Acute-on-chronic liver failure; prevalence, causes, predisposing factors, and outcome

Abstract

Aim:

Until now, there has been disagreement regarding the prevalence, causes, predisposing factors, and outcome of ACLF (Acute-on-chronic liver failure). As a result, we have undertaken this research study.

Background:

ACLF is a complex syndrome with a poor prognosis.

Methods:

In this cross-sectional study, we evaluated the prevalence, causes, predisposing factors, and outcomes of adult cirrhotic patients with ACLF and acute decompensation (AD). ACLF was defined based on the criteria established by APASL (Asian Pacific Association for the Study of the Liver). The severity of organ failure was assessed using both EASL-CLIF (European Association for the Study of the Liver- Chronic Liver Failure) and NACSELD (North American Consortium for the Study of End-Stage Liver Disease) scores. To investigate the impact of different independent variables on mortality, survival analysis methods were used.

Results:

A total of 156 patients' data were analyzed in this study. The mean age of patients with ACLF (56.62±16.19 years) was significantly lower compared to the AD group (62.30±14.28 years). Nonalcoholic steatohepatitis and infection were the most common causes and predisposing factors in both AD and ACLF groups, respectively, but the difference between the two groups was not statistically significant. The most common organ failures observed were hepatic encephalopathy and respiratory failure. The probability of death at any given time for was significantly higher in ACLF patients than in the AD group (log rank test; P<0.001). The results of Cox regression analysis revealed that low blood pressure (HR 0.97; 95% CI 0.96-0.99; P<0.001) and decreased blood pH (HR 0.53; 95% CI 0.28-0.99; P=0.04) were significant risk factors associated with increased mortality.

Conclusion:

ACLF patients had a lower average age and higher mortality rates compared to AD. Nonalcoholic steatohepatitis was found to be the most common underlying disease in ACLF patients, while infections were identified as the predominant predisposing factor. All cases of mortality in the ACLF group were categorized as grade 3 and 4 based on the EASL-CLIF severity score. Hemodynamic instability and metabolic acidosis emerged as the most significant risk factors associated with increased mortality.

Introduction

The prevalence of liver disease is on the rise globally. The progression of liver disease, starting from fibrosis and advancing to cirrhosis, along with its associated complications, contributes significantly to mortality in affected individuals. Acute-on-chronic liver failure (ACLF), a relatively recent entity, is usually presented with both hepatic and extrahepatic organ failures. When predisposing factors such as viral hepatitis, drug-induced liver injury, and alcoholic hepatitis occur in the presence of chronic liver disease, it can lead to a condition known as ACLF (1-3).

Studies on ACLF have demonstrated a direct correlation between systemic inflammation and the severity of the syndrome. The intensity of systemic inflammation is associated with a higher number of organ failures at the time of enrollment and increased short-term mortality. Bacterial infections are among the most common triggers of systemic inflammation and are frequently observed in cases of ACLF. In the context of sepsis, excessive inflammation can lead to collateral tissue damage and necrotic cell death, resulting in the release of damage-associated molecular patterns (DAMPs). These DAMPs can perpetuate inflammation by interacting with pattern-recognition receptors, which are also activated by pathogens (4-6).

ACLF should be distinguished from acute decompensated (AD) cirrhosis, which is characterized by the sudden development of ascites, hepatic encephalopathy, variceal bleeding, or spontaneous bacterial peritonitis (SBP) but without the presence of organ failure (3, 7).

ACLF is defined with various criteria established by organizations such as Asian Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF), and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) (1, 2). Despite the variation in definitions, patients with ACLF consistently face a poor prognosis. The severity of organ failure can be evaluated using either the EASL-CLIF or NACSELD scores. In hospitalized patients with cirrhosis, the NACSELD score may be indicative of futility, whereas the EASL-CLIF score is associated with predicting the prognosis at 28 days (8, 9).

There has been ongoing debate regarding the causes, predisposing factors, and outcomes of ACLF, and no reports have addressed this matter in Iran. Therefore, we undertook this study at Namazi Hospital, the referral center for individuals with liver disease in southern Iran.

