Letter to the Editor: Characteristics of peripheral blood lymphocyte subpopulations in acute-on-chronic liver failure: A call for further exploration

Abstract

A recent study by Peng et al, published in the recent issue of World Journal of Gastroenterology, investigated the characteristics of peripheral blood lymphocyte subsets (PBLSs) and immune reconstitution patterns in patients with acute-on-chronic liver failure (ACLF) following liver transplantation. The findings revealed significant PBLS deficiencies in ACLF patients, with reduced natural killer (NK) cell counts potentially contributing to the progression of compensated cirrhosis to liver failure. While data from the current study suggest a potential correlation between the two, the constrained clinical data pool and insufficient external validation render the precise mechanism through which NK cells influence ACLF progression incompletely elucidated. Future research should be conducted across multiple centers and extend to a prolonged follow-up period. Furthermore, the current research data are exclusively derived from patients with hepatitis B virus-associated ACLF, thus lacking generalizability. Lastly, greater attention should be paid to immune cell functional changes, while incorporating factors such as postoperative infections and transplant rejection reactions. We assessed the strengths and limitations of this study and proposed future research directions to refine the research model and deepen our understanding of PBLSs characteristics in acute exacerbations of ACLF.

Key Words: Acute-on-chronic liver failure; Peripheral blood lymphocyte subpopulations; Natural killer cell; Hepatitis B virus; Gastroenterology

Core Tip: We recently read an enlightening study by Peng et al, published in the recent issue of World Journal of Gastroenterology that established a connection between peripheral blood lymphocyte subpopulations and acute-on-chronic liver failure in liver transplant recipients. This research urges us to view liver failure from a systemic rather than a single-liver perspective. The study results indicate that natural killer (NK) cell counts are significantly lower in patients with acute-on-chronic liver failure compared to those with decompensated cirrhosis. This finding provides valuable insights into the role of NK cells in liver transplant prognosis.

TO THE EDITOR

Acute-on-chronic liver failure (ACLF) is a severe form of acutely decompensated cirrhosis. The European Association for the Study of the Liver defines it as a critical condition characterized by organ failure and a high short-term mortality risk[1,2]. I read with interest the study by Peng et al[1], published in the recent issue of World Journal of Gastroenterology, which included 44 patients with ACLF, 16 patients with acute decompensated cirrhosis, 23 patients with compensated cirrhosis, and 20 healthy volunteers as the control group. Based on this, a retrospective single-center study was established. The findings demonstrated a significant reduction in peripheral blood lymphocyte subsets (PBLSs) in ACLF patients. Compared to compensated cirrhosis patients, ACLF patients exhibited further decreased natural killer (NK) cell counts. Notably, after liver transplantation, ACLF patients showed rapid recovery of NK cells and B cells. However, cluster of differentiation (CD) 3⁺ T cells and CD4⁺ T cells decreased 14 days post-transplantation and returned to pre-transplant levels by day 21.

Above all, several unresolved issues require further discussion. Notably, this study suggests that the reduction in NK cell numbers within PBLSs may accelerate the progression from compensated cirrhosis to liver failure, though the underlying mechanisms remain unverified. Studies indicate that NK cell depletion is more pronounced in patients with early allograft dysfunction (EAD) compared to those without. EAD was defined as the presence of one or more previously defined indicators of liver injury and function in postoperative laboratory analysis: Total bilirubin ≥ 10 mg/dL on day 7, an international normalized ratio ≥ 1.6 on day 7, and alanine or aspartate aminotransferase > 2000 IU/L on day 1[3]. During injury, NK cells in the peripheral blood are recruited to the liver. These NK cells are then activated in the transplanted liver through ligand-mediated recruitment, ultimately inducing hepatocyte apoptosis and resulting in post-transplant EAD[4]. This study demonstrates that NK cells in peripheral blood can induce apoptosis of transplanted hepatocytes. In conclusion, the aforementioned studies demonstrate that changes in peripheral blood NK cells not only reflect pre-transplant liver failure but also represent post-transplant changes. Furthermore, we can correlate NK cell-specific immune markers with specific clinical outcomes (e.g., 30-day mortality rate and graft-vs-host disease-free survival).

At the same time, given that we are assessing peripheral blood lymphocytes, we should focus on changes in immune cell function rather than merely emphasizing their quantitative alterations. In the future, study need to add various methods to detect the functional changes of cells, such as interferon (IFN)-γ secretion flow cytometry, granulase B expression or cytotoxicity detection, to improve the model. The study confirmed that NK cell quantity affects liver transplant function. Otherwise, single-cell multi-omics studies in the acute cellular rejection (ACR) group revealed a significant upregulation of cytotoxic receptor activation in CD56^dimCD16⁺ NK cells from days 7 to 19 post-liver transplantation. The ACR group also exhibited higher levels of inflammatory NK cells and enhanced IFN-γ secretion, indicating substantial functional changes in NK cells following liver transplantation[5]. The two studies demonstrate that NK cells influence liver transplant prognosis through both quantitative and functional changes.

However, the retrospective and single-center design of the study introduced inherent limitations, including selection bias, potential data inaccuracies, challenges in controlling for confounding variables, limited sample size, and so on. Understanding the dynamic molecular mechanisms and immune responses of ACLF is crucial for developing prognostic tools, targeted therapies, and personalized treatment approaches. For example, single-cell multimodal analysis can be employed to map the dynamic trajectory of hepatitis B virus (HBV)-ACLF immune responses and characterize the evolution of PBLSs[6]. Previous studies have demonstrated that systemic inflammation precedes organ failure in patients with HBV-associated pre-ACLF. These patients rapidly progress to ACLF with similarly high short-term mortality rates[7]. This primarily indicates that systemic inflammation, or more specifically, lymphocytes in peripheral blood, may contribute to the development of ACLF. However, the aforementioned conclusions are based on HBV-associated ACLF and cannot be extended to alcohol-related ACLF in Europe. Therefore, they have certain limitations, and future research should explore non-HBV-associated ACLF to expand the universality of these conclusions. Secondly, future research should expand both the sample size and the number of clinical centers to ensure the findings are generalizable. Additionally, extending the follow-up period is crucial. One study has established an HBV-ACLF liver transplant model. This model can assess postoperative mortality rates and identify risk factors for one-year mortality, but it has not yet incorporated peripheral blood lymphocyte subpopulations, such as NK cells, as indicators. Therefore, this study aims to extend the follow-up period to three to five years to further confirm the role of NK cells in the prognosis of HBV-related ACLF patients after liver transplantation. Finally, NK cells and other relevant indicators will be incorporated into the aforementioned model to refine its performance[8].

Finally, we need to include key factors such as preoperative and postoperative infections and transplant rejection. These factors may also affect the number and functional changes of peripheral blood lymphocyte subpopulations. First, during cohort construction, stratified analysis will be conducted based on patients’ preoperative infection status and postoperative infection outcomes to maintain the balance of confounding variables across subgroups. Second, commonly used clinical rejection biomarkers (e.g., donor-specific antibodies, donor-derived cell-free DNA, etc.) will be included as covariates to fully characterize the pathophysiological alterations associated with rejection. Finally, multivariate regression analyses (e.g., Cox proportional hazards model, logistic regression model) will be employed to systematically account for infection, rejection, and other potential confounding factors (e.g., age, underlying comorbidities, immunosuppressive regimens, etc.), thereby more precisely elucidating the association between PBLS and ACLF following liver transplantation.

Figure 1 illustrates the overall framework of ACLF transplantation-related research, covering pre- and post-transplant factors, immune indicator changes, clinical outcomes, and research optimization directions.

Figure 1 This diagram illustrates the overall framework of acute-on-chronic liver failure transplantation-related research, covering pre- and post-transplant factors, immune indicator changes, clinical outcomes, and research optimization directions. ACLF: Acute-on-chronic liver failure; PBLS: Peripheral blood lymphocyte subset; NK: Natural killer.

Most importantly, we now understand that changes in peripheral blood NK cells not only indicate pre-transplant liver failure, but also reflect post-transplant changes. Future research should focus on changes in PBLSs, especially NK cells, after liver transplantation, which will lay the foundation for post-transplant patient management and innovative diagnostic methods.

ACKNOWLEDGEMENTS

The authors thank all members of Xu Laboratory for helpful advice about the manuscript.