Hepatitis: Adinolfi LE

Lonardo A, Adinolfi LE, Petta S, Craxì A, Loria P. · Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy. · Expert Rev Anti Infect Ther. · Pubmed #19344243 No free full text.

Abstract: Type 2 diabetes (T2D) and HCV infection are common conditions involving, respectively, at least 170 and 130 million people worldwide. However, the distribution of such cases does not overlap in the same age groups in different geographic areas. Following pioneering reports of increased prevalence of T2D in HCV-positive cirrhosis, interest concerning the relationship between HCV and T2D has escalated. HCV is able to induce insulin resistance (IR) directly and the role of specific viral genotypes responsible for such effect is disputed. IR has consistently been found to be closely linked to fibrosis in HCV infection, although also typically associated with T2D in prefibrotic stages. HCV infection could be associated with a reduced prevalence of metabolic syndrome owing to virus-associated reduction in BMI (reported in population but not clinical studies) and hypobetaliproteinemia. A three- to ten-fold increased risk of HCV infection was reported among diabetic patients in comparison with different control groups and a meta-analysis showed a 1.8-fold excess risk of T2D among HCV-positive compared with HBV-positive patients. Moreover, HCV positivity is associated with an increased risk of T2D in patients receiving liver or kidney transplantations. T2D and IR are independent predictors of a more rapid progression of liver fibrosis and impaired response to antiviral treatment in chronic hepatitis C. Patients with cirrhosis and T2D have an increased susceptibility to hepatic encephalopathy and hepatocellular carcinoma (HCC). However, the beneficial effects of antiviral treatment on IR and T2D are controversial. Theoretically, glycemic control in chronic hepatitis C, and particularly in cirrhotic patients, could improve the prognosis and the response to antivirals, although the evidence for this is limited. Future studies should elucidate the relationship between insulin signaling, HCV and interferon signaling, entity of cardiovascular risk in patients with HCV infection, the potential role of 'metabolic' strategies added to antiviral treatment schedules, the impact of IR on liver failure, portal hypertension and HCC, particularly in patients managed in a transplant setting.

Lonardo A, Loria P, Adinolfi LE, Carulli N, Ruggiero G. · Unità Operativa di Medicina Interna e Gastroenterologia, Nuovo Ospedale Civile-Estense di Baggiovara, Modena, Italy. · J Viral Hepat. · Pubmed #16436124 No free full text.

Abstract: The overall prevalence of steatosis in patients with Hepatitis C virus (HCV) chronic infection is 55.5% (range 34.8-81.2%). This is a two to threefold increase compared with the prevalence of steatosis in chronic hepatitides because of other aetiologies and of the figures expected on the grounds of a steatosis-HCV chance association. HCV genotype 3 (HCV-3) has specific epidemiological features; furthermore, as compared with HCV-non-3 genotypes, it is associated with a higher prevalence (74.1%vs 47.9%, P < 0.01) and with more severe grades of steatosis (prevalence of grade 3 steatosis 29.6 vs 5.5 P < 0.01). Host and viral factors play a role, although to a variable extent, in the pathogenesis of HCV-3 and non-3 steatosis. HCV load and body mass index are associated with steatosis in HCV-3 and in HCV-non-3 patients respectively. Serum cholesterol levels and liver steatosis at baseline follow an inverse relationship in HCV infection. As hypocholesterolaemia corrects only in those sustained responders to antiviral treatment both in genotype 3 and in non-3 genotypes, the occurrence of a virally induced, acquired and reversible hypobetalipoproteinaemia seems plausible. Steatosis affects the natural course of HCV infection: it is associated with fibrosis, a possible mediator of increased risk to develop type 2 diabetes, it impairs the response to antiviral treatment in HCV-3 patients and might constitute a risk factor for the development of hepatocellular carcinoma. These observations indicate the need to evaluate the efficacy of combined antiviral and 'metabolic' approaches vs standard antiviral regimes in patients with steatosis and HCV chronic infection.

Adinolfi LE, Durante-Mangoni E, Zampino R, Ruggiero G. · Internal Medicine and Hepatology, Second University of Naples, Naples, Italy. · Aliment Pharmacol Ther. · Pubmed #16225474 links to  free full text

Abstract: Steatosis is a common feature of chronic hepatitis C, and may be caused directly by the virus, as in genotype 3 infection, or be associated with host metabolic factors. The interaction of hepatitis C virus core protein with the lipoprotein secretion pathways causes the characteristic alterations of lipid metabolism observed in hepatitis C virus-related steatosis. Several pathogenic mechanisms are likely involved into the pathogenesis of hepatitis C virus-related steatosis, including hyper-homocysteinaemia, hypoadiponectinaemia and insulin resistance. Steatosis is a major determinant of the liver damage progression in chronic hepatitis C (CHC), and negatively affects the response rate to the interferon (IFN)-based anti-viral treatment. Moreover, recent evidence suggests that steatosis may contribute to liver carcinogenesis. Chronic hepatitis C is a recognized risk factor for type 2 diabetes and it could be implicated into the pathogenesis of atherosclerosis. The role of hepatitis C virus (HCV)-related steatosis in these epidemiological associations remains to be determined.

