Presentación de un caso de agranulocitosis por propiltiouracilo / Presentation of a case of agranulocytosis caused by propylthiouracil

Se estudió una paciente de 33 años de edad con antecedentes patológicos de Bocio tiroideo difuso desde hace 8 años, que acude al cuerpo de guardia por presentar falta de aire, fiebre de 39-40 °C, dolor de garganta y palpitaciones hace alrededor de tres días. Al examen físico se le constató exoftalmos, mucosas hipocoloreadas y faringe purulenta y punteada de color blanquecina, artralgia y taquicardia. Referente a los exámenes complementarios presentó anemia, leucopenia y pancitopenia luego de haber consumido propiltiouracilo (50mg) por un período prolongado; por lo que se concluye como agranulocitosis como consecuencia de una reacción adversa al propiltiouracilo. Luego de ser tratada la paciente se recupera de su gravedad con el uso de factores estimulantes de colonias de granulocitos(AU)

A female 33-year-old patient with an 8-year history of diffuse thyroid goiter presents at the emergency service with shortness of breath, a 39-40ºC fever, a sore throat and palpitation of 3 days' evolution. Physical examination revealed exophthalmos, hypopigmented mucosas, a purulent pharynx dotted with whitish spots, arthralgia and tachycardia. Complementary tests found anemia, leukopenia and pancytopenia upon consumption of propylthiouracil (50 mg) for a long period. The diagnosis is agranulocytosis resulting from an adverse reaction to propylthiouracil. After being treated the patient recovered from her severe status with the use of granulocyte colony stimulating factors(AU)

Propylthiouracil-induced agranulocytosis as a rare complication of antithyroid drugs in a patient with Graves' disease

SUMMARY INTRODUCTION: 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. CASE: 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. DISCUSSION: 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. CONCLUSION: 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.

RESUMO INTRODUÇÃO: A doença de Graves (DG) é uma doença autoimune caracterizada por hipertireoidismo. As drogas antitireoidianas (DAT) são opções terapêuticas disponíveis. A agranulocitose é uma complicação rara, potencialmente fatal desta terapia. Neste estudo, relatamos um caso de agranulocitose induzida por propiltiouracil (PTU) em paciente com DG e as dificuldades do manejo clínico. RELATO DE CASO: RNBA, sexo masculino, 30 anos, com DG, tratado com PTU. Evoluiu com faringoamigdalite, sendo o PTU suspenso e antibióticos, filgrastim, propranolol e prednisona, iniciados. Devido à descompensação do hipertireoidismo, iniciou carbonato de lítio (CL), dexametasona e a solução de Lugol. A tireoidectomia total (TT) foi realizada com boa evolução pós-operatória. DISCUSSÃO: Descrevemos caso de paciente jovem, sexo masculino, com DG. Para o tratamento do hipertireoidismo, as tionamidas são opções efetivas. A agranulocitose induzida por DATs é uma complicação rara, definida como a ocorrência de contagem de granulócitos <500/mm3 após uso de dats. PTU foi suspenso e foram prescritos filgrastim e antibiótico. O radioiodo (RAI) ou a cirurgia são alternativas terapêuticas. Devido a problemas com o uso de DAT, a TT foi proposta. A preparação pré-operatória foi realizada com betabloqueador, glicocorticoide, CL e solução de Lugol. A colestiramina também é uma opção para controlar o hipertireoidismo. A TT foi realizada sem complicações pós-operatórias. CONCLUSÃO: A agranulocitose induzida por drogas antitireoidianas é uma complicação rara. Com a contraindicação às DATs, RAI e cirurgia são opções terapêuticas definitivas para DG. Os betabloqueadores, glicocorticoides, CL, iodo e a colestiramina podem ser uma terapia adjuvante para o hipertireoidismo.

Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis

To evaluate the association of either propylthiouracil or methimazole treatment for hyperthyroidism during pregnancy with congenital malformations, relevant studies were identified by searching Medline, PubMed, the Cochrane Library and EMBASE. We intended to include randomized controlled trials, but no such trials were identified. Thus, we included cohort studies and case-control studies in this meta-analysis. A total of 7 studies were included in the meta-analyses. The results revealed an increased risk of birth defects among the group of pregnant women with hyperthyroidism treated with methimazole compared with the control group (odds ratio 1.76, 95% confidence interval 1.47-2.10) or the non-exposed group (odds ratio 1.71, 95% confidence interval 1.39-2.10). A maternal shift between methimazole and propylthiouracil was associated with an increased odds ratio of birth defects (odds ratio 1.88, 95% confidence interval 1.27-2.77). An equal risk of birth defects was observed between the group of pregnant women with hyperthyroidism treated with propylthiouracil and the non-exposed group (odds ratio 1.18, 95% confidence interval 0.97-1.42). There was only a slight trend towards an increased risk of congenital malformations in infants whose mothers were treated with propylthiouracil compared with in infants whose mothers were healthy controls (odds ratio 1.29, 95% confidence interval 1.07-1.55). The children of women receiving methimazole treatment showed an increased risk of adverse fetal outcomes relative to those of mothers receiving propylthiouracil treatment. We found that propylthiouracil was a safer choice for treating pregnant women with hyperthyroidism according to the risk of birth defects but that a shift between methimazole and propylthiouracil failed to provide protection against birth defects. .

Plasmaférese pré-tireoidectomia em paciente com tireotoxicose e hepatotoxicidade por propiltiouracil: relato de caso / Plasmapheresis before thyroidectomy in a patient with thyrotoxicosis and hepatotoxicity by propylthiouracil: case report

A tireotoxicose é uma rara síndrome clínica decorrente da exacerbação do hipertireoidismo, de etiologia e fatores desencadeantes diversos. A abordagem terapêutica pode ser realizada por meio de medicamentos para bloqueio da síntese, secreção e/ou inibição da ação periférica hormonal, além de terapia dirigida aos fatores desencadeantes. Entretanto, em casos refratários, a plasmaférese surge como importante opção de tratamento. Relatamos o caso de um paciente com doença de Graves, internado com quadro de hepatotoxicidade grave por propiltiouracil, que evoluiu com tireotoxicose, sendo indicada plasmaférese para rápida redução dos hormônios tireoidianos, em preparo para a tireoidectomia total.

Thyrotoxicosis is a rare clinical syndrome resulting from an exacerbation of hyperthyroidism, with various etiology and triggering factors. Its approach may be accomplished by blocking the synthesis of hormones, their secretion and/or inhibition of their peripheral action, besides treating the triggering factors. However, in refractory cases, plasmapheresis appears as an important option for treatment. We report a patient with Graves' disease who was admitted with thyrotoxicosis and signs of severe hepatotoxicity induced by propylthiouracil. Plasmapheresis was indicated, with the aim of rapidly reducing thyroid hormones in the preparation for total thyroidectomy.

Autoinmunidad inducida por drogas: a propósito de un caso / Drug-induced auto-immunity: on account of a case

Se presenta el caso de una paciente de 35 años con antecedentes de enfermedad de Basedow-Graves, en tratamiento con propiltiouracilo (PTU), consumidora de pasta base y cocaína, que ingresa por fenómenos trombóticos en extremidades. Presenta en forma brusca falla respiratoria severa, que requiere manejo en UCI. Al laboratorio inmunológico destacan: ANA (+), AntiDNA (+), Anti-Ro (+), Anti-cardiolipinas IgG (+). Se realiza una revisión de las entidades autoinmunes más frecuentes asociadas al uso de drogas.

It presents the case of a 35-year old patient with a history of Basedow Graves disease, under treatment with Propiltiouracile (PTU), crack and cocaine user, who was admitted on thrombotic phenomena in her limbs. She presents sudden severe respiratory failure that requires handling at ICU. Under immunologic lab tests, the following stand out: ANA (+), Anti-DNA (+), Anti-Ro (+), Anti-cardiolipines IgG (+). A checkup is made of the most frequent auto-immune entities associated to drug abuse.

[Antithyroid drugs induced vasculitis]

