Comparative study between nadolol and 5-isosorbide mononitrate vs. endoscopic band ligation plus sclerotherapy in the prevention of variceal rebleeding in cirrhotic patients: a randomized controlled trial.

BACKGROUND: After variceal bleeding, cirrhotic patients should receive secondary prophylaxis. AIM: To compare nadolol plus 5-isosorbide mononitrate (5-ISMN) with endoscopic band ligation. The end points were rebleeding, treatment failure and death. METHODS: One hundred and nine cirrhotic patients with a recent variceal bleeding were randomized: nadolol plus 5-ISMN in 57 patients and endoscopic band ligation in 52 patients. RESULTS: The mean follow-up was 17 and 19 months in nadolol plus 5-ISMN and endoscopic band ligation groups, respectively. No differences were observed between groups in upper rebleeding (47% vs. 46%), variceal rebleeding (40% vs. 36%), failure (32% vs. 22%), major complications (7% vs. 13.5%) and death (19% vs. 20%), respectively. The actuarial probability of remaining free of rebleeding, failure and deaths were similar in both groups. Time to rebleeding shows that endoscopic band ligation patients had an early rebleed, with a median of 0.5 month (95% CI: 0.0-4.2) compared with patients from nadolol plus 5-ISMN, 7.6 months (95% CI: 2.9-12.3, P < 0.013). Multivariate analysis indicated that outcome-specific predictive factor(s) for rebleeding was Child A vs. B + C (P < 0.01); for failure was Child A vs. B + C (P < 0.02); and for death ascites (P < 0.01) and rebleeding (P < 0.02). CONCLUSION: This trial suggests no superiority of endoscopic band ligation over nadolol plus 5-ISMN mononitrate for the prevention of rebleeding in cirrhotic patients.

Splenic hypofunction in cirrhosis is not associated with increased risk for infections.

BACKGROUND/AIM: Pitted cell count has been described as a sensitive marker of splenic function. Recently, pitted cell count was shown to be increased in patients with alcoholic liver disease, and also to be associated with an increased susceptibility to infection. Therefore, our aim in the present study was to assess splenic function in a group of patients with cirrhosis and to determine its possible role in the development of infections. METHODS: Splenic function was assessed during hospitalization in 44 patients diagnosed as having cirrhosis, and was compared to 18 healthy subjects. Function was evaluated by counting the number of pitted cells in peripheral blood films. Results were the mean value of two independent counts and were expressed as number of pitted cells/100 erythrocytes. RESULTS: The mean percentage of pitted cells in peripheral blood of cirrhotic patients was significantly greater than that assessed in controls (3.5 +/- 3.7% vs. 1.6 +/- 0.9%, P < 0.01, Mann-Whitney U test). Eighteen patients with cirrhosis (36%) had counts greater than 3.4% (mean + 2 SD of the control group). There were no significant differences between patients with counts above or below 3.4% in terms of liver tests, platelet and reticulocyte counts, the presence of complications, Child-Pugh score and the prevalence of infections. There was no difference in pitted cell count between alcoholic and non-alcoholic cirrhotic patients (3.8 +/- 3.4% vs. 3.1 +/- 2.8% respectively, P, NS). Moreover, the mortality rate and the occurrence of infections were similar in patients with normal and increased pitted cell counts during 1-year follow-up. CONCLUSION: The increased number of pitted cells in patients with cirrhosis is not related to heptic function and does not represent a risk factor for infections.

[Spontaneous peritonitis in the patient with cirrhosis, our experience]. / Peritonitis espontánea en el cirrótico, nuestra experiencia.

Due to scarce printed information in our country, the incidence regarding spontaneous peritonitis observed during two years in 76 ascites episodes, found in 63 patients with hepatic cirrhosis, is analysed retrospectively. Thirteen patients (17%), showed spontaneous peritonitis and the relationship man-woman was 5 to 1; 70% of the germs found in the ascites fluid was of enteric origin, mainly Escherichia Coli. In three patients the diagnosis was made by both counting the leucocytes and the clinical symptoms, in spite of the negative culture. There were no significant differences in the presence of humoral complications or alterations when patients appeared with sterile ascites and spontaneous peritonitis, but there were differences with the death rate which was 7.9% (5/63), in the former and 38% (5/13), in infected ascites; 80% of the dead patients showed renal deficiency at the end of the evolution and a relationship with the use of aminoglucosides can not be discarded. The search for spontaneous peritonitis in the cirrhotic patient, as a routine, seems to have the same incidence among as, as the one described in the literature.

