Hepatitis: Guido M

Puoti C, Guido M, Mangia A, Persico M, Prati D, Anonymous00025. · Department of Gastroenterology and Internal Medicine, E. De Santis Hospital, Via A. Grandi 43, 00045 Genzano, Rome, Italy. · Dig Liver Dis. · Pubmed #12846410 No free full text.

Abstract: An ad hoc committee appointed by the Italian Association for the Study of the Liver (AISF) proposed these Practice Guidelines for the management of HCV carriers with persistently normal aminotransferase levels. Only stringent ALT determinations will make it possible to distinguish these subjects from those in temporary biochemical remission. The overall prevalence in Italy has been estimated between 1.5 and 10.6%. HCV RNA quantitation and genotype determination are not predictors of the presence and severity of liver damage nor correlate with the outcome of the disease, and should not be used in clinical practice for the management and surveillance of HCV carriers with normal ALT. Only a minority of HCV carriers with normal ALT levels show a normal morphological picture (true 'healthy carriers'). Disease activity is mild in most cases; fibrosis is generally mild and cirrhosis is very rare. Histological activity, as monitored by sequential liver biopsies, seems to have very slow evolution. HCV carriers should not undergo liver biopsy on a routine basis. Liver biopsy can be reasonably proposed only in selected cases. Until the results of studies with PEG interferon plus ribavirin are available, HCV carriers should not receive antiviral treatment outside controlled experimental studies.

Guido M, Bortolotti F. · Department of Diagnostic Sciences & Special Therapies, University of Padova, Padova, Italy. · Gut. · Pubmed #18559378 No free full text.

This publication has no abstract.

Mangia A, Burra P, Ciancio A, Fagiuoli S, Guido M, Picciotto A, Fabrizi F, Anonymous00319. · Division of Gastroenterology, General Hospital, IRCCS, San Giovanni Rotondo - Italy. · Int J Artif Organs. · Pubmed #18286451 No free full text.

Abstract: The management of hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) is complex and represents a particular concern since numerous issues, such as antiviral therapy in dialysis patients and post renal transplant, and prevention of HCV spread within dialysis units, remain unresolved. An enormous body of literature has been published on HCV in the CKD population; however, clinical evidence on important issues is mostly based on uncontrolled clinical trials or retrospective surveys. The aim of this paper is to provide a systematic review of the literature. Responses to the critical issues have been developed by a consensus of experts, endorsed by the Italian Association for the Study of the Liver (AISF) and some clinical recommendations have been added.

Farinati F, Cardin R, Bortolami M, Burra P, Russo FP, Rugge M, Guido M, Sergio A, Naccarato R. · Dipartimento di Scienze Chirurgiche e Gastroenterologiche, Sezione di Gastroenterologia, Policlinico Universitario, Università di Padova, Padova, Italy. · J Viral Hepat. · Pubmed #18070284 No free full text.

Abstract: Epidemiological evidence clearly identifies chronic infection with hepatitis C virus (HCV) as a major risk factor for the development of hepatocellular carcinoma (HCC). Among the mechanisms that have been implicated in the pro-carcinogenic effect of HCV infection, an increased production of reactive oxygen species in the liver seems to have a major pathogenetic role in leading from chronic inflammation to cancer. Recent data have also demonstrated that HCV is capable of inducing this active production of free radicals per se, not just through inflammation, a feature peculiar to this virus and the specific activity of its core protein. This paper provides an overview of the inter-relationships between HCV, liver damage, free radical production and HCC, describing at least in part the complex network involving DNA oxidative damage, cytokine synthesis, proto-oncogene activation and oestrogen receptor expression, that may all be deeply involved in liver carcinogenesis.

Bortolotti F, Guido M. · Clinica Medica 5, University of Padua, Italy. · J Pediatr Gastroenterol Nutr. · Pubmed #17414134 No free full text.

