Acute-on-chronic liver failure (ACLF) is the extreme of the spectrum of acute decompensation (AD) of chronic liver diseases. Defining and diagnosing this condition is of utmost importance for the early recognition of patients at high risk of progression to liver transplantation or death [1].

Currently, the most commonly used definitions of ACLF are the one proposed by the Chronic Liver Failure Consortium (CLIF-C), affiliated to the European Association for the Study of the Liver, the one proposed by the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC) and the one proposed by the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) [1–4].

When it was compared to the definition of ACLF proposed by AARC, the CLIF-C definition proved to have a better prognostic performance [5–8]. When the AARC definition was compared to the NACSELD one, there was no significant difference in the ability to predict patient survival [9].

Considering the paucity of studies comparing the performance of the different criteria and the fact that the definitions proposed by CLIF-C and NACSELD have not been compared yet, this study aimed to compare the prognostic performance of these three definitions of ACLF.

One hundred and fifty-seven patients were considered eligible for the study through the ICD-10 codes (K70–K77). Five of them were excluded for not having AD of cirrhosis, 6 others were excluded due to inadequate follow-up, and 146 individuals were finally included in the study. Of these, 100 (68.5%) were men, and the mean age was 59.5 years (SD=10.4). The most frequent etiologies of cirrhosis were hepatitis C (42.5%) and alcohol (41.8%). Forty-three (29.4%) patients fulfilled criteria for ACLF according to CLIF-C, 14 (9.5%) patients met criteria for ACLF according to AARC, and 6 (4.1%) patients fulfilled criteria for ACLF according to NACSELD. Patients had 28-day mortality of 53.5%, 50.0% and 83.3% when they were diagnosed with ACLF according to CLIF-C, AARC and NACSELD definitions respectively. At 90 days, mortality was 78.0% (2 patients were lost to follow-up and excluded from the analysis), 64.3% and 100% according to the same definitions. The flowchart of the study is shown in Fig. 1, and clinical and laboratory characteristics of patients are demonstrated in Table 1.

Fig. 1.

Flowchart of patients through the study.

ICD-10: International Classification of Diseases, 10th revision; ACLF: acute-on-chronic liver failure; CLIF-C: Chronic Liver Failure Consortium; NACSELD: North American Consortium for the Study of End-stage Liver Disease; AARC: Asian Pacific Association for the Study of the Liver-ACLF Research Consortium.

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Kaplan–Meier survival analyses were carried out according to ACLF definition. According to CLIF-C definition, median survival of patients with ACLF was 27.0 days (95% CI: 19.3–34.7), while that of patients with AD was 483.6 days (95% CI: 425.0–542.2, p<0.001). According to NACSELD definition, median survival of patients with ACLF was 4.0 days (95% CI: 0–12.4 days), whereas that of patients with AD was 402.5 days (95% CI: 348.2–456.8, p<0.001). Finally, according to AARC definition, median survival of patients with ACLF was 27.0 days (95% CI: 0–104.0 days), while that of patients with AD was 410.7 days (95% CI: 354.9–466.5, p=0.003).

Considering the ROC curves, AUC for the CLIF-C definition of ACLF was 0.710 regarding 28-day mortality, and 0.760 for 90-day mortality. The AUC for the NACSELD definition was 0.561 for 28-day mortality, and 0.555 for 90-day mortality. Finally, the AUC for the AARC definition was 0.560 regarding 28-day mortality, and 0.554 concerning 90-day mortality. When CLIF-C definition was compared to the others (NACSELD and AARC), it proved to be more accurate in predicting death both at 28 and 90 days. On the other hand, there was no significant difference between the performances of NACSELD and AARC definitions (Fig. 2). Sensitivity, specificity, negative predictive value and positive predictive value of the three different ACLF definitions regarding mortality are demonstrated in Table 2. In addition to evaluating the performances of the different ACLF definitions regarding 28-day and 90-day mortalities, CLIF-C ACLF score was also evaluated and had an AUC of 0.833 (95% CI: 0.757–0.893) and 0.823 (0.746–0.885) respectively (data not shown).

Fig. 2.

Receiver operating characteristic (ROC) curves, area under the curve (binomial exact 95% confidence interval)*, and ROC curves pairwise comparisons for 28-day and 90-day mortalities according to CLIF-C, AARC, and NACSELD criteria for acute-on-chronic liver failure.

*AUC estimations and AUC pairwise comparisons used DeLong et al. method; 95% CI is binomial exact and not ±1.96 standard error. CLIF-C: Chronic Liver Failure Consortium; NACSELD: North American Consortium for the Study of End-stage Liver Disease; AARC: Asian Pacific Association for the Study of the Liver-ACLF Research Consortium; AUC: area under the curve.

