Impacts of the development of acute-on-chronic liver failure and bacterial infections on ß-cell function and glucose homeostasis in patients with liver cirrhosis.

BACKGROUND: The pathogenesis involved in glucose metabolism disorders (GMDs) in patients with liver cirrhosis remains unclear. AIMS: We investigated the effects of acute-on-chronic liver failure (ACLF) development and bacterial infections (BIs) on pancreatic ß-cell function and glucose homeostasis in individuals with liver cirrhosis. METHODS: A retrospective analysis was conducted on 327 patients experiencing acute deterioration of liver cirrhosis. Oral glucose tolerance tests (OGTTs) and OGTT-based ß-cell function indices were employed to assess ß-cell function and glucose homeostasis. Univariate and multivariate logistic regression analyses were employed to identify GMD-associated risk factors. RESULTS: Both the development of ACLF and BIs significantly increased the prevalence of GMDs. Both ACLF and BIs markedly elevated the homeostasis model of assessment 2-insulin resistance (HOMA2-IR). ACLF significantly impaired glucose-stimulated insulin secretion, as evidenced by reduced insulinogenic index (IGI). Patients with GMDs exhibited significantly lower IGI levels than those without GMDs. Independent risk factors associated with GMDs were prothrombin activity (odds ratio [OR]=0.981, 95% confidence interval [CI]: 0.960-0.995), HOMA2-IR (OR=1.749, 95% CI: 1.130-2.707), and IGI (OR=0.963, 95% CI: 0.947-0.978). CONCLUSIONS: In liver cirrhosis, the onset of ACLF impairs glucose-stimulated insulin secretion from ß-cells. Both liver impairment and BIs contribute to increased insulin resistance, ultimately disturbing glucose homeostasis.

VariScreen secures the screening of high-risk varices in patients with hepatitis B virus-related cirrhosis beyond Baveno VI criteria.

We aimed to validate the performance of the ratio of the platelet count (PLT) to liver stiffness measurement (LSM) in excluding high-risk varices (HRVs) in patients with hepatitis B virus (HBV)-related compensated cirrhosis beyond Baveno VI criteria. A total of 310 patients were assessed. The performances of the PLT:LSM ratio (PLER), PLER adjusted for the international normalized ratio, etiology, age, and sex (PLEASE), and the sequential algorithm for HRV screening (VariScreen) in excluding HRVs were evaluated and compared with those of expanded Baveno VI criteria (LSM <25 kPa and PLT >110×109/L, EB6C); PLT >150×109/L and model for end-stage liver disease score = 6 (P150M6 criterion); PLT >120×109/L and albumin >36 g/L (P120A36 criterion); and albumin-bilirubin (ALBI) grade and PLT score (ALBI-PLT score). Among the enrolled patients, 43 (13.9%) had HRVs. The area under the receiver operating characteristic curve of PLER for predicting HRVs (0.771, 95% confidence interval, 0.720-0.817) was significantly higher than that for PLT and LSM (p < 0.01). PLER was an independent risk factor for HRVs. VariScreen, PLEASE, and PLER could spare 20 (6.5%), 91 (29.4%), and 60 (19.4%) endoscopies, with 0, 3 (3.3%), and 1 (1.7%) HRVs missed, respectively. The EB6C and P120A36 criteria could spare 45 (14.5%) and 36 (11.6%) endoscopies, with 1 (2.2%) and 1 (2.8%) HRVs missed, respectively. The P150M6 criterion and ALBI-PLT score missed 6.8% and 10.3% of HRVs, respectively. We found that PLER performed better than other non-invasive tests. VariScreen secured the screening of HRVs in patients with HBV-related cirrhosis beyond Baveno VI criteria.

Bacterial Infections Confer a Risk of Progression to Acute-on-Chronic Liver Failure in Patients with HBV-Related Compensated Cirrhosis During Severe Hepatitis Flares.

