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Background and aims: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis. Methods: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram. Results: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively. Conclusions: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection.

Aims Fontan operation represents the surgical palliative option for congenital heart disease with single ventricle physiology. With the improvement of surgical and percutaneous technique, we are facing a growing population of patients with an unique pathophysiology and potential complications. Methods and results Patients that underwent Fontan palliation in our centre between 1993 and 2016 were included in this prospective study. We excluded patients with major congenital renal anomalies, those that underwent cardiac transplantation, and redo-Fontan patients. All the subjects underwent clinical evaluation, laboratory exams with complete renal and hepatic function, transient hepatic elastography, and complete cardiac evaluation. We used Schwartz equation for estimating glomerular filtration rate in patients younger than 18 years, and CDK-EPI equation for adult patients. We enrolled 35 patients, 46% female (N = 16), and 54% male (N = 19). Medium age was 17 years old, median age 15 years old (range: 10–31 years old). Medium time from Fontan completion was 160 months (range: 57–340 months). Regarding to cardiac anatomy, 10 patients had functional single left ventricle (FSLV, 28.5%) and 21 a functional single right ventricle (FSRV, 60%); 4 patients had undetermined single ventricle (11.5%). Total cavo-pulmonary connection (TCPC) with intracardiac lateral tunnel was performed in 7 patients (20%, N = 7), whereas 28 patients had TCPC with external conduit (80%). Data from echocardiographic evaluation showed a medium EF established with Simpson’s method of 60% in patients with FSLV; patients with a FSRV or undetermined single ventricle had a medium FAC of 41.1%, with 15.1% having a reduced FAC Conclusions Our population showed an higher prevalence of FSRV Fontan patients, with an expected lower systolic function compared with FSLV. 2D evaluation of systolic function showed a linear inverse correlation with renal function, suggesting that Fontan patients need a closer renal monitoring. Hepatic stiffness, which is a warning sign of potential hepatic cirrhosis need to be monitored in all Fontan patients, especially those with a worse AV valve insufficiency.

Aims In Fontan patients, the pathophysiology of diastolic function and its relationship with systemic complications are still not well understood. Methods and results This is a prospective study including patients who underwent Fontan completion in our centre between 1993 and 2016. We excluded patients with major congenital renal anomalies, those who underwent cardiac transplantation and redo-Fontan patients. All the subjects underwent clinical evaluation, laboratory exams with complete renal and hepatic function, transient hepatic elastography, and complete cardiac evaluation. We used Schwartz equation for estimating glomerular filtration rate in patients younger than 18 years, and CDK-EPI equation for adult patients. We enrolled 35 patients, 46% female (N = 16), and 54% male (N = 19). Medium age was 17 years old (range: 10–31 years old). Medium time from Fontan completion was 160 months (range: 57–340 months). Ten patients had a functional single left ventricle (FSLV, 28.5%) and 21 a functional single right ventricle (FSRV, 60%); four patients had an undetermined single ventricle (11.5%). Data from renal function assessment showed a prevalence of stage 2 chronic kidney disease (eGFR: 60–89 ml/min 1.73 mq). Of those, 11% with creatinine-based equation and 26% (N = 9) when using cystatin C-based equation, with one patients showing a moderate reduced loss of kidney function (eGFR: 40–59 ml/min/1.73 mq). Most of the patients with reduced eGFR measured with cystatin C were FSRV (89%). None had laboratory markers of acute tubular damage, but four patients had signs of chronic tubular dysfunction with elevation of beta 2 microglobulin (13%). Echocardiographic evaluation of diastolic function showed two patients with baseline E/A 12). All of them were FSRV patients (100%). Interestingly, statistical correlation between diastolic parameters and renal function showed a significant association between tubular damage parameters, such as alfa1microglobulin and beta2microglobulin, and E/E′ (Pearson’s R 0.4 and 0.48, respectively, P Conclusions Fontan-related nephropathy is associated with worsening diastolic function, which was more represented in FSRV patients. Diastolic function is also associated with liver disease in Fontan patients. Those data suggest renal and liver function should be closely monitored in patients with impaired diastolic function.

Introduction Neurologic and neuropsychiatric manifestations sometimes provide the first evidence of an unknown HCV infection. These conditions develop with a variable ranging of morbidity, including: "brain fog," fatigue, subtle cognitive and attention impairment, but also with more severe complications or acute presentation, like encephalomyelitis, encephalopathy, stroke and peripheral nerves involvement. Evidence acquisition We performed a systematic literature search on PubMed, Cochrane Library and Web of Science databases for articles only in English language, that assessed the relationship between "DAA treatment and neurologic disorders" and after the attainment of SVR in full reports of cases that received the DAA schedule from January 2015 to December 2019. The following terms were used: "chronic Hepatitis C," "HCV," "DAA," "direct-acting antiviral," "SVR," "sustained virologic response," peripheral neuropathy" and "neurologic diseases or disorders." Evidence synthesis HCV infection does not only involve the liver, causing cirrhosis and hepatocellular carcinoma (HCC), but also induces extrahepatic manifestations (EHM), mainly due to a complex immune disease, that damage small and medium vessels, called "mixed cryoglobulinemic vasculitis" (MCV). This kind of mechanism generates most of the HCV-induced neurological damages. Since 2015, the availability of direct-acting antiviral (DAA) oral molecules interfering with HCV replication has completely revolutionized therapeutic options and the target population, which now includes patients aged 12 to 80 years and with advanced liver disease. Relevant was the highlighted DAA effectiveness by achievement of a sustained virologic response (SVR) in about 95% of cases, showing a great tolerability. Conclusions This favorable effect has arisen in a wide category of patients infected by HCV, including subjects with cirrhosis and complications and/or with EHM, who showed a significant improvement of their symptoms and the disease regression. In this concise review, we examine the clinical outcomes after the introduction of the DAA for the treatment of chronic hepatitis C (CHC), focusing on the neurologic disorders and concluding that there is a strong amelioration of neurologic conditions in several cases, particularly, after attaining the viral eradication with a favorable course in most treated cases.

