propylthiouracil and Neutropenia

Agranulocytosis is known to be a rare side effect of thionamides. This complication puts pregnant patients at particular risk for infections. Obstetricians caring for such patients have the difficult task of deciding between conservative or surgical management.. The patient is a 37-year-old gravida 4 para 3 Hispanic woman at 11 weeks of gestation with recently diagnosed hyperthyroidism who presented with a neutropenic fever and ecthyma as a complication of thionamide use. She subsequently underwent a thyroidectomy and then had a spontaneous abortion on postoperative day 2.. This patient had life-threatening thyrotoxicosis complicated by neutropenic fever and infection, likely caused by a reaction to thionamides. She quickly recovered with broad-spectrum antibiotics. She could not be restarted on methimazole or propylthiouracil as a result of agranulocytosis and thus underwent thyroidectomy.

Topics: Adrenergic beta-1 Receptor Antagonists; Adult; Antithyroid Agents; Atenolol; Drug Eruptions; Ecthyma; Female; Humans; Hyperthyroidism; Methimazole; Neutropenia; Pregnancy; Pregnancy Complications; Propylthiouracil; Staphylococcal Skin Infections; Staphylococcus aureus

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

Topics: Aged; Anti-Inflammatory Agents; Antithyroid Agents; Fatal Outcome; Female; Gangrene; Humans; Methylprednisolone; Neutropenia; Propylthiouracil; Skin

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

A 3 year old child with Graves' disease and mitral valve prolapse became neutropenic on carbimazole therapy. She was switched to propylthiouracil but the neutropenia recurred. She was treated with radioiodine but required two doses of 113 MBq and then 198 MBq five months later before becoming hypothyroid. The mitral valve prolapse resolved when she was euthyroid on thyroxine replacement. Antithyroid drugs, surgery, and radioiodine all have a place in the management of the thyrotoxic child.

Topics: Antithyroid Agents; Carbimazole; Child, Preschool; Echocardiography; Female; Graves Disease; Humans; Iodine Radioisotopes; Mitral Valve Prolapse; Neutropenia; Propylthiouracil; Thyrotoxicosis

Although antineutrophil antibodies are thought to be involved in drug-induced neutropenia, neither the precise mechanisms nor the particular antigens on the neutrophil surface have yet been clarified. Recently, we examined a patient with Graves' disease who developed antineutrophil cytoplasmic antibodies (ANCA) after propylthiouracil treatment and exhibited neutropenia. Because several target antigens of ANCA are expressed on the surface of neutrophils, it was suggested that ANCA might contribute to neutropenia. The patient's serum bound specifically to neutrophils and HL-60 cells differentiated into granulocytes, and lysed the HL-60 cells via a complement-mediated mechanism. Furthermore, two representative ANCA antigens, proteinase 3 and myeloperoxidase, significantly inhibited both the binding and cytotoxicity of the serum. Finally, tumour necrosis factor-alpha, which is known to up-regulate cell surface expression of several ANCA antigens, enhanced both the binding and cytotoxicity of the serum. These findings suggest that ANCA induced by propylthiouracil contributed to leucopenia through a complement-mediated mechanism.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoimmunity; Complement Activation; Cytotoxicity, Immunologic; Female; Granulocytes; Graves Disease; HL-60 Cells; Humans; Middle Aged; Neutropenia; Propylthiouracil

A 31-year-old woman presented with neutropenia due to thionamide drug therapy for Graves' disease. She also reported 8 weeks of amenorrhoea and had a positive pregnancy test. Her drug therapy was discontinued and her neutropenia resolved uneventfully. The hyperthyroidism recurred a week later. After consideration of all treatment options, it was decided to observe until 14 weeks when an elective thyroidectomy was planned. Mother and fetus were monitored closely and both tolerated moderate hyperthyroidism well. At 14 weeks the patient underwent a total thyroidectomy after rendering her euthyroid with a short course of sodium ipodate. Labour was induced at 41 weeks. Delivery was complicated by fetal distress and precipitated a forceps delivery. A 3250 g male infant was born with poor Apgar score and required 2 h of ventilation. At 1 year, the child had reached all developmental milestones at appropriate times. Both mother and fetus may tolerate moderate thyrotoxicosis well in early pregnancy, an alternative that should be considered when thionamide drug therapy is contraindicated.

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Infant, Newborn; Male; Neutropenia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Second; Propylthiouracil; Thyroidectomy

We describe two Caucasian women with the concurrence of Graves' disease and the moyamoya phenomenon (radiological evidence of collateral cerebral blood vessels like "puffs of smoke" due to cerebrovascular occlusive disease). One patient presented with acute cerebrovascular ischemia due to Moyamoya disease shortly after radioactive iodine therapy for Graves' disease and the second presented with Graves' disease 10 years after being diagnosed with moyamoya dysplastic cerebral vessels. The optimal treatment of hyperthyroidism in these patients is unknown; however, careful control of the hyperthyroidism by any modality seems reasonable. Our limited experience suggests that antithyroid drugs and radioactive iodine therapy are rational options. Thyroidectomy appears to be a safe therapeutic alternative, although long-term efficacy may be difficult to assure. Both of our patients had to be treated twice for hyperthyroidism. Whether Graves' disease and Moyamoya coexist because of an aggressive autoimmune mechanism is a concept that remains to be settled.

Topics: Adult; Female; Granulocyte Colony-Stimulating Factor; Graves Disease; Humans; Iodine Radioisotopes; Middle Aged; Moyamoya Disease; Neutropenia; Propylthiouracil; Thyroidectomy; Triiodothyronine

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

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

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