Guresh Kumar

Healthy Donor Fecal Microbiota Transplantation in Steroid-Ineligible Severe Alcoholic Hepatitis: A Pilot Study

© 2017 by the AGA Institute 1542-3565/

Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial

36.00 http://dx.doi.org/10.1016/j.cgh.2016.10.029 Patients with untreated severe alcoholic hepatitis (SAH) have 50% 28-day survival; much worse in the steroid-ineligible group. Gut dysbiosis is common and plays a role in the development and progression of alcoholic liver disease. We undertook to modulate gut microbiota in patients with SAH through healthy donor fecal microbiota transplantation (FMT) therapy.

Impaired monocyte-macrophage functions and defective toll-like receptor signaling in hepatitis E virus-infected pregnant women with acute liver failure

Background and aims Carvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices. Methods Consecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices. Results Baseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (−8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group. Conclusions Carvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis. Trial registration number NCT01196507; post-results.

Point -of -care testing (POCT) in molecular diagnostics: Performance evaluation of GeneXpert HCV RNA test in diagnosing and monitoring of HCV infection

Acute viral hepatitis resulting due to hepatitis E viral infection (AVH‐E) is often serious in pregnancy and could result in acute liver failure (ALF). The role of monocytes and macrophages (mono‐macs) in the pathogenesis of AVH‐E and development of ALF‐E in pregnancy is unclear. We investigated the functions of mono‐macs in pregnant (P), AVH‐E (n = 44), ALF‐E (n = 12), healthy controls (HC; n = 20) and compared with nonpregnant (NP) AVH‐E (n = 10), ALF‐E (n = 5), and HC (n = 10). We also recruited non‐hepatitis E virus‐related pregnant (P), ALF‐NE (n = 5) and non‐pregnant (NP), ALF‐NE (n = 12) patients with ALF. Mono‐macs, dendritic cell (DC) phenotypes, and Toll‐like receptor (TLR) expressions were studied by flow cytometry and reverse‐transcriptase polymerase chain reaction. Mono‐macs functionality was determined by analyzing their phagocytic activity and reactive oxygen species (ROS) generation by using flow cytometry. Frequency of mono‐macs and DCs was increased during HEV infection compared to HC (P < 0.001). Macrophages were increased (P < 0.002) in ALF‐E(P) compared to ALF‐NE(P). The macrophage phagocytic activity and Escherichia coli‐induced ROS production was significantly impaired in ALF‐E(P) compared to AVH‐E(P) (P < 0.001), ALF‐E(NP), and ALF‐NE(P) patients (P < 0.02). TLR3 and TLR9 expression and downstream MYD88 signalling molecules IRF3 and IRF7 were significantly down‐regulated in ALF‐E(P) (P < 0.00) compared to AVH‐E(P) and ALF‐NE(P). Conclusion: Functionality of mono‐macs is impaired in pregnant ALF‐E patients compared to AVH‐E(P). Reduced TLR3 and TLR7 expression and TLR downstream‐signaling molecules in pregnant ALF‐E patients suggests inadequate triggers for the innate immune responses contributing to development and severity of ALF‐E. Studies using TLR agonists to activate mono‐macs may be of use and in vitro studies should be undertaken using patient samples.(Hepatology 2015;62:1683–1696)

Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver.

BACKGROUND Molecular testing at the point-of-care may turn out to be game changer for HCV diagnosis and treatment monitoring, through increased sensitivity, reduced turnaround time, and ease of performance. One such assay GeneXpert® has recently been released. OBJECTIVES Comparative analysis between performances of GeneXpert® and Abbott HCV-RNA was done. STUDY DESIGN 174 HCV infected patients were recruited and, one time plasma samples from 154 patients and repeated samples from 20 patients, obtained at specific treatment time-points (0, 4, 12 and 24) weeks were serially re-tested on Xpert®. RESULTS Genotype 3 was the commonest, seen in 80 (66%) of the cases, genotype 1 in 34 (28.3%), genotype 4 in 4 (3.3%) and genotypes 2 and 5 in 1 (0.8%) each. Median HCV RNA load was 4.69 log10 (range: 0-6.98log10) IU/ml. Overall a very good correlation was seen between the two assays (R2=0.985), concordance of the results between the assays was seen in 138 samples (89.6%). High and low positive standards were tested ten times on Xpert® to evaluate the precision and the coefficient of variation was 0.01 for HPC and 0.07 for the LPC. Monitoring of patients on two different regimes of treatment, pegylated interferon plus ribavirin and sofosbuvir plus ribavirin was done by both the systems at baseline, 4, 12 and 24 weeks. Perfect correlation between the assays in the course of therapy at different treatment time- point in genotypes 3 and 1 was seen. CONCLUSION The study demonstrates excellent performance of the Xpert® HCV assay in viral load assessment and in treatment course monitoring consistency.

