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The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, n = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the 'territory' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.
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Hipertensão Portal , Cirrose Hepática Biliar , Veia Porta , Hipertensão Portal/patologia , Hipertensão Portal/fisiopatologia , Animais , Cirrose Hepática Biliar/patologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/fisiopatologia , Masculino , Humanos , Feminino , Veia Porta/patologia , Vênulas/patologia , Ratos , Adulto , Pressão na Veia Porta , Pessoa de Meia-Idade , Modelos Animais de Doenças , Fígado/patologia , Fígado/irrigação sanguínea , Ratos Sprague-Dawley , Ductos Biliares/patologia , Adulto Jovem , AdolescenteRESUMO
Ductular reaction and fibrosis are hallmarks of many liver diseases including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Liver fibrosis is the accumulation of extracellular matrix often caused by excess collagen deposition by myofibroblasts. Ductular reaction is the proliferation of bile ducts (which are composed of cholangiocytes) during liver injury. Many other cells including hepatic stellate cells, hepatocytes, hepatic progenitor cells, mesenchymal stem cells, and immune cells contribute to ductular reaction and fibrosis by either directly or indirectly interacting with myofibroblasts and cholangiocytes. This review summarizes the recent findings in cellular links between ductular reaction and fibrosis in numerous liver diseases.
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Fígado Gorduroso , Hepatopatias , Humanos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/patologia , Fibrose , Cirrose Hepática/metabolismo , Ductos Biliares/metabolismo , Ductos Biliares/patologiaRESUMO
It has been suggested that alcohol consumption protects against Parkinson's disease (PD). Here we assessed postmortem tissue samples from the brains and livers of 100 subjects with ages at death ranging from 51 to 93. Twenty percent of these subjects were demented. We used standardized assessment strategies to assess both the brain and liver pathologies (LP). Our cohort included subjects with none, mild, moderate, and severe LP caused by alcohol consumption. We noted a significant negative correlation of categorical data between liver steatosis and α-synuclein (αS) in the brain and a significant negative correlation between the extent of liver steatosis and fibrosis and the extent of αS in the brain. There was a significant negative association between the observation of Alzheimer's type II astrocytes and αS pathology in the brain. No association was noted between LP and hyperphosphorylated τ (HPτ). No significant correlation could be seen between the extent of LP and the extent of HPτ, amyloid ß protein (Aß) or transactive DNA binding protein 43 (TDP43) in the brain. There were significant correlations observed between the extent of HPτ, Aß, αS, and TDP43 in the brain and between liver steatosis, inflammation, and fibrosis. Subjects with severe LP displayed a higher frequency of Alzheimer's type II astrocytes compared to those with no, or mild, LP. The assessed protein alterations were not more prevalent or severe in subjects with Alzheimer's type II astrocytes in the brain. In all cases, dementia was attributed to a combination of altered proteins, i.e., mixed dementia and dementia was observed in 30% of those with mild LP when compared with 13% of those with severe LP. In summary, our results are in line with the outcome obtained by the two recent meta-analyses suggesting that subjects with a history of alcohol consumption seldom develop an α-synucleinopathy.
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Encéfalo , Fígado , alfa-Sinucleína , Humanos , alfa-Sinucleína/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Fígado/patologia , Fígado/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Consumo de Bebidas Alcoólicas/patologia , Consumo de Bebidas Alcoólicas/metabolismo , Astrócitos/patologia , Astrócitos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Proteínas de Ligação a DNA/metabolismoRESUMO
The toxicity of ATR-107, a human anti-interleukin-21 receptor (IL-21R) monoclonal antibody (mAb), was evaluated in CD-1 mice and cynomolgus monkeys after single-dose intravenous (IV) administration, and in Sprague-Dawley (SD) rats and cynomolgus monkeys after weekly IV and subcutaneous (SC) administration in 13-week toxicity studies that included recovery. Adverse liver necrosis, diffuse bridging fibrosis, and higher liver enzymes occurred in rats in the low-dose IV group (10 mg/kg), but not at 50 or 250 mg/kg IV, and not following SC administration despite overlapping systemic ATR-107 exposures. Similar findings were not seen in mice or cynomolgus monkeys. A series of investigative rat toxicity studies showed liver findings only occurred after administration of at least 3 weekly doses, only occurred in rats that developed anti-drug antibodies (ADAs), and the incidence was associated with higher ADAs titers. However, the presence of ADAs did not always result in liver injury. Liver findings did not occur in nude rats, which had high ATR-107 exposures and no ADAs. These findings suggest an adaptive immune response with formation of ADAs was necessary for development of ATR-107-related liver findings, and that liver injury can occur in rats secondary to development of ADAs following repeated administration of a human therapeutic mAb.
