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Relationships between haemodynamic alterations and the development of ascites or refractory ascites in patients with cirrhosis.

OBJECTIVE: In patients with cirrhosis, the relationships between haemodynamic alterations and the development of ascites or the occurrence of refractory ascites are unknown. The aim of the present study was to compare haemodynamic measurements obtained in patients with non-refractory ascites to haemodynamic measurements obtained in patients without ascites and in patients with refractory ascites. METHODS: A cohort of 121 patients was prospectively studied, of whom 29 patients did not have ascites, 45 had non-refractory ascites and 47 had refractory ascites. Splanchnic, renal and systemic haemodynamics were measured in all patients. RESULTS: The hepatic venous pressure gradient was significantly higher in patients with non-refractory ascites than in patients without ascites (18.5 +/- 0.8 mmHg versus 15.8 +/- 0.7 mmHg). Renal and systemic haemodynamics did not significantly differ between patients with non-refractory ascites and patients without ascites. The glomerular filtration rate and renal blood flow were significantly lower in patients with refractory ascites than in patients with non-refractory ascites (77 +/- 4 versus 107 +/- 5 ml/min and 867 +/- 62 versus 1,008 +/- 68 ml/min, respectively). Splanchnic and systemic haemodynamics did not significantly differ between patients with refractory ascites and patients with non-refractory ascites. CONCLUSIONS: In patients with cirrhosis, an increase in portal hypertension was the sole haemodynamic alteration related to the development of ascites. Renal vasoconstriction (and subsequent renal hypoperfusion and hypofiltration) was the only haemodynamic alteration related to the occurrence of refractory ascites. The development of ascites or refractory ascites was not associated with any alteration in systemic haemodynamics.

Aldosterone↗

Clinical value of tumour markers and serum-ascites albumin gradient in the diagnosis of malignancy-related ascites.

To determine the clinical value of tumour markers in the diagnosis of malignancy-related ascites (not including hepatocellular carcinoma), serum and ascitic fluid levels of carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 19-9, tissue polypeptide antigen and serum-ascites albumin gradient were determined in 66 patients with cirrhotic ascites, 28 patients with hepatocellular carcinoma and ascites, and 29 patients with malignancy-related ascites. Three tumour markers and serum-ascites albumin gradient showed significant difference between patients with malignancy-related ascites and those without: serum carcinoembryonic antigen (26.4 +/- 31.5 vs 4.8 +/- 4.6 ng/mL, P < 0.01), ascitic fluid carcinoembryonic antigen (118.4 +/- 196.5 vs 2.0 +/- 1.4 ng/mL, P < 0.01), ascitic fluid carbohydrate antigen 19-9 (12,933 +/- 25,496 vs 23 +/- 67 U/mL, P < 0.01) and serum-ascites albumin gradient (1.1 +/- 0.4 vs 2.0 +/- 0.4 g/dL, P < 0.01). At the best cut-off levels chosen from near 95% of the data in those without malignancy-related ascites, the sensitivity, specificity and accuracy to diagnose malignancy-related ascites were, respectively, 65.5%, 93.6%, 87.0% using serum carcinoembryonic antigen > or = 10 ng/mL; 69.0%, 94.7%, 88.6% using ascitic fluid carcinoembryonic antigen > or = 5 ng/mL; 65.5%, 93.6%, 87.0% using ascitic fluid carbohydrate antigen 19-9 > or = 50 U/mL; 62.1%, 98.9%, 90.2% using serum-ascites albumin gradient < 1.1 g/dL. Although serum-ascites albumin gradient offered the best diagnostic accuracy and specificity, its sensitivity was not good enough. Our study indicates that serum-ascites albumin gradient and tumour markers are not sensitive parameters in the diagnosis of malignancy-related ascites.

Ascites↗

The value of ascites adenosine deaminase activity and interferon gamma level in discriminating tuberculous from non-tuberculous ascites.

