Risk Factors of Neurological Complications in Severe Fever Patients with Thrombolytic Syndrome: A Single-Center Retrospective Study in China.

BACKGROUND Severe fever with thrombocytopenia syndrome is a serious insect-borne infectious disease caused by the Huaiyangshanbanyang virus. We conducted a retrospective study to identify risk factors for neurological complications caused by the virus. MATERIAL AND METHODS We included 121 patients who had severe fever with thrombocytopenia syndrome and were admitted to our hospital from 2013 to 2020. Patients' laboratory test results and clinical data were collected. Univariate and multivariate regression were used for statistical analysis. RESULTS Patients with neurological complications had higher mortality rates and longer hospital stays and disease duration than did patients without neurological complications. The neurological symptoms with the highest incidence rates were involuntary tremors (tongue and mandible), cognitive disorder, and limb tremors. Patients with neurological complications had a higher incidence of abnormal heart rhythms. Subcutaneous bleeding, pulmonary rales, percentage of neutrophils, increased lactate dehydrogenase and C-reactive protein levels, and decreased chloride ion concentration were closely related to the occurrence of neurological complications. The significant decrease in chloride ion concentration within 1 to 5 days of disease onset may be a risk factor for predicting the occurrence of neurological complications in patients with severe fever with thrombocytopenia syndrome. CONCLUSIONS Early monitoring of subcutaneous bleeding, pulmonary rales, electrocardiogram changes, and biochemical indicators in patients with severe fever with thrombocytopenia syndrome can predict the occurrence of neurological complications.

[Quantifiable changes in HBeAg expression predict therapeutic efficacy of peg-interferon alfa-2a in patients with HBeAg-positive chronic hepatitis B].

OBJECTIVE: To investigate whether quantifiable changes in serum levels of hepatitis B e antigen (HBeAg) in response to 24 weeks of pegylated-interferon alfa-2a (Peg-IFN-a 2a) treatment are predictive of therapeutic efficacy at 48 weeks of treatment in HBeAg-positive chronic hepatitis B (CHB) patients and to investigate the efficacy of using an individualized antiviral treatment strategy. METHODS: Ninety-six HBeAg-positive CHB patients with detectable HBeAg at week 24 of Peg-IFN-a 2a treatment were categorized according to the quantitative change in HBeAg (vs. pre-treatment baseline): group A, HBeAg decline more than 2 log; group B, HBeAg decline between 1 - 2 log; group C, HBeAg decline less than 1 log, which was then randomly divided into two sub-groups: C1 and C2. Group A, B, and C1 patients continued the original therapy for an additional 24 weeks, while group C2 patients were supplemented with lamivudine (3TC + Peg-IFN-a 2a) for the additional 24 weeks of treatment. All patients underwent liver biopsy at the end of treatment (week 48), and HBV covalently-closed circular (ccc)DNA was quantified as a measure of therapeutic efficacy. A, B, and C1 between-group multiple comparisons were made by the Nemenyi test; C1 and C2 between-group comparison was made by the Mann-Whitney U test. The significance of between-group differences in decreased HBV cccDNA vs. HBeAg/anti-HBe seroconversion was made by the Chi-squared test. RESULTS: At week 48, the mean decrease of serum HBV cccDNA in each group was: A, 5.8 log10 copy/ml; B, 3.8 log10 copy/ml; C1, 2.8 log10 copy/ml; C2, 5.7 log10 copy/ml. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01); however, the difference between group B and C1 did not reach statistical significance (P = 0.19). The mean decrease of HBeAg in each group was: A, 2.7 log10 S/CO; B, 1.9 log10 S/CO; C1, 0.9 log10 S/CO; C2, 1.6 log10 S/CO. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01). The rate of patients who achieved undetectable HBV DNA in each group was: A, 87.5%; B, 34.5%; C1, 17.4%; C2, 85.0%. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01). The HBeAg seroconversion rates were: A, 75.0%; B, 24.1%; C1, 13.0%; C2, 25.0%. Statistically significant differences were observed only for group A vs. B and C1 (P less than 0.01). Finally, group A achieved greater reduction in levels of cccDNA in liver tissues than B or C1 (P less than 0.01); however, the differences between B and C1 and between C1 and C2 did not reach statistical significance. CONCLUSION: CHB patients who showed an HBeAg decline of more than 2 log at week 24 of Peg-IFN-a 2a treatment had better treatment outcome at week 48 than those who showed HBeAg decline less than 2 log at week 24. Augmenting the Peg-IFN-a 2a treatment with 3TC can improve the clinical response. A change of quantifiable HBeAg at week 24 of Peg-IFN-a 2a treatment may be a useful predictor of therapeutic efficacy of a 48-week antiviral regimen.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Protective effects of ursodeoxycholic acid against immune-mediated liver fibrosis in rats.

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA), a natural component of bile, has been synthesized to treat cholestatic liver diseases such as primary biliary cirrhosis. Broad biochemical changes in UDCA-treated patients suggest beneficial effects of UDCA beyond stimulating hepatobiliary secretion and possible efficacy of the medicine in treating cirrhosis of other causes. The aim was to explore the potential benefit of UDCA in controlling immune-mediated hepatic fibrosis. METHODOLOGY: We applied the rat experimental model of liver fibrosis induced by intraperitoneal injection of porcine serum. UDCA was administered orally during the course of the serum injections. RESULTS: Compared with the untreated group, the rats treated with UDCA ended with significantly higher body weight, lower liver weight, and lower spleen weight. The treated groups also demonstrated less severe liver fibrosis, with significantly lowered hepatic expression of type I and type III collagens, in terms of both mRNA and proteins. Moreover, serum levels of hyaluronic acid (HA), laminin (LN), type IV collagen (C IV), and type III procollagen (PC III) were also lower in the UDCA-treated animals. CONCLUSION: UDCA deters development of immune-mediated liver fibrosis by inhibiting the expression of collagen and other extracelluar matrix components.

TRIB3 promotes hepatocellular carcinoma growth and predicts poor prognosis.

BACKGROUND: Tribbles pseudokinase 3 (TRIB3) is a member of the tribbles-related family, which is involved a lot of cellular processes and multiple cancers, such as breast cancer, colorectal cancer, renal cell carcinomas, and lung cancer. However, the expression pattern and biological function of TRIB3 in hepatocellular carcinoma (HCC) has not yet been completely elucidated. METHODS: The expression of TRIB3 and clinicopathological characteristics were evaluated by HCC tissue microarray and qPCR analysis. Lentivirus packaging and transfection were employed to establish cell lines with TRIB3 overexpression or knockdown. The biological functions of TRIB3 in the growth of HCC were determined using MTT and crystal violet assays. Tumor growth was monitored in a xenograft model in vivo. RESULTS: The expression of TRIB3 was upregulated in HCC tissue samples compared to paired normal tissues in 45 patients examined by qPCR assay. TRIB3 expression was significantly correlated with HCC tumor size and prognosis in postoperative patients by analysis of the TRIB3 expression data and HCC clinical features. Forced expression of TRIB3 significantly promoted HCC growth in vitro. In contrast, downregulation of TRIB3 inhibited cell growth in vitro. Moreover, knockdown of TRIB3 suppressed tumorigenesis of HCC cells in vivo. CONCLUSION: TRIB3 promotes growth abilities of HCC cells both in vitro and in vivo and predicts poor prognosis of HCC patients, which serves as a prognostic marker and might provide a potential therapeutic candidate for patients with HCC.

[Dynamics of hepatitis B virus covalently closed circular DNA after serum virology response].

OBJECTIVE: To explore the dynamics of hepatitis B virus covalently closed circular DNA (cccDNA) and optimal duration of treatment after serum virology response. METHODS: HBV cccDNA in liver biopsies and the serum HBV DNA were quantified by real time PCR, the serum makers were detected by enzyme-linked immunosorbent assay. RESULTS: (1) The cccDNA in biopsy samples continued to decrease after serum virology responded. (2) The longer the treatment after serum virology response, the lower the cccDNA level in liver tissue. (3) Anti-HBe positive patients had lower cccDNA in liver tissue than anti-HBe negative patients. (4) cccDNA in liver tissue was undetectable in 12 out of the 18 case anti-HBe(+) patients. Serum virology response lasted 35 months and anti-HBe(+) lasted 30 months. CONCLUSION: After serum virology responded, the longer the treatment, the lower the liver cccDNA. The cccDNA is undetectable in about 2/3 of the patients if the serum virological clearance lasts more than 35 months and anti-HBe lasts more than 30 months.

[Pathogenesis of liver fibrosis in patients with chronic hepatitis B].