Abstract: Cirrhosis is the final stage of chronic liver damage of various etiologies. It used to be considered an irreversible lesion, but enormous advances in our understanding of hepatic cellular and molecular biology in the past 2 decades have challenged this view. There is now substantial evidence that cirrhosis can be a reversible process. This concept is supported by an increasing number of clinical reports showing the disappearance of cirrhotic lesions from liver biopsies taken from patients cured of their liver disease. The reversal of cirrhosis usually occurs in patients with short-lived liver disease, after the successful treatment of the underlying liver damage. Recently, however, we observed the spontaneous reversal of cirrhosis after the loss of hepatitis B viremia in 2 men, 21 and 28 years old, who had developed cirrhosis as young children. Several questions and controversial issues concerning the definition of advanced cirrhosis, the limitations of liver biopsy (eg, sampling, interpretation error), and the applicability of noninvasive methods to the assessment of fibrosis, are being addressed. Future prospects include the possibility of antifibrotic therapy to prevent fibrosis or favor its degradation.

Anonymous00331, Demetris AJ, Adeyi O, Bellamy CO, Clouston A, Charlotte F, Czaja A, Daskal I, El-Monayeri MS, Fontes P, Fung J, Gridelli B, Guido M, Haga H, Hart J, Honsova E, Hubscher S, Itoh T, Jhala N, Jungmann P, Khettry U, Lassman C, Ligato S, Lunz JG, Marcos A, Minervini MI, Mölne J, Nalesnik M, Nasser I, Neil D, Ochoa E, Pappo O, Randhawa P, Reinholt FP, Ruiz P, Sebagh M, Spada M, Sonzogni A, Tsamandas AC, Wernerson A, Wu T, Yilmaz F. · No affiliation provided · Hepatology. · Pubmed #16871565 No free full text.

Abstract: Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.

Guido M, Rugge M. · Università Degli Studi di Padova, Azienda Ospedale, Padova, Italy. · Semin Liver Dis. · Pubmed #15085489 No free full text.

Abstract: In chronic viral hepatitis, liver biopsy is performed to grade and stage liver damage. Liver biopsy samples are usually taken with a needle using a percutaneous procedure. This method produces a core of tissue representing approximately 1/50,000th of the liver mass, which raises concern about how representative a needle biopsy can be. A critical review of the literature reveals methodological limits unacceptable in this era of evidence-based medicine. Integrating earlier experience with more recently produced data indicates that a biopsy sample 2 cm or more in length containing at least 11 complete portal tracts should be reliable for grading and staging chronic viral hepatitis.

Nicoletti R, Porro CA, Brighetti G, Monti D, Pagnoni G, Guido M, Rubichi S, Franceschi C. · Department of Communication, University of Bologna, 40122 Bologna, Italy. · Vaccine. · Pubmed #15364434 No free full text.

Abstract: To investigate the possible influence of stimulation of the immune system on cognitive tasks, healthy volunteers were vaccinated against hepatitis B and tested over a 6 month-period in a simple reaction times and the Stroop task. In general, the "Stroop effect" demonstrates that both the name and meaning of a word are automatically processed even when voluntary attention is trying hard not to process them. Unlike placebo group, vaccinated subjects showed a persistent lack of the classical Stroop effect. These findings may be explained by a constraint satisfaction model of the Stroop task, assuming a selective weakening of the connection matrix, and suggest that immune-cognitive effects may occur, besides the well known immune-cognitive influences like those elicited by emotional stress.

Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, Gamberini MR, Schwartz E, Cohen AR. · Department of Laboratory Medicine and Pathobiology, Toronto General Hospital and University of Toronto, ON, Canada. · Blood. · Pubmed #12176871 links to  free full text

Abstract: Patients with thalassemia major require lifelong chelation therapy to prevent iron-induced organ damage. The orally active chelator deferiprone has been proposed as an alternative for patients unable or unwilling to use deferoxamine. One report has concluded that deferiprone may worsen hepatic fibrosis in patients with thalassemia, whereas others have found no detrimental effect. A panel of 3 pathologists evaluated 112 coded liver biopsies obtained from 56 patients before and after deferiprone therapy. Fibrosis was scored with the Laennec and Ishak systems. The mean interval between liver biopsies was 3.1 years (range, 1.2-4.9 years). In 11 patients seronegative for hepatitis C, fibrosis scores before and after therapy were 1.12 +/- 1.07 and 0.97 +/- 0.84 (P =.42) with the use of the Ishak system, and 0.71 +/- 0.65 and 0.70 +/- 0.53 (P =.91) with the Laennec system. Among 45 patients seropositive for hepatitis C, fibrosis scores before and after therapy were 1.91 +/- 1.13 and 2.04 +/- 1.30 (P =.43) with the use of the Ishak system and 1.26 +/- 0.73 and 1.35 +/- 0.90 (P =.41) with the Laennec system. When the data set was limited to biopsies that each contained 6 or more portal tracts (31 patients), analysis still showed no significant change in fibrosis with time. With the use of the Laennec system, the fibrosis score did not increase by more than one level in any patients without hepatitis C; it increased by more than one level in 1 patient with hepatitis C; and it did not decrease by more than one level in any of the 56 patients. This analysis of the largest collection of liver biopsies reported to date in patients receiving deferiprone demonstrates no evidence of deferiprone-induced progression of hepatic fibrosis during long-term therapy.