Lonardo A, Loria P, Adinolfi LE, Andreana A, Ruggiero G, Carulli N. · UO di Medicina Interna e Gastroenterologia, Ospedale Civile di Modena. · Ann Ital Med Int. · Pubmed #15859390 No free full text.

Abstract: Hepatic steatosis is the hallmark of nonalcoholic fatty liver disease (NAFLD), which is the consequence of multiple metabolic derangements among which insulin resistance plays a pivotal role. Steatosis is, also, a feature of hepatitis C virus (HCV) infection. However, in chronic hepatitis C, the prevalence of steatosis is 2.5-fold more elevated than that expected by a chance concurrence with NAFLD, suggesting that HCV may be implied in the development of steatosis. As observed in NAFLD, in patients infected with HCV genotype 1 steatosis is associated with an increased body mass index. On the other hand, in patients infected with genotype 3 the extent of steatosis strictly correlates with the viral load indicating that steatosis is mainly "virus-related". Regardless of the "metabolic" or "viral" etiology, hepatic steatosis in HCV contributes to the progression of liver fibrosis, to the development of hepatocellular carcinoma and to an impaired response to interferon treatment. Features such as obesity, insulin resistance and type 2 diabetes mellitus are shared by NAFLD and HCV-associated steatosis. In addition, HCV infection, directly or through steatosis, favors the development of type 2 diabetes mellitus. Hyperlipidemia is an independent predictor of the development of NAFLD, but not of HCV-associated steatosis. Arterial hypertension is common in nonalcoholic steatohepatitis patients, and HCV infection has recently been acknowledged as an independent risk factor for atherosclerosis. The role of iron in the progression of both NAFLD and HCV-associated steatosis remains controversial while lipoperoxidation and oxidative stress are pathogenic mechanisms shared by both. Some metabolic risk factors may be shared by both HCV-associated steatosis and NAFLD although the disease progression and pathophysiological background may be different. Preliminary data suggest that the therapeutic options for NAFLD may also be useful to improve HCV-associated steatosis.

Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. · Division of Internal Medicine and Gastroenterology, Modena City Hospital, Italy. · Gastroenterology. · Pubmed #14762795 No free full text.

Abstract: Nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV)-related liver disease are common in the general population, but their concurrence is 2- to 3-fold higher than would be expected by chance alone. In patients with chronic HCV infection, steatosis is attributable to a variable combination of the mechanisms considered to play a role in the pathogenesis of NAFLD--insulin resistance in the obese and in the lean subject--along with a direct effect of HCV on hepatic lipid metabolism that leads to triglyceride accumulation through inhibition of export proteins that are required for very low density lipoprotein (VLDL) assembly and secretion. Accumulating evidence suggests that steatosis contributes to the progression of fibrosis in HCV-related disease in a pattern similar to that observed in NAFLD. Potential mechanisms of this effect include the increased sensitivity of steatotic livers to oxidative stress and cytokine-mediated injury. Steatosis-related hepatic insulin resistance may also play a role through the profibrogenic effects of the compensatory hyperinsulinemia and provides a potential explanation for the association between HCV and type 2 diabetes mellitus. Indeed, an appreciation of the importance of fat in HCV has recently led to trials of adjuvant therapy for HCV directed at steatosis-associated disease mechanisms, with encouraging results reported for various modalities, including weight loss and antioxidants. Future therapy should be aimed at exploiting the interactions of HCV with host insulin and lipid metabolism, particularly in nonresponders to standard antiviral schedules.

Durante-Mangoni E, Iardino P, Utili R, Adinolfi LE, Ruggiero G. · Department of Internal Medicine, Second University of Naples Medical School, Napoli, Italy. · Antivir Ther. · Pubmed #16964833 No free full text.

Abstract: BACKGROUND: Pegylated-interferon-alpha (peg-IFN-alpha) is the mainstay of treatment for chronic hepatitis C (CHC). Treatment is often complicated by neutropaenia due to inhibition of haematopoiesis. However, there are no data on the kinetics of granulocyte-colony stimulating factor (G-CSF), a major neutrophil growth factor, in this setting. We therefore evaluated G-CSF synthesis in CHC patients on peg-IFN-alpha treatment. METHODS: A total of 40 CHC patients were studied. None had pre-existing haematological disorders, or hepatitis B virus or HIV coinfection. For controls, 30 healthy subjects were used. Laboratory examinations, including liver function tests, were performed at baseline and monthly over treatment and follow-up. Serum G-CSF was measured in all patients and controls at baseline and in a subgroup of 20 CHC patients also at weeks 2, 4, 24, 48 and 72 after treatment start. RESULTS: CHC patients had a significantly lower pre-treatment neutrophil count (3,256 +/- 1,197 versus 3,804 +/- 859; P = 0.03). Notwithstanding, they showed lower baseline G-CSF serum levels than healthy controls (16.1 +/- 6.2 versus 19.4 +/- 7.5; P = 0.048). Consistently, baseline G-CSF levels were poorly correlated with the neutrophil count in CHC patients (r = -0.2; P = 0.2). Moreover, serum G-CSF levels did not increase in any of the 20 CHC patients during peg-IFN-alpha treatment, despite declining neutrophil counts. CONCLUSIONS: The lower neutrophil counts observed in CHC might be related to an absolute deficiency in G-CSF production. In the human model of neutropaenia induced by peg-IFN-alpha, we show that endogenous G-CSF levels are not physiologically up-regulated to overcome the decline in neutrophil counts. Our study provides a rationale for the evaluation of recombinant human G-CSF treatment in peg-IFN-alpha-induced neutropaenia.

