune Diseases; Blood Glucose; Glucagon; Glucose Tolerance Test; Graves Disease; Humans; Insulin; Kinetics; Male; Methimazole; Middle Aged

Topics: Aged; Autoimmune Diseases; Female; Humans; Hyperthyroidism; Hypoglycemia; Insulin Antibodies; Methimazole

Topics: Adult; Autoantibodies; Autoimmune Diseases; Carbimazole; Cross-Sectional Studies; Female; Graves Disease; Humans; Hypoglycemia; Insulin Antibodies; Male; Methimazole; Syndrome; Taiwan

Some patients with the insulin autoimmune syndrome have circulating insulin that is heterogeneous. We used reverse phase high performance liquid chromatographic analysis to identify the forms of plasma insulin in patients with this syndrome and compared the results with those in patients with insulin-treated diabetes and patients with hyperinsulinism. Under acidic conditions, free insulin dissociated from insulin antibodies eluted from Bio-Gel P-30 columns as a single peak. When such insulin fractions were applied to reverse phase high performance liquid chromatography, a major insulin peak emerged with the same retention time as standard human insulin in all six patients with the syndrome. In addition, a minor insulin peak was consistently found at relatively high acetonitrile concentrations. However, this hydrophobic insulin also was found in two of four insulin-treated diabetic patients and in one of two hyperinsulinemic patients who did not have insulin antibodies. Preliminary characterization of the variant insulin revealed that it has a molecular size between those of proinsulin and insulin and retains the immunoreactivity of insulin, but not C-peptide. It may be an aggregate of insulin molecule or proinsulin intermediates. Since the variant insulin was not found only in patients with the insulin autoimmune syndrome, it seems unlikely that an altered endogenously produced insulin induces the generation of autoantibodies to insulin in this syndrome.

Topics: Adult; Aged; Autoimmune Diseases; Chromatography, High Pressure Liquid; Diabetes Mellitus; Female; Humans; Hyperinsulinism; Insulin; Male; Methimazole; Middle Aged; Molecular Weight; Proinsulin

Topics: Autoimmune Diseases; Graves Disease; Humans; Methimazole; T-Lymphocytes; Thyroid Diseases

In 16 untreated patients with hyperthyroidism due to Graves' disease, serum antidouble stranded DNA antibody, measured by RIA, was positive (greater than 20 U/ml) in 14. In methimazole-treated patients with T3-suppressible thyroid uptake, anti-DNA antibody was found in 9% (3 of 35). The frequency of positive tests in methimazole-treated patients with T3-nonsuppressible thyroid uptake and in surgically treated patients was 24% (5 of 21) and 57% (4 of 7), respectively. Among anti-DNA antibody-negative (less than 9 U/ml) and weakly positive (10-19 U/ml) patients, those with T3-suppressible thyroid uptake had lower anti-DNA antibody titers than those with T3-nonsuppressible thyroid uptake. Among 32 patients with Hashimoto's thyroiditis, anti-DNA antibody was positive in 7. None of the patients with simple goiter had positive or weakly positive anti-DNA antibody results. Although the quantity of antibodies did not correlate well in individual patients, the rates of positive TSH binding-inhibiting immunoglobulin and anti-DNA antibody tests were roughly comparable in these patient groups. None of these patients with thyroid disease associated with anti-DNA antibody had clinical or other serological evidence suggestive of systemic lupus erythematosus or related collagen vascular disorders. The finding of anti-DNA antibody provides a new aspect of immunological abnormality associated with hyperthyroidism of Graves' disease.

Topics: Antibodies, Antinuclear; Autoimmune Diseases; Female; Goiter; Graves Disease; Humans; Lupus Erythematosus, Systemic; Male; Methimazole; Thyroiditis, Autoimmune; Thyroxine; Triiodothyronine

Topics: Animals; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Carbimazole; Graves Disease; Humans; Hyperthyroidism; Immunity, Cellular; Immunosuppressive Agents; Methimazole; Propylthiouracil; Thiourea; Thyroid Hormones

Evidence has been accumulated that the anti-thyroid drugs used in the treatment of Graves' disease may have immunosuppressive properties but the exact mechanism of action is still unclear. In the present study, we have investigated the in vitro effect of carbimazole (CBZ) on the expression of lymphocyte differentiation antigens and on suppressor cell activity. The incorporation of radiolabelled methimazole (35S-MMI, the active metabolite of CBZ) by resting and mitogen stimulated lymphocytes was also investigated. CBZ at concentrations of 60 microM significantly inhibited the expression of the receptor for interleukin-2 (as defined by the anti-TAC monoclonal antibody [MoAb]) by lymphocytes stimulated with phytohaemagglutinin. The expression of an early activation antigen (as characterized by the 4F2 MoAb) was not affected. Twenty-four hour pre-incubation of cells with different concentrations of CBZ or medium alone did not change the lymphocyte response to mitogenic stimulation, thus suggesting no effect of the compound on suppressor cell function. Finally, there were no significant differences in the uptake of 35S-MMI between resting and stimulated lymphocytes. These data suggest that the immunosuppressive effect of CBZ may be due to its effect of reducing the expression of the receptor for interleukin-2 on lymphocytes undergoing full activation. This property of CBZ could be of relevance in the therapy of autoimmune thyroid diseases (not only Graves' disease) which are characterised by the presence of activated T cells in the thyroid and in circulation.

