11th Symposium of portal hypertension 17.–18. June 2022 Banská Štiavnica

Adverse childhood experiences as a background for alcoholic liver disease – cohort analysis of risk score in ALD and non-ALD cirrhosis patients in comparison with the control group

K. K. Šulejová, S. Selčanová Adamcová, D. J. Havaj, N. Bystrianska, D. Žilinčanová, D. Líška, E. Liptáková, Ľ. Skladaný

HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica

The alcoholic liver disease represents the main cause of liver cirrhosis in the Slovak republic. An important position in the development of addiction has childhood trauma. Child abuse, neglect, and other traumatic experiences contribute to the development of risky patterns of behavior leading to the evolution of cirrhosis. The Adverse Childhood Experience Questionnaire is a rating scale evaluating the main risky domains for the development of addiction, and it could play as an indicator for cirrhosis development. In the following period, we evaluated adverse childhood experiences by the 10-item questionnaire in all patients enrolled in the local register of cirrhosis. The endpoint of this study was to assess the risk score for ALD and non- ALD groups in contrast with the cut-off value for the peril of addiction. According to the questionnaire, we tried to analyze the high-risk domain for the development of alcoholic liver disease. Finally, we compared the ACE risk score in ALD, non-ALD, and control groups, which were represented by university students. ACE score in a cohort of patients with alcohol cirrhosis reached 3.21 points (2.88–3.54 points). In comparison, the ACE score in non-ALD cirrhosis was 1.26 points, and in the cohort of university students 1.32 points. The main domains of ACE for ALD were sexual and physical abuse, alcohol addiction, and depression in the family. The higher score in ACE-Q refl ects grave childhood trauma which represents the risk for addiction and correlates with the prevalence of ALD-cirrhosis in our local register. We assume that a higher number of points from ACE-Q could predict the development of alcoholic hepatitis and alcoholic cirrhosis and simultaneously could be a useful predictive tool for recurrence of thy abuse after liver transplantation.

Alcoholic hepatitis as a trigger of ACLF

N. Bystrianska, D. Žilinčanová

HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica

Alcohol-associated liver disease (ALD) is one of the main causes of chronic liver disease worldwide. Slovakia ranks first in the world in prevalence of decompensated cirrhosis with alcohol-associated liver disease being the leading etiology. Severe alcoholic hepatitis (SAH) is the most aggressive form of ALD with high short-term mortality. The only recommended treatment option – corticosteroids (CS) show modest short and none long-term survival benefit. Nearly 50% of patients do not respond to CS (non-responders, No-Re) or they have contraindications for their use (non-eligible, Ne). Moreover, ACLF occurs frequently during the course of SAH and contributes to worse prognosis of these patients. Unfortunately, there is no alternative treatment for these patients. Recently, fecal microbiota transplantation has gained attention as a potential therapeutic approach for ALD. We aimed to evaluate the impact of FMT on survival in NoRe and Ne patients with SAH. From 1/ 2018 to 1/ 2022, we performed FMT in 30 patients with SAH. Inclusion criteria: adult with severe form of acute alcoholic hepatitis, non-responder to CS treatment according to the Lille model or not eligible for CS based on their contraindications, informed consent. Exclusion Criteria: uncontrolled active infection, presence of untreated large / high-risk / bleeding esophageal varices, too sick for any therapy / futility (chronic extrahepatic organ failures, no potential for recovery, etc), malignancy except for hepatocellular carcinoma in Milan criteria. Intervention consisted of preparation of frozen fecal transplant donated from healthy unrelated donors after routine screening. Then a single dose (100 ml) was administered via upper GI tract and repeated at five consecutive days. We recorded demographic, clinical and laboratory parameters before and after FMT. We analyzed 30 patients with SAH, 25 pts were non-responders and 5 patients were non-eligible, 20 pts were men and 10 pts were women. Mean age, MELD-Na score a Maddrey function were 49 years, 28.7 points, 71.5 points. 25 patients had ACLF (ACLF grade 1 – 13 pts, ACLF grade 2 – 10 pts and ACLF grade 3 – 2 pts). Our data showed significant decrease in bilirubin on day 7 and on day 30 after FMT, decrease in CRP and ACLF grade on day 30. We did not find significant change in MELD score and INR after FMT. Kaplan-Meier curve showed improvement in survival of FMT patients compared to historical control of patients with SAH (No-Re and Ne),but result was not statistically singificant (P = 0.089). As predictors of FMT failure we indetified MELD score ≥30, MDR score ≥90 and ACLF grade 2–3 (P = 0.016; P = 0.024; P = 0.01). Possible predictors seem to be hepatic venous pressure gradient (HVPG) ≥16 mmHg and liver frailty index (LFI) >4.5 (frail), survival of this group of patients was worse, but result was not statistically significant (P = 0.32; P = 0.6). We did not confirm that Altamirano histologic scoring system determine prognosis of patients with SAH. Severe alcoholic hepatitis is a clinical syndrome associated with high mortality, especially in group of patients No-Re and Ne. FMT is one of the alternative treatment options and seems to improve survival in patients who present at admission with MELD-Na score ≤30, MDR ≤90 or ACLF grade 0–1. We need more and larger studies to prove benefit of FMT.

