Introduction "ACLF Monthly Review" is a special academic review column on ACLF invited by the editorial department of Hepatology Digest, created by the Chinese Acute-on-Chronic Liver Failure Consortium (Ch-CLIF-C). Each month, this column focuses on a specific area related to ACLF, aiming to popularize the concept and significance of ACLF and help readers quickly understand developments in the field. This column is intended to benefit both liver disease experts and researchers who need to understand current hotspots in the field, as well as frontline clinical practitioners who require practical knowledge.This month’s review explains the types, triggers, prognosis, and related research of clinical courses of decompensated cirrhosis, particularly focusing on the progress of pre-ACLF. It aims to provide a reference for early diagnosis and prognosis of pre-ACLF and ACLF in clinical practice. Lastly, important ACLF-related literature updated on PubMed from May 21, 2024, to June 20, 2024, is briefly reviewed.
Editor-in-Chief:
Wenyi Gu: Resident physician at Renji Hospital, Shanghai Jiao Tong University School of Medicine. PhD candidate at University Hospital Münster, Germany, and MD from Frankfurt University, Germany. Master’s degree from Renji Hospital, Shanghai Jiao Tong University School of Medicine, mentored by Professor Hai Li. Currently focusing on portal hypertension and related complications of cirrhosis and ACLF.
Topic Review
Previous European PREDICT studies published two articles: “The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology” and “PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.” The former first described four distinct clinical courses of acutely decompensated cirrhosis. Besides patients diagnosed with ACLF upon admission, others include those developing ACLF after admission with high short-term mortality risk, referred to as pre-ACLF. The third clinical course is unstable decompensated cirrhosis (UDC), characterized by frequent hospitalizations due to progressive decompensating events or new acute decompensating events, with relatively lower mortality risk compared to pre-ACLF. The fourth clinical course is stable decompensated cirrhosis (SDC), where patients rarely require hospitalization and have very low one-year mortality risk. Regardless of the clinical course, acute decompensation of cirrhosis is marked by rapid deterioration in the patient’s health. The latter article reveals the triggers for the progression of cirrhosis or acute decompensation leading to ACLF. European studies found that over half of the patients had no clear triggers. Among those with identifiable triggers, bacterial infections and severe alcoholic hepatitis accounted for 97% of all acute decompensation and ACLF triggers. Although the type of trigger is unrelated to mortality, the number of triggers is. Specific prevention and treatment strategies for these events may improve patient prognosis.
The latest EU MICROB-PREDICT project focuses on the role of microbiota changes and the so-called “bacterial translocation” phenomenon in the progression of liver disease, especially ACLF. In many cases, liver disease patients experience deterioration without clear triggers, attracting significant attention from the MICROB-PREDICT study. In these cases, certain bacteria translocate from the gut to other body parts through a “gut leak” phenomenon, causing infections and exacerbating the disease.
Currently, understanding the association between the microbiota in different body sites, the progression of cirrhosis, the occurrence of ACLF, and related clinical complications is limited. The MICROB-PREDICT project aims to explore these relationships by analyzing the microbiota composition in different body sites in detail. This project not only conducts academic research but also hopes to open new avenues for treatment and prevention of liver disease by understanding these patterns.
In the study, the MICROB-PREDICT team selected 93 patients with decompensated cirrhosis with valid mucosal samples from 1,300 subjects in the PREDICT study. By collecting blood, saliva, and stool samples, as well as upper and lower gastrointestinal mucosal samples from these patients at multiple time points, they analyzed microbiota changes across different disease stages—ACLF, pre-ACLF, UDC, and SDC.
Researchers used 16S rRNA sequencing technology to reveal how the microbiota changes with disease progression in different clinical courses of cirrhosis. This in-depth study not only provides new insights into the impact of microbiota changes on liver disease but may also guide future more effective treatment strategies.
The latest microbiota research by the MICROB-PREDICT team has yielded a series of remarkable findings that are of significant scientific and clinical value in understanding ACLF progression:
- Association between disease severity and microbial load: As cirrhosis severity increases, microbial load and diversity (alpha diversity) in patients’ blood increase, indicating a positive correlation between disease severity and microbial complexity in the blood.