Methods

Ethical approval

This study received approval from the Ethics Committee of Shiraz University of Medical Sciences (IR.SUMS.MED.REC.1401.064) and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki for medical research. Prior to the study, written informed consent was obtained from all patients to review their medical records.

Study patients

This retrospective cross-sectional study was conducted at Namazi Hospital, a referral center in southern Iran, spanning from April 2019 to May 2022. The study aimed to assess and compare the prevalence, causes, predisposing factors, and outcomes of ACLF and AD groups. To evaluate the impact of various independent variables on mortality, which served as the primary outcome measure, survival analysis using the following statistical methods was employed. Throughout the hospitalization period, extensive data were collected, including medical records, demographic information, presence of comorbidities, clinical features, number and type of complications, etiology of cirrhosis, and hematological indices at admission (such as platelet count, white blood cell count, international normalized ratio, renal function tests, and liver biochemical tests). Patient follow-up was conducted for one month to gather survival information.

Inclusion and exclusion criteria

All adult patients (18 years or older) with cirrhosis hospitalized for AD or ACLF were considered potentially eligible for inclusion in the study. The diagnosis of AD or ACLF was determined based on the following criteria. However, certain exclusion criteria were applied, including a history of liver transplantation, presence of hepatocellular carcinoma, human immunodeficiency virus (HIV) infection, previous severe comorbid conditions unrelated to liver disease (such as kidney, heart, lung diseases, malignancy, etc.), presence of liver disease without meeting the criteria for AD or ACLF, and uncooperative patients.

Study definitions

Cirrhosis was diagnosed by a combination of laboratory tests, radiologic imaging, or liver biopsy. As organ failure typically occurs in the advanced stages of ACLF (1), we utilized the APASL criteria for early diagnosis. According to this criteria, ACLF was defined as the presence of jaundice (serum bilirubin greater than or equal to 5 mg/dL) and coagulopathy (international normalized ratio greater than or equal to 1.5), accompanied by ascites and/or hepatic encephalopathy within a four-week period in a patient with a previously diagnosed or undiagnosed chronic liver disease (1, 10). The severity of organ failure was evaluated using both the EASL-CLIF and NACSELD scores (1). The severity score components based on EASL-CLIF criteria included organ failures such as liver, kidney, brain, respiratory system, circulation, and coagulation. These organ failures were assessed using the CLIF-consortium organ failures score, which can be calculated using the score calculator available at https://www.efclif.com/scientific-activity/score-calculators/clif-c-aclf (1, 9). According to NACSELD criteria, ACLF was defined by the presence of at least two out of four severe extrahepatic organ failures. These included shock (defined as a mean arterial pressure [MAP] <60 mm Hg or a reduction of 40 mmHg in systolic blood pressure from baseline, despite adequate fluid resuscitation and cardiac output), grade III/IV hepatic encephalopathy based on the West Haven Criteria, requirement for renal replacement therapy, and need for mechanical ventilation (1, 8). AD of cirrhosis was defined as the sudden development of ascites, hepatic encephalopathy, variceal bleeding, or SBP without the presence of organ failure (7).

Statistical analysis

The statistical analyses were conducted using SPSS software version 26.0 (SPSS, USA). Continuous variables were presented as mean ± standard deviation (SD), while categorical data were expressed as percentages. Parametric and non-parametric tests were employed to analyze differences in variables. Categorical variables were described as frequencies (percentages %) and compared using chi-squared or Fisher's exact tests. Kaplan-Meier curves and log-rank tests were utilized for survival analysis, comparing the AD and ACLF groups. Cox regression analysis was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI), evaluating the risk associated with various independent variables on hospital mortality, as the main outcome, considering the length of hospital stay. In the regression analysis, variables with a univariate analysis p-value of less than 0.3 were included in the multivariate analysis. A two-tailed p-value of less than 0.05 was considered statistically significant.

