Shwu-Ling Wu

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

Abstract 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 10 ng/mL; 69.0%, 94.7%, 88.6% using ascitic fluid carcinoembryonic antigen 5 ng/mL; 65.5%, 93.6%, 87.0% using ascitic fluid carbohydrate antigen 19–9 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.

Effects of long-term administration of octreotide on sodium retention and atrial natriuretic peptide in carbon tetrachloride-induced cirrhotic rats

BACKGROUND/AIMS To realize the roles of peripheral vasodilatation and atrial natriuretic peptide in the formation of cirrhotic ascites, the effects of long-term administration of octreotide on carbon tetrachloride-induced cirrhotic rats were evaluated. METHODS Urine sodium excretion, hemodynamics, plasma atrial natriuretic peptide levels, renin activities and aldosterone concentrations were compared between cirrhotic and control rats (protocol 1); and between octreotide- (65 micrograms/kg, twice daily for 10 days, subcutaneously) and placebo-treated (5% dextrose) cirrhotic rats (protocol 2). In an in vitro experiment, right atrial tissue of cirrhotic rats was incubated with different concentrations of octreotide to evaluate the release of atrial natriuretic peptide (protocol 3). RESULTS Cirrhotic rats had significantly lower urine sodium excretion and systemic vascular resistance, and significantly higher plasma atrial natriuretic peptide levels, renin activities and aldosterone concentrations than control rats. Compared with placebo-treated cirrhotic rats, octreotide caused increased urine sodium excretion (-10 +/- 4% vs. 13 +/- 8% from baseline values, p < 0.05) and systemic vascular resistance (2.6 +/- 0.1 vs. 3.3 +/- 0.3 mmHg.min.100 g.ml-1, p < 0.05); and decreased plasma atrial natriuretic peptide levels (166.7 +/- 24.8 vs. 234.0 +/- 19.2 pg/ ml, p < 0.05), renin activities (2.45 +/- 0.49 vs. 4.36 +/- 0.53 ng.ml-1.h-1, p < 0.01) and aldosterone concentrations (290.2 +/- 40.0 vs. 483.3 +/- 82.6 pg/ml, p < 0.05). In the in vitro experiment, right atrial release of atrial natriuretic peptide of cirrhotic rats was not significantly changed when incubated with different concentrations of octreotide. CONCLUSIONS Octreotide ameliorates renal sodium retention and suppresses plasma levels of atrial natriuretic peptide of ascitic cirrhotic rats with a novel mechanism via, at least partly, the modification of peripheral vascular resistance.

Role of endotoxaemia in hyperdynamic circulation in rats with extrahepatic or intrahepatic portal hypertension

This study investigated the role of endotoxaemia in the development of hyperdynamic circulation observed in rats with extrahepatic (high collateralization) or intrahepatic (low collateralization) portal hypertension. Compared with sham‐operated rats, decreased mean arterial pressure and systemic vascular resistance were detected on days 1, 4 and 14 following partial portal vein ligation. By day 1, the cardiac index of portal vein‐ligated rats was similar to that of sham‐operated rats and progressively increased, thereafter, reaching statistically higher values on days 4 and 14. No differences in plasma endotoxin levels were found between portal vein‐ligated and sham‐operated rats throughout the observation period. Both carbon tetrachloride‐induced cirrhotic rats with and without ascites had a higher cardiac index and lower systemic vascular resistance than those of control rats, and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma endotoxin levels were higher in cirrhotic rats with ascites (8.6±2.0 pg/mL; P < 0.01) than those of control rats (2.2±0.3 pg/mL) and cirrhotic rats without ascites (2.4±0.6 pg/mL). These results suggest that factors other than endotoxaemia play a role in the development of hyperdynamic circulation observed in rats with extrahepatic portal hypertension and cirrhotic rats without ascites, but that endotoxaemia may contribute to the maintenance of hyperdynamic circulation found in cirrhotic rats with ascites. The severity of liver disease may be a more important factor than the presence of portosystemic shunting for the development of endotoxaemia in portal hypertensive states.

Serum pancreas-specific protein in acute pancreatitis. Its clinical utility in comparison with serum amylase.

To compare the clinical utility of serum pancreas-specific protein and serum amylase in the diagnosis of acute pancreatitis, the study was conducted in 134 normal subjects and 70 patients (36 with acute pancreatitis and 34 with other acute abdominal diseases as control group). The serum level of pancreas-specific protein in 134 healthy adults was 29.6 +/- 1.6 micrograms/l, with 95% within 7.3-67.2 micrograms/l. The upper reference limit was set at 70 micrograms/l. Serum levels of pancreas-specific protein and amylase within 12 h of arrival were significantly higher in patients with acute pancreatitis than in the control group (647.3 +/- 79.3 versus 33.8 +/- 4.8 micrograms/l (p < 0.0001) and 2536 +/- 344 versus 175 +/- 35 IU/l (p < 0.0001)). No significant difference in the levels of pancreas-specific protein was noted between biliary and alcoholic pancreatitis or between severe and mild attacks. The sensitivity, specificity, and accuracy of diagnosing acute pancreatitis were 100%, 94.1%, and 97.1% with serum pancreas-specific protein > 70 micrograms/l and 97.2%, 91.2%, and 94.3% with serum amylase > 360 IU/l. The result demonstrated that pancreas-specific protein may be a good serum marker in the diagnosis of acute pancreatitis.

Chronic inhibition of nitric oxide ameliorates splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension

BACKGROUND Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. METHODS Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (approximately 25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. RESULTS As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P < 0.001) without modulating portal pressure (P > 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P < 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P < 0.05). CONCLUSIONS Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity.Background: Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. Methods: Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (~25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. Results: As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P < 0.001) without modulating portal pressure (P > 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P < 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P < 0.05). Conclusions: Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity.

Effects of prostacyclin inhibition on splanchnic Hyposensitivity to glypressin in a hemorrhage-transfused rat model of Portal hypertension

Background: Hyposensitivity to vasopressin is a well-documented phenomenon in animals with portal hypertension and patients with cirrhosis and hemorrhage. Similar findings exist with infusion of glypressin (a long-acting vasopressin analogue), and this phenomenon could be ameliorated by inhibition of nitric oxide (NO) synthase. Besides NO, excessive formation of prostacyclin (PGI2) has been shown to play an important role in the development of hyperdynamic circulation and the mediation of hyporeactivity to vasoconstrictors in portal-hypertensive states. This study was designed to investigate whether the blockade of PGI2 activity by indomethacin infusion could enhance the portal-hypotensive effect of glypressin in portal-hypertensive rats with bleeding. Methods: Portal hypertension was induced by partial portal vein ligation (PVL). Fourteen days after operation systemic and portal hemodynamics were measured in stable or bleeding PVL rats receiving intravenous glypressin (0.07 mg/kg) or indomethacin (5 mg/kg) followed by glypressin infusion. In rats with a hypotensive hemorrhage 4.5 ml of blood was withdrawn, and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. Results: Splanchnic hyposensitivity to glypressin was shown in hemorrhage-transfused PVL rats. Indomethacin infusion did not cause significant systemic and portal-hemodynamic changes in bleeding PVL rats (P > 0.05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin and potentiated the increases in mean arterial pressure induced by glypressin infusion in bleeding PVL rats. Conclusions: The improvement of splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension by the administration of indomethacin suggests that PGI2 has in the development of this hyposensitivity.

Evidence against a role for endotoxin in the hyperdynamic circulation of rats with prehepatic portal hypertension.

