Intravenous BCAA infusion does not lead to a sustained recovery from overt HE in ACLF – An open label randomized clinical trial

Background –Hepatic encephalopathy(HE) in acute-on-chronic liver failure(ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study efficacy of intravenous branched chain amino acids(IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24h, day 3 & day 7. Primary outcome was improvement in encephalopathy by ≥ 1 grade at 72 hours. Patients and Methods –EASL defined ACLF patients with overt HE were assessed and randomized into experimental arm (IV-BCAA - 500mL/day for 3 days + Lactulose;n=39) and comparator arm (Lactulose alone;n=37). Six patients developed COVID-19 after randomization & were excluded (4-experimental arm & 2-comparator arm). Results –Of 222 screened patients, 70 (35 in each arm) were included in analysis. Baseline characteristics including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7;P = 0.86) and CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7;P = 0.65) were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%;P=0.14). Improvement in HESA by ≥1 grade at 24h occurred in 14 patients (40%) in BCAA arm and 6 patients (17.1%) in control group (P=0.03) which translated to shorter ICU stay. Median change in HESA at 24h was more in BCAA arm than control arm(P=0.006) which was not sustained at day 3 or 7. Ammonia levels did not correlate with grade of HE (Spearman's correlation coefficient(ρ) = - 0.0843;P=0.29). Conclusion Intravenous BCAA does not lead to a sustained improvement in HE grade in ACLF. Trial registration no NCT04238416 (clinicaltrials.gov)

Scientific debrief: cirrhosis

Globally, hepatitis C (26%), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from nonalcoholic fatty liver disease (8%) is small but increasing. Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acuteon-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure, Cardiovascular alterations including portal hypertension trigger the formation of portocaval shunts and varices. Systemic under filling and arterial hypotension is compensated by vasoconstriction but might decline into a state of aggravated portal hypertension and cirrhotic cardiomyopathy, leading to a hyperdynamic state, microvascular dysfunction and reduced organ perfusion culminating in decompensation. The immune system is dysfunctional showing a contrary co-existence of immune paralysis and immune overstimulation leading to secondary infections and inflammatory response syndrome aggravating cardiovascular alterations but also initiating tissue injury and metabolic alteration. This transition from compensated to decompensated cirrhosis is characterised by the occurrence of ascites, variceal bleeding and/or hepatic encephalopathy or organ failures (in the case of ACLF. Precipitating events for ACLF vary between Western countries (bacterial infection, alcohol intake) and Eastern countries (flare of HBV, superimposed HAV or HEV). In the majority of patients, systemic inflammation is a major driver of progression from compensated to decompensated cirrhosis. Once the first episode of AD develops, systemic inflammation follows a chronic course, with transient periods of aggravation due to proinflammatory precipitants or bursts of bacterial translocation resulting in repeated episodes of AD. The multistate model describing the clinical outcomes of decompensated cirrhosis has been well validated. State 3 is defined by the occurrence of variceal bleeding alone, state 4 by any single non-bleeding event, state 5 by any 2 or more events and the late decompensate state by any event with organ failures either with or without ACLF. 5-year mortality across states from 3 to 5 is in the order of, respectively: 20%, 30%, 88%. With late decompensation mortality ranges between 60 and 80% at 1 year. Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes. Aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, management of hepatic encephalopathy (HE), ascites, hepatorenal syndrome, non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue, and reduce the risk of hepatocellular carcinoma. New disease-modifying agents are expected to be identified in the next few years by systematic drug repurposing and the development of novel molecules currently undergoing pre-clinical or early clinical testing. COVID-19 continues to pose a significant healthcare challenge throughout the world. Comorbidities including diabetes and hypertension are associated with a significantly higher mortality risk. Cirrhosis is associated with an increased risk of all-cause mortality in COVID-19 infection compared to non-cirrhotic patients. Patients with cirrhosis should be considered for targeted public health interventions to prevent COVID-19 infection, such as shielding and prioritisation of vaccination.

Pre-existing chronic liver disease is associated with poor outcome in patients with SARS-CoV2 infection

COVID-19 is characterized by predominant respiratory and gastrointestinal symptoms. Liver enzymes derangement is seen in 15-55% of the patients. Cirrhosis is characterized by immune dysregulation, leading to concerns that these patients may be at increased risk of complications following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with metabolic dysfunction-associated fatty liver (MAFLD) had shown a 4-sixfold increase in severity of COVID-19, and its severity and mortality increased in patients with higher fibrosis scores. Patients with chronic liver disease had shown that cirrhosis is an independent predictor of severity of COVID-19 with increased hospitalization and mortality. An international European registry study included 756 patients with chronic liver disease from 29 countries reports high mortality in patients with cirrhosis (32%). Data of 228 patients collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19 (APCOLIS study) showed that SARSCoV- 2 infection produces acute liver injury in 43% of CLD patients without cirrhosis. Additionally, 20% of compensated cirrhosis patients develop either ACLF or acute decompensation. In decompensated cirrhotics, the liver injury was progressive in 57% of patients, with 43% mortality. Patients with CLD and associated diabetes and obesity had a worse outcome. Liver related complications were seen in nearly half of the decompensated cirrhotics, which were of greater severity and with higher mortality. Increase in Child Turcotte Pugh (CTP) score and model for end-stage liver disease (MELD) score increases the mortality in these patients. In a subsequent study of 532 patients from 17 Asian countries was obtained with 121 cases of cirrhosis. An APCOLIS risk score was developed, which included presence of comorbidity, low platelet count, AKI, HE and respiratory failure predicts poor outcome and an APCOLIS score of 34 gave a sensitivity and specificity of 79.3%, PPV of 54.8% and NPV of 92.4% and predicted higher mortality (54.8% vs 7.6%, OR = 14.3 [95 CI 5.3-41.2], p<0.001) in cirrhosis patients with Covid-19. The APCOLIS score is helpful in triaging and prognostication of cirrhotics with Coivd-19. The impact of COVID-19 on patients with cirrhosis due to non-alcoholic fatty liver disease (NASH-CLD) was separately studied in 177 NASH-CLD patients. Obese patients with diabetes and hypertension had a higher prevalence of symptomatic COVID. Presence of diabetes [HR 2.27], fraility [HR 2.68], leucocyte counts [HR 1.69] and COVID-19 were independent predictors of worsening liver functions in patients with NASH-CLD. Severity of Covid in Cirrhosis could also be assessed by measuring ICAM1 the Intercellular Adhesion Molecule, an indicator of Endothelial Injury Marker. in Cirrhosis with Covid 19 Immunosuppression should be reduced prophylactically in patients with autoimmune liver disease and post-transplantation with no COVID-19. Hydroxychloroquine and remdesivir are found to be safe in limited studies in a patient with cirrhosis and COVID-19. And is safe in cirrhosis patients. However, flare of AIH has been reported in AIH patients. For hepatologists, cirrhosis with COVID-19 is a pertinent issue as the present pandemic cause severe disease in patients with chronic liver disease leading to more hospitalization and decompensation.

Viral Hepatitis and Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a potentially reversible syndrome that develops in patients with cirrhosis or with underlying chronic liver disease (CLD) and is characterized by acute decompensation, organ failure, and high short-term mortality. Hepatitis A and hepatitis E are major causes of ACLF. Hepatitis B may also cause ACLF through a flare of hepatitis B, acute infection, or reactivation. Besides supportive care, nucleoside/nucleotide analog therapy should also be initiated in this setting. Nonhepatotropic viruses may rarely also cause ACLF with the severe acute respiratory syndrome coronavirus 2 virus recently being identified with poorer outcomes in those with underlying CLD.

Sequelae of SARS-CoV-2 infection including post-COVID syndrome.

Infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) can cause a variety of gastroenterological symptoms. A relevant proportion of patients complain of symptoms typical of gastroenteritis;the number of patients affected by gastroenterological symptoms has increased with the spread of the omicron variants. Furthermore, there are also signs of liver involvement in infected people. In the acute phase, increased liver enzymes and acute decompensation of pre-existing liver disease are observed, which can deteriorate into acute-on-chronic liver failure. Long-term sequelae of a SARS-CoV-2 infection must be distinguished from this. These sequelae can manifest either as direct infection- or therapy-associated sequelae, such as the development of secondary sclerosing cholangitis after intensive care therapy or as symptoms in the context of a post-coronavirus disease (COVID) syndrome. The pathophysiology leading to the development of a post-COVID syndrome is still unclear;here, the influence of the intestinal microbiome is discussed. This review article presents acute gastroenterological symptoms and long-term sequelae of a SARS-CoV-2 infection, which we are increasingly confronted with in clinical practice.Copyright © 2023, The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.

COVID-19 and liver diseases.

In patients with coronavirus disease 2019 (COVID-19), hepatic involvement occurs in up to 53% of all cases. Via the primary target for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the angiotensin-converting enzyme 2 (ACE2) receptor, expressed on cholangiocytes, sinusoidal endothelial cells, and hepatocytes, direct damage to the liver may occur. Furthermore, indirect (= not receptor-mediated) damage to the liver plays a crucial role in the context of COVID-19 due to severe systemic inflammation with cytokine storm, hepatic thrombosis, and systemic hypoxia. In COVID-19, liver enzymes are considered significant predictors of outcome. Thus, it is essential to rule out other causes of liver enzyme elevation, such as other viral infections, drug-induced liver injury, and metabolic, autoimmune and other liver diseases. Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is highly relevant in treating critically ill patients in the intensive care unit (ICU). Risk factors for SSC-CIP include high doses of catecholamines, high positive end-expiratory pressure (PEEP), and extracorporeal membrane oxygenation (ECMO) therapy. Early recognition of this disease and treatment by endoscopic retrograde cholangiography (ERC) is crucial. Furthermore, liver transplantation should be evaluated. Some patients with COVID-19 are diagnosed with SSC, which is termed COVID-19-associated SSC. COVID-19-associated SSC and SSC-CIP are comparable with regard to clinical phenotype, risk factors, prognosis, and graft-free survival. Patients with pre-existing liver disease are not at increased risk for infection with SARS-CoV-2 but show more severe clinical courses of COVID-19 than patients without pre-existing liver disease. Patients with pre-existing liver cirrhosis may develop acute-on-chronic liver failure (ACLF) upon infection with SARS-CoV-2. ACLF has a high mortality rate, which must be treated in the ICU.Copyright © 2023, The Author(s).

Chronic Liver Disease and Cirrhosis are Associated with Worse Outcomes Following SARS-CoV-2 Infection.

Background and aims: Studies evaluating the impact of SARS-CoV-2 on chronic liver disease (CLD) are limited and have focused mostly on hospitalized patients or those with cirrhosis. We aim to evaluate the impact of underlying CLD on patient outcomes following COVID-19 using a one of the largest COVID-19+CLD cohorts to date. Methods: Data from the COVID-19 Research Database (https://covid19researchdatabase.org) were evaluated from April 1, 2020, to August 31, 2021, to determine whether concurrent CLD was associated with worse outcomes within 30 day of COVID-19 diagnosis, including need for hospitalization, pneumonia, severe pneumonia, respiratory failure, and multiorgan failure. Among patients with COVID-19+CLD, risks of liver decompensation and acute on chronic liver failure (ACLF) were evaluated, stratified by presence of cirrhosis. Adjusted multivariate logistic regression models evaluated the impact of CLD on COVID-19 outcomes. Results: In total, 1,208,905 unique patients with COVID-19 were identified; 44,008 (3.6%) had concurrent CLD, among which 6515 (14.8%) had cirrhosis. Compared to patients without CLD, COVID-19+CLD patients were significantly more likely to require hospitalization (aOR 1.65, 95% CI 1.61-1.69), develop pneumonia (aOR 1.11, 95% CI 1.08-1.14), severe pneumonia (aOR 1.74, 95% CI 1.62-1.86), respiratory failure (aOR 1.14, 95% CI 1.10-1.17), and multiorgan failure (aOR 1.84, 95% CI 1.72-1.97), P < 0.0001 for all. Among COVID-19+CLD patients, underlying cirrhosis was associated with even higher risk of these poor outcomes, and higher risk of acute liver decompensation or ACLF. Conclusions: Among one of the largest studies to date evaluating patients with COVID-19 and CLD, underlying CLD is associated with significantly greater risk of poor outcomes following SARS-CoV-2 infection, particularly among cirrhotic patients.

63rd Annual Conference of the Indian Society of Gastroenterology, ISGCON 2022

The proceedings contain 380 papers. The topics discussed include: fecal microbiota transplantation with anti-inflammatory diet followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis - a randomized controlled trial;gut microbial dysbiosis, gut barrier integrity, and severity of chronic pancreatitis: exploring a mechanistic link using an experimental model;acanthosis nigricans-a rare cutaneous association in progressive familial intrahepatic cholestasis type 3;liver mass presenting as acute cardiorespiratory failure;role of serum phosphate levels in acute-on-chronic liver failure patients to predict short-term mortality;association of liver dysfunction in corona virus disease-19 patients;diabetic with emphysematous liver abscess: a case report;non HFE hemochromatosis - the uncommon variant;granulomatous disease with hepatic involvement in a South Indian female;epidemiological profile of acute hepatitis patients hospitalized in a tertiary care center in Western India;and a prospective randomized comparative four arm intervention study of efficacy and safety of saroglitazar and vitamin E in patients with non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis - an interim analysis.