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Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4 days post intravenous administration to â¼2 weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal administration of empty capsids or a "promoterless genome" vector, suggesting that liver injury after cerebrospinal fluid dosing in nonhuman primates is driven by viral transduction and transgene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration of rituximab/everolimus with intrathecal dosing failed to block AAV-driven hepatotoxicity. Self-complementary AAV-induced acute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type 1 interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the usefulness of this nonclinical species in that context.
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Doença Hepática Induzida por Substâncias e Drogas , Terapia Genética , Animais , Humanos , Macaca fascicularis/genética , Administração Intravenosa , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/terapia , Dependovirus/genética , Dependovirus/metabolismo , Vetores Genéticos/genéticaRESUMO
OBJECTIVE: To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder. STUDY DESIGN: Patients with genetically confirmed NP-C (NPC1, n = 31; NPC2, n = 3) and liver involvement before age 6 months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining. RESULTS: At initial evaluation (median age, 17 days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68+ storage cells in 15. Serum alpha-fetoprotein concentration measured in 21 patients was elevated in 17. Plasma oxysterol concentrations were increased in the 16 patients tested. Four patients died within 6 months of life, including 3 from liver involvement. In patients who survived beyond age 6 months (median follow-up, 6.1 years), cholestasis regressed in all, and portal hypertension regressed in all but 1; 25 patients developed neurologic involvement, which was fatal in 16 patients. CONCLUSIONS: Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C.
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Hepatopatias , Doença de Niemann-Pick Tipo C , Humanos , Lactente , Recém-Nascido , alfa-Fetoproteínas/análise , Colestase/etiologia , Hepatomegalia/etiologia , Hipertensão Portal/etiologia , Doença de Niemann-Pick Tipo C/sangue , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/imunologia , Estudos Retrospectivos , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Hepatopatias/imunologia , Hepatopatias/patologia , Fígado/imunologia , Fígado/patologia , Biópsia , Cirrose Hepática/etiologia , Biomarcadores/sangue , Oxisteróis/sangueRESUMO
Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance of histopathological effects seen in livers of mice exposed to HFPO-DA for human health risk assessment, histopathological effects were summarized from hematoxylin and eosin (H&E)-stained sections in several repeat-dose toxicity studies in mice. Findings across studies revealed histopathological changes consistent with peroxisomal proliferation, whereas two reports of steatosis could not be confirmed in the published figures. In addition, mechanisms of hepatocellular death were assessed in H&E sections as well as with the apoptotic marker cleaved caspase-3 (CCasp3) in newly cut sections from archived liver blocks from select studies. A comparison of serially CCasp3 immunolabeled and H&E-stained sections revealed that mechanisms of hepatocellular death cannot be clearly discerned in H&E-stained liver sections alone as several examples of putatively necrotic cells were positive for CCasp3. Published whole genome transcriptomic data were also reevaluated for enrichment of various forms of hepatocellular death in response to HFPO-DA, which revealed enrichment of apoptosis and autophagy, but not ferroptosis, pyroptosis, or necroptosis. These morphological and molecular findings are consistent with transcriptomic evidence for peroxisome proliferator-activated receptor alpha (PPARα) signaling in HFPO-DA exposed mice.
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Carcinoma Hepatocelular , Fluorocarbonos , Neoplasias Hepáticas , Camundongos , Humanos , Animais , Fluorocarbonos/toxicidadeRESUMO
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH) increases the risk for liver cirrhosis. Noninvasive tests for NAFLD/NASH exist, but they are unreliable and thus liver biopsy remains the standard for diagnosis and new noninvasive diagnostic approaches are of great interest. The aim of this study was to test whether the serum levels of fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) could be used as a diagnostic tool for NASH. METHODS: Patients who underwent bariatric surgery and simultaneous liver biopsy were identified. Biopsies were assigned a NAFLD activity score (NAS). MMP9- and FABP4- Enzyme-linked Immunosorbent Assays (ELISAs) on serum samples were performed. The serum levels of FABP4/MMP9 were compared and different models to predict NASH were developed. RESULTS: A total of 84 patients were included, 28 patients (33.3%) were diagnosed with NASH. Higher concentrations of MMP9 in NASH patients (p < 0.01) were detected. FABP4 concentrations were not significantly increased. A moderate correlation between the NAS and MMP9 concentrations (r = 0.32, P < 0.01) was observed. The neural network model fit best with the dataset, with an area under the curve (AUC) of 83% and an accuracy of 88%. CONCLUSION: Serum MMP9 levels are increased in patients with NASH and should routinely be measured in patients with obesity, but further investigations are needed to improve noninvasive NASH diagnosis.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Metaloproteinase 9 da Matriz , Cirrose Hepática/patologia , Obesidade/patologia , Proteínas de Ligação a Ácido Graxo , Biópsia , Fígado/patologia , BiomarcadoresRESUMO
Liver regeneration has been studied for many decades, and the mechanisms underlying regeneration of normal liver following resection are well described. However, no less relevant is the study of mechanisms that disrupt the process of liver regeneration. First of all, a violation of liver regeneration can occur in the presence of concomitant hepatic pathology, which is a key factor reducing the liver's regenerative potential. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or to directly stimulate liver regeneration. This review describes the known mechanisms of normal liver regeneration and factors that reduce its regenerative potential, primarily at the level of hepatocyte metabolism, in the presence of concomitant hepatic pathology. We also briefly discuss promising strategies for stimulating liver regeneration and those concerning methods for assessing the regenerative potential of the liver, especially intraoperatively.
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Regeneração Hepática , Fígado , Fígado/metabolismo , Hepatócitos/metabolismo , HepatectomiaRESUMO
Abuse with hepatotoxic agents is a major cause of acute liver failure. The search for new criteria indicating the acute or chronic pathological processes is still a challenging issue that requires the selection of effective tools and research models. Multiphoton microscopy with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM) are modern label-free methods of optical biomedical imaging for assessing the metabolic state of hepatocytes, therefore reflecting the functional state of the liver tissue. The aim of this work was to identify characteristic changes in the metabolic state of hepatocytes in precision-cut liver slices (PCLSs) under toxic damage by some of the most common toxins: ethanol, carbon tetrachloride (CCl4) and acetaminophen (APAP), commonly known as paracetamol. We have determined characteristic optical criteria for toxic liver damage, and these turn out to be specific for each toxic agent, reflecting the underlying pathological mechanisms of toxicity. The results obtained are consistent with standard methods of molecular and morphological analysis. Thus, our approach, based on optical biomedical imaging, is effective for intravital monitoring of the state of liver tissue in the case of toxic damage or even in cases of acute liver injury.
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Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Humanos , Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/diagnóstico por imagem , Falência Hepática Aguda/metabolismo , Etanol/toxicidade , Tetracloreto de Carbono/toxicidadeRESUMO
Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment. Notwithstanding, histopathology revealed drug-induced hepatitis, marked glycogen depletion, necrosis and steatosis. Strikingly, the genomic study revealed diclofenac to desynchronize the liver clock with manifest inductions of its components CLOCK, NPAS2 and BMAL1. The > 4-fold induced CRY1 expression underscored an activated core-loop, and the dose dependent > 60% reduction in PER2mRNA repressed the negative feedback loop; however, it exacerbated hepatotoxicity. Bioinformatics enabled the construction of gene-regulatory networks, and we linked the disruption of the liver-clock to impaired glycogenesis, lipid metabolism and the control of immune responses, as shown by the 3-, 6- and 8-fold induced expression of pro-inflammatory CXCL2, lysozyme and ß-defensin. Additionally, diclofenac treatment caused adrenocortical hypertrophy and thymic atrophy, and we evidenced induced glucocorticoid receptor (GR) activity by immunohistochemistry. Given that REV-ERB connects the circadian clock with hepatic GR, its > 80% repression alleviated immune responses as manifested by repressed expressions of CXCL9(90%), CCL8(60%) and RSAD2(70%). Together, we propose a circuitry, whereby diclofenac desynchronizes the liver clock in the control of the hepatic metabolism and immune response.
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Relógios Circadianos , Animais , Suínos , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Diclofenaco/farmacologia , Porco Miniatura , Fígado/metabolismo , Proteínas CLOCK/metabolismo , Transdução de SinaisRESUMO
In the context of chronic viral infections, the hepatic microenvironment dictates the outcome of the disease by influencing propagation of virus and regulation of cytotoxic CD8+ T cell response. Nevertheless, such regulation could be beneficial as it resolves the disease or could be detrimental as it causes liver pathological consequences. Liver pathology is a hallmark of chronic viral infection in both human and murine models. Such models show viral infection of hepatocytes and subsequent direct hepatic damage. Other compelling studies showed that liver injury was a consequence of overshooting CD8+ T cells response in experimental mice, so-called immune-mediated liver pathology. This review highlights the viral-induced immune mediated aspects of liver pathology based on the lymphocytic choriomeningitis virus (LCMV) and Hepatitis virus settings.
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Coriomeningite Linfocítica , Animais , Linfócitos T CD8-Positivos , Humanos , Fígado/patologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T CitotóxicosRESUMO
In clinical practice, the Ishak Score system would be adopted to perform the evaluation of the grading and staging of hepatitis according to whether portal areas have fibrous expansion, bridging with other portal areas, or bridging with central veins. Based on these staging criteria, it is necessary to identify portal areas and central veins when performing the Ishak Score staging. The bile ducts have variant types and are very difficult to be detected under a single magnification, hence pathologists must observe bile ducts at different magnifications to obtain sufficient information. This pathologic examinations in routine clinical practice, however, would result in the labor intensive and expensive examination process. Therefore, the automatic quantitative analysis for pathologic examinations has had an increased demand and attracted significant attention recently. A multi-scale inputs of attention convolutional network is proposed in this study to simulate pathologists' examination procedure for observing bile ducts under different magnifications in liver biopsy. The proposed multi-scale attention network integrates cell-level information and adjacent structural feature information for bile duct segmentation. In addition, the attention mechanism of proposed model enables the network to focus the segmentation task on the input of high magnification, reducing the influence from low magnification input, but still helps to provide wider field of surrounding information. In comparison with existing models, including FCN, U-Net, SegNet, DeepLabv3 and DeepLabv3-plus, the experimental results demonstrated that the proposed model improved the segmentation performance on Masson bile duct segmentation task with 72.5% IOU and 84.1% F1-score.
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Processamento de Imagem Assistida por Computador , Redes Neurais de Computação , Ductos Biliares , Processamento de Imagem Assistida por Computador/métodos , FígadoRESUMO
Opisthorchis viverrini (Ov) infection causes hepatobiliary diseases and is a major risk factor for cholangiocarcinoma. While several omics approaches have been employed to understand the pathogenesis of opisthorchiasis, effects of Ov infection on the host systemic metabolism and fecal microbiota have not been fully explored. Here, we used a 1H NMR spectroscopy-based metabolic phenotyping approach to investigate Ov infection-induced metabolic disturbances at both the acute (1 month postinfection, 1 mpi) and chronic (4 mpi) stages in hamsters. A total of 22, 3, and 4 metabolites were found to be significantly different in the liver, serum, and urine, respectively, between Ov+ and Ov- groups. Elevated levels of hepatic amino acids and tricarboxylic acid (TCA)-cycle intermediates (fumarate and malate) were co-observed with liver injury in acute infection, whereas fibrosis-associated metabolites (e.g., glycine and glutamate) increased at the chronic infection stage. Lower levels of lipid signals ((CH2)n and CH2CH2CO) and higher levels of lysine and scyllo-inositol were observed in serum from Ov+ hamsters at 1 mpi compared to Ov- controls. Urinary levels of phenylacetylglycine (a host-bacterial cometabolite) and tauro-ß-muricholic acid were higher in the Ov+ group, which coexisted with hepatic and mild kidney fibrosis. Furthermore, Ov+ animals showed higher relative abundances of fecal Methanobrevibacter (Archaea), Akkermansia, and Burkholderia-Paraburkholderia compared to the noninfected controls. In conclusion, along with liver and kidney pathologies, O. viverrini infection resulted in hepatic and mild renal pathologies, disturbed hepatic amino acid metabolism and the TCA cycle, and induced changes in the fecal microbial composition and urinary host-microbial cometabolism. This study provides the initial step toward an understanding of local and systemic metabolic responses of the host to O. viverrini infection.
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Neoplasias dos Ductos Biliares , Opistorquíase , Opisthorchis , Animais , Ductos Biliares Intra-Hepáticos , Cricetinae , Rim , Fígado , Opistorquíase/complicaçõesRESUMO
The liver is a major site of lipoprotein synthesis and metabolism. Liver manifestations of chronic visceral ASMD include hepatomegaly, fibrosis, elevated liver enzymes and a pro-atherogenic lipid profile. Measurements of sphingomyelin (SM) levels in liver biopsies and lyso-SM in plasma were used as pharmacodynamic biomarkers. Five adult patients with chronic visceral ASMD were enrolled in a 26-week phase 1b trial of enzyme replacement therapy (ERT) with olipudase alfa (NCT01722526) followed by an ongoing long-term extension study (NCT02004704). We compare the changes in hepatic SM levels, plasma lyso-SM, and lipoprotein profiles after 42 months of treatment. Progressive clearance of histologic SM storage was observed throughout the trial, along with similar reductions in plasma lyso-SM. Improvements in liver enzymes were observed at 6 months and remained stable at 42 months. Progressive reductions from baseline in pro-atherogenic lipid profiles (total cholesterol, LDL-C, VLDL-C, triglycerides) were observed at month 6 and 42. Conversely, there were progressive increases in anti-atherogenic markers, HDL-C and apolipoprotein A-I, with HDL-C increases up to 200% over baseline levels after 42 months of treatment. These data demonstrate that hepatic clearance of SM during olipudase alfa treatment over 42 months is associated with overall improvements in the lipid profiles of ASMD patients. The clinical relevance of these findings needs to be determined in the future, but we speculate that these improvements may reduce the risk for liver cirrhosis and cardiovascular disease. Trial registration: Clintrials.gov trial registration # NCT01722526.
