Published online May 27, 2024. doi: 10.4254/wjh.v16.i5.809
Revised: February 9, 2024
Accepted: April 9, 2024
Published online: May 27, 2024
Processing time: 175 Days and 1.2 Hours
Acute-on-chronic liver disease (AoCLD) accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases.
To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD.
Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (ACLF) study cohort were included in this study. The clinical characteristics and outcomes, and the 90-d survival rate associated with each clinical type of AoCLD were analyzed, using the Kaplan-Meier method and the log-rank test.
A total of 3375 patients with AoCLD were enrolled, including 1679 (49.7%) patients with liver cirrhosis acute decompensation (LC-AD), 850 (25.2%) patients with ACLF, 577 (17.1%) patients with chronic hepatitis acute exacerbation (CHAE), and 269 (8.0%) patients with liver cirrhosis active phase (LC-A). The most common cause of chronic liver disease (CLD) was HBV infection (71.4%). The most common precipitants of AoCLD was bacterial infection (22.8%). The 90-d mortality rates of each clinical subtype of AoCLD were 43.4% (232/535) for type-C ACLF, 36.0% (36/100) for type-B ACLF, 27.0% (58/215) for type-A ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE.
HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD. Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.
Core Tip: This study systematically investigated the composition, clinical characteristics, and prognosis of each subtype of acute-on-chronic liver disease (AoCLD) for the first time. In China, liver cirrhosis acute decompensation (LC-AD) is the most common clinical type of AoCLD, with a high short-term mortality rate. Attention should be given to the early diagnosis and intervention of patients with LC-AD to avoid acute decompensation-acute-on-chronic liver failure (ACLF) transition. Type C ACLF patients have the highest mortality rate, requiring early liver transplantation to improve the overall survival rate of AoCLD.
- Citation: Zhang YY, Luo S, Li H, Sun SN, Wang XB, Zheng X, Huang Y, Li BL, Gao YH, Qian ZP, Liu F, Lu XB, Liu JP, Ren HT, Zheng YB, Yan HD, Deng GH, Qiao L, Zhang Y, Gu WY, Xiang XM, Zhou Y, Hou YX, Zhang Q, Xiong Y, Zou CC, Chen J, Huang ZB, Jiang XH, Qi TT, Chen YY, Gao N, Liu CY, Yuan W, Mei X, Li J, Li T, Zheng RJ, Zhou XY, Zhao J, Meng ZJ. Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study. World J Hepatol 2024; 16(5): 809-821
- URL: https://www.wjgnet.com/1948-5182/full/v16/i5/809.htm
- DOI: https://dx.doi.org/10.4254/wjh.v16.i5.809
Chronic liver disease (CLD) includes liver cirrhosis (LC) and noncirrhotic chronic liver diseases (NC-CLDs), such as chronic viral hepatitis, alcoholic liver disease and non-alcoholic fatty liver diseases[1]. According to the latest global disease burden data, disability-adjusted life years caused by CLD accounted for 1.8% of the global burden in 2019[2], and CLD burden as well as challenges related to this disease are increasing worldwide[3,4]. Hepatitis virus variation, overlapping virus and/or bacterial infection, alcohol, drugs and other factors aggravate inflammation and/or fibrosis of the liver, even leading to LC acute decompensation (LC-AD) or liver failure[5,6]. This acute liver injury (ALI) or decom
According to the degree of ALI, AoCLD can be characterized as acute-on-chronic liver failure (ACLF) and non-ACLF[8]. According to the basic state of CLD, ACLF can be divided into three clinical types: Type A (based on chronic hepatitis), type B (based on compensated cirrhosis), and type C (based on decompensated cirrhosis)[8,9]. Non-ACLF can be further divided into chronic hepatitis with acute exacerbation (CHAE), LC active phase (LC-A), and LC-AD[8]. Studies have shown that a certain of non-ACLF AoCLDs may rapidly progress to ACLF in the absence of timely diagnosis and intervention at the initial stage of the disease, and these patients are defined as having pre-liver failure[10]. At present, most studies focus on the clinical characteristics, predictive models and prognostic factors of ACLF[11], while few studies elucidate the characteristics of non-ACLF AoCLD systematically.
This study was based on a multicenter prospective cohort of LC and NC-CLD patients, and the aim was to analyze the composition, clinical characteristics and prognosis of each clinical type of AoCLD to provide information for the accurate clinical classification of AoCLD. Rapid identification of patients with a high risk of death and administering appropriate clinical interventions for the reasonable allocation of medical resources will be helpful in reducing the short-term mortality of AoCLD patients.
The patients included in this study were from two prospective, multicenter cohorts of CLD patients with acute exacerbation enrolled in the Chinese ACLF (CATCH-LIFE) study (NCT02457637, NCT03641872)[7]. This study was approved by the Ethics Committee of Renji Hospital (the leading center of the CATCH-LIFE study), School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Signed informed consent was obtained from all patients.
The diagnostic criteria for AoCLD and its subtypes are as follows: AoCLD refers to the occurrence of ALI or AD in CLD patients under the action of various precipitants, manifested as abnormal liver function within one week or AD within one month or progression to liver failure[7]. ACLF refers to acute liver failure in patients with CLD (with or without LC), which is characterized by jaundice [total bilirubin (TB) 10 times higher than the upper limit of normal value (ULN) or daily rises ≥ 17.l μmol/L], bleeding tendency [prothrombin activity ≤ 40% or international normalized ratio (INR) ≥ 1.5], accompanied by one or more extrahepatic organ failures, and increased mortality within 28 d and 3 months after onset[8]. According to the latest view of the World Gastroenterology Organization (WGO), ACLF can be classified into three clinical types based on the basic status of CLD: Type A (based on chronic hepatitis), type B (based on compensated cirrhosis), and type C (based on decompensated cirrhosis)[9]. LC-A refers to a state in which liver fibrosis and inflammation coexist, accompanied by elevated alanine aminotransferase (ALT) level, elevated TB level, and decreased albumin (ALB) level[8]. LC-AD refers to the presence of acute gastrointestinal bleeding, hepatic encephalopathy (HE), obvious ascites, jaundice (TB > 5 mg/dL), or any combination of these symptoms in patients with LC within one month[8]. CHAE refers to intermittent elevation in transaminase exceeding 5 times the ULN or twice the baseline level in NC-CLD patients[8].
Among the CATCH-LIFE cohort, patients who received liver transplantation within 90 d after admission, NC-CLD patients with FIB-4 score < 1.45 or loss of FIB-4 value, patients with unclear decompensation history of cirrhosis, and patients who did not meet any of the diagnostic criteria for clinical classification of AoCLD were not included in this study.
The clinical and laboratory information were retrieved from the CATCH-LIFE study database, including demographic data (age, sex), etiology of basic liver disease (HBV related, alcohol related, or other), and predisposing factors (HBV reactivation, infection, alcoholism, surgery, overwork, etc.). The experimental data on admission included white blood cell count, hemoglobin (HGB), platelet (PLT) count, ALB, TB, ALT, aspartate aminotransferase (AST), prothrombin time (PT), INR, alkaline phosphatase, γ-glutamyl transferase (GGT), blood urea nitrogen (BUN), and creatinine; ascites, gastrointestinal bleeding, HE, bacterial infection and other complications were recorded and analyzed. FIB-4 was calculated according to the formula FIB-4 = [age (year) × AST (U/L)]/[PLT (109/L) × ALT, (U/L) 1/2][12]. Scores of the model for end-stage liver disease (MELD) were calculated according to the formula: R = 9.57 × ln [Cr (mg/dL)] + 3.78 × ln [TB (mg/dL)] + 11.2 × ln (INR) + 6.43 × Etiology (taking 0 for alcoholic and cholestatic liver disease and taking 1 for other causes)[13].
Patient demographic and clinical characteristics are summarized as frequency counts and percentages or medians and interquartile ranges, as appropriate. The differences in demographic and clinical characteristics between groups were examined using Fisher’s exact tests or rank sum tests where appropriate. The 28-d and 90-d survival of each clinical type of AoCLD was analyzed using the Kaplan-Meier method, and the survival rates were compared using log-rank tests. For biochemical indicators with less than 10% missing values, the multiple imputation method was used to fill in the missing values. A P value < 0.05 was considered statistically significant. All statistical analyses and visualization were carried out using R statistical software (version R 4.0, R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/).
Of the 3970 patients in the CATCH-LIFE study cohort, 595 patients were excluded, of which 246 patients received liver transplantation within 90 d of follow-up, 180 NC-CLD patients had an FIB-4 < 1.45, 9 NC-CLD patients with a missing value for FIB-4 score, 20 LC patients had an unclear history of decompensation, and 140 patients did not meet the criteria for the diagnosis of AoCLD. Finally, 3375 patients with AoCLD were included in the present study (Figure 1).
Among the 3375 AoCLD patients, 1679 (49.7%) had LC-AD, 850 (25.2%) had ACLF (including 535 with type C, 215 with type A, and 100 with type B), 577 (17.1%) had CHAE, and 269 (8.0%) had LC-A (Figure 2).
In all 3375 patients with AoCLD, the top 5 causes were HBV infection (2409 patients, 71.4%), ALD (649 patients, 19.2%), autoimmune liver disease (AILD) (308 patients, 9.1%), HCV infection (126 patients, 3.7%), and MAFLD (104 patients, 3.1%). The top 2 etiologies of LC patients and NC-CLD patients were similar, except that a higher proportion of HBV infection (87.2% vs 66.5%, P < 0.001) and a lower proportion of ALD (12.6% vs 21.3%, P < 0.001) were found in NC-CLD patients than in LC patients (Table 1). In LC patients, AILD (10.4%) ranks the third etiology, followed by Cryptogenic (6.2%), and HCV infection (4.5%). While in NC-CLD patients, MAFLD (8.7%) ranks the third etiology, followed by AILD (4.9%), and DILD (3.2%; Table 1).
| Characteristic | Overall (n = 3375) | Noncirrhosis (n = 792) | Cirrhosis (n = 2853) | P value |
| Demographics | ||||
| Sex, male | 2489 (73.7) | 606 (76.5) | 1883 (72.9) | 0.048 |
| Age, yr (mean ± SD) | 49.65 ± 12.14 | 42.51 ± 11.65 | 51.84 ± 11.43 | < 0.001 |
| Etiology | ||||
| HBV | 2409 (71.4) | 691 (87.2) | 1718 (66.5) | < 0.001 |
| HCV | 126 (3.7) | 11 (1.4) | 115 (4.5) | < 0.001 |
| ALD | 649 (19.2) | 100 (12.6) | 549 (21.3) | < 0.001 |
| AILD | 308 (9.1) | 39 (4.9) | 269 (10.4) | < 0.001 |
| MAFLD | 104 (3.1) | 69 (8.7) | 35 (1.4) | < 0.001 |
| DILD | 58 (1.7) | 25 (3.2) | 33 (1.3) | 0.001 |
| MLD | 7 (0.2) | 2 (0.3) | 5 (0.2) | 1 |
| Schistosomiasis | 49 (1.5) | 4 (0.5) | 45 (1.7) | 0.017 |
| Cryptogenic | 169 (5.0) | 10 (1.3) | 159 (6.2) | < 0.001 |
In all AoCLD patients, except 925 (27.4%) patients without a clear precipitant, bacterial infection (771 patients, 22.8%) was the most common precipitant, followed by HBV reactivation (378 patients, 11.2%), alcoholism (327 patients, 9.7%), drug-induced liver injury (230 patients, 6.8%), excessive exertion (138 patients, 4.1%), overlapping viral infection (94 patients, 2.8%), portal vein thrombosis (66 patients, 1.96%), and operation (40 patients, 1.19%; Table 2). This trend is basically consistent for the subtypes of AoCLD, except that the main precipitant of CHAE was HBV reactivation (25.8%).
| Characteristic | Overall (n = 3375) | ACLF (n = 850) | non-ACLF | |||
| Overall (n = 2525) | CHAE (n = 577) | LC-A (n = 269) | LC-AD (n = 1679) | |||
| Demographics | ||||||
| Sex, male | 2489 (73.7) | 702 (82.6) | 1787 (70.8)a | 431 (74.7) | 174 (64.7)b | 1182 (70.4) |
| Age, yr [median (IQR)] | 49.3 (41.6, 58.5) | 47.5 (40.0, 55.1) | 51.0 (42.7, 59.8)a | 42.2 (33.0, 50.0) | 50.2 (43.8, 56.3)b | 53.0 (45.5, 61.4)c,d |
| Precipitating events | ||||||
| Bacterial infection | 771 (22.8) | 311 (36.6) | 460 (18.2)a | 31 (5.4) | 41 (15.2)b | 388 (23.1)c,d |
| HBV reactivation | 378 (11.2) | 122 (14.4) | 256 (10.1)a | 149 (25.8) | 25 (9.29)b | 82 (4.9)c,d |
| Alcohol intake | 327 (9.7) | 99 (11.6) | 228 (9.0)a | 45 (7.8) | 22 (8.18) | 161 (9.6) |
| Superimposed hepatitis viruses | 94 (2.8) | 46 (5.4) | 48 (1.9)a | 18 (3.1) | 1 (0.37) | 29 (1.7) |
