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•HBV covalently closed circular DNA (cccDNA) is responsible for viral persistence decades after liver disease resolution.•A latent occult HBV infection is identified by the presence ...of the antibody to the HB-core antigen (anti-HBc).•We developed a highly sensitive droplet digital PCR assay for intrahepatic HBV cccDNA quantitation.•HBV cccDNA is detectable and quantifiable in 27 out of 100 anti-HBc-positive liver donors.•Serum anti-HBc IgG levels are associated with the finding of intrahepatic HBV cccDNA.
The accurate diagnosis of occult hepatitis B virus (HBV) infection (OBI) requires the demonstration of HBV DNA in liver biopsies of hepatitis B surface antigen-negative individuals. However, in clinical practice a latent OBI is deduced by the finding of the antibody to the hepatitis B core antigen (anti-HBc). We investigated the true prevalence of OBI and the molecular features of intrahepatic HBV in anti-HBc-positive individuals.
The livers of 100 transplant donors (median age 68.2 years; 64 males, 36 females) positive for anti-HBc at standard serologic testing, were examined for total HBV DNA by nested-PCR and for the HBV covalently closed circular DNA (HBV cccDNA) with an in-house droplet digital PCR assay (ddPCR) (Linearity: R2 = 0.9998; lower limit of quantitation and detection of 2.4 and 0.8 copies/105 cells, respectively).
A total of 52% (52/100) of the individuals studied were found to have OBI. cccDNA was found in 52% (27/52) of the OBI-positive, with a median 13 copies/105 cells (95% CI 5–25). Using an assay specific for anti-HBc of IgG class, the median antibody level was significantly higher in HBV cccDNA-positive than negative donors (17.0 7.0–39.2 vs. 5.7 3.6–9.7 cut-off index COI, respectively, p = 0.007). By multivariate analysis, an anti-HBc IgG value above 4.4 COI was associated with the finding of intrahepatic HBV cccDNA (odds ratio 8.516, p = 0.009); a lower value ruled out its presence with a negative predictive value of 94.6%.
With a new in-house ddPCR-based method, intrahepatic HBV cccDNA was detectable in quantifiable levels in about half of the OBI cases examined. The titer of anti-HBc IgG may be a useful surrogate to predict the risk of OBI reactivation in immunosuppressed patients.
The covalently closed circular DNA (cccDNA) form of the hepatitis B virus (HBV) sustains the persistence of the virus even decades after resolution of the symptomatic infection (occult HBV infection). In the present study we developed a highly sensitive method based on droplet digital PCR technology for the detection and quantitation of HBV cccDNA in the liver of individuals with occult HBV infection. We observed that the amount of HBV cccDNA may be inferred from the titer in serum of the IgG class antibody to the hepatitis B core antigen. The quantitation of this antibody may represent a surrogate to determine which patients are at the highest risk of HBV reactivation following immunosuppressive therapies.
Patients with chronic hepatitis C (CHC) and concomitant type 2 diabetes mellitus (DM) show a higher risk of developing hepatocellular carcinoma (HCC). Successful antiviral therapy has reduced the ...incidence of post-therapy HCC, but the presence of DM still represents an unfavourable predictive factor even in cured patients. Metformin (MET) is recommended as a first-line therapy for DM, and its use is associated with a significant reduction in HCC among diabetic patients with chronic liver disease of different etiology, but very few studies specifically address this issue in patients with CHC.
the aim of this review is to evaluate whether the use of MET induces a significant decrease in HCC in diabetic patients with CHC, treated or untreated with antiviral therapy.
A search of PubMed, Medline, Web of Sciences and Embase was conducted for publications evaluating the role of MET in reducing the risk of HCC in patients with DM and CHC, with no language and study type restrictions up to 30 June 2023. Only studies fulfilling the following inclusion criteria were considered: (1) data on the incidence of HCC in the follow-up of diabetic patients with CHC only; (2) follow-up ≥24 months; (3) sufficient data to establish the rate of diabetic patients with CHC treated with metformin or other antidiabetic medications; and (4) data on the type of antiviral treatment and the clinical outcome.
Three studies met the inclusion criteria. A prospective cohort study considering only patients with DM and untreated advanced CHC, or non-responders to interferon (IFN) therapy, showed that the use of MET was associated with a significant decrease in HCC incidence, liver-related death and liver transplants. A recent retrospective study focusing on a large-scale nationwide cohort of patients with CHC in Taiwan successfully treated with IFN-based therapy stratified patients into 3 groups: non-MET users, MET users and non-diabetic patients, with 5-year cumulative rates of HCC of 10.9%, 2.6% and 3.0%, respectively, showing a significantly higher HCC risk in non-MET users compared with MET users and with non-diabetic patients, while it was not significantly different between MET users and non-diabetic patients. In a recent Italian cohort study focusing on 7007 patients with CHC treated and cured with direct-acting antiviral agents (DAAs), a combined effect of DM and MET therapy was found, showing a higher incidence of HCC in diabetic patients not taking MET compared with those without DM and those with DM taking MET.
according to the current evidence, the use of MET should be encouraged in diabetic patients with CHC in order to reduce the risk of HCC; however, a well-designed randomized controlled trial is needed to establish the generalizability of the beneficial effects of MET in this particular subset of patients.
