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Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.

In the treatment of upper GI endoscopy-negative patients with heartburn and epigastric pain or burning, antacids, antireflux agents, and mucosal protective agents are widely used, alone or as add-on treatment, to increase response to proton-pump inhibitors, which are not indicated in infancy and pregnancy and account for significant cost expenditure. In this randomized, controlled, double-blind, double-dummy, multicenter trial assessing the efficacy and safety of mucosal protective agent Poliprotect (neoBianacid, Sansepolcro, Italy) vs omeprazole in the relief of heartburn and epigastric pain/burning, 275 endoscopy-negative outpatients were given a 4-week treatment with omeprazole (20 mg q.d.) or Poliprotect (5 times a day for the initial 2 weeks and on demand thereafter), followed by an open-label 4-week treatment period with Poliprotect on-demand. Gut microbiota change was assessed. A 2-week treatment with Poliprotect proved noninferior to omeprazole for symptom relief (between-group difference in the change in visual analog scale symptom score: [mean, 95% confidence interval] -5.4, -9.9 to -0.1; -6.2, -10.8 to -1.6; intention-to-treat and per-protocol populations, respectively). Poliprotect's benefit remained unaltered after shifting to on-demand intake, with no gut microbiota variation. The initial benefit of omeprazole was maintained against significantly higher use of rescue medicine sachets (mean, 95% confidence interval: Poliprotect 3.9, 2.8-5.0; omeprazole 8.2, 4.8-11.6) and associated with an increased abundance of oral cavity genera in the intestinal microbiota. No relevant adverse events were reported in either treatment arm. Poliprotect proved noninferior to standard-dose omeprazole in symptomatic patients with heartburn/epigastric burning without erosive esophagitis and gastroduodenal lesions. Gut microbiota was not affected by Poliprotect treatment. The study is registered in Clinicaltrial.gov (NCT03238534) and the EudraCT database (2015-005216-15).

The term porto-sinusoidal vascular disease (PSVD) has been recently proposed to replace the term idiopathic non-cirrhotic portal hypertension (INCPH) to describe patients with or without signs of portal hypertension and typical histological lesions involving the portal venules or sinusoids in the absence of cirrhosis. According to the new definition, the presence of known causes of liver disease as well as of portal vein thrombosis does not rule out PSVD. Therefore, the patients in whom the diagnosis of PSVD is possible are much more than the patients strictly fulfilling the diagnostic criteria for INCPH. In this setting, the clinical challenge for the hepatologist is to identify patients at risk of developing PSVD and to indicate liver biopsy to confirm the diagnosis. We describe some possible scenarios in which PSVD should always be suspected, and we provide some tools useful to reach the diagnosis of PSVD. Keywords: porto-sinusoidal vascular liver disease, idiopathic non-cirrhotic portal hypertension, portal vein thrombosis, portal hypertension

Background Hepatic encephalopathy (HE) is considered reversible regarding mental status but may not be cognitively in single-center studies. Aim To evaluate persistence of learning impairment in prior HE compared to those who never experienced HE (no-HE) in a multicenter study. Methods A total of 174 outpatient cirrhotics from three centers (94 Virginia, 30 Ohio, and 50 Rome; 36 prior HE) underwent psychometric hepatic encephalopathy score (PHES) and inhibitory control (ICT) testing at baseline and then at least 7 days apart. ICT learning (change in 2nd half lures compared to 1st half) was compared between patient groups at both visits. Change in the PHES individual sub-tests and total score between visits was compared in both groups. US versus Italian trends were also analyzed. Results HE patients had worse PHES and ICT results compared to no-HE patients at baseline. Significant improvement (1st half 7.1 vs. 2nd half 6.2, p  < 0.0001) was observed in no-HE, but not in HE (1st half 7.9 vs. 2nd half 7.8, p  = 0.1) at baseline. At retesting (median 20 days later), no-HE patients continued with significant learning (1st half 6.0 vs. 2nd half 5.4, p  < 0.0001), while HE patients again did not improve (1st half 7.8 vs. 2nd half 6.9, p  = 0.37). Between visits, no-HE patients improved significantly on four PHES sub-tests and overall score, while HE patients only improved on two sub-tests with similar overall PHES score. Trends were similar between US and Italian subjects. Conclusion In this multicenter study, prior HE patients showed persistent significant learning impairment compared to those without prior HE, despite adequate medical therapy. This persistent change should increase efforts to reduce the first HE episode.

