Nonabsorbable Disaccharides Research Articles

Research progress on albumin therapy for hepatic encephalopathy

Hepatic encephalopathy (HE) is one of the severe complications of decompensated stage cirrhosis that causes cerebral dysfunction due to hepatic insufficiency and/or portosystemic shunts, and it usually manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. The pathogenesis of HE is complex, although ammonia toxicity, oxidative stress, inflammation, intestinal dysbiosis, and others among them mainly play an important role. The treatment for HE lacks specific drugs, and the current available drugs include non-absorbable disaccharides (lactulose), antibiotics (rifaximin), and other therapies (oral branched-chain amino acids, intravenous injection of L-ornithine-L-aspartic acid, probiotics). Recent research has shown that human albumin is a safe and effective treatment for HE, improving not only cognitive function but also enhancing patients' quality of life.

The Management of Hepatic Encephalopathy from Ward to Domiciliary Care: Current Evidence and Gray Areas.

Hepatic encephalopathy (HE) is a common complication of advanced liver disease and acute liver failure. It is a condition that features several neuropsychiatric symptoms that affect mortality, morbidity and the quality of patients' and caregivers' lives. An HE diagnosis is generally an exclusion diagnosis. Once the patient is admitted to the hospital, clinical examination, blood tests and eventually neuroimaging should be performed with the aim of ruling out other causes of acute brain dysfunction. Moreover, HE is recognized using various precipitants that can potentially promote its onset, alone or in combination, and must be identified. Once the diagnostic process is complete, a correct treatment should be started. The anti-HE treatment is based on a combination of the correction of precipitants; non-absorbable antibiotics, such as rifaximin; and non-absorbable disaccharides. Once the patient is discharged from the hospital, specific anti-HE therapy should be maintained in order to prevent other HE episodes.

How does rifaximin with or without non-absorbable disaccharides compare with non-absorbable disaccharides alone for people with cirrhosis?

How does rifaximin with or without non-absorbable disaccharides compare with non-absorbable disaccharides alone for people with cirrhosis?

Rifaximin Use, Adherence and Persistence in Patients with Hepatic Encephalopathy: A Real-World Study in the South of Italy.

Real-world data on the therapeutic management of hepatic encephalopathy (HE) patients are limited. The aim of this study was to evaluate the HE medications prescribed in an Italian cohort of HE patients post-discharge and to assess the real-world rifaximin adherence and persistence over 1 year. An observation retrospective study was conducted using data retrieved from outpatient pharmaceutical databases and hospital discharge records of the Campania region. For all subjects hospitalized for HE during 2019 (cohort 1), the HE medications prescribed within 60 days after discharge were evaluated. Adherence (proportion of days covered, PDC) and persistence were estimated for rifaximin 550 mg incident users over 1 year (cohort 2). Patients with PDC ≥80% were considered adherents. Persistence was defined as the period of time from the first rifaximin prescription to the date of discontinuation. Discontinuation was assessed using the permissible gap method. In cohort 1, 544 patients were identified; 58.5% received rifaximin while 15.6% only received non-absorbable disaccharides and 25.9% did not receive any HE medications. In cohort 2, 650 users were selected; only 54.5% were adherents and 35% were persistent users at 1 year. This real-world study highlights that quality improvement in therapeutic management is needed to potentially improve the outcomes of HE patients.

Congenital Portosystemic Shunts in Dogs and Cats: Treatment, Complications and Prognosis.

Congenital portosystemic shunts (CPSS) are a common vascular anomaly of the liver in dogs and cats. Clinical signs of CPSS are non-specific and may wax and wane, while laboratory findings can raise the clinical suspicion for CPSS, but they are also not specific. Definitive diagnosis will be established by evaluation of liver function tests and diagnostic imaging. The aim of this article is to review the management, both medical and surgical, complications, and prognosis of CPSS in dogs and cats. Attenuation of the CPSS is the treatment of choice and may be performed by open surgical intervention using ameroid ring constrictors, thin film banding, and partial or complete suture ligation or by percutaneous transvenous coil embolization. There is no strong evidence to recommend one surgical technique over another. Medical treatment strategies include administration of non-absorbable disaccharides (i.e., lactulose), antibiotics, and dietary changes, and are indicated for pre-surgical stabilization or when surgical intervention is not feasible. After CPSS attenuation, short- and long-term post-surgical complications may be seen, such as post-operative seizures and recurrence of clinical signs, respectively. Prognosis after surgical attenuation of CPSS is generally favorable for dogs and fair for cats.

Old and New Precipitants in Hepatic Encephalopathy: A New Look at a Field in Continuous Evolution.

