Search

In patients with cirrhosis and portal hypertension, standing induces a reduction in cardiac index (CI) and an increase in systemic vascular resistance index. Our previous studies indicate that this abnormal hemodynamic response to standing is due to an altered myocardial function, because cirrhotic patients are unable to compensate for the reduced preload with an increase in left ventricular (LV) ejection fraction (EF) and stroke volume. To evaluate whether the cardiac dysfunction in cirrhosis is influenced by canrenone, an aldosterone antagonist, 8 patients with preascitic, nonalcoholic cirrhosis, and portal hypertension underwent echocardiographic assessment of LV function and systemic hemodynamics and determinations of plasma volume, urinary sodium excretion, and plasma renin activity (PRA), aldosterone (PAC), and norepinephrine (PNE) when on a 150-mmol/d-sodium diet (baseline), after 1 month on canrenone (100 mg/d) plus a 40-mmol/d-sodium diet and after 1 month on canrenone plus a 150-mmol/d-sodium diet. Echocardiographic evaluation was performed with the patient in the supine position and during active standing. At baseline, patients had high plasma volume and normal renal function, PRA, PAC, and PNE. CI, LVEF, and stroke volume index were also normal. Standing caused a significant reduction in CI and LVEF. After canrenone and either sodium diet, CI significantly decreased, and PRA and PNE increased in the supine position. On standing, LVEF and CI did not decrease further. Plasma volume significantly decreased only after low-sodium diet plus canrenone. In conclusion, canrenone normalizes the cardiac response to the postural challenge in patients with preascitic cirrhosis.

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.

The autonomic regulation of cardiovascular function was evaluated in 15 cirrhotic patients with ascites and in 13 healthy subjects by the autoregressive power spectral analysis (PSA) of the intervals between adjacent R waves of the electrocardiogram (RR) interval and arterial pressure variability. Total power, low frequency (LF; index of the sympathetic activity of the heart and circulation), and high frequency (HF; index of vagal tone to the heart) components of the RR interval, systolic, and diastolic arterial pressure were evaluated in the supine position and during passive tilting, together with plasma norepinephrine levels. In the supine position, no significant differences in the PSA data were observed between the control subjects and cirrhotic patients, who had higher plasma norepinephrine levels. In healthy subjects, tilting was associated with an increase in the LF of the RR interval and arterial pressure and a decrease in the HF of the RR interval. In contrast, patients with cirrhosis showed a decrease of both LF and HF. Consequently, the LF/HF ratio significantly increased in healthy subjects, whereas it was unchanged in cirrhotic patients. The LF component of the diastolic pressure also decreased during tilting in cirrhotic patients. Plasma norepinephrine increased after tilting in both groups. These results indicate that the autonomic response to passive tilting is impaired in cirrhotic patients with ascites at both the cardiac and vascular levels, as a result of an altered sympatho-vagal balance, with reduced sympathetic predominance. These alterations occurred despite an appropriate response to the tilting of plasma norepinephrine, pointing to a receptorial or postreceptorial site of the autonomic impairment.

An increased release of nitric oxide (NO), a powerful vasodilating agent, has been proposed to play a role in the pathogenesis of vasodilation and hyperdynamic circulation associated with advanced cirrhosis. We evaluated NO synthase (NOS) activity in peripheral leukocytes of 12 cirrhotic patients and 9 healthy subjects together with plasma endotoxin levels and systemic hemodynamic (by a noninvasive echocardiographic method). NOS activity was evaluated by (1) measuring the capacity of isolated polymorphonuclear cells (PMNs) and monocytes to convert [3H]arginine to [3H]citrulline; (2) measuring the ability of neutrophils and monocytes to inhibit thrombin-induced platelet aggregation and to increase guanosine 3'-5'-cyclic monophosphate content in coincubated platelets, an expression of NO release from these cells. Both neutrophils and monocytes from cirrhotic patients produced significantly higher amounts of [3H]citrulline than cells obtained from healthy subjects (P < .001 and P < .02 for neutrophils and monocytes, respectively) and were more effective than control cells in inhibiting platelet aggregation (P < .05 and P < .001, respectively for 2 x 10(6) cells) and in increasing guanosine 3'-5'-cyclic monophosphate content in coincubated platelets (P < .05 and P < .001, respectively). The anti-aggregating activity expressed by leukocytes has a pharmacological profile similar to that described for NO, because it increased after addition of superoxide dismutase, a superoxide anion scavenger, and markedly decreased after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine-methyl ester (L-NAME). Cirrhotic patients had significantly higher plasma endotoxin levels (P < .001) and cardiac index (P < .01) when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with cirrhosis and ascites have high plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides, two cardiac hormones released by the atria and ventricles, respectively. We evaluated renal hemodynamics, sodium excretion, and intrarenal sodium handling (lithium clearance method) in seven cirrhotic patients with ascites and avid sodium retention before, during, and after the infusion of synthetic human BNP, at the dose of 4 pmol/kg.min for 1 hour, which has been shown to increase renal plasma flow, glomerular filtration rate (GFR), and sodium excretion in healthy subjects without affecting systemic hemodynamics. Plasma BNP levels were 7.31 +/- 0.85 pmol/L in baseline conditions, and increased to 33.60 +/- 2.96 pmol/L at the end of the infusion (P < .01 vs. baseline). Urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP) also significantly increased during the infusion, indicating stimulation of natriuretic peptide receptors by BNP. BNP administration did not modify renal plasma flow, GFR, sodium excretion or tubular sodium reabsorption to any appreciable extent. Arterial pressure heart rate, plasma norepinephrine, and plasma renin activity (PRA) where also unchanged, whereas plasma aldosterone concentration showed a significant, 35% reduction at the end of the postinfusion period, ruling out the possibility that BNP-induced vasodilation might be responsible for failure of the peptide to induce a natriuretic response. Overactivity of antinatriuretic factors is probably the main determinant of the blunted natriuretic effect of BNP in these patients.

We evaluated hepatitis B virus DNA and hepatitis C virus RNA in sera from 110 HBsAg and IgM HBc antibody-negative heavy drinkers (50 cirrhosis, 13 chronic active hepatitis, 25 fatty liver with or without mild to moderate fibrosis, alcoholic hepatitis or both and 22 healthy alcoholic subjects) with polymerase chain reaction. Results of hepatitis C virus polymerase chain reaction were compared with those obtained with two tests (second generation recombinant immunoblot assay and enzyme-linked immunosorbent assay) used to detect hepatitis C virus antibodies. Hepatitis B virus DNA was found in three (2.7%) patients. Hepatitis C virus RNA was detected in 29 (29.8%) of the 97 subjects whose sera were well preserved for RNA extraction (42.5% cirrhosis, 83.3% chronic active hepatitis, 8% fatty liver and 0% healthy alcoholic subjects). Results obtained with second-generation recombinant immunoblot assay and enzyme-linked immunosorbent assay had a high degree of agreement with polymerase chain reaction as expected, the kappa indexes being 0.76 and 0.61, respectively. Nevertheless, five hepatitis C virus RNA-positive patients had negative recombinant immunoblot assay results, whereas all hepatitis C virus RNA-positive patients had positive or borderline enzyme-linked immunosorbent assay results. We conclude that, in Italian HBsAg-negative alcoholic patients, "inapparent" hepatitis B virus infection is rare. On the contrary, hepatitis C virus infection, as detected on hepatitis C virus polymerase chain reaction, is quite frequent, especially in patients who have cirrhosis and chronic active hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma levels of brain natriuretic peptide, a recently identified cardiac hormone with natriuretic activity, were measured in 11 healthy subjects, 13 cirrhotic patients without ascites, 18 nonazotemic cirrhotic patients with ascites and 6 patients with cirrhosis, ascites and functional kidney failure. Plasma levels of brain natriuretic peptide were similar in healthy subjects and cirrhotic patients without ascites (5.56 +/- 0.65 and 7.66 +/- 0.68 fmol/ml, respectively). In contrast, cirrhotic patients with ascites, with and without functional kidney failure, had significantly higher plasma concentrations of brain natriuretic peptide (19.56 +/- 1.37 and 16.00 +/- 1.91 fmol/ml, respectively) than did healthy subjects and patients without ascites (p less than 0.01); no significant difference was found between the two groups of cirrhotic patients with ascites with respect to this parameter. In the whole group of cirrhotic patients included in the study, brain natriuretic peptide level was directly correlated with the degree of impairment of liver and kidney function, plasma renin activity and plasma levels of aldosterone and atrial natriuretic peptide. The results of this study indicate that brain natriuretic peptide is increased in cirrhotic patients with ascites and suggest that sodium retention in cirrhosis is not due to deficiency of this novel cardiac hormone.

In a randomized double-blind trial we compared the effects of torasemide, a new loop diuretic, and furosemide in nonazotemic cirrhotic patients with ascites during a 3-day period in association with potassium canrenoate (200 mg/day) administration. Doses of loop diuretics administered in this trial (10 and 25 mg/day of torasemide and furosemide, respectively) had been shown to be equipotent in healthy subjects. Torasemide induced significantly greater natriuresis than furosemide (p less than 0.02), with a twofold greater percentage increase in basal values (day 1: 130% vs. 50%; day 2: 104% vs. 42%; and day 3: 65% vs. 26%, respectively). Body weight loss was significantly higher during torasemide (p less than 0.02) administration, and the overall decrease at the end of the treatment was twice as high for furosemide (2.5 +/- 0.6 kg vs. 1.3 +/- 0.4 kg, respectively). Diuresis was also higher during torasemide administration, but the difference was not significant (p = 0.08). The extent of kaliuresis observed during the two treatments was almost identical despite the striking differences in the natriuretic response. The effects of the two treatments on plasma electrolytes, creatinine clearance, blood urea nitrogen, mean arterial pressure, heart rate and plasma arginine vasopressin concentration were similar. Both drugs caused increases in plasma renin activity at the end of the treatment, whereas plasma aldosterone concentration slightly increased only after torasemide administration. Despite the presence of a trend toward a more pronounced effect on these parameters after torasemide administration, no significant difference between the two treatments was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been proposed that the initial event of sodium retention in cirrhosis is a peripheral arteriolar vasodilation causing underfilling of the arterial vascular compartment and stimulation of the renin-aldosterone and sympathetic nervous systems. To test this hypothesis, systolic blood pressure, sodium balance and urinary excretion of sodium and aldosterone were sequentially measured in 13 conscious spontaneously hypertensive rats submitted to a cirrhosis induction program with carbon tetrachloride and phenobarbital and in 14 control hypertensive animals. No significant differences were found between control and cirrhotic rats in any of the measured parameters during the first 7 wk of the study. The eighth week sodium retention developed in cirrhotic rats as indicated by a positive sodium balance and a marked decrease of sodium excretion. At the same time a significant reduction in systolic blood pressure and a great increase in urinary excretion of aldosterone were detected. These changes were more marked the ninth week of the study. In cirrhotic rats there was a highly significant direct correlation between systolic blood pressure and urinary sodium excretion. Postmortem examination showed a histological picture of cirrhosis in all animals given carbon tetrachloride and ascites in six of them. These results indicate that the onset of hyperaldosteronism and sodium retention in conscious spontaneously hypertensive rats with carbon tetrachloride-induced cirrhosis is chronologically related to a significant decrease in arterial pressure, thus supporting the "peripheral arterial vasodilation hypothesis" of ascites.

The ability of urine extracts to inhibit sodium and potassium-activated ATPase, cross-react with antidigoxin antibodies and induce natriuresis in rats was investigated in 10 healthy subjects, 10 cirrhotic patients without ascites (compensated cirrhotics), 27 nonazotemic cirrhotic patients with ascites and 10 cirrhotic patients with ascites and functional renal failure to assess whether reduced activity of natriuretic hormone contributes to sodium retention in cirrhosis. No significant differences were seen between healthy subjects and compensated cirrhotic patients in any of these parameters (sodium and potassium-activated ATPase inhibition = 178.5 +/- 19.8 vs. 247.4 +/- 48.7 nmol equivalent of ouabain/day; digoxinlike activity = 43.9 +/- 6.1 vs. 48.0 +/- 5.6 ng equivalent of digoxin/day; natriuretic activity = 0.36 +/- 0.15 vs. 0.63 +/- 0.27 mumol/min). Cirrhotic patients with ascites with and without functional renal failure showed significantly higher values of sodium and potassium-activated ATPase inhibition (708.1 +/- 94.0 and 529.2 +/- 53.9 nmol equivalent of ouabain/day, respectively), digoxinlike activity (136.9 +/- 7.2 and 116.3 +/- 7.9 ng equivalent of digoxin/day) and natriuretic activity (1.78 +/- 0.48 and 1.93 +/- 0.37 mumol/min) than healthy subjects and compensated cirrhotic patients. We saw no significant differences between these two groups of cirrhotic patients with ascites with respect to these parameters. In the cirrhotic patients studied, sodium and potassium-activated ATPase inhibition and antidigoxin antibodies directly correlated with the degree of impairment of hepatic and renal function, plasma renin activity and plasma levels of aldosterone and norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemorrhagic disorders are common in patients with liver cirrhosis and result from several factors including impaired platelet function. We evaluated platelet aggregation and arachidonic acid metabolism in response to standard agonists in platelet-rich plasma from 12 cirrhotic patients with mild impairment of liver function (Child A), 12 patients with severe liver dysfunction (Child B and C) and 12 healthy subjects. Platelet aggregation and thromboxane A2 production were consistently reduced in patients with severe liver impairment. To determine whether the platelet dysfunction is due to an intrinsic platelet defect or a circulating inhibitor, we measured platelet aggregation and thromboxane A2 synthesis on washed platelets in healthy subjects and in Child B and C patients. The aggregating response of washed platelets in response to thrombin, collagen and arachidonic acid was markedly reduced, suggesting an intrinsic platelet defect. The biochemical events underlying platelet aggregation were investigated by prelabeling platelets with [1-14C]arachidonic acid. Thrombin-induced activation of phospholipase C (measured as the release of [1-14C]phosphatidic acid) and phospholipase A2 (measured as the release of [1-14C]arachidonic acid and its metabolites) was greatly impaired in platelets from patients with severe liver impairment. We conclude that in advanced cirrhosis there is a severe reduction in platelet aggregatory response to physiologic agonists due to an intrinsic platelet defect which is related to an impairment of the platelet transmembrane signaling mechanism induced by receptor stimulation.