Early postoperative care in advanced chronic liver disease and after liver transplant

E. Kušíková

II^nd Department of anesthesia and critical care, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica

Early postoperative care for patients with advanced chronic liver disease (ACLD) combines challenges of care for the severely ill patient with those presented by specific surgical procedures. Especially in early postoperative period, complications that can occur are those generally expected and feared after any surgery in a severely ill patient (such as bleeding, thrombosis, respiratory, cardiovascular or renal insufficiency, exacerbations of chronic illness), as well as those inherent to the specific type of surgery. In ACLD patients, the clinical picture can be modified by organ systems alterations imposed by chronic liver disease, as well as by their acute decompensations provoked by surgery (encephalopathy, rebalanced hemostasis, hepatorenal syndrome, cirrhotic cardiomyopathy). In case of liver transplant patients, the context is broadened by the need of immunosuppression and differential diagnostics of early graft (dys)function. The success of postoperative care inevitably begins with preoperative approach, including surgery indication and timing, meticulous optimalisation of organ function and choice of surgical technique. This requires approach of a multidisciplinary team (surgeon, hepatologist, anesthetist, physiotherapist, nutritionist, hematologist), and this team is also best fit to provide early postoperative care as well. In that case the patient can most profit from the unique point of view of every specialist, integration of which allows for individualised approach to every patient and situation. n early postoperative setting, anesthesiologist can bring a bridging view and approach, understanding the perioperative surgical situation, as well as postoperative disturbances in hemodynamics and homeostasis. However, the specialty of a leader of such a multidisciplinary team is probably not as much of importance, as is the ability to talk, and, crucially, listen to one another.

Histology of ACLF (morphological score for alcoholic hepatitis)