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Considering that there is still no consensus as to which the best definition for the diagnosis of ACLF is and that the different criteria have not been sufficiently compared to this moment, this study evaluated the performance of the different ACLF definitions to determine mortality at 28 and 90 days. To the best of our knowledge, this is the first study to compare these three definitions in a head-to-head manner, demonstrating that the CLIF-C definition of ACLF has the best prognostic performance. Moreover, the use of CLIF-C definition led to diagnosing a larger number of patients with ACLF, which allowed to identify more patients who could benefit from more intensive care.

Both NACSELD and AARC definitions presented an extremely poor sensitivity for mortality prediction. Therefore, not even their small superiority over CLIF-C definition regarding specificity could compensate for the lack of sensitivity. The low sensitivity of NACSELD and AARC definitions can be explained by the restrictive nature of their diagnostic criteria for ACLF.

Despite the absence of other studies comparing all three definitions (and particularly the lack of any study comparing CLIF-C and NACSELD definitions), there are some studies which compared either CLIF-C and AARC definitions or NACSELD and AARC criteria. A retrospective study by Kim et al. compared CLIF-C and AARC criteria regarding mortality at 28 and 90 days, showing significantly lower survival rates in patients who fulfilled ACLF criteria by CLIF-C definition. Moreover, in that study, CLIF-C criteria proved to be more sensitive for the diagnosis of ACLF than AARC definition [5]. In another retrospective study published by Rajoo et al., survival rates were also lower when patients were diagnosed with ACLF according to CLIF-C definition than when they were diagnosed by AARC definition [6]. Moreover, the studies by Zhang et al. [7,8] and Wu et al. [7,8] demonstrated that patients with ACLF by AARC definition who did not meet CLIF-C criteria had a much higher survival rate than those who also met CLIF-C criteria [7,8].

Regarding the comparison between AARC and NACSELD definitions of ACLF, a recent study showed similar prognostic performances between them [9]. This study is in agreement to ours, which demonstrated the absence of significant difference between the performances of AARC and NACSELD definitions. On the other hand, in addition to what had already been suggested, our study has shown the superiority of the performance of CLIF-C definition over the performances of both other definitions. It is also noteworthy that CLIF-C ACLF score proved to have a good prognostic performance, which is in agreement to previous publications [10,11].

CLIF-C definition of ACLF had already been demonstrated to be a strong predictor of short-term mortality. In the CANONIC study [1], patients diagnosed with ACLF using this definition had mortality of 33.9% and 51.2% at 28 and 90 days respectively, while patients with AD, who did not fulfill ACLF diagnostic criteria, had 4.7% of mortality at 28 days and 14.0% of mortality at 90 days. Other studies have described similar findings [11,13,14].

In our study, the mortality of patients with ACLF by CLIF-C definition was 53.5% at 28 days and 78.0% at 90 days. Our mortality rates for ACLF patients are higher than those verified in Europe, but are similar to the ones described in other Latin-American studies [11,13,14]. A multinational effort to better understand ACLF in Latin America is currently under development (the ACLARA Study).

The present study has some limitations. Despite being a prospective cohort study, some data were lost. Nevertheless, the most relevant data were missing only for a small number of patients, so that missing data do not appear to have influenced our results.

Another limitation concerns the intrinsic differences among ACLF definitions, especially the fact that the presence of cirrhosis is a prerequisite for ACLF according to CLIF-C [1] and NACSELD [3,9] definitions, but not according to AARC definition [2,4]. In order for the comparison among the three definitions to be possible, only cirrhotic patients were included in the present study. Therefore, our results might not apply to non-cirrhotic patients.

Yet another limitation is the fact that few patients have fulfilled ACLF criteria according to AARC and especially to NACSELD definition. However, we understand that this fact is less related to a limitation of the present study, than to the excessively restrictive characteristics of those definitions, as we had already pointed out [15,16]. In our study, 29.5% of the patients fulfilled criteria for ACLF according to CLIF-C definition, which is similar to what was found by other authors [1,14]. Regarding AARC definition, we diagnosed 9.6% of our patients with ACLF, which is almost the same proportion of patients diagnosed by Kim et al. (9.5%), but well under what was found by Rajoo et al. (42.8%) [5,6]. On the other hand, only 4.1% of our patients were diagnosed with ACLF according to the NACSELD criteria, while a recent study by the NACSELD group diagnosed around 10% of their patients with ACLF using that definition [9].

In conclusion, CLIF-C definition not only allowed a greater number of patients to be diagnosed with ACLF, in such a way that these individuals might receive more intensive care, but also demonstrated better performance in predicting death at 28 and 90 days when compared to NACSELD and AARC definitions. Therefore, we understand that CLIF-C definition should be preferred for the diagnosis of ACLF.

ACLF

acute-on-chronic liver failure