OBJECTIVETo investigate the relationship of serum metalloproteinase with the severity of liver fibrosis and inflammation.

METHODSA total of 88 patients with HBV-related liver fibrosis and early cirrhosis were enrolled from six hospitals. Serum fibrosis markers including hyaluronic acid (HA), IV collagen (IV-C), aminoterminal propeptide of type III procollagen (PIIIP), laminin (LN), matrix metalloproteinases (MMP) 1, 2, 9 and tissue inhibitors of metalloproteinase (TIMP) 1, 2 levels were determined. Liver biopsies were assessed according to a modified Scheuer and Chevallier's scoring system.

RESULTSSerum TIMP1 (r=0.540) and MMP2 (r=0.314) were correlated positively with the degree of hepatic fibrosis, whereas serum MMP1 (r=-0.495) was correlated negatively. By receiver operating curve analysis (ROC), the sensitivity to distinguish the fibrosis stage 2 from stage 1 was 90.5% and the specificity was 52.0% if the cut-off value of MMP1 was 13.96 ng/ml, and the sensitivity was 91.6% and the specificity was 64.0% if the cut-off value of TIMP1 was 76.84 ng/ml. The sensitivity to distinguish cirrhosis (stage 4) from fibrosis (stage 3) was 70.7% and specificity was 80.9% if the cut-off value of MMP1 was 6.86 ng/ml, and the sensitivity was 60.5% and the specificity was 92.3% if the cut-off value of TIMP1 was 210.04 ng/ml.

CONCLUSIONSerum TIMP1, MMP1, MMP2 levels and TIMP1/MMP1 ratio could be used as serum fibrosis markers.

Adult ; Biomarkers ; blood ; Female ; Hepatitis B, Chronic ; blood ; complications ; Humans ; Liver Cirrhosis ; blood ; virology ; Male ; Matrix Metalloproteinase 1 ; blood ; Matrix Metalloproteinase 2 ; blood ; Middle Aged ; Tissue Inhibitor of Metalloproteinase-1 ; blood

OBJECTIVESTo further assess the clinical antifibrotic efficacy of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis using a randomized, double blind, and placebo controlled clinical trial.

METHODSTotal 136 patients with HBV-related fibrosis and early cirrhosis were allocated randomly into Cpd 861 treatment group and placebo group for 24 weeks treatment. Serum fibrosis markers including hyaluronic acid (HA), IV collagen (IV-C), amino terminal propeptide of type III procollagen (PIIIP), and laminin (LN) and serum MMP1, 2, 9, TIMP1, 2 level were determined before and after 24 weeks treatment. Liver biopsies before and after 24 weeks of treatment were assessed according to modified Scheuer and Chevallier's scoring system.

RESULTSTotal 52 patients in Cpd 861 treatment group and 50 patients in placebo-controlled group completed the 6 months. ALT level decreased from 68.2 U/L+/-68.6 U/L to 45.9 U/L+/-26.1 U/L, AST level decreased from 60.4 U/L+/-62.6 U/L to 46.7 U/L+/-39.0 U/L (P < 0.05) after 24 weeks treatment, whereas there was no significant change in placebo group (ALT: 65.3 U/L+/-48.3 U/L to 85.4 U/L+/-115.5 U/L; AST: 60.4 U/L+/-44.6 U/L to 77.6 U/L+/-89.6 U/L, P > 0.05). Serum fibrosis markers, including HA, IV-C, PIIIP, and LN were decreased after treatment, but there is no statistically significant compared with placebo group. Compared with placebo group, serum TIMP1 and MMP9 level decreased significantly (TIMP1 172.0 ng/ml+/-79.6 ng/ml vs 133.5 ng/ml+/-66.8 ng/ml; MMP9 116.1 ng/ml+/-88.2 ng/ml vs 80.4 ng/ml+/-79.0 ng/ml), and the ratio of TIMP1/MMP1 (48.3+/-96.3 vs 19.9+/-28.0) were also decreased after 861 treatment. In patients treated with Cpd 861, hepatic inflammatory score (from 14.0+/-6.0 to 10.2+/-6.1), fibrosis score (from 11.9+/-6.5 to 8.2+/-4.5), and relative content of collagen (from 18.9%+/-9.5% to 14.9%+/-8.4%) decreased significantly. In contrast, there was no significant change in placebo group. The reversal (fibrosis score decrease > or = 2) rate of fibrosis in Cpd 861 group was 38.9% in S2, 53.3% in S3 (precirrhotic) and 78.6% in S4 (cirrhosis), significantly higher than those in placebo group (14.3%, 25.0%, and 41.7%, respectively). The overall reversal rate was 52.0% in Cpd 861 group, and 20.0% in placebo group (P < 0.05). No serious adverse effects were observed during Cpd 861 treatment.