Fontan-associated liver disease (FALD) is an arising clinical entity that can occur long after a successful Fontan operation for correction of single ventricle (SV) congenital heart disease (CHD). Occurrence of FALD is characterized by liver cirrhosis and other hepatic complications, and determinates an increased morbidity and mortality. Currently, there is no consensus on how to stage FALD. We report here our experience by an observational study in 52 patients with SV-CHD after Fontan operation that were recruited through a period of 36 ± 9.3 months. All cases underwent lab tests and liver and cardiac imaging evaluation, including liver stiffness (LS) measurement by transient elastography (TE) (FibroScan®). According to selective criteria for liver disease, we identified 23/43 (53.5%) cases with advanced FALD that showed: older age (p &lt, 0.05), larger hepatic and cava veins diameter (p &lt, 0.05), worsened NYHA class (p &lt, 0.05), abnormal lymphocytes (p &lt, 0.01), platelet count (p &lt, 0.05), and GGT, prothrombin time (INR), albumin and cystatin C levels (p &lt, 0.05), with respect to cases without advanced FALD. LS values were significantly increased in cases with advanced FALD, at cut-off values higher than 22 kPa (p &lt, 0.001). LS, and its combined score with spleen diameter and platelet count (LSPS) successfully helped to detect 100% of cases with portal hypertension (p &lt, 0.001). In conclusion, LS can be effective to stage FALD and to uncover cases with severe risk of complications, avoiding higher morbidity and mortality related to advanced FALD.

Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.

ObjectiveThe benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.DesignWe pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.ResultsRecurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; pConclusionEffects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

Normalization procedures for the qRT-PCR analysis of miRNA in biological samples are recommended to reduce the variability caused by pre-analytical factors. Since there is no universal standardized normalization strategy for miRNA qRT-PCR studies, we conducted a throughout study to evaluate a panel of small non-coding RNAs (sncRNAs) as reference gene candidate for biomarker studies in serum samples of patients with hepatocellular carcinoma (HCC). Five sncRNAs (miR-1280, miR-1275, SNORD-116, SNORD-68, and U6) were chosen as candidate of reference genes. This study included 122 patients with HCC and was organized into a “pilot phase” consisting of 20 serum samples of HCC patients, and a “validation phase” of 102 patients. Expression level of these candidates were analyzed by qRT-PCR. Assessment of gene stability was performed using four different integrative platforms (geNorm NormFinder, Bestkeeper, and the Delta Ct method). To determine the gene stability during the follow-up of the patient, we extend the analysis of the validation cohort at T1 (1 month after treatment) and T2 (6 month after treatment). MiR-1280 was identified as the most stably expressed reference gene in both pilot and validation phase also during the follow-up. MiR-1280 appears a reliable reference gene candidate in biomarker studies.

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

Direct antiviral agents (DAAs) have excellent efficacy against chronic hepatitis C virus (HCV) infection. Despite this strength, recent studies raised concerns about an unexpected hepatocellular carcinoma (HCC) occurrence rate after DAA therapy. In this exploratory case-control study, we evaluated the potential use of miRNAs as serum biomarkers for the detection of early HCC in DAA-treated patients. In the discovery phase, the circulating miRNome was assessed in 10 matched patients with (HCC+) or without HCC (HCC&minus, ) occurrence. Microarray analysis was performed before (T0) and after one month of the DAA therapy (T1). MiRNAs discriminating HCC+ and HCC&minus, patients were validated in 60 samples by means of RT-qPCR. We estimated the time-averaged difference of a given miRNA between HCC+ and HCC&minus, patients using a bootstrapped random-effect generalized least square regression model (RE-GLS). At T0, miR-1207-5p, miR-1275, miR-3197, miR-4443, miR-3178, miR-483-5p, miR-4706, miR-4793-3p and miR-1246 discriminated HCC+ from HCC&minus, patients (p &lt, 0.05). At T1, only miR-1180-3p, miR-1228-3p, miR-4329 and miR-4484 (p &lt, 0.05) discriminated HCC+ from HCC&minus, patients. The subsequent validation phase identified miR-3197 as changing with both disease and time. Our results suggest that patients might be already committed to HCC occurrence before DAA therapy. MiR-3197 shows some potential for the identification of patients at risk of HCC during DAA treatments.

