Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?

Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver disease associated with severe morbidity and mortality. We performed updated random effects meta-analyses to evaluate the evidence for non-absorbable disaccharides (lactulose and lactitol), rifaximin and branched chain amino acids (BCAA). A meta-analysis of randomized trials showed that, compared with placebo or no intervention, non-absorbable disaccharides have beneficial effects on HE manifestations and prevention of HE episodes. The addition of rifaximin to non-absorbable disaccharides versus rifaximin alone was more beneficial than non-absorbable disaccharides used alone on both outcome measures. Likewise, a meta-analysis of randomised controlled trials found that oral BCAA supplements have beneficial effects on manifestations of HE compared with control supplements. The effect was found in a variety of clinical settings. No convincing effects of intravenous BCAA for episodic HE were identified. In conclusion, evidence-based treatment recommendations for patients with HE should include non-absorbable disaccharides combined with rifaximin or BCAA. Additional evidence is needed to evaluate the effect of combining all three interventions.     

Disaccharides in the treatment of hepatic encephalopathy

Management of hepatic encephalopathy (HE) primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as nonabsorbable disaccharides and antimicrobial agents like rifaximin. The nonabsorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and minimal hepatic encephalopathy (MHE). Lactulose significantly improves cognitive function and health-related quality of life in patients with MHE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Lactulose has also shown to be effective in primary and secondary prophylaxis of HE. Disaccharides were found to be comparable to rifaximin in recent systemic reviews in the treatment of HE however conclusion was based on inclusion of some poor quality trials. Combination therapy of disaccharides either with rifaximin, L-ornithine L-aspartate,probiotics for the treatment of HE needs further validation in large studies.     

Rifaximin and diverticular disease: Position paper of the Italian Society of Gastroenterology (SIGE)

Management of diverticular disease has significantly improved in the last decade. Antibiotic treatment is used for symptom relief and prevention of complications. In Italy, the non-absorbable antibiotic rifaximin is one of the most frequently used drugs, and it is perceived as the reference drug to treat symptomatic diverticular disease. Its non-systemic absorption and high faecal concentrations have oriented rifaximin use to the gastrointestinal tract, where rifaximin exerts eubiotic effects representing an additional value to its antibiotic activity. This position paper was commissioned by the Italian Society of Gastroenterology governing board for a panel of experts (RC, GB, BA) to highlight the indications for treatment of diverticular disease. There is a lack of rationale for drug use for the primary prevention of diverticulitis in patients with diverticulosis; thus, rifaximin use should be avoided. The cyclic use of rifaximin, in association with high-fibre intake, is safe and useful for the treatment of symptomatic uncomplicated diverticular disease, even if the cost-efficacy of long-term treatment remains to be determined. The use of rifaximin in the prevention of diverticulitis recurrence is promising, but the low therapeutic advantage needs to be verified. No evidence is available on the efficacy of rifaximin treatment on acute uncomplicated diverticulitis.     

Management of hepatic encephalopathy: focus on antibiotic therapy

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of both acute and chronic liver failure. Symptoms of HE include attention deficits, alterations of sleep patterns and muscular incoordination progressing to stupor and coma. The pathogenesis of HE is still unknown, although ammonia-induced alterations of cerebral neurotransmitter balance, especially at the astrocyte-neurone interface, may play a major role. Treatment of HE is therefore directed at reducing the production and absorption of gut-derived neurotoxic substances, especially ammonia. The non-absorbable disaccharides lactulose and lactitol were long considered as a first-line pharmacological treatment of HE, but a recent systematic review questioned their efficacy, pointing out that there is insufficient high-quality evidence to support their use. Oral antibiotics are regarded as a suitable therapeutic alternative. However, the prolonged use of antimicrobials is precluded by the possible occurrence of adverse events. Rifaximin, a synthetic antibiotic structurally related to rifamycin, displays a wide spectrum of antibacterial activity against Gram-negative and Gram-positive bacteria, both aerobic and anaerobic, and a very low rate of systemic absorption. Available evidence suggests that rifaximin - thanks to its efficacy and remarkable safety - has the highest benefit-risk ratio in the overall treatment of HE.     

