In acute injury, liver recovers completely without any scarring change or complication. However, large portion of liver is changed into fibrotic state by excessive production of extracellular matrix (ECM) under chronic injury. Excessive production of ECM results in hepatic fibrosis and repeated process of hepatic fibrosis progress into liver cirrhosis. Liver cirrhosis is an irreversible and terminal state of chronic liver disease and one of the major causes of death in Korea. To block the progression to liver cirrhosis, various studies in the field of virology and immunology have been proceeded. Recently, studies on the hepatic fibrogenesis have progressed with the development of molecular biology. Hepatic stellate cells (HSC) play a key role in the pathogenesis of hepatic fibrosis by producing ECM. The degree of hepatic fibrosis depends on the proliferation and activation of HSC and increased net production of collagen. Therefore, inhibition of HSC activation is one of the main ways to block the progression of hepatic fibrosis. Many kinds of factors such as oxidative stress, acetaldehyde, ascorbic acid, transforming growth factor-beta (TGF-beta) and carbon tetrachloride (CCl4) have been reported to activate HSC and stimulate collagen gene expression. Although there are no definite and effective antifibrogenic agents, possible candidates are antioxidants, interferon, retinoids such as beta-carotene, flavonoids, renin-angiotensin system inhibitors and peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists. We tried to evaluate the charateristics of HSC in order to develop agents that inhibit hepatic fibrogenesis.
Extracellular Matrix/*metabolism ; Fibrosis ; Humans ; Liver/blood supply/metabolism/*pathology ; Liver Cirrhosis/etiology/genetics/*metabolism

No abstract available.
Extracellular Matrix/*metabolism ; Fibrosis ; Humans ; Liver/blood supply/metabolism/*pathology ; Liver Cirrhosis/etiology/genetics/*metabolism

This study examined endogenous cannabinoid (ECB)-anandamide (AEA) and its cannabinoid receptors (CBR) in mice liver with the development of schistosoma japonicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography (HPLC) was employed to determine the concentration of AEA in the plasma of mice. Immunofluorescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28+/-7.32 and 30.55+/-7.78, and CBR2 were 28.13+/-6.42 and 52.29+/-4.24 (P<0.05). The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were (0.37+/-0.07) and (5.67+/-1.34) ng/mL (P<0.05). It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.
Arachidonic Acids/*metabolism ; Endocannabinoids/*metabolism ; Liver Cirrhosis/etiology ; Liver Cirrhosis/*metabolism ; Liver Cirrhosis/parasitology ; Polyunsaturated Alkamides/*metabolism ; Random Allocation ; Receptor, Cannabinoid, CB1/*metabolism ; Receptor, Cannabinoid, CB2/*metabolism ; Schistosomiasis japonica/*complications ; Schistosomiasis japonica/metabolism

BACKGROUND/AIMS: Nonalcoholic steatohepatitis can develop from nonalcoholic fatty liver and progress to severe liver disease such as cirrhosis. The mechanism determining the progression from fatty liver to steatohepatitis is unknown. Iron is suspected to enhance hepatic damage associated with nonalcoholic fatty liver disease (NAFLD). The aims of this study were to evaluate the relationship of serum iron indices and hepatic iron deposition with hepatic fibrosis or inflammation, and to assess whether the increased hepatic iron deposition is an independent predictor of progression to liver injury. METHODS: The biochemical and histopathological data of thirty-nine patients with NAFLD were analyzed. Liver biopsy findings were graded according to the method described by Brunt, et al. Hepatic iron concentration was available in 29 of 39 patients. RESULTS: The mean hepatic iron concentration and hepatic iron indices were 1,349+/-1,188 microgram/g dry weight and 0.9+/-0.7 microgram/g/age. Serum ferritin and body mass indices were associated with hepatic inflammation (p=0.001, p=0.006) and fibrosis (p=0.005, p=0.013). Hepatic iron concentration and hepatic iron index were not associated with hepatic inflammation and fibrosis. Multivariate analysis did not identify serum ferritin or body mass index as an independent predictor of liver injury. CONCLUSIONS: Hepatic iron deposition shows no association with the degree of hepatic inflammation or fibrosis. Hepatic iron is not an independent predictor of hepatic injury in patients with NAFLD.
Adolescent ; Adult ; Fatty Liver/complications/*metabolism ; Female ; Ferritins/blood ; Humans ; Inflammation ; Iron/blood/*metabolism ; Liver/*metabolism/pathology ; Liver Cirrhosis/*etiology/metabolism/pathology ; Male ; Middle Aged