The aim of this article is to review current information documented on antithyroid drug induced vasculitis. MEDLINE was searched for studies between 1960 and 2009 with the key words [antithyroid drugs and vasculitis], [antithyroid drugs and diffuse alveolar hemorrhage], and [antithyroid drugs and glomerolonephritis]. Ninety-two articles met the selection criteria. The data obtained showed that 15 to 46% of patients treated with propylthiouracil [PTU] developed anti-neutrophil cytoplasmic antibody [ANCA], in contrast to 0 to 3% of the patients treated with methimazole [MMI], the former being the most often reported for causing vasculitis, a disease seen most commonly in association with Graves' disease. Signs of PTU-induced vasculitis include fever, malaise, anemia, lymphadenopathy, skin lesions, arthralgia, hematuria/proteinuria, diffuse alveolar hemorrhage [DAH], pleural effusion, and crescentic glomerulonephritis. Once PTU-induced vasculitis is determined, the simple withdrawal of PTU usually causes resolution of the symptoms within 1-4 weeks. Overall prognosis of antithyroid drug-induced vasculitis is much better than that of primary vasculitis. Antithyroid medications such as PTU can induce [ANCA]-associated vasculitis. Its pathogenesis might be multifactorial. Diagnosis is based on the relationship between clinical vasculitis, and the antithyroid drugs prescribed, and the excluding of any other medical states that mimic vasculitis. After the diagnosis, antithyroid drugs should be discontinued immediately, and the prognosis is usually good

Vasculite necrotizante como manifestação de hipersensibilidade ao propiltiouracil / Necrotizing vasculitis as a manifestation of hypersensitivity to propylthiouracil

O propiltiouracil (PTU), droga empregada no tratamento do hipertireoidismo, pode provocar reações adversas em 3 por cento a 12 por cento dos pacientes, desde reações leves e frequentes, até quadros incomuns, graves e fatais. Relata-se o caso de um paciente de 14 anos de idade, em uso de PTU há três anos, que apresentou febre, bolhas hemorrágicas e úlceras necróticas, evoluindo com lesões purpúricas e nódulos violáceos em membros inferiores. A avaliação laboratorial e histológica mostrou-se compatível com vasculite cutânea leucocitoclástica, padrão encontrado nas vasculites por reação de hipersensibilidade. Após a retirada da droga antitireoidiana e a introdução de prednisona, houve regressão progressiva das lesões cutâneas. A importância deste estudo é alertar sobre a ocorrência desta grave manifestação cutâneo-sistêmica (vasculite), por droga de uso frequente em medicina interna, cuja taxa de mortalidade é de 10 por cento. É obrigatório o diagnóstico precoce, visando à retirada da droga suspeita, e, se necessário, ao uso de corticosteroides e/ou imunossupressores.

Propylthiouracil (PTU), a thyonamide class drug commonly used to treat hyperthyroidism has been reported to cause adverse reactions in 3 percent to 12 percent of patients. The side effects have been described more frequently as mild, but ocasionally severe fatal reactions may occur. We report the case of a fourteen years old patient in use of PTU for the last three years who presented with fever, hemorrhagic blisters, necrotic ulcers, and that developed purpuric lesions and nodules in lower extremities. Laboratory and histopathologic findings were compatible with skin leukocytoclastic vasculitis, a pattern found in hypersensitivity reaction vasculitis. Suspension of PTU and introduction of prednisone, induced complete remission of symptoms and healing of the skin lesions. The importance of this study is to call attention to the occurrence of serious cutaneous manifestation with a mortality rate that might reach 10 percent, associated with a systemic drug frequently used in internal medicine. Early diagnosis and withdrawal of the suspected medication is mandatory. Administration of corticosteroids and/or immunosuppressives agents must be considered.

Reacción idiosincrásica fatal al propiltiouracilo / Fatal idiosyncratic reaction to propylthiouracilo

Se presenta una paciente con hipertiroidismo por una enfermedad autoinmune del tiroides que luego de 2 semanas de tratamiento con propiltiouracilo comenzó a presentar un rash generalizado acompañado de fiebre que evolucionó rápidamente a una insuficiencia hepática aguda, fallo multiorgánico y muerte. Se demostró en la necropsia la necrosis masiva del hígado. Se revisaron las afectaciones hepáticas inducidas por reacción idiosincrásicas a medicamentos. Se recomienda instruir a los pacientes sobre posibles síntomas de hepatotoxicidad, indicar pruebas hepáticas periódicamente a los hipertiroideos tratados con antitiroideos y evitar el uso simultáneo de fenobarbital.

The case of a patient with hyperthyroidism due to an autoimmune disease of the thyroid glands that after two weeks of treatment with propylthiouracil presented a systemic rash accompanied with fever evolving quickly to an acute hepatic failure, multiorgan failure, and death, was presenetd. A massive liver necrosis was confirmed in the necropsy. The hepatic affectations induced by idiosyncratic drug reaction were reviewed. We suggest to instruct these patients on the possible symptoms of hepatotoxicity, to indicate periodical hepatic tests to hyperthyroid patients treated with antithyroid agents, and to avoid the simultaneous use of phenobarbital.

