Transient appearance of lactate dehydrogenase (LDH)-linked immunoglobulin and thyroid dysfunction at the postpartum period

Here, we report a 28-year-old woman who transiently showed lactate dehydrogenase (LDH)-linked immunoglobulin during postpartum thyroiditis. She demonstrated high levels of serum LDH (794 IU/l) and thyroid hormones 7 months after delivery. Electrophoretic isoenzyme analysis of LDH showed an abnormal broadband caused by LDH-linked immunoglobulin (IgG-kappa). Transient thyrotoxicosis due to postpartum thyroiditis improved without any specific treatment, and elevated serum concentration of LDH decreased to the normal level (395 IU/l) with disappearance of LDH-linked IgG. LDH-linked immunoglobulin may also appear at the postpartum period.     

Acute pancreatitis and parotitis induced by methimazole in a patient with Graves' disease

A wide variety of adverse effects of methimazole (MMI) have been reported. Here we report a new MMI-induced disorder, acute pancreatitis and parotitis. Three weeks after a woman started MMI treatment for Graves' disease, she developed a high fever, painful parotid swelling and dull pain in the upper abdomen with elevation of the serum levels of salivary and pancreatic enzymes. These abnormalities disappeared soon after the withdrawal of MMI. However, the same abnormalities were rapidly provoked when MMI was reintroduced. Marked increases in the leucocyte count and CRP were also observed during these episodes. The possible mechanisms of MMI-induced pancreatitis/parotitis are discussed.     

Frequency of antineutrophil cytoplasmic antibody in Graves' disease patients treated with methimazole

Retrospective studies have shown antineutrophil cytoplasmic antibody (ANCA) positivity in patients treated for Graves' hyperthyroidism; ANCA has been attributed to either antithyroid drugs or to the disease itself. The aim of this study was to determine ANCA in Graves' disease patients at diagnosis and after treatment with methimazole and to evaluate the relationship between ANCA and hyperthyroidism evolution. Thirty patients recently diagnosed with Graves' hyperthyroidism were prospectively studied. ANCA were determined by indirect immunofluorescence. ANCA autoantibodies against specific antigens (proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein (BPI), cathepsin, lysozyme, elastase, and lactoferrin) were detected by ELISA. The median observation period was 22 months. Kaplan-Meier analysis was performed to identify ANCA as an outcome variable. Twenty patients (67%) were ANCA positive before the onset of treatment, and four (19%) remained positive after 1 yr of antithyroid drug treatment. No differences were observed in any clinical or analytical features between patients with or without positive ANCA. Before treatment, BPI-positive patients required radioiodine treatment or presented relapse more rapidly than BPI-negative patients (log-rank test P < 0.0002). Patients with Graves' hyperthyroidism show positive ANCA before medical treatment, which points to a relationship with the autoimmune disease itself. Our results suggest that BPI-positive patients tend to relapse with antithyroid medication.     

Response to methimazole in Graves' disease

OBJECTIVE A variety of regimens continue to be used In the treatment of Graves' disease with antithyrold drugs. We have lnvestigated the factors which determine the initial response to methimazole (time until euthyroidism Is achieved) In Graves' disease. PATIENTS Five hundred and nine patients with Graves' disease in different European countries with normal and subnormal iodine supply. Patients were randomized to treatment with either 10 or 40mg of methimazole per day for one year, with levothyroxine supplementation as required to maintain euthyroidism. Investigations were carried out before treatment and at 3 and 6 weeks and 3, 6, 9 and 12 months. MEASUREMENTS Response was assessed by serial measurements of serum thyroid hormones. TSH receptor antibodies, thyroid autoantibodies and urinary Iodide excretion were measured centrally. Twenty-minute thyroid uptake was measured by standard techniques. Data were collected and analysed centrally. Standard techniques as well as a stepwise logistic regression model were used to examine the relations between methimazole dose, age, goitre size, presence of endocrine eye signs, thyroid hormone levels, urinary iodide excretion, thyroid uptake, Index of disease severity (Crooks), presence of TSH receptor antibodies and duration of the hyperthyroid phase. RESULTS Within 3 weeks, 40.2% of patients responded to 10mg of methimazole and 77.5% responded within 6 weeks. The corresponding figures for 40mg of methimazole were 64.6 and 92.6%. Significant associations were found between duration of hyperthyroldism and the following variables: goitre size, urinary iodide excretion, methimazole dose, presence of TSH receptor antibodies (TBIAb), Index of disease severity (Crooks) and pretreatment thyroid hormone levels. Response to methimazole was delayed In patients with large goitres, iodine excretion of ≧ 100μg/g creatinine, high pretreatment thyroid hormone levels, elevated levels of TBIAb and treatment with only 10 mg of methimazole. In the 10-mg group, 46% of patients were euthyrold within 3 weeks when urinary Iodide was <50μg/g of creatinine, and only 27% when iodide was above 100μg/g. By stepwise logistic regression, the main factors for the response to methimazole were dally dose, pretreatment T3 levels, and goitre size. CONCLUSION Methimazole dose, pretreatment serum T3 levels, and goitre size are the main determinants of the therapeutic response to methimazole In Graves' disease, at least In areas comprising low, subnormal and normal iodine supply.     

