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1.
J Gastroenterol Hepatol ; 38(6): 989-998, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36890337

RESUMO

BACKGROUND AND AIM: Staining for hepatitis B viral antigens is often done in liver biopsies from patients with chronic hepatitis B, but its correlates with clinical phenotypes are not well described. METHODS: Biopsies were collected from a large cohort of adults and children with chronic hepatitis B viral infection through the Hepatitis B Research Network. Immunohistochemical staining of sections was done for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) and then centrally read by the pathology committee. The degree of liver injury and pattern of staining were then correlated with clinical characteristics, including the clinical phenotype of hepatitis B. RESULTS: Biopsies from 467 subjects were studied, including 46 from children. Immunostaining for HBsAg was positive in 417 (90%) with scattered hepatocyte staining being the most common pattern. HBsAg staining correlated best with serum levels of HBsAg and hepatitis B viral DNA; the absence of HBsAg staining was often a prelude to loss of HBsAg from serum. HBcAg staining was positive in 225 (49%), and, while cytoplasmic staining was more frequent than nuclear staining, both nuclear and cytoplasmic positivity were often seen in the same specimen. Staining for HBcAg correlated with both level of viremia and liver injury. No biopsies from inactive carriers had stainable HBcAg, while 91% of the biopsies from those with hepatitis B e antigen-positive chronic hepatitis B stained positively for HBcAg. CONCLUSION: Immunostaining for hepatitis B viral antigens may yield helpful insights into liver disease pathogenesis but appears to add little to commonly used serological and biochemical blood tests.


Assuntos
Hepatite B Crônica , Hepatite B , Humanos , Antígenos de Superfície da Hepatite B , Hepatite B Crônica/patologia , Antígenos do Núcleo do Vírus da Hepatite B , Fígado/patologia , Hepatite B/diagnóstico , Vírus da Hepatite B/genética , DNA Viral
2.
Hepatology ; 77(2): 594-605, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35770681

RESUMO

BACKGROUND AND AIMS: Liver injury may persist in patients with HBV receiving antiviral therapy who have ongoing transcription and translation. We sought to assess ongoing HBV transcription by serum HBV RNA, translation by serum hepatitis B core related antigen (HBcrAg), and their associations with hepatic HBsAg and HBcAg staining in patients coinfected with HBV and HIV. METHODS: This is a cross-sectional study of 110 adults coinfected with HBV and HIV who underwent clinical assessment and liver biopsy. Immunohistochemistry (IHC) was performed for HBsAg and HBcAg. Viral biomarkers included quantitative HBsAg, HBV RNA, and HBcrAg. RESULTS: Participants' median age was 49 years (male, 93%; Black, 51%; HBeAg+, 65%), with suppressed HBV DNA (79%) and undetectable HIV RNA (77%) on dually active antiretroviral therapy. Overall, HBV RNA and HBcrAg were quantifiable in 81% and 83%, respectively (96% and 100% in HBeAg+, respectively). HBcAg staining was detected in 60% and HBsAg in 79%. Higher HBV RNA was associated with higher HBcAg and HBsAg IHC grades (both p < 0.0001). The HBsAg membranous staining pattern was significantly associated with higher HBV-RNA and HBcrAg levels. CONCLUSION: HBcAg and HBsAg IHC staining persisted despite viral suppression, and IHC grades and staining patterns correlated with markers of transcription (HBV RNA) and translation (HBcrAg). These data indicate that apparent HBV suppression is associated with residual transcription and translation that could contribute to liver pathology. Additional antiviral strategies directed to HBV protein expression may be useful to ameliorate liver injury.


Assuntos
Antirretrovirais , Coinfecção , Infecções por HIV , Vírus da Hepatite B , Hepatite B Crônica , Transcrição Viral , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores , Coinfecção/tratamento farmacológico , Coinfecção/imunologia , Coinfecção/fisiopatologia , Coinfecção/virologia , Estudos Transversais , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B , Antígenos E da Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/imunologia , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , RNA , Transcrição Viral/efeitos dos fármacos , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Biossíntese de Proteínas/efeitos dos fármacos
3.
Clin Gastroenterol Hepatol ; 21(1): 125-135.e8, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-34973459

