Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF).

Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It can have serious implications in terms of a patient's ability to perform complex tasks (for example driving), their earning capacity, their social and family roles. This guideline reviews current knowledge on HE definition, pathophysiology, diagnosis and treatment, both by general principles and by way of a summary of available drugs and treatment strategies. The quality of the published, pertinent evidence is graded, and practical recommendations are made. Where possible, these are placed within the Italian health service context, with reference to local diagnosis and management experience.

Qualitative and Quantitative Evaluation of Dietary Intake in Patients with Non-Alcoholic Steatohepatitis.

There are very few reports about the intake of nutrients for the development or progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to identify the dietary habits and the nutrient intake in patients with NASH, in comparison to chronic hepatitis C (HCV)-related patients. We prospectively evaluated the intake of macronutrients and micronutrients in 124 NAFLD and 162 HCV patients, compared to 2326 subjects as a control group. We noticed major differences in macro- and micronutrients intakes in NASH and HCV patients compared to controls. Proteins, carbohydrate (glucose, fructose, sucrose, maltose and amide), saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), folic acid, vitamin A and C (p < 0.0001), and thiamine (p < 0.0003) ingestion was found to be higher in patients with NASH, while total lipids, polyunsaturated fatty acid (PUFA), riboflavin and vitamin B6 daily intake were lower compared to controls (p < 0.0001). Similarly, NASH patients had significantly reduced carbohydrate intake (p < 0.0001) and an increased intake of calcium (p < 0.0001) compared to HCV positive patients. Finally, we showed in NASH males an increase in the intake of SFA, PUFA, soluble carbohydrates (p < 0.0001) and a decrease in the amount of fiber (p < 0.0001) compared to control males. In NASH female population, we showed an increase of daily total calories, SFA, MUFA, soluble carbohydrates, starch and vitamin D ingested (p < 0.0001) with a reduction of fibers and calcium (p < 0.0001) compared to control females. This study showed how NASH patients' diets, in both male and females, is affected by a profound alteration in macro- and micronutrients intake.

Gut microbiota and the liver.

Nowadays liver diseases represent one of major healthy problems in the world in terms of morbidity and mortality. The high prevalence of liver pathologies represents the key point to understand the necessity to identify the pathogenetic mechanisms that support these disorders in order to nurse them. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Gut microbiota is considered both as a promoting factor and as a potential therapeutic target of a large number of liver pathologies due to the connection between intestine and liver: the gut-liver axis. This connection influences absorption and deposition of nutrients into the liver, but also induces the activation of toll-like receptors due to the passage of pathogen-associated molecular patterns in the portal blood and therefore may start both the development of liver damage and its consequent progression to more advanced stages, including cirrhosis and hepatocarcinoma. The gut liver axis also includes the intestinal permeability (IP) degree. It is very variable and interconnected to several factors, most of them dependent from gut microbiota, that is the "lead" in the control of IP. This revue is aimed to report the more recent knowledges about gut microbiota and chronic liver disease, from liver steatosis to cirrhosis and its complications, including hepatocellular carcinoma. For these reasons, it could be useful to intervene, through suitable therapeutic approaches, on the interruption of mechanisms that underlie dysbiosis, IP increase, activation of liver inflammasome, hepatic stellate cells and hepatocarcinogenic processes in order to reduce the liver damage.