CONCLUSIONLiver fibrosis and early cirrhosis due to HBV infection in man could be definitely reversed by herbal remedy Cpd 861.

Adolescent ; Adult ; Aged ; Collagen Type IV ; blood ; Double-Blind Method ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Hepatitis B, Chronic ; complications ; drug therapy ; Humans ; Hyaluronic Acid ; blood ; Liver ; pathology ; Liver Cirrhosis ; blood ; drug therapy ; etiology ; Liver Function Tests ; Male ; Middle Aged ; Phytotherapy

Adult ; Bile Ducts, Intrahepatic ; abnormalities ; Cholestasis, Intrahepatic ; diagnosis ; etiology ; therapy ; Female ; Humans

OBJECTIVETo elucidate clinical and pathological features of primary sclerosing cholangitis (PSC) in order to improve clinician's awareness of this rare disease.

METHODSWe retrospectively analyzed clinical data and follow-up information of 27 PSC patients who were admitted to Beijing Friendship Hospital from January 1990 to November 2009. The patients were classified into classic PSC and small-duct PSC according to biochemistry and imaging results. After 3 to 6 months of therapy, those patients with serum ALT < or = 1.5, TBil < or = 2 and ALP < or = 2.5 ULN were determined as good responders. The treatment results between the two groups were compared.

RESULTS9 out of 27 cases of PSC were small duct PSC and 18 cases were large bile duct or classic PSC. Male patients (7) were less than females (20) and the average age was 47.6 years. Main clinical symptoms included jaundice (85.2%), pruritis (48.1%),fatigue (68.4 %), abdominal pain (40.7%) and fever (14.8%), main physical sign included hepatomegaly (44.4%), splenomegaly (48.1 %) and ascites (14.8%). Laboratory features included elevated IgG (81.8%), positive ANA (69.6%) and pANCA (52.9%). 22% of these PSC patients had ulcerative colitis or Sjogren's syndrome. A small percentage of patients were responsive to standard therapy, of which small duct PSC had a better response than classic PSC (66.7 % vs 33.3%, P = 0.041).

CONCLUSIONSUlcerative colitis (22.2%) is not as common as reported by western countries. Small duct PSC has a better treatment response. Searching of effective treatment regimen for large bile duct PSC is warranted in future studies.

Adolescent ; Adult ; Aged ; Cholangitis, Sclerosing ; pathology ; therapy ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Young Adult

BACKGROUNDTraumatic brain injury (TBI) is a major cause of death and disability in children and young adults worldwide. Therefore, we investigated the role of AG490 in regulating brain oedema, expression of CD40 and neurological function after TBI.

METHODSSprague Dawley rats (n = 240) were randomly divided into a sham operation group, TBI+saline group and TBI+AG490 (JAK/STAT inhibitor) group. Members of each group were euthanized at 6, 12, 24 or 72 hours after injury. Neurological severity score (NSS) was used to evaluate the severity of neurological damage. Brain water was quantitated by wet/dry weight method. The expression of CD40 was assessed by flow cytometry.

RESULTSIn both the TBI+saline group and the TBI+AG490 group, the brain water content was elevated after TBI, reached a peak at 24-hour and remained high for the rest of the period investigated; the expression of CD40 reached a peak 24 hours after TBI; the NSS was elevated after TBI and then decreased after 6 hours. Elevations in the level of CD40, degree of brain edema and NSS after TBI were significantly reduced in TBI+AG490 group.

CONCLUSIONInhibition of the JAK/STAT signalling pathway reduces brain oedema, decreases the expression of CD40 and exerts neuroprotective effects after TBI.

