Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis

doi:10.1053/j.gastro.2013.02.042

Gastroenterology

Volume 144, Issue 7, June 2013, Pages 1426-1437.e9

https://doi.org/10.1053/j.gastro.2013.02.042 Get rights and content

Background & Aims

Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD.

Methods

We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure–sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%).

Results

Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD.

Conclusions

We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.

Section snippets

Study Design

Patients were screened and enrolled from February to September 2011 in 12 European countries after the appropriate approvals were obtained. Patients were screened at liver units in 29 university hospitals; each liver unit had a regular ward, intensive care facilities, and a liver transplantation program. The policy of allocation of liver transplants was similar among study centers. The diagnosis of cirrhosis was based on previous liver biopsy findings or a composite of clinical signs and

Patients

A total of 2149 consecutive patients were screened, of whom 1343 were enrolled. A majority of patients were enrolled during the first 4 days after hospital admission (Supplementary Figure 1). In total, 817 (60.8%), 1004 (74.8%), and 1185 (88.2%) patients were enrolled 1, 2, and 4 days after hospital admission, respectively. In 158 patients (11.7%), the elapsed time between hospital admission and enrollment was more than 4 days. Reasons for the delay between hospital admission and study

Discussion

The aim of the current study was to establish the diagnostic criteria of ACLF and subsequently to assess the natural history of this syndrome. There was no “evidence-based” definition of ACLF at the time of this study, so we had to assume several important issues. First, the study was performed in patients with AD because this is an essential component of the syndrome. Here, we assumed that organ failure detected at study enrollment developed simultaneously with AD and not before. This

Acknowledgments

The authors thank the nursing staff in the units of each center for their excellent support, the patients for their participation in the study, and Nicki van Berckel for administrative support.