Endocan Serum Levels in Patients with Non-Alcoholic Fatty Liver Disease with or without Type 2 Diabetes Mellitus: A Pilot Study.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is emerging as an independent cardiovascular risk factor. Recently, Endocan has been studied as an early marker of endothelial dysfunction. Our aim was to evaluate Endocan serum levels in patients with NAFLD with or without type 2 diabetes mellitus. METHOD: We enrolled 56 patients: 19 with NAFLD and 37 with type 2 diabetes mellitus with or without NAFLD, and compared them to 25 healthy controls. Endocan serum level was measured by using the ELISA EndoMark assay. RESULTS: Endocan level was significantly higher in NAFLD subjects, compared to controls (1.23+/-1.51 vs 0.68+/-0.4 ng/mL; p=0.016). It was higher in patients with non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH) (1.12+/-1.11, 1.49+/-2.16 and 0.68+/-0.4 ng/ml vs controls, respectively), independently from presence of type 2 diabetes mellitus. The increase was more marked in patients with NASH and in those with NAFL versus controls (p=0.001 and p=0.004, respectively), but not statistically different between the two groups (p=0.448). Finally, we found a statistically relevant increase of this marker in diabetic NAFLD patients compared to those non diabetic (1.56+/-0.81 vs 0.72+/-0.58 ng/ml; p=0.01). CONCLUSION: We demonstrated an increased Endocan serum level in NAFLD patients, higher in those with type 2 diabetes mellitus and/or NASH because of an endothelial dysfunction in these pathologies.

Urotensin-II Receptor: A Double Identity Receptor Involved in Vasoconstriction and in the Development of Digestive Tract Cancers and other Tumors.

Urotensin II and Urotensin-II receptors are important molecular factors that regulate vasoconstriction and all the diseases that are linked to abnormalities in blood pressure regulation (i.e.: hypertension, kidney diseases, cirrhosis etc.). Recently, Urotensin II and its receptor have also been involved in metabolic syndrome, diabetes and schizophrenia. Recent strong findings suggest that Urotensin II and its receptor are involved in the onset and development of different epithelial cancers. Indeed, it was reported that cell growth, motility and invasion in human breast, bladder, prostate, colorectal and glioblastoma cancer cells were regulated by Urotensin II and Urotensin-II receptor axis. This axis also regulated focal adhesion kinase and small Guanosine-5'-triphosphate binding proteins that likely had a role in motility and invasion mediated by Urotensin-II receptor. Additionally, its expression on tumour tissues is variably associated to the prediction of the clinical outcome of the patients and it can be considered an alternative molecular marker to be used as prognostic factor in human cancers. In conclusion, a new weapon in the treatment of human cancers is highlighting a new scenario for the future.

Reactivation of hepatitis B virus in cancer patients treated with chemotherapy for solid tumors. Is the prophylaxis really required?

BACKGROUND: Reactivation of hepatitis B virus during cancer chemotherapy for non-hematological tumors is not fully clear. AIM: To evaluate the risk of hepatitis B virus reactivation in carriers of hepatitis B virus cancer patients treated with chemotherapy for solid tumors. METHODS: Two hundred sixty-seven patients with solid tumors were consecutively enrolled: 13 (4.8%) were hepatitis B s-antigen positive, of whom 6 were documented inactive carriers and 7 had chronic liver disease. Thirty-two patients (12%) were hepatitis B s-antigen negative/hepatitis B c-antibody positive. Hepatitis B virus inactive carriers were followed every 3 months by alanine aminotransferases, hepatitis B virus-DNA; whereas hepatitis B virus occult carriers were followed every 3 months by alanine aminotransferases and hepatitis B s-antigen. RESULTS: None of the 38 total patients with inactive or occult B infection who did not receive prophylaxis presented hepatitis B virus reactivation during the follow-up period. CONCLUSION: This study suggests that, in hepatitis B s-antigen negative patients who undergo chemotherapy for solid tumors, hepatitis B and c-antibody screening results are not relevant to clinical decision and can be avoided. Larger studies are needed to establish whether the risk of reactivation of HBV during chemotherapy is negligible in this subset of patients and they could not be monitored for HBV reactivation.

Epidemiology and Natural History of Alcoholic Liver Disease.