INTRODUCTION: The aims of this study were to investigate the risk factors for bacterial infections (BIs) and the association of BIs with the progression to acute-on-chronic liver failure (ACLF) in patients with hepatitis B virus (HBV)-related compensated liver cirrhosis and severe hepatitis flares. METHODS: A total of 237 patients were retrospectively reviewed. Baseline biochemical characteristics were compared between patients with and without the occurrence of BIs and progression to ACLF. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for ACLF before and after 1:1 propensity score matching. RESULTS: Forty-eight (20.3%) patients progressed to ACLF after admission. Additionally, 136 (57.4%) patients progressed to hepatic decompensation (HD) and 52 (21.9%) patients had BIs before the development of ACLF. Patients with BIs had significantly higher incidences of HD (84.6%) and ACLF (46.2%) than those without BIs (49.7% and 13.0%, respectively; P < 0.01). CTP score (OR 1.660, 95% CI 1.267-2.175) and MELD-Na score (OR 1.082, 95% CI 1.010-1.160) were independent risk factors for BIs. BIs (OR 4.037, 95% CI 1.808-9.061), CLIF-SOFA score (OR 2.007, 95% CI 1.497-2.691), and the MELD-Na score (OR 1.167, 95% CI 1.073-1.260) were independent risk factors for the progression to ACLF. BIs (OR 4.730, 95% CI 1.520-14.718) were also an independent risk factor for the progression to ACLF after propensity score matching. CONCLUSION: High CTP and MELD-Na scores are risk factors for BIs, and BIs are risk factors for the progression to ACLF in patients with HBV-related compensated liver cirrhosis and severe hepatitis flares.

High Albumin Level Is Associated With Regression of Glucose Metabolism Disorders Upon Resolution of Acute Liver Inflammation in Hepatitis B-Related Cirrhosis.

Background and Aim: To investigate the short-term dynamic changes and the factors associated with regression of glucose metabolism disorders in patients with hepatitis flare of chronic hepatitis B virus (HBV) infection. Methods: In this study, 118 patients with severe hepatitis flare of chronic HBV infection were prospectively studied. Oral glucose tolerance test was performed on admission and during follow-up to evaluate dynamic changes in glucose metabolism disorders. The factors associated with regression of glucose metabolism disorders were identified using univariate and multivariate logistic regression analyses. Results: The prevalence of diabetes was significantly higher in 70 (47.1%) patients with liver cirrhosis than that in 48 (16.8%) patients without liver cirrhosis. The prevalence of impaired glucose tolerance in patients with liver cirrhosis (35.7%) was significantly lower than that in patients without liver cirrhosis (47.8%). After a follow-up of 20.0 ± 18.7 days, 28 of 31 (90.3%) patients without liver cirrhosis experienced regression of glucose metabolism disorders. Additionally, 30 (54.5%) patients with liver cirrhosis experienced regression of glucose metabolism disorders after 42.0 ± 36.2 days. In patients with liver cirrhosis, those with regression of glucose metabolism disorders had significantly higher levels of homeostasis model assessment-ß-cell function, albumin (ALB), and a significantly lower level of fibrosis-4 score. ALB was identified as an independent factor associated with the regression of glucose metabolism disorders in patients with liver cirrhosis. Conclusion: Severe acute liver inflammation aggravates glucose metabolism disorders in patients with hepatitis B-related liver cirrhosis and high ALB level is associated with regression of glucose metabolism disorders upon resolution of acute liver inflammation.

Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress.