Adinolfi LE, Utili R, Tonziello A, Ruggiero G. · Division of Internal Medicine and Hepatology, Faculty of Medicine, Second University of Naples, Naples, Italy. · Gut. · Pubmed #12692056 links to  free full text

Abstract: BACKGROUND: Fifty per cent of chronic hepatitis C patients are non-responders to interferon. At present, there are no recommended therapeutic options for non-responders. AIMS: The safety and long term effect of alpha interferon induction plus ribavirin with or without amantadine in the treatment of interferon non-responsive chronic hepatitis C was evaluated. PATIENTS AND METHODS: A total of 114 consecutive patients were randomly divided into three groups with a final 2:2:1 ratio: group A (44 patients) received interferon alfa 2b, 3 million units (MU), three times a week, and oral ribavirin (1000 mg/day); group B (46 patients) received interferon 3 MU daily for the first four weeks and subsequently 3 MU three times a week, and ribavirin as in regimen A; and group C (24 patients) received interferon and ribavirin as in regimen B, plus oral amantadine hydrochloride (200 mg/day). The duration of treatment was 12 months. RESULTS: The end of treatment response for groups A and B was 25% and 29%, respectively, and for group C, 68% (p<0.005). At the end of one year of follow up, a sustained response was observed for six (25%) patients in group C, one (2%) patient in group A, and two (4%) patients in group B (p<0.002). The triple regimen was well tolerated and did not increase the frequency or severity of side effects. CONCLUSIONS: The study demonstrates that for the treatment of interferon non-responder hepatitis C patients, the association of interferon-ribavirin has a negligible long term effect whereas a triple regimen including interferon, ribavirin, and amantadine can be an effective and safe treatment.

Durante-Mangoni E, Zampino R, Portella G, Adinolfi LE, Utili R, Ruggiero G. · Second University of Naples Medical School, Department of Cellular and Molecular Biology, Federico II University Medical School, Naples, Italy. · Clin Infect Dis. · Pubmed #19591593 No free full text.

Abstract: BACKGROUND: Analysis of hepatitis C virus (HCV) RNA kinetics during antiviral therapy may allow estimation of the probability of response. METHODS: To assess clinical and virological correlates and the predictive value of first-phase HCV RNA kinetics during pegylated interferon and ribavirin treatment, we studied 119 patients with chronic hepatitis C who were treated with pegylated interferon and ribavirin. HCV RNA level was measured 5 min before and 2, 14, and 28 days after the start of treatment. For each patient the Delta(t0-t2) log(10) HCV RNA value was calculated, which indicates the relative reduction in HCV RNA level from before treatment to day 2 after logarithmic transformation. RESULTS: A Delta(t0-t2) log(10) HCV RNA value < or =0.8 showed a 95% negative predictive value for virological response, whereas one >2.5 had a 93% positive predictive value for virological response, independent of genotype and histology. The Delta(t0-t2) log(10) HCV RNA value was strictly related to final treatment outcome and could differentiate not only patients with a sustained virological response from nonresponders but also patients who experienced relapse from the former. The Delta(t0-t2) log(10) HCV RNA value was highest among patients infected with genotypes 2 and 3 and was lowest among patients infected with genotype 1. It decreased with increasing grades of fibrosis and steatosis and was also inversely related to gamma-glutamyl transpeptidase (GGT) level and HOMA-IR (homeostasis model assessment for insulin resistance) score. In multivariate analysis, [Formula: see text] log(10) HCV RNA value was the strongest predictor of sustained virological response and appeared to be independently related to viral genotype and GGT level. CONCLUSION: HCV RNA kinetics has strong predictive value. It correlates with virological and clinical parameters that are known predictors of antiviral treatment outcome, including insulin resistance. The measurement of HCV load as early as 2 days after the start of pegylated interferon and ribavirin is a useful tool for the prediction of treatment outcome in individual patients and should be used in clinical practice.

Lonardo A, Ballestri S, Adinolfi LE, Violi E, Carulli L, Lombardini S, Scaglioni F, Ricchi M, Ruggiero G, Loria P. · Università degli Studi di Modena e Reggio Emilia, Dipartimento di Medicina, Endocrinologia e Geriatria, Modena, Italy. · Can J Gastroenterol. · Pubmed #19373421 No free full text.

