Extrahepatic Organ Failure Research Articles

Acute-on-Chronic Liver Failure: Getting Ready for Prime Time?

ACLF is a clinically relevant syndrome that is epidemic worldwide and requires a dedicated multinational approach focused on prognostication and management; investigations are underway worldwide to prepare ACLF for prime time. (Hepatology 2018; 00:000-000).

Management of acute-on-chronic liver failure: an algorithmic approach.

Acute-on-chronic liver failure (ACLF) is a distinct syndrome of liver failure in a patient with chronic liver disease presenting with jaundice, coagulopathy and ascites and/or hepatic encephalopathy, developing following an acute hepatic insult and associated with high 28-day mortality. The definition though lacks global consensus, excludes patients with known distinct entities such as acute liver failure and those with end-stage liver disease. The initial Systemic Inflammatory Response Syndrome (SIRS) because of cytokine storm in relation to acute insult and/or subsequent development of sepsis due to immunoparalysis leads to extrahepatic organ failure. These cascades of events progress through a 'Golden Window' period of about 7days, subsequent to which majority of the patients develop complications, such as sepsis and extrahepatic organ failure. Prevention of sepsis, support of organs and management of organ failure (commonly hepatic, renal, cerebral, coagulation) and early referral for transplant is crucial. The APASL ACLF research consortium (AARC) liver failure score is a dynamic prognostic model for management decisions and is superior to existing models. Aggressive multidisciplinary approach can lead to a transplant-free survival in nearly half of the cases. The present review provides an algorithmic approach to management of organ failure, sepsis prevention, use of dynamic prognostic models for management decision and is aimed to improve the skills for managing and improving the outcomes of such critically ill patients.

Association Between Intestinal Microbiota Collected at Hospital Admission and Outcomes of Patients With Cirrhosis

Inpatients with cirrhosis are prone to develop acute-on-chronic liver failure (ACLF). ACLF is associated with dysbiosis of the intestinal microbiota, which might serve as a prognostic factor. We investigated whether features of the intestinal microbiota associate organ failure, transfer to intensive care, and mortality within 30 days in patients admitted to the hospital with cirrhosis. Stool samples were collected from 181 patients with cirrhosis (age 56 years; mean model for end-stage liver disease score, 21; 43% with infections) at time of admission, from multiple hospitals in North America. Patients were followed for 30 days for development of ACLF, extra-hepatic organ failures, and death or hospice care. Microbiota were analyzed by 16s rRNA sequencing for alpha diversity (within groups), beta diversity (between groups), cirrhosis dysbiosis ratio (CDR), and taxa that differed between groups with vs without negative outcomes (individual organ failures, transfer to intensive care, ACLF, death, or hospice). Regression analyses were performed using microbial and clinical variables for each outcome. ACLF developed in 8% of study subjects; 16% were transferred to intensive care and 21% died. Beta diversity of the intestinal microbiome was significantly different, whereas alpha diversity was similar, between subjects with vs without outcomes. The CDR was lower in subjects who developed ACLF, especially among those with renal failure. Taxa belonging to phylum Proteobacteria (Enterobacteriaceae, Campylobacteriaceae, and Pasteurellaceae) and Firmicutes (Enterococcaceae and Streptococcaceae) were associated with development of negative outcomes, whereas other Firmicutes members (Lachnospiraceae and Clostridiales) reduced risk of negative outcomes. Changes in the microbiota associated with extra-hepatic organ failure, transfer to intensive care, ACLF, and death, independently on logistic regression analyses. In hospitalized patients with cirrhosis, dysbiosis of the intestinal microbiota on admission (particularly changes in Protebacteria constituents) associates with increased risk of extra-hepatic organ failure, ACLF, and death, independent of clinical factors. Strategies to reduce gut dysbiosis might improve outcomes of patients with cirrhosis.

Transplantation for the Very Sick Patient—Donor and Recipient Factors

Patients with end-stage chronic liver disease (CLD) frequently deteriorate with development of a ‘frail’ state and progress to development of extra-hepatic organ failures. Making the clinical judgement when a patient is ‘too sick’ to proceed with liver transplantation is challenging; we summarise recent studies that may inform decision-making. Reports quantify the impact of both recipient and donor factors related to early post-transplant survival, with consistent adverse association of advanced donor and recipient age, under-nutrition, sarcopenia and impaired functional status, and requirement for critical care unit admission and organ support. Survival for ‘very sick’ recipients has shown progressive improvement over time, but evidence is increasing of much greater post-transplant resource use and cost. Factors associated with adverse outcomes in very sick recipients are becoming more clearly delineated. The increasing success of transplantation and exploration of its extended use must be tempered by the recognition of the consequences upon constrained clinical resources.

Low circulating chemerin levels correlate with hepatic dysfunction and increased mortality in decompensated liver cirrhosis

Nutritional status, infections, inflammation and extrahepatic organ dysfunction are critical factors for the progression of chronic liver disease. Chemerin is an immune-metabolically and chemotactically active adipokine and we hypothesized that it is associated with disease severity and prognosis in patients with advanced decompensated cirrhosis. Therefore, we measured serum concentrations of chemerin in a prospectively characterized cohort of 80 patients with decompensated cirrhosis and ascites and assessed the associations with markers of disease severity and short-term outcome at 28 days. In a subset of patients (n = 40), ascitic fluid chemerin was determined. Advanced liver disease was associated with decreased serum but not ascitic chemerin levels. Serum chemerin correlated with markers of hepatic function (total bilirubin, albumin, INR) and inversely correlated with indicators of portal hypertension (platelet count, gastrointestinal bleeding) but not with extrahepatic organ failure and systemic inflammation. Patients presenting with acute-on-chronic liver failure or infection did not exhibit altered serum or ascitic fluid chemerin concentrations. However, serum chemerin levels below 87 ng/ml predicted an increased risk for mortality or liver transplantation within 28 days independently of MELD and infections. We conclude that low serum chemerin is an independent adverse prognostic factor in patients with advanced decompensated cirrhosis.

NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis.

Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30-day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (Hepatology 2018;67:2367-2374).

ACG Clinical Guideline: Alcoholic Liver Disease.

Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.

Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis

Acute-on-chronic liver failure (ACLF) is the most life-threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45±44months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1year, 5years, and 10years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p=0.012), ascites (HR 2.53; p=0.019), model of end-stage liver disease score (HR 1.26; p<0.001) and baseline hemoglobin (HR 0.07; p=0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients. There is a need to identify predictors of acute-on-chronic liver failure (ACLF) in patients with cirrhosis in order to identify patients at high risk of developing ACLF and to plan strategies of prevention. In this study, we identified four simple predictors of ACLF: model of end-stage liver disease (MELD) score, ascites, mean arterial pressure and hemoglobin. These variables may help to identify patients with cirrhosis, at a high risk of developing ACLF, that are candidates for new strategies of surveillance and prevention. Anemia is a potential new target for treating these patients.

Slow Infusion of Furosemide and Albumin With or Without Terlipressin SIFA(T) Improves Deranged Systemic Hemodynamics and Survival in Patients With Severe Acute-On-Chronic Liver Failure (ACLF)