The effects of hepatocyte steatosis on hepatitis B virus (HBV) DNA replication and HBV-related antigen secretion are incompletely understood. The aims of this study are to explore the effects and mechanism of hepatocyte steatosis on HBV replication and secretion. Stearic acid (SA) and oleic acid (OA) were used to induce HepG2.2.15 cell steatosis in this study. The expressions of glucose-regulated protein 78 (GRP78), phosphorylation of protein kinase R-like endoplasmic reticulum (ER) kinase (p-PERK), and eukaryotic translation initiation factor 2α (p-eIF2α) were detected by Western blotting (WB). HBV DNA, HBsAg, and HBeAg in the supernatant were determined by real-time fluorescent polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Intracellular HBV DNA, HBsAg level, and HBV RNA were measured by real-time fluorescent PCR, WB, and real-time quantitative reverse transcriptase-PCR, respectively. The results showed that SA and OA significantly increased intracellular lipid droplets and triglyceride levels. SA and OA significantly induced GRP78, p-PERK, and p-eIF2α expressions from 24 to 72 h. 4-phenylbutyric acid (PBA) alleviated ER stress induced by SA. SA promoted intracellular HBsAg and HBV DNA accumulation; however, it inhibited the transcript of HBV 3.5 kb mRNA and S mRNA. The secretion of HBsAg and HBV DNA inhibited by SA or OA could be partially restored by pretreatment with PBA but not by inhibiting GRP78 expression with siRNA. Hepatocyte steatosis inhibits HBsAg and HBV DNA secretion via induction of ER stress in hepatocytes, but not via induction of GRP78.

Diabetes is associated with poor short-term prognosis in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND/PURPOSE: Associations between the disturbances in glucose homeostasis and prognosis in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remain unclear. This study was conducted to investigate the clinical characteristics of disturbances in glucose homeostasis and their associations with 90-day mortality in patients with HBV-related ACLF. METHODS: Ninety-six patients with HBV-related ACLF without pre-existing diabetes were prospectively included. Glucose abnormalities were diagnosed based on fasting plasma glucose and oral glucose tolerance test results on admission and during follow-up. Homeostasis model assessment was used to establish insulin resistance (HOMA2-IR), insulin sensitivity (HOMA2-IS) and HOMA2-ß-cell function (HOMA2-ß). Multivariate Cox proportional hazards analysis was used to identify independent risk factors for death within 90 days after admission. RESULTS: Among 96 patients with ACLF, 51 (53.1%) had diabetes, 29 (30.2%) had impaired glucose tolerance (IGT), and 17 (17.7%) had hypoglycemia. Patients with diabetes had significantly lower levels of HOMA2-ß than did patients with normal glucose tolerance. Of 22 patients with diabetes or IGT and without anti-hyperglycemic treatment, 8 (36.4%) exhibited regression of their glucose metabolism disorders after a follow-up of 32.8 ± 28.8 days, and higher platelet levels were associated with regression. Twenty-five patients (25.0%) with ACLF died of liver failure within 90 days. Diabetes [odds ratio (OR) 3.601, 95% confidence interval (CI) 1.342-9.661] and age (OR 1.045, 95% CI 1.010-1.082) were the independent risk factors associated with mortality. CONCLUSION: Impaired pancreatic ß-cell function is related to diabetes development, and diabetes is associated with high mortality in patients with chronic HBV-related ACLF.

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells.

Alpha-fetoprotein (AFP) and endoplasmic reticulum (ER) stress play multiple roles in hepatocellular carcinoma. Here, we analyzed the crosstalk between AFP and ER stress in human hepatoma cells. We induced ER stress in human hepatoma cell lines (HepG2 and SK-Hep1 cells) with thapsigargin (TG, an ER stress inducer), and mitigated ER stress with 4-phenylbutyrate acid (4-PBA, an ER stress inhibitor). AFP expression was knocked down by AFP short hairpin RNA and rescued by the pCI-AFP vector. AFP expression and ER stress were examined, and their roles in apoptosis, necroptosis, and proliferation were analyzed. TG significantly induced ER stress, apoptosis, necroptosis, and intracellular AFP protein levels, and reduced proliferation and AFP mRNA expression as well as supernatant AFP protein levels in HepG2 and SK-Hep1 cells. 4-PBA pretreatment partially reversed those changes in HepG2 cells. By contrast to AFP overexpression, knockdown of AFP significantly exacerbated TG-induced ER stress, apoptosis, and necroptosis, and decreased proliferation and the expression of activating transcription factor 6 alpha. In conclusion, ER stress causes the accumulation of AFP protein, which may be related to the reduction of AFP secretion. Accumulated AFP mitigates apoptosis and necroptosis and restores the proliferation of hepatoma cells by reducing ER stress.

