the possible interaction between HO/CO and NOS/NO pathways in the pathophysiology of portal hypertension. PATIENTS. METHODS. Figura 1. Plasma CO ...
ROLE OF CARBON MONOXIDE IN HYPERDYNAMIC CIRCULATION IN CIRRHOTIC PATIENTS Mastroianni R, 1Tarquini R, 2Santosuosso U, 1La Villa G, 1Laffi G, Masini E. Departments of Preclinical and Clinical Pharmacology, 1Internal Medicine, 2School of Medicine, University of Florence, Italy. BACKGROUND
AIM OF THE STUDY The current investigation was undertaken to investigate:
Portal hypertension is a hemodynamic syndrome mostly caused by liver cirrhosis in Western countries. It causes a series of alterations responsible for the onset of complications such as portal hypertension and concomitant splanchnic vasodilation, due to the increasing release of vasodilating factors.
the role of the HO/CO system in the hyperdynamic circulatory syndrome of human cirrhosis; the possible interaction between HO/CO and NOS/NO pathways in the pathophysiology of portal hypertension.
Liver cirrhosis is associated with endothelial dysfunction and deficiency of endothelial nitric oxide (NO) release in hepatic microcirculation. In contrast, splanchnic and systemic vasculature exhibit marked endothelial NO overproduction [1].
SYSTEMIC & SPLANCHNIC CIRCULATION
Carbon monoxide (CO), produced by heme-oxygenase (HO) pathway, has also been suggested to play a role in hepatic microcirculation. Similar to NO, CO causes smooth muscle cell relaxation through up-regulation of cGMP, via guanylate cyclase [2].
NO
Studies in animals with portal hypertension due to portal vein ligation have shown an upregulation of HO pathway; furthermore in cirrhotic patients, high CO levels in exhaled air and elevated COHb have been observed, suggesting a possible role of HO/CO system in the pathogenesis of hyperdynamic circulation in human cirrhosis [3].
HEPATIC CIRCULATION
?
NO / CO
Sensitivity to vasopressors
Sensitivity to vasopressors
Vascular resistance
Vascular resistance
GENERALISED VASODILATION
PORTAL HYPERTENSION
Systemic vasodilatation versus hepatic vasoconstriction in cirrhosis
PATIENTS
In total, 31 consecutive non-smoking in-or outpatients with liver cirrhosis at the Department of Internal Medicine, were enrolled (Table 1). The diagnosis of cirrhosis was based on patients’ history, physical examination, liver ultrasound, and laboratory findings and classified according to Child-Pugh score. Cirrhosis was hepatitis C virus-related in 27 patients and hepatitis B virus-related in 4 patients. According to Child-Pugh score 17 patients were in class A, 8 in B, 6 in C and 13 patients presented ascites. All patients had portal hypertension. No patients had infection, organic cardiovascular, renal, or pulmonary diseases, diabetes, hepatocellular carcinoma or other malignancies and recent gastrointestinal bleeding. No patients were taking β-blockers, antibiotics, or nitrates in the 30 days preceding the study. Nine healthy subjects of comparable sex and age were enrolled.
METHODS Under local anesthesia, a double-lumen venous catheter was placed in the right jugular vein under ultrasonographic guidance. One of the lumens was used to advance, under continuous fluoroscopic control, a 7F balloon-tipped catheter in the right hepatic vein. Wedge (occluded, WHVP) and free hepatic venous pressures (FHVP) were measured by inflating and deflating the balloon-tipped catheter placed in the right hepatic vein connected to an external electromechanical transducer and a polygraph. Portal pressure (HVPG) was estimated evaluating the difference between WHVP and FHVP. Liver stiffness was measured by Transient Elastography in 17 patients. Transient Elastography was performed using the FibroScan® apparatus, which consists of a 5-MHz ultrasound transducer probe mounted on the axis of a vibrator. Mild amplitude and low frequency vibrations (50 Hz) were transmitted to the liver tissue, inducing an elastic shear wave propagated through the underlying liver tissue. The velocity of the wave was related to tissue stiffness. The median value of 10 successful acquisitions, expressed in kilopascal (kPa), was kept as representative of the liver stifness measurement. Blood samples obtained from cava and suprahepatic vein were collected in EDTA-tubes and immediately centrifuged at 3000 r.p.m. for 10 min. at room temperature. Plasma was stored at –20°C until analysed. Plasma level of NO was determined evaluating nitrite/nitrate amount by Griess reaction and expressed as NOx μmol/ml plasma. Plasma CO concentration was measured using the method by Vreman et al. [4], modified in our laboratory. The amount of CO liberated into the reaction vial headspace was determined with an ultra-trace level gas detection system (RGA3 Reduction Gas Analyzer, SAES Getters, Milan, Italy) [2]. Data are reported as mean value ± SD. Statistical analysis was performed with Origin 7.5 pro statistical package (OriginLab®, Northampton, Mass). Data were analyzed by ANOVA, validated with Bonferroni correction. Correlations were assessed by Pearson's coefficient.
RESULTS Figura 2. Plasma CO levels in cava and suprahepatic
cirrhotic patients and healthy subjects.
36
veins from cirrhotic patients and healthy subjects. #
32
* CO (p.p.m)
24
12
significantly higher in cirrhotic patients (11.71±7.00 p.p.m.) than in healthy subjects (5.81 ± 1.32 p.p.m, *p
