Clinicopathological characteristics of 3 probable pediatric cases with acute severe hepatitis of unknown aetiology.

Background: Acute severe hepatitis with unknown aetiology in children (ASHep-UA) has become a global health alert. This article reported clinicopathological characteristics of 3 probable ASHep-UA cases. Methods: We respectively collected serological data and liver biopsies of 3 suspected cases of ASHep-UA. Neutralizing antibodies titer for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants were determined by virus neutralization test (VNT). Histological assessment, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for cytomegalovirus (CMV), Epstein-Barr virus (EBV), human adenoviruses (HAdV), adeno-associated virus (AAV2), human herpes virus type 6 (HHV-6) were performed to identify possible aetiologies. Results: Remarkable elevation of transaminase (median ALT level, 1100 IU/liter; median AST level, 500 IU/liter) were revealed with undetectable hepatitis A-E and non-hepatotropic virus in both sera and tissues. Weakness, jaundice, pale stools and splenomegaly were observed. Interestingly, two individuals had SARS-CoV-2 Omicron variants infection. Histologically, moderate or severe lobular necroinflammation, active interface hepatitis and portal inflammatory infiltrate with lymphocytic, plasma cells, neutrophils and eosinophilic cells were noted. Conclusions: The exact aetiology of ASHep-UA was still unknown. By reporting the 3 probable cases, we expect to enrich the clinical experience in diagnosis and treatment of ASHep-UA as well as the pathological characteristics.

Lymphocyte-to-white blood cell ratio is associated with outcome in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: The lymphocyte-to-white blood cell ratio (LWR) is a blood marker of the systemic inflammatory response. The prognostic value of LWR in patients with hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) remains unclear. AIM: To explore whether LWR could stratify the risk of poor outcomes in HBV-ACLF patients. METHODS: This study was conducted by recruiting 330 patients with HBV-ACLF at the Department of Gastroenterology in a large tertiary hospital. Patients were divided into survivor and non-survivor groups according to their 28-d prognosis. The independent risk factors for 28-d mortality were calculated by univariate and multivariate Cox regression analyses. Patients were divided into low- and high-LWR groups according to the cutoff values. Kaplan-Meier analysis was performed according to the level of LWR. RESULTS: During the 28-d follow-up time, 135 patients died, and the mortality rate was 40.90%. The LWR level in non-surviving patients was significantly decreased compared to that in surviving patients. A lower LWR level was an independent risk factor for poor 28-d outcomes (hazard ratio = 0.052, 95% confidence interval: 0.005-0.535). The LWR level was significantly negatively correlated with the Child-Turcotte-Pugh, model for end-stage liver disease, and Chinese Group on the Study of Severe Hepatitis B-ACLF II scores. In addition, the 28-d mortality was higher for patients with LWR < 0.11 than for those with LWR ≥ 0.11. CONCLUSION: LWR may serve as a simple and useful tool for stratifying the risk of poor 28-d outcomes in HBV-ACLF patients.

Role of N-acetylcysteine in liver injury due to dengue fever.

Dengue fever (DF) is a common mosquito-borne viral infection which is endemic in Southeast Asia. Liver involvement may vary from asymptomatic elevation of liver enzymes to fulminant hepatitis. Although the valuable effects of N-acetylcysteine (NAC) in paracetamol toxicity and non-paracetamol liver failure have been extensively studied, its use in DF-associated hepatitis remains unclear. We made a literature search in an online format from libraries such as PubMed, Google Scholar, and EMBASE, and selected 33 articles including original research articles, case reports, and systemic analyses. The majority of the articles reviewed had a positive outcome but treatment strategies involved NAC together with supportive care. Hence, data on sole use of NAC from large randomised control trials remain unclear.

Checkpoint inhibitor-induced gastritis followed by delayed severe hepatitis in a patient with lung metastases of head and neck squamous cell carcinoma: a case report.