Noninvasive assessment of liver fibrosis for predicting acute-on-chronic liver failure in patients with chronic hepatitis B.

BACKGROUND AND AIM: The aim of this study was to evaluate the accuracy of serum markers of liver fibrosis for predicting progression to acute-on-chronic liver failure (ACLF) in patients with acute exacerbation (AE) and severe AE (SAE) of chronic hepatitis B virus (HBV) infection. METHODS: The predictive accuracy of aminotransferase-to-platelet ratio index (APRI), Fibrosis-4, Lok index, and Forns index for progression to ACLF was evaluated via receiver operating characteristic (ROC) curve and area under the ROC (AUROC) in 441 and 130 patients with AE and SAE. RESULTS: After admission, 24 (5.8%) and 25 (19.2%) patients with AE and SAE, respectively, progressed to ACLF. The Lok index was one of the independent risk factors associated with progression to ACLF in patients with AE and SAE. The AUROC of Lok index for diagnosing liver cirrhosis was 0.815 (0.774-0.851) in patients with AE and 0.715 (0.629-0.791) in patients with SAE. The AUROC of Lok index for predicting progression to ACLF in patients with AE and SAE was 0.756 (0.711-0.797) and 0.866 (0.795-0.919), respectively. In patients with AE and SAE, the cut-off values of the Lok index for predicting ACLF were higher and lower, respectively, than those for diagnosing liver cirrhosis. CONCLUSION: The Lok index has predictive accuracy regarding progression to ACLF in patients with AE and SAE. Different thresholds of liver fibrosis are needed for determining progression to ACLF in patients with different severity of liver injury during acute exacerbation of chronic HBV infection.

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury.

OBJECTIVES: Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. METHODS: eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. RESULTS: Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. CONCLUSIONS: eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

Endoplasmic Reticulum Stress Increases Multidrug-resistance Protein 2 Expression and Mitigates Acute Liver Injury.

BACKGROUND: Multidrug-resistance protein (MRP) 2 is a key membrane transporter that is expressed on hepatocytes and regulated by nuclear factor kappa B (NF-κB). Interestingly, endoplasmic reticulum (ER) stress is closely associated with liver injury and the activation of NF-κB signaling. OBJECTIVE: Here, we investigated the impact of ER stress on MRP2 expression and the functional involvement of MRP2 in acute liver injury. METHODS: ER stress, MRP2 expression, and hepatocyte injury were analyzed in a carbon tetrachloride (CCl4)-induced mouse model of acute liver injury and in a thapsigargin (TG)-induced model of ER stress. RESULTS: CCl4 and TG induced significant ER stress, MRP2 protein expression and NF- κB activation in mice and LO2 cells (P < 0.05). Pretreatment with ER stress inhibitor 4- phenyl butyric acid (PBA) significantly mitigated CCl4 and TG-induced ER stress and MRP2 protein expression (P < 0.05). Moreover, pretreatment with pyrrolidine dithiocarbamic acid (PDTC; NF-κB inhibitor) significantly inhibited CCl4-induced NF-κB activation and reduced MRP2 protein expression (1±0.097 vs. 0.623±0.054; P < 0.05). Furthermore, hepatic downregulation of MRP2 expression significantly increased CCl4- induced ER stress, apoptosis, and liver injury. CONCLUSION: ER stress enhances intrahepatic MRP2 protein expression by activating NF-κB. This increase in MRP2 expression mitigates ER stress and acute liver injury.

Hepatocyte Endoplasmic Reticulum Stress Inhibits Hepatitis B Virus Secretion and Delays Intracellular Hepatitis B Virus Clearance After Entecavir Treatment.

