Cirrhosis Ascites Research Articles

Detection of type IV collagenase activity in malignant ascites

Type IV collagenase participates in invasion and metastasis of cancer cells. Malignant ascites is a manifestation of advanced malignant disease that is associated with invasion and metastasis of the peritoneal cavity. Thus, it is reasonable to hypothesize that type IV collagenase is linked to malignant ascites. The purpose of our study was to detect type IV collagenase activity in malignant ascites so as to provide the scientific basis for clinic diagnosis and treatment of malignant ascites. Cirrhotic ascites (n=36), tuberculous ascites (n=8) and malignant ascites (n=23) from patients with gastric cancer (n=6), colon cancer (n=5), ovarian cancer (n=8) and other cancers (n=4), including 2 hepatocellular cancers, 1 pancreatic cancer, 1 primary peritoneal carcinoma were collected by paracentesis. The ascites were made cell-free by centrifugation and stored frozen at -70 degrees C before determination. Type IV collagenase activity was determined by gelatin zymography. The activity of matrix metalloproteinases-2 and -9 could not be detected in ascites of hepatic cirrhosis and tuberculous peritonitis but could be detected in 20 and 18 out of 23 malignant ascites respectively. The positive rate of type IV collagenase (MMP-2, 87.0% and MMP-9, 78.3%) was higher than that by routine ascites tests (P<0.01) in malignant ascites. Furthermore, the activity of MMP-2 was higher than that of MMP-9 (P=0.022<0.05). Type IV collagenase is positive in malignant ascites. Detection of type IV collagenase activity is useful in qualitative diagnosis of ascites. Type IV collagenase may play an important role in malignant ascites formation.

Deficit in nitric oxide production in cirrhotic rat livers is located in the sinusoidal and postsinusoidal areas.

Intrahepatic nitric oxide (NO) production is decreased in cirrhotic livers. Our objective was to identify, in cirrhotic rat livers, intrahepatic vascular segments where the deficit of NO facilitates the effect of vasoconstrictors. By using a modified rat liver perfusion system with measurement of both the perfusion and sinusoidal (wedged hepatic vein) pressures, we studied the effect of the NO synthase blocker N(omega)-nitro-l-arginine (l-NNA) on the response to methoxamine (alpha(1)-adrenoreceptor agonist) in different segments of the intrahepatic circulation of normal and cirrhotic rat livers. l-NNA enhanced the presinusoidal, sinusoidal, and postsinusoidal responses to methoxamine in normal livers as well as the presinusoidal response in cirrhotic livers. However, l-NNA did not change the already enhanced sinusoidal/postsinusoidal response to methoxamine in cirrhotic livers. The postsinusoidal response to methoxamine was higher in cirrhotic rats with ascites than in those without ascites. We concluded that NO modulates the presinusoidal, sinusoidal, and postsinusoidal vascular tone in normal livers. NO production in cirrhotic rat livers is severely impaired in the sinusoidal and postsinusoidal areas but is preserved in the presinusoidal area, as evidenced by its normal response to l-NNA. We speculate that an increased postsinusoidal response to catecholamines may participate in the genesis of ascites in cirrhosis.

Review article: albumin for circulatory support in patients with cirrhosis.

Renal function abnormalities and ascites in cirrhosis are the final consequence of a circulatory dysfunction characterized by marked splanchnic arterial vasodilation. This causes a reduction in effective arterial blood volume and the homoeostatic activation of vasoconstrictor and sodium-retaining systems. Albumin is very effective in preventing renal failure associated with large-volume paracentesis and spontaneous bacterial peritonitis, conditions that are known to cause an impairment of circulatory function in patients with cirrhosis and ascites. Moreover, albumin administration improves survival in patients with spontaneous bacterial peritonitis. In patients with hepatorenal syndrome the administration of vasoconstrictor drugs in combination with albumin improves circulatory and renal function markedly and survival slightly. By contrast, the administration of albumin without vasoconstrictors has marginal or no effects on renal function in this setting.

