Finite treatment with nucleos(t)ide analogues (NAs) remains a great challenge for chronic hepatitis B in the clinic. This study aimed to investigate the relationship between intrahepatic quasispecies heterogeneity and the NAs off-treatment outcomes in a prospective cohort. Eighteen HBeAg-positive patients with chronic hepatitis B who achieved the cessation criteria underwent liver biopsy, and stopped treatment thereafter. Patients were followed up prospectively for 1 year. The reverse transcriptase (RT) gene of intrahepatic hepatitis B virus (HBV) was cloned and sequenced. Intrahepatic quasispecies heterogeneity and specific gene mutations were analysed using bioinformatic methods. Ten patients achieved sustained response, and eight patients developed viral relapse. The intrahepatic quasispecies Shannon entropy and nucleotide diversity within either RT or the surface (S) region of patients with sustained response were significantly higher (p < 0.05) than those of patients who had a viral relapse. Intrahepatic quasispecies Shannon entropy at the nucleotide level predicted the sustained off-treatment response (area under receiver operating characteristics curve 0.925; 95% CI 0.807-1.000; p 0.003). More positive selection sites and N-glycosylation mutations within the S region were found in patients with sustained response than in the patients with viral relapse (p < 0.01). Most of the positive selection sites in patients with sustained response were located in reported HLA-I-restricted or HLA-II-restricted epitopes. Intrahepatic quasispecies heterogeneity at the end of treatment was correlated with off-treatment outcomes in HBeAg-positive patients with chronic hepatitis B. More immune escape mutations were found within the S region in patients with sustained response. The higher intrahepatic quasispecies heterogeneity indicated a more robust immune control over HBV, which in turn maintained a sustained response after withdrawal of NAs.
Hepatic fibrinogen storage disease is a rare autosomal dominant genetic disorder characterized by hypofibrinogenemia, as well as the retention of variant fibrinogen within the hepatocellular endoplasmic reticulum. Here, we describe an asymptomatic 4-year-old boy with abnormal liver function test results and unexpected hypofibrinogenemia. Liver biopsy showed circular eosinophil inclusion bodies in the hepato-cytoplasm. Immunostaining results of eosinophil inclusion bodies were positive for fibrinogen. Following pretreatment with diastase, the inclusion bodies failed to stain with the periodic acid–Schiff technique; moreover, immunostaining results were positive for fibrinogen, but negative for alpha-1-antitrypsin. Genetic analysis identified a heterozygous missense mutation c.1201C > T (p. Arg401Trp) within the fibrinogen γ-chain ( FGG) gene and an additional single nucleotide polymorphism c.-58 A > G within the 5′-untranslated region of the fibrinogen Aα-chain ( FGA) gene. Thus, the patient was diagnosed with hepatic fibrinogen storage disease. Our results indicate that, for patients who exhibit chronic liver disease with unexpected hypofibrinogenemia, hepatic fibrinogen storage disease should be considered in the differential diagnosis. Moreover, our findings emphasize the importance of molecular diagnosis in patients with cryptogenic liver disease.
Aims. Soluble urokinase plasminogen activator receptor (suPAR) reflects the immune activation in circumstances of inflammation and infection. It has been considered as a risk biomarker associated with poor outcome in various low-grade inflammation and infectious diseases. The study is aimed at investigating whether suPAR has a predictive value with short-term survival in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Methods. Serum suPAR expression was compared among patients with different states of chronic hepatitis B virus infection. Sixty HB-ACLF patients were recruited as the training cohort and followed up for 90 days. Serum suPAR level and the clinical relevance with short-term outcome were investigated. The temporal dynamics of suPAR were evaluated in 50 HB-ACLF patients with available serum sequentially at baseline, week 2 and week 4. Another 167 HB-ACLF patients were enrolled to validate the predictive value of suPAR with respect to the prognosis. Results. Serum suPAR level was significantly increased in HB-ACLF patients compared to non-ACLF patients. In the training set of HB-ACLF, we observed higher suPAR level, INR, MELD score, and more complications in nonsurvivors than survivors. Longitudinal analysis revealed an increased trend of suPAR level in nonsurvivors during week 0 to week 4 and the modest decline in survivors. It showed that the synchronous suPAR level was higher in nonsurvivors at all indicated time points. Elevated suPAR level at baseline was identified as a strong predictor of a 90-day mortality of HB-ACLF patients. It was confirmed suPAR>16.26 ng/ml had a positive predictive value of 72.22% and a negative predictive value of 77.88% for poor outcome in the validation cohort. Conclusions. Serum suPAR level increases significantly in HB-ACLF patients and associated with a 90-day mortality. It suggests that suPAR might be a potential biomarker to predict the prognosis of HB-ACLF patients.
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