Alcohol represents the oldest substance of abuse known, existed at least as early as the Neolithic period. In the present era, almost half of the world's population consumes alcohol and it represents the third largest risk factor for disease and disability and the most prevalent cause of advanced liver disease worldwide. In fact, when alcohol consumption reaches "unsafe quantities" an Alcoholic Liver Disease (ALD) is very likely. ALD comprises a large spectrum of diseases, ranging from simple steatosis to steatohepatitis with fibrosis and cirrhosis. Alcohol related cirrhosis is responsible of almost 50% of all cirrhosis-related and 1% of all-cause deaths worldwide. Even if ALD and alcoholic cirrhosis represent a large part of liver diseases, to know exactly the global burden of these phenomena is very difficult. This is mostly due to diagnostic and nosological issues, being ALD represented by several types of diseases and the diagnosis very often based on voluntary questionnaires. Also the natural history of ALD is somewhat difficult to predict, since there is not a definite evolution between the various stages of the disease and, indeed, they may coexist in a single subject. In this brief review we will report on the global burden of ALD, the principal factors influencing its prevalence among populations and the different presentations of its natural history.

Alcoholic Hepatitis: Pathogenesis, Diagnosis and Treatment.

Alcohol represents the oldest substance of abuse known and Alcoholic Liver Disease (ALD) is the most common cause of chronic liver disease worldwide. The ALD includes a wide spectrum of injury and may lead progressively from simple steatosis to frank cirrhosis. The ALD diagnosis may be hard and it is mainly defined by the history of chronic alcohol intake, physical and laboratory abnormalities suggestive of liver disease. Abstinence is the cornerstone of ALD therapy. Although the burden on health of ALD is not negligible, in the last decades few therapeutic advances have been made. Because of the complex pathogenetic mechanisms, the therapy of ALD and especially of severe Alcoholic Hepatitis (AH), represents a thorny problem in the clinical practice. In severe forms of acute AH, some specific drug treatments, including glucorticoids or pentoxifylline, have been defined and are, at the moment, recommended by international guidelines. On the contrary, specific long-term treatments of ALD, aimed at stopping the progression of fibrosis, are not yet approved.

Postoperative Changes in Fecal Bacterial Communities and Fermentation Products in Obese Patients Undergoing Bilio-Intestinal Bypass.

We assessed the gut microbial ecology of 11 severely obese patients before and after bilio-intestinal bypass (BIB). Fecal samples were evaluated for microbial communities using 16S rDNA Illumina sequencing, real-time PCR targeting functional genes, and gas chromatography of short chain fatty acids (SCFAs). At 6 months after surgery, subjects exhibited significant improvements in metabolic markers (body weight, glucose, and lipid metabolism) compared with baseline. The fecal microbiota of post-surgery individuals was characterized by an overall decrease of bacterial diversity, with a significant reduction in Lachnospiraceae, Clostridiaceae, Ruminococcaceae, Eubacteriaceae, and Coriobacteriaceae. On the contrary, there were significant increases of genera Lactobacillus, Megasphaera, and Acidaminococcus and the family Enterobacteriaceae. The pH was decreased in fecal samples from patients after BIB and SCFA profiles were altered, with lower percentages of acetate and propionate and higher levels of valerate and hexanoate. Some changes in the bacterial populations were associated with variations in the patients' metabolic health parameters, namely Gemmiger and glucose, Lactobacillus and glucose, and Faecalibacterium and triglycerides. The results from this study of BIB patients furthers our understanding of the composition of gut microbiota and the functional changes that may be involved in improving obesity-related conditions following weight-loss surgery.

Alcoholic Liver Disease and Hepatitis C Chronic Infection.

