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Background: The role of clinically significant portal hypertension on the prognosis of cirrhotic patients undergoing hepatic resection for hepatocellular carcinoma (HCC) is debated. Aims: In this study, our aim was to assess the role of clinically significant portal hypertension after hepatic resection for HCC in patients with cirrhosis. Methods: We assessed the prognostic role of the presence of clinically significant portal hypertension (oesophageal/gastric varices/portal hypertensive gastropathy or a platelet count 100 vs 86 months, P = 0.742). Conclusions: Presence of clinically significant portal hypertension has no influence on survival of patients with well-compensated cirrhosis undergoing hepatic resection for HCC. © 2013 John Wiley & Sons A/S.

Helicobacter pylori eradication therapy is commonly prescribed in the general population. Treatment consists of drugs that are mainly metabolized by the liver cytochrome P-450 (CYP) enzymatic pool. Most H. pylori-infected patients often take drugs for comorbid illnesses, therefore increasing the potential for drug-drug interactions. We aimed to evaluate the interactions of rabeprazole, clarithromycin, and metronidazole 1-week H. pylori eradication therapy with CYP-dependent liver metabolic function in clinical practice. Ten patients referred to our unit for H. pylori infection underwent 1-week eradication therapy with rabeprazole (20 mg, b.i.d.), clarithromycin (500 mg, b.i.d.), and metronidazole (500 mg, b.i.d.). We chose the 13C-aminopyrine breath test (13C-ABT) to evaluate CYP-dependent liver function since it is noninvasive and nonharmful. All patients underwent 13C-ABT at three time points: before therapy (to), at the end of therapy (t8), and after 1 month of follow-up (t38). Mean 13C-ABT dose/hr (t0 = 14.0 +/- 5.4, t8 = 13.5 +/- 4.0, t38 = 16.1 +/- 5.6) as well as 13C-ABT cumulative dose (t0 = 2.4 +/- 1.1, t8 = 2.4 +/- 0.8, t38 = 2.6 +/- 1.0) were not statistically different at the three time points of the study. These results did not seem to be influenced by drugs being administered concomitantly. In everyday clinical practice rabeprazole-based H. pylori eradication therapy does not seem to display any significant interactions with CYP-dependent liver function, even in patients on multiple drugs.

Background & Aims: Liver biopsy examination is the gold standard to diagnose the presence of cirrhosis. The aim of this study was to evaluate the accuracy of both 13C-aminopyrine breath test (13C-ABT) and 13C-galactose breath test (13C-GBT) in the noninvasive assessment of the presence of cirrhosis in patients with chronic liver disease. Methods: We evaluated 61 patients with chronic liver disease of diverse etiologies (21 compensated cirrhosis). All patients underwent 13C-GBT and 13C-ABT, and the results were expressed as a percentage of the administered dose of 13C recovered per hour (%dose/h) and as the cumulative percentage of administered dose of 13C recovered over time (%dose cumulative). Results were analyzed according to absence vs presence of cirrhosis. Results: On average, 13C-GBT %dose/h and %dose cumulative were decreased significantly in patients with compensated cirrhosis, and the same finding was observed for 13C-ABT results from 30 to 120 minutes. 13C-GBT %dose/h at 120 minutes had 71.4% sensitivity, 85.0% specificity, and 83.7% accuracy, whereas 13C-ABT %dose cumulative at 30 minutes had 85.7% sensitivity, 67.5% specificity, and 77.1% accuracy for distinguishing between the 2 subgroups of patients. Combined assessment of 13C-GBT and 13C-ABT increased the diagnostic accuracy (80% positive predictive value) of either test alone and reached 92.5% specificity and 100% sensitivity for the diagnosis of cirrhosis. Conclusions: In patients with chronic liver disease, both 13C-GBT and 13C-ABT are useful for the diagnosis of cirrhosis. Combination of the tests increases the diagnostic yield of each test alone.

BACKGROUND: In the Western world, hepatocellular carcinoma seldom develops in patients without cirrhosis, and reports describing the characteristics of non-cirrhotic patients with hepatocellular carcinoma are rather infrequent. METHODS: We evaluated the main clinical characteristics, treatment options, and survival of patients with hepatocellular carcinoma developed in non-cirrhotic liver among the 3027 consecutive cases of hepatocellular carcinoma accrued in the Italian Liver Cancer database during the last 20 years. RESULTS: We identified 52 patients with hepatocellular carcinoma in non-cirrhotic livers (1.7% of all hepatocellular carcinomas), 42 with (80.8%) and 10 without (19.2%) chronic liver disease. In patients without chronic liver disease, median tumour diameter was greater compared to patients with chronic liver disease (7.8 versus 4.0 cm, P=0.046). Curative treatment was feasible in 20 patients (38.5%). Median overall survival was 26 months and 5-year survival rate was 23.7%. Detection of hepatocellular carcinoma outside surveillance (P=0.036), advanced hepatocellular carcinoma stage (P

Summary Background: Trans-catheter arterial chemoembolisation (TACE) is the most common palliative treatment for hepatocellular carcinoma (HCC). The therapeutic options depend both on the characteristics of the tumour and on functional staging of the cirrhosis. Aim: To evaluate the effects of TACE on the survival of cirrhotic patients with HCC according to different staging systems [Okuda score, Cancer Liver Italian Program (CLIP) score, Model for End-stage Liver Disease (MELD) score] and in relation to the side-effects of TACE. Methods: Fifty cirrhotic patients, 36 CTP class A and 14 class B, underwent 106 TACE treatments with mitoxantrone. Survival at 12, 24, and 36 months was evaluated. Results: MELD at 12 months and CLIP at 24 months were identified as significant variables associated with survival. Combined cut-offs of CLIP and of MELD identified four subgroups of patients with different survivals, at 12, 24 and 36 months, respectively: CLIP ≥ 2 and MELD ≥ 10 (63%, 20% and 0%), CLIP

Helicobacter pylori gastric infection has been associated with various digestive and extradigestive diseases. In liver disease bacterial infections have been associated with impairment of cytochrome P-450 liver metabolic activity. Moreover, infection by Helicobacter spp. seems to be linked with the development of hepatocellular carcinoma (HCC) in mice. Our aims were to evaluate the influence of H. pylori infection on cytochrome P-450 liver metabolic activity as assessed by means of monoethylglycinexylidide (MEGX) test and to assess the prevalence of H. pylori infection in patients with HCC. Ninety-six hepatitis C virus (HCV) -positive cirrhotic patients, 36 of whom had HCC, were tested for H. pylori infection by means of anti-H. pylori IgG. Patients underwent the MEGX test. Characteristics of the patients were then analyzed on the basis of the presence of H. pylori infection. Seroprevalence of H. pylori infection was similar between cirrhotic patients without (68%) or with (63.8%) HCC. Mean MEGX values were significantly (P < 0.0001) lower in H. pylori infected patients (18.2 +/- 13.9 ng/ml) as compared to the noninfected ones (46.9 +/- 17.1 ng/ml), independently of Child-Pugh's classification. These differences persisted even after subdividing patients according to the presence of HCC. In conclusion, in anti-HCV positive cirrhotic patients H. pylori infection is associated to an impairment of cytochrome P-450 liver metabolic activity. Seroprevalence of H. pylori infection in HCC patients is similar to that observed in tumor-free cirrhotics.

Thrombocytopenia is likely the most common haematological alteration that can be observed in patients affected by chronic liver disease [1]. In compensated cirrhosis, it is the most prevalent and incident peripheral blood cytopenia; in chronic hepatitis C patients, thrombocytopenia represents an obstacle to antiviral therapy in 6.5 % of patients who are otherwise good candidates for interferon treatment [2, 3]. Furthermore, besides being the hallmark of a possible increased risk of bleeding, thrombocytopenia has several diagnostic and prognostic meanings [4, 5]. This versatile use of platelet count and thrombocytopenia is supported by the multi-faceted etiology of decreased platelet count in chronic liver disease patients [1, 5]. Indeed, the platelet count is incorporated into numerous diagnostic algorithms aimed at non-invasively assessing the severity of chronic liver diseases and features of portal hypertension, can be used to pinpoint patients at higher risk of developing hepatocellular carcinoma in population studies, and is a predictor of death in cirrhotic patients with and without hepatocellular carcinoma [6–12]. The study by Hermos et al. [13] published in this issue of Digestive Diseases and Sciences describes the longitudinal course of platelet count in a large series of patients with non-hepatitis C-related chronic liver disease followed for a median of 3.3 years at the New England Veterans Administration Center, evaluating the occurrence of severe thrombocytopenia—defined as platelet count below 50 9 10/L—and significant bleeding, and the association between bleeding episodes and platelet counts. The relevance of this retrospective study lies in its ability to provide reliable data on the time-trend of platelet counts in a large cohort of chronic liver disease patients consistently followed over an adequate period of time, showing that severe thrombocytopenia occurs in a modest proportion of patients (13.4 %) and is expectedly more incident among patients with a baseline platelet count close to the threshold (i.e., 50 9 10/L). As compared to previous studies that assessed platelet count modifications over time, it has the merit of including patients with all forms of chronic liver disease while excluding patients with chronic hepatitis C virus infection where multiple causes of thrombocytopenia might have impaired interpretation of the results [14, 15]. The most important information contained in the study, however, is provided by the analyses of the association between platelet counts and bleeding episodes. Indeed, the current vision of the coagulopathy of chronic liver disease patients reflects the presence of a balanced coagulation asset despite altered blood coagulation tests, due to the lack of standardized tests able to adequately evaluate the derangement in both proand anti-coagulant factors [16]. Therefore, data regarding a possible association between platelet counts and bleeding might improve our knowledge on this topic. Overall, this study confirms that a decreased platelet count is a good indicator of the severity of chronic liver diseases, as patients with more compromised liver function and higher Model for End-stage Liver Disease (MELD) scores were prevalent in the group of patients with baseline severe thrombocytopenia. Bleeding as a primary cause of hospitalization occurred in 10.8 % of the patients, an incidence five times higher in patients with severe thrombocytopenia compared with patients with a platelet count above the lower limit of normal. Nevertheless, 98.1 % of the bleeding episodes reported in this study were gastrointestinal; unfortunately, no data were available regarding their relation to E. G. Giannini (&) Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, no.6, 16132 Genoa, Italy e-mail: egiannini@unige.it

Background: A 24-48-week course of interferon-based therapy poorly tolerated in hepatitis C virus (HCV) cirrhosis patients with thrombocytopenia. Aim of the study was to identify patients at low-risk of liver-related complications over a 12-week course of interferon-based therapy. Methods: We assessed the rate of complications and death during the first 12 weeks of interferon-based therapy in HCV cirrhotics with thrombocytopenia (platelets ≤75×109/L) enrolled in the ENABLE-1 and -2 phase 3 randomised controlled trials. Results: Overall, among 1441 patients, 89 complications (6.9%) and 10 deaths (0.7%) were observed within the first 12 weeks of therapy. At univariate analysis baseline albumin levels and Model for End Stage Liver Disease (MELD) score (≤35. g/L, p35. g/L (71.2%), one patient died (0.1%) and 17 experienced liver-related complications (1.7%). Among 667 patients with serum albumin >35. g/L and MELD score

Background and Aim Thrombocytopenia is frequently observed in patients with chronic hepatitis C virus (HCV) infection and cirrhosis, although it can also be observed in patients without cirrhosis by a virus-mediated phenomenon. This study assessed the prevalence, characteristics, and outcomes of antiviral therapy in patients with chronic HCV infection and thrombocytopenia not associated with cirrhosis. Methods The study included 1268 patients with HCV infection and thrombocytopenia enrolled in the phase 3 ENABLE studies that assessed the impact of eltrombopag on achieving a sustained virologic response to pegylated interferon and ribavirin. The study population was subdivided according to baseline FibroSURE test results into patients with non-cirrhosis (FibroSURE

Thrombocytopenia can be found in patients with chronic hepatitis related to hepatitis C virus (HCV). Both hypersplenism and decreased liver production of thrombopoietin (TPO) have been hypothesized as mechanisms responsible for thrombocytopenia.To assess the presence of relationships among platelet count, spleen size, TPO serum levels, liver histology, and liver function in a group of patients with HCV-related chronic hepatitis.Platelet count, TPO serum levels, and spleen size were assessed in 25 untreated HCV positive chronic hepatitis patients undergoing liver biopsy. These parameters were correlated to liver histology and liver function as evaluated by means of [(13)C]aminopyrine breath test (ABT).Both platelet counts (146 +/- 48 vs. 202 +/- 56 x 10(9)/1, P0.03) and TPO serum levels (103 +/- 24 vs. 158 +/- 7 1 pg/ml, P0.02) were lower among patients with high fibrosis scores as compared to patients with low fibrosis scores. Patients with thrombocytopenia as well as patients with high fibrosis scores had lower ABT results as compared to patients with normal platelet counts and patients with no or mild fibrosis, respectively. TPO serum levels were correlated to platelet count (r(s) = 0.493, P = 0.016), and negatively correlated to fibrosis stage (r(s) = -0.545, P = 0.008). Lastly, low TPO serum levels were associated to a decrease in liver function.Our study showed that in patients with chronic hepatitis related to HCV infection serum TPO levels are correlated to liver functional impairment and to the degree of liver fibrosis.

Background: There are few data on the use of the 13C-aminopyrine breath test to evaluate the severity of disease in patients with hepatitis C virus-related chronic liver disease, although these patients represent one of the most important problems in clinical hepatology. Aims: To compare 13C-aminopyrine breath test results of patients with hepatitis C virus-related chronic hepatitis and Child–Pugh class A cirrhosis with those of normal subjects, and to evaluate different methods of expressing 13C-aminopyrine breath test results. Methods: Twenty-four patients with hepatitis C virus-related chronic hepatitis and 17 patients with Child–Pugh class A cirrhosis underwent 13C-aminopyrine breath test. Breath samples were collected every 30 min up to 2 h after 13C-aminopyrine administration. 13C-Aminopyrine breath test results were expressed as a percentage of the administered dose of 13C recovered per hour (% dose/h) and the cumulative percentage of administered dose of 13C recovered over time (% dose cum). Nineteen healthy subjects served as controls. Patients with hepatitis C virus-related chronic hepatitis were divided into subgroups on the basis of histological staging and grading. Results: The 13C-aminopyrine breath test result (% dose/h) at 30 min was significantly different among the three subgroups of subjects (normal subjects, 11.5 ± 3.5; chronic hepatitis patients, 8.1 ± 4.1; cirrhosis patients, 5.0 ± 3.1; P 2) fibrosis scores to be distinguished. The 13C-aminopyrine breath test results (% dose cum) at 30, 60 and 90 min allowed discrimination between normal subjects and chronic hepatitis and cirrhosis patients. The 13C-aminopyrine breath test result (% dose cum) was also able to distinguish between normal subjects and chronic hepatitis patients with high but not low fibrosis scores. Both 13C-aminopyrine breath test results (% dose/h and % dose cum) at 120 min allowed the differentiation between normal subjects and chronic hepatitis patients with high (≥ 6) necro-inflammatory activity. Conclusions: In patients with hepatitis C virus-related chronic liver disease, the 13C-aminopyrine breath test proved to be safe and easy to perform, and was able to evaluate different degrees of liver function impairment which were partly correlated to clinical and histological evaluation. In future studies, 13C-aminopyrine breath test results should be expressed in a standardized fashion to permit comparison.

As the prevalence of obesity and insulin-resistance continues to increase in the general population, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions, thus becoming one of the leading causes of chronic liver disease worldwide. It may present as simple steatosis (NAFL) or steatohepatitis (NASH), which in turn may develop fibrosis and ultimately cirrhosis. Conventional biochemical liver test and radiological investigations are not able to provide reliable information on liver functional reserve, and liver biopsy remains the gold standard to stage NAFLD, differentiate simple steatosis from NASH, and grade fibrosis. However, liver biopsy has some limitations, and is not preferred by patients due to its invasiveness. Thus, non-invasive assessment of disease stage by using liver breath tests – which are based on hepatic clearance of non-radioactive stable 13 C-labelled drugs – may be of interest to stage disease and assess patients prognosis due to good accuracy and repeatability. These substrates are orally administered and are cleaved by enzymes specifically located in the liver thus reflecting either the microsomal, cytosolic, or mitochondrial functions. 13 C-Breath Tests have been initially oriented to differentiate broad categories of patients and more recently to refine stage differentiation in patients with early stages of liver disease. In NAFLD patients, 13 C-BTs were able to distinguish simple steatosis from NASH and had good correlation with both histological fibrosis stage and biochemical markers of fibrogenesis. Although promising results have been achieved in this field, their use in clinical practice is still restricted to a specialized niche. However, concordant data from literature conferred to 13 C-Breath Tests a potential role in providing punctual and longitudinal evaluation of patients, identifying those patients where liver biopsy may selectively be performed to stage disease, monitoring and predicting therapeutic response.

Background: Helicobacter pylori gastric infection has been associated with various digestive and extra-digestive diseases. The systemic influence of gastric H. pylori infection seems to be mediated by the release of various cytokines. In liver disease, bacterial infections have been associated with the impairment of liver metabolic function. Aims: To evaluate the influence of H. pylori infection on liver function as assessed by means of the monoethylglycinexylidide test, which depends upon liver blood flow and cytochrome P-450 activity, and the 13C-galactose breath test, which depends on cytosolic enzymatic activity and is correlated with hepatic functional mass. Moreover, to evaluate whether H. pylori-associated modifications of liver function may be related to tumour necrosis factor-α serum levels. Patients and methods: Thirty-five patients with liver cirrhosis of various aetiologies, who underwent monoethylglycinexylidide and 13C-galactose breath tests, were retrospectively evaluated for H. pylori infection by means of anti-H. pylori immunoglobulin G. The main clinical, biochemical and functional characteristics of the patients as well as their tumour necrosis factor-α serum levels were then analysed on the basis of the presence of H. pylori infection. Results: Twenty-one patients tested positive for H. pylori infection (60%), and 11 tested negative (31.4%). No clinical or biochemical differences were observed between H. pylori-infected and non-infected patients. H. pylori infection showed no difference in distribution according to Child–Pugh classes (A, 55%; B and C, 67%). The monoethylglycinexylidide test results were significantly lower at each sampling time in H. pylori-positive patients compared to H. pylori-negative patients (MEGX15, P=0.027; MEGX30, P=0.014; MEGX60, P=0.028), while 13C-galactose breath test showed no significant differences considering both cumulative percentage dose and percentage dose/h. The median tumour necrosis factor-α serum levels were no different between H. pylori-positive (16.1 pg/mL, 95% confidence interval, 8.7–28.7) and H. pylori-negative (12.3 pg/mL, 95% confidence interval, 8.7–23.4) patients. Conclusions: In cirrhotic patients, H. pylori infection seems to selectively affect cytochrome P-450 liver activity, while hepatic functional mass does not seem to be impaired. Tumour necrosis factor-α does not seem to be the mediator of this impairment. Further studies are needed to evaluate the impact of H. pylori eradication on parameters of liver function.

AIM To evaluate the long-term functional outcome of chronic hepatitis C (CHC) patients treated with interferon (IFN) therapy. METHODS Thirty-six patients with CHC were followed up for a mean of 36 months (+/- 19, SD) after a course of IFN therapy. Biochemical, virological (qualitative hepatitis C virus (HCV)-RNA and HCV genotype), and functional (monoethylglycinexylidide (MEGX) test) evaluations were carried out at the time of liver biopsy. Patients were divided into long-term responders (LTR), relapsers (RR), or non-responders (NR) according to IFN therapy outcome. At the end of follow up, patients were non-invasively re-evaluated by means of biochemistry, qualitative HCV-RNA, MEGX test, and liver ultrasonography. RESULTS A significant decrease in MEGX values was observed in all patients. However, when patients were examined according to treatment outcome, only NR and RR showed a significant decrease in liver function as compared to pretreatment levels (MEGX30, 80.5 +/- 26.8-62.9 +/- 24.2 ng/mL, P< 0.01; MEGX60, 72.9 +/- 18.1-60.5 +/- 19.7 ng/mL, P< 0.05; MEGXAUC, 3,816 +/- 1,243-3,095 +/- 1,205 ng/mL per h, P< 0.05). On the contrary, LTR patients showed no significant modifications in MEGX values at each sampling time (MEGX,5, 72.9 +/- 31.4-70.3 +/- 29.7 ng/mL; MEGX30, 84.0 +/- 27.6-71.5 +/- 21.8 ng/ mL; MEGX60, 69.5 +/- 26.8-63.2 +/- 14.4 ng/mL; MEGXAUC 4028 +/- 1,378-3,620 +/- 1,041 ng/mL per h). At the end of follow up, LTR patients showed normal liver biochemistry and negativity of serum HCV-RNA, while NR and RR patients showed a significant decrease in platelets. CONCLUSIONS In CHC patients long-term response to IFN therapy, besides favoring positive clinical and virologic long-term outcome, results in maintaining preserved liver function. Furthermore, IFN therapy seems to determine a decrease in the rate of functional disease progression, even in NR and RR. The MEGX test may be considered as a useful tool for performing serial follow up of CHC patients.

Damage to bile ducts in chronic hepatitis C is a characteristic histological lesion. Moreover, the presence of abnormal levels of γGT in these patients is also a common finding. Assessing whether the presence of bile duct lesions is indicated by biochemical abnormalities or whether virological characteristics can influence their development may help in the definition of clinical–histological relationships in chronic hepatitis C. In this study we evaluated the relationships among routine biochemical parameters, serum bile acids, and pi-class glutathione S-transferase levels, and the presence of bile duct lesions in 60 patients with chronic hepatitis C. Furthermore, we assessed whether the presence of bile duct lesion might be related to HCV genotype, HCV-RNA serum levels, and positivity for HGV-RNA. We found that γGT was the only parameter related to the presence of bile duct lesions. Although a trend towards higher serum bile acids and pi-class glutathione S-transferase levels was observed in patients with bile duct lesions, this trend did not reach statistical significance. Different HCV genotypes and RNA levels, and HGV-RNA positivity did not seem to influence the presence of bile duct damage. In conclusion we found that γGT levels point out the presence of bile duct lesions in patients with chronic hepatitis C. Since we observed a different pattern of alteration of γGT, serum bile acids, and pi-class glutathione S-transferase, we suggest that these various biochemical alterations reflect a more complex damage to bile duct structures, which is not likely represented by the common assessment of bile duct lesions. Viral factors such as HCV genotype and RNA levels as well as HGV-RNA positivity are probably not the main cause of this histological damage.

Summary. Thrombocytopenia is likely the most common haematological abnormality that can be diagnosed in patients affected by chronic liver disease. In these patients, the presence of thrombocytopenia may have significant clinical implications. In fact, it can be a limiting factor when considering invasive procedures and may hamper the outcome of antiviral therapy with interferon. The prevalence of decreased platelet count in patients with chronic hepatitis C has been assessed in various studies that evaluated heterogenous patient populations and used various platelet count threshold to identify thrombocytopenia. This review shows that the prevalence of thrombocytopenia in these patients is variable and mainly depends upon the severity of the underlying liver disease and the criterion used to identify this haematological abnormality. Furthermore, the results of this epidemiological review provide an indirect evidence that confirms the multiplicity of aetiological factors underlying the pathophysiology of thrombocytopenia in chronic hepatitis C patients. Lastly, this study shows that up to 25% of patients treated with interferon may develop some degree of thrombocytopenia, and this may be associated with decreased sustained virological response rates.

