Elevated Nitric Oxide Levels in Patients with Chronic Liver Disease and Cirrhosis Correlate with Disease Stage and Parameters of Hyperdynamic Circulation

Zusammenfassung

Chronische Lebererkrankungen sind gekennzeichnet durch Veränderungen des splanchnischen und systemischen Blutkreislaufs. Diese Veränderungen sind besonders durch eine Verminderung des peripheren Widerstands und ein erhöhtes Herzminutenvolumen gekennzeichnet. Für diese Veränderungen wird eine vermehrte Stickoxid-(NO-)Freisetzung verantwortlich gemacht.

Diese Studie wurde durchgeführt, um den Stickoxidmetabolismus, gemessen anhand der Nitratkonzentrationen im Serum und Urin, bei Patienten mit chronischer aktiver Hepatitis (CAH) und Patienten mit Leberzirrhose zu bestimmen.

Die Studie zeigte erhöhte Nitratkonzentrationen besonders in fortgeschrittenen Stadien der Leberzirrhose (Child B und C), wobei die Nitratkonzentrationen bei Patienten mit CAH und frühen Stadien der Leberzirrhose (Child A) eher niedrig oder normal waren.

Die Studie konnte einen signifikanten Zusammenhang zwischen dem Ausmaß der portalen Hypertension und den Nitratkonzentrationen darstellen. Das Vorhandensein von Aszites und ein hohes Stadium von Ösophagusvarizen korrelierte mit den Nitratkonzentrationen. Ein Zusammenhang zwischen den Nitratkonzentra­tionen und den Reninkonzentrationen im Serum konnte ebenfalls gezeigt werden. Demnach darf die Aktivierung des Renin-Angiotensin-Systems als Kompensationsmechanismus angesehen werden, der dazu dient, den niedrigen peripheren Widerstand zu antagonisieren.

Diese Studie zeigt, dass mit fortschreitender portaler Hyperten­sion ein gesteigerter Stickoxidmetabolismus zu hämodynamischen Veränderungen bei Patienten mit fortgeschrittener Leberzirrhose führt.

Abstract

Chronic liver diseases are accompanied by changes in splanchnic and systemic circulation. These changes are characterised by a reduction in peripheral vascular resistance and an increased cardiac output at rest. An increased release of nitric oxide (NO) has been proposed to play a role in the pathogenesis of vasodilatation and vascular hypocontractility. This study was designed to determine the nitric oxide metabolism measured as circulating nitrate levels in serum/urine in patients with chronic liver disease and cirrhosis. The nitrate concentrations were significantly increased in advanced degrees in cirrhosis Child B and C, and normal or even reduced in patients with chronic active hepatitis and early cirrhosis. In our study the connections between the extent of portal hypertension and nitrate levels were evident. The presence of ascites as well as the the progression of oesophageal varices were associated with higher circulating nitrate levels. The connection between increased nitric oxide production and the haemodynamic sequelae of portal hypertension is also apparent in the significant correlation between plasma renin and serum nitrate levels. Circulating nitrate levels also correlated to the serum interleukin-6 levels. This study demonstrated that the increased nitric oxide metabolism is associated with the haemodynamic alterations induced by portal hypertension.

Schlüsselwörter

Leberzirrhose - portale Hypertension - Stickoxid (NO) - Nitrat - Interleukin-6 (IL-6) - Tumor Nekrosefaktor-α (TNF-α)

Key words

Liver cirrhosis - portal hypertension - nitric oxide - nitrates - ­renine - interleukin-6 - tumour necrosis factor-α