Fiel MI, Schiano TD, Guido M, Thung SN, Lindsay KL, Davis GL, Lewis JH, Seeff LB, Bodenheimer HC. · Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Mount Sinai Medical Center, City University of New York, NY 10029, USA. · Am J Clin Pathol. · Pubmed #10631856 links to  free full text

Abstract: Increased levels of hepatic iron may impair the response of patients with chronic hepatitis C to treatment with interferon-alfa, but combination therapy with ribavirin has demonstrated efficacy in the treatment of hepatitis C. When used alone or with interferon-alfa, ribavirin may cause a dose-dependent reversible hemolytic anemia. We compared the extent and cellular localization of iron deposition in liver tissue from biopsy specimens obtained before and after 36 weeks of therapy with ribavirin or placebo for 59 patients with chronic hepatitis C. Paired slides were available for review from 26 ribavirin and 27 placebo recipients. Iron deposition was assessed using coded slides stained with Perls Prussian blue and was semi-quantitated in hepatocytes, Kupffer cells, and areas of fibrosis. The overall iron score fell by 0.96 in the placebo group and increased 1.69 in the ribavirin recipients. Iron was deposited mainly in hepatocytes; the hepatocyte iron score increased from 2.19 to 3.81 in the ribavirin group. The amount of iron staining in Kupffer cells declined in the placebo group and increased slightly in the ribavirin group. Iron changes in areas of fibrosis were minor and did not differ between groups. Increased total hepatic iron deposition occurred during a 9-month course of ribavirin. Ribavirin-associated hemolysis deposits iron preferentially in hepatocytes. This increased deposition of hepatic iron does not seem to affect the biochemical or histologic response to ribavirin therapy but may have implications for hepatocyte susceptibility to future injury.

Cesaro S, Bortolotti F, Petris MG, Brugiolo A, Cusinato R, Guido M, Rossetti F, Masiero L, Zanesco L. · Clinica Oncoematologica Pediatrica, Dipartimento di Pediatria, Università di Padova, via Giustiniani 3, 35128 Padua, Italy. · Haematologica. · Pubmed #10629594 links to  free full text

Abstract: BACKGROUND AND OBJECTIVE: Chronic hepatitis C was a frequent complication in patients treated for malignancy until the introduction of anti-HCV screening tests for blood donors. The association between chronic hepatitis C and progression to cirrhosis and hepatocellular carcinoma has been reported in about 20% and 5% of patients, respectively, within 20-30 years of infection. In adult patients, interferon has proved to be effective in decreasing the abnormal values of transaminases and the level of HCV viremia. Our purpose was to assess efficacy of and tolerance to interferon in a group of young patients who had acquired HCV infection during a period of chemotherapy. DESIGN AND METHODS: Interferon-a (IFN) was administered to 26 adolescents and young adults (13 males, age range 17-36 years; median age 24) with chronic hepatitis C, including 4 with hepatitis B virus co-infection, who had been treated for leukemia or solid tumor 5 to 19 years before joining this trial. Patients were treated with natural IFN alpha at a dose of 4 MU/m(2) thrice weekly for 12 months and followed up for another 6 months thereafter. RESULTS: Nine patients stopped treatment during the first 6 months because of side effects (2 cases) or lack of response. At the end of the trial, 8 (31%) cases had responded, with alanine amino-transferase normalization and clearance of hepatitis C virus (HCV) RNA. A sustained response was only documented in 15% of cases, however, irrespective of any hepatitis B virus co-infection. The 2 patients with HCV genotype 2 were both responders, whereas only 8% of those with genotype 1 responded. INTERPRETATION AND CONCLUSIONS: These data show that the efficacy of IFN in this series of young patients is similar to that reported for otherwise healthy adults with hepatitis C. Patients with genotype 2 are strong candidates for IFN treatment while other therapeutic strategies should be designed for patients with HCV genotype 1.