Trace elements analysis of ascitic fluid in benign and malignant diseases

Objectives: To evaluate differences in ascitic fluid trace element concentrations which might be useful in discrimination between benign and malignant ascites. Design and Methods: The concentrations of copper, zinc, magnesium and iron in ascitic fluid and venous blood in 17 patients were investigated. The relationship between these trace elements and type of disease were examined. Investigations were carried out in a group of 5 males and 5 females aged 54 to 77 yr who had cirrhosis ascites and in a group of 7 females aged 41 to 76 yr with ascites due to gynecologic neoplasms. Results: The mean ascitic fluid and serum concentrations of copper were significantly higher in neoplastic diseases compared to benign disease states (118,43 vs. 97,50, 91,14 vs. 26.90) ( p < 0,05 and p < 0,01 respectively). The zinc levels in ascitic fluid and serum were significantly different between the groups ( p < 0,01). Neoplastic patients had significantly higher ascitic fluid magnesium levels than the benign disease group (2,17 vs. 1,55, p < 0,001). The serum levels of iron were significantly lower in the neoplastic diseases group (92, 28 vs. 255, p < 0, 01). In benign diseases the concentration of zinc in ascitic fluid correlated positively with ascitic fluid copper concentrations. The concentrations of zinc and iron in malignant ascites correlate positively with the magnesium concentrations. Statistically significant negative correlations were found between ascites zinc and magnesium and magnesium and copper in cirrhotic patients and magnesium and copper in malignant diseases. Conclusions: The results showed that zinc, magnesium and iron levels were significantly different between cirrhotic and neoplastic illness. Analysis of serum and ascitic fluid trace element composition may be helpful in identifying and distinguishing the malignant and nonmalignant ascites and provides useful information on processes regulating passage of blood components into the peritoneal cavity.

Patterns of regional sympathetic nerve traffic in preascitic and ascitic cirrhosis

Overactivity of the sympathetic nervous system and portal hypertension are key factors in the development of ascites in cirrhosis. The sympathoexcitation that characterizes the more advanced stages of liver diseases is less clearly defined in preascitic cirrhosis. We measured sympathetic nerve traffic to skeletal muscle (peroneal nerve) and to skin districts by microneurography in (1) 12 Child class A cirrhotic patients with clinically significant portal hypertension (portal pressure gradient [gt ] 10 mm Hg, 14.8 [plusmn] 1.2 mm Hg, mean [plusmn] SEM) but without actual or previous ascites, (2) 16 Child class C cirrhotic patients with tense ascites, and (3) 10 patients with mild congestive heart failure, a condition paradigmatic of a marked sympathetic activation. Muscle sympathetic nerve traffic was markedly increased in Child class C subjects as compared with controls (23.9 [plusmn] 1.6 bursts/min, P [lt ] .01) and superimposable to that recorded in heart failure patients (52.9 [plusmn] 4.7 vs. 60.3 [plusmn] 2 bursts/min, P = not significant). Muscle sympathetic nerve traffic was also increased in Child class A subjects (41.6 [plusmn] 2 bursts/min, P [lt ] .01 vs. controls) although to a lesser extent (P [lt ] .05 vs. Child class C patients). Skin sympathetic nerve traffic was within the normal range in all patients. Neurohormones were all markedly increased in Child class C subjects. Only norepinephrine was increased in Child class A patients. Our data show that sympathetic nerve traffic activation (1) is already detectable in Child class A cirrhosis when clinically significant portal hypertension is present but ascites never developed and (2) is not generalized because although muscle traffic is increased, skin traffic is within normal range. The role of drugs modulating sympathoactivation should be investigated in preascitic cirrhosis. (HEPATOLOGY 2001;34:1113-1118.)

THE PATHOPHYSIOLOGIC BASIS FOR THE TREATMENT OF CIRRHOTIC ASCITES

Advances in the understanding of the pathophysiology of sodium retention and ascites formation in cirrhosis has helped improve the treatment of ascites in these patients. It is likely that further unraveling of these pathophysiologic changes will lead to the development of novel and better treatment options. For example, the development of aquaretic agents for the management of hyponatremia in cirrhosis may allow more effective use of diuretic therapy. The ultimate challenge is to use the understanding of the pathophysiology to develop new strategies to prevent the development of ascites in cirrhosis.