Background and Aim: ACLF is characterized by abrupt onset of severe liver dysfunction with extrahepatic organ failure(s) but with potential for reversal once the acute insult resolves. Although deranged systemic hemodynamics underpins extrahepatic organ failure, especially renal and circulatory failure, changes in systemic hemodynamics after recovery or after complete mobilization of ascites have not been reported. We studied systemic hemodynamics in ACLF before and after complete mobilization of ascites with slow infusion of furosemide and albumin with or without terlipressin [SIFA(T)] and its impact on determining the clinical outcomes. Methods: 25 consecutive patients with ACLF fulfilling the APASL 2014 criteria and with large ascites admitted between April 2016 and March 2017 were enrolled. Patients with active GI bleed, severe comorbidities, malignancy, BCS, <18 yrs, pregnancy were excluded. Besides the standard workup for ACLF, systemic hemodynamic parameters were determined by clinical and echocardiographic examination including cardiac index, systemic vascular resistance index and stroke work. All patients were treated with a response guided protocol with SIFA(T) for mobilization of ascites. Changes in clinical, biochemical, organ failure, hemodynamic parameters measured after resolution of ascites were compared with baseline data. Results: Seven patients died during the hospitalization (28% mortality). Systemic hemodynamics could be reassessed after complete mobilization of ascites in 18 patients using SIFA(T) regimen given for a mean period of 15.1 ± 4.6 days. At discharge there was significant improvement in all the parameters assessed (P = .000 for cardiac index, systemic vascular resistance index) as well as CTP and MELD scores (P = .000 for both). Conclusions: Complete mobilization of ascitic and third space fluid severe ACLF could be successfully achieved in 75% patients SIFA(T) with minimal adverse events. This was associated with significant improvement in liver function, improvement in organ failure), in systemic hemodynamics, and in improved survival. We suggest that improving systemic hemodynamics in ACLF with SIFA(T) therapy may reverse extra-hepatic organ failure and improve survival (Table 1).Table 1VariableAdmissionDischargePRemarksMELD30 (21–46)22 (15–31).000ΔMELD7 (1–17)CTP13 (12–14)10 (9–10.25).000ΔCTP3 (2–4.25)Creatinine1.7 ± 1.270.89 ± 0.23.000Albumin2.5 ± 0.283.3 ± 0.47.000Bilirubin11.2 ± 5.667.6 ± 4.71.000INR2.7 ± 0.802.3 ± 0.67.001UNa (mmol/L)38.9 ± 25.39384.5 ± 209.61 (max).000BSA1.82 ± 0.221.69 ± 0.19.000Heart rate97.2 ± 8.2681.9 ± 8.88.000MAP81.6 ± 6.5293.9 ± 4.98.000Systolic BP109 ± 9122 ± 8.000SV92.1 ± 25.0972.5 ± 24.44.000SVI50.9 ± 13.9543.45 ± 15.4.001Cardiac output8.9 ± 2.626.0 ± 2.28.000Cardiac index4.9 ± 1.413.6 ± 1.42.000SVR668.8 ± 234.131299.5 ± 531.45.000SVRI1206.8 ± 398.82192.7 ± 907.6.000Stroke work14.0 ± 3.9312.4 ± 4.33.013Arterial compliance2.29 ± 0.661.77 ± 0.63.000 Open table in a new tab The authors have none to declare.

Differential characteristics and prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure defined by European Association for the Study of the Liver - Chronic Liver Failure criteria.

To determine the differential characteristics and prognosis of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) detected using Asian Pacific Association for the Study of the Liver (APASL) criteria and then classified using European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. We retrospectively reviewed 316 HBV-related APASL ACLF patients treated at Beijing 302 Hospital or Beijing You'An Hospital (both Beijing, China) between February 2015 and February 2016. Clinical characteristics and mortality rates were compared among patients with different EASL-CLIF ACLF severity grades (no ACLF, and ACLF grades 1-3). According to the EASL-CLIF criteria, 138 patients had no ACLF, 123 had ACLF at enrollment, and 55 developed ACLF during hospitalization. Both 28-day and 90-day transplant-free mortality were dramatically lower in patients without EASL-CLIF ACLF (0.7% and 5.1%, respectively) than in patients with EASL-CLIF ACLF (40.7% and 63.2%, respectively; both P <0.001). Liver failure rates were similar in patients with and without EASL-CLIF ACLF, but extrahepatic organ failure was rare in patients without EASL-CLIF ACLF. Baseline serum creatinine, new bacterial infection and new acute kidney injury during hospitalization, maximum rising rates of CLIF-C ACLF score, and Model for End-stage Liver Disease score were independent predictors of EASL-CLIF ACLF after enrollment. The EASL-CLIF ACLF classification can accurately prognosticate the short-term mortality of patients with HBV-related APASL ACLF. It can also distinguish distinct clinical characteristics and prognoses in patients with and without EASL-CLIF ACLF.

Inflammasome and extrahepatic organ failure in acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute deterioration of liver function in patients with pre-existent chronic liver disease together with organ failure (OF). Six organs have been defined: brain, circulation, coagulation, kidneys, lungs and liver. Consequently, it is associated with high short-term mortality (1). The prevalence of ACLF is around 30% among patients with end-stage cirrhosis hospitalized with acute decompensation (AD). Patients are dynamically classified as having ACLF according to the number of OFs (corresponding to three grades of severity), with an increased risk of short-term death. Mortality correlates better with the early clinical course of ACLF than with the initial grade at presentation, especially between the third and seventh day after diagnosis (2).

