Acute-on-chronic liver failure (ACLF) is an increasingly recognized distinct disease entity encompassing an acute deterioration of liver function in patients with chronic liver disease. Although there are no widely accepted diagnostic criteria for ACLF, the Asia.Pacific Association for the Study of the Liver (APASL) and the American Association for the Study of Liver Disease and the European Association for the Study of the Liver (AASLD/EASL) consensus definitions are commonly used. It is obvious that the APASL and the AASLD/EASL definitions are based on fundamentally different features. Two different definitions in two different parts of the world hamper the comparability of studies. Recently, the EASL-Chronic Liver Failure Consortium proposed new diagnostic criteria for ACLF based on analyses of patients with organ failure. There are areas of uncertainty in defining ACLF, such as heterogeneity of ACLF, ambiguity in qualifying underlying liver disease, argument for infection or sepsis as a precipitating event, etc. Although the exact pathogenesis of ACLF remains to be elucidated, alteration of host response to injury, infection, and unregulated inflammation play important roles. The predisposition, infection/inflammation, response, organ failure (PIRO) concept used for sepsis might be useful in describing the pathophysiology and clinical categories for ACLF. Treatment strategies are limited to organ support but better understanding of the pathophysiology is likely to lead to discovery of novel biomarkers and therapeutic strategies in the future.
Chronic Disease ; Echocardiography ; Humans ; Liver Cirrhosis/complications ; Liver Failure/diagnosis/etiology/*pathology/prevention & control ; Liver Failure, Acute/diagnosis/etiology/*pathology/prevention & control ; Liver Transplantation ; Sepsis/complications

Objective: T lymphocyte exhaustion is an important component of immune dysfunction. Therefore, exploring peripheral blood-exhausted T lymphocyte features in patients with hepatitis B virus-related acute-on-chronic liver failure may provide potential therapeutic target molecules for ACLF immune dysfunction. Methods: Six cases with HBV-ACLF and three healthy controls were selected for T-cell heterogeneity detection using the single-cell RNA sequencing method. In addition, exhausted T lymphocyte subpopulations were screened to analyze their gene expression features, and their developmental trajectories quasi-timing. An independent sample t-test was used to compare the samples between the two groups. Results: Peripheral blood T lymphocytes in HBV-ACLF patients had different differentiation trajectories with different features distinct into eight subpopulations. Among them, the CD4(+)TIGIT(+) subsets (P = 0.007) and CD8(+)LAG3(+) (P = 0.010) subsets with highly exhausted genes were significantly higher than those in healthy controls. Quasi-time analysis showed that CD4(+)TIGIT(+) and CD8(+)LAG3(+) subsets appeared in the late stage of T lymphocyte differentiation, suggesting the transition of T lymphocyte from naïve-effector-exhausted during ACLF pathogenesis. Conclusion: There is heterogeneity in peripheral blood T lymphocyte differentiation in patients with HBV-ACLF, and the number of exhausted T cells featured by CD4(+)TIGIT(+)T cell and CD8(+)LAG3(+) T cell subsets increases significantly, suggesting that T lymphocyte immune exhaustion is involved in the immune dysfunction of HBV-ACLF, thereby identifying potential effective target molecules for improving ACLF patients' immune function.
Humans ; Hepatitis B virus ; Acute-On-Chronic Liver Failure/pathology* ; Hepatitis B, Chronic ; T-Lymphocyte Subsets/pathology* ; Receptors, Immunologic

Acute-On-Chronic Liver Failure ; blood ; pathology ; Case-Control Studies ; Cytochrome Reductases ; metabolism ; Humans ; Prospective Studies ; alpha-Fetoproteins ; metabolism

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. METHODS: In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. RESULTS: We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. CONCLUSION We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.
Animals ; Humans ; Mice ; Acute-On-Chronic Liver Failure/pathology* ; ATP-Dependent Proteases/metabolism* ; Gluconeogenesis ; Hepatocytes/pathology* ; Liver/metabolism* ; Mitochondrial Proteins/metabolism* ; Protease La/metabolism*

