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BACKGROUND: The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes. METHODS: Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted. RESULTS AND CONCLUSION: Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.
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Quimioterapia Combinada , Fármacos Gastrointestinales , Encefalopatía Hepática , Lactulosa , Recurrencia , Rifaximina , Humanos , Rifaximina/uso terapéutico , Rifaximina/administración & dosificación , Lactulosa/uso terapéutico , Lactulosa/administración & dosificación , Masculino , Persona de Mediana Edad , Método Doble Ciego , Femenino , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Adulto , Prevención Secundaria/métodos , Anciano , Resultado del TratamientoRESUMEN
The management of acute liver failure (ALF) in modern hepatology intensive care units (ICU) has improved patient outcomes. Critical care management of hepatic encephalopathy, cerebral edema, fluid and electrolytes; prevention of infections and organ support are central to improved outcomes of ALF. In particular, the pathogenesis of encephalopathy is multifactorial, with ammonia, elevated intra-cranial pressure and systemic inflammation playing a central role. Although ALF remains associated with high mortality, the availability of supportive care, including organ failure support such as plasma exchange, timely mechanical ventilation or continuous renal replacement therapy, either conservatively manages patients with ALF or offers bridging therapy until liver transplantation. Thus, appropriate critical care management has improved the likelihood of patient recovery in ALF. ICU care interventions such as monitoring of cerebral edema, fluid status assessment and interventions for sepsis prevention, nutritional support and management of electrolytes can salvage a substantial proportion of patients. In this review, we discuss the key aspects of critical care management of ALF.
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Edema Encefálico , Cuidados Críticos , Encefalopatía Hepática , Fallo Hepático Agudo , Humanos , Fallo Hepático Agudo/terapia , Fallo Hepático Agudo/etiología , Cuidados Críticos/métodos , Encefalopatía Hepática/terapia , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Edema Encefálico/terapia , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Intercambio Plasmático/métodos , Respiración Artificial/efectos adversos , Respiración Artificial/métodos , Apoyo Nutricional/métodos , Sepsis/terapia , Sepsis/complicaciones , Sepsis/etiología , Unidades de Cuidados Intensivos , Terapia de Reemplazo Renal/métodos , Trasplante de Hígado , Amoníaco/sangreRESUMEN
BACKGROUND: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that affects the prognosis of patients with liver disease and is considered an independent risk factor for hospitalization and death. Rifaximin has been approved for HE treatment. This review will analyze the effect of rifaximin on different stages of HE with differential application dosages and strategies by traditional and network meta-analyses. METHODS: We performed a systematic search of PubMed, EmBase, and Cochrane Library databases up to February 26, 2023, to identify randomized controlled trials (RCTs) about rifaximin for the prevention and treatment of HE. The outcomes included incidence of HE and HE progression, HE reversal, mortality, and adverse effects. RESULTS: A total of 21 studies were included. In the primary prevention of HE, rifaximin significantly reduced the incidence of HE (OR: 0.66; 95% CI: 0.45, 0.96; p = 0.032). In secondary prevention, rifaximin significantly reduced the risk of recurrence in patients who were in remission (OR: 0.38; 95% CI: 0.28, 0.52; p < 0.001). In the treatment of minimal HE, rifaximin significantly reduced the breakthrough of MHE to OHE (OR: 0.17; 95% CI: 0.04,0.63; p = 0.008). Rifaximin also significantly improved the clinical symptoms of MHE and OHE patients (OR: 3.76; 95% CI: 2.69, 5.25; p < 0.001). However, rifaximin did not reduce mortality at any stage in HE patients (OR: 0.79; 95% CI: 0.58, 1.08; p = 0.133). Additionally, rifaximin did not increase the risk of adverse effects (OR: 0.96; 95% CI: 0.74, 1.24; p = 0.749). In the network meta-analysis, the 400 mg T.I.D. intervention had a relative advantage for HE risks in primary and secondary prevention. In the treatment of MHE, 600 mg b.i.d. was superior in preventing the breakthrough from MHE to OHE. CONCLUSION: Rifaximin prevented HE risks and progression and improved clinical symptoms in patients with MHE but did not reduce mortality. For primary and secondary prevention, 400 mg t.i.d. could be considered. 600 mg b.i.d. could be considered in patients with MHE.
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Encefalopatía Hepática , Humanos , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Metaanálisis en Red , Rifaximina/uso terapéutico , Factores de Riesgo , Prevención SecundariaRESUMEN
Hepatic encephalopathy is described by a broad spectrum of neurological and psychiatric aberrations resulting due to advanced liver dysfunction. It is a neurological disorder due to hepatic insufficiency and/or portosystemic shunts. Its clinical presentation includes neuropsychiatric dysfunction ranging from subclinical changes to comatose state. It is a sign of poor prognosis in cirrhotics with a high 1-year mortality. Each episode of hepatic encephalopathy leads to high hospitalization rate, poor prognosis and raised burden of healthcare. Primary prophylaxis is prevention of initial occurrence and secondary prophylaxis is prevention of reappearance of hepatic encephalopathy in subjects who had prior history. Early detection and management of triggers is very important in the treatment of hepatic encephalopathy. The initial choice of treatment is still lactulose, as it is effective in minimal, overt, and recurrent hepatic encephalopathy. Rifaximin is equally effective as lactulose in managing hepatic encephalopathy and is better tolerated. Branch chain amino acids are beneficial in subjects who are protein intolerant. L-ornithine L-aspartate and probiotics are also useful in the management of hepatic encephalopathy. Rifaximin along with lactulose is effective in managing overt and recurrent hepatic encephalopathy. Large portosystemic shunts embolization and liver transplant is efficacious in certain group of patients. Nutritional therapy and fecal microbiota transplantation are newer therapies for hepatic encephalopathy but the evidences are limited, more research is required to prove their efficacy. Involvement of hospital pharmacists, telemedicine, and providing education are also beneficial in managing hepatic encephalopathy.
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Encefalopatía Hepática , Lactulosa , Rifaximina , Encefalopatía Hepática/prevención & control , Encefalopatía Hepática/tratamiento farmacológico , Humanos , Lactulosa/uso terapéutico , Rifaximina/uso terapéutico , Probióticos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Trasplante de Microbiota Fecal/métodos , Trasplante de Hígado , Prevención Secundaria/métodos , Aminoácidos de Cadena Ramificada/uso terapéutico , Prevención Primaria/métodos , DipéptidosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia (TC) a potential medicinal herb, has been ethnobotanically used as an eco-friendly supplement to manage various diseases, including cerebral fever. Earlier studies have shown that TC exhibits diverse beneficial effects, including hepatoprotective and neuroprotective effects. However, the effects of TC remain unexplored in animal models of encephalopathy including hepatic encephalopathy (HE). AIM OF THE STUDY: To evaluate the effects of TC stem extract against thioacetamide (TAA)-induced behavioural and molecular alterations in HE rats. METHODS AND MATERIALS: The extract was preliminarily screened through phytochemical and HR-LC/MS analysis. Animals were pre-treated with TC extract at doses 30 and 100 mg/kg, orally. Following 7 days of TC pre-treatment, HE was induced by administering TAA (300 mg/kg, i. p. thrice). Behavioural assessments were performed after 56 h of TAA first dose. The animals were then sacrificed to assess biochemical parameters in serum, liver and brain. Liver tissue was used for immunoblotting and histological studies to evaluate inflammatory and fibrotic signalling. Moreover, brain tissue was used to evaluate brain edema, activation of glial cells (GFAP, IBA-1) and NF-κB/NLRP3 downstream signalling via immunoblotting and immunohistochemical analysis in cortex and hippocampus. RESULTS: The pre-treatment with TC extract effective mitigated TAA-induced behavioural alterations, lowered serum LFT (AST, ALT, ALP, bilirubin) and oxidative stress markers in liver and brain. TC treatment significantly modulated hyperammonemia, cerebral edema and preserved the integrity of BBB proteins in HE animals. TC treatment attenuated TAA-induced histological changes, tissue inflammation (pNF-κB (p65), TNF-α, NLRP3) and fibrosis (collagen, α-SMA) in liver. In addition, immunoblotting analysis revealed TC pre-treatment inhibited fibrotic proteins such as vimentin, TGF-ß1 and pSmad2/3 in the liver. Our study further showed that TC treatment downregulated the expression of MAPK/NF-κB inflammatory signalling, as well as GFAP and IBA-1 (glial cell markers) in cortex and hippocampus of TAA-intoxicated rats. Additionally, TC-treated animals exhibited reduced expression of caspase3/9 and BAX induced by TAA. CONCLUSION: This study revealed promising insights on the protective effects of TC against HE. The findings clearly demonstrated that the significant inhibition of MAPK/NF-κB signalling and glial cell activation could be responsible for the observed beneficial effects of TC in TAA-induced HE rats.
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Encefalopatía Hepática , Hiperamonemia , Tinospora , Ratas , Animales , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Tioacetamida/toxicidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FN-kappa B/metabolismo , Hiperamonemia/metabolismo , Hiperamonemia/patología , Hígado , Estrés Oxidativo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/químicaRESUMEN
OBJECTIVES: Bee venom is used for medicinal purposes, including the treatment of neurological and liver diseases, but its use as a primary health care approach for preventive purposes requires further exploration. The aim of this study was to provide the first investigation into the possible protective effects of bee venom against hepatic encephalopathy, a serious neurodegenerative disease. MATERIALS AND METHODS: An experimental animal study was conducted in which healthy albino Sprague-Dawley rats were randomized into three groups: healthy, control and bee venom groups. All rats were tested for locomotor activity at the beginning and end of the study. No intervention was made in the healthy group, whereas hepatic encephalopathy was induced in the control and bee venom groups by the administration of thioacetamide (TAA) (200 mg/kg/day). The bee venom group also received bee venom (5 mg/kg/day) subcutaneously every day for 14 days prior to the TAA administration. RESULTS: The results for the final locomotor activity tests were statistically better in the bee venom group than in the control group, supporting a beneficial effect of prophylactic bee venom application. Blood ammonia levels and liver weights, determined as indicators of inflammation, were lower in the bee venom group than in the control group and were close to levels in the healthy group, but not statistically significant. CONCLUSIONS: Bee venom administration has protective effects against the development of hepatic encephalopathy and offers a promising therapeutic opportunity in preventive medicine.
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Venenos de Abeja , Encefalopatía Hepática , Enfermedades Neurodegenerativas , Animales , Ratas , Venenos de Abeja/uso terapéutico , Encefalopatía Hepática/prevención & control , Encefalopatía Hepática/veterinaria , Encefalopatía Hepática/tratamiento farmacológico , Enfermedades Neurodegenerativas/veterinaria , Ratas Sprague-DawleyRESUMEN
To date, side-to-side splenorenal shunt (SRS) and its analogues (splenosuprarenal shunts (SSRS)) are mainly used for portal hypertension. These are total portosystemic shunts characterized by total blood shunt from portal vein into inferior vena cava. The latter is fraught with a significant risk of complications such as pulmonary hypertension, decreased portal liver perfusion, liver failure and hepatic encephalopathy. Prevention of these complications is still an urgent problem in modern surgery. However, we proposed a new method of treatment, i.e. reconstruction of SRS and SSRS into selective shunt. This procedure was performed in 37 patients after 2020. We present laparoscopic reconstruction in an 11-year-old girl with portal hypertension and signs of hepatic encephalopathy identified after previous SSRS.
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Encefalopatía Hepática , Hipertensión Portal , Derivación Portosistémica Intrahepática Transyugular , Derivación Esplenorrenal Quirúrgica , Niño , Femenino , Humanos , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Hipertensión Portal/diagnóstico , Hipertensión Portal/etiología , Hipertensión Portal/cirugía , Vena Porta/diagnóstico por imagen , Vena Porta/cirugía , Derivación Esplenorrenal Quirúrgica/efectos adversosRESUMEN
BACKGROUND AND AIMS: Lactulose is the first-line drug for both treatment and secondary prophylaxis for overt hepatic encephalopathy (HE). The use of lactulose for the primary prophylaxis of HE in patients with cirrhosis and acute upper gastrointestinal bleeding (AUGIB) has been debated. Hence, we conducted this meta-analysis to assess the role of lactulose in HE prophylaxis in patients with cirrhosis and AUGIB. METHODS: A comprehensive search of literature from inception to December 2022 was performed of three databases for randomized studies comparing lactulose and placebo in patients with cirrhosis and AUGIB. Risk ratios (RR) with 95% confidence intervals were calculated for all the dichotomous outcomes. RESULTS: A total of five studies were included in the final analysis, out of which three studies had a low risk of bias, and two had a moderate risk of bias. Lactulose therapy was associated with a significantly lower risk of OHE compared to placebo, with a RR of 0.38 (0.23-0.62) and a number needed to treat of 6. There was no difference in the risk of mortality between the groups, with a RR of 0.71 (0.29-1.76). The pooled incidence rates of overall adverse events (AEs) and diarrhea with the use of lactulose therapy were 53.2% (42.2- 64.2) and 34.7% (17.7-51.7), but a majority did not require drug discontinuation. The certainty of the evidence was moderate to low. CONCLUSIONS: Prophylactic lactulose reduces the incidence of HE after AUGIB but has no effect on mortality. Diarrhea and abdominal discomfort are common AEs but do not need drug discontinuation.
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Encefalopatía Hepática , Lactulosa , Humanos , Lactulosa/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/tratamiento farmacológico , Diarrea , Hemorragia Gastrointestinal/tratamiento farmacológico , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & controlRESUMEN
Hyperammonemia is characterized by the excessive accumulation of ammonia in the body as a result of the loss of liver detoxification, leading to the development of hepatic encephalopathy (HE). These metabolic alterations carry cognitive and motor deficits and cause neuronal damage, with no effective treatment at present. In this study, we aimed to evaluate the effect of two subacute oral administrations of flaxseed oil (0.26 and 0.52 mL/kg) on short- and long-term memory, visuospatial memory, locomotor activity, motor coordination, and the neuronal morphology of the prefrontal cortex (PFC) via tests on Wistar rats with hyperammonemia. The goal was to identify its role in the regulation of cerebral edema, without liver damage causing cerebral failure. In contrast with an ammonium-rich diet, flaxseed oil and normal foods did not cause cognitive impairment or motor alterations, as evidenced in the short-term and visuospatial memory tests. Furthermore, the flaxseed oil treatment maintained a regular neuronal morphology of the prefrontal cortex, which represents a neuroprotective effect. We conclude that the oral administration of flaxseed oil prevents cognitive and motor impairments as well as neuronal alterations in rats with hyperammonemia, which supports the potential use of this oil to ameliorate the changes that occur in hepatic encephalopathy.
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Lino , Encefalopatía Hepática , Hiperamonemia , Ratas , Animales , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Encefalopatía Hepática/metabolismo , Ratas Wistar , Aceite de Linaza/farmacología , Hiperamonemia/complicaciones , CogniciónRESUMEN
Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.
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Encefalopatía Hepática , Lactulosa , Humanos , Ratones , Animales , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) can be an effective treatment for cirrhotic patients who develop variceal bleeding and ascites. However, TIPS placement is associated with an increased risk of developing hepatic encephalopathy (HE). Recently, there have been efforts to use the typical medical therapies prophylactically in patients undergoing TIPS placement to prevent post-TIPS HE. METHODS: We conducted literature searches in MEDLINE, Embase, CINAHL, Scopus, and Cochrane to examine studies that use prophylactic medical therapy for preventing post-TIPS HE. A narrative synthesis and grading of recommendations assessment assessment were done for all studies. Meta-analysis was performed for eligible studies using the Mantel-Haenszel method random-effects model. Nine hundred twenty-one articles were screened and 5 studies were included in the study after 2 levels of screening. The medications studied were rifaximin, lactulose, lactitol, L-Ornithine-L-aspartate (LOLA), albumin, and combination therapies. RESULTS: Narrative results showed that lactulose, lactitol, LOLA and albumin prophylaxis were not associated with reduction in HE occurrence or mortality. A combination of rifaximin and lactulose was found to be associated with lower occurrence of HE, and the results were not different when LOLA was added. Meta-analysis (n = 3) showed that rifaximin treatment was not associated with changes in HE occurrences. CONCLUSION: In conclusion, a vast majority of medications were not found to be effective post-TIPS HE prophylaxis when used alone. A rifaximin and lactulose combination therapy may be beneficial. Overall, there is significant limitation in the current data and more studies are needed to yield more robust meta-analysis results in the future.
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Várices Esofágicas y Gástricas , Encefalopatía Hepática , Humanos , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Lactulosa/uso terapéutico , Rifaximina , Hemorragia Gastrointestinal , Albúminas , Prevención PrimariaRESUMEN
BACKGROUND: Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia. OBJECTIVES: To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023. SELECTION CRITERIA: We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone. DATA COLLECTION AND ANALYSIS: Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay. MAIN RESULTS: We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.
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Encefalopatía Hepática , Humanos , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Rifaximina/uso terapéutico , Calidad de Vida , Amoníaco , Cirrosis Hepática/complicaciones , Disacáridos/efectos adversosRESUMEN
Microbiome therapies may be reported to be effective in hepatic encephalopathy (HE). We thus did a meta-analysis of randomized controlled trials to assess the effect of microbiome therapies for HE. We systematically searched PubMed, Web of Science, EMBASE, and Cochrane Library for randomized controlled trials that compared the different treatments for HE including probiotics, symbiotics, and fecal microbiota transplant (FMT). Meta-analysis was performed to calculate pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Twenty-one studies met our inclusion criteria (Nâ =â 1746 participants). Probiotics, synbiotics and FMT significantly reversed minimal HE (MHE) (OR: 0.41, 95% CI: 0.19-0.90, Pâ =â 0.03), reduced overt HE (OHE) development (OR, 0.41; 95% CI: 0.28-0.61 Pâ <â 0.00001)and the frequency of serious adverse events(SAEs) (OR:0.14, 95% CI: 0.04-0.47, Pâ =â 0.001), meanwhile decreased ammonia levels (WMD: -9.26, 95% CI: -16.92 to -1.61; Pâ =â 0.02), NCT level (MD = -4.41, 95% CI: -0.87 to -0.22, Pâ =â 0.04) and hospitalization rates (OR, 0.38; 95% CI: 0.19-0.79, Pâ =â 0.009) compared with placebo/no treatment. Finally, we conclude that microbiome therapies were more effective in improving MHE and preventing progression to OHE, reducing the frequency of SAEs, and decreasing ammonia levels, NCT level, and hospitalization rates when compared to placebo/no treatment.
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Encefalopatía Hepática , Microbiota , Probióticos , Simbióticos , Humanos , Amoníaco , Encefalopatía Hepática/prevención & control , Probióticos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
INTRODUCTION: Gastroesophageal varices (GOV) bleeding is a common and serious complication of advanced liver cirrhosis with a median survival of less than 2 years. Multiple guidelines have pointed out that transjugular intrahepatic portosystemic shunt (TIPS) is the rescue treatment of acute variceal hemorrhage (AVB) after failure of standard therapy and an effective second-line treatment for preventing patients with high risks from rebleeding of GOV. The safety and stability of TIPS have been greatly improved due to the improvements of related technologies and the emergence of various novel devices, but the incidence of hepatic encephalopathy (HE) after shunting (10-50%) hindered the widespread use of TIPS. The target portal vein branch might affect the incidence of HE after TIPS. The aim of this study is to compare the rate of HE in patients with hepatitis B virus (HBV) related cirrhosis receiving TIPS either the left or right branch of the portal vein with 8mm Viatorr stent for preventing rebleeding from GOV. METHODS AND ANALYSIS: This study is a multicenter randomized controlled trial comparing the influence of shunting left or right portal vein branch on post-TIPS hepatic encephalopathy for preventing rebleeding from GOV in patients with HBV-related cirrhosis. A total of 130 patients will be recruited over a period of 24 months across 5 centers in China. Eligible patients will be stratified 1:1 to constructing either a left or right portal vein shunt with an 8-mm Viatorr stent. The primary objective was to compare the incidence of post-TIPS hepatic encephalopathy between the two groups. The secondary objectives were to compare the grade and duration of hepatic encephalopathy, the rate of shunt dysfunction, the rate of variceal rebleeding, the HE-free survival, the cumulative patency rate of the stent, and the overall survival at 12 months and 24 months between two groups. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of Zhongshan Hospital of Fudan University (No. B2018-292R) and was registered at ClinicalTrials.gov (NCT03825848). All participants give written informed consent. TRIAL REGISTRATION: ClinicalTrials.gov NCT03825848. Registered on January 31, 2019 TRIAL STATUS: The first patient was recruited into our study on June 19, 2019. A total of 55 patients were recruited till May 27, 2021 (27 and 28 patients assigned to shunting the left (L Group) and right (R Group) branches of the portal vein, respectively).