AIM To assess the etiology of chronic liver diseases(CLD) from 1998 to 2014 at the outpatient clinic of Gastroenterology of the main hospital in Northwest of Italy among those dedicated to ...hepatology.METHODS A random sample of charts of patients referred to for increased liver enzymes between January 1998 and December 2006, and between January 2012 and December 2014 were reviewed. Etiology search included testing for hepatitis B virus(HBV), hepatitis C virus(HCV), autoimmune hepatitis, primary biliary cirrhosis, Wilson’s disease and hereditary hemocromatosis. A risky alcohol consumption was also considered. Nonalcoholic fatty liver disease(NAFLD) was diagnosed in patients with histological and/or ultrasound evidence of steatosis/steatohepatitis, and without other causes of CLD.RESULTS The number of patients included was 1163. Of them, 528(45%) had positivity for HCV and 85(7%) for HBV. Among the virus-free patients, 417(36%) had metabolic disorders whereas the remaining had history of alcohol abuse, less prevalent causes of CLD or concomitant conditions. In comparison to 1998-2000(41%), a reduction of HCV alone-related cases was detected during the periods 2001-2003(35%, OR = 0.75, 95%CI: 0.53-1.06), 2004-2006(33%, OR = 0.70, 95%CI: 0.50-0.97) and 2012-2014(31%, OR = 0.64, 95%CI: 0.46-0.91). On the contrary, in comparison to 1998-2000(31%), metabolic-alone disorders increased in the period 2004-2006(39%, OR = 1.37, 95%CI: 0.99-1.91) and 2012-2014(41%, OR = 1.53, 95%CI: 1.09-2.16). The other etiologies remained stable. The increase of incidence of metabolic-alone etiology during the period 2004-2006 and 2012-2014 tended to be higher in older patients(≥ 50 years) compared to younger(P = 0.058).CONCLUSION In the Northwest of Italy, during this study period, the prevalence of HCV infection decreased notably whereas that of NAFLD increased.
The causal link between chronic hepatitis C and glycometabolic alterations has been confirmed by much biochemical, clinical, and epidemiological research work, but what is still controversial is the ...long-term clinical impact of sustained virologic response (SVR) achieved by direct-acting antiviral agents (DAAs) on patients with type 2 diabetes mellitus (DM). The aim of this paper is to summarize the biochemical and clinical consequences to DM of DAA-based therapy for hepatitis C virus (HCV) infection. An electronic search of Embase, PubMed, MEDLINE, Ovid, and the Cochrane Database of Systematic Reviews was conducted for publications assessing whether clearance of HCV achieved by interferon (IFN)-free antiviral therapy determines significant changes in glycometabolic control and clinical outcomes of diabetic patients. A beneficial effect of SVR obtained by DAA therapy on DM prevention and the short-term outcome of glycometabolic alterations are acknowledged by most of the studies. Whether this effect is maintained over the long term with a significant clinical impact on diabetic and liver disease is still a matter of debate.
Patients with hepatitis C virus (HCV)-related cirrhosis treated with direct-acting antivirals (DAA) are still at risk of developing hepatocellular carcinoma (HCC). We investigated the accuracy of ...non-invasive scoring systems (NSS) for the prediction of de novo HCC development in patients treated with DAA on long-term follow-up (FU). We analyzed data from 575 consecutive patients with cirrhosis and no history of HCC who achieved a sustained virologic response (SVR) to DAA therapy. NSS (i.e., Forns index, APRI, FIB-4, ALBI, and aMAP) were calculated at 3 months after the end of therapy. Performance for de novo HCC prediction was evaluated in terms of area under the curve (AUC) and Harrell's C-index. During a median FU of 44.9 (27.8-58.6) months, 57 (9.9%) patients developed de novo HCC. All five NSS were associated with the risk of de novo HCC. At multivariate analysis, only the ALBI score resulted in being significantly and independently associated with de novo HCC development (adjusted hazard ratio = 4.91, 95% CI 2.91-8.28,
< 0.001). ALBI showed the highest diagnostic accuracy for the detection of de novo HCC at 1-, 3-, and 5-years of FU, with AUC values of 0.81 (95% CI 0.78-0.85), 0.71 (95% CI 0.66-0.75), and 0.68 (95% CI 0.59-0.76), respectively. Consistently, the best predictive performance assessed by Harrell's C-statistic was observed for ALBI (C-index = 0.70, 95% CI 0.62-0.77). ALBI score may represent a valuable and inexpensive tool for risk stratification and the personalization of an HCC surveillance strategy for patients with cirrhosis and previous history of HCV infection treated with DAA.
