Chung-Pin Li

Plasma Interleukin-6 Levels in Patients with Cirrhosis Relationship to Endotoxemia, Tumor Necrosis Factor-α, and Hyperdynamic Circulation

BACKGROUNDnLiver 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.nnnMETHODSnIn 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.nnnRESULTSnPlasma 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 Pughs 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).nnnCONCLUSIONSnPlasma 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.

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.

Clinical significance of serum auto-antibodies in Chinese patients with chronic hepatitis C: Negative role of serum viral titre and genotype

Positive serum anti‐nuclear antibody (ANA) and anti‐smooth muscle antibody (SMA) have been reported in 10–66% of patients with chronic hepatitis C virus (HCV) infection from Western countries. However, the mechanism involved in this immunological disorder is still unknown. This study was carried out to evaluate the prevalence and clinical significance of positive serum auto‐antibodies in Chinese patients with chronic hepatitis C and to assess the role of serum HCV‐RNA titre and HCV genotype in the presence of serum auto‐antibodies. Serum ANA, SMA and anti‐mitochondrial antibody (AMA) were measured in 122 patients with chronic hepatitis C. Clinical, biochemical and virological data (serum HCV‐RNA titre and HCV genotype) were compared between patients with and without serum auto‐antibodies. Fifty‐eight (48%) patients were associated with positive serum autoantibodies: 42 (34%) positive for ANA, six (5%) positive for SMA, nine (7%) positive for both ANA and SMA and one (1%) positive for AMA. Clinical parameters (age, sex, blood transfusion history), liver biochemical tests, the presence of cryoglobulinaemia or cirrhosis, and the response to interferon treatment were not significantly different between patients with and without positive serum auto‐antibodies. Serum HCV‐RNA levels and HCV genotypes were also not significantly different between the two groups. Logistic regression analysis showed that none of the previously mentioned parameters were significant predictors to associate with serum auto‐antibodies in chronic hepatitis C. We concluded that 48% of Chinese patients with chronic hepatitis C were associated with positive serum auto‐antibodies. Hepatitis C virus genotypes and serum HCV‐RNA levels were not correlated to the presence of serum auto‐antibodies. The clinical significance and actual pathogenesis of this phenomenon remain to be clarified.

Spider angiomas in patients with liver cirrhosis: role of alcoholism and impaired liver function.

BACKGROUNDnSpider angioma is a common sign in patients with liver cirrhosis, but the pathogenesis is still unclear. Alcohol and hyperestrogenemia are both possible etiologies. This study was designed to investigate the relationship of spider angiomas in patients with liver cirrhosis to alcohol, liver function test results, and plasma levels of sex hormones.nnnMETHODSnEighty-two patients with liver cirrhosis and 18 healthy subjects were enrolled in this study. The number, size, and location of the spider angiomas were recorded for all subjects. Plasma levels of estradiol and testosterone were measured.nnnRESULTSnCirrhotic patients had significantly higher estradiol/testosterone ratios (26.8 +/- 5.1 x 10(-3) versus 8.8 +/- 2.0 x 10(-3); P = 0.002) than healthy controls. Twenty-seven (33%) of the 82 cirrhotic patients had spider angiomas. Cirrhotic patients with spider angiomas were younger (56 +/- 3 versus 66 +/- 1 years; P = 0.002) and had higher serum bilirubin levels (3.3 +/- 0.6 versus 1.7 +/- 0.2 mg/dl; P = 0.002), longer prothrombin time (16.8 +/- 0.8 versus 14.8 +/- 0.4 sec; P = 0.01), and higher prevalence of alcoholism (41% versus 20%; P = 0.04) than those without. Stepwise logistic regression showed that alcoholism and serum bilirubin level were the only significant and independent predictors associated with the presence of spider angiomas in cirrhotic patients (odds ratio = 3.5; 95% confidence interval = 1.2-10.8; P = 0.03, and odds ratio = 2.8; 95% confidence interval = 1.3-5.7; P = 0.006, respectively).nnnCONCLUSIONSnAlcoholism and impaired liver function are important predictors of the presence of spider angiomas in patients with liver cirrhosis.

Autoimmune cholangitis with features of autoimmune hepatitis: Successful treatment with immunosuppressive agents and ursodeoxycholic acid

We report a 42‐year‐old Chinese female with elevated serum levels of liver aminotransferases, alkaline phosphatase, γ‐glutamyl transpeptidase, cholesterol and immunoglobulin M. Serum antimitochondrial antibody was negative, but antinuclear antibody was strongly positive. Liver histology showed features of both autoimmune cholangitis and autoimmune hepatitis. Combination therapy with immunosuppressive (prednisone and azathioprine) and choleuretic agents (ursodeoxycholic acid) was given. Serum aminotransferases and biliary enzymes showed much improvement after treatment. A follow‐up liver biopsy showed improvement of both hepatic necroinflammation and bile duct damage. Biliary enzymes rose after withdrawal of the immunosuppressive agents and declined again with reinstitution of prednisone. This case demonstrates that a combination of immunosuppressive agents and ursodeoxycholic acid may effectively treat patients with features of both autoimmune cholangitis and autoimmune hepatitis.

Gall-bladder wall thickening in patients with liver cirrhosis

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. Fortyone (53%) of 77 patients with cirrhosis had gall‐bladder wall thickening (>4mm). 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±6s, 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.

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.

Clinical, virological, immunological, and pathological significance of GB virus C/hepatitis G infection in patients with chronic hepatitis C

GB virus-C (GBV-C)/hepatitis G virus (HGV), a single-strand RNA virus, has been identified as a transfusion transmissible virus and categorized as a member of the Flaviridiae family. GBV-C/HGV superinfection in patients with chronic hepatitis C is not seen uncommonly, most likely because of the similar transmission routes. This study aimed to investigate the prevalence of GBV-C/HGV infection in 100 Chinese patients with histologically proven chronic hepatitis C, and to clarify the clinical, virological, immunological, and histopathological impact of GBV-C/HGV infection on chronic hepatitis C patients. Serum GBV-C/HGV RNA was positive in 22 (22%) of the 100 chronic hepatitis C patients. There were no significant differences in mean age, gender, and serum liver biochemical tests between GBV-C/HGV infected and non-infected chronic hepatitis C patients. The HCV genotype distribution and mean serum HCV RNA level were not significantly different between patients with and without GBV-C/HGV co-infection. The presence of serum autoantibodies (anti-nuclear antibody and anti-smooth muscle antibody) and cryoglobulinemia showed no significant difference between the two groups. Liver histopathological analysis revealed no significant difference in the grade of periportal, portal, and intralobular necro-inflammation, in the stage of fibrosis/cirrhosis, or in the presence of steatosis and lymphoid aggregation/follicle formation between patients with and without GBV-C/HGV infection. However, a higher degree of bile duct damage was noted in chronic hepatitis C patients co-infected with GBV-C/HGV infection than in those without infection (P=0.036). In conclusion, GBV-C/HGV infection had no apparent influence on the clinical, immunological, or virologic features of patients with chronic hepatitis C. However, the clinical significance of a higher degree of bile duct damage in patients with HCV and GBV-C/HGV co-infection deserves further investigation.

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.