propylthiouracil and Agranulocytosis

Thionamides, such as methimazole and propylthiouracil, are used for the management of hyperthyroidism. Agranulocytosis is a rare adverse effect of thionamides and elderly patients are especially vulnerable. Here we discuss a case of an 80-year-old woman who developed agranulocytosis and pneumonia approximately 4 weeks after starting low dose methimazole therapy. Despite aggressive treatment with broad-spectrum antibiotics and granulocyte colony stimulating factor, she developed multiorgan failure and died. Our goals are to identify risk factors common to elderly patients and hopefully improve outcomes in this population when prescribed thionamides.

Topics: Age Factors; Aged, 80 and over; Agranulocytosis; Anti-Bacterial Agents; Antithyroid Agents; Fatal Outcome; Female; Granulocyte Colony-Stimulating Factor; Humans; Hyperthyroidism; Methimazole; Propylthiouracil; Risk Factors

Propylthiouracil (PTU), methimazole (MMI) and carbimazole are indicated for the treatment of hyperthyroidism in adult and pediatric patients. The aim of this review is to present all the relevant information regarding the use of antithyroid drugs (ATD) in pediatric thyrotoxic cases, the pediatric toxicology of ATD and the warning which has recently been issued for PTU by the FDA.. Epidemiology, diagnosis and treatment of pediatric thyrotoxicosis are all presented in this article. The authors also extensively discuss the details regarding the pharmacology, bioactivation, biodisposition, bioavailability and pharmacokinetic properties of the two main ATD (MMI and PTU).. The FDA recently reported that use of PTU is associated with a higher risk for clinically serious or fatal liver injury compared to MMI in both adult and pediatric patients. They also found that congenital malformations were reported approximately three times more often with prenatal exposure to MMI compared with PTU and especially with the use of MMI during the first trimester of pregnancy. The authors believe that PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of MMI, and there are no other treatment options available. That being said, PTU may be the treatment of choice during, and just before, the first trimester of pregnancy.

Topics: Agranulocytosis; Animals; Antithyroid Agents; Carbimazole; Child; Child, Preschool; Evidence-Based Medicine; Female; Graves Disease; Humans; Hyperthyroidism; Liver Failure; Methimazole; Pregnancy; Propylthiouracil; Randomized Controlled Trials as Topic; Thyrotoxicosis; Vasculitis

Topics: Agranulocytosis; Algorithms; Antithyroid Agents; Female; Graves Disease; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Gland; Thyrotoxicosis; Thyroxine; Triiodothyronine

Thyroid hormone preparations, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly. Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leucopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis) are exceedingly rare.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Bone and Bones; Carbimazole; Cardiovascular System; Child; Collagen Diseases; Humans; Leukopenia; Liver; Methimazole; Propylthiouracil; Skin; Thyroid Hormones; Thyroxine

Topics: Agranulocytosis; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Liver Diseases; Middle Aged; Propylthiouracil

Prognosis in aplastic anemia is usually linked to the degree of hypoplasia in the bone marrow and pancytopenia in the blood. The authors were, therefore, intrigued when a patient with methimazole-associated aplastic anemia who satisfied criteria for severe disease recovered rapidly and completely once her drug was withdrawn. Review of the English language literature revealed ten fully documented cases of aplastic anemia associated with use of the antithyroid drugs methimazole, carbimazole, and propylthiouracil. Analysis of the ten and of an eleventh case presented here indicated that the disorder is typically characterized by severe pancytopenia and profound marrow hypoplasia, yet surprisingly good prognosis, ie, minimum survival of more than 70% with partial or complete recovery from symptoms and cytopenias in survivors within 2-5 weeks. The only deaths, both in the 1950s, were from brain hemorrhage in patients who were not transfused with platelets. The discrepancy between the clinical and laboratory severity of antithyroid drug-associated aplasia, on the one hand, and its relatively good prognosis and short term course, on the other, should be kept in mind when considering these patients for bone marrow transplantation or for therapy with antithymocyte globulin.

Topics: Adult; Agranulocytosis; Anemia, Aplastic; Female; Humans; Methimazole; Propylthiouracil

Topics: Adolescent; Agranulocytosis; Humans; Male; Mouth Diseases; Propylthiouracil; Thyrotoxicosis; Ulcer

Propylthiouracil and methimazole are frequently used in the management of hyperthyroidism. Two patients in whom adverse immunologic effects other than isolated agranulocytosis developed during treatment with propylthiouracil are described. A review of the literature revealed 53 similar cases over a 35-year period. Rash, fever, arthralgias and granulocytopenia were the most common manifestations. Vasculitis, particularly with cutaneous manifestations, occurs and may be fatal. The clinical evidence suggests that an immunologic mechanism is involved. A number of different autoantibodies were reported, but antinuclear antibodies were infrequent, and none of the cases met the criteria for a diagnosis of systemic lupus erythematosus. Thus, the reactions do not represent a true drug-induced lupus syndrome. Current hypotheses and experimental data regarding the cause of the reactions are reviewed. No specific clinical subgroup at high risk can be identified, and manifestations may occur at any dosage and at any time during therapy. Cross-reactivity between the two antithyroid drugs can be expected. Except for minor symptoms (e.g., mild arthralgias or transient rash), such reactions are an indication for withdrawal of the drug and the use of alternative methods to control the hyperthyroidism. In rare cases of severe vasculitis a short course of high-dose glucocorticoid therapy may be helpful.

Topics: Adult; Agranulocytosis; Antibody Formation; Cross Reactions; Drug Hypersensitivity; Female; Graves Disease; Humans; Hyperthyroidism; Immunity, Cellular; Methimazole; Middle Aged; Propylthiouracil

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

Topics: Agranulocytosis; Antithyroid Agents; Carbimazole; Eye Manifestations; Female; Follow-Up Studies; Goiter; Humans; Hyperthyroidism; Imidazoles; Methimazole; Pregnancy; Propylthiouracil; Thyroxine; Time Factors; Triiodothyronine

Topics: Agranulocytosis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Humans; Propylthiouracil; Vasculitis

Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian.. In this study, informatics methods were used to investigate if any sequence or structural similarities exist between the two associated HLA-B alleles, compared with a set of "control" alleles assumed not be associated, which could help explain the molecular basis of the adverse drug reaction. We demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a propensity to bind similar peptides, and thus at a gross level the structure of the antigen presentation region of the two alleles are not similar. We also performed multiple sequence alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular docking to compare the predicted binding poses of the drug-allele combinations.. Two residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and risk assessment.

Topics: Adaptive Immunity; Agranulocytosis; Alleles; Amino Acid Sequence; Antithyroid Agents; Asian People; Binding Sites; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; HLA-B Antigens; Humans; Medical Informatics; Methimazole; Propylthiouracil; Protein Binding; White People

Agranulocytosis occurs in 0.2-0.5% of patients treated with the antithyroid drugs (ATDs) methimazole and propylthiouracil. The objectives of this study were to evaluate the risk of ATD-related agranulocytosis in patients with amiodarone-induced thyrotoxicosis (AIT), and to compare it with the agranulocytosis risk in patients with thyrotoxicosis due to other etiologies treated with ATDs.. This was a retrospective cohort study. Participants were 14,781 adult patients with thyrotoxicosis, newly treated with an ATD between January 1, 2002, and December 31, 2015. Among them were 593 patients treated by ATDs due to AIT. The main outcome measures were incidence rates and crude and adjusted hazard ratios using univariate and multivariable Cox regression models for ATD-related agranulocytosis within one year of treatment initiation, in association with AIT.. Agranulocytosis occurred in 28 (0.19%) of patients newly treated with methimazole or propylthiouracil during the first year of follow-up. Of these 28 patients, 8/593 (1.35%) were AIT patients and 20/14,188 (0.14%) were thyrotoxic patients that was not AIT related (p < 0.001). Incidence rates were 22 (9.47-43.36) cases/1000 person-years of follow-up in AIT, and 1.79 (1.09-2.76)/1000 person-years of follow-up in non-AIT thyrotoxicosis (p < 0.0001). In univariate Cox regression analysis, risk for ATD agranulocytosis associated with AIT was 9.71 (4.28-22.05) compared to the risk in non-AIT thyrotoxicosis. In a multivariable model, adjusting for age, sex, body mass index, smoking history, year of cohort entry, diabetes mellitus, hypertension, renal failure, beta blockers, calcium channel blockers, anti-aggregants, and dose of ATDs, the risk associated with AIT was 5.70 (2.14-15.21). In a model adjusted for a propensity score to receive amiodarone, risk for ATD agranulocytosis associated with AIT was 6.32 (1.22-32.70).. ATD use is associated with a higher risk for agranulocytosis in patients with AIT.

