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Background: Few large population-based studies have compared the occurrence of peptic ulcer bleeding (PUB) in cirrhotic and noncirrhotic patients., Aims: To investigate if cirrhotic patients have higher risk of PUB than the general population and to identify possible risk factors of PUB in cirrhotic patients., Methods: Using the National Health Insurance Research Database, a nationwide population-based dataset in Taiwan and matching age, gender, comorbidities and ulcerogenic medication by propensity score, 4013 cirrhotic patients, 8013 chronic hepatitis patients and 7793 normal controls were compared. The log-rank test was used to analyse differences in accumulated PUB-free survival rates between the groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB in all patients and identified risk factors of PUB in cirrhotic patients., Results: During the 7-year follow-up, cirrhotic patients had significantly higher incidences of PUB than chronic hepatitis patients and controls, respectively (P < 0.001 by log-rank test). By Cox proportional hazard regression analysis, cirrhosis was independently associated with increased risk of PUB (hazard ratio: 4.22; 95% CI 3.37-5.29, P < 0.001) after adjusting for age, gender, economic status, underlying comorbidities and ulcerogenic medication. Age, male, diabetes, chronic renal disease, history of gastro-oesophageal variceal bleeding and use of nonsteroidal anti-inflammatory drugs were risk factors for PUB in cirrhotic patients., Conclusion: Cirrhotic patients have a significantly higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like age, gender, economic status, underlying comorbidities and ulcerogenic medication., (© 2012 Blackwell Publishing Ltd.)

Objective: Clonidine is an α(2)-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of β-adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine-diuretic response rate, favourable predictors and genetic components of the clonidine-diuretic response in patients with cirrhosis with refractory ascites., Methods: 270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine-diuretics association. The primary end point was clonidine-diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate., Results: Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine-diuretics response rate was 55-60%. In patients with cirrhosis, the prevalence of ARDA(2)C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA(2)C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA(2)C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response., Conclusions: These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites.

Background and Aim: The model for end-stage liver disease (MELD) is used to predict the outcome of patients with cirrhosis. Incorporation of serum sodium (Na) into MELD may further increase its prognostic ability. Two Na-containing MELD models, MELD-Na and MELDNa, were proposed to enhance the prognostic ability. This study compared the predictive accuracy of these models for acute decompensated hepatitis., Methods: We investigated the outcome of 182 patients with acute decompensated hepatitis., Results: Twenty (11%) patients died at 3 months. The MELD-Na and MELDNa both had significantly higher area under the receiver operating characteristic curve (AUC) in comparison to MELD (MELD-Na: 0.908, MELDNa: 0.895, MELD: 0.823, p=0.004 and 0.001, respectively). Among 96 patients without specific antiviral treatment, the MELD-Na and MELDNa consistently had significantly higher AUC than the MELD (MELD-Na: 0.901, MELDNa: 0.882, MELD: 0.810, p=0.008 and 0.004, respectively). Three independent indicators, pre-existing cirrhosis (odds ratio [OR]: 5.67, 95% confidence interval [CI]: 1.72-18.7), serum albumin<3.7 g/dL (OR: 5.68, 95% CI: 1.18-27.03) and serum sodium (Na)<138 mequiv./L (OR: 10.0, 95% CI: 2.08-47.62), were associated with 3-month mortality., Conclusion: MELD-Na and MELDNa provide better prognostic accuracy than the MELD for patients with acute decompensated hepatitis. The adequacy of liver reserve determines the outcome of these patients., (Copyright (c) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Terlipressin or octreotide given alone has been used as the first-line pharmacological treatment for acute variceal bleeding. In portal hypertensive animals, pre-infusion of octreotide followed by the addition of terlipressin has an additive or complementary effect on splanchnic hemodynamics. The current study was aimed at evaluating such a combination treatment in patients with cirrhosis and portal hypertension., Methods: Patients were randomly assigned to receive either a placebo (n = 11) or an intravenous infusion of octreotide 100 microg/h after an initial bolus of 100 microg (n = 13). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after octreotide or placebo, and 60 min after terlipressin., Results: Placebo administration did not affect any of the hemodynamic values. Terlipressin administration resulted in expected changes in hepatic venous pressure gradient, hepatic blood flow and systemic hemodynamics. In contrast, octreotide administration significantly decreased hepatic blood flow but did not affect other hemodynamic values. After terlipressin administration, significant hemodynamic changes were observed that were similar to the hemodynamic changes with terlipressin alone. The magnitude of changes in hepatic venous pressure gradient, cardiac index and systemic vascular resistance were no different between the two groups of patients. The heart rate was significantly lower in patients receiving octreotide plus terlipressin than those receiving terlipressin alone., Conclusion: The current study showed that a combination of octreotide and terlipressin did not exert an additive effect in reducing hepatic venous pressure gradient in patients with cirrhosis. In addition, the systemic hemodynamic changes were comparable between the two groups.

Objectives: Terlipressin reduces portal pressure in cirrhotic patients mainly through intense splanchnic vasoconstriction that decrease portal venous inflow. Hepatic blood flow may also be reduced by terlipressin. Prazosin (an alpha1-adrenoceptor antagonist) has also been proposed to decrease portal pressure in cirrhotic patients possibly through a decrease in the intrahepatic vascular resistance. The current study was aimed to evaluate whether a combination of prazosin and terlipressin exerts more beneficial effects than terlipressin alone., Methods: Patients were randomly assigned to receive either a placebo (n = 12) or an oral administration of prazosin 2 mg (n = 12). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after prazosin or placebo, and 30 min after terlipressin., Results: Placebo administration did not affect any hemodynamic values. Terlipressin administration, on the other hand, resulted in expected changes on the hepatic venous pressure gradient, hepatic blood flow, and systemic hemodynamics. In contrast, prazosin significantly decreased hepatic venous pressure gradient with an increased hepatic blood flow and intrinsic hepatic clearance. After terlipressin administration, a further decrease in hepatic venous pressure gradient was observed with preservation of hepatic blood flow and intrinsic hepatic clearance. The magnitude of decrease in hepatic venous pressure gradient was more profound in patients receiving prazosin plus terlipressin than in those receiving terlipressin alone. However, the magnitude of changes in systemic hemodynamics was no different between the two groups of patients., Conclusions: The current study showed that a combination of prazosin and terlipressin resulted in a more profound reduction of hepatic venous pressure gradient with a preservation of hepatic blood flow and intrinsic hepatic clearance than did terlipressin alone. However, the combined therapy did not modify the systemic hemodynamic effects exerted by terlipressin.

Portopulmonary hypertension is now recognized as one of the pulmonary complications of chronic liver disease. However, previous studies reported that the incidence ranged from 0.25% to 2%, excluding fortuitous coincidence. In this study, we aimed to determine the variant hemodynamic and clinical features of portopulmonary hypertension in an area with a high prevalence of viral cirrhosis. After reviewing the hemodynamic data of 322 patients with portal hypertension admitted to the Taipei Veterans General Hospital between 1987 and 1999, we found 10 with portopulmonary hypertension. The overall incidence was, therefore, 3.1% in all patients with portal hypertension. Most of the patients with portopulmonary hypertension experienced exertional dyspnea. The survival times ranged from 2 to 86 months. In our series, most of the patients who died, died of complications related to cirrhosis and portal hypertension, but not of complications related to pulmonary hypertension. This study suggested that portopulmonary hypertension was not a frequent complication in cirrhotic patients and was not associated with an adverse outcome.

To investigate the postprandial gallbladder motility, including emptying and refilling, in cirrhotic patients and to evaluate the relationship to the presence of gallstones and various humoral mediators, 82 patients with liver cirrhosis and 40 age- and sex-matched healthy subjects were enrolled into this study. Postprandial gallbladder volumes were measured with ultrasonography every 15 min for 2 hr. Plasma levels of estradiol, testosterone, substance P, and nitrate/nitrite were also measured. Cirrhotic patients showed a higher prevalence of gallstones than healthy subjects (41% vs 15%, P = 0.003), and the prevalence increased with the progression of liver cirrhosis (Child-Pugh class A: 26%, B: 44%, and C: 65%, P = 0.02). Plasma levels of estradiol, testosterone, and substance P, and nitrate/nitrite and estradiol/testosterone ratios were not different between cirrhotic patients with and without gallstones. However, postprandial refilling of the gallbladders was significantly impaired in patients with cirrhosis, especially in those combined with gallstones. There was no significant difference in the postprandial gallbladder motility between cirrhotic patients with and without elevated plasma levels of estradiol, testosterone, and substance P and nitrate/nitrite, and estradiol/testosterone ratios. Gallstones were common in patients with liver cirrhosis and the prevalence increased with the progression of liver diseases. Sex hormones, substance P, and nitrate/nitrite did not play major roles in the formation of gallstones in cirrhotic patients. Refilling of the gallbladder was significantly impaired in patients with liver cirrhosis, especially in those with gallstones, and may play an important role in the pathogenesis of gallstones.