Acute-on-chronic liver failure in patients with severe acute respiratory syndrome coronavirus 2 infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a significant impact on the lives of millions of people, especially those with other concomitant diseases, such as chronic liver diseases. To date, seven coronaviruses have been identified to infect humans. The main site of pathological action of these viruses is lung tissue. However, a substantial number of studies have proven that SARS-CoV-2 shows affinity towards several organs, including the gastrointestinal tract and the liver. The current state of evidence points to several proposed mechanisms of liver injury in patients with COVID-19 and their combination. Liver impairment is considered to be the result of the direct effect of the virus on the hepatic tissue cells, a systemic reaction consisting of inflammation, hypoxia and cytokine storm, drug-induced liver injury, with the possible contribution of a perturbed gut-liver axis. Reactivation of chronic hepatic disease could be another factor for liver impairment in patients with SARS-CoV-2 infection. Acute-on-chronic liver failure (ACLF) is a relatively new syndrome that occurs in 10%-30% of all hospitalized patients with chronic liver disease. It is crucial to recognize high-risk patients due to the increased morbidity and mortality in these cases. Several published studies have reported virus infection as a trigger factor for ACLF. However, to date, there are few relevant studies describing the presence of ACLF in patients with acute SARS-CoV-2 infection. In this minireview we summarize the current state of knowledge regarding the relation between ACLF and acute SARS-CoV-2 infection.

63rd Annual Conference of the Indian Society of Gastroenterology, ISGCON 2022

The proceedings contain 380 papers. The topics discussed include: fecal microbiota transplantation with anti-inflammatory diet followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis - a randomized controlled trial;gut microbial dysbiosis, gut barrier integrity, and severity of chronic pancreatitis: exploring a mechanistic link using an experimental model;acanthosis nigricans-a rare cutaneous association in progressive familial intrahepatic cholestasis type 3;liver mass presenting as acute cardiorespiratory failure;role of serum phosphate levels in acute-on-chronic liver failure patients to predict short-term mortality;association of liver dysfunction in corona virus disease-19 patients;diabetic with emphysematous liver abscess: a case report;non HFE hemochromatosis - the uncommon variant;granulomatous disease with hepatic involvement in a South Indian female;epidemiological profile of acute hepatitis patients hospitalized in a tertiary care center in Western India;and a prospective randomized comparative four arm intervention study of efficacy and safety of saroglitazar and vitamin E in patients with non-alcoholic fatty liver disease/ non-alcoholic steatohepatitis - an interim analysis.

Intravenous Branched Chain Amino Acid Infusion Is Associated with Early but Ill-Sustained Recovery of Overt Hepatic Encephalopathy in Acute-on- Chronic Liver Failure: A Pilot Protocol

Background: Hepatic encephalopathy (HE) in acute-on- chronic liver failure (ACLF) is associated with significant morbidity and mortality. There is paucity of data regarding HE management in patients with ACLF and most of the evidence is extrapolated from patients with cirrhosis. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE scores at 24h, day 3 & day 7. Duration of ICU stay and survival at days 7 and 28 was compared. Method(s): CANONIC ACLF patients with HE grades >= 2 were assessed for eligibility and randomized into two groups -experimental arm (IV-BCAA -500mL/ day for 3 days + Lactulose;n=39) and comparator arm (Lactulose alone;n=37). Six patients developed COVID-19 after randomization & were excluded (4-experimental arm & 2-comparator arm). Grade of HE was assessed by West Haven Classification and Hepatic Encephalopathy Scoring Algorithm (HESA). ACLF severity was determined by CLIF-C ACLF and MELD scores. All patients received standard of care for HE and ACLF management. Result(s): Both groups were similar in baseline characteristics including grade of HE (2.85 +/- 0.75 vs 2.82 +/- 0.66;P = 0.864) and CLIF-C ACLF score (54.19 +/- 5.55 vs 54.79 +/- 5.74;P = 0.655). Overall survival was 40% at 28 days (48.5% vs 31.4%;P=0.143). Significant improvement in HESA score by >=1 grade at 24h was seen in 14 patients (40%) in BCAA arm and 6 patients (17.14%) in control group (P=0.034) which translated to a shorter ICU stay in the BCAA arm (Table 1). Median change in HESA score at 24h was significantly more in BCAA arm than control arm (P=0.006), however, this was not sustained at day 3 or 7. Ammonia levels did not correlate with the grade of HE (Spearman's correlation coefficient(rho) = -0.0843;P=0.295). Conclusion(s): Intravenous BCAA leads to early but ill-sustained improvement in grade of HE and reduced ICU stay in ACLF.

