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Bio composites as nacre show outstanding mechanical properties which surpasses those of their single constituents. This is due to their complex structure, in which the small building blocks of the hard component are embedded in a softer matrix, thus combining strength and toughness. This combination makes such materials interesting for various applications, e.g. for tooth replacement materials but also for industrial structural materials. Therefore, the interest is to develop scalable processes for the production of artificial composites. In this work a Nano Spray Dryer is used to produce polymer-encapsulated magnetite particles from a magnetite-polymer-suspension. A Design of Experiment study is conducted which identified the suspension composition as the major influencing factor on the product properties. The particles are then warm-compacted and the composite pellets are examined for their mechanical properties and structure. With this method composites with bending strength of 91.2 MPa and Young's modulus of 9.2 GPa were produced.

Background: PEG (percutaneous endoscopic gastrostomy) is a well established endoscopic procedure for enteral feeding. However, patients with a shorter life expectancy will not benefit from PEG tube placement. Furthermore, some specific evolving diseases will never benefit from PEG. The aim of the study focuses on short and long term mortality rates after PEG tube placement in a referral gastroenterology centre (Geneva University Hospital). 219 patients were enrolled in this study. Patients and methods: All patients scheduled for a PEG procedure between January 2011 and December 2014 were included. Nine patient parameters were collected for further analysis as well as the main underlying disease requiring PEG tube placement. Patients were subsequently divided into 4 groups according to underlying disease: Group 1) swallowing disorders of neurologic origin; Group 2) swallowing disorders associated with upper digestive tract neoplasia ; Group 3) nutritional support for a non GI reason ; Group 4) Other. Results: 219 patients had undergone a PEG tube placement. 33 patients died within 60 days after the procedure. After one year, 71 patients died. Global survival was 870 days. The nutritional support group had the better survival rate with 1276 days compared to the swallowing groups and others. The multivariate analysis has highlighted the underlying disease as the only associated parameter with short and long term mortality. Conclusions: PEG tube placement is associated with high short and long term mortality depending on the underlying disease. We outlined the potential role of PEG tube insertion as a supportive transient approach for nutritional support.

BACKGROUND Refractory ascites (RA) is a frequent complication of cirrhosis, requiring large volume paracentesis or placement of a transjugular intrahepatic portosystemic shunt (TIPSS). The automated low-flow ascites pump (alfapump, Sequana Medical AG, Zurich, Switzerland) is an innovative treatment option for patients with RA. AIM To assess safety and efficacy of this treatment in patients with a contraindication to TIPSS. METHODS Fifty-six patients (43 males; mean age 62 years) from centres in Germany, Switzerland, UK and Spain were included and followed for up to 24 months. Complications, device deficiencies, paracentesis frequency and patient survival were recorded. RESULTS At the time of this analysis, 3 patients completed the 24-month observation period, monitoring of 3 was ongoing, 9 underwent liver transplantation, 17 patients were withdrawn due to serious adverse events and 23 patients died. Most frequently observed technical complication was blocking of the peritoneal catheter. Twenty-three pump-related reinterventions (17 patients) and 12 pump exchanges (11 patients) were required during follow-up. The pump system was explanted in 48% of patients (in 17 patients due to serious adverse events, in 9 at the time of liver transplantation and in 1 due to recovery from RA). Median frequency of paracentesis dropped from 2.17 to 0.17 per month. CONCLUSIONS The alfapump can expand therapeutic options for cirrhotic patients with RA. Continuous drainage of ascites in a closed loop automated system led to significant reduction in paracentesis frequency. Technical and procedural improvements are required to reduce the rate of adverse events and reinterventions. https://clinicaltrials.gov/ct2/show/NCT01532427.

The beneficial effects of the use of albumin, either alone or combines with other treat- ments, have been demonstrated in patients with various complications of cirrhosis. Therefore, albumin should be administred in patients with spontaneous bacterial peritonitis in association with antibiotics, and in association with terlipressin in patients with type 1 hepatorenal syndrome. Albumin use reduces the occurrence of paracentesis-related circulatory dysfunction, in patients with large ascites undergoing paracentesis. So far, the beneficial effect of albumin has not been demonstrated, neither for infections other than spontaneous bacterial peritonitis nor for hepatic encephalopathy. This article provides an overview of the data evaluating the effects of albumin in patients with cirrhosis.

Both the general theory of crime andcriminal culture theories offer manyexpectations and assumptions regarding thecauses of crime and the characteristics ofoffenders. The former asserts that crimeis associated with low self-control. Thelatter, that cultural norms developthat are criminogenic. This paperchallenged three assumptions of thosetheories by examining 481 fraudoffenders. Results demonstrated: (1)individuals higher in the occupationalhierarchy are more likely to commit fraud, (2) offenders are more likely to operatealone and (3) when accomplices areinvolved, they are less likely to beinternal to the institution. The firstfinding contradicts the general theory ofcrime, whilst the second and thirdcontradicts criminal culture theories. Ourfindings suggest that a unitary theory maynot be able to account for such offences. The implications of this study may helpinfluence policing and policy regarding theway in which fraud is approached andunderstood.

Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

Regenerative medicine aims to replace a body function or specific cell loss. It includes therapies at the forefront of modem medicine, issuing from translational biomedical research. Transplantation of organs and cells has revolutionized the management of patients for whom medical treatment is a failure. Unfortunately, organ shortage is limiting treatment possibility. As an example, among the 15,000 patients with type I diabetes in Switzerland, only approximately 30 can receive a pancreas or an islet transplant per year. Second example, 500 patients die each year in Switzerland from alcoholic cirrhosis because no treatment is available. Transplantation of islet cells, hepatocytes, mesenchymal stem cells or dopaminergic neurons represents hope fora therapy available for large populations of patients.

A method for measurement of subdermal fat thickness in dairy cows by digitizing cross-sections of ultrasonic scans was investigated. A commercial ultrasonic system was modified for acquiring and presenting A-mode and B-mode ultrasonic images. Two sites were selected for a series of successive measurements: one was on the flat area of the rear of the rump between the pin bone and the tail head; the other was between 12th and 13th ribs, below the back rump. Several points were measured in each site. Two probe holders were fabricated to fit each site and to ensure successive measurements at exactly the same points. A 7.5-MHz probe was used. Both A and B scans were conducted and recorded on videotape. A computer program was written to acquire and digitize data from A-mode scans to a depth of 30 mm. An algorithm located signal peaks to distinguish among skin, subdermal fat and muscle, and then calculated thickness of layers at each point. A trial was conducted to evaluate the use of this system to detect body condition changes of the dairy cow during lactation. Six cows were monitored and measured from calving to late lactation: subdermal fat was ultrasonically measured weekly, and cows were scored weekly for body condition and weighed daily. It was concluded that successful ultrasonic measurements for body condition assessment, to detect energy balance changes, depend on accurate and reliable standardization of measurements, at a responsive site. The between-ribs site was more responsive, and a single point (usually just below the spine) provided sufficient data for the required purpose. Given the conditions described, the system can measure quantitatively changes of subdermal fat thickness in lactating dairy cows.

Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.

Ascites becomes refractory to medical treatment in nearly 10% of cirrhotic patients, who then require repeated large-volume paracentesis. In this prospective study we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 30 patients with refractory ascites. TIPS was successful in all and resulted in a 54% reduction in portacaval gradient (from 22.8 +/- 0.8 to 10.4 +/- 0.6 mm Hg). Ascites became easily controlled with diuretics in 26 patients following TIPS. Ascites recurrence associated with shunt stenosis was observed during follow-up in eight patients; revision could be undertaken in five of them and resulted in good control of ascites. In responders, a marked decrease in plasma aldosterone and renin activity, a reduction in serum creatinine, and a rise in urinary sodium excretion were observed. Creatinine and inulin clearances improved significantly; PAH clearance remained unchanged. However, new-onset or worsening hepatic encephalopathy was seen in 14 patients. Severe disabling chronic encephalopathy occurred in five patients; it could be reversed successfully by balloon occlusion of the shunt in three. The cumulative survival rate was 41 and 34% at 1 and 2 years, respectively. In summary, TIPS can control refractory ascites in a majority of patients but is associated with a high rate of chronic disabling HE. In addition, the survival rate is poor. Randomized trials are needed to evaluate the exact role of TIPS in the management of refractory ascites. It is unlikely to improve survival but can ameliorate quality of life in nontransplant candidates and be useful as a bridge to transplantation, in particular, to improve denutrition associated with longstanding tense ascites.

Liver tests abnormalities during pregnancy should encourage the clinician to seek liver diseases of pregnancy. The liver diseases of pregnancy are those proper to pregnancy including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, all the "hypertensive" related diseases and acute fatty liver of pregnancy. These pathologies can involve the vital prognosis of the mother and the child. An adequate management reduces maternal-fetal complications. Close monitoring of pregnancy with sometimes induction of labour and verification of the normalization of liver tests after childbirth are essential.