To delineate the clinical roles of plasma cytokine or endotoxin levels in the natural course of infection in patients with decompensated cirrhosis, 66 cirrhotic patients were studied within a 1.5-year period. Plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-8 and endotoxin were determined on days 1, 4 and 7 after admission when hospital infection was suspected and 4 months later. A total of 24 patients (36.4%) were proven to be infected during hospitalization (group A), while 42 others were not infected (group B). Fever occurred in a very high proportion (22/24) of group A patients. Baseline levels of TNF-alpha (37.7+/-15.2 compared with 8.7+/-1.2 pg/ml; P<0.01) and IL-6 (180.5+/-20.5 compared with 24.6+/-7.5 pg/ml; P<0.0001) were higher in group A patients, while IL-1beta, IL-8 and endotoxin levels were not significantly different between the two groups. For patients with hospital infection, IL-6 levels determined during the episode were significantly higher than baseline levels. Using IL-6 >80 pg/ml as a baseline cut-off level to diagnose bacterial infection, the sensitivity, specificity and accuracy were 87.5, 100 and 95.5% respectively. The one-year cumulative probability of mortality (61.1% compared with 23.7%; P<0.001) and of bacterial re-infection (72.2% compared with 18.4%; P<0.0001) was higher in group A than in group B. Plasma TNF-alpha and IL-6 levels determined at 4 months were not different between the two groups. In conclusion, fever or elevated plasma IL-6 levels in patients with decompensated cirrhosis calls for early antibiotic treatment to prevent life-threatening bacterial infection. Bacterial infection is likely to recur in those patients with increased IL-6 levels, while severe episodes of infection occur in patients with increased TNF-alpha levels.

Objective: Mastalgia is occasionally found in patients with liver cirrhosis, especially in those receiving spironolactone for treatment of ascites. The pathogenesis is still unclear. Estrogen excess in cirrhotic patients and estrogenic effects of the spironolactone are possible leading causes. Treatment directed against the preponderance of estrogenic stimulation in these patients has never been investigated. This study was designed to investigate the efficacy and safety of tamoxifen, an estrogen antagonist, on mastalgia in patients with liver cirrhosis., Methods: A total of 16 male cirrhotic patients with mastalgia were randomly assigned to two groups. One group was treated with tamoxifen (20 mg p.o., b.i.d.) for 1 month, followed by placebo for the next month. The other group was treated in the reverse order. All patients received spironolactone for ascites and/or peripheral edema, and the drug was continued during the study period. The size of the breasts and the degree of breast pain and tenderness were recorded in all subjects before and after the treatment periods. Serum levels of estradiol and testosterone were measured using the radioimmunoassay method., Results: Of the 16 patients, 14 experienced a decrease or disappearance of the breast pain and/or tenderness during the tamoxifen treatment period, whereas only two of the 16 patients felt an improvement during the placebo period (p < 0.05). There were significant improvements in the breast pain and tenderness scores and decreases in the breast sizes during the tamoxifen treatment period (before vs after: 1.4+/-0.3 vs 0.4+/-0.2, p = 0.002; 1.9+/-0.2 vs 0.5+/-0.2, p < 0.001; and 6.8+/-0.6 vs 5.5+/-0.6 cm, p = 0.02, respectively), whereas no obvious change was seen during the placebo period. Serum levels of estradiol and testosterone did not change significantly after the tamoxifen or placebo treatments (p > 0.05). No major side effects were noted during the therapeutic periods., Conclusions: Tamoxifen is effective and safe in the management of mastalgia in male cirrhotic patients taking spironolactone.

It has been reported that the serum uric acid levels in patients with cirrhosis were decreased compared with healthy subjects. These studies suggested that the lower serum uric acid levels in cirrhotic patients were attributed mainly to an increased effective vascular volume, and consequently to an excessive renal clearance of uric acid. However, the previous observations are challenged by a recent hypothesis for the pathogenesis of hyperdynamic circulation and formation of ascites in cirrhosis. The current study was undertaken to reevaluate serum uric acid levels in patients with cirrhosis. Ninety-eight cirrhotic patients with normal renal functions were included in this study. All biochemical and hemodynamic data were utilized for analysis. The mean serum uric acid level (mean, 6.1+/-1.2 mg/dL; range, 2.7-9.1 mg/dL) was higher than that of the age- and sex-matched healthy control subjects (mean, 5.5+/-1.3 mg/dL; range, 2.9-8.1 mg/dL; p = 0.018). Using multiple regression analysis it was determined that the serum uric acid level was not related to the severity of liver disease, cardiac index, systemic vascular resistance, and hepatic venous pressure gradient but was related closely to age (r = 0.210, p = 0.026) and effective renal plasma flow (r = -0.677, p < 0.0001). Compared with cirrhotic patients without ascites, those with ascites had a significantly higher serum uric acid level (6.7+/-1.6 mg/dL vs. 5.6+/-1.7 mg/dL, p < 0.05) and lower effective renal plasma flow (396+/-125 mL/min vs. 445+/-149 mL/min, p < 0.05). In conclusion, for cirrhotic patients with normal serum creatinine levels, the current study shows that the mean serum uric acid level is higher than that of healthy control subjects. It is not related to the severity of liver failure and systemic and portal hemodynamics, but is related closely to renal functions, especially the renal plasma flow.

Background: Hemostatic changes in liver disease are complicated. An overall evaluation of the main hemostatic parameters in patients with different degrees of cirrhosis of the liver has not been reported in Taiwan., Methods: A series of hemostatic tests and parameters including activated partial thromboplastin time, prothrombin time, thrombin time, bleeding time, factor VIII assay, antithrombin activity, fibrinogen, plasminogen, protamine sulfate test, fibrin(ogen) degradation products, D-dimer, thrombin-antithrombin complex (measured by modified antithrombin), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1, euglobulin lysis test and venous occlusion test were performed in 51 patients with cirrhosis of the liver and 33 healthy controls. Among the cirrhotics, 18 were classified as Child-Pugh group A, 16 were B and 17 were C., Results: Plasminogen, antithrombin and platelet count decreased progressively, starting with group A, then B and then C, relative to the controls. Factor VIII, activated partial thromboplastin time, prothrombin time, bleeding time, D-dimer and fibrin(ogen) degradation products increased progressively starting with group A, to B and then C, relative to controls. Severity of cirrhosis correlated with hemostatic changes. No significant change in the fibrinolytic response after challenge with the venous occlusion test was found in either Child-Pugh groups A, B, C or the controls, though progressive increases in tPA were found starting with group A, to B and then C, relative to controls., Conclusions: Our study proved a close relationship between the severity of cirrhosis and hemostatic changes. Activated partial thromboplastin time was better than bleeding time or thrombin time to demonstrate the severity of liver damage and hemostatic change in cirrhosis. Because the deterioration of coagulation function and increased fibrinolytic activity paralleled the severity of liver cirrhosis, adequate treatment for cirrhotic bleeding should not only correct the coagulation defects, but should also lower the increasing fibrinolytic activity.

Objective: Octreotide has potentially beneficial effects in patients with cirrhosis. However, the effects of octreotide on central hemodynamics and oxygen use have not been established. The present study was undertaken to evaluate the effect of octreotide on central hemodynamics and oxygen use in patients with viral cirrhosis., Methods: Twenty-five patients with cirrhosis were enrolled in the study. They were randomly assigned to receive either placebo (n = 10) or a continuous infusion of 100 microg/h of octreotide after an initial 100-microg bolus (n = 15). Hemodynamic measurements and oxygenation values were obtained before and 60 min after octreotide or placebo administration., Results: Placebo administration did not have any effect on hemodynamic and oxygenation values. In patients who received octreotide, systemic hemodynamic values including cardiac index, mean arterial pressure, and systemic vascular resistance were not affected. The mean pulmonary arterial pressure tended to increase after octreotide administration but was statistically insignificant. There was a significant increase in pulmonary arterial vascular resistance, whereas the pulmonary capillary wedge pressure and right atrial pressure were significantly decreased. Arterial oxygen tension, systemic oxygen uptake, and oxygen extraction ratio were significantly decreased after octreotide administration, whereas oxygen transport as well as arterial and mixed venous oxygen contents remained unchanged., Conclusions: In patients with viral cirrhosis, octreotide administration exerted a significant effect on pulmonary circulation. It also resulted in a decrease in systemic oxygen uptake and oxygen extraction ratio. These results suggested that octreotide may impair tissue oxygenation in patients with viral cirrhosis.

Background: Nitric oxide (NO) plays an important role in the pathogenesis of the hyperdynamic circulation observed in portal hypertensive states. Interferon (IFN)-alpha can stimulate NO formation directly or indirectly via cytokines. However, IFN-alpha concentrations seem to increase or decrease in cirrhotic patients. This study investigated the plasma concentration of IFN-alpha in patients with cirrhosis and its relationship to systemic and portal hemodynamics., Methods: Thirty-six patients with cirrhosis and 47 healthy controls had blood samples taken for the determination of plasma concentrations of IFN-alpha by enzyme-linked immunosorbent assay. Systemic and portal hemodynamics were measured in patients with cirrhosis on the same day of blood sampling using Swan-Ganz catheterization and the thermodilution technique., Results: As compared with healthy subjects, patients with cirrhosis demonstrated a significantly higher IFN-alpha detectable rate (> 3 pg/ml, 14.9% vs 36.1%, p < 0.05). In cirrhotic patients, the IFN-alpha detectable rates were similar between those with and without decompensation, a hepatic venous pressure gradient greater than 12 mmHg, or the presence of large esophageal varices (p > 0.05). There was no significant difference in the systemic vascular resistance or hepatic venous pressure gradient between cirrhotic patients with and without a detectable plasma IFN-alpha concentration., Conclusions: Plasma IFN-alpha concentrations tended to increase in patients with cirrhosis. However, IFN-alpha concentrations do not play a role in the hyperdynamic circulation observed in patients with cirrhosis.

Background: It has been suggested that increased blood haemoglobin attenuates splanchnic vasodilatation in portal-hypertensive rats by nitric oxide inactivation. However, the haemodynamic effect of anaemia in cirrhotic patients of varying severity has been rarely discussed. The aim of this study was to evaluate the influence of anaemia on systemic and splanchnic haemodynamics in cirrhotic patients of differing severity., Methods: Two hundred and twenty-five cirrhotic patients were included in this study. All biochemical and haemodynamic results were utilized for analysis. Anaemia was defined as a haemoglobin level below the cut-off value of 12 g/dL, which might best predict low systemic vascular resistance., Results: Compared with non-anaemic patients, anaemic patients had decreased mean arterial pressure (90 +/- 1 vs 95 +/- 1 mmHg, P = 0.002), and decreased systemic vascular resistance (1022 +/- 25 vs 1227 +/- 30, P < 0.0001), and increased cardiac index (4.3 +/- 0.1 vs 3.8 +/- 0.1 L/min per m2, P < 0.0001) and increased hepatic venous pressure gradient (16.7 +/- 0.5 vs 14.4 +/- 0.6 mmHg, P = 0.006). Haemoglobin concentration exerted an influence on the degree of vasodilatation in cirrhotic patients, with Child-Pugh's A class (but not in Child-Pugh's B and C classes), and in patients without ascites (but not in patients with ascites)., Conclusions: It was concluded that anaemia has a negative effect on hyperdynamic circulation in patients with early cirrhosis which is not observed in patients with advanced cirrhosis.

Objective: Cutaneous spider angioma is a common sign observed in patients with liver cirrhosis, but its pathogenesis is still unclear. Increased plasma levels of estrogen, vascular dilation, and neovascularization are possible etiologies. This study was designed to investigate the relationship of spider angiomas in patients with nonalcoholic liver cirrhosis to the plasma levels of sex hormones and various vasodilators and hemodynamic parameters., Methods: A total of 60 patients with nonalcoholic liver cirrhosis and 20 healthy subjects were included in this study. The number, size, and location of the spider angiomas were recorded. Plasma levels of estradiol, testosterone, substance P, calcitonin gene-related peptide, and nitrate/nitrite and forearm hemodynamics were measured., Results: Cirrhotic patients showed higher plasma estradiol/testosterone ratios (28.3+/-47.2 x 10(-3), median 10.5 x 10(-3) vs 8.2+/-8.3 x 10(-3), median 5.7 x 10(-3), p = 0.003) and levels of nitrate/ nitrite (29.9+/-17.5, median 23.8 vs 21.4+/-10.0, median 20.6 micromol/L, p = 0.01) and substance P (47.5+/-62.5, median 29.2 vs 15.2+/-7.7, median 12.3 pg/ml, p < 0.001) than healthy controls. Sixteen (27%) of the 60 cirrhotic patients had spider angiomas. Cirrhotic patients with spider angiomas disclosed higher plasma levels of substance P (84.7+/-105.3, median 53.1 vs 34.5+/-30.7, median 25.8 pg/ml, p = 0.006) and serum levels of bilirubin (3.9+/-3.8, median 1.9 vs 1.9+/-1.9, median 1.2 mg/dl, p = 0.02) than those without. Stepwise logistic regression showed substance P was the only significant and independent predictor associated with the presence of spider angiomas in cirrhotic patients (odds ratio = 3.0, 95% confidence interval = 1.4-6.6, p = 0.01)., Conclusion: Plasma levels of substance P are elevated in patients with nonalcoholic cirrhosis and may play an important role in the pathogenesis of spider angiomas.

Background/aims: The risk factors for esophageal variceal rebleeding are little known. Variceal pressure is one of the major determinants of variceal rupture, but the relationship between variceal pressure and variceal rebleeding during maintenance sclerotherapy has not been determined. This study was undertaken to evaluate the relationship between variceal pressure/gradient change and variceal rebleeding during maintenance sclerotherapy., Methods: Patients with liver cirrhosis and recent esophageal variceal hemorrhage underwent consecutive variceal pressure measurements by direct puncture of the varices before each elective sclerotherapy., Results: In 46 patients, the initial variceal pressure was no different regardless of age, sex, underlying etiology or hepatic reserve. Variceal pressure was higher in large varices, varices with more severe red wale markings, and varices with slower reduction in size during maintenance sclerotherapy. A larger volume of sclerosant was required to eradicate large varices, varices with more severe red wale markings, and varices with slower reduction in size during maintenance sclerotherapy. There was a positive correlation between initial variceal pressure and total amount of sclerosant (r=0.485, p=0.001). Initial variceal pressure was not related to rebleeding. Variceal pressure increased more in patients with rebleeding from varices per se (n=7) than in those without rebleeding (n= 24). There was no difference in pressure change between patients without rebleeding (n=24) and those with rebleeding from variceal ulcers (n=7)., Conclusions: Large varices, severe red color signs and slow reduction in variceal size were associated with higher initial variceal pressure, and more sclerosant was required to eradicate the varices. An increase in variceal pressure during maintenance sclerotherapy indicates a higher risk of variceal rebleeding, but not of variceal ulcer rebleeding.

Background: Laboratory diagnosis of disseminated intravascular coagulation (DIC) is difficult in patients with cirrhosis of the liver due to the complicated hemostatic changes of DIC. More recently, newer molecular hemostatic markers have been used to improve the diagnosis of DIC. This study evaluated the ability of the more advanced hemostatic tests to diagnose DIC in patients with cirrhosis of the liver., Methods: A series of hemostatic tests and parameters including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), factor VIII assay, antithrombin (AT) activity, fibrinogen, plasminogen, protamine sulfate test (PST), fibrin (ogen) degradation product (FDP), D-dimer, thrombin-antithrombin complex (TAT) (measured by modified antithrombin, ATM), euglobulin lysis test (ELT) and platelet count were performed in 51 patients with cirrhosis of the liver. A diagnosis of DIC was made according to the following parameters and criteria: a) platelets less than 80 x 10(9)/l; b) PT greater than 1.5, c) APTT greater than 1.3; d) TT greater than 24 sec; e) AT less than 60%; f) ATM greater than 14.7 ng/ml (normal, mean +/- 3 SD); g) fibrinogen less than 1.50 g/l; h) positive PST; i) D-dimer greater than 1.0 microgram/ml; j) FDP greater than 20 micrograms/ml; k) ELT less than 150 min; l) plasminogen less than 50%. DIC was diagnosed if six or more of the above items were present, and at least two of them were item (a) to (h), and at least two were item (g) to (l)., Results: Although eight patients had results that fitted the diagnostic criteria of DIC by using the more advanced tests, only two of them were diagnosed with DIC by conventional testing. The concentration of factor VIII in these eight patients did not markedly decrease., Conclusions: New tests are not necessary to improve the diagnosis of DIC in patients with cirrhosis of the liver.

Objectives: Cirrhotic patients with upper gastrointestinal bleeding are prone to bacterial infection. The aim of this study was to investigate the efficacy of prophylactic intestinal decontamination with oral ciprofloxacin for the prevention of bacterial infections in cirrhotic patients with upper gastrointestinal bleeding., Methods: A total of 120 cirrhotic patients with acute upper gastrointestinal bleeding were enrolled. Sixty patients received ciprofloxacin 500 mg twice daily given orally or through nasogastric tube immediately after upper gastrointestinal endoscopic examination; drug administration continued for 7 days. The remaining 60 patients, who received placebo, served as controls., Results: The incidence of proven bacterial infection in the ciprofloxacin-treated group was significantly lower than that of placebo group (10% vs 45%, p < 0.001). The incidences of bacteremia, spontaneous bacterial peritonitis, and urinary tract infection in the ciprofloxacin-treated group were significantly lower than those in the placebo group (0% vs 23%, 3.3% vs 13%, and 5% vs 18%, respectively; p < 0.05, respectively). Multivariate logistic regression analysis showed that a lack of prophylactic treatment with ciprofloxacin and severity of cirrhosis were the independent significant predictors for cirrhotic patients with acute gastrointestinal bleeding with infection., Conclusions: Prophylactic intestinal decontamination with oral ciprofloxacin is effective in the prevention of bacterial infections in patients with cirrhosis who were suffering from acute upper gastrointestinal hemorrhage.

