Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The haem oxygenase (HO)/carbon monoxide (CO) system has been implicated as a modulator of hepatobiliary function. This study investigated HO expression in the process of cirrhosis development, as well as its relationship to nitric oxide synthase (NOS). Liver cirrhosis was induced in rats by chronic bile duct ligation (BDL). HO mRNA expression was evaluated by competitive RT-PCR, while protein expression was determined by immunoblotting and immunohistochemistry. In liver tissue where cirrhosis had fully developed, the expression levels of HO-1 were greatly enhanced at both mRNA and protein level compared with sham livers. Immunohistochemistry showed that HO-1 was induced in hepatocytes and enhanced in some of the Kupffer-like cells in BDL livers. In contrast, there was no difference between the sham and the BDL livers for the expression levels of HO-2. Interestingly, administration of the NOS inhibitor aminoguanidine (AG) or N(G)-nitro-L-arginine methyl ester inhibited HO-1 expression. To study further the role of HO-1 in the development of liver cirrhosis, hepatocytes were isolated from the rats at different time points after BDL operation. HO-1 was expressed in hepatocytes at high levels during the early onset of cirrhosis but dropped slightly at a later stage of cirrhosis. Zinc protoporphyrin IX (ZnPP), an HO inhibitor, blocked HO-1 expression in hepatocytes from BDL cirrhotic rats, but enhanced the activity of inducible NOS (iNOS) in BDL hepatocytes. In conclusion, HO-1 was induced in the hepatocytes of rats undergoing cirrhosis, suggesting that HO-1 plays a role in the development of liver cirrhosis. Induction of HO-1 may be mediated partially by iNOS. However, once it is induced, HO-1 may be important in modulating iNOS activity, thus playing a protective role in liver cirrhosis.
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PMID:Expression of haem oxygenase in cirrhotic rat liver. 1257 34

Hepatopulmonary syndrome has yet not been sufficiently assessed in noncirrhotic portal hypertension. The prevalence of hepatopulmonary syndrome was determined in 31 consecutive patients with noncirrhotic portal hypertension (19 idiopathic portal hypertension, 7 portal vein thrombosis, 5 congenital hepatic fibrosis) and 46 patients with liver cirrhosis. Contrast echocardiography was carried out in all patients. Macroaggregated albumin lung perfusion scans were performed in patients with positive contrast echocardiogram. Hepatopulmonary syndrome was detected in 5 (10.8%) cirrhotic and 3 (9.7%) noncirrhotic portal hypertensive patients (2 idiopathic portal hypertension, 1 portal vein thrombosis). All patients with hepatopulmonary syndrome had an increased shunt fraction (13-62%) and a decreased diffusion capacity of carbon monoxide (40-79%), and 7 of them were hypoxemic (PaO2, 31.6-69.8 mm Hg). These findings show that hepatopulmonary syndrome may occur in both liver cirrhosis and noncirrhotic portal hypertension and that portal hypertension is the predominant etiopathogenic factor related to hepatopulmonary syndrome.
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PMID:Hepatopulmonary syndrome in noncirrhotic portal hypertensive patients. 1275 70

Carbon monoxide, a product of the heme-oxygenase (HO) pathway, is an important endogenous vasoactive substance. Production of CO has not been assessed in human cirrhosis. The aim of this study was to assess production of CO in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP). CO concentration in the exhaled air and blood carboxyhemoglobin (COHb) levels, as estimates of total HO activity, were determined in 16 healthy subjects, 32 noninfected cirrhotic patients (20 with ascites), and 19 patients with SBP, all nonsmokers. Noninfected cirrhotic patients had a CO concentration in the exhaled air and COHb levels significantly higher compared with values of healthy subjects (2.3 +/- 0.2 ppm vs. 0.7 +/- 0.1 ppm and 1.0% +/- 0.1% vs. 0.6% +/- 0.1%, respectively; P <.05 for both). Patients with ascites had the highest values. Both CO concentration in the exhaled air and COHb levels were very high in patients with SBP (5.6 +/- 0.6 ppm and 1.9% +/- 0.2%; P <.01 vs. the other 2 groups) and decreased slowly after resolution of the infection, reaching values similar to those of noninfected patients 1 month after SBP. In patients with SBP, there was a significantly direct correlation between CO and plasma renin activity (PRA) (r = 0.71, P <.001). In conclusion, these results support the existence of increased CO production in human cirrhosis, which further increases in the setting of SBP. Increased CO production may participate in the disturbance of circulatory function that occurs during severe bacterial infections in cirrhosis.
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PMID:Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis. 1288 90

Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.
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PMID:Role of the heme oxygenases in abnormalities of the mesenteric circulation in cirrhotic rats. 1460 Feb 47

Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1-13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.
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PMID:Mechanism of dichloroacetate-induced hypolactatemia in humans with or without cirrhosis. 1528 Oct 24

1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.
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PMID:Role of heme oxygenase/carbon monoxide pathway on the vascular response to noradrenaline in portal hypertensive rats. 1574 3

Pulmonary vascular abnormalities occurring in the setting of liver disease have been increasingly recognized as important clinical entities that influence survival and liver transplant candidacy in affected patients. The most common such abnormality, the hepatopulmonary syndrome, is found in 15% to 20% of patients with cirrhosis. These disorders have no effective medical therapies. Experimental models of hepatopulmonary syndrome have identified a sequence of hepatic and pulmonary endothelial alterations that lead to nitric oxide and carbon monoxide-mediated intrapulmonary vasodilatation. A key role for shear stress-mediated pulmonary endothelial endothelin B receptor overexpression and cholangiocyte ET-1 production and release has emerged as a mechanism for local nitric oxide production in the lung. How these alterations are influenced by bacterial translocation and the systemic hyperdynamic circulatory state and whether similar changes occur in human disease are areas of ongoing investigation.
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PMID:Mechanisms of pulmonary vascular complications of liver disease: hepatopulmonary syndrome. 1575 49

In the belief that the advantages stemming from a minimally invasive approach are significant, particularly in cirrhosis patients, we decided to apply this technique in the treatment of a group of patients suffering from HCC associated with cirrhosis. Sixteen patients (10 men, 6 women; mean age 60.1 years) underwent laparoscopic surgery for HCC associated with well compensated HCV-related liver cirrhosis (Child-Pugh class A; mean tumour size 2.9 cm). Seven of these lesions were located in the left liver and 9 in the right lobe. Laparoscopy was performed with a CO2 pneumoperitoneum (12-14 mmHg). The Pringle manoeuvre was not used. There was one conversion to laparotomy due to inadequate exposure. We performed 13 non-anatomical resections, 1 VI segmentectomy and 1 anatomical left lobectomy. None of the patients required blood transfusions. One patient died of severe respiratory distress syndrome on postoperative day 3. Major morbidity included 2 moderate postoperative ascites successfully resolved with conservative treatment. To date (mean follow-up: 18 months) no recurrences at the resection site or port-site metastases have been observed. Limited laparoscopic liver resections for HCC in cirrhotic patients are technically feasible and safe when careful selection criteria are adopted (hepatic involvement limited and located in the left or anterior right segments, tumour size smaller than 5 cm, Child-Pugh class A).
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PMID:[Laparoscopic liver resection without a Pringle maneuver for HCC in cirrhotic patients]. 1583 34

Cirrhosis is associated with the development of a hyperdynamic circulation, which is secondary to the presence of systemic vasodilatation. Several mechanisms have been postulated to be involved in the development of systemic vasodilatation, including increased synthesis of nitric oxide, hyperglucagonaemia, increased carbon monoxide synthesis, and activation of K(ATP) channels in vascular smooth muscle cells in the systemic and splanchnic arterial circulation. Hydrogen sulphide (H2S) has recently been identified as a novel gaseous transmitter that induces vasodilatation through activation of K(ATP) channels in vascular smooth muscle cells. In this brief review, we comment on what is known about H2S, vascular and neurological function, and postulate its role in the pathogenesis of the vascular abnormalities in cirrhosis.
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PMID:Hydrogen sulphide and the hyperdynamic circulation in cirrhosis: a hypothesis. 1617 60

A 73-year-old man was diagnosed as having hepatitis C virus-related liver cirrhosis 11 years ago. Two years ago, he developed hepatocellular carcinoma in segment 6 of the right lobe and received radiofrequency ablation. This time, he was admitted to our hospital with a local recurrence in segment 6 of the liver. Standard sonography could not visualize the lesion clearly. However, carbon dioxide-enhanced sonogram clearly showed the whole lesion, so a needle electrode could be inserted precisely, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, complete tumor necrosis was achieved without the need to perform additional ablation. In conclusion, carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization is useful for complete cure of localized tumors, such as recurrent hepatocellular carcinoma, which cannot be detected clearly by conventional sonography.
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PMID:Carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization for sonographically undetectable hepatocellular carcinoma. 1620 Oct 70


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