Tetrahydrobiopterin (BH4) is an essential cofactor in NO synthesis by endothelial nitric oxide synthase (eNOS) enzymes. It has been previously suggested that reduced intrahepatic BH4 results in a decrease in intrahepatic NO and contributes to increased hepatic vascular resistance and portal pressure in animal models of cirrhosis. The main aim of the present study was to evaluate the relationship between BH4 and portal hypertension (PHT). One hundred ninety-three consecutive patients with chronic liver disease were included in the study. Liver biopsy, measurement of BH4 and hepatic venous pressure gradient (HVPG) were performed. Hepatic fibrosis was classified using the Laennec fibrosis scoring system. BH4 levels were determined in homogenized liver tissues of patients using a high performance liquid chromatography (HPLC) system. Statistical analysis was performed to evaluate the relationship between BH4 and HVPG, grade of hepatic fibrosis, clinical stage of cirrhosis, Child-Pugh class. A positive relationship between HVPG and hepatic fibrosis grade, clinical stage of cirrhosis and Child-Pugh class was observed. However, the BH4 level showed no significant correlation with HVPG or clinical features of cirrhosis. BH4 concentration in liver tissue has little relation to the severity of portal hypertension in patients with chronic liver disease.
Adult ; Aged ; Biopterin/*analogs & derivatives/analysis ; *Chromatography, High Pressure Liquid ; Chronic Disease ; Elasticity Imaging Techniques ; Female ; Hepatic Veins/physiology ; Humans ; Hypertension, Portal/complications/*diagnosis/metabolism ; Liver/pathology ; Liver Cirrhosis/ultrasonography ; Liver Diseases/complications/*diagnosis/metabolism ; Male ; Middle Aged ; Nitric Oxide/metabolism ; Portal Pressure ; Regression Analysis ; Severity of Illness Index

Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and alpha-smooth muscle actin (alpha-SMA) were conducted with control group. The immunohistochemical stains for CD31 and alpha-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication.
Actins/metabolism ; Antigens, CD31/metabolism ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Camptothecin/*analogs & derivatives/therapeutic use ; Chemotherapy, Adjuvant ; Colonic Neoplasms/*drug therapy ; Fluorouracil/therapeutic use ; Humans ; Hypertension, Portal/etiology ; Immunohistochemistry ; Leucovorin/therapeutic use ; Liver Cirrhosis/*diagnosis/etiology/pathology ; Liver Neoplasms/secondary/surgery ; Male ; Middle Aged ; Organoplatinum Compounds/*administration & dosage/adverse effects/therapeutic use ; Splenomegaly/*diagnosis/etiology ; Thrombocytopenia/etiology ; Tomography, X-Ray Computed

The lymphatic system is part of the circulatory system and plays a key role in normal vascular function. Its failure plays a crucial role in the development and maintenance of various diseases including liver diseases. Lymphangiogenesis (the growth of lymphatic vessels) and changes in the properties of lymphatic vessels are associated with pathogenesis of tumor metastases, ascites formation, liver fibrosis/cirrhosis and portal hypertension. Despite its significant role in liver diseases and its importance as a potential therapeutic target for those diseases, the lymphatic vascular system of the liver is poorly understood. Therefore, how the lymphatic vascular system in general and lymphangiogenesis in particular are mechanistically related to the pathogenesis and maintenance of liver diseases are largely unknown. This article summarizes: 1) the lymphatic vascular system; 2) its role in liver tumors, liver fibrosis/cirrhosis and portal hypertension; and 3) its role in ascites formation.
Ascites/*etiology ; Humans ; Hypertension, Portal/complications/pathology ; Liver Cirrhosis/complications/pathology ; Liver Diseases/complications/*pathology ; Liver Neoplasms/complications/pathology ; Lymphangiogenesis ; Lymphatic Vessels/metabolism/physiopathology