1. Portal hypertension and hyperdynamic circulation have been postulated to play a role in the pathogenesis of portal hypertensive gastropathy. Administration of octreotide to portal hypertensive rats has been shown to reduce portal pressure and ameliorate hyperdynamic circulation. 2. This study investigated the effects of chronic administration of octreotide on systemic and portal haemodynamics and the development of portal hypertensive gastropathy in carbon tetrachloride-induced cirrhotic rats. 3. After 12 weeks of carbon tetrachloride induction, cirrhotic rats were randomly assigned to receive either placebo (5% dextrose in water) or octreotide (65 micrograms/kg in 5% dextrose in water) subcutaneously twice daily for 10 days. Haemodynamic studies with a thermodilution technique and gastric morphometric analyses were performed at 10 days after treatment. 4. In cirrhotic rats, octreotide treatment induced a significant increase in systemic vascular resistance (2.7 +/- 0.2 versus 3.4 +/- 0.2 mmHg/ml.min-1.100 g-1, P < 0.05) and decrease in portal pressure (12.5 +/- 1.2 versus 9.9 +/- 0.5 mmHg, P < 0.05) compared with placebo-treated rats. In addition, octreotide treatment significantly reduced the mean cross-sectional area of gastric mucosal vessels (2290 +/- 145 versus 1810 +/- 101 micron 2, P < 0.05). 5. This study shows that chronic octreotide treatment ameliorates the development of portal hypertensive gastropathy in cirrhotic rats. The effect of octreotide on portal hypertensive gastropathy may, at least partly, be due to the alleviation of portal hypertension and hyperdynamic circulation.

Objectives: Nitric oxide has been proposed as being responsible for the hyperdynamic circulation observed in portal hypertensive states. Substance P, a neuropeptide partly cleared by liver, induces vasodilation through the activation of the endothelial nitric oxide pathway. This study investigated the plasma levels of substance P in cirrhotic patients and the relationship of these levels to systemic and portal hemodynamics., Methods: Sixty-four patients with cirrhosis and 53 healthy controls had blood samples taken for determining plasma values of substance P by ELISA. Systemic and portal hemodynamics were measured on the same day of blood sampling using a Swan-Ganz catheterization and thermodilution technique., Results: Plasma levels of substance P were higher in cirrhotic patients than in healthy controls (45.7 +/- 2.0 vs 32.9 +/- 1.0 pg/ml, p < 0.001) and directly correlated with Child-Pugh's score (r = 0.52, p < 0.0001). Compared with compensated cirrhotic patients, decompensated cirrhotic patients had higher plasma levels of substance P accompanied by a lower systemic vascular resistance and higher hepatic venous pressure gradient. There was no significant correlation between plasma levels of substance P and systemic vascular resistance and hepatic venous pressure gradient. In addition, no significant difference in plasma levels of substance P was observed between cirrhotic patients with and cirrhotic patients without a hepatic venous pressure gradient > 12 mm Hg or between patients with and patients without large esophageal varices., Conclusions: Plasma levels of substance P are increased in patients with cirrhosis and may contribute to the pathogenesis and/or maintenance of hyperdynamic circulation in decompensated patients. The severity of cirrhosis is more important than portal hypertension and the severity of esophageal varices for the development of increased plasma substance P levels.

Gall-bladder wall thickening is commonly seen in patients with cirrhosis, but its exact causes have not been well established. We evaluated clinical, biochemical and haemodynamic data of patients with cirrhosis with respect to the presence of thickening of the gall-bladder wall. After excluding patients who presented with gallstones, acute or chronic cholecystitis, heart failure, a serum creatinine level greater than 2 mg/dL and/or a serum alanine aminotransferase level greater than 400 U/L, 77 patients with cirrhosis (75 male, two female; mean age 58 +/- 8 years) were enrolled in the study. Clinical, biochemical, ultrasound and haemodynamic data were obtained in every patient. Forty-one (53%) of 77 patients with cirrhosis had gall-bladder wall thickening (> 4 mm). Compared with patients with a normal gall-bladder wall, patients with gall-bladder wall thickening had significantly lower serum albumin levels (3.6 +/- 0.6 vs 2.9 +/- 0.7 gm/dL, respectively; P < 0.05), a longer prothrombin time (13 +/- 6 vs 16 +/- 6 s, respectively; P < 0.05), more patients with Child-Pugh class C (6 vs 37%, respectively; P < 0.05) and more patients with ascites (8 vs 50%, respectively; P < 0.05). In addition, compared with patients with a normal gall-bladder wall, those patients with gall-bladder wall thickening had a higher hepatic venous pressure gradient (13.9 +/- 4.5 vs 17.1 +/- 4.1 mmHg, respectively; P < 0.01) and a lower systemic vascular resistance (SVR; 1144 +/- 332 vs 1010 +/- 318 dyn.s/cm5, respectively; P < 0.05). Using a multivariate analysis, the presence of ascites and SVR lower than 900 dyn.s/cm5 were independently correlated with the presence of gall-bladder wall thickening, while a hepatic vein pressure gradient greater than 10 mmHg had only a marginally significant association. The presence of ascites, decreased SVR and portal hypertension are related to the occurrence of gall-bladder wall thickening in patients with cirrhosis, indicating that the development of gall-bladder wall thickening may be multifactorial.

The role of gastric secretion has been controversial in patients with cirrhosis. Except for studies of gastric secretion in cirrhotic patients who underwent a shunt operation, there is no report correlating gastric secretion with portal pressure in patients with cirrhosis. In this study, we evaluated gastric secretion in cirrhotic patients and correlated it with hemodynamic parameters. Within 12 months, 20 normal volunteers and 16 cirrhotic patients were enrolled. Gastric secretion was assessed in all patients, but portal pressure hemodynamic studies were performed only in cirrhotic patients. We found that the median basal acid output, maximal acid output, and basal pepsin output in the controls (1.41 mmol/h, 9.2 mmol/h, and 0.02 mg/h, respectively) and in the cirrhotic patients (0.6 mmol/h, 7.84 mmol/h, and 1.5 mg/h, respectively) were not statistically different. However, maximal pepsin output was lower in the cirrhotic patients (1.5 mg/h) than in the normal subjects (5.14 mg/h) (p < 0.05). Gastric secretion correlated poorly with hepatic venous pressure gradient (HVPG) and the presence of congestive gastropathy in cirrhotic patients. The severity of congestive gastropathy correlated poorly with HVPG. Helicobacter pylori has difficulty replicating in the stomach when HVPG is > 14 mm Hg. We conclude that patients with cirrhosis have a lower maximal pepsin output than that of the healthy subjects. Gastric secretion correlates poorly with HVPG and the presence of congestive gastropathy in patients with cirrhosis.

Large volume paracentesis (4.8 to 15.5 liters) was performed in 42 patients with post-hepatitic cirrhosis and massive ascites, not only to derive parameters capable of predicting the development of severe clinical hypotension after large volume paracentesis, but also to determine the optimal time to introduce preventive volume expanders. Systemic hemodynamics were sequentially measured for 72 hours in thirty-two patients. Severe clinical hypotension occurred in 13 (31.0%) patients 4-62 hours from the start of paracentesis. Univariate analysis, with the Mantel-Cox test used to compare Kaplan-Meier curves, and the subsequent multivariate analysis by stepwise Cox regression procedure were utilized to identify two variables, withdrawn ascitic fluid greater than 7.5 liters (p = 0.0121) and the absence of peripheral edema (p = 0.0148), reaching statistical significance to predict the occurrence of severe clinical hypotension. Compared to the baseline value, the cardiac output of patients not developing severe clinical hypotension increased (6.26 +/- 0.66 vs. 6.65 +/- 0.69 liter/min, p < 0.01) one hour from the start of paracentesis and right atrial pressure decreased (11.2 +/- 2.4 vs. 8.7 +/- 2.3 mmHg, p < 0.05). The cardiac output returned to the baseline value at the 9th hour. Based on the results presented herein, we can conclude that severe clinical hypotension occurs in a high percentage of patients with post-hepatitic cirrhosis and massive ascites within 72 hours from the start of large volume paracentesis. At potential risk of this occurring are those patients without peripheral edema and withdrawn ascitic fluid greater than 7.5 liters. Volume expanders should be introduced before 4th hour from the start of large volume paracentesis.