Intrathyroidal concentrations of methimazole in patients with Graves' disease

A sensitive gas chromatographic-mass spectrometric method enabled us to study intrathyroidal concentrations of methimazole in 20 euthyroid patients with Graves' disease on treatment with carbimazole and T4. There was no difference between patients receiving a final dose of carbimazole (10 mg), known to be totally bioactivated to methimazole (6.1 mg), 3-6 h before thyroid excision (518 ng/g thyroid tissue +/- 90 SEM) and patients who received the same dose 17-20 h before excision (727 ng/g thyroid tissue +/- 157 SEM), indicating a slow intrathyroidal turnover of the drug. On the other hand, the serum concentrations were much higher in the first group (102 ng/ml +/- 5 SEM vs. 16 ng/ml +/- 3 SEM), reflecting a short plasma half-life of the drug. The intrathyroidal concentrations of methimazole ranged from 230-1895 ng/g among individual glands but were similar in pieces from different parts of a single gland. These methimazole concentrations are lower than the concentrations reported by others to have an immunosuppressive action on lymphocytes in vitro.     

Anti-nuclear antibody, anti-DNA, and aCL in Graves' disease patients treated with propyluracil or methimazole

One hundred and forty patients with Graves' disease [32 new patients, 54 treated with propylthiouracil (PTU) for a mean of 27.2 months and 54 treated with methimazole (MMI) for a mean of 48.6 months] were tested for anti-thyroid microsomal antibody (AMA), anti-thyroglobulin antibody (ATA), thyroid binding inhibitory immunoglobulin (TBII), and the non organ specific autoantibodies [i.e., anti-nuclear antibody (ANA), anti-double stranded DNA antibody (anti-dsDNA Ab), anti-cardiolipin antibody (aCL Ab) and anti-beta2-glycoprotein I antibody (IgG beta2GPI)]. Treatment with MMI or PTU produced a significant difference in IgG aCL Ab production but not in ANA, dsDNA Ab, IgM aCL or IgG beta2GPI. For those treated with MMI but not those treated with PTU, ANA and anti-dsDNA Ab were positively correlated. IgG and IgM aCL Ab were positively correlated overall and for those on MMI but not PTU treatment. No significant difference was found for any of the four non organ specific antibodies in AMA positive or negative patients but there was a significant difference in IgG aCL positivity rates for ATA positive and negative patients. On the other hand, ANA negative patients were significantly more likely to have higher TBII values. These results suggest that the appearance of the non organ specific autoantibodies is probably largely a coincidental effect of polyclonal activation - except, perhaps, for IgG aCL, which may be related to treatment.     

Glucagon binding autoantibodies in a patient with hyperthyroidism treated with methimazole

A 47-yr-old woman who had previously received methimazole (MMI) treatment for hyperthyroidism was found to have glucagon binding autoantibodies in plasma. She had never received glucagon. The binding substances were detected in plasma at the time of a glucagon RIA. [125I]Glucagon binding was inhibited only by porcine glucagon and porcine glicentin, and dissociated at acid pH. The substances proved to be glucagon binding antibodies (immunoglobulin G, L-chain K-type), as determined by ammonium sulfate and radioprecipitation. There were no clinical manifestations related the presence of these autoantibodies. In a survey of 91 patients with thyroid disease, 3 patients whose plasma bound [125I]glucagon were identified among 41 with hyperthyroidism who were receiving MMI treatment. Such binding was not found in plasma from untreated hyperthyroid patients, those receiving propylthiouracil or those with chronic thyroiditis. These findings suggest that the development of glucagon antibodies in hyperthyroidism may be associated with MMI treatment.     