E. Honsová

AeskuLab Pathology and Charles University, Prague, Czech Republic

Alcohol abuse represents a frequent cause of chronic liver disease which is characterized in morphology by steatosis, steatohepatitis, and variable grade of fibrosis that can progress to cirrhosis with complications including hepatocellular carcinoma. Morphological features of alcohol liver disease (ALD) are well described and few proposals for specific grading and staging systems have been made, but universally accepted system for the full clinical spectrum of ALD is currently lacking. Patients with severe alcoholic hepatitis (AH) represent complicated clinical scenarios. Usual presentation includes jaundice and systemic inflammatory response syndrome and may progress to acute-on-chronic liver failure. Severe AH has mortality of up to 30–40% at 1 month from the initial presentation. An accurate prediction of the risk of death is required for patient’s care. Several clinical and histopathological scores were developed for prediction of short-term mortality. The alcoholic hepatitis histologic score (Altamirano score) uses 4 histological parameters and has been proposed for assessing outcomes in AH patients. However, other studies did not confirm similar results. One of the most commonly used arguments is a limited size of a biopsy sample. Majority of patients with AH have ascites and coagulation disorders, the transjugular route is preferred for liver biopsy. Such a biopsy sample is frequently very thin and sometimes in small fragments. It would be very much appreciated to have a simple system to predict the further development of severe disease. However, in this endeavor we cannot completely omit biological complexity of AH. Severe liver dysfunction affects function of many organs, and on the other hands, functions of other organs (gut permeability and microbiome, kidney disease, vulnerability to infection, and many metabolic and circulatory conditions) have influence on the liver function. Narrowing this biological complexity to 4 problematic morphological features and considered them as valuable prognostic markers represents somewhat risky strategy. To predict a fate of patients suffering from severe AH, we need to direct research to this disregarded area, and then use the results of more sophisticated research activities.

HEV and other viruses as a triggers

S. Fraňková

Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Chronic liver disease (CLD) is characterized by gradual and constant injury to the liver tissue caused by a wide number of aetiologies. Various factors may influence its progression or improvement. Acute-on-chronic liver failure (ACLF), a newly recognized clinical entity seen in patients with CLD, including cirrhosis, and is associated with high short- and medium-term morbidity and mortality. ACLF is a syndrome that defines a subgroup of cirrhotic patients who develop organ failure following hospital admission with or without an identifiable precipitating event and have increased mortality rates. The definition provided by the APASL in 2009 characterizes ACLF as an “acute hepatic insult manifesting as jaundice (serum bilirubin ≥85 micromoles/ l) and coagulopathy (INR ≥1.5, or prothrombin time <40%) complicated within four weeks by clinical ascites and/ or encephalopathy in a patient with previously diagnosed or undiagnosed CLD/ cirrhosis”. The term precipitating event defines the acute insult, most often a bacterial infection and sepsis. Acute hepatitis A or E or reactivation of hepatitis B infection are the leading causes of acute insult in ACLF. Among the non-infectious aetiologies, alcoholrelated liver injury is the major cause of acute worsening of CLD. Hepatitis E virus (HEV) is a non-enveloped virus with a positive-sense single-stranded RNA genome belonging to the Hepeviridae family. HEV has been classified into eight genotypes: genotypes 1 to 4 and 7 have been shown to infect humans. Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis globally. HEV infections result in a spectrum of reported manifestations, including acute infections, mostly asymptomatic, chronic hepatitis in individuals with immunosuppression and/ or chronic liver disease, mainly associated with genotype HEV-3 and HEV-4, extrahepatic manifestations, fulminant hepatitis in pregnant women, when the infecting genotype is 1, and ACLF in patients with underlying liver diseases. When HEV causes acute hepatitis in patients with the underlying chronic liver disease, it may worsen rapidly to ACLF, leading to very high mortality. The typical disease course of patients with ACLF is the appearance of organ failure, which progresses to multi-organ failure and death. Many publications have reported HEV as one of the leading causes of ACLF in Asia and Africa, where HEV is endemic. The mortality rate of HEV-related ACLF (HEV-ACLF) ranges from 0% to 67%, with a median of 34%, and these patients benefit from admission to the intensive care unit. The treatment goals are to prevent further deterioration in liver function, support failing organs and support the rapid elimination of the virus. Ribavirin may be an effective and safe drug for the treatment of HEV-ACLF. Liver transplantation is required in selected patients to improve survival.