Because of the anatomical position and its unique vascular system, the liver is susceptible to the exposure to the microbial products from the gut. Although large amount of microbes colonize in the gut, translocation of the microbes or microbial products into the liver and systemic circulation is prevented by gut epithelial barrier function and cleansing and detoxifying functions of the liver in healthy subjects. However, when the intestinal barrier function is disrupted, large amount of bacterial products can enter into the liver and systemic circulation and induce inflammation through their receptors. Nowadays, there have been various reports suggesting the role of gut flora and bacterial translocation in the pathogenesis of chronic liver disease and portal hypertension. This review summarizes the current knowledge about bacterial translocation and its contribution to the pathogenesis of chronic liver diseases and portal hypertension.
Antigens, CD14/metabolism ; Bacterial Translocation ; Gastrointestinal Tract/*microbiology ; Humans ; Hypertension, Portal/metabolism/*pathology ; Liver/metabolism/*microbiology ; Liver Cirrhosis/metabolism/*pathology ; Receptors, Cytoplasmic and Nuclear/metabolism ; Toll-Like Receptors/metabolism

Adult ; Arsenic Poisoning ; pathology ; Chronic Disease ; Hemosiderin ; metabolism ; Hemosiderosis ; metabolism ; pathology ; Humans ; Hypertension, Portal ; chemically induced ; metabolism ; pathology ; Liver Cirrhosis ; chemically induced ; metabolism ; pathology ; Male ; Pancytopenia ; chemically induced ; metabolism ; pathology ; Splenomegaly ; chemically induced ; metabolism ; pathology

Portal hypertensive gastropathy (PHG) is a term used to define the endoscopic findings of gastric mucosa with a characteristic mosaic-like pattern with or without red spots, and a common finding in patients with portal hypertension. These endoscopic findings correspond to dilated mucosal capillaries without inflammation. The pathogenesis of PHG in not well known, but portal hypertension and some humoral factors seem to be crucial factors for its development. Pharmacological (e.g. propranolol), or interventional radiological (such as transjugular intrahepatic portosystemic shunt) procedures may be useful in preventing re-bleeding from PHG. The classic features of gastric antral vascular ectasia (GAVE) syndrome include red, often haemorrhagic lesions predominantly located in the gastric antrum which can result in significant blood loss. Although the pathogenesis of GAVE is not clearly defined, it seems to be a separate disease entity from PHG, because GAVE generally does not respond to a reduction of portal pressures. Endoscopic ablation (such as argon plasma coagulation) is the first-line treatment of choice. This review will focus on the incidence, clinical importance, etiology, pathophysiology, and treatment of PHG and GAVE syndrome in the setting of portal hypertension.
Esophageal and Gastric Varices/*diagnosis/etiology/therapy ; Gastric Antral Vascular Ectasia/*diagnosis/etiology/therapy ; Gastric Mucosa/metabolism/pathology ; Humans ; Hypertension, Portal/*complications ; Portasystemic Shunt, Transjugular Intrahepatic ; Vasodilator Agents/therapeutic use

Female ; Humans ; Hypertension, Portal ; etiology ; immunology ; Male ; Proliferating Cell Nuclear Antigen ; metabolism ; Spleen ; immunology ; metabolism ; pathology

OBJECTIVETo identify the differentially expressed genes associated with hypersplenism in patients with portal hypertension.

METHODSThe total RNA were extracted from the macrophages isolated from normal spleen and the spleen of patients with portal hypertension and reversely transcribed to cDNA with the incorporation of fluorescent (cy3 and cy5)-labeled dCTP to prepare the hybridization probes. After hybridization of Biostar-H140s chip containing 14,112 spots of cDNAs with the prepared probes, the gene chip was scanned for fluorescence intensity to screen the differently expressed genes. Three gene chips were used for hybridization and only the genes with differential expression in all the three chips were considered to associate with hypersplenism in patients with portal hypertension.

RESULTSTotaling 896, 1330 and 898 genes were identified to be differentially expressed by the three chips, respectively, and 121 genes (0.86%) showed differential expression in all the three chips, including 21 up-regulated known genes and 73 down-regulated known genes. The differently expressed genes were functionally related with ion channels and transport proteins, cyclins, cytoskeleton, cell receptors, cell signal transduction, metabolism, immunity, and so forth. These genes might be involved in hypersplenism in the condition of portal hypertension.

CONCLUSIONcDNA microarray-based screening of differentially expressed genes in the macrophages in the spleen may provide new insights into the pathogenesis of hypersplenism in patients with portal hypertension.

Female ; Gene Expression Profiling ; Humans ; Hypersplenism ; etiology ; genetics ; Hypertension, Portal ; complications ; genetics ; Macrophages ; metabolism ; Male ; Oligonucleotide Array Sequence Analysis ; methods ; Spleen ; metabolism ; pathology

BACKGROUNDPortacaval shunt (PCS) prevent hepatotrophic factors from flowing into the liver, but they enter directly the systemic circulation and worsen liver injury. This study was designed to investigate the effects of hepatotrophic factors through the portal vein on the liver in rats with portal hypertension after portacaval shunt.

