Editor's Note: Acute-on-chronic liver failure (ACLF) is a complex syndrome characterized by acute deterioration of liver function on a background of chronic liver disease, accompanied by liver and/or extrahepatic organ failure. The short-term mortality rate of internal medicine comprehensive treatment is as high as 50% to 90%. Early prediction of ACLF occurrence in patients, achieving the shift of treatment milestones, will effectively improve patient prognosis. Due to differences in the etiology of ACLF, underlying chronic liver disease, research population, etc., in different countries and regions, there are differences or controversies in the definition, diagnostic criteria, clinical classification, and prognosis assessment of ACLF, which bring challenges to frontline clinical diagnosis and treatment. At the 32nd Asia-Pacific Association for the Study of the Liver (APASL) annual meeting, Professor Jun Li's team from the First Affiliated Hospital of Zhejiang University School of Medicine was invited to report the latest progress of the ACLF early warning model based on a prospective, multicenter cohort study in China, showcasing the strength of Chinese standards to the world. The report content is now organized into a text for readers to enjoy.


ACLF, with its complex triggers and unclear pathogenesis, exhibits high mortality rates under internal medicine comprehensive treatment. In European and American populations, alcoholic liver cirrhosis predominates (60.3%), with severe bacterial infections being the primary cause of ACLF [1]. Conversely, in the Asia-Pacific region, hepatitis B virus (HBV) infection is the most common underlying disease. Within HBV-infected populations, HBV activation due to various reasons (spontaneous activation, viral mutation, and drug resistance, etc.) is the main trigger for ACLF occurrence (59.1%) [2-3]. Hence, conducting global multicenter, prospective studies and establishing unified ACLF diagnostic criteria and prognostic scores based on evidence-based medicine becomes an urgent requirement for the future.

ACLF Diagnosis: Which of the Four Major Criteria is Superior?

Currently, there is a lack of unified definitions and diagnostic criteria for ACLF internationally. Commonly used ACLF definitions include: the European Association for the Study of the Liver ACLF standard (EASL-ACLF), the Asia-Pacific Association for the Study of the Liver expert consensus (APASL-ACLF), the North American Consortium for the Study of End-Stage Liver Disease ACLF diagnostic criteria (NACSELD-ACLF), and the Chinese Group for the Study of Severe Hepatitis B (COSSH-ACLF) standard, among others (Figure 1).

  1. EASL-ACLF: Defined as a specific syndrome in patients with cirrhosis, emphasizing the importance of extrahepatic organ failure. Its characteristics include acute decompensation of liver function (AD), organ failure, and high short-term mortality. The occurrence of ascites, hepatic encephalopathy, gastrointestinal bleeding, and/or bacterial infection is defined as AD; some patients without a history of AD may also develop ACLF; organ failure includes liver, kidney, brain, respiratory system, circulatory system, and coagulation function, among others.
  2. NACSELD-ACLF: Defines ACLF as the presence of at least two severe extrahepatic organ failures on the basis of cirrhosis, including shock, grade III/IV hepatic encephalopathy (HE), renal replacement therapy (RRT), or mechanical ventilation, with high short-term (30-day) mortality. This criterion is only applicable to patients with infected AD and is less commonly used.
  3. APASL-ACLF: Defines ACLF as acute liver injury on the basis of chronic liver disease/cirrhosis, emphasizing liver failure, with jaundice [serum bilirubin ≥5 mg/dL (85μmol/L)] and coagulation dysfunction [international normalized ratio (INR) ≥1.5 or prothrombin activity <40%] as the main manifestations, accompanied by ascites and/or hepatic encephalopathy within 4 weeks, with a high 28-day mortality. The absence of extrahepatic organ failure does not affect diagnosis.
  4. COSSH-ACLF: Based on the results of a prospective multicenter cohort study, this Chinese standard considers HBV-ACLF as a clinical syndrome with acute deterioration of liver function and liver or extrahepatic organ failure occurring on the basis of HBV infection-induced chronic liver disease (regardless of whether cirrhosis occurs). The new standard allows for the early diagnosis of ACLF in nearly 20% more patients and addresses the inadequacies of the EASL-ACLF standard in the HBV population.