Topics: Adult; Aged; Agranulocytosis; Amiodarone; Antithyroid Agents; Female; Humans; Male; Methimazole; Middle Aged; Proportional Hazards Models; Propylthiouracil; Retrospective Studies; Risk; Thyrotoxicosis

Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism. Antithyroid drugs (ATDs) are available as therapy. Agranulocytosis is a rare but potentially fatal complication of this therapy. In this study, we report agranulocytosis induced by propylthiouracil (PTU) in a patient with GD and the difficulties of clinical management.. RNBA, male, 30 years old, with GD, treated with propylthiouracil (PTU). He progressed with pharyngotonsillitis. Then, PTU was suspended and antibiotic, filgrastim, propranolol, and prednisone were initiated. Due to the decompensation of hyperthyroidism, lithium carbonate, dexamethasone, and Lugol's solution were introduced. Total thyroidectomy (TT) was performed with satisfactory postoperative progression.. We describe here the case of a young male patient with GD. For the treatment of hyperthyroidism, thioamides are effective options. Agranulocytosis induced by ATDs is a rare complication defined as the occurrence of a granulocyte count <500/mm3 after the use of ATDs. PTU was suspended, and filgrastim and antibiotics were prescribed. Radioiodine (RAI) or surgery are therapeutic alternatives. Due to problems with ATD use, a total thyroidectomy was proposed. The preoperative preparation was performed with beta-blocker, glucocorticoid, lithium carbonate, and Lugol solution. Cholestyramine is also an option for controlling hyperthyroidism. TT was performed without postoperative complications.. Thionamide-induced agranulocytosis is a rare complication. With a contraindication to ATDs, RAI and surgery are definitive therapeutic options in GD. Beta-blockers, glucocorticoids, lithium carbonate, iodine, and cholestyramine may be an adjunctive therapy for hyperthyroidism.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Graves Disease; Humans; Male; Propylthiouracil; Rare Diseases; Thyroid Function Tests; Thyroidectomy

Topics: Agranulocytosis; Anti-Bacterial Agents; Antithyroid Agents; Drug Substitution; Emergencies; Female; Humans; Hyperthyroidism; Lung Abscess; Methimazole; Middle Aged; Propylthiouracil; Tomography, X-Ray Computed

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.

Topics: Agranulocytosis; Antithyroid Agents; Carbimazole; Case-Control Studies; Female; Genome-Wide Association Study; HLA-B Antigens; Humans; Linkage Disequilibrium; Methimazole; Polymorphism, Single Nucleotide; Predictive Value of Tests; Propylthiouracil

Antithyroid drug (ATD)-induced agranulocytosis is a rare but life-threatening disease. Clinical features of ATD-induced agranulocytosis and outcomes remain incompletely understood.. Patients with clinically diagnosed ATD-induced agranulocytosis were retrospectively studied, involving 9690 patients who were referred for radioiodine treatment during a 15-year period (2000-2015) in China. There were 114 cases of agranulocytosis attributable to ATD included, and their clinical characteristics and therapy outcomes were analyzed.. The female-to-male ratio of ATD-induced agranulocytosis was 10.4:1. The mean age (±standard deviation) of the patients with ATD-induced agranulocytosis was 41.7 ± 12.3 years. The methimazole and propylthiouracil doses given at the onset were 22.9 ± 8.0 mg/day and 253.6 ± 177.5 mg/day, respectively. ATD-induced agranulocytosis occurred in 45.1%, 74.3%, and 88.5% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. Fever (78.9%) and sore throat (72.8%) were the most common symptoms when agranulocytosis was diagnosed. The mean recovery time of agranulocytosis was 13.41 ± 7.14 days. Recovery time in the granulocyte colony-stimulating factor (G-CSF)-treated group (12.7 ± 6.0 days) did not differ from that in the group not treated with G-CSF (16.4 ± 10.6 days; p = 0.144). Treatment with (131)I was successful in 87/98 patients (88.8%). The success rate of (131)I was equivalent (p = 1.000) between the groups receiving methimazole (88.2%, 75/85) and propylthiouracil (92.3%, 12/13).. This largest single-institution study in China shows that ATD-induced agranulocytosis tends to occur within the first 12 weeks after the onset of ATD therapy. For patients with ATD-induced agranulocytosis, G-CSF does not improve the recovery time of agranulocytosis, and (131)I is an optimal treatment approach.

Topics: Adult; Agranulocytosis; Antithyroid Agents; China; Female; Granulocyte Colony-Stimulating Factor; Humans; Hyperthyroidism; Male; Methimazole; Middle Aged; Propylthiouracil; Retrospective Studies; Treatment Outcome

Agranulocytosis is a serious adverse effect of antithyroid drugs (ATDs) and mainly develops within three months after the start of uninterrupted ATD treatment. Agranulocytosis can also develop for the first time after interruption and subsequent resumption of the same ATD treatment. However, little is known with regard to agranulocytosis that develops after resumption of the same ATD treatment.. We investigated the characteristics of patients who developed agranulocytosis during their second or later course of ATD treatment.. A total of 81 patients at our hospital were diagnosed with ATD-induced agranulocytosis. In 14 of the cases (methimazole (MMI), n=10; propylthiouracil (PTU), n=4), the agranulocytosis developed for the first time in the context of the second or later course of treatment with the same ATD; those patients were designated the "resumed group." The 35 patients (MMI, n=28; PTU, n=7) who developed agranulocytosis during their first uninterrupted course of ATD therapy were designated the "first group.". The median total duration of ATD treatment before the diagnosis of agranulocytosis was 559 days (range 86-1775 days), and the median interval between the final day of the previous course and the first day of the course in which agranulocytosis was diagnosed was 916.5 days (range 153-8110 days). There were no cases in which agranulocytosis developed when treatment with the same ATD was resumed after discontinuation for less than five months. The difference between the start of ATD treatment in the course in which agranulocytosis was diagnosed and the time interval at which agranulocytosis was diagnosed was similar when comparing the first group and the resumed group (39 (20-98) days in the first group vs. 32.5 (21-95) days in the resumed group; n.s.). There were no significant differences between the groups in terms of granulocyte count at the time agranulocytosis was diagnosed, mortality rate, or the interval between the diagnosis of agranulocytosis and recovery.. When ATD treatment is resumed, patient follow-up is essential in order to monitor for the development of agranulocytosis.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antithyroid Agents; Drug Monitoring; Electronic Health Records; Female; Granulocytes; Graves Disease; Hospitals, Urban; Humans; Japan; Leukopoiesis; Male; Methimazole; Middle Aged; Propylthiouracil; Time Factors; Young Adult

