methimazole and Thyroiditis

Immune checkpoint inhibitors act to restore T cell-mediated antitumor immunity. By this nature, these cancer immunotherapy drugs are associated with various immune-related adverse events such as thyroid dysfunction. We describe a case of thyrotoxicosis secondary to a programmed cell death 1 (PD-1) immune checkpoint inhibitor, pembrolizumab. A 30-year-old female was started on pembrolizumab immunotherapy for stage III small cell carcinoma of the ovary, hypercalcemic type. Thirteen days after her second cycle of therapy, she presented with symptoms consistent with thyrotoxicosis. A thyroiditis was diagnosed by thyroid function tests and ultrasonography. She was originally treated with prednisone and metoprolol for possible Grave's disease. Pertechnetate thyroid scan was more consistent with thyroiditis secondary to pembrolizumab. She underwent a total thyroidectomy 10 days after initial presentation for refractory thyrotoxicosis despite maximal medical therapy. Her symptoms resolved and thyroid function tests significantly improved. Pathology was consistent with severe thyroiditis. Immune microenvironment may play a role in the expression of programmed cell death protein 1 ligand 1 (PD-L1). Chronic inflammation surrounding tumor upregulates PD-L1 expression on tumor cells by the release of cytokines, which acts to inhibit tumor destruction. We suggest that our patient had an undetected chronic inflammation of the thyroid, specifically Hashimoto's thyroidits, which predisposed her to thyroid destruction when taking pembrolizumab. Understanding that an inflammatory environment impacts thyroid toxicity to PD-1 inhibitor therapy is novel and should be further studied.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antithyroid Agents; Carcinoma, Small Cell; Female; Graves Disease; Humans; Methimazole; Ovarian Neoplasms; Thyroid Gland; Thyroidectomy; Thyroiditis

Interferon-induced thyroiditis (IIT) is a major clinical problem for patients receiving interferon-alpha (IFN-α) therapy. But, destructive thyroiditis followed by Graves' disease associated with IFN-α therapy is very rarely reported. Herein, we report a rare case of pegylated IFN-α (pegIFN-α) induced destructive thyroiditis followed by Graves' disease in a patient with HCV infection. A 31-yr-old woman suffered from chronic active hepatitis C and was treated with pegIFN-α and ribavirin for 12 months. Results of a thyroid function test and autoantibody levels were normal before IFN-α therapy was initiated. Destructive thyrotoxicosis appeared seven months after the initiation of IFN-α therapy, followed by Graves' thyrotoxicosis two months after the cessation of therapy. The diagnoses of destructive thyroiditis and Graves' disease were confirmed by the presence of TSH receptor antibodies in addition to Tc-99m scintigraphy findings. The patient's antithyroglobulin antibody titer increased gradually during IFN-α therapy and remained weakly positive after IFN-α therapy was discontinued.

Topics: Adult; Antiviral Agents; Female; Graves Disease; Hepatitis C, Chronic; Humans; Interferon-alpha; Methimazole; Propranolol; Thyroiditis

