L E Adinolfi

Università degli Studi di Modena e Reggio Emilia, Modène, Emilia-Romagna, Italy

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Publications (127)517.88 Total impact

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    ABSTRACT: To evaluate steatosis, insulin resistance (IR) and patatin-like phospholipase domain-containing 3 (PNPLA3) and their relation to disease progression in hepatitis B and C viruses (HCV-HBV) co-infected patients.
    World journal of hepatology. 09/2014; 6(9):677-684.
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    ABSTRACT: Hepatitis C virus (HCV) is a successful pathogen on the grounds that it exploits its host's metabolism to build up viral particles; moreover it favours its own survival by inducing chronic disease and the development of specific anatomic changes in the infected organ. Steatosis, therefore, is associated with HCV infection by necessity rather than by chance alone. Approximately 6% of HCV patients have steatohepatitis. Interestingly, HCV steatosis occurs in the setting of multiple metabolic abnormalities (hyperuricemia, reversible hypocholesterolemia, insulin resistance, arterial hypertension and expansion of visceral adipose tissue) collectively referred to as "hepatitis C-associated dysmetabolic syndrome" (HCADS). General, nonalcoholic fatty liver disease (NAFLD)-like, mechanisms of steatogenesis (including increased availability of lipogenic substrates and de novo lipogenesis; decreased oxidation of fatty substrates and export of fatty substrates) are shared by all HCV genotypes. However, genotype 3 seemingly amplifies such steatogenic molecular mechanisms reported to occur in NAFLD via more profound changes in microsomal triglyceride transfer protein; peroxisome proliferator-activated receptor alpha; sterol regulatory element-binding proteins and phosphatase and tensin homologue. HCV steatosis has a remarkable clinical impact in as much as it is an acknowledged risk factor for accelerated fibrogenesis; for impaired treatment response to interferon and ribavirin; and development of hepatocellular carcinoma. Recent data, moreover, suggest that HCV-steatosis contributes to premature atherogenesis via both direct and indirect mechanisms. In conclusion, HCV steatosis fulfills all expected requirements necessary to perpetuate the HCV life cycle. A better understanding of the physiology of HCADS will likely result in a more successful handling of disease with improved antiviral success rates.
    World journal of gastroenterology : WJG. 06/2014; 20(23):7089-7103.
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    ABSTRACT: Hepatitis C virus (HCV) infection represents a major health issue worldwide due to its burden of chronic liver disease and extrahepatic manifestations including cardiovascular diseases, which are associated with excess mortality. Analysis of published studies supports the view that HCV infection should be considered a risk factor for the development of carotid atherosclerosis, heart failure and stroke. In contrast, findings from studies addressing coronary artery disease and HCV have yielded conflicting results. Therefore, meta-analytic reviews and prospective studies are warranted. The pathogenic mechanisms connecting HCV infection, chronic liver disease, and atherogenesis are not completely understood. However, it has been hypothesized that HCV may promote atherogenesis and its complications through several direct and indirect biological mechanisms involving HCV colonization and replication within arterial walls, liver steatosis and fibrosis, enhanced and imbalanced secretion of inflammatory cytokines, oxidative stress, endotoxemia, mixed cryoglobulinemia, perturbed cellular and humoral immunity, hyperhomocysteinemia, hypo-adiponectinaemia, insulin resistance, type 2 diabetes and other components of the metabolic syndrome. Understanding these complex mechanisms is of fundamental importance for the development of novel therapeutic approaches to prevent and to treat vascular complications in patients with chronic HCV infection. Currently, it seems that HCV clearance by interferon and ribavirin treatment significantly reduces non-liver-related mortality; moreover, interferon-based treatment appears to decrease the risk of ischemic stroke.
    World Journal of Gastroenterology 04/2014; 20(13):3410-3417. · 2.55 Impact Factor
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    ABSTRACT: To evaluate in anti-HCV-positive patients the clinical impact of the rs35761398 variant of the CNR2 gene leading to the substitution of Gln (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with Arg (R).
    PLoS ONE 02/2014; 9(6):e99450. · 3.53 Impact Factor
  • International journal of cardiology 01/2014; · 6.18 Impact Factor