Agranulocytosis is a serious complication of antithyroid drugs (ATD) treatment of thyrotoxicosis. The aim of our work was to assess the occurrence of agranulocytosis in Graves disease (GD) patients admitted for radioactive iodine 131I (RAI) treatment to our thyroid unit.. We analyzed retrospectively a cohort of 603 GD patients (500 women and 103 men; mean age 51.5 ± 12.7 years) who received RAI between 1999 and 2012. Of them, 327 (54 %) patients were originally treated with carbimazole (CBZ), 215 (36 %) with methimazole (MMI) and 61 (10 %) with propylthiouracil (PTU).. Agranulocytosis due to ATD was the cause of RAI treatment in 7 patients of 603. All of them were women (mean age 48.7 years; range 23-78). In 4 patients, agranulocytosis occurred on MMI treatment, and in 3 patients on CBZ. After recalculation of CBZ to the equipotent dose of MMI, the mean ATD dose was 22.4 mg MMI/day (range 9-40). No agranulocytosis due to PTU was found in our cohort. The time from beginning ATD treatment to agranulocytosis was 20-41 days. In 5 patients there was a development of fever, while in 2 patients the complication was diagnosed from routine blood count. The mean duration of agranulocytosis was 5.9 days (range 4-8).. Agranulocytosis incidence in our cohort of patients was 1.2 %, while in most reports the prevalence ranged from 0.2 to 0.5 %. In all patients, agranulocytosis occurred early, and in one third it was asymptomatic when found. The aim of our report is to bring attention to a relatively rare, but potentially serious, complication of ATD treatment.

Topics: Adult; Aged; Agranulocytosis; Antithyroid Agents; Carbimazole; Female; Graves Disease; Humans; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Propylthiouracil; Retrospective Studies

Topics: Abdomen, Acute; Agranulocytosis; Antithyroid Agents; Enterocolitis, Neutropenic; Fatal Outcome; Humans; Male; Middle Aged; Propylthiouracil

Agranulocytosis is a rare but serious complication of antithyroid drug (ATD) therapy. Characteristics of agranulocytosis have been reported in only a small number of patients.. We studied 754 cases of ATD-induced agranulocytosis reported over 30 years. The age distribution and sex ratio were compared with those in 12 503 untreated Graves' patients at Kuma Hospital. The annual number of new Graves' patients in Japan was estimated from the Japan Medical Data Center Data Mart-Pharmacovigilance health insurance receipt database.. Agranulocytosis developed within 90 days after starting ATD therapy in most patients (84.5%). The methimazole dose given at onset was 25.2 ± 12.8 mg/d (mean ± SD). The mean age was 43.4 ± 15.2 years, and the male to female ratio was 1:6.3. When compared with patients at Kuma Hospital, patients with agranulocytosis were older (P < .001) and more females (P < .0001). Of 211 patients with more than 1 granulocyte measurement before onset, 131 (62%) showed normal counts (>1000/μL) within 2 weeks before onset, demonstrating real sudden onset of agranulocytosis. In contrast, some of the 20 patients with more than 4 measurements showed gradual decreases in granulocyte counts. Analysis of physician reports for 30 fatal cases revealed that some deaths might have been prevented. The number of new Graves' patients treated with ATD was estimated at about 35 000 per year, and the incidence rate of agranulocytosis was 0.1% to 0.15% in Japan.. This is the largest study of agranulocytosis. Agranulocytosis tends to occur abruptly within 3 months after initiation of ATD therapy, although it develops gradually in some patients. Providing every patient with sufficient information on agranulocytosis is critical.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Agranulocytosis; Anemia, Aplastic; Antithyroid Agents; Drug Therapy, Combination; Female; Graves Disease; Hospitals, Urban; Humans; Incidence; Japan; Leukopoiesis; Male; Methimazole; Middle Aged; Pancytopenia; Pharmacovigilance; Propylthiouracil; Sex Distribution

This study is aimed to explore the relationship between bone marrow characteristics and clinical prognosis of antithyroid drug (ATD) induced agranulocytosis. A retrospective study was conducted in the first affiliated hospital of the University of South China. A total of 33 hospitalized patients diagnosed with ATD-induced agranulocytosis were analyzed. The bone marrow characteristics were classified into two types. Type I was characterized by reduction or absence of granulocytic precursors and type II was recognized as hypercellular bone marrow with dysmaturity of granulocytic cells. Bone marrow of 20 cases (61%) were characterized with type I whereas 13 cases (39%) with type II. The median duration of neutrophil recovery and high-grade fever were 4.7 ± 1.0 days and 3.6 ± 2.5 days respectively for type II, compared to 8.0 ± 2.8 days and 8.6 ± 3.1 days for type I (p < 0.01 in both compared groups). However, there was no significant difference between the two types in terms of age, median duration of drug administration before the diagnosis of agranulocytosis, the amount of neutrophil count on admission and the total administration dose of granulocyte-colony stimulating factor (G-CSF) before bone marrow examination. Two cases of type I died of complications from infection. This study showed that the bone marrow characteristics of ATD-induced agranulocytosis could be classifed into two types. Also, the clinical prognosis was closely related to the bone marrow features. Type I is the dominant type which is usually associated with worse clinical prognosis compared to type II.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Bone Marrow; Cell Differentiation; China; Female; Fever; Granulocyte Colony-Stimulating Factor; Granulocyte Precursor Cells; Hospitals, University; Humans; Hyperthyroidism; Male; Methimazole; Middle Aged; Prognosis; Propylthiouracil; Retrospective Studies; Young Adult

Topics: Adult; Agranulocytosis; Antithyroid Agents; Female; Granulocyte Colony-Stimulating Factor; Graves Disease; Humans; Propylthiouracil; Treatment Outcome

Although antithyroid drug (ATD)-induced hematopoietic damage is a significant concern, it has not been comprehensively investigated.. Our objective was to describe the clinical features of ATD-induced hematopoietic damage.. This was a retrospective cohort study in Tokyo, Japan.. Between January 1983 and December 2002, 50,385 patients at Ito Hospital were diagnosed with Graves' disease. We retrospectively reviewed their medical, pathological, and laboratory records between January 1983 and December 2010.. Incidence and clinical features of ATD-induced agranulocytosis and pancytopenia were evaluated.. Of 55 patients with documented hematopoietic damage, 50 had agranulocytosis and 5 had pancytopenia. All of them received ATD, either methimazole (n = 51) or propylthiouracil (n = 4). Median intervals between initiation of ATD therapy and the onset of agranulocytosis and pancytopenia were 69 d (range, 11-233 d) and 41 d (range, 32-97 d), respectively. Either anemia or thrombocytopenia was also documented in seven of the 50 patients with agranulocytosis. Agranulocytosis was the first manifestation of hematopoietic damage in four of the five patents with pancytopenia. Hematopoietic damage recovered with supportive measures including granulocyte colony-stimulating factor (n = 37), steroids (n = 10), and other supportive measures (n = 8) in 54 patients, whereas the remaining patient died of complications from infection. This study failed to identify the risk factors for ATD-induced hematopoietic damage.. This study showed that ATD cause hematopoietic changes, which are occasionally severe and potentially fatal. The pathogenesis of agranulocytosis and pancytopenia might overlap, and additional studies are warranted to clarify this and to establish an optimal treatment strategy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antithyroid Agents; Child; Cohort Studies; Female; Graves Disease; Hematopoiesis; Humans; Japan; Male; Methimazole; Middle Aged; Pancytopenia; Propylthiouracil; Retrospective Studies; Tokyo; Young Adult

Agranulocytosis is a life-threatening disorder characterised by a greatly decreased number of circulating neutrophils below 500/μL. This article presents two cases of agranulocytosis in patients treated with pegylated interferon and ribavirin due to chronic hepatitis C. Interferon induced hyperthyroidism, which required the use of a tyreostatic. Anti-thyroid drugs (ATD) used to treat hyperthyroidism can cause agranulocytosis. The synergistic reaction of ATD and interferon on bone marrow cannot be excluded.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Hyperthyroidism; Interferon alpha-2; Interferon-alpha; Methimazole; Middle Aged; Polyethylene Glycols; Propylthiouracil; Recombinant Proteins; Ribavirin; Time Factors; Viral Load

Propylthiouracil (PTU) is an antithyroid drug which is known to cause drug-induced vasculitis. PTU is implicated in 80-90% of cases of anti-neutrophil cytoplasm circulating antibody (ANCA)-associated vasculitis caused by anti-thyroid drugs which induce ANCA production. Sweet's syndrome is characterized by fever, leucocytosis, neutrophilia and the sudden onset of painful skin lesions. The pathology of the disease is still unclear. Cytokine dysregulation including interleukin-6 and endogenous granulocyte colony-stimulating factor (G-CSF) are thought to play a role in the pathogenesis of Sweet's syndrome. PTU and G-CSF are known to cause Sweet's syndrome and other neutrophilic dermatosis. The presence of ANCA can have a diagnostic value in Sweet's syndrome. Systemic corticosteroids are the first-line therapy for both diseases. Here we report a female patient with Graves' disease who developed ANCA and Sweet's syndrome after using PTU and G-CSF.