Effect of methimazole on warfarin anticoagulation in a case of Graves' disease.

The article describes a case of Graves' disease treated with methimazole and examines the influence of methimazole-induced alterations of thyroid hormone concentrations during warfarin therapy. A 22-year-old woman presented at our endocrinology outpatient clinic with palpitations, sweating, fatigue, tremors, and diarrhea. She had a pain in her right leg and had difficulty walking. Her thyroid profile was consistent with hyperthyroidism. The patient was treated with warfarin 5 mg once a day for deep vein thrombosis for 2 days. Since a therapeutic range of International Normalized Ratio levels could not be achieved, methimazole was stopped due to drug-drug interaction. Lithium was started instead. A euthyroid state was obtained in 2 weeks together with a therapeutic International Normalized Ratio level. Interactions between warfarin and drugs that alter thyroid hormone concentrations have been reported; however, the extent and significance of the interaction between methimazole and warfarin have been inadequately described. Concomitant therapy with warfarin and antithyroid drugs should be managed by frequent monitoring of both thyroid function and the International Normalized Ratio. Lithium is employed only to provide temporary control of thyrotoxicosis in patients who cannot take thionamide and iodide. The administration of lithium alone or in combination with other drugs is shown to be an effective method of controlling hyperthyroidism when conventional antithyroid drugs show adverse effects or become insufficient. When warfarins are used together with antithyroid medications, adequate anticoagulation may not be obtained due to drug-drug interactions. Lithium can be an alternative drug for antithyroid medication in patients on warfarin therapy.     

Impairment of prednisolone disposition in patients with Graves' disease taking methimazole

This study was undertaken to determine the effect of methimazole on the pharmacokinetics of iv prednisolone in patients with Graves' disease. Twenty women were studied, including eight with severe infiltrative ophthalmopathy who had taken methimazole and T4 for at least 4 months, six with severe infiltrative ophthalmopathy who had undergone subtotal thyroidectomy and, therefore, required no antithyroid treatment, and six age-matched normal women. All were euthyroid. Each women received 0.54 mg/kg prednisolone as an iv bolus dose. Plasma total and unbound prednisolone concentrations were measured at multiple times during a 10-h study period by high pressure liquid chromatography and equilibrium dialysis. The clearance of both total and unbound prednisolone was increased significantly in the women receiving methimazole therapy compared to values in both control groups. The volume of distribution at steady state was similar in all groups. These results suggest that patients receiving methimazole have enhanced prednisolone metabolism and, therefore, they may require higher prednisolone doses.     

Short-term treatment of Graves' disease with methimazole in high versus low doses

Abstract. Objectives . To compare the relapse rates in Graves' disease the first 2 years after methimazole 60 mg day^?1 combined with thyroxine versus a titration regimen with methimazole alone, and to look for possible prognostic factors. Design . A randomized, open, prospective study. Methimazole was given for 6 months in both groups, and thyroid status evaluated every 3rd month during the first year, and every 6th month during the second year. Setting . The study was performed at our outpatient clinic with patients referred from primary care. Subjects . Fifty-six patients were included. One became pregnant and one dropped out during the treatment period. Furthermore, nine patients in the high-dose and four in the low-dose group stopped the treatment because of side-effects. Thus, 19 patients in the high- and 22 in the low-dose group completed 6 months with methimazole. Results . In those tolerating the treatment, the relapse rates in the high- and low-dose groups were 26.3 vs. 59.1% (P < 0.05), 42.1 vs. 77.3% (P < 0.02); and 57.9 vs. 77.3% (NS) after 3, 12 and 24 months, respectively. The corresponding relapse rates calculated on an ‘intention to treat’ basis were: 51.7 vs. 66.7%; 62.1 vs. 81.5%; 72.4 vs. 81.5% (NS). The thyroid volume was significantly (P < 0.05) larger in those that relapsed (17.8 ± 2.9 vs. 11.6 ± 1.2 mL; mean ± SEM). Conclusions . In those tolerating the treatment, methimazole significantly reduced the relapse rate the 1st year when given in a high dose. However, the relapse rates in both groups, and the number of side-effects in the high-dose group, were unacceptably high.     

Thyroid-stimulating antibody in a patient with euthyroid Graves' disease

We report an 11-year-old girl with euthyroid Graves' disease. She was referred to our clinic because of left exophthalmos without other symptoms suggestive of hyperthyroidism. Her serum concentration of free thyroxine (FT4) and free triiodothyronine (FT3) were normal, but thyroid-stimulating hormone (TSH) was below normal and impaired TSH response to TSH releasing hormone (TRH) was found. Although the sera were positive for anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb), both titers were not as high as usually observed in Graves' disease. Three months later, she developed hyperthyroidism and was treated with propylthiouracil. Within 2 weeks of the initiation of therapy, all symptoms except exophthalmos disappeared, and after 2 months of treatment TRAb was negative though TSAb remained positive. TSAb is therefore a good indicator to use in the diagnosis and follow-up of euthyroid Graves' disease and should be measured in patients with exophthalmos of unknown origin, even in children.     

Relapse of Graves' disease in a patient with pheochromocytoma

We describe a patient with right adrenal tumor detected incidentally. The tumor was diagnosed as pheochromocytoma by endocrinological and radiological studies, and was removed surgically. Graves' disease, which had been in remission for more than two decades after discontinuation of antithyroid drug treatment, relapsed during preoperative evaluation of pheochromocytoma when the patient was treated with alpha- and beta1-adrenergic antagonists. Administration of methimazole resulted in a rapid improvement of thyroid function and the patient remained euthyroid on small doses of methimazole. This case may suggest possible involvement of excessive catecholamine secretion and beta2-adrenergic receptor activation by pheochromocytoma in the relapse of Graves' disease.     

Malignant hyperthermia in a patient with Graves' disease during subtotal thyroidectomy.

We report the case of a 31-year-old man with Graves' disease who manifested malignant hyperthermia during subtotal thyroidectomy. His past medical history and family history were unremarkable. Before surgery, his condition was well controlled with propylthiouracil, beta-adrenergic blocker and iodine. During the operation, anesthesia was induced by intravenous injection of vecuronium and thiopental, followed by suxamethonium for endotracheal intubation. Anesthesia was maintained with nitrous oxide and sevoflurane. One hour after induction of anesthesia, his end tidal carbon dioxide concentration (ET(CO2)) increased from 40 to 50 mmHg, heart rate increased from 90 to 100 beats per min and body temperature began to rise at a rate of 0.3 degrees C per 15 min. Suspecting thyroid storm, propranolol 0.4 mg and methylprednisolone 1,500 mg were administered, which, however, had little effect. Despite the lack of muscular rigidity, the diagnosis of malignant hyperthermia was made based on respiratory acidosis. Sevoflurane was discontinued and dantrolene was given by intravenous bolus. Soon after the treatment, ET(CO2), heart rate and body temperature started to fall to normal levels. His laboratory findings showed abnormally elevated serum creatine phosphokinase and myoglobin but normal thyroid hormone levels. Since dantrolene is efficacious in thyrotoxic crisis and malignant hyperthermia, an immediate intravenous administration of dantrolene should be considered when a hypermetabolic state occurs during anesthesia in surgical treatment for a patient with Graves' disease.     

A case of hypersensitivity syndrome induced by methimazole for Graves' disease.

Drug-induced hypersensitivity syndrome is one of the most severe forms of drug eruption and is characterized by high fever and multiorgan involvement. Reactivation of human herpesvirus-6 (HHV-6) or cytomegalovirus (CMV) has been suggested to be involved in this syndrome, although the exact role of these viruses remains elusive. We report the case of a 50-year-old Japanese male with Graves' disease who developed hypersensitivity syndrome caused by the antithyroid drug methimazole (MMI). After treatment with MMI 30 mg three times daily for 1(1/2) months, the patient developed generalized exfoliative erythematous eruption and high fever. Cessation of treatment with the drug improved his condition. Readministration of MMI worsened his clinical features. Treatment with high-dose methylprednisolone for 6 days and subsequent administration of prednisolone 20 mg twice daily improved his clinical manifestations. Elevated titers of anti-HHV-6 immunoglobulin G (IgG) and anti-CMV IgG antibodies were observed, and these gradually decreased during the clinical course, indicating reactivation of HHV-6 and CMV. Drug-induced lymphocyte stimulation test for MMI was negative. This is the first reported case of MMI-induced hypersensitivity syndrome associated with the reactivation of HHV-6 and CMV.     

Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease

CONTEXT: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat hyperthyroidism caused by Graves' disease (GD), there is still no clear conclusion about the choice of drug or appropriate initial doses. OBJECTIVE: The aim of the study was to compare the MMI 30 mg/d treatment with the PTU 300 mg/d and MMI 15 mg/d treatment in terms of efficacy and adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Patients newly diagnosed with GD were randomly assigned to one of the three treatment regimens in a prospective study at four Japanese hospitals. MAIN OUTCOME MEASURES: Percentages of patients with normal serum free T(4) (FT4) or free T(3) (FT3) and frequency of adverse effects were measured at 4, 8, and 12 wk. RESULTS: MMI 30 mg/d normalized FT4 in more patients than PTU 300 mg/d and MMI 15 mg/d for the whole group (240 patients) at 12 wk (96.5 vs. 78.3%; P = 0.001; and 86.2%, P = 0.023, respectively). When patients were divided into two groups by initial FT4, in the group of the patients with severe hyperthyroidism (FT4, 7 ng/dl or more, 64 patients) MMI 30 mg/d normalized FT4 more effectively than PTU 300 mg/d at 8 and 12 wk and MMI 15 mg/d at 8 wk, respectively (P < 0.05). No remarkable difference between the treatments was observed in patients with initial FT4 less than 7 ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with PTU and significantly lower with MMI 15 mg/d compared with MMI 30 mg/d. CONCLUSIONS: MMI 15 mg/d is suitable for mild and moderate GD, whereas MMI 30 mg/d is advisable for severe cases. PTU is not recommended for initial use.     

Graves' disease with markedly elevated serum immunoglobulin E

A 37-year-old female with Graves' disease was reported. An abnormally high concentration of serum IgE was observed by radioimmuno-sorbent test before treatment. Laboratory findings showed no evidence of atopic diseases or other known diseases with hyperglobulinemia E. There is no reported case of Graves' disease associated with remarkably elevated plasma IgE level. In the present patient, a further elevation of serum IgE concentration was observed when the dose of methimazole reached about 500 mg in total. Allergic mechanism may be the cause of this phenomenon. Serum IgE level was decreased gradually after replacement of methimazole by propylthiouracil. IgE level was not parallel with thyroid functions, and even when her thyroid function was normalized after subtotal thyroidectomy, IgE concentration was still increased around 900 IU/ml. The mechanism of hyperglobulinemia E in this case was discussed.     

丙基硫氧嘧啶与甲巯咪唑对Graves病患者细胞因子的影响

将64例Graves病(GD)患者分为甲巯咪唑组(MMI,n=30)和丙基硫氧嘧啶组(PTU,n=34),20名健康志愿者作为对照组.采集各组患者治疗前、治疗后3、6个月血清,分别用酶标记免疫吸附法检测血浆白细胞介素(IL)-2、IL-6及促甲状腺素受体抗体(TRAb)的水平.结果显示,2组治疗前一般情况比较差异无统计学意义.2组用药后6个月IL-2、IL-6水平较治疗前差异均有明显统计学意义(P＜0.05),随时间延长IL-2逐渐升高,IL-6逐渐降低;用药6个月后MMI组IL-6水平较PTU组明显降低(P＜0.05).2组治疗前TRAb水平无显著差异,2组治疗后3和6个月TRAb差异均有统计学意义(均P＜0.01),随时问增加逐渐下降.IL-2/IL-6比值在同一组治疗3、6个月后均较治疗前明显升高(P＜0.05).治疗6个月后MMI组较PTU组更高(P＜0.05).GD治疗前血清中IL-6水平与FT3、FT4呈正相关,IL-2水平与FT3、FT4和TRAb呈负相关;治疗3、6个月后,IL-2、IL-6与FT3、FT4无明显相关性;MMI组治疗前后IL-2、IL-6水平均与TRAb相关.这些结果提示,MMI较PTU更具有改善GD患者自身免疫的作用.     

Remission of insulin autoimmune syndrome in a patient with Grave's disease by treatment with methimazole.

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.