The impact of serum thyroid-stimulation hormone levels on the outcome of hepatitis B virus related acute-on-chronic liver failure: an observational study.

BACKGROUND: Thyroid dysfunction has been reported in severe liver diseases. The aim of this study was to analyze the impact of serum thyroid-stimulation hormone (TSH) levels on the prognosis of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS: This retrospective cohort study included 1,862 patients with HBV-related ACLF. Risk factors associated with 30-day and 90-day survival, hazard ratios (HRs), and 95% confidence intervals (CIs) for TSH were estimated using Cox proportional hazards regression. The Area Under the ROC curve (AUROC) analysis was carried out, and the cut-off values were calculated. After grouping by the cut-off value, survival was compared between the groups using the log-rank test. This study data is from the "Survival Cohort Study (SCS)", which has been registered at ClinicalTrials.gov (NCT03992898). RESULTS: Multivariate analysis indicated that an elevated TSH level was a highly significant predictor for 30-day survival (HR = 0.743, 95% CI: 0.629-0.878, P < 0.001) and 90-day survival (HR = 0.807, 95% CI: 0.717-0.909, P < 0.001). The AUROC of TSH level for 30-day and 90-day mortality were 0.655 and 0.620, respectively, with the same best cut-off values of 0.261 µIU/mL. Log-rank test showed that the group with higher TSH level had higher 30-day (78.5%, 95% CI: 76.1%-80.9% vs. 56.9%, 95% CI: 53.4%-60.4%; P < 0.001) and 90-day survival rate (61.5%, 95% CI: 58.6%-64.4% vs. 42.8%, 95% CI: 39.3%-46.3%; P < 0.001). Similar findings were observed in subgroups analysis. After adjusting for age and other risk factors, the higher level of TSH remained associated with 30-day survival (HR = 0.602, 95% CI: 0.502-0.721, P < 0.001) and 90-day survival (HR = 0.704, 95% CI, 0.609-0.814, P < 0.001). CONCLUSIONS: Serum TSH level significantly correlate with HBV-related ACLF patients' survival and may be of value for predicting 30-day and 90-day survival of patients with HBV-related ACLF.

Safety and efficacy of Thymosin α1 in the treatment of hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial.

BACKGROUND/PURPOSE OF THE STUDY: Mortality from hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is high. Severe infection is the most important complication that affects the outcomes of ACLF patients. Thymosin α1 (Tα1) can improve immune imbalance and this study aimed to investigate the safety and efficacy of Tα1 treatment for HBV-related ACLF. METHODS: From 2017 to 2019, 120 patients with HBV-related ACLF were enrolled in this open-label, randomized, and controlled clinical trial (ClinicalTrial ID: NCT03082885). The control group (N = 58) was treated with standard medical therapy (SMT) only. The experimental group (N = 56) was subcutaneously injected with 1.6 mg of Tα1 once a day for the first week and then twice a week from week 2 to week 12. RESULTS: The 90-day cumulated liver transplantation free survival rate of the Tα1 group was 75.0% (95% confidence interval 63.2-86.8%) versus 53.4% (95% confidence interval 39.7-67.1%) for the SMT group (p = 0.030). No significant difference was found in the survival using competitive risk analysis. The incidences of new infection and hepatic encephalopathy in the Tα1 group were much lower than those in the SMT group (32.1% vs 58.6%, p = 0.005; 8.9% vs 24.1%, p = 0.029, respectively). Mortality from severe infection in the SMT group was higher than in the Tα1 group (24.1% vs 8.9%, p = 0.029). CONCLUSION: Tα1 is safe for patients with HBV-related ACLF and significantly improves the 90-day liver transplantation-free survival rate. There may be a subgroup which may benefit from Tα1 therapy by the mechanism of preventing infection.

Derivation and Validation of a Nomogram for Predicting 90-Day Survival in Patients With HBV-Related Acute-on-Chronic Liver Failure.

Background: Conventional prognostic models do not fully reflect the severity of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to establish an effective and convenient nomogram for patients with HBV-related ACLF. Methods: A nomogram was developed based on a retrospective cohort of 1,353 patients treated at the Third Affiliated Hospital of Sun Yat-sen University from January 2010 to June 2016. The predictive accuracy and discriminatory ability of the nomogram were determined by a concordance index (C-index) and calibration curve, and were compared with current scoring systems. The results were validated using an independent retrospective cohort of 669 patients consecutively treated at the same institution from July 2016 to March 2018. This study is registered at ClinicalTrials.gov (NCT03992898). Results: Multivariable analysis of the derivation cohort found that independent predictors of 90-day survival were age, white blood cell (WBC) count, hemoglobin (Hb), aspartate aminotransferase (AST), total bilirubin (TBil), international normalized ratio, serum creatinine (Cr), alpha fetoprotein (AFP), serum sodium (Na), hepatic encephalopathy (HE), pre-existing chronic liver disease(PreLD), and HBV DNA load. All factors were included in the nomogram. The nomogram calibration curve for the probability of 90-day survival indicated that nomogram-based predictions were in good agreement with actual observations. The C-index of the nomogram was 0.790, which was statistically significantly greater than those for the current scoring systems in the derivation cohort (P < 0.001). The results were confirmed in the validation cohort. Conclusions: The proposed nomogram is more accurate in predicting the 90-day survival of patients with HBV-related ACLF than current commonly used methods.

Effect of HELLP syndrome on acute kidney injury in pregnancy and pregnancy outcomes: a systematic review and meta-analysis.

BACKGROUND: HELLP syndrome may increase adverse pregnancy outcomes, though the incidence of it is not high. At present, the impact of HELLP syndrome on P-AKI (acute kidney injury during pregnancy) and maternal and infant outcomes is controversial. Thus, we conducted a meta-analysis to find out more about the relationship between HELLP syndrome and P-AKI and pregnancy outcomes. METHODS: We systematically searched PubMed, Embassy and Cochrane Databases for cohort studies and RCT to assess the effect of HELLP syndrome on P-AKI and maternal and infant outcomes. Study-specific risk estimates were combined by using fixed-effect or random-effect models. RESULTS: This meta-analysis included 11 cohort studies with a total of 6333 Participants, including 355 cases of pregnant women with HELLP syndrome and 5979 cases that without. HELLP syndrome was associated with relatively higher risk of P-AKI (OR4.87 95% CI 3.31 ~ 7.17, P<0.001), fetal mortality (OR1.56 95% CI 1.45 ~ 2.11, P<0.001) and Maternal death (OR3.70 95% CI 1.72 ~ 7.99, P<0.001). CONCLUSIONS: HELLP syndrome is associated with relatively higher risk of P-AKI, fetal mortality and maternal death.

Dexamethasone in outcome of patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) caused by hepatitis B virus (HBV) is a severe disease with high mortality. Immune injury plays an important role during the early stage of the disease. Our research aimed to investigate the safety and efficacy of dexamethasone therapy for patients with HBV-related ACLF. METHODS: A total of 134 inpatients with HBV-induced ACLF were enrolled from January 2009 to December 2012. All the patients received the standard medicine treatment (SMT), among whom 31 cases underwent additional dexamethasone injection for three times (dexamethasone treatment [DMT] Group). A total of 35 patients (SMT Group) matched for baseline characters served as controls. Both the groups were followed up for 12 weeks. The survival rates, liver functions, and complications were recorded. RESULTS: The 12-week cumulative survival rates were 45.7% (16/35)and 48.4% (15/31) for SMT Group and DMT Group, respectively, and no significant differences were found (P = 0.959). There were no dramatic differences in liver function and model for end-stage liver disease (MELD) score at 1, 2, 4, 8, and 12 weeks between two groups. There were no significant differences in the incidence of complications (i.e. infection, gastrointestinal bleeding, encephalopathy, hepatorenal syndrome, and ascites) from 1 to 12 weeks between Group SMT and Group DMT. More than 40 ages, MELD score more than 28 and encephalopathy were independent risk factors for the mortality of patients. CONCLUSIONS: Dexamethasone cannot improve liver functions and 12-week survival rates of patients with HBV-related ACLF. Age, MELD score, and encephalopathy are independent risk factors.

[To investigate the opportunity of entecavir treatment for HBeAg-negative acute-on-chronic liver].

OBJECTIVE: To explore relations between the opportunities and effects of internal general treatment added Entecavir on acute-on-chronic liver failure (ACLF) of HBeAg-negative chronic hepatitis B in different score ranges of acute-on-chronic liver failure severity. METHODS: A total of 108 ACLF of HBeAg-negative chronic hepatitis B patients with different ACLF severity score were treated with internal general treatment added Entecavir. The liver failure severity scores, HBV-DNA loads during the initiation of therapy, recovery phase and in deathbed phase, courses of Entecavir administration and mortalities were studied. RESULTS: For 19 patients with high ACLF score (> or = 12), the difference in ACLF score between pre and post-treatment was not significant. The difference in HBV-DNA load between pre and post-treatment was not significant and the mortality was 18/19. For 30 patients with higher intermediate ACLF score (8-11), the difference in ACLF score between pre and post-treatment was not significant. The difference in HBV-DNA load between pre and post-treatment was significant, and the mortality was 66.67% (20/30). For 36 patients with lower intermediate ACLF score (5-7), the difference in ACLF score between pre and posttreatment was not significant. The difference in HBV-DNA load between pre and post-treatment was significant, and the mortality was 30.56% (11/36). For 23 patients with low ACLF score (< or = 4), the difference in ACLF score between pre and post-treatment was significant. The difference in HBV-DNA load between pre and post-treatment was significant, and the mortality was 8.70% (2/23). CONCLUSIONS: A novel acute-on-chronic liver failure scoring system can syllabify differentiate the relations between the opportunities and efficacies on the Entecavir treatment for HBeAg-negative ACLF.

Imbalance of interleukin-17-producing CD4 T cells/regulatory T cells axis occurs in remission stage of patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND AND AIM: Although regulatory T cells (Treg) and interleukin-17-producing CD4 T cells (Th17) have been demonstrated to play opposing roles in inflammation-associated diseases, their frequency and balance in different stages of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remain unknown. METHODS: Fourteen patients with HBV-associated ACLF were studied and defined into different stages according to disease activity. Circulating Th17 cells and Treg cells were analyzed by flow cytometry, and the cytokines were quantitated by enzyme-linked immunosorbent assay. Results were correlated with temporal changes in viral load, disease progression and compared with 30 chronic hepatitis B (CHB) subjects and 18 healthy subjects. RESULTS: We showed a significantly higher frequency of circulating Th17 cells in the remission stage of ACLF when compared with the progression stage, the CHB group, or normal controls. However, the frequency of circulating Treg cells was significantly lower in the remission stage of ACLF when compared with the progression stage or the CHB group. The increase in Th17 cells and concomitant decrease in Treg cells created an imbalance in the remission stage of ACLF patients, which negatively correlated with disease progression. In addition, we showed that ACLF patients in the remission stage had an altered profile of cytokines that regulated the induction of Th17 cells and Treg cells. CONCLUSIONS: ACLF patients in the remission stage had an imbalance of Th17 to Treg cells, which could be used as a prognostic marker to predict disease progression. This imbalance could play a role in the immunopathogenesis of HBV-related ACLF.

What MELD score mandates use of entecavir for ACLF-HBV HBeAg-negative patients?

AIM: To investigate optimal timing for therapeutic efficacy of entecavir for acute-on-chronic hepatitis B liver failure (ACLF-HBV) in hepatitis B e antigen (HBeAg)-negative patients. METHODS: A total of 109 inpatients with ACLF-HBV were recruited from the Department of Infectious Diseases of the Third Affiliated Hospital, Sun Yat-sen University from October 2007 to October 2010. Entecavir 0.5 mg/d was added to each patient's comprehensive therapeutic regimen. Patients were divided into three groups according to model for end-stage liver disease (MELD) score: high (≥ 30, 20 males and 4 females, mean age 47.8 ± 13.5 years); intermediate (22-30, 49 males and 5 females, 45.9 ± 12.4 years); and low (≤ 22, 28 males and 3 females, 43.4 ± 9.4 years). Statistical analysis were performed using SPSS 11.0 software. Data with normal distribution were expressed as mean ± SD and comparisons were made with Student's t tests. A value of P < 0.05 was considered statistically significant. Viral loads were related exponentially and logarithmic data were used for analysis. RESULTS: For 24 patients with MELD score ≥ 30, treatment lasted 17.2 ± 16.5 d. Scores before and after treatment were significantly different (35.97 ± 4.87 and 40.48 ± 8.17, respectively, t = -2.762, P = 0.011); HBV DNA load was reduced (4.882 ± 1.847 copies log(10)/mL to 3.685 ± 1.436 copies log(10)/mL); and mortality rate was 95.83% (23/24). Of 54 patients with scores of 22-30, treatment lasted for 54.0 ± 43.2 d; scores before and after treatment were 25.87 ± 2.33 and 25.82 ± 13.92, respectively (t = -0.030, P = 0.976); HBV DNA load decreased from 6.308 ± 1.607 to 3.473 ± 2.097 copies log(10)/mL; and mortality was 51.85% (28/54). Of 31 patients with scores ≤ 22, treatment lasted for 66.1 ± 41.9 d; scores before and after treatment were 18.88 ± 2.44 and 12.39 ± 7.80, respectively, (t = 4.860, P = 0.000); HBV DNA load decreased from 5.841 ± 1.734 to 2.657 ± 1.154 copies log(10)/mL; and mortality was 3.23% (1/31). CONCLUSION: For HBeAg-negative patients with ACLF-HBV, when entecavir was added to comprehensive therapy, a MELD score ≥ 30 predicted very poor prognosis due to fatal liver failure.

[The relationship of HBeAg status with HBV DNA loads, MELD scores in patients with acute-on-chronic hepatitis B liver failure during terminal phases].

OBJECTIVE: To investigate the relationship and clinical significances of HBeAg status with serum HBV DNA loads, model for end-stage liver disease (MELD) scores in patients with acute-on-chronic hepatitis B liver failure during terminal phase. METHODS: 120 fatal patients were enrolled. At three phases of 0 -14 d, 15-28 d and 29-90 d before death, they were detected serum HBeAg, HBV DNA loads order meanwhile MELD scores were calculated. RESULTS: In 51 patients with HBeAg positive, HBV DNA levels were (5.25 +/- 1.99), (5.45 +/- 1.47) and (6.06 +/- 1.77) log10 copies/ml while MELD scores were (30.33 +/- 5.25), (26.36 +/- 6.43) and (20.13 +/- 6.47) respectively. In 69 patients with HBeAg negative,HBV DNA loads were (5.14 +/- 1.84), (5.49 +/- 1.75 ) and (4.62 +/- 1.65) log10 copies/ml while MELD scores were 32.38 +/- 9.95, 28.17 +/- 6.82 and 26.19 +/- 5.56 in sequence. Compared with the same phase between HBeAg-positive group and HBeAg-negative group, significant differences in both HBV DNA loads and MELD scores were found only at the phase of 29-90 d (P < 0.05). In multiple comparisons among three phases, regardless of the HBeAg status,there wasn't significant difference for HBV DNA loads (P > 0.05). But increasing MELD scores are associated with the disease exacerbation and significant differences were found (P < 0.05). CONCLUSIONS: To initiate acute-on-chronic hepatitis B liver failure, serum HBV DNA loads of HBeAg-positive patients are higher than that of HBeAg-negative ones. Once ACLF has been initiated,sustained high HBV DNA loads may promote the disease worsened and be fatal regardless of the HBeAg status.

[Small interfering RNA targeting to hepatitis B virus X gene and 5-aza-2'-deoxycytidineon inhibited growth of the subcutaneous implanted tumor of hepatocellular carcinoma in nude mice].

OBJECTIVE: To investigate the anti-tumor effect of small interfering RNA targeting to HBV X gene (X-siRNA) and 5-aza-2'-deoxycytidine (5-aza-dC) on HBV-related hepatocellular carcinoma. METHODS: X-siRNA and control siRNA were synthesized. HepG2/GFP-HBx cells were treated with X-siRNA, and the levels of HBV X mRNA were detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Nude mice were inoculated with HepG2/GFP and HepG2/GFP-HBx cells subcutaneous respectively to establish implant models of hepatocellular carcinoma, and were treated with X-siRNA, 5-aza-dC alone or in combination, and tumor growth was observed. The methylation of p16 gene promoter was detected by methylation specific polymerase chain reaction (MSP). RESULTS: RT-PCR showed the expression of HBV X mRNA in HepG2/GFP-HBx cells was inhibited markedly by X-siRNA. The nude mice experiment showed that the gross tumor volume was much bigger in HepG2/GFP-HBx group than that in HepG2/GFP group (P < 0.05). The growth of palpable tumors in X-siRNA or 5-aza-dC treatment group notably decreased (P < 0.05). MSP analysis showed that p16 gene methylation was observed in HepG2/ GFP-HBx-caused palpable tumors, while no methylation was detected in HepG2/GFP group. However, after treatment with X-siRNA or 5-aza-dC, p16 gene methylation reduced. CONCLUSIONS: HBV X-siRNA and methylation inhibitor can inhibit the growth of hepatoma cells via reversing p16 methylation.

[Major constituent proteins in donkey hide and their interaction].

OBJECTIVE: To analyze the constituent proteins in donkey hide, the key ingredient for Ejiao, an important traditional Chinese medicine for the blood-related conditions, in hope to eventually decipher the biochemical mechanism behind Ejiao's prominent medicinal efficacy. METHOD: Two methods were employed to extract proteins in donkey skin. One used TriPure isolation reagent to extract the total proteins in donkey skin. Another used 1% sodium dodecyl sulfate (SDS) to heat the sample at 100 degrees C overnight. And then sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and capillary HPLC were used to analyze the component of proteins. RESULT: There are not only collagen alpha1 (I) and collagen alpha2 (I), but also serum albumin in donkey skin. The content is over 25% in total proteins with the method of TriPure isolation reagent. The content of donkey serum albumin is up to 20% with the method of 1% SDS heating. And two bands, molecular weight are nearly 200 kDa,were found on 7.5% SDS-PAGE. Extracted these proteins to analyze with capillary HPLC, they were found to be the complex products of collagen and serum albumin of donkey. CONCLUSION: Donkey serum albumin is a main protein component in the hide, which is a clue to expose is the effect of Ejiao on blood.

[Effects of glutamine granules on protein metabolism in trauma patients].

OBJECTIVE: To evaluate the effect of glutamine granules on protein metabolism in severe burns and trauma patients. METHODS: 120 patients with severe burns, multiple trauma and post operation who met the requirements of the protocol joined this double-blind randomized controlled, multi-center clinical trail. Patients were randomly divided into two groups: placebo control group (P group, 60 patients) and glutamine granules treatment group (GLN group, 60 patients). There was isonitrogenous and isocaloric intake in both groups, GLN and P group patents had been given glutamine granules or placebo (glycine) at 0.5 g.kg(-1).d(-1) for 7 days, respectively. The level of plasma glutamine, protein and urine nitrogen exclude were determined, wound healing rate of burn area and hospital stay were recorded, and then observed the complication and side effect. RESULTS: After 7 days of taking glutamine granules orally, plasma GLN concentration was significant higher than that in P group (592.50 +/- 185.23 micro mol/L vs. 407.41 +/- 190.22 micro mol/L) (P < 0.01). Plasma prealbumin and transferrin in GLN group were significant higher than those in P group (P < 0.01), but the concentration of total protein and albumin were no marked changes compare with P group (P > 0.05). The capacity of urine nitrogen exclude in GLN group were significant lower than that in P group. Additional, the wound healing rate was faster and hospital stay days was shorter than P group (P < 0.05), and the occurrence of glutamine granules side effect was seldom. CONCLUSION: Taking glutamine could promote protein synthesis, abate protein decompose, ameliorate wound healing rate and reduce hospital stay obviously.