BACKGROUNDSomafostatin receptors (SSTRs) have been suggested to involve in mediating the effect of somatostatin on hepatic stellate cells (HSCs) in an activation-dependent way. We, therefore, try to investigate the relationship between expression of SSTRs and activation of rat HSCs.

METHODSHSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation. SSTR1-5 mRNA levels in the differentiated first passage HSCs were detected by means of a reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR1-5 in normal as well as fibrotic livers was measured by immunohistochemical staining.

RESULTSSSTR mRNA and SSTR could not be found in freshly isolated rat HSCs or normal rat liver. However, SSTR1-3 mRNA appeared as HSCs became wholly activated, and could also be identified on the membrane of activated HSCs in the perisinusoid space, fibrous septa, etc.

CONCLUSIONThe expression of SSTR1-3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.

Animals ; Liver ; cytology ; metabolism ; Liver Cirrhosis ; etiology ; Male ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Receptors, Somatostatin ; genetics

Portal hypertension (PHT) is associated with hemodynamic changes in intrahepatic, systemic, and portosystemic collateral circulation. Increased intrahepatic resistance and hyperdynamic circulatory alterations with expansion of collateral circulation play a central role in the pathogenesis of PHT. PHT is also characterized by changes in vascular structure, termed vascular remodeling, which is an adaptive response of the vessel wall that occurs in response to chronic changes in the environment such as shear stress. Angiogenesis, the formation of new blood vessels, also occurs with PHT related in particular to the expansion of portosystemic collateral circulation. The complementary processes of vasoreactivity, vascular remodeling, and angiogenesis represent important targets for the treatment of portal hypertension. Systemic and splanchnic vasodilatation can induce hyperdynamic circulation which is related with multi-organ failure such as hepatorenal syndrome and cirrhotic cadiomyopathy.
Collateral Circulation/physiology ; Endothelial Cells/metabolism ; Hemodynamics ; Hepatic Stellate Cells/metabolism ; Hypertension, Portal/*etiology ; Liver Circulation/physiology ; Liver Cirrhosis/*etiology ; Splanchnic Circulation/physiology

PURPOSE: Using FibroScan(R) to obtain a reliable liver stiffness measurement (LSM) may require more than 10 valid measurements (VMs), according to the manufacturer's recommendations. However, this requirement lacks scientific evidence in support thereof. We investigated the minimal number of VMs required to assess liver fibrosis without significant loss of accuracy in patients with chronic hepatitis B (CHB) and C (CHC) and predictors of discordance between LSM and liver biopsy (LB). MATERIALS AND METHODS: Between January 2005 and December 2009, we prospectively enrolled 182 patients with CHB and 68 patients with CHC who were to undergo LB and LSM before starting antiviral treatment. Only LSMs with at least 10 VMs were considered reliable. The Batts and Ludwig scoring system was used for histologic assessment. RESULTS: The mean age and body mass index were 46.0 years and 23.4 kg/m2 in patients with CHB and 49.7 years and 23.1 kg/m2 in those with CHC, respectively. The median elasticity scores from the first 3, first 5, and all VMs taken significantly predicted fibrosis stages > or =F2 and F4 (all p<0.05) without significant differences (all p>0.05 by DeLong's method). Alanine aminotransferase (ALT) was the only predictor of discordance in fibrosis stage as estimated by the median elasticity score from the first 3 VMs and by LB in patients with CHB, whereas no significant predictor was identified in those with CHC. CONCLUSION: After comparison of patients who had more than 10 valid measurements for LSM, three VMs may be enough to assess liver fibrosis using LSM without significant loss of accuracy in patients with CHC and patients with CHB. However, ALT should be considered when interpreting LSM for patients with CHB.
Adult ; Alanine Transaminase/metabolism ; Female ; Hepatitis B, Chronic/*complications/metabolism ; Humans ; Liver/metabolism/pathology ; Liver Cirrhosis/*diagnosis/etiology/metabolism ; Male ; Middle Aged ; Prospective Studies