Oxidant-antioxidant status in Indian patients with carcinoma of posterior one-third of tongue

Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End‐Stage Liver Disease (ρ = ‐0.582, P < 0.001) and Childs scores (P < 0.038). BMs of cirrhosis patients with higher Model of End‐Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin‐1β (P = 0.004), tumor necrosis factor‐α (P = 0.040), and interferon‐γ (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell‐derived factor 1 (P = 0.03) compared to those with lower Model of End‐Stage Liver Disease scores (≤15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction. Conclusions: Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273‐1288)

A randomized trial comparing terlipressin and noradrenaline in patients with cirrhosis and septic shock.

OBJECTIVE Cancer of posterior one-third of tongue is seen in 0.43% of total world population. Worldwide, cancer of tongue constitutes 5% of the total cancer incidence. Squamous cell cancer of head and neck is the most common cancer encountered in India. Oxidative stress is potentially harmful to cells and ROS are involved in multistage carcinogenesis, in initiation and promotion. Moreover, the extent of ROS-induced oxidative damage can be exacerbated by decreased efficiency of antioxidant defense mechanisms. The aim of this study was to assess the alterations in the circulating lipid peroxide, antioxidant components and the activities of defense enzymes in patients with cancer of posterior one-third of tongue, with respect to healthy controls in the Indian population. METHODS 60 patients with newly diagnosed, histologically proven cases of locally advanced squamous cell carcinoma (Stage III-IVa) of posterior one-third of tongue were recruited into the study. 60 healthy controls, without history or laboratory evidence of malignancy and inflammatory disorder, were also included in the study, after obtaining informed consent. Single blood samples were taken from patients, before start of therapy and controls. Lipid peroxides, conjugated dienes, reduced glutathione (GSH), vitamin C and E were estimated using standard methods. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) were assayed using commercially available kits from Randox, UK. RESULTS The pre-treatment levels of plasma lipid peroxide and conjugated dienes were significantly elevated in patients with carcinoma of posterior one-third of tongue, as compared with controls (p=0.001). Significantly lowered levels of GSH, GPx, SOD and antioxidant vitamins were observed in cancer patients, when compared to control subjects (p=0.001). Pearsons correlation analysis showed a highly statistitically significant negative correlation between pro-oxidant and anti-oxidant levels in patients. CONCLUSION Increased levels of oxidative stress markers and decreased levels of antioxidants in carcinoma of posterior one-third of tongue suggest that oxidative stress markers play a significant role in the pathophysiology of tongue cancer. These findings may suggest possible use of antioxidant supplementation as prophylactic agents for prevention and treatment of tongue cancer. A larger patient cohort for therapeutic response after treatment with a longer follow-up period studies might yield more significant data on their probable use as predictors of chemoradiosensitivity of cancer of tongue.

Systemic Inflammatory Response Syndrome in Acute on Chronic Liver Failure- Relevance of ‘Golden Window’- a Prospective Study

The choice of vasopressor for treating cirrhosis with septic shock is unclear. While noradrenaline in general is the preferred vasopressor, terlipressin improves microcirculation in addition to vasopressor action in non‐cirrhotics. We compared the efficacy and safety of noradrenaline and terlipressin in cirrhotics with septic shock.

Impact of family history of metabolic traits on severity of NASH related cirrhosis: a cross‐sectional study

Systemic inflammatory response syndrome (SIRS) is an early marker of sepsis and ongoing inflammation and has been reported in large proportion of acute‐on‐chronic liver failure (ACLF) patients. Whether sepsis is the cause or the result of liver failure is unclear and is vital to know. To address this, the study investigated the course and outcome of ACLF patients without SIRS/sepsis.

Cystatin C predicts acute kidney injury and mortality in cirrhotics: A prospective cohort study

Familial aggregation of metabolic traits with fatty liver disease is well documented. However, there is scarcity of data regarding such association with non‐alcoholic steatohepatitis (NASH)‐related cirrhosis. This study was aimed to explore the association of family history of metabolic traits with severity of cirrhosis.