Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites: a randomized, double-blind, placebo-controlled, single ascending dose study.

BACKGROUND: RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney. AIM: To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone. METHODS: Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment. RESULTS: RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4-17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of > 2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis. CONCLUSION: RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and 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.

Low albumin gradient ascites complicating severe pseudomembranous colitis.

Pseudomembranous colitis (PMC) is a frequently severe, sometimes fatal iatrogenic disease that is antibiotic-associated in almost all cases. The most common clinical features of PMC include abdominal pain, watery diarrhea, fever, leukocytosis, hypoalbuminemia, and hypovolemia. Ascites, not considered a well-known feature of PMC, is fairly common, based on a review of the English language literature but has not been characterized fully. This case report describes 5 patients with PMC who presented with low serum-ascites albumin gradient (SAAG) and neutrocytic ascites, without evidence of infectious, malignant, or inflammatory peritoneal disease, which has not been reported previously. In 1 patient, massive low SAAG ascites was the presenting manifestation of PMC, a feature also not reported previously. Three of the 5 (60%) patients had acquired immunodeficiency syndrome. The characteristics of the fluid specimens in these 5 patients and the possible pathogenetic mechanisms are proposed. The findings suggest that PMC should be included in the differential diagnosis of low SAAG ascites, especially in patients with acquired immunodeficiency syndrome.

Analysis of long-term endoscopic surveillance during follow-up after variceal sclerotherapy from a 13-year experience.

PURPOSE: To evaluate the course of patients with bleeding esophageal varices treated with endoscopic sclerotherapy after obliterating varices and to determine the cost benefits of long-term endoscopic surveillance from a retrospective analysis of a 13-year experience. LOCATION: University-affiliated teaching hospital and county facility. METHODS: Patients whose varices were obliterated by endoscopic sclerotherapy were considered for the study if they had a minimum of 12 months of follow-up. Sclerotherapy was initially performed weekly, increasing intervals to eventual yearly treatments. Varices were reobliterated if they reformed. Variables assessed were rebleeding, mortality, employment status, and cost based on allowable and reimbursed Medicare rates. RESULTS: Of 324 patients who achieved variceal obliteration, analysis included 104 eligible patients who were followed up for > 12 months (41 +/- 28). Varices reformed in 73 patients (71%), mostly in the first year after obliteration or reobliteration. Abstinent alcoholic patients were least likely to reform varices. Nineteen patients (18%) had 23 rebleeding episodes, and in 10 patients (10%) portalsystemic shunt was placed. Survival was 84% and bleeding-related mortality was 6%. Significantly more patients were employed while on the program compared with entry. The yearly cost of treating variceal reformers ($2,117) was significantly higher than variceal nonreformers ($1,735), but the overall cost of maintaining a patient on a chronic sclerotherapy program was relatively small. CONCLUSIONS: The low rebleeding, low mortality, and relatively low cost in patients managed long term by chronic sclerotherapy underscores the benefits of this treatment program.

Diagnostic features of tuberculous peritonitis in the absence and presence of chronic liver disease: a case control study.

PURPOSE: To determine diagnostic features of tuberculous peritonitis (TBP) in the absence and presence of chronic liver disease. PATIENTS AND METHODS: Thirty-four patients with TBP (13 without [Group I] and 21 with chronic liver disease [Group II] and 26 controls with cirrhosis and uninfected ascites (Group III) were studied. RESULTS: The clinical features in Groups I and II were similar and all patients had elevated ascitic fluid total mononuclear cell count. In Groups I, II, and III, respectively, ascitic fluid protein was > 25 g/L in 100% (13/13), 70% (14/20), and 0% (0/26); serum-ascites albumin gradient (SAAG) was > 11 g/L in 0% (0/13), 52% (11/21), and 96% (25/26), (0% [0/13], 71% [15/21], and 96% [25/26] after correction for serum globulin); and ascitic fluid lactate dehydrogenase (LDH) level was > 90 U/L in 100% (12/12), 84% (16/19), and 0% (0/20), respectively. In Groups I and II combined, ascitic fluid acid-fast stain was negative in all but Mycobacterium tuberculosis culture was positive in 45% (10/22); peritoneal nodules occurred in 94% (31/33), granulomas in 93% (28/30), and positive peritoneal M tuberculosis culture in 63% (10/16). CONCLUSIONS: In patients with suspected TBP, ascitic fluid protein of > 25 g/L, SAAG of < 11 g/L and LDH of > 90 U/L have high sensitivity for the disease. With coexistent chronic liver disease, a lower protein level and higher SAAG are usually not helpful but LDH > 90 U/L is a useful parameter for screening. Diagnosis is best confirmed by laparoscopy with peritoneal biopsy and M tuberculosis culture.