Topics: Adult; Agranulocytosis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Female; Granulocyte Colony-Stimulating Factor; Graves Disease; Humans; Neutropenia; Propylthiouracil; Skin; Sweet Syndrome; Thyroid Gland

Hyperthyroidism is mainly caused by Graves' disease and toxic adenoma or multinodular goiter. In Europe, treatment of both disorders is usually started with antithyroidal drugs such as methimazole. Complications include agranulocytosis and the risk is dose-dependent. The starting dose of methimazole should not exceed 15-20 mg/d. Propylthiouracil can cause severe liver failure, leading to liver transplantation or death. Propylthiouracil, therefore, should not be used as first line agent and is only recommended when an antithyroid drug is to be started during the first trimester of pregnancy or in individuals who have experienced adverse responses to methimazole. Toxic adenoma is finally treated with radioioidine. To reduce the risk of treatment failure, antithyroidal drugs should be stopped at least one week prior to radioiodine. For Graves' disease, remission is unlikely if antibodies against the TSH-receptor remain above 10 mU/l after 6 months of antithyroidal treatment and radioiodine or thyroidectomy can be recommended. Thyroidectomy should be performed as (near) total thyreoidectomy.

Topics: Adenoma; Agranulocytosis; Antithyroid Agents; Female; Goiter, Nodular; Graves Disease; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Neoplasms; Thyroidectomy

Thionamide-induced agranulocytosis in pregnancy is a rare event that poses unique therapeutic challenges.. A 37-year-old woman developed agranulocytosis while taking propylthiouracil in the third trimester. After she took broad-spectrum antibiotics and discontinued propylthiouracil, her neutrophil counts recovered. She was initially managed expectantly but later underwent an uncomplicated total thyroidectomy at 35 weeks of gestation because of patient choice coupled with worsening thyrotoxicosis.. In circumstances in which thionamides are contraindicated, management options of hyperthyroidism in pregnancy are limited. The proximity to term in the third trimester makes expectant management an attractive approach when maternal thyroid indices are stable, allowing for a choice of postpartum therapies without the worry of fetal implications. However, this strategy carries risks, and thyroidectomy in the third trimester can be a safe alternative.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Female; Graves Disease; Humans; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, Third; Propylthiouracil; Thyroidectomy

Topics: Adult; Agranulocytosis; Antibodies, Antineutrophil Cytoplasmic; Bone Marrow Diseases; Female; Graves Disease; Humans; Plasma Cells; Propylthiouracil; Vasculitis

Topics: Agranulocytosis; Animals; Anura; History, 20th Century; Humans; Hyperthyroidism; Iodine; Larva; Physical Examination; Propylthiouracil; Receptors, Thyrotropin; Thyroid Diseases

Thionamide induced agranulocytosis is associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) in some patients. This poses a particular challenge when it occurs during pregnancy.. To report a case of a 31-year-old woman with Graves' disease who presented at 11 weeks gestation with propylthiouracil induced agranulocytosis.. After cessation of propylthiouracil the patient developed recurrent thyrotoxicosis, and underwent an elective subtotal thyroidectomy at 23 weeks gestation.. The patient required postoperative thyroxine replacement therapy. Subsequent pregnancy was uneventful and she delivered a healthy baby boy at 41 weeks gestation. As part of our routine work up for agranulocytosis we measured C-ANCA levels, which were significantly elevated.. This case highlights the association of propylthiouracil induced ANCA positivity and agranulocytosis. Second trimester subtotal thyroidectomy was safe and effective in treating this pregnant patient's thyrotoxicosis.

Topics: Adult; Agranulocytosis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Graves Disease; Humans; Pregnancy; Pregnancy Complications; Propylthiouracil; Term Birth; Thyroidectomy; Thyrotoxicosis

Relapse and exacerbation of Graves' disease during pregnancy is rare, and thionamide induced agranulocytosis is an uncommon side effect. We report a case of a pregnant woman in her 24th week of gestation that experienced a relapse of Graves' disease that was complicated by propylthiouracil induced agranulocytosis. Following the discontinuation of propylthiouracil and administration of a broad-spectrum of antibiotics, agranulocytosis subsided within 10 days. A total thyroidectomy to avoid any future relapse was planned and a short course of a beta-adrenergic blocker and Lugol solution were prescribed before the operation. At the 28th week of gestation, a total thyroidectomy was performed without complications and thyroxine replacement therapy was commenced. At the 40th week of gestation, labor was induced and a 3,370 g healthy male infant was born without clinical features of thyrotoxicosis. We report herein on the patient and the treatment options for this rare and complicated case.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Female; Graves Disease; Humans; Pregnancy; Pregnancy Complications; Propylthiouracil; Recurrence; Thyroidectomy

Plasmapheresis, also known as therapeutic plasma exchange, is used in the treatment of several disorders. Temporary improvement after plasmapheresis in cases with thyrotoxicosis has been reported. A 55-year-old woman presented with agranulocytosis induced by propylthiouracil and clinical signs of heart failure. Three sessions of plasmapheresis were performed. We observed an improvement of thyroid hormone levels and clinical findings as well. Plasmapheresis can be an option when drug treatment of thyrotoxicosis fails.

Topics: Agranulocytosis; Antithyroid Agents; Female; Humans; Hyperthyroidism; Middle Aged; Plasmapheresis; Propylthiouracil

To determine the frequency and spectrum of serious adverse drug reactions (ADRs) to thionamide antithyroid drugs.. Data spontaneously reported to the UK-wide pharmacovigilance agency, The Committee on Safety of Medicines (Yellow Card Scheme), between 1963 and 2003 were analysed to determine the spectrum and relative frequency of ADRs to carbimazole and propylthiouracil. Representative data on the number of dispensed prescriptions were available from 1981, and were used as a denominator to estimate relative reporting rates of ADRs attributed to the drugs.. Between 1981 and 2003 there were 5.23 million prescriptions for thionamide drugs in England and Scotland, 94% of which were for carbimazole. Neutrophil dyscrasia (agranulocytosis and neutropenia) accounted for 49% of all fatalities attributed to these medications. The median time reported for the appearance of neutrophil dyscrasia was 30 days of treatment, but there was a wide range (7-875 days). Neutrophil dyscrasia was more frequently fatal in subjects over 65 years of age; 13.8%vs. 1.2% of fatal reports in younger subjects [odds ratio (OR) 12.90; 5-95% confidence intervals (CI) 1.45-114.92]. Since 1981, reports of most ADRs, including neutrophil dyscrasia, were made significantly more frequently per propylthiouracil prescription dispensed than per carbimazole prescription.. Detailed data about ADRs to these compounds, and their patient demography, based on a large number of reports are described. Neutrophil dyscrasia is the commonest life-threatening ADR to thionamides. The excess of ADR reports for propylthiouracil compared to carbimazole could reflect genuine differences in toxicity between the compounds, the relative unfamiliarity of UK physicians with propylthiouracil, or the higher use of propylthiouracil in certain patient groups.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Agranulocytosis; Antithyroid Agents; Carbimazole; Humans; Middle Aged; Neutropenia; Propylthiouracil; United Kingdom

In this study, we retrospectively analyzed 18 patients in whom antithyroid drug (ATD)-induced agranulocytosis developed during treatment of Graves' disease. All patients were more than 20 years of age, and we saw no correlation between age and the development of agranulocytosis. In 17 of 18 patients, ATD-induced agranulocytosis developed within 2 to 12 weeks of starting ATD treatment. Development of agranulocytosis was related to the dose of ATD. In some patients, agranulocytosis developed abruptly, and even weekly routine WBC and granulocyte counts failed to predict all case occurrences. Fever and sore throat were the earliest symptoms of agranulocytosis; patients who developed either of these symptoms were closely monitored immediately with WBC and granulocyte count examinations. In this series of patients, treatment with granulocyte-macrophage colony stimulating factor (GM-CSF) increased the granulocyte counts, whereas the effectiveness of glucocorticoid treatment was not confirmed.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Female; Glucocorticoids; Granulocyte-Macrophage Colony-Stimulating Factor; Graves Disease; Humans; Leukocyte Count; Male; Methimazole; Middle Aged; Propylthiouracil; Retrospective Studies

Topics: Agranulocytosis; Antithyroid Agents; Aspergillosis; Carbimazole; Humans; Lung Diseases, Fungal; Propylthiouracil

Topics: Aged; Agranulocytosis; Antithyroid Agents; Aspergillosis; Carbimazole; Fatal Outcome; Female; Humans; Lung Diseases, Fungal; New Zealand; Propylthiouracil; Risk Factors

The use of propylthiouracil (PTU) for the treatment of Graves' disease is associated with few adverse effects such as skin eruptions, liver dysfunction, and agranulocytosis. Furthermore, recent studies described the development of antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis and vasculitis in patients treated with PTU. Here we investigated whether PTU therapy per se is associated with the appearance of ANCA in patients with Graves' disease. We analyzed 119 serum samples from 117 patients with Graves' disease treated with either PTU (n = 56), or methimazole (MMI) (n = 21), as well as untreated patients (n = 42). Myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were tested by enzyme-linked immunosorbent assay (ELISA) kits. MPO-ANCA was negative in all patients treated with MMI therapy and untreated patients. However, MPO-ANCA was detected in 21 (37.5%) of 56 patients treated with PTU therapy. Furthermore, two patients who were negative for MPO-ANCA became positive after PTU therapy. The proportion of patients positive for MPO-ANCA increased with the prolongation of PTU therapy, but did not correlate with age, gender, and positive antithyroperoxidase (TPO) antibody. Among 21 MPO-ANCA positive patients, 12 had no symptoms, but 9 patients complained of myalgia, arthralgia, or common cold like symptoms after the appearance of MPO-ANCA. Three patients developed agranulocytosis or granulocytopenia, but none showed abnormal urinary findings. Our results suggest that PTU per se is associated with the production of MPO-ANCA in patients with Graves' disease.

Topics: Adult; Aged; Agranulocytosis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoantibodies; Female; Graves Disease; Humans; Iodide Peroxidase; Male; Middle Aged; Myeloblastin; Peroxidase; Propylthiouracil; Serine Endopeptidases

To analyse the routine WBC count's effect on predicting antithyroid drugs-induced agranulocytosis developing and risk factors of antithyroid drugs-induced agranulocytosis.. Retrospective analysis of 18 Graves' cases with agranulocytosis induced by antithyroid drugs during 1984-1995.. Most of antithyroid drugs-induced agranulocytosis happens 2-12 weeks after the administration of antithyroid drug, and are related with the drug's doses. Some agranulocytosis happens abruptly, routine WBC and granulocyte count can not predict some agranulocytosis developing. Fever and throat sore are the intitial symptoms of agranulocytosis, if it happens, the WBC and granulocyte count must be checked immediately. The treatment of granulocyte-macrophage colony stimulating factor is effective, the corticosteroid therapy seems not to be useful for the recovery of granulocyte count.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Female; Graves Disease; Humans; Male; Methimazole; Middle Aged; Propylthiouracil; Retrospective Studies

This prospective study was designed to investigate the usefulness of granulocyte count measurements 4 hours after injection of granulocyte colony-stimulating factor (G-CSF) for detecting recovery from antithyroid drug (ATD)-induced granulocytopenia or agranulocytosis. Granulocyte and white blood cell counts were measured 4 hours and 24 hours after patients with ATD-induced granulocytopenia had been given an injection of 75 micrograms of G-CSF (1.1 to 1.9 micrograms/kg; 1.5 +/- 0.2 micrograms/kg [mean +/- standard deviation]). Thirty-seven patients were studied and divided into three groups based on their initial granulocytopenic granulocyte count: 28 with mild (granulocyte count 0.501 to 1.0 x 10(9)/L), 6 with moderate (granulocyte count 0.101 to 0.5 x 10(9)/L), and 3 with severe (granulocyte count less than 0.1 x 10(9)/L) ATD-induced granulocytopenia. Twenty-five of the 28 patients with mild granulocytopenia and 4 of the 6 patients with moderate granulocytopenia were found to have recovered from the granulocytopenia both 4 hours and 24 hours after injection, and their granulocyte counts remained normal thereafter. However, the other 3 patients with mild granulocytopenia, 2 patients with moderate granulocytopenia, and all 3 patients with severe granulocytopenia had not recovered by either 4 or 24 hours after the G-CSF injection. Despite daily G-CSF injections, the granulocyte continued to decrease in most cases. It took 2 to 11 days for these counts to recover from granulocytopenia. These results indicate that granulocyte count measurement 4 hours after injection of G-CSF is useful for detecting recovery from ATD-induced granulocytopenia or agranulocytosis and for predicting disease severity. Accordingly, its measurement enables physicians to make an appropriate decision about whether a patient with ATD-induced granulocytopenia should be treated in the hospital or in the outpatient clinic.

Topics: Adolescent; Adult; Agranulocytosis; Antithyroid Agents; Female; Granulocyte Colony-Stimulating Factor; Granulocytes; Graves Disease; Humans; Kinetics; Leukocyte Count; Male; Methimazole; Middle Aged; Propylthiouracil; Prospective Studies

We report here a patient with recurrent Graves' disease on hemodialysis. She also suffered from angina pectoris, which was probably a manifestation of Graves' disease due to the increased oxygen demands in the presence of fixed coronary lesions. Although antithyroid drugs induced mild granulocytopenia, propylthiouracil (PTU) or methimazole (MMI) was not discontinued during the administration of granulocyte colony-stimulating factor (G-CSF). The patient received sodium iodine-131 therapy, and became euthyroid with no chest pain. To our knowledge, this is the first case that illustrated the usefulness of G-CSF for antithyroid drug-induced granulocytopenia prior to thyroid ablation for Graves' disease complicated with chronic renal failure and angina pectoris.

Topics: Agranulocytosis; Angina Pectoris; Antithyroid Agents; Female; Granulocyte Colony-Stimulating Factor; Graves Disease; Humans; Iodine Radioisotopes; Kidney Failure, Chronic; Methimazole; Middle Aged; Propylthiouracil; Renal Dialysis

Topics: Aged; Agranulocytosis; Bone Marrow; Heart Failure; Humans; Hyperthyroidism; Leukocyte Count; Male; Propylthiouracil

Two premenopausal female patients with Graves' hyperthyroidism and propylthiouracil (PTU)-induced agranulocytosis are presented. The first patient, age 47, received 300 mg of PTU per day and developed agranulocytosis within 6 weeks of the commencement of therapy. There were no granulocytes in the peripheral smear and a bone marrow biopsy demonstrated an absence of the entire myeloid cell line as well as the presence of many granulomas. The second patient, age 39, received PTU 1600 mg per day for two and half weeks and then 2 days of methimazole, 200 mg per day. She developed complete agranulocytosis on peripheral smear within 3 weeks of the initiation of therapy. Her bone marrow biopsy demonstrated maturation arrest of the granulocytic cell line at the myelocyte stage. In addition to discontinuing their antithyroid drugs, both patients were treated with G-CSF subcutaneously. The first patient received 300 micrograms of G-CSF on days 2 and 4 after discontinuing PTU with the appearance of 4.7 x 10(9)/L granulocytes and granulocyte precursors on day 4. The second patient received 575 micrograms of G-CSF for 2 days and 300 micrograms for 1 additional day beginning on the third day after discontinuing antithyroid drugs. On the second treatment day there were 5.8 x 10(9)/L granulocytes and granulocyte precursors on the peripheral smear. A comparison to previously published cases on antithyroid drug induced agranulocytosis suggests that the use of G-CSF decreased the amount of time required for marrow recovery after the cessation of the offending drug.

Topics: Adult; Agranulocytosis; Bone Marrow; Female; Granulocyte Colony-Stimulating Factor; Granulocytes; Graves Disease; Hematopoietic Stem Cells; Humans; Middle Aged; Propylthiouracil; Recombinant Proteins

The primary objective of this study was to ascertain the effectiveness of granulocyte colony-stimulating factor in the treatment of antithyroid drug-induced granulocytopenia of varying degree. Sixteen patients with Graves' disease with antithyroid drug-induced granulocytopenia (granulocyte counts < 1.0 x 10(9)/L) each received a daily dose of 75 micrograms of granulocyte colony-stimulating factor administered subcutaneously. Within 24 hours of the first injection, the granulocyte count increased (0.6 to 12.3 x 10(9)/L) in all 10 patients with mild granulocytopenia (granulocyte counts between 0.5 and 1.0 x 10(9)/L) and all three with moderate granulocytopenia (granulocyte counts < 0.5 x 10(9)/L). The three remaining patients with severe granulocytopenia (agranulocytic), whose granulocyte counts were zero, did not recover from granulocytopenia until the 6th, 7th, and 14th days of treatment with granulocyte colony-stimulating factor. Examination of bone marrow taken at the onset of the disease in all three agranulocytic patients showed a prominent decrease in granulocytic series, while identical examination in six of eight patients with mild to moderate granulocytopenia showed close to normal granulocytic series. There was no elevation of serum granulocyte colony-stimulating factor concentration in four patients with mild granulocytopenia and one with moderate granulocytopenia at the onset of their disease, whereas those of the remaining three patients with severe granulocytopenia (agranulocytic) increased at onset of agranulocytosis. This information led us to conclude that: (1) granulocyte colony-stimulating factor is effective in the treatment of antithyroid drug-induced mild to moderate granulocytopenia and (2) in severe agranulocytic cases, granulocyte colony-stimulating factor is not effective. Accordingly, we were again reminded of the importance of early diagnosis and treatment of antithyroid drug-induced agranulocytosis.

Topics: Adult; Aged; Agranulocytosis; Female; Granulocyte Colony-Stimulating Factor; Graves Disease; Humans; Male; Methimazole; Middle Aged; Propylthiouracil; Recombinant Proteins

Aiming to know the incidence and evolution of major adverse reactions to propylthiouracil in patients with hyperthyroidism, we performed a retrospective analysis of 586 patients treated between 1982 and 1992. All known complications associated to the use of propylthiouracil were considered major adverse reactions, when other causes were discarded. Eight patients (1.4% of the sample) had major adverse reactions: three had agranulocytosis, 3 hepatitis, 1 cholestasis and 1 vasculitis. All had a good evolution after discontinuing the drug. The patients with agranulocytosis were treated with antibiotics and the patient with cholestasis received prednisone. We conclude that major adverse reactions to propylthiouracil are infrequent, that they occur preferentially during the first months of treatment, earlier after reexposure and that there was no associated mortality.

Topics: Adolescent; Adult; Agranulocytosis; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Hyperthyroidism; Male; Middle Aged; Propylthiouracil; Retrospective Studies; Vasculitis

Topics: Adult; Agranulocytosis; Graves Disease; Humans; Liver; Methimazole; Propylthiouracil

Topics: Aged; Agranulocytosis; Female; Humans; Middle Aged; Propylthiouracil; Recurrence; Thyrotoxicosis

Topics: Agranulocytosis; Antithyroid Agents; Depression, Chemical; Female; Graves Disease; Humans; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Tablets; Thyroid Hormones

This study was aimed at establishing the importance of routine monitoring of white blood cell counts in patients with Graves' disease receiving antithyroid drug treatment. In the 12-year period from 1975 to 1987, 15,398 patients with Graves' disease receiving treatment with antithyroid drugs were seen at our clinic. Of these, 55 (0.4%) were found to have agranulocytosis. Agranulocytosis was defined as a granulocyte count of 0.5 x 10(9)/L or less. In only 12 of the 55 patients was agranulocytosis detected after the occurrence of infection (symptomatic; classic agranulocytosis). The remaining 43 patients were asymptomatic when agranulocytosis was detected during routine white blood cell count monitoring. However, 14 of these 43 patients became symptomatic several days after withdrawal of antithyroid drug treatment despite antimicrobial treatment (asymptomatic to symptomatic). Twenty-nine patients who were treated appropriately had no symptom of infection throughout the course of the disease, despite the absence of or an extremely small number of granulocytes in circulation (asymptomatic). These results suggest that a "routine monitoring" of the white blood cell count could be the most effective way of predicting and detecting agranulocytosis due to antithyroid drug treatment.

Topics: Adult; Agranulocytosis; Female; Granulocytes; Graves Disease; Humans; Leukocyte Count; Male; Methimazole; Propylthiouracil

The authors studied 389 Graves' hyperthyroid patients receiving either high propylthiouracil (PTU) or methimazole (MMI) daily doses or low doses to evaluate whether adverse effects were related to the thionamide drugs or its daily dose regimen. Group 1 patients (n = 286) received high PTU (728 +/- 216 mg/day, n = 92) or MMI (60 +/- 19 mg/day, n = 94) doses, and group 2 patients (n = 103) were treated with low PTU (255 +/- 85 mg/day, n = 39) or MMI (23 +/- 10 mg/day, n = 64) doses. Major adverse effects were observed in 11 (2.8%) patients. Of these, four (1.0%) had agranulocytosis, two (0.5%) were granulocytopenic and five (1.3%) had hepatotoxicity. Agranulocytosis occurred in two patients from each group, 0.7% and 1.9%, respectively from group 1 and group 2. There was no significant difference between the groups or the types of thionamide. There also was no correlation with the patients' age. All of the patients were hyperthyroid, and its onset occurred in the first to third month of treatment. Full recovery was achieved in all cases after drug withdrawal. Four of 5 patients with hepatotoxicity were treated with high PTU doses, and one patient received low MMI doses (p less than .05). All patients were euthyroid. Arthralgias, skin rash and gastric intolerance, the minor adverse effects of thionamides studied, were observed in 52 (13.4%) of the patients. Although no significant differences were found, most of the patients experiencing side effects were from group 1 an received MMI therapy. These adverse effects did not demand drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Agranulocytosis; Chemical and Drug Induced Liver Injury; Child; Dose-Response Relationship, Drug; Drug Eruptions; Graves Disease; Humans; Hyperthyroidism; Joints; Methimazole; Middle Aged; Pain; Propylthiouracil; Stomach Diseases

Agranulocytosis is an infrequent but potentially fatal complication of anti-thyroid drugs. There is little information regarding the use of a second anti-thyroid drug when initial therapy results in agranulocytosis. This report summarises a case of recurrent agranulocytosis following the consecutive administration of carbimazole and propylthiouracil.

Topics: Agranulocytosis; Carbimazole; Female; Humans; Middle Aged; Propylthiouracil; Recurrence

The mechanism for agranulocytosis induced by antithyroid drugs is not established. The few available studies have proposed an immune-mediated process against mature granulocytes. We investigated the effect of methimazole and propylthiouracil and serum from a patient with methimazole-induced agranulocytosis on marrow myeloid colony growth. In the presence of normal serum or patient's recovery serum, antithyroid drugs had no effect on the growth of CFU-GM colonies from normal or patient's marrow. However, the patient's serum obtained during agranulocytosis inhibited the in vitro myeloid colony growth from both autologous and allogeneic bone marrow. These results are compatible with an immune-mediated mechanism for methimazole-induced agranulocytosis rather than a direct toxic effect of the drug on abnormally sensitive cells.

Topics: Adult; Agranulocytosis; Bone Marrow; Colony-Forming Units Assay; Female; Graves Disease; Humans; Methimazole; Propylthiouracil; Stem Cells

A patient with agranulocytosis and myeloid marrow hypoplasia following a second exposure to propylthiouracil (PTU) was studied for antibodies against mature blood cells and bone marrow precursor cells. During the acute phase of the agranulocytosis, significant growth inhibition of the myeloid committed progenitor cells (CFU-GM) was found following incubation with complement, indicating the presence of in-vivo cell bound cytotoxic antibodies. Using immunofluorescence and complement dependent cytotoxicity techniques it was demonstrated that acute phase and recovery phase sera contained circulating antibodies, reactive not only with differentiated granulocytes and monocytes but also with myeloid and erythroid (BFU-E/CFU-E) progenitor cells. Complement dependent lysis of the progenitor cells was facilitated by preincubation with PTU. These results indicate that the agranulocytosis was mediated by a PTU dependent antibody that affected both mature blood cells and bone precursor cells.

Topics: Aged; Agranulocytosis; Antibodies; Bone Marrow; Cell Separation; Complement System Proteins; Cytotoxicity, Immunologic; Female; Flow Cytometry; Granulocytes; Hematopoietic Stem Cells; Humans; Monocytes; Propylthiouracil

A 38-year-old man with Graves' disease taking propylthiouracil (PTU) for 6 years developed neutropenia and marked splenomegaly. After subtotal thyroidectomy with discontinuance of PTU the patient remained asymptomatic for the last two and half years. The serum obtained during the period of neutropenia demonstrated opsonic activity to neutrophils of the patient as well as of normal volunteers. This opsonic antineutrophil activity was located in the IgG fraction of the serum. Furthermore, PTU at the concentration (0.1-1.0 micrograms/ml) attainable in the patient's serum significantly stimulated [3H] thymidine incorporation in the patient's lymphocytes. These findings indicate that the patient developed autoimmune neutropenia by producing opsonic antineutrophil antibodies in association with the PTU therapy.

Topics: Adult; Agranulocytosis; Autoantibodies; Autoimmune Diseases; Graves Disease; Humans; Lymphocytes; Male; Neutropenia; Neutrophils; Propylthiouracil; Splenomegaly; Thyroidectomy

We review the cases of hepatic injury from propylthiouracil, methimazole and carbimazole in the English language literature and compare them to cases of agranulocytosis in a recent review. The data on hepatotoxicity confirm the findings for agranulocytosis that low-dose methimazole is safer than propylthiouracil and that methimazole toxicity is more common over 40 years old. In contrast, propylthiouracil hepatotoxicity often occurs in younger patients. Most cases of hepatic injury occur in the first few months of drug therapy as with agranulocytosis. The reason that methimazole typically causes cholestatic hepatitis while propylthiouracil causes cytotoxic hepatitis remains unknown.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Carbimazole; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Male; Methimazole; Middle Aged; Propylthiouracil

Studies of in vitro immunoreactivity to propylthiouracil (PTU), methimazole (MMI), and carbimazole (CARB), as assessed by peripheral blood lymphocyte transformation and 2 antibody tests, were carried out in 12 patients with Graves' hyperthyroidism who had developed agranulocytosis during treatment with PTU (11 patients) or CARB (1 patient) from 1 week to 10 yr earlier. Significant lymphocyte transformation responses to antithyroid drugs (stimulation indices greater than mean +/- 2 SD for normal subjects) were found in 5 of 6 patients tested, in 1 patient to PTU only, in 3 patients to MMI only, and in 1 patient to both PTU and MMI, but in none of 10 patients currently being treated with PTU who did not develop agranulocytosis. Circulating antibodies causing neutrophil agglutination in the presence of antithyroid drugs were demonstrated, using the indirect Coombs test, in 5 of 7 patients tested, in 2 patients to PTU only, in 3 patients to CARB only and in 1 patient (the only one tested with MMI) to PTU and MMI. Lymphocyte transformation and antibody tests to PTU were both carried out in 6 patients. Of these, both tests were positive in one patient, both negative in 3 patients, and 1 negative and 1 positive in 2 patients. In the 1 patient in whom both tests were carried out with CARB (patient 3), tests were negative, whereas in the 1 patient in whom both tests were carried out with MMI (patient 3), 1 test was positive, whereas the other was negative. Thus, in patients in whom both tests were carried out using the same drug, correlation between lymphocyte transformation responses and the detection of neutrophil antibodies was found in 5 of 6 cases. Antibodies reactive with neutrophils were also detected in 2 of the 5 patients tested using an enzyme-linked immunosorbent assay. In this test antibodies to PTU or MMI were not demonstrated. Possible mechanisms for the neutrophil depression in relation to these findings are discussed. It is concluded that patients with Graves' disease may be prone to develop this complication of antithyroid drug therapy because of underlying immunological abnormalities.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antithyroid Agents; Autoantibodies; Carbimazole; Female; Graves Disease; Humans; In Vitro Techniques; Lymphocyte Activation; Male; Methimazole; Middle Aged; Neutrophils; Propylthiouracil

Agranulocytosis developed in a patient who was receiving propylthiouracil. Using a microgranulocytotoxicity assay, serum taken from the patient was shown to be strongly granulocytotoxic when tested against the patients granulocytes and those obtained from two of eight normal subjects. Tests for granulocyte agglutinins and for lymphocytotoxicity were negative. Granulocytotoxic activity decreased as the patient's peripheral granulocyte count recovered. Cytotoxicity was shown to be mediated by a complement-dependent IgM antibody.

Topics: Adult; Agranulocytosis; Antibodies; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Epitopes; Female; Granulocytes; Humans; Immunoglobulin M; Leukocyte Count; Propylthiouracil

Topics: Adult; Agranulocytosis; Autoimmune Diseases; Graves Disease; Humans; Lupus Erythematosus, Systemic; Male; Neutropenia; Propylthiouracil; Splenomegaly

The records of all patients with antithyroid drug-related agranulocytosis at two Boston hospitals (Group 1, 14 patients), as well as the published case reports of 36 patients with this syndrome (Group 2) were reviewed. The clinical characteristics of these patients were then compared with those of 50 hyperthyroid patients who had taken antithyroid medication without untoward hematologic reactions (Group 3). The mean ages of patients in Group 1 and Group 2 were significantly greater than that of Group 3 (50.6 +/- 16 years versus 35.7 +/- 13.7 years, p less than 0.001; 46.3 +/- 18.7 years versus 35.7 +/-- 13.7 years, p less than 0.02). By chi-square analysis, the relative risk of developing agranulocytosis in patients over age 40 was 6.4 times that among younger patients (p less than 0.001). The mean doses of methimazole in Group 1 and Group 2 were significantly higher than that in Group 3 (43.8 +/- 9.9 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.001; 40.7 +/- 15.7 mg/d versus 29.5 +/- 10.4 mg/d, p less than 0.02), with and 8.6-fold increased risk of agranulocytosis with doses greater than 40 mg/d (p less than 0.01). In contrast, the mean doses of propylthiouracil did not differ among the three groups. These data suggest that antithyroid drugs should be administered cautiously to patients over age 40. Because no cases of agranulocytosis were seen with methimazole doses less than 30 mg/d, low-dose methimazole therapy may be safer than high-dose therapy or treatment with conventional doses of propylthiouracil.