The Fontan operation is the current surgical procedure to treat single-ventricle congenital heart disease, by splitting the systemic and pulmonary circulations and thus permitting lifespan to adulthood for the majority of newborns. However, emerging data are showing that Fontan-associated liver disease (FALD) is an increasing related cause of morbidity and mortality in patients with the Fontan circuit. We described the clinical, laboratory, and transient elastography (TE) findings in a case series of adults with the Fontan circuit, and also correlated data with post-mortem histological features, aimed to define the prognostic value of TE in the staging of FALD. All patients presented signs of a long-standing Fontan failure, characterized by reoperation need, systemic ventricle dysfunction, and FALD stigmata (liver and spleen enlargement, portal vein and inferior vena cava dilation, and abnormal liver function tests). Liver and spleen stiffness (LS and SS) values were indicative of significant liver fibrosis/cirrhosis and the presence of suggestive portal hypertension (LS mean 35.9; range 27.3–44.7 kPa; SS mean 42.1, range 32.2–54.5 kPa). Post-mortem evaluations confirmed a gross hepatic architecture distortion in all cases. All patients died from severe complications related to liver dysfunction and bleeding. TE correlated well with pathological findings and FALD severity. We propose this validated and harmless technique to monitor liver fibrosis extension and portal hypertension over time in Fontan patients, and to identify the optimal timing for surgical reoperations or orthotopic-heart transplantation (OHT), avoiding a higher risk of morbidity and mortality in cases with severe FALD.

Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs.The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days.Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment.These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors.Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Background: Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. Aim: To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Methods: Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Results: Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count

Introduction: In a previous study, based on PITER cohort data, it was reported that of patients, undergoing direct acting antiviral (DAA) therapy, 30%-44%, are at risk of potential drug-drug interactions (DDI). Aim: We aimed to evaluate the prospective profile of elbasvir/grazoprevir (EBR/GZR) efficacy and safety combined with real life comedication profile. Method: Data from 312 patients (mean age 63 ± 10 years; 44% male, 90% of genotype 1.85% fibrosis stage ≤ F3, 15% with child A cirrhosis), enrolled in PITER by 15 clinical centers and treated with EBR/GZR, with at least three months of follow up after the end of treatment, were evaluated. Comedication profiles (no changes, drugs interrupted, or modified as posology, or those added) were evaluated and the potential DDI were assigned according to HepC Drug Interactions. Results: The SVR12 was reached in 299 (96%) patients. Gender, age, fibrosis stage, previous interferon therapy, diabetes and fatty liver were not related to failure by logistic regression analysis. Of 312 treated patients, 187 (60%) had at least one comorbidity (median: 2 range: 1–6 comorbidities). Follow up data on comedications used were available in 182 patients (21% have taken 1 drug, 24% two drugs, and the remaining 55% from 3–10 drugs). Of 328 comedications used during the DAA therapy, 3% were modified in posology, 2% were interrupted and 3% were new drugs added. None of changes was due to potential DDI. None but statins (in 2% of patients) were reported to require monitoring by HepC Drug Interactions. EBR/GZR was well tolerated. An increase in ALT levels (lower than 3 times of normal levels), were observed in 12 (4%) patients during the DAA therapy. Conclusion: EBR/GZR demonstrated high cure rates and a good safety profile. No drug-drug interactions were recorded in this cohort of treated patients with different comorbidities and comedications used.

Introduction: Hepatitis C is a major health problem: approximately 170 million people are infected with the hepatitis C virus worldwide. It is unclear whether chronic hepatitis C affects atherosclerosis and whether it can cause endothelial and/or autonomic nervous system (ANS) dysfunction. Materials and methods: From April 2008 through April 2009, we studied 76 patients with biopsyconfirmed chronic hepatitis C and no evidence of cirrhosis, ascites, portal hypertension, encephalopathy, or hepatocellular carcinoma. The age-, sex-, BMI- and cardiovascular risk factor- matched control group comprised 76 healthy, HCV-negative individuals with no evidence of liver, autoimmune, or immunoproliferative diseases and no history of cardiovascular events. Twenty five of the hepatitis C patients were treatment-naive; the other 51 had been treated with interferon (but only 25 had persistent virological responses). Color Doppler sonography was used to measure the intima-media-thickness (IMT) of the common and internal carotid arteries. Endothelial function was assessed in the brachial artery with the flow-mediated-dilatation (FMD) test. The ANS was assessed with the tilt, laying to standing, Valsalva, hand grip, deep breath, and stroop tests. Results: The case group (mean age 52 + 13 years) had a significantly higher internal carotid IMT (0.86 + 0.3 vs 0.67 + 0.1 mmfor controls; p = 0.002). Chronic hepatitis C was also associated with an odds ratio for carotid plaque formation (reflected by an IMT > 1.3 mm) of 2.15. Cases also had significantly reduced FMD in the brachial artery (0.46 + 0.9 vs 0.76 + 0.7 for controls; p = 0.005) and significantly altered sympathetic and parasympathetic function (p = 0.001 vs controls in the Valsalva, hand grip, deep breath, and stroop tests). Within the case group, all alterations were more severe in patients with significant viremia. Discussion: Our findings suggest that chronic hepatitis C may be a nonclassic cardiovascular risk factor since it seems to influence the onset of pre-atherosclerotic lesions and to promote atherosclerotic plaque formation in patients with pre-existing increases in carotid IMT. It also seems to cause dysfunctions of the vascular endothelium and ANS. Conclusions: Chronic hepatitis C may increase cardiovascular risk and promote ANS dysfunctions, particularly when patients have experienced treatment failure and have persistent viremia. These patients may require cardiovascular and neurologic follow-up.

SERPINB3 is a serine protease inhibitor with pleiotropic functions. It is involved in several physiological and pathological processes, where it appears to exert antiapoptotic effects. Little is known about its expression on immune system cells, the major players in mechanisms of viral defense and autoimmune disorders. The aim of this study was to characterize the expression of SERPINB3 on the surface of peripheral blood mononuclear cell subsets in both normal subjects and in patients with chronic viral infections and autoimmune diseases. Sixty-two patients were analyzed by flow cytometric analysis, including 45 with hepatitis C virus (HCV)-related chronic liver disease and 17 with systemic lupus erythematosus (SLE). SERPINB3 was expressed on B lymphocytes in 79% of the controls, in 32% of the HCV-infected patients and in none of the SLE patients. Surface localization of SERPINB3 was confirmed by confocal microscopy. SERPINB3 positivity was associated with CD27 reactivity ( r = 0.98), but not to other activation molecules (CD69, CD71, CD86 and CXCR3). SERPINB3 is physiologically expressed on the surface of CD27+ B lymphocytes, but its expression is reduced in HCV viral infection and not detectable in SLE patients. These results may suggest a role for SERPINB3 in B-cell defects typically found in viral infections and autoimmune disorders.

The current standard of care for the treatment of chronic hepatitis C virus (HCV) infection is combination therapy with Peg-interferon (IFN) alpha-2a or alpha-2b type plus ribavirin (RBV). This antiviral schedule can in fact avoid the three fold mortality rates associated to untreated cases with HCV infection, by inducing viral eradication and liver damage regression, so as to define the patients “definitively cured” from liver disease. This analysis describes the modalities of antiviral treatment in the Veneto region, in particular the therapy-schedule mainly used and compares the cost-effectiveness of treatment with the 2 available Peg-IFNs with strategies proposed as in the every day practice. Twelve on line hepatologic units, centralized by a network program on “Surveillance and Control of HCV Infection in the Veneto Region”, prospectively collected data and, of these, we evaluated 450 subjects that underwent antiviral therapy for chronic hepatitis or cirrhosis. A post hoc retrospective analysis of cases treated from January 2003 to December 2005 was performed, grouping the study population in 166 cases treated with Peg-IFN alpha-2a (Pegasys®, Roche, fixed-dose of 180 μg/weekly) and 284 that received Peg-IFN alpha-2b (Peg-Intron®, Schering-Plough, weight-adjusted-dose from 50 to 150 μg/weekly), both in combination therapy with ribavirin (Copegus®, Roche, or Rebetol®, Schering-Plough, weight-adjusted-dose of 15 mg/kg/daily). Epidemiological characteristics and cumulative rate of end-of-therapy response and Sustained Virological Response (SVR) were similar in the 2 groups, but 78% of cases treated with Peg-IFN alpha-2b and RBV received a significantly lower dose with respect to the weight-adjusted dose. This event conditioned efficacy to therapy as demonstrated in cases that received a < 1 μg/kg dose with respect to those treated with > 1 μg/kg (respectively SVR: 49% vs 66%, p < 0,01), particularly in genotype HCV-1 (SVR: 29% vs 51%, p = 0,01), known to be more resistant to IFN-therapy. The overall cost of antiviral therapy in this study population was about € 3,528,000/450 treated cases and considering the 269 that reached SVR (98 and 171, respectively by Peg-IFN alpha-2a or 2b and RBV therapy), the cost/SVR was € 15,632 and € 11,672 in the 2 groups. In conclusion, the optimization of Peg-IFN therapy, that is the use of the full dose, particularly in cases treated with a weight-adjusted Peg-IFN alpha-2b and RBV, at the standard of care dosage of 1.5 μg/kg/week and 15 mg/kg/day respectively, will allow a better efficacy, especially in genotype HCV-1 with an increase of 11% in SVR (43% to 54%) at a lower cost.

The most effective treatment of chronic hepatitis C (HCV) available to date is represented by interferon-α (IFN-α), alone or in combination with ribavirin. However, the therapy presents adverse effects, including depressive symptoms. As IFN-α can cause an alteration of the tryptophan metabolism and a consequent reduced synthesis of serotonin, we have designed a study aimed to investigate the effect of IFN-α therapy on the serum levels of tryptophan and on the development of depression in patients affected by the hepatitis C virus. Nine patients with HCV were enrolled while treated with IFN-α2a (3 MU thrice/week) plus ribavirin (15 mg/kg/day) for six months. All patients were evaluated by a hepatologist and received two self-administered scales [Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS)]. Blood samples were collected before treatment and at one month and six months of therapy. Tryptophan, 5-hydroxytryptophan and serotonin were analysed by HPLC with a spectrofluorometric detector. In all cases, a significant decrease of serum tryptophan concentrations from baseline (17.60 ± 1.08 mg/ml) to one month (13.94 ± 1.18 mg/ml) and six months (12.68 ± 0.64 mg/ml) with an increase of symptoms of depression was obtained, whereas 5-hydroxytryptophan and serotonin levels did not show any variation during the therapy from baseline values. The preliminary results suggest that IFN-α plays a role in serum tryptophan reduction and the development of depressive symptoms.

This study is aim to investigate concurrent long-term psychiatric, cognitive and neurophysiological measures of alpha-IFN neurotoxicity in the treatment of chronic viral hepatitis.Twenty patients with HCV hepatitis were enrolled while treated with alpha-IFN (3-6 MU t.i.w. for 6-12 months). Neurotoxicity was evaluated by psychiatric [Hamilton Depression Rating Scale (HAM-D), Hamilton Scale for Anxiety (HAM-A), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI-Y)], complete cognitive and neurophysiological assessments (EEG spectral analysis, P300). Patients were assessed at baseline (t0), 2 (t1) and 6 months (t2) since the beginning of therapy.Depression scores significantly increased (HAM-D: t0=4.4+/-2.6; t1=8.9+/-3.9, p0.001; and t2=7.7+/-3.8, p0.001). A concurrent increase was shown also for anxiety (HAM-A: t0=6.0+/-3.2; t1=9.6+/-4.5, p0.005; and t2=9.1+/-4.5, p0.005). Significant neurophysiological effects were also detected: increase of alpha power (p0.05) in frontal derivations, reduction of the mean dominant frequency (p0.005) and increase of theta power (p0.05) in parietal derivations. In contrast, no significant cognitive changes occurred.The study was performed on a relative small sample of patients mainly with observational intentions. Biological data (e.g. blood cytokines samples) are not available: they could have given useful information about biological mechanisms related to the alterations observed.Alpha-IFN treatment caused a time-dependent induction of symptoms of mild depression, concurrent anxiety and EEG changes. These psychiatric and neurophysiological changes can better explain the pharmacological profile of alpha-IFN and could help to address research on at risk population and, particularly, during pegylated-IFN therapy.

Background/Aims: In chronic hepatitis C, interferon-alpha (α-IFN) and ribavirin combination therapy improves sustained response compared to α-IFN monotherapy, both in naive patients and in previous α-IFN relapsers, but the efficacy of such therapy remains limited in non-responder cases. The aim of this study was to assess whether the pattern of response to α-IFN alone may predict sustained response to combination therapy during retreatment. Methods: Fifty previous α-IFN relapsers and 50 previous α-IFN non-responders were retreated with a high α-IFN dose (6 MU/thrice weekly for 2 months; induction phase) and then randomised to continue with α-IFN alone (3 MU/thrice weekly) or to receive combination therapy (3 MU/thrice weekly of α-IFN and 1000–1200 mg/daily of ribavirin) for an additional 6 months according to the biochemical response to α-IFN shown after the induction phase. All patients were also evaluated for virological and histological response. Results: Eleven of 25 (44%) relapsers treated with combination therapy and 4/25 (16%) treated with α-IFN alone achieved a sustained response. The corresponding figures among non-responders were 1/25 (4%) and 0/25, respectively. Among 26 patients with a complete ALT and HCV-RNA response after 2 months of α-IFN, sustained response was seen in 11/14 (79%) treated with combination therapy and in 4/12 (33%) treated with α-IFN alone ( p =0.05). On the other hand, of 74 cases still HCV-RNA positive after 2 months of α-IFN alone, biochemical and virological end of therapy response was better with combination therapy (11/36; 30.5%) compared to α-IFN alone (4/38; 10.5%), but only one patient developed a sustained response (1/36; 3%). Conclusions: The retreatment with a 6-month combination therapy was associated with a high rate of sustained response only in patients showing a complete biochemical and virological response to α-IFN alone. Longer retreatment with combination therapy may be needed to achieve a sustained response in patients without a prompt virological response to α-IFN.

Approximately 75%-85% of patients with chronic hepatitis C virus (HCV) infection do not have a sustained response when treated with interferon (IFN). Limited information exists on the efficacy of retreatment with IFN alone in these patients. The aim of this study was to define the efficacy of IFN retreatment in chronic hepatitis C.Ninety-two patients with chronic hepatitis C who had shown transient or no response to recombinant IFN-alpha were randomly retreated with different schedules of lymphoblastoid IFN-alpha and followed up for 12 months after therapy to define biochemical and virological response.None of 26 initial nonresponders obtained a sustained response with retreatment, independent of the schedule used. Thirteen of 66 patients (20%; 95% confidence interval [CI], 10.9-31.3) with transient response during the primary cycle developed a sustained biochemical and virological response when retreated, including 3 of 41 (7%; 95% CI, 1.5-9.9) of those receiving the same schedule and 10 of 25 (40%; 95% CI, 21.1-61.3; P0.004) of those retreated with a higher dosage and for a longer period. Shorter disease duration (P = 0.02), higher alanine aminotransferase (P = 0.002) and lower gamma-glutamyltransferase levels (P = 0.004), HCV genotype other than HCV-1 (P = 0.03), and a negative serum HCV-RNA test at the end of the primary cycle (P = 0.000) were associated with sustained response.Patients with chronic hepatitis C who have a relapse after a complete response to a 6-month IFN-alpha treatment should be retreated for 12 months. Nonresponders should not be retreated with IFN alone.

Alpha-interferon (IFN-α) is an effective treatment for chronic hepatitis C, but only 20% to 30% of patients are apparently cured with the currently recommended schedule of 3 MU given three times a week for 6 months. To evaluate the efficacy of more aggressive treatment regimens, we have conducted a randomized trial in 174 patients with chronic hepatitis C using three different schedules: (1) 12-month treatment starting with 6 MU/three times a week and decreasing the dose on the basis of serum alanine transaminase (ALT) activities (group A: 59 cases); (2) fixed dose of 3 MU three times a week for 12 months (Group B: 61 cases), (3) fixed dose of 6 MU three times a week for 6 months (Group C: 54 cases). Patients were evaluated during therapy for biochemical and virological response and followed for at least 12 months after therapy to assess long-term efficacy and liver histological outcome. The genotype of infecting HCV was also analyzed in all patients, and predictors of response were determined by multivariate analysis. Serum ALT became normal during therapy in 76% of patients (95% confidence interval [CI]: 63 to 86), 65% (CI: 52 to 77), and 74% (CI: 60 to 85) in groups A, B, and C, respectively (P = NS). The corresponding figures for sustained response 12 months after therapy were 49% (CI: 36 to 62), 31% (CI: 20 to 44), and 28% (CI: 16 to 42) (A vs. B, P = .06; A vs. C, P = 0.03). Eighty-six percent of patients with sustained response cleared HCV-RNA from serum and 72% improved histologically. Patients infected with HCV genotypes 2a and 3 had higher sustained response rates than those with 1b, independent of treatment schedule. In patients infected with genotype 1b, the rate of sustained response was related to dose and duration of therapy being 28% with schedule A, 16% with schedule B, and 9% with schedule C. Multivariate analysis indicated that younger age (P = .016), shorter disease duration (P = .003), and infection with HCV genotypes 2a (P = .0017) and 3 (P = .0083) were independent predictors of sustained response. These results indicate that sustained response to IFN-α in chronic hepatitis C is affected by dose and duration of therapy, particularly in patients infected with HCV genotype 1b.

Eight Italian patients with chronic hepatitis C were treated intravenously with natural β-interferon (β-IFN) to assess primary biochemical and virological response and also to investigate the relation to the genotype of infecting HCV. Each patient received 6 MU of β-IFN daily for 6 days a week for a period of 2 months. Five patients (62.5%) showed complete normalization of alanineaminotransferase (ALT) and 6 cases (including all 5 with normal ALT) became HCV-RNA negative. ALT normalization occurred within 7–40 days of therapy. Seven patients were infected by HCV-1b and 4 (58%) of them became HCV-RNA negative with normal ALT at the end of therapy while one patient, infected by HCV-2a, became HCV-RNA negative but maintained elevated ALT values. Six months after cessation of β-IFN all 8 patients were HCV-RNA positive in serum but 3 of them had normal ALT, including one case in whom normalization had occurred after therapy. These results indicate that HCV activity, including that of HCV-1b can be efficiently suppressed by intravenous β-IFN therapy in Caucasian patients with chronic hepatitis C, as previously described in similar cases in Japan. The rate of sustained biochemical and virologic response was, however, lower in our patients compared to what has been described previously, suggesting that further studies are needed to define the optimum regimen to achieve eradication of HCV infection.

Three main patterns of response are seen when interferon-alpha (IFN-alpha) is used for the treatment of chronic hepatitis C: 1 sustained response with alanine-aminotransferase (ALT) normalization that is maintained after cessation of therapy, with or without clearance of serum hepatitis C virus (HCV) RNA; 2 transient response with ALT normalization during therapy followed by relapse after its withdrawal, and 3 no response with no or only partial reduction in ALT levels. In order to define variables that could predict each of these three types of response we studied 321 cases of chronic hepatitis C treated with IFN-alpha in two consecutive trials conducted in our Unit. By univariate analysis, age45 years (P0.01), known disease duration60 months (P0.01), normal gamma-glutamyl-transpeptidase (gamma GT) levels (P0.01) and infection by HCV genotype 2 or HCV genotype 3 (P0.01) were found to be statistically associated with sustained response while age45 years (P0.01), body weight (P = 0.05), cirrhosis (P0.01) and elevated gamma GT levels (P0.01) were associated with no response. By multivariate analysis sustained response was predicted by HCV genotype 2 (P0.01) and HCV genotype 3 (P0.01), known disease duration (P0.01), patient's age (P0.05) and associated with the use of a more aggressive treatment schedule (P0.05). Transient response with relapse was predicted by known duration of disease (P0.05), HCV genotype 1 (P0.05) and female sex (P0.05). No response was statistically associated with elevated gamma GT levels (P0.01), higher body weight (P0.05) and with the less aggressive regimen of 3 MU of natural IFN-alpha given three times weekly for 6 months (P0.05). These results indicate that the HCV genotype as well as the schedule of treatment greatly affect the pattern of response to IFN in chronic hepatitis C and allow us to define criteria to predict which type of response is more likely in individual patients.

Summary Introduction Hepatitis C is a major health problem: approximately 170 million people are infected with the hepatitis C virus worldwide. It is unclear whether chronic hepatitis C affects atherosclerosis and whether it can cause endothelial and/or autonomic nervous system (ANS) dysfunction. Materials and methods From April 2008 through April 2009, we studied 76 patients with biopsy-confirmed chronic hepatitis C and no evidence of cirrhosis, ascites, portal hypertension, encephalopathy, or hepatocellular carcinoma. The age-, sex-, BMI- and cardiovascular risk factor-matched control group comprised 76 healthy, HCV-negative individuals with no evidence of liver, autoimmune, or immunoproliferative diseases and no history of cardiovascular events. Twenty five of the hepatitis C patients were treatment-naive; the other 51 had been treated with interferon (but only 25 had persistent virological responses). Color Doppler sonography was used to measure the intima-media-thickness (IMT) of the common and internal carotid arteries. Endothelial function was assessed in the brachial artery with the flow-mediated-dilatation (FMD) test. The ANS was assessed with the tilt, laying to standing, Valsalva, hand grip, deep breath, and stroop tests. Results The case group (mean age 52 ± 13 years) had a significantly higher internal carotid IMT (0.86 ± 0.3 vs 0.67 ± 0.1 mm for controls; p = 0.002). Chronic hepatitis C was also associated with an odds ratio for carotid plaque formation (reflected by an IMT ≥ 1.3 mm) of 2.15. Cases also had significantly reduced FMD in the brachial artery (0.46 ± 0.9 vs 0.76 ± 0.7 for controls; p = 0.005) and significantly altered sympathetic and parasympathetic function (p = 0.001 vs controls in the Valsalva, hand grip, deep breath, and stroop tests). Within the case group, all alterations were more severe in patients with significant viremia. Discussion Our findings suggest that chronic hepatitis C may be a nonclassic cardiovascular risk factor since it seems to influence the onset of pre-atherosclerotic lesions and to promote atherosclerotic plaque formation in patients with pre-existing increases in carotid IMT. It also seems to cause dysfunctions of the vascular endothelium and ANS. Conclusions Chronic hepatitis C may increase cardiovascular risk and promote ANS dysfunctions, particularly when patients have experienced treatment failure and have persistent viremia. These patients may require cardiovascular and neurologic follow-up.

The performance of transient elastography in primary biliary cirrhosis has yet to be fully established.To assess: (1) the performance of transient elastography in identifying significant fibrosis in primary biliary cirrhosis by comparison with surrogate markers (AST platelet ratio index (APRI), FIB-4, Fibroindex, Forns, aspartate aminotransferase/alanine aminotransferase ratio); (2) the correlation between liver stiffness and Mayo score prognostic index.One hundred and twenty patients with primary biliary cirrhosis were consecutively enrolled. The performance of each marker and of liver stiffness was compared with histological staging and METAVIR at time of liver biopsy.The area under receiver operating characteristic (ROC) of liver stiffness were 0.87, 0.88, 0.99 for histological stage ≥II, ≥III and =IV and 0.89, 0.92, 0.99 for METAVIR ≥2, ≥3 and =4. Transient elastography alone proved better able in identifying any grade of fibrosis or cirrhosis than noninvasive markers. Combining each surrogate marker with transient elastography did not improve the area under ROC. Transient elastography correlated positively with the Mayo score (P0.001). Logistic regression analysis showed that transient elastography was associated with an advanced fibrosis (P0.001).Transient elastography proved a simple, reliable and useful method for assessing liver fibrosis in primary biliary cirrhosis, whereas noninvasive surrogate markers proved unsatisfactory in predicting significant fibrosis.

Two hundred and thirty-four patients with chronic non-A, non-B hepatitis, 86% positive for anti-HCV by ELISA, were treated with recombinant interferon-α 2a or with natural (human-leukocytes-derived) interferon-α using different dosage and periods of administration. Interim analysis of follow-up data indicate that 65–70% of patients treated initially with 6 MU, thrice weekly, of recombinant interferon-α 2a achieved a complete biochemical response (normalization of alanine aminotranferase: ALT) during therapy compared to 56–58% of those treated with 3 MU, thrice weekly, of recombinant or natural interferon-α. A 12-month schedule of interferon administration appeared superior to a 6-month schedule in reducing the probability of reactivation of liver disease after therapy withdrawal, although further data are needed to confirm such a conclusion. The probability of response to interferon in terms of maintaining normal ALT after withdrawal did not appear to be influenced by sex, while it was significantly higher in patients aged below 45 years and in those without cirrhosis.