The diagnosis of tuberculous ascites is often difficult because of the subtle clinical clues, poorly discriminative biochemical assays, delayed results of bacteriological studies and hazards of laparoscopy. Therefore, the role of ascites adenosine deaminase (ADA) activity and interferon-gamma (IFN-delta) level in distinguishing tuberculous from other causes of ascites was examined in 50 patients with ascites. Following bacteriologic culture, seventeen (34%) patients were found to have tuberculous ascites; nine (59.9%) of them had also schistosomal hepatic fibrosis (SHF). Therefore, 36% (9 out of 25) of all patients with SHF included in the study, had coexistent peritoneal tuberculosis despite the presence of transudative ascites and unrecognized clinical features. Ascites ADA activity was significantly higher in tuberculous than in other causes of ascites (P < 0.001) regardless of the presence of an underlying liver disease. A cut-off of 28 U/L reached a sensitivity of 94.4% and a specificity of 100%. A direct correlation was found between ascites ADA activity and total proteins in the tuberculous group (r = 0.613) and the only false-negative result occurred in a patient with SHF and low-ascites protein. Ascites IFN-delta level was also significantly higher in tuberculous ascites with or without SHF than in other causes of ascites (P < 0.05). A cut-off of 26 pg/ml reached a sensitivity of 81% and a specificity of 100%. There was no correlation between ascites ADA activity and IFN-delta level in the tuberculous group (r = 0.329). Based on the results of the present study, it can be concluded that tuberculous ascites should be considered as an important cause of ascites particularly in patients with underlying liver disease. Ascites ADA activity was more sensitive than ascites IFN-delta in diagnosing tuberculosis (TB). It has proved to be an easy, rapid, safe and reliable method for routine use in the early diagnosis of tuberculous ascites.

Adenosine Deaminase↗

Lymphocyte subsets and cytokines in ascitic fluid of decompensated cirrhotic patients with and without spontaneous ascites infection.

BACKGROUND AND AIM: Spontaneous ascites infection is a frequently encountered and important complication of decompensated liver cirrhosis. The immune system plays an important role in the development or eradication of this infection. A number of compositional and functional alterations in immune system cells have been demonstrated in cirrhotic patients; however, there is a lack of knowledge about this issue in ascitic infections. The aim of the present study was to evaluate lymphocyte subsets and levels of some ascitic and lymphocytic intracytoplasmic cytokines in decompensated cirrhotic patients with or without spontaneous ascites infection. METHODS: The study population consisted of 45 decompensated cirrhotic patients (32 men, 13 women) with different etiologies. Patients with ascitic polymorphonuclear leukocyte count > or =250/mm(3) and/or positive ascitic bacterial cultures were classified as the "infected group". Comparison was made between the infected and non-infected group for the following parameters: ascites leukocyte counts and differentiations; ascitic fluid protein; albumin levels and serum-ascites albumin gradients; flow cytometric detection of cell surface markers for ascitic T, B and natural killer lymphocytes; intracytoplasmic interleukin (IL)-2, IL-4, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma; levels of ascitic IL-8, IL-10, IL-12 and TNF-alpha; and soluble Fas antigen and soluble Fas ligand. RESULTS: The CD4/CD8 ratio was significantly decreased and expression of T cell receptor-gammadelta was increased in the infected group. Furthermore, ascites TNF-alpha levels were also elevated in this group. Ascitic IL-8, IL-10, IL-12 and TNF-alpha levels were significantly higher in patients with positive ascitic bacterial culture. CONCLUSIONS: These results suggest that a cytotoxic, especially Th1, immune response predominates in ascites infections. It also demonstrates that TNF-alpha might be involved in the pathogenesis of ascites infections.

Ascites↗

Ascitic fluid pH and lactate: insensitive and nonspecific tests in detecting ascitic fluid infection.