Type 2 amiodarone-induced thyrotoxicosis (AIT) is a destructive thyroiditis usually responsive to glucocorticoids; however, recent surveys showed that many expert thyroidologists worldwide use thionamides for type 2 AIT patients.. The objective of the study was to compare the effectiveness of methimazole (MMI) or prednisone (GLU) in type 2 AIT patients who had a short cure time according to a published predictive model.. This was a matched retrospective cohort study.. The study was conducted at a university center.. Forty-two untreated type 2 AIT patients with a predicted cure time < or = 40 d were divided into two groups (MMI and GLU groups). After matching for the predicted cure time, patients in the GLU group were selected in a 1:1 ratio to patients in the MMI group.. Patients were treated with GLU or MMI for 40 d. Patients still thyrotoxic after 40 d continued glucocorticoids if in the GLU group or were switched to prednisone (MMI-GLU group) if in the MMI group.. Time and rate of cure (healing) at 40 d were measured.. Patients still thyrotoxic after 40 d were 23.8 +/- 9.3% in the GLU group and 85.7 +/- 7.6% in the MMI group (P = 0.000). The GLU and MMI-GLU groups did not significantly differ in the nonhealing rate at 40 d (P = 0.730). When patients in the MMI group were treated with glucocorticoids, 94.1% patients achieved euthyroidism within 40 d. However, the global median cure time (MMI period + prednisone period) was longer (60 d, 95% confidence interval 53.5-66.5 d) in the MMI-GLU group than the GLU group (21 d, 95% confidence interval 15.1-26.9 d).. Glucocorticoids are the first-line treatment in type 2 AIT, whereas thionamides play no role in this destructive thyroiditis.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Antithyroid Agents; Case-Control Studies; Cohort Studies; Female; Glucocorticoids; Humans; Kaplan-Meier Estimate; Male; Methimazole; Middle Aged; Prednisone; Retrospective Studies; Thyroiditis; Thyrotoxicosis

Thyrotoxicosis occurs more frequently during the post-partum period than at other times in women of childbearing age. Graves' disease and post-partum thyroiditis are two major causes of thyrotoxicosis in this period. The major task lies in differentiation of these two diseases in the post-partum period; since throtoxicosis caused by post-partum thyroiditis usually does not require treatment. The radioiodine uptake is elevated or normal in Graves' disease and low in post-partum thyroiditis, and TSH-receptor antibodies are positive in Graves' and negative in post-partum thyroiditis. Post-partum thyrotoxicosis due to Graves' disease may be treated with radioiodine but it requires radiation safety measurements for infant and is contraindicated if the mother is breast-feeding. Antithyroid drugs are the mainstay of the treatment of post-partum thyrotoxicosis. Recent investigations conclude that neither propylthiouracil nor methimazole cause any alterations in thyroid function and physical and mental development of infants breast-fed by lactating thyrotoxic mothers, and both can be safely administered in moderately high doses during lactation.

Topics: Antithyroid Agents; Breast Feeding; Female; Graves Disease; Humans; Infant, Newborn; Iodine Radioisotopes; Methimazole; Propylthiouracil; Puerperal Disorders; Radiotherapy; Thyroidectomy; Thyroiditis; Thyrotoxicosis; Thyrotropin; Thyroxine; Triiodothyronine

Amiodarone-induced thyrotoxicosis (AIT) type 1 occurs in subjects with an underlying thyroid disease, whereas type 2 AIT is a form of destructive thyroiditis. Our hypothesis was that the common practice of thyroid testing before prescription of amiodarone would reduce the incidence of pure type 1 AIT, though a stringent classification may be difficult (mixed type AIT).. Thyroid testing before and after treatment of AIT (n = 12) and the response to combined antithyroid and glucocorticoid treatment (n = 11) were recorded in a consecutive series of patients seen at a university hospital.. Some criteria for type 1 AIT were fulfilled in 3 patients, but the diagnosis of a mixed form AIT was more likely in 2 of these. Type 2 AIT was diagnosed in the other 9 patients, while 6 patients had diffuse hypoechoic goitre. The median time to euthyroidism (defined as normal fT3 concentration) under thionamide and prednisolone (starting dose 20 to 75 mg/d) was 2 months (interquartile range 1 to 2.7 months). Thionamide treatment was stopped after a median duration of 5.7 months (interquartile range 4.2 to 8.7 months) and glucocorticoids were completely withdrawn after 6.7 months (5.5 to 8.7 months).. Nowadays, isolated type 1 AIT is rarely found and destructive thyroiditis (as type 2 AIT or mixed form) is the predominant cause of AIT. To accelerate recovery, we prescribed thionamide and glucocorticoids simultaneously as first-line therapy once contraindications for the use of steroids had been ruled out.

