Propranolol reduces systemic oxidative stress and endotoxemia in cirrhotic patients with esophageal varices.

BACKGROUND: The aim of the study was to investigate the effect of propranolol on systemic oxidative stress and endotoxemia in patients with liver cirrhosis and clinically significant portal hypertension evidenced by the presence of esophageal varices. METHODS: Fourteen patients with liver cirrhosis and esophageal varices, not previously been treated with non-selective beta-blockers (NSBB), were prospectively started on propranolol and followed up for three months. Serum early and late lipid peroxidation products (lipid hydroperoxides [LOOH] and malondialdehyde [MDA], respectively), and endotoxin concentrations in peripheral blood were measured. Fourteen age- and sex-matched healthy individuals were used as controls. RESULTS: Patients with liver cirrhosis presented significantly higher systemic oxidative stress and endotoxin concentrations compared to healthy controls (P<0.001). Propranolol treatment for one month significantly reduced serum MDA (P<0.05), LOOH (P<0.01), and endotoxin levels (P<0.01) compared to pre-treatment values, whilst LOOH reached control levels. At three months of propranolol treatment, serum LOOH did not differ significantly from the one-month values, whilst serum endotoxin and MDA levels were further reduced between 3- and 1-month period (P<0.05 and P<0.01, respectively), with the latter reaching control levels. Amelioration of systemic endotoxemia at the one- and three-month follow-up intervals (compared to pre-treatment values) was not correlated with the respective reductions in serum MDA and LOOH. CONCLUSIONS: This is the first study to show that NSBB treatment in liver cirrhosis exerts a significant systemic antioxidant action. This effect seems to be, at least partly, independent of their beneficial effects on intestinal barrier function and endotoxemia.

Male hepatitis C patients' sexual functioning and its determinants.

OBJECTIVE: The aim of the study was to detect sexual impairment in male hepatitis C virus patients and determine its associations. PATIENTS AND METHODS: A total of 61 male hepatitis C virus patients were enrolled in this cross-sectional study. Sexual functioning was assessed using the International Index of Erectile Function. Health-related quality of life (HRQOL) was evaluated using the Greek version of the Short Form 36 Health Survey, and the presence and severity of anxiety and depression were assessed using the Greek version of the Hospital Anxiety and Depression Scale. RESULTS: Noncirrhotic patients showed clinically significant dysfunction, mainly in intercourse (59.6%) and overall satisfaction (57.4%). Erectile functioning and desire were correlated with depression (r=-0.520, P=0.000 and r=-0.473, P=0.000), anxiety (r=-0.443, P=0.000 and r=-0.428, P=0.001), physical (r=0.427, P=0.001 and r=0.329, P=0.012), and mental (r=0.379, P=0.003 and r=0.432, P=0.001) HRQOL, platelet count (r=-0.357, P=0.012 and r=0.366, P=0.010), and international normalized ratio (INR) levels (r=-0.373, P=0.013 and r=-0.440, P=0.003). Erection was also correlated with albumin levels (r=0.310, P=0.032). Orgasmic functioning was associated significantly with platelet count (r=0.322, P=0.024) and INR levels (r=-0.425, P=0.004). Intercourse satisfaction was significantly related to depression (r=-0.435, P=0.001) and anxiety (r=-0.335, P=0.008) levels, physical (r=0.374, P=0.004) and mental (r=0.300, P=0.022) HRQOL, platelet count (r=0.333, P=0.020), and INR levels (r=-0.373, P=0.013), and overall satisfaction was significantly correlated with depressive (r=-0.435, P=0.001) and anxiety (r=-0.278, P=0.033) symptoms, mental HRQOL (r=0.340, P=0.010), platelet count (r=0.316, P=0.029), and INR levels (r=-0.332, P=0.030). CONCLUSION: Hepatitis C is accompanied by poor sexual functioning even in the absence of cirrhosis and different correlations emerge for distinct subdomains of male sexuality.

Lactate serum concentrations during treatment with nucleos(t)ide analogues in hepatitis B with or without cirrhosis.

OBJECTIVE: The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues. PATIENTS AND METHODS: One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy. RESULTS: None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class. CONCLUSION: None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.

Could antioxidants be the "magic pill" for cirrhosis-related complications? A pathophysiological appraisal.

Patients with liver cirrhosis are prone to serious complications by almost all systems, leading to high morbidity rates and even death. Although the functional and structural derangement of diverse vital organs developed in the course of advanced liver disease is the result of one entity (cirrhosis) there are various treatment modalities for each system's complications, which are often ineffective. Identification of the link which connects the complications of cirrhosis from diverse systems might lead to a global, simple and more effective treatment approach for patients with cirrhosis. Accumulating evidence from experimental and clinical studies suggests that intestinal barrier dysfunction and subsequent gut-derived endotoxemia represent an important common pathogenetic mechanism in the development of diverse complications of cirrhosis. Intestinal oxidative stress seems to be a pivotal factor of gut barrier dysfunction in cirrhosis through promotion of enterocyte apoptosis, modulation of intestinal tight junctions and impairment of intestinal brush border function. In parallel, oxidative stress plays a fundamental role in the aggravation of liver injury and in the structural and/or functional derangements of diverse organs complicating the course of cirrhosis. Our hypothesis is that antioxidant treatments could prevent in a global way virtually all cirrhosis-related complications acting in two crucial levels in the pathophysiological cascade of events: (a) in a primary level, which is the gut-liver axis by ameliorating gut-derived endotoxemia, through prevention of intestinal oxidative stress and its associated gut barrier dysfunction, concurrently conferring direct antioxidant protection in the liver tissue and (b) in a secondary level, which refers to the diverse organs whose function is affected by liver cirrhosis, by preventing their oxidant-related structural and functional derangements.

Pentoxifylline: a first line treatment option for severe alcoholic hepatitis and hepatorenal syndrome?

Although favourable results of pentoxifylline (PTX) used in treatment of severe alcoholic hepatitis patients with a Maddrey discriminant function score > or = 32 have been previously reported, it is not currently recommended as a first line treatment for alcoholic hepatitis owing to lack of evidence for its efficacy as compared to the standard treatment with corticosteroids. In a very recent issue of World Journal of Gastroenterology, Dr. De BK and colleagues compared for the first time the two treatment modalities head to head in a randomized controlled study, demonstrating the advantage of PTX over corticosteroids in terms of patients' survival and risk-benefit profile. The advantage of PTX over corticosteroids in survival of patients with severe alcoholic hepatitis was found to be related to the prevention of hepatorenal syndrome in their study. This study raises the question of the use of PTX as a standard treatment for severe alcoholic hepatitis. Considering the fact that PTX presented a spectacular efficiency in prevention of hepatorenal syndrome in their study as well as that previous studies have shown that this effect is possibly related to a primary renoprotective action because it is irrelevant of tumor necrosis factor-alpha synthesis inhibition or improved liver function, we tempted to speculate that PXT might be an effective option for prevention and/or treatment of hepatorenal syndrome complicating other forms of advanced liver disease. This attractive theory remains to be elucidated by pressing future studies in view of the lack of effective treatment modalities for hepatorenal syndrome.

Ultrasonography in differentiation between chronic viral hepatitis and compensated early stage cirrhosis.

AIM: To assess the value of gray scale (GS) and colour Doppler ultrasonography (CDU) in differentiating the progression of chronic viral hepatitis (CVH) and compensated liver cirrhosis (CIR). METHODS: Seventy-two patients and 32 normal individuals who were used as controls were studied. Forty-four patients suffered from CVH and 28 from CIR. All patients were underwent to liver biopsy. Multiple qualitative and quantitative variables were studied in liver, portal vein (PV), hepatic artery (HA) and spleen with GS and CDU. On the basis of the obtained CDU data, several known indexes were calculated. In addition, alternative indices [PV diameter (D)/time average mean velocity (VTAM), HA/PV VTAM ratio] were calculated and studied. RESULTS: ROC analysis showed that PV congestion index, PV D/VTAM and HA/PV VTAM indices had the best sensitivity and specificity in discriminating CVH from CIR. Stepwise discriminant analysis showed that 88.9% of the originally grouped cases could be correctly classified by the three qualitative and four quantitative variables selected as statistically significant predictors. Among the CVH patients who underwent to biopsy, statistically significant changes were found in those at fibrosis stage 5 compared to fibrosis stages 1-4. CONCLUSION: Simple GS and CDU parameters discriminate CVH from CIR. The alternative Doppler indexes can accurately differentiate chronic virus hepatitis from cirrhosis. These indexes can be used in monitoring chronic virus hepatitis and avoiding unnecessary biopsies.

Potential role of hepatic progenitor cells expression in cases of chronic hepatitis C and their relation to response to therapy: a clinicopathologic study.

BACKGROUND: This study investigates the correlation of hepatic progenitor cells (HPC) expression with treatment response in patients with chronic hepatitis C. DESIGN: The study comprised 77 liver biopsies with chronic hepatitis C (HCV). All patients were PCR-HCV (+) and received antiviral therapy with interferon or pegylated interferon alpha-2b and ribavirin. Twenty-nine patients were assigned as responders (group A), 29 as nonresponders (group B) and 19 as relapsers (group C). Ten normal liver biopsies were used as controls. Liver paraffin sections were subjected (a) to immunohistochemistry using antibodies for cytokeratins 19 (CK19) and 7 (CK7), alpha-fetoprotein (AFP), leukocyte common antigen (LCA) and CD34 antigen (b) to in situ hybridization for AFP mRNA and (c) to immunohistochemistry+in situ hybridization. Results were expressed as % of positive cells following morphometric analysis. RESULTS: HPC expression was present in all 87 specimens. In the control biopsies, rare HPC were detected. In the CH cases and according to AFP mRNA expression, the grade for % HPC expression was: group B: 53.2+/-2.6> group C: 48.37+/-1.8> group A: 31.4+/-1.6 (group A vs B P<0.01, group A vs C P<0.01, group B vs C P>0.05. Double stain revealed that HPC coexpressed CK19/AFP mRNA, CK7/AFP mRNa and AFP protein/AFP mRNA. HPC-percentages were directly correlated with total HAI score (P<0.01), fibrosis stage (P<0.01), and transaminase values (P<0.05). CONCLUSIONS: This study demonstrates that in cases of chronic hepatitis C, the significant association of HPC expression with the severity of disease and more specifically with the response to treatment implies that HPC development and proliferation may provide additional prognostic information and predict prognosis in such cases.

Hepatocellular carcinoma in hepatectomized patients: biologic and therapeutic implications.

UNLABELLED: The macroscopic and microscopic features of 60 hepatocellular carcinomas (HCC) were investigated and correlated with patients' disease-free survival. PATIENTS AND METHODS: The study included 60 HCCs removed, by partial hepatectomy, from an equal number of patients. In these tumors, several macroscopic and microscopic features were assessed, graded and correlated with disease-free survival. RESULTS: HCCs begin as small, well-differentiated tumors that have an increased proliferation rate and neovascularization. Vascular invasion, which is the strongest predictor of disease recurrence, correlated significantly with tumor number and size, the predominant and worst degree of differentiation, and the apoptosis/mitosis ratio. In the absence of macroscopic or large vessel invasion, the largest tumor size (p = 0.006), apoptosis/mitosis ratio (p = 0.03) and number of tumors (p = 0.04) were independent predictors of disease-free survival. CONCLUSION: This study showed that, in humans, the prognosis of HCC depends on several biological factors. Aggressive biological behavior (vascular invasion and recurrence) correlated significantly with: a) alterations in the apoptosis/mitosis ratio and b) architectural and cellular alterations.

Potential role of bcl-2 and bax mRNA and protein expression in chronic hepatitis type B and C: a clinicopathologic study.

Bcl-2 oncoprotein regulates programmed cell death by providing a survival advantage to rapidly proliferating cells, and bax protein promotes apoptosis by enchanting cell susceptibility to apoptotic stimuli. In this study, we assessed the expression of bcl-2 and bax in liver biopsies from patients with chronic hepatitis (CH) Type B (HBV) and C (HCV). The study comprised 65 liver biopsies from 65 patients with HBV (n = 37) and HCV (n = 28) and 10 normal liver biopsies as controls. The HAI score ranged from 3/18-13/18, and the fibrosis Stage, from 1-6 (7 HBV/10 HCV). Pathologic examination included the following: (1) immunohistochemical stains in paraffin sections for bcl-2 and bax protein expression, (2) Western blot analysis (bcl-2 and bax protein levels evaluation), (3) ISH (detection of bcl-2 and bax mRNA), and (4) ISH (TUNEL-ABI [apoptotic body index]). In CH cases, both bcl-2 and bax protein and mRNA were detected in portal and intralobular lymphocytes and in cholangiolar epithelial cells in interface areas and fibrous bands. Bax protein and mRNA was expressed within hepatocytes and epithelial cells of interlobular ducts in portal tracts. Bcl-2 mRNA was present in periportal hepatocytes only in cases with Stage 5-6 fibrosis. Western blot analysis showed a decreased bcl-2 and an increased bax expression toward advanced fibrotic stages. In CH cases, ABI was reverse correlated with the percentage of bcl-2 expression and was correlated directly with the percentage of bax expression (P <.001). The results of this study suggest that in cases of chronic HBV or HCV infection, bax may be involved in the hepatocyte cycle regulation during infection, whereas its expression in intraportal bile duct epithelium implies that this protein enhances susceptibility of these particular cells to apoptosis. The increased bax expression and ABI in fibrosis Stages 1-5, imply that they are responsible for hepatocytes depletion through apoptosis, during progress of liver fibrosis and fibrous tissue accumulation, until cirrhosis is established. Bcl-2 mRNA expression in periportal hepatocytes only in Stages 5 and 6 suggests that this oncogene is involved in the late stages of progressive liver fibrosis and failure and furthermore that periportal hepatocytes are resistant to apoptosis. Bcl-2 expression, in cholangioles of interface area, suggests that this oncoprotein may be involved in growth regulation of these epithelial cells. Further research is warranted to specify the exact role of apoptosis and apoptotic genes involved in liver fibrosis process in cases of chronic HBV and HCV infection. This may lead to new strategies in the management of human liver disease to prevent the progression to chronic liver failure.

A case of relapsing Guillain-Barré syndrome associated with exacerbation of chronic hepatitis B virus hepatitis.

A patient with two episodes of acute polyradiculoneuropathy (Guillain-Barré syndrome) that both occurred during exacerbation of chronic hepatitis B and separated by a 2-year asymptomatic interval is described. The possible causative relation between the neuropathy and the chronic hepatitis B is discussed.

The potential role of bcl-2 mRNA and protein exression in hepatocellular carcinomas.

BACKGROUND: The bcl-2 gene regulates programmed cell death by providing a survival advantage to rapidly proliferating cells. In several malignant tumors bcl-2 presence has been associated with favorable prognosis. In the liver, bcl-2 is expressed in bile ductular cells and tumors of biliary origin. This study investigates the expression of bcl-2 mRNA and protein in hepatocellular carcinomas (HCC). MATERIALS AND METHODS: The study comprised 35 primary HCC resected from 35 patients; 21 males and 14 females, aged from 43-59 years. The tumors were graded according to Edmondson criteria. In 28 cases HCC was developed on the background of cirrhotic liver. In 9 instances the patients received chemoembolization before surgery. The presence of bcl-2 mRNA was assessed on paraffin-embedded, 4 microm-thick sections, using a standard in situ hybridization method with a commercially available bcl-2 probe (Maxim Biotech, USA), while the streptavidin-biotin immunohistochemical technique was employed to detect bcl-2 protein expression using the monoclonal anti-bcl-2 antibody (DAKO, USA). The results were expressed as % of tumor-positive cells following morphometric analysis. RESULTS: The in situ hybridization study revealed bcl-2 mRNA expression in 25 out of 35 (70%) HCC. In addition, bcl-2 mRNA was detected in hyperplastic cholangioles within fibrous septae in the periphery of the tumors. Immunohistochemical staining failed to reveal any bcl-2 protein expression in tumor cells of HCC, whereas hyperplastic cholangioles of the fibrous septae, in the periphery of the tumors and intratumoral lymphocytes displayed a strong-positive cytoplasmic (perinuclear) stain. No significant correlations were recorded between bcl-2 mRNA expression and tumor histological pattern, grade, stage and the use of previous chemoembolization. CONCLUSION: In hepatocellular carcinomas, the bcl-2 gene is frequently present but its protein product is absent. This suggests a post-translational mechanism of bcl-2 protein degradation, indicating that bcl-2 does not play a substantial role in the progress of hepatocellular carcinoma.

Expresssion of bcl-2 oncoprotein in cases of acute and chronic viral hepatitis type B and type C: a clinicopathologic study.

The bcl-2 gene is involved in the regulation of programmed cell death by providing a survival advantage to rapidly proliferating cells. This study investigates bcl-2 protein expression in liver biopsies with acute or chronic viral hepatitis B (HBV) or C(HCV). The study comprised 60 liver biopsies with hepatitis B or C. These included 10 biopsies from cases with acute lobular hepatitis (ALH), and 50 with chronic hepatitis (CH). In addition, 10 liver biopsies were used as controls. In CH cases, HAI grade ranged from 3/18 to 15/18, and stage from 1 to 6 (6HBV/8HCV). Immunohistochemical bcl-2 expression was assessed using the streptavidin-biotin method and the presence of apoptotic cells was evaluated by TUNEL method. Immunohistochemical and in situ hybridization (TUNEL) results were expressed following morphometric analysis. In CH cases, bcl-2 was detected in portal and intralobular lymphocytes, and in cholangiolar epithelial cells of the interface area. In ALH and control cases, bcl-2 was expressed only in lymphocytes. Lymphocytic bcl-2 expression was correlated directly with categories A, C and D of HAI (P < 0.001), whereas the degree of fibrosis was reversibly correlated to bcl-2 expression. In conclusion, in cases of chronic hepatitis, bcl-2 expression in cholangioles of interface area suggests that this oncoprotein may be involved in regulation of growth of these epithelial cells.