Abstract: BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C feature steatosis and insulin resistance (IR), conditions associated with the metabolic syndrome (MS). OBJECTIVES: To assess the prevalence of MS and determinants of IR in patients with NAFLD and chronic hepatitis C. METHODS: Ninety-three consecutive patients with NAFLD, 97 with chronic hepatitis C virus (HCV) genotypes 1 and 2, and 182 'healthy' controls without steatosis were enrolled in the present study. The prevalence of MS was assessed by modified Adult Treatment Panel III criteria and IR by the homeostasis model assessment of insulin resistance (HOMA-IR). IR was defined as the 75th percentile of the HOMA-IR of control subjects. RESULTS: While the prevalence of IR was similar in NAFLD and HCV-infected subjects (70.0% and 78.7%, respectively), the prevalence of MS was significantly higher in NAFLD patients than in HCV-infected patients (27.9% versus 4.1%) and in controls (5.6%). With multivariate analysis, IR was predicted by body mass index (OR 1.263; 95% CI 1.078 to 1.480) and triglyceridemia (OR 1.011; 95% CI 1.002 to 1.020) in NAFLD and by sex (OR for female sex 0.297; 95% CI 0.094 to 0.940) and fibrosis stage (OR 2.751; 95% CI 1.417 to 5.340) in chronic hepatitis C. CONCLUSIONS: IR is independently associated with body mass index and triglyceridemia in NAFLD, sex and fibrosis in chronic HCV infection, and has a higher prevalence in NAFLD and chronic hepatitis C than in controls. However, the frequency of MS in HCVinfected patients, similar to that of controls, is significantly lower than that seen in NAFLD patients. The current diagnostic criteria of MS are more likely to 'capture' patients with NAFLD than with chronic hepatitis C, although both groups are insulin resistant.

Zampino R, Ingrosso D, Durante-Mangoni E, Capasso R, Tripodi MF, Restivo L, Zappia V, Ruggiero G, Adinolfi LE. · Departments of Internal Medicine and Hepatology, F Cedrangolo, Second University of Naples, Naples, Italy. · J Viral Hepat. · Pubmed #18482281 No free full text.

Abstract: SUMMARY: (A) A reduced activity of microsomal triglyceride transfer protein (MTP), a key enzyme of assembly/secretion of lipoproteins, is related to HCV steatosis. Host genetic background may influence development of steatosis. The aim of the study was to investigate the association between MTP-493 G/T gene polymorphism, fat liver accumulation and fibrosis progression in HCV infected patients. A total of 102 naïve patients with liver biopsy proven chronic hepatitis C were evaluated for MTP-493 G/T gene polymorphism, HCV RNA, HCV genotype, HOMA-IR, serum adiponectin, TNF-alpha and serum lipid levels. HCV genotype 3 infected patients carrying the T allele of the MTP gene polymorphism showed higher degree of steatosis than those carrying GG genotype (3.45 +/- 0.37 vs 1.30 +/- 0.45, respectively; P < 0.001). MTP'T' allele carriers also had higher HCV RNA serum levels (P < 0.01) and hepatic fibrosis (P < 0.001). Irrespective of MTP genotype, patients with HCV genotype 3 had lower levels of cholesterol, ApoB, HDL and LDL. In HCV genotype non-3 infected patients no parameters were associated with MTP gene polymorphism. In conclusion the presence of T allele of MTP-493G/T gene polymorphism predisposes patients infested with HCV genotype 3 to develop higher degree of fatty liver accumulation.

Vidali M, Tripodi MF, Ivaldi A, Zampino R, Occhino G, Restivo L, Sutti S, Marrone A, Ruggiero G, Albano E, Adinolfi LE. · Department of Medical Sciences, University Amedeo Avogadro of East Piedmont, Novara, Italy. · J Hepatol. · Pubmed #18164507 No free full text.

Abstract: BACKGROUND/AIMS: The contribution of oxidative stress to the pathogenesis of chronic hepatitis C (CHC) is still poorly elucidated. This study investigated the relationship between oxidative stress, insulin resistance, steatosis and fibrosis in CHC. METHODS: IgG against malondialdehyde-albumin adducts and HOMA-IR were measured as markers of oxidative stress and insulin resistance, respectively, in 107 consecutive CHC patients. RESULTS: Oxidative stress was present in 61% of the patients, irrespective of age, gender, viral load, BMI, aminotransferase level, histology activity index (HAI) and HCV genotype. Insulin resistance and steatosis were evident in 80% and 70% of the patients, respectively. In the patients infected by HCV genotype non-3, but not in those with genotype 3 infection HOMA-IR (p<0.03), steatosis (p=0.02) and fibrosis (p<0.05) were higher in the subjects with oxidative stress than in those without. Multiple regression analysis revealed that, HOMA-IR (p<0.01), fibrosis (p<0.01) and oxidative stress (p<0.05) were independently associated with steatosis, whereas steatosis was independently associated with oxidative stress (p<0.03) and HOMA-IR (p<0.02). Steatosis (p<0.02) and HAI (p=0.007) were also independent predictors of fibrosis. CONCLUSIONS: In patients infected by HCV genotype non-3, oxidative stress and insulin resistance contribute to steatosis, which in turn exacerbates both insulin resistance and oxidative stress and accelerates the progression of fibrosis.