Topics: Adult; Aged; Amiodarone; Antithyroid Agents; Carbimazole; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Male; Methimazole; Middle Aged; Prednisolone; Prospective Studies; Thyroiditis; Thyrotoxicosis; Treatment Outcome

Topics: Adrenal Insufficiency; Adult; Anesthetics, Intravenous; Anti-Inflammatory Agents; Antithyroid Agents; Cholecystectomy; Estradiol; Etomidate; Female; Fentanyl; Humans; Hydrocortisone; Hyperthyroidism; Methimazole; Polyendocrinopathies, Autoimmune; Postoperative Complications; Thyroiditis

A 28-year-old woman with thyroid hemiagenesis, who had been diagnosed as having Graves' disease, became pregnant during the course of methimazole treatment. The treatment was terminated in the second trimester. She delivered a normal infant at full term. She became thyrotoxic 3 months after the delivery, hypothyroid 6 months after the delivery, and finally euthyroid 11 months after the delivery without undergoing any treatment. This clinical course indicates that she developed silent thyroiditis after the delivery. A diagnosis of thyroid hemiagenesis was made on the basis of ultrasonography of the thyroid and 99mTc-pertechnetate thyroid scintiscan.

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Pregnancy; Pregnancy Complications; Puerperal Disorders; Thyroid Gland; Thyroiditis

Nonobese diabetic (NOD) mice and a derived strain, NOD.H.2h4, have been used as a model for experimental spontaneous thyroiditis and thyroiditis induced by iodide excess after a goiter-inducing period. Some authors have proposed that iodide, given after methimazole or propylthiouracil, is capable of inducing apoptosis in thyroid cells and that anti-thyroid drugs can modulate the expression of apoptosis components such as Fas and its ligand (Fas-L). Here we evaluated the effect of potassium iodide (20 microg/animal for 4 days, i.p.) given to NOD mice at the 10th week of life after exposure to methimazole (1 mg/ml) in drinking water from the 4th to the 10th week of life. Fas, Fas-L and Bcl-w expression were analyzed semiquantitatively by RT-PCR immediately after potassium iodide administration (group MI44D) or at week 32 (MI32S). Control groups were added at 10 (C10) and 32 weeks (C32), as well as a group that received only methimazole (CM10). An increase in the expression of Fas-L and Bcl-w (P<0.01, ANOVA) was observed in animals of group MI44D, while Fas was expressed at higher levels (P = 0.02) in group C32 (72.89 +/- 47.09 arbitrary units) when compared to group C10 (10.8 +/- 8.55 arbitrary units). Thus, the analysis of Fas-L and Bcl-w expression in the MI44D group and Fas in group C32 allowed us to detect two different patterns of expression of these apoptosis components in thyroid tissue of NOD mice.

Topics: Animals; Antithyroid Agents; Apoptosis; Disease Models, Animal; Electrophoresis; Fas Ligand Protein; fas Receptor; Gene Expression; Male; Membrane Glycoproteins; Methimazole; Mice; Mice, Inbred NOD; Potassium Iodide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Gland; Thyroiditis

Graves' disease is an autoimmune disorder characterized by the presence of antibodies against thyrotropin receptor (TRAb). Stem cell factor (SCF), derived from bone marrow, is known to promote lymphohematopoiesis. To investigate the relation between the alteration in plasma levels of SCF, thyroid hormone status, and TRAb measured by thyrotropin binding inhibition (TBI), 13 untreated, 21 treated, and 4 relapsed hyperthyroid Graves' disease patients, 21 patients with Hashimoto's thyroiditis, 6 patients with subacute thyroiditis, and 11 control subjects were examined. In untreated hyperthyroid Graves' disease patients, serum levels of thyroxine (T4) and triiodothyronine decreased rapidly by methimazole treatment, and TBI decreased progressively, but variably. Simultaneously, the elevated plasma levels of SCF decreased gradually and progressively. The plasma levels of SCF correlated curvilinearly with the serum levels of T4. In 4 patients with relapsed hyperthyroid Graves' disease, TBI was marginally positive in 3 patients and negative in 1, but plasma levels of SCF were elevated significantly in all 4 patients. In patients with subacute thyroiditis and Hashimoto's thyroiditis with or without T4 replacement, plasma levels of SCF did not differ from that of controls. These findings indicate that the elevation of plasma levels of SCF relates to the longstanding thyrotoxic state and that short-term thyrotoxicosis does not significantly affect plasma levels of SCF. It remains to be determined whether the elevation in plasma levels of SCF is induced by excess thyroid hormone, reflecting the hypermetabolic state, or whether the elevation of plasma levels of SCF contributes to stimulation of lymphocytes producing TRAb.

