Tuberculose pleural : a propósito de um caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014Pleural Tuberculosis is a disease associated with the Mycobacterium tuberculosis infection that should be considered in every patient with an undiagnosed pleural effusion. The clinical presentation is nonspecific. The identification of mycobacteria in the pleural fluid and /or pleural tissue is the gold standard for the diagnosis. A presumptive diagnosis can be made by the identification of an exudate with predominance of lymphocytes in the pleural fluid and a granulomatous inflammatory process in the pleural tissue histopathology. Biological markers - adenosine deaminase and interferon γ - are also useful for establishing the diagnosis. Although the infection usually resolves spontaneously, the treatment with antituberculostatic chemotherapy is crucial to prevent recurrences. This paper presents the case of a 42 years old patient with a pleural effusion of undetermined etiology. A thoracoscopy with biopsy of the pleural tissue was performed. The analysis of the pleural fluid revealed an exudate with predominance of lymphocytic cells and elevated levels of adenosine deaminase. Quadruple antituberculostatic empiric therapy was initiated after the identification of acid-fast bacilli on a smear of the pleural tissue. The definitive etiologic diagnosis was established after the identification of the Mycobacterium tuberculosis in the cultural exam of the pleural tissue.A Tuberculose (TB) pleural é uma patologia associada à infecção pelo complexo Mycobacterium tuberculosis que deve ser equacionada em todos os indivíduos com derrame pleural de etiologia indeterminada. A apresentação clínica é inespecífica. A identificação da micobactéria no líquido e/ou tecido pleural representa o gold standard do diagnóstico. O diagnóstico presuntivo pode ser efectuado através da identificação de um exsudado com predomínio de células linfocíticas no líquido pleural e de um processo inflamatório granulomatoso na análise histopatológica do tecido pleural. Marcadores biológicos - adenosina desaminase (ADA) e interferão γ (INF-γ) - são igualmente úteis para o diagnóstico. Apesar de ser comum a infecção resolver espontaneamente, a terapêutica antituberculostática é fulcral para prevenir recidivas. Neste trabalho apresenta-se o caso de uma doente de 42 anos com um derrame pleural de etiologia indeterminada. Foi efectuada uma toracoscopia, com realização da biopsia do tecido pleural. Na análise do líquido pleural identificou-se um exsudado com predomínio linfocítico e com elevação dos níveis do ADA. Foi iniciada terapêutica antituberculostática quádrupla empiricamente, após a identificação de bacilos álcool-ácido resistentes (BAAR) no exame microscópico do tecido pleural. O diagnóstico etiológico definitivo foi estabelecido através da identificação do complexo Mycobacterium tuberculosis no exame cultural do tecido pleural

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway