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1.
Cell Transplant ; 29: 963689719896559, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32166974

RESUMO

We investigated the safety of using umbilical cord-lining stem cells for liver regeneration and tested a novel method for stem cell delivery. Stem cells are known by their ability to repair damaged tissues and have the potential to be used as regenerative therapies. The umbilical cord's outer lining membrane is known to be a promising source of multipotent stem cells and can be cultivated in an epithelial cell growth medium to produce cell populations which possess the properties of both epithelial cells and embryonic stem cells-termed cord-lining epithelial cells (CLEC). Hepatocytes are epithelial cells of the liver and their proliferation upon injury is the main mechanism in restoring the liver. Earlier studies conducted showed CLEC can be differentiated into functioning hepatocyte-like cells (HLC) and can survive in immunologically competent specimens. In this study, we chose a porcine model to investigate CLEC as a treatment modality for liver failure. We selected 16 immune competent Yorkshire-Dutch Landrace pigs, with a mean weight of 40.5 kg, for this study. We performed a 50% hepatectomy to simulate the liver insufficient disease model. After the surgery, four pigs were transplanted with a saline scaffold while seven pigs were transplanted with a HLC scaffold. Five pigs died on the surgical table and were omitted from the study analysis. This study addressed the safety of transplanting human CLEC in a large animal model. The transplant interfaces were evaluated and no signs of cellular rejection were observed in both groups.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32147592

RESUMO

BACKGROUND & AIMS: Progression of liver fibrosis still occurs in some patients with chronic hepatitis B virus (HBV) infection despite antiviral therapy. We aimed to identify risk factors for fibrosis progression in patients who received antiviral therapy. METHODS: We conducted a longitudinal study of patients with chronic HBV infection and liver biopsies collected before and after 78 weeks of anti-HBV therapy. Fibrosis progression was defined as Ishak stage increase ≥ 1 or as predominantly progressive classified by P-I-R system (Beijing Classification). Levels of HBV DNA and HBV RNA in blood samples were measured by real-time quantitative PCR. HBV RNA in liver tissue was detected by in situ hybridization. RESULTS: A total of 239 patients with chronic HBV infection with paired liver biopsies were included. Among the 163 patients with significant fibrosis at baseline (Ishak ≥ stage 3), fibrosis progressed in 22 patients (13%), was indeterminate in 24 patients (15%), and regressed in 117 patients (72%). Univariate and multivariate analyses revealed that independent risk factors for fibrosis progression were higher rate of detected HBV DNA at week 78 (odds ratio, 4.84; 95% CI, 1.30-17.98; P=.019) and alcohol intake (odds ratio, 23.84; 95% CI, 2.68-212.50; P=.004). HBV DNA was detected in blood samples from a significantly higher proportion of patients with fibrosis progression (50%) at week 78 than patients with fibrosis regression (19%) or indeterminate fibrosis (26%) (P=.015), despite low viremia (20-200 IU/mL) in all groups. The decrease of serum HBV RNA from baseline in the fibrosis regression group was larger than that in the fibrosis progression group. CONCLUSIONS: In a longitudinal study of patients with chronic HBV infection, we associated liver fibrosis progression at week 78 of treatment with higher rates of detected HBV DNA. We propose that a low level of residual HBV may still promote fibrosis progression, and that patients' levels of HBV DNA should be carefully monitored.

3.
Liver Int ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31758650

RESUMO

BACKGROUND & AIMS: Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ-induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI. METHODS: Patients diagnosed with drug-induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow-up data were analysed. RESULTS: Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54-70) years. The median latency period was 45 (range, 29-90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0 U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4 µmol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N = 23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow-up was 26.3 months with recovery in 37 patients within 6 months. No patients died or required transplantation. CONCLUSIONS: BGZ-induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6 months, and none developed end-stage liver disease or died.

4.
Lab Invest ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745210

RESUMO

The stimulator of interferon genes (STING) in macrophages plays a crucial role in nonalcoholic fatty liver disease (NAFLD) progression. However, there is a lack of evidence from large samples of patients to validate a deleterious role for STING in NAFLD. Moreover, sources of STING-expressing cells that are related to NAFLD remain to be definitively characterized. To investigate STING expression and explore its correlation with NAFLD progression in human subjects, our study involved liver samples from 98 NAFLD subjects and 8 controls. STING and p-TBK1 expression in nonparenchymal liver cells was analyzed and correlated with NAFLD pathological features. Numbers of STING+ cells were increased in livers from nonalcoholic steatohepatitis (NASH) patients compared with controls, especially in the liver portal tract of NASH patients with fibrosis (p < 0.05). Moreover, numbers of STING+ cells in livers of NASH patients were increased with aggravation of inflammation grade and fibrosis stage (p < 0.05). STING was mainly expressed in macrophages, including monocyte-derived macrophages (CCR2+, S100A9+), Kupffer cells (CD68+) and CD163+ macrophages. Compared with controls, numbers of STING+/CCR2+ and STING+/S100A9+ cells were significantly increased in livers from NASH patients with fibrosis and positively correlated with liver inflammation grade and fibrosis stage (p < 0.05). However, numbers of STING+/CD68+ and STING+/CD163+ cells were significantly increased in livers from NASH patients with advanced fibrosis and correlated only with aggravation of fibrosis stage (p < 0.05). Furthermore, compared with controls, NASH patients exhibited significantly increased STING+/p-TBK1+ cell numbers. In a coculture system, the amount of p-TBK1 and the mRNAs of IL1ß and IL6 in THP1 macrophages, as well as the amount of α-SMA and the mRNAs of Col1a1, Fn and TGFß1 in LX2 cells were significantly increased upon STING activation in macrophages (p < 0.05). Therefore, increased STING expression in MoMFs appears to be indicative of NAFLD progression, and STING could be a new target for NAFLD therapy.

5.
Hepatology ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600834

RESUMO

Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. Clinical trials use the NASH Clinical Research Network (CRN) system for semiquantitative histological assessment of disease severity. Interobserver variability may hamper histological assessment, and diagnostic consensus is not always achieved. We evaluate a novel second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) imaging-based tool to provide an automated quantitative assessment of histological features pertinent to NASH. Images were acquired by SHG/TPEF from 219 nonalcoholic fatty liver disease (NAFLD)/NASH liver biopsy samples from seven centers in Asia and Europe. These were used to develop and validate qFIBS, a computational algorithm that quantifies key histological features of NASH. qFIBS was developed based on in silico analysis of selected signature parameters for four cardinal histopathological features, that is, fibrosis (qFibrosis), inflammation (qInflammation), hepatocyte ballooning (qBallooning), and steatosis (qSteatosis), treating each as a continuous rather than categorical variable. Automated qFIBS analysis outputs showed strong correlation with each respective component of the NASH CRN scoring (P < 0.001) (qFibrosis [r = 0.776], qInflammation [r = 0.557], qBallooning [r = 0.533], and qSteatosis [r = 0.802]) and high area under the receiver operating characteristic curve (AUROC) values (qFibrosis [0.870-0.951; 95% confidence interval (CI), 0.787-1.000; P < 0.001], qInflammation [0.820-0.838; 95% CI, 0.726-0.933; P < 0.001 ), qBallooning [0.813-0.844; 95% CI, 0.708-0.957; P < 0.001], and qSteatosis [0.939-0.986; 95% CI, 0.867-1.000; P < 0.001]) and was able to distinguish differing grades/stages of histological disease. Performance of qFIBS was best when assessing degree of steatosis and fibrosis but performed less well when distinguishing severe inflammation and higher ballooning grades. Conclusion: qFIBS is an automated tool that accurately quantifies the critical components of NASH histological assessment. It offers a tool that could potentially aid reproducibility and standardization of liver biopsy assessments required for NASH therapeutic clinical trials.

6.
Sci Rep ; 9(1): 15446, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659188

RESUMO

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation. We report an immune-permissive murine model of liver cirrhosis with full clinical correlates of decompensated liver disease, and allows testing efficacy of stem cell transplantation. Liver cirrhosis was induced in Nod-scid gamma(NSG) mice with oral thioacetamide(TA) and compared to controls over 12 months. 4 month TA treated cirrhotic mice were then transplanted intrasplenically with 2million human fetal liver progenitor cells(HFH) and compared with cirrhotic controls 2 months after transplantation. NSG-TA mice developed shrunken and nodular livers with histological evidence of fibrosis as compared to controls. This was associated with evidence of worsening decompensated liver disease, with jaundice, hypoalbuminemia, coagulopathy, and encephalopathy in NSG-TA mice. Transplantation of HFH resulted in improvement in both fibrosis and markers of decompensated liver disease. We have demonstrated that NSG-TA mice can recapitulate the full clinical picture of structural and functional cirrhosis, both of which can be improved by transplantation of human fetal liver cells. This model serves as a valuable tool for validation of in vivo liver stem cell transplantation and opens up opportunities for studying the mechanism how stem cells reverse fibrosis.

7.
Mod Pathol ; 32(12): 1795-1805, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300804

RESUMO

Histologically, drug-induced liver injury could be classified into acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. The correlation between these histologic patterns and long-term clinical outcomes has not been well established. Therefore, we conducted a retrospective cohort study to investigate the association of histologic patterns and long-term clinical outcomes defined as biochemical normalization, persistent abnormal liver biochemistry or death at designated time points. In this study, biochemical classification was determined by R-values; histologic injury pattern was determined by morphological features. Predictive ability of clinical outcomes by these two classifications was assessed using Receiver Operating Characteristic Curves. Logistic regression was performed to identify histologic factors associated with outcomes. Totally, 88 patients with drug-induced liver injury were included for final analysis. Biochemical and histologic classification were consistent in 50 (57%) cases. 53 (60%) cases showed biochemical normalization within 6 months, and a further 11 (13%), 16 (18%), and 6 (7%) cases within 1, 2, and 3 years, respectively. Compared with biochemical classification, histologic injury pattern had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P < 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P < 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. In conclusion, histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification. Moderate bile duct loss is an important histologic feature associated with persistent biochemical abnormality at 6 months, 1 year, and 2 years.

8.
Liver Int ; 39(2): 389-400, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30066422

RESUMO

BACKGROUND & AIMS: Polygonum Multiflorum Thumb (PMT), an ancient anti-aging Chinese herb known traditionally as He Shou Wu, has side effects of liver toxicity. To determine the main clinical and pathological characteristics of liver toxicity induced by PMT and the clinical course after its cessation. METHODS: Data of patients, diagnosed as drug-induced liver injury and hospitalised in Beijing Friendship Hospital from August 2005 to August 2017, were retrospectively reviewed. Clinical, pathological data and outcome after cessation of He Shou Wu were obtained and analysed. Kruskal-Wallis and Chi-square (χ2 ) tests were performed. RESULTS: Twenty-nine patients with He Shou Wu-induced liver injury were enrolled. The median age was 53 years (range 15-74) and 75.9% (22/29) were women. The most common symptom was jaundice (79.3%, 23/29). Of nine patients with liver biopsies, six showed acute cholestatic hepatitis, two acute, and one chronic hepatocellular injury pattern. The latency, liver chemistries and outcomes were comparable between pure He Shou Wu (5 patients) and its compounds (24 patients). Twenty-five of 29 patients (86.2%) had normal serum alanine aminotransferase levels after 45 days (range: 10-138 days) and total bilirubin of 46 days (range: 0-551 days). One patient was rechallenged with He Shou Wu and two developed autoimmune features. One patient died of liver failure and three had chronic persistent liver injury. CONCLUSIONS: The main clinicopathological injury pattern of He Shou Wu-induced liver injury is moderate to severe hepatitis with or without cholestasis. Most patients recover completely; however, chronic disease and death do occur.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/induzido quimicamente , Medicamentos de Ervas Chinesas/toxicidade , Polygonum/toxicidade , Adolescente , Adulto , Idoso , Pequim , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Feminino , Humanos , Icterícia/etiologia , Fígado/patologia , Falência Hepática/induzido quimicamente , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/toxicidade , Estudos Retrospectivos , Adulto Jovem
9.
Sci Rep ; 8(1): 16016, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375454

RESUMO

Current liver fibrosis scoring by computer-assisted image analytics is not fully automated as it requires manual preprocessing (segmentation and feature extraction) typically based on domain knowledge in liver pathology. Deep learning-based algorithms can potentially classify these images without the need for preprocessing through learning from a large dataset of images. We investigated the performance of classification models built using a deep learning-based algorithm pre-trained using multiple sources of images to score liver fibrosis and compared them against conventional non-deep learning-based algorithms - artificial neural networks (ANN), multinomial logistic regression (MLR), support vector machines (SVM) and random forests (RF). Automated feature classification and fibrosis scoring were achieved by using a transfer learning-based deep learning network, AlexNet-Convolutional Neural Networks (CNN), with balanced area under receiver operating characteristic (AUROC) values of up to 0.85-0.95 versus ANN (AUROC of up to 0.87-1.00), MLR (AUROC of up to 0.73-1.00), SVM (AUROC of up to 0.69-0.99) and RF (AUROC of up to 0.94-0.99). Results indicate that a deep learning-based algorithm with transfer learning enables the construction of a fully automated and accurate prediction model for scoring liver fibrosis stages that is comparable to other conventional non-deep learning-based algorithms that are not fully automated.


Assuntos
Diagnóstico por Imagem , Processamento de Imagem Assistida por Computador/métodos , Cirrose Hepática/diagnóstico por imagem , Algoritmos , Animais , Biomarcadores , Biópsia , Colágeno/metabolismo , Aprendizado Profundo , Diagnóstico por Imagem/métodos , Processamento de Imagem Assistida por Computador/normas , Cirrose Hepática/patologia , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Microscopia , Ratos , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X
10.
Mod Pathol ; 31(8): 1191-1200, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29700417

RESUMO

In this new era of successful long term suppression of hepatitis B viral replication and consistent eradication of hepatitis C virus the necessity for routine pre-treatment biopsies has often been eliminated. Thus, whether there is utility to perform liver biopsy in chronic viral hepatitis is undergoing re-examination. In response to these changing needs, we have developed a new staging system, the Beijing Classification, for assessment of biopsy specimens from patients with chronic viral hepatitis. The most important novelty of the Beijing Classification is that it includes not only extent (stage) of fibrosis, but the quality of fibrosis, namely if the specimen shows predominantly regressive vs. progressive features (or is indeterminantly balanced between the two), the P-I-R score. This histologic distinction between regressive and progressive fibrosis, while invoked in this particular setting of chronic viral hepatitis, may have applicability to all forms of chronic liver disease. Thus, the review contains a description of the concepts of regression and progression with the aim of empowering pathologists to apply them in histopathologic-clinical correlation research as well as in the specific clinical setting for which it was developed. Also, in light of changing clinical needs, grading of necroinflammatory activity and staging of fibrosis are simplified into three point scales. These simplifications should aid the general diagnostic pathologist in being comfortable and confident in assessing biopsy specimens as the criteria for their distinction are far more precise, with significantly reduced "gray zones" of prior grading/staging systems.


Assuntos
Hepatite B Crônica/patologia , Hepatite C Crônica/patologia , Cirrose Hepática/classificação , Cirrose Hepática/patologia , Progressão da Doença , Humanos , Cirrose Hepática/virologia
11.
Sci Rep ; 8(1): 2989, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29445243

RESUMO

Current widely used semiquantitative histological assessment methods are insensitive to identify subtle changes of liver fibrosis. Therefore, to precisely assess therapeutic efficacy on chronic hepatitis B (CHB), we explored the utility of qFibrosis (a fully-quantitative morphometric method employing second harmonic generation/two photon excitation fluorescence) in liver fibrosis evaluation. Fibrosis changes were evaluated by Ishak fibrosis scoring and qFibrosis in CHB patients with paired liver biopsies before and after 78 weeks' antiviral therapy. A total of 162 patients with qualified paired biopsies were enrolled. Ishak fibrosis scoring revealed that 42.6% (69/162) of the patients achieved fibrosis regression (≥1-point decrease), 51.9% (84/162) remained stable, and 5.5% (9/162) showed progression (≥1-point increase). qFibrosis showed similar trends in the groups of regression and progression patients as evaluated by Ishak. However, in Ishak stable patients, qFibrosis revealed hitherto undetected changes, allowing for further subcategorization into regression ("Regression by qFibrosis"; 40/84, 47.6%), stable (29/84, 34.5%), and progression ("Progression by qFibrosis"; 15/84, 17.9%) groups. These newly fine-tuned categories were supported by changes of morphological parameters of fibrosis, collagen percentage area, and liver stiffness measurements. In conclusion, qFibrosis can be used to quantitatively identify subtle changes of liver fibrosis in CHB patients after antiviral therapy.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/diagnóstico , Fígado/patologia , Adulto , Antivirais/uso terapêutico , Biópsia , Colágeno/metabolismo , Progressão da Doença , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Humanos , Fígado/metabolismo , Cirrose Hepática , Masculino , Avaliação de Resultados da Assistência ao Paciente , Resultado do Tratamento
12.
Hepatology ; 68(1): 113-126, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29360137

RESUMO

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. CONCLUSION: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).


Assuntos
Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/classificação , Idoso , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Radiografia , Terminologia como Assunto
13.
Stem Cells ; 36(1): 103-113, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28960647

RESUMO

Liver progenitor cells have the potential to repair and regenerate a diseased liver. The success of any translational efforts, however, hinges on thorough understanding of the fate of these cells after transplant, especially in terms of long-term safety and efficacy. Here, we report transplantation of a liver progenitor population isolated from human fetal livers into immune-permissive mice with follow-up up to 36 weeks after transplant. We found that human progenitor cells engraft and differentiate into functional human hepatocytes in the mouse, producing albumin, alpha-1-antitrypsin, and glycogen. They create tight junctions with mouse hepatocytes, with no evidence of cell fusion. Interestingly, they also differentiate into functional endothelial cell and bile duct cells. Transplantation of progenitor cells abrogated carbon tetrachloride-induced fibrosis in recipient mice, with downregulation of procollagen and anti-smooth muscle actin. Paradoxically, the degree of engraftment of human hepatocytes correlated negatively with the anti-fibrotic effect. Progenitor cell expansion was most prominent in cirrhotic animals, and correlated with transcript levels of pro-fibrotic genes. Animals that had resolution of fibrosis had quiescent native progenitor cells in their livers. No evidence of neoplasia was observed, even up to 9 months after transplantation. Human fetal liver progenitor cells successfully attenuate liver fibrosis in mice. They are activated in the setting of liver injury, but become quiescent when injury resolves, mimicking the behavior of de novo progenitor cells. Our data suggest that liver progenitor cells transplanted into injured livers maintain a functional role in the repair and regeneration of the liver. Stem Cells 2018;36:103-113.


Assuntos
Fígado/patologia , Transplante de Células-Tronco/métodos , Animais , Diferenciação Celular , Modelos Animais de Doenças , Células-Tronco Fetais , Humanos , Camundongos
14.
Am J Clin Pathol ; 148(6): 502-512, 2017 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-29165568

RESUMO

Objectives: Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG). Methods: SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens. Results: Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2. Conclusions: SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods.


Assuntos
Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adolescente , Adulto , Fatores Etários , Biópsia/métodos , Criança , Progressão da Doença , Feminino , Fibrose , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Adulto Jovem
15.
J Hepatol ; 66(6): 1231-1240, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28189756

RESUMO

BACKGROUND & AIMS: A wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response in obstructive cholestasis is poorly elucidated. Pericanalicular actin is known to accumulate during obstructive cholestasis. Therefore, we hypothesized that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response to obstructive cholestasis. METHODS: In vivo investigations were performed in a bile duct-ligated mouse model. Actomyosin contractility was assessed using sandwich-cultured rat hepatocytes transfected with various fluorescently labeled proteins and pharmacological inhibitors of actomyosin contractility. RESULTS: Actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex; and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2-8µm). Importantly, we show that these vesicles aid in the regurgitation of bile from the bile canaliculi. CONCLUSION: Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis. LAY SUMMARY: Bile canaliculi expand and contract in response to the amount of secreted bile, and resistance from the surrounding actin bundles. Further expansion due to bile duct blockade leads to the formation of inward blebs, which carry away excess bile to prevent bile build up in the canaliculi.


