Cyclic treatment of chronic hepatic encephalopathy with rifaximin. Results of a double-blind clinical study.

BACKGROUND: Chronic hepatic encephalopathy (HE) represents a frequent and serious complication of chronic liver disease. Aim of the study is to comparatively evaluate the effect of rifaximin, lactitol and their combination in treating chronic HE. METHODS: Forty out-patients (29 males, 11 females, mean age: 59 years, range 40-70), with viral liver cirrhosis and chronic HE (1st-2nd degree) were studied. HE was assessed by considering: mental state, asterixis, number connection test (NCT), arterial blood ammonia levels. Patients were randomly assigned to the following treatments: rifaximin (plus sorbitol as placebo) (group R); lactitol (group L); rifaximin plus lactitol (group RL). All treatments were continued for 15 days for 3 cycles, intervalled by 15 days of washout. RESULTS: The 3 treatments reduced HE, but with different efficacy: patients of group R and RL significantly (p<0.05) documented a faster improvement in HE degree, a higher percentage of patients which normalized mental state and NCT, a faster improvement of asterixis and a longer persistence of normal ammonia levels than patients of group L. CONCLUSIONS: Rifaximin in combination with lactitol or sorbitol represents an effective and safe treatment of chronic HE.

Non-alcoholic fatty liver disease in an area of southern Italy: main clinical, histological, and pathophysiological aspects.

BACKGROUND/AIMS: Studies on non-alcoholic fatty liver disease (NAFLD) have included chronic liver damage attributed to various causes. Our investigation was held to observe the main clinical, histological, and pathophysiological aspects of NAFLD in patients not exposed to any known cause of chronic liver disease. METHODS: We evaluated, in 84 in-patients (male/female, 66/18; median age, 36 years), the clinical and biochemical characteristics of NAFLD, and particularly its association with diabetes, dyslipidemia, hyperinsulinemia and/or with the increase of parameters of oxidative stress (blood levels of malonyldialdehyde, 4-hydroxynonenal and total plasma antioxidant capacity). RESULTS: Ninety percent of patients had an increased body mass index (BMI), 35% had dyslipidemia, 40% had sub-clinical diabetes (only 3% had overt diabetes), 60% had hyperinsulinemia, and more than 90% had enhanced levels of lipid peroxidation markers. In 48 patients who had consented to liver biopsy, we found: 14 with simple steatosis, 32 with steatohepatitis, and two with cirrhosis. CONCLUSIONS: Our data indicate that in our country, NAFLD may occur in young males with an increased BMI, with or without hyperinsulinemia, dyslipidemia and diabetes, generally associated with disorders of redox status, and that it may be differentiated from steatosis to steatohepatitis or cirrhosis only with a liver biopsy.

Relationship of blood trace elements to liver damage, nutritional status, and oxidative stress in chronic nonalcoholic liver disease.

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.

Can dietary intake influence plasma levels of amino acids in liver cirrhosis?

BACKGROUND: Modifications in plasma amino acid patterns in cirrhotics are attributed to impaired liver function, being more evident in alcoholic than in viral cirrhosis. AIM: To evaluate whether diet influences plasma amino acid concentrations in different aetiological groups of cirrhotics. PATIENTS: Study population comprised 40 patients with cirrhosis (25 virus- and 15 alcohol-related], all Child A, and 30 healthy subjects (controls). METHOD: A food frequency and quality questionnaire was utilized to determine dietary history and alcohol intake. Nutritional status was evaluated by anthropometric method. Amino acids were determined, on venous blood samples, using a specific analyzer while cysteine was evaluated by fluorescent high power liquid chromatography RESULTS: The total daily intake of calories, proteins, lipids, and carbohydrates was similar in all individuals. Food quality distinguished the cirrhotics from the controls, but not the different aetiological groups of cirrhotics. Plasma cysteine levels were significantly lower, while aromatic amino acids and methionine were significantly higher, in all cirrhotics (p<0.001 and p<0.01, respectively, versus controls). The decrease in cysteine and the increase in other amino acids were more marked in alcoholics (p<0.01). CONCLUSIONS: Ethanol intake, but not diet, further enhances the changes in plasma aromatic amino acids, methionine and cysteine induced by impaired liver function in patients with cirrhosis, suggesting a direct interference of alcohol in their metabolism.

