Zhongyuan Yang

Bio: Zhongyuan Yang is an academic researcher from Huazhong University of Science and Technology. The author has contributed to research in topics: Retrospective cohort study & Prospective cohort study. The author has an hindex of 2, co-authored 5 publications receiving 25 citations.

Complications constitute a major risk factor for mortality in hepatitis B virus-related acute-on-chronic liver failure patients: a multi-national study from the Asia-Pacific region.

Abstract: Cirrhosis is a controversial determinant of mortality in HBV-related acute-on-chronic liver failure (HBV–ACLF). The present study aimed to explore the effects of cirrhosis and the associated risk factors, especially its complications, on the outcome of HBV–ACLF. A prospective–retrospective cohort of 985 patients was identified from the APASL–ACLF Research Consortium (AARC) database and the Chinese Study Group. Complications of ACLF (ascites, infection, hepatorenal syndrome, hepatic encephalopathy, upper gastrointestinal bleeding) as well as cirrhosis and the current main prognostic models were measured for their predictive ability for 28- or 90-day mortality. A total of 709 patients with HBV–ACLF as defined by the AARC criteria were enrolled. Among these HBV–ACLF patients, the cirrhotic group showed significantly higher mortality and complications than the non-cirrhotic group. A total of 36.1% and 40.1% of patients met the European Association for the Study of Liver (EASL)–Chronic Liver Failure consortium (CLIF-C) criteria in the non-cirrhotic and cirrhotic groups, respectively; these patients had significantly higher rates of mortality and complications than those who did not satisfy the CLIF-C criteria. Furthermore, among patients who did not meet the CLIF-C criteria, the cirrhotic group exhibited higher mortality and complication rates than the non-cirrhotic group, without significant differences in organ failure. The Tongji prognostic predictor model score (TPPMs), which set the number of complications as one of the determinants, showed comparable or superior ability to the Chinese Group on the Study of Severe Hepatitis B–ACLF score (COSSH–ACLFs), APASL–ACLF Research Consortium score (AARC–ACLFs), CLIF-C organ failure score (CLIF–C OFs), CLIF-C–ACLF score (CLIF-C–ACLFs), Model for End-Stage Liver Disease score (MELDs) and MELD–sodium score (MELD–Nas) in HBV–ACLF patients, especially in cirrhotic HBV-–ACLF patients. Patients with two (OR 4.70, 1.88) or three (OR 8.27, 2.65) complications had a significantly higher risk of 28- or 90-day mortality, respectively. The presence of complications is a major risk factor for mortality in HBV–ACLF patients. TPPM possesses high predictive ability in HBV–ACLF patients, especially in cirrhotic HBV–ACLF patients.

Plasma perfusion combined with plasma exchange in chronic hepatitis B-related acute-on-chronic liver failure patients

Abstract: Artificial liver support systems (ALSS) have been shown to significantly reduce mortality in patients with acute-on-chronic liver failure (ACLF). However, the characteristics of patients who would benefit most from ALSS treatment are poorly understood. This study aimed to delineate the indicators for ALSS and evaluate the effectiveness of plasma perfusion combined with plasma exchange (PP + PE) in patients with hepatitis B virus-related ACLF (HBV-ACLF). A total of 898 patients with HBV-ACLF in a single center were enrolled retrospectively. Propensity score matching (PSM) was used in case-paired analysis. Hepatic or extra-hepatic organ failures were defined by Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) criteria. Complications included ascites, infection, hepatopulmonary syndrome, hepatorenal syndrome, hepatic encephalopathy and upper gastrointestinal bleeding. Numbers of organ failures or complications were used for risk stratification. Among all patients, 418 patients received standard medical therapy (SMT) and 480 received PP + PE plus SMT. After one-to-one paired PSM within the two groups without risk stratification, 293 pairs were enrolled. The PP + PE group displayed significantly lower mortality risk in both 28- and 90-day observation durations. When stratified, patients with two or more organ failures or complications from the PP + PE group showed greater decrease in mortality risk. Moreover, PP + PE treatment significantly increased the resolution of organ failures and complications and ameliorated the development of new organ failures and complications. PP + PE treatment significantly reversed organ failures and ameliorated the development of new organ failures and complications, thus reducing mortality risk of patients with HBV-ACLF.

Establishment and validation of a prognostic model for hepatitis B virus‑related acute-on-chronic liver failure patients with bacterial infection.

Abstract: Background Bacterial infection is one of the most frequent complications in acute-on-chronic liver failure (ACLF), which leads to high mortality. However, a specific prognostic model for ACLF patients with bacterial infection has not been well established. Aim To establish and validate a nomogram for predicting 30-day mortality of hepatitis B virus-related ACLF (HBV-ACLF) patients with bacterial infection. Methods A total of 513 ACLF patients for HBV reactivation were enrolled in the prospective cohort, and 224 patients with bacterial infection were for derivation. Independent predictors were identified using multivariate logistic model and then assembled into a nomogram to predict 30-day mortality. The performance of the nomogram was assessed based on its calibration, discrimination and clinical utility in a retrospective cohort of 192 HBV-ACLF patients with bacterial infection. Results Age, total bilirubin, lactate dehydrogenase, international normalized ratio and soluble interleukin-2 receptor were shown to be independent risk factors for 30-day mortality of HBV-ACLF patients with bacterial infection and the nomogram was constructed. The nomogram showed a good calibration and discrimination in the derivation cohort, with an area under the receiver operating characteristic curve (AUC) of 0.883. Application of the nomogram in the validation cohort also showed a good calibration and discrimination, with the AUC of 0.852. Decision curve analysis confirmed the clinical utility of the nomogram. Conclusion The nomogram was established and validated for predicting 30-day mortality of HBV-ACLF patients with bacterial infection, which may facilitate optimal therapeutic strategies to improve the prognosis of these patients.