Assuntos
Actomiosina/fisiologia , Ductos Biliares/fisiopatologia , Colestase/fisiopatologia , Animais , Canalículos Biliares/patologia , Canalículos Biliares/fisiopatologia , Refluxo Biliar/fisiopatologia , Fenômenos Biomecânicos , Colestase/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Pressão , Ratos , Ratos Wistar
16.
Gut Liver ; 11(3): 401-408, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-27965475

RESUMO

Background/Aims: Comparison of the accuracy of magnetic resonance elastography (MRE) and diffusion weighted imaging (DWI) for the diagnosis of liver fibrosis in patients with chronic hepatitis B (CHB). Methods: In this retrospective analysis, we investigated 63 patients with CHB and liver fibrosis. DWI was performed with both breath-hold (DWI-BH) and free-breathing (DWI-FB) sequences (b=0, 500). The mean liver stiffness and apparent diffusion coefficient (ADC) were calculated by drawing regions of interest maps. Fibrosis staging according to the METAVIR system was independently performed by an experienced pathologist. A receiver operating curve (ROC) analysis was conducted to determine the accuracy of MRE, DWI-BH and DWI-FB in the detection and stratification of liver fibrosis. The performance of the detection of significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) was also evaluated by comparing areas under the ROC. Results: There was a moderate and significantly negative correlation between the ADC values and liver stiffness. The accuracies for the detection of ≥F2/≥F3/F4 stage fibrosis with DWI-FB, DWI-BH and MRE were 0.84/0.76/0.72, 0.72/0.83/0.79 and 0.99/0.99/0.98, respectively. The performance of MRE was significantly better than DWI-FB and DWI-BH. There were no significant differences between the performance of DWI-FB and DWI-BH. Conclusions: MRE is more accurate than DWI for the detection and stratification of liver fibrosis in CHB.


Assuntos
Imagem de Difusão por Ressonância Magnética/estatística & dados numéricos , Técnicas de Imagem por Elasticidade/estatística & dados numéricos , Hepatite B Crônica/diagnóstico por imagem , Cirrose Hepática/diagnóstico por imagem , Adulto , Idoso , Área Sob a Curva , Imagem de Difusão por Ressonância Magnética/métodos , Técnicas de Imagem por Elasticidade/métodos , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Fígado/virologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
17.
Hepatology ; 65(5): 1438-1450, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28027574

RESUMO

Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate, which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir-based therapy for 78 weeks. Progressive, indeterminate, and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. CONCLUSION: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017;65:1438-1450).


Assuntos
Hepatite B Crônica/patologia , Fígado/patologia , Adulto , Antivirais/uso terapêutico , Biópsia , Feminino , Fibrose , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade
18.
Eur Radiol ; 26(2): 398-406, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26032879

RESUMO

OBJECTIVES: Comparison of magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) for differentiating malignant and benign focal liver lesions (FLLs). METHODS: Seventy-nine subjects with 124 FLLs (44 benign and 80 malignant) underwent both MRE and DWI. MRE was performed with a modified gradient-echo sequence and DWI with a free breathing technique (b = 0.500). Apparent diffusion coefficient (ADC) maps and stiffness maps were generated. FLL mean stiffness and ADC values were obtained by placing regions of interest over the FLLs on stiffness and ADC maps. The accuracy of MRE and DWI for differentiation of benign and malignant FLL was compared using receiver operating curve (ROC) analysis. RESULTS: There was a significant negative correlation between stiffness and ADC (r = -0.54, p < 0.0001) of FLLs. Malignant FLLs had significantly higher mean stiffness (7.9kPa vs. 3.1kPa, p < 0.001) and lower mean ADC (129 vs. 200 × 10(-3)mm(2)/s, p < 0.001) than benign FLLs. The sensitivity/specificity/positive predictive value/negative predictive value for differentiating malignant from benign FLLs with MRE (cut-off, >4.54kPa) and DWI (cut-off, <151 × 10(-3)mm(2)/s) were 96.3/95.5/97.5/93.3% (p < 0.001) and 85/81.8/88.3/75% (p < 0.001), respectively. ROC analysis showed significantly higher accuracy for MRE than DWI (0.986 vs. 0.82, p = 0.0016). CONCLUSION: MRE is significantly more accurate than DWI for differentiating benign and malignant FLLs. KEY POINTS: • MRE is superior to DWI for differentiating benign and malignant focal liver lesions. • Benign lesions with large fibrous components may have higher stiffness with MRE. • Cholangiocarcinomas tend to have higher stiffness than hepatocellular carcinomas. • Hepatocellular adenomas tend to have lower stiffness than focal nodular hyperplasia. • MRE is superior to conventional MRI in differentiating benign and malignant liver lesions.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Neoplasias Hepáticas/patologia , Imagem por Ressonância Magnética/métodos , Adulto , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Fígado/patologia , Masculino , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
19.
Gastroenterology ; 150(2): 355-7.e3, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26551551