Durante-Mangoni E, Zampino R, Marrone A, Tripodi MF, Rinaldi L, Restivo L, Cioffi M, Ruggiero G, Adinolfi LE. · Internal Medicine & Hepatology, Second University of Naples Medical School, Napoli, Italy. · Aliment Pharmacol Ther. · Pubmed #17059516 No free full text.

Abstract: BACKGROUND: Steatosis and insulin resistance (IR) have a pathogenic role in chronic hepatitis C (HCV). Adipocytokines balance modulates hepatic lipid content and IR. AIM: To evaluate serum adipocytokines and relationship with virological, histological and metabolic parameters in chronic HCV. METHODS: Adiponectin and tumour necrosis factor-alpha (TNF-alpha) levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 161 non-diabetic chronic HCV patients. RESULTS: Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of TNF-alpha, HOMA, alanine aminotransferase, gamma-glutamiltransferase and Histological Activity Index (HAI) and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Higher tumour necrosis factor-alpha levels were observed in patients with low adiponectin levels. The extension of steatosis was inversely correlated with adiponectin levels. A correlation between grade of steatosis with HOMA-IR and fibrosis was observed. HCV genotype 3-infected patients showed lower adiponectin levels than those with other genotypes. An independent predictor of low adiponectin levels in genotype 3 infection was the extension of steatosis. Liver fibrosis score was associated with steatosis, HAI and age. CONCLUSIONS: Chronic HCV patients with steatosis showed a serum adiponectin/TNF-alpha imbalance that is associated with IR. Reduced adiponectin levels may be involved in the pathogenesis of steatosis, which in turn accelerates progression of fibrosis in chronic HCV.

Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, Adinolfi LE, Asselah T, Jonsson JR, Smedile A, Terrault N, Pazienza V, Giordani MT, Giostra E, Sonzogni A, Ruggiero G, Marcellin P, Powell EE, George J, Negro F, Anonymous00041. · IRCSS de Bellis, Castellana Grotte, Italy. · Gastroenterology. · Pubmed #16697727 No free full text.

Abstract: BACKGROUND & AIMS: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. METHODS: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. RESULTS: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. CONCLUSIONS: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Marrone A, Zampino R, Karayannis P, Cirillo G, Cesaro G, Guerrera B, Ricciotti R, del Giudice EM, Utili R, Adinolfi LE, Ruggiero G. · Internal Medicine and Hepatology, Second University of Naples, Napoli, Italy. · Aliment Pharmacol Ther. · Pubmed #16197491 links to  free full text

Abstract: BACKGROUND: Drug-resistant mutants may emerge in patients with chronic hepatitis B receiving lamivudine therapy. AIM: To evaluate whether different viral mutational patterns may be associated with clinical reactivation during lamivudine treatment in patients with chronic B hepatitis. METHODS: Eight anti-hepatitis B e-positive patients with (group A) and 14 patients without clinical exacerbation (five anti-hepatitis B e-positive, group B1; nine hepatitis B e antigen-positive, group B2) during lamivudine treatment were investigated. RESULTS: 'Polymerase region': M204V/I variants were found in all group A patients, but in none of group B1 (P=0.0007) and in four of nine of group B2 (44%; P=0.02) patients. The L180M substitution was detected in four of eight (50%) of group A and in none of groups B1 and B2. 'Core promoter': the double basic core promoter (A1762T/G1764A) variant was detected in seven of eight (87%) of group A and in one of five (20%; P=0.03) of group B1 and one of nine (11%; P=0.002) of group B2 patients. 'Precore': the G1896A stop codon mutation was present in seven of eight (87%) of group A and in zero of five (P=0.004) of group B1 and one of nine (11%; P=0.002) of group B2. CONCLUSIONS: Different mutational patterns were observed in the lamivudine-treated patients with and without exacerbation. There was an association of the basic core promoter and stop codon mutations with lamivudine resistance in patients with disease exacerbation.

Lonardo A, Lombardini S, Scaglioni F, Carulli L, Ricchi M, Ganazzi D, Adinolfi LE, Ruggiero G, Carulli N, Loria P. · Unità Operativa di Medicina Interna e Gastroenterologia, Nuovo Ospedale Civile-Estense, Via Giardini, Baggiovara, Modena 41100, Italy. · J Hepatol. · Pubmed #16168516 No free full text.

