C. Loguercio

Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.

We report the evidence-based Italian Association for the Study of Liver guidelines for the appropriate diagnosis and management of patients with nonalcoholic fatty liver disease in clinical practice and its related research agenda. The prevalence of nonalcoholic fatty liver disease varies according to age, gender and ethnicity. In the general population, the prevalence of nonalcoholic fatty liver disease is about 25% and the incidence is of two new cases/100 people/year. 2-3% of individuals in the general population will suffer from nonalcoholic steatohepatitis. Uncomplicated steatosis will usually follow a benign course. Individuals with nonalcoholic steatohepatitis, however, have a reduced life expectancy, mainly owing to vascular diseases and liver-related causes. Moreover, steatosis has deleterious effects on the natural history of HCV infection. Nonalcoholic fatty liver disease is usually diagnosed in asymptomatic patients prompted by the occasional discovery of increased liver enzymes and/or of ultrasonographic steatosis. Medical history, complete physical examination, etiologic screening of liver injury, liver biochemistry tests, serum lipids and insulin sensitivity tests should be performed in every patient. Occult alcohol abuse should be ruled out. Ultrasonography is the first-line imaging technique. Liver biopsy, the gold standard in diagnosis and prognosis of nonalcoholic fatty liver disease, is an invasive procedure and its results will not influence treatment in most cases but will provide prognostic information. Assessment of fibrosis by composite scores, specific laboratory parameters and transient elastography might reduce the number of nonalcoholic fatty liver disease patients requiring liver biopsy. Dieting and physical training reinforced by behavioural therapy are associated with improved nonalcoholic fatty liver disease. Diabetes and the metabolic syndrome should be ruled out at timed intervals in nonalcoholic fatty liver disease. Nonalcoholic steatohepatitis patients should undergo periodic evaluation of cardiovascular risk and of advancement of their liver disease; those with nonalcoholic steatohepatitis-cirrhosis should be evaluated for early diagnosis of hepatocellular carcinoma.

Apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo

Background: Fresh fruit and vegetables exert multiple biological effects on the gastrointestinal mucosa. Aim: To assess whether apple extracts counteract oxidative or indomethacin induced damage to gastric epithelial cells in vitro and to rat gastric mucosa in vivo. Methods: Apple extracts were obtained from freeze dried apple flesh of the “Annurca” variety. Cell damage was induced by incubating MKN 28 cells with xanthine-xanthine oxidase or indomethacin and quantitated by MTT. In vivo gastric damage was induced by indomethacin 35 mg/kg. Intracellular antioxidant activity was determined using the (2,2′-azinobis (3-ethylbenzothiazolin-6-sulfonate) method. Malondialdehyde intracellular concentration, an index of lipid peroxidation, was determined by high pressure liquid chromatography with fluorometric detection. Results: (1) Apple extracts decreased xanthine-xanthine oxidase or indomethacin induced injury to gastric epithelial cells by 50%; (2) catechin or chlorogenic acid (the main phenolic components of apple extracts) were equally effective as apple extracts in preventing oxidative injury to gastric cells; and (3) apple extracts (i) caused a fourfold increase in intracellular antioxidant activity, (ii) prevented its decrease induced by xanthine-xanthine oxidase, (iii) counteracted xanthine-xanthine oxidase induced lipid peroxidation, and (iv) decreased indomethacin injury to the rat gastric mucosa by 40%. Conclusions: Apple extracts prevent exogenous damage to human gastric epithelial cells in vitro and to the rat gastric mucosa in vivo. This effect seems to be associated with the antioxidant activity of apple phenolic compounds. A diet rich in apple antioxidants might exert a beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species.

Gut microbiota and probiotics in chronic liver diseases

There is a strong relationship between liver and gut: the portal system receives blood from the gut, and intestinal blood content activates liver functions. The liver, in turn, affects intestinal functions through bile secretion into the intestinal lumen. 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. Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of complications of liver cirrhosis, such as infections, hepatic encephalopathy, spontaneous bacterial peritonitis, and renal failure. Probiotics have been suggested as a useful integrative treatment of different types of chronic liver damage, for their ability to augment intestinal barrier function and prevent bacterial translocation. This review summarizes the main literature findings about the relationships between gut microbiota and chronic liver disease, both in the pathogenesis and in the treatment by probiotics of the liver damage.

Glutathione prevents ethanol induced gastric mucosal damage and depletion of sulfhydryl compounds in humans.

Whether parenteral administration of reduced glutathione prevented ethanol induced damage to and depletion of sulfhydryl compounds in the human gastric mucosa was investigated. Ten healthy volunteers underwent endoscopy on three separate occasions. Gastric mucosal damage was induced by spraying 80% ethanol on to the gastric mucosa through the biopsy channel of the endoscope. The gastric mucosal score, total sulfhydryls, glutathione, and cysteine were evaluated in basal conditions and after ethanol administration with and without pretreatment with parenteral glutathione. Glutathione significantly decreased the extent of ethanol induced macroscopic injury to the mucosa of the gastric body and antrum. Glutathiones protective effect is associated with appreciable inhibition of ethanol induced depletion of gastric sulfhydryl compounds. This is the first report of protection against ethanol induced gastric mucosal damage by a sulfhydryl containing agent in humans.

Trace Elements and Chronic Liver Diseases

The relationships between chronic liver diseases and trace element (TE) contents are debated. Particularly, no defined data are available about the TE levels in viral liver disease patients with or without malnutrition. In this study we evaluated blood and plasma levels of various trace elements in patients with HCV-related chronic liver disease, at different stages of liver damage (8 patients with chronic hepatitis and 32 with liver cirrhosis) with or without malnutrition. We also studied 10 healthy volunteers as control group. We found that cirrhotic subjects had a significant decrease of blood levels of Zn and Se, independently on the nutritional status, whereas plasma levels of Fe were significantly reduced only in malnourished cirrhotic patients. Our data indicate that liver impairment is the main cause of the blood decrease of Se and Zn levels in patients with non alcoholic liver disease, whereas the malnutrition affects Fe levels only.

Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

BACKGROUND & AIMS Helicobacter pylori have become resistant to antimicrobial agents, reducing eradication rates. A 10-day sequential regimen that contains levofloxacin was efficient, safe, and cost saving in eradicating H pylori infection in an area with high prevalence of clarithromycin resistance. We performed a noninferiority randomized trial to determine whether a 5-day levofloxacin-containing quadruple concomitant regimen was as safe and effective as the 10-day sequential regimen in eradicating H pylori in previously untreated patients. METHODS We randomly assigned patients with H pylori infection to groups that were given 5 days of concomitant therapy (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, levofloxacin 500 mg twice daily, and tinidazole 500 mg twice daily; n = 90) or 10 days of sequential therapy (esomeprazole 40 mg twice daily, amoxicillin 1g twice daily for 5 days followed by esomeprazole 40 mg twice daily, levofloxacin 500 mg twice daily, and tinidazole 500 mg twice daily for 5 more days; n = 90). Antimicrobial resistance was assessed by the E-test. Efficacy, adverse events, and costs were determined. RESULTS Intention-to-treat analysis showed similar eradication rates for concomitant (92.2%; 95% confidence interval [CI], 84.0%-95.8%) and sequential therapies (93.3%; 95% CI, 86.9%-97.3%). Per-protocol eradication results were 96.5% (95% CI, 91%-99%) for concomitant therapy and 95.5% for sequential therapy (95% CI, 89.6%-98.5%). The differences between sequential and concomitant treatments were 1.1% in the intention-to-treat study (95% CI; -7.6% to 9.8%) and -1.0% in the per-protocol analysis (95% CI; -8.0% to 5.9%). The prevalence of antimicrobial resistance and incidence of adverse events were comparable between groups. Concomitant therapy cost

Clinical trial on the efficacy of a new symbiotic formulation, Flortec, in patients with irritable bowel syndrome: a multicenter, randomized study.

