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1.
Liver Int ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32153096

RESUMO

BACKGROUND & AIMS: Liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (GGT), have been suggested as surrogate markers of various cardiovascular diseases. However, previous studies assessed liver enzymes only once at baseline. We investigated the association between liver enzyme variability and the risk of mortality and cardiovascular outcomes in general population. METHODS: A total of 6 496 271 subjects participating in ≥3 health examinations within the previous 5 years including the index year (2009-2010) were included. Variability was measured using variability independent of the mean. Cox proportional hazard models adjusting demographic factors, comorbidities, blood pressure, total cholesterol, glomerular filtration rate and baseline liver enzyme level were used. RESULTS: During a median follow-up of 6 years, there were 106 413 deaths (1.6%), 53 385 myocardial infarctions (MI, 0.8%), 65 143 atrial fibrillations (AF, 1.0%) and 50 139 congestive heart failures (CHF, 0.7%). High variability in AST, ALT and GGT was associated with a higher risk for all-cause mortality, MI, AF and CHF. The degree of association was largest for GGT variability. For the highest quartile of GGT variability relative to the lowest quartile, the hazard ratios (95% confidence intervals) were 1.32 (1.28-1.35) for all-cause mortality, 1.16 (1.11-1.20) for MI, 1.28 (1.18-1.38) for AF and 1.25 (1.20-1.30) for CHF. These findings were consistent regardless of alcohol consumption, body mass index and degree of fatty liver. Sensitivity analysis also revealed similar results. CONCLUSIONS: Higher visit-to-visit variability of liver enzymes was an independent predictor of all-cause mortality and cardiovascular events.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32128882

RESUMO

BACKGROUND AND AIM: As the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, patients with both NAFLD and chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is also frequently found. This study aimed to investigate the clinical impact of concurrent NAFLD on the prognosis of patients with CHB-related HCC. METHODS: Patients with CHB-related HCC who underwent surgical resection were consecutively selected from August 2009 to December 2013. The association between histologically proven concurrent NAFLD and clinical outcomes were analyzed. Propensity score (PS) matching was adapted to adjust for baseline characteristics. We also investigated the presence of nonalcoholic steatohepatitis (NASH) among patients with NAFLD and its association with clinical outcomes. RESULTS: Among 338 CHB-related HCC patients selected, 196 patients (58.0%) were diagnosed with concurrent NAFLD. The median follow-up duration was 74.9 months. The patients with NAFLD tended to have better recurrence-free survival (RFS; log-rank, P = 0.16) and had significantly better overall survival (OS; log-rank, P = 0.004) than those without NAFLD. However, the survival benefit of the concurrent NAFLD was not significant in a multivariable Cox analysis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73, P = 0.84) or an analysis after PS matching (log-rank, P = 0.57). Regarding the presence or absence of NASH, no differences in the RFS (log-rank, P = 0.61) and OS (log-rank, P = 0.26) were found. CONCLUSIONS: Concurrent NAFLD was not associated with both RFS and OS in patients with CHB-related HCC after adjusting for baseline characteristics. Moreover, NAFLD patients with NASH did not have significantly different clinical outcomes compared with NAFLD patients without NASH.

3.
Eur J Gastroenterol Hepatol ; 32(3): 378-385, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32011388

RESUMO

OBJECTIVES: Hepatocellular carcinoma can develop after hepatitis C virus eradication. We developed a new hepatocellular carcinoma risk score (HCC-SVR score) based on independent predictors for chronic hepatitis C after sustained virological response. METHODS: Between 2003 and 2016, a total of 1193 patients with chronic hepatitis C who achieved sustained virological response through antiviral therapy were included (669 for training cohort and 524 for validation cohort). The HCC-SVR score was developed using multivariate Cox proportional hazards regression modelling. RESULTS: Hepatocellular carcinoma (n = 19) occurred more frequently in older, male patients and was associated with liver cirrhosis; hypertension; diabetes; lower platelet count; higher alpha-fetoprotein, aspartate, and alanine aminotransferase; lower total cholesterol; and higher fibrosis-4 index (FIB-4) (all P < 0.05). FIB-4 (hazard ratio = 1.080), male gender (hazard ratio = 8.189), and higher alpha-fetoprotein (hazard ratio = 1.060) independently predicted hepatocellular carcinoma (all P < 0.05). HCC-SVR score successfully predicted hepatocellular carcinoma development risk [area under receiver operating characteristic curve (AUC) = 0.771, 0.857, and 0.911 at 2, 4, and 6 years, respectively]. The cumulative incidence rate of hepatocellular carcinoma differed significantly among groups stratified by HCC-SVR risk score (0-2 points, low; 3-7 points, intermediate; 8-9 points, high risk) (all P < 0.05 by log-rank test). HCC-SVR score was maintained in a validation cohort (n = 524) (AUC = 0.728 at 2 years, 0.737 at 4 years, and 0.809 at 6 years). CONCLUSION: The HCC-SVR score enables risk stratification for hepatocellular carcinoma development at sustained virological response in patients with chronic hepatitis C.