METHODSIntrahepatic portal hypertension (IHPH) was induced by intragastric administration of carbon tetrachloride, and end-to-side PCS was performed. Eight normal rats served as controls, and eight rats with IHPH served as IHPH model (IHPH group). Another 32 rats with IHPH-PCS were randomly subdivided into 4 groups: normal saline (NS) given to 8 rats, hepatocyte growth factor (HGF) 8, insulin (INS) 8, hepatocyte growth factor and insulin (HGF + INS) 8. Hepatotrophic factors were infused into the portal vein through an intravenous catheter. Portal venous pressure (PVP) was measured. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were tested biochemically and those of hyaluronic acid (HA) and laminin (LN) were measured by radioimmunoassay. Hepatic fibrosis was assessed histologically and the expression of collagens type I and III were detected immunohistochemically. Ultrastructural change of hepatocytes and the number of mitochondria were observed under an electron microscope. The data were compared between groups and subgroups by Student-Newman-Keuls procedure with SPSS10.0.

RESULTSPVP was significantly higher in the IHPH rats than in the control rats (P < 0.05). The levels of serum ALT, AST, HA, and LN, hepatic fibrosis score, the amount of collagen deposition, collagens type I and III increased more significantly in the IHPH group than in the control rats (P < 0.05). The number of mitochondria decreased more significantly in the IHPH rats than in the control rats (P < 0.05). The levels of serum ALT, AST, HA and LN as well as hepatic fibrosis score, the amount of collagen deposition, and the amount of collagens type I and III in the HGF and HGF + INS rats were significantly lower than those in the NS rats (P < 0.05). The damage to hepatocyte ultrastructure was markedly alleviated and the number of mitochondria was increased more significantly in the HGF and HGF + INS rats than in the NS rats under an electron microscope.

CONCLUSIONSPerfusion of exogenous hepatotrophic factors through the portal vein can alleviate liver injury, minimize the damage to the ultrastructure of hepatocyte, protect liver function, and lessen hepatic fibrosis in rats with portal hypertension after PCS.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Extracellular Matrix ; metabolism ; Hepatocyte Growth Factor ; pharmacology ; Hypertension, Portal ; metabolism ; pathology ; surgery ; Insulin ; pharmacology ; Liver ; drug effects ; pathology ; ultrastructure ; Liver Cirrhosis, Experimental ; drug therapy ; Male ; Portacaval Shunt, Surgical ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate c-myc proto-oncogene expression and the relationship of PCNA protein expression of extrahepatic vascular smooth muscle cell in patients with portal hypertension and normal vessels.

METHODSRT-PCR was used to demonstrate the expression of c-myc mRNA and immuno-chemistry strain was performed to detect the expression of PCNA protein in splenic veins of 28 patients with portal hypertension and 12 normal vessels.

RESULTSThe straining of PCNA protein was (29.8 +/- 4.7)% in splenic veins with portal hypertension, Normal vessels did not detect PCNA protein expression (P < 0.01); RT-PCR showed that the expression of c-myc mRNA in PCNA-positive control and in negative control of splenic veins with portal hypertension were (7.61 +/- 1.04)% and (3.82 +/- 0.92)%, respectively. There ws different between two groups (P < 0.01) and significant different (P < 0.01) when compared with (1.01 +/- 0.21)% in normal vessels.

CONCLUSIONSThe c-myc was immediate-early gene when it modulated proliferation of vascular smooth muscle cell. Hemodynamic disturbance of portal vein system activate the proto-oncogene of smooth muscle cells in splenic vein of patients with portal hypertension, promoting the proliferation, migrating and phenotypic change and resulting in vascular remodelling of splenic veins.

Adult ; Aged ; Cell Proliferation ; Female ; Gene Expression ; Genes, myc ; genetics ; Humans ; Hypertension, Portal ; genetics ; pathology ; In Vitro Techniques ; Male ; Middle Aged ; Muscle, Smooth, Vascular ; cytology ; metabolism ; Myocytes, Smooth Muscle ; cytology ; Proliferating Cell Nuclear Antigen ; metabolism ; RNA, Messenger ; genetics ; Splenic Vein ; cytology ; metabolism