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1.
PLoS One ; 16(4): e0249614, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822817

RESUMO

BACKGROUND: Data on the role of hypothyroidism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are conflicting, although selective Thyroid Hormone Receptor (THR)-ß agonists have been identified as potential therapy in patients with non-alcoholic steatohepatitis (NASH). Therefore, we investigated the association between hypothyroidism and NAFLD histological features potentially associated with progressive liver disease. METHODS: Between 2014 and 2016, consecutive patients with histologically proven NAFLD and frozen serum available for thyroid function tests assessment were included. NAFLD was staged according to the NAFLD Activity Score (NAS), and fibrosis according to Kleiner. NASH was defined as NAS ≥4, significant fibrosis as F2-F4 and significant steatosis as S2-S3. Thyroid function tests (TFT; TSH, FT3, FT4, rT3), TPO-Ab and Tg-Ab were also assessed. RESULTS: Fifty-two patients were analyzed: median age 54 years, 58% females, LSM 7.8 kPa, 27% diabetics, 14% hypothyroid. At histology, NASH was present in 21 (40%), F2-F4 in 28 (54%) and S2-S3 in 30 (58%) patients. Rates of hypothyroidism were similar independently of the presence of NASH (p = 0.11), significant fibrosis (p = 0.21) or steatosis (p = 0.75). However, hypothyroid patients displayed a higher NAS (p = 0.02) and NASH (p = 0.06) prevalence. At multivariate analysis, TFT were not independently associated with histology. CONCLUSION: Hypothyroidism was highly prevalent in NAFLD patients, and was associated with increased NAFLD activity, but not with fibrosis and steatosis severity. Thus, thyroid dysfunction might play a direct and/or indirect in the pathogenesis of NAFLD and NASH.

2.
Transpl Int ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33730421

RESUMO

Multiple plastic stent (MPS) for biliary anastomotic stricture (AS) after liver transplantation requires multiple procedures with consequent costs. To compare the success, adverse events and treatment-related costs of fully covered self-expandable metal stents (FCSEMS) versus MPS. Thirty liver transplant (LT) patients with clinically relevant naïve AS were prospectively randomized to FCSEMS or MPS, with stent numbers increased at 3-month intervals. Treatment costs per patient were calculated for endoscopic retrograde cholangiopancreatography (including all devices and stents) and overall hospital stay. Radiological success was achieved in 73% of FCSEMS (median indwelling period of 6 mos) and 93% of MPS patients (P = NS) (median period of 11 mos). AS recurrence occurred in 36% of FCSEMS and 7% of MPS patients (P = NS), and AS re-treatment was needed in 53% and 13% (P < 0.01), respectively, during follow-up of 60 (34-80) months. Stents migrated after 29% and 2.6% of FCSEMS and MPS procedures, respectively (P < 0.01). Including re-treatments, long-term clinical success was achieved in 28/30 (93%) patients. Overall treatment-related costs were similar between groups. In the subgroup of LT patients in clinical remission after first-line treatment, treatment costs were 41% lower per FCSEMS patient compared with MPS patients. FCSEMS did not perform better than MPS. FCSEMS migration increased the rate of re-treatment and costs.

5.
J Pathol ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586163

RESUMO

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

6.
Am J Gastroenterol ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33606382

RESUMO

Nonselective ß-blockers improve decompensation-free survival in viremic hepatitis C virus compensated cirrhotic patients with clinically significant portal hypertension, but their protective role after sustained virological response by direct-acting antiviral (DAA) is undefined. We evaluated the incidence of decompensation in DAA-cured Child-A patients without high-risk varices. During the 49-month (12-60) follow-up, only one of 148 patients decompensated (ascites), with a 4-year cumulative risk of 1%, but decompensation was associated with hepatocellular carcinoma. The risk of decompensation in DAA cured hepatitis C virus compensated Child-A cirrhotic patients with clinically significant portal hypertension but without high-risk varices is negligible; thus, questioning the need for nonselective ß-blocker treatment in this setting (see Visual abstract, Supplemental Digital Content, 1, http://links.lww.com/AJG/B861).

7.
Aliment Pharmacol Ther ; 53(6): 733-744, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33465257

RESUMO

BACKGROUND: An accurate, single-point differential diagnosis between HBeAg-negative infection (ENI) and chronic hepatitis B (CHB) is an unmet need. AIMS: To assess the diagnostic value of the new hepatitis B core-related antigen (HBcrAg) assay. METHODS: A retrospective anonymised data analysis was performed in a multicentre European (nine centres and six countries) cohort of 1582 consecutive HBsAg-positive/HBeAg-negative subjects classified according to EASL guidelines as: 550-CHB, 710-ENI and 322-GZ (grey-zone, HBV-DNA <20 000 IU/mL). RESULTS: Mean age was 44 (±13.2 y), 59% were men; HBV genotypes were 15% A, 2% B, 2% C, 45% D, 9% E, 1% F and 26% unknown. Median HBV-DNA serum levels were 2.2 (1.5-2.7), 3.5 (3.2-3.8) and 5.6 (4.8-6.6) logIU/mL in ENI, GZ and CHB, P < 0.0001. HBsAg serum levels (HBsAgsl) were comparable in CHB and GZ, but lower in ENI (2.9 [2.1-3.6] logIU/mL), P < 0.0001. HBcrAg serum levels (HBcrAgsl) were <3 logU/mL in 90.7% (644/710) ENI, 75.2% (242/322) GZ and 4.7% (26/550) CHB (P < 0.0001). Median HBcrAgsl were 4.8 (3.9-5.7), 2.5 (2.0-2.9) and 2.0 (2.0-2.5) logU/mL in CHB, GZ and ENI, (P < 0.0001). ROC-AUCs for HBcrAg and HBsAg were 0.968 (95% CI, 0.958-0.977) and 0.732 (95% CI, 0.704-0.760) respectively. The optimal HBcrAgsl cut-off to distinguish CHB from ENI was 3.14 logU/mL (95% CI, 3.02-3.25, 91% SE, 93% SP and 92.4% DA). HBcrAgsl were associated with HBV genotypes (P < 0.001, one-way ANOVA) but using genotype-specific cut-offs, HBcrAg DA remained unchanged with overlapping 95% CI. CONCLUSION: The HBcrAg assay showed high diagnostic performance in the accurate single-point identification of patients with HBeAg-negative CHB, independently of HBV genotype. This should prompt future prospective studies to confirm its diagnostic role in clinical practice.


Assuntos
Antígenos E da Hepatite B , Hepatite B Crônica , Adulto , DNA Viral/genética , Feminino , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos
8.
J Viral Hepat ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33260272

RESUMO

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under effective long-term oral antiviral therapy, but its pathogenesis in the setting of long-standing inhibition of viral replication has not been completely elucidated. We investigated whether species of circulating cell-free DNA (cfDNA) may be involved in the process of hepatocarcinogenesis in treated CHB patients. Serum samples were obtained from HBeAg-negative CHB patients with (HCC cases, n=37) or without HCC development during the first 5 years of oral antiviral therapy (controls, n=74). HCC cases and controls were matched 1:2 for age, sex and platelets. Determination of different circulating cfDNA species (before HCC diagnosis in HCC cases) including total cfDNA quantity, levels of Alu repeat DNA and RNAse P coding DNA, copies of mitochondrial DNA and levels of 5-methyl-2'-deoxycytidine as indicator of DNA methylation was performed. HCC cases compared to controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, P=0.042) and RNAse P coding DNA (68 vs 15 genomic equivalent, P<0.001). In contrast, median cfDNA concentration, Alu115 levels, Alu247/Alu115 ratio as an index of DNA integrity and mitochondrial DNA copies did not differ significantly between HCC cases and controls. Receiver operating characteristic curve analysis showed that levels RNAse P coding DNA offered good prediction of subsequent HCC development (c-statistic: 0.80, P<0.001). In conclusion, serum levels of RNAse P coding DNA are increased years before HCC diagnosis and could be potentially helpful in the prediction of the HCC risk in treated HBeAg-negative CHB patients.

9.
Antiviral Res ; : 104992, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33279523

RESUMO

Long-term treatment with nucleos(t)ide analogs (NAs) is the current first line therapy for patients with chronic hepatitis B (CHB), recommended by most of the current guidelines. NAs prevent disease progression, liver failure, decrease the risk of hepatocellular carcinoma (HCC), and have favorable safety profiles. However, low rates of on-therapy functional cure (hepatitis B surface antigen [HBsAg] loss), which is regarded as the optimal end point, prevent many patients from stopping NA therapy with the need for a lifelong treatment. The higher likelihood of HBsAg loss associated with stopping as compared to continuing NAs has got a lot of attention lately. Recommendations regarding endpoints allowing for safely stopping NA therapy differ between the different international guidelines. Whereas in HBeAg-positive patients, HBeAg seroconversion with at least one year of consolidation therapy is an accepted endpoint of treatment, the recommendations for HBeAg-negative ones differ. Some guidelines propose ≥ 3 years of HBV DNA undetectability to stop NA while others regard HBsAg loss as the only acceptable endpoint to therapy. Stopping NA can lead to substantial rates of virologic relapses and consequent ALT flares in some of them. Moreover, no reliable predictor(s) of post-NA relapses have been identified so far. Quantitative HBsAg is becoming an increasingly promising marker to predict safe NA cessation. On the other hand, investigating the role of the immune system in mediating sustained virologic responses after NA withdrawal is needed to suggest immunological biomarkers to safely stop NA. In this article, we will review relevant literature regarding NA stopping rules and discuss promising viral and immunological biomarkers to predict antiviral responses and thus to help identify patients who are more likely to achieve HBsAg seroclearance.

10.
J Viral Hepat ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33306247

RESUMO

In routine clinical practice, HCV-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the pre-defined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years and 53 (14.5%) patients were HIV-coinfected. Liver cirrhosis was observed in 251 (68.8%) subjects and the most represented genotypes were 1b (n=168, 46%) and 3 (n=59, 16.2%). DAA were discontinued a median of 1 (IQR 1-4) weeks before the pre-defined EOT, with 164 (44.9%) patients stopping DAAs at least two weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n=2/4) vs 99.1% (n=109/110) for ≥4 weeks, p=0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3%(n=25/30) vs 94.6%(n=209/221) for ≥8 weeks, p=0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.

11.
J Hepatol ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33220331

RESUMO

BACKGROUND & AIMS: Data on patients with chronic hepatitis C virus (HCV) infection who failed voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment and rescue treatment options for these patients are limited. METHODS: Samples of 40 patients with HCV genotypes (GT) 1-4 who failed VOX/VEL/SOF as retreatment were collected within the European Resistance Study Group. Population based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: The majority of VOX/VEL/SOF failure patients were infected with HCV GT3a (n=18, 45%) or GT1a (n=11, 28%) and had cirrhosis (n=28, 70%). Previous treatments included a NS3-inhibitor (30%), a NS5A-inhibitor (100%) and SOF (85%). Baseline RASs available in a subgroup of patients before VOX/VEL/SOF (78%) included rarely NS3 RAS with exception of Q80K in GT1a (40%), typical NS5A RASs pattern in the majority of patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure available in 98% of patients showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n=2) or with sofosbuvir±ribavirin (n=15), VOX/VEL/SOF±ribavirin (n=4) or VEL/SOF and ribavirin (n=1) for 12 to 24 weeks. Sustained virologic response was achieved in 15/19 (79%) patients with final treatment outcome. Of these, two GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF and G/P+SOF+R, respectively, and two patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3 and GT1a infected patients with cirrhosis and was not associated with specific RASs pattern within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in the majority of patients.

12.
J Hepatol ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33188902

RESUMO

BACKGROUND AND AIMS: In chronic HBV infection, exhausted HBV-specific CD8 T cells express misregulated mitochondrion and proteasome functions. To better characterize the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion we analyzed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to target simultaneously both mitochondrial and proteostasis functions were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in chronic HBV patients. METHODS: Lysosome-mediated degradation pathways were analyzed by flow cytometry in virus-specific CD8 T cells from chronic HBV patients, in comparison to patients able to resolve spontaneously HBV infection and healthy subjects. Mitochondrial function, intracellular proteostasis and cytokine production were evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol and oleuropein and their metabolites, either alone or in combination with other bioactive compounds. RESULTS: HBV-specific CD8 T cells of chronic patients showed impaired autophagic flux. A significant improvement of mitochondrial, proteostasis and antiviral CD8 functions was elicited by resveratrol and oleuropein. Cytokine production was also enhanced by synthetic metabolites which correspond to those generated by resveratrol and oleuropein metabolism in vivo, suggesting that these polyphenols may display their effect also after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalizing effect of mt-antioxidants and of PD-1/PD-L1 blockade. CONCLUSION: Targeting simultaneously multiple altered intracellular pathways with the combination of mitochondria-antioxidants and natural polyphenols may represent a promising strategy in the perspective of novel immune reconstitution therapies to treat chronic HBV infection.

13.
Cell Rep Med ; 1(4): 100060, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-33205065

RESUMO

Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) to complete its infection cycle and causes severe hepatitis, with limited therapeutic options. To determine the prospect of T cell therapy in HBV/HDV co-infection, we study the impact of HDV on viral antigen processing and presentation. Using in vitro models of HBV/HDV co-infection, we demonstrate that HDV boosts HBV epitope presentation, both in HBV/HDV co-infected and neighboring mono-HBV-infected cells through the upregulation of the antigen processing pathway mediated by IFN-ß/λ. Liver biopsies of HBV/HDV patients confirm this upregulation. We then validate in vitro and in a HBV/HDV preclinical mouse model that HDV infection increases the anti-HBV efficacy of T cells with engineered T cell receptors. Thus, by unveiling the effect of HDV on HBV antigen presentation, we provide a framework to better understand HBV/HDV immune pathology, and advocate the utilization of engineered HBV-specific T cells as a potential treatment for HBV/HDV co-infection.

15.
JCI Insight ; 5(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33055418

RESUMO

Many mutation analyses of the HBV genome have been performed in the search for new prognostic markers. However, the Kozak sequence preceding precore was covered only infrequently in these analyses. In this study, the HBV core promoter/precore region was sequenced in serum samples from European inactive HBV carriers. Quadruple mutation GCAC1809-1812TTCT was found with a high prevalence of 42% in the Kozak sequence preceding precore among all HBV genotypes. GCAC1809-1812TTCT was strongly associated with coexistence of basal core promoter (BCP) double mutation A1762T/G1764A and lower HBV DNA levels. In vitro GCAC1809-1812TTCT lead to drastically diminished synthesis of pregenomic RNA (pgRNA), precore mRNA, core, HBsAg, and HBeAg. Calculation of the pgRNA secondary structure suggests a destabilization of the pgRNA structure by A1762T/G1764A that was compensated by GCAC1809-1812TTCT. In 125 patients with HBV-related cirrhosis, GCAC1809-1812TTCT was not detected. While a strong association of GCAC1809-1812TTCT with inactive carrier status was observed, BCP double mutation was strongly correlated with cirrhosis, but this was only observed in absence of GCAC1809-1812TTCT. In conclusion, our data reveal that GCAC1809-1812TTCT is highly prevalent in inactive carriers and acts as a compensatory mutation for BCP double mutation. GCAC1809-1812TTCT seems to be a biomarker of good prognosis in HBV infection.

17.
Dig Liver Dis ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32917546

RESUMO

BACKGROUND AND AIMS: The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV. PATIENTS AND METHODS: Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naïve and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated. RESULTS: The SVR12 rate was 99.4% (319/321; 95% CI: 97.8-99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (289/290) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively. CONCLUSION: Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials.

20.
Hepatology ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32762045

RESUMO

BACKGROUND AND AIMS: Genetic factors and steatosis predispose to hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus; however, their impact in patients with cirrhosis cured by direct-acting antivirals (DAAs) is still undefined. We assessed the association between a genetic risk score (GRS) of hepatic fat accumulation, combining variants in PNPLA3 (patatin-like phospholipase domain containing 3), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TM6SF2 (transmembrane 6 superfamily member 2), GCKR (glucokinase regulator), and HCC in patients treated with DAAs. APPROACH AND RESULTS: We considered 509 consecutive patients with HCV cirrhosis (defined histologically or when liver stiffness ≥12 kPa) treated with DAAs. HCC was diagnosed according to international recommendations. GRS was calculated from the weighted impact of single variants on hepatic fat content quantified by H1 spectrometry in the general population (Dallas Heart Study). During a median follow-up of 43 (3-57) months after DAA start, 36 of 452 (8%) patients developed de novo HCC, 4-year cumulative probability being 9% (95% confidence interval 7%-12%). Male sex (hazard ratio [HR] 2.54, P = 0.02), diabetes (HR 2.39, P = 0.01), albumin (HR 0.35, P = 0.001), and GRS score >0.597 (HR 2.30, P = 0.04) were independent predictors of de novo HCC. In contrast, single genetic risk variants were not useful in stratifying HCC risk. The proportion of patients who developed HCC according to the combination of the independent risk factors ranged from 11% to 67%. HCC recurred in 28 of 57 (49%) patients with previous history; diabetes and ethnicity were the only independent predictors of HCC recurrence. CONCLUSIONS: In a large cohort of DAA-treated patients with cirrhotic HCV, GRS was associated with de novo HCC independently of classical risk factors, including liver disease severity. These data suggest that hepatic fat (i.e., lipotoxicity) promotes HCC in this setting and may represent a target for chemoprevention. Combination of clinical and genetic predictors may improve HCC risk stratification.

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