Portal vein thrombosis following endoscopic variceal sclerotherapy. Prospective controlled comparison in patients with cirrhosis.

The association between portal vein thrombosis (PVT) and prior endoscopic variceal sclerotherapy has been suggested but remains unproven. The aim of this study was to compare the incidence of PVT in patients who had received sclerotherapy for esophageal variceal hemorrhage to a control group of cirrhotic patients with portal hypertension who had not received sclerotherapy. Doppler ultrasound was used to assess PVT in 48 patients (group 1) who had received sclerotherapy for variceal hemorrhage as well as in 52 patients (group 3) with cirrhosis and portal hypertension who had not received sclerotherapy. Assessment of PVT was made at the time of surgery in 24 patients (group 2) who had received sclerotherapy for variceal hemorrhage, failed therapy, and had portacaval shunt surgery or received liver transplantation for liver failure. One patient had splenectomy for symptoms related to a massively enlarged spleen. The incidence of PVT in group 1 was 10%, in group 2 was 13%, and in group 3 was 10%. The incidence of PVT in the three groups was not significantly different statistically. In this controlled study of patients with cirrhosis and portal hypertension, sclerotherapy does not increase the incidence of PVT.

Variceal bleeding. Can it be prevented?

Esophageal and gastric varices develop as a consequence of portal hypertension and advanced chronic liver disease. Bleeding from these varices causes high mortality and morbidity. The exact mechanism leading to rupture of varices is unknown, but portal pressure, intravariceal pressure, and increased variceal wall tension may be factors. Large varices are most likely to bleed, and some studies suggest that red wales on varices may predict bleeding risk. Surgery and endoscopic sclerotherapy are not useful for preventing initial variceal bleeding, but nonselective beta-adrenergic blocking drugs have been shown to be beneficial in primary prophylaxis. Proper selection of patients and careful monitoring of side effects during treatment enhance successful outcomes.

Variceal bleeding. What are the treatment options?

Management of variceal hemorrhage is complex and can be difficult. Initially, the severity of the bleeding episode must be assessed and the intravascular volume repleted. Several treatment options are available. A trial of pharmacologic therapy (eg, vasopressin) may control acute bleeding. Temporary balloon tamponade of varices is helpful if bleeding continues. Endoscopic sclerotherapy and variceal ligation appear to be equally beneficial, although fewer complications have been reported with the latter. Transjugular intrahepatic portacaval shunt (TIPS) and portal-systemic shunt surgery are alternatives when endoscopic therapy fails; TIPS is preferred in patients awaiting liver transplantation. Ultimately, the choice of treatment is based on the expertise available at each medical center.

Fulminant reactivation of hepatitis B due to envelope protein mutant that escaped detection by monoclonal HBsAg ELISA.

The detection of a fatal case of reactivation of hepatitis B, in a previously vaccinated Indonesian patient after withdrawal of chemotherapy for lymphoma, was delayed because HBsAg was negative in a widely used monoclonal-antibody-based ELISA. The serum was later found to be strongly reactive for HBsAg by the polyclonal radioimmunoassay and for HBV DNA. PCR sequencing revealed a substitution of arginine for glycine at position 145 of HBsAg in the major neutralising epitope cluster, the a determinant, as well as a 2-aminoacid insertion of asparagine and threonine between positions 122 and 123, immediately upstream of this determinant.

Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities.