4.
Gut Liver ; 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31816672

RESUMO

Background/Aims: The risk for colonoscopic postpolypectomy bleeding (PPB) in patients with chronic liver disease (CLD) remains unclear. We determined the incidence and risk factors for colonoscopic PPB in patients with CLD, especially those with liver cirrhosis. Methods: We retrospectively reviewed the medical records of patients with CLD who underwent colonoscopic polypectomy at Seoul National University Hospital between 2011 and 2014. The study endpoints were immediate and delayed PPB. Results: A total of 1,267 consecutive patients with CLD were included in the study. Immediate PPB occurred significantly more often in the Child-Pugh (CP) B or C cirrhosis group (17.5%) than in the CP-A (6.3%) and chronic hepatitis (4.6%) groups (p<0.001). Moreover, the incidence of delayed PPB in the CP-B or C cirrhosis group (4.4%) was significantly higher than that in the CP-A (0.7%) and chronic hepatitis (0.2%) groups (p<0.001). The independent risk factors for immediate PPB were CP-B or C cirrhosis (p=0.011), a platelet count <50,000/µL (p<0.001), 3 or more polyps (p=0.017), endoscopic mucosal resection or submucosal dissection (p<0.001), and polypectomy performed by trainees (p<0.001). The independent risk factors for delayed PPB were CP-B or C cirrhosis (p=0.009), and polyps >10 mm in size (p=0.010). Conclusions: Patients with CP-B or C cirrhosis had an increased risk for bleeding following colonoscopic polypectomy.

5.
Cancers (Basel) ; 11(11)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31689972

RESUMO

BACKGROUND: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. METHODS: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre- and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). RESULTS: The changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37-3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54-8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. CONCLUSION: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

6.
Gut Liver ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31640304

RESUMO

Background/Aims: Prognostic models are lacking for patients with recurrent hepatocellular carcinoma (HCC) following surgical resection. This study devised and validated a new hepatoma arterial-embolization prognostic (HAP) score optimized for use in patients undergoing treatment with transarterial chemoembolization (TACE) for recurrence subsequent to surgical resection of HCC. Methods: Training cohort (n=424) and validation cohort (n=350) patients with recurrent HCC after resection treated with TACE between 2003 and 2016 were enrolled. Cox regression and area under the receiver operating characteristic curve (AUC) analyses were used to identify risk factors for survival and to calculate the predictive performance of risk scores, respectively. Results: The median age of the study population was 59.2 years. α-Fetoprotein >400 ng/mL (hazard ratio [HR]=1.815), serum albumin ≤3.5 g/dL (HR=1.966), tumor number ≥2 (HR=1.425), tumor size >5 cm at resection or recurrence (HR=1.356), segmental portal vein invasion at resection or recurrence (HR=2.032), and time from resection to recurrence ≤1 years (HR=1.849) independently predicted survival (all p<0.05). The postoperative HAP (pHAP) model based on the rounded HRs of these variables showed an AUC of 0.723 for predicting survival at 3 years, which was significantly higher than AUCs of other HAP-based models, including HAP, modified HAP, and modified HAP-II scores (0.578-0.621) (all p<0.05). The accuracy of pHAP was maintained in the entire cohort (n=774; AUC=0.776 at 3 years). Conclusions: A new pHAP score optimized for patients treated with TACE due to recurrent HCC after resection showed acceptable accuracy and was externally validated. Further studies of means by which to select treatment options other than TACE for high-risk patients according to pHAP scores are warranted.

