key: cord-0993355-ersapcw7
authors: Balcar, Lorenz; Semmler, Georg; Pomej, Katharina; Simbrunner, Benedikt; Bauer, David; Hartl, Lukas; Jachs, Mathias; Paternostro, Rafael; Bucsics, Theresa; Pinter, Matthias; Trauner, Michael; Mandorfer, Mattias; Reiberger, Thomas; Scheiner, Bernhard
title: Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute‐on‐chronic liver failure
date: 2021-05-28
journal: United European Gastroenterol J
DOI: 10.1002/ueg2.12089
sha: c82999f1c4858908e9eb2f12fccef03f13b9681f
doc_id: 993355
cord_uid: ersapcw7

INTRODUCTION: Recently, based on data from the PREDICT study, the European Foundation for the Study of Chronic Liver Failure (EF‐CLIF) consortium proposed pathophysiological/prognostic groups in hospitalized patients with cirrhosis: stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre‐acute‐on‐chronic liver failure (pre‐ACLF), and ACLF. We evaluated the outcomes of these subgroups in a real‐life cohort of hospitalized patients with cirrhosis. METHODS: Patients with cirrhosis developing first AD between 09/2010 and 12/2017 at the Vienna General Hospital were evaluated for this retrospective analysis. RESULTS: Two hundred and ten patients with cirrhosis (aged 57.6 ± 11.8 years) including n = 45 (21.4%) SDC, n = 100 (47.6%) UDC, n = 28 (13.3%) pre‐ACLF, and n = 37 (17.6%) with ACLF were considered. The proposed AD subgroups discriminated between patients with favorable (1‐year mortality: SDC: 6.7% and UDC: 19.6%) and dismal prognosis (90‐day mortality: pre‐ACLF: 42.9%). Interestingly, systemic inflammation gradually increased (e.g., C‐reactive protein, SDC: 0.9 mg/dl, vs. UDC: 2.0 mg/dl vs. pre‐ACLF: 3.2 mg/dl, p < 0.001) while renal function was progressively deteriorating (creatinine levels, SDC: 0.8 mg/dl vs. UDC: 0.9 mg/dl vs. pre‐ACLF: 1.2 mg/dl, p < 0.001) across prognostic subgroups in patients with cirrhosis. DISCUSSION: The recently proposed pathophysiological/prognostic EF‐CLIF subgroups are also reproduceable in a real‐life cohort of cirrhotic patients. As ACLF is a common and important complication, patients at risk of pre‐ACLF at index AD should be evaluated and if disease proceeds, been treated early and aggressively to avoid excessive mortality.

cute-on-chronic liver failure (ACLF) is a recently defined syndrome occurring in patients with cirrhosis. 1 According to the European Foundation for the Study of Chronic Liver Failure (EF-CLIF) consortium, ACLF is distinct from acute decompensation (AD) and is characterized by pronounced systemic inflammation and development of extrahepatic organ failures, 1 as defined by the sequential organ failure(s) assessment (SOFA) score. 2 Potential precipitating events triggering AD and/or organ failures in patients with cirrhosis include hepatotoxic injury caused by alcohol abuse or drug-induced liver injury, bacterial, fungal, or viral infections (including SARS-CoV-2 3 ), flares of autoimmune liver diseases, invasive procedures, or major bleedings. [4] [5] [6] However, next to these identifiable triggers, no precipitating triggers can be found in up to 44% of ACLF cases. 4, 6 Nevertheless, systemic inflammation due to release of pathogen-associated molecular patterns 7 resulting from bacterial translocation or release of danger-associated molecular patterns due to tissue injury or cellular necrosis/necroapoptosis 8 play an important role in the development of AD and/or ACLF. 9, 10 The clinical course of ACLF is very dynamic with potentially rapid worsening or improvement. Even though ACLF most commonly develops in patients with previous decompensation, ACLF may also occur during the first episode of AD. 4, 11 Moreover, ACLF development is the strongest predictor of mortality in patients with acute variceal bleeding. 12 Due to the high clinical relevance of ACLF, research in this area has been strongly supported by international consortia leading to the establishment of the EF-CLIF definition in 2013 following the CANONIC trial. 4 Just recently, first results of the second trial supported by the EF-CLIF consortium, the PREDICT (Predicting Acute-on-Chronic Liver Failure in Cirrhosis) study, have been published: Within this study, the investigators were able to distinguish between three distinct clinical courses following AD, which differ with regards to pathophysiology and outcomes. The first group, termed pre-ACLF, showed a high short-term mortality and were characterized by pronounced systemic inflammation. The second group, patients with unstable decompensated cirrhosis (UDC), were characterized by a high number of hospital readmissions and complications associated with severe portal hypertension (PH). The last group, termed stable decompensated cirrhosis (SDC), included patients with a lower risk of hospital admissions and mortality. 13 Importantly, these three clinical courses have not been validated in other cohorts with longer follow-up (FU) and more extensive patient characterization with regard to hemodynamic state and severity of PH. Therefore, the aim of this study was to retrospectively describe the clinical course of patients who developed first AD in a real-world setting at a tertiary care center, stratified by prognostic groups. Moreover, patients initially presenting with ACLF were included as a comparator. 15 orthotopic liver transplantation (OLT), and liverrelated mortality were extracted from patients' medical records.

