Hepatology : official journal of the American Association for the Study of Liver Diseases
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Dimethyl sulfoxide (DMSO) is commonly used in biological studies to dissolve drugs and enzyme inhibitors with low solubility. Although DMSO is generally thought of as being relatively inert, it can induce biological effects that are often overlooked. An example that highlights this potential problem is found in a recent report demonstrating a pathogenic role for natural killer T (NKT) and natural killer (NK) cells in acetaminophen-induced liver injury (AILI) in C57Bl/6 mice in which DMSO was used to facilitate acetaminophen (APAP) dissolution. We report that NKT and NK cells do not play a pathologic role in AILI in C57Bl/6 mice in the absence of DMSO. Although AILI was significantly attenuated in mice depleted of NKT and NK cells prior to APAP treatment in the presence of DMSO, no such effect was observed when APAP was dissolved in saline. Because of this unexpected finding, the effects of DMSO on hepatic NKT and NK cells were subsequently investigated. When given alone, DMSO activated hepatic NKT and NK cells in vivo as evidenced by increased NKT cell numbers and higher intracellular levels of the cytotoxic effector molecules interferon-gamma (IFN-gamma) and granzyme B in both cell types. Similarly, when used as a solvent for APAP, DMSO again increased NKT cell numbers and induced IFN-gamma and granzyme B expression in both cell types. ⋯ These data demonstrate a previously unappreciated effect of DMSO on hepatic NKT and NK cells, suggesting that DMSO should be used cautiously in experiments involving these cells.
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Randomized Controlled Trial Multicenter Study
Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial.
Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin receptor antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective vasopressin V(2) receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium < or =130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 mg, 12.5 mg, or 25 mg once daily) versus placebo. Duration of treatment was 14 days and all patients received spironolactone at 100 mg/day. Satavaptan treatment was associated with improved control of ascites, as indicated by a reduction in body weight (mean change at Day 14 was +0.49 kg [+/-4.99] for placebo versus +0.15 kg [+/-4.23], -1.59 kg [+/-4.60] and -1.68 kg [+/-4.98] for the 5 mg, 12.5 mg, and 25 mg doses, respectively; P = 0.05 for a dose-effect relationship overall) and a parallel reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium (mean change from baseline to day 5 was 1.3 +/- 4.2, 4.5 +/- 3.5, 4.5 +/- 4.8, and 6.6 +/- 4.3 mmol/L for the placebo group and the groups on satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively; P < 0.01 for all compared to placebo). Thirst was significantly more common in patients treated with satavaptan compared to those treated with placebo, whereas the frequency of other adverse events was similar among groups. ⋯ The V(2) receptor antagonist satavaptan improves the control of ascites and increases serum sodium in patients with cirrhosis, ascites, and hyponatremia under diuretic treatment.
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Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case-control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes x second x cm(-5), and pulmonary capillary wedge pressure < or = 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right-sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio = 2.90, 95% confidence interval 1.20-7.01, P = 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio = 4.02, 95% confidence interval 1.14-14.23, P = 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio = 0.24, 95% confidence interval 0.09-0.65, P = 0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension. ⋯ Female sex and autoimmune hepatitis were associated with an increased risk of portopulmonary hypertension, whereas hepatitis C infection was associated with a decreased risk in patients with advanced liver disease. Hormonal and immunologic factors may therefore be integral to the development of portopulmonary hypertension.
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Randomized Controlled Trial Multicenter Study
Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial.
A beneficial effect of recombinant activated factor VII (rFVIIa) in Child-Pugh class B and C patients with cirrhosis who have variceal bleeding has been suggested. This randomized controlled trial assessed the efficacy and safety of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child-Pugh > 8; Child-Pugh B = 26%, C = 74%) were randomized equally to: placebo; 600 microg/kg rFVIIa (200 + 4x 100 microg/kg); or 300 microg/kg rFVIIa (200 + 100 microg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hours after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24-hour bleeding, or failure to prevent rebleeding or death at day 5. Secondary endpoints included adverse events and 42-day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (P = 0.37). There was no significant difference in 5-day mortality between groups; however, 42-day mortality was significantly lower with 600 microg/kg rFVIIa compared with placebo (odds ratio 0.31, 95% confidence interval = 0.13-0.74), and bleeding-related deaths were reduced from 12% (placebo) to 2% (600 microg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. ⋯ Treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Therefore, decision on the use of this hemostatic agent in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting. Adverse events were comparable across groups.