Topics: Adolescent; Adult; Age Factors; Aged; Agranulocytosis; Female; Graves Disease; Humans; Male; Methimazole; Middle Aged; Propylthiouracil; Sex Factors

Observations in a patient with recurrent hyperthyroidism, each time associated with neutropenia which resolved after therapy, prompted a chart review of other patients referred for radioactive iodine therapy. Of 99 untreated patients, 18 had neutrophil counts of less than 2,000/cu mm. After therapy with either thionamides or 131I, 41 of 53 (77%) evaluable patients had an increase in neutrophil count. Eleven of these evaluable patients had neutropenia before therapy; after therapy, all 11 had an increase in their neutrophil counts into the normal range, with a mean increase of 170%. In one patient, studies on the mechanism of neutropenia indicate that bone marrow production and reserve remain normal and that circulating neutrophils are normally marginated. A decreased neutrophil circulation time may be the cause of neutropenia associated with hyperthyroidism.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Female; Humans; Hyperthyroidism; Iodine Radioisotopes; Leukocyte Count; Male; Middle Aged; Neutropenia; Neutrophils; Propylthiouracil; Retrospective Studies

A 45-year-old woman with thyrotoxicosis developed agranulocytosis after treatment with propylthiouracil. When the thyrotoxicosis recurred, accompanied by a severe psychotic reaction, administration of antithyroid medication was recommenced. The patient was given methimazole instead of propylthiouracil but, 10 weeks later, agranulocytosis again occurred. This is, to the best of our knowledge, the first report of a case in which agranulocytosis followed treatment with both propylthiouracil and methimazole in the same patient.

Topics: Agranulocytosis; Female; Humans; Hyperthyroidism; Methimazole; Middle Aged; Propylthiouracil; Recurrence

Topics: Agranulocytosis; Drug Hypersensitivity; Female; Humans; Middle Aged; Plasmapheresis; Propylthiouracil; Vasculitis

The authors describe the case of a 49-year-old woman who developed a goiter, mild symptoms of hyperthyroidism, and grossly elevated thyroid function tests after 2 years of treatment with lithium carbonate. Thyroid microsomal autoantibodies were also present. She was retreated with propylthiouracil and improved, but within 3 months she developed agranulocytosis. Propylthiouracil was discontinued, and the patient was treated with antibiotics and recovered. She was then given 131I to control her hyperthyroidism. The case is an example of the rare association of hyperthyroidism with lithium, which usually suppresses thyroid function, and demonstrates that lithium carbonate cannot prevent agranulocytosis caused by propylthiouracil.

Topics: Agranulocytosis; Bipolar Disorder; Drug Therapy, Combination; Female; Humans; Hyperthyroidism; Lithium; Lithium Carbonate; Middle Aged; Propylthiouracil; Thyroid Hormones

Topics: Agranulocytosis; Chemical and Drug Induced Liver Injury; Humans; Middle Aged; Propylthiouracil

Topics: Adult; Agranulocytosis; Female; Humans; Hyperthyroidism; Hypocalcemia; Propylthiouracil

Propylthiouracil and methimazole are used widely in the treatment of hyperthyroid disorders. The most important complication of the use of these drugs is depression of the neutrophilic granulocyte count. Granulocytopenia occurs in about 4 percent and agranulocytosis occurs in about 0.3 percent of treated patients. Although this depression of the granulocyte count is reversible after the drug is discontinued, serious infection frequently accompanies agranulocytosis and accounts for almost all deaths related to the drugs. It is important to be aware of the clinical features of granulocytopenic reactions due to antithyroid drugs.

Topics: Agranulocytosis; Humans; Hypothyroidism; Methimazole; Propylthiouracil

A method has previously been described which detected xenogeneic and allogeneic antibodies to human granulocytes by their inhibition of the normal phagocytosis-associated hexose monophosphate shunt (HMS) activity. This method was used to study three patients with acute agranulocytosis secondary to antithyroid drug administration. Two patients with methimazole and one patient with propylthiouracil induced agranulocytosis were studied. Serum samples from each of these three patients taken during the acute phase of agranulocytosis had inhibitory effects on phagocytosis-associated HMS activity in leukocytes from both normal donors and the patients after their full recovery from agranulocytosis. IgM but not IgG prepared from acute sera in two patients was also inhibitory. Disruption of IgM disulfide bonds by dithiothreitol destroyed its inhibitory activity. The possibility of drug-dependent immune destruction of leukocytes in these patients is discussed.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Drug Hypersensitivity; Female; Granulocytes; Graves Disease; Humans; Immunoglobulin M; Leukopenia; Methimazole; Phagocytosis; Propylthiouracil; Remission, Spontaneous

Topics: Adult; Agranulocytosis; Female; Humans; Male; Methimazole; Propylthiouracil

Topics: Agranulocytosis; Anemia, Hemolytic; Child; Female; Humans; Hyperthyroidism; Propylthiouracil

Topics: Acetaminophen; Adult; Aged; Agranulocytosis; Animals; Blood Transfusion; Carbon Dioxide; Carbon Radioisotopes; Felty Syndrome; Female; Glucose; Humans; Immunoglobulin G; In Vitro Techniques; Isoantibodies; Leukocytes; Methyldopa; Polystyrenes; Prednisone; Primidone; Propylthiouracil; Rabbits

Topics: Adolescent; Agranulocytosis; Alkaline Phosphatase; Bone Resorption; Calcium; Drug Eruptions; Female; Humans; Hypercalcemia; Hyperthyroidism; Iodine Isotopes; Phosphorus; Propylthiouracil; Serum Albumin; Thyroid Hormones; Thyroidectomy; Thyrotropin; Vitamin D

Topics: Adolescent; Agranulocytosis; Child; Child, Preschool; Drug Hypersensitivity; Female; Fever; Humans; Hyperthyroidism; Kidney Glomerulus; Leukocyte Count; Leukopenia; Lupus Erythematosus, Systemic; Male; Propylthiouracil; Urticaria

Topics: Agranulocytosis; Aminopyrine; Chloramphenicol; Chlorpromazine; Diuretics; Humans; Organomercury Compounds; Propylthiouracil; Quinolines; Sulfanilamide; Sulfanilamides; Sulfonamides; Toxicology

Topics: Adolescent; Agranulocytosis; Basal Metabolism; Black People; Humans; Hyperthyroidism; Imidazoles; Iodine Isotopes; Propylthiouracil; Thyroid Function Tests; Thyroidectomy; Thyrotoxicosis; Toxicology

Topics: Agranulocytosis; Heart Failure; Hyperthyroidism; Propylthiouracil; Thiouracil; Thyrotoxicosis

Topics: Agranulocytosis; Propylthiouracil; Thiouracil

Topics: Agranulocytosis; Chemical and Drug Induced Liver Injury; Death; Humans; Hyperthyroidism; Propylthiouracil; Thiouracil

Topics: Agranulocytosis; Goiter; Graves Disease; Humans; Propylthiouracil; Thiouracil; Thyrotoxicosis

Topics: Agranulocytosis; Humans; Propylthiouracil; Thiourea

Topics: Agranulocytosis; Humans; Propylthiouracil

Topics: Agranulocytosis; BCG Vaccine; Biological Phenomena; Physiological Phenomena; Propylthiouracil; Thiouracil; Thiourea; Tuberculosis

Topics: Agranulocytosis; Propylthiouracil; Thiourea

Topics: Agranulocytosis; Humans; Jaundice; Liver Diseases; Porphyrias; Propylthiouracil