Detection of high levels of Survivin-immunoglobulin M immune complex in sera from hepatitis C virus infected patients with cirrhosis.

AIM: The identification and surveillance of patients with liver dysfunctions and the discovering of new disease biomarkers are needed in the clinical practice. The aim of this study was to investigate on Survivin-immunoglobulin (Ig)M immune complex (IC) as a potential biomarker of chronic liver diseases. METHODS: Serum levels of Survivin-IgM were measured using an enzyme-linked immunoassay that had been standardized and validated in our laboratory in 262 individuals, including healthy subjects and patients with chronic viral hepatitis, cirrhosis and hepatocellular carcinoma (HCC). RESULTS: Survivin-IgM IC was lower in healthy subjects (median, 99.39 AU/mL) than in patients with chronic viral hepatitis (median, 148.03 AU/mL; P = 0.002) or with cirrhosis (median, 371.00 AU/mL; P < 0.001). Among patients with cirrhosis, those with hepatitis C virus (HCV) infection showed the highest level of Survivin-IgM IC (median, 633.71 AU/mL; P < 0.001). The receiver-operator curve analysis revealed that Survivin-IgM accurately distinguishes HCV correlated cirrhosis from chronic viral hepatitis (area under the curve [AUC], 0.738; sensitivity, 74.5%; specificity, 70.7%). A multivariate logistic regression model, including Survivin-IgM IC, aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT) ratio increased the prediction accuracy for the identification of the cirrhotic HCV patients (AUC, 0.818; sensitivity, 87.2%; specificity, 65.9%). Conversely, Survivin-IgM IC significantly decreased in HCC patients (median, 165.72 AU/mL; P = 0.022). CONCLUSION: Our results suggest that Survivin-IgM immune complex may be used as a potential biomarker for liver damage, particularly for the identification of the HCV-related cirrhotic population.

HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b.

BACKGROUND: The impact of viral subtype on the rate of sustained virological response (SVR) to antiviral therapy in patients chronically infected with hepatitis C genotype 1 subtype 1a and 1b has not been extensively investigated. The aim of this study is to determine whether the HCV genotype 1 subtypes 1a and 1b respond differently to treatment with PEGylated interferon (PEG-IFN) plus ribavirin. METHODS: For 48 weeks, 388 "naïve"genotype 1 patients were treated weekly with PEG-IFN α-2a or PEG-INF α-2b combined with daily ribavirin (1000-1200 mg/day). The numbers of patients in whom HCV-RNA was undetectable were compared after 4 (rapid virological response, RVR), 12 (early virological response, EVR), and 48 (end treatment virological response, ETR) weeks of treatment as well as 24 weeks after the last treatment (sustained virological response, SVR). RESULTS: The rate of SVR was higher in subtype 1a patients than subtype 1b patients (55% vs. 43%; p < 0.02). Multiple logistic regression analysis showed that infection with genotype 1a (odds ratio(OR) : 1.8; 95% confidence interval (CI): 1.4 to 4.1), age < 50 years (OR:7.0; 95% CI 1.1 to 21.2), alanine aminotransferase level (ALT)<100 IU/ml (OR:2.1; 95% CI: 1.3 to3.5), HCV-RNA < 5.6 log10 IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9) and fibrosis score < S3 (OR: 3.8; 95% CI:3.2 to 7.4), were all independent predictors of SVR. CONCLUSION: Dual antiviral therapy is more effective against HCV subtype 1a than against subtype 1b and this difference is independent of other factors that may favour viral clearance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01342003.

Treatment of hepatitis C virus carriers with persistently normal alanine aminotransferase levels with peginterferon alpha-2a and ribavirin: a multicentric study.