9 less than sequential therapy. CONCLUSIONS Five days of levofloxacin-containing quadruple concomitant therapy is as effective and safe, and less expensive, in eradicating H pylori infection than 10 days of levofloxacin-containing sequential therapy.

Incidence of altered glucose tolerance in liver cirrhosis

Objectives Efficacy of symbiotics in patients with irritable bowel syndrome (IBS) remains unknown. Methods Patients were randomized to a prebiotic (n=135), or a symbiotic formulation containing Lactobacillus paracasei B21060 (Flortec, n=132). Primary efficacy was the responder rate for pain and global relief of symptoms in the overall population and in patients with predominant diarrhea (n=47). Post hoc time-trend analyses for changes within each treatment were carried out. Results Patients with absent/mild pain amounted to 54.7% in the symbiotic group and to 57.4% in the prebiotic group at treatment week 4, and to 53.9% and 53.4% at the end of treatment. Patients with amelioration of well-being were, respectively, 60.7% versus 61.7% at treatment week 4, and 63.3% versus 60.9% at the end of treatment. Within each treatment group, patients with absent/mild pain increased in the Flortec and the prebiotic group, but time trend analyses were significant only for Flortec (P=0.019). In IBS-predominant diarrhea, Flortec significantly reduced bowel movements, pain, and IBS scores. Conclusions To improve pain and well-being, Flortec is encouraging in patients with diarrhea predominant IBS. To establish its efficacy for the majority of IBS patients, Flortec has to be compared with an inert placebo in future work.

Relationship of Blood Trace Elements to Liver Damage, Nutritional Status, and Oxidative Stress in Chronic Nonalcoholic Liver Disease

Even though the association between liver cirrhosis and glucose tolerance alterations has been well documented, no data are available on the incidence of this association. In this paper we firstly report the results of a 4-year prospective longitudinal study performed on well-compensated cirrhotic patients with a normal glucose tolerance, in order to evaluate the incidence of glucose tolerance alterations with respect to liver efficiency during the time. The incidence of a diabetic response to a standard OGTT was 4.4% after a 1-year and 21.2% after a 4-year follow-up in stable cirrhotics. These figures are significantly higher than in the general population of our country. This large incidence was even significantly higher in cirrhotics with worsening liver efficiency at the end of the study (35.3%, P < 0.0001). Sex, family history of diabetes, alcoholic aetiology of the cirrhosis, and increment of portal hypertension do not seem to have any significant influence on the frequency of altered glucose tolerance. Therefore, we propose that liver cirrhosis and its worsening play a primary role as diabetogenic risk factors.

Rifaximin in the treatment of hepatic encephalopathy.

Trace elements are involved in chronic liver diseases because these elements may have a direct hepatic toxicity or may be decreased as a consequence of the impaired liver function, particularly in patients with alcoholic cirrhosis and/or malnutrition. In this study, we determined plasma and erythrocytes trace elements in 50 inpatients with nonalcoholic chronic liver disease (11 with biopsy-proven chronic hepatitis, 39 with cirrhosis [16 in stage A according to Child-Pugh criteria, 23 Child B+C]), and in a control group of 10 healthy subjects by the proton induced x-ray emission method. The relationship between trace element concentration and the extent of liver damage, the nutritional status (by anthropometric evaluations), and various blood markers of oxidative stress—reduced glutathione, total lipoperoxides and malonyldialdehyde—was investigated. We found that cirrhotics had a significant decrease of Fe, Zn, Se, and GSH levels in the plasma and of GSH and Se in the erythrocytes with respect to the control and chronic hepatitis groups. GSH levels were related to the degree of liver damage; a significant direct correlation was observed among Se, Zn, and GSH plasma values and between GSH and Se in the erythrocytes. The trace element decrease was, on the contrary, independent of the degree of liver function impairment and only partially affected by the nutritional status. Data indicate that liver cirrhosis, even if not alcohol related, induces a decrease of Se and Zn and that, in these patients, an oxidative stress is present, as documented by the significant correlation between Se and GSH. The plasma Br level was higher in cirrhotics with respect to the control and chronic hepatitis groups.