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)

Lactulose Works in the Large Bowel: But How Does It Improve Hepatic Encephalopathy in a Patient Without a Large Bowel?

Introduction: Lactulose is a non-absorbable disaccharide which acts in the large bowel, and is commonly used in the treatment of hepatic encephalopathy. We present an interesting case of altered mental status due to hepatic encephalopathy successfully managed with lactulose in a patient with history of total colectomy. Case Description/Methods: A 67-year-old male with non-alcoholic cirrhosis and inflammatory bowel disease (IBD) post total proctocolectomy with a continent ileostomy known as a Kock-pouch (K-pouch) presented to the hospital with flu like symptoms and altered mental status. He was subsequently found to be positive for COVID-19. At the time of initial evaluation, the patient was obtunded with an elevated ammonia level of 91 umol/L. Colorectal surgery was consulted as the patient was not able to empty his K-pouch. Recently, he complained of inability to catheterize and with bleeding from the stoma. Initial catheterization with a Water's tube yielded 400 cc of effluent. Nasogastric tube was placed through which he was receiving lactulose 30 mg q8 hours. The patient's mental status improved within 24 hours. The patient ultimately underwent flexible pouchoscopy with endoscopic dilation and placement of a 22 French mushroom catheter for decompression of the K-pouch. Discussion(s): Lactulose is a non-absorbable disaccharide composed of galactose and fructose. The small intestine does not have the enzymes required to breakdown lactulose so it reaches the large bowel in its original form. In the large bowel, it is metabolized by colonic bacteria into monosaccharides and then to volatile fatty acids, hydrogen and methane. Lactulose decreases both the production and absorption of ammonia mainly through the presence of gut bacteria. The question arises as to how lactulose decreased ammonia levels in this patient without a large bowel. One proposed mechanism is the translocation of bacteria normally found in the large bowel to the small intestine. Small Intestinal Bacterial Overgrowth (SIBO), is a condition causing an increased number of bacteria in the small intestine. Patients with IBD and structural abnormalities are at increased risk of developing SIBO. Lactulose is commonly used in the diagnosis through the administration of lactulose and subsequent measurements of hydrogen and methane gas in expired air. This condition, in our patient with history of ulcerative colitis and colectomy, is a proposed mechanism of the efficacy of lactulose in the treatment of hepatic encephalopathy.

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.

A Case Report of Ivermectin-Induced Liver Failure

Introduction: Ivermectin is an antiparasitic medication that is primarily metabolized by the liver. During the COVID-19 pandemic, researchers demonstrated that Ivermectin successfully inhibited the replication of SARS-COV-2 in vivo, but current research has failed to demonstrate clinical benefit for treatment of COVID-19. Despite this, misinformation campaigns have misled patients to ingest Ivermectin at concentrations meant for domestic animals. Here, we present a case of acute liver failure secondary to the use of Ivermectin. Case Description/Methods: A 61-year-old man with medical history of ischemic cardiomyopathy with last echocardiogram showing ejection fraction at 21%, atrial fibrillation on warfarin for oral anticoagulation, and previously treated Hepatitis C presented with generalized weakness and yellowish discoloration of the skin worsening over the last two weeks. The patient denied significant alcohol use, acetaminophen use, or illicit drugs. He admitted to injecting himself with two doses of weight-based horse ivermectin, for COVID prophylaxis, two weeks prior to his presentation. Physical exam was pertinent for scleral icterus and hepatomegaly with no abdominal tenderness. Initial labs revealed elevated liver chemistries in a mixed pattern (Figure 1). Acute hepatitis panel, HSV, and CMV were negative. Hepatitis C antibodies were positive, but the patient was in sustained virologic response. Full workup for chronic liver disease was unremarkable. Ultrasound revealed hepatosplenomegaly with patent portal and hepatic vasculature. Subsequently, the patient developed hepatic encephalopathy along with his coagulopathy, raising concern for acute hepatic failure. The patient was transferred to the ICU and started on NAcetylcysteine, rifaximin, and supportive care. The patient recovered well and fortunately did not require liver transplant. Discussion(s): While the FDA recommends against the use of Ivermectin for COVID-19, many continue to inappropriately consume it. Ivermectin-induced liver failure is a rare but deadly side effect. Given our patient's rapid onset of symptoms post-self injection of Ivermectin, his liver injury was presumed to be related to Ivermectin. The drug interaction between Ivermectin and warfarin had worsened the patients coagulopathy. Physicians should be aware of the ways Ivermectin overdose may clinically present to avoid delayed treatment. This case demonstrates the detriments of perpetuation of medical misinformation to care.