7.
Gut Liver ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31533399

RESUMO

Background/Aims: Patients with an intermediate stage of hepatocellular carcinoma (HCC) represent a highly heterogeneous population; therefore, many models have been proposed to predict the survival of these patients. The aim of this study was to evaluate the prognostic performance of a novel subclassification for tumors classified as Barcelona Clinic Liver Cancer (BCLC) stage B using the Model to Estimate Survival in Ambulatory HCC patients (MESIAH). Methods: This analysis was based on 377 patients with HCC treated at Seoul National University Hospital (training cohort) and 189 patients at the Soonchunhyang University Bucheon Hospital (validation cohort). Four subclassification systems were tested: MESIAH; original BCLC B subclassification (B1, B2, B3, and B4); modified model A (B1, B2, and B3+B4); and modified model B (B1, B2+B3, and B4). Results: Median survival progressively decreased from stage B1 through stages B2 to B3 according to the new MESIAH subclassification (p<0.001). Moreover, significantly different survival among contiguous stages was observed. In the multivariable Cox regression, the MESIAH subclassification was an independent predictor of overall survival (p<0.001). In terms of discrimination and calibration, MESIAH performed better than the original BCLC B subclassification, modified model A and modified model B. Conclusions: The MESIAH model would be an effective tool for stratifying heterogeneous BCLC stage B cancer, and the ability of this model to predict survival is better than that of the other previously proposed models.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31490415

RESUMO

OBJECTIVES: Hepatocellular carcinoma can develop after hepatitis C virus eradication. We developed a new hepatocellular carcinoma risk score (HCC-SVR score) based on independent predictors for chronic hepatitis C after sustained virological response. METHODS: Between 2003 and 2016, a total of 1193 patients with chronic hepatitis C who achieved sustained virological response through antiviral therapy were included (669 for training cohort and 524 for validation cohort). The HCC-SVR score was developed using multivariate Cox proportional hazards regression modelling. RESULTS: Hepatocellular carcinoma (n = 19) occurred more frequently in older, male patients and was associated with liver cirrhosis; hypertension; diabetes; lower platelet count; higher alpha-fetoprotein, aspartate, and alanine aminotransferase; lower total cholesterol; and higher fibrosis-4 index (FIB-4) (all P < 0.05). FIB-4 (hazard ratio = 1.080), male gender (hazard ratio = 8.189), and higher alpha-fetoprotein (hazard ratio = 1.060) independently predicted hepatocellular carcinoma (all P < 0.05). HCC-SVR score successfully predicted hepatocellular carcinoma development risk [area under receiver operating characteristic curve (AUC) = 0.771, 0.857, and 0.911 at 2, 4, and 6 years, respectively]. The cumulative incidence rate of hepatocellular carcinoma differed significantly among groups stratified by HCC-SVR risk score (0-2 points, low; 3-7 points, intermediate; 8-9 points, high risk) (all P < 0.05 by log-rank test). HCC-SVR score was maintained in a validation cohort (n = 524) (AUC = 0.728 at 2 years, 0.737 at 4 years, and 0.809 at 6 years). CONCLUSION: The HCC-SVR score enables risk stratification for hepatocellular carcinoma development at sustained virological response in patients with chronic hepatitis C.

9.
Cancers (Basel) ; 11(9)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484287

RESUMO

BACKGROUND AND AIMS: Several models have been developed to predict tumor the recurrence of hepatocellular carcinoma (HCC) after liver transplantation besides the conventional Milan criteria (MC), including the MoRAL score. This study aimed to compare the prognostication power of the MoRAL score to most models designed so far in the Eastern and Western countries. METHODS: This study included 564 patients who underwent living donor liver transplantation (LDLT) in three large-volume hospitals in Korea. The primary and secondary endpoints were time-to-recurrence, and overall survival (OS), respectively. The performance of the MoRAL score was compared with those of other various Liver transplantation (LT) criteria, including the Milan criteria, University of California San Francisco (UCSF) criteria, up-to-seven criteria, Kyoto criteria, AFP model, total tumor volume/AFP criteria, Metroticket 2.0 model, and Weill Cornell Medical College group model. RESULTS: The median follow-up duration was 78.1 months. Among all models assessed, the MoRAL score showed the best discrimination function for predicting the risk of tumor recurrence after LT, with c-index of 0.78, compared to other models (all p < 0.001). The MoRAL score also represented the best calibration function by Hosmer-Lemeshow test (p = 0.15). Especially in the beyond-MC sub-cohort, the MoRAL score predicted tumor recurrence (c-index, 0.80) and overall survival (OS) (c-index, 0.70) significantly better than any other models (all p < 0.001). When the MoRAL score was low (<314.8), the five-year cumulative risks of tumor recurrence and death were excellent in beyond-MC (27.8%, and 20.5%, respectively) and within-MC (16.3%, and 21.1%, respectively) sub-cohorts. CONCLUSIONS: The MoRAL score provides the most refined prognostication for predicting HCC recurrence after LDLT.