Development and Validation of a Clinical Predictive Model for Bacterial Infection in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure

Abstract: Bacterial infection is one of the most frequent complications in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), which leads to high mortality. However, a predictive model for bacterial infection in HBV-ACLF has not been well established. This study aimed to establish and validate a predictive model for bacterial infection in two independent patient cohorts. Admission data from a prospective cohort of patients with HBV-ACLF without bacterial infection on admission was used for derivation. Bacterial infection development from day 3 to 7 of admission was captured. Independent predictors of bacterial infection development on multivariate logistic regression were used to develop the predictive model. External validation was performed on a separate retrospective cohort. A total of 377 patients were enrolled into the derivation cohort, including 88 patients (23.3%) who developed bacterial infection from day 3 to 7 of admission. On multivariate regression analysis, admission serum globulin (OR 0.862, 95% CI 0.822–0.904; P < 0.001), interleukin-6 (OR 1.023, 95% CI 1.006–1.040; P = 0.009), and C-reactive protein (OR 1.123, 95% CI 1.081–1.166; P < 0.001) levels were independent predictors for the bacterial infection development, which were adopted as parameters of the predictive model (GIC). In the derivation cohort, the area under the curve (AUC) of GIC was 0.861 (95% CI 0.821–0.902). A total of 230 patients were enrolled into the validation cohort, including 57 patients (24.8%) who developed bacterial infection from day 3 to 7 of admission, and the AUC of GIC was 0.836 (95% CI 0.782–0.881). The Hosmer–Lemeshow test showed a good calibration performance of the predictive model in the two cohorts (P = 0.199, P = 0.746). Decision curve analysis confirmed the clinical utility of the predictive model. GIC was established and validated for the prediction of bacterial infection development in HBV-ACLF, which may provide a potential auxiliary solution for the primary complication of HBV-ACLF.

Proton Pump Inhibitor Therapy Increases the Risk of Spontaneous Bacterial Peritonitis in Patients with HBV-Related Acute-on-Chronic Liver Failure.

Abstract: Spontaneous bacterial peritonitis (SBP) is a common infection in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). SBP significantly increases the mortality rate and medical costs. The association between proton pump inhibitor (PPI) use and SBP remains unclear. We conducted a retrospective study to investigate the association between PPI use and SBP in patients with HBV-related ACLF and to explore the risk factors for SBP. We compared the SBP incidence between the PPI and non-PPI groups before and after propensity score matching and explored the association between the duration and type of PPI and SBP occurrence. Risk factors for SBP occurrence were determined by univariate and multivariate logistic regression analysis. The SBP incidence was higher in the PPI group than in the non-PPI group before and after propensity score matching. The SBP incidence increased for elevated MELD scores in PPI users. There was a similar SBP incidence in both different types and durations of PPI users. MELD score, old age, male sex, and high WBC count were significant independent risk factors for SBP in PPI users with HBV-related ACLF in the hospital. PPI therapy increases the risk of SBP development in patients with HBV-related ACLF. MELD score, old age, male sex, and high WBC count could serve as predictors of SBP in PPI users. Caution should be taken regarding PPI use, especially for patients with MELD scores > 30.

Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment

Abstract: The term acute-on-chronic liver failure (ACLF) defines an abrupt and life-threatening worsening of clinical conditions in patients with cirrhosis or chronic liver disease. In recent years, different definitions and diagnostic criteria for the syndrome have been proposed by the major international scientific societies. The main controversies relate to the type of acute insult (specifically hepatic or also extrahepatic), the stage of underlying liver disease (cirrhosis or chronic hepatitis) and the concomitant extrahepatic organ failure(s) that should be considered in the definition of ACLF. Therefore, different severity criteria and prognostic scores have been proposed and validated. Current evidence shows that the pathophysiology of ACLF is closely associated with an intense systemic inflammation sustained by circulating pathogen-associated molecular patterns and damage-associated molecular patterns. The development of organ failures may be a result of a combination of tissue hypoperfusion, direct immune-mediated damage and mitochondrial dysfunction. Management of ACLF is currently based on the supportive treatment of organ failures, mainly in an intensive care setting. For selected patients, liver transplantation is an effective treatment that offers a good long-term prognosis. Future studies on potential mechanistic treatments that improve patient survival are eagerly awaited.

Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure.