- Importance of sample site: The study highlights that alpha and beta diversity of the microbiota are significantly affected by the sample site, emphasizing the critical impact of different body site microbiota environments on disease progression.
- Association between specific microbial composition and disease characteristics: In smaller intestinal regions, such as the duodenum and blood, specific microbial taxa show a direct association with clinical events, further confirming the close link between microbial composition and disease characteristics.
- Relationship between temporal changes in the microbiota and ACLF: Dynamic analysis of samples at different time points reveals greater variability in the microbiota of patients developing ACLF, possibly related to bacterial translocation from the gut to other body sites, a key factor in disease deterioration.
In summary, these findings underscore the important role of the microbiota in ACLF progression and highlight the importance of considering the microbiota in predicting, diagnosing, and treating ACLF. These discoveries provide a scientific basis for future targeted treatment strategies and offer new perspectives for understanding the microbiota’s role in pre-ACLF and ACLF progression. They enhance our understanding of this complex disease mechanism and point the way for future clinical practice.
Summary and Review of ACLF Research in the Past Month
From May 21, 2024, to June 20, 2024, a total of 17 ACLF-related papers were published on PubMed, covering diagnosis, prognosis, treatment, and pathogenesis.
1.Liu, J., MacNaughtan, J., Kerbert, A. J. C., … Jalan, R. (2024). Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis. Gut, 73(7), 1183–1198. (IF=23.0)
Summary: This study aims to evaluate the therapeutic potential and potential nutritional risks of Yaq-001, a non-absorbable, gut-restricted adsorbent, in cirrhosis and ACLF. Yaq-001 effectively captures large biological molecules (such as bacterial toxins) and smaller molecular gut targets due to its excellent adsorption capacity. The study constructed cirrhosis and ACLF models (bile duct ligation with or without LPS injection) and found that two weeks of oral Yaq-001 treatment significantly improved gut permeability, reduced liver injury, inhibited fibrosis, decreased portal pressure, and improved brain and kidney function, significantly reducing mortality in ACLF models. In cirrhosis models, Yaq-001 restored microbiota balance and reduced inflammation, cell death, cellular senescence, and TLR signaling. Further, in early and progressive cirrhosis models (CCl4 induction for 6 or 12 weeks), six weeks of oral Yaq-001 treatment significantly improved liver function indicators and histopathological performance, and in vitro gut organoid experiments confirmed its significant reduction of gut permeability. A 12-week clinical trial showed that Yaq-001 had good safety and tolerability compared to placebo in cirrhosis patients.
Review: This study demonstrates that Yaq-001 shows potential in preventing cirrhosis progression in animal models, effectively reducing liver injury and fibrosis, and improving ACLF animal survival rates. The study proposes a novel treatment strategy by regulating the gut microbiota and its metabolites through non-antibiotic means to protect the liver and reduce damage to other organs. However, there are differences between animal and human microbiota, and these results need to be verified in human clinical trials. Although Yaq-001 showed bile acid adsorption ability in vitro, its effect on bile acid levels in the BDL model is unclear, requiring further research. The survival rate improvement in ACLF models by Yaq-001 needs more research support, and current clinical trials only evaluated a single dose. Future studies should explore dose ranges to determine the optimal dosing regimen.
2.Zhang, X., Hu, Y., Wang, W., … & Zhao, C. (2024). IRGM/Irgm1 increases autophagy to inhibit activation of NLRP3 inflammasome in inflammatory injury induced acute liver failure. Cell death discovery, 10(1), 272. (IF=6.1)
Summary: This study aims to verify the hypothesis that IRGM/Irgm1 regulates autophagy to inhibit the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines, thereby preventing or alleviating the progression of liver failure. The study prospectively included 10 HBV-ACLF patients and 10 healthy controls, detecting the expression of IRGM/Irgm1, NLRP3 inflammasome (NLRP3, ASC, and caspase-1), autophagy-related proteins (LC3II, P62), and inflammatory factors (IL-1β, TNF-α) in the liver. Autophagy was induced by rapamycin in an acute liver failure (ALF) mouse model, further studying the expression of Irgm1, NLRP3 inflammasome, autophagy-related proteins, and inflammatory factors. Additionally, Irgm1 was knocked down using shRNA in LPS-induced AML12 cells to study the effects of Irgm1 deficiency on autophagy and inflammation. Results: (1) Compared to controls, IRGM and autophagy-related proteins (LC3II, P62) were significantly downregulated in HBV-ACLF patients and ALF mouse models, while NLRP3 inflammasome (NLRP3, ASC, caspase-1) was significantly upregulated (P<0.05); (2) Rapamycin-induced autophagy improved the activation of the NLRP3 inflammasome in ALF mouse models, reducing inflammation and necrosis; (3) Irgm1 knockdown reduced autophagy in AML12 cells and significantly upregulated NLRP3 inflammasome activation (P<0.05).
Review: Previous studies have shown that increased NLRP3 inflammasome and related cytokines (IL-1β, IL-18) in damaged liver tissue are associated with the severity of liver injury caused by HBV-ACLF. Reducing inflammation by inactivating the NLRP3 inflammasome in liver failure patients may mitigate tissue damage and improve prognosis. This study confirms that IRGM/Irgm1, as part of the mechanism, prevents liver failure by upregulating autophagy, inhibiting NLRP3 inflammasome activation, and reducing pro-inflammatory cytokine production and release. This study provides new experimental evidence for exploring autophagy and inflammation regulation mechanisms in liver failure. IRGM/Irgm1 can be considered a potential molecular target for treating liver failure.
3.Zhu, Z. Y., Huang, X. H., Jiang, H. Q., & Liu, L. (2024). Development and validation of a new prognostic model for patients with acute-on-chronic liver failure in intensive care unit. World journal of gastroenterology, 30(20), 2657–2676. (IF=4.3)
Summary: This study retrospectively analyzed 938 ACLF patients (diagnosed based on EASL-CLIF criteria) in the MIMIC database and successfully developed and validated a new nine-variable-based ACLF prognostic model: the MIMIC ACLF model. Variables include ln(age) × 2.2 + ln(WBC count) × 0.22 – ln(mean arterial pressure) × 2.7 + respiratory failure × 0.6 + renal failure × 0.51 + brain failure × 0.31 + ln(total bilirubin) × 0.44 + ln(INR) × 0.59 + ln(potassium) × 0.59, with organ failure diagnosis based on the CLIF-OF score. The model significantly improved prediction of 28-day and 90-day mortality in ACLF patients, with AUCs of 0.81 and 0.79, outperforming existing CLIF-C ACLF, MELD, and MELD-Na scores. Further risk stratification of ACLF patients revealed significant differences in mortality between different risk groups (P<0.0001). The MIMIC ACLF model also showed superior predictive performance in internal validation, with AUCs of 0.80/0.76 for predicting 28-day and 90-day mortality, significantly higher than CLIF-C ACLF, MELD, and MELD-Na scores. External validation using the large multi-center ICU database eICU and a single-center cohort from Hebei Medical University Second Hospital confirmed the model’s predictive performance and stability. Additionally, the research team developed an online calculator based on the MIMIC ACLF score, allowing easy prediction of individual 28/90-day mortality in ACLF patients using readily available variables, greatly facilitating the model’s application in clinical practice.
Review: This study developed and validated a new prognostic model (MIMIC ACLF) for ACLF patients, overcoming the shortcomings of existing prognostic scores with good predictive performance. The development of risk stratification and an online calculator based on the MIMIC ACLF score aids in the rapid risk assessment of ACLF patients and guides patient management. However, the retrospective design of the study inherently risks bias, and external validation cohorts were based on online databases and small single-center cohorts. Future research should validate the predictive accuracy of the MIMIC ACLF model in multi-center, long-term follow-up prospective cohorts.