Patients with cirrhosis who are hospitalized for an acute decompensation (AD) and also have organ failure(s) are at high risk of short-term death. These patients have a syndrome called Acute-on-Chronic Liver Failure (ACLF). ACLF is now considered as a new syndrome that it is distinct from "mere" AD not only because of the presence of organ failure(s) and high short-term mortality but also because of younger age, higher prevalence of alcoholic etiology of cirrhosis, higher prevalence of some precipitants (such as bacterial infections, active alcoholism), and more intense systemic inflammatory response. ACLF is a new syndrome also because severe sepsis or severe alcoholic hepatitis do not account for 100% of the observed cases; in fact, almost 50% of the cases are of "unknown" origin. In other words, severe sepsis, severe alcoholic hepatitis and ACLF of "unknown origin" are subcategories of the syndrome.
Acute-On-Chronic Liver Failure/complications/mortality/*pathology ; Age Factors ; Cytokines/metabolism ; Hepatitis, Alcoholic/complications ; Humans ; Liver Cirrhosis/*complications/diagnosis ; Sepsis/complications ; Severity of Illness Index ; Survival Rate

Animals ; Biotransformation ; Cell Line, Tumor ; Cell Proliferation ; Culture Media ; Diazepam ; pharmacokinetics ; Fibroblasts ; metabolism ; pathology ; Hepatitis, Chronic ; blood ; complications ; Humans ; Liver Failure, Acute ; blood ; etiology ; Liver Neoplasms ; metabolism ; pathology ; Plasma

Critical Illness ; DNA, Viral ; blood ; genetics ; Genotype ; Hepatitis B Surface Antigens ; blood ; genetics ; Hepatitis B virus ; classification ; genetics ; physiology ; Hepatitis B, Chronic ; pathology ; virology ; Humans ; Liver Failure, Acute ; pathology ; virology ; Mutation ; Promoter Regions, Genetic ; genetics ; Virus Replication

OBJECTIVETo investigate the expression and role of augmenter of liver regeneration (ALR) in hepatic failure.

METHODSALR polyclonal antibody was prepared and purified. Serum ALR in patients with hepatic failure, chronic hepatitis B and healthy persons were quantified by ELISA, ALR mRNA in hepatic tissues were quantified by real-time PCR.

RESULTSDifferent serum ALR levels foreshowed different outcomes for hepatic failure patients: The liver function was restored in 6 patients with higher ALR level [(1613.5+/-369.6) pmol/ml], and the liver function was deteriorated in 12 patients with lower ALR level [(462.3+/-235.8) pmol/ml]. ALR level in patients with chronic hepatitis B [(969.2+/-332.5) pmol/ml] was similar to that in healthy persons [(806.9+/-240.8) pmol/ml]. ALR mRNA level in hepatic failure patients receiving OLT (103.45 copies/microl) was lower than that in chronic hepatitis B patients (104.37 copies/microl) and healthy persons (104.31 copies/microl), ALR mRNA level in chronic hepatitis B and healthy persons was similar.

CONCLUSIONThese findings suggest serum ALR level reflected ALR mRNA level in liver and is helpful in estimating the survival time of patients with hepatic failure.

Animals ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Expression ; Hepatitis B, Chronic ; blood ; metabolism ; pathology ; Hepatocytes ; metabolism ; Humans ; Liver ; metabolism ; pathology ; Liver Failure, Acute ; blood ; metabolism ; pathology ; Liver Regeneration ; Mice ; Mice, Inbred BALB C ; Polymerase Chain Reaction ; methods ; Prognosis ; Proteins ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Recombinant Proteins ; genetics ; metabolism

OBJECTIVETo evaluate the clinical efficacy and safety of Yinchen Zhufu Decoction (, YCZFD) in the treatment of acute-on-chronic liver failure caused by hepatitis B virus (HBV-ACLF) with cold pattern in Chinese medicine (CM).