The presence of steatosis is a common histological finding in patients with chronic hepatitis C (CHC). The causes of the severity of this condition are not yet clear, although both metabolic and viral factors supposedly are involved. In this study our aim was to examine the possible influence that leptin levels, hepatitis C virus (HCV) RNA levels, and hepatitis G virus (HGV) infection have on the severity of steatosis and on the presence and degree of fibrosis in patients with CHC.One hundred eighty-two CHC patients with histological findings of steatosis were chosen from among a cohort of patients referred to our center for staging of liver disease. Among them 48 CHC patients were accurately selected so as to rule out possible confounding factors for the presence of steatosis (diabetes mellitus, hyperlipemia, obesity, alcohol). Leptin levels, HCV RNA levels, and HCV genotype, and the presence of HGV RNA were assessed in these patients and related to histological findings.We found that leptin levels in CHC patients were similar to those in healthy subjects. No relationship was found between leptin levels and severity of steatosis. HCV RNA levels, HCV genotype, and the presence of HGV infection were no different among CHC patients with various degrees of steatosis. Leptin was not related to different degrees of fibrosis, whereas higher viral load was the only parameter associated to higher fibrosis scores.These findings suggest that the degree of steatosis in patients with CHC does not seem to depend on serum leptin levels or on viral factors, at least as far as HCV viremia and genotype and HGV infection are concerned. The severity of fibrosis does not seem to be influenced by leptin levels, whereas HCV viral load does seem to play some role.

Objectives: To study whether determining alpha-glutathione S-transferase (α-GST) might improve the assessment of chronic hepatitis C (CHC) patients with near normal alanine aminotransferase levels (NNA). Design and methods: We studied 119 viraemic CHC patients. They were subdivided into two groups according to the pattern of alanine aminotransferase (ALT) alteration, i.e. consistently above (HA) or below (NNA) twice the upper normal value. In these patients we assessed α-GST and correlated its levels to clinical, histological, and virological findings, further evaluating whether α-GST might improve the assessment of CHC patients with NNA. Results: α-GST showed a significant correlation with aminotransferases, though not with histological necroinflammatory activity and fibrosis or with hepatitis C virus RNA levels. Twenty-seven patients had NNA (23%), and within this subgroup of patients α-GST identified a subset of patients with a higher viral load. Conclusions: α-GST in CHC patients is related to hepatocellular necrosis parameters, but unrelated both to histology and to viraemia. However, in patients with NNA, α-GST identified a subgroup of patients with a higher viral load. In this subgroup of patients α-GST alteration likely represents the expression of a more severe damage. Because this injury is not detectable by the usual biochemical or histological work-up, we suggest that α-GST could a useful tool for monitoring liver damage over time.

Background Hepatitis C virus infection accounts for varying severity of chronic liver disease. Clinical manifestations of infection have been related to different virus genotypes, with conflicting results. Design We performed a cross-sectional study on a Northern-Italian group of patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma related to hepatitis C virus infection in order to verify the association of different viral strains and the outcomes of viral disease. Methods Two hundred and seventy-one patients referred to our unit for liver disease were studied and clinical, biochemical, histological, and functional parameters were investigated. Results Different viral genotypes were not associated with peculiar findings in any of the degrees of liver disease. However, a progressive age increase was associated with disease severity, although clinical and functional staging of cirrhotic patients with hepatocellular carcinoma was better compared to tumour-free cirrhotic patients. There was an increased prevalence of genotype 1 b related to the age of the patients. In multivariate regression analysis the patients'age and apparent duration of infection were independently associated with the presence of cirrhosis and only the age of patients was associated to hepatocellular carcinoma. Conclusions In the population we studied age of the patients seemed to be a determinant conditioning disease severity, likely reflecting older infections and long-standing liver disease. The prevalence of certain genotypes in varying degrees of liver disease could be an epiphenomenon which might also be explained by the changing prevalence of infecting strains over the past decades.

The ratio of serum aspartate aminotransferase to alanine aminotransferase (AST/ALT ratio) has been proposed as a noninvasive method of assessing liver fibrosis and cirrhosis. Our aims were to confirm the usefulness of the AST/ALT ratio in diagnosing cirrhosis noninvasively as well as to verify the existence of a relationship between the ratio and liver functional impairment. In all, 348 patients (177 with chronic hepatitis, 171 with cirrhosis) were retrospectively evaluated and the AST/ALT ratio was related to monoethyl glycine xylidide (MEGX) formation. Moreover, in a subgroup of 54 patients we analyzed the relationships among the AST/ALT ratio and indocyanine green clearance and half-life. The AST/ALT ratio was able to separate patients with mild fibrosis from those with severe fibrosis and cirrhosis. The AST/ALT ratio, MEGX, prothrombin activity, and platelet count were selected by multivariate analysis as variables associated with cirrhosis. The AST/ALT ratio showed significant correlations both with MEGX formation and with indocyanine green clearance and half-life. The alterations of indocyanine green kinetics, which depend upon liver blood flow and uptake, were likely due to progressive fibrosis. These findings might partially explain the increase in the AST/ALT ratio as disease progresses.

