Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed.

Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701.

Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701

SUMMARY Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

RESUMO A hepatotoxicidade à flucloxacilina é rara e classifica-se como idiossincrática, uma vez que é dependente da suscetibilidade individual, não expectável e independente da dose. Apresentamos o caso de um homem, 74 anos, antecedentes de gamapatia monoclonal e hábitos alcoólicos de 24 g/dia, com quadro de astenia, anorexia, náuseas, desconforto abdominal e febrícula com três dias de evolução. Referência a dois ciclos de antibioterapia com flucloxacilina por erisipela (três meses e duas semanas antes da admissão). Analiticamente com AST 349 U/L, ALT 646 U/L, FA 302 U/L, GGT 652 U/L, bilirrubina total 3,3 mg/dL, bilirrubina direta 2,72 mg/dL. Excluídas etiologias infecciosa, autoimune, metabólica, bem como patologia das vias biliares por colangio-RM. Biópsia hepática mostrou esteatose multifocal ligeira (predominantemente microvesicular); alterações acentuadas nas áreas centrolobulares (dilatação sinusoidal, congestão acentuada, hemorragia e colapso multifocal de hepatócitos); expansão das áreas portais com constituição de pontes; ductos biliares proliferados e infiltrado inflamatório de densidade variável, predominantemente de tipo mononucleado. Tipagem de HLA-B*5701 positiva. Agravamento analítico atingindo bilirrubina total 24,1 mg/dL, com desenvolvimento de icterícia, prurido e colúria. Admitida a hepatotoxicidade, iniciou terapêutica com ácido ursodesoxicólico. Verificou-se evolução favorável, sem evidência de coagulopatia ou encefalopatia. A normalização analítica foi, no entanto, lenta, com evolução para cronicidade. Os autores apresentam este caso para alertar para a possibilidade de hepatotoxicidade moderada a grave à flucloxacilina, antibiótico de uso comum na prática clínica e associação com o alelo HLA-B*5701 relatada na literatura.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

SUMMARY Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed.

RESUMO A vasculite de Churg-Strauss, granulomatose eosinofílica com poliangeíte (EGPA), é uma vasculite sistêmica que afeta vasos de pequeno e médio calibre. É rara e pertence ao grupo de vasculites associadas a anticorpos anticitoplasma de neutrófilos (Anca). Apresenta-se um homem de 37 anos, com antecedentes de asma, que recorre ao SU por tosse produtiva com dois meses de evolução, dispneia ocasional em esforço, febre (uma semana de evolução), astenia e anorexia. Ao exame objetivo apresentava-se subfebril e taquicárdico. Analiticamente com leucocitose (17,00 x10^9/L) e eosinofilia de 20,0% (3,4 X10^9/L), creatinina de 1,5 mg/dL, discreta alteração das provas de função hepática e PCR de 10,82 mg/dL. Na radiografia de tórax objetivava-se infiltrado na base pulmonar direita. Por elevada suspeita de EGPA, iniciou prednisolona 80 mg desde a admissão. Anca MPO+, com restante estudo de autoimunidade negativo. Realizou TC tórax (sob corticoterapia) sem alterações de relevo, bem como lavado bronco-alveolar, sem sinais macroscópicos de hemorragia alveolar. Por sedimento urinário ativo, proteinúria na faixa nefrótica (6,56 g/24h) e lesão renal aguda, realizou biópsia renal que revelou glomerulonefrite crescêntica pauci-imune, com achados predominantemente agudos (no contexto de Vasculite Anca-MPO - EGPA). Após biópsia, realizou três pulsos de 1 g de metilprednisolona e iniciou ainda ciclofosfamida. Ficou assintomático e com recuperação da função renal. Este caso realça a importância de integração de todos os achados num só cenário a fim de evitar que escape o diagnóstico de uma doença mais complexa e com um tratamento específico.

Autoimmune Polyglandular Syndrome type 2

SUMMARY Autoimmune polyglandular syndrome type 2 (APS 2) is defined by the presence of Addison's disease (AD) associated with autoimmune thyroid disease and/or Type 1 diabetes mellitus (T1DM). It is a rare disease, affecting about 1.4-2 cases/100,000 inhabitants. Its less frequent clinical presentation is the combination of AD, Graves' disease, and T1DM. We present the case of a 42-year-old woman with a history of total thyroidectomy due to Graves' disease, type 2 diabetes mellitus, and hypertension, who sought the ED due to asthenia, dizziness, nausea, and vomiting. She reported having stopped antihypertensive therapy due to hypotension and presented a glycemic record with frequent hypoglycemia. On physical examination, she had cutaneous hyperpigmentation. She had no leukocytosis, anemia, hypoglycemia, hyponatremia or hyperkalemia, and a negative PCR. Serum cortisol <0.5 ug/dl (4,3-22,4), urine free cortisol 9 ug/24h (28-214), ACTH 1384 pg/mL (4,7-48,8), aldosterone and renin in erect position of 0 pg/ml (41-323) and 430.7 uUI/ml (4.4-46.1) respectively. Quantiferon TB was negative; computerized axial tomography of the adrenals showed no infiltrations, hemorrhage, or masses. The 21-hydroxylase antibody assay was positive. B12 vitamin was normal, anti-GAD antibodies were positive, anti-insulin, anti-IA2, and anti-transglutaminase antibodies were all negative. The patient started insulin therapy and treatment for AD with prednisolone and fludrocortisone with good clinical response. This case aims to alert to the need for high clinical suspicion in the diagnosis of AD. Since this is a rare autoimmune disease, it is important to screen for other autoimmune diseases in order to exclude APS.

RESUMO A síndrome poliglandular autoimune tipo 2 (SPGA2) é definida pela presença de doença de Addison (DA) associada à doença tiroideia autoimune e/ou diabetes mellitus tipo 1 (DMT1). Trata-se de uma doença rara, afetando cerca de 1,4-2 casos/100.000 habitantes. A apresentação clínica menos frequente é a combinação de DA, doença de Graves e DMT1. Apresenta-se mulher de 42 anos, com antecedentes de tiroidectomia total por doença de Graves, diabetes mellitus tipo 2 e hipertensão, que recorre ao SU por quadro arrastado de astenia, emagrecimento, tonturas, náuseas e vômitos. Referia ter suspendido terapêutica anti-hipertensora por hipotensão e apresentava registro glicêmico com hipoglicemias frequentes. Ao exame físico, salientava hiperpigmentação cutânea. Analiticamente sem leucocitose, anemia, hipoglicemia, hiponatremia ou hipercaliemia, PCR negativa. Cortisol sérico matinal <0,5 ug/dl (4,3-22,4), cortisol livre na urina 9 ug/24h (28-214), ACTH 1.384 pg/mL (4,7-48,8), aldosterona e renina em posição ereta de 0 pg/mL (41-323) e 430,7 uUI/mL (4,4-46,1), respectivamente. Realizado estudo complementar para averiguar causa de insuficiência suprarrenal primária. Quantiferon TB negativo, tomografia axial computadorizada das suprarrenais sem infiltrações, hemorragia ou massas. Anticorpos anti-21-hidroxilase positivos. Foi aprofundada a investigação com vitamina B12 normal, anti-GAD positivo, anti-insulina, anti-IA2, antitransglutaminase, negativos. Nesse contexto, a doente iniciou insulinoterapia e tratamento dirigido para a DA com prednisolona e fludrocortisona, com boa resposta clínica. Este caso tem como objetivo alertar para a necessidade de elevada suspeição clínica no diagnóstico de DA. Sendo esta uma doença autoimune rara, é importante rastrear outras doenças autoimunes no sentido de excluir SPGA.

Autoimmune Polyglandular Syndrome type 2.

Autoimmune polyglandular syndrome type 2 (APS 2) is defined by the presence of Addison's disease (AD) associated with autoimmune thyroid disease and/or Type 1 diabetes mellitus (T1DM). It is a rare disease, affecting about 1.4-2 cases/100,000 inhabitants. Its less frequent clinical presentation is the combination of AD, Graves' disease, and T1DM. We present the case of a 42-year-old woman with a history of total thyroidectomy due to Graves' disease, type 2 diabetes mellitus, and hypertension, who sought the ED due to asthenia, dizziness, nausea, and vomiting. She reported having stopped antihypertensive therapy due to hypotension and presented a glycemic record with frequent hypoglycemia. On physical examination, she had cutaneous hyperpigmentation. She had no leukocytosis, anemia, hypoglycemia, hyponatremia or hyperkalemia, and a negative PCR. Serum cortisol <0.5 ug/dl (4,3-22,4), urine free cortisol 9 ug/24h (28-214), ACTH 1384 pg/mL (4,7-48,8), aldosterone and renin in erect position of 0 pg/ml (41-323) and 430.7 uUI/ml (4.4-46.1) respectively. Quantiferon TB was negative; computerized axial tomography of the adrenals showed no infiltrations, hemorrhage, or masses. The 21-hydroxylase antibody assay was positive. B12 vitamin was normal, anti-GAD antibodies were positive, anti-insulin, anti-IA2, and anti-transglutaminase antibodies were all negative. The patient started insulin therapy and treatment for AD with prednisolone and fludrocortisone with good clinical response. This case aims to alert to the need for high clinical suspicion in the diagnosis of AD. Since this is a rare autoimmune disease, it is important to screen for other autoimmune diseases in order to exclude APS.

Lymphocyte subsets in alcoholic liver disease.

AIM: To compare lymphocyte subsets between healthy controls and alcoholics with liver disease. METHODS: The patient cohort for this study included individuals who were suspected to have alcoholic liver disease (ALD) and who had undergone liver biopsy (for disease grading and staging, doubts about diagnosis, or concurrent liver disease; n = 56). Normal controls included patients who were admitted for elective cholecystectomy due to non-complicated gallstones (n = 27). Formalin-fixed, paraffin-embedded liver biopsy specimens were sectioned and stained with hematoxylin and eosin and Perls' Prussian blue. The non-alcoholic steatohepatitis score was used to assess markers of ALD. Lymphocyte population subsets were determined by flow cytometry. T lymphocytes were identified (CD3(+)), and then further subdivided into CD4(+) or CD8(+) populations. B lymphocytes (CD19(+)) and natural killer (NK) cell numbers were also measured. In addition to assessing lymphocyte subpopulation differences between ALD patients and controls, we also compared subsets of alcoholic patients without cirrhosis or abstinent cirrhotic patients to normal controls. RESULTS: The patient cohort primarily consisted of older men. Active alcoholism was present in 66.1%. Reported average daily alcohol intake was 164.9 g and the average lifetime cumulative intake was 2211.6 kg. Cirrhosis was present in 39.3% of the patients and 66.1% had significant fibrosis (perisinusoidal and portal/periportal fibrosis, bridging fibrosis, or cirrhosis) in their liver samples. The average Mayo end-stage liver disease score was 7.6. No hereditary hemochromatosis genotypes were found. ALD patients (n = 56) presented with significant lymphopenia (1.5 × 10(9)/L ± 0.5 × 10(9)/L vs 2.1 × 10(9)/L ± 0.5 × 10(9)/L, P < 0.0001), due to a decrease in all lymphocyte subpopulations, except for NK lymphocytes: CD3(+) (1013.0 ± 406.2/mm(3) vs 1523.0 ± 364.6/mm(3), P < 0.0001), CD4(+) (713.5 ± 284.7/mm(3) vs 992.4 ± 274.7/mm(3), P < 0.0001), CD8(+) (262.3 ± 140.4/mm(3) vs 478.9 ± 164.6/mm(3), P < 0.0001), and CD19(+) (120.6 ± 76.1/mm(3) vs 264.6 ± 88.0/mm(3), P < 0.0001). CD8(+) lymphocytes suffered the greatest reduction, as evidenced by an increase in the CD4(+)/CD8(+) ratio (3.1 ± 1.3 vs 2.3 ± 0.9, P = 0.013). This ratio was associated with the stage of fibrosis on liver biopsy (r s = 0.342, P = 0.01) and with Child-Pugh score (r s = 0.482, P = 0.02). The number of CD8(+) lymphocytes also had a positive association with serum ferritin levels (r s = 0.345, P = 0.009). Considering only patients with active alcoholism but not cirrhosis (n = 27), we found similar reductions in total lymphocyte counts (1.8 × 10(9)/L ± 0.3 × 10(9)/L vs 2.1 × 10(9)/L ± 0.5 × 10(9)/L, P = 0.018), and in populations of CD3(+) (1164.7 ± 376.6/mm(3) vs 1523.0 ± 364.6/mm(3), P = 0.001), CD4(+) (759.8 ± 265.0/mm(3) vs 992.4 ± 274.7/mm(3), P = 0.003), CD8(+) (330.9 ± 156.3/mm(3) vs 478.9 ± 164.6/mm(3), P = 0.002), and CD19(+) (108.8 ± 64.2/mm(3) vs 264.6 ± 88.0/mm(3), P < 0.0001). In these patients, the CD4(+)/CD8(+) ratio and the number of NK lymphocytes was not significantly different, compared to controls. Comparing patients with liver cirrhosis but without active alcohol consumption (n = 11), we also found significant lymphopenia (1.3 × 10(9)/L ± 0.6 × 10(9)/L vs 2.1 × 10(9)/L ± 0.5 × 10(9)/L, P < 0.0001) and decreases in populations of CD3(+) (945.5 ± 547.4/mm(3) vs 1523.0 ± 364.6/mm(3), P = 0.003), CD4(+) (745.2 ± 389.0/mm(3) vs 992.4 ± 274.7/mm(3), P = 0.032), CD8(+) (233.9 ± 120.0/mm(3) vs 478.9 ± 164.6/mm(3), P < 0.0001), and CD19(+) (150.8 ± 76.1/mm(3) vs 264.6 ± 88.0/mm(3), P = 0.001). The NK lymphocyte count was not significantly different, but, in this group, there was a significant increase in the CD4(+)/CD8(+) ratio (3.5 ± 1.3 vs 2.3 ± 0.9, P = 0.01). CONCLUSION: All patient subsets presented with decreased lymphocyte counts, but only patients with advanced fibrosis presented with a significant increase in the CD4(+)/CD8(+) ratio.