BACKGROUND/AIMS Excessive formation of nitric oxide may mediate the generalized vasorelaxation and hyporesponsiveness to vasoconstrictors observed in portal hypertensive states. Endotoxin, released from the bowel and detoxified by the liver, could stimulate inducible nitric oxide synthase directly or indirectly via the cytokine cascade. This study investigated the effect of chronic intraperitoneal injection of polymyxin B, a neutralizing antagonist of endotoxin, on the hemodynamics of partially portal vein-ligated (PVL) rats. METHODS Concomitantly with endotoxin (600 EU) and dactinomycin (80 microg), polymyxin B (0.1 mg) or normal saline (N/S) was administered via an intraperitoneal route to male Sprague-Dawley rats. Twenty-four hours later, mean arterial pressure was determined. In PVL rats polymyxin B (0.1 mg in 5 cc N/S) or N/S was given intraperitoneally twice daily from 2 days prior to operation until 5 days (short-term) or 14 days (long-term) after the operation. Long-term polymyxin B- or N/S-treated sham-operated rats were included as controls. Hemodynamic studies with a thermodilution technique were performed at the end of treatment. Blood samples were collected from another series of PVL rats with long-term treatment to determine plasma levels of endotoxin and tumor necrosis factor-alpha. Plasma levels of endotoxin and tumor necrosis factor-alpha were measured by Limulus assay and the ELISA method, respectively. RESULTS With the dosage of 0.1 mg polymyxin B, hypotension in rats subjected to endotoxin and dactinomycin administration could be corrected (polymyxin B vs. placebo: 130.0+/-7.7 vs. 108.8+/-6.7 mm Hg, p<0.05). However, long-term or short-term treatment with the same dosage of polymyxin B failed to ameliorate the hyperdynamic circulation of PVL rats. In addition, long-term treatment with polymyxin B did not change systemic and portal hemodynamics in sham-operated rats. Plasma levels of endotoxin and tumor necrosis factor-alpha were comparable in PVL rats treated with long-term polymyxin B or N/S (p>0.05). CONCLUSIONS Our findings do not support the role of endotoxin in the hyperdynamic circulation of PVL rats.

Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide.

BACKGROUND It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.

Hemodynamic Studies and Esophageal Morphometric Analyses in Portal Hypertensive Rats with Left Adrenal Vein Ligation

BACKGROUND Despite many attempts to create esophageal varices in experimental animals, most of them have failed. This study investigated whether rats with partial portal vein ligation (PVL) and left adrenal vein ligation (LAL) develop hyperdynamic circulation and dilated esophageal submucosal veins as compared with sham-operated (Sham) plus LAL rats. METHODS Two series of experiments were performed to measure (a) systemic and portal hemodynamics and (b) the cross-sectional area of esophageal submucosal veins in Sham, PVL, Sham plus LAL, and PVL plus LAL rats. Hemodynamic studies with a thermodilution technique and esophageal morphometric analyses were performed 14 days after the operation. RESULTS PVL rats with or without LAL had a significantly lower mean arterial pressure and systemic vascular resistance accompanied by a significantly cardiac index and portal pressure than Sham rats with or without LAL (P < 0.05). LAL did not induce changes in mean arterial pressure, cardiac index, systemic vascular resistance, hear rate, or portal pressure in either Sham or PVL rats (P > 0.05). The mean cross-sectional area of esophageal submucosal veins in PVL rats with LAL (7340 +/- 833 microns2) was significantly larger than that in Sham rats with LAL (4236 +/- 556 microns2; P < 0.05). There was no significant difference in the mean cross-sectional area of esophageal submucosal veins between PVL and Sham rats without LAL. CONCLUSIONS PVL rats with LAL developed hyperdynamic circulation similar to PVL rats without LAL. In addition, PVL plus LAL rats had larger esophageal submucosal veins than Sham plus LAL rats. This study shows that the esophageal submucosal veins of the 14-day partially portal vein-ligated rats with LAL resemble the structural abnormalities observed in human esophageal varices, suggesting that this model could be useful to investigate this entity.