Focus on faecal microbiota transplantation through inflammation modulation in severe alcoholic hepatitis

K. Šoltýs^1,2, L. Messingerová^3–5, P. Olejníková³, L. Bírošová³, M. Lichvár⁶, Ľ. Skladaný⁷

¹ Department of Microbiology and Virology, Comenius University in Bratislava

² Comenius University Science Park, Comenius University, Bratislava

³ Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava

⁴ Institute of Molecular Physiology and Genetics, Centre of Bioscences SAS, Slovak Academy of Sciences, Bratislava

⁵ Sanitas Slovaca, Agency for Health Development in Slovakia, Tornaľa

⁶ Geneton Ltd., Bratislava

⁷ HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica

Introduction: Slovakia still ranks among the first countries in alcoholic hepatitis in the world. The clinical outcomes of the regular alcohol beverage consumption results to prognosed 180-day mortality. So far, there is no efficient treatment that could grant long-term survival. Elevated consumption of alcohol is associated with gut microbiota dysbiosis, gut leakage, proinflammatory cytokine and reactive oxygen species production as a result of innate and adaptive immunity activation. Production of TNF by Kupffer cells leads to clinicopathological syndrome. To maintain the eubiosis, modulation through diet, probiotics, prebiotics, or antibiotics represents one of the indirect ways of handling the disease. Faecal microbiota transplantation is considered to be the one of the most promising tools for direct dysbalanced gut microbiota composition modification and recovery. Aim: The aim of the study was to determine the gut microbiota composition of patients with severe alcoholic hepatitis (SAH) in the course of faecal microbiota transplantation and investigate the possible ways of host-microbiota interaction through modulation of immune system. Methods: The analysed cohort of individuals included gender and age balanced group of 22 healthy controls and 36 patients suff ering from SAH of that 13 underwent faecal microbial transplantation (FMT). Patients’ samples were collected at the 2nd SMU Department of Internal Medicine at of F. D. Roosevelt General Hospital of Banská Bystrica, Slovak republic while the control samples were provided by the Department of Nutrition and Food Quality Assessment, Faculty of Chemical and Food Technology STU in Bratislava, Slovak republic. Gut microbiota composition was analysed using faecal samples that were collected and immediately stored at –80 °C until DNA isolation and sequencing. library preparation based on 16S rRNA amplification. Barcoded samples were pooled together and sequenced on Illumina MiSeq platform. Bacterial composition was determined bioinformatically using SILVA database and statistically evaluated with one-tailed ANOVA or Student’s T-test. CDR index was calculated according to Bajaj et al, 2018. To determine the effect of FMT on the immunity status the neutrophil to lymphocyte ratio (NLR) was calculated for patients with and without FMT. Results: Dysbalanced gut microbiota of SAH patients was typical with elevated levels of pathogens and opportunistic pathogens including Enterococcus, Eggerthella, Fusobacterium and decrease of beneficial bacteria like Faecalibacterium, Eubacterium, Coprococcus, Barnesiella and Roseburia. Significant reduction in butyrate-producers Ruminococcacea and Lachnospiraceae, but also Bacteroidaceae was typical for all patients. Although use of the CDR index was not supportive in terms of beneficial effect of FMT, application of FMT increased the abundance of Ruminococaceae and decreased the abundance of Lachnospiraceae what lead to improvement of previously dysbalanced ratio of these two families. Promising, but not significant shift in Firmicutes to Bacteroidetes ratio (F/ B) towards the gut composition of healthy controls and 2-fold increase of Actinobacteria after FMT was also observed. Neutrophils-to-lymphocytes ratio (NLR) showed that FMT is associated with better outcome; NLR of FMT survivals 7days after FMT was lower than of the passed away ones (P ≤0,05) and more favourable for survivals with FMT vs. no FMT (P ≤0,02). Conclusion: Current study shows that implementation of novel treatment approaches can improve the gut microbiota balance, although its composition hardly resembles the one of the healthy individuals. Faecal microbiota transplantation can be the way to modulate the inflammatory status and increase the survival rates of patients. Since the gut microbiome is represented not only by microorganisms, but by a complex molecules and metabolites associated with their function, ongoing analysis need to be carried out to optimize and determine its members playing the key role in host-microbiota interaction. Despite supportive results still further investigation is necessary to answer challenging questions.