Complimentary Medicine (Tinospora cordifolia/Gulvel/Guduchi) Induced Liver Injury

Tinospora cordifolia is a wild herb found in the hills of Western Maharashtra, has been utilized in Ayurvedic medicine to treat hepatitis as a hepatoprotective agent. Furthermore, during the current COVID 19 pandemic, it has recently been ingested by the general public as an immune booster. The purpose of this study was to describe the hepatotoxic effects of Tinospora cordifolia and the clinical outcomes. The study was conducted in Western India's multispecialty tertiary care center. Twenty individuals with impaired liver function test (LFTs), a history of Tinospora cordifolia ingestion, and no additional etiologies were included. These patients were followed until their LFT levels stabilized or they died. We observed 20 patients who had taken Tinospora cordifolia and had clinical hepatitis as well as abnormal LFT. The Roussel Uclaf Causality Assessment Method (RUCAM) score for all of these individuals was larger than 6(6.7+/-0.3), indicating causation. The severity of the presentation and course ranged from mild to severe, with 95% (n=19/20) of patients recovering with supportive care, while one death is due to acute on chronic liver failure. The average time to recovery was 72.6 +/-9.6 days. With large doses, Tinospora cordifolia may induce hepatotoxicity most likely in genetically vulnerable elderly. It is important to raise awareness among community about the risks of the unchecked and indiscriminate use of herbal products and their toxicities. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

LivR Well, a 28-day, community-based liver optimization program for patients with acute-on-chronic liver failure: A feasibility study

Background and Aim: Acute-on-chronic liver failure (ACLF) is a global health care challenge, with a 28-day mortality rate of 33.9% and 30-day readmission rate of 37%.1,2 Management of ACLF is often complicated by multiorgan involvement, need for intensive care support, sarcopenia/frailty, and lack of universally accepted diagnostic criteria.3,4 Health care resource utilization is high. Our aims were to assess the safety, efficacy, acceptability, and cost of LivR Well, a new model of intensive, multidisciplinary ambulatory care for patients with ACLF. Method(s): We conducted a prospective, single-arm, mixed-methods study at Monash Health, a large Victorian tertiary network. Adult patients were enrolled from the inpatient ward, emergency department, or outpatient clinic in the first 28 days after a formal diagnosis of ACLF. ACLF was defined using Asian Pacific Association for the Study of the Liver criteria (an acute hepatic insult manifesting as jaundice and coagulopathy, complicated by ascites and/or encephalopathy within 4 weeks).5 Study criteria and the LivR Well intervention are shown in Figure 1. Patients were admitted to hospital in the home and received nursing visits up to 3 times a week and a weekly clinic medical review. Patients accessed physiotherapy, pharmacy, dietetics, social work, addiction medicine, and neuropsychiatry if appropriate. Blood test results were monitored weekly, and patients were followed up for 12 weeks. Health-related quality of life (HRQoL) was measured using EQ-5D and the Chronic Liver Disease Questionnaire (CLDQ) at baseline and Week 6. A qualitative substudy was undertaken to assess acceptability, with interviews performed between Weeks 6 and 12. The primary outcome was safety. Secondary outcomes were readmission, liver disease severity, HRQoL, symptom burden (CLDQ), acceptability, and health care resource utilization. Result(s): Fifty-nine patients (median age, 51 years [IQR, 45-59];66% male) were enrolled between March 2021 and April 2022. Forty-four patients completed the 28-day program, with two deaths (at Days 16 and 27), one drop-out due to COVID-19 requiring isolation, eight patients discharged due to failure to attend, and four patients who remain active in the program. There were no reported adverse events. Alcohol misuse was the most frequent liver disease etiology (73%). There was a significant reduction in median Model for End-Stage Liver Disease-Sodium (MELDNa) score from 16 at baseline (IQR, 12-21) to 15 at Day 28 (IQR, 11-18;P < 0.001). Sarcopenia prevalence decreased from baseline to Day 28 but did not reach statistical significance (27% vs 19%, P = 0.48). HRQoL significantly improved from a median baseline CLDQ score of 4.34 (IQR, 3.37-5.08) to 4.75 (IQR, 3.97-5.81;P = 0.02), with specific improvement in the domains of activity (P = 0.04), fatigue (P = 0.02), and worry (P = 0.001). The qualitative study highlighted universal themes of high acceptability, improved health literacy/insight, and increased autonomy. The median self-reported health perception using a visual analog scale significantly improved from 64% (IQR, 42-77%) to 72% (IQR, 50-80%;P = 0.05). The 28-day mortality rate was 3%, and the 30-day readmission rate was 14%. The median LivRWell program cost was A$4947. The total 6-month median direct health care cost for each LivR Well patient improved from a median of A$30 913 before LivR Well (IQR, $11 201-$61 464) to $784 after LivR Well (IQR, $0-$18 117;P < 0.001). The total direct health care cost for this cohort was reduced by 71%, from $1.16 million before to $335 000 after LivR Well, largely driven by a 40% reduction in 30-day readmission. Conclusion(s): LivR Well is a world-first multidisciplinary ambulatory care program for patients with ACLF. Our feasibility study supported the safety, potential efficacy, and cost-effectiveness of such an intervention, with lower than expected 30-admission, 28-day mortality, and total health care cost for this complex cohort. There was a small, but significant improvement in MELD-Na score, HRQoL, and self-rep rted health perception. We are further evaluating the clinical and economic impact of LivR Well as part of a randomized controlled trial comparing it with standard ambulatory care.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis.

Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

The negative impact of the pandemic on hospital admissions, morbidity and 30-day mortality for acute cirrhosis decompensation: a tertiary care perspective

Background and aims: The global pandemic has inevitably diverted resources away from management of chronic diseases, including cirrhosis, where up to 40% of patients are readmitted with new cirrhosis decompensation events. Whilst there is increasing knowledge on COVID-19 infection in liver cirrhosis, little is described on the impact of the pandemic on decompensated cirrhosis admissions and outcomes, which was the aim of this study. Method: A single-centre, retrospective study, evaluated decompensated cirrhosis admissions to a tertiary London hepatology and transplantation centre, from October 2018 to February 2021. Patients were included if they had an admission with cirrhosis decompensation defined as new onset jaundice or ascites, infection, encephalopathy, portal hypertensive bleeding or renal dysfunction. Admissions were excluded if they lasted <24 hours,were elective or occurred post liver-transplant. Results: Therewere 351 admissions in the pre-COVID period (October 2018 to February 2020) and 240 admissions during the COVID period (March 2020 to February 2021), with an average of 20.4 admissions per month throughout. Patients transferred in from secondary centres had consistently higher severity scores during the COVID period (UKELD 58 versus 54;p = 0.007, MELD Na 22 versus 18;p = 0.006, AD score 55.0 versus 51.0;p = 0.055). The proportion of ITU admissions pre versus during-COVID stayed constant (22.9% versus 19.2%), but there was a trend towards increased ICU admissions with acute-on-chronic liver failure (ACLF) (73.9% versus 63.8% prepandemic). Of those admitted to the intensive care without ACLF, there was a significant increase in EF-CLIF acute decompensation (AD) scores during the COVID period (58 versus 48, p = 0.009). In addition, there was a trend towards increased hospital re-admission rates during the COVID period (29.5% versus 21.5%, p = 0.067). When censored at 30 days, time to death post discharge was significantly reduced during the COVID period (p < 0.05) with a median time to death of 35 days compared to 62 days pre-COVID.(Figure Presented)Conclusion: This study provides a unique perspective on the impact that the global pandemic had on the clinical course and characteristics of decompensated cirrhosis admissions. The findings of increased early mortality and re-admissions, and higher AD scores, indicating increased disease morbidity, highlight the need to maintain resourcing on providing high-level hepatology care. Given that COVID-19 will likely be a chronic issue, alternative care pathways such as remote monitoring may need adoption to facilitate continuity of care post-discharge and to reduce readmission rates and morbidity in the future

Sarcopenia as a predictor of mortality and complications in cirrhosis patients-A prospective cohort study

Background and aims: Sarcopenia is a promising tool for prognostication of cirrhosis.EWGSOP2 guidelines define sarcopenia based on muscle strength, muscle quantity or quality and physical performance. Many previous studies didn’t use a standardized definition of sarcopenia and was based on skeletal muscle measurement by CT or MRI.Ultrasound guided thigh muscle thickness (TMT) measurement is a validated, cost effective and easy method for assessment of muscle quantity.There is paucity of Indian studies analysing prognostic role of sarcopenia in cirrhosis. To study the predictive role of sarcopenia on mortality and complications in cirrhosis patients. Method: This was a prospective cohort study with 120 consecutive patients each in sarcopenia and no sarcopenia groups. Sarcopeniawas diagnosed based on EWGSOP2 guidelines using ultrasound guided measurement of TMT.They were followed up for 6 months.Kaplan- Meier analysis with LogRank test was used to compare survival and Cox proportional hazards modelwas used for multivariate analysis to determine risk factors of mortality. Results: Cirrhosis patients with sarcopenia[N1 = 120, M:F = 80:40, Median age-58yrs (51–64)] and without sarcopenia[N2 = 120, M:F = 93:27, Median age-54yrs (46.25–60)] were enrolled.Six month cumulative survival was 56.7% and 76.7% in sarcopenia and no sarcopenia groups respectively (p = 0.001).Six month cumulative survival in severe and non-severe sarcopenia was 23.9% and 70% respectively (p = 0.001).Age, sex, nutritional status, sarcopenia status, CTP score, MELD score, Bilirubin, Albumin, INR and Sodium were significantly associated with survival.A multivariate analysis showed sarcopenia (HR = 1.283, 95%CI 1.092–2.130, p = 0.031), female sex (HR = 1.851, 95%CI 1.106–3.097, p = 0.019), CTP class C (HR = 1.447, 95%CI 1.252–1.794, p = 0.002) and MELD score>15 (HR = 1.116, 95%CI 1.056– 2.203, p = 0.05) as independent predictors of mortality. Development of complications like ascites, HE, Covid infection and UGI bleed were significantly higher in sarcopenia group, while SBP, AKI, cellulitis, UTI, HCC and ACLF were not statistically significant between two groups.(Figure Presented) Figure 1. Survival curves in both groups (Log rank p = 0.001) Conclusion: Sarcopenia is an independent prognostic marker of mortality in cirrhosis and is associated with increased risk of complications like ascites, HE, Covid infection and UGI bleed. Severe sarcopenia has even poorer outcome. It appears that addition of sarcopenia to existing scoring systems of cirrhosis will improve prognostication of patients

Intravenous branched chain amino acid infusion is associated with early but ill-sustained recovery of overt hepatic encephalopathy in acute-on-chronic liver failure: a pilot protocol

Background and Aim: Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. There is limited evidence regarding HE management in patients with ACLF. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24h, day 3 & day 7. Duration of ICU stay and survival at days 7 and 28 was compared. Methods: CANONIC ACLF patients with HE grades>=2 were randomized into two groups - experimental arm (IV-BCAA - 500mL/day for 3 days + Lactulose;n=39) and comparator arm (Lactulose alone;n=37). Six patients developed COVID-19 after randomization & were excluded (4-experimental arm & 2-comparator arm). HE Grade was assessed by West Haven Classification and Hepatic Encephalopathy Scoring Algorithm (HESA). ACLF severity was determined by CLIF-C ACLF and MELD scores. All patients received standard of care. Results: Both groups were similar in baseline characteristics including grade of HE (2.85 ± 0.75 vs 2.82 ± 0.66;P = 0.864) and CLIF-C ACLF score (54.19 ± 5.55 vs 54.79 ± 5.74;P = 0.655). Overall survival was 40% at 28 days (48.5% vs 31.4%;P=0.143). Significant improvement in HESA score by 1 grade at 24h was seen in 14 patients (40%) in BCAA arm and 6 patients (17.14%) in control group (P=0.034) which translated to shorter ICU stay in the BCAA arm. Median change in HESA score at 24h was significantly more in BCAA arm than control arm (P=0.006), however, this was not sustained at day 3 or 7. Ammonia levels did not correlate with HE grade (Spearman correlation coefficient (-0.0843;P=0.295). Conclusion: Intravenous BCAA leads to early but ill-sustained improvement in grade of HE and reduced ICU stay in ACLF.

SARS-CoV-2 infection in patients with underlying chronic liver disease is associated with significantly greater risk of liver decompensation and acute on chronic liver failure

Objectives: Chronic liver disease (CLD) patients are hypothesized to have greater risks of liver decompensation following SARS-CoV-2 infection. Data evaluating COVID-19 in CLD patients remains sparse. We aim to evaluate whether SARS-CoV-2 infection in CLD patients is associated with increased risks of liver decompensation or acute on chronic liver failure (ACLF). Materials and Methods: Using the Common Data Schema from COVID-19 Research Database, a large U.S. database containing over 72 million linked patients with both electronic health records and claims data, we evaluated CLD patients with (CLD - COVID-19) vs. without COVID-19 (CLD without COVID-19). Patients had minimum 6-months follow-up until censoring event or end of study period (August 31, 2021) to evaluate incident liver decompensation (i.e. ascites, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, liver failure) and incident ACLF (EASL-CLIF definition). Outcomes were evaluated using adjusted multivariate Cox proportional hazards models. Results: Among 923,671 adults with CLD (44.7% women, 12.4% cirrhosis), 3.8% had CLD - COVID-19 and 96.3% had CLD without COVID-19. Over a median follow-up of 242-267 days, when compared to CLD without COVID-19, CLD - COVID-19 patients had significantly greater risk of liver decompensation (HR 1.22, 95% CI 1.13-1.32, p<0.001) and ACLF (HR 1.54, 95% CI 1.17-2.03, p<0.01). Among CLD patients with cirrhosis at baseline, COVID- 19 was similarly associated with higher risk of ACLF (HR 1.66, 95% CI 1.26-2.19, p<0.001). When evaluating individual organ failures in patients with ACLF, CLD - COVID-19 vs. CLD without COVID- 19 was associated with significantly greater risks of cardiovascular failure (HR 4.75, p<0.001), respiratory failure (HR 5.80, p<0.001), and renal failure (HR 3.93, p<0.001). Conclusion: Among a large U.S. cohort evaluating COVID-19 in CLD patients, SARS-CoV-2 infection was associated with significantly greater risks of liver decompensation and ACLF in patients with underlying CLD. The primary drivers of ACLF were the increased risks of cardiovascular failure, respiratory failure, and renal failure associated with COVID-19.

Comparative analysis of acute on chronic liver failure related to herbs and anti-tubercular drugs

Objectives: Liver injury precipitated by drugs and herbal medicines( DHMs) can have variable presentations and outcomes. In Indian subcontinent, drug induced liver injury due to Anti-tubercular drugs( ATDs) and inadvertent herbs induced liver injury (HILI) are common. Comparative natural history and outcome of acute-onchronic liver failure(ACLF) due to common DHMs is largely unknown. Materials and Methods: Consecutive in-patients with ACLF precipitated by herbs or ATDs(year 2010-2021) were compared for baseline clinical profile, disease severity, histological features and organ failures. Treatment outcomes and predictors of in-hospital mortality were also analyzed. Results: 529 patients presented with ACLF related to HILI(ACLF-H, n = 430) and ATDs(ACLF-D, n = 99) [Mean Age-47.6 - 14 years, mean MELD score and HVPG were 29.1 - 5.4 and 15.5 - 3.4 mmHg respectively]. 61.4% patients had underlying histological cirrhosis. 21.2% patients had additional superadded acute insult [severe alcoholic hepatitis(n = 66), acute hepatitis E or A(n = 24/15)]. Twelve percent ACLF-H patients presented with clinical cholestasis, autoimmune hepatitis(n = 18) and hypersensitivity reactions(n = 4). Most common recognizable agent associated with ACLF-H was Tinospora cordifolia (n = 35,8.1%), inadvertently used in Indian households during the COVID-19 pandemics. Patients with ACLF-H as compared to ACLF-D had higher male preponderance (70.9% vs. 54.5%;p-0.002) and peripheral eosinophilia (6.4% vs. 1%;p-0.03), clinical cholestasis (19.6% vs 10.8%;p-0.05) and acute kidney injury (44.4% vs. 28.3%;p-0.003) at presentation. Use of plasma exchange(18.5%) had no impact on outcomes. None of the patients underwent liver transplantation. In-hospital mortality(19.2%) was higher in ACLF-D compared to HILI ACLF-H (31.3% vs. 17.2%;p-0.002). Presence of AKI [HR:5.5 (95%CI:2.78 to 11.1)], hepatic encephalopathy[HR:4.4(95%CI:1.76 to 11)] and pneumonia[ HR:7.2(95%CI: 3.59 to 14.65)] were independent predictors of mortality. Conclusion: Herbs and anti-tubercular drugs are common precipitants of ACLF in India and have high in-hospital mortality resulting from sepsis and organ(s) failure. In the absence of specific treatment options, prevention and early and careful monitoring of liver functions is of utmost importance.