Ascitic fluid pH and lactate concentration have been proposed as useful tests for the detection of ascitic fluid infection. However, past studies involved small numbers of infected patients, and all did not use optimal culture techniques. This large study was performed using highly sensitive culture methods and sought (a) to compare the sensitivity, specificity and accuracy of pH and lactate to that of the ascitic fluid neutrophil count and (b) to determine whether evaluation of ascitic fluid pH or lactate (or arterial-ascitic fluid pH or lactate gradient) would result in improved decision-making regarding empirical treatment of suspected ascitic fluid infection. Analysis of 206 ascitic fluid specimens obtained in 175 patients, including 101 infected specimens, revealed that ascitic fluid (or arterial-ascitic fluid) pH and lactate were less than 50% sensitive in detecting bacterial peritonitis and that these tests did not improve clinical decision-making about empirical treatment of suspected ascitic fluid infection. Although statistically significant differences in ascitic fluid pH were detected between infected samples and control samples, these differences did not appear to be clinically helpful. The ascitic fluid pH was 0% sensitive in detecting the presence of bacteria in the absence of neutrophils (i.e., no such specimens had a pH lower than 7.35). Ascitic fluid pH correlated well with neutrophil count and appears to be, at least in part, an indirect measure of the presence of neutrophils in ascitic fluid. Measurement of pH or lactate (or arterial-ascitic fluid gradients) is not helpful in the clinical management of infected ascitic fluid.

Ascites↗

The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites.

OBJECTIVE: To compare the serum-ascites albumin gradient to the exudate-transudate concept in the classification of ascites. DESIGN: Prospective collection of ascitic fluid data from patients with well-characterized causes of ascites. SETTING: Hepatology inpatient and outpatient ward and consult service of a large, urban hospital. PATIENTS: A total of 901 paired serum and ascitic fluid samples were collected from consecutive patients with all forms of ascites. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The utility of the serum-ascites albumin gradient and the old exudate-transudate concept (as defined by ascitic fluid total protein concentration [AFTP]) were compared for their ability in discriminating the cause for ascites formation. RESULTS: The albumin gradient correctly differentiated causes of ascites due to portal hypertension from those that were not due to portal hypertension 96.7% of the time. The AFTP, when used as defined in the old exudate-transudate concept, classified the causes of ascites correctly only 55.6% of the time. This resulted in part because the AFTP of most spontaneously infected samples (traditionally expected to be exudates) was low, and the AFTP of most cardiac ascites samples (traditionally expected to be transudates) was high. CONCLUSIONS: The exudate-transudate concept should be discarded in the classification of ascites. The serum-ascites albumin gradient is far more useful than the AFTP as a marker for portal hypertension, but the latter remains a useful adjunct in the differential diagnosis of ascites.

Albumins↗

[Concentration of lipids in ascitic fluid and the concentration gradient of albumin in blood and ascites: diagnostic significance].

The aim of this study was to test the diagnostic value of ascitic fluid cholesterol and triglycerides concentrations and of serum-ascites albumin concentration gradient in the differentiation between cirrhotic and malignant ascites. These biological parameters were determined, on the one hand in 34 cirrhotic patients, 6 of them having an hepatocellular carcinoma and 6 others having a spontaneous bacterial peritonitis and, on the other hand, in 16 patients with malignant ascites, 13 of them having an abdominal extra-hepatic or pelvic cancer, and 3 others having an extra-abdominal cancer with multiple liver metastases. Ascitic carcinoembryonic antigen assay and ascitic fluid cytology were also done in the 50 patients. In differentiating the cirrhotic patients from those with malignancy, ascitic fluid cholesterol concentration (discriminating value less than 1.1 mmol/l) ascitic fluid triglycerides concentration (discriminating value 0.5 mmol/l) and serum-ascites albumin concentration gradient (discriminating value greater than 11 g/l) allowed a diagnostic efficiency of 0.92, 0.80 and 0.77, respectively. Ascitic fluid cytology showed presence of malignant cells in 3/6 patients with hepatocellular carcinoma associated with cirrhosis, in 9/16 patients having a malignant ascites, and was negative in other patients. Ascitic carcinoembryonic antigen assay was abnormal only in 3/16 patients with malignant ascites. These results suggest that measurement of ascitic fluid cholesterol concentration must be included in the initial evaluation of patients with ascites of unknown origin.

Albumins↗

Proteases and antiproteases related to the coagulation system in plasma and ascites--an approach to differentiate between malignant and cirrhotic ascites.

The concentrations of several proteases and antiproteases known to be present in ascites were tested in plasma and ascitic fluid with regard to their ability to separate ascites according to malignant or nonmalignant disease. Seventeen patients with proven malignant ascites and 37 with ascites due to liver cirrhosis were included. Activities of plasminogen, alpha 2-antiplasmin, antithrombin-III, and factor V, and the concentration of alpha 1-protease inhibitor were significantly higher in the plasma of patients with malignant ascites than in cirrhotic patients. Fibronectin, plasminogen, alpha 2-macroglobulin, alpha 1-protease inhibitor, antithrombin-III, and albumin revealed higher concentrations or activities in malignant ascites than in cirrhotic ascites. Due to a wide variation of most parameters, only fibronectin, antithrombin III, and alpha 1-protease inhibitor in ascites had a sensitivity and specificity higher than 90% for malignant ascites. When the specific protein/albumin ratio was used, only the accuracy of fibronectin was increased reaching a sensitivity and specificity of 100%. The plasma/ascites gradients of the proteins assessed differed significantly, that of fibronectin being much higher (22 +/- 7) than that of all other proteins. In malignant ascites fibronectin concentration was only correlated with alpha 1-protease inhibitor concentration but not with the concentration or activity of all other proteins, while in cirrhotic ascites most proteins revealed a positive correlation. The determination of the fibronectin concentration or the fibronectin/albumin ratio in ascites can differentiate malignant and nonmalignant ascites. All other proteases and antiproteases assessed are of lesser value for this purpose, although most are significantly increased in ascites and plasma of patients with malignant disorders.

Antithrombin III↗

The ascites to serum amylase ratio identifies two distinct populations in acute pancreatitis with ascites.

BACKGROUND/AIM: While the characteristics of ascites in the setting of chronic pancreatitis are well established, little has been written about the characteristics of spontaneous, clinically apparent ascites in the setting of acute pancreatitis. Our aim was to define the characteristics of clinically apparent ascites complicating acute pancreatitis, particularly with regard to outcomes. METHODS: We performed a search of our hospital's discharge records for ICD codes 577.0 (acute pancreatitis) and 789.5 (ascites). Clinical and laboratory variables in survivors and nonsurvivors were compared using a Mann-Whitney U test. RESULTS: We identified 59 records of which 25 cases had ascites fluid analysis. Only the ascites amylase (p = 0.033) and the ascites to serum amylase ratio (p = 0.002) correlated with mortality. Setting a cutoff of 1, the ascites to serum amylase ratio achieved a sensitivity of 83% and a specificity of 92% as a predictor of mortality. CONCLUSIONS: The ascites to serum amylase ratio identifies 2 sets of patients with ascites complicating acute pancreatitis. In patients with a high ratio, ascites may result from a localized duct disruption. In patients with a low ratio ascites may be secondary to comorbid conditions or a capillary leak. In acute pancreatitis with clinically apparent ascites, the ascites to serum amylase ratio may be a predictor of mortality.

Acute Disease↗

Mobilization of malignant ascites with diuretics is dependent on ascitic fluid characteristics.

Serial ascites and plasma volumes were measured during diuresis in nine patients with ascites caused by peritoneal carcinomatosis, four patients with chylous malignant ascites, and three patients with portal hypertension-related ascites caused by massive hepatic metastases. Oral diuretics were given to achieve an adequate natriuresis on a sodium-restricted diet. During the study period (7.8 +/- 3.2 days), patients with peritoneal carcinomatosis and chylous ascites lost 0.49 +/- 0.31 and 0.51 +/- 0.42 kg/day in weight, respectively, with negligible change in ascites volumes (-0.03 +/- 0.11 and 0.02 +/- 0.09 L/day). Patients with ascites caused by massive hepatic metastasis lost 1.06 +/- 0.15 kg/day in weight (P = 0.01 for massive hepatic metastasis vs. peritoneal carcinomatosis) and 0.23 +/- 0.13 L/day of ascites (P less than 0.05 vs. other groups). Plasma volume changes were not significantly different among the three groups. Patients with edema (9/16) had a greater natriuresis and daily weight loss. Three patients with peritoneal carcinomatosis and one with chylous ascites developed renal dysfunction or symptomatic hypotension. No patient with massive hepatic metastasis developed these complications. In patients with ascites caused by peritoneal carcinomatosis or chylous malignant ascites there is no mobilization of ascites, whereas in patients with massive hepatic metastasis, ascites may be mobilized with diuretics.

