Treatment with metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis.

BACKGROUND & AIM: Despite treatment with glucocorticoids, mortality remains high in patients with severe alcoholic hepatitis. Oxidative stress and depletion of mitochondrial glutathione are implicated factors in liver injury. The aim of this study was to evaluate the impact of the addition of metadoxine, a drug which possesses a multifactorial mechanism of action, including antioxidant properties, to standard treatment with glucocorticoids in patients with severe alcoholic hepatitis. MATERIAL AND METHODS: This randomized open label clinical trial was performed in Mexico's General Hospital (Registry Key DIC/10/107/03/043). We randomized 70 patients with severe alcoholic hepatitis. The first group received prednisone (40 mg/day), and the second group received prednisone (40 mg/day) plus metadoxine tablets (500 mg three times daily). The duration of treatment in both groups was 30 days. Survival at 30 and 90 days, development of complications, adverse events and response to treatment (Lille model) were assessed. RESULTS: In the group receiving metadoxine, significant improvements were observed, as follows: survival at 30 days (74.3 vs. 45.7%, P = 0.02); survival at 90 days (68.6 vs. 20.0%, P = 0.0001). There was less development or progression of encephalopathy (28.6 vs. 60.0%, P = 0.008) and hepatorenal syndrome (31.4 vs. 54.3%, P = 0.05), and the response to treatment (Lille model) was higher in the metadoxine group (0.38 vs. 0.63, P = 0.001; 95% CI 0.11 to 0.40). There were no differences between groups regarding the development or progression of variceal hemorrhage or infection. The incidence of adverse events, mainly gastrointestinal, was similar in both groups. CONCLUSIONS: Addition of metadoxine to glucocorticoid treatment improves the short-term survival of patients with severe alcoholic hepatitis and diminishes the development or progression of encephalopathy and hepatorenal syndrome.

PROTON PUMP INHIBITORS INCREASE THE OVERALL RISK OF DEVELOPING BACTERIAL INFECTIONS IN PATIENTS WITH CIRRHOSIS.

BACKGROUND: Acid suppression has been associated with adverse events; such as, enteric infections. Proton pump inhibitors (PPI) are frequently prescribed in patients with cirrhosis, but is unclear if PPI are associated with the development of bacterial infections in these patients. OBJECTIVE: To assess the impact of PPI intake on the development of bacterial, viral and fungal infections in patients with cirrhosis. METHODS: An observational, retrospective, historic cohort study. The exposed cohort included patients with cirrhosis with chronic use of PPI. The non-exposed cohort had not been using PPI. The follow-up period was 3 years, searching in the medical records for any events of bacterial infection confirmed by bacteriological culture. RESULTS: One hundred and thirteen patients met the selection criteria, 44 (39%) had chronic use of PPI; of them, 28 (63.6%) patients had not a clear clinical indication to justify the prescription of PPI. Twenty four (21.2%) patients developed bacterial infections during the follow-up period. In the univariate analysis, decompensated cirrhosis (Child B/C), presence of ascites, history of variceal bleeding, and chronic consumption of PPI were risk factors related to the development of infections. But, in the adjusted multivariate analysis only the chronic use of PPI was associated with development of infections (RR=3.6; 95% CI=1.1-12.3; P=0.04). CONCLUSION: There is an over-prescription of PPI without a justified clinical indication. The long-term consumption of PPI in patients with cirrhosis is associated with the development of bacterial infections; therefore these drugs must be carefully prescribed in this specific population.

Primary Prophylaxis to Prevent the Development of Hepatic Encephalopathy in Cirrhotic Patients with Acute Variceal Bleeding.

