Organ/system
0
1
2
3
4
Liver (bilirubin, mg/dL)
< 1.2
≥ 1.2 to ≤ 1.9
≥ 2 to ≤ 5.9
≥ 6 to < 12
≥ 12
Kidney (creatinine, mg/dL)
< 1.2
≥ 1.2 to ≤ 1.9
≥ 2 to < 3.5
≥ 3.5 to < 5
≥ 5
Or use of renal replacement therapy
Cerebral (HE grade)
No HE
1
2
3
4
Coagulation (INR)
< 1.1
≥ 1.1 to < 1.25
≥ 1.25 to < 1.5
≥ 1.5 to < 2.5
≥ 2.5 or Platelets ≤ 20 ´ 109/L
Circulation (MAP, mmHg)
≥ 70
< 70
Dopamine ≤ 5 or dobutamine or terlipressin
Dopamine > 5 or E ≤ 0.1 or NE ≤ 0.1
Dopamine > 15 or E > 0.1 or NE > 0.1
Lungs PaO/FiO2 or SpO2/FiO2
> 400 or > 512
> 300 to ≤ 400 or > 357 to ≤ 512
> 200 to ≤300 or > 214 to ≤ 357
> 100 to ≤ 200 or > 89 to ≤ 214
≤ 100 or ≤ 89
The issue “relatively high short-term mortality rate” was defined as a mortality rate equal or greater than 15 % within a period of 28 days. This figure represents approximately 50 % of the short-term mortality rate associated with severe sepsis or septic shock in the general population [10]. Although debatable, the inclusion of a short-term mortality-rate threshold in the definition of ACLF was unanimously supported because it has important therapeutic implications, i.e., indication of early invasive therapeutic procedures and/or liver transplantation.
Table 25.2 shows the short-term mortality in patients included in the CANONIC study. Mortality rate was clearly related to the presence and number of organ failures as defined by the CLIF-SOFA score. Also, renal dysfunction (as defined by a serum creatinine of 1.5–1.9 mg/dl) and/or moderate (grade 1–2) hepatic encephalopathy, when associated to organ failure were also found to predict prognosis. Based on the presence of organ failure and of short-term mortality rate equal or greater than 15 % after enrolment, the following groups of patients were excluded and included from the diagnosis of ACLF:
Table 25.2
Diagnostic criteria of ACLF and inclusion criteria in the APACHE study
Number and types of organ failures | No kidney dysfunction and no mild-to-moderate hepatic encephalopathy | Kidney dysfunction and/or mild/moderate hepatic encephalopathy |
|---|---|---|
No organ failure | 20/577 (3.5) | 19/329 (5.8) |
Single liver failure | 4/75 (5.3) | 11/36 (30.6) |
Single cerebral failure | 2/26 (7.7) | 1/5 (20.0) |
Single coagulation failure | 1/22 (4.6) | 2/11 (18.2) |
Single circulation/lung failure | 1/18 (5.6) | 2/8 (25.0) |
Single kidney failure | 9/58 (15.5) | 7/30 (23.3) |
Two organ failures | 19/75 (25.3) | 12/32 (37.5) |
Three to four organ failures | 19/25 (76.0) | 6/12 (50.0) |
Five to six organ failures | 6/8 (75.0) | 2/2 (100.0) |
1.
Excluded: (a) No organ failure; (b) Single nonrenal organ failure with serum creatinine < 1.5 mg/dl and no hepatic encephalopathy.
2.
Included: (a) Single renal failure; (b) Single nonrenal organ failure plus renal dysfunction and/or grade 1–2 hepatic encephalopathy; (c) two or more organ failures.
Table 25.3 shows the classification of patients with ACLF according to grades of severity. The prevalence of ACLF among patients admitted to hospital with decompensated cirrhosis was 30 % (20 % at admission and 10 % during hospitalization) and the overall 28-day mortality rate was 33 %. According to the number of organ/system failures, ACLF is stratified into three grades with different prognosis: grade-1 (one organ failure, 28-day mortality rate 22 %), grade 2 (two organ failures, 28-day mortality rate 32 %), and grade 3 (three or more organ failures, 28-day mortality rate 73 %).