RESUMO

BACKGROUND & AIMS: The contribution of the novel biomarkers, hepatitis B virus (HBV) RNA and HBV core-related antigen (HBcrAg), to characterization of HBV-human immunodeficiency virus (HIV) coinfection is unclear. We evaluated the longitudinal dynamics of HBV RNA and HBcrAg and their association with classical HBV serum biomarkers and liver histology and viral staining. METHODS: HBV-HIV co-infected adults from 8 North American centers entered a National Institutes of Health-funded prospective cohort study. Demographic, clinical, serological, and virological data were collected at entry and every 24 to 48 weeks for up to 192 weeks. Participants with HBV RNA and HBcrAg measured ≥2 times (N = 95) were evaluated; 56 had paired liver biopsies obtained at study entry and end of follow-up. RESULTS: Participants had a median age of 50 years; 97% were on combination anti-viral therapy. In hepatitis B e antigen (HBeAg)+ participants, there were significant declines in HBV RNA and HBcrAg over 192 weeks that tracked with declines in HBeAg, hepatitis B surface antigen, HBV DNA, and hepatitis B core antigen (HBcAg) hepatocyte staining grade (all P < .05). In HBeAg- participants, there were not significant declines in HBV RNA (P = .49) and HBcrAg (P = .63), despite modest reductions in hepatitis B surface antigen (P < .01) and HBV DNA (P = .03). HBV serum biomarkers were not significantly related to change in hepatic activity index, Ishak fibrosis score, or hepatocyte HBcAg loss (all P > .05). CONCLUSIONS: In HBV-HIV coinfected adults on suppressive dually active antiviral therapy, the use of novel HBV markers reveals continued improvement in suppression of HBV transcription and translation over time. The lack of further improvement in HBV serum biomarkers among HBeAg- patients suggests limits to the benefit of combination anti-viral therapy and provide rationale for additional agents with distinct mechanisms of action.


Assuntos
Coinfecção , Infecções por HIV , Antígenos do Núcleo do Vírus da Hepatite B , Vírus da Hepatite B , Hepatite B Crônica , Replicação Viral , Adulto , Humanos , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Biomarcadores/sangue , Coinfecção/diagnóstico , DNA Viral , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/isolamento & purificação , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Estudos Prospectivos , RNA Viral/sangue
4.
Int J Mol Sci ; 23(10)2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35628140

RESUMO

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial ß-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.


Assuntos
Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ácidos Graxos Ômega-3 , Gastroenteropatias , Microbioma Gastrointestinal , Animais , Antineoplásicos/farmacologia , Bactérias/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Ômega-6/farmacologia , Gastroenteropatias/tratamento farmacológico , Irinotecano/farmacologia , Camundongos , RNA Ribossômico 16S/genética
6.
Cancer Cell ; 40(1): 103-108.e2, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-34990570

RESUMO

Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses in a subset. Neutralization of alpha, beta, gamma, and delta SARS-CoV-2 variants is impaired relative to wildtype, regardless of vaccine type. Regardless of viral variant, mRNA1273 is the most immunogenic, followed by BNT162b2, and then Ad26.COV2.S. Neutralization of more variants (breadth) is associated with a greater magnitude of wildtype neutralization, and increases with time since vaccination; advancing age associates with a lower breadth. The concentrations of anti-spike protein antibody are a good surrogate for breadth (positive predictive value of =90% at >1,000 U/mL). Booster SARS-CoV-2 vaccines confer enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with the current vaccines increases the breadth of responses against variants.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Neoplasias/imunologia , SARS-CoV-2/imunologia , Idoso , Envelhecimento/imunologia , Antígenos Virais/imunologia , Feminino , Humanos , Imunização Secundária , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
7.
Clin Infect Dis ; 74(11): 1914-1924, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34698347

RESUMO

BACKGROUND: Fatty liver disease (FLD) and hepatitis B virus (HBV) infection occur commonly in human immunodeficiency virus (HIV). FLD resolution is associated with improvement in lipoproteins in HIV-uninfected patients. We evaluated changes in FLD in an HBV/HIV-coinfected cohort. METHODS: One hundred eight HBV/HIV-coinfected adults with baseline liver biopsies were followed every 24 weeks (median, 166 weeks) and 60 had follow-up biopsies. Baseline FLD categories (none, ≥5% steatosis, steatohepatitis), their change, and relationships with clinical and lipid/lipoprotein parameters were explored using multivariable modeling. RESULTS: Median age was 50 years, and 93% were male. At baseline 30% had FLD. With control for lipid-lowering medications and body mass index, low-density lipoprotein (LDL) cholesterol (LDL-C), LDL particle concentration (LDL-P), and apolipoprotein B (apoB) decreased and adiponectin increased over time (all P < .05); On follow-up (vs baseline), there was no significant difference in FLD category (P = .85); 60% remained without FLD, 17% had unchanged, 12% worsening, and 12% improved FLD. Baseline low-density lipoproteins (LDL-C, LDL-P, small LDL-P) and apoB appeared highest in those with unchanged FLD status (all P < .05). No associations between changes in FLD across follow-up (worsening/improvement vs unchanged) and lipid/lipoproteins changes were identified. CONCLUSIONS: In this cohort, there was no significant change in FLD prevalence over a relatively short timeframe. Baseline atherogenic lipids appeared highest in those with persistent steatosis or steatohepatitis, suggesting potentially increased cardiovascular risk in this group, but an independent relationship between individual-level change in FLD status and lipid/lipoprotein levels across follow-up was not observed.