| Portal vein thrombosis | 66 (2.0) | 6 (0.7) | 60 (2.4)a | 0 (0.0) | 1 (0.37) | 59 (3.5)c,d |
| Surgery | 40 (1.2) | 5 (0.6) | 35 (1.4) | 1 (0.2) | 2 (0.74) | 32 (1.9)d |
| Drug use | 230 (6.8) | 94 (11.1) | 136 (5.4)a | 55 (9.5) | 12 (4.46) | 69 (4.1)d |
| Physiological exhaustion | 138 (4.1) | 56 (6.6) | 82 (3.3)a | 28 (4.9) | 10 (3.72) | 44 (2.6)d |
| Undefined | 925 (27.4) | 164 (19.3) | 761 (30.1)a | 181 (31.4) | 86 (32.0) | 494 (29.4) |
| Complications | ||||||
| HE | ||||||
| Non-overt HE | 3080 (91.3) | 726 (85.4) | 2354 (93.2) | 570 (98.8) | 265 (98.5) | 1519 (90.5) |
| Grade I-II | 233 (6.90) | 94 (11.1) | 139 (5.50)a | 7 (1.21) | 3 (1.12)b | 129 (7.68)c,d |
| Grade III-IV | 62 (1.84) | 30 (3.53) | 32 (1.27)a | 0 (0.00) | 1 (0.37)b | 31 (1.85)c,d |
| Gastrointestinal bleeding | 520 (15.4) | 38 (4.47) | 482 (19.1)a | 0 (0.00) | 0 (0.00) | 482 (28.7)c,d |
| Ascites | 1662 (49.2) | 515 (60.6) | 1147 (45.4)a | 24 (4.16) | 6 (2.23) | 1117 (66.5)c,d |
| Biochemical indicators, [median (IQR)] | ||||||
| WBC (× 109/L) | 4.91 (3.57, 6.90) | 6.61 (4.75, 9.01) | 4.49 (3.23, 6.12)a | 4.90 (4.08, 6.09) | 4.09 (3.11, 5.48)b | 4.35 (2.95, 6.26)c,d |
| HGB (g/L) | 117 (95.0, 135) | 120 (104, 135) | 116 (92.0, 135)a | 140 (130, 153) | 122 (108, 137)b | 104 (83.0, 122)c,d |
| PLT (×109/L) | 89.0 (56.0, 137) | 91.0 (62.0, 129) | 89.0 (55.0, 140) | 143 (114, 179) | 85.0 (59.8, 132)b | 72.0 (48.0, 111)c,d |
| PT (s) | 13.9 (1.69, 18.4) | 20.6 (2.57, 26.8) | 13.2 (1.45, 16.3)a | 11.8 (1.29, 14.4) | 1.90 (1.21, 14.8) | 14.2 (1.58, 17.0)c,d |
| INR | 1.44 (1.21, 1.82) | 2.13 (1.77, 2.65) | 1.32 (1.15, 1.52)a | 1.17 (1.05, 1.34) | 1.23 (1.10, 1.46)b | 1.38 (1.22, 1.59)c,d |
| ALT (IU/mL) | 89.0 (32.0, 448) | 209 (73.7, 611) | 62.3 (27.0, 359)a | 723 (416, 1137) | 89.6 (39.8, 252)b | 38.2 (22.4, 80.4)c,d |
| AST (IU/mL) | 114 (47.1, 313) | 198 (105, 451) | 84.0 (39.2, 258)a | 432 (256, 748) | 102 (51.8, 212)b | 54.0 (31.0, 106)c,d |
| AKP (IU/L) | 127 (92.0, 172) | 148 (117, 190) | 119 (84.7, 164)a | 130 (103, 168) | 127 (92.0, 168) | 112 (77.0, 161)c,d |
| GGT (IU/L) | 78.8 (38.0, 152) | 78.0 (48.6, 127) | 79.0 (33.8, 161)a | 151 (97.3, 231) | 106 (41.0, 190)b | 54.3 (25.0, 117)c,d |
| TB (mg/dL) | 4.33 (1.68, 13.7) | 20.1 (14.1, 27.4) | 2.53 (1.33, 5.96) | 3.37 (1.71, 8.38) | 2.17 (1.34, 3.34)b | 2.44 (1.23, 5.85)c,d |
| ALB (g/L) | 31.7 (27.5, 36.0) | 30.7 (27.3, 33.8) | 32.1 (27.6, 36.8)a | 38.2 (34.1, 41.5) | 33.5 (29.0, 37.4)b | 30.2 (26.3, 34.0)c,d |
| CRE (mg/L) | 0.77 (0.64, 0.94) | 0.81 (0.65, 1.08) | 0.76 (0.64, 0.91)a | 0.76 (0.64, 0.86) | 0.75 (0.61, 0.92) | 0.77 (0.64, 0.93)d |
| BUN (mmol/L) | 4.60 (3.50, 6.60) | 4.40 (3.28, 6.60) | 4.68 (3.60, 6.60)a | 3.90 (3.12, 4.70) | 4.39 (3.70, 5.47)b | 5.30 (3.85, 7.51)c,d |
| Na (mmol/L) | 138 (135, 141) | 136 (133, 139) | 139 (136, 141)a | 139 (137, 141) | 140 (137, 142) | 138 (136, 141)c,d |
| MELD score [median (IQR)] | 11.5 (5.92, 18.2) | 21.9 (18.5, 25.9) | 8.75 (4.60, 13.0)a | 7.79 (3.81, 12.1) | 6.56 (3.55, 9.58)b | 9.50 (5.09, 13.7)c,d |