Abstract: BACKGROUND/AIMS: To ascertain whether the etiology of hepatic steatosis modulates insulin resistance (IR) and to determine the predictors of IR. METHODS: We studied IR through HOMA IR in 146 subjects, 99 of whom had ultrasonographic and/or histologic steatosis. Twenty-two had familial heterozygous hypobetalipoproteinemia (FHBL), 48 had non-alcoholic fatty liver disease (NAFLD), 34 HCV infection (17 with HCV1b, 17 with HCV3a) and 42 were healthy controls without steatosis. RESULTS: Steatosis was present in 77.3% of FHBL and, by enrolment criteria, in all NAFLD and HCV cases. Overall HOMA-IR correlated with BMI and GGT (P<0.01). FHBL and healthy groups had similar HOMA-IR and GGT values, whereas higher levels were observed in HCV and NAFLD. HCV3a and FHBL patients were hypolipidemic. HOMA-IR was similar in FHBL patients and controls and lower than in HCV and NAFLD. FHBL patients had a high extent of steatosis, similar to that observed in HCV3a, but lower grading and staging than NAFLD and HCV. At multivariate analysis, steatosis and GGT predicted HOMA-IR. CONCLUSIONS: Data suggest that not all hepatic fat associates with IR. FHBL patients, for some aspects, resemble HCV3a infection, possibly suggesting a shared steatogenic mechanism. Among steatotic patients serum GGT levels is the independent predictor of IR.

Adinolfi LE, Ingrosso D, Cesaro G, Cimmino A, D'Antò M, Capasso R, Zappia V, Ruggiero G. · Division of Internal Medicine and Hepatology, Second University of Naples, Faculty of Medicine, Naples, Italy. · Hepatology. · Pubmed #15834927 No free full text.

Abstract: The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r = 0.367; P = .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 micromol/L, respectively (P = .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P = .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR = 7.1), HAI (OR = 3.8), liver fibrosis (OR = 4.0), and HCV genotype 3 (OR = 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P = .03), HAI (P = .0001), and steatosis (P = .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC.

Durante-Mangoni E, Iardino P, Resse M, Cesaro G, Sica A, Farzati B, Ruggiero G, Adinolfi LE. · Divisions of Internal Medicine and Hepatology, Second University of Naples Medical School, Napoli, Italy. · J Clin Gastroenterol. · Pubmed #15492610 No free full text.

Abstract: GOALS: To assess the impact of interferon treatment on celiac disease onset in hepatitis C patients and to clarify its clinical relevance and outcome. BACKGROUND: Hepatitis C is associated with autoimmunity, which can be exacerbated by interferon treatment. Cases of celiac disease activation during interferon treatment have been reported. STUDY: Retrospective evaluation of 534 hepatitis C patients with or without symptoms compatible with celiac disease onset during interferon treatment and 225 controls. Anti-transglutaminase antibodies were assayed. HLA-DQA1 and -B1 loci were typed. Upper gastrointestinal endoscopy was applied to confirm the diagnosis in antibody-positive patients. RESULTS: Anti-transglutaminase antibodies were detected before treatment in 1.3% of hepatitis C patients and in 0.4% of controls (not significant). Eighty-six percent of patients with anti-transglutaminase antibodies showed activation of celiac disease while on interferon. Symptoms ranged from mild to severe, and interferon had to be discontinued in 2 of 7 (29%) patients. Symptoms disappeared in 6 of 7 patients after interferon withdrawal. Onset of symptoms compatible with celiac disease during interferon therapy was significantly associated with the presence of anti-transglutaminase antibodies (OR 53). CONCLUSIONS: In hepatitis C patients, the activation of silent celiac disease during interferon treatment is almost universal and should be suspected, but it uncommonly requires interferon treatment discontinuation. Symptoms subside after interferon withdrawal.

Zampino R, Marrone A, Durante Mangoni E, Santarpia L, Sica A, Tripodi MF, Utili R, Ruggiero G, Adinolfi LE. · Division of Internal Medicine and Hepatology, Faculty of Medicine, Second University of Naples, Naples, Italy. · J Med Virol. · Pubmed #15042645 No free full text.

Abstract: Antibodies against envelope glycoprotein 1 and 2 (anti-E1/E2) have been suggested to influence HCV replication levels. Hepatitis B virus (HBV) may interfere with hepatitis C virus (HCV) replication. At present there are no data on anti-E1/E2 antibody responses or on the effect of interferon (IFN) treatment in HBV-HCV co-infection. Accordingly, we evaluated serum anti-E1/E2 antibodies in 50 patients (median age, 26.5; males, 30) with chronic hepatitis, 38 with HCV and 12 with HBV-HCV co-infection, who had undergone alpha-IFN treatment. Before starting IFN, the HCV group showed higher HCV-RNA levels (bDNA assay) than the HBV-HCV group (median 3.75 vs. 0.64 x 10(6) Eq/ml, respectively; P < 0.05). Similarly, the anti-E2 levels (EIA assay) were higher in the HCV group than in the HBV-HCV (mean +/- SD, 53.8 +/- 54.58 vs. 24.5 +/- 41.50 U/ml, respectively; P < 0.02), and the prevalence of anti-E2 was also higher in the HCV group (94 vs. 58%, respectively; P < 0.007). No correlation was found between anti-E1/E2 antibodies and the HCV-RNA levels. The prevalence of E1/E2 antibodies was similar in the different HCV genotypes. Higher baseline levels of anti-E2 antibodies and a decrease or disappearance of anti-E2 antibodies during IFN were associated with IFN sustained response in both groups, whereas no reduction in the anti-E1/E2 levels was observed in non-responders. The data show that HBV co-infection influences both HCV replication and the anti-E1/E2 antibody production. High pre-treatment levels of anti-E2 antibodies and their decrease or disappearance during interferon treatment are often associated with HCV clearance in sustained responders, irrespective of the HCV genotype.