OBJECTIVE: To explore the role of sinusoidal endothelial cell in the development of liver fibrosis, and to dissect the relationship among hepatic microcirculation disorders, hepatic sinusoidal capilarization and liver fibrosis. METHODS: Liver biopsy was performed in fifty-six patients with chronic hepatitis B. The liver tissues were observed under light microscope and transmitted electronic microscope. RESULTS: Of 56 cases, 39 cases were mild hepatitis, 10 were moderate hepatitis, and 7 were severe hepatitis. The morphology of hepatic stellate cells (HSCs) was similar to that of fibroblasts in the tissues of the patients with chronic hepatitis B. Collagenous fibers were deposited around the hepatic stellate cells. Electron-dense materials were deposited between sinusoidal endothelial cell and hepatic stellate cell. The size and amount of fenestraes of sinusoidal endothelial cells were reduced in 53 of 56 cases. The consecutive or inconsecutive membrane-like materials were observed along sinusoidal endothelial cells in 20 cases. Collagen fibers were observed in the space of Disse in 15 cases. Even in the patients with normal hepatic functions, red blood cells aggregation and microthrombi could be observed in the liver tissues. CONCLUSION: Sinusoidal endothelial cells are involved in development of liver fibrosis by interacting with hepatic stellate cells. Hepatic microcirculation disorders and sinusoidal capillarization are important changes in the early stage of liver fibrosis.

Effects of heparin on liver fibrosis in patients with chronic hepatitis B.

AIM: To evaluate the effects of heparin on liver fibrosis in patients with chronic hepatitis B. METHODS: Fifty-two cases under study were divided into two groups, group A and group B. The two groups were given regular treatment and heparin/low molecular weight heparin (LMWH) treatment respectively. Hepatic functions, serum hyaluronic acid (HA) and type IV collagen levels were measured before and after the treatment, and six cases were taken liver biopsy twice. RESULTS: After treatment, hepatic functions became significantly better in both groups. Serum HA and type IV collagen levels in group B compared with group A, decreased significantly after treatment. Collagen proliferation also decreased in group B after treatment. CONCLUSION: Heparin/LMWH can inhibit collagen proliferation in liver tissues with hepatitis B.

Effect of ursodeoxycholic acid on TGF beta1/Smad signaling pathway in rat hepatic stellate cells.

BACKGROUND: Hepatic fibrosis is the key stage of the pathological progress from hepatic injury to cirrhosis. Ursodeoxycholic acid (UDCA) has been known as having significant clinical therapeutic effects on chronic liver diseases. Our research aimed to study the effect of UDCA on the signaling pathway of transforming growth factor beta1 (TGFbeta1)/Smad and discuss its possible molecular mechanisms of inhibiting hepatic fibrosis. METHODS: Rat hepatic stellate cells were cultured in vitro and randomly assigned to 4 groups. Group A was control group, with only DMEM culture medium applied, and groups B, C, D were experimental groups, with different doses of UDCA (1.0 mmol/L, 0.5 mmol/L and 0.25 mmol/L respectively) added into their DMEM culture medium for further culture of 24 hours and 48 hours. The protein expressions of TGFbeta1, TGF type I receptor, Smad3, Smad4 and Smad7 were measured by Western blotting, as well as the expressions of TGFbeta1, Smad3, Smad7 and cAMP response element (CREB) binding protein (CBP) mRNA by real-time PCR. SPSS 11.5 statistical package was adopted for data analyses. RESULTS: Compared with control group, the mRNA expressions of TGFbeta1 in the high and middle UDCA dose groups for 24 hours and 48 hours significantly decreased (P < 0.05), the protein expressions of TGFbeta1 in the two above groups for 48 hours and in the high dose group for 24 hours significantly decreased (P < 0.05). The protein and mRNA expressions of Smad3 in each UDCA dose group for 24 hours and 48 hours significantly decreased, with significant difference among different UDCA dose groups and between that of 24 hours and 48 hours observed (P < 0.05). The protein and mRNA expressions of Smad7 in the high and middle UDCA dose groups for 24 hours and 48 hours significantly increased. The CBP mRNA expression in each UDCA dose group for 24 hours and 48 hours significantly decreased (P < 0.05), with significant difference among different UDCA dose groups observed (P < 0.05). CONCLUSION: UDCA could curb the development of hepatic fibrosis through affecting the signaling pathway of TGFbeta1/Smad by inhibiting the expressions of TGFbeta1, Smad3 and CBP and increasing the expression of Smad7.

Ginkgo Biloba Extract EGb 761 Alleviates Hepatic Fibrosis and Sinusoidal Microcirculation Disturbance in Patients with Chronic Hepatitis B.