Animals ; Brain Edema ; metabolism ; Brain Injuries ; drug therapy ; CD40 Antigens ; analysis ; Flow Cytometry ; Janus Kinases ; metabolism ; Male ; Neuroprotective Agents ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; STAT Transcription Factors ; metabolism ; Tyrphostins ; therapeutic use

BACKGROUNDC-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in cerebral ischemia. Although the mechanistic basis for this activation of JNK1/2 is uncertain, oxidative stress may play a role. The purpose of this study was to investigate whether the activation of JNK1/2 is associated with the production of endogenous nitric oxide (NO).

METHODSIschemia and reperfusion (I/R) was induced by cerebral four-vessel occlusion. Sprague-Dawley (SD) rats were divided into 6 groups: sham group, I/R group, neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole, 7-NI) given group, inducible nitric oxide synthase (iNOS) inhibitor (2-amino-5,6-dihydro-methylthiazine, AMT) given group, sodium chloride control group, and 1% dimethyl sulfoxide (DMSO) control group. The levels of protein expression and phospho-JNK1/2 were detected by Western blotting and the survival hippocampus neurons in CA1 zone were observed by cresyl violet staining.

RESULTSThe study illustrated two peaks of JNK1/2 activation occurred at 30 minutes and 3 days during reperfusion. 7-NI inhibited JNK1/2 activation during the early reperfusion, whereas AMT preferably attenuated JNK1/2 activation during the later reperfusion. Administration of 7-NI and AMT can decrease I/R-induced neuronal loss in hippocampal CA1 region.

CONCLUSIONJNK1/2 activation is associated with endogenous NO in response to ischemic insult.

Animals ; Blotting, Western ; Brain Ischemia ; enzymology ; Enzyme Inhibitors ; Hippocampus ; cytology ; metabolism ; Indazoles ; pharmacology ; Male ; Mitogen-Activated Protein Kinase 8 ; metabolism ; Mitogen-Activated Protein Kinase 9 ; metabolism ; Neurons ; cytology ; metabolism ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type II ; antagonists & inhibitors ; Phosphorylation ; drug effects ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the malignant tendency of liver basophilic cells in rats by examining the liver dynamic pathological changes during the hepatocarcinogenesis induced by diethylnitrosamine (DEN).

METHODSOne hundred forty male Sprague-Dawley rats, about 200 g each, were randomly divided into a normal group and a model group. The model group rats were administered 1% DEN intragastrically once a week for 14 weeks. The normal control group rats were given saline instead of DEN. Seven to ten rats of the model group were sacrificed at 2, 3, 5, 8, 10, 12, 14, 18 weeks. The remaining rats were followed to the end of the experiment at 26 weeks. Histopathological changes of the livers were analyzed, and the localization of GST-P and PCNA in the livers were detected in situ by immunohistochemistry.

RESULTSAccording to the characteristics of the lesions in the model group, histological liver change patterns were categorized into three phases: (1) liver injury phase (2 to 5 weeks) with centrilobular necrosis, a small amount of collagen deposition in the necrotic regions with fibrous septa development and cell proliferation; (2) the cirrhosis phase (8 to 12 weeks) with significant hepatocellular regeneration and collagen deposition. As the regenerative nodules and fibrous septa formed, cirrhosis with uniform sized nodules developed in all the rats at 12 weeks. In the regenerative nodules, significant hepatocellular metamorphosis was seen; (3) In the carcinomatous transformation and nodular remodeling phase (after 14 weeks), two types of cancer, namely hepatocellular carcinoma and cholangiocarcinoma were found. Incidence of the cancer was 62.5% at 18 weeks. Basophilic cell lesions appeared beginning at 10 weeks. Pale bodies were seen in some basophilic cells. Small cell changes appeared starting at 12 weeks. Some of these cells containing droplets like lipid vacuoles, invaded into the surrounding liver tissues. Both basophilic cell lesions and small cell changes were all positive for proliferating cell nuclear antigen (PCNA).

CONCLUSIONDevelopment of foci of basophilic small cells, with cells containing lipid vacuoles and pale bodies, and invading into the surrounding liver tissues are the changes highly suggestive of an early hepatocellular carcinoma transformation.