11.
BMC Cancer ; 19(1): 523, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151419

RESUMO

BACKGROUND: Several randomized controlled trials have shown that adjuvant immunotherapy with autologous cytokine-induced killer (CIK) cells prolongs recurrence-free survival (RFS) after curative treatment for hepatocellular carcinoma (HCC). We investigated the efficacy of adjuvant immunotherapy with activated CIK cells in real-world clinical practice. METHODS: A total of 59 patients who had undergone curative surgical resection or radiofrequency ablation for stage I or II HCC, and subsequently received adjuvant CIK cell immunotherapy at two large-volume centers in Korea were retrospectively included. Propensity score matching with a 1:1 ratio was conducted to avoid possible bias, and 59 pairs of matched control subjects were also generated. The primary endpoint was RFS and the secondary endpoints were overall survival and safety. RESULTS: The median follow-up duration was 28.0 months (interquartile range, 22.9-42.3 months). In a univariable analysis, the immunotherapy group showed significantly longer RFS than the control group (hazard ratio [HR], 0.42; 95% CI, 0.22-0.80; log-rank P = 0.006). The median RFS in the control group was 29.8 months, and the immunotherapy group did not reach a median RFS. A multivariable Cox proportional hazard analysis showed that immunotherapy was an independent predictor for HCC recurrence (adjusted HR, 0.38; 95% CI, 0.20-0.73; P = 0.004). The overall incidence of adverse events in the immunotherapy group was 16/59 (27.1%) and no patient experienced a grade 3 or 4 adverse event. CONCLUSIONS: The adjuvant immunotherapy with autologous CIK cells after curative treatment safely prolonged the RFS of HCC patients in a real-world setting.


Assuntos
Carcinoma Hepatocelular/terapia , Células Matadoras Induzidas por Citocinas/transplante , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/terapia , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , República da Coreia , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo
12.
Eur Radiol ; 29(12): 6499-6507, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31175413

RESUMO

OBJECTIVES: To evaluate the diagnostic performance of attenuation imaging (ATI) in the detection of hepatic steatosis compared with a histopathology gold standard. METHODS: We prospectively enrolled 108 consecutive patients (35 males; median age, 54.0 years) who underwent percutaneous liver biopsy for evaluation of diffuse liver disease between January 2018 and November 2018 in a tertiary academic center. Grayscale ultrasound examination with ATI was performed just before biopsy, and an attenuation coefficient (AC) was obtained from each patient. The degree of hepatic steatosis, fibrosis stage, and necroinflammatory activity were assessed on histopathologic examination. The significant factor associated with the AC was found by a linear regression analysis, and the diagnostic performance of the AC for the classification into each hepatic steatosis stage was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: The distribution of hepatic steatosis grade on histopathology was 53/11/22/16/6 for none/mild (< 10%)/mild (≥ 10%)/moderate/severe steatosis, respectively. The area under the ROC curve, sensitivity, specificity, and optimal cutoff AC value for detection of hepatic steatosis ranged from 0.843-0.926, 74.5-100.0%, 77.4-82.8%, and 0.635-0.745, respectively. Multivariate analysis revealed that the degree of steatosis was the only significant determinant factor for the AC. CONCLUSIONS: The AC from ATI provided good diagnostic performance in detecting the varying degrees of hepatic steatosis. The degree of steatosis was the only significant factor affecting the AC, whereas fibrosis and inflammation were not. KEY POINTS: • Attenuation imaging (ATI) is based on two-dimensional grayscale ultrasound images that can incorporate into routine ultrasound examinations with less than 2 min of acquisition time. • ATI provided good diagnostic performance in detecting the varying degrees of hepatic steatosis with an area under the ROC curves ranging from 0.843 to 0.926, and there was no technical failure in this study indicating high applicability of this technique. • The degree of hepatic steatosis was the only significant factor affecting the result of ATI examination.