BACKGROUND: Few clinical data are available regarding the effect of Ginkgo biloba extract (EGb 761) on liver microcirculation and fibrosis. This randomized, controlled trial is to investigate the effect of Ginko biloba extract EGb 761 on liver fibrosis and hepatic microcirculation in patients with chronic hepatitis B. METHODS: Sixty-four patients with chronic hepatitis B were randomized for intention-to-treat. Thirty-two patients were assigned to treated group receiving EGb 761 plus polyunsaturated phosphatidylcholine (Essentiale), 32 patients received Essentiale as controls. Blood samples were taken for measurement of transforming growth factor beta-1 (TGF-ß1), platelet activate factor (PAF), endothelin 1 (ET-1). Twenty-six patients in treated group and 21 patients in control group underwent liver biopsies for histology before and after treatment. Ultrastructural study for sinusoidal microcirculation before and after treatment was carried out on 10 randomly selected patients in each group. RESULTS: In the treated group, after EGb 761 treatment, there was a significant reduction of blood TGF- ß1, PAF and ET-1 (p<0.05), whereas this was not observed in the controls. After treatment in both groups, there were significant decrease of ALT, TBil and PT (p<0.05), and significant increase of ALB (p<0.05). Hepatic inflammation and fibrosis significantly alleviated in the treated group, but not in the controls. After EGb 761 treatment, electron microscopy showed red blood cell aggregates and microthrombosis disappeared or decreased in sinusoids; collagen deposits in sinusoidal lumen and Disse space reduced; sinusoidal capillarization alleviated. CONCLUSIONS: EGb 761 can improve sinusoidal microcirculation, alleviate inflammation and inhibit fibrosis through multiple mechanisms, it is effective in the treatment of chronic liver diseases.

Synthetic chenodeoxycholic acid derivative, HS-1200, induces apoptosis of human hepatoma cells via a mitochondrial pathway.

We investigated whether HS-1200 has anti-proliferation effects on human hepatoma cells in vitro. Here, chromatin condensation, DNA ladder formation and proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) were observed after treatment of HS-1200, indicating the occurrence of apoptotic cell death, which was associated with up-regulation of Bax, cleaved-caspase-3 and cleaved-caspase-9. Inhibition of caspase-9 rescued HS-1200-induced apoptosis. Furthermore, cells treated with HS-1200 showed a reduction in mitochondrial membrane potential (Deltapsi(m)) and caused cytochrome c release into the cytosol. The results indicated that synthetic chenodeoxycholic acid HS-1200 could induce cell apoptosis in BEL7402 human hepatoma cell line, via a Bax/cytochrome c/caspase-9 independent pathway. This study suggested that HS-1200 is potentially useful as an apoptosis inducer for the treatment of hepatocellular carcinoma.

[Clinical impact of gamma-glutamyl transpeptidase messenger RNA subtypes on early diagnosis of hepatocellular carcinoma].

BACKGROUND & OBJECTIVE: It has been reported that hepatocellular carcinoma (HCC) expresses gamma-glutamyl transpeptidase (GGT) with unique carbohydrate moieties compared with normal liver GGT enzymes, this unique GGT was used as a marker for the diagnosis of HCC. However, the genomic changes in GGT relating to the development of HCC are not known. This study was designed to explore the relationship between alteration in GGTmRNA subtypes and the development of HCC, and to seek a new method for early diagnosis of HCC. METHODS: Three GGTmRNA subtypes (F, H, P) were determined bu using RT-PCR in normal liver tissues, diseased liver tissues without HCC, cancerous and noncancerous tissues from the livers with HCC, noncancerous tissues from secondary carcinoma of liver and peripheral blood of all cases. RESULTS: The main subtype of GGTmRNA was type F in normal liver tissues, liver tissues from noncancerous liver diseases and paracancerous tissues from secondary carcinoma of liver. The prevalence of subtype H was significantly higher in cancerous tissues, adjacent paracancerous and distal cancerous tissues from the livers with HCC than that in tissues from normal livers and noncancerous liver diseases (P < 0.05). The prevalence of subtype F in cancerous tissues was significantly lower than that in tissues from normal livers and noncancerous liver diseases (P < 0.05). Among 26 patients with HCC, GGTmRNA-H in peripheral blood was found in 12 cases. In 10 HCC patients with negative AFP, GGTmRNA-H in peripheral blood was found in 5 cases. CONCLUSIONS: The changes of GGTmRNA subtypes are closely related to the development of HCC, and the analysis of GGT genes might be a sensitive assay to monitor the hepatic cell canceration.