O fenótipo hepático da doença de Gaucher e dos distúrbios congênitos da glicosilação

Pacientes com DG tiveram diferença significativa de parâmetros nucleares hepatocelulares (área nuclear 28,16 ± 9,45 vs 26,88 ± 9,42 μm², p=0,006; dimensão fractal média 1,11 ± 0,06 vs 1,09 ± 0,09, p=0,005; e absorbância 4,88 ± 2,52 vs 7,68 ± 4,60, p=0,014) e de parâmetros canaliculares (absorbância 88,24 ± 59,80 vs 173,52 ± 76,78, p=0.001; relação perímetro-Feret 2,70 ± 0,56 vs 2,79 ± 0,66, p=0,006). Etapa 3) 33 pacientes tiveram 19 genes sequenciados, com identificação de 95 variantes (sendo 4 novas). Foi encontrada segregação de variante com fenótipo em 3 genes (A2M, CYBRD1 e TF), e diferenças no teste de carga na comparação com duas bases de dados populacionais em 5 genes (CP, CYBRD1, PSAP, TF e TFR2). A variante CYBRD1 rs10455 foi associada a uma diminuição de chance de osteonecrose (razão de chances de 0,08, intervalo de confiança 0,01 – 0,64, valor p de 0,004) no teste de segregação e com uma menor gravidade geral de doença no teste de carga. Etapa 4) Doze pacientes foram incluídos no estudo com ETH, com elastografia média de 5,25 kPa; aproximadamente metade dos pacientes com DG apresentaram algum grau de fibrose; o escore APRI teve uma área abaixo da curva de 0,701, sendo o mais acurado dos 3 escores testados. Esse teste mostrou sensibilidade 100% e especificidade 100% para detecção de pacientes com fibrose F2 ou superior utilizando-se os pontos de corte 0,201 e 0,604. Objetivo 2) foram incluídos 42 pacientes no estudo de coorte de pacientes com DCGs. Foram encontrados: grande aumento dos marcadores de dano hepatocelular, mas não biliar, com tendência à normalização após os 5 anos de idade nos pacientes com DCGs tipo I, mas não naqueles com tipo II; todos os tipos de esteatose e todos os graus de fibrose, sendo que 3 pacientes apresentaram cirrose; à pesquisa histológica em pacientes com cirrose, houve completa prevalência de acúmulo hepatocelular de glicogênio e completa ausência de hemossiderose. Conclusão: o fenótipo hepático da DG e dos DCGs é amplo e variado, com diversos pontos convergentes e divergentes entre essas doenças. Os DCGs de tipos I e II têm evoluções similares internamente, mas distintas entre si. A histomorfometria foi capaz de identificar alterações morfológicas canaliculares e hepatocelulares previamente não-descritas em pacientes com DG e que podem ajudar a explicar o fenótipo desses pacientes. A variante CYBRD1 rs10455 mostrou-se promissora como modificadora da DG. O escore APRI possui acurácia adequada ao seu uso clínico como preditor de fibrose na DG.Introduction: Gaucher disease (GD) and the congenital disorders of glycosylation (CDGs) are inborn errors of metabolism with a broad and highly variable phenotype. Still understudied in GD and the CDGs is the set of pathophysiological manifestations that arise from the liver tissue – the hepatic phenotype. Objectives: 1) to describe and analyze the hepatic phenotype of GD; 2) to describe and analyze the clinical hepatic phenotype of the CDGs. Methods: for objectives 1), the following steps were performed: 1) describing and analyzing the hepatic phenotype of GD at a clinical level in a cohort study with acquisition of clinical, laboratorial, imaging, histological, and molecular genetic data; 2) describing and analyzing quantitatively, at the histological level, the hepatic phenotype of GD with the development of a new computerized analysis method (histomorphometry) of hepatocellular nuclei and biliary canaliculi in tissue in liver biopsy samples; 3) investigation of modifier factors of GD – candidate genes were sequenced by next-generation sequencing, with correlation of molecular findings with clinical (phenotypic segregation analysis) and populational (burden test) data using the populational databases gnomAD and ABraOM; step 4), transient hepatic elastography (THE) was used and the APRI, FIB-4, and NFS scores calculated for patients with GD. For objective 2), a cohort of patients with CDGs was used, with acquisition of clinical, laboratorial, imaging, histological, and molecular genetic data. Results: Objective 1), step 1) forty-two patients were included in the GD cohort study. Findings included: a high prevalence of abnormalities in hepatocellular and biliary markers both before and during treatment; a significant increase in the prevalence of steatosis after initiation of treatment with enzyme replacement therapy (ERT); evidence for hemosiderosis, canalicular cholestasis, and liver fibrosis in a high proportion of investigated patients; and the presence of steatohepatitis in 2 patients (a previously undescribed feature of GD). Step 2) At the histomorphometric study of patients with GD 4 liver biopsy samples of GD patients and 4 of healthy controls were included. GD patients had significant differences in hepatocellular nuclear parameters (nuclear area 28.16 ± 9.45 vs 26.88 ± 9.42 μm², p=0.006; average fractal dimension 1.11 ± 0.06 vs 1.09 ± 0.09, p=0.005; and corrected absorbance 11 4.88 ± 2.52 vs 7.68 ± 4.60, p=0.014) and in canalicular parameters (absorbance 88.24 ± 59.80 vs 173.52 ± 76.78, p=0.001; perimeter-to-Feret ratio 2.70 ± 0.56 vs 2.79 ± 0.66, p=0.006). Step 3) 33 patients were sequenced for 19 genes, identifying 95 variants (4 of which were novel). Variants in 3 genes were positive for phenotypic segregation (A2M, CYBRD1, and TF), and burden test was positive for both populational databases in 5 genes (CP, CYBRD1, PSAP, TF, and TFR2). The CYBRD1 rs10455 variant was associated with a decreased chance of osteonecrosis in the segregation analysis (odds ratio = 0.08, confidence interval 0.01-0.64, p-value = 0.004) and with a decreased overall disease severity in the burden test, being a strong candidate for a modifier variant. Step 4) Twelve patients were included in the study, with a mean elastography results of 5.25 kPa; approximately half of the DG patients had some degree of liver fibrosis; the APRI score had an area under the curve of 0.701, being the most accurate of the tested scores. This score was 100% sensitive and 100% specific for the detection of patients with an F2 or higher degree of fibrosis at the cut-off respectively of 0.201 and 0.640. Objective 2) Forty-two patients were included the CDG cohort study. Findings included: a stark increase in hepatocellular, but not biliary, markers with a trend towards normalization after 5 years of age in type I CDG patients but not in type II patients; all types of steatosis and all degrees of fibrosis were present, with cirrhosis in 3 patients; at histology of patients with cirrhosis, all patients had hepatocellular glycogen build-up, and none had hemosiderosis. Conclusion: the hepatic phenotype of GD and the CDGs is broad and varied, with many converging and diverging features between those pathologies. CDGs types I and II are internally similar but externally different regarding the hepatic natural history. Histomorphometry was able to identify canalicular and hepatocellular features which had not been described previously in GD, and which may help to explain some aspects of their clinical phenotype. The CYBRD1 rs10455 variant is promising as a putative modifier of GD. The APRI score has adequate accuracy for a clinical use as a fibrosis predictor in GD