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Várices Esofágicas y Gástricas , Encefalopatía Hepática , Derivación Portosistémica Intrahepática Transyugular , Humanos , Vena Porta/diagnóstico por imagen , Vena Porta/cirugía , Várices Esofágicas y Gástricas/cirugía , Várices Esofágicas y Gástricas/complicaciones , Encefalopatía Hepática/etiología , Encefalopatía Hepática/epidemiología , Encefalopatía Hepática/prevención & control , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Derivación Portosistémica Intrahepática Transyugular/métodos , Resultado del Tratamiento , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Hemorragia Gastrointestinal/prevención & control , Recurrencia Local de Neoplasia , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)- 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management.
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Encefalopatía Hepática , Ratas , Animales , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Tioacetamida/toxicidad , Ratas Wistar , Amoníaco/efectos adversos , Amoníaco/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Hígado/metabolismo , Estrés Oxidativo , Citocinas/metabolismoAsunto(s)
Embolización Terapéutica , Várices Esofágicas y Gástricas , Encefalopatía Hepática , Derivación Portosistémica Intrahepática Transyugular , Humanos , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Resultado del Tratamiento , Cirrosis Hepática , Hemorragia Gastrointestinal/prevención & controlAsunto(s)
Embolización Terapéutica , Várices Esofágicas y Gástricas , Encefalopatía Hepática , Derivación Portosistémica Intrahepática Transyugular , Humanos , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Resultado del Tratamiento , Cirrosis Hepática , Hemorragia Gastrointestinal/prevención & controlRESUMEN
BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is placed important role in the therapy of complications of portal hypertension, there is still no suitable criterion for a reduction in portosystemic gradient (PSG), which can both reduce PSG and maximize clinical results and minimize hepatic encephalopathy (HE). AIM: To compare the clinical outcomes and incidence of HE after one-third PSG reduction during TIPS in patients with variceal bleeding and refractory ascites. METHODS: A total of 1280 patients with portal-hypertension-related complications of refractory ascites or variceal bleeding who underwent TIPS from January 2016 to January 2019 were analyzed retrospectively. Patients were divided into group A (variceal hemorrhage and PSG reduced by one third, n = 479); group B (variceal hemorrhage and PSG reduced to < 12 mmHg, n = 412); group C (refractory ascites and PSG reduced by one third, n = 217); and group D (refractory ascites and PSG reduced to < 12 mmHg of PSG, plus medication, n = 172). The clinical outcomes were analyzed. RESULTS: By the endpoint of follow-up, recurrent bleeding was no different between groups A and B (χ 2 = 7.062, P = 0.374), but recurrent ascites did differ significantly between groups C and D (χ 2 = 14.493, P = 0.006). The probability of total hepatic impairment within 3 years was significantly different between groups A and B (χ 2 = 11.352, P = 0.005) and groups C and D (χ 2 = 13.758, P = 0.002). The total incidence of HE differed significantly between groups A and B (χ 2 = 7.932, P = 0.016), groups C and D (χ 2 = 13.637, P = 0.007). There were no differences of survival rate between groups A and B (χ 2 = 3.376, P = 0.369, log-rank test), but did differ significantly between groups C and D (χ 2 = 13.582, P = 0.014, log-rank test). CONCLUSION: The PSG reduction by one third may reduce the risk of HE, hepatic function damage and achieve good clinical results.
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Várices Esofágicas y Gástricas , Encefalopatía Hepática , Hipertensión Portal , Derivación Portosistémica Intrahepática Transyugular , Humanos , Várices Esofágicas y Gástricas/cirugía , Várices Esofágicas y Gástricas/complicaciones , Derivación Portosistémica Intrahepática Transyugular/efectos adversos , Derivación Portosistémica Intrahepática Transyugular/métodos , Ascitis/etiología , Estudios Retrospectivos , Hemorragia Gastrointestinal/prevención & control , Hemorragia Gastrointestinal/complicaciones , Hipertensión Portal/cirugía , Hipertensión Portal/complicaciones , Encefalopatía Hepática/epidemiología , Encefalopatía Hepática/etiología , Encefalopatía Hepática/prevención & control , Resultado del Tratamiento , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugíaRESUMEN
BACKGROUND: Rifaximin is an oral antimicrobial drug with a broad-spectrum effect. It locally regulates the function and structure of intestinal bacteria and decreases intestinal endotoxemia. We aimed to investigate the preventive role of rifaximin in recurrent episodes of hepatic encephalopathy in cases with a history of hepatic diseases. METHODS: We searched PubMed, Scopus, and Web of Science for the relevant studies using the following search strategy: "(Rifaximin) OR (Xifaxan) AND (cirrhosis) OR (encephalopathy)." We assessed the risk of bias using Cochrane's risk of bias tool. We included the following outcomes: recurrence of hepatic encephalopathy, adverse events, mortality rate, and time to the first episode of hepatic encephalopathy from the time of randomization (days). We performed the analysis of homogeneous data under the fixed-effects model, while analysis of heterogeneous data was performed under the random-effects model. RESULTS: We analyzed data obtained from 999 patients from 7 included trials. The overall risk ratio proved that the rifaximin group was associated with a lower recurrence rate than the control group (risk ratio [RR] = 0.61[0.50, 0.73], P = .001). We found no significant variation in both groups regarding adverse events (RR = 1.08 [0.89, 1.32], P = .41), and mortality rates (RR = 0.98 [0.61, 1.57], P = .93). The overall risk of bias results was low. CONCLUSION: The meta-analysis showed that in patients allocated to the rifaximin group, the incidence rate of hepatic encephalopathy was significantly lower when compared with those in the control group with no difference in both groups regarding adverse events and mortality rates.
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Encefalopatía Hepática , Hepatopatías , Rifamicinas , Humanos , Rifaximina/uso terapéutico , Encefalopatía Hepática/prevención & control , Encefalopatía Hepática/etiología , Hepatopatías/complicaciones , Cirrosis Hepática/complicaciones , Sesgo , Rifamicinas/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is often used in patients with cirrhosis to manage portal hypertension-related complications. Unfortunately, 35-50% of patients develop overt hepatic encephalopathy (HE) after TIPS. However, data on lactulose and rifaximin to prevent post-TIPS HE is limited. Therefore, we aimed to perform a network meta-analysis to investigate the efficacy of multiple pharmacological regimens in the prevention of post-TIPS HE. METHODS: A comprehensive search strategy to identify reports of studies of rifaximin use on post-TIPS hepatic encephalopathy was constructed using truncated keywords, phrases, and subject headings developed in Embase. This strategy was translated to MEDLINE, Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection, with all searches performed on 10 February 2022. No publication date or language limits were used. RESULTS: The initial search identified 72 studies, and 56 studies were screened after removing duplicates. Five studies, two randomized controlled trials (RCTs) and three retrospective studies, met our inclusion criteria and were included in the final analysis. A total of 840 patients were included, with 65% male. Our meta- analysis did not find a statistically significant difference between lactulose vs placebo/no prophylaxis, nor rifaximin vs placebo/no prophylaxis, nor rifaximin plus lactulose vs placebo/no prophylaxis in the reduction of post-TIPS HE. CONCLUSIONS: Rifaximin alone, lactulose alone, and rifaximin plus lactulose did not significantly reduce the development of post-TIPS HE. Based on the P-scores of the three treatment groups, the combination of rifaximin plus lactulose showed the most promising trend towards preventing post-TIPS HE. More studies, especially large RCTs, are warranted.