RESUMO

There have been increasing reports of food-borne zoonotic transmission of hepatitis E virus (HEV) genotype 3, which causes chronic infections in immunosuppressed patients. We performed phylogenetic analyses of the HEV sequence (partial and full-length) from 1 patient from the Middle East who underwent liver transplantation, and compared it with other orthohepevirus A sequences. We found the patient to be infected by camelid HEV. This patient regularly consumed camel meat and milk, therefore camelid HEV, which is genotype 7, might infect human beings. Our finding links consumption of camel-derived food products to post-transplantation hepatitis E, which, if detected at early stages, can be cured with antiviral therapy and reduced administration of immunosuppressive agents.


Assuntos
Camelus/virologia , Contaminação de Alimentos , Vírus da Hepatite E/patogenicidade , Hepatite E/virologia , Hepatite Crônica/virologia , Transplante de Fígado/efeitos adversos , Carne/virologia , Leite/virologia , Zoonoses , Animais , Antivirais/uso terapêutico , Genótipo , Hepatite E/diagnóstico , Hepatite E/tratamento farmacológico , Hepatite E/transmissão , Vírus da Hepatite E/genética , Hepatite Crônica/diagnóstico , Hepatite Crônica/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Filogenia , Fatores de Tempo , Resultado do Tratamento
20.
J Hepatol ; 63(5): 1173-80, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26119687

RESUMO

BACKGROUND & AIMS: A broad range of hepatocellular nodules has been reported in hepatic vascular disorders. It is not clear whether hepatocellular adenoma (HCA) in this context share the same characteristics as conventional HCA. The aim of this study was to carry out a retrospective multicenter survey of hepatocellular nodules associated with hepatic vascular disorders. METHODS: Forty-five cases were reviewed, including 32 Budd-Chiari syndrome (BCS). Benign nodules were subtyped using the HCA immunohistochemical panel. RESULTS: Nodules with a HCA morphology were observed in 11 cases. Six originated in BCS: two were liver fatty acid binding protein (LFABP) negative (one with malignant transformation); two expressed glutamine synthetase (GS) and nuclear b-catenin, two expressed C reactive protein (CRP). Among three cases with portal vein agenesis, one nodule was LFABP negative, two expressed GS and nuclear b-catenin, both with malignant transformation. In a Fallot tetralogy case, there were multiple LFABP negative nodules with borderline features and in a hepatoportal sclerosis case, the nodule looked like an inflammatory HCA. Two additional cases had nodules expressing CRP, without typical characteristics of inflammatory HCA. CONCLUSION: HCA of different immunohistochemical phenotype can develop in hepatic vascular disorders; they may have a different behavior compared to conventional HCA and be more at risk of malignant transformation.


Assuntos
Adenoma de Células Hepáticas/complicações , Biomarcadores Tumorais/biossíntese , Síndrome de Budd-Chiari/complicações , Carcinoma Hepatocelular/complicações , Neoplasias Hepáticas/complicações , Adenoma de Células Hepáticas/metabolismo , Adenoma de Células Hepáticas/patologia , Síndrome de Budd-Chiari/metabolismo , Síndrome de Budd-Chiari/patologia , Proteína C-Reativa/biossíntese , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica , Proteínas de Ligação a Ácido Graxo/biossíntese , Glutamato-Amônia Ligase/biossíntese , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos
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