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

Changes in metabolic state of the liver after intravenous fructose (250 mg/kg) load were evaluated by P-31 MR spectroscopy. Study was performed in eight healthy volunteers and six patients with liver cirrhosis. In the spectra of the cirrhotic livers the fructose load caused no significant increase in PME peak, which suggested that fructose metabolism of the cirrhotic livers had impediments before the fructose-1-phosphate stage. Also shown in the spectra of the cirrhotic livers was the significant drop of Pi, PDE, and ATP peaks. This might reflect the low concentration of Pi, PDE and ATP in the cirrhotic livers.
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PMID:[Effect of intravenous fructose load on the P-31 MR spectrum of the cirrhotic liver]. 203 18

31P-MR spectroscopy was performed in 12 patients with focal and diffuse liver disease and in ten normal controls, using surface coils. Results so far show a significantly increased concentration of PME/beta-ATP and of PDE/beta-ATP in patients with liver metastases and in one patient with hepatic involvement by malignant lymphoma. The spectra of liver cirrhosis and fatty livers showed no characteristic changes.
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PMID:[In vivo 31-phosphorus magnetic resonance spectroscopy of liver diseases]. 216 78

Clinical studies using 31P and 1H MRS with a whole body 2.0 T MRI/MRS system are described. In most cases, techniques to quantitate absolute molar concentrations of metabolites in various organs were used. In the brain, AIDS, chronic stroke, and white matter lesions were associated with alterations of brain 31P metabolites. Epilepsy was associated with increased pH in the seizure focus. In the heart, dilated cardiomyopathy was associated with increased PDE/ATP while PCr/ATP was unchanged. In the liver, alcoholic hepatitis and cirrhosis were associated with diminished hepatic ATP while alcoholic hepatitis had increased pH and cirrhosis had decreased pH. This allowed differentiation of normal liver, alcoholic hepatitis, and alcoholic cirrhosis without biopsy. In the prostate, malignancy was associated with increased PME/ATP and decreased PCr/ATP. The PME/PCr was greatly increased in malignant prostate with no overlap in normals. Other cancers outside the brain had increased PME and effective treatment was often associated with diminished PME. 1H MRS of the brain was performed using ISIS and outer volume suppression pulses for volume localization. Excellent high resolution 1H water-suppressed spectra were obtained at echo times as short as 30 ms, showing well resolved peaks for lactate, N-acetylaspartate, glutamate, choline, creatinine, and inositol. 1H MRS demonstrated that the uptake of ethanol by the brain was slower than the rise of ethanol in blood. 31P spectroscopic imaging of the brain with resolution of 2.25 x 2.25 x 2.5 cm produced metabolic images and high resolution spectra from desired regions of interest.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical magnetic resonance spectroscopy of brain, heart, liver, kidney, and cancer. A quantitative approach. 270 9

31P-MRS using DRESS was used to compare absolute liver metabolite concentrations (PME, Pi, PDE, gammaATP, alphaATP, betaATP) in two distinct groups of patients with chronic diffuse liver disorders, one group with steatosis (NAFLD) and none to moderate inflammation (n=13), and one group with severe fibrosis or cirrhosis (n=16). All patients underwent liver biopsy and extensive biochemical evaluation. A control group (n=13) was also included. Absolute concentrations and the anabolic charge, AC=[PME]/([PME]+[PDE]), were calculated. Comparing the control and cirrhosis groups, lower concentrations of PDE (p=0.025) and a higher AC (p<0.001) were found in the cirrhosis group. Also compared to the NAFLD group, the cirrhosis group had lower concentrations of PDE (p=0.01) and a higher AC (p=0.009). No significant differences were found between the control and NAFLD group. When the MRS findings were related to the fibrosis stage obtained at biopsy, there were significant differences in PDE between stage F0-1 and stage F4 and in AC between stage F0-1 and stage F2-3. Using a PDE concentration of 10.5mM as a cut-off value to discriminate between mild, F0-2, and advanced, F3-4, fibrosis the sensitivity and specificity were 81% and 69%, respectively. An AC cut-off value of 0.27 showed a sensitivity of 93% and a specificity of 54%. In conclusion, the results suggest that PDE is a marker of liver fibrosis, and that AC is a potentially clinically useful parameter in discriminating mild fibrosis from advanced.
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PMID:Separation of advanced from mild fibrosis in diffuse liver disease using 31P magnetic resonance spectroscopy. 1764 74

