Chi-Jen Chu

Prognostic value of Plasma endotoxin levels in patients with cirrhosis

BACKGROUNDnEndotoxemia has frequently been observed in patients with cirrhosis. Previous studies have shown that cirrhotic patients with endotoxemia have a higher mortality than those without. We evaluated the clinical value of plasma endotoxin level in predicting short-term (3 months) and long-term (2 years) survival among cirrhotic patients and compared it with the Child-Pugh score.nnnMETHODSnPlasma endotoxin levels were determined in 102 cirrhotic patients without clinical evidence of infection by a quantitative Limulus assay. The patients were followed up for 3 months to assess short-term survival and for 2 years for long-term survival.nnnRESULTSnPlasma endotoxin levels increased progressively as liver function deteriorated. In short-term survival analysis, plasma endotoxin levels were significantly higher in non-survivors than those in survivors (10.6 +/- 2.2 pg/ml versus 5.8 +/- 0.5 pg/ml; P < 0.05). Both plasma endotoxin and serum bilirubin levels, but not the Child-Pugh score, were significant factors in predicting short-term survival in multivariate analysis. In long-term survival analysis, plasma endotoxin levels did not differ significantly between survivors and non-survivors (6.1 +/- 0.6 pg/ml versus 7.3 +/- 1.1 pg/ml; P > 0.05) and was not an independent predictor of long-term survival. In contrast, both Child-Pugh score and serum bilirubin levels were significant predictors of long-term survival in multivariate analysis.nnnCONCLUSIONSnIn patients with cirrhosis, plasma endotoxin levels progressively increase as liver function deteriorates and may be useful in predicting short-term survival.

Treatment of mastalgia with tamoxifen in male patients with liver cirrhosis: a randomized crossover study

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.

Evaluation of Gallbladder Motility in Patients with Liver Cirrhosis

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.

Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver 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 × 10−3, median 10.5 × 10−3vs 8.2 ± 8.3 × 10−3, median 5.7 × 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 μmol/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.

Simvastatin for rats with thioacetamide-induced liver failure and encephalopathy.

Background and Aim:u2002 Nitric oxide (NO) inhibition aggravates hepatic damage and encephalopathy and increases mortality in rats with thioacetamide (TAA)‐induced acute liver failure. Statins enhance NO synthase expression beyond their lipid‐lowering capability, but the impact on encephalopathy remains unexplored. The aim of this study was to assess the effects of simvastatin on rats with TAA‐induced acute liver damage and hepatic encephalopathy.

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

BACKGROUND/AIMSnExcessive 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.nnnMETHODSnConcomitantly 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.nnnRESULTSnWith 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).nnnCONCLUSIONSnOur 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.

BACKGROUNDnIt 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.nnnMETHODSnPlasma 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.nnnRESULTSnCirrhotic 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).nnnCONCLUSIONSnExcessive 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

BACKGROUNDnDespite 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.nnnMETHODSnTwo 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.nnnRESULTSnPVL 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.nnnCONCLUSIONSnPVL 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.

Prolonged bleeding time: A new clinical manifestation of hepatocellular carcinoma?

The association between prolonged bleeding time and hepatocellular carcinoma (HCC) has not been well studied. We investigated whether bleeding time is prolonged in cirrhotic patients with HCC and studied the role of clinical characteristics, tumour size, and laboratory data in predicting bleeding time prolongation. After excluding patients that presented with blood dyscrasia and uraemia, 58 cirrhotic patients with HCC, 106 cirrhotic patients without HCC, and 44 age‐ and sex‐matched healthy subjects were included in the study. Bleeding time, imaging studies, clinical characteristics and biochemical data were obtained for every patient. Cirrhotic patients with and without HCC had longer bleeding times (554±68 and 535±32s, respectively) compared with healthy controls (357±13s, P < 0.05). Hepatocellular carcinoma patients with a large tumour burden (> 5 cm in diameter) had a significantly longer bleeding time than those patients without (663±105 vs 376±23s, respectively, P < 0.05). After excluding patients with a platelet count ≤ 80 000/mm3, cirrhotic patients classified as Child‐Pughs grading A and with a large tumour burden had longer bleeding times (580±87s) than patients with a small tumour burden (≤ 5 cm in diameter) and cirrhotic patients without HCC (371±22 and 416±29s, respectively, P < 0.05). In cirrhotic patients with HCC, higher serum bilirubin levels, a Child‐Pughs grading C, and a tumour size > 5 cm in diameter were found to be significant predictors for prolonged bleeding time on univariate analysis. On multivariate analysis, both tumour size > 5 cm in diameter and a Child‐Pughs grading C (odds ratio, 95% confidence interval and P value were measured as 38.5, 2.8–534.7, < 0.001, and 10.5, 0.9–117.6, 0.02, respectively) were the significant independent predictors. A significant correlation existed between tumour diameter and bleeding time (r= 0.44, P < 0.01). In conclusion, these results suggest that prolonged bleeding time may be categorized as a new clinical manifestation in patients with HCC. In addition to cirrhosis, HCC itself may also participate in the pathogenesis of bleeding time prolongation.

Combination Interferon α-2b Plus Ribavirin Therapy in Patients with Chronic Hepatitis C with Resistance to or Relapse after Interferon Monotherapy

Backgrounds and Objective: Previous studies in Caucasian patients showed treatment of chronic hepatitis C (CHC) patients with interferon and ribavirin was well tolerated, and produced a higher response rate in patients non-responded or relapsed to previous interferon monotherapy. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. The objective of this clinical trial is to evaluate the efficacy and tolerability of the combination of interferon α-2b plus Ribavirin in CHC patients who relapsed from or not responding to previous interferon therapy. Methods: Twenty-one Chinese CHC patients (19 males, 2 females, mean age: 47.5±9.2 years) who were non-responded or relapsed from previous interferon treatment received 3 MU of interferon α-2b, three times a week. plus ribavirin (1000 mg/day if body weight ＜75kg or 1200mg/day if body weight ＞75kg) for 24 weeks. Sustained virological response was defined as disappearance of serum HCV RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Results: Among 21 CHC patients, 20 patients completed the treatment and one withdrew from the study due to adverse event. Using intent-to-treat analysis, 11 patients (52%) had undetectable HCV RNA at the end of treatment. However, the sustained virological response was achieved in 2 patients (9.5%) 24 weeks after stopping of treatment. These two patients with sustained virological response were both genotype non-1 and pretreatment serum HCV RNA level ＜5 million copies/mL by branched DNA signal amplification assay, while the other 19 patients without sustained virological response were either HCV genotype 1 or pretreatment serum HCV RNA level ＞5 million copies/mL (P＜0.01). Conclusions: The sustained virological response rate was 9.5% in CHC patients non-responded or relapsed from previous interferon therapy and re-treated with interferon α-2b and ribavirin. HCV genotype and pretreatment HCV RNA level were important factors in predicting the retreatment sustained virological response.