Adinolfi LE. · No affiliation provided · Am J Gastroenterol. · Pubmed #14638367 No free full text.

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Adinolfi LE, Utili R, Andreana A, Tripodi MF, Marracino M, Gambardella M, Giordano M, Ruggiero G. · Institute of Medical Therapy, Faculty of Medicine, Second University of Naples, Italy. · Dig Dis Sci. · Pubmed #11508667 No free full text.

Abstract: The role of HCV RNA levels and host factors in the severity of liver injury was studied. Enrolled were 298 consecutive liver biopsy-proven chronic hepatitis (CH) C patients (179 men; median age: 52 years, range 19-68; CH, 198; cirrhosis, 100) and 18 chronic hepatitis C with normal ALT. HCV genotypes were: 1a, 4.3%; 1b, 53%; 2a/c, 28%; 3a, 7%; 4, 1.3%, and mixed 6.4%. Serum HCV RNA levels were similar for all genotypes (median: 2.8 x 10(6) eq/ml; range <0.2-69). In patients with chronic hepatitis without cirrhosis, the serum HCV RNA levels reflected the grade of liver necroinflammatory activity (R = 0.45; P < 0.001) and the stage of fibrosis (R = 0.51; P < 0.001), regardless of age, gender, HCV genotype, hepatic steatosis, and hepatic iron overload. Patients with high serum HCV RNA levels (> or =3 x 10(6) eq/ml) had higher ALT values (P < 0.002) than those with lower HCV RNA levels. Patients with normal ALT showed low HCV RNA levels (median: 0.82 x 10(6) eq/ml) and histological features of minimal or mild chronic hepatitis. Cirrhotic patients showed significantly lower levels of viremia than those with chronic hepatitis with a similar HAI. The data of a subgroup of 62 patients with an established time of infection showed that for a similar duration of disease, patients with serum HCV RNA levels > or =3 x 10(6) eq/ml had a significantly higher fibrosis score than those with lower levels. HAI and fibrosis score were significantly higher in patients with HCV RNA levels > or =3 x 10(6) eq/ml and grade 3-4 steatosis than those with lower HCV RNA levels and steatosis grades. The data indicate that the liver damage is correlated with the HCV RNA levels and that a high viral load acts together with steatosis in accelerating the progression of liver injury.

Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. · Internal Medicine & Hepatology, Second University of Naples, Naples, Italy. · Hepatology. · Pubmed #11391523 No free full text.

Abstract: The role of steatosis in the progression of liver damage in chronic hepatitis C (CHC) was studied. Enrolled were 180 consecutive liver biopsy-proven CHC patients and 41 additional subjects with a known duration of infection. We evaluated the histological activity index (HAI), grade of fibrosis and steatosis, body mass index (BMI; kg/m(2)), distribution of body fat, HCV genotype, and levels of HCV RNA. Eighty six (48%) patients showed steatosis, and a higher prevalence was observed in genotype 3a infection (P <.01). A correlation between the grade of steatosis and fibrosis was observed (P <.001). Fibrosis was also associated with age (P <.001). After adjusting for age, the association between steatosis and fibrosis remained significant. The grade of steatosis also correlated with the HAI (P <.007) with a significant increase in periportal necrosis. No relation was found between steatosis and age, gender, iron storage, or levels of HCV RNA. Patients with a high grade of steatosis (>30%) showed higher serum levels of gamma-GT and ALT (P <.001). Overall, steatosis was not significantly associated to BMI. Analysis by single genotype showed a significant association between the grade of steatosis and BMI in type 1 infection r =.689; P <.001) and with levels of HCV RNA in type 3a infection r =.786; P <.001). Visceral fat distribution rather than BMI proved to be associated with steatosis (P <.001). Data obtained from patients with a known date of infection confirmed that steatosis grades 3-4 were associated with a higher annual rate of fibrosis progression, and showed that alcohol and steatosis act together in increasing fibrosis (P <.05). Our data indicate that steatosis is an important cofactor in increasing liver necroinflammatory activity and in accelerating fibrosis in CHC. Visceral obesity and genotype 3a play a role in the development of steatosis.

Adinolfi LE, Giordano MG, Andreana A, Tripodi MF, Utili R, Cesaro G, Ragone E, Durante Mangoni E, Ruggiero G. · Institute of Medical Therapy, Second University of Naples, Naples, Italy. · Br J Haematol. · Pubmed #11380442 No free full text.

