Search

Liver cirrhosis is characterized by a long course that lasts between 15 and 20 years. The natural history of this disease depends mainly on the occurrence and progression of single complications which are today more fully understood and therefore more treatable. More specifically, those complications involving hemodynamic mechanisms have been extensively studied in recent years. Indeed, the mechanisms involved in the occurrence of sodium positive balance and ascites, with or without renal dysfunction, have been clarified. It is now possible to distinguish between two different stages in the presence of hemodynamic modifications. In the first stage, an increasing accumulation of water and sodium may occur, leading to an increase in total plasma flow. Subsequently, there is a period of vascular instability and finally, the progressive appearance of typical signs of hyperdynamic circulation. During the second stage, cardiac function may be modified and consequently profoundly altered. The early administration of diuretics (antialdosteronics) seems to be capable of modifying cardiac dysfunction, leading to a return towards a physiological status through a rapid increase in diuresis and natriuresis and a decrease in plasma volume.

Ascites is the most frequent major complication of liver cirrhosis. Even if a significant decrease in renal clearances may be observed in the first stages of chronic active hepatitis, true renal impairment, often with the typical signs of hepatorenal syndrome, only occurs in patients with ascites, especially when tense and refractory. Experimental and clinical data suggest the presence of primary sodium and water retention, perhaps as a consequence of an increase in intrahepatic hydrostatic pressure. The abnormal sodium retention leads to plasma volume expansion, followed by decreased peripheral vascular resistances and increased cardiac output. This second stage concords with the peripheral arterial vasodilation theory, characterized by an increase in total blood volume, but with a decrease in effective arterial blood volume. This discrepancy leads to the activation of sympathetic nervous and renin-angiotensin-aldosterone systems. This activation, while protective against splanchnic and systemic vasodilation, provoked by the increased availability of nitric oxide and other vasodilating substances, induces renal vasoconstriction. This phenomenon can be considered as the basis of the progressive renal failure that leads to hepatorenal syndrome, favored by progressive exhaustion of the renal autacoid vasodilating substances. The first therapeutic approach to ascites is sequential and based on diuretic administration. Subsequently, paracentesis with albumin infusion is carried out, as well as transjugular intrahepatic portosystemic shunting, surgical portosystemic shunting, and liver transplantation: these procedures are essential for the treatment of hepatorenal syndrome.

The role of hepatitis B virus (HBV) and hepatitis C virus (HCV) as a major cause of chronic liver disease is now accepted worldwide. This study was aimed at evaluating the natural history of the disease in patients with virus-induced chronic active hepatitis or cirrhosis, and the influence played by age, sex and etiology, liver function tests and by the occurrence of different complications. We retrospectively examined the clinical records of 506 inpatients: 194 were affected by chronic active hepatitis (125 males, 69 females, mean age 45 +/- 11 years, 146 HCV- and 48 HBV-related), and 312 by cirrhosis without clinical evidence of portal hypertension (178 males, 134 females, mean age 53 +/- 9 years, 249 HCV- and 63 HBV-related). The occurrence of cirrhosis in the chronic active hepatitis group was then calculated, together with the occurrence of complications and the cumulative mortality rate of established cirrhosis. During follow-up 93 patients with chronic hepatitis developed cirrhosis. The cumulative probability of developing cirrhosis in this group was 6.64% at 5 years, 56.1% at 10 years and 86.8% at 15 years. These patients were therefore included in the cirrhosis group for the final analysis, so that a total of 405 cirrhotic patients were evaluated: these patients had a cumulative survival rate of 99.1% at 5, 76.8% at 10 and 49.4% at 15 years. Comparing the age-adjusted death rate of our patients with the general Italian population, we observed that in patients with liver cirrhosis it was 3.14 and 2.84 times higher in men and women, respectively. Bilirubin was an independent indicator of survival. Several complications, such as esophageal varices, ascites, jaundice, hemorrhage, hepatic encephalopathy and hepatocellular carcinoma significantly reduced the survival rate and were indicated as major complications, while thrombocytopenia, cholelithiasis and diabetes did not affect survival and thus were called minor complications. Incidence of hepatocellular carcinoma was very high especially in males, without correlation with etiology. In conclusion, the progression of virus-induced chronic active hepatitis to cirrhosis is not influenced by sex and etiology. Similarly, the different etiology does not modify the natural history of cirrhosis while the occurrence of one or more major complications significantly shortens survival. The longer survival rate observed in patients with cirrhosis included in this study is probably due to the selective inclusion of patients with early disease and no evidence of portal hypertension.

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.

Refractory ascites, that is ascites which cannot be mobilized by low sodium diet and maximal doses of diuretics (up to 400 mg spironolactone or potassium canrenoate and 160 mg furosemide per day), occurs in 5% of cirrhotic patients with ascites. The development of refractory ascites is mainly related to the progression of arterial vasodilation-mediated vascular underfilling and to the imbalance between reduced synthesis of renal vasodilating factors (especially renal prostaglandins) and extreme activation of vasoconstricting systems. Further features include increased sodium reabsorption in the proximal tubule and altered pharmacokinetics and pharmacodynamics of diuretics. In patients with impaired renal function (as is the case for most patients with refractory ascites), the marked reduction of renal perfusion and glomerular filtration rate, with the consequent decrease of filtered sodium load, becomes the main pathogenetic factor. The principal therapeutic options for refractory ascites include repeated paracentesis and implantation of the LeVeen shunt. Paracentesis is a rapid and safe procedure to remove ascites, but it does not correct sodium retention. Ascites recurrence, therefore, may occur after a brief interval. The LeVeen shunt allows for better long-term control of ascites, but severe complications may supervene, and shunt occlusion is common. Neither therapeutic procedure improves survival. Different experimental therapeutic procedures have been proposed. Administration of ornipressin corrects hyperdynamic circulation and improves renal function. Thromboxane synthase inhibitors, by reducing renal synthesis of thromboxane A2, potentiate the diuretic and natriuretic response to furosemide. More invasive procedures, including portosystemic shunt and transjugular intrahepatic stent, are rarely used in the treatment of refractory ascites.(ABSTRACT TRUNCATED AT 250 WORDS)