Check Point SOS! A Case of Cemiplimab-Associated Sinusoidal Obstruction Syndrome

Introduction: Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), is a clinical syndrome characterized by hepatomegaly, right-upper quadrant pain, and ascites that occurs most commonly in the setting of high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT). The diagnosis can be confirmed on biopsy. Cemiplimab is an immune checkpoint inhibitor recently approved for the treatment of cutaneous squamous cell carcinoma. There are currently no known reports of immune checkpoint inhibitor-related VOD/SOS. Case Description/Methods: A 58-year-old female with a history of locally advanced basal cell carcinoma of the left eye treated with six months of Cemipilimab presented with ascites. On admission, labs were notable for a total bilirubin of 1.2, mildly elevated liver function tests, alkaline phosphatase 884, and international normalized ratio 2.1. A diagnostic tap revealed a high SAAG ascites that was negative for infection. A comprehensive serological workup for viral, metabolic and autoimmune causes was unrevealing. A transjugular liver biopsy demonstrated a hepatic venous pressure gradient of 18mmHg, nodular regenerative hyperplasia (NRH), and portal venopathy. The patient was discharged on steroids but returned one month later for recurrent ascites and worsening bilirubin to 12.6 (direct 7.3);COVID PCR was negative. A full rheumatologic and vasculitis workup was unremarkable. Repeat biopsy (Figure 1) demonstrated moderate NRH changes, prominent central vein sclerosis with fibrous obliteration, signs of SOS/ VOD and central venulitis with fibrotic changes with sinusoidal portal hypertension. Discussion(s): VOD occurs most often with hematopoietic stem cell transplantation, and chemotherapeutic agents. Here we present the first case of checkpoint inhibitor-induced VOD/SOS. Despite discontinuation of the offending agent and a trial of steroids, the patient's clinical course continued to deteriorate. She eventually developed refractory ascites and portosystemic encephalopathy. She was deemed not a candidate for liver transplant given her underlying malignancy. She was transitioned to home hospice before further treatment, such as Defibrotide could have been pursued. VOD associated with immune checkpoint inhibition should be considered in the differential of patients who develop new onset liver dysfunction and ascites while receiving these medications (Figure Presented).

L-Ornithine-L-Aspartate and Intermittent Renal Replacement Therapy in Fulminant Hepatitis A: A Case Report

Hepatitis A is a common viral infection worldwide that is transmitted via the fecal-oral route. Since the introduction of an efficient vaccine, the incidence of infection has decreased but the number of cases has risen due to widespread community outbreaks among unimmunized individuals. Classic symptoms include fever, malaise, dark urine, and jaundice, and are more common in older children and adults. People are often most infectious 14 days prior to and 7 days following the onset of jaundice. We will discuss the case of a young male patient, diagnosed with acute hepatitis A, leading to fulminant hepatitis refractory to conventional therapy and the development of subsequent kidney injury. The medical treatment through the course of hospitalization was challenging and included the use of L-ornithine-L-aspartate and prolonged intermittent hemodialysis, leading to a remarkable outcome. Hepatitis A is usually self-limited and vaccine-preventable;supportive care is often sufficient for treatment, and chronic infection or chronic liver disease rarely develops. However, fulminant hepatitis, although rare, can be very challenging to manage as in the case of our patient.Copyright © 2023 The Author(s).

Cirrhosis and COVID-19: Diffuse venous thrombosis and its clinical implication

A 60-year-old woman with Hepatitis C infection, cirrhosis, recurrent hepatic hydrothorax, and hepatocellular carcinoma was hospitalized with Coronavirus disease-2019 (COVID-19). After her initial discharge, she was re-admitted three weeks later with decompensated liver disease. Imaging revealed extensive thrombosis in the portal vein, superior mesenteric vein, splenic vein and bilateral brachial veins. Given the acute onset and extent of the thrombosis, the patient received therapeutic anticoagulation despite elevated prothrombin time/ international normalized ratio, thrombocytopenia and low fibrinogen. Cirrhotic patients with COVID-19 maybe at high risk of thrombosis, which can present with significant hepatic decompensation.Copyright © 2022 The Author(s)

A Review on Therapeutic Potential of Indian Herbal Plants to Counter Viral Infection and Disease Pathogenesis

Herbal plant extracts or purified phytocomponents have been extensively used to treat several diseases since ancient times. The Indian Ayurvedic system and Chinese traditional medicines have documented the medicinal properties of important herbs. In Ayurveda, the polyherbal formulation is known to exhibit better therapeutic efficacy compared to a single herb. This review focuses on six key ayurvedic herbal plants namely, Tinospora cordifolia, Withania somnifera, Glycyrrhiza glabra/Licorice, Zingiber officinale, Emblica officinalis and Ocimum sanctum. These plants possess specific phytocomponents that aid them in fighting infections and keeping body healthy and stress-free. Plants were selected due to their reported antimicrobial and anti-inflammatory effects in several diseases and effectiveness in controlling viral pathogenesis. An ad-vanced literature search was carried out using Pubmed and google scholar. Result(s): These medicinal plants are known to exhibit several protective features against various diseases or infections. Here we have particularly emphasized on antioxidant, anti-inflammatory, anti-microbial and immunomodulatory properties which are common in these six plants. Recent literature analysis has revealed Ashwagandha to be protective for Covid-19 too. The formulation from such herbs can exhibit synergism and hence better effectiveness against infection and related dis-eases. The importance of these medicinal herbs becomes highly prominent as it maintains the har-monious balance by way of boosting the immunity in a human body. Further, greater mechanistic analyses are required to prove their efficacy in fighting infectious diseases like Covid-19. It opens the arena for in-depth research of identifying and isolating the active components from these herbs and evaluating their potency to inhibit viral infections as polyherbal formulations.Copyright © 2023 Bentham Science Publishers.

Hepatic Coma Secondary to Fontan Conduit Thrombosis.

Introduction: The Fontan procedure is used to treat congenital heart defects and has improved long-term survival. Long-term complications include liver disease due to congestive hepatopathy. Fontan-related cirrhosis can manifest with ascites, gastrointestinal bleeding and encephalopathy. Case description: A 43-year-old man with history of Fontan surgery was admitted with COVID-19 pneumonia. There was rapid clinical and neurological deterioration, with coma and shock. CT imaging showed thrombosis of the Fontan conduit. The patient was successfully subjected to recanalization of the Fontan circulation, with progressive improvement of coma. Discussion: Fontan-associated liver disease is a major complication following the Fontan procedure. Clinicians must be aware of this pathology during patient follow-up. LEARNING POINTS: The Fontan procedure has improved the long-term survival of patients with single ventricle pathology.Fontan-associated liver disease is a result of haemodynamic changes associated with Fontan circulation; complications include hepatic encephalopathy and coma.Patients with Fontan circulation should be evaluated over time in order prevent and treat systemic complications.

Clinico-demographic Profile and Outcome of Scrub Typhus in North Eastern State of India

Scrub typhus is a form of bacterial Zoonosis caused by Orintia tsutsugamushi usually presents as Acute febrile illness with multiorgan involvement as a complication and is associated with significant mortality. This study aims to document the clinico-demographic profile, laboratory parameters and complication of Scrub Typhus in North Eastern Hilly State of Tripura with background of tropical climate. This retrospective study was conducted at Tripura Medical College, including 42 patients admitted with acute febrile illness between June, 2020 to December, 2021 during the era of COVID-19 Pandemic. The diagnosis was established by Rapid card test, Lateral Flow Metry Assay (LFA) followed by confirmation through IgM, ELISA test and pathognomic Eschar where feasible. The clinlical, demographic and laboratory profile were documented and analysed. Post rainy season and people from rural area with farming background were mostly affected population. Apart from Fever and Flu like symptom, respiratory and Gastrointestinal (GI) symptoms were more prominent feature. Pathognomic skin lesion eschar was found in maximum cases followed by shortness of breath, GI involvement and Renal failure. Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI), Hepatic encephalopathy and meningitis were the serious complications. While evaluating cases of acute febrile illness with multiorgan involvement clinician should have high index of suspicion for Scrub typhus specially resource poor areas of North Eastern (NE) state of India so that early detection and time bound intervention may help to reduce the mortality.Copyright © 2022 Indian Medical Association. All rights reserved.