A study conducted 15-year ago showed that only 13.5% of chronic alcoholics developed alcohol-induced liver damage, which misled some people to believe a lack of relationship between the amount of alcohol and the occurrence of liver disease. However, it is true that a significant correlation exists between per capita consumption and the prevalence of cirrhosis. Alcoholic fatty liver is observed in most of chronic alcoholics even though the severity is not uniform. Abstinence remains the cornerstone of therapy for alcoholic liver disease (ALD). There is also consensus for the use of corticosteroids and pentoxifylline in severe alcoholic hepatitis maintaining good nutritional status to treat comorbidities in all forms of ALD, and liver transplantation in the end-stage ALD patients who can stop drinking for 6 months pre-transplantation period. Several clinical trials targeting tumor necrosis factor (TNF-alpha) and reducing oxidative stress have not been successful at this time. There is still a large field of alcohol research to explore in order to go farther in the area of pathophysiology. We need to understand a role of various cytokines and immune cells in the development of ALD to have more treatment tools to cope with ALD.
Alcohols/metabolism ; Cytochrome P-450 CYP2E1/metabolism ; Fatty Liver, Alcoholic/pathology/therapy ; Humans ; Liver Cirrhosis, Alcoholic/pathology/therapy ; Liver Diseases, Alcoholic/*etiology/pathology/therapy ; Oxidative Stress

Animals ; Elasticity Imaging Techniques ; Extracellular Matrix ; metabolism ; Humans ; Liver ; metabolism ; pathology ; Liver Cirrhosis ; diagnosis ; drug therapy ; etiology ; Liver Diseases ; complications ; Mice ; Retrospective Studies

OBJECTIVEThe aim of this study was to explore the diagnostic value of liver stiffness measurement combined with serum high-sensitivity C-reactive protein detection in HBV-related cirrhosis patients complicated with primary liver cancer.

METHODSA total of 156 previously untreated chronic hepatitis B-related cirrhosis patients and 50 healthy subjects were included in this study. The 156 patients were divided into two groups: those with primary liver cancer (67 cases) and without liver cancer (89 cases). The 50 healthy subjects were considered as normal control group. Liver stiffness measurement (LSM) was conducted and serum high-sensitivity C-reactive protein (CRP) level was assayed in all the 156 patients and 50 normal individuals, and their measurement values were statistically compared and analyzed.

RESULTSThe LSM value was (39.72±29.05) kPa in the liver cancer patients, significantly higher than the (27.81±18.46) kPa in the cirrhosis alone patients and (4.25±0.74) kPa in the healthy controls (P<0.01 for both). Serum hs-CRP levels in the liver cancer patients was 5.81mg/L, significantly higher than 1.78 mg/L in the cirrhosis alone patients and 0.38mg/L in healthy controls, (P<0.01 for both). The higher the grade of LSM values was, the positive rate of CRP was higher in the cirrhosis patients complicated with primary liver cancer. In patients with LSM values ≥27.6 kPa, the serum CRP positive rate was 64.2% in patients with primary liver cancer, significantly higher than the 38.0% in patients with cirrhosis alone (P<0.01). In the 67 HBV-related cirrhosis patients complicated primary liver cancer, the LSM value and serum hs-CRP level in AFP-positive patients were (48.95±28.59) kPa and 4.91 mg/L, respectively, higher than those in the AFP-negative patients (28.64±26.83) kPa and 4.16 mg/L, but with a non-significant difference (P>0.05).

CONCLUSIONLiver stiffness measurement combined with serum high-sensitivity C-reactive protein detection may have potential diagnostic implications as a marker of primary liver cancer occurrence in patients with HBV-related cirrhosis.

Biomarkers ; C-Reactive Protein ; metabolism ; Elasticity Imaging Techniques ; Fibrosis ; Hepatitis B, Chronic ; complications ; metabolism ; Humans ; Liver Cirrhosis ; etiology ; metabolism ; virology ; Liver Neoplasms