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Aterosclerose/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Esfingomielina Fosfodiesterase/administração & dosagem , Adolescente , Adulto , Idoso , Aterosclerose/genética , Aterosclerose/patologia , Terapia de Reposição de Enzimas , Feminino , Humanos , Lipídeos/genética , Lipoproteínas/biossíntese , Lipoproteínas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/genética , Esfingomielina Fosfodiesterase/genética , Esfingomielinas/genética , Adulto JovemRESUMO
Human and experimental studies have shown that chronic schistosomiasis mansoni protects against metabolic disorders through direct and indirect pathways. This study aims to investigate the co-morbidity between the acute schistosomiasis and nonalcoholic fatty liver. To address this, male C57BL/6 mice fed a high-fat chow (60% fat) or standard chow (10% fat) for 13 weeks and later infected with 80 Schistosoma mansoni cercariae. Mice were assigned into four groups: uninfected fed standard (USC), uninfected fed high-fat chow (UHFC), infected fed standard (ISC), and infected fed high-fat chow (IHFC). Blood sample and tissues were obtained at nine weeks post-infection (acute schistosomiasis) by necropsy. UHFC mice showed higher body mass, visceral adiposity, impaired glucose tolerance, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), triglyceride (TG), and liver steatosis compared to USC mice. IHFC mice showed lower blood lipid levels, blood glucose, improved glucose tolerance, body mass, and liver steatosis (macro and microvesicular) compared to UHFC mice. IHFC showed more massive histopathological changes (sinusoidal fibrosis, hepatocellular ballooning, and inflammatory infiltrates) compared to ISC. In conclusion, the co-morbidity results in both beneficial (friend) and detrimental (foe) for the host. While the acute schistosomiasis improves some metabolic features of metabolic syndrome, comorbidity worsens the liver injury.
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Síndrome Metabólica/epidemiologia , Esquistossomose mansoni/epidemiologia , Análise de Variância , Animais , Área Sob a Curva , Biomphalaria/parasitologia , Comorbidade , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Granuloma/etiologia , Granuloma/patologia , Intestinos/parasitologia , Fígado/patologia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Esquistossomose mansoni/complicações , Esquistossomose mansoni/metabolismo , Aumento de PesoRESUMO
Emerging information suggests that liver pathological states may affect the expression and function of membrane transporters in the gastrointestinal tract and the kidney. Altered status of the transporters could affect drug as well as endogenous compounds handling with subsequent clinical consequences. It seems that changes in intestinal and kidney transporter functions provide the compensatory activity of eliminating endogenous compounds (e.g., bile acids) generated and accumulated due to liver dysfunction. A literature search was conducted on the Ovid and PubMed databases to select relevant in vitro, animal and human studies that have reported expression, protein abundance and function of the gastrointestinal and kidney operating ABC (ATP-binding cassette) transporters and SLC (solute carriers) carriers. The accumulated data suggest that liver failure-associated transporter alterations in the gastrointestinal tract and kidney may affect drug pharmacokinetics. The altered status of drug transporters in those organs in liver dysfunction conditions may provide compensatory activity in handling endogenous compounds, affecting local drug actions as well as drug pharmacokinetics.
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Transportadores de Cassetes de Ligação de ATP/metabolismo , Trato Gastrointestinal/metabolismo , Rim/metabolismo , Falência Hepática/metabolismo , Farmacocinética , Proteínas Carreadoras de Solutos/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Transporte Biológico , Humanos , Fígado/metabolismo , Modelos AnimaisRESUMO
Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in hepatocyte homeostasis, as well as drug handling. However, there is no available information about the impact of liver pathology on the transporter levels and function. The study was aimed to quantify SLC16A1 mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography-tandem mass spectrometry (LC---MS/MS)) in the livers of patients diagnosed, according to the standard clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to Child-Pugh score. Downregulation of SLC16A1/MCT1 levels was observed in all liver pathology states, significantly for ALD. The progression of liver dysfunction, from Child-Pugh class A to C, involved the gradual decline in SLC16A1 mRNA and MCT1 protein abundance, reaching a clinically significant decrease in class C livers. Reduced levels of MCT1 were associated with significant intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1 abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all studied liver pathologies. Overall, the study demonstrates that SLC16A1/MCT1 is involved in liver pathology, especially in ALD.