Alcoholic and virus C hepatitis currently represent the main causes of chronic liver disease worldwide. Every year many people die and are subjected to complex hospitalization and medical assistance due to these pathologies. Alcoholic liver disease and hepatitis C virus chronic infection are often present in the same patient. These two pathologies sinergically act in determining the onset and progression of liver damage that, from the chronic hepatitis staging, may rapidly progress to fibrosis, cirrhosis and hepatocellular carcinoma. In this review we analysed physiopathological aspects and biomolecular interactions that relate ethanol and hepatitis C virus in determining liver damage; moreover we took into account the effect on the natural history of liver disease deriving from the co-presence of these pathologies. Therefore we paid particular attention to the ability of ethanol and hepatitis C virus to in inducing oxidative stress or lipid accumulation, and analyzed the basic mechanisms of fibrogenesis that both diseases have got, amplified by their co-presence in the same patient. Finally we paid attention to the oncogenetic mechanisms inducing hepatocellular carcinoma and variability of response to antiviral therapy that derives from alcohol abuse in a subject affected by C hepatitis.

Targeting gut-liver axis for the treatment of nonalcoholic steatohepatitis: translational and clinical evidence.

Nonalcoholic fatty liver disease (NAFLD) is widely emerging as the most prevalent liver disorder and is associated with increased risk of liver-related and cardiovascular mortality. Recent experimental and clinical studies have revealed the pivotal role played by the alteration of gut-liver axis in the onset of fatty liver and related metabolic disturbances. Gut-liver cross talk is implicated not only in the impairment of lipid and glucose homeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis, which characterize nonalcoholic steatohepatitis (NASH), the evolving form of NAFLD. The gut microbiota has been recognized as the key player in the gut-liver liaison and because of its complexity can act as a villain or a victim. Gut microbiota not only influences absorption and disposal of nutrients to the liver, but also conditions hepatic inflammation by supplying toll-like receptor ligands, which can stimulate liver cells to produce proinflammatory cytokines. Thus, the modification of intestinal bacterial flora by specific probiotics has been proposed as a therapeutic approach for the treatment of NASH. In this review, we summarized the evidence regarding the role of gut-liver axis in the pathogenesis of NASH and discussed the potential therapeutic role of gut microbiota modulation in the clinical setting.

Silybin-Phosphatidylcholine Complex Protects Human Gastric and Liver Cells from Oxidative Stress.

BACKGROUND/AIM: Silybin is the main component of silymarin with antioxidant, anti-inflammatory and cytoprotective actions. Our aim was to compare the effect of silybin used as single substance, silybin-phosphatidylcholine complex (SilPho), and derivatives of silybin (MannpSil, GalpSil, GlcpSil, LactpSil) on MKN28 and HepG2 cell viability and cell death, in vitro, after induction of oxidative stress. MATERIALS AND METHODS: Oxidative stress was induced by incubating HepG2 and MKN28 cells with xanthine oxidase in the presence of its substrate xanthine. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide assay. Determination of Malondialdehyde (MDA) in MKN28 cells was performed by high-performance liquid chromatography. Quantitative analysis of apoptotic cells was carried-out using annexin. RESULTS: SilPho and new silybin glycoconjugates did not affect cell viability, while silybin induced about 50% cell death in both MKN28 and in HepG2 cells. Pre-treatment of cells with silybin and new silybin glycoconjugates (before oxidative stress induction) did not affect cell viability, while SilPho had a protective effect. Exposure of MKN28 cells to oxidative stress caused a two-fold increase in cellular MDA concentration compared to untreated cells. Moreover, pre-treatment with SilPho, but not with silybin, significantly prevented oxidative stress-induced increase in cellular Malondialdehyde. Moreover, silybin induced apoptosis potentiated by oxidative stress, while SilPho did not induce any effect. Oxidative stress caused cell death primarily by necrosis, antagonized by SilPho. CONCLUSION: The protective effect of SilPho is partially due to inhibition of radical oxidative species.

Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism.