de Arias AE, Haworth SE, Belli LS, Burra P, Pinzello G, Vangeli M, Minola E, Guido M, Boccagni P, De Feo TM, Torelli R, Cardillo M, Scalamogna M, Poli F. · Department of Regenerative Medicine, Organ and Tissue Transplantation Immunology, Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy. · Liver Transpl. · Pubmed #19326408 No free full text.

Abstract: In 20% to 30% of infected individuals, hepatitis C virus (HCV) can cause cirrhosis and hepatocellular carcinoma, for which liver transplantation is the best treatment available. HCV re-infection is universal, and hepatitis disease recurrence occurs in most cases with a 30% probability of progression to graft cirrhosis at 5 years post-transplant. The immunological response to HCV involves natural killer (NK) cells and killer cell immunoglobulin-like receptors (KIRs), which specifically recognize human leukocyte antigen (HLA) class I antigens present on target cells. The effector functions of NK cells are influenced by inhibitory KIR interaction with self-HLA class I ligands, with HLA-C being the most predominant. This study examines the roles of KIR genotypes and their HLA ligands in both HCV disease recurrence and its progression. A total of 151 patients were included in the cohort, and their clinical details were recorded. Liver biopsies were used to define the absence/presence of recurrent hepatitis, the degree of fibrosis, and the progression to cirrhosis over a 10-year period. Mismatching of KIR-HLA-C ligands between donor-recipient pairs was associated with the recurrence of hepatitis (P = 0.008). The presence of KIR2DL3 in the recipient correlated with progression to liver fibrosis (P = 0.04). The mismatching of HLA-KIR ligands favored the progression of the recurrent hepatitis to fibrosis only in the presence of KIR2DL3 (P = 0.04). These preliminary results indicate that the KIR genotype and KIR-HLA-C ligand compatibility play roles in the recurrence and progression of hepatitis C disease in liver transplant recipients.

Sebastiani G, Halfon P, Castera L, Pol S, Thomas DL, Mangia A, Di Marco V, Pirisi M, Voiculescu M, Guido M, Bourliere M, Noventa F, Alberti A. · Venetian Institute of Molecular Medicine, Padova, Italy. · Hepatology. · Pubmed #19291784 No free full text.

Abstract: The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (> or =F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. CONCLUSION: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers.

Ferrara F, Ventura P, Vegetti A, Guido M, Abbati G, Corradini E, Fattovich G, Ferrari C, Tagliazucchi M, Carbonieri A, Orlandini A, Fagiuoli S, Boninsegna S, Minola E, Rizzo G, Belussi F, Felder M, Massari M, Pozzato G, Bonetto S, Rovere P, Sardini C, Borghi A, Zeneroli ML, Toniutto P, Rossi E, Pietrangelo A. · Department of Internal Medicine, Center for Hemochromatosis, University Hospital of Modena, Italy. · Am J Gastroenterol. · Pubmed #19209167 No free full text.

Abstract: OBJECTIVES: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome. METHODS: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome. RESULTS: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043). CONCLUSIONS: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.

De Martin E, Senzolo M, Boninsegna S, Guido M, Masier A, Germani G, Tomat S, Brolese A, Neri D, Cillo U, Gambato M, Russo FP, Farinati F, Burra P. · Department of Surgical and Gastroenterological Sciences, Gastroenterology, Padova University, Padova, Italy. · Transplant Proc. · Pubmed #18675104 No free full text.