Acknowledgements: This study was funded by Department of Internal Medicine and HEGITO (Hepatology, Gastroenterology and Liver Transplantation), F.D. Roosevelt University Hospital, Slovakia.

Transfer factor efficacy in the management of cirrhosis-associated immune dysfunction

D. J. Havaj, Ľ. Skladaný

HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica

In the background course of cirrhosis, acute decompensation, and ACLF syndrome is a wide spectrum of alterations in an innate and adaptive immune response, which represent cirrhosis-associated immune dysfunction. The CAID comprises two key components – dysregulated inflammation and immune paralysis differently expressed in patients with clinical decompensation and ACLF. These changes contribute to the development of organ-specific complications and increase the risk of problematic infections. The possibilities for modulation of the dysfunctional immune response are currently limited. Transfer factor is a low-molecular-weight lymphocyte extract capable of transferring antigen-specific cell-mediated immunity. It is used as adjuvant immune-modulation therapy in patients with a cell-mediated immunity disorder and severe infection. The aim of this study is to assess the effect of the transfer factor in patients with acute decompensation and ACLF. We will retrospectively analyze the cohort of patients with acute decompensation and ACLF listed in the Register HEGITO 7 between 08/ 2016 and 01/ 2018. The part of these patients was treated by transfer factor. We will assess the potential effect of this treatment in comparison to the control group.

The evidence regarding body composition parameters in patients with non-alcoholic fatty liver disease: a systematic review of longitudinal studies and meta-analysis

D. Matis¹, P. Hegyi^1–3, B. Teutsch^1,3, T. Tornai⁴, F. Dembrovszky^1,3, B. Erőss^1–3, S. Váncsa^1–3, G. Pár⁵

¹ Centre for Translational Medicine, Semmelweis University, Budapest, Hungary

² Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary

³ Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary

⁴ Department of Gastroenterology, University of Debrecen, Hungary

⁵ Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary

Introduction: Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most common causes of chronic liver disease worldwide and represents a global public health problem. The most effective treatment for NAFLD is weight loss, however, it has been shown that body composition has a crucial effect on NAFLD resolution. Anyhow, most studies on this topic were cross-sectional and therefore could not demonstrate a causal relationship between certain parameters and NAFLD resolution. Aims & methods: In this systematic review and meta-analysis, we aim to evaluate the correlation between different body composition parameter change and the resolution of NAFLD in longitudinal studies. Methods: This study was registered on PROSPERO under registration number CRD42021278584. A systematic search was performed in Embase, MedLine (via PubMed), and Cochrane Central Register of Controlled Trials (CENTRAL) up to September 26, 2021. Studies were eligible if they reported on the correlation between the change of hepatic steatosis state and the change of various body composition parameters in adults with NAFLD. We calculated pooled correlation coefficients (R) with 95% confidence intervals (CIs) using random effect model. We separated Spearman’s and Pearson’s correlation analysis. Results: Out of 21,612 altogether, we included 14 studies in our quantitative and qualitative synthesis. Based on three studies containing 175 patients we found a moderate correlation between visceral adipose tissue (VAT) decrease and liver fat content reduction (Pearson’s R = 0.33; CI: 0.19–0.46). Similarly, in two studies with 85 patients, VAT change showed moderate correlation with steatosis decrease from Spearman’s correlation (R = 0.49; CI: 0.22–0.69). On the other hand, subcutaneous adipose tissue (SAT) change showed moderate correlation with steatosis reduction in two studies (N = 163, Pearson’s R = 0.42; CI: 0.29–0.54). We also analyzed the correlation between body fat mass, visceral fat rating, skeletal muscle area, and muscle body weight ratio change and steatosis reduction, however, we included only one study in each analysis. Conclusion: We found a moderate correlation between the VAT and SAT content change and liver fat reduction. Body composition parameter measurement should be introduced in the management of NAFLD.