Background and Aim: Variceal bleeding is the second most important precipitating factor related to the development of episodic hepatic encephalopathy; but to date there are no recommendations to prevent this complication. The aim of this study was to compare if primary prophylaxis with lactulose or L-ornithine L-aspartate or rifaximin, in cirrhotic patients with variceal bleeding, is better than placebo for avoiding the development of hepatic encephalopathy. Methods: A randomized, double-blind, placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT02158182) which included cirrhotic patients with variceal bleeding, without minimal or clinical hepatic encephalopathy at admission. Findings: 87 patients were randomized to one of four groups. The basal characteristics were similar between groups. Comparatively with placebo, the frequency with regard to the development of hepatic encephalopathy was as follows: lactulose (54.5% versus 27.3%; OR = 0.3, 95% CI 0.09-1.0; P = 0.06); L-ornithine L-aspartate (54.5% versus 22.7%, OR = 0.2, 95% CI 0.06-0.88; P = 0.03); rifaximin (54.5% versus 23.8%; OR = 0.3, 95% CI 0.07-0.9; P = 0.04). There was no significant difference between the three groups receiving any antiammonium drug (P = 0.94). In the group receiving lactulose, 59.1% had diarrhea, and 45.5% had abdominal discomfort, bloating, and flatulence. Two patients (10%) treated with lactulose and a patient (4.5%) in the placebo group developed spontaneous bacterial peritonitis due to E. coli; one of them died due to recurrent variceal bleeding. There were no other adverse effects. Conclusions: Antiammonium drugs, particularly L-ornithine L-aspartate and rifaximin, proved to be effective in preventing the development of hepatic encephalopathy in those cirrhotic patients with variceal bleeding.

Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets.

Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1 (GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted, GLP-1 is quickly degraded by dipeptidyl peptidase-4 (DPP-4). Therefore, DPP-4 inhibitors are able to extend the activity of GLP-1. Currently, GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors, such as the farsenoid X receptor, also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, farnesoid X receptor-α, or the small heterodimeric partner. Finally, pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion, inhibit mucosal adherence by bacteria, and stimulate host immunity. In animal models, probiotics prevent obesity, decrease transaminase levels, and improve IR and liver histology in NASH.

Mean platelet volume as a novel predictor of systemic inflammatory response in cirrhotic patients with culture-negative neutrocytic ascites.

AIM: To identify a mean platelet volume (MPV) cutoff value which should be able to predict the presence of bacterial infection. METHODS: An observational, analytic, retrospective study. We evaluated medical records of cirrhotic patients who were hospitalized from January 2012 to January 2014 at the Gastroenterology Department of "Hospital General de México Dr. Eduardo Liceaga", we included 51 cirrhotic patients with ascites fluid infection (AFI), and 50 non-infected cirrhotic patients as control group. Receiver operator characteristic curves were used to identify the best cutoff value of several parameters from hematic cytometry, including MPV, to predict the presence of ascites fluid infection. RESULTS: Of the 51 cases with AFI, 48 patients (94.1%) had culture-negative neutrocytic ascites (CNNA), 2 (3.9%) had bacterial ascites, and one (2%) had spontaneous bacterial peritonitis. Infected patients had greater count of leucocytes and polymorphonuclear cells, greater levels of MPV and cardiac frequency (P < 0.0001), and lower mean arterial pressure compared with non-infected patients (P = 0.009). Leucocytes, polymorphonuclear count, MPV and cardiac frequency resulted to be good or very good predictive variables of presence of AFI in cirrhotic patients (area under the receiving operating characteristic > 0.80). A cutoff MPV value of 8.3 fl was the best to discriminate between cirrhotic patients with AFI and those without infection. CONCLUSION: Our results support that MPV can be an useful predictor of systemic inflammatory response syndrome in cirrhotic patients with AFI, particularly CNNA.

Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis.

AIM: To evaluate the impact of metadoxine (MTD) on the 3- and 6-mo survival of patients with severe alcoholic hepatitis (AH). METHODS: This study was an open-label clinical trial, performed at the "Hospital General de México, Dr. Eduardo Liceaga". We randomized 135 patients who met the criteria for severe AH into the following groups: 35 patients received prednisone (PDN) 40 mg/d, 35 patients received PDN+MTD 500 mg three times daily, 33 patients received pentoxifylline (PTX) 400 mg three times daily, and 32 patients received PTX+MTD 500 mg three times daily. The duration of the treatment for all of the groups was 30 d. RESULTS: In the groups treated with the MTD, the survival rate was higher at 3 mo (PTX+MTD 59.4% vs PTX 33.3%, P = 0.04; PDN+MTD 68.6% vs PDN 20%, P = 0.0001) and at 6 mo (PTX+MTD 50% vs PTX 18.2%, P = 0.01; PDN+MTD 48.6% vs PDN 20%, P = 0.003) than in the groups not treated with MTD. A relapse in alcohol intake was the primary independent factor predicting mortality at 6 mo. The patients receiving MTD maintained greater abstinence than those who did not receive it (74.5% vs 59.4%, P = 0.02). CONCLUSION: MTD improves the 3- and 6-mo survival rates in patients with severe AH. Alcohol abstinence is a key factor for survival in these patients. The patients who received the combination therapy with MTD were more likely to maintain abstinence than those who received monotherapy with either PDN or PTX.