Spontaneous bacterial peritonitis by Pasteurella multocida under treatment with rifaximin

Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis. Recently, rifaximin, a non-absorbable antibiotic which is used to prevent recurrent hepatic encephalopathy, has been proposed as effective prophylaxis for SBP. Here, we present an unusual case of SBP under treatment with rifaximin. A 50-year-old woman with liver cirrhosis was admitted because of tense ascites and abdominal pain. She was under long-term oral prophylaxis with rifaximin due to hepatic encephalopathy. Paracentesis revealed SBP caused by Pasteurella multocida, which was sensitive to multiple antibiotics, including rifaximin. Treatment with ceftriaxone resulted in rapid resolution of the peritonitis and restoration of the patient. Since P. multocida is usually transmitted from pets, the patient’s cat was tested and could be identified as the most likely source of infection. This case should elicit our awareness that uncommon pathogens and unusual routes of transmission may lead to SBP, despite antibacterial prophylaxis with non-absorbable antibiotics. Nevertheless, such infections may still remain sensitive to systemic therapy with conventional antibiotics.     

Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis

Minimal hepatic encephalopathy (MHE) corresponds to the earliest stage of hepatic encephalopathy (HE). MHE does not present clinically detectable neurological-psychiatric abnormalities but is characterized by imperceptible neurocognitive alterations detected during routine clinical examination via neuropsychological or psychometrical tests. MHE may affect daily activities and reduce job performance and quality of life. MHE can increase the risk of accidents and may develop into overt encephalopathy, worsening the prognosis of patients with liver cirrhosis. Despite a lack of consensus on the therapeutic indication, interest in finding novel strategies for prevention or reversion has led to numerous clinical trials; their results are the main objective of this review. Many studies address the treatment of MHE, which is mainly based on the strategies and previous management of overt HE. Current alternatives for the management of MHE include measures to maintain nutritional status while avoiding sarcopenia, and manipulation of intestinal microbiota with non-absorbable disaccharides such as lactulose, antibiotics such as rifaximin, and administration of different probiotics. This review analyzes the results of clinical studies that evaluated the effects of different treatments for MHE.     

Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial.

Preliminary data suggest that rifaximin a new non-absorbable rifamycin-derivate, has beneficial effects on chronic portal systemic encephalopathy (PSE). To compare the efficacy and safety of rifaximin vs neomycin in the treatment of the hyperammoniemic state of PSE, 30 cirrhotic patients with grade I to III of PSE were randomly allocated to one of two groups: group A (15 patients) receiving rifaximin (400 mg/8h) and group B (15 patients) neomycin (1gr/8h). The duration of treatment was 21 consecutive days. Age, sex, hepatic and renal function, level of PSE, EEG and number connection test were similar in both groups. A significant decrease in blood ammonia levels was observed at the end of the treatment period in both groups; moreover rifaximin produced an earlier reduction of blood ammonia levels. The neuropsychic syndrome related to the PSE improved in both groups without significant difference. No side effects attributable to therapy were observed in the rifaximin group. These results indicate that, rifaximin is at least as effective as neomycin in the achievement and maintenance of low blood ammonia levels in cirrhotics with chronic PSE.     

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy and can affect up to 80% of cirrhotic patients. By definition, it has no obvious clinical manifestation and is characterized by neurocognitive impairment in attention, vigilance and integrative function. Although often not considered to be clinically relevant and, therefore, not diagnosed or treated, MHE has been shown to affect daily functioning, quality of life, driving and overall mortality. The diagnosis of MHE has traditionally been achieved through neuropsychological examination, psychometric tests or the newer critical flicker frequency test. A new smartphone application (EncephalApp Stroop Test) may serve to function as a screening tool for patients requiring further testing. In addition to physician reporting and driving restrictions, medical treatment for MHE includes non-absorbable disaccharides (eg, lactulose), probiotics or rifaximin. Liver transplantation may not result in reversal of the cognitive deficits associated with MHE.     

Lessons from “real life experience” of rifaximin use in the management of recurrent hepatic encephalopathy

BACKGROUND Hepatic encephalopathy(HE) is a major complication of cirrhosis with independent prognostic significance. The current management of HE is mainly based on lactulose. Rifaximin has been shown to decrease the risk of HE recurrence in patients with episodic forms. HE can also be persistent. However,there is no drug support recommendation for rifaximin use in this setting.AIM To assess the effectiveness of rifaximin in the management of recurrent episodes of HE and recurrent acute exacerbations on persistent HE, in "real life conditions".METHODS In this retrospective study, using a within-subjects design, we collected data of patients treated with rifaximin for HE in two liver diseases centers, during the six-month period before and during the six-month period after the initiation of rifaximin. The primary effectiveness endpoint was the total number of HE events involving hospitalization.RESULTSRifaximin was introduced for prevention of recurrent HE episodes in 29 out of 62 patients with normal mental status between episodes and for prevention of recurrent acute exacerbations on persistent HE in 33 out of 62 patients. In the"prevention of recurrent HE episodes" group, fewer HE events(0.79 vs 1.78; P =0.013) were reported during the period of time when rifaximin was used. In the"prevention of recurrent acute exacerbations on persistent HE" group, there was no significant difference in the number of HE-events(1.48 vs 1.77; P = 0.582).CONCLUSION In this real-life experience, the effectiveness of rifaximin was confirmed in the prevention of HE episodes recurrence but was not proved in the prevention of acute exacerbations recurrence on persistent HE.     

Antibiotics for the treatment of hepatic encephalopathy

The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.     

Retrospective cross‐sectional pilot study of rifaximin dosing for the prevention of recurrent hepatic encephalopathy

Standard treatment for hepatic encephalopathy (HE) includes medications that reduce ammonia and bacterial translocation in the gut. Rifaximin can be used off‐label for the reduction of overt HE. The study purpose was to determine efficacy of traditional rifaximin dosing (400 mg three times daily) compared with newer dosing (550 mg twice daily) via readmission rates for the prevention of recurrent HE. This was a retrospective, observational, cross‐sectional pilot study conducted in a tertiary medical center. A total of 226 patients 18–89 years of age with documentation of HE via ICD‐9 code who started rifaximin therapy while inpatient between April 2009 and June 2014 were evaluated. Data collected included rifaximin dosing, other medications used to treat HE, duration of therapy, time to readmission, and various laboratory values. There were no differences in readmission rates at 30 days, 60 days, or 6 months between treatment groups. Additionally, there was no difference in the odds of readmission between the treatment groups (OR = 0.77, 95% CI: [0.201, 4.365], P = 0.718). Patients had a low overall probability of readmission over the observational period. Based on average wholesale price data, the cost for a 9‐day supply of rifaximin for the 400‐mg dosing regimen is $952.56 versus $605.16 for the 550‐mg dosing regimen. The rifaximin 550‐mg dosing strategy should be utilized in hospitalized patients for the prevention of recurrent HE as there was no difference in readmission rate or time to readmission between dosing groups. The 550‐mg regimen had a lower acquisition cost for a 9‐day duration of treatment in the studied institution.     

Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications

Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint",characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined,and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover,in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis(SBP),hepatic encephalopathy(HE),and,portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic,immune-modulating and anti-inflammatory activity,a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE,and also to prevent the development of SBP,to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality,triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.     

Evaluation of the Long-term Administration of Rifaximin for More than Three Years in the Treatment of Repeated and Recurrent Overt Hepatic Encephalopathy

The patient was a 65-year-old man with alcoholic liver cirrhosis who had been admitted to hospital 5 times for repeated and recurrent overt hepatic encephalopathy (HE) despite numerous therapies, including disaccharide, branched-chain amino acid (BCAA) formula, L-carnitine and zinc. After the additional administration of rifaximin (1,200 mg/day orally), his consciousness level was well controlled for 3 years without any adverse effects. The long-term administration of rifaximin may be useful and safe for managing recurrent overt HE, although the maintenance dosage and duration of rifaximin and safety should be evaluated in patients with ameliorated HE.     