Assuntos
Fígado Gorduroso/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Ultrassonografia/métodos , Adulto , Biópsia , Biópsia por Agulha , Estudos de Avaliação como Assunto , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
13.
Liver Int ; 39(9): 1776-1785, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31162879

RESUMO

BACKGROUND & AIMS: There is no proven treatment for ursodeoxycholic acid (UDCA)-refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long-term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA-refractory PBC. METHODS: Patients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel-Byar method. RESULTS: A total of 100 UDCA-refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow-up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87-8.27, P < 0.001). Among 58 non-cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR = 0.12, P = 0.04). Hepatic deterioration (Child-Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR = 0.12, P = 0.04). CONCLUSIONS: In patients with UDCA-refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration.

14.
Gut Liver ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31060115

RESUMO

Background/Aims: Renal toxicity is a concern in patients with chronic hepatitis B taking nucleotide analogues, such as adefovir (ADV) and tenofovir disoproxil fumarate (TDF). We sought to determine the long-term renal effects of nucleotide analogue treatment versus entecavir (ETV) treatment. Methods: In this retrospective single-center study, we selected 87 patients who were treated with ADV and subsequently with TDF from June 2008 to December 2013. ETV-treated patients were matched by treatment duration. We analyzed the creatinine increase over 0.5 mg/dL, glomerular filtration rate (GFR) decrease over 25%, phosphorus decrease under 2.0 mg/dL, and dose reduction of antiviral agents. Results: The median follow-up period was 60.0 months for both groups. The incidence of liver cirrhosis was higher in the ADV-TDF group than in the ETV group (32.2% vs 74.7%, p<0.01). Creatinine increased in both groups during follow-up, but the difference was not significant (5.7% and 2.3%, p=0.44). In addition, GFR decreased more often in the ADV-TDF group than in the ETV group (31.0% and 14.9%, p=0.01). After multivariate Cox regression analysis, ADV-TDF treatment was significantly associated with a GFR decrease over 25% (hazard ratio, 2.10; 95% confidence interval, 1.08 to 4.10; p=0.03) after adjusting for the baseline GFR decrease. Conclusions: Patients taking nucleotide analogues had a significantly higher number of renal events than did those taking ETV. Clinicians should be aware of the development of renal toxicity in this patient population. Further long-term studies are warranted.

15.
J Clin Gastroenterol ; 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31033805

RESUMO

BACKGROUND AND GOALS: Although nonalcoholic fatty liver disease (NAFLD) is a risk factor of hepatocellular carcinoma (HCC), it is unclear whether NAFLD additionally increases the risk of HCC among chronic hepatitis B (CHB) patients. This study evaluated the association between NAFLD and the risk of HCC in patients whose hepatitis B virus (HBV) was well controlled. STUDY: This study included consecutive CHB patients whose serum HBV DNA levels were continuously suppressed <2000 IU/mL with antiviral treatment. Fatty liver was radiologically diagnosed. Patients with concomitant hepatitis C infection, autoimmune hepatitis, or excessive alcohol use were excluded. RESULTS: Among 826 patients, 86 patients (10.4%) developed HCC during the study period (median, 43.1 mo). The patients with NAFLD (N=260) had a significantly higher risk for HCC compared with patients without NAFLD (N=566) (adjusted hazard ratio, 1.67; 95% confidence interval, 1.05-2.63; P=0.03) after adjustment for age, the presence of cirrhosis, hepatitis B envelop antigen positivity, low-level viremia and hypertension. There was significant association between incomplete biochemical response (IBR) (alanine aminotransferase levels ≥40 IU/L) and the presence of NAFLD (P<0.001 by χ test). IBR at the time of virological response was associated with a significantly higher risk of HCC development (adjusted hazard ratio, 1.63; 95% confidence interval, 1.06-2.54; P=0.03). CONCLUSIONS: NAFLD increases the risk of HCC in patients with CHB in whom HBV is effectively suppressed by antivirals. Patients with IBR should be suspected of concurrent NAFLD. Further study is warranted to evaluate whether improvement of NAFLD might decrease the risk of HCC development.

