Proposal Of A Prediction Scoring System Based On PIRO Concept And Pathogenesis Of NK Cells In ACLF

Background: Acute-on-chronic liver failure (ACLF) is characterized by a sudden deterioration of underlying chronic liver disease, resulting in increased rates of mortality.Until recently there was no precise prognostic system of ACLF. Hepatitis B virus (HBV) is the major reason for ACLF in eastern countires. An abnormality in natural killer (NK) cells mediated cellular immunity is believed to be a contributing factor for the pathogenesis.Our aims are : 1) to validate Chronic Liver Failure- Sequential Organ Failure Assessment score SOFA score (CLIF-SOFAs) proposed by (European Association for the Study of the Liver-chronic liver failure, EASL-CLIF) for predicting clinical course severity in patients with HBV-ACLF; 2) to develop a clinical scoring system based on the PIRO concept(Predisposition, Injury, Response and Organ failure) for patients with HBV-ACLF; 3) to evaluate the characteristic of NK cells in patiens with HBV-ACLF.Methods: A retrospective study was conducted in 3,872 patients diagnosed as ACLF according to Asian Pacific Association for the Study of the Liver (APASL) criteria. CLIF-SOFAs was compared to a new simpler CLIF-organ failure score (CLIF-C OFs) and two conventional scoring systems [Model for End-stage Liver Disease score (MELDs) and MELD-Nas] in predicting clinical course severity of patients with HBV-ACLF. Furthermore,1,019 patients with HBV-ACLF defined by APASL criteria from a prospective study were analyzed according to PIRO components. Variables associated with mortality were selected into the prediction model. Based on the regression coefficients, a score for each PIRO component was developed, and a classification tree was used to stratify patients into different nodes Flow cytometric method was used to detect the absolute numbers and subgroups of NK cells, and analyze the cytotoxicity and killing ability of NK cells in patients with HBV-ACLF. The final clinical scoring system was then validated using an independent cohort(n=195).Results: In the retrospective study, we found that the patients with higher initial ACLF grades according to EASL-CLIF definition had significantly severe clinical course (P=0.009).The area under the receiver operating characteristics (AU-ROCs) for CLIF SOFAs, CLIF-C OFs, MELDs, and MELD-Nas were 0.637, 0.624, 0.650 and 0.635, respectively (All P >0.05). In the prospective study, factors significantly associated with 28-, 90-, and 180-day mortality were: P: age and ACLF type; I: drug use, infection, surgery, and variceal bleeding;R: systemic inflammatory response syndrome, spontaneous bacteria peritonitis, and pneumonia; and O: CLIF-C OFs. The AU-ROC for the combined PIRO model for 28-, 90-,and 180-day mortality were all 0.76. Based on the scores for each of the PIRO components and the cut-offs estimated from the classification tree, patients were stratified into different nodes with different estimated mortality. This new clinical scoring system was validated in an independent validation cohort, which provided similar patterns of mortality distribution in the tree nodes. The peripheral numbers of NK cells were decreased in patients with HBV-ACLF. The cytotoxic CD56dimCD16bright NK cells were significantly decreased in HBV infected patients. The CD56brightCD16- subgroup was expanded in patients with CHB and the CD56dimCD16- subgroup was expanded in patients with ACLF. The activating receptors of NKG2D, NKp30, NKp44, and NKp46 were increased in patients with ACLF.The inhibitory receptors of CD158a were increased, though the receptors of CD158b were decreased in patients of ACLF. The function of NK cells including cytotoxicity and killing activity were both downregulated in patients with HBV. Even if after interleukin (IL)-12/15 stimulation, interferon (INF)-? and tumor necrosis factor (TNF)-? produced by patients with ACLF were still less than those produced by healthy controls.Conclusions: There was no significant difference between CLIF-SOFAs, CLIF-C OFs,MELDs and MELD-Nas for predicting clinical course severity in patients with HBV-ACLF.Based on the PIRO concept, a new clinical scoring system was developed, allowing stratification into different clusters using the different scores obtained in each PIRO component. The proposed system will likely help to stratify patients at different risk, defining individual management plans, assessing criteria for specific therapies, and predicting outcomes. Patients with HBV-ACLF had lower numbers and decreased functions of cytotoxic NK cells.