Background/Aims: Endothelin-1 (ET-1) is a potent vasoconstrictor that may be involved in the pathogenesis of splanchnic and renal hemodynamic changes associated with portal hypertension. The aim of this study was to measure the concentration of ET-1 and of its precursor Big endothelin-1 (Big ET-1) in the systemic circulation as well as in the splanchnic and renal venous beds and to evaluate changes after the relief of portal hypertension following transjugular intraheptic portosystemic shunt placement. Methods: Plasma concentrations of ET-1 and of Big ET-1 were measured in the vena cava, renal vein, hepatic vein and portal vein in ten patients with cirrhosis and refractory ascites before and 1–2 months after transjugular intrahepatic portosystemic shunt. The porto-caval gradient, creatinine clearance, plasma aldosterone and renin activity, as well as daily urinary sodium excretion were measured at the same time. Results: The plasma concentration of ET-1 and Big ET-1, respectively, in peripheral blood of normal volunteers were 0.28±03 and 3.95±0.34 pg/ml; the concentrations of both peptides were higher in patients with cirrhosis, both in vena cava (0.61±0.14 and 10.01±1.47 pg/ml), hepatic vein (0.62±0.13 and 13.93±1.77 pg/ml), portal vein (1.21±0.12 and 17.84±1.98 pg/ml) and renal vein (0.76±0.12 and 14.21±1.55 pg/ml). Moreover ET-1 and Big ET-1 concentrations were more elevated in the portal vein that in the vena cava (+98% and +70%) and slightly higher in the renal vein as compared to the vena cava (+25% and +42%). After transjugular intrahepatic portosystemic shunt, a rise in creatinine clearance and urinary sodium excretion (+49%; and +53%) was observed together with a marked reduction in plasma aldosterone and renin activity (−59% and −49%). ET-1 and Big ET-1 concentrations remained unchanged in the vena cava whereas a significant reduction of ET-1 and Big ET-1 occured both in the portal vein (−43% and − 44%) and in the renal vein (−53% and −29%). Portal vein and renal vein concentrations of both peptides became similar to vena cava levels. Conclusions: Splanchnic and renal hemodynamic changes occurring in patients with cirrhosis and refractory ascites could be related to the production of ET-1 by splanchnic and renal vascular beds. This was abolished by transjugular intrahepatic portosystemic shunt, which could explain the exacerbation of systemic vasodilation and the improvement in renal perfusion observed after the procedure.

Increasing evidence suggests that manganese deposition is responsible for the T1-weighted magnetic resonance imaging (MRI) signal hyperintensity consistently observed in pallidum of cirrhotic patients. However, the relationship between blood manganese and the etiology or severity of liver disease, as well as the neurological symptomatology in these patients, has not been well established. In the present study, blood manganese concentrations were measured by atomic absorption spectrometry together with MRI and neurological evaluation in 57 cirrhotic patients with various etiologies and severity of liver disease. Blood manganese concentrations were elevated in 67% of cirrhotic patients and were significantly higher in patients with previous portacaval anastomoses or transjugular intrahepatic portosystemic shunt (TIPS). Pallidal signal hyperintensity was observed in 88% of patients, and significant correlations were demonstrated between blood manganese and pallidal index (PI) (a measure of pallidal signal hyperintensity), as well as Child-Pugh score. Assessment of extrapyramidal symptoms using the Columbia rating scale revealed a significant incidence of tremor, rigidity, or akinesia in up to 89% of cirrhotic patients. However, there was no significant correlation between blood manganese and extrapyramidal symptoms, although severity of akinesia was significantly greater in Child-Pugh C patients. Extrapyramidal symptoms could result from a toxic effect of manganese on basal ganglia dopaminergic function. These findings further support a role for manganese in the etiology of pallidal MRI signal hyperintensity in patients with chronic liver disease.

Concentrations of zinc, copper and manganese were measured by atomic absorption spectrometry in samples of globus pallidus obtained at autopsy from 9 patients with chronic liver disease and an equal number of age-matched controls. Manganese concentrations were significantly increased several fold (p < 0.01) in globus pallidus of liver disease patients accompanied by smaller but significant 2-fold increases of copper. Zinc concentrations, on the other hand, were within normal limits. Increased pallidal manganese offers a cogent explanation for the observed T1-weighted MRI signal hyperintensity in pallidum of cirrhotic patients. Increased copper content in brain suggests the existence of common pathophysiologic mechanisms in inherited (Wilson Disease) and acquired hepatocerebral disorders.

The liver plays a key role in coagulation as all clotting factors except for factor VIII are synthetized by hepatocytes. In cirrhotic patients, there is a decrease of clotting factors and a thrombocytopenia. Those parameters usually modify routine coagulation tests and may suggest that cirrhotic patients are at a higher risk of bleeding. However, studies have shown that these patients are rather at risk for thrombosis. The reason is a concomitant decrease of coagulation inhibitors factors that is not detected in routine laboratory coagulation tests. The coagulation system in cirrhotic patient is a balance of pro and anti-coagulants. This balance may be affected by co-factors such as renal failure or infection. Artificial correction of laboratory values by transfusion of blood products may be rather deleterious (e.g. volume overload, TRALI).