ACLF was defined according to the EF-CLIF criteria. 4 Organ failure and organ dysfunction were defined according to the CLIF SOFA score. 16 Clinical data on potential precipitating factors/events were collected at the time of first AD and of ACLF development. Significant alcohol consumption was defined as ≥3 drinks per day in men and ≥2 drinks per day in women. 17 Severe alcoholic hepatitis (ASH) was defined by a significant alcohol consumption combined with a CLIF-C AD score ≥50, serum bilirubin values ≥3 mg/dl and AST >50 IU/L. 6 Major bleeding was diagnosed in patients presenting with a hemoglobin decrease of ≥2 g/dl or patients requiring blood products. Life-threatening gastrointestinal bleeding was diagnosed in patients with major bleeding accompanied by hemorrhagic shock and need for vasopressor therapy. 18 Septic shock was diagnosed in patients with proven bacteremia, circulatory dysfunction and need for vasopressor therapy. 6

Patients with AD were stratified according to the PREDICT study 13 into four prognostic categories: SDC included patients who were neither readmitted, nor developed ACLF during short-term FU (3 months). UDC patients had ≥1 readmission but did not develop ACLF within 3 months. Pre-ACLF patients developed ACLF within the next 3 months. ACLF group included patients who developed ACLF at the time of their first episode of AD. SDC patients were screened for the occurrence of re-compensation. Re-compensation was defined as no need for diuretic or hepatic encephalopathy (HE) treatment as well as no further decompensating events during long-term FU.

Hepatic venous pressure gradient (HVPG) measurements were obtained at the Vienna Hepatic Hemodynamic Lab according to a standardized protocol 19 using a specifically designed balloon catheter (Pejcl Medizintechnik) 20 as previously described. 21 Transjugular liver biopsy specimens were either obtained by using an aspiration or the TruCut biopsy set. 19, 22 The results of HVPG measurements were only considered for this study if they were obtained within 6 months of the date of AD.

Hepatic decompensation was defined as the development of ascites, HE, or variceal bleeding for the first time. 23 Among others, infections and ASH were considered as precipitating events of AD.

Survival was evaluated using data obtained from the National Death Registry provided by Statistics Austria. This data set included information on the date and reason (ICD-10 codes) of death as stated on the death certificate as well as the date of the last hospitalization in an Austrian hospital. Based on these data and additional information obtained by chart review, the cause of death was likely attributable to liver disease (i.e., liver-related death) or excluded to be liver-related. 

This study was performed in accordance with the Helsinki Declaration and approved by the local ethics committee of the Medical University of Vienna (MUV-EK-1774/2019). Due to the retrospective design of this study, the need for written-informed consent was waived by the ethics committee.