Assuntos
Coinfecção , Fígado Gorduroso , Infecções por HIV , Hepatite B , Adulto , Apolipoproteínas B , LDL-Colesterol , Fígado Gorduroso/complicações , Feminino , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepatite B/complicações , Vírus da Hepatite B , Humanos , Lipoproteínas , Masculino , Pessoa de Meia-Idade
8.
Am J Gastroenterol ; 116(8): 1686-1697, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33840726

RESUMO

INTRODUCTION: Fatty liver disease (FLD) influences liver disease progression and liver cancer risk. We investigated the impact of FLD on liver disease severity in a large North American cohort with chronic hepatitis B virus (HBV). METHODS: Liver biopsies from 420 hepatitis B surface antigen-positive adults enrolled in the Hepatitis B Research Network and who were not on HBV therapy in the previous month were evaluated for inflammation and fibrosis. Steatohepatitis was based on steatosis, hepatocyte ballooning ± Mallory-Denk bodies, and perisinusoidal fibrosis. Models evaluated factors associated with steatohepatitis, and the associations of steatohepatitis with fibrosis, and longitudinal alanine aminotransferase, aspartate aminotransferase, and Fibrosis-4. RESULTS: The median age was 42 years, 62.5% were male, and 79.5% were Asian. One hundred thirty-two (31.4%) patients had FLD (77 [18.3%] steatosis only, 55 [13.1%] steatohepatitis). Older age, overweight/obesity, and diabetes were associated with steatohepatitis. Steatohepatitis (vs no FLD) was associated with 1.68 times higher risk of advanced fibrosis at baseline (95% confidence interval, 1.12-2.51), and there was an indication of higher incident cirrhosis rate during follow-up. Steatohepatitis vs no FLD was also independently associated with, on average, 1.39 times higher alanine aminotransferase (P < 0.01) and 1.25 times higher Fibrosis-4 (P = 0.04) across 4 years. DISCUSSION: Coexisting steatosis occurred in nearly a third of adults (13% had steatohepatitis) with chronic HBV in this North American cohort who underwent liver biopsies. Steatohepatitis was associated with advanced fibrosis and higher biochemical measures of hepatic inflammation over time. Therefore, in addition to viral suppression, screening for and managing metabolic abnormalities is important to prevent disease progression in HBV.


Assuntos
Fígado Gorduroso/epidemiologia , Hepatite B Crônica/complicações , Adolescente , Adulto , Fatores Etários , Idoso , Biópsia , Progressão da Doença , Fígado Gorduroso/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fatores de Risco
9.
Hepatology ; 74(3): 1174-1189, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33743541

RESUMO

BACKGROUND AND AIMS: Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined. APPROACH AND RESULTS: Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm3 and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P = 0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P = 0.58). CONCLUSIONS: In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.


Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite B Crônica/tratamento farmacológico , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Coinfecção , Quimioterapia Combinada , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Infecções por HIV/complicações , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Humanos , Lamivudina/uso terapêutico , Fígado/patologia , Masculino , Pessoa de Meia-Idade , América do Norte , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico , Resultado do Tratamento , Adulto Jovem
10.
Ultrasound Med Biol ; 46(4): 972-980, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32005510