Epidemiology and Disease Burden of Alcohol Associated Liver Disease.

Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.

Neuropsychiatric Sequelae of Hyperammonemia: Clinical Pearls for the CL Psychiatrist

Background/Significance: Hyperammonemia is known to cause acute and chronic neurotoxicity, and one of the most well-known clinical sequelae of hyperammonemia is encephalopathy (Ali, 2022). Valproic acid (VPA) has often been associated with inducing hyperammonemia (Baddour, 2018). Discussant will review a case of a patient with altered metal status and elevated ammonia level. Literature review will cover current literature on non-hepatic hyperammonemia, clinical grading of hepatic encephalopathy, and treatment options. Case: A 74-year-old male with schizoaffective disorder, bipolar type, and past medical history of CKD stage III and COVID-19 associated cognitive sequelae was being evaluated for behavioral dysregulation and psychosis attributed to acute psychiatric decompensation. Home medications included benztropine, aripiprazole tabs with aripiprazole long-acting injectable as well as VPA. After confirming medication adherence and obtaining a sub-therapeutic VPA level of 44 mcg/mL on admission, the VPA dose was increased from 1500mg qhs to 1750 mg qhs to manage agitation. After initial improvement, the patient developed lethargy with altered sensorium and inattention. Work-up revealed a VPA level of 106 mcg/mL, prompting discontinuation of VPA. Additionally, labs showed an ammonia level of 38 mumol/L, which increased to 51mumol/L a few days later. Discussion(s): While encephalopathy resulting from hepatic failure is well studied, there are fewer studies on the approach to and neuropsychiatric sequelae of non-hepatic hyperammonemia, often with varied reference values. The differential diagnosis for non-hepatic causes of hyperammonemia is broad, most notable for VPA, as well as carbamazepine and inborn errors of metabolism (Kalra, 2020). Additionally, there have been case reports on the interaction between VPA and other antipsychotics such as risperidone, which may be associated with an increased risk of hyperammonemia (Davoudi-Monfared, 2019). However, guidance is limited on evaluating asymptomatic versus symptomatic hyperammonemia. Treatment options include addressing underlying etiology as well as management of active symptoms. Conclusion/Implications: Given the neurotoxic effects of ammonia, it is important for the Consultation-Liaison Psychiatrist to consider non-hepatic hyperammonemia as an etiology of altered mental status, especially considering the effects of medications such as VPA. Further research on the clinical presentation of non-hepatic hyperammonemia and the longitudinal effects of hyperammonemia is necessary to determine the role of trending elevated values. References: Davoudi-Monfared, E., Radmehr, M., Ghaeli, P., & Mousavi, M. (2019). A Case Series of Severe Hyperammonemia Encephalopathy Related to Valproate: Can Antipsychotics Increase the Risk?. Iranian journal of psychiatry, 14(3), 248-252. Kalra A, Norvell JP: Cause for confusion: noncirrhotic hyperammonemic encephalopathy. Clin Liver Dis (Hoboken). 2020, 15:223-7. Ali R, Nagalli S. Hyperammonemia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;2022 Jan-. Available from: Baddour, E., Tewksbury, A., & Stauner, N. (2018). Valproic acid-induced hyperammonemia: Incidence, clinical significance, and treatment management. The mental health clinician, 8(2), 73-77. Copyright © 2022

Severe progression of autoimmune hepatitis in a young COVID-19 adult patient: A case report

Rationale: The impact of COVID-19 in patients with autoimmune liver disease treated with immunosuppressive therapy has not been described so far. This case report describes the clinical course of a patient with autoimmune hepatitis (AIH) who developed COVID-19 and the features of cytokine syndrome leading to its deterioration in our intensive care unit. Patient's Concern: A 28-year-old male presented with generalized anasarca for two weeks and chronic liver disease for 8 months. Diagnosis: AIH and Covid-19 with features of cytokine storm syndrome. Interventions: Intravenous furosemide, mannitol, syrup lactulose, steroids (prednisolone 40 mg), azathioprine 1 mg/kg body weight, rifaximin, vitamin K, and blood products. Outcomes: The patient had hepatic encephalopathy and AIH and died on the 10th day after admission despite ventilatory support, sustained low-efficiency hemodialysis, and resuscition. Lessons: The dramatic release of cytokines and the inflammatory-immune responses not only alter the pathophysiology but also affects the onset and severity of disease progression in patients with AIH.

Effect of COVID-19 on presentations of decompensated liver disease in Scotland

The COVID-19 pandemic has presented unique challenges. Beyond the direct COVID-related mortality in those with liver disease, we sought to determine the effect of lockdown on people with liver disease in Scotland. The effect of lockdown on those with alcohol-related disease is of interest;and whether there were associated implications for a change in alcohol intake and consequent presentations with decompensated disease.We performed a retrospective analysis of patients admitted to seven Scottish hospitals with a history of liver disease between 1 April and 30 April 2020 (n=111) and compared across the same time in 2017, 2018 and 2019 (n=348). We also repeated an intermediate assessment based on a single centre to examine for delayed effects between 1 April and 31 July 2020 (n=89) compared to the same time period in 2017–2019 (n=284). Information was collected on patient demographics, disease characteristics, length of stay and inpatient mortality.We found that results and outcomes for patients admitted in 2020 were similar to those in previous years in terms of morbidity, mortality, and length of stay. In the Scotland-wide cohort: admission UKELD (United Kingdom Model for End-Stage Liver Disease) (56 (52–60) vs 54 (50–60);p<0.01), inpatient mortality ((10.9% vs 8.6%);p=0.499) and length of stay (8 days (4–15) vs 7 days (4–13);p=0.140). In the single centre cohort: admission UKELD (57 (53–62) vs 57 (53–60);p=0.246), inpatient mortality ((13.7% vs 10.1%;p=0.373) and length of stay (7 days (4–14) vs 7 days (3.5–14);p=0.525)).In the Scotland wide cohort, patients admitted in 2020 had a significantly higher serum sodium at presentation (137 (132–140) vs 135 (130–138) p<0.01)This group also had lower rates of HCC (1.8% vs 7.2%;p=0.04)In the single centre cohort, patients admitted in 2020 had lower rates of hepatic encephalopathy (21.3% vs 35.9%;p=0.01) and were less likely to be admitted due to decompensation (70.8% vs 82.7%;p=0.01). This assessment of immediate and medium-term lockdown impacts on those with chronic liver disease suggested a minimal effect on the presentation of decompensated liver disease to secondary care in terms of patient outcomes.

*CHILDREN WITH ACUTE SEVERE HEPATITIS OF UNDETERMINED ETIOLOGY HAVE A SYSTEMIC T CELL ACTIVATION AND INTERFERON GAMMA (IFN-gamma) ACTIVITY REMINISCENT OF HEMOPHAGOCYTIC HISTIOCYTOSIS: A POTENTIAL ROLE FOR T CELL AND IFN-gamma DIRECTED THERAPIES