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Comparison of a Novel Score “NOD−ACLF” to Other Established Prognostic Scores for Prediction of Mortality in APASL−ACLF Patients: A Cohort Study from a Tertiary Care Center of North India
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Commonly used prognostic scores for acute on-chronic liver failure (ACLF) have complex calculations. We tried to compare the simple counting of numbers and types of organ dysfunction to these scores, to predict mortality in ACLF patients.
In this prospective cohort study, ACLF patients diagnosed on the basis of Asia Pacific Association for Study of the Liver (APASL) definition were included. Severity scores were calculated. Prognostic factors for outcome were analysed. A new score, the Number of Organ Dysfunctions in Acute-on-Chronic Liver Failure (NOD-ACLF) score was developed.
Among 80 ACLF patients, 74 (92.5%) were male, and 6 were female (7.5%). The mean age was 41.0±10.7 (18–70) years. Profile of acute insult was; alcohol 48 (60%), sepsis 30 (37.5%), variceal bleeding 22 (27.5%), viral 8 (10%), and drug-induced 3 (3.8%). Profiles of chronic insults were alcohol 61 (76.3%), viral 20 (25%), autoimmune 3 (3.8%), and non-alcoholic steatohepatitis 2 (2.5%). Thirty-eight (47.5%) were discharged, and 42 (52.5%) expired. The mean number of organ dysfunction (NOD-ACLF score) was ->4.5, simple organ failure count (SOFC) score was >2.5, APASL ACLF Research Consortium score was >11.5, Model for End-Stage Liver Disease-Lactate (MELD-LA) score was >21.5, and presence of cardiovascular and respiratory dysfunctions were significantly associated with mortality. NOD-ACLF and SOFC scores had the highest area under the receiver operating characteristic to predict mortality among all these.
The NOD-ACLF score is easy to calculate bedside and is a good predictor of mortality in ACLF patients performing similar or better to other scores.
Exploring the Prevalence, Predictors, and Impact of Bacterial Infections to Guide Empiric Antimicrobial Decisions in Cirrhosis (EPIC-AD)
2024, Journal of Clinical and Experimental Hepatology
This study delved into cirrhosis-related infections to unveil their epidemiology, risk factors, and implications for antimicrobial decisions.
We analyzed acutely decompensated cirrhosis patients (n = 971) from North India between 2013–2023 at a tertiary center. Microbiological and clinical features based on infection sites (EASL criteria) and patient outcomes were assessed.
Median age was 45 years; 87% were males with 47% having alcoholic hepatitis. Of these, 675 (69.5%) had infections; 305 (45%) were culture-confirmed. Notably, 71% of confirmed cases were multi-drug resistant organisms (MDRO)-related, chiefly carbapenem-resistant (48%). MDRO prevalence was highest in pulmonary (80.5%) and skin-soft-tissue infections (76.5%). Site-specific distribution and antimicrobials were suggested. Predictive models identified prior hospitalization [OR:2.23 (CI:1.58–3.14)], norfloxacin prophylaxis [OR:2.26 (CI:1.44–3.55)], prior broad-spectrum antibiotic exposure [OR:1.61 (CI:1.12–2.30)], presence of systemic inflammatory response-SIRS [OR:1.75 (CI: 1.23–2.47)], procalcitonin [OR:4.64 (CI:3.36–6.40)], and HE grade [OR:1.41 (CI:1.04–1.90)], with an area under curve; AUC of 0.891 for infection prediction. For MDRO infection prediction, second infection [OR: 7.19 (CI: 4.11–12.56)], norfloxacin prophylaxis [OR: 2.76 (CI: 1.84–4.13)], CLIF-C OF [OR: 1.10 (CI: 1.01–1.20)], prior broad-spectrum antibiotic exposure [OR: 1.66 (CI: 1.07–2.55)], rifaximin [OR: 040 (0.22–0.74)] multisite [OR: 3.67 (CI: 1.07–12.56)], and polymicrobial infection [OR: 4.55 (CI: 1.45–14.17)] yielded an AUC of 0.779 and 93% specificity. Norfloxacin prophylaxis, multisite infection, mechanical ventilation, prior broad-spectrum antibiotic exposure, and infection as acute precipitant predicted carbapenem-resistant infection (AUC: 0.821). Infections (culture-proven or probable), MDROs, carbapenem/pan-drug resistance, and second infections independently linked with mortality (P < 0.001), adjusted for age, leucocytosis, and organ failures. A model incorporating age [HR:1.02 (CI: 1.01–1.03), infection [HR:1.52 (CI: 1.05–2.20)], prior hospitalization [HR:5.33 (CI: 3.75–7.57)], norfloxacin [HR:1.29 (CI: 1.01–1.65)], multisite infection [HR:1.47 (CI:1.06–2.04)], and chronic liver failure consortium-organ failure score; CLIF-C OF [HR:1.17 (CI: 1.11–1.23)] predicted mortality with C-statistics of 0.782 (P < 0.05).
High MDRO burden, especially carbapenem-resistant, necessitates urgent control measures in cirrhosis. Site-specific epidemiology and risk models can guide empirical antimicrobial choices in cirrhosis management.
The Story of Ammonia in Liver Disease: An Unraveling Continuum
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Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.
Continuous renal replacement therapy and survival in acute liver failure: A systematic review and meta-analysis
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Acute liver failure (ALF) is a rare syndrome leading to significant morbidity and mortality. An important cause of mortality is cerebral edema due to hyperammonemia. Different therapies for hyperammonemia have been assessed including continuous renal replacement therapy (CRRT). We conducted a systematic review and meta-analysis to determine the efficacy of CRRT in ALF patients.
We searched MEDLINE, EMBASE, Cochrane Library, and Web of Science. Inclusion criteria included adult patients admitted to an ICU with ALF. Intervention was the use of CRRT for one or more indications with the comparator being standard care without the use of CRRT. Outcomes of interest were overall survival, transplant-free survival (TFS), mortality and changes in serum ammonia levels.
In total, 305 patients underwent CRRT while 1137 patients did not receive CRRT. CRRT was associated with improved overall survival [risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70–0.99, p-value 0.04, I² = 50%] and improved TFS (RR 0.65, 95% CI 0.49–0.85, p-value 0.002, I² = 25%). There was a trend towards higher mortality with no CRRT (RR 1.24, 95% CI 0.84–1.81, p-value 0.28, I² = 37%). Ammonia clearance data was unable to be pooled and was not analyzable.
Use of CRRT in ALF patients is associated with improved overall and transplant-free survival compared to no CRRT.
High Mortality With Non-O1/Non-O139 Vibrio cholera Bacteraemia in Patients With Cirrhosis
2024, Journal of Clinical and Experimental Hepatology
Data on non-O1/non-O139 Vibrio cholera (NOVC) infection in liver disease is limited. We studied the clinical features and outcome of patients with cirrhosis with non-NOVC bacteraemia and/or spontaneous bacterial peritonitis (SBP) when compared to non-extended spectrum beta lactamase (non-ESBL) Escherichia coli (E. coli).
Hospital information system of patients with cirrhosis admitted with bacteraemia and/or SBP from 2010 to 2020 was searched to include patients with NOVC infection. Non-ESBL E. coli bacteraemia/bacterascites were chosen as a comparator group, matched for the date of admission within 5 days of index case. Propensity score matching (PSM) was done for patient's age and Child score to compare outcome at discharge between NOVC-infected and E. coli–infected cirrhotic patients.
There were 2545 patients admitted with bacteraemia and/or SBP during the study period; 29 had NOVC isolated (M:F = 23:6; age: 39, 18–54 years; median, range; model for end-stage liver disease [MELD] score: 25, 12–38; Child score: 11, 10–12.5) from either blood (26), ascites (3), or both (8). Of these, 26 isolates were pan-sensitive to antibiotic sensitivity tests. Fifty-three patients with non-ESBL E. coli were isolated (M: F = 43:10; age: 48; 18–69 years; MELD score: 25, 20–32; Child score:12,11–13) from blood (31), ascites (17), or both (5) within the selected time frame. Of these, 48 isolates were sensitive to the empirical antibiotics initiated.
After PSM, in comparison with 29 non-ESBL E. coli patients (age: 41, 18–55 years; MELD score: 24, 19–31; Child score: 12, 11–13), NOVC patients had higher incidence of circulatory failure at admission (14 [49 %] vs 4 [13 %]; P: 0.01) and significantly higher in-hospital mortality (15 [52 %] vs 6 [20 %];P: 0.028].
Bacteraemia due to non-O1/non-O139 strains of V. cholera, is an uncommon cause of bacteraemia or bacterascites in patients with cirrhosis and is associated with high incidence of circulatory failure and significant mortality.
Liver Transplantation in Chronic Liver Disease and Acute on Chronic Liver Failure- Indication, Timing and Practices
2024, Journal of Clinical and Experimental Hepatology
Liver transplantation (LT) is the second most common solid organ transplantation worldwide. LT is considered the best and most definitive therapeutic option for patients with decompensated chronic liver disease (CLD), hepatocellular carcinoma (HCC), acute liver failure (ALF), and acute-on-chronic liver failure (ACLF). The etiology of CLD shows wide geographical variation, with viral hepatitis being the major etiology in the east and alcohol-related liver disease (ALD) in the west. Non-alcoholic fatty liver disease (NAFLD) is on an increasing trend and is expected to be the most common etiology on a global scale. Since the first successful LT, there have been radical changes in the indications for LT. In many circumstances, not just the liver disease itself but factors such as extra-hepatic organ dysfunction or failures necessitate LT. ACLF is a dynamic syndrome that has extremely high short-term mortality. Currently, there is no single approved therapy for ACLF, and LT seems to be the only feasible therapeutic option for selected patients at high risk of mortality. Early identification of ACLF, stratification of patients according to disease severity, aggressive organ support, and etiology-specific treatment approaches have a significant impact on post-transplant outcomes. This review briefly describes the indications, timing, and referral practices for LT in patients with CLD and ACLF.