Inibidores de bomba protônica aumentam o risco geral de desenvolver infecções bacterianas em pacientes com cirrose / Proton pump inhibitors increase the overall risk of developing bacterial infections in patients with cirrhosis

ABSTRACT BACKGROUND: Acid suppression has been associated with adverse events; such as, enteric infections. Proton pump inhibitors (PPI) are frequently prescribed in patients with cirrhosis, but is unclear if PPI are associated with the development of bacterial infections in these patients. OBJECTIVE: To assess the impact of PPI intake on the development of bacterial, viral and fungal infections in patients with cirrhosis. METHODS: An observational, retrospective, historic cohort study. The exposed cohort included patients with cirrhosis with chronic use of PPI. The non-exposed cohort had not been using PPI. The follow-up period was 3 years, searching in the medical records for any events of bacterial infection confirmed by bacteriological culture. RESULTS: One hundred and thirteen patients met the selection criteria, 44 (39%) had chronic use of PPI; of them, 28 (63.6%) patients had not a clear clinical indication to justify the prescription of PPI. Twenty four (21.2%) patients developed bacterial infections during the follow-up period. In the univariate analysis, decompensated cirrhosis (Child B/C), presence of ascites, history of variceal bleeding, and chronic consumption of PPI were risk factors related to the development of infections. But, in the adjusted multivariate analysis only the chronic use of PPI was associated with development of infections (RR=3.6; 95% CI=1.1-12.3; P=0.04). CONCLUSION: There is an over-prescription of PPI without a justified clinical indication. The long-term consumption of PPI in patients with cirrhosis is associated with the development of bacterial infections; therefore these drugs must be carefully prescribed in this specific population.

RESUMO CONTEXTO: A supressão de ácido tem sido associada a efeitos adversos, tais como infecções entéricas. Inibidores da bomba protônica são frequentemente prescritos em pacientes com cirrose, mas não está claro se o inibidor de bomba de próton (IBP) está associado ao desenvolvimento de infecções bacterianas nesses pacientes. OBJETIVO: Avaliar o impacto da ingestão de IBP no desenvolvimento de infecção bacteriana, viral e fúngica em pacientes com cirrose. MÉTODOS: Foi realizado estudo de coorte observacional, retrospectivo, histórico. A coorte exposta incluiu pacientes com cirrose e com uso crônico de IBP. A coorte de não expostos não estava usando IBP. O período de seguimento foi de 3 anos, procurando-se nos registros médicos qualquer evento de infecção bacteriana, confirmada pela cultura bacteriológica. RESULTADOS: Cento e treze pacientes preencheram os critérios de seleção, 44 (39%) pacientes faziam uso crônico de IBP; deles, 28 (63,6%) não tinham uma indicação clínica clara para justificar a prescrição de IBP. Vinte e quatro (21,2%) pacientes desenvolveram infecções bacterianas durante o período de seguimento. Na análise univariada, cirrose descompensada (Child B/C), presença de ascite, história de hemorragia varicosa e consumo crônico de IBP foram fatores de risco relacionados ao desenvolvimento de infecções. Porém, na análise multivariada ajustada, somente o uso crônico de IBP foi associado ao desenvolvimento de infecções (RR=3,6; 95% CI = 1.1-12.3; P=0,04). CONCLUSÃO: Há uma prescrição excessiva de PPI sem uma indicação clínica justificada. O consumo de longo prazo do IBP em pacientes com cirrose é associado ao desenvolvimento de infecções bacterianas. Portanto, essas drogas devem ser cuidadosamente prescritas nesta população específica.