Granulocyte Colony-Stimulating Factor Improves Prednisolone Responsiveness and 90-Day Survival in Steroid-Eligible Severe Alcohol-Associated Hepatitis: The GPreAH Study a Randomized Trial.

INTRODUCTION: Severe alcohol-associated hepatitis (SAH) carries high 1-month mortality. Corticosteroids provide a modest 28-day but not 90-day survival benefit, due to development of infections and organ failures. Granulocyte colony-stimulating factor (GCSF) has shown promise in patients with SAH by its immunomodulatory and regenerative capabilities. We studied the safety and efficacy of combination (GCSF + prednisolone, GPred) therapy in management of steroid-eligible patients with SAH. METHODS: Steroid eligible patients with SAH (discriminant function scores 32-90) were randomized to receive prednisolone (GrA, n = 42), GPred (GrB, n = 42), or GCSF alone (GrC, n = 42). GCSF was given as 150-300 mcg/d for 7 days followed by every third day for a maximum of 12 doses in 1 month. Prednisolone 40 mg/d was given for 7 days and continued for 28 days in responders (Lille score <0.45). RESULTS: Baseline characteristics of patient groups were comparable. On intention-to-treat analysis, the primary endpoint of 90-day survival was achieved in 64.3% (27/42) in prednisolone, 88.1% (37/42) in GPred, and 78.6%(33/42) in GCSF groups, respectively ( P = 0.03, prednisolone vs GPred). The 28-day survival was not different between the groups (85.7%, 95.2%, and 85.7%, respectively [ P = 0.27]). The GPred group had more responders by day 7 (71.4% vs 92.9% vs 76.2%, P = 0.037) and had greater reduction in discriminant function (-7.33 ± 4.78, -24.59 ± 3.7, -14.59 ± 3.41, P = 0.011) and MELDNa (-1.69 ± 1.26, -7.02 ± 1.24, -3.05 ± 0.83, P = 0.002) by day 90. The prednisolone-only group had higher incidence of new infections (35.7%, 19%, 7.1%, respectively, P < 0.002). Acute kidney injury (33.3%, 7.1%, 11.9%, P = 0.002), hepatic encephalopathy (35.7%, 9.5%, 26.2%, P = <0.001), and rehospitalizations (59.5%, 14.3%, 30.9%, P =<0.01) were lower in the GPred group. CONCLUSION: Addition of GCSF to prednisolone improves steroid responsiveness and 90-day survival with fewer infections and new onset complications in patients with SAH.

Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial.

Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet [PLT] count), and its use may avoid unnecessary blood component transfusion in patients with advanced cirrhosis and significant coagulopathy who have nonvariceal upper gastrointestinal (GI) bleeding. A total of 96 patients with significant coagulopathy (defined in this study as INR >1.8 and/or PLT count < 50 × 109 /L) and nonvariceal upper GI bleed (diagnosed after doing upper gastrointestinal endoscopy, which showed ongoing bleed from a nonvariceal source) were randomly allocated to TEG-guided transfusion strategy (TEG group; n = 49) or standard-of-care (SOC) group (n = 47). In the TEG group, only 26.5% patients were transfused with all three blood components (fresh frozen plasma [FFP], PLTs, and cryoprecipitate) versus 87.2% in the SOC group (P < 0.001). Although 7 (14.3%) patients in the TEG group received no blood component transfusion, there were no such patients in the SOC group (P = 0.012). Also, there was a significantly lower use of blood components (FFP, PLTs, and cryoprecipitate) in the TEG group compared with the SOC group. Failure to control bleed, failure to prevent rebleeds, and mortality between the two groups were similar. Conclusion: In patients with advanced cirrhosis with coagulopathy and nonvariceal upper GI bleeding, TEG-guided transfusion strategy leads to a significantly lower use of blood components compared with SOC (transfusion guided by INR and PLT count), without an increase in failure to control bleed, failure to prevent rebleed, and mortality.

Efficacy of Granulocyte Colony-stimulating Factor in the Management of Steroid-Nonresponsive Severe Alcoholic Hepatitis: A Double-Blind Randomized Controlled Trial.

Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score > 0.45) are limited. We assessed the efficacy and safety of granulocyte colony-stimulating factor (G-CSF) in steroid nonresponders. A randomized, double-blind, single-center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G-CSF (12 doses, 300 µg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G-CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28-day mortality was comparable between the groups (21.4%, G-CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G-CSF but not in the placebo group, the Model for End-Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 (P = 0.002) and Maddrey's discriminant function from 74.8 ± 22.8 to 57.4 ± 31 (P = 0.26). Infections were less common (28% versus 71%; P < 0.001) with lower 90-day mortality (35.7% versus 71.4%; P = 0.04) in the G-CSF than in the placebo group. On Cox regression analysis, receiving G-CSF (hazard ratio, 0.37; SD, 0.14-0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7-10.3; P = 0.002) predicted day-90 outcomes in steroid nonresponsive SAH. Patients tolerated G-CSF without any major adverse events. Conclusion: Approximately one-quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G-CSF is safe and helps to reduce the disease severity and 90-day mortality in these patients.

Intractable hepatic encephalopathy in cirrhotic patients: mid-term efficacy of balloon-occluded retrograde portosystemic shunt obliteration.

PURPOSE: To evaluate the efficacy and intermediate-term outcome of balloon-occluded retrograde transvenous obliteration (BRTO) for the treatment of hepatic encephalopathy (HE) secondary to portosystemic shunt (PSS) in cirrhotic patients. MATERIALS AND METHODS: Institutional review board (IRB) approval was obtained for this study and hospital records of patients who underwent BRTO, from August 2011 to August 2015, were analyzed. Based on the inclusion and exclusion criteria, 39 patients (age, 54.07 ± 9.1 years (37-67 years); 33 males and 6 females) with cirrhosis and spontaneous PSS were included. Clinical and laboratory parameters and HE grade were evaluated in all patients before and after the procedure. RESULTS: Forty sessions of BRTO were attempted in 39 patients. Follow-up imaging revealed complete obliteration of the treated PSS in all patients with clinical success in 37 patients (94.9%). The 1-, 2-, 3-, 4-, 5-, 6-, and 7-year HE-free survival rates among responders were 91.7%, 91.7%, 88.8%, 85.5%, 80.8%, 80.8%, and 80.8% respectively and overall survival rates were 89.7%, 82.1%, 76.9%, 74.4%, 74.4%, 64.8%, and 64.8% respectively. Logistic regression highlighted Child-Turcotte-Pugh (CTP) score at 6 months as a positive predictive factor of HE recurrence with a cutoff of ≥ 9. Five patients (12.8%) had fever and leukocytosis and 1 (2.6%) patient developed spontaneous bacterial peritonitis after the procedure. CONCLUSION: BRTO is an effective treatment for refractory HE in cirrhotics secondary to large PSS with a few possible complications. KEY POINTS: • BRTO is an effective and safe treatment for refractory HE, arising from PSS in cirrhotic patients. • Patients with preserved liver function show better outcome and CTP score is the most important predictor of relapse during follow-up.

Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis.

Albumin is a potent scavenger of reactive oxygen species (ROS). However, modifications in albumin structure may reduce its antioxidant properties and modulate its immune-regulatory functions. We examined alterations in circulating albumin in severe alcoholic hepatitis (SAH) patients and their contribution to neutrophil activation, intracellular stress, and alteration in associated molecular pathways. Albumin modifications and plasma oxidative stress were assessed in SAH patients (n = 90), alcoholic cirrhosis patients (n = 60), and healthy controls (n = 30) using liquid chromatography/mass spectrometry and spectrophotometry. Activation and intracellular ROS were measured in healthy neutrophils after treatment with purified albumin from the study groups. Gene expression of SAH neutrophils was analyzed and compared to gene expression from healthy neutrophils after stimulation with purified albumin from SAH patient plasma. SAH-albumin showed the highest albumin oxidative state (P < 0.05) and prominent alteration as human nonmercaptalbumin 2 (P < 0.05). Plasma oxidative stress (advanced oxidative protein product) was higher in SAH versus alcoholic cirrhosis patients and healthy controls (P < 0.05). Neutrophil gelatinase-associated lipocalin, myeloperoxidase, and intracellular ROS levels were highest in SAH-albumin-treated neutrophils (P < 0.05). Genes associated with neutrophil activation, ROS production, intracellular antioxidation, and leukocyte migration plus genes for proinflammatory cytokines and various toll-like receptors were overexpressed in SAH neutrophils compared to healthy neutrophils (P < 0.05). Expression of the above-mentioned genes in SAH-albumin-stimulated healthy neutrophils was comparable with SAH patient neutrophils, except for genes associated with apoptosis, endoplasmic reticulum stress, and autophagy (P < 0.05). CONCLUSIONS: In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro-oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (Hepatology 2017;65:631-646).

