Elettra Lorenzano

Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites.

BACKGROUND/AIMS beta-blockers effectively prevent first variceal bleeding (FVB) in cirrhotic patients. In patients with ascites, however, their use might be precluded by a high rate of contraindications and side effects. We compared the efficacy and applicability of nadolol and isosorbide-mononitrate (IsMn) in preventing FVB in a population of cirrhotic patients at high risk of variceal bleeding with ascites, who can be frequently intolerant to beta-blockers. METHODS A total of 80 consecutive cirrhotic patients with ascites and esophageal varices (25% average risk of bleeding at 1 year) were considered, 28 were excluded due to contraindications and 52 were randomly assigned to receive nadolol (n=25) or IsMn (n=27). RESULTS Frequency of contraindications was greater for beta-blockers than IsMn (35 versus 0%, P=0.001). During 21.3+/-11.6 months of follow-up, side effects forced six patients taking nadolol and four taking IsMn to stop treatment. Bleeding occurred in two patients taking nadolol and ten taking IsMn. The probability of bleeding was significantly lower in the nadolol group (P<0.05), whereas overall survival was similar (seven patients on IsMn and eight on nadolol died, P=0.3). CONCLUSIONS In patients with ascites IsMn is tolerated but ineffective while nadolol is effective but less tolerated.

Atrial natriuretic factor in cirrhotic patients with tense ascites: Effect of large-volume paracentesis

The plasma levels of atrial natriuretic factor in liver cirrhosis can be affected by various factors, such as ascites, renal function, use of diuretics drugs and dietary sodium intake. Moreover, the influence of high intra-abdominal pressure on cardiac atrial natriuretic factor release in patients with tense ascites has not been investigated. The aim of the present study was to evaluate the circulating levels of atrial natriuretic factor and their relationships to plasma renin activity, aldosterone concentration, and urinary sodium excretion in 45 cirrhotic patients divided into 4 groups: (a) cirrhotics without ascites; (b) nonazotemic cirrhotics with ascites; (c) cirrhotics with ascites and functional renal failure; and (d) cirrhotics with ascites taking diuretics. In some patients with tense ascites, atrial natriuretic factor was also measured after rapid abdominal relaxation by large volume paracentesis. Plasma levels of atrial natriuretic factor obtained in 13 healthy control subjects after 5 days on a 40-50 mEq sodium daily intake were 22.8 +/- 3.3 pg/ml. Mean plasma atrial natriuretic factor levels were normal in patients without ascites (35.1 +/- 11.4 pg/ml) and in those with ascites taking diuretics (27 +/- 9.2 pg/ml), but elevated in patients with ascites not taking diuretics (59.6 +/- 12 pg/ml) and in those with ascites and functional renal failure (58.5 +/- 16.6 pg/ml). These data show that plasma atrial natriuretic factor levels are elevated only in cirrhotic patients who are ascitic and not taking diuretics. In these patients atrial natriuretic factor levels were directly correlated with urinary sodium excretion, even though sodium balance was positive. This could be the consequence of the contrasting effects of antinatriuretic factors, as suggested by the inverse relationships between atrial natriuretic factor and urinary sodium on the one hand and plasma renin activity and plasma aldosterone concentration on the other. Twenty-six patients with tense ascites (12 taking diuretics and 14 not) were treated with rapid large-volume paracentesis (6500 +/- 330 ml of ascitic fluid removed in 168 +/- 16 min). At the end of the procedure, plasma atrial natriuretic factor levels had increased in all patients (from 45.5 +/- 10.1 to 100 +/- 17 pg/ml), whereas plasma renin activity and plasma aldosterone concentration had decreased (from 10.3 +/- 1.6 to 7 +/- 1.3 ng/ml/h, and 1160 +/- 197 to 781 +/- 155 pg/ml, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Octreotide long-term treatment in patients with portal hypertension : persistent inhibition of postprandial glucagon response without major changes in renal function

BACKGROUND/AIMS Octreotide acutely decreases splanchnic blood flow and postprandial portal pressure in patients with portal hypertension. Inhibition of glucagon release parallels the hemodynamic changes. We studied the hormonal and renal effects of long-term treatment with octreotide (100 microg s.c., t.i.d., immediately before meals, for 2 weeks) in 12 patients with cirrhosis and portal hypertension. METHODS Postprandial blood levels of glucagon, insulin and glucose, and renal function tests were monitored in a study where patients acted as their own controls. Eleven patients completed the study, octreotide being discontinued in one patient who developed jaundice after 6 days of therapy. RESULTS Long-term treatment did not cause any change in fasting hormonal levels measured 12 h after the last injection of octreotide. However, pre-prandial injection of octreotide induced a marked fall in blood glucagon (163+/-49 pg/ml, after 20 min, vs. 254+/-71 pg/ml, basal; p<0.01), thus preventing the postprandial response occurring without treatment (322+/-102 pg/ml, 30 min-peak, vs. 249+/-77 pg/ml, basal; p<0.03). Inhibition of postprandial glucagon was maintained after 2 weeks of therapy (159+/-33 pg/ml, after 20 min, vs. 237+/-54 pg/ml, basal; p<0.01). Octreotide abolished the insulin postprandial response with no major change in glycemic control. Treatment had no long-term effect on renal plasma flow (effective renal plasma flow: 596+/-79 ml/min, baseline, vs. 609+/-71 ml/min, at 2 weeks; p>0.5), glomerular filtration rate (glomerular filtration rate: 99+/-11 vs. 99+/-12 ml/min; p>0.5), blood urea and creatinine, whereas it induced a mild decrease in plasma electrolyte levels (p<0.02). CONCLUSIONS Long-term octreotide treatment persistently suppresses the postprandial glucagon response of patients with portal hypertension without causing deterioration in their renal function.

Skeletal muscle water and electrolytes in chronic renal failure. Effects of long-term regular dialysis treatment.

Skeletal muscle water, Cl, Na and K were studied in 24 patients with predialysis chronic renal failure (CRF) and in 16 patients under regular dialysis treatment (RDT) for 8-16 years; 35 healthy controls were also examined. Total Cl, Na and water (Clm, Nam, TW) were high in both CRF and RDT groups (p less than 0.001); high TW in CRF was due to both extra (ECW) and intracellular (ICW) fractions, which were calculated from Cl space; in RDT only ECW was increased and ICW was normal. Muscle K was diminished in CRF, in reference to both muscle fat free dry solids and ICW, and it was slightly but significantly higher than normal in RDT. The findings demonstrate that high cell volume and low intracellular K observed in CRF are fully corrected by long-term hemodialysis, probably because these abnormalities are mainly related to cell function disturbances due to uremic state. On the contrary, the persistence of high total Cl, Na and muscle ECW seems to be an expression of expanded extracellular fluid volume.

Cleavage of high molecular weight kininogen in ascites and plasma of patients with cirrhosis

The vasoactive peptide bradykinin may be involved in the pathogenesis of vasodilation, which has been considered the initiating event of ascites formation in cirrhotic patents. Since bradykinin is generated through the cleavage of high molecular weight kininogen (HK) by kallikrein, we looked for the cleavage of HK by an immunoblotting technique in plasma and ascitic fluid of 28 patients with cirrhosis of different etiology. The majority of patients showed massive cleavage of HK in ascitic fluid (median 50% of total HK; range 23-100%). Patients with severe ascites had more cleaved HK in plasma (29%; range 8-38%) than normal subjects (22%; range 11-32) (P = 0.02). Patients with high levels of plasma renin activity (5-60 ng/ml/hour), which is considered a consequence of peripheral vasodilation, had more plasma cleaved HK (31%; range 18-38)(p = 0.0097) than normals. Thus, our data support the view that cleavage of HK could play a role in the pathogenesis of vasodilation and ascites formation in patients with decompensated cirrhosis.

Pattern of plasma cyclic nucleotides and related hormones in liver cirrhosis and hepatocellular carcinoma.

Abstract To evaluate the pattern of plasma cyclic adenosine 3′,5‵-monophosphate, cyclic guanosine 3‵,5‵-monophosphate, atrial natriuretic factor and glucagon levels in different stages of chronic liver diseases, we measured these variables in 20 normal subjects, 25 patients with genetic hemochromatosis, associated with liver cirrhosis in 19 cases and not in six, eight patients with compensated and 15 with decompensated alcoholic or posthepatitic cirrhosis, and 12 with hepatocellular carcinoma. All variables were within the normal range in non-cirrhotic hemochromatotic patients. Cyclic adenosine 3‵,5‵-monophosphate levels were within the normal range (9.5–15.7 nmol/l) in hemochromatotic cirrhotics and elevated in other patients. Cyclic guanosine 3‵,5‵-monophosphate, atrial natriuretic factor and glucagon were above the normal ranges (1.92–5.91 nmol/l, 8.8–62.7 ng/l, and 39–165 ng/l, respectively) in most patients with cirrhosis both with and without hemochromatosis and in most individuals with hepatocellular carcinoma. Cyclic guanosine 3‵,5‵-monophosphate correlated with atrial natriuretic factor in the former groups but not in the latter. These findings indicate that glucagon and atrial natriuretic factor hypersecretion is an early event in cirrhosis, regardless of its etiology. In hepatocellular carcinoma, the underlying cirrhosis may account for most hormonal and metabolic changes although cyclic guanosine 3‵,5‵-monophosphate increases could also be due to the neoplastic process per se.

Effects of imidazole-salicylate on renal function and the diuretic action of furosemide in cirrhotic patients with ascites

Imidazole-salicylate is a non-steroidal anti-inflammatory drug with limited inhibitory effects on prostaglandin synthesis. The renal effects of this drug were investigated by a double-blind cross-over study in 10 patients with cirrhosis and ascites. Two therapeutic doses of imidazole-salicylate (750 mg each) were given at midnight and 08:00 h and 80 mg of furosemide were injected intravenously at 09:00 h. The same procedure was followed on another day but a placebo replaced imidazole-salicylate. Renal function (creatinine clearance, free water and electrolyte excretions) and urinary excretion of prostaglandin E, 6-keto-prostaglandin F1 alpha and thromboxane B2 were evaluated for 8 h after the first dose of the drug and for 2 h after furosemide injection. Platelet thromboxane production was also determined 9 h after the first administration of drug or placebo. Imidazole-salicylate did not affect renal function or inhibit kidney prostanoid production either under basal conditions or after the stimulating effect of furosemide. On the contrary, imidazole-salicylate significantly inhibited platelet thromboxane production (45.8 +/- 9 vs. 69.4 +/- 7.5 ng/ml, P < 0.05). These results suggest that imidazole-salicylate is an anti-inflammatory drug that can be given to patients with decompensated cirrhosis without risk of inhibiting kidney prostaglandin synthesis or the renal response to furosemide.