| Mortality (LT free) | ||||||
| 28-d | 278 (8.24) | 203 (23.9) | 75 (2.97)a | 1 (0.17) | 2 (0.74) | 72 (4.29)c,d |
| 90-d | 492 (14.6) | 326 (38.4) | 166 (6.57)a | 7 (1.21) | 8 (2.97) | 151 (8.99)c,d |
Compared with non-ACLF AoCLD patients, ACLF patients showed higher levels of TB (20.1 mg/dL vs 2.53 mg/dL, P < 0.001) and INR (2.13 vs 1.32, P < 0.001; Table 2). The levels of TB (20.7 mg/dL vs 19.2 mg/dL, P < 0.05) and INR (2.21 vs 2.05, P < 0.05) were significantly higher in patients with type C ACLF than in patients with type A ACLF (Table 3).
| Characteristic | Type A (n = 215) | Type B (n = 100) | Type C (n = 535) |
| Demographics | |||
| Sex, male | 175 (81.4) | 87 (87.0) | 440 (82.2) |
| Age, yr [median (IQR)] | 42.0 (34.0, 49.9) | 46.9 (39.7, 54.2)a | 49.2 (43.0, 57.0)b,c |
| Precipitating events | |||
| HBV reactivation | 33 (15.3) | 11 (11.0) | 78 (14.6) |
| Bacterial infection | 54 (25.1) | 34 (34.0) | 223 (41.7)b |
| Alcohol intake | 21 (9.77) | 8 (8.00) | 70 (13.1) |
| Superimposed hepatitis viruses | 13 (6.05) | 9 (9.00) | 24 (4.49) |
| Portal vein thrombosis | 0 (0.00) | 2 (2.00) | 4 (0.75) |
| Surgery | 2 (0.93) | 0 (0.00) | 3 (0.56) |
| Drug use | 29 (13.5) | 6 (6.00) | 59 (11.0) |
| Physiological exhaustion | 19 (8.84) | 7 (7.00) | 30 (5.61) |
| Undefined | 55 (25.6) | 34 (34.0) | 75 (14.0)b,c |
| Complications | |||
| Hepatic encephalopathy | |||
| Non-overt HE | 186 (86.5) | 96 (96.0) | 444 (83.0) |
| Grade I-II | 20 (9.30) | 3 (3.00) | 71 (13.3)b |
| Grade III-IV | 9 (4.19) | 1 (1.00) | 20 (3.74)b |
| Gastrointestinal bleeding | 0 (0.00) | 0 (0.00) | 38 (7.10)b,c |
| Ascites | 69 (32.1) | 10 (10.0)a | 436 (81.5)b,c |
| Biochemical indicators [median (IQR)] | |||
| WBC (× 109/L) | 6.84 (5.27, 8.88) | 6.23 (4.58, 8.67) | 6.66 (4.64, 9.16) |
| HGB (g/L) | 131 (118, 144) | 126 (108, 136)a | 116 (98.0, 130)b,c |
| PLT (× 109/L) | 121 (91.0, 154) | 89.0 (62.0, 130)a | 80.0 (52.5, 116)b,c |
| PT (s) | 20.2 (2.35, 26.5) | 22.5 (19.0, 27.6)a | 20.2 (2.52, 26.6)b |
| INR | 2.05 (1.72, 2.48) | 2.08 (1.76, 2.50) | 2.21 (1.81, 2.75)c |
| ALT (IU/mL) | 531 (200, 1131) | 231 (90.7, 607)a | 133 (53.2, 388)b,c |
| AST (IU/mL) | 318 (170, 743) | 230 (121, 482)a | 170 (91.0, 342)b,c |
| AKP (IU/L) | 152 (124, 198) | 155 (120, 198) | 146 (113, 186) |
| GGT (IU/L) | 88.0 (57.0, 141) | 82.0 (54.0, 132) | 72.0 (43.0, 118)c |
| TB (mg/dL) | 19.2 (13.7, 25.8) | 20.3 (14.2, 25.5) | 20.7 (14.2, 28.5)c |
| ALB (g/L) | 32.1 (29.5, 35.2) | 31.4 (28.4, 33.9)a | 29.9 (26.8, 33.1)b,c |
| CRE (mg/L) | 0.77 (0.61, 0.94) | 0.75 (0.61, 0.94) | 0.86 (0.68, 1.13)b,c |
| BUN (mmol/L) | 3.51 (2.87, 4.55) | 3.92 (2.94, 6.05)a | 5.00 (3.65, 8.11)b,c |
| Na (mmol/L) | 137 (135, 140) | 137 (133, 140) | 136 (131, 138)b,c |
| MELD score [median (IQR)] | 19.9 (17.4, 24.1) | 20.7 (17.9, 25.4) | 22.6 (19.3, 26.8)b,c |
| Mortality (LT free) | |||
| 28-d | 38 (17.7) | 18 (18.0) | 147 (27.5)b,c |
| 90-d | 58 (27.0) | 36 (36.0) | 232 (43.4)b,c |
In both non-ACLF and ACLF patients, the levels of ALT, AST, HGB, PLT, and ALB showed a decreasing trend (P < 0.001) with underlying liver disease, namely, chronic hepatitis (CHAE, type A ACLF), compensated cirrhosis (LC-A, type B ACLF), and decompensated cirrhosis (LC-AD, type C ACLF; Tables 2 and 3). In non-ACLF patients, significantly higher incidences of ascites, HE, and gastrointestinal bleeding were found in LC-AD patients than in CHAE and LC-A patients (P < 0.001; Table 3). Similarly, in patients with ACLF, significantly higher incidences of ascites, HE, and gastrointestinal bleeding were found in type C ACLF than in type A and type B ACLF patients (P < 0.001; Table 3).
In this study of 3375 patients with AoCLD, the cumulative liver transplantation (LT)-free mortality at 28 and 90 d was 8.2% (278/3375) and 14.6% (492/3375), respectively. The 28-d LT-free mortalities for each clinical subtype of AoCLD were 24.0% (203/850) for ACLF, 4.3% (72/1679) for LC-AD, 0.7% (2/269) for LC-A, and 0.2% (1/577) for CHAE (Table 3). For each subtype of ACLF, the 28-d LT-free mortalities were 27.5% (147/535) for type C, 18.0% (18/100) for type B, and 17.7% (38/215) for type A (Table 3). The 90-d LT-free mortalities for each clinical subtype of AoCLD were 38.4% (326/850) for ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE (Table 2). The 90-d LT-free mortalities of each subtype of ACLF were 43.4% (232/535) for type C, 36.0% (36/100) for type B, and 27.0% (58/215) for type A (Table 3).
The survival curves showed that the 28-d and 90-d survival rates were higher in non-ACLF patients than in ACLF patients (P < 0.001; Figure 3A and B). In non-ACLF patients, LC-A patients showed similar 28-d and 90-d survival rates to CHAE patients (P > 0.05), which were significantly higher than those of LC-AD patients (P < 0.05) (Figure 3C and D). In patients with ACLF, the 28-d and 90-d survival rates were similar in patients with type A and type B ACLF (P > 0.05) but significantly higher than those in patients with type C ACLF (P < 0.05; Figure 3E and F).
The main findings of the present study are as follows: HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD, followed by ACLF, CHAE, and LC-A. The patients with CHAE or type A ACLF presented a profile of significant elevation in serum ALT and TB, while LC-AD and type C ACLF patients were characterized by the occurrence of various complications. Patients with LC-A or type B ACLF presented less elevation in serum ALT and TB than patients with CHAE or type A ACLF and fewer complications than LC-AD and type C ACLF patients. In all subtypes of AoCLD patients, the 90-d LT-free mortality of ACLF was more than 27.0%, while in non-ACLF, the 90-d LT-free mortalities were less than 5% in LC-A and CHAE and approximately 9.0% in LC-AD. Notably, LC-AD accounts for approximately 50% of all AoCLD patients, with a 90-d LT-free mortality of nearly 10%; thus, extensive attention should be given to LC-AD patients in the clinical setting.
In terms of the causes of CLD, the results from the present study were consistent with the epidemiological data of CLD in China[14]. HBV infection is the absolute dominant cause (> 71% of cases), far higher than other causes. On the other hand, with the improvement of living standards of Chinese residents, the incidence of ALD has gradually increased[15]. In the present study, ALD was the second leading cause of CLD, especially in LC patients, in whom 21% of cases were caused by ALD. AILD is the third leading cause of CLD, accounting for approximately 10% of cases in general. Recent findings indicated that the prevalence of AILD is increasing in the Asia-Pacific region[16,17]. Therefore, more attention should be given to the prevention and treatment of ALD and AILD, in addition to the control of chronic HBV infection.
In terms of the precipitant of AoCLD, this study found that bacterial infection and HBV reactivation contributed to one-third of cases. Other precipitants, such as alcohol and drug abuse, participated in the occurrence and development of AoCLD independently or synergistically with other precipitants. These results are consistent with those reported previously[18-20]. In particular, bacterial infection accounts for over 40% of the AD-ACLF transition (transition of acute compensation to ACLF) in patients with type C ACLF. In the AD-ACLF transition, precipitants such as bacterial infection play a key role in initiating an inflammatory storm, which can directly or indirectly activate immune cells and inflammatory cytokine pathways, leading to massive or submassive necrosis of liver cells[21]. LC patients are prone to bacterial infection due to the dysfunction/decompensation of liver function, with increased intestinal permeability and bacterial translocation and compromised immunity. Bacterial infection may initiate imbalance in pro-inflammatory/anti-inflammatory systems, leading to systemic inflammatory response syndrome and multiple organ dysfunction syndrome, which further promote disease progression and significantly increase the incidence of AD-ACLF transition[22-24]. Bacterial infection has been shown to be an independent risk factor for ACLF development in AD patients within 28 d[25]. Therefore, to reduce the morbidity of AoCLD and the incidence of adverse events, attention should be given to managing the precipitants contributing to the CLD-AoCLD transition, in particular, early identification and control of bacterial infection in patients with decompensated cirrhosis.
This study revealed that individual subtypes of AoCLD display distinct clinical characteristics. CHAE and type A ACLF, which occur based on NC-CLD, show significant increases in ALT and AST (indicating active inflammation in the liver), while LC-A and type B ACLF, which occur based on compensated LC, show relatively less increase in ALT and AST levels, and LC-AD and type C ACLF, which occur based on decompensated LC, show the least increased levels of ALT and AST. From the pathophysiological view of CLD, with the gradual aggravation of basic liver disease (chronic hepatitis, compensatory cirrhosis, decompensated cirrhosis), the number of functional liver cells is decreasing, leading to gradually reduced liver reserve capacity and less transaminase production. Accordingly, less transaminase is released into the blood in the case of liver cell damage[26]. On the other hand, cirrhosis-related complications, such as ascites, variceal bleeding, HE, or nonobstructive jaundice, frequently occur in patients with LC-AD or type C ACLF, attributed to diffuse liver fibrosis with obvious portal hypertension[27]. Once a complication occurs, patients with LC-AD or type C ACLF are prone to other complications[27]. Therefore, attention should be given to the prevention and timely management of cirrhosis-related complications to improve the quality of life and life span of patients with LC.
This study also found that the levels of HGB and PLT showed a downward trend with the aggravation of basic liver disease. The reasons are as follows: In patients with LC-AD and type C ACLF, HGB levels might be reduced for various reasons, including esophageal and gastric varices rupture and bleeding, chronic malnutrition caused by portal hypertensive gastropathy, reduced EPO production, and reduction in bone marrow hematopoietic stem cells due to inflammatory stimulation[28,29]. A decrease in PLT may be caused mainly by hypersplenism and might also be associated with secondary immune dysfunction in liver failure[30], and a low level of PLT has been shown to be associated with 90-d adverse outcomes of AoCLD[31]. In contrast, with the aggravation of basic liver disease, BUN levels showed an upward trend. Patients with LC-AD or type C ACLF may experience visceral vasodilation due to portal hypertension, ascites, and hemodynamic instability, which can activate the renin-angiotensin aldosterone system, leading to renal vasoconstriction and inadequate renal perfusion and resulting in a decrease in the glomerular filtration rate and an increase in BUN and Cr[32]. Therefore, patients are prone to renal failure, electrolyte disorders, and other complications.
Whether ACLF develops from LC or NC-CLD, all three clinical types of ACLF show significant increases in bilirubin and INR. In patients with ACLF, there is a sharp decrease in the ability to metabolize bilirubin and synthesize coagulation factors due to massive necrosis of hepatocytes, which leads to elevated bilirubin, prolonged PT or increased INR[33]. Studies have shown that a rapid rise in TB or INR in the short term suggests an acute exacerbation and deterioration of the condition in CLD patients, with a high risk of developing ACLF[34,35]. Therefore, TB and INR should be strictly monitored to identify those at high risk early in patients with AoCLD.
The prognosis of patients with AoCLD varies significantly among subtypes. In non-ACLF AoCLD, with or without LC, if decompensation does not occur, the 28-d and 90-d mortality rates are very low (less than 3.0%). In contrast, all ACLF patients have relatively high short-term mortality, among which patients with type C ACLF have significantly higher 28-d and 90-d mortality than those with type A and type B ACLF. This result suggests that due to severe insufficiency of liver reserve function and the instability of portal hypertension-portal systemic circulation, ACLF occurring on the basis of decompensated LC becomes the most critical type of ACLF, with a high cumulative incidence of adverse events, which is consistent with previous reports[36]. Therefore, attention should be given to LC patients with acute decompensation or who experienced previous decompensatory events to reduce the incidence rate of type C ACLF and give priority to liver transplantation for type C ACLF patients to reduce mortality.
Our research has the following advantages. First, this was a multicenter study, with 15 research centers covering 95% of the population of China, which is representative of China's demography, ensuring the reliability of our conclusions. Second, this study used the WGO ACLF classification to compensate for the lack of type A ACLF in the EASL ACLF diagnostic criteria and type C ACLF in the APSAL ACLF diagnostic criteria. Finally, the description of the composition and clinical characteristics of each subtype of AoCLD is helpful for clinicians to classify and manage patients with the best clinical decisions.
Of course, this study also had certain limitations. First, the data of this study came from a high incidence area of HBV, so this study does not represent the characteristics of global CLD patients. Second, patients with liver diseases were diagnosed mainly based on laboratory and imaging data, without liver histologic evidence; thus, a small number of patients with NC-CLD diagnosed by imaging may have early cirrhosis, while in other patients with NC-CLDs, objective evidence of CLD may be lacking. To avoid this situation, patients with an FIB-4 < 1.45 were excluded from this study since many studies have shown that an FIB-4 < 1.45 is highly specific for excluding NC-CLD with mild or no liver fibrosis[37-39]. Finally, we excluded patients receiving liver transplantation, which may have some potential impact on the outcomes. However, in most ACLF studies, it is a common practice to use transplant-free mortality as the primary outcome to obtain the natural prognosis of patients[40].
This study systematically investigated the composition, clinical characteristics, and prognosis of each subtype of AoCLD for the first time. In China, LC-AD is the most common clinical type of AoCLD, with a high short-term mortality rate. Attention should be given to the early diagnosis and intervention of patients with LC-AD to avoid AD-ACLF transition. Type C ACLF patients have the highest mortality rate, requiring early liver transplantation to improve the overall survival rate of AoCLD.
We thank the following Chinese (Acute on) Chronic Liver Failure Consortium members and participants for their contributions to this study: Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University—Liang Qiao, Yan Zhang, Tong-Yu Wang, Dan-dan Wu, Shan Yin, Wenyi Gu; Centre of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University—Qun Zhang, Yi-Xin Hou; Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University)—Shu-Ning Sun, Xiao-Mei Xiang; Department of Infectious Disease, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University—Jun Chen, Ze-Bing Huang; Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology—Yan Xiong, Cong-Cong Zou; Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University—Bei-Ling LI, Xiu-Hua Jiang, Ting-Ting Qi; Department of Hepatology, The First Hospital of Jilin University—Na Gao, Chun-Yan Liu; Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine—Qin Lei, Sen Luo, Yuan-Yuan Chen; Department of Infectious Disease, The First Hospital of Zhejiang University—Hao-Tang Ren; Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University—Xue Mei, Jie-Fei Wang, Liu-Juan Ji; Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University—Tao Li, Jing Li; Liver Disease Centre, The First Affiliated Hospital of Xinjiang Medical University—Rong-Jiong Zheng, Xin-Yi Zhou; Department of Infectious Disease, Henan Provincial People’s Hospital—Hui-Ming Jin; Infectious Disease Center, The Affiliated Hospital of Logistics University of People’s Armed Police Force—Hai Li, Qing Zhang, Xue-Qun Zheng; and Department of Infectious Disease, Fuzhou General Hospital of Nanjing Military Command—Shao-Yang Wang, Tao-Fa Lin.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country/Territory of origin: China
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade C
P-Reviewer: Rashidi-Alavijeh J, Germany S-Editor: Li L L-Editor: A P-Editor: Cai YX
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