Portal hypertensive gastropathy is a potential cause of bleeding in patients with liver cirrhosis. Studies on its natural history have often included patients submitted to endoscopic or pharmacological treatment for portal hypertension. A total of 222 cirrhotic patients with mild degree of portal hypertension (i.e., with no or small varices at entry, without previous gastrointestinal bleeding and medical, endoscopic, or angiographic treatment) were followed up with upper endoscopy every 12 months for 47 +/- 28 months. Upon enrollment 48 patients presented portal hypertensive gastropathy (43 mild and 5 severe) and the presence of esophageal varices was the only independent predictor of the presence of this gastric lesion at multivariate analysis. The incidence of portal hypertensive gastropathy was 3.0% (1.1-4.9%) at 1 yr and 24% (18.1-29.9%) at 3 yr, while the progression was 3% (1-6.9%) at 1 yr and 14% (4.2-23.8%) at 3 yr. The presence of esophageal varices and the Child-Pugh class B or C at enrollment were predictive of the incidence of portal hypertensive gastropathy, while only Child-Pugh class B or C was correlated with the progression from mild to severe, at multivariate analysis. During follow-up 16 patients bled from portal hypertensive gastropathy (9 acutely and 7 chronically) and one patient died of exsanguination from this lesion. The natural history of portal hypertensive gastropathy is significantly influenced by the severity of liver disease and severity of portal hypertension. Acute bleeding from portal hypertensive gastropathy is infrequent but may be severe.

Oral glutamine challenge is a method to increase blood ammonia and may be used to study the ammonia lowering effect of drugs potentially useful in hepatic encephalopathy (HE). We tested its influence on the psychometric performance of 18 cirrhotic patients without HE. Twelve nonencephalopatic cirrhotic patients were studied before and after glutamine load (20 g in 100 mL tap water) and six patients before and after placebo (100 mL tap water) by using the Number Connection Test (NCT), the Covert Visual Attention Orienting Test (CVAOT), and the Scan Test (SCT). Blood ammonia increased significantly after glutamine (from 79 +/- 34 to 211 +/- 66 microg/dL) but not after placebo (from 94 +/- 41 to 88 +/- 26). No difference in the NCT was found before and after glutamine load or placebo. The CVAOT was similar after glutamine challenge and placebo, nor any interaction between Loads (glutamine or placebo) x Cue position was found, suggesting that glutamine load did not influence attention-orienting. SCT results were also similar after glutamine and placebo, suggesting a lack of influence on the working memory. Glutamine challenge is a safe method to induce hyperammonemia in nonencephalopatic cirrhotic patients and, therefore, to study the efficacy of ammonia lowering treatments.

Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (-37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days ( <0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (€345.61 vs €252.23; +37%). Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting.

