Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.

The high rate of sustained viral response (SVR) to boceprevir or telaprevir-based triple therapy in hepatitis C (HCV)-related, non-cirrhotic naïve patients or relapsers to previous antiviral treatment leads clinicians to believe that the impact of metabolic host factors on SVR is minimal when triple therapy is used, unlike what is observed with the peginterferon and ribavirin schedules. This concept is strongly expressed by some opinion leaders on the basis of the data derived from sub-analyses of registrative trials as well as from a post-hoc analysis of the phase II C208 clinical trial. The perception of unrestrainable therapeutic success with the use of newer, more powerful antivirals is now reinforced by the brilliant results obtained with sofosbuvir, an HCV NS5B polymerase inhibitor, as well as by the data from the phase II and III studies on the various combinations of second-generation NS3/4A inhibitors and NS5A and/or NS5B inhibitors. However, a great deal of concern has emerged from the real world scenario in which patients are often older and have more comorbidities than patients in the "world of trials". Furthermore, many of them have advanced fibrosis and previous failure with peginterferon and ribavirin treatment. Some data from the recent literature suggest that the host metabolic factors may play a minor but non-negligible role in these difficult-to-treat patients, an issue that will hopefully be investigated in further studies. This editorial aims to provide a detailed analysis of the role that host metabolic factors played in the past and what role they may play in the era of direct antiviral agents.

Dear Editor, The staging of liver fibrosis in chronic hepatitis C (CHC) is mandatory for both starting antiviral therapy and for starting a surveillance program for the early diagnosis of HCC. Considering that liver biopsy (LB) is “the best but not the gold standard” for the evaluation of fibrosis owed to possible limitations in the sample specimen and histological interpretation [1], the noninvasive evaluation of significant and severe fibrosis by means of direct or indirect biochemical and “ultrasound” fibrosis indexes is a highly complementary tool in the management of Chronic Hepatitis C (CHC). Some algorithms which are using a combination of direct and indirect fibrosis tests have been validated [2], but the interesting goal of the paper of Crisan et al. [3] was to combine a simple, inexpensive test with more complex noninvasive models (NITs) or Transient Elastography (TE). The gain in diagnostic accuracy of various combinations was about 10 %, and this could help to avoid a significant number of LBs. The main limitation of this study was the length of the LB sample which was below the limit of adequate staging and grading of liver disease, and thus may have limited the discriminant performance of NITs and particularly of TE. However, paradoxically the partial reliability of the histological staging, that is usual in clinical practice, highlighted the potential value of the NITs in fibrosis staging. In this context, it is likely that all NITs showed an underestimated ability to distinguish in both significant and severe fibrosis which is fundamentally depends on a histological bias. In fact, the diagnostic accuracy of the various NITs proved to be lower than in the literature data [4]. The combination of APRI or FIB4 in more complex models or in measurements of liver stiffness allows for the compensation of this histological gap. Particularly, in identifying significant fibrosis the combinations of APRI and FIB4 with Fibro meter showed a very high PPV which can safely allow us to avoid LB, while in discriminant severe fibrosis (practically cirrhosis) both APRI and FIB4 combined with Fibro test showed an NPV that may have delayed surveillance for HCC. In this study, APRI increased the diagnostic ability of TE to identify significant fibrosis (from 64.55 % to 79.78 %), and both APRI and FIB4 to identify severe fibrosis (from 79.66 to 85.71 and to 87.83, respectively). Considering the relatively high cost of TE, Fibro test and Fibro meter, the diagnostic gain allows us to improve the cost/benefit ratio of these more complex tests. This study shows how the diagnostic performance of an expensive test can be improved by combining it with an inexpensive test. Thus, a synchronous evaluation provides a more reliable tool to distinguish the CHC patients in order to identify fibrosis staging, likely reducing LB in clinical practice.