Animals ; Basophils ; pathology ; Carcinoma, Hepatocellular ; pathology ; Hepatocytes ; pathology ; Liver Neoplasms, Experimental ; pathology ; Male ; Precancerous Conditions ; pathology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo develop a diagnostic model comprising clinical and serum markers for assessing HBV-related liver fibrosis.

METHODS270 chronic hepatitis B patients were randomly allocated to either an estimation group (195 cases) or a validation group (75 cases). Liver biopsies were done and staging of fibrosis was assessed. Twenty-six common clinical and serum markers were analyzed initially in the estimation group to derive a predictive model to discriminate the stages of fibrosis. The model created was then assessed with ROC analysis. It was also applied to the validation group to test its accuracy.

RESULTSAmong 13 variables associated with liver fibrosis selected by univariate analysis, age, gamma glutamyltranspeptidase (GGT), hyaluronic acid (HA), and platelet count (PLT) were identified by multivariate logistic regression analysis as independent factors of fibrosis. A fibrosis index constructed from the above four markers was established. In ROC analysis, the AUC was 0.889 for the estimation group and 0.850 for the validation group for discriminating > or =S3 from < or=S2. Using the optimal cutoff score 3.0, the sensitivity of the index was 90.2%, the specificity 76.1%, and the accuracy was 82%. There was a positive linear relationship between the index scores and the fibrosis stages (r = 0.731, P<0.001). The AUC for identifying > or=S2 was 0.873 with sensitivity/specificity of 79%/82%, cutoff score 2.2; The AUC for identifying S4 was 0.872 with sensitivity/specificity of 83%/75%, cutoff score 5.4. There were no significant differences in diagnostic efficacy in the model between the estimation and the validation group (P>0.05).

CONCLUSIONA model for assessment of liver fibrosis was established with easily accessible markers. It appears to be sensitive, accurate and reproducible, suggesting it could be used to assist or replace liver biopsy to detect dynamic changes of HBV-related liver fibrosis.

Adolescent ; Adult ; Aged ; Female ; Forecasting ; Hepatitis B, Chronic ; complications ; diagnosis ; Humans ; Liver Cirrhosis ; diagnosis ; etiology ; Logistic Models ; Male ; Middle Aged

Animals ; Glutathione Transferase ; biosynthesis ; Liver Neoplasms, Experimental ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVESTo analyze the frequency and the clinical and virological features of HBeAg-negative and HBeAg-positive chronic hepatitis B.

METHODSFour hundred and seventeen chronic hepatitis B patients, 286 males and 131 females seen in our center were studied. Liver biopsies were taken from 83 patients.

RESULTSThe cases with HBeAg-negative chronic hepatitis B were 241 (57.8%), with an average age of 43.7+/-10.8 and a history of 16.8+/-8.5 years. HBeAg-positive chronic hepatitis B cases were 176 (42.2%), with an average age of 36.95+/-11 and a history of 12.3+/-8.0 years. HBeAg-negative patients were significantly older (P < 0.01) in age and had a longer disease history. ALT levels and the percentage of HBV DNA were higher than 10(5) copies/ml in HBeAg-negative patients and were significantly lower than those in the HBeAg-positive patients [(37.66+/-32.93) U/L vs. (82.09+/-107.57) U/L, 38.2% vs. 94.3%, P < 0.01]. Liver biopsies from 47 HBeAg-negative patients showed that the number of cases with inflammation scores of G1, G2, G3 and G4 were 5, 27, 14, 1 and the number of cases with fibrosis scores of S1, S2, S3 and S4 were 10, 12, 5, 20, respectively. In the 36 HBeAg-negative patients the respective number of cases with inflammation scores of G1, G2, G3 and G4 were 5, 14, 15, 2, and with fibrosis scores of S1, S2, S3, S4 were 8, 12, 6, 10. Although histopathological inflammation and fibrosis scores had no statistical difference between HBeAg-negative and positive patients (P > 0.05), 53.2% patients of HBeAg-negative group and 44.5% patients of HBeAg-positive group had a fibrosis score of >or= S3.

CONCLUSIONDespite lower serum ALT and HBV DNA, HBeAg-negative chronic hepatitis B still has a significant disease progression. This observation may help to develop better clinical management in HBeAg-negative chronic hepatitis B patients.

Adult ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; blood ; pathology ; Humans ; Liver ; pathology ; Male ; Middle Aged