The Frontal-subcortical syndrome

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O impacto específico de toxinas urêmicas em domínios cognitivos : uma revisão

One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms ‘uric acid’, ‘indoxyl sulfate’, ‘p-cresyl sulfate’, ‘homocysteine’, ‘interleukins’ and ‘parathyroid hormone’. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros

Misdiagnosis of Streptococcus gallolyticus endocarditis

Death certificate inaccuracy is of major concern both in the public health domain and in individual health care, since it may yield untruthful data on the incidence, prevalence, and lethality of medical entities, and may hamper prophylactic measures among those who share, with the deceased, the common genetic, environmental, or behavioral risk factors. An effective way to settle this haziness relies on the increase of autopsy performance, increasing manifold the exactitude as well as facing surprising diagnoses. In this report, the authors present the case of a middle-aged woman who sought medical care because of back pain accompanied by weight loss. She died suddenly and unexpectedly in the Emergency Room. In this case, due to the unusual clinical presentation and the patient’s unexpected death, the causa mortis would not have been elucidated if the autopsy had not been undertake

Haemodialysis improves uraemic patients' cognition : a pilot study

Uraemia is a state of elevated plasma urea well related to a low cognitive profile. Although renal transplantation has been proved to improve cognition in these patients, little is known about how haemodialysis act on this scenario. Here we aimed to conduct a pilot study to fathom the presence and magnitude of a possible benefit of haemodialysis in cognition. Our main instrument was the Montreal Cognitive Assessment (MoCA) test, a tool designed to allow for a sensitive score for cognitive impairment. Although preliminary, our data were significant (p=0.012) to suggest that haemodialysis might be an important tool for cognitive improvement of end-stage kidney disease patients, tough not sufficient for a full cognitive recovery

Case report: Aplastic anaemia and gray matter heterotopias in an autopsy of a 17-year-old puerperal woman

In this report, we present an autopsy case of a 17-year-old girl with aplastic anaemia in the puerperal context, along with the presence of four independent nodular gray matter heterotopias in brain slices. The case is remarkable both by the rareness of the cause of death – septicaemia resulting from immunodepression due to aplastic anaemia in the obstetric context – and the brain morphologic findings unrelated to any known clinical manifestation. Immunohistochemistry was performed in order to ensure the precision of the diagnoses.