Abstract: Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure(s) and high short-term mortality. ACLF frequently occurs in close temporal relationship to a precipitating event, such as acute alcoholic, drug-induced or viral hepatitis or bacterial infection and, in cases without precipitating events, probably related to intestinal translocation of bacterial products. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. This hyperinflammatory state ultimately impairs the host defensive mechanisms of immune cells, rendering ACLF patients immunocompromised and more vulnerable to secondary infections, and therefore to higher organ dysfunction and mortality. In this review, we describe the prevailing characteristics of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on cells of the innate immune system (i.e., monocytes and neutrophils), their triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]), their effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) and the consequences on tissue immunopathology. In addition, this review includes a chapter discussing new emerging therapies based on the modulation of leukocyte function by the administration of pleiotropic proteins such as albumin, Toll-like receptor 4 antagonists, interleukin-22 or stem cell therapy. Finally, the importance of finding an appropriate intervention that reduces inflammation without inducing immunosuppression is highlighted as one of the main therapeutic challenges in cirrhosis.

APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients.

Abstract: Chronic hepatitis B virus (HBV) infection is currently incurable. Long-term treatment with potent and safe nucleos(t)ide analogs (NAs) can reduce hepatocellular carcinoma (HCC) and cirrhosis-related complications through profound viral suppression. However, indefinite therapy raises several crucial issues with pros and cons. Because seroclearance of hepatitis B surface (HBsAg) as functional cure is not easily achievable, a finite therapy including sequential 48-week pegylated interferon therapy may provide an opportunity to facilitate HBsAg seroclearance by the rejuvenation of exhausted immune cells. However, the cost of stopping NA is the high incidence of virological relapse and surge of alanine aminotransferase (ALT) levels, which may increase the risk of adverse outcomes (e.g., decompensation, fibrosis progression, HCC, or liver-related mortality). So far, the APASL criteria to stop NA treatment is undetectable HBV DNA levels with normalization of ALT; however, this criterion for cessation of treatment is associated with various incidence rates of virological/clinical relapse and more than 40% of NA-stoppers eventually receive retreatment. A very intensive follow-up strategy and identification of low-risk patients for virological/clinical relapse by different biomarkers are the keys to stop the NA treatment safely. Recent studies suggested that decreasing HBsAg level at the end-of-treatment to < 100–200 IU/mL seems to be a useful marker for deciding when to discontinue NAs therapy. In addition, several viral and host factors have been reviewed for their potential roles in predicting clinical relapse. Finally, the APASL guidance has proposed rules to stop NA and the subsequent follow-up strategy to achieve a better prognosis after stopping NA. In general, for both HBeAg-positive and HBeAg-negative patients who have stopped treatment, these measurements should be done every 1–3 months at the minimum until 12 months.

Diagnostic Accuracy of Procalcitonin for Bacterial Infection in Liver Failure: A Meta-Analysis.

Abstract: The purpose of our studies was to systematically assess the accuracy and clinical value of plasma calcitonin in patients with liver failure complicated with bacterial infection. In this study, we included prospective observational studies or randomized controlled trials on PCT. The quality of the studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Heterogeneity, pooled diagnostic odds ratio (DOR), pooled sensitivity, pooled specificity, pooled positive likelihood ratio, pooled negative likelihood ratio, the area under the summary receiver operating characteristic curve (SROC), and metaregression analysis were performed using Stata16.0 software. Consequently, the studies revealed substantial heterogeneity (I2 = 96, 95% confidence interval (95% CI) = 94–99). The results of meta-analysis using random effect models suggested that the combined DOR was 10.67 (95% CI = 3.73–30.53). In addition, the threshold effect analysis showed that the threshold effect was 0.23 and the correlation coefficient was −0.48, indicating that there was no threshold effect. In the forest map, the DOR of each study and the combined DOR are not distributed along the same line, and Q = 2.2 × 1014, . Furthermore, the metaregression analysis of PCT study design, bacterial infection site, and mean age displayed that the values were >0.05. The combined sensitivity was 0.77 (95% CI = 0.54–0.90), the combined specificity was 0.76 (95% CI = 0.70–0.82), the combined positive likelihood ratio was 3.25 (95% CI = 2.33–4.52), the combined negative likelihood ratio was 0.30 (95% CI = 0.14–0.67), and the combined AUC was 0.80 (95% CI = 0.76–0.83). In conclusion, PCT has moderate diagnostic value for adult liver failure complicated with bacterial infection, and it is a better auxiliary diagnostic index for liver failure with bacterial infection. However, the results of procalcitonin must be carefully interpreted combined with medical history, physical examination, and microbiological assessment.

Acute-on-Chronic Liver Failure in Cirrhosis.

Abstract: Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated chronic liver disease. It is characterised by high 28-day mortality, the presence of one or more organ failures (OFs) and a variable but severe grade of systemic inflammation. Despite the peculiarity of each one, every definition proposed for ACLF recognizes it as a proper clinical entity. In this paper, we provide an overview of the diagnostic criteria proposed by the different scientific societies and the clinical characteristics of the syndrome. Established and experimental treatments are also described. Among the former, the most relevant are directed to support organ failures, treat precipitating factors and carry out early assessment for liver transplantation (LT). Further studies are needed to better clarify pathophysiology of the syndrome and discover new therapies.