Use of rifaximin in gastrointestinal and liver diseases

Rifaximin is a broad spectrum oral antibiotic with antimicrobial activity against Gram-positive and Gramnegative aerobic and anaerobic bacteria. It is poorly absorbed and thus has a highly favorable safety profile. Rifaximin has been shown to be effective in the treatment of traveler's diarrhea, functional bloating and irritable bowel syndrome, small bowel bacterial overgrowth and in the prevention of recurrent overt hepatic encephalopathy. In addition, there is emerging evidence for a possible beneficial effect of rifaximin in the treatment of uncomplicated diverticular disease and in the prevention of recurrent diverticulitis. The use of rifaximin is associated with a low incidence of development, or persistence of spontaneous bacterial mutants. Moreover, the development of important drug resistance among extra-intestinal flora during rifaximin therapy is unlikely because of minimal systemic absorption and limited cross-resistance of rifaximin with other antimicrobials. This review addresses the current and emerging role of rifaximin in the treatment of gastrointestinal and liver disorders.     

Hepatic encephalopathy: A review of its pathophysiology and treatment

Opinion statement Hepatic encephalopathy (HE) is a broad spectrum of neuropsychiatric manifestations usually affecting individuals with end-stage liver disease. The presence of HE is a poor prognostic sign, with 1-year mortality rates of almost 60%. There is much debate about the underlying mechanisms that result in this syndrome; however, elevated plasma and central nervous system ammonia levels are considered key factors in its pathogenesis. Initial evaluation of the patient presenting with overt HE should include a careful search for predisposing factors, including underlying infection, gastrointestinal (GI) bleeding, electrolyte disturbances, hepatocellular carcinoma, dehydration, hypotension, and excessive use of benzodiazepines, psychoactive drugs, or alcohol. The mainstay of treatment for many years has been nonabsorbable disaccharides, particularly lactulose. Alternative treatments, which usually are second line in patients who do not respond to lactulose, include zinc, antibiotics (neomycin, metronidazole, and rifaximin), ornithine aspartate, sodium benzoate, probiotics, and surgical intervention. Accepted treatments for HE are associated with significant unpleasant side effects, including diarrhea, renal failure, neuropathy, and other GI disturbance. Newer therapies are still in development, and most are awaiting human trials in order to confirm their benefit. These include manganese chelators, L-carnitine, N-methyl-D-aspartate receptor antagonists, blood purification dialysis system, and an intravenous combination of sodium benzoate and phenylacetate.     

Quality of life in patients with minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) represents the mildest type of hepatic encephalopathy (HE). This condition alters the performance of psychometric tests by impairing attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients, depending of the diagnostic tools used for the diagnosis. MHE is related to falls, to an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life (QoL) and their socioeconomic status. MHE is detected in clinically asymptomatic patients through appropriate psychometric tests and neurophysiological methods which highlight neuropsychological alterations such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency evoked cognitive potentials and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment such as non-absorbable disaccharides, poorly absorbable antibiotics such rifaximin, probiotics and branched chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, to date the treatment of MHE is not routinely recommended apart from on a case-by-case basis. Aim of this review is analyze the burden of MHE on QoL of patients and provide a brief summary of therapeutic approaches.     

Pathophysiology and management of hepatic encephalopathy 2014 update: Ammonia toxicity and hyponatremia

Hyperammonemia is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia elicits astrocyte swelling and causes brain edema. In addition, hyponatremia, a condition frequently observed in hepatic cirrhosis, also exacerbates brain edema, potentially becoming a factor that exacerbates HE. Therefore, as a treatment strategy for HE, alleviating ammonia toxicity is essential. In addition to restricting protein intake, synthetic disaccharides such as lactulose and lactitol, probiotics that improve gut flora, and rifaximin, an antibiotic with poor bioavailability, are also administrated. Additionally, branched‐chain amino acids and carnitine have also been administrated. Moreover, we investigated the current trend in the concomitant use of drugs with different mechanisms of action. In Japan, the V2 receptor antagonist tolvaptan can be administrated to hepatic cirrhosis patients with fluid retention. This drug is also useful as a countermeasure for hyponatremia in hepatic cirrhosis, and elucidating its effects in HE patients may therefore become an agenda in the future. These observations indicate that ammonia toxicity, gut flora control and low sodium control are major focuses in HE improvement and long‐term prognosis.     

Antibiotics for inflammatory bowel disease: do they work?