Figure 1. Comparison of Common ACLF Definitions and Diagnostic Criteria

(Taken from the presenter’s slides)

ACLF Prognostic Assessment: Which of the Five Scores is Stronger?

ACLF progresses rapidly, and accurately assessing its prognosis early can provide clinical guidance, improve outcomes. The Child-Turcotte-Pugh score (CTP score), Model for End-Stage Liver Disease (MELD) score, and MELD-Na score are commonly used liver scores, but numerous studies indicate their sensitivity and specificity in predicting ACLF prognosis are poor. Therefore, scholars both domestically and internationally, based on the aforementioned ACLF diagnostic criteria, have established and updated various ACLF prognostic scoring models, including the CLIF-C ACLF score, COSSH-ACLF score, COSSH-ACLF II score, APASL-AARC score, and NACSELD-ACLF score, among others (Figure 2).

Figure 2. Comparison of Four Prognostic Scoring Systems for ACLF

(Taken from the presenter’s slides)

ACLF Early Warning Assessment: Achieving Primary Prevention

Currently, research primarily focuses on prognostic assessment of ACLF, with relatively fewer studies on ACLF early warning assessment systems. The PREDICT study is a prospective, observational study from Europe [4], which included a total of 1071 patients with acute decompensated cirrhosis (AD), divided into three groups: Pre-ACLF (n=218), UDC (n=233), and SDC (n=620). With prolonged follow-up time, the occurrence rate of ACLF per week gradually increased in the Pre-ACLF subgroup. Bacterial infection, severe alcoholic hepatitis, hemorrhagic shock, and toxic encephalopathy were associated with the progression of AD, and proactive prevention and treatment of these events can improve patient prognosis. However, this study did not successfully establish a reliable model for predicting ACLF occurrence.

Turning to China, Professor Jun Li’s research team led a prospective, multicenter, open large cohort study involving 16 centers nationwide [5], which established the Chinese standard (COSSH-ACLF) for HBV-ACLF diagnosis and a stratified prognostic scoring system. Based on the COSSH open research cohort, 1373 patients with HBV cirrhosis who experienced acute decompensation or severe liver injury on the basis of chronic hepatitis B were prospectively enrolled. LASSO-Cox regression and orthogonal partial least squares discriminant analysis (OPLS-DA) results showed that total bilirubin (TB), international normalized ratio (INR), alanine aminotransferase (ALT), and ferritin were the best indicators for predicting ACLF occurrence within 7 days. A COSSH-onset-ACLF early warning model was constructed based on these indicators [COSSH-onset-ACLFs = 0.101 × ln(ALT) + 0.819× ln(TB) + 2.820 × ln(INR) + 0.016 × ln(ferritin)].

Figure 3. Data Results from LASSO-Cox Regression and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA)

(Taken from the presenter’s slides)

The predictive efficacy results of the analysis scoring model show that the concordance index (C-index) of COSSH-onset-ACLFs for predicting ACLF occurrence at 7/14/28 days (0.928/0.925/0.913) are significantly higher than the other five scores (CLIF-C ACLF-Ds, MELDs, MELD-Nas, COSSH-ACLFs, CLIF-C ACLFs; all p-values <0.001), and there is a noticeable improvement in the predictive error reduction rate.

Figure 4. C-index Analysis Results

 (Taken from the presenter’s slides)

Time-dependent ROC analysis shows that COSSH-onset-ACLFs have the highest AUROC at each time point (0.939/0.939/0.926); Probability Density Function (PDF) analysis shows the overlap of scores between patients who develop ACLF and those who do not under each scoring system, with COSSH-onset-ACLFs exhibiting the smallest overlap coefficient (7/14/28 days: 30.2%/30.3%/33.4%).

Figure 5. Time-Dependent ROC Analysis Results

(Taken from the presenter’s slides)

Probability Density Function (PDF) analysis shows the overlap of scores between patients who develop ACLF and those who do not under each scoring system, with COSSH-onset-ACLFs exhibiting the smallest overlap coefficient (7/14/28 days: 30.2%/30.3%/33.4%).