BACKGROUND/AIMS: To evaluate, in clinical practice, the efficacy and safety of combined antiviral treatment in hepatitis C virus (HCV) carriers with normal alanine aminotransferase (ALT) levels. METHODS: Eighty-eight HCV carriers with persistently normal ALT levels were enrolled. All patients received peginterferon (PEG-IFN) alpha-2a 180 microg once weekly plus ribavirin (RBV) 800 mg/day for 24 weeks (HCV-2 and -3) or 1000-1200 mg/day for 48 weeks (HCV-1). RESULTS: Rapid virological response (RVR) was seen in 66/88 patients (75%): 19/32 HCV-1 (59%), 40/46 HCV-2 (87%) and 7/10 HCV-3 patients. Younger patients, leaner subjects and patients with non-1 genotype or lower baseline HCV RNA levels were more likely to achieve an RVR. Sustained virological response (SVR) was seen in 69/88 patients (78%): 20/32 HCV-1 patients (62%), 41/46 HCV-2 patients (89%) and 8/10 (80%) HCV-3 patients. The overall SVR rate was 88% in patients with RVR (58/66) and 50% in those without RVR. CONCLUSIONS: The combination of PEG-IFN alpha-2a and RBV produces, in patients with normal ALT, virological response rates that are comparable or even higher than those obtained in patients with elevated ALT levels. Thus, we suggest that in selected cases immediate therapy might be preferred to a 'wait-and-see' policy.

Quantitation of tissue polypeptide antigen (TPA) in hepatic and systemic circulation in patients with chronic liver diseases.

BACKGROUND AND AIM: Abnormal serum tissue polypeptide antigen (TPA) values are commonly found in patients with chronic liver damage and liver cirrhosis even in the absence of malignancies. The aim of this study was to compare serum TPA levels in patients with cirrhosis, to examine correlations between TPA levels and the degree of portal hypertension, and to evaluate TPA concentrations in paired hepatic and peripheral blood samples. METHODS: A total of 128 patients with chronic liver disease of various severity were studied prospectively. TPA concentrations in hepatic vein and peripheral blood were determined, and Hepatic Vein Pressure Gradient (HVPG) was measured. RESULTS: TPA levels were significantly higher in patients with cirrhosis than in those with chronic hepatitis, and in systemic circulation than in hepatic vein blood. Peripheral but not hepatic TPA levels did correlate with the HVPG. Subjects with clinically significant portal hypertension (HVPG > 10 mmHg) showed significantly higher peripheral TPA levels than those with HVPG < 10 mmHg. CONCLUSIONS: Our data suggest that the increased TPA levels observed in cirrhotic patients and the high systemic-to-hepatic blood TPA gradient are probably due to the presence of portal-systemic shunts rather than to hepatic necro-inflammatory activity. In clinical practice, TPA determination could help us to identify and to follow up cirrhotic patients with more severe portal hypertension.

Antiviral treatment of HCV carriers with persistently normal ALT levels.

Approximately 30% of patients with chronic HCV infection show persistently normal alanine aminotransferase levels (PNAL). The prevalence of HCV carriers with normal liver seems to be very low (less than 15-20%). Liver disease is usually minimal/mild and fibrosis is generally absent or minimal, although the association of normal alanine aminotransferase (ALT) with cirrhosis or with liver cancer has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with PNAL than with abnormal ALT. Although the majority of data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis, several studies reported a significant progression of fibrosis in approximately 20-30% of the patients with ALT normality, and the development of HCC in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up, in particular in patients harboring genotype 2. As to antiviral treatment, it has been clearly stated that it no longer seems reasonable to affirm that sustained response rates for patients with normal ALT levels are any different than those for patients with elevated ALT levels when the combination of pegylated interferon (IFN) and ribavirin is used. The issue at hand is whether or not patients with mild disease should be treated. There are numerous other factors which impact on this decision, including genotype, histology, patients motivation, symptoms, co-morbid illness, and the age of the patient.

Predicting efficacy and safety outcomes in patients with hepatitis C virus genotype 1 and persistently 'normal' alanine aminotransferase levels treated with peginterferon alpha-2a (40KD) plus ribavirin.

BACKGROUND: Currently, the approved dosage of ribavirin has not been studied in patients with 'normal' alanine aminotransferase (ALT) levels. METHODS: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently 'normal' ALT levels treated with peginterferon alpha-2a (40KD) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks. RESULTS: Model-based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently 'normal' ALT levels had received the standard weight-adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently 'normal' ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group. CONCLUSIONS: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight-adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline.

Hepatitis C virus with normal transaminase levels.

Approximately 30% of patients with chronic HCV infection show persistently normal alanine aminotransferase (PNALT) levels. The majority of these patients have some degree of histological liver damage. Controversies still exist regarding the definition of 'persistent' alanine aminotransferase (ALT) normality, and the natural history and optimal management of chronic hepatitis C with normal ALT. Although patients with HCV infection and normal ALT have been historically excluded from antiviral treatment, with the advent of the new treatment with PEG-interferon plus ribavirin, it has been suggested that the issue of whether or not to treat subjects with PNALT should be re-evaluated, and that antiviral treatment should be useful at least in selected subsets of patients.

Nerve growth factor involvement in liver cirrhosis and hepatocellular carcinoma.

AIM: To define NGF (nerve growth factor) and its high-affinity receptor trkA(NGF) presence and distribution in fibrotic liver and in HCC, and to verify if NGF might have a role in fibrosis and HCC. METHODS: Intracellular distribution of NGF and trkA(NGF) were assessed by immunohistochemistry and immuno-electron microscopy in liver specimens from HCC, cirrhosis or both. ELISA was used to measure circulating NGF levels. RESULTS: NGF and trkA(NGF) were highly expressed in HCC tissue, mainly localized in hepatocytes, endothelial and some Kupffer cells. In the cirrhotic part of the liver they were also markedly expressed in bile ducts epithelial and spindle-shaped cells. Surprisingly, in cirrhotic tissue from patients without HCC, both NGF and trkA(NGF) were negative. NGF serum levels in cirrhotic and/or HCC patient were up to 25-fold higher than in controls. CONCLUSION: NGF was only detected in liver tissue with HCC present. Intracellular distribution suggests paracrine and autocrine mechanisms of action. Better definition of mechanisms may allow for therapeutic and diagnostic/prognostic use of NGF.

Liver steatosis: The new epidemic of the Third Millennium. Benign liver state or silent killer?

Until the end of the 90's of the last century, rather little attention was paid to the issue of the non-alcoholic fatty liver disease (NAFLD), perhaps due to the fact that the newly discovered hepatitis C virus did attract a paramount interest of hepatologists and researchers. On the other side, fatty liver was considered a relatively uncommon cause of liver damage, occurring almost exclusively in obese females, often associated with non-insulin dependent diabetes mellitus (NIDDM), and with a relatively benign prognosis. Due to the complexity of international available guidelines, we decide to approach the main unsolved issues on this topic in the form of a dialog between a hepatologist and a man suffering from NAFLD, trying to give evidence-based answers to the more frequently asked questions from patients and their GPs. This is the third instalment of the Trilogy of Dr. Calm, a skilled hepatologist who will try to clearly explain to his patient Mr. Frightened the natural history of NAFLD, the diagnostic workup, indications for liver biopsy and suggested medical treatments, advicing him on the importance of dietary intervention and lifestyle modifications.

Surveillance of patients with chronic hepatitis C not on antiviral therapy: a practical approach.

Surveillance of patients with HCV-related chronic liver disease (CHC) not on antiviral therapy is mandatory, because of the risk of worsening of the disease and progression to cirrhosis and its lethal complications. Unfortunately, data from the literature are scarce, and sometimes there are differences among experts and discrepancies between recommendations. Furthermore, the wide range of diagnostic tests and the continuous development of new diagnostic tools not rarely results in expensive, redundant and not justified surveillance programs. The identification of the optimal frequency of follow-ups constitutes another source of difficulties for the physicians. The purpose of this article is to provide practicing physicians with published criteria for performing a cost-effective and adequate surveillance program for patients with CHC not on antiviral treatment. On the basis of randomized controlled trials (RCTs), metanalysis, and international guide-lines and Consensus Conference statements we have attempted to outline a cost-effective surveillance program for HCV carriers with normal aminotransferases (ALT), for responders to previous interferon (IFN) treatment and for patients with CHC non-eligible for antiviral therapy. This surveillance strategy relies upon the judicious use of un-expensive and widely available tests.