The currently recommended therapy for chronic hepatitis C (HCV) is a combination of pegylated interferon-alpha (PEG-IFN alpha) and ribavirin. Psychiatric disorders, including depression, are frequent in HCV patients under therapy. We investigated the effect of the antiviral treatment on tryptophan (Trp) metabolism along both serotonin pathway (via 5-hydroxytryptophan, 5-HTP) and kynurenine (Kyn) pathway and on the onset of depressive symptoms in patients with HCV. The key enzyme of the Kyn pathway is indoleamine 2,3-dioxygenase (IDO), an intracellular haem protein enzyme expressed in several tissues. It was also investigated the influence of the therapy with PEG-IFN-alpha-2a or PEG-IFN-alpha-2b plus oral ribavirin and possible differences between genders. Free and total Trp, 5-hydroxytryptophan (5-HTP) and Kyn serum concentrations and the presence of depressive symptoms [Beck Depression Inventory (BDI) scores] were evaluated in 45 patients with HCV infection treated with PEG-IFN alpha-2a or -2b at four different times: baseline (before treatment), 1 and 6 months during therapy, and 3 months after the end of therapy. The concentration of serum total TRP (free + protein bound) as well as that of 5-HTP significantly decreased after 1 and 6 months of therapy, and then returned to baseline values 3 months after the end of therapy, while the levels of free TRP did not vary significantly during and after the therapy. On the contrary, the time course of Kyn markedly arose during treatment, paralleled by a significant increase of [Kyn/Trp] × 10 3 ratio, an index used to measure IDO activity. No significant difference was detected between males and females neither between PEG-IFN-alpha-2a or -2b treatment. The BDI scores significantly increased during therapy, and returned to baseline values 3 months after the end of therapy. Our results support the hypothesis that the increased IDO-mediated tryptophan metabolism along the Kyn pathway, leading to plasma Trp depletion and a decline of serotonin pathway, concurs to the development of depressive symptoms observed in HCV patients undergoing IFN-alpha therapy. © 2010 Elsevier Masson SAS. All rights reserved.

About 30% of the patients with chronic hepatitis develop a progressive liver disease and one of the most intriguing issues is the detection of noninvasive markers for fibrosis stage and disease progression. High levels of squamous cell carcinoma antigen (SCCA)-immunoglobulin M (IgM) are detectable in hepatocellular carcinoma and their increase in cirrhotic patients can predict tumour development. As SCCA-IgM can also be detectable at low percentages in patients with chronic hepatitis, the aim of this study was to assess SCCA-IgM complexes in relation to disease outcome in this group of patients. An ELISA assay was used to determine the presence of SCCA-IgM in 188 patients with chronic hepatitis and in 100 controls. An additional serum sample was available after a median period of 6 years in 57 untreated patients: these patients were subdivided in group A, including eight patients with a fibrosis score increase > or =2 in a second liver biopsy and group B, including 49 patients without fibrosis progression during a similar follow up. SCCA-IgM complexes were detectable in 63 of 188 (33%) patients but in none of the controls. A significant increase of SCCA-IgM levels over time was observed in patients with fibrosis progression (mean +/- SD: 117 +/- 200 U/mL/year), but not in those without histologic deterioration (mean +/- SD: -8.8 +/- 31 U/mL/year, P < 0.0001). In conclusion, monitoring SCCA-IgM levels over time appears a useful approach to identify patients with chronic hepatitis at higher risk for cirrhosis development.

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.

Background The serpin squamous cell carcinoma antigen (SCCA, SERPINB3) has been found over-expressed in primary liver cancer and at lower extent in cirrhosis and chronic hepatitis. A novel SCCA-1 variant (SCCA-PD), presenting a single mutation in the reactive centre (Gly351Ala), has been recently identified (rs3180227). Aim To explore SCCA-1 polymorphism in patients with HCV infection as single etiologic factor and different extent of liver disease. Methods One hundred and fourty-eight patients with chronic HCV infection (45 chronic hepatitis, 53 cirrhosis, 50 HCC) and 50 controls were evaluated. SCCA-1 polymorphism was studied by restriction fragment length polymorphism and confirmed randomly by direct sequencing. Circulating SCCA–IgM complex was determined by ELISA. Results SCCA-PD was detected with higher frequency in cirrhotic patients (45.3%, odds ratio = 2.62; 95%CI 1.13–6.10, p = 0.038) than in patients with chronic hepatitis or in controls (24.4% and 24%, respectively). Intermediate figures were found in hepatocarcinoma (36.0%). SCCA–IgM in serum was lower in patients carrying SCCA-PD than in wild type patients and the difference was statistically significant in cirrhotic patients (mean ± S.D. = 117.45 ± 54.45 U/ml vs. 268.52 ± 341.27 U/ml, p = 0.026). Conclusions The newly identified SCCA-PD variant was more frequently found in liver cirrhosis, suggesting that patients carrying this polymorphism are more prone to develop progressive liver fibrosis.