PURPOSE: To determine whether hydrogen-1 magnetic resonance (MR) spectroscopy of the brain allows detection of subclinical hepatic encephalopathy (SCHE). MATERIALS AND METHODS: In a double-blind study, overt hepatic encephalopathy (HE) and SCHE (defined with clinical and neuropsychiatric tests) were compared by means of H-1 MR spectroscopic criteria--reduction in cerebral myo-inositol (< 2 standard deviations [SDs] from normal) and choline (< 2 SDs from normal) with or without increased cerebral glutamine (> 1 SD from normal)--in 20 patients with cirrhosis. RESULTS: Concordance between MR spectroscopic and neuropsychiatric test results was 94% (kappa = 0.84). MR spectroscopy allowed diagnosis of SCHE in nine of nine patients (100%) and of HE in seven of eight (88%). Myo-inositol depletion alone had 80%-85% sensitivity for detection of HE and SCHE. CONCLUSION: H-1 MR spectroscopy allows accurate diagnosis of SCHE, and the results suggest an important role for myo-inositol in psychomotor and visuopractic functions.

Peritoneal Kaposi's sarcoma: a cause of ascites in acquired immunodeficiency syndrome.

The investigation of ascites in a homosexual man with acquired immunodeficiency syndrome and mucocutaneous Kaposi's sarcoma (KS) revealed only numerous purplish nodules of KS in the parietal and serosal peritoneum, observed at laparoscopy. KS lesions of the peritoneum, a finding not reported in the literature previously, was the only and likely cause of ascites in our patient. Increased red cells and high serum-ascites albumin gradient in a patient with acquired immunodeficiency syndrome should suggest the possibility of peritoneal KS as a cause of ascites.

Investigative studies in portal hypertension.

Portal hypertension usually results from progressive chronic liver disease and is manifested by the development of communications between portal and systemic circulation, termed collateral vessels. Bleeding from collateral vessels in the submucosa of the esophagus and stomach is a potentially fatal condition that is frequently treated with either endoscopic sclerotherapy or endoscopic variceal ligation; portal-systemic shunts are placed when these treatments fail. There are a wide range of investigative studies available to detect portal hypertension and to assess abnormalities in the portal circulation. These are helpful to determine treatment strategies for primary prophylaxis of variceal hemorrhage and to prevent rebleeding. A number of research investigations are designed to understand the mechanisms for bleeding from varices and to determine the pathophysiological basis for treatment.

Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices.

BACKGROUND: Endoscopic sclerotherapy is an accepted treatment for bleeding esophageal varices, but it is associated with substantial local and systemic complications. Endoscopic ligation, a new form of endoscopic treatment for bleeding varices, may be safer. We compared the effectiveness and safety of the two techniques. METHODS: In this randomized trial we compared endoscopic sclerotherapy and endoscopic ligation in 129 patients with cirrhosis who had proved bleeding from esophageal varices. Sixty-five patients were treated with sclerotherapy, and 64 with ligation. Initial treatment for acute bleeding was followed by elective retreatment to eradicate varices. The patients were followed for a mean of 10 months, during which we determined the incidence of complications and recurrences of bleeding, the number of treatments needed to eradicate varices, and survival. RESULTS: Active bleeding at the first treatment was controlled by sclerotherapy in 10 of 13 patients (77 percent) and by ligation in 12 of 14 patients (86 percent). Slightly more sclerotherapy-treated patients had recurrent hemorrhage during the study (48 percent vs. 36 percent for the ligation-treated patients, P = 0.072). The eradication of varices required a lower mean (+/- SD) number of treatments with ligation (4 +/- 2 vs. 5 +/- 2, P = 0.056) than with sclerotherapy. The mortality rate was significantly higher in the sclerotherapy group (45 percent vs. 28 percent, P = 0.041), as was the rate of complications (22 percent vs. 2 percent, P less than 0.001). The complications of sclerotherapy were predominantly esophageal strictures, pneumonias, and other infections. CONCLUSIONS: Patients with cirrhosis who have bleeding esophageal varices have fewer treatment-related complications and better survival rates when they are treated by esophageal ligation than when they are treated by sclerotherapy.