The present study investigated plasma levels of interleukin-8 (IL-8) in patients with post-hepatitic cirrhosis and correlated it with the severity of liver diseases and haemodynamic parameters. Plasma IL-8 levels were significantly higher in 57 post-hepatitic cirrhotic patients (7.5 +/- 1.8 pg/mL; P < 0.005) than those in 41 healthy subjects (2.0 +/- 0.2 pg/mL). Elevated (> 5 pg/mL) plasma IL-8 levels were found in up to 30% of cirrhotic patients. In cirrhotic patients, plasma IL-8 levels progressively increased in relation to the severity of liver dysfunction (4.5 +/- 1.0, 4.9 +/- 1.4 and 20.5 +/- 8.3 pg/mL for Pugh's class A, B and C, respectively; P < 0.005). A significant correlation was observed between plasma IL-8 levels and serum bilirubin levels (r = 0.72; P < 0.001). There were no differences in the hepatic venous pressure gradient (15.4 +/- 1.1 vs 15.1 +/- 0.9 mmHg; P > 0.05) and systemic vascular resistance (1119 +/- 118 vs 1199 +/- 54 dyn.s/cm5; P > 0.05) between cirrhotic patients with and without elevated plasma IL-8 levels. In addition, plasma IL-8 levels did not correlate with hepatic venous pressure gradient (r = 0.26; P > 0.05) and systemic vascular resistance (r = -0.24; P > 0.05). These results demonstrate that plasma IL-8 levels are increased in patients with post-hepatitic cirrhosis. The severity of liver cirrhosis is an important factor for the occurrence of enhanced IL-8 levels. IL-8 does not play a role in the hyperdynamic circulation observed in patients with post-hepatitic cirrhosis.

Background: Liver cirrhosis with portal hypertension is associated with hyperdynamic circulation characterized by generalized vasodilatation and increased cardiac output and regional blood flows. Patients with liver cirrhosis present with increased levels of interleukin-6 (IL-6), which may inhibit vascular smooth-muscle contraction. We investigated whether increased plasma IL-6 levels contribute to the pathogenesis of hyperdynamic circulation observed in cirrhotic patients and whether they are correlated with plasma tumor necrosis factor-alpha (TNF-alpha) and endotoxin concentrations., Methods: In 58 consecutive cirrhotic patients and 34 healthy subjects the plasma concentrations of TNF-alpha and IL-6 were measured with enzyme-linked immunosorbent assay, and endotoxin determinations with a limulus assay. In addition, 52 cirrhotic patients underwent a hemodynamic study using Swan-Ganz catheterization., Results: Plasma TNF-alpha, IL-6, and endotoxin levels were significantly higher in cirrhotic patients than in healthy subjects (7.3 +/- 0.2 versus 5.8 +/- 0.1 pg/ml, 6.4 +/ 0.8 versus 2.0 +/- 0.2 pg/ml, and 7.6 +/- 1.2 versus 2.8 +/- 0.3 pg/ml, respectively; p < 0.01). In cirrhotic patients the plasma levels of TNF-alpha IL-6, and endotoxin progressively increased in relation to the severity of liver dysfunction (graded by Pugh's classification). A significant correlation was observed between plasma TNF-alpha and IL-6 levels (r = 0.48, p < 0.001), whereas no correlation was observed between plasma endotoxin levels and plasma TNF-alpha and IL-6 levels. Plasma IL-6 levels correlated negatively with systemic vascular resistance in patients with cirrhosis (r = 0.5, p < 0.01)., Conclusions: Plasma IL-6 levels are increased in patients with cirrhosis. The severity of liver cirrhosis is an important factor for the occurrence of increased IL-6 levels. IL-6 may play a role in the hyperdynamic circulation observed in patients with cirrhosis.

Plasma glucagon concentrations were measured in 160 cirrhotic patients (Pugh's grade A in 52 patients, Pugh's grade B in 64 patients and Pugh's grade C in 44 patients). These values were compared with plasma glucagon concentrations in 57 age and sex-matched healthy subjects. Systemic and portal haemodynamic measurements, effective renal plasma flow and creatinine clearance were recorded for each patient. Plasma glucagon levels were significantly increased in cirrhotic patients compared with healthy subjects. In addition, plasma glucagon levels were higher in cirrhotic patients with ascites than in those without ascites and were increased in relation to the severity of cirrhosis as assessed by Pugh's score. Multiple linear regression found that only Child-Pugh's score was estimated to be an independent predictor of hyperglucagonaemia in cirrhotic patients. However, in patients with different degrees of oesophageal varices and in patients without oesophageal varices, plasma glucagon concentrations were no different among the different groups of patients, but were still higher than plasma glucagon concentrations in healthy subjects. In contrast, plasma glucagon levels were negatively correlated with mean arterial pressure and systemic vascular resistance. The results of the present study suggest that impairment of liver function plays, in part, a role in increased plasma glucagon levels observed in patients with cirrhosis. In addition, these data support the hypothesis that hyperglucagonaemia may contribute, at least in part, to the pathogenesis of peripheral arterial vasodilatation in cirrhosis with portal hypertension.

Background: Colonic vascular ectasias and colorectal varices have been observed in patients with cirrhosis. However, the pathogenesis of these vascular lesions has not been established., Methods: We enrolled 35 cirrhotic patients and 20 normal controls in this study. All received colonoscopic examinations and measurements of plasma glucagon levels. Portal pressure measurements were performed in all the cirrhotic patients., Results: Colonic vascular ectasias occurred more commonly in cirrhotic patients than in controls (17 of 35 versus 0 of 20; p = 0.009) and more commonly in cirrhotic patients with ascites than in those without (15 of 24 versus 2 of 11; p = 0.038). However, the presence of colonic vascular ectasias was not related to the hepatic venous pressure gradient or plasma glucagon levels. Colorectal varices also occurred more commonly in cirrhotic patients than in controls (16 of 35 versus of 1 of 20; p = 0.034), but the hepatic venous pressure gradient, plasma glucagon levels, and severity of cirrhosis were not related to the presence of colorectal varices., Conclusions: Portal hypertension per se and increased plasma glucagon levels may not play an important role in the pathogenesis of colonic vascular ectasias or colorectal varices in patients with cirrhosis.

Renin-angiotensin system plays a prominent role in the sodium and water homeostasis. In addition, activation of renin-angiotensin system frequently occurs in patients with cirrhosis and ascites. Theoretically, administering of angiotensin converting enzyme inhibitors can enhance sodium and water retention in cirrhotic patients with ascites. In this study, we evaluate the role of low-dose captopril on renal function changes, renal plasma flow and hemodynamics in patients with cirrhosis and ascites. Fifty patients are randomly assigned to receive captopril or placebo for 14 days. Renal functions, renal plasma flow, plasma renin activity, plasma aldosterone concentration and systemic and hepatic hemodynamics are measured before and after treatment. Our results indicate that placebo administration did not affect any of the parameter measured in this study. The finding that low-dose captopril significantly increases plasma renin activity suggests that the dose used in this study effectively blocks the enzyme activity. However, low-dose captopril does not affect renal plasma flow, renal functions and systemic and hepatic hemodynamics. Results in this study demonstrate that inhibition of angiotensin converting enzyme alone may not improve sodium and water retention in cirrhotic patients with ascites.

Background/aims: This study aimed to evaluate the effect of octreotide on total effective vascular compliance, measured during rapid volume expansion, in patients with posthepatitic cirrhosis., Methods: Twenty-nine patients with posthepatitic cirrhosis were randomly assigned to receive a 100-micrograms/h infusion of octreotide after a 100-micrograms bolus (n = 15), or a placebo (n = 14). Hemodynamic measurements were recorded before and 30 min after drug administration. Thereafter, rapid volume expansion was performed in each patient and hemodynamic measurements were repeated immediately after volume expansion., Results: Before volume expansion, placebo administration did not affect any of the hemodynamic values, while the hepatic blood flow was significantly decreased following octreotide administration. After volume expansion, the hemodynamic changes were similar between patients receiving octreotide and the placebo. However, the increase in right atrial pressure from the beginning to the end of volume expansion was higher and the total effective vascular compliance was lower in patients receiving octreotide (+3.5 +/- 0.3 mmHg, p = 0.05 and 1.69 +/- 0.16 ml.mmHg-1.kg-1, p < 0.05) compared to patients receiving placebo (+2.5 +/- 0.3 mmHg, 2.60 +/- 0.34 ml.mmHg-1.kg-1)., Conclusions: The present study suggests that octreotide decreased total effective vascular compliance in patients with posthepatitic cirrhosis. It is possible that, in patients with posthepatitic cirrhosis, venoconstriction was induced following octreotide administration.