The HCV protease inhibitor telaprevir associated with peginterferon-alpha and ribavirin, was widely used in the recent past as standard treatment in HCV genotype-1 infected patients. Telaprevir improves the sustained virology response rates, but at the same time increases the frequency of adverse cutaneous reactions. However, mechanisms through which telaprevir induces cutaneous lesions are not yet defined. A 50-year-old woman, affected by HCV genotype 1b, was admitted to our Department for a telaprevir-related severe cutaneous eruptions, eight weeks after starting a triple therapy (telaprevir associated with Peginterferon-alpha and ribavirin). Mechanisms of cutaneous reactions were investigated by skin tests with non-irritating concentrations of telaprevir and by activating in vitro T lymphocyte with different concentrations. Immediate and delayed responses to skin testing were negative, but the drug-induced lymphocytes activation was significantly higher as compared to patient's baseline values and to parallel results obtained in three healthy subjects (p < 0.05). In conclusion, adverse cutaneous reactions of our patient were caused by a telaprevir-induced T-cell dependent immune mechanism.

Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma and Child-Pugh A or B cirrhosis.

Sorafenib confers a survival benefit for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) A liver cirrhosis. At present, limited data exists with regard to the safety and efficacy of sorafenib in treating CP-B HCC patients. The present study describes the use of sorafenib in patients with HCC and CP-A or -B cirrhosis. Clinical data was obtained from patients with HCC who were treated with sorafenib at the Department of Clinical and Experimental Medicine, Second University of Naples (Naples, Italy) and were analyzed retrospectively in terms of tumor response, tolerance and survival. The treatment outcomes were analyzed according to the respective CP status. The adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 3.0, and the tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.2. In total, 26 patients received sorafenib at 400 mg twice daily. The median age was 69 years (range, 58-81 years) and the ratio of males to females was 18:8. Overall, 15 patients were infected with the hepatitis C virus (HCV), eight with HBV and three were co-infected with HCV/HBV. In total, 20 (77%) patients presented with an underlying CP-A (CP-A5 and CP-A6) cirrhosis and six (23%) with CP-B (CP-B7). Previous treatments included surgery (n=4), transarterial chemoembolization (n=5) and percutaneous ethanol injection or radiofrequency interstitial thermal ablation (n=12). A partial response was observed in three patients (12%), a stable disease lasting at least 12 weeks in 13 patients (50%) and a progression of disease in 10 patients (38%). The median overall survival (OS) time was 7.4 months [95% confidence interval (CI), 3.2-11.6) and the median progression-free survival (PFS) time was 3.7 months (95% CI, 1.9-5.5). The median OS and PFS times differed between patients with CP-A and CP-B, with a trend (P=0.06) toward a worse outcome in those with CP-B, although this was not statistically significant. The CP-A and CP-B groups experienced a similar incidence in the majority of AEs. A reduction in dose was required in 59% of the patients. The CP-A5, CP-A6 and CP-B7 patients tolerated sorafenib similarly, and derived comparable clinical and survival benefits.

Focus on emerging drugs for the treatment of patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in Western countries and is increasingly being recognized in developing nations. Fatty liver disease encompasses a spectrum of hepatic pathology, ranging from simple steatosis to non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and end-stage liver disease. Moreover, NAFLD is often associated with other metabolic conditions, such as diabetes mellitus type 2, dyslipidemia and visceral obesity. The most recent guidelines suggest the management and treatment of patients with NAFLD considering both the liver disease and the associated metabolic co-morbidities. Diet and physical exercise are considered the first line of treatment for patients with NAFLD, but their results on therapeutic efficacy are often contrasting. Behavior therapy is necessary most of the time to achieve a sufficient result. Pharmacological therapy includes a wide variety of classes of molecules with different therapeutic targets and, often, little evidence supporting the real efficacy. Despite the abundance of clinical trials, NAFLD therapy remains a challenge for the scientific community, and there are no licensed therapies for NAFLD. Urgently, new pharmacological approaches are needed. Here, we will focus on the challenges facing actual therapeutic strategies and the most recent investigated molecules.

Non alcoholic fatty liver: epidemiology and natural history.