Hemostatic and hemodynamic effects of vasopressin analogue DDAVP in patients with cirrhosis.

Desmopressin (DDAVP), a synthetic analogue of vasopressin, has been shown to improve the bleeding time in patients with cirrhosis. The duration of this effect and the hemodynamic changes associated with DDAVP have not been studied so far. To evaluate these issues, 14 cirrhotics with portal hypertension were studied in basal conditions and after DDAVP (0.3 uk/kg). In 8 patients, hemostatic tests were done at basal conditions and 1, 3, 6 and 24 hs after drug administration. In the remaining 6 patients, mean arterial pressure, cardiac output, portal and femoral blood flows were evaluated. Hemodynamic parameters were measured by Doppler ultrasound. DDVP caused a marked decrease in bleeding time at 1, 3, 6 and 24 hs (14 +/- 9 vs 8 +/- 3, 7 +/- 4, 6 +/- 4 and 8 +/- 4 min, respectively); the decrease was maximal and statistically significant at 6 hs (55 +/- 15%, p < 0.02) after DDAVP infusion. Bleeding time reduction was observed in every patient studied. In the hemodynamic study, DDAVP caused a mild but significant decrease in mean arterial pressure (12 +/- 8%, p < 0.05); no significant changes were observed in the rest of hemodynamic parameters studied. These findings show that DDAVP can be used to shorten the bleeding time for a period of at least 24 hs in patients with cirrhosis, without deleterious hemodynamic effects. This beneficial effect may be of potential relevance in the medical management of patients with chronic liver diseases.

Clinical trial: short-term effects of combination of satavaptan, a selective vasopressin V2 receptor antagonist, and diuretics on ascites in patients with cirrhosis without hyponatraemia--a randomized, double-blind, placebo-controlled study.

BACKGROUND: There is little information on the effects of vaptans in patients with cirrhosis. AIM: To investigate the short-term effects of satavaptan, a selective vasopressin V2 receptor antagonist on ascites in cirrhosis without hyponatraemia. METHODS: A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double-blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20-25 mg/day. RESULTS: Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was -0.36 kg (+/-3.03) for placebo vs. -2.46 kg (+/-3.11), -2.08 kg (+/-4.17) and -2.28 kg (+/-3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar. CONCLUSIONS: The administration satavaptan for a 14-day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

Pilot study: Gelafundin (polygeline) 4% plus antibiotics in the treatment of high-risk cirrhotic patients with spontaneous bacterial peritonitis.

BACKGROUND: Cirrhotic patients with spontaneous bacterial peritonitis (SBP) have elevated rates of renal impairment and mortality. It has been shown that cefotaxime plus albumin infusion decrease renal impairment compared with antibiotic treatment alone, in patients with serum bilirubin >4 mg/dL or creatinine >1 mg/dL. AIM: To assess clinical outcomes of high-risk cirrhotic patients with SBP who were treated with antibiotics associated with Gelafundin (polygeline) 4%. METHODS: Twenty nine cirrhotic patients with SBP and serum bilirubin >4 mg/dL or creatinine >1 mg/dL were enrolled. Ceftriaxone was administered in doses of 2 g/day and Gelafundin 4% was given intravenously at 1.5 g/kg of body weight at the time of the diagnosis, followed by 1 g/kg on day 3. Renal impairment was defined as nonreversible deterioration of renal function during hospitalization. RESULTS: Eight patients (27.5%) had basal renal failure. Infection resolved in 28 (96.6%) patients. Renal impairment occurred in four patients (13.8%), and three patients (10.4%) died during hospitalization. Mortality within 90 days after discharge was 34.5% (10 patients). CONCLUSION: The rates of renal impairment and mortality in high-risk patients with SBP suggest that Gelafundin 4% administration given with ceftriaxone may be a less expensive therapeutic alternative to albumin.