The prevalence of gastric ulcer and its relationship to the severity of cirrhosis and degree of portal hypertension was evaluated in 245 cirrhotic patients, and compared with 245 age- and sex-matched healthy subjects. Portal and systemic haemodynamic studies were performed in cirrhotic patients. The prevalence of gastric ulcer in cirrhotic patients was 20.8%, which was significantly higher than the 4.0% found in healthy controls. Using a multivariate logistic regression model, the hepatic venous pressure gradient was found to be the only predictor of the prevalence of gastric ulcer in cirrhotic patients to present with gastric ulcer. The hepatic venous pressure gradient was significantly higher in cirrhotic patients with gastric ulcer than in those without (17.3 +/- 4.4 vs 15.5 +/- 5.0 mmHg, P = 0.01). Other variables, including sex, smoking, cardiac output and severity or aetiology of cirrhosis did not show significant differences between the two patient groups. The prevalence of gastric ulcer in cirrhotic patients whose hepatic venous pressure gradient was below 12 mmHg (4.5%) was similar to that observed in the healthy controls (4.0%). However, when the hepatic venous pressure gradient was > 12 mmHg, the prevalence of gastric ulcer (24.4%) was significantly higher than that in control subjects. However, the incidence of gastric ulcer was not related to the degree of portal hypertension. In conclusion, the prevalence of gastric ulcer in cirrhotic patients was found to be significantly higher than in the age- and sex-matched healthy subjects. Portal hypertension with a hepatic venous pressure gradient > 12 mmHg may be an important factor contributing to the increased prevalence of gastric ulcer observed in patients with liver cirrhosis.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) often cause renal dysfunction in cirrhotic patients with ascites through inhibition of prostaglandin synthesis. However, their renal effects in cirrhotic patients without ascites are controversial. In addition, the role of prostaglandins in cirrhotic patients with ascites and in non-ascitic cirrhotic patients receiving NSAIDs also remains elusive. Thus we evaluated the chronic renal effects of indomethacin and misoprostol in 9 cirrhotic patients with ascites (protocol 1) and 21 cirrhotic patients without ascites (protocol 2)., Methods: The patients of protocol 1 received 200 micrograms of misoprostol every 6 h for 7 consecutive days. In protocol 2, 11 patients received 25 mg indomethacin three times a day for 7 consecutive days. The other 10 patients received 25 mg indomethacin three times a day plus 200 micrograms misoprostol every 6 h for 7 consecutive days. Renal function tests, plasma renin activity, and plasma aldosterone concentration were measured before and after treatment., Results: In protocol 1, misoprostol tended to reduce the urinary sodium excretion (p = 0.08). In protocol 2, indomethacin alone greatly impaired renal plasma flow (p < 0.05), creatinine clearance (p < 0.05), blood urea nitrogen (p < 0.05), and serum creatinine (p = 0.06) in 11 patients. Similar magnitudes of renal dysfunction were observed in the other 10 patients despite the concomitant misoprostol treatment., Conclusion: Chronic administration of misoprostol may have caused a negative natriuretic effect in cirrhotic patients with ascites. In cirrhotic patients without ascites chronic administration of indomethacin may induce a renal dysfunction that cannot be reversed by misoprostol.

Background/aims: Increased plasma endothelin levels have been reported in patients with cirrhosis. However, the relationship between plasma endothelin concentrations and hyperdynamic circulation or renal functions has not been documented., Methods: We measured the plasma endothelin-1 and endothelin-3 concentrations using radioimmunoassay in 96 patients with cirrhosis (Pugh's A in 26, Pugh's B in 45 and Pugh's C in 25) and compared these values to 56 age- and sex-matched healthy subjects. Systemic and portal hemodynamic measurements, effective renal plasma flow, creatinine clearance, plasma aldosterone concentration and plasma renin activity were recorded for each patient., Results: Plasma endothelin-1 and endothelin-3 levels were significantly increased in patients with cirrhosis compared to healthy subjects. Additionally, plasma endothelin-1 and endothelin-3 values were higher in patients with cirrhosis and ascites than in those without ascites. Moreover, plasma endothelin-1 levels increased in relation to the severity of cirrhosis. On the other hand, modest negative correlations were found between endothelin-1 and creatinine clearance or effective renal plasma flow., Conclusions: Plasma endothelin-1 and endothelin-3 levels are increased in patients with cirrhosis compared to healthy subjects. The increase in plasma endothelin-1 levels is related at least in part to the severity of cirrhosis. Increased endothelin-1 levels may possibly contribute to renal dysfunction in patients with cirrhosis.

Background: The prevalence of duodenal ulcer increases in cirrhotic patients. However, the pathogenesis remains unclear., Methods: The prevalence of duodenal ulcer and their relationship to cirrhosis and portal hypertension were evaluated in 325 cirrhotic patients, and compared with 325 age- and sex-matched healthy subjects. Portal and systemic hemodynamic studies were performed in all cirrhotic patients. Histological examination of gastric antral mucosa for Helicobacter pylori (H. pylori) was performed in 16 cirrhotic patients with duodenal ulcer and in 34 cirrhotic patients without duodenal lesions., Results: The prevalence of duodenal ulcer in cirrhotic patients was 9.5% (31 out of 325), significantly higher than 4.0% (13 out of 325) in the healthy controls (p = 0.007), but was not related to the severity of liver cirrhosis. The positive rate of H. pylori was not different between cirrhotic patients with duodenal ulcer and those without duodenal lesions (9/16 vs. 18/34, p > 0.05). The hepatic venous pressure gradient was also not different between these groups (17.2 +/- 5.1 vs. 16.1 +/- 4.9 mmHg, p > 0.05). Other variables including sex, smoking, and etiology of cirrhosis did not show significant differences., Conclusions: The prevalence of duodenal ulcer is significantly higher in cirrhotic patients than in the age- and sex-matched healthy subjects. The severity of cirrhosis, the presence of H. pylori or portal hypertension per se does not play an important role in the increased prevalence of duodenal ulcer in cirrhotic patients.

The haemodynamic effects of a combination of propranolol and clonidine were evaluated in 20 patients with post-hepatitic cirrhosis. Haemodynamic measurements were taken before and 30 min after an intravenous injection of 0.1 mg/kg of propranolol. Thereafter, each patient was given an oral dose of 150 micrograms of clonidine and re-measured 60 min later. In this series, eight patients were defined as 'non-responders' (a decrease in hepatic venous pressure gradient of < 10%) after propranolol treatment. Of both the responders and non-responders, propranolol caused expected decreases in the cardiac index and heart rate while mean arterial pressure remained unchanged. Of the propranolol responders, a significant decrease in hepatic venous pressure gradient was observed. After the addition of clonidine, in both the responders and non-responders there was a further decrease in hepatic venous pressure gradient with a concurrent drop in mean arterial pressure, but cardiac index and heart rate remained unaltered. In conclusion, the combination of propranolol and clonidine in post-hepatitic cirrhotic patients enhanced the reduction of portal pressure achieved by propranolol alone. The beneficial effects of the combination of the two in the reduction of portal pressure appeared to be similar in both the propranolol responders and non-responders. However, the drop in mean arterial pressure following the addition of clonidine may be hazardous to cirrhotic patients.

The preliminary results of a prospective double-blind controlled trial of colchicine in 100 patients with hepatitis B virus-related cirrhosis are reported. The patients, 94 males and 6 females, aged 32-80, were assigned to receive either 1 mg of colchicine or an identical placebo orally on a daily basis. The duration of the follow up ranged from 15 to 51 months (median 26 months). Seventy percent had histological proof of cirrhosis. On entry, 80 patients were in Child-Pugh class A, 19 were in class B, and one was in class C. Compared to the placebo group, there was no improvement in the colchicine group after a 24-month follow up in any of the biochemistry data, for example, serum albumin, alkaline phosphatase, alanine and aspartate aminotransferase, bilirubin, and prothrombin time. The difference in the cumulative survival rates at 51 months did not reach statistical significance (p = 0.8) in either group. There was no histological improvement in 30 patients who were willing to undergo repeated liver biopsies. No trend toward improvement of the hepatic pressure gradient was observed in these patients. The serum levels of aminopropeptide of type III procollagen increased significantly in patients in both groups after 24 months of therapy (1.07 +/- 0.06 vs. 1.36 +/- 0.06 U/ml in the colchicine group, 0.93 +/- 0.09 vs. 1.25 +/- 0.07 U/ml in the placebo group; p < 0.05). In addition, neither the clinical deterioration of cirrhosis nor death was prevented in patients receiving colchicine therapy. This report indicates that colchicine has no effect in the treatment of HBV-related postnecrotic cirrhosis.

Single total paracentesis (4.8-11 L) was performed in 23 patients with hepatitis B surface antigen (HBsAg)-positive cirrhosis and massive ascites and its effects on systemic and hepatic haemodynamics and renal function were examined over 5 days. Severe hypotension occurred in six (26.1%) patients from 6 to 54 h after paracentesis. In the remaining 17 patients, compared to the baseline, there was an increase in the cardiac output (6.1 +/- 0.3 vs 6.7 +/- 0.3 L/min, P < 0.001) and a decrease in right atrial pressure (8.8 +/- 0.8 vs 4.3 +/- 0.7 mmHg, P < 0.001), systemic vascular resistance (1160 +/- 61 vs 976 +/- 50 dyne.s.cm-5, P < 0.001), and wedged hepatic venous pressure 30 min after completion of paracentesis. After 5 days, right atrial pressure, systemic vascular resistance and wedged hepatic venous pressure returned to baseline, while the cardiac output dropped to a level lower than the baseline (5.7 +/- 0.7 L/min, P < 0.05). Hepatic venous pressure gradient had returned to baseline after 5 days. Serial tests of serum creatinine level showed an increase from day 3 (1.34 +/- 0.14 vs 1.04 +/- 0.10 mg/dL, P < 0.05). On day 5, creatinine clearance (55.7 +/- 5.4 vs 41.9 +/- 5.3 mL/min, P < 0.05) and effective renal plasma flow (351 +/- 32 vs 293 +/- 29 mL/min, P < 0.05) were decreased, compared to the baseline. Based on these data, infusion of a volume expander may be necessary for total paracentesis to avoid systemic haemodynamic complications in non-alcoholic cirrhosis.