Hepatic encephalopathy (HE) is a common complication in patients with advanced liver disease. It is a brain dysfunction characterized by neurological and psychiatric symptoms that significantly affects quality of life, morbidity and mortality of patients. HE has various precipitants that can potentially promote its onset, alone or in combination. Among the historically well-known precipitants, such as infections, gastrointestinal bleeding, dehydration, electrolyte disorders and constipation, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitating factors of HE. The identification, management and correction of these factors are fundamental for effective HE treatment, in addition to pharmacological therapy with non-absorbable disaccharides and/or antibiotics.

A curious case of confusion

A curious case of confusion

Minimal Hepatic Encephalopathy Affects Daily Life of Cirrhotic Patients: A Viewpoint on Clinical Consequences and Therapeutic Opportunities

Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of "overt" HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.

Pacient s jaterní cirhózou na interním oddělení, intervence případného abúzu alkoholu

Liver cirrhosis represents a common condition with substantial mortality. Manifestation and progression of ascites, hepatic encephalopathy or gastrointestinal bleeding are among main reasons for hospital admission. Infections represent another specific area in cirrhotic patients. Timely and correct diagnosis and therapy of these conditions are the mainstay of optimal outcome. Manifestation of complications of liver cirrhosis significantly deteriorates prognosis of the patient. Ascites in portal hypertension develops as a result of sodium and consequently water retention. Therapy comprises of restriction of sodium intake, diuretic therapy with combination of spironolactone and furosemide, alternatively large-volume paracentesis. Hepatic encephalopathy comprises a spectrum of neuropsychiatric abnormalities from subtle changes to overt desorientation and asterixis to hepatic coma. Treatment includes correcting of predisposing conditions, administering of non-absorbable disaccharides or rifaximin. The most common cause of bleeding in a cirrhotic patient is oesophageal bleeding. Therapy is complex including hemodynamic stabilisation, antibiotic prophylaxis, vasoactive and endoscopic treatment. Infections are common causes of decompensation and occurrence of complications of advanced chronic liver disease. Their unfavourable outcome is a result of a complex immune disorder in cirrhotic patients. Specific type of infection in cirrhosis is spontaneous bacterial peritonitis, which has to be always excluded with diagnostic paracentesis. The mainstay of successful therapy of infections is timely and vigorous broad spectrum antibiotic therapy which can significantly improve otherwise unfavourable outcome of these patients.

Is rifaximin better than nonabsorbable disaccharides in hepatic encephalopathy?: A meta-analysis.

Background:The purpose of the present meta-analysis was to compare the efficacy of rifaximin and nonabsorbable disaccharides (NADs) in hepatic encephalopathy (HE).Methods:After the registration of the present meta-analysis on INPLASY, all procedures were performed according to PRISMA 2020. Relevant literature was retrieved on PubMed, Embase, and the Cochrane Library up to September 5, 2021. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the enrolled studies, and Review Manager software (version 5.3) was used to analyze the clinical efficacy, blood ammonia and adverse effects.Results:Six studies with 559 patients were included in the present meta-analysis. There were no significant differences in the basic characteristics of the included studies. Analysis of the complete resolution of HE showed that rifaximin was better than NADs (risk ratio [RR] = 1.87, 95% confidence interval [CI] = 1.03–3.39, P = .04). However, there were no significant differences in mental status (RR = 1.04, 95% CI = 0.92–1.18, P = .53), blood ammonia level (standard mean difference = −0.02, 95% CI = −0.40–0.02, P = .08), or drug adverse drug effects (OR = 0.43, 95% CI = 0.10–1.77, I2 = 56%, P = .24) between the rifaximin and NADs treatment groups.Conclusion:Rifaximin is not superior to NADs in the treatment of HE.

Efficacy and Safety of Rifaximin Versus Placebo or Other Active Drugs in Critical ill Patients With Hepatic Encephalopathy.

Objective: Rifaximin has been approved for use as a first-line therapy for secondary prophylaxis of hepatic encephalopathy (HE). This article is to update existing evidence on efficacy and safety of rifaximin treatment and prevention for HE. Methods: We systematically searched multiple databases until January 31 2021. The studies compared rifaximin vs. placebo or other active drugs (i.e., nonabsorbable disaccharides, other antibiotics, L-ornithine-L-aspartate (LOLA), and probiotics) for patients with overt HE (OHE), minimal HE (MHE), and recurrent HE. Results: Twenty-eight randomized controlled trials with a total of 2979 patients were included. Compared with the controls, rifaximin significantly reduced HE grade (OHE: RR = 1.11, 95% CI = 1.02–1.21), improved the cognitive impairments (MHE: RR = 1.82, 95% CI = 1.12–2.93) and prevented the risk of HE recurrent episodes (RR = 1.33, 95% CI = 1.18–1.49). No statistical difference was observed in mortality between rifaximin and their controls (RR = 0.82, 95% CI = 0.54–1.24). The incidence of total adverse events in rifaximin-treated groups was significantly lower than that in the controls during the treatment period (RR = 0.73, 95% CI = 0.54–0.98). In addition, rifaximin treatment was better than other active drugs in improving psychometric indicators (mental state, flapping tremor and portosystemic encephalopathy (PSE) index) and reducing the risk of rehospitalization in HE patients. Conclusion: Rifaximin therapy is effective and well-tolerated in different types of HE, which might be recommended as an alternative to conventional oral drugs in clinical settings.