Adult↗

Ascitic fluid analysis in peritoneal carcinomatosis: comparison of various biochemical tests with ascitic cirrhotics.

Owing to the high false-negative rate of cytological examinations, various biochemical tests have been investigated to search for an alternative method to differentiate between the most frequent causes of ascites formation, i.e. cirrhosis of the liver and peritoneal carcinomatosis. For this purpose, serum and ascitic fluid samples of 71 ascitic patients (54 due to cirrhosis of the liver and 17 due to peritoneal carcinomatosis) were prospectively and simultaneously collected. Eleven major parameters were analyzed, and, of them, ascitic fluid protein, albumin, cholesterol, fibronectin and serum-ascitic gradient of protein and albumin were found to be useful. The serum-ascitic fluid albumin gradient was not as useful as described in the literature and, if clinically applied, the best cut-off value should be raised up to 1.5 gm/dl. Neither as useful was the serum-ascitic fluid protein gradient. Ascitic cholesterol and ascitic fibronectin were more accurate than the ascitic total protein, ascitic albumin and serum-ascitic gradient of protein and albumin in the diagnosis of peritoneal carcinomatosis. Of these tests, an ascitic fluid fibronectin concentration greater than 40 micrograms/ml was the most accurate parameter (diagnostic accuracy 96.2%) that could solely help to establish the diagnosis of peritoneal carcinomatosis.

Adult↗

Serum-ascites albumin concentration gradient: a physiologic approach to the differential diagnosis of ascites.

Serum-ascites albumin concentration gradient, a parameter of oncotic pressure gradient reflecting presence or absence of portal hypertension, was compared with the usual parameters of ascitic fluid analysis in the differential diagnosis of ascites. Twenty-nine patients with liver disease and 15 patients with malignant neoplasm were prospectively studied. The group with malignant neoplasm showed higher ascitic fluid total protein level (3.70 +/- 1.28 vs. 1.66 +/- 1.20 g/dl), ascites to serum ratio of total protein level (0.58 +/- 0.14 vs. 0.26 +/- 0.14), ascitic fluid lactic dehydrogenase level (756 +/- 693 vs. 151 +/- 125 U/L), ascites to serum ratio of lactic dehydrogenase level (1.13 +/- 0.79 vs. 0.35 +/- 0.22), and lower serum-ascites albumin gradient (0.72 +/- 0.30 vs. 1.85 +/- 0.45) (p less than 0.001 for all parameters). Results of the serum-ascites albumin gradient overlapped the least between the two groups: all but 1 patient with malignant ascites while only 1 patient with liver disease had a gradient lower than 1.1. We conclude that the serum-ascites albumin gradient offers the best diagnostic discrimination between ascites caused by liver disease and ascites caused by a neoplasm.

Ascites↗

Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment.

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.

Aged↗

Malignancy-related ascites and ascitic fluid "humoral tests of malignancy".

A large number of ascitic fluid tests, e.g., fibronectin and cholesterol, have been proposed as helpful in detecting malignancy as the cause of ascites. Unfortunately, these "humoral tests of malignancy" are nonspecific. Although the ascitic fluid concentrations of these proteins or protein-bound substances tend to be quite high in patients with peritoneal carcinomatosis and low in the setting of cirrhotic ascites, the problem is that patients with tuberculous peritonitis, cardiac ascites, pancreatitis ascites, etc. usually have values in the malignancy range, i.e., false-positive results. This can lead to an extensive search for a nonexistent tumor, with confusion and anxiety for patient and physician. The cytology is the single best test to order when peritoneal carcinomatosis is suspected; its sensitivity approaches 100%. However, peritoneal carcinomatosis is only one of several mechanisms by which tumors can cause ascites. No one test can be expected to detect tumors as the cause of these diverse mechanisms of ascites formation. The serum-ascites albumin gradient is a helpful test in classifying ascitic fluid specimens into portal-hypertension-related and non-portal-hypertension-related categories. An elevated serum alpha-fetoprotein test can be useful in raising suspicion of hepatocellular carcinoma. Careful analysis of ascitic fluid, without measurement of "humoral tests of malignancy," combined with information obtained from the history and physical examination, usually lead to an accurate diagnosis of the cause of ascites.

Ascites↗