Pembrolizumab, an anti-programmed death-1 (PD-1) receptor monoclonal antibody, is an effective first-line therapy for metastatic head and neck squamous cell carcinoma. Immune-related adverse events (irAEs) are well-described complications of PD-1 inhibitors, and multiorgan irAEs are known to occur occasionally. We report a patient with pulmonary metastases of oropharyngeal squamous cell carcinoma (SCC), who developed gastritis followed by delayed severe hepatitis and recovered with triple immunosuppressant therapy. A 58-year-old Japanese male with pulmonary metastases of oropharyngeal SCC who was treated with pembrolizumab, subsequently developed new-onset appetite loss and upper abdominal pain. Upper gastrointestinal endoscopy revealed gastritis and immunohistochemistry revealed pembrolizumab-induced gastritis. The patient developed delayed severe hepatitis at 15 months after initiating pembrolizumab treatment, presenting "Grade 4 aspartate aminotransferase increase" and "Grade 4 alanine aminotransferase increase." Impaired liver function persisted despite pulse corticosteroid therapy with intravenous methylprednisolone 1,000 mg/day, followed by oral prednisolone 2 mg/kg/day and oral mycophenolate mofetil 2,000 mg/day. Tacrolimus, which reached target serum trough concentrations of 8-10 ng/mL, gradually improved irAE grades from Grade 4 to Grade 1. The patient responded well to triple immunosuppressant therapy comprising prednisolone, mycophenolate mofetil, and tacrolimus. Therefore, this immunotherapeutic approach could be effective for multiorgan irAEs in patients with cancer.

Understanding public perceptions in social media responses to posts about acute severe hepatitis of unknown etiology in Indonesia: a qualitative study.

BACKGROUND: Acute Severe Hepatitis of Unknown Etiology (ASHUE) emerged as a new global outbreak in Indonesia early May 2022, coinciding with the COVID-19 pandemic. This study aimed to understand public reactions and responses to the emergence of ASHUE Indonesia and to Government-led disease prevention responses. Understanding how the public perceived government-led preventive messaging about the hepatitis outbreak is crucial to controlling viral spread - particularly given the rapid and unforeseen emergence of ASHUE coincided with COVID-19 and public trust in the Indonesian Government to manage health outbreaks was already tenuous. METHODS: Social media users' responses to information disseminated via Facebook, YouTube, and Twitter were analyzed to understand public perceptions about ASHUE outbreak and their attitudes toward Government-led prevention measures. Data were extracted on a daily basis from 1st May 2022 to 30th May 2022 and analyzed manually. We inductively generated the codes, from which we formed a construct and then grouped to identify themes. RESULTS: A total of 137 response comments collected from 3 social medial platforms were analyzed. Of these, 64 were from Facebook, 57 were from YouTube, and 16 were from Twitter. We identified 5 main themes, including (1) disbelief in the existence of the infection; (2) suspicion about a potential new business after COVID-19; (3) suspicion that COVID-19 vaccine(s) are the cause; (4) religion-related fatalism and (5) trust in government measures. CONCLUSIONS: The findings advance knowledge about public perceptions, reactions and attitudes towards the emergence of ASHUE and the efficacy of disease countermeasures. The knowledge from this study will provide an understanding of why disease prevention measures might not be followed. It can be used to develop public awareness programs in Indonesia about both the ASHUE and its possible consequences and the available healthcare support.

Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure.

AIM: Heavy alcohol consumption is the most common etiology of acute-on-chronic liver failure (ACLF) in Japan. In some patients, ACLF is associated with a fatal outcome in less than 6 months. We evaluated the prognosis of patients with alcohol-related ACLF in our cohort and explored the prognostic factors. METHODS: Forty-six patients with alcoholic liver cirrhosis who fulfilled the Japanese diagnostic criteria for ACLF, including those classified as extended and/or probable, were enrolled in this study. Serum concentrations of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were measured. We assessed prognosis and identified factors associated with survival. RESULTS: During the median 33-day observation period, 19 patients died, and 3 patients underwent living donor liver transplantation. Cumulative survival rates of patients treated without liver transplantation were 69, 48, 41, and 36% at 1, 3, 6, and 12 months, respectively. Eighteen of the 19 deceased patients died within 6 months after ACLF diagnosis. Serum concentrations of inflammatory cytokines were significantly elevated, and patients who underwent liver transplantation or who died within 6 months after admission had significantly higher serum IL-6 levels than the survival group. Multivariate analysis identified IL-6 > 23.3 pg/mL at admission and model for end-stage liver disease (MELD) score ≥ 25 on day 4 of admission as significant independent factors for mortality within 6 months. CONCLUSION: Serum IL-6 level and Day-4 MELD were prognostic factors for alcohol-related ACLF. Early liver transplantation is a potential treatment option for patients whose prognosis is expected to be poor.

Severe hepatitis E infection in pregnancy: a case report.