RESUMO

In this study, we evaluated the diagnostic accuracy of shear wave elastography (SWE) for differentiating high-risk non-alcoholic steatohepatitis (hrNASH) from non-alcoholic fatty liver and low-risk non-alcoholic steatohepatitis (NASH). Patients with non-alcoholic fatty liver disease scheduled for liver biopsy underwent pre-biopsy SWE. Ten SWE measurements were obtained. Biopsy samples were reviewed using the NASH Clinical Research Network Scoring System and patients with hrNASH were identified. Receiver operating characteristic curves for SWE-based hrNASH diagnosis were charted. One hundred sixteen adult patients underwent liver biopsy at our institution for the evaluation of non-alcoholic fatty liver disease. The area under the receiver operating characteristic curve of SWE for hrNASH diagnosis was 0.73 (95% confidence interval: 0.61-0.84, p < 0.001). The Youden index-based optimal stiffness cutoff value for hrNASH diagnosis was calculated as 8.4 kPa (1.67 m/s), with a sensitivity of 77% and specificity of 66%. SWE may be useful for the detection of NASH patients at risk of long-term liver-specific morbidity and mortality.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Biomarcadores , Biópsia com Agulha de Grande Calibre , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Crohns Colitis 360 ; 1(2): otz009, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31423487

RESUMO

AIM: The aim of this study was to determine the immunologic effects and safety of oral anti-CD3 in patients with ulcerative colitis (UC). METHODS: An open-label pilot study of orally delivered anti-CD3 was performed in patients with moderate-to-severe UC. The primary end points were changes in immunologic parameters and evaluation for safety. RESULTS: Six subjects received oral OKT3. Biologic effects of oral anti-CD3 included significantly increased proliferation in response to anti-CD3 and anti-inflammatory gene expression profile in peripheral blood mononuclear cells. No serious treatment-related adverse events occurred. CONCLUSION: Orally delivered anti-CD3 resulted in immunologic changes in patients with UC.

12.
Cancer Immunol Res ; 7(9): 1485-1496, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315913

RESUMO

The tumor microenvironment in leukemia and solid tumors induces a shift of activated CD8+ cytotoxic T cells to an exhausted state, characterized by loss of proliferative capacity and impaired immunologic synapse formation. Efficient strategies and targets need to be identified to overcome T-cell exhaustion and further improve overall responses in the clinic. Here, we took advantage of the Eµ-TCL1 chronic lymphocytic leukemia (CLL) and B16 melanoma mouse models to assess the role of the homophilic cell-surface receptor SLAMF6 as an immune-checkpoint regulator. The transfer of SLAMF6+ Eµ-TCL1 cells into SLAMF6-/- recipients, in contrast to wild-type (WT) recipients, significantly induced expansion of a PD-1+ subpopulation among CD3+CD44+CD8+ T cells, which had impaired cytotoxic functions. Conversely, administering anti-SLAMF6 significantly reduced the leukemic burden in Eµ-TCL1 recipient WT mice concomitantly with a loss of PD-1+CD3+CD44+CD8+ T cells with significantly increased effector functions. Anti-SLAMF6 significantly reduced leukemic burden in the peritoneal cavity, a niche where antibody-dependent cellular cytotoxicity (ADCC) is impaired, possibly through activation of CD8+ T cells. Targeting of SLAMF6 affected tumor growth not only in B cell-related leukemia and lymphomas but also in nonhematopoietic tumors such as B16 melanoma, where SLAMF6 is not expressed. In vitro exhausted CD8+ T cells showed increased degranulation when anti-human SLAMF6 was added in culture. Taken together, anti-SLAMF6 both effectively corrected CD8+ T-cell dysfunction and had a direct effect on tumor progression. The outcomes of our studies suggest that targeting SLAMF6 is a potential therapeutic strategy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Imunomodulação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Biomarcadores , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunomodulação/genética , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/patologia , Melanoma Experimental , Camundongos , Camundongos Knockout , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Microambiente Tumoral/imunologia
13.
J Ultrasound Med ; 38(1): 103-111, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29761535