The effects of octreotide on postprandial hemodynamic responses were evaluated in 20 patients with postnecrotic cirrhosis. They were randomly assigned to receive either a 100-micrograms bolus with a 100-micrograms/h infusion of octreotide or a placebo. Placebo administration did not affect any of the hemodynamic values. However, after a liquid meal of 500 kcal, postprandial increases in the hepatic venous pressure gradient and hepatic blood flow were observed in patients receiving placebo, while the systemic hemodynamic values remained unchanged. In contrast, in patients receiving octreotide, the hepatic blood flow was significantly decreased 30 min after administration, while the hepatic venous pressure gradient and the systemic hemodynamic values were not affected. After ingestion of a meal, the mean values of the hepatic blood flows were not significantly different from basal values. Moreover, the wedged hepatic venous pressure, the hepatic venous pressure gradient and the systemic hemodynamic values were not affected by meal ingestion. However, during octreotide infusion, hepatic blood flow 30 min after the meal had a tendency to increase compared to before the meal. In conclusion, octreotide inhibited the postprandial increase in portal pressure in patients with postnecrotic cirrhosis. In addition, octreotide decreased hepatic blood flow in the fasting state. When given before a meal, the increase in blood flow induced by the meal restored the hepatic blood flow to basal levels.

A prolonged bleeding time (> 540 s), measured with a Simplate single template device, was found in 0% of 50 patients with chronic hepatitis and 38% of 154 cirrhotic patients. Cirrhotic patients with a prolonged bleeding time (n = 59) had lower platelet counts (P < 0.001) and a longer prothrombin time (P < 0.001) and activated partial thromboplastin time (P < 0.001) compared with cirrhotic patients with a normal bleeding time (n = 95). A weak but significant negative correlation existed between the bleeding time and platelet count in cirrhotic patients (n = 154, r = -0.3668, P < 0.001). Patients with decompensated cirrhosis had a longer bleeding time in comparison to patients with compensated cirrhosis (621 +/- 39 vs 478 +/- 27 s, respectively, P < 0.01). The prolonged bleeding time was also discovered in 25% of 83 cirrhotic patients with a platelet count > 80 x 10(9)/L and a prothrombin time < 17 s (usually taken as safe limits for invasive procedures). Twenty-seven of the 83 cirrhotic patients received a haemodynamic study by Swan-Ganz catheterization. A lower systemic vascular resistance was found in cirrhotic patients with an abnormal bleeding time than in cirrhotic patients with a normal bleeding time (844 +/- 57 vs 1171 +/- 60 dyne.s.cm-5, respectively, P < 0.001), whereas both groups had similar hepatic venous pressure gradient (16.2 +/- 1.2 vs 18.1 +/- 1.4 mmHg, respectively, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between the severity of cirrhosis and systemic and hepatic haemodynamic values was evaluated in 193 patients with cirrhosis, most of whom were diagnosed with post-necrotic cirrhosis. It was found that the hepatic venous pressure gradient and cardiac output in Pugh's A patients (13.6 +/- 4.8 mmHg and 6.2 +/- 1.6 L/min, mean +/- s.d.) were significantly lower than in both Pugh's B (16.8 +/- 4.3 mmHg and 7.3 +/- 2.1 L/min) and Pugh's C (18.8 +/- 5.5 mmHg and 7.4 +/- 2.3 L/min) patients (P < 0.01), respectively. In contrast, the systemic vascular resistance in Pugh's A patients (1232 +/- 369 dyn/s per cm5) was significantly higher than in both Pugh's B (1016 +/- 345 dyn/s per cm5) and Pugh's C (935 +/- 234 dyn/s per cm5) patients (P < 0.01), respectively. Additionally, not only was there a positive correlation found between Pugh's score and cardiac output and hepatic venous pressure gradient, but a negative correlation was found between Pugh's score and systemic vascular resistance. It was also confirmed that the degree of portal hypertension and the hyperdynamic circulation were more severe in patients with ascites than in those without ascites. However, there were no statistically significant differences in hepatic venous pressure gradient among patients with F1, F2 and F3 esophageal varices (15.7 +/- 4.0, 17.0 +/- 4.8 and 18.0 +/- 4.8 mmHg, respectively). It is concluded that in those patients with cirrhosis, the severity of cirrhosis is closely related to the degree of the hyperkinetic circulatory state and portal hypertension.

One hundred and fifty cirrhotic patients with or without esophageal varices and/or gastric varices were investigated by endoscopy and hepatic venous catheterization to evaluate differences in the degree of portal hypertension, main portal venous diameter and frequency of portal systemic encephalopathy. Hemodynamic values were correlated with varices size as assessed by endoscopy. Patients with large gastric varices had wedged hepatic venous pressures and hepatic venous pressure gradients which were lower than patients with esophageal varices only, but similar to patients without varices. In addition, in patients with large gastric varices, a decrease in the diameter of the main portal vein and an increase in the incidence of chronic portal systemic encephalopathy were noted. Our results implied that patients with large gastric varices presented different hemodynamic features including the degree of portal hypertension and the incidence of portal systemic encephalopathy from patients with esophageal varices only.

The effect of portal hypertension on plasma sex steroid levels was studied in 49 patients with hepatitis B virus-related postnecrotic cirrhosis. In accordance with the Child-Pugh classification, 18 patients were classified as grade A, 15 grade B and 16 grade C. At the same time, 25 males who were admitted for physical check-up served as normal controls. Serum testosterone levels decreased (3.31 +/- 2.03 vs. 5.65 +/- 0.13 ng/ml) and estrone levels increased (0.16 +/- 0.08 vs. 0.09 +/- 0.02 ng/ml) significantly in patients with cirrhosis compared to the levels obtained in the controls. Moreover, these changes were associated with an increased severity of cirrhosis (P < 0.05 when severity increased from grade A to C). Hemodynamic values regarding hepatic venous pressure gradient and cardiac output demonstrated significant differences in patients from grade A to C, but the correlation between these two parameters was poor (r = 0.3242). The hepatic venous pressure gradient, the only direct measurement of portal hypertension, did not correlate with any of the measured hormone levels in patients with cirrhosis. There was, however, a highly significant negative correlation between cardiac output and testosterone levels (r = -0.8754, P < 0.01) and a positive correlation between cardiac output and estrone levels (r = 0.7522, P < 0.05) in grade C patients. On the basis of these results, we concluded that gonadal dysfunction is a common finding in patients with hepatitis B related postnecrotic cirrhosis, especially in those with decompensated liver function. The relationship between cardiac output and severity of liver disease suggests that the degree of portosystemic shunting probably increases as liver disease worsens.(ABSTRACT TRUNCATED AT 250 WORDS)

The pressure of oesophageal varices was determined by fine needle direct puncture in 19 patients with hepatitis B surface antigen (HBsAg)-positive cirrhosis after the first episode of variceal bleeding before endoscopic sclerotherapy. Both the stability and reliability of the measurement of intravariceal pressure by fine needle puncture were confirmed. Seven patients received intravenous 1 mL normal saline. Intravariceal pressure did not change before and after injection of normal saline (16.3 +/- 4.0 vs 16.0 +/- 4.0 mmHg, P > 0.05). Twelve patients received intravenous 1 units vasopressin and this caused a significant reduction in intravariceal pressure (15.6 +/- 2.6 vs 10.3 +/- 2.9 mmHg, P < 0.0001). The average basal intravariceal pressure in these patients was 15.8 +/- 3.1 mmHg. After intravariceal pressure was recorded, the needle was left in situ and endoscopic sclerotherapy commenced immediately. During the investigation, no adverse reaction or complication was encountered. It was concluded that the measurement of intravariceal pressure by fine needle direct puncture followed by immediate sclerotherapy is a safe and simple method to evaluate the short-term effect of drug prevention from oesophageal variceal bleeding and that vasopressin causes reduction of intravariceal pressure.

Somatostatin has been used to effectively control acute variceal haemorrhage, with conjectured mechanisms on portal hypertension. We, therefore, evaluated the effects of somatostatin on hepatic and systemic haemodynamics in 15 patients with hepatitis B-related cirrhosis and portal hypertension. All patients received an intravenous, continuous infusion of somatostatin 250 micrograms/h, following a bolus injection of 250 micrograms. In systemic haemodynamics, the mean arterial pressure (MAP) increased (P < 0.05), associated with a reflex bradycardia within 3 min following bolus injections, compared with basal values. The right atrial pressure, pulmonary capillary wedge pressure, inferior vena cava pressure, cardiac index, and systemic vascular resistance remained unaffected after drug infusion. In hepatic haemodynamics, the wedge hepatic vein pressure remained unchanged after drug administration. However, there was an increase in free hepatic vein pressure (FHVP; P < 0.05), and a trend toward a decrease in the hepatic vein pressure gradient (HVPG; P = 0.063), within 3 min after bolus injection. Furthermore, the hepatic blood flow decreased significantly at 10 and 30 min after somatostatin infusion (P < 0.05). The effective sinusoidal perfusion assessed by indocyanine green infusion also decreased progressively at 10 min (P = 0.057) and 30 min (P < 0.05). We concluded that somatostatin, at the dose used in this study, caused a transient and bolus-related vasoconstrictive effect, resulting in increases in MAP and FHVP, a decrease in heart rate, and a trend toward lower HVPG. In addition, somatostatin reduced the hepatic blood flow and effective sinusoidal perfusion which may be hazardous to cirrhotic patients during variceal haemorrhage.