METHODSThis is a multi-center randomized controlled trial of integrative treatment of CM and Western medicine (WM) for the management of HBV-ACLF patients. A total of 200 HBV-ACLF patients with cold pattern were equally randomly assigned to receive YCZFD and WM (integrative treatment) or WM conventional therapy alone respectively for 4 weeks. The primary end point was the mortality for HBV-ACLF patients. Secondary outcome measures included Model for End-Stage Liver disease (MELD) score, liver biochemical function, coagulation function and complications. Adverse events during treatment were reported.

RESULTSThe mortality was decreased 14.28% in the integrative treatment group compared with WM group (χ(2) =6.156, P=0.013). The integrative treatment was found to signifificantly improve the MELD score (t=2.353, P=0.020). There were statistically signifificant differences in aspartate transaminase, total bilirubin, indirect bilirubin, direct bilirubin and prothrombin time between the two groups (P<0.05 or P<0.01). The complications of ascites (χ(2)=9.033, P=0.003) and spontaneous bacteria peritonitis (χ(2)=4.194, P=0.041) were improved signifificantly in the integrative treatment group. No serious adverse event was reported.

CONCLUSIONSThe integrative treatment of CM and WM was effective and safe for HBV-ACLF patients with cold pattern in CM. The Chinese therapeutic principle "treating cold pattern with hot herbs" remains valuable to the clinical therapy. (Trial registration No. ChiCTR-TRC-10000766).

Acute-On-Chronic Liver Failure ; complications ; drug therapy ; mortality ; virology ; Adult ; Ascites ; complications ; Demography ; Drugs, Chinese Herbal ; adverse effects ; pharmacology ; therapeutic use ; Electrolytes ; Female ; Hepatitis B ; complications ; drug therapy ; mortality ; physiopathology ; Hepatitis B virus ; physiology ; Humans ; Integrative Medicine ; Liver ; drug effects ; pathology ; physiopathology ; virology ; Liver Function Tests ; Male ; Peritonitis ; complications ; Time Factors ; Treatment Outcome

OBJECTIVETo investigate the dynamics and clinical significance of serum hepatitis B virus (HBV) DNA levels during the terminal phase of acute-on-chronic liver failure (ACLF) with different hepatitis B e antigen (HBeAg) status.

METHODSOne-hundred-and-seven patients with terminal ACLF were tested for HBeAg status by electrochemiluminescence immunoassay and serum HBV DNA levels by real-time PCR at three chronological time ranges, representing increasing severity of disease phases prior to death (day 0): 29-56 d, 15-28 d, and 0-14 d.

RESULTSIn the 37 HBeAg(+) patients, HBV DNA levels at above-mentioned phases were 6.10+/-1.63, 5.61+/-1.50, and 5.29+/-1.96 log10 copies/mL. In the 70 anti-HBe(+) patients, HBV DNA levels were 4.63+/-1.82, 5.81+/-1.78, and 4.93+/-1.73 log10 copies/mL. Phase to phase comparisons revealed that the HBV DNA level in the HBeAg(+) group was significantly higher than that in the anti-HBe(+) group at 29-56 d (P less than 0.05), and that 15-28 d and 0-14 d were not significantly different (P more than 0.05). Intragroup comparisons of phases revealed no significant differences in the HBeAg(+) group (P more than 0.05), but a significant difference between 15-28 d and 0-14 d (P less than 0.05) for the anti-HBe(+) group.

CONCLUSIONSerum levels of HBV DNA in patients with HBeAg positivity are higher than those in patients with anti-HBe positivity as the disease phase of ACLF nears fatality. Following the deterioration to liver failure, the HBV DNA load in HBeAg(+) patients remains stable while that in anti-HBe(+) patients decreases.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; DNA, Viral ; blood ; End Stage Liver Disease ; blood ; virology ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; blood ; pathology ; Humans ; Liver Failure, Acute ; blood ; virology ; Male ; Middle Aged ; Viral Load ; Young Adult