Non Alcoholic Fatty Liver Disease (NAFLD), defined as the presence of a significant amount of lipid accumulation in the liver (at least in 5% of hepatocytes), represents a challenging issue for the Hepatologists. NAFLD is not represented by a single entity, but rather by two different entities that have different natural history and evolution that range from simple fat accumulation in the liver (without any consequence), to necroinflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The reason of these differences has to be found in the host characteristics and associated risk factors. Globally, its prevalence among liver diseases, and in the general population, is rising in the recent years along with its associated conditions: obesity, insulin resistance, metabolic syndrome and diabetes. This increment, together with the reported clinical conditions, may be accounted for changes in dietary habits and the increase of sedentary lifestyle. Its diffusion seems to be pandemic, given that it is beginning to affect the populations in the developing world due to the spread of Western lifestyle. This is particularly worrying in young adults and children in what seems to have become the main cause of liver disease. Even if the real rate of global incidence of NAFLD are not known, its worldwide prevalence in general population is estimated to be 20-30% in Western Countries and 5-18% in Asia and it is increasing over time. In this review we will report on the global and regional prevalence of NAFLD, the principal risk factors and the natural history of its different presentations.

New silibinin glyco-conjugates: synthesis and evaluation of antioxidant properties.

New silibinin glyco-conjugates have been synthesized by efficient method and in short time. Exploiting our solution phase strategy, several structurally diverse silibinin glyco-conjugates (gluco, manno, galacto, and lacto-) were successfully realized in very good yields and in short time. In preliminary study to evaluate their antioxidant and neuroprotective activities new derivatives were subjected to DPPH free radical scavenging assay and the Xanthine oxidase (XO) inhibition models assay. Irrespective of the sugar moiety examined, new glyco-conjugates are more than 50 times water-soluble of silibinin. In the other hand they exhibit a radical scavenging activities slightly higher than to silibinin and XO inhibition at least as silibinin.

Skin Adverse Events During Dual and Triple Therapy for HCV-Related Cirrhosis.

INTRODUCTION: Dermatological adverse events are an existing concern during treatment of hepatitis C virus infection. Peginterferon/ribavirin treatment is associated with well-characterized dermatological lesions tending towards a uniform entity of dermatitis. New telaprevir- or boceprevir-based triple-therapy has led to significant improvements in sustained virological response rates, although associated with an increase in cutaneous adverse events compared peginterferon/ribavirin alone. CASE PRESENTATION: We report a case of a patient who discontinued telaprevir because of severe skin eruptions and who, during ribavirin and interferon treatment, after a period free of skin lesions, developed new dermatological lesions different than those experienced during telaprevir treatment. CONCLUSIONS: Several adverse effects are associated to anti-HCV drugs, hence appropriate skin care management and follow-up are very important. A careful anamnesis before the initiation of triple therapy is necessary to identify previous dermatological diseases that could increase skin adverse effects incidence.

Eradication of Helicobacter pylori infection: which regimen first?

Helicobacter pylori (H. pylori) is a well-known human pathogen that plays an essential role in the pathogenesis of chronic gastritis, peptic ulcer disease, and gastric malignancies. Although H. pylori is susceptible to several antimicrobials, this infection has proven challenging to cure because of the increasing prevalence of bacterial strains that are resistant to the most commonly used antimicrobials, particularly clarithromycin. An effective (i.e., > 90%) first-line therapy is mandatory for avoiding supplementary treatments and testing, and more importantly for preventing the development of secondary resistance. This study reviews the recent literature on first-line therapies for H. pylori. The eradication rates following standard triple therapy (a proton pump inhibitor plus amoxicillin and clarithromycin) for H. pylori infection are declining worldwide. Several first-line strategies have been proposed to increase the eradication rate, including extending the treatment duration to 14 d, the use of a four-drug regimen (bismuth-containing quadruple, sequential, and concomitant treatments), and the use of novel antibiotics, such as fluoroquinolones. However, the efficacy of these regimens is controversial. A first-line eradication regimen should be based on what works best in a defined geographical area and must take into account the prevalence of antimicrobial resistance in that region.