Metabolic associated fatty liver disease is associated with a more severe acute pancreatitis: a prospective cohort analysis of 2053 cases

S. Váncsa^1–3, Z. Sipos¹, R. Nagy^1–4, K. Ocskay^1,2, F. Juhász^1,2, M. Földi^1,4, Á. Vincze⁵, P. Sarlós⁵, J. Bajor⁵, F. Izbéki⁶, M. Papp⁷, Z. Vitális⁷, J. Hamvas⁸, L. Czakó⁹, N. Faluhelyi¹⁰, O. Farkas¹⁰, E. Miklós¹, A. Mikó^1,11, P. J. Hegyi^2,3, M. Macarie¹², S. Galeev¹³, E. Ramirez Maldonado¹⁴, V. Sallinen¹⁵, I. Török¹², A. Mickevicius^16,17, B. Erőss^1–3, A. Párniczky^1,2,4, A. Szentesi^1,18, G. Pár^1,5, P. Hegyi^1–3,18

¹ Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary

² Centre for Translational Medicine, Semmelweis University, Budapest, Hungary

³ Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary

⁴ Heim Pál National Pediatric Institute, Budapest, Hungary

⁵ Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary

⁶ Szent György University Teaching Hospital of Fejér County, Székesfehérvár, Hungary

⁷ Department of Internal Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary

⁸ Peterfy Hospital, Budapest, Hungary

⁹ Department of Medicine, University of Szeged, Szeged, Hungary

¹⁰ Department of Radiology, Medical School, University of Pécs, Pécs, Hungary

¹¹ Department of Medical Genetics, Medical School, University of Pécs

¹² County Emergency Clinical Hospital – Gastroenterology and University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania

¹³ Saint Luke Clinical Hospital, St. Petersburg, Russia

¹⁴ General Surgery, Consorci Sanitari del Garraf, Sant Pere de Ribes, Barcelona, Spain

¹⁵ Department of Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland

¹⁶ Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania

¹⁷ Clinics of Abdominal Surgery, Nephrourology and Gastroenterology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

¹⁸ Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary

Background: We have shown in a meta-analysis that fatty liver disease (FLD) influences the outcomes of acute pancreatitis (AP). The aim of this study was to further analyze the prognostic role of metabolic associated fatty liver disease (MAFLD) in AP in a prospective cohort. Materials and methods: We identified our cohort from the multicentric prospective International Acute Pancreatitis Registry run by the Hungarian Pancreatic Study Group (222254-1/ 2012/ EKU). AP was diagnosed by the revised Atlanta criteria. For the diagnosis of MAFLD in addition to the presence of liver steatosis diagnosed with abdominal imaging one of the following criteria was positive: overweight or obesity, type 2 diabetes mellitus, or metabolic dysregulation. Outcomes of interest were in-hospital mortality, AP severity. We performed multivariate logistic regression analysis to analyze the effect of MAFLD on outcomes of AP and calculated odds ratios (ORs) with 95% confidence intervals (95% CIs). P <0.05 was considered as statistically significant. Results: Out of the 2,053 AP cases analyzed, 801 (39%) were diagnosed with MAFLD. Baseline characteristics of the MAFLD and non-MAFLD groups did not differ significantly, only for the proportion of men, alcohol, and hypertriglyceridemia induced AP. We did not find significant difference between the groups regarding in-hospital mortality (OR = 0.81; CI: 0.4–1.59), however the overall odds of moderately severe and severe AP were higher in the MAFLD group (OR = 1.40; CI: 1.09–1.79). In the subgroup of patients with one (OR = 1.43; CI: 1.05–1.92) or three positive MAFLD criteria (OR = 1.75; CI: 1.02–2.96), however, not with two positive criteria (OR = 1.23; CI: 0.85–1.77). Conclusion: Although we did not find an increased odds of in-hospital mortality, the odds of moderately severe and severe AP was higher in the MAFLD group.