Two antenna stations were designed, installed in the return alleys of the milking parlor of the University of Illinois dairy farm, and tested over a three-month period to automatically identify cows passing through the alleys after each milking. This article describes the design procedure and lab tests conducted to obtain a sensor antenna installation which would detect each working transponder automatically on cows passing through the station in the return alleys. The system was specifically designed for integrating with electronic scales for automatic acquisition of body weights as cows exited the milking parlor.

A scale for automatically weighing dairy cows was developed and tested. The scale consists of a weigh bridge supported by two load bars placed in the return alley of a milking parlor. When a cow walks over the weigh bridge, each load bar generates an analog signal. A summing amplifier combines the signals. An ADC-1 data acquisition device digitizes and transmits the amplifier output to the serial port of a computer. A program written in C records the cow’s weight and identification number. At the end of milking, another program processes the recorded raw data and computes the measured weight of each cow detected.

Cirrhotic cardiomyopathy is defined as structural and functional cardiac abnormalities occurring in patients with cirrhosis, in the absence of any other associated cardiac disease. Its main clinical features include systolic and diastolic dysfunctions, and electrophysiological changes. Cirrhotic cardiomyopathy is generally clinically latent and is unmasked when the patient is exposed to major physiological stress or after some procedures, thus leading to an overt cardiac failure. Pathogenic mechanisms include impaired beta-adrenergic receptor signal transduction and increased activity of cardio-depressor pathways. A certain reversibility has been shown in the medium-long term after a liver transplantation. This article proposes to review the physiopathological mechanisms underlying these abnormalities, their clinical impacts, and the management options.

Both alcoholic and non-alcoholic steatohepatitis share common histological findings and the risk of developing cirrhosis. Liver biopsy is required for the diagnosis, and the aim of treatment is to prevent cirrhosis. In alcoholic steatohepatitis, abstinence from alcohol is associated to prednisone in a severe form, as defined by a Maddrey's score32. Due to common pathogenic mechanisms, we recommend that coexisting metabolic alterations that are commonly observed in non-alcoholic steatohepatitis should also be treated in alcoholics. Thus, weight reduction, physical exercise, improvement of insulin sensitivity and reduction of oxidative stress, all may be beneficial both in alcoholic and non-alcoholic steatohepatitis.

Alcoholic steatohepatitis includes steatosis, inflammatory changes and hepatocellular damage. In severe form, jaundice and hepatic failure persist for several weeks, while non severe alcoholic steatohepatitis may follow an insidious course towards cirrhosis. Except for alcohol consumption, nonalcoholic steatohepatitis shares histological features and pathogenic mechanisms with alcoholic steatohepatitis, and is associated to the development of cirrhosis over time. Thus, given the increasing epidemics of the metabolic syndrome in industrialized countries, it is likely that alcoholic cirrhosis has been overdiagnosed in the past years. Obesity, insulin resistance and the oxidative stress including iron-mediated oxidative stress are involved both in alcoholic and non-alcoholic steatohepatitis.