Results

A total of 156 patients' data were included in the analysis, with 85 (54.5%) in AD group and 71 (45.5%) in ACLF group. Of the participants, 101 (64.7%) were male and 55 (35.3%) were female. The mean age (SD) of the participants was 59.72 (15.39) years, ranging from 18 to 93 years. Patients in the ACLF group had a significantly lower mean age (56.62±16.19 years) compared to those in the AD group (62.30±14.28 years). Table 1 provides a summary of the clinical and demographic characteristics of the participants in the AD and ACLF groups. The mortality rate was significantly higher in the ACLF group (69%) compared to the AD patients (27.1%). The most common organ failures observed were hepatic encephalopathy and respiratory failure, both of which were significantly more common in the ACLF group compared to AD patients.

Table 1.

Clinical and demographic characteristics of cirrhotic patients with acute decompensation (AD, n=85) and acute-on-chronic liver failure (ACLF, n=71)

Variables	AD; N (%)	ACLF; N (%)	P value
Gender1 Male Female	54 (63.5%) 31 (36.5%)	47 (66.2%) 24 (33.8%)	0.74
Age (yrs.); Mean ± SD2	62.30±14.28	56.62±16.19	0.02
Jaundice1	41 (48.2%)	71 (100.0%)	< 0.001
Ascites1	53 (62.4%)	60 (84.5%)	0.002
Hepatic encephalopathy1	75 (88.2%)	68 (95.8%)	0.14
Variceal bleeding 1	23 (27.1%)	29 (40.8%)	0.09
Mean arterial pressure (mm Hg); Mean ± SD2	86.40±17.36	74.70±21.74	<0.001
Spontaneous bacterial peritonitis1	14 (16.5%)	25 (35.2%)	0.009
Coagulopathy ((INR>=1.5) 1	53(62.4%)	71(100.0%)	<0.001
Renal failure (Creatinine>=2 mg/dl)1	24(28.2%)	31(43.7%)	0.06
Severe respiratory failure (Tracheal intubation)1	29(34.1%)	54(76.1%)	<0.001
Opium use1	21 (24.7%)	25 (35.2%)	0.16
Cigarette smoking1	18 (21.2%)	22 (31.0%)	0.20
Length of stay in hospital (days); Mean ± SD2	7.71±9.46	6.86±6.56	0.52
Length of stay in ICU (days); Mean ± SD2	0.88±2.52	1.89±3.14	0.03
Mortality1	23 (27.1%)	49 (69.0%)	< 0.001

Notes: ¹ Chi-square Test; ² Independent Samples T-Test

Regarding liver biochemical tests, with the exception of albumin, the blood levels of other laboratory parameters, including aspartate transaminase, alanine transaminase, alkaline phosphatase, and bilirubin, were significantly higher in ACLF patients compared to the AD group. A comparison of the laboratory parameters between the two groups is presented in Table 2.

Table 2.

Laboratory parameters of cirrhotic patients with acute decompensation (AD, n=85) and acute-on-chronic liver failure (ACLF, n=71)

Variables	AD; N (%)	ACLF; N (%)	P value
White blood cells; μl1	7.73±5.17	11.95±17.43	0.05
Hemoglobin; g/dL1	10.15±2.53	10.09±2.73	0.78
Platelet; mcL2	90305.88±60146.85	106169.01±122909.72	0.30
Partial thromboplastin time (PTT); seconds1	44.33±17.17	50.20±17.69	0.001
International normalized ratio (INR)2	1.97±0.86	2.82±1.45	<0.001
Aspartate transaminase; IU/L1	95.48±187.65	201.21±409.20	<0.001
Alanine transaminase; IU/L1	53.84±78.31	128.76±312.57	<0.001
Alkaline phosphatase; IU/L2	344.95±165.77	442.78±219.87	0.002
Serum albumin; g/dl1	2.87±0.53	5.55±24.14	0.11
Serum protein; g/dl1	5.68±1.01	5.56±1.24	0.32
Total bilirubin; mg/dL2	3.37±3.41	11.00±6.64	<0.001
Direct bilirubin; mg/dL2	1.60± 1.78	5.30±3.96	<0.001
Blood urea nitrogen; mg/dL1	33.31±24.60	47.99±33.06	0.007
Sodium; mEq/L1	134.19±14.93	134.92±13.97	0.08
Potassium; mEq/L2	4.59±0.89	5.08±1.12	0.003
Calcium; mg/dL2	8.55±0.74	8.60±0.76	0.67
Phosphorus; mg/dL1	3.79±1.29	3.93±1.31	0.24
Uric acid; mg/dL1	5.35±2.48	5.43±2.99	0.46
Erythrocyte sedimentation rate 1	36.57±28.48	46.74±37.17	0.08
C-reactive protein 1	35.79±34.95	49.12±41.73	0.09
Creatinine; mg/dL1	1.93±2.05	2.27±2.05	0.43
Blood PH1	7.41±0.12	7.34±0.15	<0.001
Blood Hco3; mEq/L2	19.86±5.39	18.78±8.18	0.34
Partial pressure of oxygen (PaO2); mmHg1	96.48±70.51	85.18±52.10	0.72
partial pressure of carbon dioxide (PCo2): mmHg1	30.06±8.30	32.37±9.62	0.15

Notes: ¹ Mann–Whitney test; ² Independent Samples T-Test

In general, nonalcoholic steatohepatitis (NASH) accounted for 58.3% of the cases, followed by viral hepatitis at 21.8%. However, as shown in Table 3, there was no statistically significant difference between the AD and ACLF groups in terms of the causes of cirrhosis. Overall, infections (34.6%), variceal bleeding (19.9%), and alcoholic hepatitis (4.5%) were identified as the most common predisposing factors among the participants. Again, there was no statistically significant difference between the AD and ACLF groups regarding these predisposing factors (Table 3).

Table 3.

Causes of cirrhosis and predisposing factors in the development of acute decompensation (AD, n=85) versus acute-on-chronic liver failure (ACLF, n=71)

Variables	AD; N (%)	ACLF; N (%)	P value 1
Causes of Cirrhosis Nonalcoholic fatty liver disease Viral2 Autoimmune liver disease3 Cryptogenic Others4	54(63.5%) 15(17.6%) 5(5.9%) 7(8.2%) 4(4.7%)	37(52.1%) 19(26.8%) 2(2.8%) 9(12.7%) 4(5.6%)	0.41
Predisposing factors Infection Variceal bleeding Alcohol Unknown	25(29.4%) 15(17.6%) 5(5.9%) 40(47.1%)	29(40.8%) 16(22.5%) 2(2.8%) 24(33.8%)	0.22

Notes: ¹ Chi-square Test; ² HBV and HCV hepatitis, ³ Including autoimmune hepatitis (n:4) and primary sclerosing cholangitis (n:2), primary biliary cirrhosis (n:1), ⁴ Including cardiac (n:4), alcoholic, (n:1), Wilson (n:1), Hemochromatosis (n:1), Budd Chiari (n:1)

In the subgroup of ACLF patients, the severity of the disease was assessed using two different criteria (EASL-CLIF and NACSELD) at different time points, as shown in Table 4. Based on the EASL-CLIF criteria, all deaths occurred in grades 3 and 4. Additionally, the mortality rate in the group meeting the NACSELD criteria was significantly higher than the group that did not meet the criteria (p-value<0.001).

Table 4.

Comparison of severity of acute-on-chronic liver failure¹ (n=71) based on different criteria (EASL-CLIF versus NACSELD) over time

Variables	EASL-CLIF ; N (%)				P-value	NACSELD ; N (%)		P-value
	Grade 0 7(9.9%)	Grade 1 4(5.6%)	Grade 2 10(14.1%)	Grade 3 50(70.4%)		Yes	No
Length of stay in hospital (days)2 First week Second week Third week More than 3 weeks	6(85.7%) 0(0.0%) 1(14.3%) 0(0.0%)	3(75.0%) 1(25.0%) 0(0.0%) 0(0.0%)	7(70.0%) 2(20.0%) 0(0.0%) 1(10.0%)	35(70.0%) 8(16.0%) 4(8.0%) 3(6.0%)	0.896	37(71.2%) 8(15.4%) 3(5.8%) 4(7.7%)	14(73.7%) 3(15.8%) 2(10.5%) 0(0.0%)	0.59
Mortality1	0(0.0%)	0(0.0%)	2(20.0%)	47(94.0%)	<0.001	48(92.3%)	1(5.3%)	<0.001

Notes: ¹ACLF was defined based on Asian Pacific Association for the Study of the Liver (APASL); ² Chi-square Test

Abbreviations: EASL-CLIF, European Association for the Study of the Liver-Chronic LIver Failure; NACSELD, and North American Consortium for the Study of End-Stage Liver Disease

The mean (SD) hospital length of stay for patients in the AD and ACLF groups were 7.71 (9.46) days and 6.86 (6.56) days, respectively. In the survival analysis, the Kaplan-Meier curve (Figure 1) and log-rank test demonstrated that the probability of death at any given time in ACLF patients was significantly higher than in the AD group (p-value<0.001).