Misdiagnosis of Streptococcus gallolyticus endocarditis

Death certificate inaccuracy is of major concern both in the public health domain and in individual health care, since it may yield untruthful data on the incidence, prevalence, and lethality of medical entities, and may hamper prophylactic measures among those who share, with the deceased, the common genetic, environmental, or behavioral risk factors. An effective way to settle this haziness relies on the increase of autopsy performance, increasing manifold the exactitude as well as facing surprising diagnoses. In this report, the authors present the case of a middle-aged woman who sought medical care because of back pain accompanied by weight loss. She died suddenly and unexpectedly in the Emergency Room. In this case, due to the unusual clinical presentation and the patient’s unexpected death, the causa mortis would not have been elucidated if the autopsy had not been undertake

Nuclear morphometry and chromatin texture changes in hepatocellular carcinoma samples may predict outcomes of liver transplanted patients

Background: Nuclear changes are typical in the carcinogenesis of hepatocellular carcinoma (HCC). Morphometry and chromatin texture analysis are quantitative methods for their quantification. In this study, we analyzed nuclear morphometry and chromatin texture parameters in samples of hepatocellular carcinoma from liver transplant patients and their associations with clinicopathologic variables. Methods: Samples of HCC and adjacent tissue from 34 individuals were collected in tissue microarray blocks. Stained slides were microphotographed using an optical microscope and nuclear parameters analyzed in ImageJ (FracLac plug-in). ROC curve analysis was used to find accurate cut-offs for differentiation of neoplastic and non-neoplastic cells. The inter-rater agreement was also evaluated. Results: Nuclear morphometric and textural differences were observed between the samples of HCC and adjacent tissue of liver transplant patients. Lower mean gray value (p=0.034) and Feret diameter (p=0.024) were associated with higher Model for End-Stage Liver Disease (MELD) scores. Nuclei with larger area (p=0.014) and larger Feret diameter (p=0.035) were associated with lower survival. Lower aspect ratio was associated with HCC recurrence after the transplant (p=0.048). The cut-off of 1.13 μm (p= < 0.001) for aspect ratio and cut-off of 21.15 μm (p=0.038) for perimeter were established for the differentiation of neoplastic and non-neoplastic cells. The morphometric analysis was reproducible to area, circularity, Feret diameter, mean gray value and aspect ratio between observers (p= < 0.001). Conclusions: Nuclear morphometric differences between the HCC and the adjacent tissue samples were associated with prognostic variables (MELD scores, recurrence and survival) and may predict liver transplant patients’ outcomes

Nuclear morphometry and chromatin texture changes in hepatocellular carcinoma samples may predict outcomes of liver transplanted patients

BACKGROUND: Nuclear changes are typical in the carcinogenesis of hepatocellular carcinoma (HCC). Morphometry and chromatin texture analysis are quantitative methods for their quantification. In this study, we analyzed nuclear morphometry and chromatin texture parameters in samples of hepatocellular carcinoma from liver transplant patients and their associations with clinicopathologic variables. METHODS: Samples of HCC and adjacent tissue from 34 individuals were collected in tissue microarray blocks. Stained slides were microphotographed using an optical microscope and nuclear parameters analyzed in ImageJ (FracLac plug-in). ROC curve analysis was used to find accurate cut-offs for differentiation of neoplastic and non-neoplastic cells. The inter-rater agreement was also evaluated. RESULTS: Nuclear morphometric and textural differences were observed between the samples of HCC and adjacent tissue of liver transplant patients. Lower mean gray value (p = 0.034) and Feret diameter (p = 0.024) were associated with higher Model for End-Stage Liver Disease (MELD) scores. Nuclei with larger area (p = 0.014) and larger Feret diameter (p = 0.035) were associated with lower survival. Lower aspect ratio was associated with HCC recurrence after the transplant (p = 0.048). The cut-off of 1.13 μm (p =  \u3c 0.001) for aspect ratio and cut-off of 21.15 μm (p = 0.038) for perimeter were established for the differentiation of neoplastic and non-neoplastic cells. The morphometric analysis was reproducible to area, circularity, Feret diameter, mean gray value and aspect ratio between observers (p =  \u3c 0.001). CONCLUSIONS: Nuclear morphometric differences between the HCC and the adjacent tissue samples were associated with prognostic variables (MELD scores, recurrence and survival) and may predict liver transplant patients\u27 outcomes