S11.1 IMPACT OF ALCOHOL DRINKING ON THE PROGRESSION AND TREATMENT OF CHRONIC HEPATITIS C AND B {#article-title-2} In chronic hepatitis C, male gender, older age, excessive alcohol consumption, immunosuppressive regimen, and HIV infection are independent risk factors of hospitalization. It is important to outline that alcohol abuse and HCV (and to a lesser extent HBV) frequently coexist in the same patient. Several studies have shown increased rate of fibrosis progression and development of cirrhosis in drinking HCV subjects compared with nondrinking HCV subjects. The structure of the interaction between lifetime daily alcohol intake and HCV is additive for consumption between 50 g to 125g /day and multiplicative for consumption above 125 g/day. It seems that alcohol increases apoptosis, lipid peroxidation and oxidant stress. Chronic alcohol intake is linked to a decreased therapeutic response to interferon, which may be corrected by alcohol withdrawal. Nevertheless, large data are still needed to assess HCV treatment efficacy in heavy drinkers. Although less data are available as compared to HCV infection, alcohol consumption also impacts fibrosis progression in chronic hepatitis B and blunts the risk of hepatocellular carcinoma. In terms of treatment, the potential negative impact of chronic alcohol consumption seems more likely to be related to a poor compliance rather than to a decrease in antiviral activity of oral drugs. Thus, patients with chronic hepatitis B and C should be advised to stop or at least to reduce alcohol consumption. # S11.2 DRUGS IN ALCOHOL ABUSERS: A POTENTIAL THERAPEUTIC MISADVENTURE {#article-title-3} It is generally accepted that drugs should be used with extreme caution in patients with chronic liver disease, due to alterations in xenobiotic metabolism, or interference with hemodynamic compensatory mechanisms (NSAIDs and renal failure for example). In addition to the commonly reported adverse events associated with drugs, patients with alcohol misuse should be considered at increased risk of drug-induced liver injury. The reasons for this include, 1) an overinduction of the cytochrome P-450 2E1 (involved in alcohol metabolism as well as other xenobiotics), with the risk of increased production of toxic metabolites and consecutive decreased glutathion reserve, 2) a decreased antioxidants stores (glutathion, vitamins), favoured by chronic alcohol and a poor nutritional status, and 3) the presence of a compensated or decompensated underlying alcoholic liver disease. Accordingly, hepatic steatosis (macro- or microvesicular), almost always associated with excessive alcohol consumption, increases the sensitivity of the liver to additional injury. Alcoholic steatohepatitis that frequently arises in a patient with underlying cirrhosis may not be clinically evident in mild to moderate presentations. Thus, a number of commonly prescribed drugs may either potentiate liver injury and therefore influence the natural history of alcoholic liver disease, or precipitate an acute episode in these patients with alcohol abuse. NSAIDs may induce microvesicular steatosis, and double the risk of gastrointestinal bleeding in the alcoholic patient. The risk of paracetamol hepatotoxicity, probably overestimated in the past, is increased by starvation and poor nutritional status. In the absence of such conditions, a daily dose of 2 grams can be given. Drugs that mimic alcoholic lesions (amiodarone, tamoxifen, diltiazem, nifedipine) should not be administered. The risk of fibrosis progression and cirrhosis described with the antirheumatic agent methotrexate is associated with the regular use of alcohol, as well as the cumulative dose. However, in the absence of liver fibrosis, methotrexate can be prescribed to patients with regular alcohol consumption using provided that non-invasive markers are used for monitoring. Overall, drug prescription in patients with alcohol abuse should be carefully evaluated with regards to indication, absolute contraindication, and risks. Liver function tests, non-invasive markers of fibrosis and liver biopsy should be used to detect drug-induced liver injury. # S11.3 THE OBESE ALCOHOLIC: NASH/ASH INTERACTIONS {#article-title-4} The strict separation between alcoholic and non-alcoholic liver fatty liver disease (NAFLD) is increasingly recognized as deceitful. In fact, a large number of individuals presenting with excessive alcohol consumption, have significant metabolic risk factors, such as obesity, diabetes, dyslipidemia, and hypertension. On the other hand, patients with metabolic risk factors often have concomitant alcohol consumption, that although modest may be a significant co-factor in progression of the disease. In fact, according to a population-based study of Health in Pomerania, it was found a broad overlap between obesity and excessive alcohol consumption (Volzke, WJG, 2012). Furthermore, both entities have similar histopathological patterns. Several years ago, we showed that the clinical and biochemical presentation of a group of ambulatory (stable) alcoholic hepatitis patients was very similar to that of non-alcoholic steatohepatitis patients (Pinto, DDS, 1996), and also found that survival was similar in that particular subset of patients (Cortez-Pinto, DDS, 2003). The interaction of metabolic risk factors and alcohol consumption was demonstrated in several studies. Ecksted et al. have shown in a group of 71 NAFLD patients, that heavy episodic drinking associated with a marked increase on the probability of fibrosis progression after a median follow-up of 12.3 years (Ecksted et al, Scand J Gastro, 2009). Also, in a population –based study, of about 10000 individuals, with a mean follow-up of about 30 years, that the interaction of raised BMI and alcohol consumption had a supra-additive effect, demonstrating clearly the synergistic effect of alcohol and increased BMI on causing liver disease (Hart, BMJ, 2010). It was also shown in a group of NASH patients, that any alcohol consumption markedly increased the risk of hepatocellular carcinoma (Ascha et al, Hepatology, 2010). In summary, fatty-liver disease is a disease of multiple causes, where management has to be individualized, based on the specific risk factors of each patient. # S11.4 HEPATOCELLULAR CARCINOMA IN ALCOHOLIC CIRRHOSIS: ROLE OF HOST-ENVIRONMENT INTERACTIONS {#article-title-5} The incidence of hepatocellular carcinoma (HCC) is rising with alcoholic cirrhosis as a major risk factor. While the causal role of alcohol in the development of liver cirrhosis is undisputed, its modulating impact in hepatocarcinogenesis is just emerging. HCC develops in 1-2% of cirrhotics per year whereas only a small fraction of HCC cases develop in non-cirrhotic alcoholic patients emphasizing cirrhosis as a priming condition. Among the mechanisms leading to HCC are interactions between dietary or environmental carcinogens ingested along with alcohol. Alcohol induces cytochrome P450 2E1 (CYP2E1) leading to activation of several procarcinogens, including nitrosamines. Induced CYP2E1 produces toxic and mutagenic acetaldehyde and results in increased oxidative stress with subsequent lipid peroxidation. The second enzyme system by which alcohol is metabolized is alcohol dehydrogenase (ADH), and genetic variation of ADH1B and ADH1C genes code for enzymes with altered activities. An association between the more active ADH1C*1-allele and alcohol-associated malignancies, including HCC, was demonstrated. Furthermore, alcohol interacts with methyl group transfer and thus causes impaired hepatic detoxification capacity by reducing glutathione, and altered methylation of oncogenes and tumor suppressor genes. Heavy alcohol consumption reduces hepatic retinoic acid levels causing enhanced cell proliferation and malignant transformation. Genetic studies identified a variation within the gene coding for PNPLA3 as a significant risk factor for developing alcoholic cirrhosis. Carriage of PNPLA3 variant rs738409 is particularly frequent in alcoholic cirrhotics with HCC. Functionally, variant PNPLA3 rs738409 codes for an enzyme leading to increased lipogenesis supporting the lipotoxicity hypothesis underlying HCC evolution.

Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

We report the case of a 32-year-old man with a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland associated with Sjogren syndrome. He underwent an upper endoscopy as part of the screening of a gastric localization which showed a diffuse non-specific gastritis. However, endoscopic ultrasonography (EUS) evidenced a focal wall thickening of the vertical portion of the smaller curvature. EUS-guided biopsies of this area disclosed a MALT lymphoma, whereas biopsies under endoscopy concluded to mild chronic gastritis. The search for Helicobacter pylori infection remained negative. Four months after treatment with anti-CD20 antibodies, EUS showed a diminution of the abnormal thickening of the second layer. Regression was confirmed histologically on new EUS-guided biopsies. MALT lymphoma is usually considered a localized disease; however, dissemination is probably more frequent than initially believed. Our case reflects the importance of a systematic screening for a gastric localization in patients with MALT lymphoma of the salivary glands. In this situation, association to autoimmune disease such as Sjogren syndrome is more likely to explain the gastric location than infection with H. pylori. Endoscopic ultrasonography has a major impact for the staging of gastric MALT lymphoma, but may also help diagnose focal infiltration by the disease.

Microvesicular steatosis is a potentially severe manifestation of valproic acid hepatotoxicity due to an acquired impairment of mitochondrial function. Tests currently used to investigate mitochondrial fonction are cumbersome and cannot be used routinely. We report on a noninvasive breath test using [13C]methionine for estimation of mitochondrial function in a case of pure severe valproic acid overdose-induced microvesicular changes. The initially abnormal breath test improved together with the recovery of liver failure. In conclusion, this observation suggests that the [13C]methionine breath test may provide a noninvasive estimate of hepatic mitochondrial function in vivo.

To identify factors associated with liver steatosis in chronic hepatitis C.Occurrence and severity of liver steatosis in 254 chronic hepatitis C patients were compared with presence of alcohol abuse, body mass index (BMI)26, history of intravenous drug addiction and hepatitis C virus (HCV) genotype. Steatosis was found in 109 (43%) patients. The occurrence of steatosis was significantly associated with ongoing alcohol abuse (P=0.03) or HCV genotype 3 (P= 0.003), but not with BMI26. A moderate to severe steatosis was present in 60% of patients infected with HCV genotype 3, irrespective of the presence of alcohol abuse, BMI26 or history of intravenous drug addiction. Using a multivariable stepwise logistic regression analysis, infection with genotype 3 had an odds ratio (OR) of 10 (95% confidence interval (CI)=4.56-22) for a liver steatosis, whereas the presence of a cirrhosis at histology had an OR=0.256 (95% CI=0.07-0.92).A moderate to severe degree of steatosis of the liver is a morphological sign suggestive of infection with HCV genotype 3, independent of other risk factors of a fatty liver, but it may disappear at late stages of the disease.

The clinical features of peritonitis are usually absent in cirrhotic patients with an ascitic fluid infection, raising the interest for specific biological markers of inflammation.We prospectively measured the plasma and ascitic fluid levels of procalcitonin, an innovative infection parameter, interleukin-6, and C-reactive protein in 20 cirrhotics with or without spontaneous bacterial peritonitis. The patient's condition was followed-up for 12 weeks after paracentesis.None of the 10 patients with spontaneous bacterial peritonitis presented with severe systemic signs of infection. Procalcitonin level in plasma, but not in ascites, was significantly higher in patients with spontaneous bacterial peritonitis compared to controls (0.74 +/- 0.6 vs. 0.2 +/- 0.1 ng/mL, P0.05). Interleukin-6 levels in ascites were similar between groups. C-reactive protein concentrations were higher both in plasma and in ascitic fluid in patients with spontaneous bacterial peritonitis compared to controls (85.3 +/- 63 vs. 18.6 +/- 19 mg/dL, 24.6 +/- 25 vs. 4.5 +/- 4 mg/dL, P0.05, respectively). Three patients with spontaneous bacterial peritonitis died, but the outcome was not related to the concentrations of biological markers.In spontaneous bacterial peritonitis, procalcitonin measurement is not an accurate diagnostic test, possibly due to the absence of systemic inflammatory response syndrome in this condition. In addition, the diagnostic value of C-reactive protein is limited by the wide overlap between values.