References

• 1 Vallance P, Moncada S. Hyperdynamic circulaion in cirrhosis: A role for nitric oxide?.  Lancet. 1991;  337 March 30
• 2 Hartleb M, Michielsen P P, Dziurkowska-Marek A. The role of nitric oxide in portal hypertensive systemic and portal vascular pathology.  Acta Gastroenterol Belg. 1997;  60 (3) 222-232
• 3 Campillo B, Borries P N, Benvenuti C. et al . Serum and urinary nitrate levels in liver cirrhosis: endotoxemia, renal function and hyperdynamic circulation.  J Hepatol. 1996;  25 (5) 707-714
• 4 Martin P Y, Xu D L, Niederberger M. et al . Upregulation of endothelial constitutive NOS: a majorrole in the increased nitric oxide production in cirrhotic rats.  Am J Physiol. 1996;  270 (3Pt2) F494-499
• 5 Matsumoto A, Ogura K, Hirata Y. et al . Increased nitric oxide in the exhaled air of patients with decompensated liver cirrhosis.  Ann J Intern Med. 1995;  123 (2) 110-113
• 6 Woitas R P, Heller J, Stoffel-Wagner. et al . Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis.  Hepatology. 1997;  26 (4) 858-864
• 7 Amaro M J, Bartolome J, Pardo M. et al . Decreased nitric oxide production in chronic viral hepatitis B and C.  J Med Virol. 1997;  51 326-331
• 8 Ishak K. et al . Histological grading and staging of chronic hepatitis.  J Hepatology. 1995;  22 696-699
• 9 Jungersten L, Edlund, A, Petersson A S. et al . Plasma nitrate as an index of nitric oxide formation in man: analyses of kinetics an confounding factors.  Clin Phydiol. 1996;  16 (4) 369-379
• 10 Tsikas D, Gutzki F M. et al . Measurement of nitrite and nitrate in biolog­ical fluids by gas chromatography-mass spectrometry and by Griess assay: Problems with Griess assay-solutions by gas chromatography-mass spectrometry.  Anal Biochem. 1997;  244 208-220
• 11 Tsikas D, Frölich J C. Determination of nitrite as pentafluorobenzyl ­derivative by RP-HPLC and UV-detection with and without ion-pair extract ion.  Fresenius J Anal Chem. 1992;  34 256-260
• 12 Ratge D, Baumgardt G, Knoll E. et al . Plasma free and conjugated catecholamines in diagosis and localization of pheochromocytoma.  Clin Chem Acta. 1983;  132 229-235
• 13 Shijo H, Yokoyama M, Ota K. et al . Nitrate kinetics in patients with compensated cirrhosis: correlation with haemodynamics.  Am J Gastroenterol. 1996;  91 (10) 2190-2194
• 14 Hori N, Wiest R, Groszmann R J. Enhanced release of nitric oxide in response to changes in flow and shear stress in the superior mesenteric arteries of portal hypertensive rats.  Hepatology. 1996;  28 1467-1473
• 15 Cahill P A, Redmond E M, Hodges R. et al . Increased endothelial nitric oxide synthetase activity in the hyperdynamic vessels of portal hypertensive rats.  J Hepatol. 1996;  25 (3) 370-378
• 16 Pateron D, Tazi K, Sogni P. et al . Role of aortic nitric oxide synthase 3 (eNOS) in the systemic vasodilation of portal hypertension.  Gastro­enterology. 2000;  119 196-200
• 17 Tazi K, Barrière E, Moreau R. et al . Role of shear stress in aortic eNOS up-regulation in rats with biliary cirrhosis.  Gastroenterology. 2002;  122 1869-1877
• 18 Yokomori H, Oda M, Ogi M. et al . Enhanced expression of endothelial nitric oxide synthase and caveolin-1 in human cirrhosis.  Liver. 2002;  22 (2) 150-158
• 19 Nadaud S, Phillippe M, Arnal J F. et al . Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow.  Circ Res. 1996;  79 857-863
• 20 Chou T F, Wu M S, Chien C T. et al . Enhanced expression of nitric oxide synthase in the early stage after increased pulmonary blood flow in rats.  Eur J Cardiothorac Surg. 2002;  21 (2) 331-336
• 21 Wattanasirichaigoon S, Gordon F D, Resnick R H. Hyperdynamic circulation in portal hypertension: a comparative model of arterio-venous fistula.  Med Hypotheses. 2000;  55 (1) 77-87
• 22 Lee F Y, Lu R H, Tsai Y T. et al . Plasma Interleukin-6 levels in patients with cirrhosis.  Scan J Gastroenterol. 1996;  31 500-505
• 23 Genesca J, Gonzalez A, Segura R. et al . Interleukin-6, Nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis.  Am J Gastroenterol. 1999;  94 (2) 372-376
• 24 Niiya T, Murakami M, Aoki T. et al . Immediate increase of portal pressure, reflecting shear stress, induced liver regeneration after partial hepatectomy.  J Hepatobiliary Pancreat Surg. 1999;  6 (3) 275-280