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Gaurav Pande,1 Manjunath Hatti,1 Mohit Kumar Rai,2 Praveer Rai,1 Kamlesh Kumar,1 Krishna VP,1 Abhimanyu Nehra,1 Sudeep Kumar,3 Smarak Ranjan Rout,3 Sourav Kumar Mishra,3 Dinesh Kumar,4 Umesh Kumar,4 Prabhaker Mishra,5 Abdul Majeed,1 Vivek Anand Saraswat,1,&ast; Kritika Singh,2 Harshit Singh,2 Durga Prasanna Misra,2 Vikas Agarwal2,&ast; 1Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; 2Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; 3Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; 4Department of Advanced Spectroscopy and Imaging, Center of Biomedical Research, Lucknow, India; 5Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India&ast;These authors contributed equally to this workCorrespondence: Vikas Agarwal, Unit III, Clinical Immunology and Rheumatology, SGPGIMS, Raebareli Road, Lucknow, India, Tel +918004904390, Fax +91522268812, Email vikasagr@yahoo.comBackground and Aims: Acute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcomes. Severely deranged systemic hemodynamics and decreased effective arterial blood volume contribute to tissue damage and organ failure. Response-guided therapy with albumin, vasoconstrictors, and furosemide may help overcome effective hypovolemia, improve diuresis and impact survival.Methods: In the observation cohort, 230 patients with ACLF (CANONIC criteria) with ascites (≥Grade II) and ACLF ≥Grade I were enrolled. A total of 136 patients (GROUP I) received response-guided (urine sodium > 80mmol/day) slow albumin-furosemide infusion ± terlipressin (SAFI ± T), while 94 patients (GROUP II) received standard medical therapy. Twenty-eight-day survival, ascites mobilization (nil or grade 1), and adverse events were noted. In another mechanistic cohort (n = 40), laboratory evidences for improvement in various pathophysiological alterations; gut permeability, endotoxemia, cytokine storm, neutrophil dysfunction, and hemodynamic alterations following SAFI ± T/Noradrenaline (NAdr) were evaluated.Results: Age, gender, CLIF-C-ACLF, SOFA and MELD scores, ACLF grades and urine sodium were not different between the two groups in the observation cohort. Ascites was mobilized in 102/136 in GROUP I (SAFI ± T) and 23/94 in GROUP II (p < 0.05). Twenty-eight-day survival was significantly higher in GROUP I = 103/136 (75.7%) vs GROUP II = 50/94 (53.2%), (P = < 0.001). All those who were unable to reach urine sodium > 80 mmol/day died. Four patients in GROUP I developed scrotal gangrene. In the mechanistic cohort, 72% of patients survived with significant improvement in gut permeability, endotoxemia, serum cytokines, neutrophil dysfunction, and hemodynamic alterations.Conclusion: Ascitic fluid mobilization by response-guided SAFI ± T/NAdr therapy improves survival by improving splanchnic and systemic hemodynamics, decreasing gut congestion, gut permeability, and endotoxemia, improving neutrophil functions, and reducing pro-inflammatory cytokines in circulation.Graphical Abstract: Keywords: urine sodium, hemodynamics, renal artery resistive index, cytokines, neutrophil extracellular traps

Minimal hepatic encephalopathy (MHE) and hyperammonemia are seen in patients with extrahepatic portal venous obstruction (EHPVO). Inflammation has been shown to play an important role in the pathogenesis of hepatic encephalopathy in cirrhotics. This study assessed serum pro-inflammatory cytokines and their correlation with hyperammonemia, (1)H-magnetic resonance (MR) spectroscopy-derived brain glutamine, and diffusion tensor imaging (DTI)-derived metrics in patients with EPHVO, with and without MHE.Neuropsychological tests, DTI, (1)H-MR spectroscopy, and estimation of blood ammonia and pro-inflammatory cytokines (tumor necrosis factor-α[TNF-α] and interleukin-6 [IL-6]) were done in 20 patients with EHPVO and eight healthy controls.Pro-inflammatory cytokines (TNF-α and IL-6), blood ammonia, brain glutamine, and mean diffusivity were increased in both patient groups, as compared to controls. Patients with MHE (n-12) had significantly higher TNF-α, IL-6, blood ammonia, brain glutamine, and mean diffusivity, signifying brain edema, than controls. A significant, positive correlation was seen between TNF-α and IL-6 and between blood ammonia and TNF-α, IL-6, and brain glutamine. Significant, positive correlations of TNF-α, IL-6, and blood ammonia with mean diffusivity values were seen in various brain regions, including spectroscopy voxel-derived mean diffusivity.Patients with extrahepatic portal vein obstruction have inflammation and hyperammonemia made evident by higher blood TNF-α, IL-6, ammonia, and brain glutamine levels. A significant correlation between hyperammonemia, pro-inflammatory cytokines, and cerebral edema on DTI in various brain regions suggests that both these factors play a role in the pathogenesis of MHE in these patients.

Acute-on-chronic liver failure (ACLF), acute liver failure (ALF) and chronic liver disease (CLD) are common forms of liver failure and present with similar clinical profiles. The aim of this study was to compare brain metabolite alterations in all the three groups of patients with controls, using in vivo proton magnetic resonance spectroscopy (MRS), and to look for any significant differences in metabolites that may help in differentiating between these three conditions.Nine patients with ACLF, 10 with ALF, 10 patients with CLD and 10 age-matched controls were studied. The relative concentrations of N-acetylaspartate (NAA), choline (Cho), glutamine/glutamate (Glx) and myoinositol (mI) with respect to creatine (Cr) were measured.ACLF (3.07+/-0.72), ALF (4.39+/-1.25) and CLD (3.15+/-0.69) patients exhibited significantly increased Glx/Cr ratios compared with controls (2.14+/-0.42). The NAA/Cr ratio was significantly decreased in both ACLF (mean=0.84+/-0.28) and CLD (mean=0.97+/-0.21) patients as compared with that in controls (mean=1.24+/-0.20). No significant difference among ALF, ACLF and CLD patients was noted in the Cho/Cr ratios. ACLF patients showed significantly lower mI/Cr and Glx/Cr ratios compared with the ALF group.In vivo proton MRS-derived cerebral metabolite alterations in hepatic encephalopathy owing to ALF are significantly different from the one owing to ACLF and CLD; these may be due to the differences in the pathogenesis of these two overlapping clinical conditions.