Background: 30-50% of pediatric acute liver failure (PALF) is of unknown cause, or indeterminate PALF (iPALF), which frequently results in transplantation. A subset of iPALF is characterized by T-cell activation. Some children with acute severe hepatitis of unknown etiology (SH-u) can evolve to iPALF. Hemophagocytic Lymphohistiocytosis (HLH) is a well-defined hyper-inflammatory condition characterized by marked T-cell activation and frequent severe liver involvement. We postulated SH-u evolving to iPALF has hyper-inflammatory immune signatures that are identifiable before fulfilling PALF criteria, and might overlap with those seen in HLH. We compared the immune dysregulation signatures of children with HLH to children with SH-u, PALF cases with known etiologies, and healthy pediatric controls (HC). Method(s): Between 2019-2021, we prospectively enrolled 14 patients hospitalized with SH-u and 7 patients with PALF of known etiologies. Age dependent standard of care diagnostic studies were performed. SH-u was defined as ALT> 500, INR < 2, and no hepatic encephalopathy. HLH enrollees fulfilled the 2004 diagnostic criteria. High dimension T-cell immunophenotyping, cytokine and chemokine profiling (71-plex) was done for SH-u, HLH (n=5), and HC (n= 16) peripheral blood samples. T cell activation was prospectively identified by co-expression of surface activation markers HLA-DR and CD38. Based on immune studies in HC, CD8 effector memory (EM) activation of >9% distinguished patients with significant T cell activation from HC. This cutoff of >9% was therefore used to identify SH-u patients with T cell activation. Normally distributed data were compared by either a two-tailed t-test or an ordinary One-Way Anova test with Turkey's multiple comparison test. Non-normally distributed data were compared by either the Mann-Whitney test or Kruskal-Wallis test with Dunn's multiple comparisons test. P Values < 0.05 were deemed significant. Result(s): Subjects ranged in age from 4 days to 19 years old. There were no age or sex differences between the groups. One SH-u patient had prior COVID infection, but no subject met MIS-c criteria. Two SH-u patients ultimately evolved to PALF criteria with INR> 2. All patients with SH-u had higher CD8 EM T-cell activation (mean +/- SEM = 43.7+/-6.3%;range 9.2 to 81.3;p<0.0001), which was significantly higher than HC (2.9+/-0.5%) and PALF of known etiology (4.0+/-0.9%) . However, the amplitude of T-cell activation was lower in the SH-u group relative to the HLH group (90.3+/-2.7%;p<0.0001), as shown in Figure 1. A similar trend in T cell activation was noted in the CD4 compartment. Overall, the activation in the CD8 compartment was much greater than in CD4. SH-u patients had a decreased CD4/CD8 ratio compared to the PALF group. Despite higher T cell activation in patients with SH-u compared to PALF, ferritin, often used to screen for hyper-inflammation, was lower in the SH-u group when compared to PALF group (1240+/-609 vs. 39517+/-32149;p<0.05) and very significantly lower than HLH (32415 +/- 14845;p =0.002). 50% of patients with SH-u etiology had ferritin < 500 mg/L. Cytopenia (hemoglobin < 9 g/dL, ANC < 1000/mL, platelets < 100,000/mL) is characteristic of patients with HLH. Despite overlapping T cell activation with HLH, the SH-u cohort had only 2 patients with this feature: one with thrombocytopenia and one with neutropenia. Supportive of this higher T cell activation, we noted chemokines driven by IFN-gamma, CXCL9 and CXCL10, to be elevated in SH-u compared to HCs and comparable to HLH patients. As a proof of concept, 1 patient with SH-u and thrombocytopenia underwent treatment with Emapalumab (an IFN-gamma blocking antibody) along with other immune modulators both with complete liver, immune, and platelet count recovery. Conclusion(s): Our cohort of SH-u was associated with significant T-cell activation. In addition, our patients with HLH and SH-u with T cell activation had similar increased IFN-gamma activity. Despite this T cell activation, ferritin values were significantly lower in SH-u compared to PALF without T cell activation. Ferritin may not be a reliable screening test to identify SH-u patients with significant T cell activation. If validated in a larger well-defined population of SH-u, the results may suggest a role for IFN-gamma blocking agents in a subgroup of SH-u prior to PALF or before bone marrow failure development.

Determination of a reasonable threshold of total bilirubin for the diagnosis of hepatitis B virus- associated acute -on - chronic liver failure. (Theme Issue: New progress in the treatment of hepatobiliary tumors in the new era of immunotherapy.) [Chinese]

Objective: To investigate a reasonable threshold d total bilirubin for the diagnosis of hepatitis B virus - related acute - on -chronic liver failure (HBV - ACLF), and to realize accurate early diagnosis.

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.