This randomized controlled trial was conducted to compare the efficacy of intravenous infusion of octreotide (a synthetic long-acting somatostatin analogue) with vasopressin in 48 cirrhotic patients with endoscopically proven bleeding esophageal varices. Twenty-four patients received a continuous infusion of octreotide 25 micrograms/h for 24 h after an initial bolus of 100 micrograms and another 24 patients received a continuous infusion of vasopressin 0.4 U/min for 24 h. Bleeding was initially controlled after 6 h of drug infusion in 88% (21/24) and 54% (13/24) of the patients treated with octreotide and vasopressin respectively (p = 0.03). Complete control of bleeding after 24 h of drug infusion was achieved in 15 (63%) patients receiving octreotide and in 11 (46%) patients receiving vasopressin (p > 0.05). Side effects during drug infusion such as headache, chest pain and abdominal pain were significantly lower in the octreotide group (3/24) than in the vasopressin group (11/24). Serum gastrin and insulin levels fell significantly following octreotide infusion, but plasma glucose levels remained unchanged. Mortality related to bleeding esophageal varices was no different between the two groups. This report showed that octreotide infusion was more effective and had fewer side effects than vasopressin in initial controlling of acute esophageal variceal bleeding until an elective endoscopic sclerotherapy could be performed.

The influence of octreotide and somatostatin on liver metabolic activity were studied in 16 patients with cirrhosis that was positive for hepatitis B surface antigen (HBsAg). In patients receiving a 50 micrograms bolus and a 50 micrograms/hr infusion of octreotide, the hepatic blood flow, hepatic clearance, and the maximum velocity/metabolic elimination rate constant (Vmax/km) were significantly reduced after octreotide infusion compared with basal values. Similarly, the hepatic blood flow, hepatic clearance, and Vmax/km were significantly decreased in patients receiving a 250 micrograms bolus and a 250 micrograms/hr infusion of somatostatin. The extraction ratio and the systemic hemodynamic values, including cardiac index, heart rate, mean arterial pressure, and systemic vascular resistance, showed no significant changes in patients receiving either octreotide or somatostatin. These findings suggest that, as with somatostatin, octreotide reduced hepatic blood flow and impaired liver metabolic activity in patients with HBsAg-positive cirrhosis. These effects may have important clinical implications in the management of bleeding esophageal varices in patients with cirrhosis.

In patients with cirrhosis the renal response to amino acid infusion is controversial. In addition, the renal and systemic metabolic effects of amino acids are unknown. Therefore, the present study examined the effects of amino acids on renal hemodynamics, renal and systemic oxygen (O2) consumption, and hormones in patients with cirrhosis. Twelve patients received an 8% amino acid solution for 30 minutes at a rate providing 250 mg of amino acids/kg body wt. Renal blood flow increased by 45% (P less than 0.05) and the glomerular filtration rate by only 9% (P greater than 0.05). Renal vascular resistance decreased by 23% (P less than 0.05), and renal perfusion pressure did not change significantly. Renal and systemic O2 consumption and pulmonary artery plasma glucagon level significantly increased. There were no significant changes in plasma osmolality, plasma volume, and plasma atrial natriuretic peptide concentrations. In conclusion, the results show that amino acid-induced renal vasodilation caused hyperperfusion but not renal hyperfiltration in patients with cirrhosis. In addition, renal hyperemia was associated with renal and systemic hypermetabolism.

The hemodynamic effects of octreotide were studied in 20 patients with hepatitis B-related cirrhosis. In patients receiving a 100-micrograms bolus and a 100-micrograms/h infusion, heart rate, cardiac index, and systemic vascular resistance showed no significant changes, whereas right atrial pressure, pulmonary capillary wedge pressure, and inferior vena cava pressure decreased significantly after octreotide infusion compared with basal values. In contrast, in patients receiving a 50-micrograms bolus and a 50-micrograms/h infusion, all the systemic hemodynamic values were unaffected. In both groups of patients receiving two different doses of octreotide, the estimated hepatic blood flow, hepatic indocyanine green clearance, and wedge hepatic venous pressure were significantly reduced at 60 minutes after octreotide administration compared with basal values, whereas the hepatic venous pressure gradient remained unchanged. It is concluded that the two different doses of octreotide administration result in the reduction of the wedge hepatic venous pressure and the hepatic blood flow of a similar magnitude, whereas the hepatic venous pressure gradient is unaffected. Octreotide induces discrepant systemic hemodynamic response; this effect is dose related.

In a prospective study of 103 consecutive cirrhotic patients a high prevalence (43%) of anorectal varices was found compared with only 2% in 103 age- and sex-matched control subjects (p less than 0.001). However, there was no significant difference between the prevalences of hemorrhoids in cirrhotic patients and in control subjects (79% vs. 83%, p greater than 0.05). The hepatic venous pressure gradient of cirrhotic patients with anorectal varices was similar to cirrhotic patients without anorectal varices (14 +/- 6 mmHg, n = 22, vs. 16 +/- 7 mmHg, n = 39, p greater than 0.05. There was no significant difference in the hepatic venous pressure gradient between cirrhotic patients with and without hemorrhoids (15 +/- 6 mmHg, n = 47, vs. 16 +/- 8 mmHg, n = 14, p greater than 0.05). The prevalence of anorectal varices and hemorrhoids in cirrhotic patients had no relation to Child-Pugh's grading, esophageal varices with and without sclerotherapy and ascites. We conclude that anorectal varices are common in cirrhotic patients. Anorectal varices and hemorrhoids are not related to the degree of portal pressure.

We measured the hemodynamic effects of intravenous vasopressin, ketanserin (a 5-hydroxytryptamine-2 receptor blocker), and vasopressin plus ketanserin in 33 patients with hepatitis B-related cirrhosis. Thirteen patients received vasopressin alone (0.66 units/min), ten patients ketanserin alone (10 mg), and ten patients vasopressin followed by vasopressin plus ketanserin. Vasopressin alone reduced the hepatic venous pressure gradient (from 18 +/- 5, mean +/- S.D., to 9 +/- 3 mmHg, p less than 0.0001) and cardiac output (p less than 0.0001), but increased mean arterial pressure (p less than 0.005), mean pulmonary arterial pressure (p less than 0.0001), pulmonary capillary wedge pressure (p less than 0.0001), and systemic vascular resistance (p less than 0.001). There was no significant change in heart rate. Ketanserin alone produced a significant fall in the hepatic venous pressure gradient (from 16 +/- 4 to 13 +/- 3 mmHg, p less than 0.0001), mean arterial pressure (p less than 0.005), mean pulmonary arterial pressure (p less than 0.005), and pulmonary capillary wedge pressure (p less than 0.005). Heart rate, cardiac output, and systemic vascular resistance were not significantly changed. The addition of ketanserin to vasopressin corrected most of the systemic hemodynamic disturbances produced by vasopressin. This combination did not lead to a further reduction in the hepatic venous pressure gradient. We conclude that intravenous ketanserin reduces portal pressure in patients with hepatitis B-related cirrhosis. The addition of ketanserin to vasopressin improves the detrimental systemic hemodynamic effects of vasopressin without further reducing the portal pressure.

In an attempt to evaluate the effect of quinidine in the treatment of patients with cirrhosis and muscle cramps, 31 cirrhotic patients with muscle cramps were randomly divided into two groups and given orally 400 mg of quinidine sulfate per day or placebo, respectively. Baseline clinical and laboratory data for these two groups were similar. Four weeks after oral administration of quinidine, the number of cramps significantly decreased from 14.4 +/- 1.7 (mean +/- S.E.) to 4.4 +/- 1.1 episodes (p less than 0.0001), but it remained unchanged in the placebo group (from 11.8 +/- 1.0 to 11.5 +/- 1.5 episodes, p greater than 0.05). In addition, 88% of the 16 patients on quinidine and 13% of the 15 patients on a placebo showed a greater than 50% reduction in the number of cramps during a 4-week treatment period (p less than 0.0001). The peak and trough serum levels of quinidine in patients having received quinidine for 2 weeks were 1.3 +/- 0.1 and 0.7 +/- 0.1 mg/l, respectively. There was a significant relationship between serum quinidine concentrations and attenuation of cramps. No significant adverse effect was observed during the study, except for five (31%) patients who developed mild diarrhea after quinidine therapy. Diarrhea subsided spontaneously or was controlled by medications without the interruption of quinidine therapy. It was concluded that quinidine is a safe and effective drug for the treatment of cirrhotic patients with muscle cramps.