Ethanol consumption, amino acid and glutathione blood levels in patients with and without chronic liver disease.

BACKGROUND: Ethanol abuse and liver cirrhosis cause a reduction of glutathione blood levels; liver cirrhosis induces an alteration of the plasma amino acid pattern. We evaluated whether or not ethanol abuse affects amino acid levels, particularly those that are involved in metabolizing glutathione in the plasma and erythrocytes of chronic alcohol abusers with or without liver cirrhosis. METHODS: We studied 10 chronic alcohol abusers without liver cirrhosis, 10 with alcoholic cirrhosis, 10 affected by hepatitis C virus-related cirrhosis, and 10 healthy subjects. Glutathione, y-glutamyl-cysteine, and cysteine were determined by fluorescent HPLC, glutamic acid, glycine, and other free amino acids by cation exchange chromatography both in the plasma and erythrocytes of all studied subjects. RESULTS AND CONCLUSIONS: In both alcoholics and cirrhotics, we found a significant increase of plasma-aromatic amino acid and methionine levels, whereas glutathione was significantly reduced. The erythrocytes of these patients showed a significant increase of cysteine, glutamic acid, and glycine; gamma-glutamylcysteine was normal; and glutathione and other free amino acids were significantly decreased. Data suggest that, independent of liver cirrhosis, ethanol abuse affects the metabolism of amino acids and glutathione in both the plasma and the erythrocytes.

Determination of plasma alpha-glutathione-S-transferases in chronic alcohol abusers: relationship with alcohol intake and liver involvement.

UNLABELLED: Alpha-gluthathione-S-transferases (alpha-GSTs) are enzymes involved in the cellular detoxifying processes; elevated circulating alpha-GSTs activity is considered to be an early index of liver damage. Glutathione (GSH) is the substrate for alpha-GST action. THE AIMS OF OUR STUDY WERE: (1) to evaluate plasma GSH levels and alpha-GST activity in chronic alcohol abusers with or without liver cirrhosis; (2) to define the relationship between these two biochemical parameters; (3) to establish their clinical relevance in patients with alcohol abuse and/or liver damage. We studied 69 subjects (18 healthy subjects and 51 chronic alcohol abusers: 29 without liver cirrhosis and 22 with). Plasma alpha-GST activity was determined on baseline samples and every following day for a total of 10 days in five alcoholics by HEPKIT (Alpha-Biotech, Biotrin International, Dublin, Ireland). GSH was determined on all subjects' baseline samples by fluorescent high-performance liquid chromatography. Alcohol intake was evaluated in all patients by determining blood-alcohol concentrations. Significant increases in plasma alpha-GSTs were observed in 9/29 (31%) alcoholics and 3/22 (13.6%) cirrhotics irrespective of their alcohol intake. GSH was significantly lower than normal values (P < 0.001) in all alcoholics with or without cirrhosis (controls 10.4 +/- 4.8; alcoholics without cirrhosis 3.9 +/- 1.4; alcoholics with cirrhosis 3.3 +/- 1.6). No correlation was observed between plasma alpha-GST and GSH levels. Our data indicate that: (1) alpha-GST activity does not correlate with GSH levels in the plasma; (2) alpha-GSTs do not have clinical relevance as markers of recent alcohol intake; (3) in cirrhotics, alpha-GST does not provide more information than other liver function tests. However, plasma alpha-GST determination may be useful in selecting a subgroup of alcoholics in whom routine biochemical markers of liver damage are within reference ranges.

Free radicals and not acetaldehyde influence the circulating levels of glutathione after acute or chronic alcohol abuse: in vivo and in vitro studies.

BACKGROUND: The oxidation of ethanol and acetaldehyde enhances the production of various free radicals involved in membrane lipoperoxidation, and decreases glutathione levels. AIMS: We evaluated the effects of acute and chronic ethanol use in vivo, with or without the administration of S-adenosyl-methionine (SAME, 2 g I.v.), and the effects of ethanol and acetaldehyde in vitro, on the erythrocyte levels of malonyldialdehyde and glutathione, and of its principal synthesizing enzymes, gamma-glutamyl-cysteine-synthetase and glutathione-synthetase. METHODS: Twelve healthy volunteers (age range 26-44 years, median 32 years) and 20 chronic alcohol abusers without liver disease (age range 26-57 years, median 44 years) were studied. Malonyldialdehyde was evaluated by thiobarbituric acid; glutathione and its enzymes by high performance liquid chromatography using a fluorescent detector. RESULTS: In the healthy subjects, an acute load of ethanol induced a significant decrease in plasma levels of glutathione, which was inhibited by the infusion of S-adenosyl-methionine. In the erythrocytes of alcoholic patients, glutathione and glutathione-synthetase were decreased while malonyldialdehyde was increased. In vitro, acetaldehyde did not affect either the glutathione or the glutathione-related enzyme levels. CONCLUSIONS: Our data suggest that the alterations in glutathione metabolism in the erythrocytes of alcoholics may be due principally to the production of free radicals, as supported by the high levels of malonyldialdehyde observed.

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.

Effect of alcohol abuse and glutathione administration on the circulating levels of glutathione and on antipyrine metabolism in patients with alcoholic liver cirrhosis.

Glutathione (GSH) is a principal cellular scavenger of free radicals. Chronic alcohol abuse, as well as liver disease, induces a decrease of hepatic GSH. We evaluated the effect of GSH administration (2.4 g day-1 in saline i.v. for 15 days) on the concentration of GSH in plasma and erythrocytes and on liver function tests, including galactose and antipyrine tests. We studied 40 alcoholic cirrhotic patients: 22 treated with GSH (10 persistent alcohol abusers and 12 weaning from alcohol during the study) and 18 treated with saline only (8 persistent alcohol abusers and 10 abstainers). Treatment with GSH improved the concentration of GSH in plasma and erythrocytes only in abstainers from alcohol; it did not affect liver function tests or galactose clearance. Persistent alcohol consumption significantly prolonged antipyrine metabolism; GSH administration counteracted this effect.

[Evaluation of the total hepatic function after treatment with fosinopril in hypertensive patients with liver cirrhosis]. / Valutazione della funzionalità epatica globale dopo trattamento con fosinopril in pazienti ipertesi affetti da cirrosi epatica.

Fosinopril is distinguished from other ACE inhibitors by a pharmacokinetic pecularity in the sense that is can be metabolized either by liver or kidney. This was the rationale of the present research the aim of which was to verify if administered to patients with liver cirrhosis the drug was liable to alter global liver function and ability to metabolize drugs. Eight cirrhotic males, mean age 56 years, also suffering from high blood pressure, were studied. In these patients, liver and kidney function tests (BUN, creatinine blood level, serum and urinary electrolytes, creatinine clearance, calcium and phosphor blood level, transaminases, alkaline phosphatase prothrombin time, cholinesterase, gamma-glutamyl-transpeptidase) were carried out at baseline and after 30 days' fosinopril treatment (1 capsule every morning in the fasting state); in addition total functioning liver mass was assessed by the galactose test, and drug-metabolizing capacity by the antipyrine test. Treatment resulted in a significant improvement of pressure values in all patients (p < 0.01) and did not alter liver and kidney function parameters. Besides, no side effects were registered, especially no case of orthostatic hypotension. The antipyrine test was not influenced by fosinopril treatment. Therefore, short-term treatment with this ACE-inhibitor can be concluded to be effective and not to cause additional alterations of liver function in patients with liver cirrhosis.