A growing amount of evidence indicates that the intestinal flora plays a pathogenic role in inflammatory bowel disease (IBD): hence, the use of anti-bacterial agents as ancillary treatment in patients with ulcerative colitis, or Crohn's disease. While the results with anti-tubercular agents remain inconclusive, antibiotic treatment in IBD is usually carried out with either metronidazole or ciprofloxacin, or both. Controlled trials are scarce and, although both antibiotics appear to provide clinical benefit, definitive conclusions cannot be drawn and precise therapeutic guidelines cannot be suggested. The best results are achieved in the long-term treatment of Crohn's disease and in the management of pouchitis, or of perianal Crohn's disease. Long-term tolerability of antibiotic treatment may be poor due to the appearance of systemic side-effects. The use of non-absorbable anti-bacterial agents such as rifaximin deserves further investigation.     

Variceal bleeding and portal hypertensive gastropathy

Cirrhosis can be the end stage of any chronic liver disease. At the time of diagnosis of cirrhosis varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, large size of varices and the presence of endoscopic red colour signs but only one-third of patients who have variceal haemorrhage have the above risk factors. Recent interest has been directed at identifying haemodynamic factors that may reflect the pathophysiological changes which lead to variceal bleeding, e.g. it has been confirmed that no bleeding occurs if HVPG falls below 12 mmHg and also a hypothesis has been put forward in which bacterial infection is considered a trigger for bleeding. Pharmacological treatment with beta-blockers is safe, effective and is the standard long-term treatment for the prevention of recurrence of variceal bleeding. Combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for reduction in HVPG response needs further study, and surrogate markers of pressure response need evaluation. If endoscopic treatment is chosen, variceal ligation is the modality of choice. The combination of simultaneous variceal ligation and sclerotherapy does not offer any benefit. However, the use of additional sclerotherapy for the complete eradication of small varices after variceal ligation needs to be evaluated. The results of current prospective randomized controlled trials comparing variceal ligation with pharmacological treatment are awaited with great interest. Finally, the use of transjugular intrahepatic portosystemic shunt (TIPS) for the secondary prevention of variceal bleeding is not substantiated by current data, as survival is not improved and because of its worse cost-benefit profile compared to other treatments. In contrast, there still is a role for the selective surgical shunts in the modern management of portal hypertension. The ideal patients should be well compensated cirrhotics, who have had troublesome bleeding - either who have failed at least one other modality of therapy (drugs or ligation), have bled from gastric varices despite medical or endoscopic therapy, or live far from suitable medical services. Recently, ligation has been compared to beta-blockers for primary prophylaxis but so far there is no good evidence to recommend banding for primary prophylaxis, if beta-blockers can be given.     

Prevention and treatment of traveler's diarrhea. Focus on antimicrobial agents

Diarrhea, mostly due to bacterial infection of the gut, is the most frequent health complaint in the international traveler, affecting 20-70% of the traveling population depending on the destination and other factors. It is usually benign and self-limiting in nature, but symptoms may occasionally be distressing causing modifications of normal activities and sometimes confinement to bed or hospitalization. Prevention of traveler's diarrhea should ideally be based on dietary restrictions, but experience shows that this target is extremely difficult to achieve. Antibiotic chemoprophylaxis should be restricted to selected groups of travelers at risk of severe complications of diarrhea or when diarrhea-driven alterations of planned activities are highly undesirable (critical trips). The effectiveness of alternative prophylactic approaches, such as vaccination or the use of probiotics, still awaits confirmation. Treatment of mild diarrheal cases without intestinal symptoms may be limited to rehydration with or without antimotility agents. When antibiotic therapy is considered, non-absorbable antibiotics, such as rifaximin, may be considered a valid alternative to systemic antibiotics to treat uncomplicated cases, leaving fluoroquinolones and/or azithromycin for use in more severe cases or when invasive pathogens are suspected. Indeed, therapeutic use of doxycycline and trimethoprim-sulfamethoxazole (TMP-SMX) is limited by widespread resistance of many enteropathogens. The addition of loperamide or other antimotility agents usually provides symptom relief and further shortens the duration of illness and may be therefore safely adopted in the healthy adult unless dysentery is present.