Carlos Guarner

Background: Frailty is a predictive factor of hospitalization, falls, and mortality in patients with cirrhosis, regardless of the degree of liver failure. The aim was to analyze whether a multifactorial intervention consisting of home-based exercise, branched-chain amino acids, and a multistrain probiotic can improve frailty in these patients. Methods: Outpatients with cirrhosis were classified according to the Liver Frailty Index (LFI). Prefrail and frail patients were randomized into 2 groups. The intervention group was assigned to a multifactorial intervention consisting of exercise at home, branched-chain amino acid supplements, and a multistrain probiotic for 12 months. The control group received standard care. All patients were prospectively followed up every 3 months for 1 year to determine LFI, incidence of falls, emergency room visits, hospitalizations, and mortality. Results: Thirty-two patients were included: 17 patients were assigned to the intervention group and 15 to the control group. In the intervention group, the baseline LFI decreased at 3, 6, 9, and 12 months (p = 0.019 for overall change with respect to the control group). The change in LFI (ΔLFI) at 12 months was −0.71 ± 0.24 in the intervention group and −0.09 ± 0.32 in the control group (pp = 0.03) and emergency room visits (10% vs. 44%, p = 0.04) than patients in the control group. Conclusions: A long-term multifactorial intervention that included exercise at home, branched-chain amino acids, and a multistrain probiotic improved frailty in outpatients with cirrhosis and was associated with a decrease in the incidence of clinical events such as falls and emergency room visits.

To explore the potential mechanisms underlying the effects of a probiotic in cirrhotic patients, we analyzed the blood metabolome using proton nuclear magnetic resonance (¹H-NMR) spectroscopy in 32 patients with cirrhosis and cognitive dysfunction or falls. Patients were randomized to receive a multistrain probiotic or placebo for 12 weeks. Among the 54 metabolites identified, the only significant changes in the probiotic group were an increase in glutamine, a decrease in glutamate, and an increase in the glutamine/glutamate ratio. In the placebo group, glutamate increased and the glutamine/glutamate ratio decreased. Our results suggest the multistrain probiotic could influence glutamine/glutamate metabolism, increasing the capacity of ammonia detoxification.

Probiotics can prevent pathological bacterial translocation by modulating intestinal microbiota and improving the gut barrier. The aim was to evaluate the effect of a fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 on bacterial translocation in rats with carbon tetrachloride (CCl₄)-induced cirrhosis. Sprague-Dawley rats treated with CCl₄ were randomized into a probiotic group that received fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 in drinking water or a water group that received water only. Laparotomy was performed one week after ascites development. We evaluated bacterial translocation, intestinal microbiota, the intestinal barrier and cytokines in mesenteric lymph nodes and serum. Bacterial translocation decreased and gut dysbiosis improved in the probiotic group compared to the water group. The ileal β-defensin-1 concentration was higher and ileal malondialdehyde levels were lower in the probiotic group than in water group. There were no differences between groups in serum cytokines but TNF-α levels in mesenteric lymph nodes were lower in the probiotic group than in the water group. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 decreases bacterial translocation, gut dysbiosis and ileal oxidative damage and increases ileal β-defensin-1 expression in rats treated with CCl₄, suggesting an improvement in the intestinal barrier integrity.

Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG‐guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute β‐blocker response were evaluated at baseline and HVPG measurements were repeated at 2‐4 weeks to determine chronic response. In the HVPG‐guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between‐group baseline characteristics were similar. During long‐term follow‐up (median of 24 months), mortality was lower in the HVPG‐guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35‐0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29‐0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46‐0.99). The survival probability was higher with HVPG‐guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32‐1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23‐0.99). HVPG‐guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). Conclusion: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using β‐blockers and ligation. HVPG‐guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693‐1707).

The most reliable indicators for post-ERCP acute pancreatitis are elevated amylase levels and abdominal pain 24 hours after ERCP. As ERCP is often performed on an outpatient basis, earlier diagnosis is important. We aimed to identify early predictors of post-ERCP pancreatitis. We prospectively analyzed IL-6, IL-10, TNFα, CRP, amylase and lipase before and 4 hours after ERCP, and studied their association with abdominal pain. We included 510 patients. Post-ERCP pancreatitis occurred in 36 patients (7.1%). IL-6, IL-10, TNFα and CRP were not associated with post-ERCP pancreatitis. Levels of amylase and lipase were higher in patients with pancreatitis (522 U/L and 1808 U/L vs. 78 U/L and 61 U/L, respectively; p < 0.001). A cut-off of 218 U/L for amylase (x2.2 ULN) and 355 U/L for lipase (x6 ULN) had a negative predictive value of 99.2% and 99.5%, respectively. Amylase and lipase present a good correlation (Pearson coefficient 0.912). Among 342 (67.1%) patients without abdominal pain at 4 hours, post-ERCP pancreatitis was diagnosed in 8 (2.3%). Only 4 of these patients presented amylase or lipase > 3 ULN. Amylase and lipase were the only markers of post-ERCP pancreatitis 4 hours after the procedure.

Summary: Background: Hospital mortality in patients with spontaneous bacterial peritonitis (SBP) is high despite albumin treatment, particularly in those with worse liver and/or renal function.Aim: To determine the independent predictive factors of in‐hospital mortality and to create and validate a predictive model of mortality in patients with SBP.Methods: We analysed all cirrhotic patients with high‐risk SBP (serum urea ≥11 mmol/L and/or serum bilirubin ≥68 μmol/L) between 2001 and 2011. We developed a predictive model of in‐hospital mortality and validated this in a different cohort.Results: We included 118 high‐risk SBP episodes treated with antibiotics and albumin. In‐hospital mortality was 33/118 (28%). The independent predictive factors of in‐hospital mortality at SBP diagnosis were serum urea, blood leucocyte count, Child–Pugh score and mean arterial pressure. A predictive model including these four variables showed a discrimination accuracy (AUC) of 0.850, 95% CI 0.777–0.922. A cut‐off point of 0.245 showed a sensitivity of 0.85 and specificity of 0.75. The in‐hospital mortality was 28/49 (57.1%) in patients with a model value ≥0.245, and 5/69 (7.2%) in patients with a model value P < 0.001). The validation series included 161 patients with an in‐hospital mortality of 40/161 (24.8%), 30/77 (39.0%) in patients with a model value ≥0.245, and 10/84 (11.9%) in those with a model value P < 0.001).Conclusions: We developed and validated a predictive model of mortality that includes serum urea, blood leucocyte count, Child–Pugh score and mean arterial pressure in high‐risk patients with spontaneous bacterial peritonitis. These findings may help to identify patients who would benefit from additional therapeutic strategies.

The progression of cirrhosis is associated with alterations in the composition of the gut microbiome. To assess microbial translocation, we compared the serum microbial composition of patients with and without ascites and characterized the ascitic fluid microbiome using 16S rDNA high-throughput sequencing data. A complex and specific microbial community was detected in the serum and ascitic fluid of patients with cirrhosis but barely detectable in the serum of healthy controls. The serum microbiome of patients with ascites presented higher levels of lipopolysaccharide binding protein, a marker of microbial translocation, associated with higher diversity and relative abundance of Clostridiales and an unknown genus belonging to the Cyanobacteria phylum compared to patients without ascites. The composition of the fecal microbiome was also more altered in patients with than without ascites, confirming previous studies on fecal microbiome. We propose that alteration of the serum and fecal microbiome composition be considered indicators of cirrhosis progression.

Patients with cirrhosis often have functional limitations, decreased muscle mass, and a high risk of falls. These variables could improve with exercise. The aim was to study the effects of moderate exercise on functional capacity, body composition and risk of falls in patients with cirrhosis. Twenty-three cirrhotic patients were randomized to an exercise programme (n = 14) or to a relaxation programme (n = 9). Both programmes consisted of a one-hour session 3 days a week for 12 weeks. At the beginning and end of the study, we measured functional capacity using the cardiopulmonary exercise test, evaluated body composition using anthropometry and dual energy X-ray absorptiometry, and estimated risk of falls using the Timed Up&Go test. In the exercise group, cardiopulmonary exercise test showed an increase in total effort time (pTrial Registration: ClinicalTrials.gov NCT01447537