GOALS To characterize the clinical and treatment pattern in a large population of hepatitis B virus (HBV) patients managed at tertiary referral centers in clinical practice. BACKGROUND Successful treatment, either with interferon (IFN) or nucleos(t)ide analogs (NUCs), of chronic HBV infection is associated with improved long-term patient outcome. However, in clinical practice, the actual management of these patients is not well characterized, and data regarding treatment pattern in this setting are lacking. METHODS In this cross-sectional study, we evaluated 505 patients chronically infected with HBV alone and who had at least 1-year follow-up. We assessed indication to, rate of, and type of treatment as well as the characteristics of treated patients. RESULTS Overall prevalence of positivity for HBe antigen was 19.3%, and the majority of patients had chronic hepatitis (47.5%). Non-Italian patients represented approximately one third of the population (27.1%). Among patients with indication to antiviral therapy (n=318), treatment was actually carried out in 264 patients (83.0%), prevalently with NUCs (65.9%). IFN-treated patients were younger (P

BACKGROUND AND OBJECTIVES: Data regarding the safety and efficacy of antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) in patients with sickle-cell disease (SCD) and hepatitis C virus (HCV) infection are scanty. In this study, our aim was to evaluate the safety and efficacy of antiviral therapy with PEG-IFN and low-dose RBV in patients with SCD and chronic HCV infection receiving hydroxyurea in Saudi Arabia. DESIGN AND SETTINGS: This was a prospective interventional study conducted between January 2009 and September 2012 at the outpatient departments of Haematology and Hepatology/Gastroenterology of a tertiary care hospital in Saudi Arabia. PATIENTS AND METHODS: We studied 8 treatment-naive patients (5 males, 63%) with chronic hepatitis C and SCD receiving hydroxyurea who were treated with PEG-IFN alpha-2a (180 μg weekly) and low-dose RBV (200 mg daily). Early virological response (EVR) and sustained virological response (SVR) rates were assessed in all patients. RESULTS: All patients were infected with HCV genotype 1 (n=6.8%) or 4 (n=22%). EVR was obtained in 3 patients (38%) and SVR in 6 patients (7%). During the study, there was no increase in the number of blood units transfused and emergency visits due to painful crises. CONCLUSION: in Saudi Arabian patients with SCD and chronic HCV infection on hydroxyurea, PEG-IFN and low-dose RBV treatment proved to be efficacious and safe.

Background HCC patients are heterogeneous in terms of both tumor and liver factors. Alpha-fetoprotein (AFP) is an important prognostic tumor marker for those patients with elevated AFP levels. Aims To examine the differences in HCC patients with high or low AFP levels in blood and evaluate the prognostic parameters in low AFP patients. Methods A cohort of 2,440 HCC patients from 11 Italian medical centers was studied. AFP-positive patients were compared to AFP-negative ones, and the blood and tumor parameters of AFP-negative patients were examined. Results Low blood AFP levels were found in 58% of the total cohort, in 64% of patients with small HCCs, and in 51% of patients with large HCCs. In patients with large tumors, platelet and gamma glutamyl transpeptidase (GGTP) levels, tumor multifocality and portal vein thrombosis (PVT) incidence were all greater than in patients with small tumors, regardless of AFP status. Patients with higher AFP levels had worse survival rates than those with low AFP in each tumor size group. In patients with small tumors, the elevated AFP was associated with significantly increased PVT and worse survival. In patients with large tumors, the elevated AFP was associated with significantly higher GGTP, ALKP, and bilirubin levels, as well as with increased PVT and multifocality, and worse survival. Low-AFP patients with high GGTP levels had worse survival than patients with low GGTP levels. Conclusion Patients with low AFP were the majority in this cohort, and patients with elevated GGTP had worse prognosis than those with low GGTP. GGTP may be a useful tumor and prognosis marker in low-AFP patients. AFP-negative patients are important to identify due to their enhanced survival.

Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness.

BACKGROUND: α-Fetoprotein (AFP) is a biomarker commonly used in the management of patients with hepatocellular carcinoma (HCC), although the possible determinants of its serum levels in these patients have not been adequately explored. For this study, the authors evaluated the relevance of demographic, clinical, and oncologic factors to the presence of elevated AFP levels in large cohort of patients with HCC. METHODS: In 4123 patients with HCC who were managed by the Italian Liver Cancer Group, AFP levels were assessed along with their association with demographic, biochemical, clinical, and oncologic characteristics. Patients were subdivided according to the presence of elevated AFP (ie, >10 ng/mL). RESULTS: AFP levels were elevated in 62.4% of patients with HCC. Multivariate logistic regression analysis indicated that being a woman (odds ratio [OR], 1.497; 95% confidence interval [95%CI], 1.250-1.793; P < .0001), the presence of cirrhosis (OR, 1.538; 95% CI, 1.050-2.254; P = .027), liver disease with viral etiology (OR, 1.900; 95% CI, 1.589-2.272; P < .0001), an elevated alanine aminotransferase level (OR, 1.878; 95% CI, 1.602-2.202; P < .0001), a low albumin level (OR, 1.301; 95% CI, 1.110-1.525; P = .012), an HCC tumor size >2 cm (OR, 1.346; 95% CI, 1.135-2.596; P = .001), multinodular HCC (OR, 1.641; 95% CI, 1.403-1.920; P < .0001), and the presence of vascular invasion (OR, 1.774; 95% CI, 1.361-2.311; P < .0001) were associated independently with elevated levels of AFP. Both the median AFP level and the proportion of patients who had elevated levels increased with decreasing degrees of HCC differentiation (P < .0001). CONCLUSIONS: Sex and features of chronic liver disease were identified as nontumor characteristics that influence serum AFP levels in patients with HCC. These findings should be taken into account as limitations in interpreting the oncologic meaning of this biomarker in clinical practice.