Background: The aim of this study was to explore the effects of endoplasmic reticulum (ER) stress on hepatitis B virus (HBV) replication and the antiviral effect of entecavir (ETV). Methods: Thapsigargin (TG) and stearic acid (SA) were used to induce ER stress in HepG2.2.15 cells and HepAD38 cells that contained an integrated HBV genome, while ETV was used to inhibit HBV replication. The expression levels of glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic translation initiation factor 2 subunit alpha (p-eIF2α) were measured by western blotting. Intracellular HBV DNA was determined by qPCR; HBsAg by western blotting; HBV RNA by real-time RT-qPCR; HBsAg and HBeAg in supernatants by enzyme-linked immunosorbent assay (ELISA); and HBV DNA in supernatants by qPCR. Results: TG and SA induced ER stress in HepG2.2.15 cells and HepAD38 cells from 12 to 48 h post treatment. However, 4-phenylbutyric acid (PBA) partly alleviated the TG-induced ER stress. Moreover, TG inhibited HBsAg, HBeAg, and HBV DNA secretion from 12 to 48 h, while different concentrations of SA inhibited HBsAg and HBV DNA secretion at 48 h. TG promoted intracellular HBV DNA and HBsAg accumulation and the transcription of the HBV 3.5-kb mRNA and S mRNA. PBA treatment restored the secretion of HBsAg and HBV DNA. Finally, ER stress accelerated extracellular HBV DNA clearance but delayed intracellular HBV DNA clearance after ETV treatment. Conclusions: Hepatocyte ER stress promoted intracellular HBV DNA and HBsAg accumulation by inhibiting their secretion. Our study also suggested that hepatocyte ER stress delayed intracellular HBV DNA clearance after ETV treatment.

Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury.

INTRODUCTION AND OBJECTIVES: Necroptosis and endoplasmic reticulum (ER) stress has been implicated in acute and chronic liver injury. Activated eukaryotic initiation factor 2 alpha (eIF2α) attenuates protein synthesis and relieves the load of protein folding in the ER. In this study, we aimed to analyze the impact of eIF2α phosphorylation on hepatocyte necroptosis in acute liver injury. MATERIALS AND METHODS: Male BALB/c mice were injected with tunicamycin or d-galactosamine, and LO2 cells were incubated with tunicamycin to induce acute liver injury. 4-Phenylbutyric acid (PBA) and salubrinal were used to inhibit ER stress and eIF2α dephosphorylation, respectively. We analyzed the eIF2α phosphorylation, ER stress, and hepatocyte necroptosis in mice and cells model. RESULTS: Tunicamycin or d-galactosamine significantly induced ER stress and necroptosis, as well as eIF2α phosphorylation, in mice and LO2 cells (p<0.05). ER stress aggravated tunicamycin-induced hepatocyte necroptosis in mice and LO2 cells (p<0.05). Elevated eIF2α phosphorylation significantly mitigated hepatocyte ER stress (p<0.05) and hepatocyte necroptosis in mice (34.37±3.39% vs 22.53±2.18%; p<0.05) and LO2 cells (1±0.11 vs 0.33±0.05; p<0.05). Interestingly, tumor necrosis factor receptor (TNFR) 1 protein levels were not completely synchronized with necroptosis. TNFR1 expression was reduced in d-galactosamine-treated mice (p<0.05) and cells incubated with tunicamycin for 12 and 24h (p<0.05). ER stress partially restored TNFR1 expression and increased necroptosis in tunicamycin-incubated cells (p<0.05). CONCLUSIONS: These results imply that ER stress can mediate hepatocyte necroptosis independent of TNFR1 signaling and elevated eIF2α phosphorylation can mitigate ER stress during acute liver injury.

Risk factors for progression to acute-on-chronic liver failure during severe acute exacerbation of chronic hepatitis B virus infection.