Porto-pulmonary hypertension in decompensated cirrhosis and refractory ascites

Porto-pulmonary hypertension in decompensated cirrhosis and refractory ascites

Porto-pulmonary hypertension in decompensated cirrhosis and refractory ascites

Porto-pulmonary hypertension in decompensated cirrhosis and refractory ascites

The Efficacy of Low Dose Captopril Adjuvant for Natriuresis in Patient with Liver Cirrhosis with Ascites Who Have Received Furosemide and Spironolacton

B ackg r ou nd : The ideal therapy for ascites in liver cirrhosis is a low sodium diet and a combination of furosemide and spironolacton. However, this still sometimes does not produce satisfactory Results, even after increasing the dose of the diuretic. Such failure occurs due to the influence of the Renin Angiotensin Aldosterone (RAA) system. Low doses of ACE inhibitors (captopril) should improve renal blood flow and increase filtration at the glomeruli, thus increasing natriuresis without causing haemodynamic imbalance. Study aim: To discover the natriuretic and diuretic effects of low dose captopril adjuvant in patients with liver cirrhosis who have received furosemide and spironolacton by measuring urinary sodium and 24-hour urine output. Materials and method: This study was conducted on in- and out- patients with liver cirrhosis and Ascites at the Dr. Kariadi Central Public Hospital, Semarang, who met the inclusion and exclusion criteria. The study took place from June 1st, 1997 to March 31st, 1998, and included 40 cases of liver cirrhosis with ascites. Study design: Open comparative randomized clinical trial with permuted blocks. All of the patients received a low fat diet, 40 mg of furosemide, 3x50 mg of spironolacton for 2 weeks, and patients with a urinary sodium level was below 80 mEq/L were randomized into two groups: group A receiving 3 x 6.25 mg of captopril, and group B receiving standard therapy. Results : V a r i a b l e Pre- treatment Post – treatment p Group A : Urinary sodium level (meq/L) 65.450 ± 16.577 109.950 ± 49.109 0.001 24-hour urine output (cc) 1138.750 ± 480.438 1381.250 ± 394.441 0.004 Group B: Urinary sodium level (meq/L) 68.30 ± 12.85 91.750 ± 64.04 0.103 24-hour urine output (cc) 1390 ± 448.27 1392.50 ± 713.46 0.988 The pre- and post- treatment Results for Group A were significantly different. The pre- and post- treatment Results for Group B were not significantly different. Conclusion: Low dose (3 x 6.25 mg) captopril adjuvant in patients with liver cirrhosis and ascites who have received standard doses of furosemide and spironolacton could increase natriuresis and diuresis without causing haemodynamic imbalance. Key w o r d s : Captopril, liver cirrhosis, ascites

Pathophysiology, diagnosis and treatment of ascites in cirrhosis

Ascites is the most common complication of patients with cirrhosis; its development constitutes the first and most important manifestation of the disease and is an indication for liver transplantation. During the last decade significant advances have been made in regard to the pathogenesis and treatment of ascites. The description of a new hypothesis, the identification of new vasoactive factors involved in the pathogenesis of arterial vasodilation and the introduction of different therapeutic modalities (therapeutic paracentesis, transjugular intrahepatic portosystemic shunt, aquaretics drugs and liver transplantation) are all proof of this. Similarly, the description of predictive factors for the survival of patients with cirrhosis has been of major importance for the identification of candidates for liver transplantation. This chapter reviews current knowledge on the pathophysiology, diagnosis and treatment of ascites in patients with cirrhosis.

Value of telomerase activity in the differential diagnosis of benign and malignant ascites

OBJECTIVE: To evaluate telomerase activity as a marker for the differentiation of benign and malignant ascites. METHODS: Exfoliated cells were harvested from various kinds of ascitic fluid and telomerase activity was determined by TRAP-PCR-ELISA (tartrate-resistant acid phosphatase–polymerase chain reaction–enzyme-linked immunosorbent assay). RESULTS: Telomerase activity could not be detected in the ascites of hepatic cirrhosis or peritoneal tuberculosis but was detected in 29 of 34 (85.2%) cancerous ascites. CONCLUSIONS: Telomerase activity may be present in cancerous ascites and could be used as a marker for the differential diagnosis of benign and malignant ascites.