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    ABSTRACT: Cerebrovascular diseases are leading cause of death worldwide. Plaque rupture and embolization account for one-third of ischemic stroke. The causes are not fully known, but inflammation plays a pathogenic role. Recently, HCV infection has been identify as risk of atherosclerosis. HCV replicates within carotid plaques and brain endothelia cells; moreover, HCV patients showed higher levels of inflammation. Thus, we hypothesized that subjects carrying HCV are at higher risk of stroke. Accordingly, we evaluated prevalence and role of HCV infection in patients with stroke. A priori sample size was calculated. Overall, 820 consecutive patients were enrolled, 123 with stroke and, as control, 697 age- and gender-matched (295 with COPD; 402 with diseases other than HCV-associated). Patients were evaluated for HCV and conventional risk of stroke. Prevalence of HCV was higher in patients with stroke than that observed in control (26.8% vs. 6.6%, p = 0.0001). An analysis of stroke patients showed that those HCV positive were younger (p = 0.017) had lower serum levels of cholesterol (p = 0.001), triglycerides (p = 0.045), and higher serum levels of inflammation markers (ESR, p = 0.001; CRP, p = 0.0001; fibrinogen, p = 0.012). A multivariate analysis showed that HCV infection was an independent risk factor of stroke (O.R. 2.04, 95% C.I. 1.69-2.46; p = 0.0001). A secondary analysis showed that HCV patients had higher (p = 0.031) prevalence of past ischemic heart disease. HCV infected patients are at higher and earlier risk of stroke. Inflammation is a key mediator. Clinicians in clinical practice and researchers in future trials should take into account these new findings.
    Atherosclerosis 11/2013; 231(1):22-26. · 3.71 Impact Factor
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    ABSTRACT: The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.
    World journal of hepatology. 10/2013; 5(10):528-540.
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    ABSTRACT: The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3-16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel-Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p = 0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance.
    European Journal of Clinical Microbiology 10/2013; · 3.02 Impact Factor
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    ABSTRACT: The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis.
    Journal of Viral Hepatitis 08/2013; 20(8):517-23. · 3.08 Impact Factor
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    ABSTRACT: Hepatitis C virus core antigen (HCVcoreAg) may be measured in serum with a sensitive, recently validated assay. Beyond its value as a marker of viral infection, there are little data on its relation with clinical, histological, and virological parameters. In this study, the significance of HCVcoreAg levels was studied in a prospective cohort of 114 patients with chronic hepatitis C. HCVcoreAg was measured by a commercial chemiluminescent microparticle immunoassay. Clinical and virological data included quantitative HCV-RNA, HCV genotype, ALT, GGT, IL28B rs12979860 polymorphism as well as liver histology parameters. HCVcoreAg levels were correlated significantly with HCV-RNA (r = 0.56; P < 0.0001) but also with ALT levels (r = 0.258; P < 0.01) and liver necroinflammatory activity (r = 0.205; P < 0.04). Patients harbouring HCV genotype 3 showed lower levels of HCVcoreAg than both genotype 1 and two patients. In genotype 3, a direct correlation between steatosis and HCVcoreAg was found. Levels of HCVcoreAg also varied according to the IL28B genotype. These data suggest that the evaluation of HCVcoreAg serum levels may provide relevant data for the baseline clinical evaluation of chronic hepatitis C patients. HCVcoreAg serum levels may be a useful tool to further the understanding of chronic hepatitis C pathobiology. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 07/2013; · 2.37 Impact Factor
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    ABSTRACT: BACKGROUND: & Aims: The cannabinoid receptor 2 (CB2) has been implicated in liver disease. The single nucleotide polymorphism rs35761398 in CNR2, which encodes the CB2, substitutes glutamine (Q) 63 with arginine (R) and reduces the function of the gene product. We investigated the effects of CNR2 rs35761398 in patients with hepatitis C virus (HCV) infection. METHODS: We studied 169 consecutive patients with asymptomatic chronic hepatitis (tested positive for anti-HCV and HCV-RNA) at 2 liver units in southern Italy; first liver biopsy samples were collected from July 2009 through December 2011. All patients were naive to antiviral therapy; CNR2 genotype was determined by PCR analysis. RESULTS: Patients with CB2-63 QQ variant had higher serum levels of aminotransferase than those with CB2-63 QR or RR variants; they also had higher histologic activity