The Model for End-Stage Liver Disease (MELD) score is an important and well established tool for assessing prognosis in patients with liver cirrhosis. It has been suggested that the longitudinal evaluation of the MELD score may reflect the progression of liver failure more reliably and therefore be more useful in prognostic assessment.To assess the prognostic meaning of MELD score modifications in a cohort of cirrhotic patients in whom clinical and biochemical workup was carried out at least twice during a minimum interval of 30 days.Forty-six cirrhotic patients were longitudinally evaluated for a median follow-up of 365 days. After initial assessment, all the patients had at least one clinical and biochemical reevaluation during follow-up, which was performed no less than 1 month after initial evaluation. MELD was calculated at entry and at second evaluation. DeltaMELD was calculated as MELD at second evaluation minus MELD at entry. DeltaMELD/time was calculated as DeltaMELD divided by time elapsed between initial assessment and second evaluation expressed in months.During follow-up, 13 patients died (28%). The median interval between clinical evaluations was 120 days. MELD scores at entry (13 +/- 4 vs 16 +/- 6, P = 0.0516) and DeltaMELD (0 +/- 4 vs 4 +/- 2, P = 0.0028) were significantly different between patients who died and those who survived during the 1-year follow-up. All the patients who died during follow-up showed an increase of at least 1 unit in DeltaMELD/time (sensitivity = 100%), and all the patients who survived showed a decrease of more than 1 unit in DeltaMELD/time (specificity = 100%).Longitudinal evaluation of the MELD score provides important prognostic information that seems to complete the prognostic definition provided by "static" MELD. Prospective studies in larger series are needed to validate the prognostic use of MELD modifications over time.

Introduction Percutaneous endoscopic gastrostomy (PEG) is the method of choice for long-term nutrition in patients with longstanding eating difficulties due to pathological entities that impair swallowing. The feeding catheters are designed to be removed by external traction or by endoscopy. Aim To evaluate the feasibility of the cut-and-push method as a possible safe alternative to the pullout method for removal of soft PEG devices with a large caliber. Methods Patients with 20 French (Fr) or larger soft PEG system were enrolled for PEG removal by the cut-and-push technique. The replacement catheters were 2 Fr larger than the original ones. Patients were observed at 24 and 72 hours via home nursing care and then weekly for 1 month for signs of intestinal obstruction, tube leakage, or blockage. Results Seventy-nine patients (52 men; mean age 67 years) underwent the procedure: 42 due to leakage and 37 due to blockage. Mean time before tube removal was 4.8 months (range, 3-8). PEG devices were 20 Fr and 24 Fr in 57 (72.2%) and 22 (27.8%) cases, respectively. Collection of the inner component from stool was reported within 48 hours in 63 cases (80%). No cases of intestinal obstruction or other severe adverse events due to the inner component being eliminated throughout the intestine were observed in any patient during the study. Conclusions The cut-and-push method employed for removal of a soft PEG tube with a large caliber seems to be safe and can be performed when removal by external traction may determine the occurrence of peristomal complications or jeopardize PEG replacement.

Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV.Patients with HCV infection and thrombocytopenia (platelet count75,000/μL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy.More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/μL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2.Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Thrombocytopenia may represent a barrier to optimal management of chronic liver disease patients undergoing invasive procedures, or who need to be treated with interferon-based antiviral therapy. Eltrombopag is a thrombopoietic drug that acts upon binding thrombopoietin receptor and stimulates megakaryocytopoiesis and platelet production.A summary of the preclinical studies and of studies carried out in patients with chronic liver disease with eltrombopag are presented in this paper. Data are based on abstracts from journal articles and international conferences found in a PubMed search of literature published up to November 2012.Eltrombopag has shown to be capable of reducing the need for platelet transfusion in thrombocytopenic patients with advanced liver disease undergoing invasive procedures and help increase the sustained virological response rate to interferon-based antiviral therapy in patients with chronic hepatitis C who were poor candidates to treatment because of thrombocytopenia. In chronic liver disease patients, the possible benefits of eltrombopag administration should be accurately weighed against the adverse events profile of the drug due to possible concerns regarding the occurrence of thromboembolic events and the potential for decompensation of chronic liver disease.