Hepatitis E virus causes self limiting hepatitis most of the times but, during pregnancy it can lead to severe hepatitis along with various complications thereby increasing the mortality. Case presentation: A 27-year-old woman gravida two, para one at 38 weeks and 6 days of gestation presented with multiple episodes of nonbilious vomiting, severe dehydration, and later developed right upper quadrant abdominal pain. The patient had a positive serological test for the hepatitis E virus, and liver enzymes were severely elevated. Under supportive treatment she delivered a healthy baby, and her liver enzymes returned to normal levels after 2 weeks of delivery. Clinical discussion: Although the hepatitis E virus usually causes self-limiting hepatitis, it can quickly progress to severe hepatitis, liver failure, and even death during pregnancy. Immunological change with a Th2 biased response and increased hormonal levels during pregnancy could possibly facilitate the development of severe liver damage. No particular drug has been approved for the treatment of hepatitis E viral infection in pregnant women, and the commonly used drugs are contraindicated due to the risk of teratogenicity. Supportive therapy and intensive monitoring are the core management techniques for hepatitis E virus infection in pregnant women. Conclusion: Due to the high mortality risk, pregnant women should try to avoid possible exposure to the hepatitis E virus, but once infected, symptomatic therapy is the mainstay.

Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study.

Background: Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Methods: Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. Findings: In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. Interpretation: COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. Funding: This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

Acute severe non-A-E-hepatitis of unknown origin in children - A 30-year retrospective observational study from north-west Germany.

BACKGROUND & AIMS: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. We aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic. METHODS: We analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to 16 May 2022. We separated cases into a historic cohort (1990-2018) and a COVID-19 era cohort (2019-2022). RESULTS: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were HHV-6 (4), CMV, HSV, EBV(3). Sixty-nine patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. Twenty-five patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died. CONCLUSIONS: Acute non-A-E-hepatitis in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in our current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in our centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases. IMPACT AND IMPLICATIONS: As the current epidemic of severe acute non-A-E-hepatitis cases in children highlights our limited understanding in the field, we aim to describe current cases, characterizing the presentation over time, and defining similarities and discrepancies before and during the COVID-19 pandemic. Our data show a rising incidence of non-A-E-hepatitis cases since the beginning of the COVID-19 pandemic. These cases were not associated with adenoviral infections, suggesting that the recently described accumulation of adenovirus infections in relationship to hepatitis is a new trigger for a known phenomenon, rather than a new disease entity. Therefore, the role of protective isolation and subsequent lack of contact with trivial infections in children during the pandemic should be the subject of further examinations. We expect our data to contribute to a better understanding of severe acute hepatitis in childhood, increased vigilance for this potentially lethal disease beyond the current epidemic, and ultimately improved clinical diagnosis and care.

The Role of Off-Therapy Viral Kinetics in the Timing and Severity of Flares in Hepatitis B e Antigen-Negative Patients.

BACKGROUND & AIMS: Hepatitis B flare occurs earlier and is more severe in patients stopping tenofovir (TDF) compared with entecavir (ETV). This study investigated relationship between hepatitis B virus (HBV) kinetics, onset timing, and the severity of flares. METHODS: Hepatitis B e antigen-negative chronic hepatitis B patients who developed off-ETV or off-TDF hepatitis flare were recruited. Their HBV kinetics and the severity of flares were compared between patients with early (<6 months) and late (between 6 and 24 months) flares. Propensity score matching was performed at 1:1 adjusting for age, sex, cirrhosis, and end-of-treatment (EOT) hepatitis B surface antigen between off-ETV and off-TDF flares. RESULTS: After propensity score matching, 76% and 15% of each 107 off-TDF and off-ETV patients, respectively, developed early flare. A much steeper HBV DNA upsurge (ΔHBV DNA/month) was observed in off-TDF than off-ETV flares (2.12 vs 0.73 log10 IU/mL; P < .01). Greater ΔHBV DNA/month correlated with earlier timing and higher peak alanine aminotransferase levels of flares. ΔHBV DNA/month ≥2.5 log10 IU/mL was an independent factor for severe off-TDF flare, and ≥1 log10 IU/mL was a predictor for severe off-ETV flares. CONCLUSIONS: Greater HBV DNA upsurge rate (ΔHBV DNA/month) ≥1 log10 IU/mL is a key factor for an earlier onset and more severe flare. More frequent ΔHBV DNA/month ≥1 log10 IU/mL in off-TDF than off-ETV flares may explain why off-TDF flare mostly occurred early and was more severe. More stringent monitoring in those with ΔHBV DNA/month ≥1 log10 IU/mL at flare, especially ≥2.5 log10 IU/mL in early off-TDF flares, is important for timely retreatment to prevent decompensation.

Updated information regarding acute severe hepatitis of unknown origin in children: Viewpoints of and insights from pediatricians.

Recently, the morbidity of acute severe hepatitis of unknown origin in children (SHIC) has tended to decrease, but this condition should not be ignored because of its uncertain but severe nature. The current study briefly summarizes updated information regarding the epidemiological, clinical, and etiological aspects of SHIC based on the newest information available. Opinions from pediatricians are also presented. In light of the status quo of SHIC and COVID-19 globally, several suggestions are proposed to improve future studies, which could help to further explore the underlying mechanisms of SHIC in the context of COVID-19.

Acute severe hepatitis of unknown origin in children in Canada.

Background: In spring 2022, a series of reports from the United Kingdom and the United States identified an increase in the incidence of acute severe hepatitis in children. The Public Health Agency of Canada (PHAC) collaborated with provincial/territorial health partners to investigate in Canada. Clinical hepatitis, or inflammation of the liver, is not reportable in Canada, so to determine if an increase was occurring above historical levels, the baseline incidence in Canada was estimated. This article estimates the pre-existing baseline incidence of acute severe hepatitis of unknown origin in children in Canada using administrative databases. It further summarizes the outbreak investigation using information from the national case report forms. Methods: A committee with representatives from PHAC and provincial/territorial health partners was established to investigate current cases in Canada. A national probable case definition and case report form were developed, and intentionally created to be highly sensitive to capture all potential cases for etiological investigations. To estimate a nationally representative baseline incidence, hospitalization data were extracted from the Discharge Abstract Database and was combined with data from Québec from the Ministère de la Santé et des Services sociaux. Results: Twenty-eight probable cases of acute severe hepatitis of unknown origin in children were reported between October 1, 2021, to September 23, 2022, by six provinces: British Columbia=1; Alberta=5; Saskatchewan=1; Manitoba=3; Ontario=14; and Québec=4. The estimated national baseline incidence was an average of 70 cases annually, or 5.8 cases per month. Conclusion: There was no apparent increase above the estimated historical baseline levels.

The neutrophil-to-lymphocyte ratio represents a systemic inflammation marker and reflects the relationship with 90-day mortality in non-cirrhotic chronic severe hepatitis.

OBJECTIVES: To investigate the relationship between systemic inflammatory response and short-term mortality in patients with non-cirrhotic chronic severe hepatitis (CSH) by using several indicators of inflammation including neutrophil-to-lymphocyte ratio (NLR), neutrophil (NEU), white blood cell (WBC), platelet-to lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). METHODS: Data were collected from two prospectively enrolled CATCH-LIFE noncirrhotic cohorts. Cox regression analysis was used to investigate the association between systemic inflammatory biomarkers and 90-day liver transplant (LT)-free mortality. A generalized additive model (GAM) was used to illustrate the quantitative curve relationship between NLR and 90-day LT-free mortality. Kaplan-Meier method was used to estimate the 90-year LT-free survival. RESULTS: The prevalence of CSH was 20.5% (226/1103). The 28-day and 90-day LT-free mortality rates were 17.7% and 26.1%, respectively, for patients with non-cirrhotic CSH. Patients with no infection accounted for 75.0% of all CSH patients, and NLR was independently associated with 90-day LT-free mortality. NLR of 2.9 might be related to disease deterioration in CSH patients without infection. CONCLUSIONS: NLR may be an independent risk factor for 90-day LT-free mortality in patients with non-cirrhotic chronic liver disease. A NLR of 2.9 as the cut-off value can be used to predict disease aggravation in CSH patients without infection.

A review on acute, severe hepatitis of unknown origin in children: A call for concern.

Hepatitis is defined as the inflammatory reaction of the liver parenchyma. It is either acute, which resolves within six months or may be chronic. An outbreak of severe, acute hepatitis of unknown origin in children was reported in nearly all World Health Organisation (WHO) regions except in the Africa. As per the recent update on the 26th of May, approximately 650 cases have met the WHO's probable criteria. While some are yet to be confirmed, the WHO warns that the figure may be underestimating the real situation. The observed clinical presentation includes outstanding immoderate levels of transaminases, vomiting from the previous presentation, pale/mild stools, and jaundice. So far, the viruses which can cause viral hepatitides, like Hepatitis A, B, C, D, and E, have not been detected in any of the identified cases. Some literature reported human enteric adenovirus type 41F in the majority of cases aged sixteen or younger, with few cases of co-infection with SARS-CoV-2. Currently, only several hypotheses have discussed the causality of the outbreak. However, no consensus has been reached. During this outbreak, it is important to adhere to both hand and body hygiene, general infection and control prevention strategies, and lastly, case presentation matching the criteria of case definition set by the WHO. Said identified cases should be reported to concerned health authorities on an urgent basis and must be kept under proper surveillance.

Severe acute hepatitis of unknown aetiology in children-what is known?

The ongoing investigations into clusters of children affected by severe acute hepatitis of unknown aetiology have put our global capacity for a coordinated, effective response to the test. The global health community have rapidly convened to share data and inform the response. In the UK, where most cases were initially identified, a coordinated public health and clinical research response was rapidly initiated. Since then, cases have been reported from other countries, predominantly from higher-income countries. While agencies are keeping an open mind to the cause, the working hypothesis and case notifications raise important questions about our capacity to detect emerging cases in lower-resourced settings with a recognised lack of access to diagnostics even for commonly circulating viruses such as hepatitis A. The limited capability to generate integrated global pathogen surveillance data is a challenge for the outbreak investigations, highlighting an urgent need to strengthen access to diagnostics, with a focus on lower-resourced settings, to improve the capacity to detect emerging diseases to inform care and to improve outcomes and outbreak control.

[Analysis of clinical features and prognosis of acute severe autoimmune hepatitis].

Objective: To analyze the clinical features and prognosis of acute severe autoimmune hepatitis (AIH). Methods: A retrospective analysis of the clinical data of patients with acute severe AIH admitted to our hospital from 2008 to 2019 was divided into acute AIH (A-AIH) and chronic acute AIH (AC-AIH) according to the presence or absence of liver diseases. Patients' general condition, liver biochemistry, immunology, histological features of liver, hormonal therapies prognosis and related factors were analyzed. Results: A total of 41 cases [39 females, age (54.24 ± 10.55) years] were collected. Alanine aminotransferase (ALT) and total bilirubin (TBil) were significantly increased, and the international normalized ratio (INR) was > 1.5. Acute lobular inflammation was the feature of acute and severe AIH in the histology of liver. The serum IgG level was (28.36 ± 8.35) g / L. The positive rate of antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) was 82.9%, and 17.1%, respectively. Over 70% of acute severe AIHs were AC-AIH. The duration of onset of AC-AIH was > 8 weeks, while most A-AIHs < 8 weeks, and the differences between the two groups were statistically significant (P = 0.001). The mortality rate within 30 days after hormonal treatment was 19.5%. There were statistically significant differences in TBil, Model for End-Stage Liver Disease (MELD) score and leukocyte count between the death and survival group. Conclusion: The mortality rate in acute severe AIH is high, and most of them have the basis of chronic liver disease. Serum IgG level, autoantibodies and acute lobular inflammation are important factors for diagnosis. The prognosis of hormonal therapy is related to the patients' condition and course of disease.

Diagnosis and Clinical Management of Acute Severe Hepatitis of Unknown Origin: Operational Recommendation of Peking Union Medical College Hospital.

Around 450 cases of acute severe hepatitis of unknown origin in children have been reported in 21 countries and region globally since April 2022, which has exceeded the past annual incidences of related regions, and has aroused wide concern. Affected patients were predominantly children under 16 years of age, presented with symptoms of acute hepatitis with markedly elevated liver enzymes, and had been ruled out of common viral infections such as hepatitis A, B, C, D, and E. Similar cases have not been reported in China yet. However, considering that the severe acute hepatitis has involved worldwide areas, still with unknown origin, and incidences of severity is relatively high, we formulated this recommendation to standardize diagnosis and treatment of acute severe hepatitis of unknown origin in Peking Union Medical College Hospital, to get fully prepared to the possible public health events.

Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment.

The term acute-on-chronic liver failure (ACLF) defines an abrupt and life-threatening worsening of clinical conditions in patients with cirrhosis or chronic liver disease. In recent years, different definitions and diagnostic criteria for the syndrome have been proposed by the major international scientific societies. The main controversies relate to the type of acute insult (specifically hepatic or also extrahepatic), the stage of underlying liver disease (cirrhosis or chronic hepatitis) and the concomitant extrahepatic organ failure(s) that should be considered in the definition of ACLF. Therefore, different severity criteria and prognostic scores have been proposed and validated. Current evidence shows that the pathophysiology of ACLF is closely associated with an intense systemic inflammation sustained by circulating pathogen-associated molecular patterns and damage-associated molecular patterns. The development of organ failures may be a result of a combination of tissue hypoperfusion, direct immune-mediated damage and mitochondrial dysfunction. Management of ACLF is currently based on the supportive treatment of organ failures, mainly in an intensive care setting. For selected patients, liver transplantation is an effective treatment that offers a good long-term prognosis. Future studies on potential mechanistic treatments that improve patient survival are eagerly awaited.