Evidence of post-glomerular arterial vasoconstriction as a mechanism preserving glomerular filtration rate in patients with cirrhosis and recent ascites development

Evidence of post-glomerular arterial vasoconstriction as a mechanism preserving glomerular filtration rate in patients with cirrhosis and recent ascites development

Serum Uric Acid Levels in Patients With Cirrhosis: A Reevaluation

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.

Measurement of renal arterial blood flow velocity by Doppler ultrasonography in chronic liver disease

Doppler ultrasonography was used to measure hepatic hemodynamics in patients with chronic liver disease. We investigated the relationships among the velocity of renal arterial blood flow by Doppler ultrasonography, neurohormonal parameters and human atrial natriuretic peptide (hANP) in chronic liver disease. These parameters were measured in 45 patients with chronic liver disease (15 patients with chronic hepatitis and 30 patients with liver cirrhosis) and 16 healthy subjects. Patients with liver cirrhosis were classified into nine patients with ascites responsive to the conventional treatment, one with refractory ascites and 20 without ascites. Renal arterial velocity was obtained from measurements in the main renal artery (RA) in the cortex. The resistive index (RI) (=(peak systolic velocity−minimum diastolic velocity)/peak systolic velocity) in different areas of the kidney was significantly higher in patients with liver cirrhosis than in patients with chronic hepatitis and healthy subjects. Among cirrhotic patients, RI was higher in patients with ascites than in those without ascites. The RI decreased from the hilum of the kidney to the outer parenchyma in both patients with chronic liver disease and healthy subjects. Neurohormonal parameters tended to be higher but this difference was not significant in patients with liver cirrhosis, especially in those with ascites. Serum hANP levels were positively correlated with main renal arterial RI ( r=0.728, P<0.5), segmental arterial RI ( r=0.729, P<0.05), interlobar arterial RI ( r=0.919, P=0.001) and interlobular aterial RI ( r=0.720, P<0.05) in cirrhotic patients with ascites but no correlation was found with the RI of the peripheral artery in the cortex. On the other hand, in patients without ascites, serum hANP was positively correlated with renal arterial RI, even with the RI of the cortical artery. In addition to measurement of hANP, measurement of renal arterial RI from the hilum to the cortical artery of the kidney by Doppler ultrasonography is beneficial for differentiating stage between with and without ascites in liver cirrhosis and for evaluating changes in systemic and renal hemodynamics. Neurohormonal parameters and hANP were related to the presence or absence of liver cirrhosis. The serum level of hANP is useful for estimating hyperdynamic circulation in liver cirrhosis.

Effectiveness of Recombinant Human Serum Albumin in the Treatment of Ascites in Liver Cirrhosis: Evidence from Animal Model

1. To investigate the effectiveness of recombinant human serum albumin (rHSA) in the treatment of ascites in liver cirrhosis, we examined its effect on rats with carbon tetrachloride-induced liver cirrhosis. 2. Twenty-five percent rHSA was administered intravenously at a dose of 0.25 to 1.0 g/kg for 2 days to rats with liver cirrhosis accompanied by ascites retention and hypoalbuminemia. 3. rHSA dose dependently decreased abdominal circumference, a clinical index of ascites, with significant difference at a dose of 1.0 g/kg. 4. Although there was no significant difference, rHSA increased blood colloid osmotic pressure (b-COP) and urine volume (UV) in a nearly dose-dependent manner, with significant negative correlation between changes from baseline value in these parameters and in abdominal circumference. 5. These findings suggest that rHSA has abdominal circumference-decreasing action associated with b-COP improvement and UV increase and that it could be effective as a therapeutic drug for ascites in patients with liver cirrhosis accompanied by hypoalbuminemia.

Management of ascites in cirrhosis

Ascites is one of the earliest and most common complications of patients with cirrhosis. A typical circulatory dysfunction characterized by arterial vasodilation, high cardiac output and stimulation of vasoactive systems is commonly present in these patients and is associated with a poor prognosis. The treatment of ascites has been based on the combination of a low-sodium diet and the administration of diuretics. The reintroduction of paracentesis and the recent introduction of the transjugular intrahepatic portosystemic shunt (TIPS) are the most relevant innovations in the treatment of ascites during the past two decades, although controlled trials in large series of patients are needed to delineate whether TIPS is a safe and useful treatment for these patients.