Auto-imunidade ANCA (Anticorpo Anti-Citoplasma de Neutrófilos) positiva induzida por propiltiouracil: relato de caso e revisão da literatura / Antineutrophil Cytoplasmic Antibody (Anca)-Associated autoimmune disease induced by propylthiouracil

A terapêutica com drogas antitireoidianas pode ser acompanhada de efeitos colaterais. Propiltiouracil (PTU) pode induzir vasculites anticorpo anti-citoplasma de neutrófilos (ANCA) positivas, na maioria das vezes relacionadas ao subtipo mieloperoxidase (ANCA-MPO). O nosso objetivo é relatar o caso de uma paciente com doença de Graves que desenvolveu auto-imunidade induzida por PTU, com manifestações cutâneas, pulmonares e renais, associadas à positividade do ANCA. O exame anátomo-patológico pulmonar revelou hemorragia difusa e a biópsia renal demonstrou glomeruloesclerose segmentar e focal. Foi tratada com pulsoterapia com corticóides e ciclofosfamida, com boa evolução clínica. Este caso enfatiza a necessidade de detecção e tratamento precoce deste efeito adverso relativamente raro do PTU.

Antithyroid drugs sometimes cause severe complications. Propylthiouracil (PTU) can be associated to ANCA positive vasculitis, most often related to myeloperoxidase subtype (ANCA-MPO). Our objective is to describe a female patient with Graves' disease, who developed PTU induced-autoimmune disease, with cutaneous, pulmonary, and renal lesions, associated with ANCA. Histopathological examination revealed diffuse pulmonary hemorrhage, and focal segmental glomerulosclerosis at the kidney biopsy. She was treated with systemic corticosteroid therapy and cyclophosphamide, with clinical improvement. This case highlights the need for greater awareness of this relatively rare adverse effect of propylthiouracil.

Vasculitis ANCA-positivo en pacientes hipertiroideos usuarios de propiltiouracilo: Report of four cases / Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis associated to the use of propylthiouracil

Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis is an uncommon complication of the use of propylthiouracil. When it occurs, it affects multiple organs as any systemic vasculitis. We report three females and one male, aged 30, 40, 43 and 41 years respectively, that after a lapse of 12 to 28 months of propylthiouracil use, presented clinical signs of vasculitis. All had high titers of ANCA against myeloperoxidase. In three patients, a skin biopsy confirmed the diagnosis. The condition subsided when propylthiouracil was discontinued, but one female patient required the use of prednisone.

Hemorragia alveolar difusa associada ao uso de propiltiouracil / Diffuse alveolar haemorrhage associated with propylthiouracil

Propiltiouracil pode causar um número de reações adversas, incluindo leucopenia, rash, febre e artrite; entretanto, complicações pulmonares são extremamente raras. Recentemente, o propiltiouracil tem sido descrito como causa de vasculite associada à presença de anticorpo anticitoplasma de neutrófilos (ANCA), resultando em hemorragia alveolar e síndrome pulmão-rim. Os autores apresentam o caso de uma mulher de 81 anos, que desenvolveu hemorragia alveolar e microhematúria,durante tratamento com propiltiouracil.

Diffuse Alveolar Hemorrhage Associated with Antineutrophil Cytoplasmic Antibody levels in a Pregnant Woman Taking Propylthiouracil

Propylthiouracil (PTU) is known to be a potential cause of antineutrophil cytoplasmic antibody (ANCA) positive small vessel vasculitis, resulting in glomerulonephritis and diffuse alveolar hemorrhage (DAH). Herein, we describe a 25-year-old pregnant woman who developed a perinulcear ANCA (p-ANCA) and myeloperoxidase ANCA (MPO-ANCA) positive DAH during PTU therapy. The patient improved after corticosteroid therapy and discontinuation of the PTU. Methimazole was prescribed in spite of the risk of recurrence of DAH because of the pregnancy. The patient is currently free from pulmonary problems. Our case shows that the alternative agent, methimazole, can be used to treat hyperthyroidism in a pregnant patient with PTU associated DAH.

Leukocytoclastic vasculitis: a rare manifestation of propylthiouracil hypersensitivity

We report a case of leukocytoclastic vasculitis as a manifestation of propylthiouracil hypersensitivity. A 66-year-old woman with a history of a toxic adenoma was referred for evaluation of a purpuric rash on the legs and buttocks bilaterally. She was biochemically hyperthyroid. Biopsy of the skin lesions revealed leukocytoclastic vasculitis. Propylthiouracil therapy was discontinued, and methimazole started. The purpuric rash resolved and surgical treatment for toxic adenoma resulted in euthyroid state. This report indicated that leukocytoclastic vasculitis should be considered in the differential diagnosis of patients with a vasculitic rash. The discontinuation of the propylthiouracil was associated with disappearance of the lesions

Neutropenia inducida por propiltiouracilo en paciente con síndrome de Down e hipertiroidismo / Neutropenia induced by propylthiouracil in patient with down syndrome and hyperthyroidism

Se presenta el caso de un paciente de sexo masculino de 10 años de edad, con antecedente de síndrome de Down, que consulta por cuadro de hipertiroidismo compatible con enfermedad de Base-dow-Graves. Recibe tratamiento con propiltiouracilo en dosis de 5 mg/kg/día. Veinte días después de iniciado el tratamiento, desarrolla agranulocitosis secundaria al uso de PTU. Se realiza una revisión sobre el hipertiroidismo en pacientes con síndrome de Down, el tratamiento de esta patología, y las reacciones adversas más frecuentes descritas en relación al uso de PTU.

Sudden sensorineural hearing loss: a case report supporting the immunologic theory

Sudden sensorineural hearing loss (SSNHL) is one of the autoimmune diseases of the inner ear (AIED), which is characterized by a hearing loss of above 30 decibels in at least three contiguous audiometric frequencies over a time course of 72 hours or shorter. Its cause can be found in only 10 percent to 15 percent of patients. Histopathologic findings have reported retrograde neuronal degeneration and atrophy of Corti's organ and of the vascular stria. This paper describes a case of a middle-aged female patient undergoing a treatment for hyperthyroidism who developed bilateral SSNHL. The patient was treated with methylprednilisone (1mg/kg/day) for three days with considerable hearing improvement. This treatment was followed by lung and kidney tuberculosis. The immune mechanism of this entity and the possibility of interconnected participation of the antigen type, of an autoimmune disease and of bacterial infection are discussed

Antineutrophilic cytoplasmic antibody-positive systemic vasculitis associated with propylthiouracil therapy: report of 2 children with Graves' disease.

Systemic vasculitis is a rare complication of therapy with antithyroid medication. Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis has been described in patients treated with propylthiouracil (PTU) and methimazole (MMI). The majority of cases have underlying Graves' disease. The authors report 2 children who developed ANCA-associated systemic vasculitis during PTU therapy of Graves' disease. One patient, after PTU treatment for 3 years, developed severe systemic vasculitis. After 3 weeks of arthritis, she abruptly presented with hematuria, proteinuria and edema concomitant with anemia. Her serum creatinine was elevated, to 6 mg/dl. Renal biopsy revealed crescentic glomerulonephritis. After admission, she developed intracerebral hemorrhage and pulmonary hemorrhage. She had positive perinuclear-ANCA (p-ANCA) with a titer of 1:160. Despite intensive therapy with immunosuppressive agents and plasmapheresis, as well as discontinuation of PTU, she died of the complications of severe systemic vasculitis. The other patient developed fever, arthralgia and leukocytoclastic vasculitis of the skin during treatment with PTU for about 2 years. Her symptoms and skin lesions disappeared after discontinuation of PTU. However, she has had a persistently high titer of p-ANCA 1:320 through 17 months follow-up time. Thus, patients who are treated with PTU can develop ANCA-positive vasculitis in a mild or severe form. Therefore, they should be carefully followed and monitored, not only for their thyroid status but also the serious complications of PTU.

Hepatite aguda colestática pelo propiltiouracil. Relato de caso / Acute cholestatic hepatitis induced by propylthiouracil. case report

Propylthiouracil is widely used to treat patients with hyperthyroidism. However, propylthiouracil-induced hepatitis is an uncommon entity. The case of a 15-year-old boy treated with propylthiouracil for hyperthyroidism who developed a cholestatic acute hepatitis is reported. Viral, metabolic and autoimmune liver diseases were excluded and liver biopsy showed a pattern suggestive of drug-induced cholestatic hepatitis. After discontinuing the drug, there was a progressive resolution of symptoms and normalization of liver biochemical tests. Despite its rarity, patients receiving propylthiouracil are exposed to develop severe hepatotoxicity