Portal hypertension commonly accompanies liver cirrhosis, and development of oesophageal varices is among the major complications of portal hypertension. Patients with cirrhosis should be screened for the presence of oesophageal varices when portal hypertension is diagnosed. To reduce the increasing burden of endoscopy units, some studies have attempted to identify parameters for non-invasive prediction of the presence of oesophageal varices. We read with great interest the article by Giannini et al ( Gut 2003; 52 :1200–5). Besides the confirmation of proposed platelet count:spleen diameter ratio in predicting the presence of oesophageal varices in patients with liver cirrhosis, we introduced a new measurement for predicting oesophageal varices. Our preliminary study included 58 patients with cirrhosis who underwent a complete biochemical investigation, upper digestive endoscopy and ultrasonographic examination. Right liver lobe diameter:albumin ratio has been calculated and correlated with the presence and grade of oesophageal varices. All patients gave their written consent, …

SummaryBackground Helicobacter pylori treatment failure is becoming an emergent problem in clinical practice. Shorter treatment duration should improve compliance to therapy and keep an acceptable H. pylori eradication rate.Aims To evaluate the efficacy of two rabeprazole, high‐dose levofloxacin and tinidazole‐based regimens as ‘rescue’ treatment for H. pylori eradication in an open‐label, randomized, pilot study carried out in a clinical practice setting.Methods Eighty‐five consecutive patients who have previously failed at least one H. pylori eradication attempt were randomized to receive rabeprazole (20 mg, b.d.), levofloxacin (500 mg, b.d.) and tinidazole (500 mg, b.d.) either for 4 (4‐day RLT, n = 42) or 7 days (7‐day RLT, n = 43). Cure of H. pylori infection was assessed by means of 13C‐urea breath test.Results The 7‐day RLT achieved 84% (95% CI: 69–93%) and 86% (95% CI: 72–95%) eradication rates in intention‐to‐treat and per‐protocol analyses respectively. The shorter treatment obtained an 83% (95% CI: 69–93%) eradication rate in both intention‐to‐treat and per‐protocol analysis. Both regimens were well tolerated, although patients who received the 4‐day RLT reported fewer side‐effects.Conclusions In patients who have previously failed at least one H. pylori eradication attempt, both 4‐ and 7‐day rabeprazole, high‐dose levofloxacin, tinidazole‐based regimens are effective in curing the infection in more than 80% of patients.

Objective Noninvasive evaluation of fibrosis is an on-going effort in the management of chronic hepatitis C. This study was planned to noninvasively evaluate fibrosis staging.Design We evaluated the biochemical, functional [aminopyrine breath test (ABT)] and ultrasonographic variables of 75 chronic hepatitis C patients.Results Clinical [body mass index (BMI)], biochemical [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelets (PLT)] and ratio indexes, together with the ABT, showed a higher relationship with fibrosis: initial (score <= 2) versus evident (score > 2) fibrosis: BMI (24 +/- 2 vs. 26 +/- 2, P = 0.0007), AST (56 +/- 36 vs. 88 +/- 65, P = 0.0159), ALT (92 +/- 54 vs. 139 +/- 108, P = 0.0290), PLT (220 +/- 64 vs. 173 +/- 61, P = 0.0007), PLT/spleen diameter ratio (PLT/SPD) (2133 +/- 786 vs. 1540 +/- 681, P = 0.0003), AST/platelet count ratio index (APRI) (0.80 +/- 0.87 vs. 1.51 +/- 1.47, P = 0.0010), ABT%d/h30 min (10.8 +/- 4.5 vs. 7.6 +/- 3.8, P = 0.0007), ABT%d/cum120 min (8.9 +/- 3.3 vs. 6.5 +/- 3.1, P = 0.0007). Considering the differences between fibrosis score 2 and 3 patients, BMI, ABT and PLT/SPD ratio proved to be statistically significant. Multivariate stepwise analysis (with and without BMI) identified two models for distinguishing between initial and evident fibrosis: Model 1: -0.569 +(BMI x 0.107) + (APRI x 0.169)-(PLT/SPD x 0.304), and Model 2: 2.376 + (APRI x 0.152)-(ABTd/h30 x 0.043)-(PLT/SPD x 0.249). These models showed concordance in identifying or ruling out evident fibrosis in 76% and 78.7% of the patients respectively. The PLT/SPD ratio also showed 78.7% concordance with the histological score.Conclusions These results suggest that noninvasive evaluation of fibrosis in chronic hepatitis C may be considered an effective tool thanks to the use of an inexpensive, reproducible ratio index.