RESUMO

OBJECTIVES: To assess performance of shear wave elastography for evaluation of fibrosis and the histologic stage in patients with autoimmune liver disease (ALD) and to validate previously established advanced fibrosis cutoff values in this cohort. METHODS: Shear wave elastography was performed on patients with ALD with an Aixplorer ultrasound system (SuperSonic Imagine, Aix-en-Provence, France) using an SC6-1 transducer. The median estimated tissue Young modulus was calculated from sets of 8 to 10 elastograms. A blinded, subspecialty-trained pathologist reviewed biopsy specimens. The METAVIR classification was used to stage liver fibrosis and necroinflammation. Steatosis was graded from 0 to 4+. The Kendall τ-b correlation test was performed to identify the correlation between the estimated tissue Young modulus and fibrosis, steatosis, and the necroinflammatory score. The Spearman correlation test was performed to identify the correlation between the estimated tissue Young modulus and clinical data. The diagnostic performance of shear wave elastography for differentiating METAVIR stage F2 or higher from F0 and F1 fibrosis was evaluated by a receiver operating characteristic (ROC) curve analysis. RESULTS: Fifty-one patients with ALD were analyzed. The estimated tissue Young modulus was positively correlated with the fibrosis stage and necroinflammation score (r = 0.386; P < .001; r = 0.338; P = .002, respectively) but not steatosis (r = -0.091; P = .527). Serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin values were positively correlated with the estimated tissue Young modulus (r = 0.501; P < .001; r = 0.44; P = .001; r = 0.291; P = .038). The serum albumin value was negatively correlated (r = -0.309; P = .033). The area under the ROC curve was 0.781 (95% confidence interval, 0.641-0.921) for distinguishing F2 or greater fibrosis from F0 and F1 fibrosis. Based on the ROC curve, an optimal cutoff value of 9.15 kPa was identified (sensitivity, 83.3%; specificity, 72.7%). CONCLUSIONS: Shear wave elastography is a novel noninvasive adjunct to liver biopsy in evaluation and staging of patients with ALD, showing the potential for serial evaluations of disease progression and treatment responses.


Assuntos
Doenças Autoimunes/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Hepatopatias/diagnóstico por imagem , Doenças Autoimunes/complicações , Doenças Autoimunes/patologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Hepatopatias/complicações , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
14.
Microbiome ; 6(1): 205, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30424806

RESUMO

BACKGROUND: Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS. RESULTS: Here we show that gut microbiome mediates the preventive effect of estrogen (17ß-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17ß-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17ß-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17ß-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters. CONCLUSIONS: In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.


Assuntos
Estradiol/farmacologia , Estrogênios/farmacologia , Microbioma Gastrointestinal/fisiologia , Síndrome Metabólica/prevenção & controle , Proteobactérias/metabolismo , Caracteres Sexuais , Fosfatase Alcalina/biossíntese , Animais , Carga Bacteriana , Transplante de Microbiota Fecal , Feminino , Isoflavonas/farmacologia , Lipopolissacarídeos/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Ultrasound Med Biol ; 44(12): 2749-2758, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30266215

RESUMO

This study validates a non-invasive, quantitative technique to diagnose steatosis within tissue. The proposed method is based on two fundamental concepts: (i) the speed of sound in a fatty liver is lower than that in a healthy liver and (ii) the quality of an ultrasound image is maximized when the beamformer's speed of sound matches the speed in the medium under examination. The method uses image brightness and sharpness as quantitative image-quality metrics to predict the true sound speed and capture the effects of fat infiltration, while accounting for the transmission through subcutaneous fat. Ex vivo testing on sheep liver, mouse livers and tissue-mimicking phantoms indicated the technique's ability to predict the true speed of sound with errors less than 0.5% and to quantify the inverse correlation between fat content and speed of sound.


Assuntos
Fígado Gorduroso/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Ultrassonografia/métodos , Animais , Modelos Animais de Doenças , Fígado/diagnóstico por imagem , Camundongos , Imagens de Fantasmas , Reprodutibilidade dos Testes , Ovinos
16.
Ultrasound Med Biol ; 44(11): 2209-2222, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30143339

RESUMO

We evaluated variation in fibrosis staging caused by depth, pre-load force and measurement off-axis distance on different ultrasound shear wave elastography (SWE) systems prospectively in 20 patients with diffuse liver disease. Shear wave speed (SWS) was measured with transient elastography, acoustic radiation force impulse (ARFI) and 2-D shear wave elastography (SWE). ARFI and 2-D-SWE measurements were obtained at different depths (3, 5 and 7 cm), with different pre-load forces (4, 7 and 10N and variable) and at 0, 2 and 4cm off the central axis of the transducer. A single, blinded pathologist staged fibrosis using the METAVIR system (F0-F4). Area under the receiver operating characteristic curve was charted to differentiate significant fibrosis (F ≥ 2). Depth was the only factor found to influence ARFI-derived values; no acquisition factors were found to affect 2-D-SWE SWS values. ARFI and 2-D-SWE for diagnosis of significant fibrosis at a depth of 7cm along the central axis had good diagnostic performance (areas under the receiver operating characteristic curve: 0.92 and 0.82, respectively), comparable to that of transient elastography. Further investigation of this finding will likely be of interest.