Intraductal Sonography in Patients With Portal Cavernoma Cholangiopathy.

Intraductal sonography generates high-resolution images of the entire length of the biliary tree and peribiliary tissues, including 3-dimensional dual- and muti-plane reconstructions to depict complex anatomy. Portal cavernoma cholangiopathy (previously called portal biliopathy) can have multiple etiologies of obstructive cholestasis in the same patient, which can be difficult to define even with advanced imaging techniques.We describe 2 difficult cases of portal cavernoma cholangiopathy in which intraductal sonography helped in clinical management decisions. We think that intraductal sonography should be part of the standard management algorithm for patients with portal cavernoma cholangiopathy and describe the intraductal sonographic correlates of the cholangiographic changes in this condition.

Alcohol-Associated Liver Diseases: Spectrum, Nomenclature, and Definitions.

Alcohol-associated liver disease (AALD) is a global health problem with increasing incidence with associated high morbidity and mortality. Patients with AALD have varied clinical presentation encompassing a spectrum ranging from alcoholic steatosis, alcoholic steatohepatitis to alcohol-associated fibrosis/cirrhosis, which can be either compensated or decompensated. We need uniformity in defining each of the stages of AALD, which will help in both research and patient care. Algorithmic approach using noninvasive tests like enhanced liver fibrosis score, elastography, and fibrosis-4 scores can help in early diagnosis in addition to the presence of any red flags (low albumin, low platelet count, and raised transaminases).

Prevalence and clinicopathological Spectrum of Auto-Immune Liver Diseases & Overlap syndrome.

Aims: Autoimmune liver diseases (AILD) represent a spectrum of related yet distinct immune-mediated disorders. The literature on the prevalence of these AILDs in Indian population is scarce. This study aims to assess the prevalence and clinicopathological spectrum of various AILDs especially the overlap syndrome. Materials and Methods: A 10-year (2011-2020) cross-sectional, retrospective observational study of histological proven cases of AILD was conducted. Clinical, demographic, and laboratory parameters were retrieved. Two pathologists independently reviewed the liver biopsies and reassessed 18 histopathological parameters. Results: During the study period, 17664 liver biopsies were received, out of which 1060 (6%) biopsies of AILD were identified. After exclusion, we had 721 cases which revealed a distribution of autoimmune hepatitis (AIH)-64.7%, primary biliary cholangitis (PBC)-14.8%, primary sclerosing cholangitis (PSC)-7.6%, overlap AIH-PBC 11%, and overlap AIH-PSC 1.7%. AIH patients had significantly higher prevalence for severe lobular inflammation (27%, P ≤ 0.001), several lobular plasma cells (37%, P ≤ 0.001), central perivenulitis (30%, P ≤ 0.001), hepatic rosettes (51%, P ≤ 0.001), and necrosis (35.5%, P ≤ 0.001), while PBC patients had significantly higher frequency of florid duct lesions (11.2%, P ≤ 0.001), duct loss (83.17%, P ≤ 0.001), bile duct damage (76.6%, P ≤ 0.001), and periportal copper deposits (19.6%, P ≤ 0.001). Overlap AIH-PBC group had the highest proportion of severe portal inflammation (27.5%, P ≤ 0.001), prominent portal plasma cells (75%, P ≤ 0.001), moderate interface activity (53.7%, P ≤ 0.001), Mallory-Denk bodies (27.5%, P ≤ 0.001), and periportal cholate stasis (25%, P ≤ 0.001). Conclusion: Prevalence of biopsy-proven AILDs in our study cohort is 6%. AIH (64.7%) is the most common AILD followed by PBC (14.8%). Overlap syndrome (AIH-PBC) showed prevalence of 11%.

Comparison of Balloon-Occluded Thrombolysis with Catheter-Directed Thrombolysis in Patients of Budd-Chiari Syndrome with Occluded Direct Intrahepatic Portosystemic Shunt.

Objectives Direct intrahepatic portosystemic shunt (DIPS) stent placement is an effective treatment for patients with Budd-Chiari syndrome (BCS); however, thrombotic occlusion of DIPS stent remains a cause of concern. The purpose of this study is to describe a novel technique of balloon-occluded-thrombolysis (BOT) for occluded DIPS stent, and compare it with the conventional catheter-directed-thrombolysis (CDT). Methods In this retrospective study, the hospital database was searched for BCS patients who underwent DIPS revision for thrombotic stent occlusion between January 2015 and February 2021. Patients were divided into CDT group and BOT group. The groups were compared for technical success, total dose of thrombolytic agent administered, duration of hospital stay, and primary assisted stent patency rates at 1- and 6-month follow-up. Results CDT was performed in 12 patients, whereas 21 patients underwent BOT. Complete recanalization was achieved in 66.7% (8 of 12) patients of CDT group as compared to 81% (17 of 21) patients of BOT group (nonsignificant difference, p = 0.420). BOT group had a short hospital stay (1.8 ± 0.7 vs. 3.5 ± 1.0 days) and required less dose of thrombolytic agent ([2.2 ± 0.4]x10 5 IU versus [8.3 ± 2.9]x10 5 IU of urokinase) as compared to the CDT group and both differences were statistically significant ( p < 0.001). Further, 6-month patency rate was higher in BOT group as compared to CDT group ( p = 0.024). Conclusion The novel BOT technique of DIPS revision allows longer contact time of thrombolytic agent with the thrombi within the occluded stent. This helps in achieving fast recanalization of thrombosed DIPS stent with a significantly less dose of thrombolytic agent required, thus reducing the risk of systemic complications associated with thrombolytic administration.

Serum IgG level in autoimmune liver diseases and its significance: Is there a need to revisit existing criteria? Experience from a tertiary care center.

BACKGROUND: Serum immunoglobulin G (IgG) level is elevated in autoimmune liver diseases (AILDs), especially autoimmune hepatitis (AIH). However, its utility is limited in current practice as different criteria propose different cut-off values leading to considerable ambiguity. MATERIALS AND METHODS: A cross-sectional study was conducted among patients with AILD who underwent a liver biopsy over a ten-year period. From 17644 liver biopsies, 630 patients were included and divided into three groups-AIH (455 patients), primary biliary cholangitis (PBC) (97 patients), and overlap (78 patients). Clinical and laboratory details were collected and histological findings were reviewed. Non-cirrhotic non-alcoholic steatohepatitis (NASH) cases were taken as the control group for IgG level comparison. RESULTS: Among AIH patients, IgG values of >2 times the upper limit of normal (ULN) were associated with significant elevation of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and necroinflammatory activity. IgG level of >1.1 times ULN lacks specificity in differentiating AIH from the control group. The receiver operating characteristic (ROC) curve demonstrates maximum sensitivity and specificity at a cut-off value of >1.3 times ULN. CONCLUSION: Serum IgG cut-off value for diagnosing AIH, either in isolation or as a component of overlap syndrome, needs revision and uniformity. IgG value of >2 times ULN in AIH is associated with severe AIH. A new cut-off value of >1.3 times ULN is proposed.

Combined hepatocellular cholangiocarcinoma in hepatectomy specimens: A clinicopathologic analysis.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon form of primary liver carcinoma. It is heterogenous in terms of morphology, immunohistochemistry, radiology, and clinical features; making it a challenging entity for diagnosis. Aims: The purpose of the present study was to evaluate clinicopathological characteristics of patients with cHCC-CCA. Settings and Design: Retrospective observational study. Materials and Methods: The patients diagnosed with cHCC-CC were identified from hepatic surgical specimens and were evaluated. Statistical Analysis: Survival was estimated as per Kaplan-Meier method. Results: Out of six patients, five had undergone resection while one had liver transplant. Five were male and one was female and the mean age was 52 years. Tumor markers revealed raised serum alfa-fetoprotein and CA19.9 in four and three patients, respectively. Five of the liver specimens were cirrhotic. Diagnosis was predominantly based on tumor morphology. All cases were of Allen and Lisa type B and cHCC-CCA as per WHO (2019) classification. Stem cell features <5% were noted in two cases. Immunohistochemistry for programmed death 1/programmed death ligand 1 (PD1/PDL1) was negative in both the hepatocellular and cholangiocellular components in all six cases. Mismatch repair (MMR) protein expression was retained in two and deficient in four cases. The median follow-up after surgery was 21.3 months (range, 5-46.2 months). Five patients had intrahepatic and/or extrahepatic recurrence on follow-up after surgery. The median recurrence-free survival was estimated at 13.1 months (95% CI 5.67-20.6). Three patients had received salvage treatment. The median overall survival was estimated at 20 months (95% CI 0-45.3). Conclusions: The present study highlights the role of morphology in the diagnosis of cHCC-CCA. The choice of locoregional and/or systemic therapy after surgery may be individualized based on the clinicopathological characteristics.

Tolerance of standard dose albumin infused over 6 hrs for treatment of spontaneous bacterial peritonitis-A randomized controlled trial.

BACKGROUND AND AIMS: Twenty per cent albumin (1.5 g/kg at diagnosis and 1 g/kg on day three, infused over six-hour duration) is recommended particularly in high-risk spontaneous bacterial peritonitis (SBP). Whether reduced dose albumin infusion is as effective as the standard dose albumin infusion is not clear. The aim of this study was to compare standard dose albumin infusion with reduced dose albumin infusion in acute kidney injury (AKI) development or progression in patients with cirrhosis and high-risk SBP. METHODS: Sixty-three patients were randomized to the standard dose albumin arm (n = 31) and reduced dose albumin arm (n = 32, 0.75 g/kg at diagnosis and 0.5 g/kg 48 h later). The albumin was infused over six-hour duration in both groups. When the patient developed respiratory distress, the albumin infusion was stopped and that dose (i.e. of day one or day three) was not restarted and no attempt was made to finish the whole dose of that day. However, the next dose was started at the pre-calculated infusion rate if there was no evidence of respiratory distress at the start of next infusion. RESULTS: All 31 patients in standard dose and two (6.25%) in the reduced dose group developed symptomatic circulatory overload (p < 0.001), with infusions being stopped prematurely. The actual albumin dose received on day one was similar in both groups and only slightly higher in the standard dose group on day three. Resolution of SBP, progression of AKI to higher stage, in-hospital mortality and 28 days' mortality were similar in both groups. CONCLUSIONS: For treatment of SBP, standard dose albumin infusion (1.5 g/kg at diagnosis and 1 g/kg 48 hours later) infused over six hours is not tolerated by Indian patients. The effectiveness of standard dose albumin infused over more prolonged periods, as compared to reduced dose albumin, should be evaluated in further studies. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT04273373 .

Fecal microbiota transplantation compared with prednisolone in severe alcoholic hepatitis patients: a randomized trial.

BACKGROUND: Severe alcoholic hepatitis (SAH) has high 90-day mortality. Prednisolone therapy has shown modest survival benefits over placebo at 28 but not 90 days. Fecal microbial transplantation (FMT) has shown promise in these patients. We compared the efficacy and safety of the two therapies in SAH patients. METHODS: Steroid eligible SAH patients were randomized in an open-label study to prednisolone (n = 60) 40 mg/day for 28 days (assessed at day-7 for continuation) or healthy donor FMT (n = 60) through naso-duodenal tube, daily for seven days. Primary outcome of study was day-90 survival. RESULTS: Patients in prednisolone and FMT arms were comparable at baseline (discriminant function score 65 ± 16.2 and 68 ± 14, MELD score 17.1 and 16.5, respectively). Of 120 patients, 112 [prednisolone-57; FMT-55] completed trial. As per intention-to-treat analysis, 90-day survival was achieved by 56.6% (34/60) patients in prednisolone and 75% (45/60) in FMT group (p = 0.044, FMT HR = 0.528, 95%CI 0.279-0.998). Secondary outcome of 28-day survival [78.33% (47/60) and 88.33% (53/60) (p = 0.243, FMT HR = 0.535, 95%CI 0.213-1.34)] with comparable severity scores over time between both arms. Infections accounted for 11 (19.3%) and 2 (3.6%) deaths in prednisolone and FMT groups, respectively (p = 0.01). Path-tracing showed a slow establishment of microbiota and alpha diversity (Shannon index) improvement by day-28 (p = 0.029). FMT resulted in 23 new taxa by day-28, reduction from baseline in pathogenic taxa [Campylobacter (19-fold, p = 0.035), anaerobes (Parcubacteria, Weisella and Leuconostocaceae)], and increase of Alphaproteobacteria [~ sevenfold, p = 0.047] and Thaumarcheota (known ammonia oxidizer, p = 0.06). Lachnospiraceae (p = 0.008), Prevotella and Viellonella communities in gut favored survival (p < 0.05). CONCLUSION: In severe alcoholic hepatitis, FMT is safe and improves 90-day survival and reduces infections by favorably modulating microbial communities. It can be a useful alternative to prednisolone therapy.

Tadalafil improves erectile dysfunction and quality of life in men with cirrhosis: a randomized double blind placebo controlled trial.

BACKGROUND AND AIMS: Patients with cirrhosis have high prevalence of erectile dysfunction (ED). The aim of this study was to study the efficacy and safety of tadalafil for ED in patients with cirrhosis. METHODS: 140 cirrhotic males with ED were randomized into tadalafil 10 mg daily (n = 70) or placebo (n = 70) for 12 weeks. ED was diagnosed if erectile function (EF) domain score was < 25 in International Index of Erectile Function (IIEF) questionnaire. The erectile function domain consists of six questions concerning erection frequency, erection firmness, frequency of partner penetration, frequency of maintaining erection after penetration, ability to maintain erection to completion of intercourse and confidence in achieving and maintaining erection. Primary outcome was proportion of patients having an increase in > 5 points in EF domain of the IIEF. Generalized Anxiety Disorder 7 (GAD-7) questionnaire was used for screening and severity measuring of GAD. The presence of depression was screened using the Patient Health Questionnaire (PHQ-9) and the assessment of health related quality of life was done using the Short Form (36) Health Survey. RESULTS: At the end of 12 weeks, more patients in tadalafil group achieved > 5 points increase in the EF domain of the IIEF when compared with the placebo group [44(62.9%) vs. 21(30%), p < 0.001]. At the end of 12 weeks, patients receiving tadalafil had significantly more change in scores on the erectile function domain, orgasmic function domain, intercourse satisfaction domain, overall satisfaction domain, erection vaginal penetration rates and successful intercourse; significantly more decline in the GAD-7 and PHQ-9 scores; significantly more improvement in scores of five of the eight domains of SF-36 (general health perception, vitality score, social functioning, role emotional and mental health) and the mental component summary rates when compared with placebo. The development of side effects and the changes in HVPG were not significantly different between the two groups. CONCLUSIONS: Tadalafil therapy may enhance erectile function, improve anxiety, depression and quality of life; and is well tolerated by men with cirrhosis (CTP score < 10) and ED. However, further larger and long-term studies are needed to confirm these results and look for rarer side effects of using tadalafil in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03566914; first posted date: June 25, 2018.

Alcohol associated liver cirrhotics have higher mortality after index hospitalization: Long-term data of 5,138 patients.

BACKGROUND/AIMS: Liver cirrhosis is an important cause of morbidity and mortality globally. Every episode of decompensation and hospitalization reduces survival. We studied the clinical profile and long-term outcomes comparing alcohol-related cirrhosis (ALC) and non-ALC. METHODS: Cirrhosis patients at index hospitalisation (from January 2010 to June 2017), with ≥1 year follow-up were included. RESULTS: Five thousand and one hundred thirty-eight cirrhosis patients (age, 49.8±14.6 years; male, 79.5%; alcohol, 39.5%; Child-A:B:C, 11.7%:41.6%:46.8%) from their index hospitalization were analysed. The median time from diagnosis of cirrhosis to index hospitalization was 2 years (0.2-10). One thousand and seven hundred seven patients (33.2%) died within a year; 1,248 (24.3%) during index hospitalization. 59.5% (2,316/3,890) of the survivors, required at least one readmission, with additional mortality of 19.8% (459/2,316). ALC compared to non-ALC were more often (P<0.001) male (97.7% vs. 67.7%), younger (40-50 group, 36.2% vs. 20.2%; P<0.001) with higher liver related complications at baseline, (P<0.001 for each), sepsis: 20.3% vs. 14.9%; ascites: 82.2% vs. 65.9%; spontaneous bacterial peritonitis: 21.8% vs. 15.7%; hepatic encephalopathy: 41.0% vs. 25.0%; acute variceal bleeding: 32.0% vs. 23.7%; and acute kidney injury 30.5% vs. 19.6%. ALC patients had higher Child-Pugh (10.6±2.0 vs. 9.0±2.3), model for end-stage liver-disease scores (21.49±8.47 vs. 16.85±7.79), and higher mortality (42.3% vs. 27.3%, P<0.001) compared to non-ALC. CONCLUSION: One-third of cirrhosis patients die in index hospitalization. 60% of the survivors require at least one rehospitalization within a year. ALC patients present with higher morbidity and mortality and at a younger age.

Fecal microbiota transplantation in alcohol related liver diseases.

The current standard of care for severe alcoholic hepatitis (SAH) has several limitations in that only up to one-third of patients are eligible for steroid therapy. Additionally, steroids have their own issues: a portion of patients do not respond, while there is doubtful long-term benefit in those who do and a large proportion are ineligible to receive steroids entirely and hence have no definitive options for treatment. As such, there is a large gap between the problem and the available solutions. Alcohol causes dysbiosis and also disrupts gut barrier function, consequently promoting the translocation of microbial lipopolysaccharide into the portal circulation and liver. Therefore, probiotics, prebiotics, antibiotics, or transplantation of gut microbiota are likely to attenuate the dysbiosis-related liver insult. Fecal microbiota transplantation (FMT) is expected to have a role in managing alcoholic liver disease in general and SAH in particular by correcting dysbiosis, the primary insult. Results from mouse studies have suggested beyond doubt that alcohol-related liver injury is transferrable and also treatable by adopting FMT from suitable donors. Initial human trials from our center have affirmed benefits in human subjects with SAH as well, with both improvements in disease severity and as well as the rate of survival. Further studies addressing the head-to-head comparison of steroids and FMT are ongoing. Available preliminary data are promising and FMT and/or gut microbial modulation might become the standard of care in the near future for managing alcohol-related liver diseases, especially alcoholic hepatitis, with greater applicability, improved acceptability, and minimal side effects.

Salvage Balloon Occluded Retrograde Transvenous Obliteration for Gastric Variceal Bleed in Cirrhotic Patients With Endoscopic Failure to Control Bleed/Very Early Rebleed: Long-term Outcomes.

AIMS: To analyze the outcomes of balloon occluded retrograde transvenous obliteration (BRTO) as salvage therapy in cirrhotic patients with gastric variceal bleed (GVB) after failed endotherapy or very early rebleeds. We assessed for technical/clinical success of BRTO and transplantation-free survival. MATERIAL AND METHODS: Patients with GVB who underwent BRTO as salvage therapy (between 2011 and 2017) were analyzed. Rebleed rate, Child Pugh score (CTP), Model for end-stage liver disease (MELD) values were calculated at 1,6,12, and 24 months follow-up. RESULTS: Fifty-two patients who underwent BRTO as salvage therapy were assessed for rebleed rate and transplantation-free survival. Technical success was 100% with rebleed rate being 1.9% (n = 1) and clinical success rate of 92.3% (n = 48) at 12-months follow-up and transplantation-free one-year survival of 90.4% (n = 47). Five patients (9.6%) failed to achieve one-year transplantation-free survival. Four patients died within 30 days; one rebleed, 3 (all Child C) progressive liver and multiorgan failure and one required liver transplantation (day 88) after BRTO. Thus, a total of 4 of 9 (44.4%) Child C patients failed to achieve one-year transplantation-free survival. Improvement in liver functions was noted in the rest with improved CTP, MELD scores, and albumin levels in the 12-month follow-up. Six of 52 (11.5%) developed new onset medically manageable ascites, whereas 7 of 52 (13.5%) had progression of esophageal varices at 12-months follow-up requiring prophylactic band ligation in follow-up. CONCLUSIONS: Salvage BRTO is a safe and effective procedure for patients with acute GVB with failure to control bleed with endotherapy or very early rebleed after endotherapy. Salvage BRTO has good short/long-term outcomes with lower rebleed, higher survival, and improved liver disease severity.

Viscoelastic test-based bleeding risk score reliably predicts coagulopathic bleeding in decompensated cirrhosis and ACLF patients.

BACKGROUND AND AIMS: Coagulopathic bleeding risk prediction is challenging in decompensated cirrhosis (DC) by conventional assays. Viscoelastic tests (VETs) are likely to be more useful for assessing coagulation status in these patients. We investigated whether the VET (Sonoclot) parameters with fibrinogen could predict coagulopathic bleeding in these patients. PATIENTS AND METHODS: Coagulation parameters studied in 874 patients [124 compensated cirrhosis (CC), 521 DC, and 229 acute-on-chronic liver failure (ACLF)] and 190 controls. DC patients were enrolled in derivation (n = 266) and validation (n = 255) cohorts. Sonoclot variables [activated clotting time (ACT), clot rate (CR), platelet function (PF), time to peak (TP) and peak amplitude (PA)] and fibrinogen levels were measured. Coagulopathic bleeding was recorded along with 1-year survival. RESULTS: DC patients had prolonged ACT (p < 0.001), depressed CR (p = 0.059), reduced PF (p = 0.09), longer TP (p < 0.001) and smaller PA (p < 0.001), compared to CC and controls (p < 0.001 each). In derivation cohort, 32.3% patients had coagulopathic bleeding. Cox regression analysis of derivation cohort revealed; ACT > 190 s, PF < 1.25 and fibrinogen < 1.2 g/l could predict coagulopathic bleeding and were used to develop a bleeding risk score. In validation cohort; this score was comparable, correlated to real events, and had similar bleed free events with time. The score was also useful in predicting bleed in ACLF patients. In DC patients, 1-year mortality was higher those who bled and received transfusions. CONCLUSION: Viscoelasticity-based bleeding risk score using ACT, PF and fibrinogen, predicts coagulopathic bleeding in DC patients and should be useful in rationalizing transfusion of blood products. We designed a viscoelastic test-based bleeding risk score which is useful in advanced liver disease to predict the coagulation-related bleeding. This figure shows the lower bleeding-free events in advanced cirrhosis with each incremental bleeding risk score.

COVID-19 in Liver Transplant Recipients - A Series with Successful Recovery.

The severe acute respiratory syndrome corona virus-2 (referred to as SARS CoV2) pandemic had a great impact on public life in general as well as on populations with pre-existing disease and co-morbidities. Liver transplant and immunosuppressant medication predisposes to more severe disease and is often associated with poor outcome. The clinical features, disease course, treatment and process of modulating the immunosuppression is challenging. Here, we describe the clinical presentation, treatment and outcomes in six liver transplant recipients. Out of those six patients, three had mild, one had moderate and one had severe COVID-19, and one was asymptomatic. The immunosuppression minimization or withdrawal was done based upon the clinical severity. Consideration of tocilizumab and/o convalescent plasma as well as antivirals i.e. remdesvir done in severe cases. The routine practice of prophylactic anticoagulation, consideration of repurposed drugs (i.e. teicoplanin and doxycycline), and watchful monitoring of asymptomatic recipients helped to achieve an uneventful recovery.