Hepatitis B as a trigger of ACLF

J. Šperl

Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Acute-on-chronic liver failure (ACLF) is defined as the exacerbation of chronic liver disease initiated by a precipitating event. Liver complications or decompensation and rapid disease progression lead to high organ failure risk and high short-term mortality. ACLF usually occurs following a precipitating event in the context of chronic liver diseases. In Western countries, alcoholism-induced cirrhosis is the main reason for ACLF. However, in Asia countries, hepatitis B virus (HBV) infection is the main cause of ACLF. Severe systemic infl ammation is an essential factor in HBV-ACLF. However, the initial CHB-ACLF events are unclear. In 2009, the Asian Pacific Association for the Study of the Liver (APASL) provided the first consensus on ACLF, defined as “an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within four weeks by ascites and/ or encephalopathy.” The 2014 definition was further expanded to include “high 28-day mortality”. The European Association for the Study of the Liver-chronic liver failure Consortium (EASL-CLIF) managed the European multicentre observational study (CANONIC), the most comprehensive registry to understand outcomes and precipitating factors of ACLF. The CANONIC investigators adapted the Sequential Organ Failure Assessment (SOFA) to their cohort to predict short-term mortality (CLIF-C ACLF). The CANONIC group proposed an algorithm for the management of patients with ACLF. The proposed management strategy for patients with ACLF was based on mortality rate data from the CANONIC study. The first step was the assessment of ACLF grade on days 3–7 after initiation of medical management, including organ support. Liver transplantation should be assessed in all patients with ACLF, and liver transplantation should be performed as early as possible in patients with ACLF grade 2 and grade 3. In the case of contraindication of liver transplantation, the presence of four or more organ failures and a CLIF-C ACLF score of >64 on days 3–7 after diagnosis could indicate the futility of care. World Gastroenterology Organisation, conscious of the differences between Western and Eastern definitions, provided some suggestions to improve the diagnostic criteria of ACLF and suggested determining their validity using prospective studies. Wu et al. assessed 1322 Chinese patients with acute decompensation of cirrhosis or severe liver injury due to chronic HBV using the CLIF-C ACLF criteria, with the exception of cirrhosis. CLIF-C ACLF criteria, with the exception of cirrhosis, identified 391 patients with ACLF. Ninety and two patients with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF, and 28 with ACLF with cirrhosis caused by non-HBV aetiologies. The short-term (28/ 90 days) mortality of the patients with HBV-ACLF was significantly higher than those of those with non-HBV-ACLF. Total bilirubin of more than 12 mg/ dL and an international normalized ratio (INR) ≥1.5 were proposed as the new diagnostic parameters of HBV-ACLF. Four hundred seventy-seven patients (19.3% in addition) were diagnosed with HBV-ACLF using the new criteria. The authors proposed a new prognostic score that was better in the prediction of short-term mortality than the previous five scores. The new criteria diagnosed more patients with an HBV- ACLF allowing them to receive timely intensive management. Liver transplantation is an effective therapy to reduce mortality and increase survival rates in HBV-ACLF patients. However, the lack of donor organs is a major barrier to urgent liver transplantation. Non-biological artificial liver support devices (ALS) remove circulating toxins using dialysis-based techniques. However, ALS provide no significant survival benefit. Bio-artificial devices incorporating porcine or human hepatic cells have been developed to replace hepatic detoxification and synthetic functions. But, these devices, including extracorporeal liver assist devices, have not been tested in ACLF patients. Anti-viral therapy is required for long-term prognosis. Nucleoside and nucleotide analogs (NUCs) with anti-HBV activity (Tenofovir alafenamide, Tenofovir disoproxil fumarate, and Entecavir) have been reported to improve the transplant-free survival rate in ACLF patients. However, waiting for the NUCs effect should not delay liver transplantation in patients with severe liver failure. Long-term use of NUCs also induces acute kidney injury. Interferon-alpha-based treatment is contraindicated in all the HBV flares. Additionally, glucocorticoid administration in the early phase of HBV-ACLF could improve short-term survival.

Liver Transplantation for Acute-on-Chronic Liver Failure (ACLF)

P. Trunečka

Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

ACLF is very serious condition characterized by hepatic and extrahepatic organ failure with high 28-days mortality (overall 32.8%) in patients with known chronic liver disease, typically liver cirrhosis. Live expectancy of those affected is limited and depends on disease severity expressed by the number of organ failure: 90-days mortality is ranging from 41% for patients with ACLF-1, to 55% for those with ACL-2 and 78% for patients with ACLF- 3 (three or more failing organs), and this is considerably higher than mortality of patients with liver cirrhosis even with signs of acute decompensation. As conservative treatment is often unsuccessful, liver transplantation could be valid option for well selected patients suffering of ACLF. Several recent studies have demonstrated that if patients with ACLF are transplanted expeditiously, their posttransplant outcome is acceptable, achieving 1-year survival rate of 87.3% in the most recent study (June 2022). Based on this study from several US centres on recipients transplanted in 2018 a 2019 for ACLF defined using EASL-CLIF criteria (N = 318), there was no difference in 1-year survival rate between patients with ACLF-1 (88.5%), ACLF –2 (87.8%), and ACLF-3 (85.7%), P = 0,26. Moreover patients with circulatory failure hadn’t worse survival (82.3%) than patients without signs of circulatory failure (89.6%), P = 0.32. Surprisingly, there was decreased survival in patients with ACLF-3 and portal vein thrombosis (57.1%) in comparison with those with ACLF-3 and patent vena cava (91.9%), P <0.001. On multivariate analysis of risk factors for patient’s death after transplantation for ACLF-3, only portal vein thrombosis and recipient age were independent risks factors. Similar recipient population was studied in Europe (N = 234). The overall 1-year survival probability after transplant for ACLF was 81%, ranging from 88.6% for ACLF-1 to 78.9% for those transplanted for ACLF-3. Multivariate analysis revealed presence of multi drug resistant organism (MDRO) infection, arterial lactate >4 mmol/ l, and need for renal replacement therapy at transplant as independent risks of death posttransplant. There were strong association between age above 60, presence of MDRO infection and number of organ failure and death or withdrawal from waiting list. Most patients were transplanted within short period of time: median 8 days, Q1-Q3: 3.0–19.5 days, death or withdrawal from WL appeared in median 9.8 days, Q1–Q3: 1.4–17.1 days since listing. Despite possible acceptable results not all ACLF patients are suitable candidates for liver transplantation, prudent selection is essential to avoid futile liver transplantation. Paramount problem of current situation are existing allocation systems that usually give low priority to patients having chronic liver condition, mostly based on MELD or MELD-Na score that not accurately express the risks associate with ACLF. Although patients with ACLF-1 could be given donor liver timely under MELD-Na allocation policy, this is not the case for candidates with ACLF-3, as their 14-days mortality rate, according to recent study is even higher than in patients listed with acute liver failure. Bridging patients with ACLF to transplantation in acceptable condition is great challenge for current intensive care practice. During the decade from ACLF definition, there is a lot of knowledge accumulated that could assist in patient’s management. Infection is often insult triggering the onset of ACLF. Despite urgent need of transplantation, sepsis should be managed prior to transplantation, that should be postponed if fever above 39° persists, or leucopenia (<500/ mm3), or respiratory tract infection or spontaneous bacterial peritonitis is treated less than 72 hours. A lot of experience was collected on alcoholic hepatitis as a frequent cause of ACLF. Long time being 6-months rule a solid base for denying patients with alcoholic liver disease listing for transplantation, many reports of successful selection of recently drinking candidates for emergency transplantation has shown that there is an option for these “lost sheep” to get long term profit from liver replacement if strict protocol of multilayer selection is followed. Overall, ACLF is demanding condition deserving attention to all steps of patient management in the course of liver transplantation process, particularly the multidisciplinary intensive care pre- and posttransplant, surgery itself, and organization including changes in patient selection and organ allocation policy.