Changes in thyroid function in patients with liver failure and their clinical significance: A clinical study of non-thyroidal illness syndrome in patients with liver failure.

BACKGROUND: Non-thyroidal illness syndrome (NTIS) develops in a large proportion of critically ill patients and is associated with high risk for death. We aimed to investigate the correlation between NTIS and liver failure, and the short-term mortality of patients with these conditions. METHODS: The clinical data of 87 patients with liver failure were collected retrospectively, 73 of them were randomly selected for an observational study and to establish prognostic models, and 14 for model validation. Another 73 sex- and age-matched patients with mild chronic hepatitis were randomly selected as a control group. Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured. The clinical characteristics of patients with liver failure and NTIS were analyzed. The follow-up of patients lasted for 3 months. Additionally, the values for predicting short-term mortality of model for end-stage liver disease (MELD), Child-Turcotte-Pugh (CTP), chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores, FT3-MELD model, and FT3 were evaluated. RESULTS: The observation group had significantly lower FT3 (2.79 ± 0.71 vs. 4.43 ± 0.75 pmol/L, P < 0.001) and TSH [0.618 (0.186-1.185) vs. 1.800 (1.570-2.590) mIU/L, P < 0.001], and higher FT4 (19.51 ± 6.26 vs. 14.47 ± 2.19 pmol/L, P <0.001) than the control group. NTIS was diagnosed in 49 of the patients with liver failure (67.12%). In the observation group, patients with NTIS had a higher mortality rate than those without (63.27% vs. 25.00%, P = 0.002). Across the whole cohort, the 3-month mortality was 50.68%. The international normalized ratios (INR) were 2.40 ± 1.41 in survivors and 3.53 ± 1.81 in deaths (P = 0.004), the creatinine (Cr) concentrations were 73.27 ± 36.94 µmol/L and 117.08 ± 87.98 µmol/L (P = 0.008), the FT3 concentrations were 3.13 ± 0.59 pmol/L and 2.47 ± 0.68 pmol/L (P < 0.001), the MELD scores were 22.19 ± 6.64 and 29.57 ± 7.99 (P < 0.001), the CTP scores were 10.67 ± 1.53 and 11.78 ± 1.25 (P = 0.001), and the CLIF-SOFA scores were 8.42 ± 1.68 and 10.16 ± 2.03 (P < 0.001), respectively. FT3 was negatively correlated with MELD score (r = -0.430, P < 0.001). An FT3-MELD model was established by subjecting FT3 concentration and MELD score to logistic regression analysis using the following formula: Logit(P) = -1.337 × FT3+0.114 × MELD+0.880. The area under the receiver operating characteristic (ROC) curve was 0.827 and the optimal cut-off value was 0.4523. The corresponding sensitivity and specificity were 67.6% and 91.7%. The areas under the ROC curve for FT3 concentration, MELD score, CTP score, and CLIF-SOFA score were 0.809, 0.779, 0.699, and 0.737, respectively. CONCLUSIONS: Patients with liver failure often develop NTIS. FT3-MELD score perform better than CTP and CLIF-SOFA scores in predicting mortality in patients with liver failure. Thus, the FT3-MELD model could be of great value for the evaluation of the short-term mortality of such patients.

Advances in psychometric tests for screening minimal hepatic encephalopathy: From paper-and-pencil to computer-aided assessment.

Minimal hepatic encephalopathy (MHE) is a major neuropsychiatric complication of liver cirrhosis and portosystemic shunting. Although MHE produces a spectrum of cognitive impairments in the domains of short-term attention, working memory, and executive function, it generally does not present with obvious clinical manifestation on conventional assessments. Paper-and-pencil psychometric tests, such as the psychometric hepatic encephalopathy score and the repeatable battery for the assessment of neuropsychological status, are recommended to diagnose MHE. However, these tests are neither rapid nor convenient to use in practice. To facilitate repeated testing in clinic and follow-up, computer-aided psychometric tests, such as the scan test, Cognitive Drug Research assessment battery, inhibitory control test, EncephalApp Stroop App, and critical flicker frequency, have been used to screen for MHE among patients with liver cirrhosis. The aim of this review was to describe the progression from the utility of paper-and-pencil to computer-aided psychometric tests for MHE screening in clinical practice.

Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis.

Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrum of manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The anti-inflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE.

Indocyanine green clearance test combined with MELD score in predicting the short-term prognosis of patients with acute liver failure.

BACKGROUND: Acute liver failure (ALF) is an acute severe deterioration of liver function with high mortality. Early and accurate prognostic assessment of patients with ALF is critically important. Although the model for end-stage liver disease (MELD) scores and King's College Hospital (KCH) criteria are well-accepted as predictive tools, their accuracy is unsatisfactory. The indocyanine green (ICG) clearance test (ICGR15, ICG retention rate at the 15 minutes) is a sensitive indicator of liver function. In this study, we investigated the efficacy of the ICGR15 for the short-term prognosis in patients with ALF. We compared the predictive value of ICGR15 with the MELD scores and KCH criteria. METHODS: Sixty-nine patients who had been diagnosed with ALF were recruited retrospectively. ICGR15 had been performed by ICG pulse spectrophotometry and relevant clinical and laboratory indices were analyzed within 24 hours of diagnosis. In addition, the MELD scores and KCH criteria were calculated. RESULTS: The three-month mortality of all patients was 47.83%. Age, serum total bilirubin and creatinine concentrations, international normalized ratio for prothrombin time, ICGR15, MELD scores and KCH criteria differed significantly between surviving and deceased patients. A positive correlation was observed between ICGR15 and MELD scores (r=0.328, P=0.006). The ICGR15-MELD model, Logit(P)=0.096XICGR15+0.174XMELD score-9.346, was constructed by logistic regression analysis. The area under the receiver operating characteristic curve was 0.855. When set the cut-off point to -0.4684, the sensitivity was 87.90% and specificity, 72.20%. The area under the receiver operating characteristic curve of the ICGR15-MELD model (0.855) was significantly higher than that of the ICGR15 (0.793), MELD scores (0.776) and KCH criteria (0.659). Based on this cut-off value, the patients were divided into two groups. The mortality was 74.36% in the first group (ICGR15-MELD≥-0.4686) and 13.33% in the second group (ICGR15-MELD<-0.4686), with a significant difference between the two groups (X(2)=25.307, P=0.000). CONCLUSION: The ICGR15-MELD model is superior to the ICGR15, MELD scores, and KCH criteria in predicting the short-term prognosis of patients with ALF.

Correlation between interleukin-6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis.

OBJECTIVE: Previous studies have shown that elevated serum levels of interleukin-6 (IL-6) correlate with the severity of overt hepatic encephalopathy (OHE) in cirrhotic patients. However, the correlation between serum IL-6 levels and plasma ammonia levels in these patients remains unclear. Therefore, the present study investigated this correlation between both variables in cirrhotic patients with OHE. METHODS: Fifty-five cirrhotic patients with various grades of OHE, 29 cirrhotic patients without OHE, and 30 healthy controls were recruited. Concentrations of plasma ammonia and serum IL-6 were simultaneously measured. RESULTS: In cirrhotic patients with OHE, the severity of OHE, represented by the West Haven criteria, correlated with serum IL-6 levels (r=0.43, P<0.05) and plasma ammonia levels (r=0.59, P<0.05). IL-6 and ammonia were found to be significant independent predictors of OHE severity (P<0.05 for both variables). Furthermore, the severity of liver cirrhosis, determined by Child-Pugh scores, correlated with serum IL-6 levels (r=0.45, P<0.05) and plasma ammonia levels (r=0.68, P<0.05) in these patients. Moreover, there was a significant positive correlation between serum IL-6 levels and plasma ammonia levels (r=0.58, P<0.05) in cirrhotic patients with OHE, but not in patients without OHE (r=0.42, P>0.05) or healthy controls (r=0.27, P>0.05). The correlation between IL-6 and ammonia was independent of infectious precipitating factors. CONCLUSIONS: The results of the present study suggest that IL-6 might be involved in the mechanism by which ammonia contributes to the pathogenesis of OHE. There is also evidence of a potential synergistic interaction between proinflammatory cytokines and ammonia in the pathogenesis of OHE.

[Induction of anti-hepatocellular carcinoma immunity by Hyper-IL-6 gene in vivo].

AIM: To prepare the mouse hepatocellular carcinoma (HCC) cells with the stable expression of Hyper-IL-6 and explore the possibility of inducing active anti-HCC immune response by Hyper-IL-6 gene. METHODS: Hyper-IL-6 gene was transfected into mouse HCC cells MM45T.Li using Lipofectamine(TM);2000. G418-resistant clones named MM45T-HIL-6 were selected and detected for the expression of Hyper-IL-6 gene by RT-PCR and ELISA. Mouse HCC cells transfected with pEGFP-C1, named MM45T-mock, were prepared as controls. Tumor models were established by injecting subcutaneously 5×10(5); cells of MM45T.Li, MM45T- mock and MM45T-HIL-6 on the right anterior limb of BALB/c mouse, respectively. In vivo experiments were performed to observe the tumorigenicity of MM45T.Li, MM45T-mock and MM45T-HIL-6. The levels of CD4(+); and CD8(+); T cells in mouse peripheral blood were detected by flow cytometry (FCM). RESULTS: RT-PCR and ELISA showed that Hyper-IL-6 gene was expressed in the MM45T-HIL-6 cells, but not in the control cells. We observed that the tumorigenicity of MM45T-HIL-6 decreased compared with control cells after they were inoculated subcutaneously into mice. FCM results indicated that the levels of CD4(+); and CD8(+); T cells in the peripheral blood significantly increased in the mice inoculated with MM45T-HIL-6 compared with the ones inoculated with MM45T.Li and MM45T-mock cells (P<0.05). CONCLUSION: The mouse HCC cells with the stable expression of Hyper-IL-6 can induce active anti-HCC immune response after inoculated subcutaneously into mice.

Relationship between interleukin-6 and ammonia in patients with minimal hepatic encephalopathy due to liver cirrhosis.

AIM: Previous studies have shown significantly elevated levels of interleukin (IL)-6 in cirrhotic patients with minimal hepatic encephalopathy (MHE), but the relationship between circulating levels of IL-6 and ammonia is unclear. The aim of this study is to investigate the relationship between both variables in cirrhotic patients with MHE. METHODS: Psychometric tests including number connection test part A (NCT-A) and digit symbol test (DST) were performed to diagnose MHE in 85 cirrhotic patients. Simultaneously, circulating levels of IL-6 and ammonia were measured. RESULTS: Thirty-two (37.6%) cirrhotic patients were diagnosed with MHE. IL-6 and ammonia were the independent predictors of the presence of MHE (P < 0.05 for both variables). Circulating levels of IL-6 and ammonia correlated with the severity of MHE represented by results of NCT-A (r = 0.56, P < 0.05 and r = 0.39, P < 0.05, respectively) and DST (r = -0.48, P < 0.05 and r = -0.47, P < 0.05, respectively). Moreover, there was a significant correlation between circulating levels of IL-6 and those of ammonia in patients with MHE (r = 0.61, P < 0.05), and a positive additive interaction was found between IL-6 and ammonia on the presence of MHE, with a significant synergy index of 1.51 (95% confidence interval = 1.12-3.46). CONCLUSION: The present study demonstrates a significant correlation and a positive additive interaction between IL-6 and ammonia in cirrhotic patients with MHE, suggesting that IL-6 may have a potential synergistic relationship with ammonia in the induction of MHE.

Clinical efficacy and safety of lactulose for minimal hepatic encephalopathy: a meta-analysis.

OBJECTIVE: To evaluate the clinical efficacy of lactulose in patients with minimal hepatic encephalopathy (MHE). METHODS: Randomized controlled trials (RCTs) comparing lactulose with placebo or with no intervention in the management of MHE that were conducted from January 1990 to July 2011 were searched from MEDLINE, EMBASE, SCI, Cochrane Controlled Trials Register, and China Biological Medicine Database. Studies with a Jadad score higher than 3 were included in the meta-analysis and evaluated using RevMan5.0 software for relative risk (RR) or weighted mean difference (WMD) with 95% confidence intervals (95% CI). Sensitivity analysis was performed on the ethnical differences and quality of the trials. Publication bias was observed using an inverted funnel plot. RESULTS: Nine studies with 434 patients were included in the meta-analysis. Compared with placebo or no intervention, lactulose significantly reduced the risk of no improvement in neuropsychological tests (RR: 0.52, 95% CI: 0.44-0.62, P<0.00001), the time required for the completion of the number connection test-A (WMD: -26.95, 95% CI: -37.81 to -16.10, P<0.00001), and the mean number of abnormal neuropsychological tests (WMD: -1.76, 95% CI: -1.96 to -1.56, P<0.00001). Furthermore, the meta-analysis also showed that lactulose prevented the progression to overt hepatic encephalopathy (RR: 0.17, 95% CI: 0.06-0.52, P=0.002), reduced blood ammonia levels (WMD: -9.89 µmol/l, 95% CI: -11.01 to -8.77 µmol/l, P<0.00001), and improve health-related quality of life (WMD: -6.05, 95% CI: -6.30 to -5.20, P<0.00001). However, no significant difference was observed in the mortality of patients with MHE (RR: 0.75, 95% CI: 0.21-2.72, P=0.66), and lactulose significantly increased the incidence of diarrhea (RR: 4.38, 95% CI: 1.35-14.25, P=0.01). CONCLUSION: Lactulose has significant beneficial effects for patients with MHE compared with placebo or no intervention.

HIV/AIDS epidemiology and prevention in China.

OBJECTIVE: To review HIV/AIDS epidemic history, current situation and prevention policy in China. Data sources Information included in this article was identified by searching PUBMED (1997 - 2006) online resources using the key terms "HIV/AIDS", "epidemic", "prevention", and "China". Study selection Original milestone articles and critical reviews written by major pioneer investigators of the field were selected. RESULTS: The key issues related to the HIV/AIDS epidemic situation in China and Chinese government prevention policy were summarized. HIV/AIDS epidemic groups and trends for HIV transmission were discussed. CONCLUSION: In January 2006, 650 000 people were estimated to be living with HIV in China. The overall HIV/AIDS epidemic is at a low level (0.05%) and concentrated in several at risk populations. However, the data show that new cases of HIV infection are growing every year and spreading from at risk populations to the general population. Premier WEN Jia-bao announced the "Four frees and one care" policy and the Chinese government has developed a series of programs with strong policy measures to stop the spread of HIV/AIDS in China.

Prognostic factors for chronic severe hepatitis and construction of a prognostic model.

BACKGROUND: Chronic severe hepatitis is a serious illness with a high mortality rate. Discussion of prognostic judgment criteria for chronic severe hepatitis is of great value in clinical guidance. This study was designed to investigate the clinical and laboratory indices affecting the prognosis of chronic severe hepatitis and construct a prognostic model. METHODS: The clinical and laboratory indices of 213 patients with chronic severe hepatitis within 24 hours after diagnosis were analyzed retrospectively. Death or survival was limited to within 3 months after diagnosis. RESULTS: The mortality of all patients was 47.42%. Compared with the survival group, the age, basis of hepatocirrhosis, infection, degree of hepatic encephalopathy (HE) and the levels of total bilirubin (TBil), total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), blood creatinine (Cr), blood sodium ion (Na), peripheral blood leukocytes (WBC), alpha-fetoprotein (AFP), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) were significantly different in the group who died, but the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and hemoglobin (HGB) were not different between the two groups. At the same time, a regression model, Logit (P) =1.573XAge+1.338XHE-1.608XCHO+0.011XCr-0.109XNa+1.298XINR+11.057, was constructed by logistic regression analysis and the prognostic value of the model was higher than that of the MELD score. CONCLUSIONS: Multivariate analysis excels univariate analysis in the prognosis of chronic severe hepatitis, and the regression model is of significant value in the prognosis of this disease.

[The correlation of HBeAg expression and HBV-DNA in serum or peripheral blood mononuclear cells in patients with chronic hepatitis B].

OBJECTIVE: To study the relationship between HBeAg expression and HBV-DNA in serum and peripheral blood mononuclear cells (PBMCs). METHODS: 208 patients with chronic hepatitis B were included in this present study. HBV-DNA in the PBMCs were performed by polymerase chain reaction (PCR), with the serum HBV-DNA level being determined by the way of fluoresces quantities PCR (FQ-PCR). Meanwhile, HBV-GM was also detected via enzyme-linked immunosorbent assay (ELISA). RESULTS: There were 106 patients for positivity in the HBV-DNA level of PBMCs with 102 for negativity, in which the HBV-DNA high levels (HBV DNA load > or = 1.0E5) in serum were 91.5%, 45.1% (chi2=52.12, P>0.01) respectively, with 76.4% and 50.9% (chi2=21.55, P>0.01) for the positive percentage of HBeAg expression. CONCLUSION: A significantly positive correlation was found between HBV-DNA in PBMCs and serum HBV-DNA along with the positive percentage of HBeAg, indicating that obvious PBMCs' increase infected by HBV in patients with positivity of HBeAg and high level of serum HBV-DNA.