Color Doppler EUS (CD-EUS) allows minimally invasive measurement of azygos blood flow (AzBF) in portal hypertension, but further validation of the method is needed. Because a limited number of patients has been studied, the acute hemodynamic effects of somatostatin and octreotide on AzBF and gastric mucosal perfusion are poorly defined in portal hypertension.A double-blind hemodynamic study was designed to assess rapid changes in AzBF over a 60-minute period after intravenous administration of somatostatin, octreotide, and placebo in 30 stable patients with biopsy-proven cirrhosis. AzBF was measured by using both CD-EUS and the invasive thermal dilution technique in the first 10 patients (phase 1). Then, with CD-EUS alone, the hemodynamic study was extended to a further 20 patients (phase 2). In addition, gastric mucosal perfusion changes were assessed by using laser Doppler flowmetry at endoscopy.In phase 1, the 2 methods for AzBF measurement showed significant correlations both for baseline values (r = 0.685) and for AzBF changes over 60 minutes after drug administration (r = 0.733). In phase 2, a reduction was observed in AzBF 10 minutes after octreotide or somatostatin administration (-47% and -23%, p0.0001 vs. placebo, p = 0.058 vs. placebo, respectively). After 60 minutes of somatostatin infusion, AzBF increased 27% over placebo values (p0.04). Gastric mucosal perfusion was transiently reduced 5 minutes after octreotide or somatostatin (-21% and -32%, respectively, p0.02 vs. placebo).This is the first study to validate CD-EUS AzBF measurement with reference to the invasive thermodilution technique in cirrhosis. It confirmed the transient effects of somatostatin and octreotide on both AzBF and gastric mucosal perfusion. In addition, a significant rebound phenomenon after 60 minutes of continuous intravenous somatostatin infusion was observed.

Severe cases of pseudomembranous colitis (PMC) may be associated with intraperitoneal fluid accumulation. However, the characteristics of the liquid are seldom described. Specifically, neutrocytic ascites has only been reported once. We report a case of a severe PMC complicated by a highly neutrocytic ascites which remained culture-negative. We discuss the possible mechanisms leading to ascites formation in this condition and review ascitic fluid characteristics in patients with PMC.

Transjugular intrahepatic portosystemic shunt (TIPS) is used increasingly as a treatment for refractory ascites. The aim of the present study was to determine the prognostic value of different parameters in predicting a favorable evolution following TIPS in a cohort of 53 cirrhotic patients without organic renal disease and with refractory ascites.Patients were classified as good responders if they survived more than 6 months, without severe chronic hepatic encephalopathy and with good control of ascites. The prognostic value for a good outcome was evaluated using age, creatinine clearance, plasma renin activity, plasma aldosterone, and Pugh score.Good control of ascites was obtained in 90%. The cumulative survival rate was 54% at 6 months, 48% at 1 yr, and 39% at 2 yr. The vast majority of patients died of complications of hepatic insufficiency. Severe chronic hepatic encephalopathy developed in 26%. Overall, a good clinical response was observed in 47%. Creatinine clearance was identified as the only pre-TIPS factor to be significantly and independently associated with a good clinical response to TIPS for refractory ascites. A good clinical response was observed in 57% of patients with a creatinine clearance36 ml/min compared to 9% of those with a clearance36 ml/min (p0.01). This cutoff point in creatinine clearance had a sensitivity of 96% and a specificity of 36%; positive predictive and negative predictive values were 57% and 90%, respectively.TIPS might be useful for the treatment of refractory ascites in cirrhotic patients without severe renal function impairment. However, the TIPS usefulness still has to be demonstrated compared to large volume paracentesis or Leveen shunt. In patients with poor renal function or with liver failure after TIPS, liver transplantation should be considered.