Novel Agents in the Management of Hepatic Encephalopathy: A Review.

Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.

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.

Hepatic Encephalopathy: Diagnosis and Management.

Type C hepatic encephalopathy (HE) is a brain dysfunction caused by severe hepatocellular failure or presence of portal-systemic shunts in patients with liver cirrhosis. In its subclinical form, called “minimal hepatic encephalopathy (MHE), only psychometric tests or electrophysiological evaluation can reveal alterations in attention, working memory, psychomotor speed and visuospatial ability, while clinical neurological signs are lacking. The term “covert” (CHE) has been recently used to unify MHE and Grade I HE in order to refer to a condition that is not unapparent but also non overt. “Overt” HE (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor and coma. Based on its time course, OHE can be divided in Episodic, Recurrent or Persistent. Episodic HE is generally triggered by one or more precipitant factors that should be found and treated. Unlike MHE, clinical examination and clinical decision are crucial for OHE diagnosis and West Haven criteria are widely used to assess the severity of neurological dysfunction. Primary prophylaxis of OHE is indicated only in the patient with gastrointestinal bleeding using non-absorbable antibiotics (Rifaximin) or non-absorbable disaccharides (Lactulose). Treatment of OHE is based on the identification and correction of precipitating factors and starting empirical ammonia-lowering treatment with Rifaximin and Lactulose (per os and enemas). The latter should be used for secondary prophylaxis, adding Rifaximin if HE becomes recurrent. In recurrent/persistent HE, the treatment options include fecal transplantation, TIPS revision and closure of eventual splenorenal shunts. Treatment of MHE should be individualized on a case-by-case basis.

Leaky Gut and Gut-Liver Axis in Liver Cirrhosis: Clinical Studies Update.

Portal blood flows into the liver containing the gut microbiome and its products such as endotoxin and bacterial DNA. The cirrhotic liver acts and detoxifies as the initial site of microbial products. In so-called “leaky gut,” the increased intestinal permeability for bacteria and their products constitutes an important pathogenetic factor for major complications in patients with liver cirrhosis. Prolonged gastric and small intestinal transit may induce intestinal bacterial overgrowth, a condition in which colonic bacteria translocate into the small gut. Cirrhotic patients further show gut dysbiosis characterized by an overgrowth of potentially pathogenic bacteria and a decrease in autochthonous nonpathogenic bacteria. Pathological bacterial translocation (BT) is a contributing factor in the development of various severe complications. Bile acids (BAs) undergo extensive enterohepatic circulation and play important roles in the gut-liver axis. BT-induced inflammation prevents synthesis of BAs in the liver through inhibition of BA-synthesizing enzyme CYP7A1. A lower abundance of 7α-dehydroxylating gut bacteria leads to decreased conversion of primary to secondary BAs. Decreases in total and secondary BAs may play an important role in the gut dysbiosis characterized by a proinflammatory and toxic gut microbiome inducing BT and endotoxemia, as addressed in my previous reviews. Selective intestinal decontamination by the use of various antimicrobial drugs for management of complications has a long history. Lactobacillus GG decreasing endotoxemia is reported to improve the microbiome with beneficial changes in amino acid, vitamin and secondary BA metabolism. Current approaches for hepatic encephalopathy are the use of nonabsorbable antibiotics and disaccharides. Probiotics may become an additional therapeutic option for advanced liver cirrhosis. (Gut Liver 2021;15:-676)

Overt hepatic encephalopathy: management and prevention of recurrence.

Most patients with overt hepatic encephalopathy are managed in an acute hospital setting. The mainstays of treatment are non-absorbable disaccharides, To prevent a recurrence, and thus further hospital admission, the focus is on identifying and avoiding precipitants, optimising nutrition and prescribing medication including rifaximin-α*†.