Assuntos
Técnicas de Imagem por Elasticidade/instrumentação , Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transdutores , Adulto Jovem
17.
Science ; 359(6380): 1161-1166, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29420262

RESUMO

Polymorphisms in C1orf106 are associated with increased risk of inflammatory bowel disease (IBD). However, the function of C1orf106 and the consequences of disease-associated polymorphisms are unknown. Here we demonstrate that C1orf106 regulates adherens junction stability by regulating the degradation of cytohesin-1, a guanine nucleotide exchange factor that controls activation of ARF6. By limiting cytohesin-1-dependent ARF6 activation, C1orf106 stabilizes adherens junctions. Consistent with this model, C1orf106-/- mice exhibit defects in the intestinal epithelial cell barrier, a phenotype observed in IBD patients that confers increased susceptibility to intestinal pathogens. Furthermore, the IBD risk variant increases C1orf106 ubiquitination and turnover with consequent functional impairments. These findings delineate a mechanism by which a genetic polymorphism fine-tunes intestinal epithelial barrier integrity and elucidate a fundamental mechanism of cellular junctional control.


Assuntos
Junções Aderentes/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Doenças Inflamatórias Intestinais/genética , Fosfoproteínas/metabolismo , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/metabolismo , Animais , Células CACO-2 , Células HEK293 , Humanos , Imunoprecipitação , Mucosa Intestinal/patologia , Camundongos , Camundongos Mutantes , Fosfoproteínas/genética , Polimorfismo Genético , Proteólise , Risco , Ubiquitinação/genética
18.
Dig Dis Sci ; 62(8): 2021-2034, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28424943

RESUMO

BACKGROUND AND AIMS: Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. METHODS: Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. RESULTS: Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. CONCLUSIONS: IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.


Assuntos
Fosfatase Alcalina/administração & dosagem , Suplementos Nutricionais , Fígado Gorduroso Alcoólico/prevenção & controle , Alanina Transaminase/sangue , Animais , Técnicas de Cocultura , Citocinas/análise , Citocinas/sangue , Etanol , Fígado Gorduroso Alcoólico/sangue , Fígado Gorduroso Alcoólico/enzimologia , Feminino , Células Estreladas do Fígado/enzimologia , Hepatócitos/enzimologia , Intestinos/enzimologia , Lipogênese , Lipopolissacarídeos/sangue , Fígado/química , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Ativador de Plasminogênio Tecidual , Triglicerídeos/análise
19.
Ultrasound Med Biol ; 43(6): 1125-1133, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28341490

RESUMO

The purpose of this study was to determine the validity of previously established ultrasound shear wave elastography (SWE) cut-off values (≥F2 fibrosis) on an independent cohort of patients with chronic liver disease. In this cross-sectional study, approved by the institutional review board and compliant with the Health Insurance Portability and Accountability Act, 338 patients undergoing liver biopsy underwent SWE using an Aixplorer ultrasound machine (SuperSonic Imagine, Aix-en-Provence, France). Median SWE values were calculated from sets of 10 elastograms. A single blinded pathologist evaluated METAVIR fibrosis staging as the gold standard. The study analyzed 277 patients with a mean age of 48 y. On pathologic examination, 212 patients (76.5%) had F0-F1 fibrosis, whereas 65 (23.5%) had ≥F2 fibrosis. Spearman's correlation of fibrosis with SWE was 0.456 (p < 0.001). A cut-off value of 7.29 kPa yielded sensitivity of 95.4% and specificity of 50.5% for the diagnosis of METAVIR stage ≥F2 liver fibrosis in patients with liver disease using the SuperSonic Imagine Aixplorer SWE system.


Assuntos
Algoritmos , Técnicas de Imagem por Elasticidade/métodos , Interpretação de Imagem Assistida por Computador/métodos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Módulo de Elasticidade , Feminino , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resistência ao Cisalhamento , Estresse Mecânico , Adulto Jovem
20.
Cell Rep ; 17(11): 2955-2965, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27974209

RESUMO

Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis.


Assuntos
Hexosiltransferases/genética , Doenças Inflamatórias Intestinais/genética , Proteínas de Membrana/genética , Animais , Apoptose , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/genética , Glicosilação , Hexosiltransferases/metabolismo , Humanos , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/patologia , Proteínas de Membrana/metabolismo , Camundongos
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