In total, 222 patients with ACLD and AD/ACLF within the study period were identified ( Figure 1 ). Of these, 12 patients were diagnosed with HCC out of Milan or had undergone OLT prior to the date of first evaluable hepatic decompensation and were therefore excluded. Finally, 210 patients were included in this retrospective analysis (173 patients with AD/37 patients with ACLF). While information on first AD was available in 160, further decompensation (i.e., the first sufficiently documented AD episode) was considered as baseline in 50 patients ( Figure 1 ; Table 1 ).

Alcohol-related liver disease was the most common etiology (n = 98, 56.6%). Development of ascites was the most common AD BALCAR ET AL. Table 1; Table S1 ).

Main reasons for hospitalization were ascites in 67.1% (n = 116), followed by gastrointestinal bleeding in 16.2% (n = 28), overt HE in 8.7% (n = 15), bacterial infections in 5.2% (n = 9), and other reasons in 2.9% (n = 5), as displayed in Supplementary Table S1 .

As a comparator, we also included a cohort of patients who developed ACLF during first AD. At baseline, the ACLF group had worst organ functions as indicated by significantly higher disease severity scores (Child-Pugh score, ACLF: 10.9 ± 1.9 versus pre-ACLF: 9.5 ± 1.9 versus UDC: 9.6 ± 1.8 versus SDC: 8.8 ± 2.0, p < 0.001) and MELD score (ACLF: 25 

First, we evaluated the outcomes of patients after first evaluable AD at 3 months within the proposed groups ( Figure 2 ). According to the definition of SDC and UDC, these patients did not develop ACLF within 3 months. Additionally, none of these patients died within the first 3 months. However, outcomes in the pre-ACLF cohort were significantly worse. While 

Second, we evaluated the outcomes of patients at 12 months after first evaluable decompensation according to the prognostic groups ( Figure 3) Figure 4 ). Figure S1 ; Table S5 ). Figure S1 demonstrates the maximum ACLF grades and the associated clinical outcomes at the end of FU. Presence of other organ failures was comparable between the two groups (Table S6 ).

The same applied to potential triggers of ACLF development-no statistically significant differences could be observed. However, patients developing ACLF at baseline were more commonly affected by more than one potential trigger, compared to pre-ACLF patients (>1: Table S6 .

cirrhosis. This syndrome is characterized by a high short-term mortality 4 and may develop at any time in patients with compensated or decompensated cirrhosis. 24 Recently, and due to increased scientific efforts in this area, pathophysiological mechanisms are increasingly understood. [25] [26] [27] However, prediction of ACLF development remains a challenge in clinical routine 13 and apart from treatment of triggering factors, there are no ACLF-specific therapeutic options. 28, 29 Therefore, studies evaluating the natural course of decompensated cirrhosis and ACLF are required.

In this study, we applied the recently described natural history subgroups to a large "real-life" cohort of patients with cirrhosis developing hepatic decompensation. In contrast to the PREDICT study, 13 we aimed at defining the prognostic groups already at the first decompensation event and not at a random event during FU; however, this might not always be possible in clinical reality due to late patient referral to hepatology units. Therefore, we also included a subgroup of patients, in whom the first decompensation event could not be determined. Still, we believe to assess potential differences in the patients' outcomes according to first decompensation or second decompensation after re-compensation. In addition, and to complete the natural history subgroups proposed by the PREDICT study, we could show that nearly every fifth inpatient in our series (17.6%) fulfilled ACLF criteria at the time of first AD. 4, 24 The CANONIC trial defined ACLF by a 28-day mortality rate of ≥15%, which increases with every consecutive organ failure. 4 In the PREDICT study, short-and long-term mortality rates were low in SDC and moderate in UDC patients (90-day mortality rates: SDC:

0.0% vs. UDC: 21.0%, 1-year mortality rates: SDC: 9.5% vs. UDC 35.6%), whereas pre-ACLF patients showed the worst outcomes (90day mortality rates: 53.7%, 1-year mortality rates: 67.4%). 13 This can also be explained by the group definition, as the pre-ACLF group includes patients who did not improve with initial management, had higher inflammation parameters and developed organ dysfunction within a short period of time. Importantly, the PREDICT findings are comparable to those observed in our study in which we calculated a and 5 were rather small). However, HVPG was only available in a small proportion of our patients and larger studies will be needed to confirm these findings.