Association of chronic active hepatitis and HLA B35 in patients with hepatitis B virus.

Fifty-one patients with chronic active hepatitis were typed for their HLA-A, B, C, and DR antigens. We observed a significant increase in the antigen frequency of HLA B35 in patients compared with controls.

Noninvasive measurement of portal venous blood flow in patients with cirrhosis: effects of physiological and pharmacological stimuli.

The present study aims to evaluate the usefulness of combined pulse Doppler-real-time ultrasonography as a noninvasive method for the measurement of portal blood flow in man. This measurement technique was performed on 12 healthy subjects and 20 patients with portal hypertension. Ten patients (group 1) were evaluated prior to and after ingestion of a standard meal (Ensure Plus) or placebo. In the remaining 10 patients (group 2), the effects of isosorbide dinitrate (5 mg/SL) administration or placebo were studied. In group 1, food intake caused a significant increase of portal blood flow (from 1038 +/- 539 to 1572 +/- 759 ml/min, P less than 0.02); this effect was due to a significant rise in mean blood velocity (from 18.5 +/- 3.7 to 23.9 +/- 3.9 cm/sec, P less than 0.02). In group 2, isosorbide dinitrate significantly reduced portal blood flow (from 985 +/- 491 to 625 +/- 355 ml/min, P less than 0.05); a significant decline of mean blood velocity (from 18.8 +/- 4.5 to 14.5 +/- 2.5 cm/sec, P less than 0.02) was observed. Placebo administration had no significant hemodynamic effects in either group. Our results suggest that Doppler measurements gave accurate noninvasive estimations of portal blood flow and that this technique may be used to monitor physiological and pharmological stimuli in patients with portal hypertension.

Dextran administration avoids hemodynamic changes following paracentesis in cirrhotic patients. A safe and inexpensive option.

Paracentesis associated with albumin administration has been shown to be a safe and useful procedure in the treatment of patients with cirrhosis and ascites. Given the high cost of albumin, 20 patients with cirrhosis and ascites were treated in an open study, with daily paracentesis using dextran 70, an inexpensive volume expander, instead of albumin. In the first 10 patients, hemodynamic evaluation was performed in basal conditions, after each paracentesis (5 liter), and after dextran infusion. Twelve hours after each paracentesis without expansion, a significant drop in pulmonary capillary wedge pressure from 9.5 +/- 1.0 to 7.1 +/- 1.7 (P less than 0.01) and a reduction in cardiac output from 6.6 +/- 1.0 to 5.0 +/- 1.9 (NS) were observed. Moreover, the hematocrit rose significantly from 36.8 +/- 5.6 to 39.2 +/- 4.8 (P less than 0.01). These parameters returned to baseline values after the administration of 84 +/- 14 ml of dextran 70 for each 1000 ml of ascites removed. The other 10 patients received dextran 70 simultaneously with the paracentesis without hemodynamic control. No significant changes in renal and hepatic functions were observed at the end of the study. The mean volume of ascites removed was 12.3 +/- 4.6 liter. Two patients developed hyponatremia that required no treatment. No patient developed renal failure. One patient died because of gastrointestinal bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Epithelioid hemangioendothelioma of the liver: report of two cases.

This report describes two patients with hepatic epithelioid hemangioendothelioma: a 33-year-old woman and a 28-year-old man. The first case presented with a palpable abdominal mass and has survived without treatment for 6 years since diagnosis, with ascites but a good general condition. The other patient presented with abdominal pain and cholestasis. He had a rapid course and death occurred 6 months after the onset of symptoms. Histologically the tumors consisted of a proliferation of neoplastic cells with an angiogenic tendency embedded in a myxohyaline stroma. Positivity for the factor VIII-related antigen, for UEA-I and for vimentin and negativity for keratin of the neoplastic cells in the immunohistochemical investigation permitted identification of their endothelial origin. In both cases, the initial diagnosis was erroneous.

Pharmacokinetics of Dextran-70 in patients with cirrhosis and ascites undergoing therapeutic paracentesis.

BACKGROUND/AIM: Dextran-70 is frequently used as a plasma expander in patients with cirrhosis treated with large-volume paracentesis to prevent post-paracentesis hypovolemia, which is thought to develop after 24 h following the procedure. However, there are no studies on Dextran-70 pharmacokinetics in cirrhosis. METHODS: Nine patients with alcoholic cirrhosis and tense ascites treated with a 5-1 paracentesis were given 500 ml of Dextran-70. Blood samples to measure the plasma concentration of dextran were obtained 15 and 30 min, 1, 2, 3, 6, 12 and 24 h and 2 and 6 days after the end of the infusion. Nine healthy volunteers were studied in identical fashion after infusion of 100 ml of Dextran-70. The plasma concentration of dextran was determined by the anthrone method. A bicompartmental model was used to analyze the pharmacokinetic parameters. RESULTS: There were no significant differences between patients with cirrhosis and controls in the volume of distribution (7.7 +/- 0.6 vs. 7.3 +/- 1.21), half-life of the first and second component of plasma disappearance (2.96 +/- 0.69 and 80.3 5.9 h in patients with cirrhosis vs 2.82 +/- 0.69 and 67.1 +/- 10.7 h in controls). CONCLUSIONS: The pharmacokinetics of Dextran-70 in patients with cirrhosis and ascites after large-volume paracentesis is similar to that in controls. This may explain why Dextran-70 is less effective than albumin in preventing paracentesis-induced hypovolemia, which starts after most Dextran fraction has disappeared from plasma.

Terlipressin is more effective in decreasing variceal pressure than portal pressure in cirrhotic patients.

BACKGROUND/AIMS: Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin. METHODS: Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later. RESULTS: No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance. CONCLUSIONS: Our results demonstrate that terlipressin produces significant and prolonged decreases in variceal pressure and variceal wall tension and has intrinsic effects on portal pressure and systemic hemodynamics. Variceal pressure provides a better assessment of the effects of terlipressin administration on esophageal varices than hepatic venous pressure gradient.

Antigenic markers of hepatocellular carcinoma.

One hundred thirty-five hepatocellular carcinomas were examined for the presence of antigenic tumor markers by the avidin-biotin-peroxidase complex method. Ninety-seven were from the US and 38 came from Argentina. The following markers were tested: alpha-fetoprotein (AFP), alpha-1-antitrypsin (AAT), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), hepatitis D delta antigen (HD delta Ag), and Mallory's bodies (MB). In the US cases, AFP was present in 43%, AAT in 41%, HBsAg in 17%, and MB in 48%. Both HBcAg and HD delta Ag were absent. In the cases from Argentina, AFP was found in 26% and AAT in 18%. None of the other antigens were seen. Thirteen US tumors expressed three antigens and two four antigens simultaneously. This study reveals in humans a heterogenous expression of antigens by neoplastic hepatocytes with geographic differences, possibly due to multiple factors such as alcohol consumption or prevalence of hepatitis B infection.

Long-term efficacy of torsemide compared with frusemide in cirrhotic patients with ascites.

BACKGROUND: Torsemide is a new loop diuretic that has shown, in short-term studies, to induce a longer and higher diuretic and natriuretic action than frusemide. However, torsemide long-term effects and complications have not been sufficiently investigated. The aim was to compare the efficacy and safety of torsemide versus frusemide in cirrhotic patients with uncomplicated ascites. METHODS: Forty-six patients were randomized in two groups to receive torsemide 20 mg/day (n = 22) or frusemide 40 mg/day (n = 24). Both drugs were administered in association with spironolactone 200 mg/day. The initial doses of diuretics were increased every 3 days up to 60, 120 and 400 mg/day, respectively, if the body weight loss was less than 300 g/day or natriuresis was below 50 mEq/day. RESULTS: Torsemide induced a significantly greater diuretic response than frusemide at 24 h and the maximum diuresis while mean diuresis was similar in both groups. Natriuresis was also higher with torsemide but the difference was not significant. The body weight loss, the treatment period, the ascites resolution and complications were similar in both groups. Diuretic doses were increased in two patients treated with torsemide and in nine patients treated with frusemide (P < 0.05). CONCLUSIONS: These results show that torsemide is as effective and safe as frusemide for long-term treatment of cirrhotic patients with ascites.

Patients with ascites have higher variceal pressure and wall tension than patients without ascites.

OBJECTIVE: It has been suggested that ascites is a risk factor for variceal bleeding. Recently, it has been demonstrated that total paracentesis decreases variceal pressure. However, no data are available showing the basal variceal pressure in patients with and without ascites. METHODS: We studied 76 cirrhotic patients, 49 with and 27 without ascites. Variceal pressure was measured by direct puncture. Variceal size, variceal pressure gradient, and variceal wall tension were also obtained. RESULTS: No demographic differences were observed between the groups. Child score was higher (9.7+/-1.5 vs 7.8+/-2.1, p < 0.001) and serum albumin lower (2.6+/-0.6 vs 3.0+/-0.7 mg %, p < 0.02) in ascitic than in nonascitic patients, respectively. Variceal pressure and variceal pressure gradient were significantly higher in patients with ascites than in those without ascites (25.0+/-6 vs 20.4+/-4.6 mm Hg, p < 0.001 and 18.75+/-4.7 vs 13.70+/-4.1 mm Hg, p < 0.0001, respectively). The variceal wall tension was significantly higher in patients with ascites (71.0+/-25.1 mm Hg/mm) than in those without ascites (55.1+/-22.1 mm Hg/mm, p < 0.03). No relationship was observed between variceal pressure gradient and liver function. Ascites patients included in Child-Pugh grade A+B presented a similar variceal pressure to Child C patients (18.5+/-4.2 vs 19.3+/-5.7 mm Hg, respectively, p = ns). In addition, no relationship was observed between variceal pressure gradient and etiology of cirrhosis. CONCLUSION: Our results demonstrate that patients with ascites have significantly higher variceal pressure and wall tension than patients without ascites. These results suggest that patients with ascites may be at risk for variceal bleeding.

Treatment of pruritus of primary biliary cirrhosis with rifampin.

Pruritus can be a debilitating symptom in patients with chronic cholestasis. Based on previous reports of its efficacy, we evaluated the impact of rifampin on the pruritus associated with primary biliary cirrhosis. Fourteen patients were included in a randomized, crossover study. After a 15-day washout period, subjects were followed for three weeks. During the first and third week, patients received 600 mg of rifampin or placebo; no treatment was administered during the second week. Pruritus was subjectively scored on a scale from 0 to 100. With rifampin, pruritus disappeared in 11 patients and partially improved in three; with placebo, only two had a partial response (P less than 0.001). Six patients with a prior poor or no response to cholestyramine improved with rifampin. No changes in biochemical tests or side effects were observed during this period. We conclude that short-term administration of rifampin relieves pruritus in primary biliary cirrhosis. When administered over a period of eight months in an open study, the relief of pruritus was maintained, while one individual developed an allergic reaction. Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.

Analysis of clinical course and prognosis of culture-positive spontaneous bacterial peritonitis and neutrocytic ascites. Evidence of the same disease.

The clinical significance and prognosis of culture-negative neutrocytic ascites in cirrhotic patients is a controversial topic. In the present study, the clinical and humoral presentation and the short- and long-term prognosis were analyzed in 36 patients with cirrhosis and culture-positive spontaneous bacterial peritonitis and in 28 patients with cirrhosis and ascitic fluid polymorphonuclear count greater than 250/mm3, a negative ascitic fluid culture, and without previous antibiotic therapy. On admission there were no significant differences between groups related to age, sex, alcoholism, fever, abdominal pain, serum albumin, serum urea, serum creatinine, Child-Pugh score, polymorphonuclear count, and total protein concentration in ascitic fluid. A greater frequency of positive blood culture was found in patients with spontaneous bacterial peritonitis (15/21 vs 2/18) (P < 0.001). Mortality during the first episode was 36% in patients with spontaneous bacterial peritonitis and 46% in patients with culture-negative neutrocytic ascites (NS). Mortality during follow-up was high and survival probability at 12 months was 32% in spontaneous bacterial peritonitis and 31% in culture-negative neutrocytic ascites. The probability of recurrence at 12 months was 33% in spontaneous bacterial peritonitis and 34% in culture-negative neutrocytic ascites. Our results show that spontaneous bacterial peritonitis and culture-negative neutrocytic ascites are variants of the same disease with a high mortality and poor prognosis.