Current surveillance strategy for patients with nonalcoholic fatty liver disease (NAFLD) at risk of hepatocellular carcinoma (HCC) development is unsatisfactory. We aimed to investigate the ...diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), glypican-3 (GPC-3), adiponectin, leptin and interleukin-6 (IL-6), alone or in combination, for the discrimination between NAFLD patients with or without HCC. The biomarkers were investigated in a cohort of 191 NAFLD patients (median age 62, 54–68 years; 121 males and 70 females) with advanced fibrosis/cirrhosis, 72 of whom had a diagnosis of HCC. PIVKA-II showed the best performance for the detection of HCC with an area under the curve (AUC) of 0.853, followed by adiponectin (AUC = 0.770), AFP (AUC = 0.763), GPC-3 (AUC = 0.759) and by IL-6 (AUC = 0.731), while the leptin values were not different between patients with and without HCC. The accuracy of the biomarkers’ combination was assessed by a stratified cross-validation approach. The combination of age, gender, PIVKA-II, GPC-3 and adiponectin further improved the diagnostic accuracy (AUC = 0.948); the model correctly identified the 87% of the patients. In conclusion, we developed a model with excellent accuracy for the detection of HCC that may be useful to improve the surveillance of NAFLD patients at risk of tumor development.
Intrahepatic oxidative stress is a key driver of inflammation and fibrogenesis in non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of extracellular Nicotinamide ...phosphoribosyltransferase (eNAMPT) and extracellular nicotinic acid phosphoribosyltransferase (eNAPRT) for the detection of advanced fibrosis. eNAMPT and eNAPRT were tested in 180 consecutive biopsy-proven NAFLD patients and compared with liver stiffness (LS) and the FIB-4 score. eNAMPT was similarly distributed across fibrosis stages, whereas eNAPRT was increased in patients with advanced fibrosis (
= 0.036) and was associated with advanced fibrosis (OR 1.08,
= 0.016). A multiple stepwise logistic regression model containing significant variables for advanced fibrosis (eNAPRT, type 2 diabetes, age, male sex, ALT) had an area under the curve (AUC) of 0.82 (Se 89.6%, Sp 67.3%, PPV 46.7%, NPV 93.8%) when compared to that of LS (0.79; Se 63.5%, Sp 86.2%, PPV 66.0%, NPV 84.8%) and to that of the FIB-4 score (0.73; Se 80.0%, Sp 56.8%, PPV 44.9%, NPV 86.6%). The use of eNAPRT in clinical practice might allow for the better characterization of NAFLD patients at higher risk of disease progression.
Chronic viral hepatitis determines significant morbidity and mortality globally and is caused by three main etiological actors (Hepatitis B Virus, Hepatitis C Virus, and Hepatitis D Virus) with ...different replicative cycles and biological behaviors. Thus, therapies change according to the different characteristics of the viruses. In chronic hepatitis B, long term suppressive treatments with nucleoside/nucleotide analogues have had a dramatic impact on the evolution of liver disease and liver-related complications. However, a conclusive clearance of the virus is difficult to obtain; new strategies that are able to eradicate the infection are currently objects of research. The therapy for Hepatitis D Virus infection is challenging due to the unique virology of the virus, which uses the synthetic machinery of the infected hepatocyte for its own replication and cannot be targeted by conventional antivirals that are active against virus-coded proteins. Recently introduced antivirals, such as bulevertide and lonafarnib, display definite but only partial efficacy in reducing serum HDV-RNA. However, in combination with pegylated interferon, they provide a synergistic therapeutic effect and appear to represent the current best therapy for HDV-positive patients. With the advent of Direct Acting Antiviral Agents (DAAs), a dramatic breakthrough has occurred in the therapeutic scenario of chronic hepatitis C. Cure of HCV infection is achieved in more than 95% of treated patients, irrespective of their baseline liver fibrosis status. Potentially, the goal of global HCV elimination by 2030 as endorsed by the World Health Organization can be obtained if more global subsidised supplies of DAAs are provided.
Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. ...Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.
The response to treatment with biologic drugs, in patients with Crohn’s disease, could be associated with changes in gut microbiota composition. The aim of our study was to analyse the modification ...of microbiota during adalimumab therapy in patients with Crohn’s disease. We performed a prospective study in patients with Crohn’s disease analysing gut microbiota before start of adalimumab therapy (T0) and after six months of therapy (T1). Among the 20 included patients, the phylum Proteobacteria fell from 15.7 ± 3.5% at T0 to 10.3 ± 3.4% at T1 (p = 0.038). Furthermore, the trend in relation to therapeutic success was analysed. Regarding bacterial phyla, Proteobacteria decreased in patients in whom therapeutic success was obtained, passing from a value of 15.8% (± 4.6%) to 6.8 ± 3.1% (p = 0.049), while in non-responder patients, percentages did not change (T0 = 15.6 ± 5.7%, T1 = 16.8 ± 7.6%, p = 0.890). Regarding the Lachnospiraceae family, in patients with normalization of C reactive protein six 6 months of adalimumab therapy, it increased from 16.6 ± 3.1% at T0 to 23.9 ± 2.6% at T1 (p = 0.049). In conclusion, in patients who respond to Adalimumab therapy by decreasing inflammation, there is a trend of intestinal eubiosis being restored.
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