Figure 1.

Kaplan–Meier chart for probability of death at any time in acute decompensation (AD, n=85) versus acute-on-chronic liver failure (ACLF, n=71)

Cox regression analysis was conducted to assess the HR of independent variables on mortality, taking into account the length of hospital stay. The results showed that low blood pressure (HR 0.97; 95% CI 0.96-0.99; p-value<0.001) and decreased blood pH (HR 0.53; 95% CI 0.28-0.99; p-value=0.04) significantly increased the risk of mortality. These findings are summarized in Table 5.

Table 5.

Cox regression analysis in ACLF patients (n=71) to estimate hazard ratio (HR) and 95% confidence interval (CI) to assess independent variables associated with mortality considering length of hospital stay

Variable	Univariate model		Multivariate model
	HR (95% CI)	P value	HR (95% CI)	P value
Mean arterial pressure (mm Hg)	0.97(0.95-0.98)	<0.001	0.97(0.96-0.99)	<0.001
Blood PH ≥7.35 <7.35 (Metabolic Acidosis)	0.39(0.29-0.71) 1	0.002	0.53(0.28-0.99) 1	0.04
Spontaneous bacterial peritonitis	1.18(0.66-2.09)	0.58	1.07(0.59-1.95)	0.82
Potassium level; mEq/L	1.43(1.10-1.87)	0.008	1.11(0.81-1.51)	0.53
Hepatic encephalopathy	0.35(0.05-2.57)	0.30	0.54(0.07-4.07)	0.55
Variceal bleeding	0.73(0.40-1.35)	0.31	0.55(0.29-1.03)	0.06
Renal failure	0.51(0.29-0.91)	0.02	0.585(0.33-1.05)	0.07

Discussion

This cross-sectional study, which is the first report from Iran, revealed that approximately 45% of hospitalized cirrhotic patients had ACLF. The most common underlying diseases associated with ACLF were nonalcoholic steatohepatitis and viral hepatitis, while the most common predisposing factors were infections and variceal bleeding. Although patients with ACLF were significantly younger than those in the AD group, the mortality rate and length of stay in the intensive care unit were higher in the ACLF patients compared to the AD group. All recorded mortality cases, based on the EASL-CLIF severity score, were associated with grade 3 and 4. Hemodynamic instability and metabolic acidosis emerged as significant risk factors contributing to increased mortality.

ACLF is a complex syndrome with controversial pathophysiology, clinical features, and treatment (3, 7). Differentiating between the terms "Acute Decompensation”, "Acute-on-Chronic Liver Failure", and "irreversible chronic end-stage liver disease" is important, although there is currently no universally accepted definition for these terms. AD is characterized by the sudden onset of complications of cirrhosis such as ascites, variceal bleeding, and hepatic encephalopathy. ACLF, on the other hand, occurs when precipitating events, such as viral hepatitis, drug-induced liver injury, alcoholic hepatitis, or variceal bleeding, lead to both hepatic and extrahepatic organ failure. It is important to note that both AD and ACLF have the potential for reversibility. There are three major definitions of ACLF used in different parts of the world, which are APASL, EASL-CLIF, and NACSELD (1). In the APASL criteria, because the presence of extrahepatic organ failure is not mandatory for the diagnosis of ACLF, it can be diagnosed in the early stages (1, 10).

EASL-CLIF criteria for ACLF are based on the assessment of organ failures, which can affect the liver, kidney, brain, respiratory system, circulation, and coagulation. ACLF diagnosed according to EASL-CLIF criteria is associated with high short-term mortality rates. Importantly, ACLF can develop with or without a history of AD (9). NACSELD defines ACLF based on the requirement of having at least two severe extrahepatic organ failures (1, 8).

The common characteristics among all the aforementioned definitions of ACLF include the rapid deterioration of chronic liver disease and a high risk of mortality. It is important to note that these definitions primarily reflect the prognosis of the condition rather than serving as a definite definition of ACLF itself. Furthermore, in all these definitions, liver failure is potentially reversible, which is a distinguishing feature of ACLF compared to "irreversible -chronic end-stage liver disease". Until the underlying pathogenesis of ACLF is fully understood, it is best considered as a syndrome. Prognostic markers that predict the outcome of ACLF should be distinguished from diagnostic markers that confirm the presence of ACLF (1).

The pathophysiology of ACLF remains a subject of controversy. The literature suggests that infections, alcoholic hepatitis, variceal bleeding, and drug-induced liver injury can act as predisposing factors for the development of ACLF. Additionally, other potential precipitating factors include hepatic injury resulting from ischemia due to hypotension, congestion from cardiac failure, and acute infections caused by hepatitis A and E viruses, particularly in the Middle East and Asia (5, 7, 11-13).

It is unknown whether the inflammation observed in ACLF is specific to this condition or is a result of the precipitating factors mentioned earlier. Various mechanisms have been proposed to explain the role of inflammation in the development of organ failure in ACLF, including the production of nitric oxide, tissue damage, and mitochondrial dysfunction. For instance, acute kidney injury, which occurred in approximately 40% of our ACLF patients, could be a result of inflammation-induced nitric oxide production, leading to splanchnic vasodilation mediated by nitric oxide, reduced effective arterial blood volume, and decreased glomerular filtration rate (4, 11, 14, 15).

The most commonly identified precipitating event for ACLF is infection. Patients with cirrhosis are at significantly higher risk of developing severe bacterial infections and are twice as likely to die from sepsis compared to individuals without cirrhosis (16-18). Approximately 40–50% of hospital admissions for patients with cirrhosis are attributed to sepsis, with one of the most common types of infection being SBP (19, 20). This finding is consistent with our study, where we observed that approximately one third of ACLF patients had SBP. The predisposition for sepsis in cirrhosis is influenced by various factors. Genetic factors play a role, particularly in the development of SBP, where specific polymorphic variants of NOD2 and TLR2 have been associated. Additionally, cirrhosis is characterized by a complex interplay of compromised cellular and humoral immune defenses and immunodeficiency, which further deteriorate with the progression of liver disease (21-23). The compromised immune system and altered gut barrier function in cirrhotic patients contribute to their increased susceptibility to infections. These factors collectively contribute to the increased susceptibility of cirrhotic patients to infections and sepsis. Prompt recognition and appropriate management of infections are crucial in preventing the progression of ACLF and improving patient outcomes (16-18).

In the literature, acute alcoholic hepatitis is recognized as another common precipitant of systemic inflammation frequently associated with ACLF. However, only a few of our ACLF patients in the study were predisposed by alcoholic hepatitis. In patients with ACLF related to primary liver injury, systemic inflammation can arise from the release of damage-associated molecular patterns (DAMPs) by necrotic hepatocytes. Additionally, in cases of alcoholic hepatitis, systemic inflammation can also result from pathogen-associated molecular patterns (PAMPs) associated with infections, which are common in patients with alcoholic hepatitis. Therefore, both the release of DAMPs from hepatocyte necrosis and the presence of PAMPs from concurrent infections contribute to the systemic inflammation observed in ACLF patients with alcoholic hepatitis (2, 24).

Variceal bleeding was identified as the second most common predisposing factor for the induction of ACLF in our study. The precise mechanisms by which variceal bleeding may precipitate ACLF not fully understood. In patients with severe variceal bleeding, liver ischemia can occur, leading to hepatocyte necrosis and subsequent inflammation induced by damage-associated molecular patterns (DAMPs). Furthermore, variceal bleeding can create a predisposition for the development of bacterial infections. The combination of these factors contributes to the potential development of ACLF in patients with variceal bleeding (2, 25, 26).