Abstract: BACKGROUND AND AIM: Hepatitis C virus (HCV)-related cirrhosis is one of the leading indication for liver transplantation (LT) and a major risk factor for the development of hepatocellular carcinoma (HCC). HCV recurrence after LT is universal. This study evaluated HCV recurrence and survival in patients transplanted for HCV and HCC. METHODS: We evaluated all adults transplanted for HCV cirrhosis between January 1999 and December 2006, HCC was diagnosed on the explant and HCV recurrence confirmed on protocol liver biopsies performed at 6 months and yearly after LT. The sustained viral response (SVR) was defined as HCV-RNA undetectable at 6 months after therapy discontinuation. The patient survival rates were assessed with Kaplan-Meier curves and the chi-square test was used when appropriate. RESULTS: Two hundred sixteen patients underwent LT for HCV including 153 men and 63 women of mean age 54 years with a mean follow-up of 35 months. There were 71 (33%) HCC(+) patients. At 1, 3, and 5 years from LT severe fibrosis (Scheuer 3-4) due to the HCV recurrence was reported in 18%, 14%, and 11% for HCC(+) and 14%, 16%, and 28% for HCC(-) patients respectively (P=NS). HCC recurred only in 3 (4%) patients at a mean follow-up of 3 years. Patients who received antiviral treatment after LT were 10% HCC(+) and 12% HCC(-) patients (P=NS). SVR was seen in 3/7 (43%) of HCC(+) and in 10/18 (55%) of HCC(-) patients (P=NS). At 1, 3, and 5 years the patient survivals was 91%, 86%, and 86% for HCC(+) and 94%, 86%, and 83% for HCC(-) patients, respectively (P=NS). CONCLUSIONS: Severe fibrosis due to HCV recurrence, which increases over time, involves one third of transplanted patients at 5 years after LT. The long-term survival was identical among HCC(+) compared to HCC(-) recipients. The recurrence of HCC was negligible and did not affect patient survival.

Bortolotti F, Verucchi G, Cammà C, Cabibbo G, Zancan L, Indolfi G, Giacchino R, Marcellini M, Marazzi MG, Barbera C, Maggiore G, Vajro P, Bartolacci S, Balli F, Maccabruni A, Guido M, Anonymous00325. · Clinica Medica 5, University of Padua, Padua, Italy. · Gastroenterology. · Pubmed #18439604 No free full text.

Abstract: BACKGROUND & AIMS: The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS: From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS: Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS: Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

Burra P, Masier A, Morisco F, Di Leo V, Zorzi M, Senzolo M, Marchini F, Guido M, Canova D, Floreani A, Burroughs AK. · Gastroenterology Section, Department of Surgical and Gastroenterological Sciences, University of Padova, via Giustiniani 2, 35128 Padova, Italy. · Dig Liver Dis. · Pubmed #18372225 No free full text.

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection is often clinically silent in haemodialysed (HD) patients and their immune response may modulate liver damage in HCV infection. IL-10 and TGF-beta1 could play a role in this setting as, IL-10 down-regulates hepatic fibrosis, while TGF-beta1 is a pro-fibrotic cytokine. AIM: To evaluate the role of IL-10 and TGF-beta1 in HD/HCV+ patients. PATIENTS: 71 HD/HCV+ patients (58 with normal [HD/HCV-N] and 13 with high serum transaminases [HD/HCV-H]), 40 non-uremic patients with chronic hepatitis C (HCV+), 56 HD anti-HCV- patients and 20 healthy volunteers (H). METHODS: IL-10 and TGF-beta1 serum levels were assessed using ELISA tests. Liver histology was assessed by Ishak's score. RESULTS: IL-10 serum levels were significantly higher in HD patients, both HCV+ (3.7+/-0.4 pg/ml; p<0.01) and HCV- (3.8+/-0.8 pg/ml; p<0.05) than in non-uremic HCV patients (2.3+/-0.4 pg/ml). Among the HD/HCV+ patients, IL-10 serum levels were similar in HD/HCV-N and in HD/HCV-H patients. Among the HD/HCV+ patients, IL-10 serum levels were similar in those with moderate histological damage compared to those with mild damage. TGF-beta1 serum levels were significantly lower in HD patients, both HCV+ (4.6+/-0.9 ng/ml) and HCV- (6.0+/-0.9 ng/ml) than in non-uremic HCV+ patients (8.1+/-1.1 ng/ml; p<0.001 and p<0.01, respectively), but similar to the values found in H (5.3+/-0.9 ng/ml; p=n.s.). No correlation was seen between IL-10 and TGF-beta1 serum levels in any of the groups considered. CONCLUSIONS: Patients on haemodialysis treatment to have high levels of IL-10, which remain high even when patients are anti-HCV+, whereas the opposite is true of TGF-beta1. The cytokine pattern observed in HD patients is compatible with the hypothesis explaining the relatively benign evolution of HCV-related liver disease in HD patients, and has a pathophysiological role.