Acute-on-chronic liver failure: a time to step forward.

Acute-on-chronic liver failure (ACLF) is defined as a syndrome characterized by acute deterioration of liver function on a chronic liver disease, associated with extrahepatic organ failure and high short-term mortality (≥ 15%). This concept represents a disruption in the traditional spectrum of liver diseases, particularly in liver cirrhosis. ACLF may appear during liver disease ranging from compensated to long-standing cirrhosis. Despite the heterogeneity of definitions, it is clear that ACLF results from different types of precipitants in patients with underlying chronic liver disease, mimicking the prognosis of acute liver failure. In this scenario, some new prognostic scores have been proposed instead of MELD or Child-Pugh scores. In the current issue, a retrospective Portuguese study (N = 177) carried out by Barosa et al. explored the usefulness of CLIF scores identifying high mortality rates among cirrhotic patients suffering from ACLF5.

Time trends in the health care burden and mortality of acute on chronic liver failure in the United States.

Cirrhosis and ACLF represent a substantial and increasing health and economic burden in the United States; these data highlight an urgent need for research on pathophysiological mechanisms and effective therapy as well as for education of health care providers of its importance in the care of patients with cirrhosis. (Hepatology 2016;64:2165-2172).

Clinical features and significance of cirrhosis-associated immune dysfunction

Cirrhosis-associated immune dysfunction (CAID) refers to immunodeficiency and systemic inflammation in cirrhotic patients and is the characteristic pathophysiological change of liver cirrhosis of various causes. The phenotype of CAID changes dynamically with the progression of liver cirrhosis. In patients with stable cirrhotic ascites, CAID is manifested as "pro-inflammatory" state, and in patients with severe decompensated liver cirrhosis complicated by extrahepatic organ failure, it is manifested as "immunodeficiency". CAID affects the clinical manifestations and prognosis of liver cirrhosis, aggravates the condition of cirrhotic patients, and increases the risk of infection. This article briefly introduces the mechanism, features, and clinical significance of CAID.

Acute-on-chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a distinct entity that differs from acute liver failure and decompensated cirrhosis in timing, presence of treatable acute precipitant, and course of disease, with a potential for self-recovery. The core concept is acute deterioration of existing liver function in a patient of chronic liver disease with or without cirrhosis in response to an acute insult. The insult should be a hepatic one and presentation in the form of liver failure (jaundice, encephalopathy, coagulopathy, ascites) with or without extrahepatic organ failure in a defined time frame. ACLF is characterized by a state of deregulated inflammation. Initial cytokine burst presenting as SIRS, progression to CARS and associated immunoparalysis leads to sepsis and multi-organ failure. Early identification of the acute insult and mitigation of the same, use of nucleoside analogue in HBV-ACLF, steroid in severe alcoholic hepatitis, steroid in severe autoimmune hepatitis and/or bridging therapy lead to recovery, with a 90-day transplant-free survival rate of up to 50%. First-week presentation is crucial concerning SIRS/sepsis, development, multiorgan failure and consideration of transplant. A protocol-based multi-disciplinary approach including critical care hepatology, early liver transplant before multi-organ involvement, or priority for organ allocation may improve the outcome. Presentation with extrahepatic organ involvement or inclusion of sepsis as an acute insult in definition restricts the therapy, i.e., liver transplant or bridging therapy, and needs serious consideration. Augmentation of regeneration, cell-based therapy, immunotherapy, and gut microbiota modulation are the emerging areas and need further research.

The use of MELD scores in critically ill cirrhotic patients

The Model for End-Stage Liver Disease (MELD) was originally created to predict survival following transjugular intrahepatic portosystemic shunt and was subsequently found to accurately predict mortality in patients with end-stage liver disease. It has been used in the United States for liver allocation since 2002, and implementation of the MELD score resulted in a reduction in total number of deaths on the waitlist and a reduction in waiting time. Critically ill cirrhotic patients have an in-hospital mortality greater than 50%. Although the MELD score was also found to be an accurate predictor of in-ICU mortality and in-hospital mortality after ICU admission in critically ill cirrhotic patients, the Sequential Organ Failure Assessment (SOFA) score appears to perform better in many studies. The Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure (CLIF-C ACLF) score was later developed by using specific cut-points for each organ failure score system in CLIF patients to predict mortality in patients with ACLF. Neither the MELD nor SOFA score independently predicts post-liver transplantation mortality in cirrhotic patients with extrahepatic organ failure and should not be use as a delisting criterion for these patients. More data are needed to determine the accuracy of the CLIF-C ACLF score in predicting post-liver transplantation outcomes. Prospective evaluation of critically ill cirrhotic patients is needed to optimize liver organ allocation.

Hepatic Encephalopathy Is Associated With Mortality in Patients With Cirrhosis Independent of Other Extrahepatic Organ Failures.

Although survival times have increased for patients with cirrhosis, hepatic encephalopathy (HE) remains a major complication and its relative contribution toward mortality in North America is unclear. We investigated whether HE is associated with mortality independent of extrahepatic organ failures (EHOFs). We collected data from the North American Consortium for Study of End-stage Liver Disease database of hospitalized patients with cirrhosis at tertiary-care centers. EHOFs were defined as need for ventilation (respiratory failure), dialysis (renal failure), or shock (circulatory failure). We analyzed in-hospital and 30-day mortality for patients with varying HE grades and EHOF using adjusted models. We analyzed data from 1560 patients, 516 with HE (371 grade 1-2 and 145 grade 3-4). Patients with maximum HE grade 3-4 HE during hospitalization had a higher median model for end-stage liver disease (MELD) score (22) than patients with HE grade 1-2 (MELD score, 19) or no HE (MELD score, 18) (P < .0001). Thirty-day mortality for patients with HE grade 3-4 was significantly higher (38%) than for patients with HE grade 1-2 (8%) or no HE (7%). A total of 107 patients had 2 or more EHOFs, with or without HE; 151 had 1 EHOF and 1302 had no organ failure. Unadjusted mortality was highest for patients with HE of grade 3-4 with 2 EHOFs (n=44). On regression analysis, HE severity was significantly associated with in-hospital and 30-day mortality, independent of any EHOF, white blood cell count, systemic inflammatory response syndrome, or MELD score (odds ratio, 3.3; P < .0001). In an analysis of more than 1500 patients hospitalized for cirrhosis, HE of grade 3 or 4 was associated with higher in-hospital and 30-day mortality, independently of failure of other organs.

Acute-on-chronic liver failure in India: The Indian National Association for Study of the Liver consortium experience.

The aim of this study was to analyze etiologies and frequency of hepatic and extrahepatic organ failures (OFs) and outcome of acute-on-chronic liver failure (ACLF) at 10 tertiary centers in India. In this retrospective study (2011-2014), patients satisfying Asian Pacific Association for the Study of the Liver definition of ACLF were included. Etiology of acute precipitating insult and chronic liver disease and outcomes were assessed. Occurrence and severity of OF were assessed by chronic liver failure-sequential organ failure assessment score. The mean (±SD) age of 1049 consecutive ACLF patients was 44.7 ± 12.2 years; Eighty-two percent were men. Etiology of acute precipitants included alcohol 35.7%, hepatitis viruses (hepatitis A, hepatitis B, and hepatitis E) 21.4%, sepsis 16.6%, variceal bleeding 8.4%, drugs 5.7%, and cryptogenic 9.9%. Among causes of chronic liver disease, alcohol was commonest 56.7%, followed by cryptogenic and hepatitis viruses. Predictors of survival were analyzed for a subset of 381 ACLF patients; OF's liver, renal, coagulation, cerebral, respiratory, and failure were seen in 68%, 32%, 31.5%, 22.6%, 14.5%, and 15%, respectively. Fifty-seven patients had no OF, whereas 1, 2, 3, 4, and 5 OFs were recorded in 126, 86, 72, 28, and 12 patients, respectively. The mortality increased progressively with increasing number of OFs (12.3% with no OF, 83.3% with five OFs). During a median hospital stay of 8 days, 42.6% (447/1049) of patients died. On multivariate analysis by Cox proportional hazard model, elevated serum creatinine (hazard ratio [HR] 1.176), advanced hepatic encephalopathy (HR 2.698), and requirement of ventilator support (HR 2.484) were independent predictors of mortality. Alcohol was the commonest etiology of ACLF. Within a mean hospital stay of 8 days, 42% patients died. OFs independently predicted survival.