Liver cirrhosis is associated with increased nitric oxide (NO) production in the vasculature. We have previously demonstrated that aorta from rats with liver cirrhosis have a reduced relaxant response to NO donors that is corrected by DMPPO, a PDE5-specific inhibitor. Vasodilator responses to DMPPO itself were also reduced in rings from cirrhotic rats. These results supported previous suggestions that upregulation of PDE5 in liver cirrhosis might contribute to renal sodium retention, and consequently modulate vascular reactivity in the context of increased NO production (Tahseldar-Roumieh et al. in Am. J. Physiol. Heart Circ. Physiol. 290, H481-H488, 2006). Here, we investigated the possible alteration in activity and expression of cyclic nucleotide phosphodiesterase PDE1-PDE5 in kidney and vascular tissues in rats 4 weeks after bile duct ligation. The kidney of rats with cirrhosis had increased activity of PDE1 and PDE4 but not PDE5, and increased expression of PDE1A. Unexpectedly and interestingly, there was no change in cirrhotic aorta PDE5, but an increase in PDE3 and PDE4 activity associated with increased expression of PDE3A and PDE3B. Cilostamide, a specific PDE3 inhibitor, corrected the decreased response to an NO donor in isolated aorta from cirrhotic rats, suggesting that the difference in response to NO donors was due to differences in PDE3-induced hydrolysis of cGMP or to cGMP-induced inhibition of PDE3, rather than to differences in PDE5 contribution. In conclusion, these changes in PDE isozymes could greatly contribute to NO desensitization and to the regulation of vascular and renal function in liver cirrhosis.
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PMID:PDEs1-5 activity and expression in tissues of cirrhotic rats reveal a role for aortic PDE3 in NO desensitization. 1975 18

Increasing NO bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of NO with a reduction in hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to NO in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our present study aims to evaluate the effects and mechanisms of administration of sildenafil for 1 week on the hepatic microcirculation of cirrhotic rats. Cirrhosis was induced by bile duct ligation with sham-operated rats serving as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phospho-eNOS (endothelial NO synthase), iNOS (inducible NO synthase), phospho-Akt, PDE-5 (phosphodiesterase-5) and sGC (soluble guanylate cyclase) were determined by Western blot analysis. Biosynthesis of BH4 (tetrahydrobiopterin) and GTPCH-I (GTP cyclohydrolase I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, and the protein expression of phospho-Akt, phospho-eNOS and sGC. These events were associated with reduced protein expression of PDE-5, portal perfusion pressure and portal vein pressure. In contrast, sham rats did not produce any significant change in these measurements. In conclusion, sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in the hepatic microcirculation.
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PMID:Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability. 2013 96

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based on Doppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.
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PMID:Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: A case report with 8 years follow-up. 2939 66

The concentration of fibroblast growth factor 23 (FGF23) rises progressively in renal failure (RF). High FGF23 concentrations have been consistently associated with adverse cardiovascular outcomes or death, in chronic kidney disease (CKD), heart failure or liver cirrhosis. We identified the mechanisms whereby high concentrations of FGF23 can increase the risk of death of cardiovascular origin. We studied the effects of FGF23 and Klotho in adult rat ventricular cardiomyocytes (ARVMs) and on the heart of mice with CKD. We show that FGF23 increases the frequency of spontaneous calcium waves (SCWs), a marker of cardiomyocyte arrhythmogenicity, in ARVMs. FGF23 increased sarcoplasmic reticulum Ca2+ leakage, basal phosphorylation of Ca2+-cycling proteins including phospholamban and ryanodine receptor type 2. These effects are secondary to a decrease in phosphodiesterase 4B (PDE4B) in ARVMs and in heart of mice with RF. Soluble Klotho, a circulating form of the FGF23 receptor, prevents FGF23 effects on ARVMs by increasing PDE3A and PDE3B expression. Our results suggest that the combination of high FGF23 and low sKlotho concentrations decreases PDE activity in ARVMs, which favors the occurrence of ventricular arrhythmias and may participate in the high death rate observed in patients with CKD.
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PMID:Fibroblast growth factor 23 decreases PDE4 expression in heart increasing the risk of cardiac arrhythmia; Klotho opposes these effects. 3269 40

Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
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PMID:Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. 3287 19