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Fígado/metabolismo , Fígado/patologia , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Adulto , Idoso , Animais , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , RNA Mensageiro , Espectrometria de Massas em TandemRESUMO
Schistosomiasis represents a public health problem and praziquantel is the only drug used for treatment of all forms of the disease. Thus, the development of new anti-schistosomal agents is of utmost importance to increase the effectiveness, reduce side effects and delay the emergence of resistance. The present study was conducted to report the therapeutic efficacy of PPQ-8, a new synthetic quinoline-based compound against Schistosoma mansoni. Mice were treated with PPQ-8 at day 49 post infection using two treatment regimens (20 and 40 mg/kg). Significant reductions were recorded in hepatic (62.9% and 83.6%) and intestinal tissue egg load (57.4% and 73.5%), granuloma count (75.4% and 89.1%) and diameter (26.2% and 47.3%), in response to the drug regimens, respectively. In addition, both treatment regimens induced significant decrease in liver (23.3% and 32.8%) and spleen (37.5% and 45.3%) indices. Also, there were significant reductions in mature ova, total worm and female count, which were more prominent with the higher dose. The reduction in the level of nitric oxide in the liver by both therapeutic regimens to 22.5% and 47.2% indicates the anti-oxidant activity of PPQ-8. Bright field microscopic examination of worms recovered from infected and PPQ-8-treated mice showed nearly empty intestinal caeca with no observable changes in the tegument. Our findings hold promise for the development of a novel anti-schistosomal drug using PPQ-8, but further in vitro and in vivo studies are needed to elucidate the possible mechanism/s of action and to study the effect of PPQ-8 on other human schistosomes.
Assuntos
Anti-Helmínticos/uso terapêutico , Descoberta de Drogas , Quinolinas/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Animais , Anti-Helmínticos/síntese química , Antioxidantes/síntese química , Antioxidantes/uso terapêutico , Feminino , Intestinos/parasitologia , Fígado/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Contagem de Ovos de Parasitas , Quinolinas/síntese química , Baço/parasitologiaRESUMO
CONTEXT: Core biopsy (CB) is a main tool for diagnosis of liver mass lesions. When CB is performed with fine needle aspiration (FNA), the CB may be interpreted by a cytopathologist or gastrointestinal pathologist. OBJECTIVE: This study compares interpretation of liver mass biopsy between cytopathologist and gastrointestinal pathologist in the era of subspecialty practice. DESIGN: 349 liver mass lesions with FNA and CB performed during a 5-year period were retrieved. All cases were initially interpreted by a cytopathologist and retrospectively reviewed by a gastrointestinal pathologist. RESULTS: The overall agreement was 95.1% (332/349 cases). There was agreement on 57/65 non-neoplastic cases (87.7%) with 8 (12.3%) discordant cases including 4 steatosis (steatohepatitis missed in 3 cases, 1 re-interpreted as focal nodular hyperplasia [FNH]); 3 inflammation (1 necrotizing granulomatous inflammation, 1 massive necrosis instead of fibrosing cholestatic hepatitis, and 1 hepatocellular carcinoma [HCC] was missed); and 1 initially deemed normal re-interpreted as FNH. There was agreement on 275/284 neoplastic cases (96.8%), with 9 (3.2%) discordant cases including: 2 initially interpreted as HCC (1 metastatic adrenal cortical carcinoma, 1 cholangiocarcinoma); 3 adenocarcinomas (2 further defined as prostatic primary, 1 well-differentiated neuroendocrine tumor [WDNET]); 2 metastatic carcinomas (1 tumor-induced fibrosis instead of cirrhosis, 1 LCNEC re-interpreted as WDNET); 1 poorly differentiated carcinoma (re-interpreted as LCNEC); and 1 sarcomatoid carcinoma (re-interpreted as leiomyosarcoma). CONCLUSION: Cytopathologist and gastrointestinal pathologist are highly concordant in the interpretation of neoplastic liver mass CB. Consultation may improve accuracy in certain non-neoplastic biopsies and neuroendocrine neoplasms.