Prognosis and Biomarkers in Acute-on-Chronic Liver Failure.

As formal definitions of acute-on-chronic liver failure (ACLF) have now been established, and given an increased recognition of the dynamic nature of this condition, there is a growing clinical need to assess prognosis and response to interventions. Conventional scoring systems such as Model for End-Stage Liver Disease (MELD) fail to capture the two key prognostic elements in ACLF-namely, extrahepatic organ failure and measures of systemic inflammation-and as such are limited in their prognostic accuracy. Even the best available scoring systems such as the recently described CLIF (Chronic Liver Failure) Consortium ACLF (CLIF-C ACLF) score, are at best 75% accurate and need to be applicable to all etiologies of liver disease. Thus, in the absence of "gold standard" markers of prognosis that render one scoring system superior to another, there is a need to explore other markers of pathophysiology that may better define outcome. This review addresses the evidence for markers of oxidative stress, including those reflecting the inflammasome; elements of cell death such as cytokeratins M30 and M65; and indicators of immune dysfunction, innate immune failure and gut dysbiosis. Finally, evidence for relevance of markers of organ dysfunction, including hemodynamic response, are explored along with associated mediators such as copeptin, dimethylarginines, and renin. It is anticipated that further critique and validation of emerging and relevant biomarkers will facilitate a composite score which, either alone or in combination with existing scoring systems such as CLIF-C, will enable improved prognostication and targeting of therapy in ACLF.

Acute on chronic liver failure because of acute hepatic insults: Etiologies, course, extrahepatic organ failure and predictors of mortality.

Acute on chronic liver failure (ACLF) because of precipitating factors (variceal bleed/infections) identifies cirrhotics at risk for high short-term mortality. Information on ACLF because of acute hepatic insults is lacking. The aim of the study was to evaluate acute hepatic insults in ACLF and their effect on the course and outcome. In a prospective study, 213 consecutive patients of ACLF because of acute hepatic insults were included. Etiology of acute hepatic insult, frequency of silent, and overt chronic liver disease (CLD), organ failure (OF), and outcomes were assessed. Prognostic models such as model for endstage liver disease (MELD), acute physiology and chronic health evaluation (APACHE II), and chronic liver failure-sequential organ failure (CLIF-SOFA) were evaluated. Etiologies of acute hepatic insult were hepatitis virus(es)- 81 (38%; HBV-42, HEV-39), continuous alcohol consumption-77 (33.3%), antituberculosis drugs-11 (5.2%), autoimmune hepatitis flare-5(2.3%), cryptogenic-44 (20.7%). The common causes of CLD were alcohol (n = 85/40%), HBV(n = 52/24%), and cryptogenic(n = 50/20%). The MELD, APACHE II, and CLIF-SOFA scores were similar among silent and overt CLD and did not influence outcome. Predominant etiologies of ACLF were hepatitis virus(es) reactivation or superinfection in silent CLD(52/112, 46.4%) and alcohol among overt CLD(43/101, 43%). Independent predictors of mortality included hepatic-encephalopathy (early, HR: 4.01; advanced, HR: 6.10), serum creatinine ≥1.5 mg/dl (HR: 4.53), CLIF-SOFA ≥8(HR: 1.69), and etiology of acute hepatic insult (alcohol, HR: 4.08; cryptogenic, HR: 3.18). HEV-ACLF had lower mortality (12.8% vs. 33-54% in other etiologies;P < 0.001). OF was major determinant of mortality. With increasing number of OF, mortality increased linearly(P = 0.001). Hepatitis virus(es) and continuous alcohol consumption are important causes of ACLF caused by acute hepatic insults. HEV-ACLF has lower mortality. OF is an important prognostic predictor.