Pathogenesis of ascites in cirrhosis.

Much progress has been made in the recognition of factors involved in the pathogenesis of the abnormal regulation of extracellular fluid volume in cirrhosis. It is now well established that cirrhosis induces modifications in the activity of several systemic vasoactive factors which then play a major role in the development of renal dysfunction and the formation of ascites and edema. It is also evident that intrarenal factors participate in the pathogenesis of these abnormalities. Nevertheless, the available information is still limited. The link between the diseased liver and the disturbances in the vasoactive systems is not completely known but much evidence suggests that it consists of a circulatory dysfunction that affects mainly the arterial circulation and is characterized by an inability to maintain an effective arterial blood volume within normal limits. Research on the mechanisms of this circulatory dysfunction may yield clues that will help in the design of more pathophysiologically oriented therapeutic approaches to the management of ascites.

Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis

BACKGROUND & AIMS: Paracentesis associated with plasma expanders is widely used for the treatment of ascites in cirrhosis. This study investigated the clinical importance of paracentesis-induced- circulatory dysfunction and compared the efficacy of albumin, dextran 70, and polygeline in preventing this complication. METHODS: A total of 289 cirrhotic patients with ascites were randomized to treatment by total paracentesis plus intravenous albumin (97 patients), dextran 70 (93 patients), or polygeline (99 patients). Postparacentesis circulatory dysfunction was defined as an increase in plasma renin activity on the sixth day after paracentesis of more than 50% of the pretreatment value to a level > 4 ng.mL-1.h-1. RESULTS: Postparacentesis circulatory dysfunction occurred more frequently in patients treated with dextran 70 (34.4%; P = 0.018) or polygeline (37.8%; P = 0.004) than in those receiving albumin (18.5%). The plasma expander used and the volume of ascites removed were independent predictors of this complication. Postparacentesis circulatory dysfunction persisted during follow-up and was associated with a shorter time to first readmission (1.3 +/- 0.5 vs. 3.5 +/- 0.8 months, median +/- SEM; P = 0.03) and shorter survival (9.3 +/- 4.2 vs. 16.9 +/- 4.3 months; P = 0.01). Creatinine and sodium levels in serum, and Child- Pugh score at inclusion, and postparacentesis circulatory dysfunction were independent predictors of survival. CONCLUSIONS: Postparacentesis circulatory dysfunction is not spontaneously reversible and is associated with a shorter time to first readmission and shorter survival. Albumin is the best plasma expander to prevent this complication. (Gastroenterology 1996 Oct;111(4):1002-10)

Clinical response after transjugular intrahepatic portosystemic stent shunt insertion for refractory ascites in cirrhosis.

Transjugular intrahepatic portosystemic stent shunts (TIPSS) have been used successfully to reduce portal pressure in the context of variceal haemorrhage. Recent interest has focused on the possible use of TIPSS to manage refractory ascites. To study the effect of TIPSS insertion in 18 patients with refractory ascites. Response rates were 33.3%, 50%, 33.3% and 26.7% at 1 week, 4 weeks, 3 months and 6 months, respectively. Overall mortality was 50% with a new or worsening encephalopathy rate also of 50%. Patients with lower serum bilirubin and serum creatinine prior to TIPSS insertion had greater response at 1 and 4 weeks, respectively. There was no improvement in either liver or renal function after TIPSS insertion by standard laboratory tests, although serum sodium increased in the responders after 1 month. TIPSS improves refractory ascites in only a minority of patients, and is associated with high encephalopathy and mortality rates.

Improvement in oxygenation after large volume paracentesis.

Seventeen patients with biopsy-confirmed hepatic cirrhosis and tense ascites performed reproducible pulmonary functions and had arterial blood gas analysis before and after having a therapeutic large volume paracentesis. Each patient showed significant improvement in the static lung volumes as determined by helium dilution techniques. Dynamic airflow also improved as expressed by the FVC and the FEV1. The FEV1/FVC ratio remained unchanged. Each patient showed a significant improvement in oxygenation 120 minutes after LVP. Alveolar ventilation as expressed by PaCO2 did not change. The pathophysiology that explains the improvement in oxygenation remains speculative. Large volume paracentesis appears to have a salutary effect on oxygenation, as well as on pulmonary function.