Approximately 40% of patients with ACLF do not exhibit any identifiable precipitating condition. This finding aligns with our study, which revealed that around one-third of patients did not have any predisposing factors. When examining individuals with ACLF who lack a clearly discernible precipitating event, it is possible that systemic inflammation occurs due to the translocation of bacterial pathogen-associated molecular patterns (PAMPs) from the gut lumen (2-4, 27).

In a multicenter study conducted by Moreau et al., patients experiencing AD exhibited a 28-day mortality rate of less than 5%, which was lower than the results obtained in our study (refer to Table 1). The mortality associated with ACLF demonstrated an upward trend with increasing organ failure. Specifically, patients with one failed organ had a 28-day mortality rate of approximately 20%, which further escalated to over 70% in individuals with three failed organs. Alcoholic liver disease emerged as the most common cause of ACLF, while infection was identified as the primary precipitating illness. Among the extrahepatic organs, the kidneys were most frequently affected and experienced failure in a significant number of cases. (3). In a single-center study conducted by Zhang et al., a retrospective analysis was performed on 102 patients ACLF. It was found that Hepatitis B virus infection was the leading cause of liver cirrhosis, and variceal bleeding 68.6% (70 out of 102) was responsible for the majority of hospitalizations. The distribution of ACLF patients in the mentioned study was as follows: grade 1 (30.4%, 31 out of 102), grade 2 (44.1%, 45 out of 102), and grade 3 (25.5%, 26 out of 102) (28). The findings from the two aforementioned studies differed significantly when compared to our study. In our study, approximately 70% of ACLF cases were classified as grade 3, and all mortality occurred in the EASL-CLIF group with grades 3 and 4 (refer to Table 4). Additionally, our results indicated that the most common underlying cause of chronic liver disease was non-alcoholic steatohepatitis, and the most common primary identified precipitating factors for ACLF development were infections and variceal bleeding. Among the extrahepatic organ failures observed, hepatic encephalopathy and respiratory failure were the most frequent (refer to Table 1).

It is noteworthy that patients with ACLF are best managed in the intensive care unit, and some individuals may benefit from early liver transplantation (1). As demonstrated in the Kaplan-Meier curve (see Figure 1), the probability of death at any given time was significantly higher in ACLF patients than in the AD group (log-rank test, P<0.001). When comparing the ACLF criteria of NACSELD and EASL-CLIF, it appears that the NACSELD criteria demonstrated better performance in predicting 7-day mortality. On the other hand, when it came to predicting 90-day mortality, the NACSELD criteria exhibited lower sensitivity and negative predictive value compared to the EASL-CLIF criteria (29). Based on the observations, it appears that the EASL-CLIF score could be utilized to prioritize patients who need liver transplantation (30). All mortalities in our ACLF patients were concentrated within the EASL-CLIF grade 3 and 4 categories (refer to Table 4), with hemodynamic instability and metabolic acidosis emerging as the most important risk factors for increased mortality (refer to Table 5). Certain patients with advanced stages of ACLF, specifically those experiencing three or more organ failures, may be deemed suitable for exclusive palliative care (31).

As the first research in Iran, the strength of our study was to compare the prevalence, causes, predisposing factors, and outcome of two groups (AD vs. ACLF) of hospitalized cirrhosis patients considering many confounding factors. However, it is important to note that our study has certain limitations. Firstly, it was a retrospective analysis conducted in a single center, which may limit the generalizability of the findings. Secondly, we only evaluated in-hospital outcomes, which may not capture the long-term prognosis of the patients. Despite these limitations, we tried to improve the quality and accuracy of the study by conducting complete assessments and follow-ups, including accurate recording of clinical characteristics and laboratory parameters for all participants.

Conclusion

In this study, the most common underlying disease observed in ACLF patients was nonalcoholic steatohepatitis, while infections were the most common predisposing factor. We observed that ACLF patients tended to be younger in age compared to participants with AD, and the mortality rate was significantly higher in the ACLF group. Notably, all mortality cases occurred in patients classified as grade 3 and 4 based on the EASL-CLIF severity score. Hemodynamic instability and metabolic acidosis were identified as the most significant risk factors associated with increased mortality in ACLF patients.

Conflict of interests

The authors report no conflicts of interest in this work.