BACKGROUNDPortal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) are increasingly recognised as separate entities. The pathogenic role of portal hypertension for the development of GAVE is still controversial.AIMSTo evaluate the effects of portal decompression on chronic bleeding related to GAVE in cirrhotic patients.METHODSEight patients with cirrhosis and chronic blood loss related to GAVE were included. GAVE was defined endoscopically and histologically.RESULTSAll patients had severe portal hypertension (mean portocaval gradient (PCG) 26 mm Hg) and chronic low grade bleeding. Seven patients underwent transjugular intrahepatic portosystemic shunt (TIPS) and one had an end to side portacaval shunt. Rebleeding occurred in seven patients. In these, TIPS was found to be occluded after 15 days in one patient; in the other six, the shunt was patent and the PCG was below 12 mm Hg in five. In the responder, PCG was 16 mm Hg. Antrectomy was performed in four non-responders; surgery was uneventful, and they did not rebleed after surgery, but two died 11 and 30 days postoperatively from multiorgan failure. In one patient, TIPS did not control GAVE related bleeding despite a notable decrease in PCG. This patient underwent liver transplantation 14 months after TIPS; two months after transplantation, bleeding had stopped and the endoscopic appearance of the antrum had normalised.CONCLUSIONSResults suggest that GAVE is not directly related to portal hypertension, but is influenced by the presence of liver dysfunction. Antrectomy is a therapeutic option when chronic bleeding becomes a significant problem but carries a risk of postoperative mortality.

Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.

Introduction Les troubles du sommeil, chez les cirrhotiques sont ameliores par certains anti-histaminergiques. Les effets neuropsychologiques de l’hydroxyzine, un anti-histaminergique H1 chez le cirrhotique sont mal connus. Objectifs S’assurer de l’absence de deterioration cognitive chez les patients avec cirrhose qui recoivent un anti- histaminique H1, l’hydroxyzine dans le but de retablir un rythme circadien physiologique. Methodes Trente-cinq patients cirrhotiques avec encephalopathie hepatique minime et sommeil fragmente, non deprimes, durablement abstinent d’alcool et sans traitement de psychotropes ont ete randomises en double aveugle sur une periode de 18 mois. Un bras (n = 15) a recu 25 mg/jour d’hydroxyzine, un autre (n = 18) le placebo. Une evaluation neuropsychologique, orientee sur les fonctions executives (fluence, Trail making), l’attention (code et D2) et la memoire (Buschke 16 items) a ete effectuee avant et apres traitement. Resultats Il n’y avait pas de correlation entre la severite des troubles du sommeil et des troubles cognitifs avant traitement. Tous les patients, sous hydroxyzine, ont ameliore tant subjectivement qu’objectivement leur sommeil. La moyenne de Z-score des differents tests ne montrent aucune modification (placebo t = 1.6, t2 = 1.76 ; hydroxyzine t1 = 1,2, t2 = 1,15 ; ANOVA, F (1,28) = 0,38, p = 0,54). Les moyennes de chaque test sont egalement stables. Un patient, sous hydroxyzine, a aggrave de maniere reversible son encephalopathie. Discussion Ces resultats montrent une stabilite des performances cognitives, chez les cirrhotiques avec encephalopathie hepatique sous hydroxyzine comme sous placebo, alors que cet antihistaminique H1 ameliore selectivement la rythmicite nycthemerale. L’amelioration du sommeil se fait independamment de l’evolution des performances cognitives. Conclusion Contrairement a certains autres antihistaminiques, l’hydroxyzine n’aggrave pas les fonctions cognitives et peut etre utilisee chez les patients cirrhotiques avec encephalopathie hepatique minime, avec la surveillance d’usage.

Ascites becomes refractory to medical treatment in nearly 10% of cirrhotic patients, who then require repeated large-volume paracentesis. In this prospective study we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 30 patients with refractory ascites. TIPS was successful in all and resulted in a 54% reduction in portacaval gradient (from 22.8 +/- 0.8 to 10.4 +/- 0.6 mm Hg). Ascites became easily controlled with diuretics in 26 patients following TIPS. Ascites recurrence associated with shunt stenosis was observed during follow-up in eight patients; revision could be undertaken in five of them and resulted in good control of ascites. In responders, a marked decrease in plasma aldosterone and renin activity, a reduction in serum creatinine, and a rise in urinary sodium excretion were observed. Creatinine and inulin clearances improved significantly; PAH clearance remained unchanged. However, new-onset or worsening hepatic encephalopathy was seen in 14 patients. Severe disabling chronic encephalopathy occurred in five patients; it could be reversed successfully by balloon occlusion of the shunt in three. The cumulative survival rate was 41 and 34% at 1 and 2 years, respectively. In summary, TIPS can control refractory ascites in a majority of patients but is associated with a high rate of chronic disabling HE. In addition, the survival rate is poor. Randomized trials are needed to evaluate the exact role of TIPS in the management of refractory ascites. It is unlikely to improve survival but can ameliorate quality of life in nontransplant candidates and be useful as a bridge to transplantation, in particular, to improve denutrition associated with longstanding tense ascites.