Hepatic venous pressure gradient determination in patients with hepatitis C virus-related and alcoholic cirrhosis.

OBJECTIVES: Few data exist regarding the degree of portal hypertension in hepatitis C virus (HCV)-related cirrhosis, as the majority of studies have included mainly patients with alcoholic cirrhosis. This study was aimed at comparing the severity of portal hypertension in patients with HCV-related or alcoholic cirrhosis. METHODS: In total, 59 cirrhotic patients with portal hypertension (HCV-related in 34 cases and alcoholic in 25) underwent main right hepatic vein catheterization, with determination of the wedged and free hepatic venous pressures, and of hepatic venous pressure gradient (HVPG). RESULTS: HVPG values did not differ between the two groups of patients (19.4 +/- 6.0 mmHg vs 18.5 +/- 3.5 mmHg; P = 0.51). The prevalence and degree of oesophageal and gastric varices and portal hypertensive gastropathy did not correlate with the aetiology. Patients with viral cirrhosis had a lower prevalence of previous bleeding than those with alcoholic cirrhosis, despite a similar proportion of large varices in the two groups and similar HVPG levels. In both groups of patients, HVPG did not differ between patients with previous bleeds and those without. CONCLUSIONS: The degree of portal hypertension in cirrhotic patients does not correlate with the cause of the disease. Thus, current statements on the management of portal hypertension, although based upon studies including mainly patients with alcoholic cirrhosis, can be applied also to patients with viral-related cirrhosis.

HCV carriers with persistently normal ALT Levels: not too much healthy, not true patients.

Approximately 30% of patients with chronic HCV infection show persistently normal alaninaminotransferase (ALT) levels. The majority of HCV carriers are females, and up to 40-50% of carriers harbor non-1 genotype, at least in western Europe. No association has been found between HCV type/viral load and the severity of liver damage. The prevalence of HCV carriers with normal liver seems to be very low (less than 20%). Liver disease is usually minimal/mild and fibrosis is generally absent or minimal, although the association of normal ALT with cirrhosis or with hepatocellular carcinoma has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with persistently normal ALT than with abnormal ALT. Although the majority of data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis, several studies reported a significant progression of fibrosis in approximately 20-30% of the patients with ALT normality, and the development of hepatocellular carcinoma in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up.

Laparoscopic liver resections in normal and cirrhotic livers: a retrospective analysis in a tertiary hepato-biliary unit.

BACKGROUND: Liver surgery in patients with underlying liver disease results in higher mortality and morbidity rates compared to patients without underlying liver disease. Laparoscopy seems to have good results in patients with normal liver in terms of postoperative outcomes, but is more challenging in cirrhotic patients. Aim of this study was to evaluate the feasibility of laparoscopic liver resection both in normal and cirrhotic livers, and secondary endpoint was to compare the surgical results. METHODS: We retrospectively evaluated 105 patients who underwent laparoscopic liver resection between November 2001 and January 2012. Candidates for laparoscopic liver resection were divided into two groups according to the presence or absence of an underlying liver disease. RESULTS: 105 patients (52.4% males, median age 56.1 years) were enrolled, and 37.1% had liver cirrhosis. Hepatocellular carcinoma in hepatitis C virus-related cirrhosis (89.7%) and liver metastases (57.6%) were the main indications for surgery in patients with cirrhosis and non-cirrhotic livers, respectively. None of the patients died post-operatively. Cirrhotic patients had greater blood loss (100 vs 50 ml; p<0.012) and longer hospital stays (6 vs 4 days; p<0.031) compared to non-cirrhotics. CONCLUSIONS: Laparoscopic liver resections are safe and feasible procedures in both patients with cirrhotic and non-cirrhotic livers.

How to manage HBeAg-negative chronic HBV infection with normal alanine aminotransferase levels in clinical practice?

Many HBsAg-positive/HBeAg-negative patients show normal alanine aminotransferase levels. However, in this group of patients two different virological and clinical subsets do exist: inactive HBV carriers and patients with chronic hepatitis B with transient virological and biochemical remission. Natural history and outcome, severity of liver damage and need for liver biopsy and antiviral treatment differ significantly between these groups of patients. It is not always easy to distinguish between inactive HBV carriers and patients suffering from HBeAg-negative chronic hepatitis with transient disease remission, as they share similar biochemical (normal serum ALT values) and virological (HBeAg negativity and low HBV DNA levels) features. In clinical practice, it is very important to differentiate inactive carriers from patients with chronic hepatitis B with spontaneous transient remission, as the former have a good prognosis with a very low risk of complications, while the latter have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Thus, a careful assessment and adequate follow-up periods are needed. The aim of this review, written in the form of a dialog between a hepatologist and a newly diagnosed patient with HBV infection and normal alanine aminotransferase levels, is to give evidence-based suggestions for the management in clinical practice of HBsAg patients, on the basis of more recent international guidelines, covering many aspects of the condition, including advice on lifestyle and vaccination, indications for liver biopsy and treatment, the types and side effects of treatment and treatment endpoints.

Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No.

Portal hypertension (PH) is a severe complication of liver cirrhosis. Measurement of the degree of portal hypertension is usually performed by measuring the hepatic venous pressure gradient (HVPG) which is the difference between the free hepatic venous pressure (FHVP) and the wedged hepatic venous pressure (WHPG). The HVPG accurately reflects the degree of PH in the majority of liver diseases. PH is defined by an increase of HVPG values above the normal upper limit of 5 mm Hg, while clinically significant PH is defined by an HVPG to ≥10 mm Hg. Although measurement of HVPG potentially has several applications, in clinical practice its major use has been related to the assessment of hemodynamic response to pharmacological therapy, in order to evaluate the efficacy of treatment and to predict the risk of rebleeding from esophageal varices. When properly performed, HVPG is a reliable, safe and good predictive tool in the management of portal hypertension. However, the need for appropriate equipment, sufficient and reliable operators and costs, have discouraged its use outside Liver Units specifically devoted to the clinical management of portal hypertension. This has diminished its applicability. Combining its use with transjugular liver biopsy and using the prognostic value of HVPG may help encourage its use.

The use of terlipressin in cirrhotic patients with refractory ascites and normal renal function: a multicentric study.

UNLABELLED: Ascites is a common complication of liver cirrhosis, occurring in more than 50-60% of the patients within 10 years of the diagnosis. In 5-10% of patients, ascites cannot be mobilized, or its early recurrence cannot be prevented by medical treatment. This condition is known as "refractory ascites". The use of terlipressin in cirrhotic patients with refractory ascites and normal renal function has not been evaluated. This prospective study was aimed at evaluating whether terlipressin in addition to standard therapy (diuretics plus albumin) might improve the outcome of refractory ascites in cirrhotic patients without HRS. PATIENTS: 26 cirrhotic patients with refractory ascites were prospectively enrolled in this study. All the patients had tense (grade 3) ascites, and 10/26 showed also massive peripheral edema. Patients received maximum diuretic treatment plus albumin and terlipressin. RESULTS: Complete response was seen in 16/26 patients. The higher response to therapy was seen during the 2nd week of treatment. 6 patients showed a decrease of at least two points in the ascites score. No differences in clinical response to treatment were seen according to the etiology of the disease. CONCLUSIONS: In conclusion, our study shows a synergistic effect of terlipressin vs treatment with albumin plus diuretics in patients with refractory ascites. One could speculate that albumin might enhance the vasoconstrictive response to terlipressin, thus contributing to counterbalance the negative effects of systemic vasodilation, which characterizes the hyperdynamic circulation of cirrhotic patients.