index (HAI) scores (8.6±3.8) than patients without the CB2-63 RR variant (5.3±3.6; P0.005) or those with the CB2-63 QR variant (5.8±3.3, P<.001). Patients with the different variants of CNR2 did not differ in fibrosis stage or steatosis score. Moderate or severe chronic hepatitis (HAI>8) was identified more frequently (55.5%) in patients with the CB2-63 QQ variant than in those with the 63 QR (20%; P<.005) or RR variant (17.4%; P<.005). In logistic regression analysis, the CB2-63 QQ variant and fibrosis score were independent predictors of moderate or severe chronic hepatitis (HAI >8; P<.0001). CONCLUSIONS: The CB2-63 QQ variant of CNR2 is associated with more severe inflammation and hepatocellular necrosis in patients with HCV infection.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 05/2013; · 5.64 Impact Factor
  • Journal of Hepatology 04/2013; 45:S14. · 9.86 Impact Factor
  • Luigi E Adinolfi, Luciano Restivo, Aldo Marrone
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    ABSTRACT: Steatosis is a complication of hepatitis C virus (HCV) infection and the mechanisms of its development are complex, involving viral and host factors. Steatosis that is prevalently viral is associated with HCV genotype 3, and steatosis that is prevalently metabolic is associated with non-3 genotypes. Viral steatosis is correlated with the level of HCV replication, whereas metabolic steatosis is related to insulin resistance. The two types of steatosis have a different impact on HCV disease and may have an additive effect. HCV infection is a multifaceted disease with hepatic and extrahepatic manifestations. There is a body of evidence indicating that HCV-related steatosis plays a role in many HCV manifestations and, thus, the presence of steatosis is a predictive factor for the development of such events. The current data show that HCV-related steatosis predicts an advanced liver disease and a more rapid progression of fibrosis, as well as an increased risk of development of hepatocellular carcinoma. Moreover, the presence of steatosis in a HCV patient has a high predictive value that the subject may have or may develop insulin resistance, diabetes and metabolic syndrome. Recently, a strict association between HCV-related steatosis and development of atherosclerosis has been demonstrated. In addition, steatosis negatively impacts response rate to interferon-based treatment, even in HCV genotype-3 infection. Therapeutic strategies to improve steatosis and, consequently, response to standard antiviral therapy and outcome of disease are wanted. The authors summarize current knowledge of impact of steatosis on the above reported clinical conditions associated with HCV infection.
    Expert review of gastroenterology & hepatology 03/2013; 7(3):205-13.
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    ABSTRACT: We describe the case of a patient with chronic hepatitis C treated with standard and pegylated-interferon (PEG-IFN) alpha and ribavirin. He developed a reversible hearing loss during the first course of PEG-IFN + ribavirin, but achieved sustained viral clearance and biochemical normalization after PEG-IFN + ribavirin re-treatment.
    Le infezioni in medicina: rivista periodica di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive 06/2012; 20(2):117-9.
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    ABSTRACT: HCV genotypes 2- or 3-infected patients with a rapid virological response (RVR) to therapy with pegylated interferon and ribavirins who have a low viral load, noncirrhotic and nonobese may be considered for a shorter course of treatment. However, no studies have assessed host-viral factors associated with relapse in genotype 2 and 3 separately. Accordingly, we assessed whether 12 weeks of pegylated interferon and ribavirin was an optimized regimen for treatment of HCV genotype 2 and 3 with positive predictors of response. Power and sample size were a priori calculated and 96 consecutive chronic hepatitis C patients (53, genotype 2 and 43, genotype 3) without cirrhosis who were not obese and who achieved a RVR to therapy with peg-IFN-α-2a and ribavirin were enrolled. Fibrosis, steatosis, homeostatic model assessment-insulin resistance and HCV RNA were predefined variables to be evaluated in relapse. An intention-to-treat analysis was performed. SVR rates were 98% and 84% for genotype 2 and 3, respectively. Analysis of genotype 3 patients who had relapse showed a negative correlation with steatosis (P < 0.0001) and HCV RNA (P < 0.015). Multivariate analysis showed that steatosis was the independent predictor of relapse (OR, 0.988; 95% CI, 0.981-0.993; P < 0.001). Genotype 3 patients with steatosis had a relapse rate of 36.4% and 15.8% in those with high and low viral load, respectively, whereas there was no relapse in those without steatosis. In conclusion, a 12-week course of therapy is sufficient for patients without cirrhosis, not obese and infected with HCV genotype 2 achieve a RVR. This is not the case for genotype 3. Steatosis is the independent predictor of relapse. New therapeutic strategies are necessary for this subgroup of HCV genotype 3.