Valenti L, Guido M, Dongiovanni P, Cremonesi L, Fracanzani AL, Fargion S. · Department of Internal Medicine, University of Milan, Milan, Italy. · Dig Liver Dis. · Pubmed #18337195 No free full text.

Abstract: Hepatic siderosis is frequent in patients with Hepatitis C virus (HCV) chronic hepatitis and considered secondary to advanced liver disease when detected in the explanted liver of cirrhotic patients submitted to transplantation. Here, we document the early recurrence of hepatic iron overload starting from host Kupffer cells and later involving hepatocytes in an Italian male submitted to liver transplantation for HCV-related cirrhosis, whose hemosiderosis was interpreted as related to a primary defect of iron handling by monocytic cells due to decreased Ferroportin-1 expression. He was negative for HFE mutations, had normal liver function, did not drink alcohol and had no erythropoietic defect. He was positive for the (CGG)(8/9) and the IVS1 -24 G>C Ferroportin-1 polymorphisms, associated with non-parenchymal iron overload, and had decreased Ferroportin-1 expression in monocytes. In conclusion, this case report documents the recurrence of progressive liver siderosis, which recalls Ferroportin disease, associated with decreased Ferroportin-1 expression in host monocytes repopulating the donor liver.

Bolognesi M, Quaglio C, Bombonato G, Guido M, Cavalletto L, Chemello L, Merkel C, Rugge M, Gatta A, Sacerdoti D. · Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy. · Liver Transpl. · Pubmed #18324620 links to  free full text

Abstract: Liver transplant recipients are a model of rapid progression of hepatitis C virus (HCV)-related liver disease, from normal to cirrhosis. The aim of the study was the analysis of the relationship between portohepatic hemodynamics and modification in liver histology during the progression of HCV liver disease after transplant. Patients transplanted for HCV cirrhosis were considered for the study. At least every 6-12 months, the portal blood flow velocity, hepatic and splenic pulsatility indices, and a portal hypertensive index (obtained from the combination of the portal blood velocity and splenic pulsatility index) were measured with echo-Doppler. Liver biopsy was performed whenever necessary. The time course of echo-Doppler parameters during the histological progression of the liver disease was analyzed. Posttransplant patients without HCV were included as controls. Forty-nine patients with histology-proven relapse of HCV hepatitis were included in the study. At the onset of recurrent hepatitis, the portal blood flow velocity significantly decreased (P < 0.001), and the splenic pulsatility index increased (P = 0.020), whereas the hepatic pulsatility index remained unchanged. In the following years, in addition to a further slight decrease in the portal blood velocity (P = 0.027), a progressive increase in the hepatic and splenic pulsatility indices was also detected (P = 0.009 and P < 0.0001, respectively). The portal hypertensive index steadily increased with the progression of the disease and was related to the degree of liver fibrosis. In conclusion, the information obtainable from splanchnic Doppler parameters can be used to monitor the progression of liver fibrosis in transplant patients with HCV reinfection.

Mangia A, Antonucci F, Brunetto M, Capobianchi M, Fagiuoli S, Guido M, Farci P, Lampertico P, Marzano A, Niro G, Pisani G, Prati D, Puoti M, Raimondo G, Santantonio T, Smedile A, Lauria F, Anonymous00030. · Liver Unit, IRCCS, Ospedale "Casa Sollievo della Sofferenza" San Giovanni Rotondo, Italy. · Dig Liver Dis. · Pubmed #18321798 No free full text.

Abstract: Molecular assays are instrumental in the clinical management of viral hepatitis. During the past years, a wide variety of molecular assays have been developed and implemented. This considerably improved the understanding of the natural history and pathogenesis of Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Hepatitis delta virus (HDV) hepatitis, but also caused uncertainties in the selection of the most appropriate assays for clinical requirements. Indeed, a rational choice and application of these assays requires adequate knowledge of the performance of the single test. Moreover, the choice of the most accurate assay for patients' needs and physicians' objectives, needs to be oriented to specific contexts, such as diagnosis, management or treatment. In the past, a hurdle in the routine use of assays for hepatitis viruses nucleic acid quantification was represented by the availability of only "home brew" methods which lacked standardization. Major improvement in addressing the use of molecular assays for viral hepatitis has been derived from recent standardization procedures that allowed a comparison between different tests after results were given as International Units. In addition, it should be reminded that, before getting into the market, molecular assays should be approved by European regulation authorities and validated using internationally recognized standards. A subsequent clinical validation should address the diagnostic accuracy of the assay. These proceedings have the aim of identifying which molecular tests, among those currently available, meet clinical requirements for each specific application.