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: A list of CANONIC study investigators is provided in the Appendix.

: Conflicts of interest The authors disclose the following: This is the first result of an initiative of several European and American investigators to potentiate research in chronic liver failure (CLIF). An assembly of European hepatologists proposed the European Association for the Study of the Liver (EASL) to endorse a consortium aimed to promote research on CLIF, to stimulate the formation of research groups in this field in Europe, and to identify potential areas of common interest with European industry. The Executive Committee of EASL accepted to endorse the consortium on June 2009 and elected V.A. and M.B. as chairman and vice-chairman, respectively, for 5 years. Twelve other EASL members proposed by the assembly were elected to form the Steering Committee. From 2009 to 2012, the EASL-CLIF Consortium received unrestricted grants from Grifols and Gambro. Grifols has prolonged its unrestricted grant for an additional 4 years. There is no other support for the consortium. The Fundació Clinic, a foundation ruled by the Hospital Clinic and University of Barcelona, administers the EASL-CLIF Consortium grants. V.A., M.B., and members of the Steering Committee have no relationship with Grifols or Gambro other than conferences in international meetings (from which they may receive an honorarium) or as investigators on specific projects unrelated to the consortium. Until now the EASL-CLIF Consortium has not performed any study promoted by pharmaceutical companies. The scientific agenda of the EASL-CLIF Consortium and the specific research protocols are made exclusively by the Steering Committee members without any participation of pharmaceutical companies. R.J. received research funding from Vital Therapies, has served on a scientific advisory board for Conatus Pharma, and received lecture fees from Gambro. P.G. has received speaker honorarium and research funding from Grifols, served on the scientific advisory board for Ferring and Sequana, and received research funding from Sequana. J.C. has served as a consultant to Ocera. A.G. has served as a consultant to CSL Behring. S.Z. has served as a consultant to Abbott, Achillion, AstraZeneca, Bristol Myers-Squibb, Boehringer Ingelheim, Gilead, Janssen Cilag, Merck, Novartis, Presidio, Roche, Santaris, and Vertex. V.A. has received grant and research support from Grifols. The remaining authors disclose no conflicts.

: Funding The CLIF Consortium is supported by an unrestricted grant from Grifols. R.M. was supported by an INSERM-APHP fellowship and J.T. by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 project 18).

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Original ResearchFull Report: Clinical—LiverAcute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Design

Patients

Discussion

Acknowledgments

Hepatology

Am J Gastroenterol

J Hepatol

Dig Liver Dis

Hepatology

J Hepatol

Hepatology

Gastroenterology

Chest

Management of varices and variceal hemorrhage in cirrhosis

N Engl J Med

Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis

Gastroenterology

Severe sepsis in cirrhosis

Hepatology

Acute-on-chronic liver failure: pathophysiological basis of therapeutic options

Blood Purif

Acute-on-chronic liver failure: concept, natural history, and prognosis

Curr Opin Crit Care

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL)

Hepatol Int

Original Research
Full Report: Clinical—Liver
Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis