Jia-Ji Jiang

Serum cytokeratin-18 in the diagnosis of non-alcoholic steatohepatitis: A meta-analysis

Identifying patients with non‐alcoholic steatohepatitis (NASH), a more aggressive form with a worse prognosis than for simple steatosis, is highly important. Liver biopsy still remains the gold standard for diagnosing NASH, but with limitations. The diagnostic value of serum cytokeratin‐18 (CK‐18) in predicting NASH is still indefinite.

Interleukin-6 as an early diagnostic marker for bacterial sepsis in patients with liver cirrhosis

OBJECTIVE Liver cirrhosis is associated with frequent bacterial infections that increase the mortality rate. However, the early diagnosis and treatment of these infections are often difficult. In this retrospective-prospective observational study, the serum levels of interleukin-6 (IL-6) and procalcitonin (PCT) were measured in 233 cirrhotic patients to evaluate the early diagnostic and prognostic values of IL-6 and PCT for cirrhotic patients. METHODS Cirrhotic patients admitted to the Liver Research Center of the First Affiliated Hospital of Fujian Medical University between 1 October 2012 and 30 June 2014 were enrolled. They showed no evidence of infection on admission, and all had first onset of fever and met the systemic inflammatory response syndrome criteria 72 hours after admission. The serum IL-6 and PCT levels were determined on admission, at the onset of fever (0 hour) and 24 and 48 hours after fever onset. RESULTS A total of 233 cirrhotic patients, including 183 men and 50 women, with a median age of 56 (46-65) years were enrolled. A training group of 159 patients was retrospectively enrolled from 1 October 2012 to 31 December 2013, and a validation group of 74 patients was prospectively enrolled from 1 January 2014 to 30 June 2014. Among these patients, 134 were diagnosed with bacterial sepsis, 96 of whom were in the training group and 38 of whom were in the validation group; infections were ultimately ruled out in 99 patients: 63 training patients and 36 validation patients. At 0 hour, the IL-6 and PCT levels as well as the proportion of neutrophils were much higher in septic patients than in nonseptic ones. The IL-6 level and proportion of neutrophils peaked upon the onset of fever, 24 hours before the PCT levels and white blood cell count, and then sharply declined. The area under the receiver operating characteristic curve of IL-6 for diagnosing sepsis was largest at the onset of fever (area under the receiver operating characteristic curve, 0.983; 95% confidence interval, 0.967-0.999). The threshold of IL-6 for diagnosis was 135 pg/mL, with a sensitivity of 94.8% and a specificity of 93.7%. These diagnostic values were also confirmed in the validation group, with a sensitivity of 97.4% and specificity of 80.6%. Eleven (11.5%) patients died, and 85 (88.5%) patients recovered in the sepsis group of training patients after a 4-week follow-up. The IL-6 level was significantly higher in the nonsurvival group than that in the survival group (1813.00 vs 472.10 pg/mL, P = .004) at the onset of sepsis. The cutoff value for predicting prognosis was 1105 pg/mL, with a sensitivity of 81.8% and a specificity of 76.5%. CONCLUSIONS The serum IL-6 levels increased earlier than the PCT in septic cirrhotic patients. The direct measurement of the serum IL-6 level can help to rapidly detect bacterial infection, thus allowing for early therapeutic decisions and prognostic predictions.

Serum Ceruloplasmin Levels Correlate Negatively with Liver Fibrosis in Males with Chronic Hepatitis B: A New Noninvasive Model for Predicting Liver Fibrosis in HBV-Related Liver Disease

Aims This study aimed to investigate associations between ceruloplasmin (CP) levels, inflammation grade and fibrosis stages in patients with chronic hepatitis B (CHB) and to establish a noninvasive model to predict cirrhosis. Methods Liver biopsy samples and sera were collected from 198 CHB patients randomized into a training group (n=109) and a validation group (n=89). CP levels were determined using nephelometric immunoassays. Relationships between CP and liver inflammation and fibrosis were analyzed by Spearman rank correlation. Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic value of CP for determining liver fibrosis in CHB. The liver pathology-predictive model was built using multivariate logistic regression analysis to identify relevant indicators. Results CP levels were lower in males than in females, lower in patients with inflammation stage G4 compared to other stages and lower in cirrhotic compared to non-cirrhotic patients. Using area under the curve (AUC) values, CP levels distinguished different stages of inflammation and fibrosis. Multivariate analysis showed that CP levels were all significantly associated with cirrhosis in males. A model was developed combining routine laboratory markers APPCI (alpha-fetoprotein [AFP], prothrombin time, and platelets [PLT] with CP) to predict fibrosis in CHB patients. The APPCI had a significantly greater AUC than FIB-4 (aspartate aminotransferase [AST]/ alanine aminotransferase [ALT]/PLT/age), APRI (AST/PLT ratio index), GPI (globin/PLT), and APGA (AST/PLT/gammaglutamyl transpeptidase [GGT]) models (all P-values<0.001). Conclusions CP levels correlate negatively and indirectly with inflammation and fibrosis stages in male CHB patients. The APPCI model uses routine laboratory variables with CP to accurately predict liver fibrosis in CHB.

A study of multiple biliary hamartomas based on 1697 liver biopsies.

Objective Multiple biliary hamartomas (MBHs) are rare benign malformations of the intrahepatic bile ducts. There are only a handful of clinical studies based on large populations on the incidence of MBHs. Materials and methods A series of 1697 consecutive liver needle biopsies was examined for the occurrence of MBHs. Results A total of six patients (0.35%, four men and two women, a 2 : 1 ratio) were confirmed by histology to have MBHs. Of the total of 1697 patients, 59 (3.5%) patients were younger than 18 years of age, 828 patients (48.8%) were between 18 and 38 years of age, and 810 patients (47.7%) were older than 38 years of age. Of the six MBHs patients, one was 17 years of age and the other five patients were older than 39 years of age. The median (range) age of the patients was 42 (17–63) years. Although nearly half (48.8%) of the biopsied patients were between 18 and 38 years of age, no MBH was found in this group. All MBHs patients were diagnosed with fibrosis/cirrhosis by initial ultrasound scanning; however, only two patients were confirmed to have cirrhosis by histological examination. Of those two patients with cirrhosis, one had concomitant congenital hepatic fibrosis and the other had concomitant cirrhotic hepatitis B. The latter patient developed hepatocellular carcinoma 1 year after biopsy. No kidney cysts were found in any of the six MBHs patients. MRI scanning was performed in four patients and the results were consistent with the histological diagnosis. Conclusion MBHs are not common in patients who undergo liver biopsy and, in this study, the occurrence was higher in the older age group.

Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss

Viral load reduction facilitates recovery of antiviral T‐cell responses. Dynamic alterations in intrahepatic viraemia clearance and immune cell reactivity during the early phase of nucleoside analogue (NA) therapy and the impact of these changes on HBeAg seroconversion are unknown. Fifteen HBeAg‐positive chronic hepatitis B (CHB) patients were treated with adefovir dipivoxil. T‐cell reactivity to HBV core and surface antigens were tested using ELISPOT assay from baseline to week 48 post‐treatment (at 4‐week intervals). Before and at week 12 of treatment, paired liver biopsies were analysed for intrahepatic HBV‐DNA and cccDNA via real‐time fluorescent PCR. In situ detection of CD4+, CD8+ T cells and NK cells was analysed by immunohistochemistry. With viral load reduction, HBV‐specific IFN‐γ‐producing CD4+ T cells in patients with HBeAg loss were greatly enhanced and reached the highest level at week 12, with further increase observed between week 36 and week 48. After 12 weeks of treatment, total intrahepatic HBV‐DNA and cccDNA had significantly decreased; however, there was no difference in the viral loads or extent of reduction between patients with and without HBeAg loss. Paralleling reduction in viral load, intrahepatic CD8+T lymphocytes increased in patients with HBeAg loss compared with baseline values. Only one patient without HBeAg loss exhibited similar results. Increased immune cells were observed in certain patients along with reduced hepatic viral loads during the second phase of HBV‐DNA decline, which could promote the recovery of antiviral immunity and facilitate HBeAg loss.

A new model for predicting liver cirrhosis in chronic hepatitis B virus carriers with low serum alanine transaminase activity

OBJECTIVES To develop a cirrhosis-predicted model in chronic hepatitis B virus carriers with alanine transarninase (ALT) less than two times the upper limit of normal (ULN). METHODS Treatment-naive patients (n=278), who had undergone liver biopsies, were randomly divided into two groups - a training group and a validation group. Thirteen bio-clinical parameters were analyzed. A liver cirrhosis-predicting model (PPT model) was constructed using multivariate analysis. The diagnostic value of the model was analyzed by the receiving operating characteristics (ROC) method and compared with other available models. RESULTS A PPT model to predict liver cirrhosis was derived from three independent predictors of liver fibrosis [platelet count (PLT), prothrombin time (PT) and total bile acid (TBA)]. PPT model predicted cirrhosis with an area under the ROC (AUROC) curve of 0.83, a positive predictive value of 86.7% and a negative predictive value of 95.2%. Compared with APRI, FIB-4, age-AST model, AP index and APGA model, PPT model had the highest correlation coefficient (r=0.49) and greater predictive performance (AUROC of 0.83). CONCLUSIONS The PPT model was accurate in predicting cirrhosis and may reduce the need for liver biopsy in chronic hepatitis B virus carriers with ALT less than two times ULN.

Hemorrhagic Complications Following Abdominal Paracentesis in Acute on Chronic Liver Failure: A Propensity Score Analysis.

AbstarctPatients with acute on chronic liver failure (ACLF) usually present with severe coagulopathy. Abdominal paracentesis is often performed in these patients. The aim of this study was to analyze the prevalence of hemorrhagic events after paracentesis and the predictive factors of this condition in ACLF populations.ACLF patients who underwent paracentesis were retrospectively enrolled within a 5-year period. A propensity score (PS) matching analysis was used to select matched cases from the overall nonhemorrhagic group to be used as the control group. Hemorrhagic complications and risk factors were examined using logistic regression analysis.A total of 602 abdominal paracenteses were carried out on 218 ACLF patients and 18 (2.99%) hemorrhagic complications were identified. The MELD scores were higher in hemorrhagic patients than overall patients before PS matching (25.77±6.65 vs 21.04 ± 7.93, P = 0.013). We matched 18 cases with bleeding events to 72 unique cases without. The hemorrhagic group had significantly lower fibrinogen levels and higher PT levels than nonhemorrhagic cases. Logistic regression analysis revealed that lower fibrinogen levels could independently predict hemorrhagic complications (OR: 0.128, 95% CI: 0.023–0.697, P = 0.017). The best cut-off value for reliable measurement of fibrinogen levels was 0.70 g/L, with a sensitivity of 76.4% and a specificity of 80.0%. The area under curve was 0.733 (95% CI 0.604–0.862, P value 0.002).Severe hemorrhagic complications occur more commonly in ALCF patients than previously thought. A low fibrinogen level is an independent predictor of bleeding events in patients with MELD >25.

Hepatitis B surface antigen in late hepatitis B infection

Hepatitis B surface antigen (HBsAg) levels are used to evaluate and monitor clinical phases of chronic hepatitis B infection but their clinical significance is unclear in the late complications, cirrhosis of the liver and hepatocellular carcinoma. This study aimed to evaluate HBsAg levels across the whole natural history of hepatitis B virus infection, including late complications. This retrospective, cross‐sectional study enrolled 838 treatment‐naive patients diagnosed with chronic hepatitis B infection at First Affiliated Hospital of Fujian Medical University between 2009 and 2012. Patients were classified into six groups: immunotolerance, immunoclearance, low replicative, negative hepatitis e (HBeAg) phases, liver cirrhosis, and hepatocellular carcinoma. Main outcome measures were serum HBsAg, HBeAg, HBV DNA, total bilirubin, albumin, alanine and aspartate aminotransferase, and quantitative correlation of HBsAg with HBV DNA. HBsAg levels declined significantly between clinical phases of infection (all P < 0.001) and were significantly lower in decompensated than in compensated cirrhosis (2.90 vs. 3.30, P < 0.001) but not significantly different between early versus advanced hepatocellular carcinoma. Significant positive correlations were observed between serum HBsAg and HBV DNA at immunoclearance and HBeAg negative phases, compensated and decompensated liver cirrhosis and advanced but not early hepatocellular carcinoma (all P < 0.001). HBsAg and HBV DNA were significantly higher in HBeAg positive patients with advanced hepatocellular carcinoma (P < 0.001). HBsAg levels differ significantly between chronic hepatitis B infection phases, decreasing progressively from chronic infection to cirrhosis and hepatocellular carcinoma. Significant correlations are found between serum HBsAg and HBV DNA. J. Med. Virol. 87:380–387, 2015.

Ceruloplasmin, a reliable marker of fibrosis in chronic hepatitis B virus patients with normal or minimally raised alanine aminotransferase

AIM To develop a non-invasive model to evaluate significant fibrosis and cirrhosis by investigating the association between serum ceruloplasmin (CP) levels and liver fibrosis in chronic hepatitis B (CHB) patients with normal or minimally raised alanine aminotransferase (ALT). METHODS Serum samples and liver biopsy were obtained from 193 CHB patients with minimally raised or normal ALT who were randomly divided into a training group (n = 97) and a validation group (n = 96). Liver histology was evaluated by the METAVIR scoring system. Receiver operator characteristic curves were applied to the diagnostic value of CP for measuring liver fibrosis in CHB patients. Spearman rank correlation analyzed the relationship between CP and liver fibrosis. A non-invasive model was set up through multivariate logistic regression analysis. RESULTS Serum CP levels individualized various fibrosis stages via area under the curve (AUC) values. Multivariate analysis revealed that CP levels were significantly related to liver cirrhosis. Combining CP with serum GGT levels, a CG model was set up to predict significant fibrosis and liver cirrhosis in CHB patients with normal or minimally raised ALT. The AUC, sensitivity, specificity, positive predictive value, and negative predictive value were 0.84, 83.1%, 78.6%, 39.6%, and 96.5% to predict liver cirrhosis, and 0.789, 80.26%, 68.38%, 62.25%, and 84.21% to predict significant fibrosis. This model expressed a higher AUC than FIB-4 (age, ALT, aspartate aminotransferase, platelets) and GP (globulin, platelets) models to predict significant fibrosis (P = 0.019 and 0.022 respectively) and revealed a dramatically greater AUC than FIB-4 (P = 0.033) to predict liver cirrhosis. CONCLUSION The present study showed that CP was independently and negatively associated with liver fibrosis. Furthermore, we developed a novel promising model (CG), based on routine serum markers, for predicting liver fibrosis in CHB patients with normal or minimally raised ALT.

Prognostic nomogram for acute-on-chronic hepatitis B liver failure

Background & Aims To establish an effective prognostic nomogram for acute-on-chronic hepatitis B liver failure (ACHBLF). Materials and Methods The nomogram was based on clinical data of 203 ACHBLF patients who admitted to the First Affiliated Hospital of Fujian Medical University from 2009 to 2014. The area under the receiver-operating characteristic curve (AUC) and calibration curve were carried out to verify the predictive accuracy ability of the nomogram. The result was validated in internal and external validation cohorts. Kaplan-Meier survival curve was used in survival analysis. Results We developed a new prognostic nomogram to predict 3-month mortality based on risk factors selected by multivariate analysis. This nomogram consisted three independent factors: age, liver to abdominal area ratio (LAAR) and model for end-stage liver disease (MELD) score. The AUC of this nomogram for survival prediction was 0.877 (95% CI 0.831–0.923), which was higher than that of MELD score, MELD-Na and Child-Turcotte-Pugh (CTP). Good agreement of calibration plot for the probability of survival at 3-month was shown between the prediction by nomogram and actual observation. These results were supported by internal and external validation studies. Conclusions The ACHBLF nomogram could predict the short-term survival for ACHBLF patients.