Sebastiani G, Vario A, Guido M, Alberti A. · Venetian Institute of Molecular Medicine, Padova, Italy. · J Viral Hepat. · Pubmed #18179453 No free full text.

Abstract: In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Few studies investigated noninvasive markers of liver fibrosis in hepatitis C virus (HCV) patients with normal alanine aminotrasferase (NALT). Eighty HCV patients with NALT and 164 HCV patients with elevated alanine aminotrasferase (EALT) who underwent a diagnostic liver biopsy were evaluated for AST-to-platelet ratio, Forns' index, AST-to-ALT ratio (AAR), Fibrotest and the recently proposed Fibroindex, using liver histology as reference standard. The primary end-point was the detection of significant fibrosis (> or =F2). Performance of noninvasive markers was expressed as specificity, sensitivity and positive (PPV) and negative (NPV) predictive value, accuracy and area under the receiver operating characteristic curve (AUROC). All noninvasive markers for liver fibrosis tested showed a poorer performance in NALT group than in EALT group. Overall, Fibrotest had the best performance in NALT group, as showed by AUROC of 0.70 and 73.5% accuracy. Performance of AAR, Forns' index and Fibroindex was poor in NALT group and it was significantly lower than in EALT group for Forns and Fibroindex (AUROC 0.6 vs 0.76 and 0.58 vs 0.74, respectively, P = 0.05). In NALT patients, PPV was high for all noninvasive markers (>87%) except for AAR, while NPV was low (<65%), thus none of them was able to reliably exclude significant fibrosis. In conclusion, performance of noninvasive-markers is significantly reduced in HCV patients with NALT. Liver biopsy may still be needed for many of these cases to correctly stage liver fibrosis. Specific noninvasive tools and possibly combination of markers should be developed and validated in this clinical setting.

Vivarelli M, Burra P, La Barba G, Canova D, Senzolo M, Cucchetti A, D'Errico A, Guido M, Merenda R, Neri D, Zanello M, Giannini FM, Grazi GL, Cillo U, Pinna AD. · Department of Surgery and Transplantation, University of Bologna, Italy. · J Hepatol. · Pubmed #17928091 No free full text.

Abstract: BACKGROUND/AIMS: To assess the effect of long-term maintenance of steroids on HCV recurrence after liver transplantation (LT), that is still controversial, a prospective multicentre trial was conducted at the centres of Bologna and Padua, Italy. METHODS: From September 2002, 47 eligible HCV positive LT recipients were randomized to receive 2 different steroid schedules in association with tacrolimus: group A: rapid tapering and withdrawal 91 days after LT group B: slow tapering and withdrawal 25 months after LT. Thirty-nine patients were assessable: 23 in group A and 16 in group B. Donor and recipient characteristics were similar in the two groups. Median follow-up was 841 days (130-1376). One hundred liver biopsies were performed, and every patient had a biopsy at month 12. RESULTS: Twenty-two out of 23 (95, 65%) patients in group A and 15 out of 16 (93, 75%) in group B had histologically-confirmed HCV recurrence. Twelve-month histology showed advanced fibrosis (score 3 or 4) in 42.1% of the patients in group A versus 7.6% in group B (P=0.03). One-and 2-year advanced fibrosis-free survival were 65.2 and 60.8 in group A and 93.7% in group B (P=0.03 and =0.02, respectively). CONCLUSIONS: Slow tapering of steroids reduced the progression of recurrent hepatitis C after LT.

Belli LS, Burroughs AK, Burra P, Alberti AB, Samonakis D, Cammà C, De Carlis L, Minola E, Quaglia A, Zavaglia C, Vangeli M, Patch D, Dhillon A, Cillo U, Guido M, Fagiuoli S, Giacomoni A, Slim OA, Airoldi A, Boninsegna S, Davidson BR, Rolles K, Pinzello G. · Hepatology and Abdominal Organ Transplantation Unit, Niguarda Hospital, Milan, Italy. · Liver Transpl. · Pubmed #17370330 links to  free full text

Abstract: In recent years, a worsening outcome of hepatitis C virus (HCV)-positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre- and post-liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV-positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post-LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow-up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan-Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV-related recurrent severe fibrosis (Ishak score 4-6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence.