Topics: Adult; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Autoimmune Diseases; Carbimazole; Female; Humans; Lymphocyte Activation; Male; Methimazole; Receptors, Antigen, T-Cell; Receptors, Immunologic; Receptors, Interleukin-2; T-Lymphocytes; T-Lymphocytes, Regulatory; Thyroid Diseases

An immune-mediated disease was produced in 9 of 17 (53%) normal healthy cats by daily p.o. administration of 150 mg of 6-propylthiouracil (PTU). This disease syndrome is characterized by lethargy, weight loss, lymphadenopathy, hemolytic anemia, a positive direct antiglobulin test (DAT) and antinuclear antibodies (ANA). The duration of drug administration before the development of a positive DAT and/or ANA ranged from 3 to 8 weeks (Mean +/- S.E.M. = 4.5 +/- 0.6), whereas the duration before the onset of clinical signs ranged from 4 to 8 weeks (6.1 +/- 0.6 weeks). On cessation of PTU administration, clinical signs resolved in all cats within 2 weeks, and the DAT and test for ANA were negative within 1 to 4 weeks (1.9 +/- 0.4 weeks). During nine PTU-rechallenge periods in four cats, both the mean time to develop a positive DAT and ANA (2.5 +/- 0.8 weeks) and the mean time to develop overt clinical signs (2.6 +/- 0.7 weeks) were shorter than similar mean times in the initial PTU treatment period (P less than .01). During nine episodes of PTU-induced disease in seven cats, PTU administration was discontinued and replaced with 150 mg of 6-propyluracil (PU), a nonsulfur analog of PTU. Resolution of both clinical and serologic signs of disease occurred in seven of the nine disease episodes within 1 to 3 weeks (2.1 +/- 0.4 weeks). In the two cats whose disease did not resolve on PU, one was sacrificed after 1 week of PU administration, without clinical or serologic resolution, because of the severity of the PTU-induced disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia, Hemolytic, Autoimmune; Animals; Antibodies, Anti-Idiotypic; Antibodies, Antinuclear; Autoimmune Diseases; Cats; Disease Models, Animal; Methimazole; Phagocytes; Propylthiouracil; Structure-Activity Relationship

Suppressor T cell function induced by concanavalin A (con A) was evaluated in patients with Graves' disease and Hashimoto's thyroiditis. Patients with Graves' disease were divided into the following two groups: (1) untreated, and (2) euthyroid during antithyroid drug (methylmercaptoimidazole) therapy. T cells (2 X 10(5)), activated by con A for 48 hours, were added to preincubated responder cells (2 X 10(5)) and re-incubated for 7 days in the presence of pokeweed mitogen (PWM). IgG produced in the culture medium was measured by radioimmunoassay and then % suppressions (IgG) were calculated. Thyroid stimulating activity (TSA) in serum was measured by McKenzie's method by means of normal human thyroid slices, and % suppressions (c-AMP) were calculated. IgG produced in lymphocyte culture medium was suppressed by added con A-activated cells in untreated and euthyroid groups of Graves' disease, Hashimoto's thyroiditis and normal controls. The value of % suppression (IgG) was reduced in each group of Graves' disease compared to normal controls. No significant relation was observed between TSA in serum and % suppression (IgG), but three cases with high serum TSA showed low % suppressions (IgG). In 12 cases of Graves' disease, % suppression (IgG) had a positive relation with % suppression (c-AMP) in same medium. The amount of c-AMP produced in thyroid slices incubated in medium, in which responder cells (8 X 10(5)), was elevated in all 7 untreated cases of Graves' disease, while not elevated in 7 euthyroid cases. The value of % suppression (c-AMP) in euthyroid cases with Graves' disease was significantly higher than that in untreated cases. The value of % suppression (IgG) was reduced and had a significant negative relation with logarithm of serum antimicrosomal antibody titer in patients with Hashimoto's thyroiditis. These results indicate that low activity of suppressor T cell had a role on antibody production, including thyroid stimulating antibody, and pathogenesis of autoimmune thyroid diseases.

Topics: Adult; Autoimmune Diseases; Concanavalin A; Cyclic AMP; Female; Graves Disease; Humans; Immunoglobulin G; Male; Methimazole; T-Lymphocytes, Regulatory; Thyroiditis, Autoimmune; Triiodothyronine

Topics: Autoimmune Diseases; Graves Disease; Humans; Hypoglycemia; Insulin Antibodies; Methimazole; Syndrome

Topics: Autoimmune Diseases; Humans; Hypoglycemia; Insulin Antibodies; Methimazole; Syndrome

The accumulation of 35S labelled methimazole (MMI) was examined in lymphocytes. No uptake of label was found in peripheral blood lymphocytes (PBL) from normal control subjects after in vitro incubation with the drug. Following administration of [35S]MMI to patients with Graves' hyperthyroidism PBL cell to plasma (C/P) 35S activity was greater than 1 in 4 of 11 patients and only in 1 of 7 other patients undergoing thyroidectomy. Thyroid lymphocytes from 2 of these patients showed some accumulation of activity. Following administration of [35S]MMI to normal rats C/P 35S ratios ranged from 1-5.6 but no 35S accumulation was found in PBL or thyroid lymphocytes from August strain rats in which experimental autoimmune thyroiditis had been produced. It is concluded that there is minimal, if any, significant accumulation of MMI in lymphocytes of patients with Graves' disease. The immunosuppressive action of MMI on lymphocyte antibody production must therefore by indirect.

Topics: Animals; Autoimmune Diseases; Graves Disease; Humans; Immunosuppression Therapy; Lymphocyte Activation; Lymphocytes; Methimazole; Rats; Rats, Inbred Strains; Thyroiditis

Topics: Adult; Autoimmune Diseases; Female; Graves Disease; Humans; Insulin Antibodies; Methimazole

Using peripheral blood lymphocytes from 8 healthy individuals and 5 patients with untreated Graves' disease, direct effects of methimazole (MMI) and propylthiouracil (PTU) on lectin-induced lymphocyte proliferative response were studied. Lymphocytes were cultured for 72 hr in the presence of lectins and antithyroid drugs. Lymphocyte DNA synthesis was counted by incorporation of 3H-thymidine. MMI at 1,000 microM enhanced lectin-induced lymphoproliferation of peripheral blood lymphocytes from both patients with Graves' disease and healthy individuals, at every point of culture time, while PTU showed a tendency toward suppression. These results suggest that this lympho-stimulation by MMI may be a causative factor related to insulin autoimmune syndrome, as deduced from the clinical reports that insulin autoimmune syndrome is, sometimes, found in patients with Graves' disease treated with MMI. This lympho-stimulation was evident regardless of the time of MMI addition, thus indicating that MMI is, by its action, a lymphoid stimulator and may lead to the insulin autoimmune syndrome in predisposed subjects with underlying Graves' disease.

Topics: Autoimmune Diseases; Concanavalin A; Graves Disease; Humans; Insulin Antibodies; Lymphocyte Activation; Methimazole; Phytohemagglutinins; Pokeweed Mitogens; Propylthiouracil; Syndrome

Experimental autoimmune thyroid disease was induced in August rats by immunization with rat thyroglobulin in complete Freund's adjuvant. Disease severity, assessed by thyroid histology and circulating levels of anti-TG antibody measured by an enzyme immunoassay, was maximal between 30 and 60 days after the initial immunization and thereafter waned. Thyroid function through the duration of the disease, assessed by measurement of serum TSH levels by RIA, remained normal. Once the natural history of the disease was established, groups of rats received methimazole (MMI) with or without T4 in their drinking water, either before or after disease induction. The animals were bled at regular intervals and killed on day 49 for histological grading of their thyroids. MMI alone (group 3) or with T4 (group 4) before disease induction significantly reduced the severity of the disease, although the effect on circulating antibody levels was less marked in the animals in group 4. In animals given MMI alone (group 5) or with T4 (group 6) after establishment of the disease, MMI again significantly reduced the severity of the established disease, although this effect was less marked in the T4 supplemented animals. MMI significantly impaired the induction and reduced the severity of experimental autoimmune thyroid disease in August rats. The ability of MMI to influence the autoimmune process may have important implications for the use of this and other agents that act on the immune system in the management of human autoimmune disease.

Topics: Animals; Antibody Formation; Autoimmune Diseases; Female; Methimazole; Rats; Rats, Inbred Strains; Thyroglobulin; Thyroiditis; Thyrotropin; Thyroxine

Topics: Aged; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Insulin Antibodies; Methimazole; Propylthiouracil

Topics: Adult; Aged; Autoimmune Diseases; Carbimazole; Goiter, Nodular; Graves Disease; Humans; Hyperthyroidism; Iodine Radioisotopes; Methimazole; Middle Aged; Thyroidectomy; Thyroxine

In a young woman who presented with hyperthyroidism and autoimmune thrombocytopenic purpura, the platelet count returned to normal following successful treatment of the hyperthyroidism. Thromboagglutinins were present, the titer declining as the patient became euthyroid. A survey of the literature revealed 48 reports of hyperthyroidism and thrombocytopenia, these disorders coexisting in 37 patients and there being no apparent cause for the lowered platelet counts in 28 of them. The clinical features and response to treatment in the latter group and in our patient are reviewed, comprising a series of 29. Of 22 patients whose hyperthyroidism was adequately treated, platelet counts returned to normal in 18 (82%). In three patients the purpura remitted despite persistent thrombocytopenia. It is estimated that in 7% of patients with autoimmune thrombocytopenic purpura, thrombocytopenia responds to treatment of an underlying thyrotoxicosis and in many of these patients the thrombocytopenia will prove resistant to other forms of therapy.

Topics: Adult; Autoimmune Diseases; Female; Humans; Hyperthyroidism; Methimazole; Prednisone; Purpura, Thrombocytopenic; Thyroidectomy