Abstract: The pathogenesis of thrombocytopenia in chronic hepatitis is not well known. This study evaluated the relationship between liver injury, serum thrombopoietin, splenomegaly and thrombocytopenia in chronic viral hepatitis. Two hundred and nine patients were enrolled, 85 with splenomegaly and 124 without. Thrombocytopenia was present in 71% and 23% of patients with or without splenomegaly respectively. In subjects with low platelet count, those with splenomegaly showed significantly lower platelet numbers than those without splenomegaly. The spleen size correlated with portal hypertension. An inverse correlation between spleen size and platelet count was observed (r = -0.54; P < 0.0001). In patients without splenomegaly, thrombocytopenia was associated with the grade of fibrosis; platelet counts were the highest in patients with fibrosis 0-2, lower in those with grade 3 (P < 0.008) and lowest in those with grade 4 (P < 0.05). These findings were independent of demographic and biochemical characteristics, hepatic necroinflammatory activity, portal hypertension and splenomegaly. Patients with normal platelet counts showed higher thrombopoietin levels than those with low platelet counts (P < 0.0001). An inverse correlation between thrombopoietin levels and fibrosis grade was observed (r = - 0.50; P < 0.0001). Median thrombopoietin levels were 58 and 27 pg/ml for fibrosis grade 0-1 and grade 4 respectively (P < 0.001). These data indicate that advanced hepatic fibrosis, causing an altered production of thrombopoietin and portal hypertension, plays the central role in the pathogenesis of thrombocytopenia in chronic viral hepatitis.

Adinolfi LE, Utili R, Andreana A, Tripodi MF, Rosario P, Mormone G, Ragone E, Pasquale G, Ruggiero G. · Institute of Medical Therapy, Faculty of Medicine, Second University of Naples, Italy. · Eur J Gastroenterol Hepatol. · Pubmed #10750650 No free full text.

Abstract: OBJECTIVE: The aim of this study was to assess the relationship between HCV genotype and histological liver injury. DESIGN: Prospective study on a cohort of patients with biopsy proven chronic hepatitis C. SETTING: University medical centre. PARTICIPANTS: Enrolled were 324 consecutive patients (male 197, median age 52 years, range 19-68; chronic hepatitis, 224; cirrhosis, 100). METHODS: HCV genotype was determined by the INNO LiPA assay and HCV RNA levels by the bDNA assay. The histological features were scored according to the histology activity index. RESULTS: The distribution of HCV genotypes was 1a, 4.6%; 1b, 52.4%; 2a/c, 27%; 3a, 8%; 4, 2%; mixed, 6%. Serum HCV RNA levels were similar for all genotypes. There was no difference in the distribution of HCV genotypes between patients with chronic hepatitis and those with cirrhosis. Patients with genotype 1b and those with type 2a/c showed a similar prevalence of cases of cirrhosis (33% versus 31%, respectively). In addition, in a subgroup of 102 patients with an established date of infection, the progression to cirrhosis occurred with a similar length of time for HCV type 1b and 2a/c (median 16 versus 15 years, respectively). Patients with HCV genotype 2a/c or mixed genotype showed a higher histology activity index than those with type 1b (P< 0.01), whereas there was no difference in the fibrosis score for the different genotypes. Patients with genotype 3a showed a significantly higher prevalence of steatosis compared to those infected with other genotypes. Alanine aminotransferase (ALT) values were higher in patients with HCV type 2a/c, 3a and mixed genotype than those with type 1 (P < 0.002). CONCLUSIONS: The data indicate that there is no association between a particular HCV genotype and the progression to cirrhosis, and that specific genotypes are associated with distinct histopathological and biochemical manifestations although none of them is correlated with an increase of the fibrosis stage.

Utili R, Zampino R, Bellopede P, Marracino M, Ragone E, Adinolfi LE, Ruggiero G, Capasso M, Indolfi P, Casale F, Martini A, Di Tullio MT. · Institute of Medical Therapy, Chair of Infectious Diseases, Pediatric Oncologic Service, 2nd University of Naples, Medical School, Naples, Italy. · Blood. · Pubmed #10590048 links to  free full text

Abstract: We conducted a long-term prospective study of 89 cancer survivor children who had acquired hepatitis B virus (HBV) and/or hepatitis C virus (HCV) during treatment for neoplasia, the aim being to evaluate the natural history of the diseases and the effect of interferon (IFN) treatment. Patients were followed up for a median period of 13 years (range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32 coinfected by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen (HBsAg) occurred more frequently in coinfected patients (19%) than in the HBV-infected (2%; P =.004), with an annual seroconversion rate of 2.1% and 0.2%, respectively (P =.008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of coinfected and in 28% of HBV-infected patients. Clearance of serum HCV-RNA was observed in 34% and 9%, respectively, of coinfected and HCV-infected patients. Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received alpha-IFN treatment. In the HBV group, 6 patients (35%) cleared serum HBV DNA and seroconverted to anti-HBe; in the HCV-group, none cleared HCV-RNA. In the coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared serum HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases showed a mild histological course with no evidence of liver cirrhosis. A reciprocal interference on viral replication between HBV and HCV may occur in coinfected patients. Treatment seems to be effective for selected cases and is justified in view of the uncertain prognosis of the disease in these patients.

Zampino R, Durante Mangoni E, Marrone A, Utili R, Ruggiero G, Adinolfi LE. · No affiliation provided · Dig Dis Sci. · Pubmed #16187175 No free full text.

This publication has no abstract.