Table 25.3
Grades of ACLF
Grades of ACLF | |
|---|---|
No ACLF | No organ failure One organ failure (liver failure, coagulation, circulatory or respiratory failure) with creatinine 1.5 mg/dL and no hepatic encephalopathy Single cerebral failure and creatinine 1.5 mg/dL |
ACLF grade 1 | Single kidney failure Single “nonkidney” organ failure with serum creatinine ranging from 1.5 to 2.0 mg/dL) and/or mild-to-moderate hepatic encephalopathy |
ACLF grade 2 | Presence of two organ failures |
ACLF grade 3 | Presence ≥ 3 organ failures |
Precipitating Events
As indicated, experts from Western countries suggested including precipitating events in the definition of ACLF. In patients included in the CANONIC study, the most common precipitating events were bacterial infections, particularly spontaneous bacterial peritonitis and pneumonia, occurring in 33 % of patients with ACLF versus 22 % in patients without ACLF. The second precipitating event in frequency was active alcoholism during the last 3 months prior to enrolment. It was present in approximately 25 % of patients with ACLF versus 15 % in patients without ACLF. In the subgroup of patients with active drinking, there were analytical data supporting acute liver injury. Interestingly, in patients with ACLF the prevalence of alcoholic cirrhosis (60 %) was higher than the prevalence of active alcoholism, indicating that alcoholic hepatitis accounts for only part of cases of ACLF in patients with alcoholic cirrhosis. There was a small proportion of other precipitating events (8 %). As a trigger, gastrointestinal hemorrhage was less frequent in patients with ACLF (13 %) than in patients without ACLF, suggesting that hemorrhage, if not associated to other complications (i.e., active drinking and/or bacterial infections) is not clearly related to the development of ACLF. Finally, and most interestingly, in a significant proportion of patients (45 %) ACLF developed in the absence of any identifiable trigger.
Mortality was similar in the presence or absence of precipitating events, indicating that although triggers are important in the development of ACLF, once it develops mortality depends of other factors such as the clinical course (see below) and number of organ failures.
ACLF is Not a Terminal Event of a Long-Standing Cirrhosis
A traditional concept is that renal failure and, therefore, ACLF is the final event in a long-standing history of decompensated cirrhosis. This concept is not supported by the results of the CANONIC study since it revealed that almost half of patients with ACLF did not have a prior history of decompensation or had developed first AD within 3 months prior ACLF. An interesting feature was that patients with no history of decompensated cirrhosis developed a more severe form of ACLF than patients with previous episodes of decompensation.
Clinical Course of ACLF
The clinical course of 388 CANONIC patients with ACLF at enrolment or that developed ACLF during hospitalization was assessed during the first 28 days to understand the natural history of the syndrome. Four major findings were observed (Thierry Gustot, unpublished observations). The first was that ACLF is an extraordinarily dynamic syndrome. In only one third of patients, ACLF did not change between diagnosis and final follow-up but even in these cases the profile was fluctuating in 35 %. In most cases, ACLF either improved (50 %) or worsened (20 %). The second was the demonstration of the reversibility of the syndrome. Resolution of ACLF was observed in 40 % of patients. The frequency of resolution was high (55 %) in patients with ACLF-1 at diagnosis, intermediate (35 %) in patients with ACLF-2, and low (15 %) in patients with ACLF-3. The third important finding is that despite the correlation of ACLF grade at diagnosis with prognosis, it is the clinical course of the syndrome which determines short-term mortality. Finally, changes in ACLF grade following diagnosis occur very rapidly (1–2 days) or rapidly (3–7 days) following diagnosis in more than 65 % of the patients. The early course of ACLF, therefore, is a major determinant of prognosis.
ACLF is Associated with Systemic Inflammation
The CANONIC study has also provided important data to understand the mechanisms of ACLF. The finding of higher white blood cell count (WBC) and serum C reactive protein (CRP) levels in patients with ACLF than in those without it suggests that systemic inflammation plays a role in the development of the syndrome [4]. This is also supported by the finding that, as WBC and CRP levels increase across ACLF grades, the intensity of systemic inflammation is higher and there are more number of organs that fail [4]. Systemic oxidative stress is increased in patients with ACLF in comparison to patients without ACLF and also correlates with the number of organ failures, which further supports systemic inflammation as a mechanism of ACLF [11].
As indicated by the CANIONIC study, in approximately 30 % of patients with ACLF, systemic inflammation was chronologically related to bacterial infections. In these patients, therefore, systemic inflammation is probably due to activation of the innate immune system cells (mainly polymorphonuclear leukocytes monocyte-macrophages and endothelial cells) by products released by bacteria (pathogen-associated molecular patterns, PAMPs ; i.e., lipopolysaccharide, lypoteichoic acid, peptidoglycan) [12]. In another 25 %, ACLF is related to excessive alcohol consumption. Although some of these patients may be infected, many of them do not fulfill criteria of a bacterial infection. In these cases, the systemic inflammatory response is probably unrelated to an infection. This condition is known as “sterile inflammation” and is typically found in diseases characterized by profound tissue damage [13]. Therefore, in patients with alcoholic hepatitis, both infection-associated and sterile systemic inflammation is a major determinant of ACLF and early mortality. The pathogenesis of sterile inflammation in alcoholic hepatitis is probably related to the release of intracellular molecules (damage-associated molecular patterns, DAMPs) from dying hepatocytes that activate the innate immune systems acting as true “internal pathogens.” However, as indicated previously, in approximately 40 % of cases with ACLF no clear precipitating event can be identified. Although the cause of systemic inflammation in these patients is unknown, it is possibly related to the release of DAMPs by the damaged liver and/or to the translocation of bacterial products (PAMPs) from the intestinal lumen into the systemic circulation. Translocation of PAMPs in the absence of infection is a well recognized feature in patients with advanced cirrhosis related to intestinal hypomotility and bacterial overgrowth, increased mucosal permeability and impaired intestinal immune system function [14].
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