Background: To evaluate the relationship between hyaluronic acid/aminopyrine breath test (HA/ABT) ratio and fibrosis score in chronic hepatitis, and between HA/ABT and clinical staging (child-turcotte-pugh'score, CTP; and model for end stage liver disease, MELD) in cirrhosis, as well as to evaluate the aspartate aminotransferase (AST)/ABT in relation to the HA/ABT. Methods: We studied 48 patients with histologically proven chronic hepatitis C (CHC) and 35 patients with compensated cirrhosis (CIR). Results: HA/ABT and AST/ABT showed a more significant correlation with the fibrosis score than HA or ABT or AST alone in the 48 CHC patients: r=0.568 (P < 0.0001), r=0.610 (P < 0.0001), r=0.450 (P=0.0021), r=-0.449 (P=0.0021), and r=0.472(P=0.0012), respectively. Progressive liver damage (fibrosis 1-2 vs fibrosis 3-6 vs cirrhosis) was significantly (P < 0.05) reflected by both HA/ABT (mean +/- SEM: 4.0 +/- 0.9 vs 18.1 +/- 4.2 vs 149.9 +/- 33.1) and AST/ABT (6.3 +/- 1.8 vs 12.7 +/- 1.6 vs 42.1 +/- 14.6). A strong relationship was found between HA/ABT and AST/ABT (r=0.755 P < 0.0001). In cirrhotic patients, the most significant relationship was observed between HA/ABT and CTP r=0.483 and P=0.0049, and MELD r=0.523 and P=0.0023. Conclusion: Considering that HA levels in chronic hepatitis depend on the progressive impairment of sinusoidal endothelial cells (SEC), related to progressive fibrosis, HA/ABT ratio would seem to be the most specific reflection of progressive impairment of the SEC. AST/ABT could be used as a possible surrogate of HA in identifying SEC impairment in chronic hepatitis.

Background. Screening for oesophageal varices represents an important part of the diagnostic work-up of cirrhotic patients. We have previously shown that the platelet count/spleen diameter ratio is a parameter that can rule out the presence of oesophageal varices safely and in a cost-effective fashion.Aim. To evaluate the prognostic and diagnostic accuracy of the platelet count/spleen diameter ratio for ruling out the presence of oesophageal varices in the follow-up of a cohort of cirrhotic patients without oesophageal varices at inclusion.Methods. After initial endoscopy, the 106 cirrhotic patients without oesophageal varices who participated in our previous study were followed-up with annual or biannual surveillance endoscopy. Patients were censored at the time of diagnosis of oesophageal varices or at their last visit, and at that time platelet count and spleen diameter were recorded. Sixty-eight patients made up the study cohort after excluding patients who were lost to follow-up or died before undergoing control endoscopy.Results. During the follow-up, 27 patients (40%) developed oesophageal varices. Patients with higher baseline platelet count/spleen diameter ratios (p < 0.0001) as well as a ratio above 909 were less likely to develop oesophageal varices (p < 0.0005). At follow-up, a platelet count/spleen diameter ratio <= 909 had 100% negative predictive value and 84% efficiency in identifying the presence of oesophageal varices.Conclusions. The use of the platelet count/spleen diameter ratio proved to be an effective means for ruling out the presence of oesophageal varices even in the longitudinal follow-up of patients. (c) 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

BACKGROUND: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.AIM: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.METHODS: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.RESULTS: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%).CONCLUSIONS: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.

ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician.In this review we provide a guide to interpreting alterations to liver enzyme levels.The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed.Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

Patients with inflammatory bowel disease have a higher risk of developing colorectal cancer. The main risk factors for colorectal cancer are not suitable targets for therapeutic intervention, and primary chemoprevention is an intriguing therapeutic option. The analogies between acetyl-salycilic acid and 5-amino-salycilic acid, and the results obtained by using acetyl-salycilic acid as a chemopreventive agent in patients with sporadic colorectal cancer have prompted the study of potential chemopreventive effects of 5-amino-salycilic acid in inflammatory bowel disease. The results of both epidemiological and experimental studies have shown that long-term 5-amino-salycilic acid treatments appear to have a chemopreventive effect. The evidence for this effect is provided by retrospective and case-control studies whose results, however, do not reach the highest grades for evidence-based recommendations. Nevertheless, these results are supported by a series of experimental studies demonstrating the multiplicity of actions of 5-amino-salycilic acid. Although data regarding the chemopreventive effect of 5-amino-salycilic acid may not be rigorous enough to meet the criteria for the highest evidence-based medicine recommendations, we feel that the argument to wait until we have Grade A evidence is not necessarily rational in this case, because discontinuation of 5-amino-salycilic acid treatment to perform a randomised controlled trial would be unethical secondary to their proven efficacy for maintenance treatment.

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 C-13-aminopyrine breath test (C-13-ABT) and C-13-galactose breath test (C-13-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 C-13-GBT and C-13- ABT, and the results were expressed as a percentage of the administered dose of C-13 recovered per hour (%dose/h) and as the cumulative percentage of administered dose of C-13 recovered over time (%dose cumulative). Results were analyzed according to absence vs presence of cirrhosis. Results: On average, C-13-GBT %dose/h and %dose cumulative were decreased significantly in patients with compensated cirrhosis, and the same finding was observed for C-13-ABT results from 30 to 120 minutes. C-13-GBT %dose/h at 120 minutes had 71.4% sensitivity, 85.0% specificity, and 83.7% accuracy, whereas C-13-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 C-13-GBT and C-13-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 C-13-GBT and C-13-ABT are useful for the diagnosis of cirrhosis. Combination of the tests increases the diagnostic yield of each test alone.

BACKGROUNDLansoprazole (LAN) is a proton pump inhibitor drug (PPI) metabolized by the P-450 liver cytochrome (CYP-450) system. LAN is used in association with antimicrobial agents in Helicobacter pylori (HP) eradication therapy. The 13C-Aminopyrine breath test (ABT) is a non-invasive tool exploring liver CYP-450 metabolic activity. Since pharmacological interactions may occur during PPI administration, we attempted to evaluate possible interference with liver CYP-450 activity during HP eradication therapy.MATERIAL/METHODSFourteen HP positive patients received LAN (30 mg b.i.d.), clarithromycin (500 mg b.i.d.) and metronidazole (500 mg b.i.d.) for one week. Prior to therapy, and at day 8, each patient underwent 13C-ABT. The 13CO2 concentration in breath samples was measured every 15 minutes from t0 to t120. Results are expressed as cumulative percentage of the administered dose of 13C recovered over time (% 13C dose cum), and as a percentage of the administered dose of 13C recovered per hour (% l3C dose/h). Comparisons were carried out by the Wilcoxon test. Data are presented as mean +/- SD.RESULTSAt day 8, mean ABT was no different from baseline values, both considering % 13C dose cum and% 13C dose/h at each sampling time (e.g.,% 13C dose cum120 which is the most expressive value of the parameters taken into consideration, baseline vs day 8: 10.88 +/- 3.81 vs 10.13 +/- 3.57).CONCLUSIONSThese results show that LAN administration and the concomitant use of antimicrobial drugs during HP eradication therapy do not seem to be associated with significant modifications in liver CYP-450 activity.

The evaluation of the presence and degree of liver fibrosis in patients with chronic liver disease is a fundamental diagnostic and prognostic issue. This is mainly due to the repercussions of liver fibrosis on liver function, whose derangement, in turn, is mainly responsible for the negative events of advanced liver disease. 13C-Breath Tests ((13/14)C-BTs) for the study of liver function were developed more than twenty years ago in order to non-invasively assess residual liver function in patients with various degrees of liver fibrosis, from minimal stages up to liver cirrhosis. Sequential studies that were performed over the years using various 13C-BT substrates showed that increasing degrees of liver fibrosis are paralleled by concomitant modifications in 13C-BT results. The 13C-BT probes that reportedly obtained interesting results were aminopyrine, galactose, and more recently phenylalanine. As the knowledge in this field evolved, probes for the study of specific functions, such as the 13C-Octanoate Breath Test were sought. Analysis of the published studies would seem to show that 13C-BTs alone, or in combination may provide a non-invasive picture of the functional alterations secondary to liver fibrosis. Further studies are needed to evaluate the diagnostic yield of the 13C-BT in particular clinical situations, such as in patients with normal static parameters of liver function, or after therapy.