Figure 6. PDF Analysis Results

(Taken from the presenter’s slides)

Calibration analysis shows that COSSH-onset-ACLFs have good consistency between the predicted probability of ACLF occurrence at 7/14/28 days and the actual ACLF occurrence probability. Risk stratification analysis shows that COSSH-onset-ACLFs can differentiate all patients into high-risk (≥6.3) and low-risk (<6.3) groups for ACLF occurrence at 7/14/28 days; patients in the high/low-risk groups have significantly different risks of ACLF occurrence at 7/14/28 days. It is worth noting that the results were further validated in an external verification group of 391 non-ACLF cases.


Figure 7. Risk Stratification Analysis Results

(Taken from the presenter’s slides)


Figure 8. COSSH-onset-ACLF Early Warning Model

(Taken from the presenter’s slides)

Latest Advances in ACLF Treatment

Currently, the treatment of ACLF still lacks specific drugs and means, with internal medicine comprehensive treatment being the mainstay. Liver transplantation (LT) is the only effective treatment, but factors such as the shortage of donor organs, variable liver quality, patient immune rejection, high cost, and high mortality rates during the transplantation waiting period limit the implementation of liver transplantation [6-7]. Therefore, it is crucial to identify patients at high risk of short-term mortality under standard treatment early in their hospitalization and determine the optimal timing for transplantation.

To address this, Professor Jun Li’s team utilized data from hospitalized patients with acute exacerbation of chronic hepatitis B in the COSSH open cohort (n=4577), calculating the survival benefit rate to reflect the expected increase in lifespan for patients undergoing LT compared to those not undergoing LT, thus identifying the high-benefit population for liver transplantation. The study results [8] showed a significant improvement in the 1-year survival rate for HBV-ACLF patients receiving LT treatment. Stratified analysis showed that the majority of ACLF patients (79.1%) had COSSH-ACLF IIs in the 7-10 point range, and these patients had a much higher net survival benefit from LT compared to patients with scores <7 or >10 (Figure 9).

Figure 9. Survival Benefit of ACLF Patients

(Taken from the presenter’s slides)

Conclusion

Due to differences in etiology and triggers, scholars from the East and West have many differences and even controversies in the definition, diagnostic criteria, and pathogenesis of ACLF. Clarifying the pathogenesis of ACLF and targeting treatment according to different pathogenic mechanisms are crucial for reducing ACLF mortality. Existing data indicate that the COSSH-onset-ACLFs early warning model, based on four simple clinical indicators, can accurately predict the occurrence of ACLF at 7/14/28 days, assisting in the early and precise identification of high-risk ACLF patients, and achieving primary disease prevention. For ACLF patients, those with COSSH-ACLF II scores of 7-10 receiving LT will obtain higher net survival benefits.

The COSSH team welcomes everyone’s attention to:

  • Liver Failure Score Mini Program
  • Liver and Bile Intelligence Officer – Official Account

References:

  1. Wu T, et al. Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure[J]. Gut, 2018, 67(12): 2181-2191.
  2. Li J, et al. Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure. J Hepatol. 2021 Nov;75(5):1104-1115.
  3. Mezzano G, et al. Global burden of disease: acute-on-chronic liver failure, a systematic review and meta-analysis. Gut. 2022 Jan;71(1):148-155.
  4. Luo J, Liang X, Xin J, et al. Predicting the onset of hepatitis B virus-related acute-on-chronic liver failure[J]. Clin Gastroenterol Hepatol, 2022 March 10.1016/j.cgh.2022.03.016.
  5. Li P, Liang X, Luo J, et al. Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: An observational cohort study[J]. Lancet Reg Health-W, 2022, 100638.
  6. Shi Y, Yang Y, Hu Y, et al. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults[J]. Hepatology, 2015, 62(1): 232-242.
  7. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis[J]. Gastroenterology, 2013, 144(7): 1426-1437. e1421-1429.
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Last updated on 2024.03.20