16.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875800

RESUMO

This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor to target HK-II. The human HCC cell line was tested as both subcutaneous and orthotopic tumor xenograft models in BALB/c nu/nu mice. The prognostic role of HK-II was evaluated in data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patients treated with sorafenib. Quantitative real-time PCR, western blot analysis, and immunohistochemical staining revealed that HK-II expression is upregulated in the presence of sorafenib. Further analysis of the endoplasmic reticulum-stress network model in two different murine HCC models showed that the introduction of additional stress by 3-BP treatment synergistically increased the in vivo/vitro efficacy of sorafenib. We found that HCC patients with increased HK-II expression in the TCGA database showed poor overall survival, and also confirmed similar results for TCGA database HCC patients who had undergone sorafenib treatment. These results suggest that HK-II is a promising therapeutic target to enhance the efficacy of sorafenib and that HK-II expression might be a prognostic factor in HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Hexoquinase/genética , Hexoquinase/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Piruvatos/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Prognóstico , Piruvatos/farmacologia , Sorafenibe/farmacologia , Análise de Sobrevida , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Hepatol ; 70(6): 1093-1102, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30794889

RESUMO

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is one the most potent nucleot(s)ide analogues for treating chronic hepatitis B virus (HBV) infection. Phenotypic resistance caused by genotypic resistance to TDF has not been reported. This study aimed to characterize HBV mutations that confer tenofovir resistance. METHODS: Two patients with viral breakthrough during treatment with TDF-containing regimens were prospectively enrolled. The gene encoding HBV reverse transcriptase was sequenced. Eleven HBV clones harboring a series of mutations in the reverse transcriptase gene were constructed by site-directed mutagenesis. Drug susceptibility of each clone was determined by Southern blot analysis and real-time PCR. The relative frequency of mutants was evaluated by ultra-deep sequencing and clonal analysis. RESULTS: Five mutations (rtS106C [C], rtH126Y [Y], rtD134E [E], rtM204I/V, and rtL269I [I]) were commonly found in viral isolates from 2 patients. The novel mutations C, Y, and E were associated with drug resistance. In assays for drug susceptibility, the IC50 value for wild-type HBV was 3.8 ±â€¯0.6 µM, whereas the IC50 values for CYE and CYEI mutants were 14.1 ±â€¯1.8 and 58.1 ±â€¯0.9 µM, respectively. The IC90 value for wild-type HBV was 30 ±â€¯0.5 µM, whereas the IC90 values for CYE and CYEI mutants were 185 ±â€¯0.5 and 790 ±â€¯0.2 µM, respectively. Both tenofovir-resistant mutants and wild-type HBV had similar susceptibility to the capsid assembly modulator NVR 3-778 (IC50 <0.4 µM vs. IC50 = 0.4 µM, respectively). CONCLUSIONS: Our study reveals that the quadruple (CYEI) mutation increases the amount of tenofovir required to inhibit HBV by 15.3-fold in IC50 and 26.3-fold in IC90. These results demonstrate that tenofovir-resistant HBV mutants can emerge, although the genetic barrier is high. LAY SUMMARY: Tenofovir is the most potent nucleotide analogue for the treatment of chronic hepatitis B virus infection and there has been no hepatitis B virus mutation that confers >10-fold resistance to tenofovir up to 8 years. Herein, we identified, for the first time, a quadruple mutation that conferred 15.3-fold (IC50) and 26.3-fold (IC90) resistance to tenofovir in 2 patients who experienced viral breakthrough during tenofovir treatment.

18.
J Bioenerg Biomembr ; 51(2): 121-129, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30746618

RESUMO

Hypoxic conditions, which large or infiltrative hypovascular tumors may encounter, also produce acidic environments. Carbonic anhydrase-IX (CA-IX), an enzyme involved in lowering pH, is overexpressed in hepatocellular carcinoma (HCC). In the present study, whether inhibition of CA-IX enhances the efficacy of a hexokinase II inhibitor in an in vivo murine model was examined and its prognostic implication in HCC patients was investigated. CA-IX expression was evaluated using quantitative real-time PCR and western blot analysis using human HCC cell lines. 3-bromopyruvate (3-BP), a hexokinase II inhibitor, and acetazolamide, a carbonic anhydrase inhibitor, were used to target hexokinase II and CA-IX in vitro and in vivo, respectively. A human HCC cell line (Huh-7) was tested as a subcutaneous tumor model in BALB/c nu/nu mice. The prognostic role of CA-IX was evaluated in the TCGA database. Quantitative real-time PCR and western blot analysis revealed that CA-IX expression was activated in the presence of 3-BP. Further analysis showed that introducing an additional stress by treating the orally active CA-IX inhibitor (acetazolamide) can synergistically increase the efficacy of 3-BP in vivo, which was confirmed using a mouse model. We also found that HCC patients with high CA-IX expression show poor overall survival in TCGA database. These results indicate CA-IX is a promising therapeutic target for enhancing the efficacy of 3-BP and can be a prognostic factor for HCC.