Sebastiani G, Vario A, Guido M, Alberti A. · Department of Clinical and Experimental Medicine, University of Padova, Padova 35100, Italy. · World J Gastroenterol. · Pubmed #17278217 links to  free full text

Abstract: AIM: To assess the performance of several non-invasive markers and of our recently proposed stepwise combination algorithms to diagnose significant fibrosis (F > or = 2 by METAVIR) and cirrhosis (F4 by METAVIR) in chronic hepatitis B (CHB). METHODS: One hundred and ten consecutive patients (80 males, 30 females, mean age: 42.6 +/- 11.3) with CHB undergoing diagnostic liver biopsy were included. AST-to-Platelet ratio (APRI), Fornso index, AST-to-ALT Ratio, Goteborg University Cirrhosis Index (GUCI), Hui's model and Fibrotest were measured on the day of liver biopsy. The performance of these methods and of sequential algorithms combining Fibrotest, APRI and biopsy was defined by positive (PPV) and negative (NPV) predictive values, accuracy and area under the curve (AUC). RESULTS: PPV for significant fibrosis was excellent (100%) with Forns and high (> 92%) with APRI, GUCI, Fibrotest and Hui. However, significant fibrosis could not be excluded by any marker (NPV < 65%). Fibrotest had the best PPV and NPV for cirrhosis (87% and 90%, respectively). Fibrotest showed the best AUC for both significant fibrosis and cirrhosis (0.85 and 0.76, respectively). Stepwise combination algorithms of APRI, Fibrotest and biopsy showed excellent performance (0.96 AUC, 100% NPV) for significant fibrosis and 0.95 AUC, 98% NPV for cirrhosis, with 50%-80% reduced need for liver biopsy. CONCLUSION: In CHB sequential combination of APRI, Fibrotest and liver biopsy greatly improves the diagnostic performance of the single non-invasive markers. Need for liver biopsy is reduced by 50%-80% but cannot be completely avoided. Non-invasive markers and biopsy should be considered as agonists and not antagonists towards the common goal of estimating liver fibrosis.

Guido M, Bortolotti F, Jara P, Giacomelli L, Fassan M, Hierro L, Nebbia G, Zancan L, Rugge M. · Department of Oncological and Surgical Sciences - Pathology Section, University of Padova, Azienda Ospedaliera, Padova, Italy. · Am J Gastroenterol. · Pubmed #17090284 No free full text.

Abstract: OBJECTIVES: Steatosis is common in adults with chronic hepatitis C, and is involved in the progression of fibrosis. Because little is known about steatosis in pediatric hepatitis C, the aims of this study were to determine the prevalence and severity of steatosis in a pediatric population with chronic hepatitis C, and to evaluate its correlation with clinical parameters. METHODS: Liver biopsies were obtained from 66 consecutive Italian and Spanish children with chronic hepatitis C (87.6% genotype 1). Grade and stage were assessed according to Ishak's system. Steatosis was scored as absent, minimal (less than 5% of steatosic hepatocytes), mild (>5%, <or=33%), moderate (>33%, <or=66%), and severe (>66%); moderate and severe scores were combined for statistical purposes. The BMI-for-age percentile (BMI%) was calculated in all cases at the time of liver biopsy. Cholesterol and triglyceride serum levels were available in 55 cases. RESULTS: The prevalence of steatosis was 27% (18/66 cases, 16/18 with genotype 1), and it was higher in Italian than in Spanish patients (10/21 vs.7/45, P= 0.01). BMI% correlated significantly with both the presence of steatosis (P= 0.002) and its severity (P= 0.000). Steatosis also correlated with serum triglyceride levels (P= 0.04). CONCLUSION: Steatosis is associated with BMI in children with chronic hepatitis C due mainly to genotype 1, and with no confounding hepatotoxic factors (alcohol or drugs). This may reflect its metabolic rather than viral origin and raise new issues in the management of children with hepatitis C.