Topics: Acute Disease; Adolescent; Adult; Aged; Antithyroid Agents; Female; Graves Disease; Humans; Male; Methimazole; Middle Aged; Recurrence; Stem Cell Factor; Thyroid Gland; Thyroiditis; Thyroiditis, Autoimmune

We have recently reported that, in patients with hyperthyroidism, the red blood cell (RBC) carbonic anhydrase I (CAI) and zinc (Zn) concentrations both reflect the patient's integrated thyroid hormone level over the preceding few months. In this study, we evaluated the clinical usefulness of determining the RBC CAI and Zn concentrations in patients with various types of thyroid disease. Six patients with painless thyroiditis (PT) had normal RBC CAI concentrations and the two patients tested had normal RBC Zn levels. In four patients with syndromes of inappropriate thyrotropin (TSH) secretion (SITSH) two euthyroid patients had normal RBC CAI and two hyperthyroid patients had subnormal RBC CAI and Zn. In a patient with Graves' disease whose plasma thyroxine (T4) and triiodothyronine (T3) concentrations changed remarkably because of poor compliance with the regimen, the change in plasma thyroid hormone levels preceded the change in the RBC CAI and Zn concentrations by 2 to 3 months. These observations suggest that the measurement of RBC CAI and Zn concentrations may be useful clinically as follows: (1) in differentiating hyperthyroid Graves' disease from transient hyperthyroidism due to destructive thyroiditis; and (2) in obtaining an accurate estimate of the extent of elevated thyroid hormone levels in hyperthyroid patients over time.

Topics: Adult; Carbonic Anhydrases; Erythrocytes; Graves Disease; Humans; Methimazole; Middle Aged; Osmolar Concentration; Thyroid Diseases; Thyroid Function Tests; Thyroid Hormones; Thyroiditis; Zinc

Hyperthyroidism occurred following primary hypothyroidism in a 46-year-old man with serologically and histologically proved chronic lymphocytic thyroiditis. Repeated thyroid biopsy specimens revealed that histologic features compatible with chronic lymphocytic thyroiditis seen at the initial hypothyroid state subsequently underwent a remarkable resolution, with titers of circulating antithyroid antibodies being reduced in correspondence with the histologic improvement. This case shows that primary hypothyroidism in adults can spontaneously evolve into a hyperthyroid state, as has been suggested previously, and that the histologic abnormalities in chronic lymphocytic thyroiditis may not necessarily be irreversible.

Topics: Antibodies; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Thyroid Gland; Thyroiditis; Thyroxine

