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Cirrhosis, a late-stage liver disease, is a growing global health burden. When patients with cirrhosis experience acute decompensation—an abrupt worsening of liver function—it can lead to serious complications, including ACLF. While infections or acute liver injury often trigger this progression, not all cases follow this pattern. This has left critical gaps in understanding why some patients deteriorate more rapidly than others.
A recent study co-led by Qing Xie (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China) and Richard Moreau (EF CLIF, Spain) addresses this knowledge gap by exploring how immune system signals contribute to disease progression. The study enrolled 394 patients hospitalized with acutely decompensated cirrhosis, analyzing blood samples to identify immune system changes that correlated with the severity of their condition. Their findings show that certain inflammatory markers in the blood, particularly those involved in type-1, type-2 and type-3 immune responses, were strong indicators of disease progression, even when obvious precipitants like infection were absent.
Type-1 immune response was shown to be significantly reduced as patients progressed to more severe phenotypes of acutely decompensated cirrhosis, particularly ACLF. The decline in blood levels of the type-1 cytokine IFN-γ, despite the need for a robust antiviral response, suggests that patients with acutely decompensated cirrhosis may experience impaired protective immune functions. This weakened type-1 response may contribute to the vulnerability of patients to secondary infections and the overall immunosuppression characteristic of ACLF.
On the other hand, the rise in IL-25, a marker of type-2 immune activity, alongside decreases in key immune signals like IL-13, suggest that the body’s ability to maintain healthy barrier tissues, such as the intestinal lining, may be compromised, potentially contributing to the development of ACLF.
In addition, the study also highlights the role of type-3 immune responses, which typically protect against bacterial and fungal infections in barrier tissues. Elevated levels of IL-6 and IL-22, two cytokines involved in type-3 immunity, were associated with worsening outcomes, including a higher risk of death within 28 days characteristic of ACLF.
“The results reported in this study should foster research addressing whether blood levels of type-1, type-2 and type-3 cytokines reflect the immune status at barrier tissues, for example the intestinal barrier which is known to be leaky in decompensated cirrhosis. If so, one, or a combination, of these cytokines might be used as biomarkers for “leaky gut” in cirrhosis and therefore address a current critical unmet need”, said co-senior author in the paper Richard Moreau, Director of EF CLIF, Spain.
Together with the distinct patterns of type-1, type-2, and type-3 immune responses observed, researchers found significant changes in circulating white blood cell counts, pointing to imbalances in immune cell production in patients with advanced liver disease, particularly in cases that progress to ACLF. “Alterations in circulating immune cells reflect abnormal skewing of hematopoiesis toward granulopoiesis and concomitant decrease in lymphopoiesis, both of which are associated with the most severe outcomes that deserves further studies”, said co-senior author in the paper Qing Xie, Chief Director of the Department of Infectious Diseases in Ruijin Hospital, China.
“This research challenges the traditional view that progression to ACLF is driven solely by infections or acute liver injury, suggesting that systemic immune dysfunction may play a critical role—even in the absence of clear external triggers. Our study developed a robust statistical procedure thanks to the collaboration with expert statistician Yujing Yao (Columbia University NY, USA)”, said co-first author in the paper Zhujun Cao, Professor at Ruijin Hospital, China. Altogether these findings represent a significant advance in the understanding of immune regulation in chronic liver disease, highlighting a more complex picture of disease progression and opening doors to new, much-needed interventions. Future research is expected to investigate immune-specific markers that reflect the status of barrier tissues, aiming to develop treatments that could improve patient care.
“The results reported in this study should stimulate research on the immune status at barrier tissues, not only with the perspective of developing new biomarkers, but also identify targets for novel therapeutic approaches”, added Moreau. “For example, future research should consider the hypothesis that defective IL-13 production plays an important role in the decrease in mucus production by intestinal goblet cells, which is a major mechanism underpinning leaky gut in cirrhosis. If this hypothesis is verified, the use of IL-13 replacement might become a new therapeutic approach against leaky gut in cirrhosis”, he explained.
Other authors on the study are Yujing Yao, Minghao Cai, Chenxi Zhang, Yuhan Liu, Haiguang Xin, Baoyan An, Hui Wang, Yide Lu, Ziqiang Li, Yaoxing Chen, Yan Huang, Min Xin, Ruokun Li, Zhuping Qian, Yi Zhou, and Xiaogang Xiang.
Cao Z, Yao Y, Cai M, Zhang C, Liu Y, Xin H, An B, Wang H, Lu Y, Li Z, Chen Y, Huang Y, Xin M, Li R, Qian Z, Zhou Y, Xiang X, Moreau R, Xie Q. Blood markers for type-1, -2, and -3 inflammation are associated with severity of acutely decompensated cirrhosis. J Hepatol. DOI: 10.1016/j.jhep.2024.10.028. Epub ahead of print.
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