P: 9 Pharmacotherapies that Specifically Target Ammonia for the Prevention and Treatment of Hepatic Encephalopathy in Adults With Crrhosis

BACKGROUND: Ammonia plays a key role in the genesis of hepatic encephalopathy (HE). Recent interest has focused on drugs which specifically target ammonia, e.g. sodium benzoate (SB), glycerol phenylbutyrate (GPB), ornithine phenylacetate (OP), AST-120, and polyethylene glycol (PEG). This study aims to evaluate the utility of these pharmacotherapies vs. placebo or non-absorbable disaccharides (NAD), for the management of HE in people with cirrhosis. L-ornithine L-aspartate is not included. METHODS: Electronic/manual searches of the literature were undertaken for relevant RCTs. The results of the meta-analyses are presented as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CIs). Bias control was assessed using the CHBG domains and the certainty of the evidence using GRADE. RESULTS: Eleven RCTs were identified involving SB (n = 1), GPB (n = 1), OA (n = 2), AST-120 (n = 2) and PEG (n = 3). Treatment periods ranged from five days to 16 weeks. All but one trial was at “high risk of bias”; the certainty of the evidence was very low for all outcomes. Nine trials, with 733 participants, reported blood ammonia concentrations. Significant reductions were observed in placebo-controlled trials evaluating SB (MD −32.00, 95% CI −46.85 to −17.15); GPB (MD −12.00, 95% CI −23.37 to −0.63); OP (MD −27.10, 95% CI −48.55 to −5.65) and AST-120 (MD −22.00, 95% CI −26.75 to −17.25). No significant differences in blood ammonia concentrations were observed when compared to NADs. Eleven trials, with 943 participants, reported mortality data, although there were no events in five trials. No beneficial or harmful effects were found in any of the trials. Seven trials, with 521 participants reported data on HE. Beneficial effects were identified for GPB vs. placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; NNTB = 6) and for PEG vs. lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB = 4); no beneficial effects were observed in the remaining three trials with extractable data (Figure 1). Ten trials, with 790 participants, reported a total of 130 serious adverse events. There was no evidence of beneficial or harmful effects of the five agents when compared to placebo or NADs. CONCLUSIONS: These agents generally reduce blood ammonia concentrations, when compared to placebo, but not when compared to NADs. Their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to fully evaluate their utility in this clinical setting.

P: 51 Aminoglycosides and Metronidazole for the Prevention and Treatment of Hepatic Encephalopathy in Adults With Cirrhosis

BACKGROUND: The EASL/AASLD guidelines stipulate that both neomycin and metronidazole may be used as alternatives for the treatment of overt HE, whereas the Italian guidelines state that these antibiotics are currently not recommended, mainly because of their potential systemic toxicity. This study aims to evaluate the utility of aminoglycosides and metronidazole vs. placebo, non-absorbable disaccharides (NAD) and other active treatment, for the management of HE in adults with cirrhosis. METHODS: Electronic/manual searches of the literature were undertaken for relevant RCTs. The results of the meta-analyses are presented as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CIs). Bias control was assessed using the CHBG domains and the certainty of the evidence using GRADE. RESULTS: Twenty RCTs evaluated aminoglycosides including neomycin (n = 15) paromomycin (n = 4), and ribostamycin (n = 1). Treatment periods ranged from 3 to 168 days. Comparators included: placebo (n = 2), NADs (n = 7), other antibiotics viz. rifaximin, erythromycin and ciproxin (n = 9) and BCAAs (n = 2). All but one trial was at 'high risk of bias'; the certainty of the evidence was low or very low for all outcomes. Twenty trials, with 1110 participants, reported mortality data, although there were no events in 12 trials. No differential beneficial or harmful effects were found in any of the trials (RR 1.10, 95% CI 0.89 to 1.42, I2 6%, P = 0.39). Seventeen trials, with 1025 participants reported data on HE. No differential beneficial or harmful effects were found in any of the trials (RR 0.89, 95% CI 0.57 to 1.39, I2 69%, P = 0.62). Twenty trials, with 1110 participants, reported 778 serious adverse events (SAEs), although there were no events in eight trials. Use of the aminoglycosides was associated with more SAEs including pneumonia and renal failure (RR 1.46, 95% CI 0.99 to 2.16, I2 0%, P = 0.06) (Figure 1). One RCT evaluated metronidazole vs. rifaximin. Treatment was administered for three days as an adjunct to oral lactulose, LOLA and thrice daily enemata. Both regimens were equally as effective; no adverse events were reported. CONCLUSIONS: Although no significant differences were observed between the effects of aminoglycosides and other interventions, in relation to death and HE, in patients with cirrhosis, their use may be associated with an increased risk of serous adverse events. The utility of metronidazole for the management of HE can not be evaluated on the basis of the available literature. Neither drug should be used routinely in this setting.

Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis.

Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by “gut-centric” therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.

Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis.

Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis.