Treatment Of Chronic Hepatic Encephalopathy Research Articles

P: 37 Probiotics Combined With Rifaximin for the Treatment of Chronic Hepatic Encephalopathy: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism Using BDL Rats

BACKGROUND: Chronic hepatic encephalopathy (HE) is a severe complication of chronic liver disease (CLD), and finding the right treatment to reduce HE episodes before liver transplant remains a challenge. Both rifaximin (non-absorbable antibiotic) and probiotics are currently used to reduce HE symptoms, but their precise effect on brain metabolites has never been studied. Our aims were: 1) to assess in vivo and longitudinally the effect of the combination of probiotics and rifaximin on bile duct ligated (BDL) rats in different brain regions; and 2) to compare these results with both non-treated (n = 17) and rifaximin-only treated rats (n = 12).1,2 METHODS: In vivo 1H-MRS at 9.4 Tesla combined with biochemical tests (plasma NH4+, bilirubin) and microbiota analysis were performed on adult Wistar rats (n = 9) before BDL3,4 (week 0) and at weeks 2, 4, 6 and 8 after surgery. Evolution of metabolites was studied using the SPECIAL sequence (TE = 2.8 ms) in the hippocampus (2 × 2.8 × 2 mm3) and cerebellum (2.5 × 2.5 × 2.5 mm3). Metabolite concentrations were estimated using LCModel and water as internal reference. Probiotics administration (VIVOMIXX®, 60 billion bacteria/kg of rat) started two weeks before BDL-surgery until the end of the study. Rifaximin (15.7 mg/kg/day = 'human-dose') was administered twice daily starting two weeks after BDL-surgery. RESULTS: All rats displayed the characteristic rise in plasma bilirubin, regardless of treatment group, as well as a similar ammonium increase (Figure 1a). The characteristic pattern of chronic HE was observed (Figure 1e): a gradual increase of brain glutamine followed by a gradual decrease in the other brain osmolytes (myo-inositol, taurine, total choline) and a later decrease of glutamate and creatine. The combination of probiotics and rifaximin improved some of the neuro-metabolic changes associated with CLD at early stages of HE (week 4) in the cerebellum: the 'probiotics + rifaximin' group showed a lower rise of brain glutamine (+33% vs +66%, Figure 1c) and a smaller decrease of creatine (−4% vs −14%). In the hippocampus, rats receiving both probiotics and rifaximin exhibited a smaller increase in brain glutamine even at week 8 after BDL compared to non-treated rats (+99% vs +136%, Figure 1d) and a smaller decrease in brain myo-inositol and glutamate (−20% vs −30% and −7% vs −13%, respectively). Also, bifidobacteria concentration was slightly higher in the 'probiotics+rifaximin' group at week 8 (Figure 1b). Finally, the administration of rifaximin associated with this probiotic showed more beneficial effects than rifaximin only, and both could be used to maintain a balanced microbiota and may provide opportunities for reducing the spread of antibiotic resistances. CONCLUSIONS: To conclude, some promising changes were induced in the neurometabolic profile of BDL-rats who were treated with this specific probiotic and rifaximin (glutamine, myo-inositol, creatine and glutamate).

Pharmacotherapy for Hepatic encephalopathy: view of Evidence-Based Medicine

Hepatic encephalopathy (HE) refers to a complex and reversible neuro-psychiatric syndrome that results from complications of acute or chronic hepatic failure, particularly alcoholic cirrhosis. It will lead to frequent life disruptions, poor quality of life and extensive use of health care resources. We conducted the review of several agents based on randomized controlled trials (RCTs) of high-quality Jadad scores (≥3) to provide effective information for clinical practice. Rifaximin appears at least to be as effective as conventional treatments, but not superior to them. L-Ornithine-L-aspartate appears to be a safe and effective treatment of chronic HE when compared with a placebo regime. Other treatments include non-absorbable disaccharides (NAD) and benzodiazepine receptor antagonists. In spite of the variability in the improvement of HE, NAD and non-absorbed antibiotics such as rifaximin offer a favorable benefit–risk ratio in the improvement of HE. Further RCTs with power calculation and a multi-centre approach with adequate population number are needed to resolve the heterogeneous results

Nutritional support in the treatment of chronic hepatic encephalopathy

The prevalence of under nutrition in cirrhotic patients is 61% and it usually progresses as the disease becomes more advanced. The deterioration in the nutritional status and its associated metabolic derangements has raised doubts about the benefits of severe and prolonged protein restriction as a treatment for hepatic encephalopathy. However, the practice of dietary protein restriction for patients with liver cirrhosis is deeply embedded among medical practitioners and dietitians. To date, no solid conclusions may be drawn about the benefit of protein restriction. However, the negative effects of protein restriction are clear, that is, increased protein catabolism, the release of amino acids from the muscle, and possible worsening of hepatic encephalopathy. In conclusion, chronic protein restriction causes progressive and harmful protein depletion and must be avoided.

Current trends in the treatment of hepatic encephalopathy

Hepatic encephalopathy (HE) is a common reversible neuropsychiatric syndrome associated with chronic and acute liver dysfunction and significant morbidity and mortality. Although a clear pathogenesis is yet to be determined, elevated ammonia in the serum and central nervous system are the mainstay for pathogenesis and treatment. Management includes early diagnosis and prompt treatment of precipitating factors (infection, gastrointestinal bleeding, electrolyte disturbances, hepatocellular carcinoma, dehydration, hypotension, and use of benzodiazepines, psychoactive drugs, and/or alcohol). Clinical trials have established the efficacy of lactulose and lactitol enemas in the treatment of acute hepatic encephalopathy. Extensive clinical experience has demonstrated the efficacy of oral lactulose and lactitol with the goal of two to three soft bowel movements a day for the treatment of chronic HE. However, lactulose and lactitol have significant gastrointestinal side effects. For patients unable to tolerate lactulose or lactitol or who still have persistent chronic HE with lactulose or lactitol, neomycin, metronidazole and rifaximin are second-line agents. More recent data supports the benefits of rifaximin used solely and as an additional agent with fewer side effects than neomycin or metronidazole. Newer therapies being investigated in humans with clinical promise include nitazoxanide, the molecular adsorbent recirculating system (MARS), L-ornithine phenylacetate, sodium benzoate, and/or sodium phenylacetate and Kremezin((R)) (AST-120).

The cost‐effectiveness and budget impact of competing therapies in hepatic encephalopathy – a decision analysis

Treatment options for hepatic encephalopathy have disparate risks and benefits. Non-absorbable disaccharides and neomycin are limited by uncertain efficacy and common dose-limiting side effects. In contrast, rifaximin is safe and effective in hepatic encephalopathy, but is more expensive. We conducted a decision analysis to calculate the cost-effectiveness of six strategies in hepatic encephalopathy: (i) no hepatic encephalopathy treatment, (ii) lactulose monotherapy, (iii) lactitol monotherapy, (iv) neomycin monotherapy, (v) rifaximin monotherapy and (vi) up-front lactulose with crossover to rifaximin if poor response or intolerance of lactulose ('rifaximin salvage'). The primary outcome was cost per quality-adjusted life-year gained. Under base-case conditions, 'do nothing' was least effective and rifaximin salvage was most effective. Lactulose monotherapy was least expensive, and rifaximin monotherapy was most expensive. When balancing cost and effectiveness, lactulose monotherapy and rifaximin salvage dominated alternative strategies. Compared to lactulose monotherapy, rifaximin salvage cost an incremental US$2315 per quality-adjusted life-year-gained. The cost of rifaximin had to fall below US$1.03/tab in order for rifaximin monotherapy to dominate lactulose monotherapy. Rifaximin monotherapy is not cost-effective in the treatment of chronic hepatic encephalopathy at current average wholesale prices. However, a hybrid salvage strategy, reserving rifaximin for lactulose-refractory patients, may be highly cost-effective.

New Management Options for End-Stage Chronic Liver Disease and Acute Liver Failure

The management of children with end-stage chronic liver disease and acute liver failure mandates a multidisciplinary approach and intense monitoring. In recent years, considerable progress has been made in developing specific and supportive medical measures, but studies and publications have mainly concerned adult patients. Therapeutic approaches to complications of end-stage chronic liver disease and acute liver failure (e.g. refractory ascites, hepatorenal syndrome, encephalopathy, and cerebral edema) that may be applied to children are reviewed in this article.Mild-to-moderate ascites should be managed by modest salt restriction and oral diuretic therapy in the first instance. Large volume paracentesis associated with colloid volume expansion and diuretic therapy may be effective for acute relief. Treatment of hepatorenal syndrome type 1 with vasopressin analogs (terlipressin) is recommended prior to liver transplantation in order to improve renal function. Prevention and treatment of chronic hepatic encephalopathy are directed primarily at controlling the events that may precipitate hepatic encephalopathy and at reducing ammonia generation and increasing its detoxification or removal. In addition to reduction of gut ammonia production using non-absorbable disaccharides such as lactulose and/or antibacterials such as neomycin, sodium benzoate may be used on a long-term basis to prevent, stabilize, or improve hepatic encephalopathy. The management of hepatic encephalopathy in acute liver failure is considerably more unsatisfactory; treatment is aimed at preventing brain edema and intracranial hypertension. Extracorporeal liver support devices are now used commonly in critically ill children with acute renal failure, advanced hepatic encephalopathy, cerebral edema, intracranial hypertension, and severe coagulopathy. Continuous renal replacement therapy could potentially help support patients until liver transplantation is performed or liver regeneration occurs. The Molecular Adsorbent Recirculating System (MARS or albumin dialysis) is the liver support system most frequently used worldwide in adults and appears to offer distinct advantages over hepatocyte-based systems. There are no specific medical therapies or devices that can correct all of the functions of the liver. Apart from a few metabolic diseases presenting with severe liver dysfunction for which specific medical therapies may preclude the need for liver transplantation, liver transplantation still remains the only definitive therapy in most instances of end-stage chronic liver disease and acute liver failure. Future research should focus on gaining a better understanding of the mechanisms responsible for liver cell death and liver regeneration, as well as developments in hepatocyte transplantation and liver-directed gene therapy.

Treatment of chronic hepatic encephalopathy by the progressive suppression of a spontaneous portacaval shunt via the umbilical vein

Femme de 67 ans ayant une cirrhose du foie posthepatite avec encephalopathie hepatique chronique invalidante due a une derivation portocave spontanee

Use of protein restriction in the treatment of chronic hepatic encephalopathy: a regional study

To identify the current regional nutritional practices, related to protein restriction in the treatment of chronic hepatic encephalopathy (CHE), used by Ohio dietitians and compare them to the current recommendations.

Pathogenesis and treatment of chronic hepatic encephalopathy

The various treatment strategies for hepatic encephalopathy are compared in the light of the available body of scientific work on the pathogenesis of the syndrome. Data on animal models of hepatic encephalopathy and in vitro studies on brain slices are discussed. Difficulties in extrapolating the results obtained to the human situation are highlighted, while results of human positron emission tomography and magnetic resonance spectroscopy studies are outlined on the background of the potential weaknesses of these non-invasive techniques.

The role of helicobacter pylori in the pathogenesis and treatment of chronic hepatic encephalopathy

The role of helicobacter pylori in the pathogenesis and treatment of chronic hepatic encephalopathy

Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1–2 hepatic encephalopathy

In 40 patients with cirrhosis on a dietary protein regimen of 1 g/kg b.w., we determined the effect on chronic hepatic encephalopathy of long-term administration of Enterococcus faecium (SF68) versus lactulose. The patients received one of the two treatments for three periods of 4 weeks, each separated by drug-free 2-week intervals. The efficacy of treatment was assessed by arterial blood ammonia concentration, mental status, number connection (Reitan's part A) test and flash-evoked visual potentials. At the end of the third period the reduction in both blood ammonia concentrations and Reitan's test times was more enhanced in patients on SF68 than in patients on lactulose. Furthermore, while patients on lactulose tended to return to basal values during drug-free intervals, responders in the SF68 group maintained improvement throughout the study. In conclusion, SF68 is at least as useful as lactulose for the chronic treatment of chronic hepatic encephalopathy; it has no adverse effects, and treatment can be interrupted for 2 weeks without losing the beneficial effects.

Rifaximin in the treatment of chronic hepatic encephalopathy; results of a multicenter study of efficacy and safety

Hepatic encephalopathy (HE) is a metabolic-neurophysiologic syndrome that occurs in patients with liver disease. One of the main pathogenic mechanisms is represented by circulating toxins produced from the intestinal metabolism of nitrogenous compounds. The therapeutic approach to HE includes drugs that eliminate ammoniaproducing bacteria. The aim of this study was to evaluate the efficacy and safety of rifaximin, a nonabsorbable antibacterial agent, in the treatment of chronic HE in a large population of cirrhotic patients. One hundred thirty-six cirrhotic patients (100 men, 36 women; mean age, 59.5 years) with clinical and biochemical signs of mild HE were studied under three different treatment protocols: one open study in which rifaximin (1200 mg/day) was administered for 21 days to 80 patients; and two randomized controlled studies, one in which rifaximin (1200 mg/day, 20 patients) and neomycin (3000 mg/day, 15 patients) were administered for 21 days and one in which rifaximin (1200 mg/day, 9 patients) and lactulose (40 gm/day, 12 patients) were administered for 21 days. In the open study, after 5 days of treatment, ammonia reached normal values in each patient; after 7 days, electroencephalographic abnormalities were present only in a few cases; and after 15 days, no patients showed neurologic signs of HE. In the rifaximin versus neomycin study, blood ammonia levels and neurologic signs significantly decreased during both treatments, but rifaximin induced an earlier disappearance of clinical and biochemical signs of HE. In the rifaximin versus lactulose study, both drugs were efficacious in reducing the neurologic signs of HE, but some patients treated with lactulose presented mild side effects at the beginning of the therapy, which disappeared in the course of treatment. This study confirms the usefulness of rifaximin in the management of cirrhotic patients with mild HE; the absence of significant side effects suggests its use even in more severe cases of HE, either alone or in association with other drugs.

Lactitol or lactulose in the treatment of chronic hepatic encephalopathy: results of a meta-analysis.

Lactitol (beta-galactosido-sorbitol) has been recently compared with lactulose for the treatment of chronic hepatic encephalopathy in a few studies, each comprising a small number of patients. The results are controversial. We studied the efficiency and tolerance of both compounds by using a meta-analysis on the basis of published controlled trials. Our study only included controlled or randomized trials comprising cirrhotic patients with chronic hepatic encephalopathy. Analyzed parameters were the portosystemic encephalopathy index of Conn after treatment, the percentage of improved patients and the percentage of patients who had ill effects related to the treatment (flatulence, diarrhea). Bibliographical screening revealed five studies comparing the effects of lactitol and lactulose in chronic hepatic encephalopathy. Four crossover studies were done that included 48 patients and one parallel study that included 29 patients. The duration of the treatment ranged from 3 to 6 mo. All studies found a similar efficiency with both drugs. However, they exhibited some discrepancies in the relative frequency of adverse reactions (flatulence). Meta-analysis showed no statistical differences in the portosystemic encephalopathy index after lactitol or lactulose treatment. The percentage of improved patients after lactitol or lactulose was similar. In contrast, the analysis revealed a higher frequency (p less than 0.01) of flatulence in patients treated with lactulose compared with those treated with lactitol. In conclusion, this meta-analysis shows no statistical difference between therapeutic effects of lactitol and lactulose, but it does show a higher frequency of flatulence with lactulose. This suggests that lactitol should be preferred to lactulose for the treatment of chronic hepatic encephalopathy.

Lactitol versus lactulose in the treatment of chronic hepatic encephalopathy: A double-blind, randomised, cross-over study

Lactitol is a disaccharide analogue of lactulose which is available as a pure crystalline powder. The efficacy of lactitol in the treatment of chronic hepatic encephalopathy was assessed in 9 cirrhotic patients in a randomised, double-blind, cross-over comparison with lactulose. The sugars were dispensed in solutions, identical in taste and appearance and with similar physico-chemical properties, which contained either 66.7 g/100 ml of lactitol or 66.7 ml (44.5 g)/100 ml of lactulose syrup. Patients were treated for periods of 3 months with each sugar, during which time they were monitored frequently by use of a number of clinical, psychometric and laboratory variables. The sugar solutions were dispensed in an initial dose of 0.75 ml/kg which was adjusted, as necessary, in order to produce two semi-soft stools per day. An adequate catharsis was achieved with a mean (+/- 1 SD) equivalent daily dose of 31.9 +/- 11.2 g of lactitol or 32.9 +/- 16.7 ml (21.9 +/- 11.1 g) of lactulose syrup. Both sugars were equally as effective in the treatment of this condition, even though events likely to cause decompensation arose in 5 patients during treatment with lactitol but in only 1 during treatment with lactulose. Side effects appeared to be more frequent during treatment with lactulose, despite the fact that the parent sugar was diluted in the trial solution; thus 5 patients experienced excessive flatulence and 8 experienced diarrhoea on lactulose compared with only 2 and 4 on lactitol, respectively. In all cases the excessive flatulence occurred independently of sugar dosage whereas the development of diarrhoea was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy

Six patients with cirrhosis and severe chronic hepatic encephalopathy were treated with bromocriptine. All showed significant overall improvement clinically and in 3, the electroencephalogram became normal. The cerebral blood flow increased significantly from 32.7 ± 2.4 (mean ± 1 SE) to 40.5 ± 1.5 ml/100 g brain/min (P < 0.05). Similarly, there were significant improvements in the cerebral oxygen consumption from 2.2 ± 0.4 to 3.3 ± 0.4 ml/100 g brain/min (P < 0.02) and in cerebral glucose consumption from 2.1 ± 0.6 to 6.6 ± 1.6 mg/100 g brain/ min (P < 0.02). Cross-over to placebo produced overall deterioration, more marked in the patients who had received the active drug for the shorter time pe riod. No serious side effects were seen; the drug was well tolerated in doses of up to 15 mg daily and is a useful treatment for chronic hepatic encephalopathy when the response to conventional therapy has been poor.

Effects of lactulose and other laxatives on ileal and colonic pH as measured by a radiotelemetry device.

Using a pH-sensitive radiotelemetering device the effect of lactulose on luminal pH in the ileum, colon, and rectum has been compared with that of two other laxative agents. Lactulose produced marked acidification of proximal colonic contents but this effect was not consistently maintained into the distal colon. Sodium sulphate acidified distal rather than proximal colonic contents. However, for a similar degree of laxation it was not possible to produce a significantly more uniform reduction of pH along the length of the colon by combining these laxatives compared with lactulose alone. Magnesium sulphate had little effect upon luminal pH except in the rectum where a significant rise occurred. These results are discussed in relation to both normal colonic physiology and to their possible relevance to the treatment of chronic hepatic encephalopathy by colonic acidification.

Treatment of Chronic Hepatic Encephalopathy

The neuropsychiatric abnormalities which accompany cirrhosis of the liver vary widely from subclinical impairment of psychometric performance to overt episodic or persistent changes in cerebral function. The pathogenesis of the syndrome is unknown although important rôles are ascribed to circulating gut-derived toxins of nitrogenous origin and to changes in central neurotransmission, particularly of the dopaminergic and GABA-ergic systems. Treatment is, therefore, based on mechanisms to reduce the production and absorption of gut-derived toxins such as decreasing and modifying dietary protein intake, altering the intestinal bacterial flora and bowel cleansing, and on mechanisms designed to modify central neurotransmitter balance either directly by use of dopaminergic agents or benzodiazepine antagonists or indirectly by use of amino-acid mixtures. Some treatment measures, such as use of non-absorbable disaccharides and vegetable protein diets, are known to be efficacious, and are the mainstays of management for all forms of the syndrome. Others are used in more specific circumstances, for example the antibiotic neomycin is effective during acute exacerbations of the syndrome, and the dopamine agonist bromocriptine provides benefit when symptoms are persistent and intractable. Certain treatments such as branched-chain amino acids and the benzodiazepine antagonist, flumazenil, are at present, of unproven value.