BACKGROUND: Acute exacerbation in patients with chronic hepatitis B virus (HBV) infection results in different severities of liver injury. The risk factors related to progression to hepatic decompensation (HD) and acute-on-chronic liver failure (ACLF) in patients with severe acute exacerbation (SAE) of chronic HBV infection remain unknown. AIM: To identify risk factors related to progression to HD and ACLF in compensated patients with SAE of chronic HBV infection. METHODS: The baseline characteristics of 164 patients with SAE of chronic HBV infection were retrospectively reviewed. Independent risk factors associated with progression to HD and ACLF were identified. The predictive values of our previously established prediction model in patients with acute exacerbation (AE model) and the model for end-stage liver disease (MELD) score in predicting the development of ACLF were evaluated. RESULTS: Among 164 patients with SAE, 83 (50.6%) had compensated liver cirrhosis (LC), 43 had progression to HD without ACLF, and 29 had progression to ACLF within 28 d after admission. Independent risk factors associated with progression to HD were LC and low alanine aminotransferase. Independent risk factors for progression to ACLF were LC, high MELD score, high aspartate aminotransferase (AST) levels, and low prothrombin activity (PTA). The area under the receiver operating characteristic of the AE model [0.844, 95% confidence interval (CI): 0.779-0.896] was significantly higher than that of MELD score (0.690, 95%CI: 0.613-0.760, P < 0.05) in predicting the development of ACLF. CONCLUSION: In patients with SAE of chronic HBV infection, LC is an independent risk factor for progression to both HD and ACLF. High MELD score, high AST, and low PTA are associated with progression to ACLF. The AE model is a better predictor of ACLF development in patients with SAE than MELD score.

Inhibiting alpha subunit of eukaryotic initiation factor 2 dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation in acute liver injury.

AIM: To investigate the impact of alpha subunit of eukaryotic initiation factor 2 (eIF2α) phosphorylation on liver regeneration. METHODS: Male BALB/c mice were intraperitoneally injected with carbon tetrachloride (CCl4) to induce liver injury. Human hepatocyte LO2 cells were incubated with thapsigargin to induce endoplasmic reticulum (ER) stress. Salubrinal, integrated stress response inhibitor (ISRIB), and DnaJC3 overexpression were used to alter eIF2α phosphorylation levels. RESULTS: CCl4 administration induced significant ER stress and eIF2α phosphorylation, and increased hepatocyte proliferation proportionally to the extent of injury. Inhibiting eIF2α dephosphorylation with salubrinal pretreatment significantly mitigated liver injury and hepatocyte proliferation. In LO2 cells, thapsigargin induced significant eIF2α phosphorylation and inhibited proliferation. Inhibiting eIF2α dephosphorylation partly restored cell proliferation during ER stress. CONCLUSIONS: In acute liver injury, inhibiting eIF2α dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation.

Development and validation of a scoring system to predict progression to acute-on-chronic liver failure in patients with acute exacerbation of chronic hepatitis B.

AIM: The aim of this study was to develop and validate a scoring system to predict the progression to acute-on-chronic liver failure (ACLF) in patients with acute exacerbation (AE) of chronic hepatitis B (CHB). METHODS: The baseline characteristics of 474 patients with AE of CHB were retrospectively reviewed; 280 and 194 patients were randomly assigned to the derivation and validation cohorts, respectively. Univariate risk factors associated with ACLF development were entered into a multivariate logistic regression. The score model was established, and its predictive value was evaluated by the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUROC). RESULTS: Hepatitis B virus (HBV) DNA, international normalized ratio (INR) of prothrombin time, and patient age were identified as independent risk factors associated with progressing to ACLF. The prediction model was established as R = -13.323 + 0.553 × log HBV-DNA (copies/mL) + 3.631× INR + 0.053 × age. The AUROCs of our prediction model were higher than those of the Model for End-stage Liver Disease (MELD) and MELD-sodium (Na) for both cohorts. At the cut-off value of -2.43, our prediction model had higher sensitivity (87.5%), specificity (73.6%), positive predictive value (23.0%), positive likelihood ratio (3.30), and lower negative likelihood ratio (0.17) in the validation cohort than those of MELD and MELD-Na. CONCLUSION: The independent risk factors associated with progressing to ACLF in patients with AE of CHB are HBV-DNA, INR, and age. Our risk prediction model is useful for predicting the development of ACLF.

Prostaglandin E1 protects hepatocytes against endoplasmic reticulum stress-induced apoptosis via protein kinase A-dependent induction of glucose-regulated protein 78 expression.

AIM: To investigate the protective effect of prostaglandin E1 (PGE1) against endoplasmic reticulum (ER) stress-induced hepatocyte apoptosis, and to explore its underlying mechanisms. METHODS: Thapsigargin (TG) was used to induce ER stress in the human hepatic cell line L02 and hepatocarcinoma-derived cell line HepG2. To evaluate the effects of PGE1 on TG-induced apoptosis, PGE1 was used an hour prior to TG treatment. Activation of unfolded protein response signaling pathways were detected by western blotting and quantitative real-time RT-PCR. Apoptotic index and cell viability of L02 cells and HepG2 cells were determined with flow cytometry and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. RESULTS: Pretreatment with 1 µmol/L PGE1 protected against TG-induced apoptosis in both L02 cells and HepG2 cells. PGE1 enhanced the TG-induced expression of C/EBP homologous protein (CHOP), glucose-regulated protein (GRP) 78 and spliced X box-binding protein 1 at 6 h. However, it attenuated their expressions after 24 h. PGE1 alone induced protein and mRNA expressions of GRP78; PGE1 also induced protein expression of DNA damage-inducible gene 34 and inhibited the expressions of phospho-PKR-like ER kinase, phospho-eukaryotic initiation factor 2α and CHOP. Treatment with protein kinase A (PKA)-inhibitor H89 or KT5720 blocked PGE1-induced up-regulation of GRP78. Further, the cytoprotective effect of PGE1 on hepatocytes was not observed after blockade of GRP78 expression by H89 or small interfering RNA specifically targeted against human GRP78. CONCLUSION: Our study demonstrates that PGE1 protects against ER stress-induced hepatocyte apoptosis via PKA pathway-dependent induction of GRP78 expression.

Acute liver failure caused by hemophagocytic lymphohistiocytosis in adults: A case report and review of the literature.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition that can be caused by a primary or acquired disorder of uncontrolled immune response. Liver injury is a common complication of HLH; however, HLH presenting as acute liver failure (ALF) has rarely been reported in adults. CASE SUMMARY: A 34-year-old man was admitted to our hospital with nausea and fatigue persisting for 2 weeks and jaundice for 1 week. He had hyperthermia at the onset of disease. At admission, he had severe liver injury with unknown etiology. The laboratory data showed that he had hyperferritinemia, thrombocytopenia, anemia, hypertriglyceridemia, and hypofibrinogenemia. Finally, a bone marrow biopsy revealed hemophagocytic cells, and he was diagnosed with HLH. The patient was treated with prednisone and plasma exchange. However, the liver function of the patient deteriorated, and he finally died of multiorgan failure. CONCLUSIONS: Reports of adult patients with ALF caused by HLH have increased, and HLH should be suspected in patients with ALF of indeterminate cause. Although the efficacy of the treatment strategy recommended by the HLH 2004 remains to be confirmed in adult patients with ALF caused by HLH, early diagnosis and prompt combined treatment with steroids and cyclosporin A or etoposide should be emphasized.

Russula subnigricans Poisoning: From Gastrointestinal Symptoms to Rhabdomyolysis.

Wild mushroom poisoning is often reported to cause acute liver or renal failure. However, acute rhabdomyolysis caused by wild mushroom poisoning has rarely been reported. We describe 7 patients of 1 family with Russula subnigricans Hongo poisoning. Their clinical manifestations varied from gastrointestinal symptoms to rhabdomyolysis, with 1 fatality. Our report provides supporting evidence that rhabdomyolysis may result from ingestion of R subnigricans mushrooms. A key to survival for patients with rhabdomyolysis caused by R subnigricans poisoning may be early recognition and intensive supportive care.