Objectives: To compare whole body and regional (arms, legs and trunk) fat mass, fat-free mineral-free mass, bone mineral content and bone mineral density, measured by DXA, in cirrhotic patients and age, sex and BMI matched healthy volunteers. Design: Cross-sectional study. Setting: Two medical research institutions. Subjects: Twenty-two non ascitic cirrhotic patients and 16 age, sex and BMI matched healthy volunteers. Interventions: The Lunar DPX whole-body X-ray densitometer with Lunar software version 3.6z (Lunar Radiation Corp., Madison WI, USA) was used. Regional analysis was performed on the arms, legs, trunk and head. Results: Compared to controls, cirrhotic patients showed a significant reduction in percentage body fat. When differentiated by gender, however, the reduction in percentage body fat was evident in female cirrhotics only, particularly in the trunk. In male cirrhotic patients fat-free mineral-free mass was reduced in absolute terms in the whole body and the limbs. For both genders and in each body segment bone mineral content and density were reduced in cirrhotics compared to controls. In cirrhotic patients bone mineral density was significantly correlated to both fat-free, mineral-free mass (r=0.85; P <0.001) and to the Physical Activity Index (r=0.52; P <0.0l). Conclusions: Two different patterns of soft tissue loss may be found in cirrhotic patients: in women lean tissue is maintained while fat stores are reduced, as in early starvation; in men lean tissue is reduced, as seen under conditions of stress. Moreover, factors influencing lean body mass, such as nutritional depletion and physical inactivity, may contribute to the reduction of bone density frequently observed in cirrhotic patients.

Polytetrafluoroethylene (PTFE)-covered stent grafts appear to have the potential to improve TIPS patency, but data available are few and controversial. The aim of this prospective nonrandomized trial was to assess TIPS safety and 1-yr patency with a new commercially available PTFE-covered stent graft in comparison with a group of historical controls treated with conventional stents. Between July 1992 and December 1999, 87 consecutive cirrhotics underwent TIPS with conventional stents, while from January 2000 to November 2001, 32 consecutive cirrhotics were treated with PTFE-covered stent grafts. All patients were followed by the same medical team according to a prospective protocol for a diagnostic work-up and a surveillance strategy. The two groups were comparable for age, sex, etiology, and severity of cirrhosis. The 1-yr probability of remaining free of shunt dysfunction tended to be higher in the covered stent group: 76.3% (95% CI = 58.7-93.9%) versus 57.5% (95% CI = 46.6-68.4%); log rank test: p = 0.055. However, stenoses inside the stent were significantly higher in patients with bare stents (88% vs 17%), while stenoses at the hepatic or portal vein were more frequent in PTFE-covered stent-graft group (50% vs 9% and 33% vs 3%, respectively), (chi2 = 15.42; df = 2.0; p = 0.0004). Stenoses inside the covered portion of the stent did not occur. One-year cumulative rebleeding, encephalopathy, and survival were similar. PTFE-covered stents are able to solve pseudointimal hyperplasia within the stent tract, but have a high incidence of hepatic or portal vein stenosis. Improvements in stent design and insertion techniques are necessary to fully achieve the potential benefit of this new device.

Polymorphonuclear (PMN) cell count in ascitic fluid is the most useful test for the diagnosis of spontaneous bacterial peritonitis (SBP). We evaluated the validity of an automated blood cell counter for the PMN determination in ascitic fluid by comparing it with the traditional hematologic method with a light microscope in a manual counting chamber. A total of 130 ascitic fluid samples were collected from 74 consecutive cirrhotics. The agreement between the two techniques was assessed according to Bland and Altman's method. The sensitivity, specificity, and positive and negative predictive values of the automated blood cell counter were calculated by considering the diagnosis of SBP as a PMN count ≥ 250 cells/mm 3, determined by the manual method as the “gold standard.” The mean PMN counts assessed by the manual method and the automated blood cell counter were 124 ± 301 cells/mm 3 and 130 ± 339 cells/mm 3, respectively ( p = 0.89, ns). The mean ± SD of the difference between manual and automated measurements was 6 ± 61 cells/mm 3, whereas the limits of agreement were +127 cells/mm 3 (95% CI = +108 to +147) and −115 cells/mm 3 (95%CI = −96 to −135). SBP was diagnosed in 11 patients. All but one were correctly identified with the automated blood cell counter, with a sensitivity of 94% and a specificity of 100%; positive and negative predictive values were 100% and 99.1%, respectively. The manual method and the automated blood cell counter have a good agreement in the PMN determination in ascitic fluid, and the automated blood cell counter is a reliable tool for rapid diagnosis of SBP.