Thionamide drugs are immunosuppressives in vitro. To examine this action in vivo, A/J mice were immunized with human thyroglobulin (hTg) (0.5 mg intraperitoneal injections for 5 d) beginning on days 6, 24, and 43 with or without methimazole (M) (0.05%) and l-thyroxine (T4) (0.1 micrograms/ml to prevent thyroid hypertrophy) in their water supply. Groups (n = 8) were killed on days 37, 42, and 59. Spontaneous splenic IgG-secreting cells determined by Staphylococcus protein A-linked sheep erythrocytes (SRBC) via indirect plaque-forming cell (PFC) assay indicated polyclonal stimulation induced by the hTg exposure (controls = 2,285 +/- 599, hTg-only = 5,570 +/- 470 PFC per 10(6) spleen cells), but this was significantly reduced in the M plus T4-treated group (3,640 +/- 415 PFC, P = 0.05). hTg antibody was measured by specific PFC assay using hTg-linked SRBC. Anti-hTg PFC were absent in controls and were 147 +/- 41, 25 +/- 8, and 173 +/- 58 PFC per 10(6) spleen cells in the hTg-only groups on days 37, 42, and 59, respectively. Anti-hTg PFC results in the M plus T4-treated animals were significantly reduced to 0, 15 +/- 5, and 63 +/- 30 anti-hTg PFC. Histological examination revealed a marked thyroiditis in hTg-only animals and a significantly reduced degree of mononuclear cell infiltration and follicular destruction in the M plus T4-treated groups (graded 1.9 compared with 3.6 in hTg-only P = less than 0.01). Examination of IgG deposition using fluorescent anti-mouse IgG revealed a similar granular pattern and degree of staining in both immunized groups. Control animals that received concurrent T4 administration alone showed similar hTg-induced murine thyroiditis to non-T4-treated animals and could not explain the apparent immunosuppression observed. In conclusion, these data demonstrated that M reduced both the splenic immune response and the degree of thyroiditis after heterologous Tg immunization, while a quantitative difference in the circulating and intrathyroidally deposited Tg antibody was not detected.

Topics: Animals; Antibody Formation; Immunization; Immunoglobulin G; Immunosuppressive Agents; Male; Methimazole; Mice; Mice, Inbred A; Spleen; Thyroglobulin; Thyroiditis; Thyroxine; Viral Plaque Assay

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.

Topics: Autoantibodies; Chromatography, Gel; Female; Glucagon; Humans; Hyperthyroidism; Immunosorbent Techniques; Methimazole; Middle Aged; Thyroiditis

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

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

We have investigated the thyroid uptake of Tl-201 in 37 patients with various types of goiter, and in six with normal thyroids. Significant thallium uptake was found in all cases in which there was thyroid enlargement, including Graves' disease, toxic thyroid nodule, primary hypothyroidism, simple goiter, Hashimoto's disease, thyroid carcinoma, and thyroid adenoma. If goiter was absent, however, there was no demonstrable uptake--e.g., in secondary hypothyroidism, subacute thyroiditis, and the normal controls. Thallium uptake did not correlate with thyroid function tests such as BMR, T3-RU, T3, T4, TSH, antithyroid antibodies, or the 24-hr I-131 uptake. In 23 patients with diffuse goiter, on the other hand, maximum Tl-201 uptake correlated well with thyroid weight: r = 0.836 (p less than 0.001); y = 0.02 x + 0.06.

Topics: Adenoma; Antithyroid Agents; Contrast Media; Goiter; Goiter, Nodular; Graves Disease; Humans; Hypothyroidism; Iodipamide; Methimazole; Radioisotopes; Radionuclide Imaging; Syndrome; Thallium; Thyroid (USP); Thyroid Diseases; Thyroid Function Tests; Thyroid Neoplasms; Thyroiditis; Thyroiditis, Autoimmune; Thyrotropin

Topics: Animals; Female; Freund's Adjuvant; Guinea Pigs; Hyperplasia; Immunization; Male; Methimazole; Microscopy, Electron; Thyroid Hormones; Thyroiditis; Thyrotropin; Triiodothyronine

Topics: Adult; Aged; Antibodies; Chronic Disease; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Isotopes; Male; Methimazole; Middle Aged; Myxedema; Propranolol; Propylthiouracil; Pulse; Thiocyanates; Thyroid Diseases; Thyroid Function Tests; Thyroiditis; Time Factors; Triiodothyronine

Topics: Chronic Disease; Diet; Goiter; Humans; Iodine; Iodine Isotopes; Methimazole; Methods; Perchlorates; Potassium; Thyroid Gland; Thyroiditis