    Journal of Viral Hepatitis 05/2012; 19(5):346-52. · 3.08 Impact Factor
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    ABSTRACT: HCV and NAFLD are associated with atherosclerosis in general population. The prevalence of atherosclerosis in chronic hepatitis C (CHC) patients is unknown. We hypothesized that HCV per se and HCV-related steatosis could favour atherosclerosis. Thus, in CHC patients we assessed: (a) the prevalence of atherosclerosis; (b) the role of HCV, cardio-metabolic risk factors and hepatic histology. Overall, 803 subjects were enrolled: (A) 326 patients with liver biopsy-proven treatment naive CHC (175 with and 151 without steatosis); (B) 477 age and gender matched controls, including 292 healthy subjects without steatosis (B1) and 185 with NAFLD (B2). Carotid atherosclerosis (CA), assessed by high-resolution B-mode ultrasonography, was categorized as either intima-media thickness (IMT: >1mm) or plaques (≥ 1.5mm). CHC patients had a higher prevalence of CA than controls (53.7% vs 34.3%; p<0.0001). Younger CHC (<50 years) had a higher prevalence of CA than controls (34.0% vs 16.0%; p<0.04). CHC patients without steatosis had a higher prevalence of CA than B1 controls (26.0% vs 14.8%; p<0.02). CHC with steatosis had a higher prevalence of CA than NAFLD patients (77.7% vs 57.8%, p<0.0001). Viral load was associated with serum CRP and fibrinogen levels; steatosis with metabolic syndrome, HOMA-IR, hyperhomocysteinemia and liver fibrosis. Viral load and steatosis were independently associated with CA. Diabetes and metabolic syndrome were associated with plaques. HCV infection is a risk factor for earlier and facilitated occurrence of CA via viral load and steatosis which modulate atherogenic factors such as inflammation and dysmetabolic milieu.
    Atherosclerosis 02/2012; 221(2):496-502. · 3.71 Impact Factor
  • Hot Topics in Viral Hepatitis 01/2012; 8(24):27-35.
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    ABSTRACT: INTRODUCTION: Chronic hepatitis C (HCV) infection is considered a metabolic disease. It is associated with a specific metabolic syndrome, HCV-associated dysmetabolic syndrome (HCADS), consisting of steatosis, hypocholesterolemia and insulin resistance/diabetes. These metabolic derangements contribute to a decrease in sustained virological response (SVR) to pegylated-interferon-α-ribavirin as standard of care (SOC), and are associated with progression of liver fibrosis. AREAS COVERED: The review, highlighting the impact of HCADS and metabolic syndrome components of HCV disease progression and SOC, discusses current knowledge and perspectives on metabolic therapeutic strategies aimed at improving SVR rate of SOC for chronic hepatitis C. EXPERT OPINION: HCV, features of HCADS and of metabolic syndrome may coexist in the same patient, thus all components of the metabolic syndrome must be assessed to individualize treatment. The results of therapeutic trials evaluating metabolic strategies combined with current SOC indicate that weight loss is a critical part of treatment which will improve both disease outcome and therapeutic response to SOC. Similarly, statins seem to improve response rate to SOC representing, once confirmed to be safe, an important therapeutic tool for HCV-infected patients. Findings from studies using insulin sensitizers combined with SOC are not conclusive and do not justify the use of this class of drugs in clinical practice.
    Expert Opinion on Pharmacotherapy 10/2011; 12(14):2215-34. · 2.86 Impact Factor
  • Luigi E Adinolfi, Luciano Restivo
    Expert review of gastroenterology & hepatology 04/2011; 5(2):147-50.
  • Journal of Hepatology 04/2010; 52. · 9.86 Impact Factor

Publication Stats

3k Citations
517.88 Total Impact Points

Institutions

  • 2009–2014
    • Università degli Studi di Modena e Reggio Emilia
      • Department of Biomedical, Metabolical and Neurosciences
      Modène, Emilia-Romagna, Italy
  • 1983–2014
    • Second University of Naples
      • Faculty of Medicine and Surgery
      Caserta, Campania, Italy
  • 2006–2009
    • Università degli Studi di Napoli L'Orientale
      Napoli, Campania, Italy
    • Nuovo Ospedale Civile di Sassuolo
      Sassuolo, Emilia-Romagna, Italy
  • 2008
    • Amedeo Avogadro University of Eastern Piedmont
      Novara, Piedmont, Italy
  • 1996
    • University of Naples Federico II
      • Department of Molecular Medicine and Medical Biotechnology
      Napoli, Campania, Italy
  • 1989
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1988–1989
    • Georgia Health Sciences University
      Augusta, Georgia, United States