Resumo: Objetivo: Descrever as características demográficas, clínicas, laboratoriais e moleculares de pacientes com deficiência de lipase ácida lisossomal. Métodos: Análise retrospectiva dos prontuários médicos de crianças com a deficiência de lipase ácida lisossomal. Resultados: Sete crianças com deficiência de lipase ácida lisossomal (5 M:2F); seis eram pardas e uma negra. As faixas etárias no início dos sintomas e no diagnóstico foram 5 anos (4 meses a 9 anos) e 6,9 anos (3 a 10 anos), respectivamente. As manifestações dos sintomas no início foram as que seguem: três pacientes apresentaram dor abdominal, um apresentou dor nos ossos/articulações devido a raquitismo e um apresentou diarreia crônica e insuficiência respiratória devido à pneumonite intersticial. Os outros não apresentaram sintomas e a suspeita clínica surgiu devido à hepatomegalia. Seis pacientes apresentaram hepatomegalia e um apresentou esplenomegalia. Dois pacientes eram irmãos. O ensaio enzimético e a análise molecular confirmaram os diagnósticos. A análise genética revelou uma variante patogênica rara (p.L89P) em três pacientes, descrita uma única vez na literatura médica e nunca descrita no Brasil. Nenhum desses pacientes tinha parentesco com os outros. A deficiência de lipase ácida lisossomal foi anteriormente descrita como uma doença recessiva autossômica, porém três pacientes eram heterozigotos e, sem dúvida, apresentaram a doença (atividade enzimática baixa, achados laboratoriais sugestivos e sintomas clínicos). Conclusão: Esta casuística afirma que a deficiência de lipase ácida lisossomal pode se manifestar com sinais e sintomas altamente heterogêneos entre os pacientes, porém deve ser considerada em crianças que apresentam sintomas gastrointestinais associados à dislipidemia. Descrevemos uma variante rara em três pacientes não relacionados que pode sugerir um genótipo brasileiro para deficiência de lipase ácida lisossomal.

Abstract Objective: To describe the demographic, clinical, laboratory and molecular characteristics of patients with lysosomal acid lipase deficiency. Methods: A retrospective review of the medical records of children with the disease. Results: Seven children with lysosomal acid lipase deficiency (5 male; 2 female); 6 were mixed race, and 1 was black. The mean ages at the first onset of symptoms and at diagnosis were 5.0 years (4 months to 9 years) and 6.9 years (3-10 years), respectively. Symptom manifestations at onset were: 3 patients had abdominal pain, one had bone/joint pain due to rickets, and 1 had chronic diarrhea and respiratory insufficiency due to interstitial pneumonitis. One was asymptomatic, and clinical suspicion arose due to hepatomegaly. Six patients had hepatomegaly, and none had splenomegaly. Two patients were siblings. Enzymatic assay and molecular analysis confirmed the diagnoses. Genetic analysis revealed a rare pathogenic variant (p.L89P) in three patients, described only once in medical literature and never described in Brazil. None of those patients were related to each other. Lysosomal acid lipase deficiency was previously described as an autosomal recessive disease, but three patients were heterozygous and undoubtedly had the disease (low enzyme activity, suggestive lab findings and clinical symptoms). Conclusion: This case series supports that lysosomal acid lipase deficiency can present with highly heterogeneous signs and symptoms among patients, but it should be considered in children presenting with gastrointestinal symptoms associated with dyslipidemia. We describe a rare variant in three non-related patients that may suggest a Brazilian genotype for lysosomal acid lipase deficiency.

OBJECTIVES: Although liver biopsy is the gold standard for determining the degree of liver fibrosis, issues regarding its invasiveness and the small amount of liver tissue evaluated can limit its applicability and interpretation in clinical practice. Non-invasive evaluation methods for liver fibrosis can address some of these limitations. The aim of this study was to evaluate the accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI), enhanced liver fibrosis (ELF), the aspartate aminotransferase-to-platelet ratio index (APRI), and the FIB-4 index compared with liver biopsy in hepatitis C. METHODS: We evaluated chronic hepatitis C patients who were followed at the Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology of University of São Paulo School of Medicine, São Paulo, Brazil, and who underwent liver biopsy. The accuracy of each method was determined by a receiver operating characteristic (ROC) curve analysis, and fibrosis was classified as significant fibrosis (≥F2), advanced fibrosis (≥F3), or cirrhosis (F4). The Obuchowski method was also used to determine the diagnostic accuracy of each method at the various stages of fibrosis. In total, 107 FibroScan®, 51 ARFI, 68 ELF, 106 APRI, and 106 FIB-4 analyses were performed. RESULTS: A total of 107 patients were included in the study. The areas under the ROC curve (AUROCs) according to fibrosis degree were as follows: significant fibrosis (≥F2): FibroScan®: 0.83, FIB-4: 0.76, ELF: 0.70, APRI: 0.69, and ARFI: 0.67; advanced fibrosis (≥F3): FibroScan®: 0.85, ELF: 0.82, FIB-4: 0.77, ARFI: 0.74, and APRI: 0.71; and cirrhosis (F4): APRI: 1, FIB-4: 1, FibroScan®: 0.99, ARFI: 0.96, and ELF: 0.94. The accuracies of transient elastography, ARFI, ELF, APRI and FIB-4 determined by the Obuchowski method were F0-F1: 0.81, 0.78, 0.44, 0.72 and 0.67, respectively; F1-F2: 0.73, 0.53, 0.62, 0.60, and 0.68, respectively; F2-F3: 0.70, 0.64, 0.77, 0.60, and 0.67, respectively; and F3-F4: 0.98, 0.96, 0.82, 1, and 1, respectively. CONCLUSION: Transient elastography remained the most effective method for evaluating all degrees of fibrosis. The accuracy of all methodologies was best at F4.

CONTEXTO E OBJETIVO: Nestina, proteína de filamento intermediário de classe VI, é altamente expressa no mesênquima portal e endotélio sinusoidal do fígado fetal humano, mas pouco expressa no endotélio de vasos portais no adulto. Além disso, durante a regeneração hepática experimental, um número crescente de células parenquimatosas nestina-positivas é observado na zona adjacente aos canais de Hering. Essas células parenquimatosas são consideradas células-tronco hepáticas ou hepatoblastos, que podem estar envolvidas na origem do carcinoma hepatocelular. Em função de relatos recentes descrevendo células parenquimatosas nestina-positivas no carcinoma hepatocelular, objetivamos usar este tipo tumoral como controle positivo para a detecção imunoistoquímica da nestina.TIPO DE ESTUDO E LOCAL: Estudo experimental realizado em hospital universitário.MÉTODOS: Cortes de um caso de carcinoma hepatocelular foram analisados em relação à expressão imunoistoquímica da nestina por microscopia confocal.RESULTADOS: Surpreendentemente, um padrão nítido com citoarquitetura semelhante a sinusoides hepáticos foi observado pela marcação por nestina em células endoteliais.CONCLUSÕES: Este padrão não havia sido descrito previamente. Os resultados preliminares mostrados aqui sugerem que células endoteliais nestina-positivas estão localizadas em nichos de células imaturas ou em proliferação. Além disto, a expressão de nestina em células endoteliais de carcinoma hepatocelular reforça o papel da angiogênese neste tipo tumoral, embora a prevalência deste padrão imuno-histopatológico precise ser determinada. Finalmente, o carcinoma hepatocelular é um controle positivo efetivo para a marcação para nestina em imunoistoquímica fluorescente.

CONTEXT AND OBJECTIVE: Nestin, a class VI intermediate filament protein, is highly expressed in the portal mesenchyme and sinusoidal endothelium of the human fetal liver, but scarcely expressed in adult portal vessel endothelium. During experimental liver regeneration, an increased number of nestin-positive parenchymal cells have been observed in the zone adjacent to the Hering canals. These parenchymal cells are regarded as hepatic stem cells or hepatoblasts, which may be involved in hepatocellular carcinogenesis. In the light of recent reports describing nestin-positive parenchymal cells in hepatocellular carcinoma, we aimed to use this tumor type as a positive control for immunohistochemical detection of nestin.DESIGN AND SETTING: Experimental study conducted at a university hospital.METHODS: Hepatocellular carcinoma sections from one case were analyzed for nestin expression by immunohistochemistry using confocal microscopy.RESULTS: Surprisingly, a conspicuous pattern resembling liver sinusoid-like cytoarchitecture was observed upon nestin staining of endothelial cells.CONCLUSIONS: This pattern has not been previously described. The preliminary results shown here suggest that nestin-positive endothelial cells are located in niches of immature or proliferative cells. Moreover, nestin expression in endothelial cells of hepatocellular carcinoma enhances the role of angiogenesis in this tumor type, although the prevalence of this immunohistopathological pattern remains to be determined. Finally, hepatocellular carcinoma is an effective positive control for nestin staining in fluorescent immunohistochemistry.