19.
Eur Radiol ; 29(6): 3122-3131, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30643939

RESUMO

OBJECTIVE: This study was conducted in order to evaluate whether the presence of nonhypervascular hepatobiliary phase (HBP) hypointense nodules can help determine the treatment method for single nodular hepatocellular carcinoma (HCC) ≤ 3 cm. METHODS: This study was approved by the institutional review board. A total of 345 patients with single nodular HCC ≤ 3 cm underwent pretreatment gadoxetic acid-enhanced MR followed by hepatic resection (n = 123) or radiofrequency ablation (RFA) (n = 222). We retrospectively analyzed the results of tumor recurrence according to the presence of nonhypervascular HBP hypointense nodules at each treatment method. RESULTS: Nonhypervascular HBP hypointense nodules were found in 18 of 123 patients treated by hepatic resection and in 63 of 222 patients who underwent RFA. The presence of nonhypervascular HBP hypointense nodules was a significant affecting factor for recurrence-free survival (RFS) after both hepatic resection (p = 0.004, hazard ratio [HR] = 2.75 [1.38-5.51]) and RFA (p = 0.004, HR = 1.78 [1.20-2.63]). In patients with nonhypervascular HBP hypointense nodules, 5-year RFS was 34.0% after hepatic resection, which was not significantly different from the 28.0% after RFA (p = 0.618). However, in patients without nonhypervascular HBP hypointense nodules, 5-year RFS was 65.0% after hepatic resection, which was significantly better than the 51.0% after RFA (p = 0.042), owing to significantly lower cumulative incidence of local tumor progression after hepatic resection (p < 0.001). CONCLUSIONS: While the presence of nonhypervascular HBP hypointense nodules on gadoxetic acid-enhanced MR taken prior to treatment was a significant predictive factor of tumor recurrence after both hepatic resection and RFA, in patients without nonhypervascular HBP hypointense nodules, hepatic resection can provide significantly better RFS than RFA. KEY POINTS: • The presence of nonhypervascular hepatobiliary phase (HBP) hypointense nodules was a significant risk factor for tumor recurrence after either hepatectomy or radiofrequency ablation (RFA). • Hepatectomy provided significantly better recurrence-free survival than RFA in patients without nonhypervascular HBP hypointense nodules. • In patients with nonhypervascular HBP hypointense nodules, recurrence-free survival after RFA was comparable to hepatectomy.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Meios de Contraste , Feminino , Gadolínio DTPA , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
20.
Biochim Biophys Acta Biomembr ; 1861(4): 729-737, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30658058

RESUMO

Hepatitis B virus X protein (HBx) functions in a variety of cellular events during the HBV life cycle. In a previous study, we reported that the HBx protein is sufficient to induce mitochondrial membrane permeabilization; however, the exact mechanism of HBx-induced mitochondrial membrane permeabilization has been not proposed. In this study, we report that HBx specifically targets cardiolipin (CL) and induces membrane permeabilization depending on CL concentration in mitochondrial outer membrane-mimic artificial liposomes. Interestingly, HBx-induced membrane permeabilization was enhanced by liposomes containing phosphatidylethanolamine, which plays a crucial role in forming a negative curvature on the membrane. We also show that the 68-117 region of HBx, which interacts with mitochondria, is necessary for membrane permeabilization. We examined the size of the pores formed by HBx and found that HBx permeates fluorescent dyes depending on the hydrodynamic diameter with a pore size of approximately 10 nm. The results of this study suggest that CL is necessary for HBx-induced membrane permeabilization and provide important information that suggests a new strategy for anti-HBV therapy.


Assuntos
Cardiolipinas/química , Vírus da Hepatite B/química , Mitocôndrias Hepáticas/química , Membranas Mitocondriais/química , Transativadores/química , Animais , Cardiolipinas/metabolismo , Vírus da Hepatite B/metabolismo , Lipossomos/química , Camundongos , Mitocôndrias Hepáticas/metabolismo , Membranas Mitocondriais/metabolismo , Permeabilidade , Transativadores/metabolismo
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