Early detection and aggressive treatment of complications especially in pre-ACLF patients is crucial, as these patients have an 434 -UNITED EUROPEAN GASTROENTEROLOGY JOURNAL extremely high short-term mortality. Interestingly, 90-day mortality was comparable between patients with pre-ACLF and ACLF at baseline; however, long-term outcome was more favorable in patients with ACLF even though these patients were sickest at baseline.

We can only speculate on the underlying reasons. First, we believe that ACLF patients at baseline were treated more aggressively due to already present organ failures, and second, in some of these patients, the underlying trigger may have stopped (e.g., alcohol consumption).

On the contrary, in pre-ACLF patients, the triggering event seemed to continue as these patients went on to develop a second event within 3 months after the index decompensation. This could be underlined by the finding that the number of patients with alcoholic liver disease (a triggering factor that may be controlled) was relatively low in the pre-ACLF group.

As demonstrated by our study, ACLF commonly progresses, while resolution of the syndrome is only rarely observed. In our cohort, only 32% of patients resolved ACLF within 3 months, which was associated with lower ACLF grades at baseline. Therefore, early detection and treatment of potential triggers and other diseasepromoting factors is essential. 42 In line, only 7% of patients underwent liver transplantation in our study. However, large retrospective and smaller prospective studies suggested that even patients with ACLF 3 are benefiting from OLT, with a 1-year survival similar to that of patients with a lower ACLF grade. [43] [44] [45] Therefore, all suitable patients with ACLF should be listed for OLT, including those with higher grade ACLF 46 and those who resolve their first ACLF episode, as the likelihood for developing a higher ACLF grade in the future is high. 47 In our study, 49% of patients with decompensated cirrhosis developed organ failures at some point, and patients who primarily recovered from ACLF are at high risk of redeveloping organ failures. Notably, we did not find any predictors for the development of ACLF during longterm FU; however, patients developing ACLF were more commonly affected by more than one potential trigger underlining the role of precipitating events for ACLF development. 6 The risk of further organ failures might be especially high in patients, in whom the triggering factors cannot be controlled. 48

Due to the retrospective design, several patients had to be excluded due to important missing data at baseline or during FU. Additionally, the retrospective design also explains why some parameters of great interest, such as IL-6, were not available in a substantial number of patients. Therefore, systemic inflammation was only measured by CRP in our study. Furthermore, patients with more advanced stage of liver disease have usually undergone a more detailed diagnostic work-up. Therefore, we cannot exclude that missing data may have been relevant, and patients with more advanced liver disease might be overrepresented in our cohort. Furthermore, we also included patients who decompensated several years ago, when ACLF was not yet properly recognized as such. However, we could demonstrate that outcome in our cohort was comparable to the more current PREDICT cohort, pointing out that unfortunately treatment of ACLF patients has not significantly improved within the last years, underlining the importance of novel therapeutic approaches.

In summary, we compared thoroughly characterized cirrhotic patients with AD across different prognostic subgroups proposed by the PREDICT study and could validate their findings in a real-life cohort. We demonstrated that ACLF is a common entity in clinical routine and should be recognized as a severe complication in patients with cirrhosis. While mortality in patients with SDC is low, long-term outcome is significantly compromised in patients with UDC. Patients with ACLF at first decompensation and especially pre-ACLF patients have a very high short-term mortality. Even though there were only few differences in baseline characteristics between the subgroups, pre-ACLF patients showed highest levels of inflammatory markers and a particularly unstable clinical course.

These patients should be identified rapidly and evaluated for early and aggressive treatment in order to prevent and/or detect the development of ACLF. Additionally, these patients should be seen in the outpatient clinic in short intervals allowing initiation of preemptive treatments (e.g., antibiotics) or timely admission for BALCAR ET AL.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.