Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome occurring in patients with chronic liver disease. In China, hepatitis B virus (HBV) is the main cause of cirrhosis. HBV related ACLF is characterized by multiple organs failure (liver, coagulation and kidney, etc.) and confers with high risk of short-term mortality. For the treatment of ACLF patients, recent studies have explored the therapeutic efficacy of extracorporeal liver support therapies, such as albumin dialysis, plasma exchange. However, the clinical efficacy remains to be fully elucidated. Liver transplantation is the most efficient way to improve the survival of ACLF patients, especially for those suffering from three or more organ failures.

Recently, a novel extracorporeal system which is called double plasma molecular adsorption system (DPMAS) has been applied for the treatment of ACLF patients. DPMAS is an extracorporeal therapeutic procedure that combines two hemoperfusion devices. During treatment, toxic plasma is isolated and purified via perfusion through two adsorbers, after which the purified plasma is reinfused back into the patient's circulation. This technique requires no massive plasma supply and avoids the risks of plasma-related allergic reactions and pathogen transmission. DPMAS can rapidly alleviate jaundice and lower serum bilirubin levels, thereby mitigating the hepatotoxic effects induced by excessive bilirubin and bile acids. Despite the widespread clinical application of DPMAS in patients with liver failure, high-quality evidence supporting its definite clinical efficacy remains insufficient.

Accordingly, this prospective, multicenter cluster-controlled study is designed to evaluate the clinical benefits of DPMAS via validated hard clinical endpoints, including short-term mortality and disease progression, and screen out suitable candidate patients. Furthermore, biological specimens including plasma, urine and feces will be collected to characterize the molecular profiles of ACLF patients receiving DPMAS treatment through multi-omics analyses.

Inclusion Criteria:

1. Hospitalized patients
2. Age >18 years
3. Chronic liver disease regardless of the etiology
4. Total bilirubin ≥ 12mg/dl and INR ≥ 1.5

Exclusion Criteria:

1. With ≥ 3 organ failures (SOFA criteria);
2. The pregnant;
3. With severe non-hepatic disease (such as chronic obstructive pulmonary disease level IV, chronic kidney disease with end-stage renal failure, myocardial infarction within 3 months before admission);
4. Human immunodeficiency virus (HIV) infection without treatment;
5. Patients with unstable hemodynamics caused by infection or acute bleeding;
6. Hospital stays <48 hours;
7. Diagnosis of hepatocellular carcinoma during screening period;
8. For the DPMAS clusters: patients decline to receive DPMAS treatment alone or in combination with PE;
9. For the SOC clusters: patients plan to receive DPMAS therapy;
10. Not suitable to participate in this study judging by researchers (e.g., patients with severe advanced pancreatic tumors, hematological tumors);
11. Not sign the informed consent.

Given the global heterogeneity of current regional diagnostic criteria for ACLF, the study enrolled a subgroup of patients with chronic liver disease (CLD) related ACLF defined by total bilirubin ≥ 12 mg/dL and INR level ≥ 1.5, which simultaneously fulfilled the diagnostic criteria recommended by Chinese and Asia-Pacific, while a considerable proportion also fulfilled the ACLF diagnostic criteria defined by European guidelines. This study population is characterized by markedly elevated bilirubin levels, making it well aligned with real-world clinical practice given that DPMAS intervention selectively targets bilirubin adsorption. Additionally, previous data have suggested that this specific patient population associated with a high rate of disease progression rate (approximately 40%) and high mortality (over 20%), further suggesting that the enrolled population is suitable for screening the optimal ACLF subgroup with favorable responses to DPMAS.